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Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.
== Genetics ==
Amyloid-beta precursor protein is an ancient and highly conserved protein. In humans, the gene APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases. Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 639 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease. Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals. The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions.
Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease. For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.
A mutation (A673T) in the APP gene protects against Alzheimer's disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro.
== Structure ==
A number of different structural domains that fold mostly on their own have been found in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together. A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain, the copper-binding domain, the complete E1 domain and the E2 domain.
== Isoform diversity ==
Amyloid-beta precursor protein is highly versatile with several isoforms generated through alternative splicing of its mRNA. The primary isoforms include APP695, APP751, and APP770, differing in their inclusion of certain exons, mainly exon 7 and 8. APP695 is predominantly expressed in neuronal cells and is crucial for normal neuronal function. APP751 and APP770 are more widely expressed in non-neuronal tissues but exhibit distinct expression patterns during neuron differentiation. The differential expression of these isoforms plays a significant role in cellular processes such as neurodevelopment, synaptic plasticity, and the pathogenesis of Alzheimer's disease. Understanding the isoform diversity of APP is essential for deciphering its various physiological and pathological roles.
== Post-translational processing ==
APP undergoes extensive post-translational modification including glycosylation, phosphorylation, sialylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments. It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis. Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.
The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. Gamma secretase activity has also been associated with lipid rafts. The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease.
== Biological function ==
Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. Experimental models of Alzheimer's disease are commonly used by researchers to gain better understandings about the biological function of APP in disease pathology and progression.
=== Synaptic formation and repair ===
The most-substantiated role for APP is in synaptic formation and repair; its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.
APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.
The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia.
=== Somatic recombination ===
In neurons of the human brain, somatic recombination occurs frequently in the gene that encodes APP. Neurons from individuals with sporadic Alzheimer's disease show greater APP gene diversity due to somatic recombination than neurons from healthy individuals.
=== Anterograde neuronal transport ===
Molecules synthesized in the cell bodies of neurons must be conveyed outward to the distal synapses. This is accomplished via fast anterograde transport. It has been found that APP can mediate interaction between cargo and kinesin and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein.
Additionally, it has been shown that the interaction between APP and kinesin is specific to the peptide sequence of APP. In a recent experiment involving transport of peptide-conjugated colored beads, controls were conjugated to a single amino acid, glycine, such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that the terminal COOH moiety of peptides is not sufficient to mediate transport.
=== Iron export ===
A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin, facilitating iron export through interaction with ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's. It has been shown that a single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation.
The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity.
As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize the iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin).
=== Hormonal regulation ===
The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC.
AβPP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle. It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production and re-entry of post-mitotic neurons into the cell cycle.
== Interactions ==
Amyloid precursor protein has been shown to interact with:
APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.
== References ==
== Further reading ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease
Amyloid+Protein+Precursor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Entrez Gene: APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Human APP genome location and APP gene details page in the UCSC Genome Browser. | Wikipedia/Amyloid_precursor_protein |
The free radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating them from free radicals.
Strictly speaking, the free radical theory is only concerned with free radicals such as superoxide ( O2− ), but it has since been expanded to encompass oxidative damage from other reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), or peroxynitrite (OONO−).
Denham Harman first proposed the free radical theory of aging in the 1950s, and in the 1970s extended the idea to implicate mitochondrial production of ROS.
In some model organisms, such as yeast and Drosophila, there is evidence that reducing oxidative damage can extend lifespan. However, in mice, only 1 of the 18 genetic alterations (SOD-1 deletion) that block antioxidant defences, shortened lifespan. Similarly, in roundworms (Caenorhabditis elegans), blocking the production of the naturally occurring antioxidant superoxide dismutase has been shown to increase lifespan. Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question.
== Background ==
The free radical theory of aging was conceived by Denham Harman in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems. This was also before anyone invoked free radicals as a cause of degenerative diseases. Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption, and 2) Rebeca Gerschman's observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen free radicals. Noting that radiation causes "mutation, cancer and aging", Harman argued that oxygen free radicals produced during normal respiration would cause cumulative damage which would eventually lead to organismal loss of functionality, and ultimately death.
In later years, the free radical theory was expanded to include not only aging per se, but also age-related diseases. Free radical damage within cells has been linked to a range of disorders including cancer, arthritis, atherosclerosis, Alzheimer's disease, and diabetes. There has been some evidence to suggest that free radicals and some reactive nitrogen species trigger and increase cell death mechanisms within the body such as apoptosis and in extreme cases necrosis.
In 1972, Harman modified his original theory. In its current form, this theory proposes that reactive oxygen species (ROS) that are produced in the mitochondria, causes damage to certain macromolecules including lipids, proteins and most importantly mitochondrial DNA. This damage then causes mutations which lead to an increase of ROS production and greatly enhance the accumulation of free radicals within cells. This mitochondrial theory has been more widely accepted that it could play a major role in contributing to the aging process.
Since Harman first proposed the free radical theory of aging, there have been continual modifications and extensions to his original theory.
== Processes ==
Free radicals are atoms or molecules containing unpaired electrons. Electrons normally exist in pairs in specific orbitals in atoms or molecules. Free radicals, which contain only a single electron in any orbital, are usually unstable toward losing or picking up an extra electron, so that all electrons in the atom or molecule will be paired.
The unpaired electron does not imply charge; free radicals can be positively charged, negatively charged, or neutral.
Damage occurs when the free radical encounters another molecule and seeks to find another electron to pair its unpaired electron. The free radical often pulls an electron off a neighboring molecule, causing the affected molecule to become a free radical itself. The new free radical can then pull an electron off the next molecule, and a chemical chain reaction of radical production occurs. The free radicals produced in such reactions often terminate by removing an electron from a molecule which becomes changed or cannot function without it, especially in biology. Such an event causes damage to the molecule, and thus to the cell that contains it (since the molecule often becomes dysfunctional).
The chain reaction caused by free radicals can lead to cross-linking of atomic structures. In cases where the free radical-induced chain reaction involves base pair molecules in a strand of DNA, the DNA can become cross-linked.
Oxidative free radicals, such as the hydroxyl radical and the superoxide radical, can cause DNA damages, and such damages have been proposed to play a key role in the aging of crucial tissues. DNA damage can result in reduced gene expression, cell death and ultimately tissue dysfunction.
DNA cross-linking can in turn lead to various effects of aging, especially cancer. Other cross-linking can occur between fat and protein molecules, which leads to wrinkles. Free radicals can oxidize LDL, and this is a key event in the formation of plaque in arteries, leading to heart disease and stroke. These are examples of how the free-radical theory of aging has been used to neatly "explain" the origin of many chronic diseases.
Free radicals that are thought to be involved in the process of aging include superoxide and nitric oxide. Specifically, an increase in superoxide affects aging whereas a decrease in nitric oxide formation, or its bioavailability, does the same.
Antioxidants are helpful in reducing and preventing damage from free radical reactions because of their ability to donate electrons which neutralize the radical without forming another. Vitamin C, for example, can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule.
== Modifications of the theory ==
One of the main criticisms of the free radical theory of aging is directed at the suggestion that free radicals are responsible for the damage of biomolecules, thus being a major reason for cellular senescence and organismal aging.: 81 Several modifications have been proposed to integrate current research into the overall theory.
=== Mitochondria ===
The mitochondrial theory of aging was first proposed in 1978, and two years later, the mitochondrial free-radical theory of aging was introduced. The theory implicates the mitochondria as the chief target of radical damage, since there is a known chemical mechanism by which mitochondria can produce ROS, mitochondrial components such as mtDNA are not as well protected as nuclear DNA, and by studies comparing damage to nuclear and mtDNA that demonstrate higher levels of radical damage on the mitochondrial molecules. Electrons may escape from metabolic processes in the mitochondria like the Electron transport chain, and these electrons may in turn react with water to form ROS such as the superoxide radical, or via an indirect route the hydroxyl radical. These radicals then damage the mitochondria's DNA and proteins, and these damage components in turn are more liable to produce ROS byproducts. Thus a positive feedback loop of oxidative stress is established that, over time, can lead to the deterioration of cells and later organs and the entire body.
This theory has been widely debated and it is still unclear how ROS induced mtDNA mutations develop. Conte et al. suggest iron-substituted zinc fingers may generate free radicals due to the zinc finger proximity to DNA and thus lead to DNA damage.
Afanas'ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals. The link between CuZnSOD and life span was demonstrated by Perez et al. who indicated mice life span was affected by the deletion of the Sod1 gene which encodes CuZnSOD.
Contrary to the usually observed association between mitochondrial ROS (mtROS) and a decline in longevity, Yee et al. recently observed increased longevity mediated by mtROS signaling in an apoptosis pathway. This serves to support the possibility that observed correlations between ROS damage and aging are not necessarily indicative of the causal involvement of ROS in the aging process but are more likely due to their modulating signal transduction pathways that are part of cellular responses to the aging process.
=== Epigenetic oxidative redox shift ===
Brewer proposed a theory which integrates the free radical theory of aging with the insulin signalling effects in aging. Brewer's theory suggests "sedentary behaviour associated with age triggers an oxidized redox shift and impaired mitochondrial function". This mitochondrial impairment leads to more sedentary behaviour and accelerated aging.
=== Metabolic stability ===
The metabolic stability theory of aging suggests it is the cells ability to maintain stable concentration of ROS which is the primary determinant of lifespan. This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for maintaining normal cell functions.
=== Mitohormesis ===
Oxidative stress may promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of ROS. In mammals, the question of the net effect of reactive oxygen species on aging is even less clear. Recent epidemiological findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease prevalence in humans (according to the theory, because they prevent the stimulation of the organism's natural response to the oxidant compounds which not only neutralizes them but provides other benefits as well).
== Challenges ==
=== Birds ===
Among birds, parrots live about five times longer than quail. ROS production in heart, skeletal muscle, liver and intact erythrocytes was found to be similar in parrots and quail and showed no correspondence with longevity difference. These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging.
== See also ==
Life extension
List of life extension-related topics
Senescence
Mitochondrial theory of ageing
== References == | Wikipedia/Free-radical_theory_of_aging |
Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the ventral anterior (VA) and ventral lateral (VL) thalamocortical projection neurons become too inhibited, and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to reduced inhibition, and thus excitation, of the thalamocortical projection neurons (VA and VL) which synapse onto the cortex. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders.
Reasons for abnormal increases or decreases of basal ganglia output are not yet well understood. One possible factor could be the natural accumulation of iron in the basal ganglia, causing neurodegeneration due to its involvement in toxic, free-radical reactions. Though motor disorders are the most common associated with the basal ganglia, recent research shows that basal ganglia disorders can lead to other dysfunctions such as obsessive–compulsive disorder (OCD) and Tourette syndrome.
== Basal ganglia circuits ==
The basal ganglia is a collective group of structures in the brain. These include the striatum, (composed of the putamen and caudate nucleus), globus pallidus, substantia nigra, and the subthalamic nucleus. Along with other structures, the basal ganglia are part of a neural circuit that is integral to voluntary motor function. It was once believed that the primary function of the basal ganglia was to integrate projections from the cerebral cortex, and project information via the thalamus to the motor cortex. Research has shown that the basal ganglia can be modeled as a group of components of parallel, re-entrant cortico-subcortical circuits, which originate in cortical areas, traverse the basal ganglia and terminate in specific areas in the frontal lobe. These areas are thought to control not only motor function but also oculomotor, prefrontal, associative, and limbic areas. Understanding these circuits has led to breakthroughs in understanding the disorders of the basal ganglia.
=== Direct pathway ===
Of all the circuits, the motor circuit is the most studied due its importance to motor disorders. The direct pathway of the motor circuit is one in which projections from the cortex travel to the putamen directly to the internal segment of the globus pallidus (GPi also known as GP-Medial) or the substantia nigra, pars reticulata (SNr) and are then directed toward the ventral anterior nucleus (VA), and the ventral lateral nucleus of the thalamus (VL) and brainstem.
Through this pathway the basal ganglia is able to initiate voluntary movements by disinhibiting thalamic neurons that drive upper motor neurons. This process is regulated by dopamine secreted by the striatum onto the D1 dopamine receptor on the SNc. Dopamine excites striatal neurons in the direct pathway. Proper striatal dopamine release is integral in the suppression of the basal ganglia output, which is needed for increased activity of the thalamic neurons. This activity in thalamic nuclei is an integral component of voluntary movement.
=== Indirect pathway ===
The indirect pathway of the motor circuit is thought to project from the cortex, to the putamen, and to the thalamus and brainstem indirectly by passing through the external segment of the globus pallidus (GPe) then the subthalamic nucleus (STN) before looping back to the internal segment of the globus pallidus (GPi). The indirect pathway is responsible for the termination of movement. The indirect pathway inhibits unwanted movements by simultaneous increase in excitatory input to other GPi and SNr neurons. Similar to the direct pathway, the indirect pathway is regulated by striatal dopamine. D2 dopamine receptors inhibit transmission via the indirect pathway. D2 receptors inhibit striatal neurons in the indirect, inhibitory pathway. This inhibitory effect of dopamine on the indirect pathway serves the same function as its excitatory effects in the direct pathway in that it reduces basal ganglia output, leading to the disinhibition of motor neurons.
== Associated disorders ==
=== Hypokinetic disorders ===
Hypokinetic disorders are movement disorders that are described as having reduced motor function. This is generally attributed to higher than normal basal ganglia output causing inhibition of thalamocortical motor neurons.
==== Parkinsonism ====
The muscle rigidity, tremor at rest, and slowness in initiation and execution of movement that are the cardinal motor symptoms of Parkinson's disease are attributed to a reduction in dopaminergic activity in the basal ganglia motor areas, particularly the putamen, due to gradually reduced innervation from the pars compacta of substantia nigra. Other motor deficits and common non-motor features of Parkinson's such as autonomic dysfunction, cognitive impairment, and gait/balance difficulties, are thought to result from widespread progressive pathological changes commencing in the lower brain stem and ascending to the midbrain, amygdala, thalamus and ultimately the cerebral cortex.
=== Hyperkinetic disorders ===
Hyperkinetic disorders are movement disorders characterized by increased uncontrollable motor function. They are caused by reduced basal ganglia output, which causes increased thalamocortical function which leads to the inability to stop unwanted movement.
==== Huntington's disease ====
Huntington's disease is a hereditary disease that causes defects in behavior, cognition, and uncontrolled rapid, jerky movements. Huntington's disease stems from a defect that consists of an expanded CAG repeat in the huntingtin gene (HTT) located on the short arm p of chromosome 4. Evidence shows that the basal ganglia in patients with Huntington's disease show a decrease in activity of the mitochondrial pathway, complex II-III. Such deficiencies are often associated with basal ganglia degeneration. This degeneration of striatal neurons projecting to GPe leads to disinhibition of the indirect pathway, increased inhibition of the subthalamic nucleus, and therefore, reduced output of the basal ganglia. The neuronal degeneration eventually causes death within 10 to 20 years.
==== Dystonia ====
Dystonia is a hyperkinetic movement disorder that is characterized by involuntary movement and the slowing of intentional movement. Though there are known causes of dystonia such as metabolic, vascular, and structural abnormalities, there are still patients with dystonia with no apparent cause. Dystonia can occur as a hyperkinetic disorder or as a side effect of hypokinetic disorders such as Parkinson's disease. Until recently it was thought that dystonia was likely caused by extreme lack of function of the direct pathway between the Putamen and the GPi. Again, it was thought that this dysfunction led to a decrease in basal ganglia output to the thalamus and a resultant increased disinhibition of the thalamic projections to the premotor and motor cortex. However recent models in mice show that the dysfunction in the cerebellum may play an equal part in dystonia.
==== Hemiballismus ====
Hemiballismus is a hyperkinetic movement disorder that causes uncontrolled movement on one side of the body. It is generally caused by damage to the subthalamic nucleus (STN). Since the internal segment of the globus pallidus (GPi) is the link in the circuit between the STN and thalamic projection, destruction of localized brain cells in the GPi via a pallidotomy has proven to serve as a useful treatment for hemiballismus.
=== Other basal ganglia diseases ===
The following diseases that generally involve the basal ganglia do not clearly fit into being either hypo- or hyperkinetic.
==== Epilepsy ====
The substantia nigra pars reticulata and its direct input structure, the subthalamic nucleus play a role in seizure propagation circuitry and have been described as seizure gating nuclei. Inhibition of these nuclei suppresses seizures in various experimental epilepsy models. Patients with seizures display some abnormal electrophysiological activity and structural changes like atrophy, altered blood perfusion and metabolism within their basal ganglia. Several case reports describe that deep brain stimulation of the subthalamic nucleus has been successful in reducing seizures. Other targeted treatment approaches have been limited to experimental settings and included local drug infusions and cell transplantation.
==== Tourette syndrome/obsessive–compulsive disorder ====
Tourette syndrome is a disorder that is characterized by behavioral and motor tics, OCD and attention deficit hyperactivity disorder (ADHD). For this reason, it is commonly believed that pathologies involving limbic, associative and motor circuits of the basal ganglia are likely. Since the realization that syndromes such as Tourette syndrome and OCD are caused by dysfunction of the non-motor loops of basal ganglia circuits, new treatments for these disorders, based on treatments originally designed to treat movement disorders are being developed.
Other regions of the brain including the thalamus and frontal cortex also contribute to Tourettes syndrome. Specifically dopamine, is thought to be central to the pathophysiology of Tourette syndrome. The basal ganglia are rich in dopamine receptors, and an imbalance in dopamine signaling can be correlated with the onset and severity of tics.
There are two forms of treatments: medication and therapy. The recommended form of therapy is Comprehensive behavioral intervention for tics. This is a form of behavioral therapy, which will help the patient with their tics and make them more voluntary. During this process they train individuals how to be more aware of their tics. And encourage changes in their day to day activities to help reduce tics. In addition to this, there are various forms of medications that can help make tics more manageable for everyday life. Medications like neuroleptics, benzamides, or atypical antipsychotics are used to decrease dopamine have been effective for the disorder. Deep brain stimulation is another solution to make tics more manageable. Unfortunately there isn’t a cure for the disorder, but the things mentioned help make tics and outbursts more manageable for an average person to live their daily life.
The key role of dopamine and Tourettes -
Increasing evidence supports the TS hypothesis, particularly regarding the dopamine receptor system.; demonstrated receptor derangement or hyposensitivity in the basal ganglia dopamine pathways plays a critical role in the diathesis for Tourette syndrome. According to most theories, Tourette’s syndrome is due to a chemical dysfunction of dopamine in those areas of the brain that are linked to movement control, resulting in the repetitive and uncontrolled tics seen in the syndrome (D2-like Dopamine Receptor Density in Tourette Syndrome Measured by PET, 1997). A few medical researches indicate that people with Tourette syndrome may have an increased dopamine activity level for some reason connected to either greater dopamine receptor sensitivity or irregular dopamine turnover patterns. The basal ganglia, a cerebral structure involved in controlling movement, is believed to be one of the sites vulnerable to dopamine abnormalities and is implicated in the pathogenesis of TS. It is thought that dopamine, norepinephrine, and serotonin neurotransmitters are not able to exchange messages properly between nerve cells in a person diagnosed with Tourette’s.
==== Sydenham's chorea ====
Sydenham's chorea is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet. It is a result of an autoimmune response that occurs following infection by group A β-hemolytic streptococci (GABHS) that destroys cells in the corpus striatum of the basal ganglia.
==== PANDAS ====
PANDAS is a controversial hypothesis that there exists a subset of children with rapid onset of obsessive–compulsive disorder (OCD) or tic disorders and that these symptoms are caused by group A β-hemolytic streptococcal (GABHS) infections. The proposed link between infection and these disorders is that an initial autoimmune reaction to a GABHS infection produces antibodies that interfere with basal ganglia function, causing symptom exacerbations. It has been proposed that this autoimmune response can result in a broad range of neuropsychiatric symptoms.
==== Dyskinetic cerebral palsy ====
Dyskinetic cerebral palsy is a type of cerebral palsy primarily associated with damage to the basal ganglia in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. Symptoms include slow, uncontrolled movements of the extremities and trunk and small, rapid, random and repetitive, uncontrolled movements known as chorea. Involuntary movements often increase during periods of emotional stress or excitement and disappear when the patient is sleeping or distracted.
==== Athymhormic syndrome ====
Athymhormic syndrome is a rare psychopathological and neurological syndrome characterized by extreme passivity, apathy, blunted affect, and a profound generalized loss of self-motivation. The syndrome is believed to be due to damage to areas of the basal ganglia or frontal cortex, specifically the striatum and globus pallidus, responsible for motivation and executive functions.
==== Lesch–Nyhan syndrome ====
Lesch–Nyhan syndrome is a rare X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), leading to uric acid build-up and a deficiency in dopamine production. Within the first few years of life, extrapyramidal involvement causes abnormal involuntary muscle contractions such as loss of motor control (dystonia), writhing motions (choreoathetosis) and arching of the spine (opisthotonus). The resemblance to dyskinetic cerebral palsy is apparent, and as a result most individuals are initially diagnosed as having cerebral palsy. Psychological behaviours can include rejecting desired treats or travel, repaying kindness with coldness or rage, failing to answer test questions correctly despite study and a desire to succeed or provoking anger from caregivers when affection is desired.
==== Wilson's disease ====
Wilson's disease is an autosomal recessive genetic disorder caused by a mutation in the copper-transport gene ATP7B, leading to excess copper build-up. About half of those affected have neurological symptoms, including parkinsonism (most commonly cogwheel rigidity, bradykinesia or slowed movements and a lack of balance) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia or dystonia.
==== Fahr's disease and calcifications ====
Fahr's disease is a rare, genetically dominant, inherited neurological disorder characterized by abnormal deposits of calcium, primarily in the basal ganglia. About 0.3–1.5% of people have asymptomatic basal ganglia calcifications.
==== Blepharospasm ====
Blepharospasm is any abnormal contraction or twitch of the eyelid. Blepharospasm may come from abnormal functioning of the brain's basal ganglia.
== Research ==
=== Gene therapy ===
Many disorders of the basal ganglia are due to the dysfunction of a localized area. For this reason, gene therapy seems viable for neurodegenerative disorders. Gene therapy is performed by replacing diseased phenotypes with new genetic material. This process is still in the early stages but early results are promising. An example of this therapy might involve implanting cells genetically modified to express tyrosine hydroxylase which, in the body, could be converted to dopamine. Increasing dopamine levels in the basal ganglia could possibly offset the effects of the Parkinson's Disease.
=== Ablation ===
Lesioning is the intentional destruction of neuronal cells in a particular area used for therapeutic purposes. Though this seems dangerous, vast improvements have been achieved in patients with movement disorders. The exact process generally involves unilateral lesioning in the sensorimotor territory of the GPi. This process is called pallidotomy. It is believed that the success of pallidotomies in reducing the effects of movement disorders may result from the interruption of abnormal neuronal activity in the GPi. This ablation technique can be viewed as simply removing a faulty piece of a circuit. With the damaged piece of the circuit removed, the healthy area of the circuit can continue normal function.
=== Deep brain stimulation ===
Deep brain stimulation involves inserting, via stereotaxic surgery, electrodes into the sensorimotor area of the brain.
These electrodes emit high-frequency stimulation to the implanted areas.
Bilateral implantation is necessary for symmetric results as well as the ability to reduce the intensity and duration of off-periods as well increase the duration of on-periods. The most effective structures used for implantations for deep brain stimulation are the internal globus pallidus (GPi) and the subthalamic nucleus (STN). This is because it is safer and more effective to alter the influence of the basal ganglia on the thalamocortical nuclei than directly altering neural activity in upper motor neuron circuits. Deep brain stimulation is a more complicated process than other therapies such as ablation. Evidence suggests that benefits of STN deep brain stimulation is due to the activation of efferents and the modulation of discharge patterns in the GPi that are propagated throughout the thalamocortical pathways. The ability to adjust stimulation protocols lends this treatment to a variety of disorders due its ability to alter the activity of basal ganglia circuits.
== See also ==
Dyskinetic cerebral palsy
== References ==
== Sources ==
Purves, Dale; Augustine, George; Fitzpatrick, David; Hall, William C.; LaMantia, Anthony; Mooney, Richard; White, Leonard E., eds. (2018). Neuroscience. Sinauer. ISBN 978-1-60535-380-7.
== External links == | Wikipedia/Basal_ganglia_disease |
The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.
== Protein aggregation ==
The first major proposed cause of neuronal death in Parkinson's disease is the bundling, or oligomerization, of proteins. The protein alpha-synuclein has increased presence in the brains of Parkinson's Disease patients and, as α-synuclein is insoluble, it aggregates to form Lewy bodies (shown to left) in neurons. Traditionally, Lewy bodies were thought to be the main cause of cell death in Parkinson's disease; however, more recent studies suggest that Lewy bodies lead to other effects that cause cell death. Regardless, Lewy bodies are widely recognized as a pathological marker of Parkinson's disease.
Lewy bodies first appear in the olfactory bulb, medulla oblongata, and pontine tegmentum; patients at this stage are asymptomatic. As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain, and in the neocortex.
This mechanism is substantiated by the facts that α-synuclein lacks toxicity when unable to form aggregates; that heat-shock proteins, which assist in refolding proteins susceptible to aggregation, beneficially affect PD when overexpressed; and that reagents which neutralize aggregated species protect neurons in cellular models of α-synuclein overexpression.
Alpha-synuclein appears to be a key link between reduced DNA repair and Parkinson's disease. Alpha-synuclein activates ATM (ataxia-telangiectasia mutated), a major DNA damage repair signaling kinase. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of non-homologous end joining. It was suggested that cytoplasmic aggregation of alpha-synuclein to form Lewy bodies reduces its nuclear levels leading to decreased DNA repair, increased DNA double-strand breaks and increased programmed cell death of neurons.
== Autophagy disruption ==
The second major proposed mechanism for neuronal death in Parkinson's disease, autophagy, is a mechanism by which inner components of the cell are broken down and recycled for use. Autophagy has been shown to play a role in brain health, helping to regulate cellular function. Disruption of the autophagy mechanism can lead to several different types of diseases like Parkinson's disease.
Autophagy dysfunction in Parkinson's disease has also been shown to lead to dysregulated mitochondria degradation.
== Changes in cell metabolism ==
The third major proposed cause of cell death in Parkinson's disease involves the energy-generating mitochondrion organelle. In Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death.
The mechanism behind mitochondrial dysfunction in Parkinson's disease is hypothesized to be centered in the PINK1 and Parkin complex, having this been shown to drive autophagy of mitochondria (also known as mitophagy). PINK1 is a protein normally transported into the mitochondrion, but can also accumulate on the surface of impaired mitochondria. Accumulated PINK1 then recruits Parkin; Parkin initiates the breakdown of dysfunctional mitochondria, a mechanism that acts as a "quality control". In Parkinson's disease, the genes coding PINK1 and Parkin are thought to be mutated so as to impair the ability of these proteins to breakdown dysfunctional mitochondria, leading to abnormal mitochondrial function and morphology, and eventually cell death. Mitochondrial DNA (mtDNA) mutations have also been shown to accumulate with age indicating that susceptibility to this mechanism of neuronal death increases with age.
Another mitochondrial-related mechanism for cell death in Parkinson's disease is the generation of reactive oxygen species (ROS). ROS are highly reactive molecules that contain oxygen and can disrupt functions within the mitochondria and the rest of the cell. With increasing age, mitochondria lose their ability to remove ROS yet still maintain their production of ROS, causing an increase in net production of ROS and eventually cell death.
As reviewed by Puspita et al. studies have demonstrated that in the mitochondria and the endoplasmic reticulum, alpha-synuclein and dopamine levels are likely involved in contributing to oxidative stress as well as PD symptoms. Oxidative stress appears to have a role in mediating separate pathological events that together ultimately result in cell death in PD. Oxidative stress leading to cell death may be the common denominator underlying multiple processes. Oxidative stress causes oxidative DNA damage. Such damage is increased in the mitochondria of the substantia nigra of PD patients and may lead to nigral neuronal cell death.
== Neuroinflammation ==
The fourth proposed major mechanism of neuronal death in Parkinson's Disease, neuroinflammation, is generally understood for neurodegenerative diseases, however, specific mechanisms are not completely characterized for PD. One major cell type involved in neuroinflammation is the microglia. Microglia are recognized as the innate immune cells of the central nervous system. Microglia actively survey their environment and change their cell morphology significantly in response to neural injury. Acute inflammation in the brain is typically characterized by rapid activation of microglia. During this period, there is no peripheral immune response. Over time, however, chronic inflammation causes the degradation of tissue and of the blood–brain barrier. During this time, microglia generate reactive oxygen species and release signals to recruit peripheral immune cells for an inflammatory response.
In addition, microglia are known to have two major states: M1, a state in which cells are activated and secrete pro-inflammatory factors; and M2, a state in which cells are deactivated and secrete anti-inflammatory factors. Microglia are usually in a resting state (M2), but in Parkinson's disease can enter M1 due to the presence of α-synuclein aggregates. The M1 microglia release pro-inflammatory factors which can cause motor neurons to die. In this case, dying cells can release factors to increase the activation of M1 microglia, leading to a positive feedback loop which causes continually increasing cell death.
== BBB breakdown ==
The fifth proposed major mechanism for cell death is the breakdown of the blood–brain barrier (BBB). The BBB has three cell types which tightly regulate the flow of molecules in and out of the brain: endothelial cells, pericytes, and astrocytes. In neurodegenerative diseases, BBB breakdown has been measured and identified in specific regions of the brain, including the substantia nigra in Parkinson's disease and hippocampus in Alzheimer's disease. Protein aggregates or cytokines from neuroinflammation may interfere with cell receptors and alter their function in the BBB. Most notably, vascular endothelial growth factor (VEGF) and VEGF receptors are thought to be dysregulated in neurodegenerative diseases. The interaction between the VEGF protein and its receptors leads to cell proliferation, but is believed to be disrupted in Parkinson's disease and Alzheimer's disease. This then causes cells to stop growing and therefore, prevents new capillary formation via angiogenesis. Cell receptor disruption can also affect the ability for cells to adhere to one another with adherens junctions.
Without new capillary formation, the existing capillaries break down and cells start to dissociate from each other. This in turn leads to the breakdown of gap junctions. Gap junctions in endothelial cells in the BBB help prevent large or harmful molecules from entering the brain by regulating the flow of nutrients to the brain. However, as gap junctions break down, plasma proteins are able to enter in extracellular matrix the brain. This mechanism is also known as vascular leakiness, where capillary degeneration leads to blood and blood proteins "leaking" into the brain. Vascular leakiness can eventually cause neurons to alter their function and shift towards apoptotic behavior or cell death.
== Impact on locomotion ==
Dopaminergic neurons are the most abundant type of neuron in the substantia nigra, a part of the brain regulating motor control and learning. Dopamine is a neurotransmitter which modulates the activity of motor neurons in the central nervous system. The activated motor neurons then transmit their signals, via action potential, to motor neurons in the spinal cord. However, when a significant percentage of the motor neurons die (about 50-60%), this decreases dopamine levels by up to 80%. This inhibits the ability for neurons to generate and transmit a signal. This transmission inhibition ultimately causes the characteristic Parkinsonian gait with symptoms such as hunched and slowed walking or tremors.
== References == | Wikipedia/Pathophysiology_of_Parkinson's_disease |
Neurodegenerative diseases are a heterogeneous group of complex disorders linked by the degeneration of neurons in either the peripheral nervous system or the central nervous system. Their underlying causes are extremely variable and complicated by various genetic and/or environmental factors. These diseases cause progressive deterioration of the neuron resulting in decreased signal transduction and in some cases even neuronal death. Peripheral nervous system diseases may be further categorized by the type of nerve cell (motor, sensory, or both) affected by the disorder. Effective treatment of these diseases is often prevented by lack of understanding of the underlying molecular and genetic pathology. Epigenetic therapy is being investigated as a method of correcting the expression levels of misregulated genes in neurodegenerative diseases.
Neurodengenerative diseases of motor neurons can cause degeneration of motor neurons involved in voluntary muscle control such as muscle contraction and relaxation. This article will cover the epigenetics and treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). See the Motor Neuron Fact Sheet for details regarding other motor neuron diseases. Neurodegenerative diseases of the central nervous system can affect the brain and spinal cord. This article will cover the epigenetics and treatment of Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). These diseases are characterized by chronic and progressive neuronal dysfunction, sometimes leading to behavioral abnormalities (as with PD), and, ultimately, neuronal death, resulting in dementia.
Neurodegenerative diseases of sensory neurons can cause degeneration of sensory neurons involved in transmitting sensory information such as hearing and seeing. The main group of sensory neuron diseases are hereditary sensory and autonomic neuropathies (HSAN) such as HSAN I, HSAN II, and Charcot-Marie-Tooth Type 2B (CMT2B). Though some sensory neuron diseases are recognized as neurodegenerative, epigenetic factors have not yet been clarified in the molecular pathology.
== Epigenetics and epigenetic drugs ==
The term epigenetics refers to three levels of gene regulation: (1) DNA methylation, (2) histone modifications, and (3) non-coding RNA (ncRNA) function. Briefly, histone-mediated transcriptional control occurs by the wrapping of DNA around a histone core. This DNA-histone structure is called a nucleosome; the more tightly the DNA is bound by the nucleosome, and the more tightly a string of nucleosomes are compressed among each other, the greater the repressive effect on transcription of genes in the DNA sequences near or wrapped around the histones, and vice versa (i.e. looser DNA binding and relaxed compaction leads to a comparatively derepressed state, resulting in facultative heterochromatin or, even further derepressed, euchromatin). At its most repressive state, involving many folds into itself and other scaffolding proteins, DNA-histone structures form constitutive heterochromatin. This chromatin structure is mediated by these three levels of gene regulation. The most relevant epigenetic modifications to treatment of neurodegenerative diseases are DNA methylation and histone protein modifications via methylation or acetylation.
In mammals, methylation occurs on DNA and histone proteins. DNA methylation occurs on the cytosine of CpG dinucleotides in the genomic sequence, and protein methylation occurs on the amino termini of the core histone proteins – most commonly on lysine residues. CpG refers to a dinucleotide composed of a cytosine deoxynucleotide immediately adjacent to a guanine deoxynucleotide. A cluster of CpG dinucleotides clustered together is called a CpG island, and in mammals, these CpG islands are one of the major classes of gene promoters, onto or around which transcription factors may bind and transcription can begin. Methylation of CpG dinucleotides and/or islands within gene promoters is associated with transcriptional repression via interference of transcription factor binding and recruitment of transcriptional repressors with methyl binding domains. Methylation of intragenic regions is associated with increased transcription. The group of enzymes responsible for addition of methyl groups to DNA are called DNA methyltransferases (DNMTs). The enzyme responsible for removal of methyl group are called DNA demethylases. The effects of histone methylation are residue dependent (e.g. which amino acid on which histone tail is methylated) therefore the resulting transcriptional activity and chromatin regulation can vary. The enzymes responsible for the addition of methyl groups to histones are called histone methyltransferases (HMTs). The enzymes responsible for the removal of methyl groups from histone are histone demethylases.
Acetylation occurs on the lysine residues found at the amino N-terminal of histone tails. Histone acetylation is most commonly associated with relaxed chromatin, transcriptional derepression, and thus actively transcribed genes. Histone acetyltransferases (HATs) are enzymes responsible for the addition of acetyl groups, and histone deacetylases (HDACs) are enzymes responsible for the removal of acetyl groups. Therefore, the addition or removal of an acetyl group to a histone can alter the expression of nearby genes. The majority of drugs being investigated are inhibitors of proteins that remove acetyl from histones or histone deacetylases (HDACs).
Briefly, ncRNAs are involved in signaling cascades with epigenetic marking enzymes such as HMTs, and/or with RNA interference(RNAi) machinery. Frequently these signaling cascades result in epigenetic repression (for one example, see X-chromosome inactivation), though there are some cases in which the opposite is true. For example, BACE1-AS ncRNA expression is upregulated in Alzheimer's disease patients and results in increased stability of BACE1 – the mRNA precursor to an enzyme involved in Alzheimer's disease.
Epigenetic drugs target the proteins responsible for modifications on DNA or histone. Current epigenetic drugs include but are not limited to: HDAC inhibitors (HDACi), HAT modulators, DNA methyltransferase inhibitors, and histone demethylase inhibitors. The majority of epigenetic drugs tested for use against neurodegenerative diseases are HDAC inhibitors; however, some DNMT inhibitors have been tested as well. While the majority of epigenetic drug treatments have been conducted in mouse models, some experiments have been performed on human cells as well as in human drug trials (see table below). There are inherent risks in using epigenetic drugs as therapies for neurodegenerative disorders as some epigenetic drugs (e.g. HDACis such as sodium butyrate) are non-specific in their targets, which leaves potential for off-target epigenetic marks causing unwanted epigenetic modifications.
== Neurodegenerative diseases of motor neurons ==
=== Amyotrophic lateral sclerosis (ALS) ===
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a motor neuron disease that involves neurogeneration. All skeletal muscles in the body are controlled by motor neurons that communicate signals from the brain to the muscle through a neuromuscular junction. When the motor neurons degenerate, the muscles no longer receive signals from the brain and begin to waste away. ALS is characterized by stiff muscles, muscle twitching, and progressive muscle weakness from muscle wasting. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first, usually the limbs. As the disease progresses most patients are unable to walk or use their arms and eventually develop difficulty speaking, swallowing and breathing. Most patients retain cognitive function and sensory neurons are generally unaffected. Patients are often diagnosed after the age of 40 and the median survival time from onset to death is around 3–4 years. In the final stages, patients can lose voluntary control of eye muscles and often die of respiratory failure or pneumonia as a result of degeneration of the motor neurons and muscles required for breathing. Currently there is no cure for ALS, only treatments that may prolong life.
==== Genetics and underlying causes ====
To date, multiple genes and proteins have been implicated in ALS. One of the common themes between many of these genes and their causative mutations is the presence of protein aggregates in motor neurons. Other common molecular features in ALS patients are altered RNA metabolism and general histone hypoacetylation.
SOD1
The SOD1 gene on chromosome 21 that codes for the superoxide dismutase protein is associated with 2% of cases and is believed to be transmitted in an autosomal dominant manner. Many different mutations in SOD1 have been documented in ALS patients with varying degrees of progressiveness. SOD1 protein is responsible for destroying naturally occurring, but harmful superoxide radicals produced by the mitochondria. Most of the SOD1 mutations associated with ALS are gain-of-function mutations in which the protein retains its enzymatic activity, but aggregate in motor neurons causing toxicity. Normal SOD protein is also implicated in other cases of ALS due to potentially cellular stress. An ALS mouse model through gain-of-function mutations in SOD1 has been developed.
c9orf72
A gene called c9orf72 was found to have a hexanucleotide repeat in the non-coding region of the gene in association with ALS and ALS-FTD. These hexanucleotide repeats may be present in up 40% of familial ALS cases and 10% of sporadic cases. C9orf72 likely functions as a guanine exchange factor for a small GTPase, but this is likely not related to the underlying cause of ALS. The hexanucleotide repeats are likely causing cellular toxicity after they are spliced out of the c9orf72 mRNA transcripts and accumulate in the nuclei of affected cells.
UBQLN2
The UBQLN2 gene encodes the protein ubiquilin 2 which is responsible for controlling the degradation of ubiquitinated proteins in the cell. Mutations in UBQLN2 interfere with protein degradation resulting in neurodegeneration through abnormal protein aggregation. This form of ALS is X chromosome-linked and dominantly inherited and can also be associated with dementia.
==== Epigenetic treatment with HDAC inhibitors ====
ALS patients and mouse models show general histone hypoacetylation that can ultimately trigger apoptosis of cells. In experiments with mice, HDAC inhibitors counteract this hypoacetylation, reactivate aberrantly down-regulated genes, and counteract apoptosis initiation. Furthermore, HDAC inhibitors are known to prevent SOD1 protein aggregates in vitro.
Sodium phenylbutyrate
Sodium phenylbutyrate treatment in a SOD1 mouse model of ALS showed improved motor performance and coordination, decreased neural atrophy and neural loss, and increased weight gain. Release of pro-apoptotic factors was also abrogated as well as a general increase in histone acetylation. A human trial using phenylbuturate in ALS patients showed some increase in histone acetylation, but the study did not report whether ALS symptoms improved with treatment.
Valproic scid
Valproic acid in mice studies restored histone acetylation levels, increased levels of pro-survival factors, and mice showed improved motor performance. However, while the drug delayed the onset of ALS, it did not increase lifespan or prevent denervation. Human trials of valproic acid in ALS patients did not improve survival or slow progression.
Trichostatin A
Trichostatin A trials in mouse ALS models restored histone acetylation in spinal neurons, decreased axon demyelination, and increased survival of mice.
=== Spinal muscular atrophy (SMA) ===
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by mutations in the SMN1 gene. Symptoms vary greatly with each subset of SMA and the stage of the disease. General symptoms include overall muscle weakness and poor muscle tone including extremities and respiratory muscles leading to difficulty walking, breathing, and feeding. Depending on the type of SMA, the disease can present itself from infancy through adulthood. As SMN protein generally promotes the survival of motor neurons, mutations in SMN1 results in slow degeneration motor neurons leading to progressive system-wide muscle wasting. Specifically, over time, decreased levels of SMN protein results in gradual death of the alpha motor neurons in the anterior horn of the spinal cord and brain. Muscles depend on connections to motor neurons and the central nervous system to stimulate muscle maintenance and therefore degeneration of motor neurons and subsequent denervation of muscles lead to loss of muscle control and muscle atrophy. The muscles of the lower extremities are often affected first followed by upper extremities and sometimes the muscles of respiration and mastication. In general, proximal muscle is always affected more than distal muscle.
==== Genetic cause ====
Spinal muscular atrophy is linked to genetic mutations in the SMN1 (Survival of Motor Neuron 1) gene. The SMN protein is widely expressed in neurons and serves many functions within neurons including spliceosome construction, mRNA axon transport, neurite outgrowth during development, and neuromuscular junction formation. The causal function loss in SMA is currently unknown.
SMN1 is located in a telomeric region of human chromosome 5 and also contains SMN2 in a centromeric region. SMN1 and SMN2 are nearly identical except for a single nucleotide change in SMN2 resulting in an alternative splicing site where intron 6 meets exon 8. This single base pair change leads to only 10–20% of SMN2 transcripts resulting in fully functional SMN protein and 80–90% of transcripts leading to a truncated protein that is rapidly degraded. Most SMA patients have 2 or more copies of the SMN2 gene with more copies resulting in a decrease in disease severity. Most SMA patients have either point mutations or a deletion in exon 7 often leading to a protein product similar to the truncated and degraded version of the SMN2 protein. In SMA patients this small amount of functional SMN2 protein product allows for some neurons to survive.
==== Epigenetic treatment through SMN2 gene activation ====
Although SMA is not caused by an epigenetic mechanism, therapeutic drugs that target epigenetic marks may provide SMA patients with some relief, halting or even reversing the progression of the disease. As SMA patients with higher copy numbers of the SMN2 gene have less severe symptoms, researchers predicted that epigenetic drugs that increased SMN2 mRNA expression would increase the amount of functional SMN protein in neurons leading to a reduction in SMA symptoms. Histone deacetylase (HDAC) inhibitors are the main compounds that have been tested to increase SMN2 mRNA expression. Inhibiting HDACs would allow for hyperacetylation of the SMN2 gene loci theoretically resulting in an increase in SMN2 expression. Many of these HDAC inhibitors (HDACi) are first tested in mouse models of SMA created through a variety of mutations in the mouse SMN1 gene. If the mice show improvement and the drug does not cause very many side effects or toxicity, the drug may be used in human clinical trials. Human trials with all of the below HDAC inhibitors are extremely variable and often impacted by the patient's exact SMA subtype.
=== Myasthenia gravis ===
Myasthenia gravis is an autoimmune disease affecting synapses at the neuromuscular junction, whereby antibodies produced primarily in the thymus gland by B-cells associate with postsynaptic nicotinic acetylcholine receptors (AChR), along with other NMJ post-synaptic receptors (MuSK-R and low-density lipoprotein receptor). These antibodies include acetylcholine receptor antibodies, MuSK antibodies, and low-density lipoprotein receptor related protein 4 antibodies (LRP4-Ab). Antibody binding to their respective receptors causes the destruction of those receptors, leading to a reduction in the number of postsynaptic acetylcholinergic receptors and a reduction in overall acetylcholine transport. Disease symptoms include muscular weakness that fatigues due to overuse, but improves with rest. Hallmark symptoms due to muscular weakness include ptosis, double vision, dysphagia, as well as aberrant speech.
Myasthenia gravis is a relatively rare disease, occurring in about 3–30 individuals per 100,000, but has been rising over the past couple decades. There exists two variations of myasthenia gravis with respect to age and gender demographics: early-onset myasthenia gravis, which has a higher incidence among females, and late-onset myasthenia gravis, which has a higher incidence among males.
==== Epigenetic factors ====
There has been extensive research on the genetic basis of myasthenia gravis, however evidence does not suggest that it is an inherited disease. There has also been extensive research on the epigenetic contribution to myasthenia gravis. DNA methylation and noncoding RNA, such as miRNA (micro RNA) and long noncoding RNA (lncRNA), are epigenetic factors that play a significant role in increasing the likelihood of acquiring myasthenia gravis. In addition, the thymus is a key organ in the immune response that is often negatively affected by abnormal miRNA expression and DNA methylation.
==== miRNA ====
Micro RNA (miRNA) are single-stranded non-coding RNAs that bind their target mRNAs. From there, they can regulate gene expression by inhibiting translation or degrading the mRNA strand, oftentimes in B-cells and T-cells of the immunological process. With respect to myasthenia gravis, abnormal miRNA function is associated with immunoregulatory pathogenesis, and each miRNA has its own unique downstream effects.
The thymus is an important endocrine organ implicated in myasthenia gravis. In normal, healthy development, the thymus shrinks in size over time. In those with thymus-associated myasthenia gravis there are correlations with thymomas in late-onset myasthenia gravis as well as thymic hyperplasia with germinal centers in early-onset myasthenia gravis, and each of these conditions can be attributed partly to irregular miRNA function. In late-onset myasthenia gravis subjects, it was shown that miRNA-12a-5p expression was increased in thymoma-associated myasthenia gravis. MiRNA-12a-5p inhibits expression of the gene FoxP3, a gene known to be associated with normal thymus development and whose alteration is attributed to thymomas. Additionally, an association between thymoma-associated myasthenia gravis and decreased miR-376a/miR-376c expression was found. Autoimmune regulation is known to be downregulated in thymoma-associated myasthenia gravis, and in thymus cells with downregulated autoimmune regulation there was simultaneous downregulation in miR-376a, miR-376c, and miRNA-12a-5p expression. In early-onset myasthenia gravis patients, 61 miRNA's were found to be either significantly downregulated or upregulated. The most downregulated miRNA was found to be miR-7-5p, whose target gene is CCL21. CCL21 is known to aberrantly recruit B-cells in the thymus of early-onset myasthenia gravis patients, and was found to be highly expressed in early-onset myasthenia gravis patients, potentially explaining the abnormally large amounts of B cells found in thymic hyperplasia.
Aside from miRNA's corresponding to altered thymus function, there are other several key miRNA's that are correlated with myasthenia gravis. MiR-15 cluster (miR-15a, miR-15b, and miR-15c) was shown to be associated with autoimmunity, in that its downregulation increased CXCL10 expression, a target gene involved in T-cell signaling. CXCL10 expression was also shown to be increased in the thymus of myasthenia gravis patients. Additionally, miR-146 was found to be upregulated in myasthenia gravis patients. In these patients with upregulated miR-146, there was a concurrent increase in proteins that correspond to a wide array of immune responses, specifically TLR4, CD40, and CD80.
==== DNA methylation ====
DNA methylation is the epigenetic process by which methyl groups are added to either adenine or cytosine bases, which results in the repression of that sequence when cytosine methylation occurs. DNA methylation was found to be a factor in increasing the likelihood of acquiring myasthenia gravis, albeit this topic has not been widely researched. Research in China has identified the gene CTLA-4 (cytotoxic T lymphocyte antigen-4) as being highly methylated in myasthenia gravis patients compared to control groups throughout the entire span of the disease. The CTLA-4 gene produces an antigen of the same name that is presented on killer T-cells and allows for the suppression of the immune response. Methylation of this gene represses production of the antigen CTLA-4—a pattern seen in a significant majority of myasthenia gravis patients—and can explain the elevated immune response seen in myasthenia gravis. Furthermore, myasthenia gravis patients with thymic abnormalities (approximately 10–20% of all myasthenia gravis patients) had even higher levels of CTLA-4 methylation than other myasthenia gravis patients. It is not extensively researched why certain genes are hypermethylated in these cases, but information on myasthenia gravis largely points to upregulation of the DNA methyltransferase genes DNMT1, DNMT3A, and DNMT3B in patients with myasthenia gravis.
In addition to CTLA-4 methylation, hypermethylation of the growth hormone secretagogue receptor gene was seen in patients with thymoma-associated late-onset myasthenia gravis. Growth hormone secretagogue receptor hypermethylation is detected in a wide variety of cancers, however only recently has been correlated with the development of thymoma-associated myasthenia gravis. Although it is seen in approximately 1/4 of thymoma-associated myasthenia gravis subjects, it is not a reliable biomarker for the disease, and its relevance to disease progression is not well known.
==== Long ncRNA ====
Long ncRNA (lncRNA) are a second type of non-coding RNA that are key post-transcriptional modifiers of protein-coding gene expression. These also play a significant role in myasthenia gravis. Their aberrant regulation can cause differential expression in downstream genes. For instance, the differential expression of lncRNA interferon gamma antisense RNA negatively regulates the expression of HLA-DRB and HLA-DOB, two genes implicated in the body's autoimmune response by differentiating endogenous and foreign proteins. As seen in myasthenia gravis patients with downregulated lethal (let)-7 lncRNA, it was also found that the level of let-7 lncRNA was negatively correlated with levels of interleukin (IL)-10, a gene responsible for inhibiting cytokine secretion/activation, antigen presentation, and macrophage activity, but also for exhibiting anti-tumor effects. Therefore, the negative correlation between let-7 lncRNA and IL-10 levels and its specific effects on myasthenia gravis development are ambiguous.
In addition to aberrant regulation of downstream target genes, lncRNA also affect expression by acting as competing endogenous RNA (ceRNA). The competing endogenous RNA theory states that transcripts sharing common miRNA binding sites can compete to bind these identical miRNAs, and in this way lncRNAs can bind miRNAs, regulating their downstream binding activity and affecting their function. In the case of myasthenia gravis, the lncRNA small nucleolar RNA host gene (SNHG) 16 regulates the expression of IL-10 by adsorbing let-7c-5p, a miRNA that commonly associates with IL-10, as a competing endogenous RNA.
==== Epigenetic treatments ====
Diagnosis of myasthenia gravis, individual prognosis, and the level of treatment needed can be determined by detecting the amounts of circulating miRNA.
Immunosuppressants represent a large category in clinical studies for myasthenia gravis treatment, as they reduce the hyperactive immunological response in T-cells presenting acetylcholine receptor-binding antigens. By overexpressing miR-146, studies show that patients with early-onset myasthenia gravis can have antigen-specific suppressive effects. This has implications in reducing the immune response of myasthenia gravis patients and improving prognosis. Likewise, miR-155 is proven to be correlated with myasthenia gravis-associated thymic inflammation and immune response. Research is being conducted whereas repression of miR-155 could reduce these aberrant effects. Lastly, the miRNA's miR-150-5p and miR-21-5p are consistently shown to be elevated in myasthenia gravis patients with acetylcholinergic receptor antibodies (in contrast to the MuSK-binding variant of myasthenia gravis), therefore these two miRNA's are reliable biomarkers in detecting this variant of myasthenia gravis.
== Neurodegenerative diseases of the central nervous system ==
=== Alzheimer's disease (AD) ===
Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. The disease is characterized behaviorally by chronic and progressive decline in cognitive function, beginning with short-term memory loss, and neurologically by buildup of misfolded tau protein and associated neurofibrillary tangles, and by amyloid-beta senile plaques amyloid-beta senile plaques. Several genetic factors have been identified as contributing to AD, including mutations to the amyloid precursor protein (APP) and presenilins 1 and 2 genes, and familial inheritance of apolipoprotein E allele epsilon 4. In addition to these common factors, there are a number of other genes that have shown altered expression in Alzheimer's disease, some of which are associated with epigenetic factors.
==== Epigenetic factors ====
ncRNA
ncRNA that is encoded antisense from an intron within the beta-amyloid cleaving enzyme gene, BACE1, is involved in AD. This ncRNA, BACE1-AS (for antisense), which overlaps exon 6 of BACE1, is involved in increasing the stability of the BACE1 mRNA transcript. As that gene's name suggests, BACE1 is an enzymatic protein that cleaves the amyloid precursor protein into the insoluble amyloid beta form, which then aggregates into senile plaques. With increased stability of BACE1 mRNA resulting from BACE1-AS, more BACE1 mRNA is available for translation into BACE1 protein.
miRNA
factors have not consistently been shown to play a role in progression of AD. miRNAs are involved in post-transcriptional gene silencing via inhibiting translation or involvement in RNAi pathways. Some studies have shown upregulation of miRNA-146a, which differentially regulates neuroimmune-related Interleukin-1R associated kinases IRAK1 and IRAK2 expression, in human AD brain, while other studies have shown upregulation or downregulation of miRNA-9 in brain.
DNA methylation
In Alzheimer's disease cases, global DNA hypomethylation and gene-specific hypermethylation has been observed, though findings have varied between studies, especially in studies of human brains. Hypothetically, global hypomethylation should be associated with global increases in transcription, since CpG islands are most prevalent in gene promoters; gene-specific hypermethylation, however, would indicate that these hypermethylated genes are repressed by the methylation marks. Generally, repressive hypermethylation of genes related to learning and memory has been observed in conjunction with derepressive hypomethylation of neuroinflammatory genes and genes related to pathological expression of Alzheimer's disease. Reduced methylation has been found in the long-term memory-associated temporal neocortex neurons in monozygotic twins with Alzheimer's disease compared to the healthy twin. Global hypomethylation of CpG dinucleotides has also been observed in hippocampus and in entorhinal cortex layer II of human AD patients, both of which are susceptible to AD pathology. These results, found by probing with immunoassays, have been challenged by studies that interrogate DNA sequence by bisulfite sequencing, a CpG transformation technique which is sensitive to CpG methylation status, in which global hypomethylation has been observed.
COX-2
At the individual gene level, hypomethylation and thus derepression of COX-2 occurs, inhibition of which reduces inflammation and pain, and hypermethylation of BDNF, a neurotrophic factor important for long-term memory. Expression of CREB, an activity-dependent transcription factor involved in regulating BDNF among many other genes, has also been shown to be hypermethylated, and thus repressed, in AD brains, further reducing BDNF transcription. Furthermore, synaptophysin (SYP), the major synaptic vesicle protein-encoding gene, has been shown to be hypermethylated and thus repressed, and transcription factor NF-κB, which is involved in immune signaling, has been shown to be hypomethylated and thus derepressed. Taken together, these results have elucidated a role for dysregulation of genes involved in learning and memory and synaptic transmission, as well as with immune response.
Hypomethylation
has been observed in promoters of presenilin 1, GSK3beta, which phosphorylates tau protein, and BACE1, an enzyme that cleaves APP into the amyloid-beta form, which in turn aggregates into insoluble senile plaques. Repressive hypermethylation caused by amyloid-beta has been observed at the promoter of NEP, the gene for neprilysin, which is the major amyloid-beta clearing enzyme in the brain. This repression of NEP could result in a feed-forward buildup of senile plaques; combined with the observed increase in AD brains of BACE1-AS and corresponding increases in BACE1 protein and amyloid beta, multiple levels of epigenetic regulation may be involved in controlling amyloid-beta formation, clearance or aggregation, and senile plaque deposition. There may be some effect of age in levels of DNA methylation at specific gene promoters, as one study found greater levels of methylation at APP promoters in AD patients up to 70 years old, but lower levels of methylation in patients greater than 70 years old. Studies on differential DNA methylation in human AD brains remain largely inconclusive possibly owing to the high degree of variability between individuals and to the numerous combinations of factors that may lead to AD.
Histone marks
Acetylation of lysine residues on histone tails is typically associated with transcriptional activation, whereas deacetylation is associated with transcriptional repression. There are few studies investigating specific histone marks in AD. These studies have elucidated a decrease in acetylation of lysines 18 and 23 on N-terminal tails of histone 3 (H3K18 and H3K23, respectively) and increases in HDAC2 in AD brains - both marks related to transcriptional repression. Age-related cognitive decline has been associated with deregulation of H4K12 acetylation, a cognitive effect that was restored in mice by induction of this mark.
==== Treatments ====
Treatment for prevention or management of Alzheimer's disease has proven troublesome since the disease is chronic and progressive, and many epigenetic drugs act globally and not in a gene-specific manner. As with other potential treatments to prevent or ameliorate symptoms of AD, these therapies do not work to cure, but only ameliorate symptoms of the disease temporarily, underscoring the chronic, progressive nature of AD, and the variability of methylation in AD brains.
Folate and other B vitamins
B vitamins are involved in the metabolic pathway that leads to SAM production. SAM is the donor of the methyl group utilized by DNA methyltransferases (DNMTs) to methylate CpGs. Using animal models, Fuso et al. have demonstrated restoration of methylation at previously hypomethylated promoters of presenilin 1, BACE1 and APP – a hypothetically stable epigenetic modification that should repress those genes and slow the progression of AD. Dietary SAM supplementation has also been shown to reduce oxidative stress and delay buildup of neurological hallmarks of AD such as amyloid beta and phosphorylated tau protein in transgenic AD mice.
AZA
Khan and colleagues have demonstrated a potential role for neuroglobinin attenuating amyloid-related neurotoxicity. 5-aza-2' deoxycitidine (AZA, or decitabine), a DNMT inhibitor, has shown some evidence for regulating neuroglobin expression, though this finding has not been tested in AD models.
Histone-directed treatments
Though studies of histone marks in AD brains are few in number, several studies have looked at the effects of HDACis in treatment of Alzheimer's disease. Class I and II HDAC inhibitors such as trichostatin A, vorinostat, and sodium butyrate, and Class III HDACis, such as nicotinamide, have been effective at treating symptoms in animal models of AD. While promising as a therapeutic in animal models, studies on the long-term efficacy of HDACis and human trials have yet to be conducted.
Sodium butyrate
Sodium butyrate is a class I and II HDACi and has been shown to recover learning and memory after 4 weeks, decrease phosphorylated tau protein, and restore dendritic spine density in the hippocampus of AD transgenic mice. Histone acetylation resulting from diffuse sodium butyrate application is especially prevalent in the hippocampus, and genes involved in learning and memory showed increased acetylation in AD mice treated with this drug.
Trichostatin A
Trichostatin A is also a class I and II HDACi that rescues fear learning in a fear conditioning paradigm in transgenic AD mice to wild type levels via acetylation on histone 4 lysine tails.
Vorinostat
Vorinostat is a class I and II HDACi that has been shown to be especially effective at inhibiting HDAC2 and restoring memory functions in non-AD models of learning deficits. One study showed vorinostat is effective at reversing contextual memory deficits in transgenic AD mice.
=== Huntington's (HD) ===
Huntington's disease (HD) is an inherited disorder that causes progressive degeneration of neurons within the cerebral cortex and striatum of the brain resulting in loss of motor functions (involuntary muscle contractions), decline in cognitive ability (eventually resulting in dementia), and changes in behavior.
==== Genetics and underlying causes ====
Huntington's is caused by an autosomal dominant mutation expanding the number of glutamine codon repeats (CAG) within the Huntingtin gene (Htt). The Htt gene encodes for the huntingtin protein which plays a role in normal development but its exact function remains unknown. The length of this CAG repeat correlates with the age-of-onset of the disease. The average person without Huntington's has less than 36 CAG repeats present within the Htt gene. When this repeat length exceeds 36, the onset of neuronal degradation and the physical symptoms of Huntington's can range from as early as 5 years of age (CAG repeat > 70) to as late as 80 years of age (CAG repeat < 39).
This CAG expansion results in mRNA downregulation of specific genes, decreased histone acetylation, and increased histone methylation. The exact mechanism of how this repeat causes gene dysregulation is unknown, but epigenome modification may play a role. For early-onset Huntington's (ages 5–15), both transgenic mice and mouse striatal cell lines show brain specific histone H3 hypoacetylation and decreased histone association at specific downregulated genes within the striatum (namely Bdnf, Cnr1, Drd2 – dopamine 2 receptor, and Penk1 – preproenkephalin). For both late- and early-onset Huntington's, the H3 and H4 core histones associated with these downregulated genes in Htt mutants have hypoacetylation (decreased acetylation) compared to wild-type Htt. This hypoacetylation is sufficient to cause tighter chromatin packing and mRNA downregulation.
Along with H3 hypoacetylation, both human patients and mice with the mutant Htt have increased levels of histone H3 lysine 9 trimethylation. This increase in H3-K9 trimethylation is linked to an increased expression of the methyltransferase ESET/SETDB1 (ERG-associated protein with SET domain (ESET)), which targets and trimethylates H3-K9 residues. It is proposed that this hypermethylation may account for the onset of specific gene repression in Htt mutants.
==== HDAC inhibitors ====
Huntington patients and both mouse and Drosophila models show histone H3 and H4 hypoacetylation. There are currently no treatments for the disease but numerous HDAC inhibitors have been tested and shown to reverse the certain symptoms caused by the Htt mutation.
=== Parkinson's disease (PD) ===
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra by causes unknown. Several genes and environmental factors (e.g. pesticide exposure) may play a role in onset of PD. Hallmarks include mutations to the alpha-synuclein gene, SNCA, as well as PARK2, PINK1, UCHL1, DJ1, and LRRK2 genes, and fibrillar accumulation of Lewy bodies from misfolded alpha-synuclein. Symptoms are most noticeably manifested in disorders of movement, including shaking, rigidity, deficits in making controlled movements, and slow and difficult walking. The late stages of the disease result in dementia and depression. Levodopa and dopaminergic therapy may ameliorate symptoms, though there is no treatment to halt progression of the disease.
==== Epigenetic factors ====
ncRNA
Reductions of miR-133b correlated to decreased numbers of dopaminergic neurons in the midbrain of PD patients. miR-132, meanwhile, is negatively correlated with dopaminergic neuron differentiation in the midbrain. miR-7 and miR-153 act to reduce alpha-synuclein levels (a hallmark of PD) but are reduced in PD brain.
DNA methylation
Neurons of PD patients show hypomethylation of tumor necrosis factor (TNF) alpha encoding sequence, overexpression of which leads to apoptosis of neurons. Cerebrospinal fluid of PD patients also shows elevated TNF alpha. Research indicates there may be a link between DNA methylation and SNCA expression. Furthermore, human and mouse models have shown reduction of nuclear DNMT1 levels in PD subjects, resulting in hypomethylated states associated with transcriptional repression.
Histone marks
alpha-synuclein, the protein encoded by SNCA, can associate with histones and prevent their acetylation in concert with the HDACs HDAC1 and Sirt2. Furthermore, it has been demonstrated that alpha-synuclein binds histone 3 and inhibits its acetylation in Drosophila. Dopamine depletion in Parkinson's disease is associated with repressive histone modifications, including reduced H3K4me3, and lower levels of H3 and H4 lysine acetylation after levodopa therapy (a common treatment of PD).
==== Treatments ====
Epigenetic treatments tested in models of PD are few, though some promising research has been conducted. Most treatments investigated thus far are directed at histone modifications and analysis of their roles in mediating alpha-synuclein expression and activity. Pesticides and paraquat increase histone acetylation, producing neurotoxic effects similar to those seen in PD, such as apoptosis of dopaminergic cells. Despite this, treatment with HDACis seems to have a neuroprotective effect.
=== Multiple sclerosis ===
Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that does not have a confirmed cause, but is widely considered to be an autoimmune disease in nature. It is indicated by demyelination of the nerves of the brain and spinal cord. Its symptoms are unique in nature and vary, but include those that have degenerative effects in the eyes and limbs. These can present themselves as numbness or atrophy, shock like sensations, paralysis, as well as lack of coordination or tremors, within the extremities. Within the eye, multiple sclerosis can cause blurriness, double vision, pain, or vision loss. Multiple sclerosis effects can be presented throughout other realms of the body, but is largely characterized by these main symptoms. Some of these can include loss of sexual or excretory function and epilepsy. While there are a few subcategories of multiple sclerosis, in most instances, the disease afflicts in a relapsing nature, where relapses of symptoms might not occur for extended periods of time, yielding more to the uncertainty of the disease. There is no known cure for MS, but measures can be taken post relapse to regain loss of function and the symptoms can be mitigated via therapeutic or medicinal means.
==== Epigenetic factors ====
Because of the outside factors that precede multiple sclerosis and the heritability typically occurring within the mother, it is thought to have an epigenetic cause. Some factors that may increase the incidence of MS are smoking, vitamin deficiency, and a history of some viral infections—which are factors that can induce epigenetic change.
===== Human leukocyte antigen-DRB1*15 allele =====
Human leukocyte antigen-DRB1*15 haplotype is a potential risk factor of MS. Because of the increased likelihood of the mother's human leukocyte antigen-DRB1*15 allele being passed onto their children, this contributes to the instances of MS being more prevalent from the mother. HLA-DRB1 is thought to be regulated via epigenetic means. The correlation of MS and this allele is speculated to be due to the presence of hypomethylation in the CpG island of HLA-DRB1, and those that carry the allele tend to exhibit this hypomethylation. HLA-DRB1 exon 2 is a particular region where evidence has shown that methylation is shown to be important in regulation. Research has furthered the evidence that variation in HLA-DRB1 DMR, which is a mechanism that is methylation regulated, that in turn regulates increased HLA-DRB1 expression, displays an increased risk for MS, and the exhibition of the disease.
===== miRNA =====
Higher levels of expression of specific types of miRNA are often seen in the brain of those afflicted, showing an association of these types of miRNA and MS. Higher expression of miR-155 and miR-326 is often associated with CD4+T cell differentiation, and with this differentiation, instances of autoimmune encephalitis occur, which is the link with which it is thought that smoking can induce epigenetic changes that increase susceptibility to MS. Higher expression levels of miR-18b, miR-493, miR-599, and miR-96 are often seen in patients diagnosed with MS. miR-145 detection appears to be a promising future diagnostic tool due to its high specificity of 90% and sensitivity of 89.5% in whole blood testing due to its capability of distinguishing healthy patients versus those with MS. A symptom associated with MS patients is white matter lesions in the brain, and these lesions when biopsied showed higher expression of miR-155, miR-326 and miR-34a. These are especially notable due to the fact that overexpression of these miRNA's cause downregulation of CD47, leading to myelin phagocytosis, because of CD47's role of inhibiting macrophage activity.
===== DNA methylation =====
MS patients can be identified through observation of abnormal DNA methylation patterns in genes responsible for inflammation and myelination factor expression. Methylation occurs in the genomic region, CpG island, and is imperative in regulation of transcription. A methylated CpG region typically is the mechanism that will silence a gene, whereas a hypomethylated region is able to induce transcription. Using methylation inhibitors it has been shown that allowing higher proliferation of T cells can be achieved by preventing silencing. Abnormalities in methylation patterns increase the generation of CD4+T auto reactive. Hypomethylation of CpG regions of the PAD2 gene, a regulator of MBP which in turn regulates myelin, is also associated with higher instances of MS. This hypomethylation leads to overexpression of the PAD2 gene. These patterns have been observed in the white matter of patients with MS. While methylation is an indicator of MS, its effects are more specialized to location in MS, for example, where these patterns are observed in white matter.
===== Histone modifications =====
Association of abnormal histone modification in MS patients can be found in lesions located in the brain, with most instances of this being observed in patients over time and in lesions located in the frontal lobe. Higher instance of histone acetylation can be seen in patients afflicted over time, but this is counteracted by lower instances of histone acetylation in lesions found on the brain early in the course of the disease. The mechanisms by which histone modifications work in the progression of MS are unconfirmed, but changes in acetylation are often associated with the disease.
===== Treatments =====
==== HDAC inhibitors ====
Trichostatin
Positive responses were observed in animal trials utilizing this HDAC inhibitor, associated with mediation of inflammatory pathways and thus resulting in lower instances of inflammatory responses in the brain. It was also shown to be effective in decreasing levels of disability when the mice were in a relapsing stage of MS. Trichostatin's mediation of symptoms is not well known but is thought to work in increasing acetylation at the H3 and H4 histones in CD4+T cells where MS patients often display differences in acetylation levels at these histones that control patients do not.
Vorinostat
Animal trials were utilized along with the testing of human myeloid dendritic cells. Not much is known about the mechanisms of vorinostat; however regulation of Th1/Th17 cytokine expression, which are responsible for inducing inflammation, were observed, thereby decreasing instances of inflammation and demyelination. Decreased patterns of T cell proliferation were also observed, similar to how trichostatin mediates disease symptoms.
Valpropic acid
Valpropic acid has been shown to have positive results in animal trials, in the mitigation of the disease by regulating the severity and duration of MS. Its mechanism is decreasing the presentation of miRNA. Its mechanism for such has been observed in rats by shifting Th1 and Th17 to Th2 (responsible for inducing inflammation), thereby downregulating miRNA expression in inflammatory cytokines, tumor mediating mechanisms, and the spine. This is another instance in which T cell expression regulation is present, by preventing proliferation through interference of its pathway, similar to trichostatin and vorinostat. Another effect of VPA is its prevention of macrophage and lymphocyte proliferation in the spinal cords of MS rats. Currently, no HDAC inhibitors are in use for the mitigation of symptoms in MS patients; however, some are in pre-clinical trials at this time.
== See also ==
Neuromuscular disease
== References == | Wikipedia/Epigenetics_of_neurodegenerative_diseases |
Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).
Although Batten disease is usually regarded as the juvenile form of NCL (or "type 3"), some physicians use the term Batten disease to describe all forms of NCL. Historically, the NCLs were classified by age of disease onset as infantile NCL (INCL), late infantile NCL (LINCL), juvenile NCL (JNCL) or adult NCL (ANCL). At least 20 genes have been identified in association with Batten disease, but juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in Battenin, the protein encoded by the CLN3 gene. It was first described in 1903.
== Signs and symptoms ==
Signs and symptoms of the disorder usually appear around ages 5–10 years, with gradual onset of vision problems or seizures. Early signs may be subtle personality and behavioral changes, slow learning or regression, repetitive speech or echolalia, clumsiness or stumbling. Slowing head growth in the infantile form, poor circulation in lower extremities (legs and feet), decreased body fat and muscle mass, curvature of the spine, hyperventilation and/or breath-holding spells, teeth grinding and constipation may occur.
Over time, affected children experience mental impairment, worsening seizures and progressive loss of sight, speech and motor skills. Batten disease is a terminal disease; life expectancy varies depending on the type or variation.
Females with juvenile Batten disease show first symptoms a year later than males, but on average die a year sooner.
== Cause ==
NCLs are a family of diseases that are inherited in an autosomal recessive manner. Collectively referred to as Batten disease, NCLs are responsible for most paediatric neurodegenerative diseases. The specific type of NCL is characterized by the age of symptomatic onset and genetic mutation involved. Currently, mutations in ten genes are believed to lead to the development of Batten disease; "the incidence is as high as one in 12,500 live births".
=== NCL diseases ===
Infantile neuronal ceroid (INCL): CLN1 encodes for the protein PPT1 which functions as a lysosomal enzyme.
Late infantile NCL (LINCL): CLN2 encodes for the protein TPP1 which serves as a lysosomal enzyme. Life expectancy is between eight and twelve years of age.
Juvenile NCL (JNCL): CLN3 encodes for CLN3, a lysosomal transmembrane protein.
Adult NCL: CLN4 has no known associated protein.
Finnish variant of late infantile NCL (fLINCL): CLN5 encodes for CLN5, a soluble lysosomal protein.
Variant of the late infantile NCL: CLN6 encodes for the protein CLN6, which serves as a transmembrane protein of the endoplasmic reticulum.
Turkish variant of late infantile NCL: CLN7 or MFSD8, encodes for MFSD8, which functions as a lysosomal transmembrane protein.
Northern epilepsy: CLN8 encodes for CLN8, a transmembrane protein of the endoplasmic reticulum.
Late infantile NCL: CLN10 or CTSD encodes for CTSD, which is a lysosomal protein which a variety of functions.
Infantile osteopetrosis: CLCN7 encodes for CLCN7.
=== Juvenile NCL: CLN3 mutation ===
The CLN3 gene is located on the short arm of chromosome 16 at gene position 12.1 (16p12.1), and mutations within this gene are the major cause of juvenile NCL. More specifically, 73% of Batten disease cases are due to a 1.02-kb deletion within this gene, CLN3, which causes a frameshift which produces a truncated mutant gene product of only 181 amino acids in length when compared to the wild-type gene product of 438 amino acids in length. Normal-functioning CLN3 encodes for a hydrophobic transmembrane protein that is mainly localized to the lysosome; however, the 181 amino acid mutant gene product was instead found to primarily localize to the endoplasmic reticulum and Golgi apparatus. The precise function of the CLN3 gene product remains unknown.
== Diagnosis ==
Batten disease is rare; misdiagnosis may lead to increased medical expenses, family stress, and the chance of using incorrect forms of treatment, which may exacerbate the patient's condition. Nevertheless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom of the disease. Partial or complete loss of vision often develops in patients who have childhood forms of Batten disease, while it is usually preserved in those with adult-onset Batten disease. Children or adults suspected of having Batten disease should initially see an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed. Though it is also seen in a variety of other diseases, a loss of ocular cells is a warning sign of Batten disease. If Batten disease is the suspected diagnosis, a variety of tests is conducted to help accurately confirm the diagnosis, including:
Blood or urine tests can help detect abnormalities that may indicate Batten disease. For example, elevated levels of dolichol in urine have been found in many individuals with NCL. The presence of vacuolated lymphocytes—white blood cells that contain holes or cavities (observed by microscopic analysis of blood smears)—when combined with other findings that indicate NCL, is suggestive for the juvenile form caused by CLN3 mutations.
Skin or tissue sampling is performed by extracting a small piece of tissue, which then is examined under an electron microscope. This can allow physicians to detect typical NCL deposits. These deposits are common in tissues such as skin, muscle, conjunctiva, and rectum. This diagnostic technique is useful, but other invasive tests are more reliable for diagnosing Batten disease.
Electroencephalogram (EEG) is a technique that uses special probes attached on to the individual's scalp. It records electrical currents/signals, which allow medical experts to analyze electrical pattern activity in the brain. EEG assists in observing if the patient has seizures.
Electrical studies of the eyes are used, because as mentioned, vision loss is the most common characteristic of Batten disease. Visual-evoked responses and electroretinograms are effective tests for detecting various eye conditions common in childhood NCLs.
Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests that allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging tests can help reveal brain areas that are decaying, or atrophic, in persons with NCL.
Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in CLN1. Acid protease is involved in CLN2. Cathepsin D is involved in CLN10.
DNA analysis can be used to help confirm the diagnosis of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling. If a family mutation has not previously been identified or if the common mutations are not present, recent molecular advances have made it possible to sequence all of the known NCL genes, increasing the chances of finding the responsible mutation(s).
== Treatment ==
Batten disease is a terminal illness; the FDA has approved Brineura (cerliponase alfa) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. Human clinical trials of a gene therapy for the CLN5 variant of Batten disease began at the University of Rochester in 2022. Palliative treatment is symptomatic and supportive. One drug, an antisense oligonucleotide, milasen, described in The New England Journal of Medicine, is believed to be the first "custom" treatment for a genetic disease. It is named after Mila Makovec, the only patient who may ever take it.
== History ==
Batten disease is named after the British pediatrician Frederick Batten, who first described it in 1903. Also known as Spielmeyer–Vogt–Sjögren–Batten disease, it is the most common form of a group of disorders called neuronal ceroid lipofuscinosis (NCL). Although Batten disease is usually regarded as the juvenile form of NCL, some physicians use the term Batten disease to describe all forms of NCL.
== Research ==
In June 1987, a phase-I clinical trial was launched at Weill Cornell Medical College of Cornell University to study a gene therapy method for treatment of the signs and symptoms of LINCL. The experimental drug works by delivering a gene transfer vector called AAV2CUhCLN2 to the brain. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children.
Researchers believe the neurological deficits common in JNCL could be due to overactive AMPA receptors in the cerebellum. To test this hypothesis, researchers administered AMPA antagonist drugs into affected mice. The motor skills of the affected mice showed significant improvement after the antagonist treatment, which supported the hypothesis that the neurological deficits in JNCL are due to overactive AMPA receptors. This research could eventually help to alleviate neurological deficits of JNCL in humans.
In November 2006, after receiving FDA clearance, neurosurgeon Nathan Selden, pediatrician Bob Steiner, and colleagues at Doernbecher Children's Hospital at Oregon Health and Science University began a clinical study in which purified neural stem cells were injected into the brain of Daniel Kerner, a six-year-old child with Batten disease, who had lost the ability to walk and talk. This patient was the first of six to receive the injection of a stem cell product from StemCells Inc., a Palo Alto biotech company. These are believed to be the first-ever transplants of fetal stem cells into the human brain. By early December, the child had recovered well enough to return home, and some signs of speech returning were reported. The main goal of phase-I clinical trials, however, was to investigate the safety of transplantation. Overall, the phase-I data demonstrated that high doses of human neural stem cells, delivered by a direct transplantation procedure into multiple sites within the brain, followed by 12 months of immunosuppression, were well tolerated by all six patients enrolled in the trial. The patients' medical, neurological, and neuropsychological conditions, following transplantation, appeared consistent with the normal course of the disease.
In 2010, Cherie and Jim Flores donated $2 million, the biggest gift in Batten disease research history, and the Beyond Batten Disease Foundation contributed $500,000 to establish laboratories for Italian researchers Drs. Ballabio, Sardiello and their colleagues at the Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital.
During 2011, the first controlled clinical trials began with the University of Rochester for a treatment for Batten Disease. The trial included 30 patients who were experiencing signs of the disease in the hope of slowing its progress.
In November 2013, Weill Medical College of Cornell University began recruiting participants for a safety study of a gene transfer vector, described as a non-randomised safety and efficacy trial.
As part of a trial began by University of Rochester in March 2014. Mycophenolate mofetil is being tested to determine its efficacy and safety using a gene transfer vector.
In April 2019, Haney et al. delivered brain soluble lysosomal enzyme TPP1 to treat the disease. Results showed an increased survival rate in late-infantile neruonal ceroid lipofuscinosis (LINCL) mice following treatment. Treatment also showed decreased neuroinflammation, a common side effect that leads to neuronal damage and death, compared to that of mice treated with just saline.
In complex diseases such as Batten, therapies that address multiple aspects of the disease at the same time have the potential for higher impact than those focusing on one aspect. "The use of several treatment strategies might offer additional benefits to patients with neurodegenerative disease, but the benefits of this approach must be weighed carefully against the additional adverse effects that combined treatments might bring," the researchers wrote. The medical team also noted that "over the past two decades, scientists and clinicians within the Batten disease community have worked to ensure that tools are in place to enable progress towards effective treatments at an unprecedented pace. "Recent progress in Batten disease research offers hope that efficient and targeted therapies will be available soon," the researchers said, noting that "the Batten disease research community is becoming a model of how effective, efficient rare disease research can be accomplished by working together."
== Charities ==
In the United Kingdom, the Batten Disease Family Association CIO (BDFA) became a registered charity in 2001 and a CIO in 2023. Its mission is "to enable everyone who is affected by Batten disease to live life to the full and secure the care and support they need until we find a cure". The charity Batten Fighters Forever (BFF) was founded by a family with two children who have the disease, and focuses on "increasing awareness and raising funds to support the treatment and care of people with Batten Disease and to assist the families of children with Batten Disease."
== See also ==
Lysosomal storage diseases
== References ==
== External links ==
Batten disease at NINDS
GeneReviews/NCBI/NIH/UW entry on Neuronal Ceroid-Lipofuscinosis
Batten FE, Mayou MS (1915). "Family Cerebral Degeneration with Macular Changes". Proceedings of the Royal Society of Medicine. 8 (Sect Ophthalmol): 70–90. doi:10.1177/003591571500801624. PMC 2003604. PMID 19978990. | Wikipedia/Batten_disease |
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of harming a human. Although biological activity in an animal model does not ensure an effect in humans, many drugs, treatments and cures for human diseases are developed in part with the guidance of animal models. Animal models representing specific taxonomic groups in the research and study of developmental processes are also referred to as model organisms. There are three main types of animal models: Homologous, Isomorphic and Predictive.
Homologous animals have the same causes, symptoms and treatment options as would humans who have the same disease.
Isomorphic animals share the same symptoms and treatments, only.
Predictive models are similar to a particular human disease in only a couple of aspects. However, these are useful in isolating and making predictions about mechanisms of a set of disease features.
== Phylogeny and genetic similarity ==
Although scientific study of animals predates Charles Darwin by several hundred years, the primary justification for the use of animals in research is based on the evolutionary principle that all organisms share some degree of relatedness and genetic similarity due to common ancestry. The study of taxonomic human relatives, then, can provide a great deal of information about mechanism and disease within the human body that can be useful in medicine.
Various phylogenetic trees for vertebrates have been constructed using comparative proteomics, genetics, genomics as well as the geochemical and fossil record. These estimations tell us that humans and chimpanzees last shared a common ancestor about 6 million years ago (mya). As our closest relatives, chimpanzees have a lot of potential to tell us about mechanisms of disease (and what genes may be responsible for human intelligence). However, chimpanzees are rarely used in research and are protected from highly invasive procedures. The most common animal model is the rodent. Phylogenic trees estimate that humans and rodents last shared a common ancestor ~80-100mya. Despite this distant split, humans and rodents have far more similarities than they do differences. This is due to the relative stability of large portions of the genome; making the use of vertebrate animals particularly productive.
Recently, genomic data has been added to techniques to make close comparisons between species and determine relatedness. Humans share about 99% of our genome with chimpanzees (98.7% with bonobos) and over 90% with the mouse. With so much of the genome conserved across species, it is relatively impressive that the differences between humans and mice can be accounted for in approximately six thousand genes (of ~30,000 total). Scientists have been able to take advantage of these similarities in generating experimental and predictive models of human disease.
== Disease models ==
Animal models serving in research may have an existing, inbred or induced disease or injury that is similar to a human condition. These test conditions are often termed as animal models of disease. The use of animal models allows researchers to investigate disease states in ways which would be inaccessible in a human patient, performing procedures on the non-human animal that imply a level of harm that would not be considered ethical to inflict on a human.
As in noted the introduction, animal models can be classified as homologous, isomorphic or predictive. Animal models can also be more broadly classified into four categories:
experimental,
spontaneous,
negative,
orphan.
Experimental models are most common. These refer to models of disease that resemble human conditions in phenotype or response to treatment but are induced artificially in the laboratory. Some examples include:
The use of metrazol (pentylenetetrazol) as an animal model of epilepsy
Immunisation with an auto-antigen to induce an immune response to model autoimmune diseases such as Experimental autoimmune encephalomyelitis
Occlusion of the middle cerebral artery as an animal model of ischemic stroke
Injection of blood in the basal ganglia of mice as a model for hemorrhagic stroke
Sepsis and septic shock induction by impairing the integrity of barrier tissues, administering live pathogens or toxins
Infecting animals with pathogens to reproduce human infectious diseases
Injecting animals with agonists or antagonists of various neurotransmitters to reproduce human mental disorders
Using ionizing radiation to cause tumors
Using gene transfer to cause tumors
Implanting animals with tumors to test and develop treatments using ionizing radiation
Genetically selected (such as in diabetic mice also known as NOD mice)
Various animal models for screening of drugs for the treatment of glaucoma
The use of the ovariectomized rat in osteoporosis research
Use of Plasmodium yoelii as a model of human malaria
Spontaneous models refer to diseases that are analogous to human conditions that occur naturally in the animal being studied. These models are rare, but informative.
Negative models essentially refer to control animals, which are useful for validating an experimental result.
Orphan models refer to diseases for which there is no human analog and occur exclusively in the species studied.
The increase in knowledge of the genomes of non-human primates and other mammals that are genetically close to humans is allowing the production of genetically engineered animal tissues, organs and even animal species which express human diseases, providing a more robust model of human diseases in an animal model.
The best models of disease are similar in etiology (mechanism of cause) and phenotype (signs and symptoms) to the human equivalent. However complex human diseases can often be better understood in a simplified system in which individual parts of the disease process are isolated and examined. For instance, behavioral analogues of anxiety or pain in laboratory animals can be used to screen and test new drugs for the treatment of these conditions in humans. A 2000 study found that animal models concorded (coincided on true positives and false negatives) with human toxicity in 71% of cases, with 63% for nonrodents alone and 43% for rodents alone.
In 1987, Davidson et al. suggested that selection of an animal model for research be based on nine considerations. These include
"1) appropriateness as an analog, 2) transferability of information, 3) genetic uniformity of organisms, where applicable, 4) background knowledge of biological properties, 5) cost and availability, 6) generalizability of the results, 7) ease of and adaptability to experimental manipulation, 8) ecological consequences, and 9) ethical implications."
== Behavioral sciences ==
Animal models observed in the sciences of psychology and sociology are often termed animal models of behavior. It is difficult to build an animal model that perfectly reproduces the symptoms of depression in patients. Animals lack self-consciousness, self-reflection and consideration; moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans. However, depression, as other mental disorders, consists of endophenotypes that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between genetic or environmental alterations and depression can be examined, which would afford a better insight into pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression.
== Challenges and criticisms ==
Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively sedentary, obese and glucose intolerant. This may confound their use to model human metabolic processes and diseases as these can be affected by dietary energy intake and exercise.
Animal models of psychiatric illness give rise to other concerns. Qualitative assessments of behavior are too often subjective. This would lead the investigator to observe what they want to observe in subjects, and to render conclusions in line with their expectations. Also, the imprecise diagnostic criteria for psychiatric illnesses inevitably lead to problems modeling the condition; e.g., since a person with major depressive disorder may experience weight loss or weight gain, insomnia or hypersomnia, we cannot with any certainty say that a rat with insomnia and weight loss is depressed. Furthermore, the complex nature of psychiatric conditions makes it difficult/impossible to translate human behaviors and deficits; e.g., language deficit plays a major role in autistic spectrum disorders, but – since rodents do not have language – it is not possible to develop a language-impaired "autistic" mouse.
== Ethics ==
Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament enacted the first law for animal protection preventing cruelty to cattle, the Cruel Treatment of Cattle Act 1822. This was followed by the Cruelty to Animals Act 1835 and the Cruelty to Animals Act 1849, which criminalized ill-treating, over-driving, and torturing animals. In 1876, under pressure from the National Anti-Vivisection Society, the Cruelty to Animals Act 1849 was amended by the Cruelty to Animals Act 1876 to include regulations governing the use of animals in research. This new act stipulated that 1) experiments must be proven absolutely necessary for instruction, or to save or prolong human life; 2) animals must be properly anesthetized; and 3) animals must be killed as soon as the experiment is over. Today, these three principles are central to the laws and guidelines governing the use of animals and research. In the U.S., the Animal Welfare Act of 1970 (see also Laboratory Animal Welfare Act) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care program see AWA policies.
In academic settings in which NIH funding is used for animal research, institutions are governed by the NIH Office of Laboratory Animal Welfare (OLAW). At each site, OLAW guidelines and standards are upheld by a local review board called the Institutional Animal Care and Use Committee (IACUC). All laboratory experiments involving living animals are reviewed and approved by this committee. In addition to proving the potential for benefit to human health, minimization of pain and distress, and timely and humane euthanasia, experimenters must justify their protocols based on the principles of Replacement, Reduction and Refinement.
Replacement refers to efforts to engage alternatives to animal use. This includes the use of computer models, non-living tissues and cells, and replacement of "higher-order" animals (primates and mammals) with "lower" order animals (e.g. cold-blooded animals, invertebrates, bacteria) wherever possible (list of common model organisms approved for use by the NIH).
Reduction refers to efforts to minimize number of animals used during the course of an experiment, as well as prevention of unnecessary replication of previous experiments. To satisfy this requirement, mathematical calculations of statistical power are employed to determine the minimum number of animals that can be used to get a statistically significant experimental result. Reduction involves methods to maximize information provided while minimizing the number of animals applied.
Refinement refers to efforts to make experimental design as painless and efficient as possible in order to minimize the suffering of each animal subject.
While significant advances have been made in the care and treatment of animals, this is an ever-evolving debate. Animal rights and protection groups such as the ASPCA, PETA and BUAV continue to advocate for the best laboratory conditions, and experimental protocols possible for animals in research. Pressure from these groups has also led to novel modes of experimentation, which does not involve the sacrifice of live animals.
One aspect of this debate; however, continues to be difficult to resolve: the classification of animals according to a hierarchy, which protects some species more than others. Next to humans, primates are the most protected species in experimentation. The rationale for this has both evolutionary and philosophical underpinnings. Because chimpanzees and other non-human primates can demonstrate intelligence, and social structure that they have a life experiences that is more cognitively complex than lower species. Conversely, this kind of moralizing of complexity of interaction and thought could be considered speciesism. Ultimately, this is an argument not likely to be resolved, however most people are more comfortable with the idea of experimentation that involves worms or flies than mice, dogs, or monkeys.
== Alternatives ==
Ethical concerns, as well as the cost, maintenance and relative inefficiency of animal research has encouraged development of alternative methods for the study of disease. Cell culture and in vitro studies provide an alternative that preserves the physiology of the living cell, but does not require the sacrifice of an animal for mechanistic studies. Human induced pluripotent stem cells can also elucidate new mechanisms for understanding cancer and cell regeneration. Imaging studies (such as MRI or PET scans) enable non-invasive study of human subjects. Recent advances in genetics and genomics can identify disease-associated genes, which can be targeted for therapies.
== See also ==
Animal models of autism
Animal models of schizophrenia
Animal testing on invertebrates
Animal testing on rodents
Animal testing
Britches (monkey)
Ensembl genome database
History of animal testing
History of model organisms
In vivo
Knockout rat
Mouse models of colorectal and intestinal cancer
== References ==
== External links ==
Transgenic Animal Models – Biomedcode
Knock Out Rat Consortium – KORC
Emice – National Cancer Institute | Wikipedia/Animal_model |
Motor neuron diseases or motor neurone diseases (MNDs) are a group of rare neurodegenerative disorders that selectively affect motor neurons, the cells which control voluntary muscles of the body. They include amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), spinal muscular atrophy (SMA) and monomelic amyotrophy (MMA), as well as some rarer variants resembling ALS.
Motor neuron diseases affect both children and adults. While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly muscle weakness. Most of these diseases seem to occur randomly without known causes, but some forms are inherited. Studies into these inherited forms have led to discoveries of various genes (e.g. SOD1) that are thought to be important in understanding how the disease occurs.
Symptoms of motor neuron diseases can be first seen at birth or can come on slowly later in life. Most of these diseases worsen over time; while some, such as ALS, shorten one's life expectancy, others do not. Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.
== Signs and symptoms ==
Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms. They come on slowly, and worsen over the course of more than three months. Various patterns of muscle weakness are seen, and muscle cramps and spasms may occur. One can have difficulty breathing with climbing stairs (exertion), difficulty breathing when lying down (orthopnea), or even respiratory failure if breathing muscles become involved. Bulbar symptoms, including difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and excessive saliva production (sialorrhea), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g. pseudobulbar affect) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen. There can be lower motor neuron findings (e.g. muscle wasting, muscle twitching), upper motor neuron findings (e.g. brisk reflexes, Babinski reflex, Hoffman's reflex, increased muscle tone), or both.
Motor neuron diseases are seen both in children and adults. Those that affect children tend to be inherited or familial, and their symptoms are either present at birth or appear before learning to walk. Those that affect adults tend to appear after age 40. The clinical course depends on the specific disease, but most progress or worsen over the course of months. Some are fatal (e.g. ALS), while others are not (e.g. PLS).
=== Patterns of weakness ===
Various patterns of muscle weakness occur in different motor neuron diseases. Weakness can be symmetric or asymmetric, and it can occur in body parts that are distal, proximal, or both. According to Statland et al., there are three main weakness patterns that are seen in motor neuron diseases, which are:
Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
Symmetric weakness without sensory loss (e.g. PMA, PLS)
Symmetric focal midline proximal weakness (neck, trunk, bulbar involvement; e.g. ALS, PBP, PLS)
=== Lower and upper motor neuron findings ===
Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement. Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle atrophy and fasciculations, and upper motor neuron (UMN) findings include hyperreflexia, spasticity, muscle spasm, and abnormal reflexes.
Pure upper motor neuron diseases, or those with just UMN findings, include PLS.
Pure lower motor neuron diseases, or those with just LMN findings, include PMA.
Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.
== Causes ==
Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved.
=== DNA damage ===
TAR DNA-binding protein 43 (TDP-43), is a critical component of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks in pluripotent stem cell-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the XRCC4-DNA ligase protein complex that then acts to repair double-strand breaks. About 95% of ALS patients have abnormalities in the nucleus-cytoplasmic localization in spinal motor neurons of TDP43. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients' spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.
=== Associated risk factors ===
In adults, men are more commonly affected than women.
== Diagnosis ==
Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases. Frequently, the diagnosis is based on clinical findings (i.e. LMN vs. UMN signs and symptoms, patterns of weakness), family history of MND, and a variation of tests, many of which are used to rule out disease mimics, which can manifest with identical symptoms.
=== Classification ===
Motor neuron disease describes a collection of clinical disorders, characterized by progressive muscle weakness and the degeneration of the motor neuron on electrophysiological testing. The term "motor neuron disease" has varying meanings in different countries. Similarly, the literature inconsistently classifies which degenerative motor neuron disorders can be included under the umbrella term "motor neuron disease". The four main types of MND are marked (*) in the table below.
All types of MND can be differentiated by two defining characteristics:
Is the disease sporadic or inherited?
Is there involvement of the upper motor neurons (UMN), the lower motor neurons (LMN), or both?
Sporadic or acquired MNDs occur in patients with no family history of degenerative motor neuron disease. Inherited or genetic MNDs adhere to one of the following inheritance patterns: autosomal dominant, autosomal recessive, or X-linked. Some disorders, like ALS, can occur sporadically (85%) or can have a genetic cause (15%) with the same clinical symptoms and progression of disease.
UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord. LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles. Both motor neurons are necessary for the strong contraction of a muscle, but damage to an UMN can be distinguished from damage to a LMN by physical exam.
=== Tests ===
Cerebrospinal fluid (CSF) tests: Analysis of the fluid from around the brain and spinal cord could reveal signs of an infection or inflammation.
Magnetic resonance imaging (MRI): An MRI of the brain and spinal cord is recommended in patients with UMN signs and symptoms to explore other causes, such as a tumor, inflammation, or lack of blood supply (stroke).
Electromyogram (EMG) & nerve conduction study (NCS): The EMG, which evaluates muscle function, and NCS, which evaluates nerve function, are performed together in patients with LMN signs.
For patients with MND affecting the LMNs, the EMG will show evidence of: (1) acute denervation, which is ongoing as motor neurons degenerate, and (2) chronic denervation and reinnervation of the muscle, as the remaining motor neurons attempt to fill in for lost motor neurons.
By contrast, the NCS in these patients is usually normal. It can show a low compound muscle action potential (CMAP), which results from the loss of motor neurons, but the sensory neurons should remain unaffected.
Tissue biopsy: Taking a small sample of a muscle or nerve may be necessary if the EMG/NCS is not specific enough to rule out other causes of progressive muscle weakness, but it is rarely used.
== Treatment ==
There are no known curative treatments for the majority of motor neuron disorders.
Physiotherapy helps maintain movement and function when someone is affected by
disability, injury or illness. This is achieved through movement and exercise, manual
therapy, education and advice. Although physiotherapy can't reverse the effects of
MND, or Kennedy's disease, it can help maintain range of movement and comfort
for as long as possible.
== Prognosis ==
The table below lists life expectancy for patients who are diagnosed with MND.
== Terminology ==
In the United States and Canada, the term motor neuron disease usually refers to the group of disorders while amyotrophic lateral sclerosis is frequently called Lou Gehrig's disease. In the United Kingdom and Australia, the term motor neuron(e) disease is used for amyotrophic lateral sclerosis, although is not uncommon to refer to the entire group.
While MND refers to a specific subset of similar diseases, there are numerous other diseases of motor neurons that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the spinal muscular atrophies group. However, they are not classified as "motor neuron diseases" by the 11th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), which is the definition followed in this article.
== See also ==
Spinal muscular atrophies
Hereditary motor and sensory neuropathies
Stephen Hawking
== References ==
== External links ==
Media related to Motor neuron diseases at Wikimedia Commons
Motor neuron diseases at NINDS | Wikipedia/Motor_neuron_diseases |
Fazio–Londe disease (FLD), also called progressive bulbar palsy of childhood, is a very rare inherited motor neuron disease of children and young adults and is characterized by progressive paralysis of muscles innervated by cranial nerves. FLD, along with Brown–Vialetto–Van Laere syndrome (BVVL), are the two forms of infantile progressive bulbar palsy, a type of progressive bulbar palsy in children.
== Signs and symptoms ==
FLD produces rapidly progressive weakness of tongue, face and pharyngeal muscles in a clinical pattern similar to myasthenia. Neuromuscular transmission may be abnormal in these muscles because of rapid denervation and immature reinnervation. Paralysis occurs secondary to degeneration of the motor neurons of the brain stem. It causes progressive bulbar paralysis due to involvement of motor neurons of the cranial nerve nuclei. The most frequent symptoms at onset of progressive bulbar paralysis of childhood has been a unilateral facial paralysis. It is followed in frequency by dysarthria due to facial weakness or by dysphagia. Palatal weakness and palpebral ptosis also have been reported in few patients. Both sexes can be affected.
== Genetics ==
Fazio–Londe disease is linked to a genetic mutation in the SLC52A3 gene on chromosome 20 (locus: 20p13). It is allelic and phenotypically similar to Brown–Vialetto–Van Laere syndrome. The condition is inherited in an autosomal recessive manner. The gene encodes the intestinal riboflavin transporter (hRFT2).
== Diagnosis ==
Symptoms of Fazio–Londe include bulbar palsy, hearing loss, facial weakness, and difficulty breathing. The disease is caused by mutations in the SLC52A2 gene and the SLC52A1 (GPR172B) genes which code for hRFT3 and hRFT1, human riboflavin transporters. Only muscle biopsy and examination of the transporter genes is considered to provide a definitive diagnosis. However, because the disease is so often fatal without treatment, and because the treatment is so inexpensive and with little risk, it is recommended that if the disease is suspected that riboflavin therapy be started immediately while testing is in progress.
== Treatment ==
The condition is treatable. High doses of oral riboflavin 5 phosphate may work, and sublingual flavin adenine dinucleotide may work.
== Prognosis ==
Onset of first symptom has been reported between 1–12 years, with a mean age of onset at 8 years. Clinical course can be divided into early (< 6 yrs age, predominance of respiratory symptoms) and late course (6–20 years of age, predominance of motor symptoms on superior limbs). Progression to involve other cranial nerve muscles occurs over a period of months or years. In the Gomez review, the facial nerve was affected in all cases while the hypoglossal nerve was involved in all cases except one. Other cranial nerves involved were vagus, trigeminal, spinal accessory nerve, abducens, oculomotor, and glossopharyngeal in this order. Corticospinal tract signs were found in 2 of the 14 patients.
The disease may progress to patient's death in a period as short as 9 months or may have a slow evolution or may show plateaus. Postmortem examination of cases have found depletion of nerve cells in the nuclei of cranial nerves. The histologic alterations found in patient with Fazio–Londe disease were identical to those seen in infantile-onset spinal muscular atrophy.
Strength may improve with administration of cholinesterase inhibitors.
== History ==
Berger, in 1876, first reported a case of 12-year-old boy with progressive bulbar paralysis. His medical history revealed a neurological illness with difficulty in swallowing liquids and solids, nasal regurgitation to liquids, nasal twang 2 years ago. He was treated for post-diptheritic bulbar palsy and had a residual bulbar weakness. Other details were not available. The child was ambulant and apparently normal until 3 months back when he developed respiratory distress and was treated at a local hospital prior to referral. He had a past history of dog bite 3 months ago for which he received five doses of anti-rabies vaccine. He was born out of a non-consanguineous marriage. The antenatal, natal, postnatal histories were insignificant. His elder sibling was healthy. This child was immunised appropriate for age. There was no family history of any neurological illness or sibling death.
== Eponym ==
It is named for the Italian pathologist Eugenio Fazio (1849–1902) and the French physician Paul Frederic Louis Londe (1864–1944).
== References == | Wikipedia/Fazio–Londe_disease |
Central nervous system diseases or central nervous system disorders are a group of neurological disorders that affect the structure or function of the brain or spinal cord, which collectively form the central nervous system (CNS). These disorders may be caused by such things as infection, injury, blood clots, age related degeneration, cancer, autoimmune disfunction, and birth defects. The symptoms vary widely, as do the treatments.
Central nervous system tumors are the most common forms of pediatric cancer. Brain tumors are the most frequent and have the highest mortality.
Some disorders, such as substance addiction, autism, and ADHD may be regarded as CNS disorders, though the classifications are not without dispute.
== Signs and symptoms ==
Every disease has different signs and symptoms. Some of them are persistent headache; pain in the face, back, arms, or legs; an inability to concentrate; loss of feeling; memory loss; loss of muscle strength; tremors; seizures; increased reflexes, spasticity, tics; paralysis; and slurred speech. One should seek medical attention if affected by these.
== Causes ==
=== Trauma ===
Any type of traumatic brain injury (TBI) or injury done to the spinal cord can result in a wide spectrum of disabilities in a person. Depending on the section of the brain or spinal cord that experiences the trauma, the outcome may be anticipated.
=== Infections ===
Infectious diseases are transmitted in several ways. Some of these infections may affect the brain or spinal cord directly. Generally, an infection is a disease that is caused by the invasion of a microorganism or virus.
=== Degeneration ===
Degenerative spinal disorders involve a loss of function in the spine. Pressure on the spinal cord and nerves may be associated with herniation or disc displacement. Brain degeneration also causes central nervous system diseases (i.e. Alzheimer's, Lewy body dementia, Parkinson's, and Huntington's diseases). Studies have shown that obese people may have severe degeneration in the brain due to loss of tissue affecting cognition.
=== Structural defects ===
Common structural defects include birth defects, anencephaly, and spina bifida. Children born with structural defects may have malformed limbs, heart problems, and facial abnormalities.
Defects in the formation of the cerebral cortex include microgyria, polymicrogyria, bilateral frontoparietal polymicrogyria, and pachygyria.
=== CNS Tumors ===
A tumor is an abnormal growth of body tissue. In the beginning, tumors can be noncancerous, but if they become malignant, they are cancerous. In general, they appear when there is a problem with cellular division. Problems with the body's immune system can lead to tumors.
=== Autoimmune disorders ===
An autoimmune disorder is a condition where in the immune system attacks and destroys healthy body tissue. This is caused by a loss of tolerance to proteins in the body, resulting in immune cells recognising these as 'foreign' and directing an immune response against them.
=== Stroke ===
A stroke is an interruption of the blood supply to the brain. Approximately every 40 seconds, someone in the US has a stroke. This can happen when a blood vessel is blocked by a blood clot or when a blood vessel ruptures, causing blood to leak to the brain. If the brain cannot get enough oxygen and blood, brain cells can die, leading to permanent damage.
== Functions ==
=== Spinal cord ===
The spinal cord transmits sensory reception from the peripheral nervous system. It also conducts motor information to the body's skeletal muscles, cardiac muscles, smooth muscles, and glands. There are 31 pairs of spinal nerves along the spinal cord, all of which consist of both sensory and motor neurons. The spinal cord is protected by vertebrae and connects the peripheral nervous system to the brain, and it acts as a "minor" coordinating center.
=== Brain ===
The brain serves as the organic basis of cognition and exerts centralized control over the other organs of the body. The brain is protected by the skull; however, if the brain is damaged, significant impairments in cognition and physiological function or death may occur.
== Diagnosis ==
=== Types of CNS disorders ===
==== Addiction ====
Addiction is a disorder of the brain's reward system which arises through transcriptional and epigenetic mechanisms and occurs over time from chronically high levels of exposure to an addictive stimulus (e.g., morphine, cocaine, sexual intercourse, gambling, etc.).
==== Arachnoid cysts ====
Arachnoid cysts are cerebrospinal fluid covered by arachnoidal cells that may develop on the brain or spinal cord. They are a congenital disorder, and in some cases may not show symptoms. However, if there is a large cyst, symptoms may include headache, seizures, ataxia (lack of muscle control), hemiparesis, and several others. Macrocephaly and ADHD are common among children, while presenile dementia, hydrocephalus (an abnormality of the dynamics of the cerebrospinal fluid), and urinary incontinence are symptoms for elderly patients (65 and older).
==== Attention deficit/hyperactivity disorder (ADHD) ====
ADHD is an organic disorder of the nervous system. ADHD, which in severe cases can be debilitating, has symptoms thought to be caused by structural as well as biochemical imbalances in the brain; in particular, low levels of the neurotransmitters dopamine and norepinephrine, which are responsible for controlling and maintaining attention and movement. Many people with ADHD continue to have symptoms well into adulthood. Also of note is an increased risk of the development of Dementia with Lewy bodies, or (DLB), and a direct genetic association of Attention deficit disorder to Parkinson's disease two progressive, and serious, neurological diseases whose symptoms often occur in people over age 65.
==== Autism ====
Autism is a neurodevelopmental disorder that is characterized by repetitive patterns of behavior and persistent deficits in social interaction and communication.
==== Brain tumors ====
Tumors of the central nervous system constitute around 2% of all cancer in the United States.
==== Catalepsy ====
Catalepsy is a nervous disorder characterized by immobility and muscular rigidity, along with a decreased sensitivity to pain. Catalepsy is considered a symptom of serious diseases of the nervous system (e.g., Parkinson's disease, Epilepsy, etc.) rather than a disease by itself. Cataleptic fits can range in duration from several minutes to weeks. Catalepsy often responds to Benzodiazepines (e.g., Lorazepam) in pill and I.V. form.
==== Encephalitis ====
Encephalitis is an inflammation of the brain. It is usually caused by a foreign substance or a viral infection. Symptoms of this disease include headache, neck pain, drowsiness, nausea, and fever. If caused by the West Nile virus, it may be lethal to humans, as well as birds and horses.
==== Epilepsy and seizures ====
Epilepsy is an unpredictable, serious, and potentially fatal disorder of the nervous system, thought to be the result of faulty electrical activity in the brain. Epileptic seizures result from abnormal, excessive, or hypersynchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, and nearly 80% of epilepsy occurs in developing countries. Epilepsy becomes more common as people age. Onset of new cases occurs most frequently in infants and the elderly. Epileptic seizures may occur in recovering patients as a consequence of brain surgery.
==== Infection ====
A number of different pathogens (i.e., certain viruses, bacteria, protozoa, fungi, and prions) can cause infections that adversely affect the brain or spinal cord.
==== Meningitis ====
Meningitis is an inflammation of the meninges (membranes) of the brain and spinal cord. It is most often caused by a bacterial or viral infection. Fever, vomiting, and a stiff neck are all symptoms of meningitis.
==== Migraine ====
A chronic, often debilitating neurological disorder characterized by recurrent moderate to severe headaches, often in association with a number of autonomic nervous system symptoms.
==== Multiple sclerosis ====
Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, meaning that the myelin sheath of neurons is damaged. Symptoms of MS include visual and sensation problems, muscle weakness, numbness and tingling all over, muscle spasms, poor coordination, and depression. Also, patients with MS have reported extreme fatigue and dizziness, tremors, and bladder leakage.
==== Myelopathy ====
Myelopathy is an injury to the spinal cord due to severe compression that may result from trauma, congenital stenosis, degenerative disease or disc herniation. The spinal cord is a group of nerves housed inside the spine that runs almost its entire length.
==== Tourette's ====
Tourette's syndrome is an inherited neurological disorder. Early onset may be during childhood, and it is characterized by physical and verbal tics. Tourette's often also includes symptoms of both OCD and ADHD indicating a link between the three disorders. The exact cause of Tourette's, other than genetic factors, is unknown.
=== Neurodegenerative disorders ===
==== Alzheimer's ====
Alzheimer's is a neurodegenerative disease typically found in people over the age of 65 years. Worldwide, approximately 24 million people have dementia; 60% of these cases are due to Alzheimer's. The ultimate cause is unknown. The clinical sign of Alzheimer's is progressive cognition deterioration.
==== Huntington's disease ====
Huntington's disease is a degenerative neurological disorder that is inherited. Degeneration of neuronal cells occurs throughout the brain, especially in the striatum. There is a progressive decline that results in abnormal movements. Statistics show that Huntington's disease may affect 10 per 100,000 people of Western European descent.
==== Lewy body dementia ====
Lewy body dementia is an umbrella term for two similar and common subtypes of dementia: dementia with Lewy bodies (DLB) and
Parkinson's disease dementia (PDD). Both are characterized by changes in thinking, movement, behavior, and mood. The two conditions have similar features and may have similar causes, and are believed to belong on a spectrum of Lewy body disease that includes Parkinson's disease.
==== Parkinson's ====
Parkinson's disease, or PD, is a progressive illness of the nervous system. Caused by the death of dopamine-producing brain cells that affect motor skills and speech. Symptoms may include bradykinesia (slow physical movement), muscle rigidity, and tremors. Behavior, thinking, sensation disorders, and the sometimes co-morbid skin condition Seborrheic dermatitis are just some of PD's numerous nonmotor symptoms. Parkinson's disease, Attention deficit/hyperactivity disorder (ADHD) and Bi-polar disorder, all appear to have some connection to one another, as all three nervous system disorders involve lower than normal levels of the brain chemical dopamine (In ADHD, Parkinson's, and the depressive phase of Bi-polar disorder.) or too much dopamine (in Mania or Manic states of Bi-polar disorder) in different areas of the brain:
== Treatments ==
There are a wide range of treatments for central nervous system diseases. These can range from surgery to neural rehabilitation or prescribed medications. The most valued companies worldwide whose leading products are in CNS Care include CSPC Pharma (Hong Kong), Biogen (United States), UCB (Belgium) and Otsuka (Japan) who are active in treatment areas like MS, Alzheimers, Epilepsy and Psychiatry.
== See also ==
Neurodegenerative disease
List of central nervous system infections
== References ==
== External links == | Wikipedia/Central_nervous_system_disease |
Proteolipid protein 1 (PLP1) is a form of myelin proteolipid protein (PLP). Mutations in PLP1 are associated with Pelizaeus–Merzbacher disease. It is a 4 transmembrane domain protein which is proposed to bind other copies of itself on the extracellular side of the membrane. In a myelin sheath, as the layers of myelin wraps come together, PLP will bind itself and tightly hold the cellular membranes together.
This gene encodes a transmembrane proteolipid protein that is the predominant myelin protein present in the central nervous system (CNS). The encoded protein functions in myelination. This protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations associated with this gene cause X-linked Pelizaeus–Merzbacher disease and spastic paraplegia type 2. Two transcript variants encoding distinct isoforms have been identified for this gene.
In melanocytic cells PLP1 gene expression may be regulated by MITF.
== Interactions ==
Proteolipid protein 1 has been shown to interact with Myelin basic protein.
== See also ==
PLP2
== References ==
== Further reading ==
== External links ==
PLP1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GeneReview/NCBI/NIH/UW entry on PLP1-Related Disorders | Wikipedia/Proteolipid_protein |
CNS demyelinating autoimmune diseases are autoimmune diseases which primarily affect the central nervous system.
== Types ==
Examples include:
Diffuse cerebral sclerosis of Schilder
Acute disseminated encephalomyelitis
Acute hemorrhagic leukoencephalitis
Multiple sclerosis (though the cause is unknown, it is sure that immune system is involved)
Transverse myelitis
Neuromyelitis optica
== Presentation ==
Since the neural impulse is inhibited in this condition it may lead to paresthesia, muscle weakness, unsteady gait, paralysis, vision loss and other motor dysfunctions.
== Causes ==
CNS demyelination autoimmune disease causes the myelin sheath to deteriorate since the sense of recognition of self is lost. The loss of the myelin insulation either disrupts or prevents neural conduction along the nerve cell's axon.
== Nervous System ==
The brain and the spinal cord are the essential components of the central nervous system and it is responsible for the integration of the signals received from the afferent nerves and initiates action. The nerve cells, known as neurons, carry impulses throughout the body and the nerve impulses are carried along the axon. These microscopic nerve fibers, where the action potential occurs, are protected by a white, fatty tissue that surrounds and insulates it, known as the myelin sheath. This insulation helps the axon of a nerve cell with the conduction and speed of the signal along the axon.
== Pathogenesis ==
The pathogenesis of the demyelination can vary. Some of the factors that contribute to the deteriorating of the myelin are due to inflammatory processes, acquired metabolic derangements, viral demyelination, and hypoxic-ischaemic demyelination.
== Diagnosis ==
== See also ==
Idiopathic inflammatory demyelinating diseases
Demyelinating disease
== References ==
== External links == | Wikipedia/CNS_demyelinating_autoimmune_diseases |
The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau). They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance. They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.
Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease are associated with tau proteins that have become hyperphosphorylated insoluble aggregates called neurofibrillary tangles. The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly, and since then they have been characterized as intrinsically disordered proteins.
== Function ==
=== Microtubule stabilization ===
Tau proteins are found more often in neurons than in non-neuronal cells in humans. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system microtubule-associated proteins (MAPs) may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.
Although tau is present in dendrites at low levels, where it is involved in postsynaptic scaffolding, it is active primarily in the distal portions of axons, where it provides microtubule stabilization but also flexibility as needed. Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.
In addition to its microtubule-stabilizing function, Tau has also been found to recruit signaling proteins and to regulate microtubule-mediated axonal transport.
=== mRNA translation ===
Tau is a negative regulator of mRNA translation in Drosophila, mouse, and human brains, through its binding to ribosomes, which results in impaired ribosomal function, reduction of protein synthesis and altered synaptic function. Tau interacts specifically with several ribosomal proteins, including the crucial regulator of translation rpS6.
=== Behavior ===
The primary non-cellular functions of tau is to negatively regulate long-term memory and to facilitate habituation (a form of non-associative learning), two higher and more integrated physiological functions. Since regulation of tau is critical for memory, this could explain the linkage between tauopathies and cognitive impairment.
In mice, while the reported tau knockout strains present without overt phenotype when young, when aged, they show some muscle weakness, hyperactivity, and impaired fear conditioning. However, neither spatial learning in mice, nor short-term memory (learning) in Drosophila seems to be affected by the absence of tau.
In addition, tau knockout mice have abnormal sleep-wake cycle, with increased wakefulness periods and decreased non-rapid eye movements (NREM) sleep time.
=== Other functions ===
Other typical functions of tau include cellular signalling, neuronal development, neuroprotection and apoptosis. Atypical, non-standard roles of tau are also under current investigation, such as its involvement in chromosome stability, its interaction with the cellular transcriptome, its interaction with other cytoskeletal or synaptic proteins, its involvement in myelination or in brain insulin signaling, its role in the exposure to chronic stress and in depression, etc.
== Genetics ==
In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively spliced, which leads to the formation of six tau isoforms. In the human brain, tau proteins constitute a family of six isoforms with a range of 352–441 amino acids. Tau isoforms are different in having either zero, one, or two inserts of 29 amino acids at the N-terminal part (exons 2 and 3) and three or four repeat-regions at the C-terminal part (exon 10). Thus, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).
The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copies of the gene, resulting in congenital defects. The risk haplotype H1H1 in iPSC-derived cortical neurons revealed a higher expression of alpha-synuclein compared to H2H2, which may explain the association of haplotype with synucleinopathies such as Parkinson's disease.
== Structure ==
Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. Tau is a phosphoprotein with 79 potential serine (Ser) and threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.
Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization. Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau. The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases. Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396. The binding of these phosphatases to tau affects tau's association with microtubules.
Phosphorylation of tau has also been suggested to be regulated by O-GlcNAc modification at various Ser and Thr residues. Elevation of O-GlcNAc has been explored as a therapeutic strategy to protect against tau hyperphosphorylation.
== Mechanism ==
The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration. The actual mechanism of how tau propagates from one cell to another is not well identified. Also, other mechanisms, including tau release and toxicity, are unclear. As tau aggregates, it replaces tubulin, which in turn enhances fibrilization of tau. Several propagation methods have been proposed that occur by synaptic contact such as synaptic cell adhesion proteins, neuronal activity and other synaptic and non-synaptic mechanisms. The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.
=== Release ===
Tau is involved in uptake and release processes, which are known as seeding. Uptake of tau protein requires the presence of heparan sulfate proteoglycans at the cell surface, which happens by macropinocytosis. On the other hand, tau release depends on neuronal activity. Many factors influence tau release such as, for example, the isoforms or MAPT mutations that change the extracellular level of tau. According to Asai and his colleagues, the spreading of tau protein occurs from the entorhinal cortex to the hippocampal region in the early stages of the disease. They also suggested that microglia were also involved in the transport process, and their actual role is still unknown.
=== Uptake ===
Tau protein has been found in the extracellular environment including Cerebrospinal fluid (CSF) and Interstitial fluid (ISF) under physiological and pathological conditions. Low-density lipoprotein receptor-related protein 1 (LRP1) has been shown as the receptor for Tau internalization into cells. However, studying Tau uptake in human neurons revealed that physiological Tau monomers mainly use LRP1 for internalization, while the uptake of pathological Tau aggregates depend on heparan sulfate proteoglycans.
=== Toxicity ===
Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanism such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activate other kinases (GSK-3 and CDK5) that cause disease-associated phosphoepitopes. The degree of toxicity is affected by different factors, such as the degree of microtubule binding. Toxicity could also happen by neurofibrillary tangles (NFTs), which leads to cell death and cognitive decline.
== Clinical significance ==
Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease, frontotemporal dementia and other tauopathies. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases. Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses.
Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies. Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.
=== Tau hypothesis of Alzheimer's disease ===
The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into paired-helical-filament (PHF) tau and neurofibrillary tangles (NFTs). The stage of the disease determines NFTs' phosphorylation. In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 199, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231. Through its isoforms and phosphorylation, tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments (PHFs) in the AD brain.
Tau mutations have many consequences, including microtubule dysfunction and alteration of the expression level of tau isoforms. Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1 (microtubule associated protein tau 1), MAPT 2 and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.
Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients. It has been well demonstrated that regions of tau six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK), can form tau PHF aggregation in AD. Apart from the PHF6, some other residue sites like Ser285, Ser289, Ser293, Ser305 and Tyr310, located near the C-terminal of the PHF6 sequences, play key roles in the phosphorylation of tau. Hyperphosphorylated tau differs in its sensitivity and its kinase as well as alkaline phosphatase activity and is, along with beta-amyloid, a component of the pathologic lesion seen in Alzheimer disease. A recent hypothesis identifies the decrease of reelin signaling as the primary change in Alzheimer's disease that leads to the hyperphosphorylation of tau via a decrease in GSK3β inhibition.
A68 is a name sometimes given (mostly in older publications) to the hyperphosphorylated form of tau protein found in the brains of individuals with Alzheimer's disease.
In 2020, researchers from two groups published studies indicating that an immunoassay blood test for the p-tau-217 form of the protein could diagnose Alzheimer's up to decades before dementia symptoms were evident.
=== Traumatic brain injury ===
Repetitive mild traumatic brain injury (TBI) is a central component of contact sports, especially American football, and the concussive force of military blasts. It can lead to chronic traumatic encephalopathy (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau. After severe traumatic brain injury, high levels of tau protein in extracellular fluid in the brain are linked to poor outcomes.
=== Prion-like propagation hypothesis ===
The term "prion-like" is often used to describe several aspects of tau pathology in various tauopathies, like Alzheimer's disease and frontotemporal dementia. True prions are defined by their ability to induce misfolding of native proteins to perpetuate the pathology. True prions, like PRNP, are also infectious with the capability to cross species. Since tau has yet to be proven to be infectious it is not considered to be a true prion but instead a "prion-like" protein. Much like true prions, pathological tau aggregates have been shown to have the capacity to induce misfolding of native tau protein. Both misfolding competent and non-misfolding competent species of tau aggregates have been reported, indicating a highly specific mechanism.
== Interactions ==
Tau protein has been shown to interact with:
Alpha-synuclein,
FYN,
Proto-oncogene tyrosine-protein kinase Src
S100B, and
YWHAZ.
== See also ==
== References ==
== Further reading ==
== External links ==
tau+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders
MR scans of variant CJD CSF tau-positive man
Overview of all the structural information available in the PDB for UniProt: P10636 (Microtubule-associated protein tau) at the PDBe-KB. | Wikipedia/Tau_protein |
Myelin basic protein (MBP) is a protein important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. MBP maintains the correct structure of myelin, interacting with the lipids in the myelin membrane.
MBP was initially sequenced in 1971 after isolation from bovine myelin membranes. MBP knockout mice called shiverer mice were subsequently developed and characterized in the early 1980s. Shiverer mice exhibit decreased amounts of CNS myelination and a progressive disorder characterized by tremors, seizures, and early death. The human gene for MBP is on chromosome 18; the protein localizes to the CNS and to various cells of the hematopoietic lineage.
The pool of MBP in the central nervous system is very diverse, with several splice variants being expressed and a large number of post-translational modifications on the protein, which include phosphorylation, methylation, deamidation, and citrullination. These forms differ by the presence or the absence of short (10 to 20 residues) peptides in various internal locations in the sequence. In general, the major form of MBP is a protein of about 18.5 Kd (170 residues).
In melanocytic cell types, MBP gene expression may be regulated by MITF.
== Gene expression ==
The protein encoded by the classic MBP gene is a major constituent of the myelin sheath of oligodendrocytes and Schwann cells in the nervous system. However, MBP-related transcripts are also present in the bone marrow and the immune system. These mRNAs arise from the long MBP gene (otherwise called "Golli-MBP") that contains three additional exons located upstream of the classic MBP exons. Alternative splicing from the Golli and the MBP transcription start sites gives rise to two sets of MBP-related transcripts and gene products. The Golli mRNAs contain three exons unique to Golli-MBP, spliced in-frame to one or more MBP exons. They encode hybrid proteins that have an N-terminal Golli amino acid sequence linked to the MBP amino acid sequence. The second family of transcripts contains only MBP exons and produces the well-characterized myelin basic proteins. This complex gene structure is conserved among species, suggesting that the MBP transcription unit is an integral part of the Golli transcription unit and that this arrangement is important for the function and/or regulation of these genes. At protein level, the concentration of MBP in the CNS is tenfold higher in sections of white matter compared with cerebral cortex.
== Structure ==
Myelin basic protein has been classified as an intrinsically disordered protein that has no stable secondary structure in solution. Like most IDPs, it has a high net charge and a low mean hydrophobicity, minimizing the hydrophobic effect that drives traditional protein folding. It does contain some exceptions to normal IDP amino acid content. For example, MBP has more arginine and less glutamic acid than most IDPs. However, this is likely because those changes are necessary for MBP to be sufficiently basic and positively charged to correctly interact with the membrane. Notably, MBP has been shown to adopt a more stable secondary structure on interaction with lipids. NMR and Cys-specific spin labeling experiments have predicted this structure to contain beta sheet and regions of amphipathic helix.
As implied by its name, myelin basic protein is significantly basic, with an isoelectric point of 10. It is thought to associate with the cell membrane through electrostatic interactions between its positive charges and negatively charged phospholipid heads of the plasma membrane. It can undergo a large variety of post-translational modifications, creating various charge isomers known as C1-C6 or C8. These modifications include phosphorylation, methylation, deamidation, citrullination, ADP-ribosylation, and N-terminal acylation . C1 is the least modified, while C8 is the most distinct, containing 6-11 additional citrullinations. Since each of these decreases its positive charge, C8 has the smallest net positive charge of the isomers. Alternations in these post-translational modifications have been associated with demyelinating diseases. Notably, MBP isolated from individuals with multiple sclerosis have had a higher degree of citrullination and a smaller positive charge. In a rare, severe form of MS known as Marburg's syndrome, the citrullination was even more extensive.
== Role in disease ==
Interest in MBP has centered on its role in demyelinating diseases, in particular, multiple sclerosis (MS). The target antigen of the autoimmune response in MS has not yet been identified. However, several studies have shown a role for antibodies against MBP in the pathogenesis of MS. Some studies have linked a genetic predisposition to MS to the MBP gene, though a majority have not.
A "molecular mimicry" hypothesis of multiple sclerosis has been suggested, in which T cells are, in essence, confusing MBP with human herpesvirus-6. Researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. Elevated levels of MBP have been found in the cerebrospinal fluid of patients with HIV infections and signs of encephalopathy, and although MBP does not seem to be a sensitive diagnostic marker of HIV encephalopathy, it has been suggested that it may serve a role as a prognostic indicator of disease progression.
It is able to show that T cells were activated by this peptide. These activated T cells also recognized and initiated an immune response against a synthetically created peptide sequence that is identical to part of human MBP. During their research, they found that the levels of these cross-reactive T cells are significantly elevated in multiple sclerosis patients.
Some research has shown that inoculating an animal with MBP to generate an MBP-specific immune response against it increases blood–brain barrier permeability. Permeability is enhanced when the animal is inoculated against non-specific proteins.
A targeted immune response to MBP has been implicated in lethal rabies infection. The inoculation of MBP generates increases the permeability of the blood–brain barrier (BBB), allowing immune cells to enter the brain, the primary site of rabies virus replication. In a study of mice infected with Silver-haired bat rabies virus (SHBRV), the mortality rate of mice treated with MBP improved 20%-30% over the untreated control group. It is significant to note that healthy uninfected mice treated with MBP showed an increase in mortality rate between 0% and 40%.
== Interactions ==
Myelin basic protein has been shown to interact in vivo with proteolipid protein 1, and in vitro with calmodulin, actin, tropomyosin, tubulin, clathrin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase and multiple molecules of the immune system.
== References ==
== Further reading ==
== External links ==
Media related to Myelin basic proteins at Wikimedia Commons
Overview of all the structural information available in the PDB for UniProt: P02686 (Myelin basic protein) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Myelin_basic_protein |
Neuronal ceroid lipofuscinosis is a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
== Signs and symptoms ==
The classic characterization of the group of neurodegenerative, lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins, with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes.
In the early infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. Adult variant NCL (ANCL or Kuf's disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later.
All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins.
== Genetics ==
Childhood NCLs are generally autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein.
Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an autosomal dominant (Parry's) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected.
Many authorities refer to the NCLs collectively as Batten disease.
== Diagnosis ==
Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patient's medical history and information from various laboratory tests.
Diagnostic tests used for NCLs include:
Skin or tissue sampling: The doctor can examine a small piece of tissue under a microscope to spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively.
Electroencephalogram or EEG: An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brain's electrical activity that suggest a patient has seizures.
Electrical studies of the eyes: These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs.
Brain scans: Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.
Enzyme assay: A recent development in diagnosis of NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test.
=== Types ===
The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.
CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.
=== Mutations ===
==== Infantile form ====
Nonsense and frameshift mutations in the CLN1 gene (located at
1p32) always induce classical INCL, while some missense mutations have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a lysosomal enzyme called palmitoyl protein thioesterase 1 (PPT1).
The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum (ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9, eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase and eventual apoptosis.
==== Late infantile form ====
The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.
On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device).
==== Juvenile form ====
All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or frameshift mutations. The wild-type CLN3 gene codes for a protein with no known function, but studies of the yeast CLN3 ortholog, the product of which is called battenin (after its apparent connections to Batten's disease, or JNCL), have suggested that the protein may play a role in lysosomal pH homeostasis. Furthermore, recent studies have also implied the protein's role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.
==== Adult dominant form ====
Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase.
Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.
== Treatment ==
Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. Several experimental treatments are under investigation.
=== Cystagon ===
In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL. Currently, two drug trials are underway for infantile NCL, both using Cystagon.
=== Gene therapy ===
A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. The trial was conducted by Weill Medical College of Cornell University and sponsored by the Nathan's Battle Foundation. In May 2008, the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the disease's progression during the 18-month follow-up period" and "suggested that higher doses and a better delivery system may provide greater benefit".
A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly".
A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate to severe impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects.
=== Flupirtine ===
A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, or the Hospital for Sick Children in Toronto.
=== Stem cells ===
On October 20, 2005, the Food and Drug Administration approved a phase-I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon.
Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or stem-cell transplants for this condition. A bone-marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.
Trials testing the effectiveness of bone-marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.
=== Immunosuppressants ===
In late 2007, Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone-marrow transplants, may be useful in slowing down the progress of juvenile NCL.
=== Enzyme replacement therapy ===
On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL.
== Epidemiology ==
Incidence can vary greatly from type-to-type, and from country-to-country.
In Germany, one study reported an incidence of 1.28 per 100,000.
A study in Italy reported an incidence of 0.56 per 100,000.
A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.
== History ==
=== 19th century ===
The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the Spielmeyer-Sjogren (juvenile) type is fully justified.
=== 1900 to 1950 ===
More fundamental observations were reported by F. E. Batten in 1903, and by Heinrich Vogt in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore, Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay–Sachs disease, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Walther Spielmeyer reported detailed studies on three siblings, who have the Spielmeyer-Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay–Sachs disease. Subsequently, however, the pathomorphological studies of Károly Schaffer made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay–Sachs disease, which caused confusion lasting about 50 years.
In 1913–14, Max Bielschowsky delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay–Sachs was the prototype.
In 1931, Torsten Sjögren, a Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease now called the Spielmeyer-Sjogren (juvenile) type is genetically separate from Tay–Sachs.
=== 1950 to today ===
Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. Simultaneously, Terry and Korey and Svennerholm demonstrated a specific ultrastructure and biochemistry for Tay–Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay–Sachs disease by Zeman and Donahue. At that time, it was proposed that the late-infantile (Jansky–Bielschowsky), the juvenile (Spielmeyer–Vogt), and the adult form (Kufs) were quite different from Tay–Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of sphingolipidoses.
Subsequently, Santavuori and Haltia showed that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type.
== References ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on Neuronal ceroid-Lipofuscinosis | Wikipedia/Neuronal_ceroid_lipofuscinosis |
Creutzfeldt–Jakob disease (CJD) is an incurable, always fatal neurodegenerative disease belonging to the transmissible spongiform encephalopathy (TSE) group. Early symptoms include memory problems, behavioral changes, poor coordination, visual disturbances and auditory disturbances. Later symptoms include dementia, involuntary movements, blindness, deafness, weakness, and coma. About 70% of sufferers die within a year of diagnosis. The name "Creutzfeldt–Jakob disease" was introduced by Walther Spielmeyer in 1922, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.
CJD is caused by abnormal folding of a protein known as a prion. Infectious prions are misfolded proteins that can cause normally folded proteins to also become misfolded. About 85% of cases of CJD occur for unknown reasons, while about 7.5% of cases are inherited in an autosomal dominant manner. Exposure to brain or spinal tissue from an infected person may also result in spread. There is no evidence that sporadic CJD can spread among people via normal contact or blood transfusions, although this is possible in variant Creutzfeldt–Jakob disease. Diagnosis involves ruling out other potential causes. An electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis. Another diagnosis technique is the real-time quaking-induced conversion assay which can detect the disease in early stages.
There is no specific treatment for CJD. Opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements. CJD affects about one person per million people per year. Onset is typically around 60 years of age. The condition was first described in 1920. It is classified as a type of transmissible spongiform encephalopathy. Inherited CJD accounts for about 10% of prion disease cases. Sporadic CJD is different from bovine spongiform encephalopathy (mad cow disease) and variant Creutzfeldt–Jakob disease (vCJD).
== Signs and symptoms ==
The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases, but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. This is accompanied by physical problems such as speech impairment, balance and coordination dysfunction (ataxia), changes in gait, and rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements. Rarely, unusual symptoms like the alien limb phenomenon have been observed. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most affected people die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years.
The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which are associated with the build-up of abnormal prion proteins forming in the brain. When brain tissue from a person with CJD is examined under a microscope, many tiny holes can be seen where the nerve cells have died. Parts of the brain may resemble a sponge where the prions were infecting the areas of the brain.
== Cause ==
CJD is a type of transmissible spongiform encephalopathy (TSE), which are caused by prions. Prions are misfolded proteins that occur in the neurons of the central nervous system (CNS). Current research suggests that small, oligomeric aggregates of PrP^Sc (rather than large fibrils) are the most neurotoxic species, interacting with cell surfaces to disrupt neuronal function . The binding of prion oligomers to normal prion protein on neurons may trigger toxic signals similar to how oligomeric β-amyloid causes synaptic damage in Alzheimer’s disease . Different conformations of PrP^Sc (often termed prion “strains”) are thought to cause the distinct subtypes of prion disease, explaining variations in clinical features and progression. They are thought to affect signaling processes, damaging neurons and resulting in degeneration that causes the spongiform appearance in the affected brain. Other forms of TSEs that are found in humans are Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, and kuru, as well as the variably protease-sensitive prionopathy and familial spongiform encephalopathy transmissible spongiform encephalopathy. Susceptibility and disease phenotype are influenced by a common polymorphism at codon 129 of the PRNP gene (methionine/valine). Notably, individuals homozygous at codon 129 are over-represented in sporadic CJD cases and tend to have shorter incubation periods.
The CJD prion is dangerous because it promotes refolding of the cellular prion protein into the diseased state. The number of misfolded protein molecules will increase exponentially and the process leads to a large quantity of insoluble protein in affected cells. This mass of misfolded proteins disrupts neuronal cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and induce other prion protein molecules to misfold in a self-sustaining feedback loop. These neurodegenerative diseases are commonly called prion diseases.
=== Transmission ===
The defective protein can be transmitted by contaminated harvested human brain products, corneal grafts, dural grafts, or electrode implants and pituitary human growth hormone, which has been replaced by recombinant human growth hormone that poses no such risk.
It can be familial (fCJD) or it may appear without clear risk factors (sporadic form: sCJD). In the familial form, a mutation has occurred in the gene for PrP, PRNP, in that family. All types of CJD are transmissible irrespective of how they occur in the person.
It is thought that humans can contract the variant form of the disease by eating food from animals infected with bovine spongiform encephalopathy (BSE), the bovine form of TSE, also known as mad cow disease. However, it can also cause sCJD in some cases.
Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, once found primarily among women and children of the Fore people in Papua New Guinea, who previously engaged in funerary cannibalism. While the men of the tribe ate the muscle tissue of the deceased, women and children consumed other parts, such as the brain, and were more likely than men to contract kuru from infected tissue.
Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that instrumentation used in such cases be immediately destroyed after use; short of destruction, it is recommended that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues. Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process chemically attacks protein at the molecular level, although more effective and practical methods involve destruction by combinations of detergents and enzymes similar to biological washing powders.
=== Genetics ===
People can also develop CJD because they carry a mutation of the gene that codes for the prion protein (PRNP), located on chromosome 202p12-pter. This occurs in only 10–15% of all CJD cases. In sporadic cases, the misfolding of the prion protein is a process that is hypothesized to occur as a result of the effects of aging on cellular machinery, explaining why the disease often appears later in life. An EU study determined that "87% of cases were sporadic, 8% genetic, 5% iatrogenic and less than 1% variant."
== Diagnosis ==
Testing for CJD has historically been problematic, due to nonspecific nature of early symptoms and difficulty in safely obtaining brain tissue for confirmation. The diagnosis may initially be suspected in a person with rapidly progressing dementia, particularly when it is also found with the characteristic medical signs and symptoms such as involuntary muscle jerking, difficulty with coordination/balance and walking, and visual disturbances. Further testing can support the diagnosis and may include:
Electroencephalography – may have characteristic generalized periodic sharp wave pattern. Periodic sharp wave complexes develop in half of the people with sporadic CJD, particularly in the later stages.
Cerebrospinal fluid (CSF) analysis for elevated levels of 14-3-3 protein and tau protein could be supportive in the diagnosis of sCJD. The two proteins are released into the CSF by damaged nerve cells. Increased levels of tau or 14-3-3 proteins are seen in 90% of prion diseases. The markers have a specificity of 95% in clinical symptoms suggestive of CJD, but specificity is 70% in other less characteristic cases. 14-3-3 and tau proteins may also be elevated in the CSF after ischemic strokes, inflammatory brain diseases, or seizures. The protein markers are also less specific in early CJD, genetic CJD or the bovine variant. However, a positive result should not be regarded as sufficient for the diagnosis. The real-time quaking-induced conversion (RT-QuIC) assay, which amplifies misfolded PrP^Sc, now plays a central role in CJD diagnosis. Second-generation RT-QuIC on cerebrospinal fluid has sensitivity in the 90–97% range and ~100% specificity in sporadic CJD, far superior to earlier CSF tests. A positive RT-QuIC (on CSF or other tissues) is now included as a criterion for probable CJD in many national surveillance center. Studies have shown RT-QuIC can also be done on olfactory mucosa swabs obtained via nasal brushing and on skin biopsies, with high diagnostic accuracy (reported sensitivities ~90–100%)
MRI with diffusion weighted inversion (DWI) and fluid-attenuated inversion recovery (FLAIR) shows a high signal intensity in certain parts of the cortex (a cortical ribboning appearance), the basal ganglia, and the thalami. The most common presenting patterns are simultaneous involvement of the cortex and striatum (60% of cases), cortical involvement without the striatum (30%), thalamus (21%), cerebellum (8%) and striatum without cortical involvement (7%). In populations with a rapidly progressive dementia (early in the disease process), MRI has a sensitivity of 91% and specificity of 97% for diagnosing CJD. The MRI changes characteristic of CJD may also be seen in the immediate aftermath (hours after the event) of autoimmune encephalitis or focal seizures.
In recent years, studies have shown that the tumour marker neuron-specific enolase (NSE) is often elevated in CJD cases; however, its diagnostic utility is seen primarily when combined with a test for the 14-3-3 protein. As of 2010, screening tests to identify infected asymptomatic individuals, such as blood donors, are not yet available, though methods have been proposed and evaluated.
=== Imaging ===
Imaging of the brain may be performed during medical evaluation, both to rule out other causes and to obtain supportive evidence for diagnosis. Imaging findings are variable in their appearance, and also variable in sensitivity and specificity. While imaging plays a lesser role in diagnosis of CJD, characteristic findings on brain MRI in some cases may precede onset of clinical manifestations.
Brain MRI is the most useful imaging modality for changes related to CJD. Of the MRI sequences, diffuse-weighted imaging sequences are most sensitive. Characteristic findings are as follows:
Focal or diffuse diffusion-restriction involving the cerebral cortex or basal ganglia. The most characteristic and striking cortical abnormality has been called "cortical ribboning" or "cortical ribbon sign" due to hyperintensities resembling ribbons appearing in the cortex on MRI. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.
Varying degree of symmetric T2 hyperintense signal changes in the basal ganglia (i.e., caudate and putamen), and to a lesser extent globus pallidus and occipital cortex.
Brain FDG PET-CT tends to be markedly abnormal, and is increasingly used in the investigation of dementias.
Patients with CJD will normally have hypometabolism on FDG PET.
=== Histopathology ===
Testing of tissue remains the most definitive way of confirming the diagnosis of CJD, although even biopsy is not always conclusive.
In one-third of people with sporadic CJD, deposits of "prion protein (scrapie)", PrPSc, can be found in the skeletal muscle or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbor significant amounts of PrPSc; however, biopsy of brain tissue is the definitive diagnostic test for all other forms of prion disease. Due to its invasiveness, biopsy will not be done if clinical suspicion is sufficiently high or low. A negative biopsy does not rule out CJD, since it may predominate in a specific part of the brain.
The classic histologic appearance is spongiform change in the gray matter: the presence of many round vacuoles from one to 50 micrometers in the neuropil, in all six cortical layers in the cerebral cortex or with diffuse involvement of the cerebellar molecular layer. These vacuoles appear glassy or eosinophilic and may coalesce. Neuronal loss and gliosis are also seen. Plaques of amyloid-like material can be seen in the neocortex in some cases of CJD.
However, extra-neuronal vacuolization can also be seen in other disease states. Diffuse cortical vacuolization occurs in Alzheimer's disease, and superficial cortical vacuolization occurs in ischemia and frontotemporal dementia. These vacuoles appear clear and punched-out. Larger vacuoles encircling neurons, vessels, and glia are a possible processing artifact.
=== Classification ===
Types of CJD include:
Sporadic (sCJD), caused by the spontaneous misfolding of prion-protein in an individual. This accounts for 85% of cases of CJD. Sporadic CJD is can be further sub-classified by molecular profile into subtypes (MM1, MV2, etc.), which correlate with certain clinical-pathologic features.
MM1 / MV1 Subtype:
Clinical Features: Accounts for approximately 75% of sCJD cases. Characterized by rapidly progressive dementia, myoclonus, and typical EEG findings.
Neuropathology: Synaptic-type PrP^Sc deposition predominantly in the cerebral cortex. Spongiform changes are widespread, with significant neuronal loss and gliosis.
MM2 Subtype:
MM2C (Cortical): Presents with a more prolonged disease course and prominent cortical involvement. Neuropathology reveals PrP^Sc deposits in the cortex with less spongiform change compared to MM1.
MM2T (Thalamic): Rare; characterized by predominant thalamic involvement, leading to sleep disturbances and autonomic dysfunction. Neuropathology shows significant PrP^Sc deposition and neuronal loss in the thalamus.
VV1 Subtype:
Clinical Features: Rare; presents at a younger age with a slower disease progression.
Neuropathology: Predominant cortical involvement with synaptic-type PrP^Sc deposition.
VV2 Subtype:
Clinical Features: Second most common subtype. Patients often present with ataxia and other cerebellar signs.
Neuropathology: Significant PrP^Sc deposition in the cerebellum and basal ganglia, with prominent spongiform changes and neuronal loss.
Familial (fCJD), caused by an inherited mutation in the prion-protein gene. This accounts for the majority of the other 15% of cases of CJD.
Acquired CJD, caused by contamination with tissue from an infected person, usually as the result of a medical procedure (iatrogenic CJD). Medical procedures that are associated with the spread of this form of CJD include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants. Variant Creutzfeldt–Jakob disease (vCJD) is a type of acquired CJD potentially acquired from bovine spongiform encephalopathy or caused by consuming food contaminated with prions. Sporadic CJD, while transmissible through tissue transplants, may not be transmitted through blood transfusion.
== Treatment ==
As of 2025, there is no cure or effective treatment for CJD. Some of the symptoms like twitching can be managed, but otherwise treatment is palliative care. Psychiatric symptoms like anxiety and depression can be treated with sedatives and antidepressants. Myoclonic jerks can be handled with clonazepam or sodium valproate. Opiates can help in pain. Seizures are very uncommon but can nevertheless be treated with antiepileptic drugs.
In 2022, results of an early-stage trial of PRN100, a monoclonal antibody against PrP, were reported: the drug appeared safe and reached the brain, but treated patients did not show clearly improved survival compared to historical controls. While not curative, this trial demonstrated the feasibility of immunotherapy for prion disease.
== Prognosis ==
Life expectancy is greatly reduced for people with Creutzfeldt–Jakob disease and the average is less than 6 months. As of 1981, no one was known to have lived longer than 2.5 years after the onset of CJD symptoms. One of the world's longest survivors of vCJD was Jonathan Simms, a Northern Irish man who lived for 10 years after his diagnosis and received experimental treatment with pentosan polysulphate. Simms died in 2011.
== Epidemiology ==
The CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC:
CJD occurs worldwide at roughly 1–1.5 cases per million people per year. Recent surveillance reports indicate a slight increase in recorded incidence in many countries over time. For example, a study made in 2020 noted that sporadic CJD incidence in the U.K. rose from 1990 to 2018, and several other countries also reported increases in CJD cases in the 2000s.
On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million people in the United States.
In the United States, CJD deaths among people younger than 30 years of age are extremely rare (fewer than five deaths per billion per year).
The disease is found most frequently in people 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.
In more than 85% of cases, the duration of CJD is less than one year (median: four months) after the onset of symptoms.
Further information from the CDC:
Risk of developing CJD increases with age.
CJD incidence was 3.5 cases per million among those over 50 years of age between 1979 and 2017.
Approximately 85% of CJD cases are sporadic and 10–15% of CJD cases are due to inherited mutations of the prion protein gene.
CJD deaths and age-adjusted death rate in the United States indicate an increasing trend in the number of deaths between 1979 and 2017.
Although not fully understood, additional information suggests that CJD rates in nonwhite groups are lower than in whites. While the mean onset is approximately 67 years of age, cases of sCJD have been reported as young as 17 years and over 80 years of age. Mental capabilities rapidly deteriorate and the average amount of time from onset of symptoms to death is 7 to 9 months.
According to a 2020 systematic review on the international epidemiology of CJD:
Surveillance studies from 2005 and later show the estimated global incidence is 1–2 cases per million population per year.
Sporadic CJD (sCJD) incidence increased from the years 1990–2018 in the UK.
Probable or definite sCJD deaths also increased from the years 1996–2018 in twelve additional countries.
CJD incidence is greatest in those over the age of 55 years old, with an average age of 67 years old.
The intensity of CJD surveillance increases the number of reported cases, often in countries where CJD epidemics have occurred in the past and where surveillance resources are greatest. An increase in surveillance and reporting of CJD is most likely in response to BSE and vCJD. Possible factors contributing to an increase of CJD incidence are an aging population, population increase, clinician awareness, and more accurate diagnostic methods. Since CJD symptoms are similar to other neurological conditions, it is also possible that CJD is mistaken for stroke, acute nephropathy, general dementia, and hyperparathyroidism.
== History ==
The disease was first described by German neurologist Hans Gerhard Creutzfeldt in 1920 and shortly afterward by Alfons Maria Jakob, giving it the name Creutzfeldt–Jakob disease. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt–Jakob disease, and it has been speculated that at least two of the people in initial studies had a different ailment. An early description of familial CJD stems from the German psychiatrist and neurologist Friedrich Meggendorfer (1880–1953). A study published in 1997 counted more than 100 cases worldwide of transmissible CJD and new cases continued to appear at the time.
The first report of suspected iatrogenic CJD was published in 1974. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways. A second case of CJD associated with a corneal transplant was reported without details. In 1977, CJD transmission caused by silver electrodes previously used in the brain of a person with CJD was first reported. Transmission occurred despite the decontamination of the electrodes with ethanol and formaldehyde. Retrospective studies identified four other cases likely of similar cause. The rate of transmission from a single contaminated instrument is unknown, although it is not 100%. In some cases, the exposure occurred weeks after the instruments were used on a person with CJD. In the 1980s it was discovered that Lyodura, a dura mater transplant product, was shown to transmit CJD from the donor to the recipient. This led to the product being banned in Canada but it was used in other countries such as Japan until 1993. A review article published in 1979 indicated that 25 dura mater cases had occurred by that date in Australia, Canada, Germany, Italy, Japan, New Zealand, Spain, the United Kingdom, and the United States.
By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans.
In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person.
Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in Physiology or Medicine in 1997 "for his discovery of Prions—a new biological principle of infection".
Yale University neuropathologist Laura Manuelidis has challenged the prion protein (PrP) explanation for the disease. In January 2007, she and her colleagues reported that they had found a virus-like particle in naturally and experimentally infected animals. "The high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid–protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions".
=== Australia ===
Australia has documented 10 cases of healthcare-acquired CJD (iatrogenic or ICJD). Five of the deaths resulted after the patients, who were in treatment either for infertility or short stature, were treated using contaminated pituitary extract hormone but no new cases have been noted since 1991. The other five deaths occurred due to dura grafting procedures that were performed during brain surgery, in which the covering of the brain is repaired. There have been no other ICJD deaths documented in Australia due to transmission during healthcare procedures.
=== New Zealand ===
A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt–Jakob disease (CJD) in 2012.
=== United States ===
In 1988 there was a confirmed death from CJD of a person from Manchester, New Hampshire. Massachusetts General Hospital believed the person acquired the disease from a surgical instrument at a podiatrist's office. In 2007 Michael Homer, former Vice President of Netscape, had been experiencing consistent memory problems which led to his diagnosis. In August 2013 the British journalist Graham Usher died in New York of CJD.
In September 2013, another person in Manchester was posthumously determined to have died of the disease. The person had undergone brain surgery at Catholic Medical Center three months before his death, and a surgical probe used in the procedure was subsequently reused in other operations. Public health officials identified thirteen people at three hospitals who may have been exposed to the disease through the contaminated probe but said the risk of anyone contracting CJD is "extremely low".
In January 2015, former speaker of the Utah House of Representatives Rebecca D. Lockhart died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016. José Baselga, clinical oncologist having headed the AstraZeneca oncology division, died in Cerdanya, March 21, 2021, from CJD. In April 2024, a report was published regarding two hunters from the same lodge who, in 2022, were found to be afflicted with sporadic CJD after eating deer meat infected with chronic wasting disease (CWD), suggesting a potential link between CWD and CJD.
== Research ==
=== Diagnosis ===
In 2010, a team from New York described detection of PrPSc in sheep's blood, even when initially present at only one part in one hundred billion (10−11) in sheep's brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay (SOFIA) and some specific antibodies against PrPSc. The technique allowed improved detection and testing time for PrPSc.
In 2014, a human study showed a nasal brushing method that can accurately detect PrP in the olfactory epithelial cells of people with CJD.
=== Treatment ===
Pentosan polysulfate (PPS) may slow the progression of the disease, and may have contributed to the longer than expected survival of the seven people studied. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulfate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 people with PPS finds no proof of efficacy because of the lack of accepted objective criteria, but it was unclear to the authors whether that was caused by PPS itself. In 2012 it was claimed that the lack of significant benefits has likely been caused because of the drug being administered very late in the disease in many patients.
Use of RNA interference to slow the progression of scrapie has been studied in mice. The RNA blocks production of the protein that the CJD process transforms into prions.
Both amphotericin B and doxorubicin have been investigated as treatments for CJD, but as yet there is no strong evidence that either drug is effective in stopping the disease. Further study has been taken with other medical drugs, but none are effective. However, anticonvulsants and anxiolytic agents, such as valproate or a benzodiazepine, may be administered to relieve associated symptoms.
Quinacrine, a medicine originally created for malaria, has been evaluated as a treatment for CJD. The efficacy of quinacrine was assessed in a rigorous clinical trial in the UK and the results were published in Lancet Neurology, and concluded that quinacrine had no measurable effect on the clinical course of CJD.
Astemizole, a medication approved for human use, has been found to have anti-prion activity and may lead to a treatment for Creutzfeldt–Jakob disease.
A monoclonal antibody (code name PRN100) targeting the prion protein (PrP) was given to six people with Creutzfeldt–Jakob disease in an early-stage clinical trial conducted from 2018 to 2022. The treatment appeared to be well-tolerated and was able to access the brain, where it might have helped to clear PrPC. While the treated patients still showed progressive neurological decline, and while none of them survived longer than expected from the normal course of the disease, the scientists at University College London who conducted the study see these early-stage results as encouraging and suggest to conduct a larger study, ideally at the earliest possible intervention.
== See also ==
Transmissible spongiform encephalopathy
Chronic wasting disease
Kuru
== References ==
== External links == | Wikipedia/Creutzfeldt-Jakob_disease |
Inflammatory demyelinating diseases (IDDs), sometimes called Idiopathic (IIDDs) due to the unknown etiology of some of them, are a heterogenous group of demyelinating diseases - conditions that cause damage to myelin, the protective sheath of nerve fibers - that occur against the background of an acute or chronic inflammatory process. IDDs share characteristics with and are often grouped together under Multiple Sclerosis. They are sometimes considered different diseases from Multiple Sclerosis, but considered by others to form a spectrum differing only in terms of chronicity, severity, and clinical course.
Multiple sclerosis for some people is a syndrome more than a single disease. As of 2019, three auto-antibodies have been found in atypical MS giving birth to separate diseases: Anti-AQP4 diseases, Anti-MOG and Anti-NF spectrums. A LHON-associated MS has also been reported, and in addition there have been inconclusive reports of TNF-α blockers inducing demyelinating disorders.
The subject is under intense research and the list of MS autoantibodies is expected to grow in the near future.
== Separated variants ==
As of 2014 several previous MS variants had been separated from MS after the discovery of a specific auto-antibody. Those autoantibodies were anti-AQP4, anti-MOG and some anti-Neurofascins.
These conditions can appear as Neuromyelitis optica (NMO), and its associated "spectrum of disorders" (NMOSD), currently considered a common syndrome for several separated diseases but with some still idiopathic subtypes. Some researchers think that there could exist an overlapping between Anti-NMDA receptor encephalitis cases and neuromyelitis optica or acute disseminated encephalomyelitis.
=== Anti-AQP4 spectrum ===
See Anti-AQP4 diseases
Originally found in neuromyelitis optica, this autoantibody has been associated with other conditions. Its current spectrum is as following:
Seropositive Devic's disease, according to the diagnostic criteria described above.
Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis.
Asian optic-spinal MS - this variant can present brain lesions like MS.
Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease.
Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem.
Some cases of tumefactive multiple sclerosis
=== Anti-MOG spectrum ===
See Anti-MOG associated encephalomyelitis
Anti-MOG associated spectrum, often clinically presented as an anti-MOG autoimmune encephalomyelitis, but can also appear as negative NMO or atypical multiple sclerosis.
The presence of anti-MOG autoantibodies has been associated with the following conditions
Some cases of aquaporin-4-seronegative neuromyelitis optica: NMO derived from an antiMOG associated encephalomyelitis,
Some cases of acute disseminated encephalomyelitis, specially the recurrent ones (MDEM)
Some cases of McDonalds-positive multiple sclerosis
isolated optic neuritis or transverse myelitis
Recurrent optic neuritis. The repetition of an idiopatic optic neuritis is considered a distinct clinical condition, and it has been found to be associated with anti-MOG autoantibodies
CRION (Chronic relapsing inflammatory optic neuritis): A distinct clinical entity from other inflammatory demyelinating diseases. Some reports consider it a form of Anti-MOG encephalomyelitis and the most recent ones consider it the main phenotype of the anti-MOG spectrum
The anti-mog spectrum in children is equally variated: Out of a sample of 41 children with MOG-antibodies 29 had clinical NMOSD (17 relapsing), 8 had ADEM (4 relapsing with ADEM-ON), 3 had a single clinical event CIS, and 1 had a relapsing tumefactive disorder. Longitudinal myelitis was evident on MRI in 76[percent]. It has also been noted that percentage of children with anti-mog antibodies respect a demyelinating sample is higher than for adults
Some NMO patients present double positive for autoantibodies to AQP4 and MOG. These patients have MS-like brain lesions, multifocal spine lesions and retinal and optic nerves atrophy.
=== Anti-neurofascin spectrum ===
See Anti-neurofascin demyelinating diseases
Some anti-neurofascin demyelinating diseases were previously considered a subtype of Multiple Sclerosis but now they are considered a separate entity, as it happened before to anti-MOG and anti-AQP4 cases. Around 10% of MS cases are now thought to be anti-Neurofascin disease in reality.
Anti-neurofascin autoantibodies have been reported in atypical cases of MS and CIDP, and a whole spectrum of Anti-neurofascin demyelinating diseases has been proposed.
Some cases of CIDP are reported to be produced by auto-antibodies against several neurofascin proteins. These proteins are present in the neurons and four of them have been reported to produce disease: NF186, NF180, NF166 and NF155.
Antibodies against Neurofascins NF-155 can also appear in MS and NF-186 could be involved in subtypes of MS yielding an intersection between both conditions.
Summarising, autoantibodies against several neurofascins can produce MS: neurofascin186 (NF186), neurofascin155 (NF155), contactin 1 (CNTN1), contactin associated protein 1 (CASPR1) and gliomedin. All of them nodal and paranodal proteins.
=== Demyelination associated with anti-TNF therapy ===
Several anti-TNF drugs like adalimumab are commonly prescribed by a number of autoimmune conditions. Some of them have been reported to produce a CNS-demyelination compatible with standard MS. Several other monoclonal antibodies like pembrolizumab, nivolumab and infliximab have been also reported to produce MS as an adverse event. Nevertheless, it is not so similar as reported in the previous references.
The reactions following Anti-TNF therapy have been diverse according to the source of the disease. Some of these cases can be classify as ADEM, using the confluent demyelination as barrier between both conditions.
In most cases, the damage fulfills all pathological diagnostic criteria of MS and can therefore be classified as MS in its own right. The lesions were classified as pattern II in the Lassman/Lucchinetti system. Some lesions also showed Dawson fingers, which is supposed to be a MS-only feature.
These recent problems with artificial anti-TNF-α autoimmunity also point to the possibility of tumor necrosis factor alpha involvement in some multiple sclerosis variants.
=== LHON-associated MS ===
Also a previous subtype of MS associated to LHON has been described (LHON-MS) It is a presentation of LHON with MS-like CNS damage.
It used to satisfy McDonalds definition for MS, but after demonstration that LHON can produce this kind of lesions, the "no better explanation" requirement does not hold anymore. It is not due to auto-antibodies, but to defective mitochondria instead.
The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia. and the lack of muscular control.
=== Relapsing anti-NMDAR encephalitis ===
Atypical Anti-NMDA receptor encephalitis (a kind of Autoimmune encephalitis) can appear in the form of relapsing optic neuritis.
== Variants still idiopathic ==
Apart from the previously cited spectrums (Anti-AQP4 diseases, Anti-MOG, and Anti-NF) there is a long list of MS variants, with possibly different pathogenesis, which are still idiopathic and considered inside the MS-spectrum.
=== Pseudotumefactive variants ===
Most atypical variants appear as tumefactive or pseudotumefactive variants (lesions whose size is more than 2 cm (0.79 in), with mass effect, oedema and/or ring enhancement) Some cases of the following have shown anti-MOG auto-antibodies and therefore they represent MS cases only partially.
Acute disseminated encephalomyelitis or ADEM, a closely related disorder in which a known virus or vaccine triggers autoimmunity against myelin. Around 40% of the ADEM cases are due to an "anti-MOG associated encephalomyelitis". It includes Acute hemorrhagic leukoencephalitis, possibly a variant of Acute disseminated encephalomyelitis
Marburg multiple sclerosis, an aggressive form, also known as malignant, fulminant or acute MS, currently reported to be closer to anti-MOG associated ADEM than to standard MS. and is sometimes considered a synonym for Tumefactive multiple sclerosis
Balo concentric sclerosis, an unusual presentation of plaques forming concentrenic circles, which can sometimes get better spontaneously.
Schilder disease or diffuse myelinoclastic sclerosis: is a rare disease that presents clinically as a pseudotumoural demyelinating lesion; and is more common in children.
Solitary sclerosis: This variant was proposed (2012) by Mayo Clinic researchers. though it was also reported by other groups more or less at the same time. It is defined as isolated demyelinating lesions which produce a progressive myelopathy similar to primary progressive MS.
=== Atypical lesion location variants ===
Also the location of the lesions can be used to classify variants:
==== Myelocortical multiple sclerosis ====
Myelocortical multiple sclerosis (MCMS), proposed variant with demyelination of spinal cord and cerebral cortex but not of cerebral white matter Several atypical cases could belong here. See the early reports of MCMS<
==== AQP4-negative Optic-spinal MS ====
Real Optic-spinal MS (OSMS) without anti-AQP4 antibodies, has been consistently reported, and it is classified into the MS spectrum.
OSMS has its own specific immunological biomarkers The whole picture is under construction and several reports exists about overlapping conditions.
==== Pure spinal MS ====
Pure spinal multiple sclerosis: Patients with clinical and paraclinical features suggestive of cord involvement of multiple sclerosis (MS)-type albeit not rigidly fulfilling the McDonald criteria Some inflammatory conditions are associated with the presence of scleroses in the CNS. Optic neuritis (monophasic and recurrent) and Transverse myelitis (monophasic and recurrent)
==== LHON associated MS ====
LHON associated MS (LHON-MS), a presentation of LHON with MS-like CNS damage, and therefore a subtype of MS according to McDonalds definition.
=== Atypical OCB variants ===
Also different classifications by body fluid biomarkers is possible:
Oligoclonal negative MS: Some reports point to the possibility of a different pathogenesis They represent around 5% of the cases which is suspected to be immunogenetically different. Their evolution is better than standard MS patients,
Oligoclonal IgM positive MS, with immunoglobulin-M Bands (IgM-Bands), which accounts for a 30-40% of the MS population and has been identified as a predictor of MS severity. It has been reported to have a poor response to interferon-beta but a better response to glatimer acetate instead
OCB's types: OCBs are made up of activated B-cells. It seems that the molecular targets for the OCB's are patient-specific.
=== Radiologically atypical variants ===
Inside well defined MS (Lesions disseminated in time and space with no other explanation) there are atypical cases based in radiological or metabolic criteria. A four-groups classification has been proposed:
Tumefactive demyelinating lesion (TDL)-onset MS
Acute disseminated encephalomyelitis (ADEM)-like MS
Multiple sclerosis with cavitary lesions: Atypical multiple sclerosis cases similar to vanishing white matter disease but etiologically different from both. Lesions similar to vanishing white matter disease
Leukodystrophy-like MS.
Other radiological classification of atypical lesions proposes the following four subtypes:
infiltrative
megacystic
Baló-like
ring-like lesions
=== Atypical clinical courses ===
In 1996, the US National Multiple Sclerosis Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis (ACCTMS) standardized four clinical courses for MS (Remitent-Recidivant, Secondary Progressive, Progressive-Relapsing and Primary progressive). Later, some reports state that those "types" were artificially made up trying to classify RRMS as a separate disease so that the number of patients was low enough to get the interferon approved by the FDA under the orphan drugs act. Revisions in 2013 and 2017 removed the Progressive-Relapsing course and introduced CIS as a variety/course/status of MS, establishing the actual classification (CIS, RRMS, SPMS and PPMS). Nevertheless, these types are not enough to predict the responses to medications and several regulatory agencies use additional types in their recommendations lide Highly active MS, Malignant MS, Aggressive MS or Rapidly progressive MS.
==== Highly Active MS ====
As of 2019, HAMS is defined as an RRMS phenotype with one or more of the following characteristics:
DSS scale of 4 points at 5 years of onset of the disease
Multiple relapses (two or more) with incomplete recovery in the ongoing year
More than 2 brain magnetic resonance imaging (MRI) studies demonstrating new lesions or increase in the size of the lesions in T2, or lesions that enhance with gadolinium despite treatment (Clinical case 1 and 2).
No response to treatment with one or more DMTs for at least one year.
There is a group of patients who have defined clinical and radiological risk factors that predict a behavior of greater risk of conversion to HAMS, without having the diagnostic criteria of HAMS in a first clinical attack have predictors of high risk.
Some other previous authors have used other definitions like:
High activity according to 2017 definition of activity
Rapid accumulation of physical and cognitive deficit, despite treatment with DMT's.
Being eligible for immunoablative therapy followed by autologous haematopoietic stem cell transplantation (aHSCT) because of a) the failure of conventional treatment, b) frequent and severe (disabling) relapses, or c) MRI activity (new T2 or gadolinium-enhancing lesions).
==== Malignant MS ====
See malignant multiple sclerosis
Occasionally, the term ‘malignant’ MS (MMS) has been used to describe aggressive phenotypes of MS, but this is another ambiguous term that—despite wide usage—means different things to different people.
In 1996, the US National MS Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis, “malignant MS” was also included, namely, “disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset.”
Many authors reserve the term malignant for fulminant forms of MS that deteriorate so rapidly from the outset as to be almost monophasic, and result in death within months to a few years. One such example is the Marburg variant of MS, which is classically characterized by extensive necrotic and/or tumefactive lesions with mass effect.
Despite recent (and increasing) emphasis on early detection of patients with aggressive MS, the original definition of MMS was not modified by the NMSS Advisory Committee in its latest publication in 2013 (Lublin et al., 2014).
==== Aggressive MS ====
Common to all definitions is the early, unexpected acquisition of disability followed by frequent relapses and highly active disease seen on MRI.
One definition can be based on EDSS score and the time to develop secondary progressive MS (SPMS) (Menon et al., 2013).
No consensus exists on the speed of progression or degree of disability sufficient for aggressive MS, but some assume that reaching an EDSS score of 6 points probably represents an upper limit beyond which the risk-benefit ratio for an aggressive treatment is unfavourable.
Pragmatically, AMS has been defined as any type of MS that is associated with repeated severe attacks and accelerated accrual of disability—put more simply, "rapidly progressive" MS.
==== Rapidly progressive multiple sclerosis ====
This kind of MS was previously reported to behave different that the standard progressive course, being linked to Connexin 43 autoantibodies with pattern III lesions (distal oligodendrogliopathy) and being responsive to plasma exchange
In very rapidly progressive multiple sclerosis the use of immunosuppressive therapy (mitoxantrone/cyclophosphamide), rituximab, autologous haematopoietic stem cell therapy or combination therapy should be considered carefully.
== Under research ==
Some auto-antibodies have been found consistently across different MS cases but there is still no agreement on their relevance:
HEPACAM: A cross-reactivity between HepaCam (GlialCam) and EBNA1 has been reported as of 2022 on 25% of MS cases
Anti-kir4.1: A KIR4.1 multiple sclerosis variant was reported in 2012 and later reported again, which could be considered a different disease (as Devic's disease did before), and can represent up to a 47% of the MS cases
Anoctamin 2: Auto-antibodies against anoctamin-2 (ANO-2), one of the ion-channel proteins, have been reported consistently since 2013
This finding is not universal. Most of the MS patients do not show auto-antibodies against ANO-2. Therefore, this points toward an ANO2 autoimmune sub-phenotype in MS.
Later reports point towards a mimicry between ANO-2 and EBV-EBNA-1 protein
Anti-NMDAR autoantibodies: There is an overlap between cases of Anti-NMDA receptor encephalitis and MS, NMO and ADEM. It also could be a confusion with Anti-NMDA receptor encephalitis in the early stages but there are also anti-NMDAR reported cases that evolve to McDonalds MS
Anti-Flotilin spectrum: The proteins Flotillin 1 and flotillin 2 have been recently identified as target antigens in some patients with multiple sclerosis. First 14 cases were reported together in the first report, and 3 new cases were reported later inside a cohort of 43 patients.
Mutations in GJB1 coding for connexin 32, a gap junction protein expressed in Schwann cells and oligodendrocytes, that usually produce Charcot-Marie-Tooth disease. In some cases also MS (as defined by McDonalds criteria) can appear in these patients.
Also an OPA1 variant exists.
There exist some reports by Drs. Aristo Vojdani, Partha Sarathi Mukherjee, Joshua Berookhim, and Datis Kharrazian of an aquaporin-related multiple sclerosis, related to vegetal aquaporin proteins.
Auto-antibodies against histones have been reported to be involved.
Anti-AQP1 could be involved in atypical MS and NMO
N-type calcium channel antibodies can produce cognitive relapses mimicking MS related cognitive decline, and may coexist with MS.
MLKL-MS: Mixed lineage kinase domain like pseudokinase (MLKL) related MS - A preliminary report has pointed out evidence of a novel neurodegenerative spectrum disorder related to it.
Other auto-antibodies can be used to establish a differential diagnosis from very different diseases like Sjögren syndrome which can be separated by Anti–Calponin-3 autoantibodies.
The correlation between this genetic mutation and MS was challenged but in 2018 has been replicated by an independent team. Notice that this results do not refer to general MS.
In general, NMO-like spectrum without known auto-antibodies is considered MS. Principal component analysis of these cases show 3 different kinds of antibody-negative patients. The metabolite discriminators of RRMS and Ab-NMOSD suggest that these groupings have some pathogenic meaning.
As MS is an active field for research, the list of auto-antibodies is not closed nor definitive. For example, some diseases like Autoimmune GFAP Astrocytopathy or variants of CIDP that affects the CNS (CIDP is the chronic counterpart of Guillain–Barré syndrome) could be included. Autoimmune variants peripheral neuropathies or progressive inflammatory neuropathy could be in the list assuming the autoimmune model for MS, together with a rare demyelinating lesional variant of trigeminal neuralgia and some NMDAR Anti-NMDA receptor encephalitis.
Venous induced demyelination has also been proposed as a hypothetical MS variant produced by CCSVI, Susac's syndrome and Neuro-Behçet's disease (MS has an important vascular component), myalgic encephalomyelitis (aka chronic fatigue syndrome).
Also leukoaraiosis can produce lesions disseminated in time and space, condition usually sufficient in the MS definition. Maybe two sub-conditions of Leukodystrophy: Adrenoleukodystrophy and Adrenomyeloneuropathy could be in the list. Specially interesting is X-linked adrenoleukodystrophy (X-ALD or CALD).
== Genetic types ==
Different behaviour has been reported according to the presence of different HLA genes.
=== HLA DRB3*02:02 patients ===
In HLA DRB3 cases, autoimmune reactions against the enzyme GDP-L-fucose synthase has been reported The same report points that the autoimmune problem could derive from the gut microbiota.
HLA-DRB1*15:01 has the strongest association with MS.
HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 are associated with independent MS susceptibility and HLA-DQβ1 position 9 with phenylalanine had the strongest effect on MS susceptibility.
Another possible type is one with auto-antibodies against GDP-L-fucose synthase. In HLA-DRB3*02:02 patients, autoimmune reactions against the enzyme GDP-L-fucose synthase has been reported The same report points that the autoimmune problem could derive from the gut microbiota.
=== Rapidly progressive multiple sclerosis ===
See malignant multiple sclerosis
This is a specially aggressive clinical course of progressive MS that has been found to be caused by a special genetic variant. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.
== Primary progressive variants ==
Some researchers propose to separate primary progressive MS from other clinical courses. PPMS, after recent findings seem to point that it is pathologically a very different disease.
Some authors think since long ago that primary progressive MS should be considered a disease different from standard MS, and it was also proposed that PPMS could be heterogeneous
Clinical variants have been described. For example, Late Onset MS. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.
For the rest of the progressive cases, it has been found that the lesions are diffuse instead of the normal focal ones, and are different under MR spectroscopy. RRMS and PPMS patients also show differences on the retinal layers yields examined under OCT.
Some authors have proposed a dual classification of PPMS, according to the shape of edges of the scars, in MS-like and ADEM-like Proteomic analysis have shown that two proteins, Secretogranin II and Protein 7B2, in CSF can be used to separate RRMS from PPMS
Recently, the hypothesis of PPMS being apart from RRMS/SPMS is taken further credibility due that it was shown that CSF from PPMS patients can carry the disease to other animals, producing neurodegeneration in mice and that Normal Appearing White Matter (NAWM) structure is also different
The predominant lesions in PPMS are slowly expanding lesions with T cells, microglial, and macrophage-associated demyelination in close similar to pattern I demyelination
As of 2019 it has been found that the profile of T-cells is different in PPMS and SPMS
== Clinical situations inside standard MS ==
MS can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour. Multiple sclerosis has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed.
MS is usually classified in clinical types, though they are unrelated to the underlying pathology. Some critical reports say that the current "types" were artificially made up, just to treat RRMS as a separate disease. In this way the number of patients was low enough to enter the orphan drugs act, and get the interferon approved by the FDA under this schema. Recent reviews state that all types are a mixture of inflammation and neurodegeneration, and that all types should be considered the same disease.
Other possible clinical courses are:
=== Preclinical MS: CIS and CDMS ===
The first manifestation of MS is the so-called Clinically isolated syndrome, or CIS, which is the first isolated attack. The current diagnosis criteria for MS do not allow doctors to give an MS diagnosis until a second attack takes place. Therefore, the concept of "clinical MS", for an MS that can be diagnosed, has been developed. Until MS diagnosis has been established, nobody can tell whether the disease one is dealing with is MS.
Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS. Preclinical MS refers to cases after the CIS but before the confirming second attack. After the second confirming attack the situation is referred to as CDMS (clinically defined multiple sclerosis).
CIS itself is sometimes considered itself as a disease entity, different from MS. Even if they share the same underlying condition CIS is not MS given that it lacks the presence of lesions. Approximately 84% of the subjects with CIS experience a second clinical demyelinating event and are diagnosed with clinically definite MS (CDMS) within 20 years.
=== RIS, subclinical, silent and prodromal MS ===
See also Radiologically isolated syndrome
Silent MS has been found in autopsies before the existence of MRI showing that the so-called "clinical definitions" cannot be applied to around 25% of the MS cases. Currently a distinction is made between "silent" and subclinical.
In absence of attacks, sometimes a radiological finding suggestive of demyelination (T2 hyperintensities) can be used to establish a pre-diagnosis of MS. This is often named "Radiologically Isolated Syndrome" (RIS). Cases before the first attack or CIS are subclinical in the sense that they do not produce clinical situations.
If a second radiological event appears without clinical consequences, the clinical situation is named "Silent MS" (Okuda criteria). Anyway, it is reported that all MS cases have an active subclinical phase before the CIS
It has been noted that some aspects of the MS underlying condition are present in otherwise healthy MS patients' relatives, suggesting a wider scope for the "silent MS" term.
In these cases Interleukin-8 is a risk for clinical conversion. It has also been proposed that always exists a subclinical phase in the beginning of every MS case, during which the permeability of the BBB can be used for diagnosis
It is also under investigation whether MS has a prodrome, i.e., a preliminary stage in which the disease exists with non-specific symptoms. Some reports point to a prodrome of several years for RRMS and decades for PPMS.
=== Aggressive multiple sclerosis ===
Relapsing-Remitting MS is considered aggressive when the frequency of exacerbations is not less than 3 during 2 years. Special treatment is often considered for this subtype. According to these definition aggressive MS would be a subtype of RRMS.
Other authors disagree and define aggressive MS by the accumulation of disability, considering it as a rapidly disabling disease course and therefore inside PPMS.
The aggressive course is associated to grey matter damage and meningeal inflammation, and presents a special intrathecal (meninges and CSF) inflammatory profile.
After the 2016 revision of the MS phenotypes, it is called Highly active multiple sclerosis
Mitoxantrone was approved for this special clinical course. Some reports point to Alemtuzumal being beneficial.
=== Pediatric and pubertal MS ===
MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns.
Pediatric MS patients tend to have active inflammatory disease course with a tendency to have brainstem / cerebellar presentations at onset. Due to efficient repair mechanisms at early life, pediatric MS patients tend to have longer time to reach EDSS 6 but reach it at earlier age.
An iron-responsive variant of MS has been reported in children.
== Controversy for the definition ==
Given that the etiology of MS is unknown, the current definitions of MS are all based on its appearance. The most commonly used definition, the McDonald criteria, requires just the presence of demyelinating lesions separated in space and time, together with the exclusion of every known demyelinating condition. However, as of 2023 most current MRI machines only pick up 60% of MS lesions, and even 7T machines only pick up 85%. The MS of MS people not discovered by MRI is found only in autopsy.
This unspecific definition has been criticized. For some people this has turned MS into a heterogeneous condition with several underlying problems. Besides, the complementary problem also exists. Given that McDonalds-MS is based just in the distribution of the lesions, even twins with the same underlying condition can be classified different
Finally, the "exclusion of every other known disease" condition also creates problems. Rightfully classified MS patients can be rightfully classified out of the spectrum when their particular underlying problem is discovered. For example, neuromyelitis optica was previously considered MS and currently is not, even if it appears that the MS definition has not changed.
Currently there is no single diagnosis test for MS that is 100% sensitive and specific.
=== Pathological and clinical definitions ===
McDonald criteria propose a clinical diagnosis based on a pathological definition, saying that the focus for diagnosis "remains on the objective demonstration of dissemination of lesions in both time and space" (DIT and DIS). But given that other diseases produce similar lesions, it is also required that those lesions cannot be explained by any other known disease.
This open definition present problems. For example, before the discovery of anti-AQP4 in 2006, most optic-spinal MS patients were classified rightfully as MS. Currently they are classified as NMO. Both diagnosis are correct even though the definition has not (apparently) changed.
According to some pathologists, a pathological definition is required because clinical definitions have problems with differential diagnosis and they always use a pathological definition on articles about post-mortem retrospective diagnosis, but for practitioners that need a diagnosis as soon as possible MS is often regarded as a pure clinical entity, defined simply by a positive result in the standard clinical case definition being then named "clinically definite MS" (CDMS, Poser) or simply "MS" (McDonald).
Both definitions lead to different results. For example, confluent subpial cortical lesions are the most specific finding for MS, being exclusively present in MS patients. but can only be detected post-mortem by an autopsy Therefore, any other diagnosis method will have false positives.
=== Other meanings of MS ===
There is no known etiology for MS and therefore no etiology-based definition is possible. Comparison to a post-mortem retrospective diagnosis is possible, but useless to practitioners and short-term researchers, and it is not usually done. Therefore, all meanings for the words "Multiple Sclerosis" are somehow diffuse.
The pathological definition based on proven dissemination in time and space has problems. For example, it leaves situations like RIS (radiologically isolated syndrome) outside the MS spectrum because the lack of proof, even in the case that this condition later could shown the same pathogenic conditions than MS cases.
Besides, usually the term "multiple sclerosis" is used to refer to the presence of the unknown underlying condition that produces the MS lesions instead to the mere presence of the lesions. The term MS is also used to refers to the process of developing the lesions.
Some authors instead speak about the biological disease vs. its clinical presentation.
Anyway, the precise meaning in each case can be normally deduced from the context.
=== Handling several clinical definitions ===
Given that several definitions of MS coexist, some authors are referring to them using whether CDMS for Poser positives, or McDonalds-MS with a prefix for McDonalds positives, including the release year in the prefix.
=== CIS and conversion to MS ===
The 2010 revision of the McDonald criteria allows the diagnosis of MS with only one proved lesion (CIS). Consistently, the later revision for the MS phenotypes in 2013 was forced to consider CIS as one of the MS phenotypes.
Therefore, the former concept of "Conversion from CIS to MS", that was declared when a patient had a second MS attack, does not apply anymore. More accurate is now to speak about conversions from the CIS phenotype to other MS phenotype.
== See also ==
Demyelinating disease
Pathophysiology of multiple sclerosis
The Myelin Project
== References == | Wikipedia/Inflammatory_demyelinating_diseases_of_the_central_nervous_system |
BioModels is a free and open-source repository for storing, exchanging and retrieving quantitative models of biological interest created in 2006. All the models in the curated section of BioModels Database have been described in peer-reviewed scientific literature.
The models stored in BioModels' curated branch are compliant with MIRIAM, the standard of model curation and annotation. The models have been simulated by curators to check that when run in simulations, they provide the same results as described in the publication. Model components are annotated, so the users can conveniently identify each model element and retrieve further information from other resources.
Modellers can submit the models in SBML and CellML. Models can subsequently be downloaded in SBML, VCML Archived 2006-12-09 at the Wayback Machine, XPP, SciLab, Octave, BioPAX and RDF/XML. The reaction networks of models are presented in some graphic formats, such as PNG, SVG and graphic Java applet, in which some networks were presented by following Systems Biology Graphical Notation. And a human readable summary of each model is available in PDF.
== Content ==
BioModels is composed of several branches. The curated branch hosts models that are well curated and annotated. The non-curated-branch provides models that are still not curated, are non-curatable (spatial models, steady-state models etc.), or too huge to be curated. Non-curated models can be later moved into the curated branch. The repository also hosts models which were automatically generated from pathways databases.
All the models are freely available under the Creative Commons CC0 Public Domain Dedication, and can be easily accessed via the website or Web Services. One can also download archives of all the models from the EBI FTP server.
BioModels announced its 31st release on June 26, 2017. It now publicly provides 144,710 models. This corresponds to 1,640 models published in the literature and 143,070 models automatically generated from pathway resources.
Deposition of models in BioModels is advocated by many scientific journals, included Molecular Systems Biology, all the journals of the Public Library of Science, all the journals of BioMed Central and all the journals published by the Royal Society of Chemistry.
== Development ==
BioModels is developed by the BioModels.net Team at the EMBL-EBI, UK, the Le Novère lab at the Babraham Institute, UK, and the SBML Team in Caltech, USA.
== Funding ==
BioModels Development has benefited from the funds of the European Molecular Biology Laboratory, the Biotechnology and Biological Sciences Research Council, the Innovative Medicines Initiative, the Seventh Framework Programme (FP7), the National Institute of General Medical Sciences, the DARPA, and the National Center for Research Resources.
== References ==
== External links ==
Official website of BioModels
Caltech Mirror site | Wikipedia/BioModels_Database |
The Goldman–Hodgkin–Katz flux equation (or GHK flux equation or GHK current density equation) describes the ionic flux across a cell membrane as a function of the transmembrane potential and the concentrations of the ion inside and outside of the cell. Since both the voltage and the concentration gradients influence the movement of ions, this process is a simplified version of electrodiffusion. Electrodiffusion is most accurately defined by the Nernst–Planck equation and the GHK flux equation is a solution to the Nernst–Planck equation with the assumptions listed below.
== Origin ==
The American David E. Goldman of Columbia University, and the English Nobel laureates Alan Lloyd Hodgkin and Bernard Katz derived this equation.
== Assumptions ==
Several assumptions are made in deriving the GHK flux equation (Hille 2001, p. 445) :
The membrane is a homogeneous substance
The electrical field is constant so that the transmembrane potential varies linearly across the membrane
The ions access the membrane instantaneously from the intra- and extracellular solutions
The permeant ions do not interact
The movement of ions is affected by both concentration and voltage differences
== Equation ==
The GHK flux equation for an ion S (Hille 2001, p. 445):
Φ
S
=
P
S
z
S
2
V
m
F
2
R
T
[
S
]
i
−
[
S
]
o
exp
(
−
z
S
V
m
F
/
R
T
)
1
−
exp
(
−
z
S
V
m
F
/
R
T
)
{\displaystyle \Phi _{S}=P_{S}z_{S}^{2}{\frac {V_{m}F^{2}}{RT}}{\frac {[{\mbox{S}}]_{i}-[{\mbox{S}}]_{o}\exp(-z_{S}V_{m}F/RT)}{1-\exp(-z_{S}V_{m}F/RT)}}}
where
Φ
{\displaystyle \Phi }
S is the current density (flux) outward through the membrane carried by ion S, measured in amperes per square meter (A·m−2)
PS is the permeability of the membrane for ion S measured in m·s−1
zS is the valence of ion S
Vm is the transmembrane potential in volts
F is the Faraday constant, equal to 96,485 C·mol−1 or J·V−1·mol−1
R is the gas constant, equal to 8.314 J·K−1·mol−1
T is the absolute temperature, measured in kelvins (= degrees Celsius + 273.15)
[S]i is the intracellular concentration of ion S, measured in mol·m−3 or mmol·l−1
[S]o is the extracellular concentration of ion S, measured in mol·m−3
== Implicit definition of reversal potential ==
The reversal potential is shown to be contained in the GHK flux equation (Flax 2008). The proof is replicated from the reference (Flax 2008) here.
We wish to show that when the flux is zero, the transmembrane potential is not zero. Formally it is written
lim
Φ
S
→
0
V
m
≠
0
{\displaystyle \lim _{\Phi _{S}\rightarrow 0}V_{m}\neq 0}
which is equivalent to writing
lim
V
m
→
0
Φ
S
≠
0
{\displaystyle \lim _{V_{m}\rightarrow 0}\Phi _{S}\neq 0}
, which states that when the transmembrane potential is zero, the flux is not zero.
However, due to the form of the GHK flux equation when
V
m
=
0
{\displaystyle V_{m}=0}
,
Φ
S
=
0
0
{\displaystyle \Phi _{S}={\frac {0}{0}}}
. This is a problem as the value of
0
0
{\displaystyle {\frac {0}{0}}}
is indeterminate.
We turn to l'Hôpital's rule to find the solution for the limit:
lim
V
m
→
0
Φ
S
=
P
S
z
S
2
F
2
R
T
[
V
m
(
[
S
]
i
−
[
S
]
o
exp
(
−
z
S
V
m
F
/
R
T
)
)
]
′
[
1
−
exp
(
−
z
S
V
m
F
/
R
T
)
]
′
{\displaystyle \lim _{V_{m}\rightarrow 0}\Phi _{S}=P_{S}{\frac {z_{S}^{2}F^{2}}{RT}}{\frac {[V_{m}([{\mbox{S}}]_{i}-[{\mbox{S}}]_{o}\exp(-z_{S}V_{m}F/RT))]'}{[1-\exp(-z_{S}V_{m}F/RT)]'}}}
where
[
f
]
′
{\displaystyle [f]'}
represents the differential of f and the result is :
lim
V
m
→
0
Φ
S
=
P
S
z
S
F
(
[
S
]
i
−
[
S
]
o
)
{\displaystyle \lim _{V_{m}\rightarrow 0}\Phi _{S}=P_{S}z_{S}F([{\mbox{S}}]_{i}-[{\mbox{S}}]_{o})}
It is evident from the previous equation that when
V
m
=
0
{\displaystyle V_{m}=0}
,
Φ
S
≠
0
{\displaystyle \Phi _{S}\neq 0}
if
(
[
S
]
i
−
[
S
]
o
)
≠
0
{\displaystyle ([{\mbox{S}}]_{i}-[{\mbox{S}}]_{o})\neq 0}
and thus
lim
Φ
S
→
0
V
m
≠
0
{\displaystyle \lim _{\Phi _{S}\rightarrow 0}V_{m}\neq 0}
which is the definition of the reversal potential.
By setting
Φ
S
=
0
{\displaystyle \Phi _{S}=0}
we can also obtain the reversal potential :
Φ
S
=
0
=
P
S
z
S
2
F
2
R
T
V
m
(
[
S
]
i
−
[
S
]
o
exp
(
−
z
S
V
m
F
/
R
T
)
)
1
−
exp
(
−
z
S
V
m
F
/
R
T
)
{\displaystyle \Phi _{S}=0=P_{S}{\frac {z_{S}^{2}F^{2}}{RT}}{\frac {V_{m}([{\mbox{S}}]_{i}-[{\mbox{S}}]_{o}\exp(-z_{S}V_{m}F/RT))}{1-\exp(-z_{S}V_{m}F/RT)}}}
which reduces to :
[
S
]
i
−
[
S
]
o
exp
(
−
z
S
V
m
F
/
R
T
)
=
0
{\displaystyle [{\mbox{S}}]_{i}-[{\mbox{S}}]_{o}\exp(-z_{S}V_{m}F/RT)=0}
and produces the Nernst equation :
V
m
=
−
R
T
z
S
F
ln
(
[
S
]
i
[
S
]
o
)
{\displaystyle V_{m}=-{\frac {RT}{z_{S}F}}\ln \left({\frac {[{\mbox{S}}]_{i}}{[{\mbox{S}}]_{o}}}\right)}
== Rectification ==
Since one of the assumptions of the GHK flux equation is that the ions move independently of each other, the total flow of ions across the membrane is simply equal to the sum of two oppositely directed fluxes. Each flux approaches an asymptotic value as the membrane potential diverges from zero. These asymptotes are
Φ
S
|
i
→
o
=
P
S
z
S
2
V
m
F
2
R
T
[
S
]
i
for
V
m
≫
0
{\displaystyle \Phi _{S|i\to o}=P_{S}z_{S}^{2}{\frac {V_{m}F^{2}}{RT}}[{\mbox{S}}]_{i}\ {\mbox{for}}\ V_{m}\gg \;0}
Φ
S
|
i
→
o
=
0
for
V
m
≪
0
{\displaystyle \Phi _{S|i\to o}=0\;{\mbox{for}}\ V_{m}\ll \;0}
and
Φ
S
|
o
→
i
=
P
S
z
S
2
V
m
F
2
R
T
[
S
]
o
for
V
m
≪
0
{\displaystyle \Phi _{S|o\to i}=P_{S}z_{S}^{2}{\frac {V_{m}F^{2}}{RT}}[{\mbox{S}}]_{o}\ {\mbox{for}}\ V_{m}\ll \;0}
Φ
S
|
o
→
i
=
0
for
V
m
≫
0
{\displaystyle \Phi _{S|o\to i}=0\;{\mbox{for}}\ V_{m}\gg \;0}
where subscripts 'i' and 'o' denote the intra- and extracellular compartments, respectively. Intuitively one may understand these limits as follows: if an ion is only found outside a cell, then the flux is Ohmic (proportional to voltage) when the voltage causes the ion to flow into the cell, but no voltage could cause the ion to flow out of the cell, since there are no ions inside the cell in the first place.
Keeping all terms except Vm constant, the equation yields a straight line when plotting
Φ
{\displaystyle \Phi }
S against Vm. It is evident that the ratio between the two asymptotes is merely the ratio between the two concentrations of S, [S]i and [S]o. Thus, if the two concentrations are identical, the slope will be identical (and constant) throughout the voltage range (corresponding to Ohm's law scaled by the surface area). As the ratio between the two concentrations increases, so does the difference between the two slopes, meaning that the current is larger in one direction than the other, given an equal driving force of opposite signs. This is contrary to the result obtained if using Ohm's law scaled by the surface area, and the effect is called rectification.
The GHK flux equation is mostly used by electrophysiologists when the ratio between [S]i and [S]o is large and/or when one or both of the concentrations change considerably during an action potential. The most common example is probably intracellular calcium, [Ca2+]i, which during a cardiac action potential cycle can change 100-fold or more, and the ratio between [Ca2+]o and [Ca2+]i can reach 20,000 or more.
== References ==
Hille, Bertil (2001). Ion channels of excitable membranes, 3rd ed., Sinauer Associates, Sunderland, Massachusetts. ISBN 978-0-87893-321-1
Flax, Matt R. and Holmes, W.Harvey (2008). Goldman-Hodgkin-Katz Cochlear Hair Cell Models – a Foundation for Nonlinear Cochlear Mechanics, Conference proceedings: Interspeech 2008.
== See also ==
Goldman equation
Nernst equation
Reversal potential | Wikipedia/GHK_flux_equation |
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introduced by a group of US clinicians in the mid-1970s, the term was adopted by the American Psychiatric Association for this symptom cluster under mood disorders in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and has become widely used since. The disorder causes the second-most years lived with disability, after lower back pain.
The diagnosis of major depressive disorder is based on the person's reported experiences, behavior reported by family or friends, and a mental status examination. There is no laboratory test for the disorder, but testing may be done to rule out physical conditions that can cause similar symptoms. The most common time of onset is in a person's 20s, with females affected about three times as often as males. The course of the disorder varies widely, from one episode lasting months to a lifelong disorder with recurrent major depressive episodes.
Those with major depressive disorder are typically treated with psychotherapy and antidepressant medication. While a mainstay of treatment, the clinical efficacy of antidepressants is controversial. Hospitalization (which may be involuntary) may be necessary in cases with associated self-neglect or a significant risk of harm to self or others. Electroconvulsive therapy (ECT) may be considered if other measures are not effective.
Major depressive disorder is believed to be caused by a combination of genetic, environmental, and psychological factors, with about 40% of the risk being genetic. Risk factors include a family history of the condition, major life changes, childhood traumas, environmental lead exposure, certain medications, chronic health problems, and substance use disorders. It can negatively affect a person's personal life, work life, or education, and cause issues with a person's sleeping habits, eating habits, and general health.
== Signs and symptoms ==
A person having a major depressive episode usually exhibits a low mood, which pervades all aspects of life, and an inability to experience pleasure in previously enjoyable activities. Depressed people may be preoccupied with or ruminate over thoughts and feelings of worthlessness, inappropriate guilt or regret, helplessness or hopelessness.
Other symptoms of depression include poor concentration and memory, withdrawal from social situations and activities, reduced sex drive, irritability, and thoughts of death or suicide. Insomnia is common; in the typical pattern, a person wakes very early and cannot get back to sleep. Hypersomnia, or oversleeping, can also happen, as well as day-night rhythm disturbances, such as diurnal mood variation. Some antidepressants may also cause insomnia due to their stimulating effect. In severe cases, depressed people may have psychotic symptoms. These symptoms include delusions or, less commonly, hallucinations, usually unpleasant. People who have had previous episodes with psychotic symptoms are more likely to have them with future episodes.
A depressed person may report multiple physical symptoms such as fatigue, headaches, or digestive problems; physical complaints are the most common presenting problem in developing countries, according to the World Health Organization's criteria for depression. Appetite often decreases, resulting in weight loss, although increased appetite and weight gain occasionally occur.
Major depression significantly affects a person's family and personal relationships, work or school life, sleeping and eating habits, and general health. Family and friends may notice agitation or lethargy. Older depressed people may have cognitive symptoms of recent onset, such as forgetfulness, and a more noticeable slowing of movements.
Depressed children may often display an irritable rather than a depressed mood; most lose interest in school and show a steep decline in academic performance. Diagnosis may be delayed or missed when symptoms are interpreted as "normal moodiness". Elderly people may not present with classical depressive symptoms. Diagnosis and treatment is further complicated in that the elderly are often simultaneously treated with a number of other drugs, and often have other concurrent diseases.
== Cause ==
The etiology of depression is not yet fully understood. The biopsychosocial model proposes that biological, psychological, and social factors all play a role in causing depression. The diathesis–stress model specifies that depression results when a preexisting vulnerability, or diathesis, is activated by stressful life events. The preexisting vulnerability can be either genetic, implying an interaction between nature and nurture, or schematic, resulting from views of the world learned in childhood. American psychiatrist Aaron Beck suggested that a triad of automatic and spontaneous negative thoughts about the self, the world or environment, and the future may lead to other depressive signs and symptoms.
=== Genetics ===
Genes play a major role in the development of depression. Family and twin studies suggest that genetic factors account for nearly 40% of the variation in risk for major depressive disorder. Like most psychiatric disorders, major depression is likely shaped by a combination of many individual genetic influences. In 2018, a genome-wide association study discovered 44 genetic variants linked to risk for major depression; a 2019 study found 102 variants in the genome linked to depression. However, it appears that major depression is less heritable compared to bipolar disorder and schizophrenia. Research focusing on specific candidate genes has been criticized for its tendency to generate false positive findings. There are also other efforts to examine interactions between life stress and polygenic risk for depression.
=== Other health problems ===
Depression can also arise after a chronic or terminal medical condition, such as HIV/AIDS or asthma, and may be labeled "secondary depression". It is unknown whether the underlying diseases induce depression through effect on quality of life, or through shared etiologies (such as degeneration of the basal ganglia in Parkinson's disease or immune dysregulation in asthma). Depression may also be iatrogenic (the result of healthcare), such as drug-induced depression. Therapies associated with depression include interferons, beta blockers, isotretinoin, contraceptives, cardiac agents, anticonvulsants, and hormonal agents. Celiac disease is another possible contributing factor.
Substance use in early age is associated with increased risk of developing depression later in life. Depression occurring after giving birth is called postpartum depression and is thought to be the result of hormonal changes associated with pregnancy. Seasonal affective disorder, a type of depression associated with seasonal changes in sunlight, is thought to be triggered by decreased sunlight.
Vitamin B2, B6 and B12 deficiency may cause depression in females.
A 2025 study found that, among more than 172,500 adults in the UK aged 39 and older, those with a history of depression experienced the onset of chronic illnesses approximately 30% earlier than those without depression.
=== Environmental ===
Adverse childhood experiences (incorporating childhood abuse, neglect and family dysfunction) markedly increase the risk of major depression, especially if more than one type. Childhood trauma also correlates with severity of depression, poor responsiveness to treatment and length of illness. Some are more susceptible than others to developing mental illness such as depression after trauma, and various genes have been suggested to control susceptibility. Couples in unhappy marriages have a higher risk of developing clinical depression.
There appears to be a link between air pollution and depression and suicide. There may be an association between long-term PM2.5 exposure and depression, and a possible association between short-term PM10 exposure and suicide.
Living alone has been found to increase the risk of depression by 42%.
== Pathophysiology ==
The pathophysiology of depression is not completely understood, but current theories center around monoaminergic systems, the circadian rhythm, immunological dysfunction, HPA-axis dysfunction, and structural or functional abnormalities of emotional circuits.
Derived from the effectiveness of monoaminergic drugs in treating depression, the monoamine theory posits that insufficient activity of monoamine neurotransmitters is the primary cause of depression. Evidence for the monoamine theory comes from multiple areas. First, acute depletion of tryptophan—a necessary precursor of serotonin and a monoamine—can cause depression in those in remission or relatives of people who are depressed, suggesting that decreased serotonergic neurotransmission is important in depression. Second, the correlation between depression risk and polymorphisms in the 5-HTTLPR gene, which codes for serotonin receptors, suggests a link. Third, decreased size of the locus coeruleus, reduced activity of tyrosine hydroxylase, increased density of alpha-2 adrenergic receptor, and evidence from rat models suggest decreased adrenergic neurotransmission in depression. Furthermore, decreased levels of homovanillic acid, altered response to dextroamphetamine, responses of depressive symptoms to dopamine receptor agonists, decreased dopamine receptor D1 binding in the striatum, and polymorphism of dopamine receptor genes implicate dopamine, another monoamine, in depression. Lastly, increased activity of monoamine oxidase, which degrades monoamines, has been associated with depression. However, the monoamine theory is inconsistent with observations that serotonin depletion does not cause depression in healthy persons, that antidepressants instantly increase levels of monoamines but take weeks to work, and the existence of atypical antidepressants which can be effective despite not targeting this pathway.
One proposed explanation for the therapeutic lag, and further support for the deficiency of monoamines, is a desensitization of self-inhibition in raphe nuclei by the increased serotonin mediated by antidepressants. However, disinhibition of the dorsal raphe has been proposed to occur as a result of decreased serotonergic activity in tryptophan depletion, resulting in a depressed state mediated by increased serotonin. Further countering the monoamine hypothesis is the fact that rats with lesions of the dorsal raphe are not more depressive than controls; the finding of increased jugular 5-HIAA in people who are depressed that normalized with selective serotonin reuptake inhibitor (SSRI) treatment, and the preference for carbohydrates in people who are depressed. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. A 2022 review found no consistent evidence supporting the serotonin hypothesis linking serotonin levels and depression.
HPA-axis abnormalities have been suggested in depression given the association of CRHR1 with depression and the increased frequency of dexamethasone test non-suppression in people who are depressed. However, this abnormality is not adequate as a diagnosis tool because its sensitivity is only 44%. These stress-related abnormalities are thought to be the cause of hippocampal volume reductions seen in people who are depressed. Furthermore, a meta-analysis yielded decreased dexamethasone suppression, and increased response to psychological stressors. Further abnormal results have been obscured with the cortisol awakening response, with increased response being associated with depression.
There is also a connection between the gut microbiome and the central nervous system, otherwise known as the Gut-Brain axis, which is a two-way communication system between the brain and the gut. Experiments have shown that microbiota in the gut can play an important role in depression, as people with MDD often have gut-brain dysfunction. One analysis showed that those with MDD have different bacteria in their guts. Bacteria Bacteroidetes and Firmicutes were most affected in people with MDD, and they are also impacted in people with irritable bowel syndrome. Another study showed that people with IBS have a higher chance of developing depression, which shows the two are connected. There is even evidence suggesting that altering the microbes in the gut can have regulatory effects on developing depression.
Theories unifying neuroimaging findings have been proposed. The first model proposed is the limbic-cortical model, which involves hyperactivity of the ventral paralimbic regions and hypoactivity of frontal regulatory regions in emotional processing. Another model, the cortico-striatal model, suggests that abnormalities of the prefrontal cortex in regulating striatal and subcortical structures result in depression. Another model proposes hyperactivity of salience structures in identifying negative stimuli and hypoactivity of cortical regulatory structures resulting in a negative emotional bias and depression, consistent with emotional bias studies.
=== Immune pathogenesis theories on depression ===
The newer field of psychoneuroimmunology, the study between the immune system and the nervous system and emotional state, suggests that cytokines may impact depression.
Immune system abnormalities have been observed, including increased levels of cytokines -cells produced by immune cells that affect inflammation- involved in generating sickness behavior, creating a pro-inflammatory profile in MDD. Some people with depression have increased levels of pro-inflammatory cytokines and some have decreased levels of anti-inflammatory cytokines. Research suggests that treatments can reduce pro-inflammatory cell production, like the experimental treatment of ketamine with treatment-resistant depression. With this, in MDD, people will more likely have a Th-1 dominant immune profile, which is a pro-inflammatory profile. This suggests that there are components of the immune system affecting the pathology of MDD.
Another way cytokines can affect depression is in the kynurenine pathway, and when this is overactivated, it can cause depression. This can be due to too much microglial activation and too little astrocytic activity. When microglia get activated, they release pro-inflammatory cytokines that cause an increase in the production of COX2. This, in turn, causes the production of PGE2, which is a prostaglandin, and this catalyzes the production of indolamine, IDO. IDO causes tryptophan to get converted into kynurenine, and kynurenine becomes quinolinic acid. Quinolinic acid is an agonist for NMDA receptors, so it activates the pathway. Studies have shown that the post-mortem brains of patients with MDD have higher levels of quinolinic acid than people who did not have MDD. With this, researchers have also seen that the concentration of quinolinic acid correlates to the severity of depressive symptoms.
== Diagnosis ==
=== Assessment ===
A diagnostic assessment may be conducted by a suitably trained general practitioner, or by a psychiatrist or psychologist, who records the person's current circumstances, biographical history, current symptoms, family history, and alcohol and drug use. The assessment also includes a mental state examination, which is an assessment of the person's current mood and thought content, in particular the presence of themes of hopelessness or pessimism, self-harm or suicide, and an absence of positive thoughts or plans. Specialist mental health services are rare in rural areas, and thus diagnosis and management is left largely to primary-care clinicians. This issue is even more marked in developing countries. Rating scales are not used to diagnose depression, but they provide an indication of the severity of symptoms for a time period, so a person who scores above a given cut-off point can be more thoroughly evaluated for a depressive disorder diagnosis. Several rating scales are used for this purpose; these include the Hamilton Rating Scale for Depression, the Beck Depression Inventory or the Suicide Behaviors Questionnaire-Revised.
Primary-care physicians have more difficulty with underrecognition and undertreatment of depression compared to psychiatrists. These cases may be missed because for some people with depression, physical symptoms often accompany depression. In addition, there may also be barriers related to the person, provider, and/or the medical system. Non-psychiatrist physicians have been shown to miss about two-thirds of cases, although there is some evidence of improvement in the number of missed cases.
A doctor generally performs a medical examination and selected investigations to rule out other causes of depressive symptoms. These include blood tests measuring TSH and thyroxine to exclude hypothyroidism; basic electrolytes and serum calcium to rule out a metabolic disturbance; and a full blood count including ESR to rule out a systemic infection or chronic disease. Adverse affective reactions to medications or alcohol misuse may be ruled out, as well. Testosterone levels may be evaluated to diagnose hypogonadism, a cause of depression in men. Vitamin D levels might be evaluated, as low levels of vitamin D have been associated with greater risk for depression. Subjective cognitive complaints appear in older depressed people, but they can also be indicative of the onset of a dementing disorder, such as Alzheimer's disease. Cognitive testing and brain imaging can help distinguish depression from dementia. A CT scan can exclude brain pathology in those with psychotic, rapid-onset or otherwise unusual symptoms. No biological tests confirm major depression. In general, investigations are not repeated for a subsequent episode unless there is a medical indication.
=== DSM and ICD criteria ===
The most widely used criteria for diagnosing depressive conditions are found in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD). The latter system is typically used in European countries, while the former is used in the US and many other non-European nations, and the authors of both have worked towards conforming one with the other. Both DSM and ICD mark out typical (main) depressive symptoms. The most recent edition of the DSM is the Fifth Edition, Text Revision (DSM-5-TR), and the most recent edition of the ICD is the Eleventh Edition (ICD-11).
Under mood disorders, ICD-11 classifies major depressive disorder as either single episode depressive disorder (where there is no history of depressive episodes, or of mania) or recurrent depressive disorder (where there is a history of prior episodes, with no history of mania). ICD-11 symptoms, present nearly every day for at least two weeks, are a depressed mood or anhedonia, accompanied by other symptoms such as "difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue." These symptoms must affect work, social, or domestic activities. The ICD-11 system allows further specifiers for the current depressive episode: the severity (mild, moderate, severe, unspecified); the presence of psychotic symptoms (with or without psychotic symptoms); and the degree of remission if relevant (currently in partial remission, currently in full remission). These two disorders are classified as "Depressive disorders", in the category of "Mood disorders".
According to DSM-5, at least one of the symptoms is either depressed mood or loss of interest or pleasure. Depressed mood occurs nearly every day as subjective feelings like sadness, emptiness, and hopelessness or observations made by others (e.g. appears tearful). Loss of interest or pleasure occurs in all, or almost all activities of the day, nearly every day. These symptoms, as well as five out of the nine more specific symptoms listed, must frequently occur for more than two weeks (to the extent in which it impairs functioning) for the diagnosis. Major depressive disorder is classified as a mood disorder in the DSM-5. The diagnosis hinges on the presence of single or recurrent major depressive episodes. Further qualifiers are used to classify both the episode itself and the course of the disorder. The category Unspecified Depressive Disorder is diagnosed if the depressive episode's manifestation does not meet the criteria for a major depressive episode.
==== Major depressive episode ====
A major depressive episode is characterized by the presence of a severely depressed mood that persists for at least two weeks. Episodes may be isolated or recurrent and are categorized as mild (few symptoms in excess of minimum criteria), moderate, or severe (marked impact on social or occupational functioning). An episode with psychotic features—commonly referred to as psychotic depression—is automatically rated as severe. If the person has had an episode of mania or markedly elevated mood, a diagnosis of bipolar disorder is made instead. Depression without mania is sometimes referred to as unipolar because the mood remains at one emotional state or "pole".
Bereavement is not an exclusion criterion in the DSM-5, and it is up to the clinician to distinguish between normal reactions to a loss and MDD. Excluded are a range of related diagnoses, including dysthymia, which involves a chronic but milder mood disturbance; recurrent brief depression, consisting of briefer depressive episodes; minor depressive disorder, whereby only some symptoms of major depression are present; and adjustment disorder with depressed mood, which denotes low mood resulting from a psychological response to an identifiable event or stressor.
==== Subtypes ====
The DSM-5 recognizes six further subtypes of MDD, called specifiers, in addition to noting the length, severity and presence of psychotic features:
"Melancholic depression" is characterized by a loss of pleasure in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early-morning waking, psychomotor retardation, excessive weight loss (not to be confused with anorexia nervosa), or excessive guilt.
"Atypical depression" is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite (comfort eating), excessive sleep or sleepiness (hypersomnia), a sensation of heaviness in limbs known as leaden paralysis, and significant long-term social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
"Catatonic depression" is a rare and severe form of major depression involving disturbances of motor behavior and other symptoms. Here, the person is mute and almost stuporous, and either remains immobile or exhibits purposeless or even bizarre movements. Catatonic symptoms also occur in schizophrenia or in manic episodes, or may be caused by neuroleptic malignant syndrome.
"Depression with anxious distress" was added into the DSM-5 as a means to emphasize the common co-occurrence between depression and anxiety, as well as the risk of suicide of depressed individuals with anxiety.
"Depression with peri-partum onset" refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth or while a woman is pregnant. DSM-IV-TR used the classification "postpartum depression", but this was changed to not exclude cases of depressed woman during pregnancy. Depression with peripartum onset has an incidence rate of 3–6% among new mothers. The DSM-5 mandates that to qualify as depression with peripartum onset, onset occurs during pregnancy or within one month of delivery.
"Seasonal affective disorder" (SAD) is a form of depression in which depressive episodes come on in the autumn or winter, and resolve in spring. The diagnosis is made if at least two episodes have occurred in colder months with none at other times, over a two-year period or longer.
=== Differential diagnoses ===
To confirm major depressive disorder as the most likely diagnosis, other potential diagnoses must be considered, including dysthymia, adjustment disorder with depressed mood, or bipolar disorder. Dysthymia is a chronic, milder mood disturbance in which a person reports a low mood almost daily over a span of at least two years. The symptoms are not as severe as those for major depression, although people with dysthymia are vulnerable to secondary episodes of major depression (sometimes referred to as double depression). Adjustment disorder with depressed mood is a mood disturbance appearing as a psychological response to an identifiable event or stressor, in which the resulting emotional or behavioral symptoms are significant but do not meet the criteria for a major depressive episode.
Other disorders need to be ruled out before diagnosing major depressive disorder. They include depressions due to physical illness, medications, and substance use disorders. Depression due to physical illness is diagnosed as a mood disorder due to a general medical condition. This condition is determined based on history, laboratory findings, or physical examination. When the depression is caused by a medication, non-medical use of a psychoactive substance, or exposure to a toxin, it is then diagnosed as a specific mood disorder (previously called substance-induced mood disorder).
== Screening and prevention ==
Preventive efforts may result in decreases in rates of the condition of between 22 and 38%. Since 2016, the United States Preventive Services Task Force (USPSTF) has recommended screening for depression among those over the age 12, provided that it would be diagnosed accurately, treated efficiently, and followed-up as needed; though a 2005 Cochrane review found that the routine use of screening questionnaires has little effect on detection or treatment. Screening the general population is not recommended by authorities in the UK or Canada for similar reasons, citing insufficient data.
Behavioral interventions, such as interpersonal therapy and cognitive-behavioral therapy, are effective at preventing new onset depression. Because such interventions appear to be most effective when delivered to individuals or small groups, it has been suggested that they may be able to reach their large target audience most efficiently through the Internet.
The Netherlands mental health care system provides preventive interventions, such as the "Coping with Depression" course (CWD) for people with sub-threshold depression. The course is claimed to be the most successful of psychoeducational interventions for the treatment and prevention of depression (both for its adaptability to various populations and its results), with a risk reduction of 38% in major depression and an efficacy as a treatment comparing favorably to other psychotherapies.
== Management ==
The most common and effective treatments for depression are psychotherapy, medication, and electroconvulsive therapy (ECT); a combination of treatments is the most effective approach when depression is resistant to treatment. American Psychiatric Association treatment guidelines recommend that initial treatment should be individually tailored based on factors including severity of symptoms, co-existing disorders, prior treatment experience, and personal preference. Options may include pharmacotherapy, psychotherapy, exercise, ECT, transcranial magnetic stimulation (TMS) or light therapy. Antidepressant medication is recommended as an initial treatment choice in people with mild, moderate, or severe major depression, and should be given to all people with severe depression unless ECT is planned. There is evidence that collaborative care by a team of health care practitioners produces better results than routine single-practitioner care.
Psychotherapy is the treatment of choice (over medication) for people under 18, and cognitive behavioral therapy (CBT), third wave CBT and interpersonal therapy may help prevent depression. The UK National Institute for Health and Care Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression because the risk-benefit ratio is poor. The guidelines recommend that antidepressants treatment in combination with psychosocial interventions should be considered for:
People with a history of moderate or severe depression
Those with mild depression that has been present for a long period
As a second line treatment for mild depression that persists after other interventions
As a first line treatment for moderate or severe depression.
The guidelines further note that antidepressant treatment should be continued for at least six months to reduce the risk of relapse, and that SSRIs are better tolerated than tricyclic antidepressants.: 305–450
Treatment options are more limited in developing countries, where access to mental health staff, medication, and psychotherapy is often difficult. Development of mental health services is minimal in many countries; depression is viewed as a phenomenon of the developed world despite evidence to the contrary, and not as an inherently life-threatening condition. There is insufficient evidence to determine the effectiveness of psychological versus medical therapy in children.
=== Lifestyle ===
Physical exercise has been found to be effective for major depression, and may be recommended to people who are willing, motivated, and healthy enough to participate in an exercise program as treatment. It is equivalent to the use of medications or psychological therapies in most people. In older people it does appear to decrease depression. Sleep and diet may also play a role in depression, and interventions in these areas may be an effective add-on to conventional methods. In studies, smoking cessation has benefits in depression.
=== Talking therapies ===
Talking therapy (psychotherapy) can be delivered to individuals, groups, or families by mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, counselors, and psychiatric nurses. A 2012 review found psychotherapy to be better than no treatment but not other treatments. With more complex and chronic forms of depression, a combination of medication and psychotherapy may be used. There is moderate-quality evidence that psychological therapies are a useful addition to standard antidepressant treatment of treatment-resistant depression in the short term. Psychotherapy has been shown to be effective in older people. Successful psychotherapy appears to reduce the recurrence of depression even after it has been stopped or replaced by occasional booster sessions.
The most-studied form of psychotherapy for depression is CBT, which teaches clients to challenge self-defeating, but enduring ways of thinking (cognitions) and change counter-productive behaviors. CBT can perform as well as antidepressants in people with major depression. CBT has the most research evidence for the treatment of depression in children and adolescents, and CBT and interpersonal psychotherapy (IPT) are preferred therapies for adolescent depression. In people under 18, according to the National Institute for Health and Clinical Excellence, medication should be offered only in conjunction with a psychological therapy, such as CBT, interpersonal therapy, or family therapy. Several variables predict success for cognitive behavioral therapy in adolescents: higher levels of rational thoughts, less hopelessness, fewer negative thoughts, and fewer cognitive distortions. CBT is particularly beneficial in preventing relapse. Cognitive behavioral therapy and occupational programs (including modification of work activities and assistance) have been shown to be effective in reducing sick days taken by workers with depression. Several variants of cognitive behavior therapy have been used in those with depression, the most notable being rational emotive behavior therapy, and mindfulness-based cognitive therapy. Mindfulness-based stress reduction programs may reduce depression symptoms. Mindfulness programs also appear to be a promising intervention in youth. Problem solving therapy, cognitive behavioral therapy, and interpersonal therapy are effective interventions in the elderly.
Psychoanalysis is a school of thought, founded by Sigmund Freud, which emphasizes the resolution of unconscious mental conflicts. Psychoanalytic techniques are used by some practitioners to treat clients presenting with major depression. A more widely practiced therapy, called psychodynamic psychotherapy, is in the tradition of psychoanalysis but less intensive, meeting once or twice a week. It also tends to focus more on the person's immediate problems, and has an additional social and interpersonal focus. In a meta-analysis of three controlled trials of Short Psychodynamic Supportive Psychotherapy, this modification was found to be as effective as medication for mild to moderate depression.
=== Antidepressants ===
Conflicting results have arisen from studies that look at the effectiveness of antidepressants in people with acute, mild to moderate depression. A review commissioned by the National Institute for Health and Care Excellence (UK) concluded that there is strong evidence that SSRIs, such as escitalopram, paroxetine, and sertraline, have greater efficacy than placebo on achieving a 50% reduction in depression scores in moderate and severe major depression, and that there is some evidence for a similar effect in mild depression. Similarly, a Cochrane systematic review of clinical trials of the generic tricyclic antidepressant amitriptyline concluded that there is strong evidence that its efficacy is superior to placebo. Antidepressants work less well for the elderly than for younger individuals with depression.
To find the most effective antidepressant medication with minimal side-effects, the dosages can be adjusted, and if necessary, combinations of different classes of antidepressants can be tried. Response rates to the first antidepressant administered range from 50 to 75%, and it can take at least six to eight weeks from the start of medication to improvement. Antidepressant medication treatment is usually continued for 6–9 months after remission, to minimize the chance of recurrence, and even up to two years of continuation is recommended.: 305–450
SSRIs are the primary medications prescribed, owing to their relatively mild side-effects, and safety. People who do not respond to one SSRI can be switched to another antidepressant, and this results in improvement in almost 50% of cases. Another option is to augment the atypical antidepressant bupropion to the SSRI as an adjunctive treatment. Venlafaxine, an antidepressant with a different mechanism of action, may be modestly more effective than SSRIs. However, venlafaxine is not recommended in the UK as a first-line treatment because of evidence suggesting its risks may outweigh benefits, and it is specifically discouraged in children and adolescents as it increases the risk of suicidal thoughts or attempts.
For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy) but more research is needed to be certain. Sertraline, escitalopram, duloxetine might also help in reducing symptoms. Some antidepressants have not been shown to be effective. Medications are not recommended in children with mild disease.
There is also insufficient evidence to determine effectiveness in those with depression complicated by dementia. Any antidepressant can cause low blood sodium levels; nevertheless, it has been reported more often with SSRIs. It is not uncommon for SSRIs to cause or worsen insomnia; the sedating atypical antidepressant mirtazapine can be used in such cases.
Irreversible monoamine oxidase inhibitors, an older class of antidepressants, have been plagued by potentially life-threatening dietary and drug interactions. They are still used only rarely, although newer and better-tolerated agents of this class have been developed. The safety profile is different with reversible monoamine oxidase inhibitors, such as moclobemide, where the risk of serious dietary interactions is negligible and dietary restrictions are less strict.
It is unclear whether antidepressants affect a person's risk of suicide. For children, adolescents, and probably young adults between 18 and 24 years old, there is a higher risk of both suicidal ideations and suicidal behavior in those treated with SSRIs. For adults, it is unclear whether SSRIs affect the risk of suicidality. One review found no connection; another an increased risk; and a third no risk in those 25–65 years old and a decreased risk in those more than 65. A black box warning was introduced in the United States in 2007 on SSRIs and other antidepressant medications due to the increased risk of suicide in people younger than 24 years old. Similar precautionary notice revisions were implemented by the Japanese Ministry of Health.
=== Other medications and supplements ===
The combined use of antidepressants plus benzodiazepines demonstrates improved effectiveness when compared to antidepressants alone, but these effects may not endure. The addition of a benzodiazepine is balanced against possible harms and other alternative treatment strategies when antidepressant mono-therapy is considered inadequate.
For treatment-resistant depression, adding on the atypical antipsychotic brexpiprazole for short-term or acute management may be considered. Brexpiprazole may be effective for some people, however, the evidence as of 2023 supporting its use is weak and this medication has potential adverse effects including weight gain and akathisia. Brexpiprazole has not been sufficiently studied in older people or children and the use and effectiveness of this adjunctive therapy for longer term management is not clear.
Ketamine may have a rapid antidepressant effect lasting less than two weeks; there is limited evidence of any effect after that, common acute side effects, and longer-term studies of safety and adverse effects are needed. A nasal spray form of esketamine was approved by the FDA in March 2019 for use in treatment-resistant depression when combined with an oral antidepressant; risk of substance use disorder and concerns about its safety, serious adverse effects, tolerability, effect on suicidality, lack of information about dosage, whether the studies on it adequately represent broad populations, and escalating use of the product have been raised by an international panel of experts.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors may be effective in treating depression. For instance, celecoxib, an NSAID, is a selective COX-2 inhibitor– which is an enzyme that helps in the production of pain and inflammation. In recent clinical trials, this NSAID has been shown helpful with treatment-resistant depression as it helps inhibit proinflammatory signaling.
Statins, which are anti-inflammatory medications prescribed to lower cholesterol levels, have also been shown to have antidepressant effects. When prescribed for patients already taking SSRIs, this add-on treatment was shown to improve anti-depressant effects of SSRIs when compared to the placebo group. With this, statins have been shown to be effective in preventing depression in some cases too.
There is insufficient high quality evidence to suggest omega-3 fatty acids are effective in depression. There is limited evidence that vitamin D supplementation is of value in alleviating the symptoms of depression in individuals who are vitamin D-deficient. Lithium appears effective at lowering the risk of suicide in those with bipolar disorder and unipolar depression by about 80%. There is a narrow range of effective and safe dosages of lithium thus close monitoring may be needed. Low-dose thyroid hormone may be added to existing antidepressants to treat persistent depression symptoms. Limited evidence suggests stimulants, such as amphetamine and modafinil, may be effective in the short term, or as adjuvant therapy. Also, it is suggested that folate supplements may have a role in depression management. There is tentative evidence for benefit from testosterone in males.
=== Electroconvulsive therapy ===
Electroconvulsive therapy (ECT) is a standard psychiatric treatment in which seizures are electrically induced in a person with depression to provide relief from psychiatric illnesses. ECT is used with informed consent as a last line of intervention for major depressive disorder. A round of ECT is effective for about 50% of people with treatment-resistant major depressive disorder, whether it is unipolar or bipolar. Follow-up treatment is still poorly studied, but about half of people who respond relapse within twelve months. Aside from effects in the brain, the general physical risks of ECT are similar to those of brief general anesthesia.: 259 Immediately following treatment, the most common adverse effects are confusion and memory loss. ECT is considered one of the least harmful treatment options available for severely depressed pregnant women.
A usual course of ECT involves multiple administrations, typically given two or three times per week, with a total of six to twelve treatments. ECT is administered under anesthesia with a muscle relaxant. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some people receive maintenance ECT.
ECT appears to work in the short term via an anticonvulsant effect mostly in the frontal lobes, and longer term via neurotrophic effects primarily in the medial temporal lobe.
=== Other ===
Transcranial magnetic stimulation (TMS) or deep transcranial magnetic stimulation is a noninvasive method used to stimulate small regions of the brain. TMS was approved by the FDA for treatment-resistant major depressive disorder (trMDD) in 2008. Recent systematic reviews have found that the effects of TMS on clinical response, remission, and severity in depression appear not to be statistically or clinically significant. The American Psychiatric Association, the Canadian Network for Mood and Anxiety Disorders, and the Royal Australia and New Zealand College of Psychiatrists have endorsed TMS for trMDD. Transcranial direct current stimulation (tDCS) is another noninvasive method used to stimulate small regions of the brain with a weak electric current. Several meta-analyses have concluded that active tDCS was useful for treating depression.
There is a small amount of evidence that sleep deprivation may improve depressive symptoms in some individuals, with the effects usually showing up within a day. This effect is usually temporary. Besides sleepiness, this method can cause a side effect of mania or hypomania. There is insufficient evidence for Reiki and dance movement therapy in depression. Cannabis is specifically not recommended as a treatment.
The microbiome of people with major depressive disorder differs from that of healthy people, and probiotic and synbiotic treatment may achieve a modest depressive symptom reduction. With this, fecal microbiota transplants (FMT) are being researched as add-on therapy treatments for people who do not respond to typical therapies. It has been shown that the patient's depressive symptoms improved, with minor gastrointestinal issues, after a FMT, with improvements in symptoms lasting at least 4 weeks after the transplant.
== Prognosis ==
Studies have shown that 80% of those with a first major depressive episode will have at least one more during their life, with a lifetime average of four episodes. Other general population studies indicate that around half those who have an episode recover (whether treated or not) and remain well, while the other half will have at least one more, and around 15% of those experience chronic recurrence. Studies recruiting from selective inpatient sources suggest lower recovery and higher chronicity, while studies of mostly outpatients show that nearly all recover, with a median episode duration of 11 months. Around 90% of those with severe or psychotic depression, most of whom also meet criteria for other mental disorders, experience recurrence. Cases when outcome is poor are associated with inappropriate treatment, severe initial symptoms including psychosis, early age of onset, previous episodes, incomplete recovery after one year of treatment, pre-existing severe mental or medical disorder, and family dysfunction.
A high proportion of people who experience full symptomatic remission still have at least one not fully resolved symptom after treatment. Recurrence or chronicity is more likely if symptoms have not fully resolved with treatment. Current guidelines recommend continuing antidepressants for four to six months after remission to prevent relapse. Evidence from many randomized controlled trials indicates continuing antidepressant medications after recovery can reduce the chance of relapse by 70% (41% on placebo vs. 18% on antidepressant). The preventive effect probably lasts for at least the first 36 months of use.
Major depressive episodes often resolve over time, whether or not they are treated. Outpatients on a waiting list show a 10–15% reduction in symptoms within a few months, with approximately 20% no longer meeting the full criteria for a depressive disorder. The median duration of an episode has been estimated to be 23 weeks, with the highest rate of recovery in the first three months. According to a 2013 review, 23% of untreated adults with mild to moderate depression will remit within 3 months, 32% within 6 months and 53% within 12 months.
=== Ability to work ===
Depression may affect people's ability to work. The combination of usual clinical care and support with return to work (like working less hours or changing tasks) probably reduces sick leave by 15%, and leads to fewer depressive symptoms and improved work capacity, reducing sick leave by an annual average of 25 days per year. Helping depressed people return to work without a connection to clinical care has not been shown to have an effect on sick leave days. Additional psychological interventions (such as online cognitive behavioral therapy) lead to fewer sick days compared to standard management only. Streamlining care or adding specific providers for depression care may help to reduce sick leave.
=== Life expectancy and the risk of suicide ===
Depressed individuals have a shorter life expectancy than those without depression, in part because people who are depressed are at risk of dying of suicide. About 50% of people who die of suicide have a mood disorder such as major depression, and the risk is especially high if a person has a marked sense of hopelessness or has both depression and borderline personality disorder. About 2–8% of adults with major depression die by suicide. In the US, the lifetime risk of suicide associated with a diagnosis of major depression is estimated at 7% for men and 1% for women, even though suicide attempts are more frequent in women.
Depressed people also have a higher rate of dying from other causes. There is a 1.5- to 2-fold increased risk of cardiovascular disease, independent of other known risk factors, and is itself linked directly or indirectly to risk factors such as smoking and obesity. People with major depression are less likely to follow medical recommendations for treating and preventing cardiovascular disorders, further increasing their risk of medical complications. Cardiologists may not recognize underlying depression that complicates a cardiovascular problem under their care.
== Epidemiology ==
Major depressive disorder affected approximately 163 million people in 2017 (2% of the global population). The percentage of people who are affected at one point in their life varies from 7% in Japan to 21% in France. In most countries the number of people who have depression during their lives falls within an 8–18% range. Lifetime rates are higher in the developed world (15%) compared to the developing world (11%).
In the United States, 8.4% of adults (21 million individuals) have at least one episode within a year-long period; the probability of having a major depressive episode is higher for females than males (10.5% to 6.2%), and highest for those aged 18 to 25 (17%). 15% of adolescents, ages 12 to 17, in America are also affected by depression, which is equal to 3.7 million teenagers. Among individuals reporting two or more races, the US prevalence is highest. Out of all the people suffering from MDD, only about 35% seek help from a professional for their disorder.
Major depression is about twice as common in women as in men, although it is unclear why this is so, and whether factors unaccounted for are contributing to this. The relative increase in occurrence is related to pubertal development rather than chronological age, reaches adult ratios between the ages of 15 and 18, and appears associated with psychosocial more than hormonal factors. In 2019, major depressive disorder was identified (using either the DSM-IV-TR or ICD-10) in the Global Burden of Disease Study as the fifth most common cause of years lived with disability and the 18th most common for disability-adjusted life years.
People are most likely to develop their first depressive episode between the ages of 30 and 40, and there is a second, smaller peak of incidence between ages 50 and 60. The risk of major depression is increased with neurological conditions such as stroke, Parkinson's disease, or multiple sclerosis, and during the first year after childbirth (Postpartum depression). It is also more common after cardiovascular illnesses, and is related more to those with a poor cardiac disease outcome than to a better one. Depressive disorders are more common in urban populations than in rural ones and the prevalence is increased in groups with poorer socioeconomic factors, e.g., homelessness. Depression is common among those over 65 years of age and increases in frequency beyond this age. The risk of depression increases in relation to the frailty of the individual. Depression is one of the most important factors which negatively impact quality of life in adults, as well as the elderly. Both symptoms and treatment among the elderly differ from those of the rest of the population.
Major depression was the leading cause of disease burden in North America and other high-income countries, and the fourth-leading cause worldwide as of 2006. In the year 2030, it is predicted to be the second-leading cause of disease burden worldwide after HIV, according to the WHO. Delay or failure in seeking treatment after relapse and the failure of health professionals to provide treatment are two barriers to reducing disability.
=== Comorbidity ===
Major depression frequently co-occurs with other psychiatric problems. The 1990–92 National Comorbidity Survey (US) reported that half of those with major depression also have lifetime anxiety and its associated disorders, such as generalized anxiety disorder. Anxiety symptoms can have a major impact on the course of a depressive illness, with delayed recovery, increased risk of relapse, greater disability and increased suicidal behavior. Depressed people have increased rates of alcohol and substance use, particularly dependence, and around a third of individuals diagnosed with attention deficit hyperactivity disorder (ADHD) develop comorbid depression. Post-traumatic stress disorder and depression often co-occur. Depression may also coexist with ADHD, complicating the diagnosis and treatment of both. Depression is also frequently comorbid with alcohol use disorder and personality disorders. Depression can also be exacerbated during particular months (usually winter) in those with seasonal affective disorder. While overuse of digital media has been associated with depressive symptoms, using digital media may also improve mood in some situations.
Depression and pain often co-occur. One or more pain symptoms are present in 65% of people who have depression, and anywhere from 5 to 85% of people who are experiencing pain will also have depression, depending on the setting—a lower prevalence in general practice, and higher in specialty clinics. Depression is often underrecognized, and therefore undertreated, in patients presenting with pain. Depression often coexists with physical disorders common among the elderly, such as stroke, other cardiovascular diseases, Parkinson's disease, and chronic obstructive pulmonary disease.
== History ==
The Ancient Greek physician Hippocrates described a syndrome of melancholia (μελαγχολία, melankholía) as a distinct disease with particular mental and physical symptoms; he characterized all "fears and despondencies, if they last a long time" as being symptomatic of the ailment. It was a similar but far broader concept than today's depression; prominence was given to a clustering of the symptoms of sadness, dejection, and despondency, and often fear, anger, delusions and obsessions were included.
The term depression itself was derived from the Latin verb deprimere, meaning "to press down". From the 14th century, "to depress" meant to subjugate or to bring down in spirits. It was used in 1665 in English author Richard Baker's Chronicle to refer to someone having "a great depression of spirit", and by English author Samuel Johnson in a similar sense in 1753. The term also came into use in physiology and economics. An early usage referring to a psychiatric symptom was by French psychiatrist Louis Delasiauve in 1856, and by the 1860s it was appearing in medical dictionaries to refer to a physiological and metaphorical lowering of emotional function. Since Aristotle, melancholia had been associated with men of learning and intellectual brilliance, a hazard of contemplation and creativity. However, by the 19th century, this association has largely shifted and melancholia became more commonly linked with women.
Although melancholia remained the dominant diagnostic term, depression gained increasing currency in medical treatises and was a synonym by the end of the century; German psychiatrist Emil Kraepelin may have been the first to use it as the overarching term, referring to different kinds of melancholia as depressive states. Freud likened the state of melancholia to mourning in his 1917 paper Mourning and Melancholia. He theorized that objective loss, such as the loss of a valued relationship through death or a romantic break-up, results in subjective loss as well; the depressed individual has identified with the object of affection through an unconscious, narcissistic process called the libidinal cathexis of the ego. Such loss results in severe melancholic symptoms more profound than mourning; not only is the outside world viewed negatively but the ego itself is compromised. The person's decline of self-perception is revealed in his belief of his own blame, inferiority, and unworthiness. He also emphasized early life experiences as a predisposing factor. Adolf Meyer put forward a mixed social and biological framework emphasizing reactions in the context of an individual's life, and argued that the term depression should be used instead of melancholia. The first version of the DSM (DSM-I, 1952) contained depressive reaction and the DSM-II (1968) depressive neurosis, defined as an excessive reaction to internal conflict or an identifiable event, and also included a depressive type of manic-depressive psychosis within Major affective disorders.
The term unipolar (along with the related term bipolar) was coined by the neurologist and psychiatrist Karl Kleist, and subsequently used by his disciples Edda Neele and Karl Leonhard.
The term major depressive disorder was introduced by a group of US clinicians in the mid-1970s as part of proposals for diagnostic criteria based on patterns of symptoms (called the "Research Diagnostic Criteria", building on earlier Feighner Criteria), and was incorporated into the DSM-III in 1980. The American Psychiatric Association added "major depressive disorder" to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), as a split of the previous depressive neurosis in the DSM-II, which also encompassed the conditions now known as dysthymia and adjustment disorder with depressed mood. To maintain consistency the ICD-10 used the same criteria, with only minor alterations, but using the DSM diagnostic threshold to mark a mild depressive episode, adding higher threshold categories for moderate and severe episodes. The ancient idea of melancholia still survives in the notion of a melancholic subtype.
The new definitions of depression were widely accepted, albeit with some conflicting findings and views. There have been some continued empirically based arguments for a return to the diagnosis of melancholia. There has been some criticism of the expansion of coverage of the diagnosis, related to the development and promotion of antidepressants and the biological model since the late 1950s.
== Society and culture ==
=== Terminology ===
The term depression is used in a number of different ways. It is often used to mean this syndrome but may refer to other mood disorders or simply to a low mood. People's conceptualizations of depression vary widely, both within and among cultures. "Because of the lack of scientific certainty," one commentator has observed, "the debate over depression turns on questions of language. What we call it—'disease,' 'disorder,' 'state of mind'—affects how we view, diagnose, and treat it." There are cultural differences in the extent to which serious depression is considered an illness requiring personal professional treatment, or an indicator of something else, such as the need to address social or moral problems, the result of biological imbalances, or a reflection of individual differences in the understanding of distress that may reinforce feelings of powerlessness, and emotional struggle.
=== Cultural dimension ===
Cultural differences contribute to different prevalence of symptoms. "Do the Chinese somatize depression? A cross-cultural study" by Parker et al. discusses the cultural differences in prevalent symptoms of depression between individualistic and collectivistic cultures. The authors reveal that individuals with depression in collectivistic cultures tend to present more somatic symptoms and less affective symptoms compared to those in individualistic cultures. The finding suggests that individualistic cultures 'warranting' or validating one's expression of emotions explains this cultural difference since collectivistic cultures see this as a taboo against the social cooperation it deems one of the most significant values.
=== Stigma ===
Historical figures were often reluctant to discuss or seek treatment for depression due to social stigma about the condition, or due to ignorance of diagnosis or treatments. Nevertheless, analysis or interpretation of letters, journals, artwork, writings, or statements of family and friends of some historical personalities has led to the presumption that they may have had some form of depression. People who may have had depression include English author Mary Shelley, American-British writer Henry James, and American president Abraham Lincoln. Some well-known contemporary people with possible depression include Canadian songwriter Leonard Cohen and American playwright and novelist Tennessee Williams. Some pioneering psychologists, such as Americans William James and John B. Watson, dealt with their own depression.
There has been a continuing discussion of whether neurological disorders and mood disorders may be linked to creativity, a discussion that goes back to Aristotelian times. British literature gives many examples of reflections on depression. English philosopher John Stuart Mill experienced a several-months-long period of what he called "a dull state of nerves", when one is "unsusceptible to enjoyment or pleasurable excitement; one of those moods when what is pleasure at other times, becomes insipid or indifferent". He quoted English poet Samuel Taylor Coleridge's "Dejection" as a perfect description of his case: "A grief without a pang, void, dark and drear, / A drowsy, stifled, unimpassioned grief, / Which finds no natural outlet or relief / In word, or sigh, or tear." English writer Samuel Johnson used the term "the black dog" in the 1780s to describe his own depression, and it was subsequently popularized by British Prime Minister Sir Winston Churchill, who also had the disorder. Johann Wolfgang von Goethe in his Faust, Part One, published in 1808, has Mephistopheles assume the form of a black dog, specifically a poodle.
Social stigma of major depression is widespread, and contact with mental health services reduces this only slightly. Public opinions on depression treatment vary. While some remain skeptical about antidepressants, recent studies show a more balanced view. Many patients recognize their benefits but have concerns about side effects and personality changes. In the UK, the Royal College of Psychiatrists and the Royal College of General Practitioners conducted a joint Five-year Defeat Depression campaign to educate and reduce stigma from 1992 to 1996; a MORI study conducted afterwards showed a small positive change in public attitudes to depression and treatment.
While serving his first term as Prime Minister of Norway, Kjell Magne Bondevik attracted international attention in August 1998 when he announced that he was suffering from a depressive episode, becoming the highest ranking world leader to admit to suffering from a mental illness while in office. Upon this revelation, Anne Enger became acting Prime Minister for three weeks, from 30 August to 23 September, while he recovered from the depressive episode. Bondevik then returned to office. Bondevik received thousands of supportive letters, and said that the experience had been positive overall, both for himself and because it made mental illness more publicly acceptable.
== References ==
=== Cited works === | Wikipedia/Clinical_depression |
Motion control photography is a technique used in still and motion photography that enables precise control of, and optionally also allows repetition of, camera movements. It can be used to facilitate special effects photography. The process can involve filming several elements using the same camera motion, and then compositing the elements into a single image. Other effects are often used along with motion control, such as chroma key to aid the compositing. Motion control camera rigs are also used in still photography with or without compositing; for example in long exposures of moving vehicles. Today's computer technology allows the programmed camera movement to be processed, such as having the move scaled up or down for different sized elements. Common applications of this process include shooting with miniatures, either to composite several miniatures or to composite miniatures with full-scale elements.
The process is also commonly used when duplication of an element which cannot be physically duplicated is required; motion control is the primary method of featuring multiple instances of the same actor in a shot that involves camera movement. For this technique, the camera typically films exactly the same motion in exactly the same location while the actor performs different parts. A blank take (with no actor in the shot) is sometimes also taken to give compositors a reference of what parts of the shot are different in each take. This, in common film-making language, is also known as shooting a "plate".
In today's film, the reference take is also useful for digital manipulation of the shots, or for adding digital elements. A simple duplication shot confines each "copy" of an element to one part of the screen. It is far more difficult to composite the shots when the duplicate elements cross paths, though digital technology has made this easier to achieve. Several basic camera tricks are sometimes utilized with this technique, such as having the hand of a body double enter a shot to interact with the actor while the duplicate's arm is to be off-screen. For the sake of compositing, the background elements of the scene must remain identical between takes, requiring anything movable to be locked down; the blank reference take can aid in resolving any discrepancies between the other shots.
Similar technology in modern film allows for a camera to record its exact motion during a shot so that the motion can be duplicated by a computer in the creation of computer generated elements for the same shot.
== History ==
Modelmaking for scenery has long been used in the film industry, but when a model is too small it often loses its illusion and becomes "obviously a model". Solving this by building a larger model introduces a dilemma: larger models are more difficult to build and often too fragile to move smoothly. The solution is to move the camera, rather than the model, and the advent of compact lightweight 35mm cameras has made machine-controlled motion control feasible. Motion-control also requires control over other photographic elements, such as frame rates, focus, and shutter speeds. By changing the frame rates and the depth of field, models can seem to be much larger than they actually are, and the speed of the camera motion can be increased or decreased accordingly.
Early attempts at motion control came about when John Whitney pioneered several motion techniques using old anti-aircraft analog computers (Kerrison Predictor) connected to servos to control the motion of lights and lit targets. His film Catalog (1961) and his brother James Whitney's film Lapis (1966) were both achieved with John's pioneering motion control system. The 1968 film 2001: A Space Odyssey pioneered motion control in two respects. The film's model photography was conducted with large mechanical rigs that enabled precise and repeatable camera and model motion. The film's finale was created with mechanically controlled slit-scan photography, which required precise camera motion control during the exposure of single frames.
The first large-scale application of motion control was in Star Wars (1977), where a digitally controlled camera known as the Dykstraflex performed complex and repeatable motions around stationary spaceship models. This enabled a greater complexity in the spaceship-battle sequences, as separately filmed elements (spaceships, backgrounds, etc.) could be better coordinated with one another with greatly reduced error. The development of the Dykstraflex was led by John Dykstra, who had numerous contributors, including Alvah J. Miller and Jerry Jeffress. In 1978, Dykstra, Miller, and Jeffress won the Academy Award for Best Visual Effects.
In the UK The Moving Picture Company had the first practical motion control rig. Designed and built in-house in 1981, it used the IMC operating system to control its various axes of movement. Peter Truckel, MPC's first in-house VFX supervisor, operated it for several years before leaving to pursue a career as a successful commercials director.
The simultaneous increase in power and affordability of computer-generated imagery in the 21st century, and the ability for Computer-generated imagery (CGI) specialists to duplicate even hand-held camera motion (see Match moving), initially made the use of motion control photography less common. However film producers and directors have come to realise the cost-saving benefit of using motion control to achieve the effects in a reliable and realistic way. CGI still struggles to be 100% photorealistic, and the time and cost to achieve photo-realistic shots far exceeds the cost of shooting the live action itself.
With the resurgence of 3D as a medium motion control has also an important role to play, especially in the production of 3D background plates on scaled-sets. Using high resolution still cameras, backgrounds can be easily shot for further use with live action and CGI character animation.
== See also ==
Dykstraflex
Motion capture, the process of recording movement
Milo Motion Control Rig
== Notes == | Wikipedia/Movement_control |
Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions of drug misuse are used in public health, medical, and criminal justice contexts. In some cases, criminal or anti-social behavior occurs when some persons are under the influence of a drug, and may result in long-term personality changes in individuals which may also occur. In addition to possible physical, social, and psychological harm, the use of some drugs may also lead to criminal penalties, although these vary widely depending on the local jurisdiction.
Drugs most often associated with this term include alcohol, amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, hallucinogens, methaqualone, and opioids. The exact cause of substance abuse is sometimes clear, but there are two predominant theories: either a genetic predisposition or most times a habit learned or passed down from others, which, if addiction develops, manifests itself as a possible chronic debilitating disease. It is not easy to determine why a person misuses drugs, as there are multiple environmental factors to consider. These factors include not only inherited biological influences (genes), but there are also mental health stressors such as overall quality of life, physical or mental abuse, luck and circumstance in life and early exposure to drugs that all play a huge factor in how people will respond to drug use.
In 2010, about 5% of adults (230 million) used an illicit substance. Of these, 27 million have high-risk drug use—otherwise known as recurrent drug use—causing harm to their health, causing psychological problems, and or causing social problems that put them at risk of those dangers. In 2015, substance use disorders resulted in 307,400 deaths, up from 165,000 deaths in 1990. Of these, the highest numbers are from alcohol use disorders at 137,500, opioid use disorders at 122,100 deaths, amphetamine use disorders at 12,200 deaths, and cocaine use disorders at 11,100.
== Classification ==
=== Public health definitions ===
Public health practitioners have attempted to look at substance use from a broader perspective than the individual, emphasizing the role of society, culture, and availability. Some health professionals choose to avoid the terms alcohol or drug "abuse" in favor of language considered more objective, such as "substance and alcohol type problems" or "harmful/problematic use" of drugs. The Health Officers Council of British Columbia — in their 2005 policy discussion paper, A Public Health Approach to Drug Control in Canada — has adopted a public health model of psychoactive substance use that challenges the simplistic black-and-white construction of the binary (or complementary) antonyms "use" vs. "abuse". This model explicitly recognizes a spectrum of use, ranging from beneficial use to chronic dependence.
=== Medical definitions ===
'Drug abuse' is no longer a current medical diagnosis in either of the most used diagnostic tools in the world, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), and the World Health Organization's International Classification of Diseases (ICD). According to the DSM, substance abuse is the abuse of one of the 10 classes of drugs which include cannabis, alcohol, caffeine, hallucinogens, hypnotics, opioids, anxiolytics, inhalants, tobacco, and sedatives as well as other, possibly unknown, substances.
=== Value judgment ===
History professor Philip Jenkins suggests that there are two issues with the term "drug abuse". First, what constitutes a drug is debatable. For instance, GHB, a naturally occurring substance in the central nervous system is considered a drug, and is illegal in many countries, while nicotine is not officially considered a "drug" in most countries.
Second, the word "abuse" implies a recognized standard of use for any substance. Drinking an occasional glass of wine is considered acceptable in most Western countries, while drinking several bottles is seen as abuse. Strict temperance advocates, who may or may not be religiously motivated, would see drinking even one glass as abuse. Some groups (Mormons, as prescribed in "the Word of Wisdom") even condemn caffeine use in any quantity. Similarly, adopting the view that any (recreational) use of cannabis or substituted amphetamines constitutes drug abuse implies a decision made that the substance is harmful, even in minute quantities. In the U.S., drugs have been legally classified into five categories; these are schedule I, II, III, IV, or V in the Controlled Substances Act. The drugs are classified on their deemed potential for abuse.
The usage of some drugs is strongly correlated. For example, the consumption of seven illicit drugs (amphetamines, cannabis, cocaine, ecstasy, legal highs, LSD, and magic mushrooms) is correlated and the Pearson correlation coefficient r>0.4 in every pair of them; consumption of cannabis is strongly correlated (r>0.5) with the usage of nicotine (tobacco), heroin is correlated with cocaine (r>0.4) and methadone (r>0.45), and is strongly correlated with crack (r>0.5)
=== Drug misuse ===
Drug misuse is a term used commonly when prescription medication with sedative, anxiolytic, analgesic, or stimulant properties is used for mood alteration or intoxication ignoring the fact that overdose of such medicines can sometimes have serious adverse effects. It sometimes involves drug diversion from the individual for whom it was prescribed.
Prescription misuse has been defined differently and rather inconsistently based on the status of drug prescription, the uses without a prescription, intentional use to achieve intoxicating effects, route of administration, co-ingestion with alcohol, and the presence or absence of dependence symptoms. Chronic use of certain substances leads to a change in the central nervous system known as a "tolerance" to the medicine such that more of the substance is needed in order to produce desired effects. With some substances, stopping or reducing use can cause withdrawal symptoms to occur, but this is highly dependent on the specific substance in question.
The rate of prescription drug misuse is fast overtaking illegal drug use in the United States. According to the National Institute of Drug Abuse, 7 million people were taking prescription drugs for nonmedical use in 2010. Among 12th graders, nonmedical prescription drug use is now second only to cannabis. In 2011, "Nearly 1 in 12 high school seniors reported nonmedical use of Vicodin; 1 in 20 reported such use of OxyContin." Both of these drugs contain opioids. Fentanyl is an opioid that is 100 times more potent than morphine, and 50 times more potent than heroin. A 2017 survey of 12th graders in the United States, found misuse of OxyContin of 2.7 percent, compared to 5.5 percent at its peak in 2005. Misuse of the combination hydrocodone/paracetamol was at its lowest since a peak of 10.5 percent in 2003. This decrease may be related to public health initiatives and decreased availability.
Avenues of obtaining prescription drugs for misuse are varied: sharing between family and friends, illegally buying medications at school or work, and often "doctor shopping" to find multiple physicians to prescribe the same medication, without the knowledge of other prescribers.
Increasingly, law enforcement is holding physicians responsible for prescribing controlled substances without fully establishing patient controls, such as a patient "drug contract". Concerned physicians are educating themselves on how to identify medication-seeking behavior in their patients, and are becoming familiar with "red flags" that would alert them to potential prescription drug abuse.
== Signs and symptoms ==
Depending on the actual compound, drug abuse including alcohol may lead to health problems, social problems, morbidity, injuries, unprotected sex, violence, deaths, motor vehicle accidents, homicides, suicides, physical dependence or psychological addiction.
There is a high rate of suicide in alcoholics and other drug abusers. The reasons believed to cause the increased risk of suicide include the long-term abuse of alcohol and other drugs causing physiological distortion of brain chemistry as well as the social isolation. Another factor is the acute intoxicating effects of the drugs may make suicide more likely to occur. Suicide is also very common in adolescent alcohol abusers, with 1 in 4 suicides in adolescents being related to alcohol abuse. In the US, approximately 30% of suicides are related to alcohol abuse. Alcohol abuse is also associated with increased risks of committing criminal offences including child abuse, domestic violence, rapes, burglaries and assaults.
Drug abuse, including alcohol and prescription drugs, can induce symptomatology which resembles mental illness. This can occur both in the intoxicated state and also during withdrawal. In some cases, substance-induced psychiatric disorders can persist long after detoxification, such as prolonged psychosis or depression after amphetamine or cocaine abuse. A protracted withdrawal syndrome can also occur with symptoms persisting for months after cessation of use. Benzodiazepines are the most notable drug for inducing prolonged withdrawal effects with symptoms sometimes persisting for years after cessation of use. Both alcohol, barbiturate as well as benzodiazepine withdrawal can potentially be fatal. Abuse of hallucinogens, although extremely unlikely, may in some individuals trigger delusional and other psychotic phenomena long after cessation of use. This is mainly a risk with deliriants, and most unlikely with psychedelics and dissociatives.
Cannabis may trigger panic attacks during intoxication and with continued use, it may cause a state similar to dysthymia. Researchers have found that daily cannabis use and the use of or low-potency indoor grown cannabis are independently associated with a higher chance of developing schizophrenia and other psychotic disorders.
Severe anxiety and depression are often induced by sustained alcohol abuse. Even sustained moderate alcohol use may increase anxiety and depression levels in some individuals. In most cases, these drug-induced psychiatric disorders fade away with prolonged abstinence. Similarly, although substance abuse induces many changes to the brain, there is evidence that many of these alterations are reversed following periods of prolonged abstinence.
=== Impulsivity ===
Impulsivity is characterized by actions based on sudden desires, whims, or inclinations rather than careful thought. Individuals with substance abuse have higher levels of impulsivity, and individuals who use multiple drugs tend to be more impulsive. A number of studies using the Iowa gambling task as a measure for impulsive behavior found that drug using populations made more risky choices compared to healthy controls. There is a hypothesis that the loss of impulse control may be due to impaired inhibitory control resulting from drug induced changes that take place in the frontal cortex. The neurodevelopmental and hormonal changes that happen during adolescence may modulate impulse control that could possibly lead to the experimentation with drugs and may lead to addiction. Impulsivity is thought to be a facet trait in the neuroticism personality domain (overindulgence/negative urgency) which is prospectively associated with the development of substance abuse.
== Screening and assessment ==
The screening and assessment process of substance use behavior is important for the diagnosis and treatment of substance use disorders. Screeners is the process of identifying individuals who have or may be at risk for a substance use disorder and are usually brief to administer. Assessments are used to clarify the nature of the substance use behavior to help determine appropriate treatment. Assessments usually require specialized skills, and are longer to administer than screeners.
Given that addiction manifests in structural changes to the brain, it is possible that non-invasive magnetic resonance imaging could help diagnose addiction in the future.
=== Targeted assessments ===
There are several different screening tools that have been validated for use with adolescents such as the CRAFFT Screening Test and in adults the CAGE questionnaire. Some recommendations for screening tools for substance misuse in pregnancy include that they take less than 10 minutes, should be used routinely, include an educational component. Tools suitable for pregnant women include i.a. 4Ps, T-ACE, TWEAK, TQDH (Ten-Question Drinking History), and AUDIT.
== Treatment ==
=== Psychological ===
From the applied behavior analysis literature, behavioral psychology, and from randomized clinical trials, several evidenced based interventions have emerged: behavioral marital therapy, motivational Interviewing, community reinforcement approach, exposure therapy, contingency management They help suppress cravings and mental anxiety, improve focus on treatment and new learning behavioral skills, ease withdrawal symptoms and reduce the chances of relapse.
In children and adolescents, cognitive behavioral therapy (CBT) and family therapy currently has the most research evidence for the treatment of substance abuse problems. Well-established studies also include ecological family-based treatment and group CBT. These treatments can be administered in a variety of different formats, each of which has varying levels of research support Research has shown that what makes group CBT most effective is that it promotes the development of social skills, developmentally appropriate emotional regulatory skills and other interpersonal skills. A few integrated treatment models, which combines parts from various types of treatment, have also been seen as both well-established or probably effective. A study on maternal alcohol and other drug use has shown that integrated treatment programs have produced significant results, resulting in higher negative results on toxicology screens. Additionally, brief school-based interventions have been found to be effective in reducing adolescent alcohol and cannabis use and abuse. Motivational interviewing can also be effective in treating substance use disorder in adolescents.
Alcoholics Anonymous and Narcotics Anonymous are widely known self-help organizations in which members support each other abstain from substances. Social skills are significantly impaired in people with alcoholism due to the neurotoxic effects of alcohol on the brain, especially the prefrontal cortex area of the brain. It has been suggested that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious, including managing the social environment.
=== Medication ===
A number of medications have been approved for the treatment of substance abuse. These include replacement therapies such as buprenorphine and methadone as well as antagonist medications like disulfiram and naltrexone in either short acting, or the newer long acting form. Several other medications, often ones originally used in other contexts, have also been shown to be effective including bupropion and modafinil. Methadone and buprenorphine are sometimes used to treat opiate addiction. These drugs are used as substitutes for other opioids and still cause withdrawal symptoms but they facilitate the tapering off process in a controlled fashion. When a person goes from using fentanyl every day, to not using it at all, they will experience a point where they need to get used to not using the substance. This is called withdrawal.
Antipsychotic medications have not been found to be useful. Acamprostate is a glutamatergic NMDA antagonist, which helps with alcohol withdrawal symptoms because alcohol withdrawal is associated with a hyperglutamatergic system.
=== Heroin-assisted treatment ===
Three countries in Europe have active HAT programs, namely England, the Netherlands and Switzerland. Despite critical voices by conservative think-tanks with regard to these harm-reduction strategies, significant progress in the reduction of drug-related deaths has been achieved in those countries. For example, the US, devoid of such measures, has seen large increases in drug-related deaths since 2000 (mostly related to heroin use), while Switzerland has seen large decreases. In 2018, approximately 60,000 people have died of drug overdoses in America, while in the same time period, Switzerland's drug deaths were at 260. Relative to the population of these countries, the US has 10 times more drug-related deaths compared to the Swiss Confederation, which in effect illustrates the efficacy of HAT to reduce fatal outcomes in opiate/opioid addiction.
=== Dual diagnosis ===
It is common for individuals with drugs use disorder to have other psychological problems. The terms "dual diagnosis" or "co-occurring disorders", refer to having a mental health and substance use disorder at the same time. According to the British Association for Psychopharmacology (BAP), "symptoms of psychiatric disorders such as depression, anxiety and psychosis are the rule rather than the exception in patients misusing drugs and/or alcohol."
Individuals who have a comorbid psychological disorder often have a poor prognosis if either disorder is untreated. Historically most individuals with dual diagnosis either received treatment only for one of their disorders or they did not receive any treatment all. However, since the 1980s, there has been a push towards integrating mental health and addiction treatment. In this method, neither condition is considered primary and both are treated simultaneously by the same provider.
== Epidemiology ==
The initiation of drug use including alcohol is most likely to occur during adolescence, and some experimentation with substances by older adolescents is common. For example, results from 2010 Monitoring the Future survey, a nationwide study on rates of substance use in the United States, show that 48.2% of 12th graders report having used an illicit drug at some point in their lives. In the 30 days prior to the survey, 41.2% of 12th graders had consumed alcohol and 19.2% of 12th graders had smoked tobacco cigarettes. In 2009 in the United States about 21% of high school students have taken prescription drugs without a prescription. And earlier in 2002, the World Health Organization estimated that around 140 million people were alcohol dependent and another 400 million with alcohol-related problems.
Studies have shown that the large majority of adolescents will phase out of drug use before it becomes problematic. Thus, although rates of overall use are high, the percentage of adolescents who meet criteria for substance abuse is significantly lower (close to 5%). According UN estimates, there are "more than 50 million regular users of morphine diacetate (heroin), cocaine and synthetic drugs".
More than 70,200 Americans died from drug overdoses in 2017. Among these, the sharpest increase occurred among deaths related to fentanyl and synthetic opioids (28,466 deaths). See charts below.
== History ==
=== APA, AMA, and NCDA ===
In 1966, the American Medical Association's Committee on Alcoholism and Addiction defined abuse of stimulants (amphetamines, primarily) in terms of 'medical supervision':
...'use' refers to the proper place of stimulants in medical practice; 'misuse' applies to the physician's role in initiating a potentially dangerous course of therapy; and 'abuse' refers to self-administration of these drugs without medical supervision and particularly in large doses that may lead to psychological dependency, tolerance and abnormal behavior.
In 1972, the American Psychiatric Association created a definition that used legality, social acceptability, and cultural familiarity as qualifying factors:
...as a general rule, we reserve the term drug abuse to apply to the illegal, nonmedical use of a limited number of substances, most of them drugs, which have properties of altering the mental state in ways that are considered by social norms and defined by statute to be inappropriate, undesirable, harmful, threatening, or, at minimum, culture-alien.
In 1973, the National Commission on Marijuana and Drug Abuse stated:
...drug abuse may refer to any type of drug or chemical without regard to its pharmacologic actions. It is an eclectic concept having only one uniform connotation: societal disapproval. ... The Commission believes that the term drug abuse must be deleted from official pronouncements and public policy dialogue. The term has no functional utility and has become no more than an arbitrary codeword for that drug use which is presently considered wrong.
=== DSM ===
The first edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (published in 1952) grouped alcohol and other drug abuse under "sociopathic personality disturbances", which were thought to be symptoms of deeper psychological disorders or moral weakness. The third edition, published in 1980, was the first to recognize substance abuse (including drug abuse) and substance dependence as conditions separate from substance abuse alone, bringing in social and cultural factors. The definition of dependence emphasised tolerance to drugs, and withdrawal from them as key components to diagnosis, whereas abuse was defined as "problematic use with social or occupational impairment" but without withdrawal or tolerance.
In 1987, the DSM-IIIR category "psychoactive substance abuse", which includes former concepts of drug abuse is defined as "a maladaptive pattern of use indicated by...continued use despite knowledge of having a persistent or recurrent social, occupational, psychological or physical problem that is caused or exacerbated by the use (or by) recurrent use in situations in which it is physically hazardous". It is a residual category, with dependence taking precedence when applicable. It was the first definition to give equal weight to behavioural and physiological factors in diagnosis. By 1988, the DSM-IV defined substance dependence as "a syndrome involving compulsive use, with or without tolerance and withdrawal"; whereas substance abuse is "problematic use without compulsive use, significant tolerance, or withdrawal". Substance abuse can be harmful to health and may even be deadly in certain scenarios. By 1994, the fourth edition of the DSM issued by the American Psychiatric Association, the DSM-IV-TR, defined substance dependence as "when an individual persists in use of alcohol or other drugs despite problems related to use of the substance, substance dependence may be diagnosed", along with criteria for the diagnosis.
The DSM-IV-TR defines substance abuse as:
A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:
Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions or expulsions from school; neglect of children or household)
Recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)
Recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct)
Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights)
the symptoms have never met the criteria for substance dependence for this class of substance
The fifth edition of the DSM (DSM-5), was released in 2013, and it revisited this terminology. The principal change was a transition from the abuse-dependence terminology. In the DSM-IV era, abuse was seen as an early form or less hazardous form of the disease characterized with the dependence criteria. However, the APA's dependence term does not mean that physiologic dependence is present but rather means that a disease state is present, one that most would likely refer to as an addicted state. Many involved recognize that the terminology has often led to confusion, both within the medical community and with the general public. The American Psychiatric Association requested input as to how the terminology of this illness should be altered as it moves forward with DSM-5 discussions. In the DSM-5, substance abuse and substance dependence have been merged into the category of substance use disorders and they no longer exist as individual concepts. While substance abuse and dependence were either present or not, substance use disorder has three levels of severity: mild, moderate and severe.
== Society and culture ==
=== Legal approaches ===
Related articles: Drug control law, Prohibition (drugs), Arguments for and against drug prohibition, Harm reduction
Most governments have designed legislation to criminalize certain types of drug use. These drugs are often called "illegal drugs" but generally what is illegal is their unlicensed production, distribution, and possession. These drugs are also called "controlled substances". Even for simple possession, legal punishment can be quite severe (including the death penalty in some countries). Laws vary across countries, and even within them, and have fluctuated widely throughout history.
Attempts by government-sponsored drug control policy to interdict drug supply and eliminate drug abuse have been largely unsuccessful. In spite of the huge efforts by the U.S., drug supply and purity has reached an all-time high, with the vast majority of resources spent on interdiction and law enforcement instead of public health. In the United States, the number of nonviolent drug offenders in prison exceeds by 100,000 the total incarcerated population in the EU, despite the fact that the EU has 100 million more citizens.
Despite drug legislation (or perhaps because of it), large, organized criminal drug cartels operate worldwide. Advocates of decriminalization argue that drug prohibition makes drug dealing a lucrative business, leading to much of the associated criminal activity.
Some states in the U.S., as of late, have focused on facilitating safe use as opposed to eradicating it. For example, as of 2022, New Jersey has made the effort to expand needle exchange programs throughout the state, passing a bill through legislature that gives control over decisions regarding these types of programs to the state's department of health. This state level bill is not only significant for New Jersey, as it could be used as a model for other states to possibly follow as well. This bill is partly a reaction to the issues occurring at local level city governments within the state of New Jersey as of late. One example of this is in the Atlantic City Government which came under lawsuit after they halted the enactment of said programs within their city. This suit came a year before the passing of this bill, stemming from a local level decision to shut down related operations in Atlantic City made in July that same year. This lawsuit highlights the feelings of New Jersey residents, who had a great influence on this bill passing the legislature. These feelings were demonstrated in front of Atlantic City City hall, where residents exclaimed their desire for these programs. All in all, the aforementioned bill was signed effectively into law just days after it passed legislature, by New Jersey Governor Phil Murphy.
=== Cost ===
Policymakers try to understand the relative costs of drug-related interventions. An appropriate drug policy relies on the assessment of drug-related public expenditure based on a classification system where costs are properly identified.
Labelled drug-related expenditures are defined as the direct planned spending that reflects the voluntary engagement of the state in the field of illicit drugs. Direct public expenditures explicitly labeled as drug-related can be easily traced back by exhaustively reviewing official accountancy documents such as national budgets and year-end reports. Unlabelled expenditure refers to unplanned spending and is estimated through modeling techniques, based on a top-down budgetary procedure. Starting from overall aggregated expenditures, this procedure estimates the proportion causally attributable to substance abuse (Unlabelled Drug-related Expenditure = Overall Expenditure × Attributable Proportion). For example, to estimate the prison drug-related expenditures in a given country, two elements would be necessary: the overall prison expenditures in the country for a given period, and the attributable proportion of inmates due to drug-related issues. The product of the two will give a rough estimate that can be compared across different countries.
==== Europe ====
As part of the reporting exercise corresponding to 2005, the European Monitoring Centre for Drugs and Drug Addiction's network of national focal points set up in the 27 European Union (EU) the member states, Norway, and the candidates' countries to the EU, were requested to identify labeled drug-related public expenditure, at the national level.
This was reported by 10 countries categorized according to the functions of government, amounting to a total of EUR 2.17 billion. Overall, the highest proportion of this total came within the government functions of health (66%) (e.g. medical services), and public order and safety (POS) (20%) (e.g. police services, law courts, prisons). By country, the average share of GDP was 0.023% for health, and 0.013% for POS. However, these shares varied considerably across countries, ranging from 0.00033% in Slovakia, up to 0.053% of GDP in Ireland in the case of health, and from 0.003% in Portugal, to 0.02% in the UK, in the case of POS; almost a 161-fold difference between the highest and the lowest countries for health, and a six-fold difference for POS.
To respond to these findings and to make a comprehensive assessment of drug-related public expenditure across countries, this study compared health and POS spending and GDP in the 10 reporting countries. Results suggest GDP to be a major determinant of the health and POS drug-related public expenditures of a country. Labeled drug-related public expenditure showed a positive association with the GDP across the countries considered: r = 0.81 in the case of health, and r = 0.91 for POS. The percentage change in health and POS expenditures due to a one percent increase in GDP (the income elasticity of demand) was estimated to be 1.78% and 1.23% respectively.
Being highly income elastic, health and POS expenditures can be considered luxury goods; as a nation becomes wealthier it openly spends proportionately more on drug-related health and public order and safety interventions.
==== United Kingdom ====
The UK Home Office estimated that the social and economic cost of drug abuse to the UK economy in terms of crime, absenteeism and sickness is in excess of £20 billion a year.
However, the UK Home Office does not estimate what portion of those crimes are unintended consequences of drug prohibition (crimes to sustain expensive drug consumption, risky production and dangerous distribution), nor what is the cost of enforcement. Those aspects are necessary for a full analysis of the economics of prohibition.
==== United States ====
These figures represent overall economic costs, which can be divided in three major components: health costs, productivity losses and non-health direct expenditures.
Health-related costs were projected to total $16 billion in 2002.
Productivity losses were estimated at $128.6 billion. In contrast to the other costs of drug abuse (which involve direct expenditures for goods and services), this value reflects a loss of potential resources: work in the labor market and in household production that was never performed, but could reasonably be expected to have been performed absent the impact of drug abuse.
Included are estimated productivity losses due to premature death ($24.6 billion), drug abuse-related illness ($33.4 billion), incarceration ($39.0 billion), crime careers ($27.6 billion) and productivity losses of victims of crime ($1.8 billion).
The non-health direct expenditures primarily concern costs associated with the criminal justice system and crime victim costs, but also include a modest level of expenses for administration of the social welfare system. The total for 2002 was estimated at $36.4 billion. The largest detailed component of these costs is for state and federal corrections at $14.2 billion, which is primarily for the operation of prisons. Another $9.8 billion was spent on state and local police protection, followed by $6.2 billion for federal supply reduction initiatives.
According to a report from the Agency for Healthcare Research and Quality (AHRQ), Medicaid was billed for a significantly higher number of hospitals stays for opioid drug overuse than Medicare or private insurance in 1993. By 2012, the differences were diminished. Over the same time, Medicare had the most rapid growth in number of hospital stays.
Canada
Substance abuse takes a financial toll on Canada's hospitals and the country as a whole. In the year 2011, around $267 million of hospital services were attributed to dealing with substance abuse problems. The majority of these hospital costs in 2011 were related to issues with alcohol. Additionally, in 2014, Canada also allocated almost $45 million towards battling prescription drug abuse, extending into the year 2019. Most of the financial decisions made on substance abuse in Canada can be attributed to the research conducted by the Canadian Centre on Substance Abuse (CCSA) which conduct both extensive and specific reports. In fact, the CCSA is heavily responsible for identifying Canada's heavy issues with substance abuse. Some examples of reports by the CCSA include a 2013 report on drug use during pregnancy and a 2015 report on adolescents' use of cannabis.
== Special populations ==
=== Immigrants and refugees ===
Immigrant and refugees have often been under great stress, physical trauma and depression and anxiety due to separation from loved ones often characterize the pre-migration and transit phases, followed by "cultural dissonance", language barriers, racism, discrimination, economic adversity, overcrowding, social isolation, and loss of status and difficulty obtaining work and fears of deportation are common. Refugees frequently experience concerns about the health and safety of loved ones left behind and uncertainty regarding the possibility of returning to their country of origin. For some, substance abuse functions as a coping mechanism to attempt to deal with these stressors.
Immigrants and refugees may bring the substance use and abuse patterns and behaviors of their country of origin, or adopt the attitudes, behaviors, and norms regarding substance use and abuse that exist within the dominant culture into which they are entering.
Another factor that can contribute to substance abuse among immigrants is the lack of support that they receive. With few social and economic resources available to them, some turn to drugs as a way to cope through the stress that they are experiencing. When examining an assimilation model it can be concluded that as immigrants settle into their new environment and adapt to the new culture they are in, the amount as which they use begins to match those of their new environment. So in some cases, the amount in which one uses decreases as they adapt to their new society.
=== Street children ===
Street children in many developing countries are a high-risk group for substance misuse, in particular solvent abuse. Drawing on research in Kenya, Cottrell-Boyce argues that "drug use amongst street children is primarily functional—dulling the senses against the hardships of life on the street—but can also provide a link to the support structure of the 'street family' peer group as a potent symbol of shared experience."
=== Musicians ===
In order to maintain high-quality performance, some musicians take chemical substances. Some musicians take drugs such as alcohol to deal with the stress of performing. As a group they have a higher rate of substance abuse. The most common chemical substance which is abused by pop musicians is cocaine, because of its neurological effects. Stimulants like cocaine increase alertness and cause feelings of euphoria, and can therefore make the performer feel as though they in some ways 'own the stage'. One way in which substance abuse is harmful for a performer (musicians especially) is if the substance being abused is aspirated. The lungs are an important organ used by singers, and addiction to cigarettes may seriously harm the quality of their performance. Smoking harms the alveoli, which are responsible for absorbing oxygen.
=== Veterans ===
Substance abuse can be a factor that affects the physical and mental health of veterans. Substance abuse may also harm personal and familial relationships, leading to financial difficulty. There is evidence to suggest that substance abuse disproportionately affects the homeless veteran population. A 2015 Florida study, which compared causes of homelessness between veterans and non-veteran populations in a self-reporting questionnaire, found that 17.8% of the homeless veteran participants attributed their homelessness to alcohol and other drug-related problems compared to just 3.7% of the non-veteran homeless group.
A 2003 study found that homelessness was correlated with access to support from family/friends and services. However, this correlation was not true when comparing homeless participants who had a current substance-use disorders. The U.S. Department of Veterans Affairs provides a summary of treatment options for veterans with substance-use disorder. For treatments that do not involve medication, they offer therapeutic options that focus on finding outside support groups and "looking at how substance use problems may relate to other problems such as PTSD and depression".
=== Sex and gender ===
There are many sex differences in substance abuse. Men and women express differences in the short- and long-term effects of substance abuse. These differences can be credited to sexual dimorphisms in the brain, endocrine and metabolic systems. Social and environmental factors that tend to disproportionately affect women, such as child and elder care and the risk of exposure to violence, are also factors in the gender differences in substance abuse. Women report having greater impairment in areas such as employment, family and social functioning when abusing substances but have a similar response to treatment. Co-occurring psychiatric disorders are more common among women than men who abuse substances; women more frequently use substances to reduce the negative effects of these co-occurring disorders. Substance abuse puts both men and women at higher risk for perpetration and victimization of sexual violence. Men tend to take drugs for the first time to be part of a group and fit in more so than women. At first interaction, women may experience more pleasure from drugs than men do. Women tend to progress more rapidly from first experience to addiction than men. Physicians, psychiatrists and social workers have believed for decades that women escalate alcohol use more rapidly once they start. Once the addictive behavior is established for women they stabilize at higher doses of drugs than males do. When withdrawing from smoking women experience greater stress response. Males experience greater symptoms when withdrawing from alcohol. There are gender differences when it comes to rehabilitation and relapse rates. For alcohol, relapse rates were very similar for men and women. For women, marriage and marital stress were risk factors for alcohol relapse. For men, being married lowered the risk of relapse. This difference may be a result of gendered differences in excessive drinking. Alcoholic women are much more likely to be married to partners that drink excessively than are alcoholic men. As a result of this, men may be protected from relapse by marriage while women are at higher risk when married. However, women are less likely than men to experience relapse to substance use. When men experience a relapse to substance use, they more than likely had a positive experience prior to the relapse. On the other hand, when women relapse to substance use, they were more than likely affected by negative circumstances or interpersonal problems.
== See also ==
== References ==
People overdose drugs to try to forget their problems at home, and some use them for fun because they saw people using drugs at television advertising them.
== External links ==
"The Science of Drug Use: A Resource for the Justice Sector". North Bethesda, Maryland: National Institute on Drug Abuse. 26 May 2020. Archived from the original on 1 September 2022. Retrieved 23 December 2021.
School-Based Drug Abuse Prevention: Promising and Successful Programs (PDF). Ottawa, Ontario: Public Safety Canada. 31 January 2018. ISBN 978-1-100-12181-9. Archived (PDF) from the original on 19 May 2021. Retrieved 23 December 2021.
Adverse Childhood Experiences: Risk Factors for Substance Misuse and Mental Health. 6 March 2013. Archived from the original on 29 June 2019 – via YouTube. Dr. Robert Anda of the U.S. Centers for Disease Control describes the relation between childhood adversity and later ill-health, including substance abuse (video) | Wikipedia/Drug_abuse |
In drug development and production, good clinical practice (GCP) is an international quality standard, which governments can then transpose into regulations for clinical trials involving human subjects. GCP follows the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and enforces tight guidelines on ethical aspects of clinical research.
High standards are required in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities, including computers and software. Quality assurance and inspections ensure that these standards are achieved. GCP aims to ensure that the studies are scientifically authentic and that the clinical properties of the investigational product are properly documented.
GCP guidelines include protection of human rights for the subjects and volunteers in a clinical trial. It also provides assurance of the safety and efficacy of the newly developed compounds. GCP guidelines include standards on how clinical trials should be conducted, define the roles and responsibilities of institutional review boards, clinical research investigators, clinical trial sponsors, and monitors. In the pharmaceutical industry monitors are often called clinical research associates.
A series of unsuccessful and ineffective clinical trials in the past were the main reason for the creation of ICH and GCP guidelines in the US and Europe. These discussions ultimately led to the development of certain regulations and guidelines, which evolved into the code of practice for international consistency of quality research.
== History ==
ICH first published the GCP guidelines in 1996 under the "E6" category and was last amended in 2016.
== Legal and regulatory status ==
European Union: In the EU, Good Clinical Practice is backed and regulated by formal legislation contained in the Clinical Trial Regulation (Officially Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC). A similar guideline for clinical trials of medical devices is the international standard ISO 14155, which is valid in the European Union as a harmonized standard. These standards for clinical trials are sometimes referred to as ICH-GCP or ISO-GCP to differentiate between the two and the lowest grade of recommendation in clinical guidelines.
United States: Although ICH GCP guidelines are recommended by the Food and Drug Administration (FDA), they are not statutory in the United States. The National Institutes of Health requires NIH-funded clinical investigators and clinical trial staff who are involved in the design, conduct, oversight, or management of clinical trials to be trained in Good Clinical Practice.
== ICH GCP overview ==
Glossary
Principles of ICH GCP
Guidelines for:
institutional review board (IRB) / independent ethics committee (IEC)
investigator
trial sponsor (industrial, academic)
clinical trial protocol and protocol amendments
investigator's brochure
essential documents
== Criticism ==
GCP has been called 'a less morally authoritative document' than the Declaration of Helsinki, lacking moral principles and guidance in the following areas:
Disclosure of conflict of interest
Public disclosure of study design
Benefit for populations in which research is conducted
Reporting of accurate results and publication of negative findings
Access to treatment after research has been conducted
Restriction of use of placebo in control group where effective alternative treatment is available
In the book Bad Pharma, Ben Goldacre mentions these criticisms and notes that the GCP rules "aren't terrible... [they are] more focused on procedures, while Helsinki clearly articulates moral principles".
== See also ==
== References ==
== External links ==
ICH Topic E 6 (R2)
Good Clinical Practice (from U.S. Food and Drug Administration) | Wikipedia/Good_clinical_practice |
A Clinical Research Coordinator (CRC) is a person responsible for conducting clinical trials using good clinical practice (GCP) under the auspices of a Principal Investigator (PI).
Good clinical practices principles have been defined by Madelene Ottosen, RN, MSN, of The University of Texas Health Science Center at Houston as:
Trials are conducted ethically, as defined by the Declaration of Helsinki, rigorously, as defined by the International Conference on Harmonization Guidelines (ICH).
Benefits outweigh risks for each patient.
Rights, safety and well-being of patients prevail over science.
All available non-clinical and clinical information on any investigational agent can support the trial as designed.
All trials are scientifically sound and clearly described.
All clinical trials have current Institutional Review Board approval.
Medical decisions and care are the responsibility of qualified health care professionals, specifically physicians and, if applicable, dentists.
Everyone involved in the clinical trial is qualified by training, education and experience.
Informed consent is given freely by every participant.
All study documentation is recorded, handled and stored to allow accurate reporting, interpretation and verification.
Confidentiality of subjects is respected and protected.
Investigational products maintain Good Manufacturing Practice in storage, manufacturing and handling.
Systems to ensure quality are implemented in all aspects of the trial.
The PI is responsible for the conduct of the trial, however, "CRCs are often involved in essential duties that have been traditionally performed by the PI, such as conducting the informed consent process and ensuring compliance with the protocol." The CRC's primary responsibility, as with all clinical research professionals, is the protection of human subjects, but the CRC has many other responsibilities. Although not inclusive, some of the CRC responsibilities include preparing the Institutional Review Board submission, writing the informed consent document, working with the institutional official in contract negotiations, developing a detailed cost analysis, negotiating the budget with the Sponsor (i.e., pharmaceutical company or granting agency), subject recruitment, patient care, adverse event reporting, preparing the case report form (CRF), submitting CRFs and other data to the Sponsor as necessary and study close-out.
== Responsibilities ==
=== Feasibility ===
A sponsor sends a feasibility questionnaire to the local research site. The Clinical Research Coordinator completes the form on behalf of the site to determine if the local site has the patient population, support staff, medical facilities, and equipment necessary to successfully carry out the study protocol.
=== Institutional Review Board submissions ===
All research involving human subjects must be approved by an Institutional Review Board (IRB). Each IRB has protocol submission requirements, which typically involve an IRB application and informed consent document. A study cannot begin without IRB approval.
=== Informed consent ===
The IRB must approve informed consent prior to study initiation, and often the CRC is liaison between the IRB and the sponsor. The sponsor sets informed consent requirements, as does the IRB. Each local IRB must review and approve the informed consent, but the CRC is responsible for communication between the IRB and the sponsor. §46.116 of the Code of Federal Regulations outlines the basic elements of informed consent as a:
Statement that the study involves research, an explanation of research purpose, expected duration of subject's participation, description of procedures, and identification of any experimental procedures
Description of any reasonably foreseeable risk or discomfort to the subject
Description of any benefits to the subject or others that can reasonably be expected
Disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject
Statement that describes extent, if any, to which confidentiality subject identity is maintained
Explanation (if more than minimal risk to test subject) as to any compensation, medical treatments available if injury occurs and, or where further information is available
List of whom to contact for pertinent questions about the research and subjects' rights, and whom to contact in the event of a research-related injury to the subject
Statement that participation is voluntary, refusal to participate involves no penalty or loss of benefits, and that the subject may discontinue participation at any time without penalty or loss of benefits
==== Additional elements ====
When appropriate, experimenters also tell each subject:
That the particular treatment or procedure may involve unforeseeable risks to the subject (or to an embryo or fetus, if relevant)
Circumstances under which investigator may end subject's participation without subject's consent
Additional costs to the subject that may result from participation in the research
Consequences of subject withdrawing from the research, and procedures for orderly termination of subject participation
That significant new findings during the research that could affect the subject's willingness to continue participation will be provided to the subject
The approximate number of subjects involved in the study
=== Contracting with pharmaceutical companies ===
The site conducting the clinical trial negotiates the clinical trial agreement (CTA) to conform to its policies and procedures. The resolution of many contractual issues requires coordination between the sponsor, the PI and the site, which is usually the responsibility of the CRC. The involvement of each party is essential to a successful CTA with mutually acceptable terms. The CTA should include terms for indemnification, confidentiality, publication, intellectual property, insurance, data safety and monitoring boards, subject injury, governing law and termination clauses.
=== Cost analysis and budget negotiations ===
To develop a cost analysis, the CRC reviews the protocol schema and determine which procedures are standard of care, versus research. Research charges are included in the budget—with personnel effort, site initiation costs, IRB fees throughout the life of the clinical trial, pharmacy costs, travel costs for the PI and CRC to attend investigator meetings, equipment, dedicated fax and computer lines, supplies, screen failures, subject stipends, subject travel costs, and any other items defined as a direct cost to the clinical trial. In addition, if the clinical trial is at an Academic Medical Center (AMC), an indirect cost rate applies to the direct study costs. The indirect rate is approximately 30% for pharmaceutical trials, and can be upwards of 50% for federal trials, depending on the AMC's federally negotiated indirect costs rate.
=== Subject recruitment ===
Prior to agreeing to conduct the clinical trial, the CRC (and the PI) determine if they have the appropriate patient population. The CRC is responsible for subject recruitment once the trial begins, or must establish the research team that recruits subjects. Viable subject recruitment must occur beforehand, as the clinical trial agreement stipulates the number of subjects the site must recruit.
=== Patient care ===
The CRC coordinates and conduct patient care visits and assures that all procedures comply with the protocol. The CRC interacts with the PI to assure the patient receives appropriate medical evaluation and care when needed and alerts the PI of any serious adverse events that occur during the study.
=== Adverse events ===
An adverse event is described as "any adverse change in health or "side-effect" that occurs in a person who participates in a clinical trial while the patient is receiving the treatment (study medication, application of the study device, etc.) or within a pre-specified period of time after their treatment has been completed." The CRC must report all adverse events to the sponsor and all serious adverse events to the IRB and sponsor.
=== Case report forms ===
The purpose of the case report form (CRF) is to collect relevant data in accordance with the protocol and in compliance with regulatory requirements. The CRC collects the data on the CRF and submit to the sponsor either electronically or paper format.
=== Electronic Data Capture ===
The electronic data capture (EDC) is an online database where the information collected on the Case Report forms (CRF), or source documents is entered. These are usually created by the study sponsor or their subcontractors.
=== Processing and shipping of laboratory samples ===
Many Clinical Trials and non-clinical research studies use laboratory assessments/samples to assess patient response and or Adverse Events. The CRC is frequently responsible for the basic laboratory preparation of labs samples such as making hematology slides, spinning and aliquoting blood samples or placing tissue in formalin or flash freezing. These blood or tissue samples may be analyzed locally or sent to central laboratories for processing and analysis. The CRC must abide by The International Air and Transportation Association regulations (IATA) for biologic sample shipments.
=== Study close ===
In accordance with the local IRB, the CRC completes IRB study close documentation and appropriately notifies study subjects, research team, and pharmacies. The CRC works with the sponsor's clinical monitor to complete outstanding monitoring findings and queries. In addition, the CRC must comply with record retention policies of the Food and Drug Administration (FDA), the ICH, and the clinical trial agreement.
== See also ==
Adverse event
Case report forms
Clinical investigator
Clinical Research Associate
Clinical monitoring
Clinical trial
Clinical trial protocol
Data monitoring committees
Declaration of Helsinki
Electronic Data Capture
Food and Drug Administration
Good clinical practice
Good manufacturing practice
Informed consent
Institutional Review Board
Medical research
New investigator
Nurses
Principal investigator
== References ==
== External links ==
Association of Clinical Research Professionals
Certified Clinical Research Professionals Society
Code of Federal Regulation §46.116 General Requirements for Informed Consent
Clinical Research Association of Canada
Clinical Research Resources (Organizations, Services, Training)
Good Clinical Practice in FDA Regulated Clinical Trials
Indirect Cost Overview
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
Italian Clinical Research Coordinators Association
OHRP Institutional Review Board Guidebook
Society of Clinical Research Associates
United States Department of Health and Human Services, Office for Human Subjects Protections (OHRP) | Wikipedia/Clinical_research_coordinator |
DrugScope was a British-based charity. The organisation was for those working in the drugs field and its aim was to inform the public about drugs, shape policy and reduce drug-related harms. It closed on 31 March 2015.
== History ==
DrugScope was formed in the year 2000 from the merger of the Institute for the Study of Drug Dependence (ISDD) and the Standing Conference on Drug Abuse (SCODA).
The charity provided information on drugs and drug use, maintaining a searchable database of over 100,000 books and journals, an online directory of treatment and other drugs services in England and Wales, a daily subscription drug and alcohol news service, and with representatives regularly in the media contributing to articles about drugs.
It published a bi-monthly magazine called Druglink, geared at those working or studying in the drugs field. It also produced a website for Key Stage 3 children (aged 11 to 14) called D-World.
== See also ==
Drug Equality Alliance
Transform Drug Policy Foundation
== References == | Wikipedia/DrugScope |
The Veterinary Medicines Directorate (VMD) is an Executive Agency of the Department for Environment, Food and Rural Affairs (Defra) seeking to protect public health, animal health, the environment and promoting animal welfare by assuring the safety, quality and efficacy of veterinary medicines in the United Kingdom.
== Responsibilities ==
The VMD is responsible for:
the assessment, issue and maintenance of all national Marketing Authorisations for veterinary medicines in accordance with European Community and UK legislation;
acting as rapporteur/co-rapporteur or reference member state/concerned member state for designated European applications for centralised or decentralised authorisations;
controls on the manufacture and distribution of veterinary medicinal products including inspections;
pharmacovigilance through the surveillance of suspected adverse reactions (SARs), through the Suspected Adverse Reaction Surveillance Scheme (SARSS) - veterinary surgeons fill in form VLM252A;
surveillance for residues of veterinary medicines in animals and animal products;
the provision and implementation of policy advice on these matters to the Health and Agriculture Ministers who jointly form the Licensing Authority for veterinary medicines under the Medicines Act 1968;
the management of the Research & Development (R&D) programme linked to veterinary medicine issues; and
the co-ordination of Defra’s work in the area of antimicrobial resistance via the DARC Group, including development of a Government Veterinary Antimicrobial Resistance Surveillance Strategy.
== History ==
VMD was first established in 1989 and from 1990 was a Next Steps Agency of the Ministry of Agriculture, Fisheries and Food (MAFF). It became an Executive Agency of Defra on 7 June 2001.
== Work of VMD ==
The work of VMD is divided into three main areas, or "businesses":
Licensing – the assessment of applications; issuing and maintenance of Marketing Authorisations; pharmacovigilance for veterinary medicines; and the licensing and inspection of manufacturers and wholesale dealers of veterinary medicines – main customers are Marketing Authorisation holders; manufacturers and importers of veterinary medicines; manufacturers of medicated animal feedingstuffs; retailers of veterinary medicines and medicated animal feedingstuffs; the veterinary profession; farmers and keepers of animals; other stakeholders include the European Medicines Agency (EMEA); DH; Food Standards Agency (FSA); and consumers.
Residues – the surveillance for residues of veterinary medicines and banned substances in home produced livestock and animal products and imported animal products, reporting of results and co-ordinating follow-up action – we have contracts with other agencies and companies who carry out work on our behalf at abattoirs and other first processing industries, on farms and at retailers of meat and other animal products, and at ports. We also work with other stakeholders including consumer representative groups, the European Commission and the FSA.
Policy – servicing, developing and implementing new policy/legislation on all aspects of veterinary medicines. Providing support to Ministers through briefing and advice on replies to correspondence and Parliamentary Questions. Day-to-day management of the veterinary medicines (R&D) programme on behalf of the Policy customer (Animal Health and Welfare Directorate, Defra) – we work closely with Ministers and officials of Defra and other Government Departments and Agencies including the FSA, the general public, industry, consumer representative groups, the European Commission, embassies and other representatives of foreign governments.
== Costs ==
Operational costs are recovered through charges to the veterinary pharmaceutical industry, the food industry, and Defra.
During 2003/2004 operational costs totalled £11,960,000:
Licensing: £4,915,000 (paid for by the veterinary pharmaceutical industry)
Statutory Residues: £3,693,000 (paid for by the food industry)
Non-statutory Residues: £1,054,000 (paid for by Defra)
Policy: £2,298,000 (paid for by Defra)
== External links ==
VMD website | Wikipedia/Veterinary_Medicines_Directorate |
Cambridge Antibody Technology Group Plc, (commonly referred to as CAT) was a biotechnology company headquartered in Cambridge, England. Its core focus was on antibody therapeutics, primarily using Phage Display and Ribosome Display technology.
Phage Display Technology was used by CAT to create adalimumab, the first fully human antibody blockbuster drug. Humira, the brand name of adalimumab, is an anti-TNF antibody discovered by CAT as D2E7, then developed in the clinic and marketed by Abbvie, formerly Abbott Laboratories. CAT was also behind belimumab, the anti-BlyS antibody drug marketed as Benlysta and the first new approved drug for systemic lupus in more than 50 years. In 2018, the Nobel Prize organisation awarded one quarter of the Nobel Prize in Chemistry to a founding member of CAT, Sir Greg Winter FRS "for the phage display of peptides and antibodies".
Founded in 1989, CAT was acquired by AstraZeneca for £702m in 2006. AstraZeneca subsequently acquired MedImmune LLC, which it combined with CAT to form a global biologics R&D division called MedImmune. CAT was often described as the 'jewel in the crown' of the British biotechnology industry and during the latter years of its existence was the subject of frequent acquisition speculation.
== History ==
CAT was founded in 1989 by Dr. David Chiswell OBE and Sir Greg Winter, with major scientific contributions from Dr. John McCafferty and the Medical Research Council (UK) (MRC). Operations began at the MRC laboratories in Cambridge. In May 1990, operations moved to the Daly Research Laboratories at Babraham Institute, Cambridge.
In 1992, CAT moved to Beech House on the Melbourn Science Park to occupy units B1 and B2. In 1993 the company expanded into unit B3, into B4 into 1995, and in 1998 into units B5, B6, B8 and B9. CAT completed the occupation of Beech House by finally occupying B7 by the late 1990s.
CAT listed on the London Stock Exchange in 1997, raising £43 million, and went through a second round of funding in 2000, raising over £90 million.
In 1999, CAT expanded into a second location in Melbourn called Cambridge House. After leaving Melbourn, CAT sold this location on to housing developers in early 2006.
In 2000, after a succession of deals that focussed on harnessing the exploitation of the human genome, CAT's share price peaked at over £50 per share.
Also in 2000, CAT decided to move out of Melbourn to a science park called Granta Park, roughly 10 miles (16 km) away. Of the buildings on the park, the first to be occupied was the Franklin Building followed, in late 2002, by a move to a new corporate headquarters at the Milstein Building.
The Franklin Building, named after Rosalind Franklin, was formally opened in 2001 by David Sainsbury, Baron Sainsbury of Turville. The Milstein Building was named after César Milstein, and had a modular design with separate laboratory (46,000 sq ft) and administration blocks (21,000 sq ft). In the same year, CAT listed on the NASDAQ.
When AstraZeneca acquired CAT in June 2006, plans were announced to occupy a new building on Granta Park, GP15, offering a further 92,000 sq ft (8,500 m2). Refurbishment of this building took approximately 18 months and the building was officially opened, in November 2008, with the name Aaron Klug Building.
=== Acquisitions ===
==== Aptein Inc. ====
On 15 July 1998, CAT completed the acquisition of Aptein Inc. This acquisition "...further strengthened its world leading position in antibody display technology...giving CAT controlling patents in the field of polysome display. Polysome display involves the use of polysomes, a type of molecule responsible for protein synthesis within the human body, to display functional antibody proteins in vitro.". Three years later David Glover, CAT's Chief Medical Officer at the time, summarised the acquisition as one which essentially acquired Aptein's patent estate
"Under the terms of the agreement CAT purchased the issued share capital and outstanding share options and warrants of Aptein for a total consideration of up to $11 million satisfied by the issue of up to 2.366 million CAT shares (an implied CAT share price of 278p.) $6 million of the consideration was satisfied by the issue of 1.290 million CAT shares on closing. The balance of the consideration of up to $5 million will be satisfied by the issue of up to 1.076 million CAT shares after Aptein's European patents have been sustained through opposition or appeal. In accordance with accounting standards the cost of acquiring this new technology has been capitalised and will be written off over the lives of the patents concerned.".
Aptein was founded by Glenn Kawasaki, who is currently, amongst other positions, CEO at Accium BioSciences.
According to an article published in Nature in 2002, that focused on the automation of proteomics,..."Normally, an mRNA molecule passes through the ribosome-like ticker-tape and is released, along with the newly synthesised protein molecule, when a sequence of three bases known as a 'stop codon' is reached. In Aptein's technology, stop codons are eliminated so that the completed antibody and its mRNA remain bound together on the ribosome. The system, which CAT is now optimising, is entirely cell-free and so is more amenable to automation. This should make it possible to construct libraries that are orders of magnitude larger than those created using phage display."
CAT published on their optimisation work with Ribosome Display, including:
The discovery of tralokinumab, a therapeutic antibody against IL-13.
An improved method for eukaryotic ribosome display
A comparison of phage and ribosome display approaches for improving antibody affinity and stability showing the advantages of ribosome display
The use of ribosome display to optimise pharmacology and "developability" of therapeutic proteins
CAT used extensive data sets from ribosome display to patent protect their anti-IL-13 monoclonal antibody, CAT-354, in a world-first of sequence-activity-relationship claims.
==== Drug Royalty Corporation Inc. ====
In 1994, CAT signed a royalty deal with Drug Royalty Corporation Inc. (DRC) such that DRC would receive future royalty revenue from CAT's products.
In January 2002, CAT made a share-based offer to buy DRC for £55 million so that it could buy out this royalty obligation. CAT valued DRC at C$3.00 a share, and this offer was initially recommended by the board of directors of DRC. On 8 March 2002 the investment company Inwest made a competing offer valuing DRC at C$3.05 per share. CAT's offer would see DRC shareholders receiving CAT shares whilst Inwest's offer would see the DRC shareholder receiving cash. DRC's board of directors changed their decision and recommended Inwest's offer. After a number of deadline extensions from CAT the offer from Inwest was accepted by the DRC shareholders. Inwest purchased DRC on 2 May 2002, and the company began operating as a private entity that continues operation today as DRI Capital.
As a result of this failure to purchase DRC, CAT's right to buy back royalty interest was triggered at a cost to CAT of C$14 million (£6.2 million) by way of 463,818 CAT shares.
==== Oxford Glycosciences ====
On 23 January 2003 CAT made a share-based offer for Oxford Glycosciences (OGS) and at an Extraordinary General Meeting shareholders voted to approve the merger. In March of this year CAT saw a decline in its share price. Discussions regarding the applicability of the royalty offset provisions for HUMIRA with Abbott Laboratories had started, and these had a negative impact on the CAT share price depressing the value of CAT's offer.
On 26 February 2003 the British-based biotechnology group Celltech subsequently made a hostile £101 million cash offer for OGS and began buying OGS shares. Some reported that this activity represented the UK biotechnology industry's first-ever bidding war. Despite this improved offer from Celltech, OGS continued to recommend the CAT offer.
Celltech continued to buy OGS shares and the OGS board pressed CAT to improve the terms of its offer as the Celltech shareholding reached 10.55%. OGS became alarmed that Celltech's share purchase would prompt CAT to walk away because, under takeover rules, it would not be able to forcibly purchase the 10.55 per cent stake Celltech owned. CAT failed to improve the terms of its bid forcing OGS to abandon the agreement.
Celltech continued buying shares and, as their stake reached 25%, so the board of OGS met to reluctantly recommend the Celltech offer. Celltech completed the purchase of OGS in April 2003. Some newspapers reported that the failure of the bid by CAT would means that CAT would have to cut some of its workforce. Celltech was itself purchased by the Belgian drugmaker UCB in mid-2004.
==== Genencor ====
On 1 November 2005 CAT announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes.
GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT. Under the original
licence agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.
CAT intended to file an Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including Non-Hodgkin lymphoma and chronic lymphocytic leukaemia, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCI's ongoing development of GCR-3888 in Hairy cell leukaemia (HCL) and paediatric acute lymphoblastic leukaemia (pALL).
CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 and CAT's language such as "CAT will support the NCI's ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.
On 16 May 2013, AstraZeneca announced that CAT-8015, now Moxetumumab, has started Phase III clinical trials.
=== Collaborations ===
CAT entered into many collaborations with technology and pharmaceutical companies, including:
Searle, 1999 – CAT signed, what was at the time, their biggest deal with Searle, the pharmaceutical arm of Monsanto. In 2000, Pharmacia & Upjohn merged with Monsanto and Searle to create Pharmacia Corporation. In 2003, Pfizer acquired Pharmacia. It is unsure as to whether the deal with Searle generated any clinical candidates.
Human Genome Sciences, 2000. GlaxoSmithKline purchased HGSI in 2012. The deal with Cambridge Antibody Technology generated, amongst others;
An anti-BLyS antibody – registered by HGSI as LymphoStat-B, also known as belimumab, and subsequently branded as Benlysta. On 16 November 2010 HGSI and GlaxoSmithKline announced the vote of the FDA advisory committee to recommend approval of belimumab for systemic lupus erythematosus. On 9 March 2011 the FDA voted 11 to 2 in favour of approving Benlysta "to treat patients with active, autoantibody-positive lupus who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives, and nonsteroidal anti-inflammatory drugs".
An anthrax therapeutic antibody – registered by HGSI as ABthrax, also known as raxibacumab. At the 2 November 2012 meeting of the Anti-Infective Drugs Advisory Committee to the US Food and Drug Administration (FDA) members "voted 16 to 1 in support of the clinical benefit of raxibacumab for the treatment of inhalational anthrax, with one abstention. In addition, the committee voted 18 – 0 in favour of the risk-benefit profile of raxibacumab".
Two anti-TRAIL receptor antibodies – mapatumumab (HGS-ETR1) and lexatumumab (HGS-ETR2). Early work by CAT and HGS scientists showed that HGS-ETR1 induces cell death in certain tumour types. Following this data, HGS exercised an option to enter into an exclusive development partnership for the antibody.
Genzyme, 2000. CAT held significant strength in the area of TGF beta with two products already – lerdelimumab (CAT-152) and metelimumab (CAT-192). The deal with Genzyme was "a broad strategic alliance to develop and commercialise human monoclonal antibodies directed against TGF-beta." All clinical indications, with the exception of ophthalmic uses, were covered by the agreement.
The deal resulted in fresolimumab (GC1008), a pan-neutralizing IgG4 human antibody directed against all three isoforms of TGF beta, which had the "potential for treating a variety of diseases". In particular Genzyme are currently using fresolimumab in trials involving immunogenic tumours.
The takeover of CAT by AstraZeneca initiated a change of control clause in the 2008 agreement that gives Genzyme the right to buy out rights to a jointly developed experimental lung drug.
In February 2011, Sanofi-Aventis purchased Genzyme for approximately US$20bn.
Immunex Corp, 2000. CAT's proprietary antibody phage display library for the discovery, development and potential commercialisation of human monoclonal antibodies was licensed to Immunex, in return for a licence fee. This deal was expanded in May 2001 where CAT shared more of the risk of drug development – a so-called "profit-sharing" deal. In 2002 Immunex was acquired by Amgen and in December 2003 CAT entered into a new, restructured agreement with Amgen, reportedly focussing in skin disease. It was also reported that, under the terms of the agreement, Amgen had taken responsibility for the further development and marketing of the therapeutic antibody candidates isolated by CAT against two targets on which the parties agreed to collaborate and would bear all the associated costs. In return, CAT received from Amgen an initial fee and potential milestone payments and royalties on future sales. As of February 2004, one candidate had been delivered by CAT to Amgen. A second candidate was the subject of a continuing research program funded by Amgen and conducted by CAT and was to be delivered to Amgen in due course.
Amgen acquired the transgenic mouse company Abgenix meaning that they had access to two different methods of human monoclonal antibody production. As of July 2009, it is not known from which technology any of their monoclonal antibody products in clinical trials have been derived.
AMRAD, 2001. AMRAD subsequently changed its name to Zenyth Therapeutics and, in mid-2006, Zenyth was acquired by CSL Limited. CAT and AMRAD had gone 50:50 with the original deal over the development of an anti-GMCSF-R antibody, which became CAM-3001. After all this corporate manoeuvring, "CSL decided to license its 50% share in the project to MedImmune...MedImmune commenced Phase I clinical trials in December 2007".
== Products and pipeline ==
CAT had a number of significant products in the pipeline. These included:
Adalimumab (D2E7) – a human monoclonal antibody to tumor necrosis factor-alpha (TNF alpha). This drug went on to be developed and marketed by Abbott Laboratories as Humira®. The royalties payable on Adalimumab sales were subject to a dispute between the two companies. In 2013, Abbott split it business in half, whereby AbbVie became responsible for its research-based pharmaceutical business, and thus Humira. Humira went on to dominate the best-selling drugs lists. In 2016, the best selling drugs list researched by Genetic Engineering & Biotechnology News, published in March 2017, details that Humira occupied the number 1 position for 2015 ($14.012 billion of sales) and 2016 ($16.078 billion). Whilst for 2017, Abbvie reports that Humira achieved $18.427billion of sales in 2017
Briakinumab (ABT-874) – a human monoclonal antibody to IL-12 and IL-23. This went on to be developed by Abbott Laboratories for treatment of psoriasis and Crohn's disease. On 11 October 2010, Abbott presented positive Phase III data.
Metelimumab (CAT-192) and fresolimumab (GC1008) are human monoclonal antibodies to transforming growth factor beta 1 (TGF-β1). Initial trials targeted the skin condition scleroderma but, after some unsuccessful clinical trial results, the product was dropped in favour of fresolimumab, which was initially developed by Genzyme. In February 2011, Sanofi-Aventis purchased Genzyme for approximately US$20 billion and, as of March 2013, Sanofi continue to list fresolimumab in their research and development portfolio.
Lerdelimumab is a human monoclonal antibody to TGF beta 2, initially developed to combat fibrotic scarring that results from glaucoma drainage surgery. The drug was branded Trabio, and development was stopped in late 2005 after unsuccessful trial results.
Bertilimumab (CAT-213) is a human monoclonal antibody to eotaxin 1. In January 2007, CAT licensed the drug for treatment of allergy disorders to iCo Therapeutics Inc., who renamed it from CAT-213 to iCo-008.
Mavrilimumab (CAM-3001) – a human monoclonal igG4 antibody to the alpha chain of granulocyte macrophage colony-stimulating factor (GM-CSF Receptor). In 2007, some elements of the local press suggested this product could be the next HUMIRA. CAM-3001 is currently being developed by MedImmune in the treatment of rheumatoid arthritis, and mentioned in the rheumatology section of AstraZeneca's pipeline in their 2008 Annual Report. The first clinical trial was initiated by MedImmune in late 2007. In 2017, Kiniksa licensed Mavrilimumab from MedImmune and, in April 2021, Kiniksa outlined the next steps for development of Mavrilimumab – including in COVID-19–related acute respiratory distress syndrome (ARDS), giant cell arteritis (GCA), and rheumatoid arthritis (RA).
Tralokinumab (CAT-354, Adtralza®) – a human monoclonal antibody (IgG4) that potently and specifically neutralises interleukin 13, a T-lymphocyte-derived cytokine that plays a key role in the development and maintenance of the human asthmatic phenotype. CAT-354 was CAT's first antibody to be discovered using ribosome display, and was further developed by developed by MedImmune. Tralokinumab was licensed by AstraZeneca to LEO Pharma for skin diseases in July 2016. On 15 June 2017, Leo Pharma announced that they were starting phase 3 clinical trials with tralokinumab in atopic dermatitis. In April 2021, Leo Pharma announced that it had received positive Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) opinion of Adtralza® (tralokinumab) for the treatment of adults with moderate-to-severe atopic dermatitis. On 22 June 2021, LEO Pharma announced that the European Commission had approved "Adtralza® (tralokinumab) as the first and only treatment specifically targeting IL-13 for adults with moderate-to-severe atopic dermatitis".
Moxetumomab pasudotox (CAT-3888) – CAT-3888 (formerly GCR-3888 and BL22) and CAT-8015 (formerly GCR-8015 and HA22) are both anti-CD22 immunotoxins comprising a modified Pseudomonas exotoxin and an anti-CD22 antibody fragment. CAT acquired these two oncology product candidates in November 2005 from Genencor, a subsidiary of Danisco. CAT-8015 is being developed by MedImmune. In Sept 2018 the US FDA approved it (as Lumoxiti) for some cases of relapsed or refractory hairy cell leukemia (HCL).
CAT-5001 (formerly SS1P) – a Pseudomonas exotoxin immunotoxin that targets mesothelin, which is a cell surface glycoprotein present on normal mesothelial cells that is over-expressed in numerous cancers including pleural and peritoneal mesothelioma, ovarian cancer and pancreatic cancer. CAT-5001 was acquired from Enzon Pharmaceuticals in May 2006.
CAT developed their display technologies further into several patented antibody discovery/functional genomics tools which were named Proximol and ProAb. ProAb was announced in December 1997 and involved high throughput screening of antibody libraries against diseased and non-diseased tissue, whilst Proximol used a free radical enzymatic reaction to label molecules in proximity to a given protein.
In September 1999, it was announced that CAT's Library product and ProAb would each receive Millennium Products status. Of the 4,000 products submitted to the Design Council for these awards, 1,012 were chosen and, to attain Millennium Product status, products had to: open up new opportunities, challenge existing conventions, be environmentally responsible, demonstrate the application of new or existing technology, solve a key problem and show clear user benefits.
== Patents ==
CAT pioneered the application of Phage Display and Ribosome Display technology for the design and development of human monoclonal antibody therapeutics and which was reflected in the breadth of the company's patent portfolio. The Cambridge patent portfolio includes about 40 families of patents, covering both technologies and products.
Three main families of major patents cover Cambridge antibody library and Phage Display technology:
'Winter II' and 'Winter/Huse/Lerner' patents cover Medimmune's processes for generating the collections of human antibody genes that comprise MedImmune Cambridge libraries. MedImmune has patents issued in Europe, South Korea, Japan, Australia and the US and a patent application is pending in Canada. These patents are co-owned by the MRC, The Scripps Research Institute and Stratagene and MedImmune currently has exclusive commercial exploitation rights, subject to certain rights held by the Medical Research Council (MRC), Scripps and Stratagene and their pre-existing licensees.
'McCafferty' covers the process by which human antibodies are displayed on phage (Phage Display) and methods of selecting antibodies to desired targets from libraries. MedImmune has patents issued in Europe, Australia, South Korea and Japan and a patent application is pending in Canada. These patents are co-owned by MedImmune and the MRC.
'Griffiths' covers the use of Phage Display technology to isolate human anti-self' antibodies that specifically bind to molecules found in the human body. CAT has patents issued in Australia, Europe and the US and patent applications are pending in Canada and Japan. This patent is co-owned by MedImmune Cambridge and the MRC.
In 2011 "The High Court of England and Wales has ruled that two patents (EP 0774511 and EP 2055777) owned by MedImmune that describe methods of phage display are invalid because of obviousness."
=== List of Patents ===
=== Patent Dispute with MorphoSys ===
The German biotechnology company MorphoSys generates human antibodies using its phage display-based 'HuCal' (Human Combinatorial Antibody Library) technology. In the late 1990s both companies found themselves jockeying for strong IP position in the area of therapeutic human antibody generation by way of a specific dispute (details on MorphoSys page).
The long, and protracted, dispute resulted which was eventually settled in late 2002 when some argued the settlement was enforced by an industry cash crunch. The 'delighted' CEO at the time, Peter Chambré, reflected that the deal put an end to the distraction to both parties caused by the litigation.
== Publications ==
Scientists at CAT pioneered the use of phage display such that variable antibody domains could be expressed on filamentous phage antibodies, as reported in a key Nature publication, "Phage antibodies: filamentous phage displaying antibody variable domains".
Other key CAT publications included:
Marks, JD; Hoogenboom, HR; Bonnert, TP; Mccafferty, J; Griffiths, AD; Winter, G (1991). "By-passing immunization. Human antibodies from V-gene libraries displayed on phage". Journal of Molecular Biology. 222 (3): 581–97. doi:10.1016/0022-2836(91)90498-U. PMID 1748994.
Vaughan, TJ; Williams, AJ; Pritchard, K; Osbourn, JK; Pope, AR; Earnshaw, JC; Mccafferty, J; Hodits, RA; et al. (1996). "Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library". Nature Biotechnology. 14 (3): 309–14. doi:10.1038/nbt0396-309. PMID 9630891. S2CID 23088502.
Carmen, S; Jermutus, L (2002). "Concepts in antibody phage display". Briefings in Functional Genomics & Proteomics. 1 (2): 189–203. doi:10.1093/bfgp/1.2.189. PMID 15239904.
Thom, G; Cockroft, AC; Buchanan, AG; Candotti, CJ; Cohe, ES; Lowne, D; Monk, P; Shorrock-Hart, CP; Jermutus, L; Minter, RR (2006). "Probing a protein-protein interaction by directed evolution". Proc Natl Acad Sci USA. 103 (20): 7619–24. Bibcode:2006PNAS..103.7619T. doi:10.1073/pnas.0602341103. PMC 1458619. PMID 16684878.
Edwards, BM; Barash, SC; Main, SH; Choi, GH; Minter, R; Ullrich, S; Williams, E; Du Fou, L; et al. (2003). "The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS". Journal of Molecular Biology. 334 (1): 103–18. doi:10.1016/j.jmb.2003.09.054. PMID 14596803.
Baker, KP; Edwards, BM; Main, SH; Choi, GH; Wager, RE; Halpern, WG; Lappin, PB; Riccobene, T; et al. (2003). "Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator". Arthritis and Rheumatism. 48 (11): 3253–65. doi:10.1002/art.11299. PMID 14613291.
== Management and notable people ==
CAT was founded by David Chiswell MBE and Sir Greg Winter, with major scientific contributions from John McCafferty.
Sir Greg Winter FRS is credited with invented techniques to both humanise (1986) and, later, to fully humanise using phage display, antibodies for therapeutic uses. Previously, antibodies had been derived from mice, which made them difficult to use in human therapeutics because the human immune system had anti-mouse reactions to them. For these developments Winter was awarded the 2018 Nobel Prize in Chemistry along with George Smith and Frances Arnold.
Dave Chiswell OBE was responsible for operational management of CAT from 1990 to 2002, including time as chief executive officer from 1996 to 2002. Chiswell announced he was standing down from CAT on 26 November 2001. During his time at CAT, Chiswell had established himself as a significant character in the biotechnology business. In 2003, Chiswell became chairman of the BioIndustry Association, and in June 2006 was awarded an OBE for services to the UK Bioscience Industry in the UK and Overseas.
CAT was governed by a board and, latterly, a Scientific Advisory Board. Members included:
César Milstein CH FRS, a Nobel Prize-winning biochemist in the field of antibody research. Milstein shared the Nobel Prize in Physiology and Medicine in 1984 with Niels Jerne and Georges Köhler.
Sir Aaron Klug OM FRS FMedSci HonFRMS, a Nobel Prize-winning laureate, was a British chemist and biophysicist, and winner of the 1982 Nobel Prize in Chemistry for his development of crystallographic electron microscopy. He sat on both the board and the scientific advisory board.
Professor Peter Garland – appointed as a non-executive director in 1990, then became non-executive chairman of the board in 1995. Garland has been the Chief Executive of Institute of Cancer Research, 1989–99 and was a fellow of University College London.
Dr Paul Nicholson – replaced Peter Garland as chairman in 2003. Nicholson was chairman when AstraZeneca bought CAT.
Peter Chambré replaced Dave Chiswell as CEO in early 2002. Chambré had been the CEO of Bespak PLC since May 1994 and, in July 2000, became the chief operating officer of the genomics company Celera. A few years after CAT, Chambré went on to hold a number of roles including director positions at BTG and Spectris, followed by an Industrialist in Residence position at 3i. Chambré went on to executive positions at Cancer Research UK, and more recently, Chambré became Chairman of the Board of Directors at Immatics biotechnologies NV, and Member of the Board of Trustees at Our Future Health.
John McCafferty developed much of the phage display technology used by CAT. McCafferty left CAT to start a group at the Wellcome Trust Sanger Institute where, as part of the ATLAS project, his group demonstrated the potential for large-scale high-throughput generation and validation of monoclonal antibodies. This work built on CAT's ProAb technology. McCafferty founded a new therapeutic antibody discovery biotechnology company, IONTAS Ltd. In 2018, McCafferty's 1990 phage research paper was cited by the Nobel committee when awarding the chemistry prize to Sir Gregory Winter, George Smith and Frances Arnold.
Kevin Johnson joined CAT in 1990, contributed to the discovery of D2E7, played a key role in CAT's initial public offering (IPO) and, by July 1997, was appointed to the Board as Research Director. In 2000, Johnson became Chief Technology Officer responsible for exploitation and development of CAT's technology platforms. In November 2002, CAT announced its intention to seek independent financing for its development of the application of antibodies on microarrays for personalised medicine, as this fell outside CAT's focus on therapeutic antibodies and Johnson positively spearheaded this push. In the event it was not possible to procure finance for this activity and, as a result, microarray activity at CAT was terminated. Johnson is currently a partner at medicxi, a venture capital firm focused on life sciences investments based on the asset-centric approach to investing. He was formerly with Index Ventures, having joined the venture capital firm in 2010.
Jane Osbourn OBE joined CAT as a senior scientist in 1993. Osbourn was a co-author of several, high-impact publications to come out of CAT. When merged with MedImmune, after the acquisition by AstraZeneca, Osbourn became the site leader of MedImmune Cambridge. Osbourn went on to chair the UK's BioIndustry Association in 2015 and, in 2019, was awarded the Order of the British Empire medal for services to "Human Monoclonal Antibody Drug Research and Development and Biotechnology".
== Awards ==
CAT's most significant award was the Prix Galien, awarded for outstanding achievement in product and technology development, in recognition of its creativity in the development of novel human monoclonal antibody therapeutics especially in relation to its product CAT-152, which was used to treat fibrotic scarring in certain ophthalmology conditions.
== See also ==
Pharmaceutical industry in the United Kingdom
== References == | Wikipedia/Cambridge_Antibody_Technology |
There are many hundreds of thousands of possible drugs. Any chemical substance with biological activity may be considered a drug. This list categorises drugs alphabetically and also by other categorisations.
This multi-page article lists pharmaceutical drugs alphabetically by name. Many drugs have more than one name and, therefore, the same drug may be listed more than once. Brand names and generic names are differentiated by capitalizing brand names.
See also the list of the top 100 bestselling branded drugs, ranked by sales.
Abbreviations are used in the list as follows:
INN = International nonproprietary name
BAN = British Approved Name
USAN = United States Adopted Name
Two-letter codes for countries
Lists of drugs
1–9 |
A | B |
C | D |
E | F |
G | H |
I | J |
K | L |
M | N |
O | P |
Q | R |
S | T |
U | V |
W | X |
Y | Z
== List of lists of drugs ==
=== General ===
List of bestselling drugs
List of drugs by year of discovery
=== By chemical structure ===
==== Depressants ====
Comparison of psychoactive alcohols in alcoholic drinks
List of benzodiazepines
==== Psychedelics ====
List of psychedelic drugs
List of 2C-* drugs
List of DO* drugs
List of substituted phenethylamines
List of substituted tryptamines
List of lysergimides
Quasi-psychedelics: List of cannabinoids
Comparison of phytocannabinoids
Synthetic cannabinoids
List of AM cannabinoids
List of CP cannabinoids
List of HU cannabinoids
List of JWH cannabinoids
==== Stimulants ====
List of cocaine analogues
List of methylphenidate analogues
List of substituted cathinones
==== Misc ====
List of antidepressants
List of androgen esters
List of corticosteroid esters
List of estrogen esters
List of tetracyclic antidepressants
List of tricyclic antidepressants
List of substituted α-alkyltryptamines
List of substituted amphetamines
List of substituted benzofurans
List of substituted methylenedioxyphenethylamines
=== By biological activity ===
List of androgen esters
List of androgens/anabolic steroids
List of anaesthetic drugs
List of antiandrogens
List of antibiotics
List of antipsychotics
List of antiviral drugs
List of corticosteroid esters
List of corticosteroids
List of designer drugs
List of drugs affected by grapefruit
List of estrogen esters
List of nasal decongestants
List of nonsteroidal anti-inflammatory drug
List of opioids
List of progestogens
List of psychedelic drugs
List of psychotropic medications
List of selective estrogen receptor modulators
List of tetracyclic antidepressants
List of tricyclic antidepressants
Lists of investigational drugs
=== By medical application ===
List of drugs known for off-label use
List of psychiatric medications
List of psychiatric medications by condition treated
List of veterinary drugs
=== By other institutional aspects ===
List of approved antidepressants
List of controlled drugs in the United Kingdom
List of drugs banned from the Olympics
List of Schedule I drugs (US)
List of Schedule II drugs (US)
List of Schedule III drugs (US)
List of Schedule IV drugs (US)
List of Schedule V drugs (US)
List of withdrawn drugs
List of World Health Organization Essential Medicines
== See also ==
Development and discovery of SSRI drugs
Channel modulator, for links to articles referring to drugs that modulate ion channels.
List of monoclonal antibodies
List of off-label promotion pharmaceutical settlements
List of schedules for drugs and poisons
List of steroid abbreviations
List of plants used for smoking
List of neurosteroids | Wikipedia/Lists_of_drugs |
The Billion-Dollar Molecule is a book by journalist Barry Werth about the founding and early research efforts of the American biotechnology company Vertex Pharmaceuticals, which was founded in 1989 by Joshua Boger and was among the first biotechnology companies to adopt an explicit strategy of rational drug design as opposed to techniques based on combinatorial chemistry.
This book is notable as an inside look at a biotechnology company, and the stresses and marketing pressures on funding research into drug design. This book is a mixture of finance and technology.
In February, 2014, Barry Werth published a follow-on book, The Antidote, that looks at Vertex 20 years later after his original effort.
== References == | Wikipedia/The_Billion-Dollar_Molecule |
Chiroscience Group Plc was a British-based biotech company, founded by Christopher Evans. The company was taken over by Celltech in 1999, which was acquired in 2004 by UCB.
== History ==
Chiroscience was born from the demise of the company Enzymatix, which was ultimately acquired by Genzyme, when Andrew Richards joined the company and convinced Evans and Peter Keen to launch Chiros, which name was quickly revised to Chrioscience. Seed funding for the company of £3 million was provided by Schroder Ventures, Apax and 3i. Chiroscience became one of the first biotechnology Initial Public Offerings in the United Kingdom in 1994.
In 1996, the company merged with the American biotech company Darwin Molecular Corporation, based in Cambridge, Massachusetts, retaining Chiroscience as its name.
By the time of its merger with Celltech in 1999, both Chris Evans and Peter Keen had left the company, leaving Andrew Richards as the sole remaining founder and member of the original management board.
== See also ==
Chirocaine, an anesthetic developed by Chiroscience
Romosozumab, discovered by Chiroscience before its acquisition by Celltech
Pharmaceutical industry in the United Kingdom
== References and notes ==
== Further reading ==
Datastream (May 8, 1996). "Chiroscience on the up". The Guardian. London, England. p. 21. Retrieved December 24, 2018 – via Newspapers.com. This shows performance of stock from May 1995 to May 1996.
Murphy, Paul (April 26, 1996). "Market report". The Guardian. London, England. p. 20. Retrieved December 24, 2018 – via Newspapers.com. On Mr. Buffet's terms, Chiroscience is nothing more than a bag of dreams. Contains a graphic showing company stock performance across 1994 to 1996.
== External links ==
UCB Group website Archived October 4, 2006, at the Wayback Machine | Wikipedia/Chiroscience |
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication.: 1.1 Adverse Drug Reaction (ADR) ADRs may occur following a single dose or prolonged administration of a drug or may result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse event (AE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not the event is associated with the administration of the drug.: 1.2 Adverse Event (AE) An ADR is a special type of AE in which a causative relationship can be shown. ADRs are only one type of medication-related harm. Another type of medication-related harm type includes not taking prescribed medications, known as non-adherence. Non-adherence to medications can lead to death and other negative outcomes. Adverse drug reactions require the use of a medication.
== Classification ==
=== Traditional ===
Type A: augmented pharmacological effects, which are dose-dependent and predictable
Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drug's primary pharmacological effect (e.g., bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug (e.g., nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects may be applied to minor type A reactions.
Type B: Type B reactions are not dose-dependent and are not predictable, and so may be called idiosyncratic. These reactions can be due to particular elements within the person or the environment.
Types A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.
Other types of adverse drug reactions are Type C, Type D, Type E, and Type F. Type C was categorized for chronic adverse drug reactions, Type D for delayed adverse drug reactions, Type E for withdrawal adverse drug reactions, and Type F for failure of therapy as an adverse drug reaction. Adverse drug reactions can also be categorized using time-relatedness, dose-relatedness, and susceptibility, which collectively are called the DoTS classification.
=== Seriousness ===
The U.S Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability — significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
Congenital abnormality
Requires intervention to prevent permanent impairment or damage
Severity is a measure of the intensity of the adverse event in question. The terms "severe" and "serious", when applied to adverse events, are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage. Seriousness usually indicates patient outcome (such as negative outcomes including disability, long-term effects, and death).
In adverse drug reactions, the seriousness of the reaction is important for reporting.
== Location ==
Some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.
== Mechanisms ==
=== Abnormal pharmacokinetics ===
==== Comorbid disease states ====
Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drug's metabolism due to disease states.
The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.
==== Genetic factors ====
Pharmacogenomics includes how genes can predict potential adverse drug reactions. However, pharmacogenomics is not limited to adverse events (of any type), but also looks at how genes may impact other responses to medications, such as low/no effect or expected/normal responses (especially based on drug metabolism).
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation.
===== Phase I reactions =====
Phase I reactions include metabolism by cytochrome P450. Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.
Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine.
===== Phase II reactions =====
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.
Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.
===== Protein binding =====
Protein binding interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:
albumin
α1-acid glycoprotein
lipoproteins
Some drug interactions with warfarin are due to changes in protein binding.
=== Drug interactions ===
The risk of drug interactions is increased with polypharmacy, especially in older adults.
==== Additive drug effects ====
Two or more drugs that contribute to the same mechanism in the body can have additive toxic or adverse effects. One example of this is multiple medications administered concurrently that prolong the QT interval, such as antiarrhythmics like sotalol and some macrolide antibiotics, such as systemic azithromycin.
Another example of additive effects for adverse drug reactions is in serotonin toxicity (serotonin syndrome). If medications that cause increased serotonin levels are combined, they can cause serotonin toxicity (though therapeutic doses of one agent that increases serotonin levels can cause serotonin toxicity in certain cases and individuals). Some of the medications that can contribute to serotonin toxicity include MAO inhibitors, SSRIs, and tricyclic antidepressants.
==== Altered metabolism ====
Some medications can either inhibit or induce key drug metabolizing enzymes or drug transporters, which when combined with other medications that utilize the same proteins can lead to either toxic or sub-therapeutic adverse effects. One example of this is a patient taking a cytochrome P450 3A4 (CYP3A4) inhibitor such as the antibiotic clarithromycin, as well as another medication metabolized by CYP3A4 such as the anticoagulant apixaban, which results in elevated blood concentrations of apixaban and greater risk of serious bleeds. Additionally, Clarithromycin is a permeability glycoprotein (P-gp) efflux pump inhibitor, which when given with apixaban (a substrate for P-gp) will lead to increased absorption of apixaban, resulting in the same adverse effects as with CYP3A4 inhibition.
== Management ==
=== Assessing causality ===
Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply.
An ADR should not be labeled as 'certain' unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR.
Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies, some ADRs may be missed as large numbers of test individuals are required to find a specific adverse drug reaction, especially for rare ADRs. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population.
=== Monitoring bodies ===
Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre. The European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies. The FDA has a reporting system called the FDA Adverse Event Reporting System, where individuals can report adverse drug events. Healthcare professionals, consumers, and the pharmaceutical industry can all submit information to this system. For health products marketed in Canada, a branch of Health Canada called The Canada Vigilance Program is responsible for surveillance. Both healthcare professionals and consumers can report to this program. In Australia, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products. In the UK, a monitoring system called the Yellow Card Scheme was established in 1964. The Yellow Card Scheme was set up to surveil medications and other health products.
== Epidemiology ==
A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals.
Medication related harm (MRH) is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals).
In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions.
In 2012, McKinsey & Company concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion.
An article published in The Journal of the American Medical Association (JAMA) in 2016 reported adverse drug event statistics from emergency departments around the United States in 2013-2014. From this article, an estimated prevalence of adverse drug events that were presented to the emergency department (ED) was 4 events out of every 1000 people. This article reported that 57.1% of these adverse drug events presented to the ED were in females. As well, out of all of the adverse drug events presented to the emergency department documented in this article, 17.6% were from anticoagulants, 16.1% were from antibiotics, and 13.3% from diabetic agents.
== See also ==
== References ==
== Further reading ==
Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy PMC 3312730
== External links == | Wikipedia/Adverse_drug_reaction |
Hebbian theory is a neuropsychological theory claiming that an increase in synaptic efficacy arises from a presynaptic cell's repeated and persistent stimulation of a postsynaptic cell. It is an attempt to explain synaptic plasticity, the adaptation of neurons during the learning process. Hebbian theory was introduced by Donald Hebb in his 1949 book The Organization of Behavior. The theory is also called Hebb's rule, Hebb's postulate, and cell assembly theory. Hebb states it as follows:
Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability. ... When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.: 62
The theory is often summarized as "Neurons that fire together, wire together." However, Hebb emphasized that cell A needs to "take part in firing" cell B, and such causality can occur only if cell A fires just before, not at the same time as, cell B. This aspect of causation in Hebb's work foreshadowed what is now known about spike-timing-dependent plasticity, which requires temporal precedence.
Hebbian theory attempts to explain associative or Hebbian learning, in which simultaneous activation of cells leads to pronounced increases in synaptic strength between those cells. It also provides a biological basis for errorless learning methods for education and memory rehabilitation. In the study of neural networks in cognitive function, it is often regarded as the neuronal basis of unsupervised learning.
== Engrams, cell assembly theory, and learning ==
Hebbian theory provides an explanation for how neurons might connect to become engrams, which may be stored in overlapping cell assemblies, or groups of neurons that encode specific information. Initially created as a way to explain recurrent activity in specific groups of cortical neurons, Hebb's theories on the form and function of cell assemblies can be understood from the following:: 70
The general idea is an old one, that any two cells or systems of cells that are repeatedly active at the same time will tend to become 'associated' so that activity in one facilitates activity in the other.
Hebb also wrote:
When one cell repeatedly assists in firing another, the axon of the first cell develops synaptic knobs (or enlarges them if they already exist) in contact with the soma of the second cell.
D. Alan Allport posits additional ideas regarding cell assembly theory and its role in forming engrams using the concept of auto-association, or the brain's ability to retrieve information based on a partial cue, described as follows:
If the inputs to a system cause the same pattern of activity to occur repeatedly, the set of active elements constituting that pattern will become increasingly strongly inter-associated. That is, each element will tend to turn on every other element and (with negative weights) to turn off the elements that do not form part of the pattern. To put it another way, the pattern as a whole will become 'auto-associated'. We may call a learned (auto-associated) pattern an engram.
Research conducted in the laboratory of Nobel laureate Eric Kandel has provided evidence supporting the role of Hebbian learning mechanisms at synapses in the marine gastropod Aplysia californica. Because synapses in the peripheral nervous system of marine invertebrates are much easier to control in experiments, Kandel's research found that Hebbian long-term potentiation along with activity-dependent presynaptic facilitation are both necessary for synaptic plasticity and classical conditioning in Aplysia californica.
While research on invertebrates has established fundamental mechanisms of learning and memory, much of the work on long-lasting synaptic changes between vertebrate neurons involves the use of non-physiological experimental stimulation of brain cells. However, some of the physiologically relevant synapse modification mechanisms that have been studied in vertebrate brains do seem to be examples of Hebbian processes. One such review indicates that long-lasting changes in synaptic strengths can be induced by physiologically relevant synaptic activity using both Hebbian and non-Hebbian mechanisms.
== Principles ==
In artificial neurons and artificial neural networks, Hebb's principle can be described as a method of determining how to alter the weights between model neurons. The weight between two neurons increases if the two neurons activate simultaneously, and reduces if they activate separately. Nodes that tend to be either both positive or both negative at the same time have strong positive weights, while those that tend to be opposite have strong negative weights.
The following is a formulaic description of Hebbian learning (many other descriptions are possible):
w
i
j
=
x
i
x
j
,
{\displaystyle \,w_{ij}=x_{i}x_{j},}
where
w
i
j
{\displaystyle w_{ij}}
is the weight of the connection from neuron
j
{\displaystyle j}
to neuron
i
{\displaystyle i}
, and
x
i
{\displaystyle x_{i}}
is the input for neuron
i
{\displaystyle i}
. This is an example of pattern learning, where weights are updated after every training example. In a Hopfield network, connections
w
i
j
{\displaystyle w_{ij}}
are set to zero if
i
=
j
{\displaystyle i=j}
(no reflexive connections allowed). With binary neurons (activations either 0 or 1), connections would be set to 1 if the connected neurons have the same activation for a pattern.
When several training patterns are used, the expression becomes an average of the individuals:
w
i
j
=
1
p
∑
k
=
1
p
x
i
k
x
j
k
,
{\displaystyle w_{ij}={\frac {1}{p}}\sum _{k=1}^{p}x_{i}^{k}x_{j}^{k},}
where
w
i
j
{\displaystyle w_{ij}}
is the weight of the connection from neuron
j
{\displaystyle j}
to neuron
i
{\displaystyle i}
,
p
{\displaystyle p}
is the number of training patterns and
x
i
k
{\displaystyle x_{i}^{k}}
the
k
{\displaystyle k}
-th input for neuron
i
{\displaystyle i}
. This is learning by epoch, with weights updated after all the training examples are presented and is last term applicable to both discrete and continuous training sets. Again, in a Hopfield network, connections
w
i
j
{\displaystyle w_{ij}}
are set to zero if
i
=
j
{\displaystyle i=j}
(no reflexive connections).
A variation of Hebbian learning that takes into account phenomena such as blocking and other neural learning phenomena is the mathematical model of Harry Klopf. Klopf's model assumes that parts of a system with simple adaptive mechanisms can underlie more complex systems with more advanced adaptive behavior, such as neural networks.
== Relationship to unsupervised learning, stability, and generalization ==
Because of the simple nature of Hebbian learning, based only on the coincidence of pre- and post-synaptic activity, it may not be intuitively clear why this form of plasticity leads to meaningful learning. However, it can be shown that Hebbian plasticity does pick up the statistical properties of the input in a way that can be categorized as unsupervised learning.
This can be mathematically shown in a simplified example. Let us work under the simplifying assumption of a single rate-based neuron of rate
y
(
t
)
{\displaystyle y(t)}
, whose inputs have rates
x
1
(
t
)
.
.
.
x
N
(
t
)
{\displaystyle x_{1}(t)...x_{N}(t)}
. The response of the neuron
y
(
t
)
{\displaystyle y(t)}
is usually described as a linear combination of its input,
∑
i
w
i
x
i
{\displaystyle \sum _{i}w_{i}x_{i}}
, followed by a response function
f
{\displaystyle f}
:
y
=
f
(
∑
i
=
1
N
w
i
x
i
)
.
{\displaystyle y=f\left(\sum _{i=1}^{N}w_{i}x_{i}\right).}
As defined in the previous sections, Hebbian plasticity describes the evolution in time of the synaptic weight
w
{\displaystyle w}
:
d
w
i
d
t
=
η
x
i
y
.
{\displaystyle {\frac {dw_{i}}{dt}}=\eta x_{i}y.}
Assuming, for simplicity, an identity response function
f
(
a
)
=
a
{\displaystyle f(a)=a}
, we can write
d
w
i
d
t
=
η
x
i
∑
j
=
1
N
w
j
x
j
{\displaystyle {\frac {dw_{i}}{dt}}=\eta x_{i}\sum _{j=1}^{N}w_{j}x_{j}}
or in matrix form:
d
w
d
t
=
η
x
x
T
w
.
{\displaystyle {\frac {d\mathbf {w} }{dt}}=\eta \mathbf {x} \mathbf {x} ^{T}\mathbf {w} .}
As in the previous chapter, if training by epoch is done an average
⟨
…
⟩
{\displaystyle \langle \dots \rangle }
over discrete or continuous (time) training set of
x
{\displaystyle \mathbf {x} }
can be done:
d
w
d
t
=
⟨
η
x
x
T
w
⟩
=
η
⟨
x
x
T
⟩
w
=
η
C
w
.
{\displaystyle {\frac {d\mathbf {w} }{dt}}=\langle \eta \mathbf {x} \mathbf {x} ^{T}\mathbf {w} \rangle =\eta \langle \mathbf {x} \mathbf {x} ^{T}\rangle \mathbf {w} =\eta C\mathbf {w} .}
where
C
=
⟨
x
x
T
⟩
{\displaystyle C=\langle \,\mathbf {x} \mathbf {x} ^{T}\rangle }
is the correlation matrix of the input under the additional assumption that
⟨
x
⟩
=
0
{\displaystyle \langle \mathbf {x} \rangle =0}
(i.e. the average of the inputs is zero). This is a system of
N
{\displaystyle N}
coupled linear differential equations. Since
C
{\displaystyle C}
is symmetric, it is also diagonalizable, and the solution can be found, by working in its eigenvectors basis, to be of the form
w
(
t
)
=
k
1
e
η
α
1
t
c
1
+
k
2
e
η
α
2
t
c
2
+
.
.
.
+
k
N
e
η
α
N
t
c
N
{\displaystyle \mathbf {w} (t)=k_{1}e^{\eta \alpha _{1}t}\mathbf {c} _{1}+k_{2}e^{\eta \alpha _{2}t}\mathbf {c} _{2}+...+k_{N}e^{\eta \alpha _{N}t}\mathbf {c} _{N}}
where
k
i
{\displaystyle k_{i}}
are arbitrary constants,
c
i
{\displaystyle \mathbf {c} _{i}}
are the eigenvectors of
C
{\displaystyle C}
and
α
i
{\displaystyle \alpha _{i}}
their corresponding eigen values.
Since a correlation matrix is always a positive-definite matrix, the eigenvalues are all positive, and one can easily see how the above solution is always exponentially divergent in time.
This is an intrinsic problem due to this version of Hebb's rule being unstable, as in any network with a dominant signal the synaptic weights will increase or decrease exponentially. Intuitively, this is because whenever the presynaptic neuron excites the postsynaptic neuron, the weight between them is reinforced, causing an even stronger excitation in the future, and so forth, in a self-reinforcing way. One may think a solution is to limit the firing rate of the postsynaptic neuron by adding a non-linear, saturating response function
f
{\displaystyle f}
, but in fact, it can be shown that for any neuron model, Hebb's rule is unstable. Therefore, network models of neurons usually employ other learning theories such as BCM theory, Oja's rule, or the generalized Hebbian algorithm.
Regardless, even for the unstable solution above, one can see that, when sufficient time has passed, one of the terms dominates over the others, and
w
(
t
)
≈
e
η
α
∗
t
c
∗
{\displaystyle \mathbf {w} (t)\approx e^{\eta \alpha ^{*}t}\mathbf {c} ^{*}}
where
α
∗
{\displaystyle \alpha ^{*}}
is the largest eigenvalue of
C
{\displaystyle C}
. At this time, the postsynaptic neuron performs the following operation:
y
≈
e
η
α
∗
t
c
∗
x
{\displaystyle y\approx e^{\eta \alpha ^{*}t}\mathbf {c} ^{*}\mathbf {x} }
Because, again,
c
∗
{\displaystyle \mathbf {c} ^{*}}
is the eigenvector corresponding to the largest eigenvalue of the correlation matrix between the
x
i
{\displaystyle x_{i}}
s, this corresponds exactly to computing the first principal component of the input.
This mechanism can be extended to performing a full PCA (principal component analysis) of the input by adding further postsynaptic neurons, provided the postsynaptic neurons are prevented from all picking up the same principal component, for example by adding lateral inhibition in the postsynaptic layer. We have thus connected Hebbian learning to PCA, which is an elementary form of unsupervised learning, in the sense that the network can pick up useful statistical aspects of the input, and "describe" them in a distilled way in its output.
== Hebbian learning and mirror neurons ==
Hebbian learning and spike-timing-dependent plasticity have been used in an influential theory of how mirror neurons emerge. Mirror neurons are neurons that fire both when an individual performs an action and when the individual sees or hears another perform a similar action. The discovery of these neurons has been very influential in explaining how individuals make sense of the actions of others, since when a person perceives the actions of others, motor programs in the person's brain which they would use to perform similar actions are activated, which add information to the perception and help to predict what the person will do next based on the perceiver's own motor program. One limitation of this idea of mirror neuron functions is explaining how individuals develop neurons that respond both while performing an action and while hearing or seeing another perform similar actions.
Neuroscientist Christian Keysers and psychologist David Perrett suggested that observing or hearing an individual perform an action activates brain regions as if performing the action oneself. These re-afferent sensory signals trigger activity in neurons responding to the sight, sound, and feel of the action. Because the activity of these sensory neurons will consistently overlap in time with those of the motor neurons that caused the action, Hebbian learning predicts that the synapses connecting neurons responding to the sight, sound, and feel of an action and those of the neurons triggering the action should be potentiated. The same is true while people look at themselves in the mirror, hear themselves babble, or are imitated by others. After repeated occurrences of this re-afference, the synapses connecting the sensory and motor representations of an action are so strong that the motor neurons start firing to the sound or the vision of the action, and a mirror neuron is created.
Numerous experiments provide evidence for the idea that Hebbian learning is crucial to the formation of mirror neurons. Evidence reveals that motor programs can be triggered by novel auditory or visual stimuli after repeated pairing of the stimulus with the execution of the motor program. For instance, people who have never played the piano do not activate brain regions involved in playing the piano when listening to piano music. Five hours of piano lessons, in which the participant is exposed to the sound of the piano each time they press a key is proven sufficient to trigger activity in motor regions of the brain upon listening to piano music when heard at a later time. Consistent with the fact that spike-timing-dependent plasticity occurs only if the presynaptic neuron's firing predicts the post-synaptic neuron's firing, the link between sensory stimuli and motor programs also only seem to be potentiated if the stimulus is contingent on the motor program.
== Hebbian theory and cognitive neuroscience ==
Hebbian learning is linked to cognitive processes like decision-making and social learning. The field of cognitive neuroscience has started to explore the intersection of Hebbian theory with brain regions responsible for reward processing and social cognition, such as the striatum and prefrontal cortex. In particular, striatal projections exposed to Hebbian models exhibit long-term potentiation and long-term depression in vivo. Additionally, models of the prefrontal cortex to stimuli ("mixed selectivity") are not entirely explained by random connectivity, but when a Hebbian paradigm is incorporated, the levels of mixed selectivity in the model are reached. It is hypothesized that Hebbian plasticity in these areas may underlie behaviors like habit formation, reinforcement learning, and even the development of social bonds.
== Limitations ==
Despite the common use of Hebbian models for long-term potentiation, Hebbian theory does not cover all forms of long-term synaptic plasticity. Hebb did not propose any rules for inhibitory synapses or predictions for anti-causal spike sequences (where the presynaptic neuron fires after the postsynaptic neuron). Synaptic modification may not simply occur only between activated neurons A and B, but at neighboring synapses as well. Therefore, all forms of heterosynaptic plasticity and homeostatic plasticity are considered non-Hebbian. One example is retrograde signaling to presynaptic terminals. The compound most frequently recognized as a retrograde transmitter is nitric oxide, which, due to its high solubility and diffusivity, often exerts effects on nearby neurons. This type of diffuse synaptic modification, known as volume learning, is not included in the traditional Hebbian model.
== Contemporary developments, artificial intelligence, and computational advancements ==
Modern research has expanded upon Hebb's original ideas. Spike-timing-dependent plasticity (STDP), for example, refines Hebbian principles by incorporating the precise timing of neuronal spikes to Hebbian theory. Experimental advancements have also linked Hebbian learning to complex behaviors, such as decision-making and emotional regulation. Current studies in artificial intelligence (AI) and quantum computing continue to leverage Hebbian concepts for developing adaptive algorithms and improving machine learning models.
In AI, Hebbian learning has seen applications beyond traditional neural networks. One significant advancement is in reinforcement learning algorithms, where Hebbian-like learning is used to update the weights based on the timing and strength of stimuli during training phases. Some researchers have adapted Hebbian principles to develop more biologically plausible models for learning in artificial systems, which may improve model efficiency and convergence in AI applications.
A growing area of interest is the application of Hebbian learning in quantum computing. While classical neural networks are the primary area of application for Hebbian theory, recent studies have begun exploring the potential for quantum-inspired algorithms. These algorithms leverage the principles of quantum superposition and entanglement to enhance learning processes in quantum systems.Current research is exploring how Hebbian principles could inform the development of more efficient quantum machine learning models.
New computational models have emerged that refine or extend Hebbian learning. For example, some models now account for the precise timing of neural spikes (as in spike-timing-dependent plasticity), while others have integrated aspects of neuromodulation to account for how neurotransmitters like dopamine affect the strength of synaptic connections. These advanced models provide a more nuanced understanding of how Hebbian learning operates in the brain and are contributing to the development of more realistic computational models.
Recent research on Hebbian learning has focused on the role of inhibitory neurons, which are often overlooked in traditional Hebbian models. While classic Hebbian theory primarily focuses on excitatory neurons, more comprehensive models of neural learning now consider the balanced interaction between excitatory and inhibitory synapses. Studies suggest that inhibitory neurons can provide critical regulation for maintaining stability in neural circuits and might prevent runaway positive feedback in Hebbian learning.
== See also ==
== References ==
== Further reading ==
Hebb, D.O. (1961). "Distinctive features of learning in the higher animal". In J. F. Delafresnaye (ed.). Brain Mechanisms and Learning. London: Oxford University Press.
Hebb, D. O. (1940). "Human Behavior After Extensive Bilateral Removal from the Frontal Lobes". Archives of Neurology and Psychiatry. 44 (2): 421–438. doi:10.1001/archneurpsyc.1940.02280080181011.
Bishop, C.M. (1995). Neural Networks for Pattern Recognition. Oxford: Oxford University Press. ISBN 978-0-19-853849-3.
Paulsen, O.; Sejnowski, T. J. (2000). "Natural patterns of activity and long-term synaptic plasticity". Current Opinion in Neurobiology. 10 (2): 172–179. doi:10.1016/S0959-4388(00)00076-3. PMC 2900254. PMID 10753798.
== External links ==
Overview Archived 2017-05-02 at the Wayback Machine
Hebbian Learning tutorial (Part 1: Novelty Filtering, Part 2: PCA) | Wikipedia/Hebbian_theory |
In discrete mathematics, and more specifically in graph theory, a vertex (plural vertices) or node is the fundamental unit of which graphs are formed: an undirected graph consists of a set of vertices and a set of edges (unordered pairs of vertices), while a directed graph consists of a set of vertices and a set of arcs (ordered pairs of vertices). In a diagram of a graph, a vertex is usually represented by a circle with a label, and an edge is represented by a line or arrow extending from one vertex to another.
From the point of view of graph theory, vertices are treated as featureless and indivisible objects, although they may have additional structure depending on the application from which the graph arises; for instance, a semantic network is a graph in which the vertices represent concepts or classes of objects.
The two vertices forming an edge are said to be the endpoints of this edge, and the edge is said to be incident to the vertices. A vertex w is said to be adjacent to another vertex v if the graph contains an edge (v,w). The neighborhood of a vertex v is an induced subgraph of the graph, formed by all vertices adjacent to v.
== Types of vertices ==
The degree of a vertex, denoted 𝛿(v) in a graph is the number of edges incident to it. An isolated vertex is a vertex with degree zero; that is, a vertex that is not an endpoint of any edge (the example image illustrates one isolated vertex). A leaf vertex (also pendant vertex) is a vertex with degree one. In a directed graph, one can distinguish the outdegree (number of outgoing edges), denoted 𝛿 +(v), from the indegree (number of incoming edges), denoted 𝛿−(v); a source vertex is a vertex with indegree zero, while a sink vertex is a vertex with outdegree zero. A simplicial vertex is one whose closed neighborhood forms a clique: every two neighbors are adjacent. A universal vertex is a vertex that is adjacent to every other vertex in the graph.
A cut vertex is a vertex the removal of which would disconnect the remaining graph; a vertex separator is a collection of vertices the removal of which would disconnect the remaining graph into small pieces. A k-vertex-connected graph is a graph in which removing fewer than k vertices always leaves the remaining graph connected. An independent set is a set of vertices no two of which are adjacent, and a vertex cover is a set of vertices that includes at least one endpoint of each edge in the graph. The vertex space of a graph is a vector space having a set of basis vectors corresponding with the graph's vertices.
A graph is vertex-transitive if it has symmetries that map any vertex to any other vertex. In the context of graph enumeration and graph isomorphism it is important to distinguish between labeled vertices and unlabeled vertices. A labeled vertex is a vertex that is associated with extra information that enables it to be distinguished from other labeled vertices; two graphs can be considered isomorphic only if the correspondence between their vertices pairs up vertices with equal labels. An unlabeled vertex is one that can be substituted for any other vertex based only on its adjacencies in the graph and not based on any additional information.
Vertices in graphs are analogous to, but not the same as, vertices of polyhedra: the skeleton of a polyhedron forms a graph, the vertices of which are the vertices of the polyhedron, but polyhedron vertices have additional structure (their geometric location) that is not assumed to be present in graph theory. The vertex figure of a vertex in a polyhedron is analogous to the neighborhood of a vertex in a graph.
== See also ==
Node (computer science)
Graph theory
Glossary of graph theory
== References ==
Gallo, Giorgio; Pallotino, Stefano (1988). "Shortest path algorithms". Annals of Operations Research. 13 (1): 1–79. doi:10.1007/BF02288320. S2CID 62752810.
Berge, Claude, Théorie des graphes et ses applications. Collection Universitaire de Mathématiques, II Dunod, Paris 1958, viii+277 pp. (English edition, Wiley 1961; Methuen & Co, New York 1962; Russian, Moscow 1961; Spanish, Mexico 1962; Roumanian, Bucharest 1969; Chinese, Shanghai 1963; Second printing of the 1962 first English edition. Dover, New York 2001)
Chartrand, Gary (1985). Introductory graph theory. New York: Dover. ISBN 0-486-24775-9.
Biggs, Norman; Lloyd, E. H.; Wilson, Robin J. (1986). Graph theory, 1736-1936. Oxford [Oxfordshire]: Clarendon Press. ISBN 0-19-853916-9.
Harary, Frank (1969). Graph theory. Reading, Mass.: Addison-Wesley Publishing. ISBN 0-201-41033-8.
Harary, Frank; Palmer, Edgar M. (1973). Graphical enumeration. New York, Academic Press. ISBN 0-12-324245-2.
== External links ==
Weisstein, Eric W. "Graph Vertex". MathWorld. | Wikipedia/Node_(graph_theory) |
Wagner's gene network model is a computational model of artificial gene networks, which explicitly modeled the developmental and evolutionary process of genetic regulatory networks. A population with multiple organisms can be created and evolved from generation to generation. It was first developed by Andreas Wagner in 1996 and has been investigated by other groups to study the evolution of gene networks, gene expression, robustness, plasticity and epistasis.
== Assumptions ==
The model and its variants have a number of simplifying assumptions. Three of them are listing below.
The organisms are modeled as gene regulatory networks. The models assume that gene expression is regulated exclusively at the transcriptional level;
The product of a gene can regulate the expression of (be a regulator of) that source gene or other genes. The models assume that a gene can only produce one active transcriptional regulator;
The effects of one regulator are independent of effects of other regulators on the same target gene.
== Genotype ==
The model represents individuals as networks of interacting transcriptional regulators. Each individual expresses
n
{\displaystyle n}
genes encoding transcription factors. The product of each gene can regulate the expression level of itself and/or the other genes through cis-regulatory elements. The interactions among genes constitute a gene network that is represented by a
N
{\displaystyle N}
×
N
{\displaystyle N}
regulatory matrix
(
R
)
{\displaystyle (R)}
in the model. The elements in matrix R represent the interaction strength. Positive values within the matrix represent the activation of the target gene, while negative ones represent repression. Matrix elements with value 0 indicate the absence of interactions between two genes.
== Phenotype ==
The phenotype of each individual is modeled as the gene expression pattern at time
t
{\displaystyle t}
. It is represented by a state vector
S
(
t
)
{\displaystyle S(t)}
in this model.
S
(
t
)
:=
(
s
1
(
t
)
,
.
.
.
,
s
N
(
t
)
)
{\displaystyle S(t)\ :=\ (s_{1}(t),\ ...,\ s_{N}(t))}
whose element
s
i
(
t
)
{\displaystyle s_{i}(t)}
denotes the expression state of gene i at time t. In the original Wagner model,
s
i
(
t
)
{\displaystyle s_{i}(t)}
∈
{
−
1
,
1
}
{\displaystyle \{-1,1\}}
where 1 represents the gene is expressed while -1 implies the gene is not expressed. The expression pattern can only be ON or OFF. The continuous expression pattern between -1 (or 0) and 1 is also implemented in some other variants.
== Development ==
The development process is modeled as the development of gene expression states. The gene expression pattern
S
(
0
)
{\displaystyle S(0)}
at time
t
=
0
{\displaystyle t=0}
is defined as the initial expression state. The interactions among genes change the expression states during the development process. This process is modeled by the following differential equations
S
l
(
t
+
τ
)
=
σ
[
∑
j
=
1
N
w
i
j
S
j
(
t
)
]
=
σ
[
h
i
]
(
t
)
,
{\displaystyle S_{l}(t+\tau )=\sigma [\sum _{j=1}^{N}w_{ij}S_{j}(t)]=\sigma [h_{i}](t),}
where
S
l
(
t
+
{\displaystyle S_{l}(t+}
τ) represents the expression state of
G
l
{\displaystyle G_{l}}
at time
t
+
τ
{\displaystyle t+\tau }
. It is determined by a filter function σ
(
x
)
{\displaystyle (x)}
.
h
i
(
t
)
{\displaystyle h_{i}(t)}
represents the weighted sum of regulatory effects (
w
i
j
{\displaystyle w_{ij}}
) of all genes on gene
G
i
{\displaystyle G_{i}}
at time
t
{\displaystyle t}
. In the original Wagner model, the filter function is a step function
σ
(
x
)
=
{
−
1
,
(
x
<
0
)
1
,
(
x
>
0
)
0
,
(
x
=
0
)
.
{\displaystyle \sigma (x)={\begin{cases}-1,&(x<0)\\1,&(x>0)\\0,&(x=0).\end{cases}}}
In other variants, the filter function is implemented as a sigmoidal function
σ
(
x
)
=
2
1
+
e
−
a
x
−
1
{\displaystyle \sigma (x)={\frac {2}{1+e^{-ax}}}-1}
In this way, the expression states will acquire a continuous distribution. The gene expression will reach the final state if it reaches a stable pattern.
== Evolution ==
Evolutionary simulations are performed by reproduction-mutation-selection life cycle. Populations are fixed at size
N
{\displaystyle N}
and they will not go extinct. Non-overlapping generations are employed. In a typical evolutionary simulation, a single random viable individual that can produce a stable gene expression pattern is chosen as the founder. Cloned individuals are generated to create a population of
N
{\displaystyle N}
identical individuals. According to the asexual or sexual reproductive mode, offspring are produced by randomly choosing (with replacement) parent individual(s) from current generation. Mutations can be acquired with probability μ and survive with probability equal to their fitness. This process is repeated until N individuals are produced that go on to found the following generation.
== Fitness ==
Fitness in this model is the probability that an individual survives to reproduce. In the simplest implementation of the model, developmentally stable genotypes survive (i.e. their fitness is
1
{\displaystyle 1}
) and developmentally unstable ones do not (i.e. their fitness is
0
{\displaystyle 0}
).
== Mutation ==
Mutations are modeled as the changes in gene regulation, i.e., the changes of the elements in the regulatory matrix
R
{\displaystyle R}
.
== Reproduction ==
Both sexual and asexual reproductions are implemented. Asexual reproduction is implemented as producing the offspring's genome (the gene network) by directly copying the parent's genome. Sexual reproduction is implemented as the recombination of the two parents' genomes.
== Selection ==
An organism is considered viable if it reaches a stable gene expression pattern. An organism with oscillated expression pattern is discarded and cannot enter the next generation.
== References ==
== External links ==
Andreas Wagner Lab Webpage | Wikipedia/Wagner's_gene_network_model |
A DNA microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to genotype multiple regions of a genome. Each DNA spot contains picomoles (10−12 moles) of a specific DNA sequence, known as probes (or reporters or oligos). These can be a short section of a gene or other DNA element that are used to hybridize a cDNA or cRNA (also called anti-sense RNA) sample (called target) under high-stringency conditions. Probe-target hybridization is usually detected and quantified by detection of fluorophore-, silver-, or chemiluminescence-labeled targets to determine relative abundance of nucleic acid sequences in the target. The original nucleic acid arrays were macro arrays approximately 9 cm × 12 cm and the first computerized image based analysis was published in 1981. It was invented by Patrick O. Brown. An example of its application is in SNPs arrays for polymorphisms in cardiovascular diseases, cancer, pathogens and GWAS analysis. It is also used for the identification of structural variations and the measurement of gene expression.
== Principle ==
The core principle behind microarrays is hybridization between two DNA strands, the property of complementary nucleic acid sequences to specifically pair with each other by forming hydrogen bonds between complementary nucleotide base pairs. A high number of complementary base pairs in a nucleotide sequence means tighter non-covalent bonding between the two strands. After washing off non-specific bonding sequences, only strongly paired strands will remain hybridized. Fluorescently labeled target sequences that bind to a probe sequence generate a signal that depends on the hybridization conditions (such as temperature), and washing after hybridization. Total strength of the signal, from a spot (feature), depends upon the amount of target sample binding to the probes present on that spot. Microarrays use relative quantitation in which the intensity of a feature is compared to the intensity of the same feature under a different condition, and the identity of the feature is known by its position.
== Uses and types ==
Many types of arrays exist and the broadest distinction is whether they are spatially arranged on a surface or on coded beads:
The traditional solid-phase array is a collection of orderly microscopic "spots", called features, each with thousands of identical and specific probes attached to a solid surface, such as glass, plastic or silicon biochip (commonly known as a genome chip, DNA chip or gene array). Thousands of these features can be placed in known locations on a single DNA microarray.
The alternative bead array is a collection of microscopic polystyrene beads, each with a specific probe and a ratio of two or more dyes, which do not interfere with the fluorescent dyes used on the target sequence.
DNA microarrays can be used to detect DNA (as in comparative genomic hybridization), or detect RNA (most commonly as cDNA after reverse transcription) that may or may not be translated into proteins. The process of measuring gene expression via cDNA is called expression analysis or expression profiling.
Applications include:
Specialised arrays tailored to particular crops are becoming increasingly popular in molecular breeding applications. In the future they could be used to screen seedlings at early stages to lower the number of unneeded seedlings tried out in breeding operations.
=== Fabrication ===
Microarrays can be manufactured in different ways, depending on the number of probes under examination, costs, customization requirements, and the type of scientific question being asked. Arrays from commercial vendors may have as few as 10 probes or as many as 5 million or more micrometre-scale probes.
=== Spotted vs. in situ synthesised arrays ===
Microarrays can be fabricated using a variety of technologies, including printing with fine-pointed pins onto glass slides, photolithography using pre-made masks, photolithography using dynamic micromirror devices, ink-jet printing, or electrochemistry on microelectrode arrays.
In spotted microarrays, the probes are oligonucleotides, cDNA or small fragments of PCR products that correspond to mRNAs. The probes are synthesized prior to deposition on the array surface and are then "spotted" onto glass. A common approach utilizes an array of fine pins or needles controlled by a robotic arm that is dipped into wells containing DNA probes and then depositing each probe at designated locations on the array surface. The resulting "grid" of probes represents the nucleic acid profiles of the prepared probes and is ready to receive complementary cDNA or cRNA "targets" derived from experimental or clinical samples.
This technique is used by research scientists around the world to produce "in-house" printed microarrays in their own labs. These arrays may be easily customized for each experiment, because researchers can choose the probes and printing locations on the arrays, synthesize the probes in their own lab (or collaborating facility), and spot the arrays. They can then generate their own labeled samples for hybridization, hybridize the samples to the array, and finally scan the arrays with their own equipment. This provides a relatively low-cost microarray that may be customized for each study, and avoids the costs of purchasing often more expensive commercial arrays that may represent vast numbers of genes that are not of interest to the investigator.
Publications exist which indicate in-house spotted microarrays may not provide the same level of sensitivity compared to commercial oligonucleotide arrays, possibly owing to the small batch sizes and reduced printing efficiencies when compared to industrial manufactures of oligo arrays.
In oligonucleotide microarrays, the probes are short sequences designed to match parts of the sequence of known or predicted open reading frames. Although oligonucleotide probes are often used in "spotted" microarrays, the term "oligonucleotide array" most often refers to a specific technique of manufacturing. Oligonucleotide arrays are produced by printing short oligonucleotide sequences designed to represent a single gene or family of gene splice-variants by synthesizing this sequence directly onto the array surface instead of depositing intact sequences. Sequences may be longer (60-mer probes such as the Agilent design) or shorter (25-mer probes produced by Affymetrix) depending on the desired purpose; longer probes are more specific to individual target genes, shorter probes may be spotted in higher density across the array and are cheaper to manufacture.
One technique used to produce oligonucleotide arrays include photolithographic synthesis (Affymetrix) on a silica substrate where light and light-sensitive masking agents are used to "build" a sequence one nucleotide at a time across the entire array. Each applicable probe is selectively "unmasked" prior to bathing the array in a solution of a single nucleotide, then a masking reaction takes place and the next set of probes are unmasked in preparation for a different nucleotide exposure. After many repetitions, the sequences of every probe become fully constructed. More recently, Maskless Array Synthesis from NimbleGen Systems has combined flexibility with large numbers of probes.
=== Two-channel vs. one-channel detection ===
Two-color microarrays or two-channel microarrays are typically hybridized with cDNA prepared from two samples to be compared (e.g. diseased tissue versus healthy tissue) and that are labeled with two different fluorophores. Fluorescent dyes commonly used for cDNA labeling include Cy3, which has a fluorescence emission wavelength of 570 nm (corresponding to the green part of the light spectrum), and Cy5 with a fluorescence emission wavelength of 670 nm (corresponding to the red part of the light spectrum). The two Cy-labeled cDNA samples are mixed and hybridized to a single microarray that is then scanned in a microarray scanner to visualize fluorescence of the two fluorophores after excitation with a laser beam of a defined wavelength. Relative intensities of each fluorophore may then be used in ratio-based analysis to identify up-regulated and down-regulated genes.
Oligonucleotide microarrays often carry control probes designed to hybridize with RNA spike-ins. The degree of hybridization between the spike-ins and the control probes is used to normalize the hybridization measurements for the target probes. Although absolute levels of gene expression may be determined in the two-color array in rare instances, the relative differences in expression among different spots within a sample and between samples is the preferred method of data analysis for the two-color system. Examples of providers for such microarrays includes Agilent with their Dual-Mode platform, Eppendorf with their DualChip platform for colorimetric Silverquant labeling, and TeleChem International with Arrayit.
In single-channel microarrays or one-color microarrays, the arrays provide intensity data for each probe or probe set indicating a relative level of hybridization with the labeled target. However, they do not truly indicate abundance levels of a gene but rather relative abundance when compared to other samples or conditions when processed in the same experiment. Each RNA molecule encounters protocol and batch-specific bias during amplification, labeling, and hybridization phases of the experiment making comparisons between genes for the same microarray uninformative. The comparison of two conditions for the same gene requires two separate single-dye hybridizations. Several popular single-channel systems are the Affymetrix "Gene Chip", Illumina "Bead Chip", Agilent single-channel arrays, the Applied Microarrays "CodeLink" arrays, and the Eppendorf "DualChip & Silverquant". One strength of the single-dye system lies in the fact that an aberrant sample cannot affect the raw data derived from other samples, because each array chip is exposed to only one sample (as opposed to a two-color system in which a single low-quality sample may drastically impinge on overall data precision even if the other sample was of high quality). Another benefit is that data are more easily compared to arrays from different experiments as long as batch effects have been accounted for.
One channel microarray may be the only choice in some situations. Suppose
i
{\displaystyle i}
samples need to be compared: then the number of experiments required using the two channel arrays quickly becomes unfeasible, unless a sample is used as a reference.
=== A typical protocol ===
This is an example of a DNA microarray experiment which includes details for a particular case to better explain DNA microarray experiments, while listing modifications for RNA or other alternative experiments.
The two samples to be compared (pairwise comparison) are grown/acquired. In this example treated sample (case) and untreated sample (control).
The nucleic acid of interest is purified: this can be RNA for expression profiling, DNA for comparative hybridization, or DNA/RNA bound to a particular protein which is immunoprecipitated (ChIP-on-chip) for epigenetic or regulation studies. In this example total RNA is isolated (both nuclear and cytoplasmic) by guanidinium thiocyanate-phenol-chloroform extraction (e.g. Trizol) which isolates most RNA (whereas column methods have a cut off of 200 nucleotides) and if done correctly has a better purity.
The purified RNA is analysed for quality (by capillary electrophoresis) and quantity (for example, by using a NanoDrop or NanoPhotometer spectrometer). If the material is of acceptable quality and sufficient quantity is present (e.g., >1μg, although the required amount varies by microarray platform), the experiment can proceed.
The labeled product is generated via reverse transcription and followed by an optional PCR amplification. The RNA is reverse transcribed with either polyT primers (which amplify only mRNA) or random primers (which amplify all RNA, most of which is rRNA). miRNA microarrays ligate an oligonucleotide to the purified small RNA (isolated with a fractionator), which is then reverse transcribed and amplified.
The label is added either during the reverse transcription step, or following amplification if it is performed. The sense labeling is dependent on the microarray; e.g. if the label is added with the RT mix, the cDNA is antisense and the microarray probe is sense, except in the case of negative controls.
The label is typically fluorescent; only one machine uses radiolabels.
The labeling can be direct (not used) or indirect (requires a coupling stage). For two-channel arrays, the coupling stage occurs before hybridization, using aminoallyl uridine triphosphate (aminoallyl-UTP, or aaUTP) and NHS amino-reactive dyes (such as cyanine dyes); for single-channel arrays, the coupling stage occurs after hybridization, using biotin and labeled streptavidin. The modified nucleotides (usually in a ratio of 1 aaUTP: 4 TTP (thymidine triphosphate)) are added enzymatically in a low ratio to normal nucleotides, typically resulting in 1 every 60 bases. The aaDNA is then purified with a column (using a phosphate buffer solution, as Tris contains amine groups). The aminoallyl group is an amine group on a long linker attached to the nucleobase, which reacts with a reactive dye.
A form of replicate known as a dye flip can be performed to control for dye artifacts in two-channel experiments; for a dye flip, a second slide is used, with the labels swapped (the sample that was labeled with Cy3 in the first slide is labeled with Cy5, and vice versa). In this example, aminoallyl-UTP is present in the reverse-transcribed mixture.
The labeled samples are then mixed with a proprietary hybridization solution which can consist of SDS, SSC, dextran sulfate, a blocking agent (such as Cot-1 DNA, salmon sperm DNA, calf thymus DNA, PolyA, or PolyT), Denhardt's solution, or formamine.
The mixture is denatured and added to the pinholes of the microarray. The holes are sealed and the microarray hybridized, either in a hyb oven, where the microarray is mixed by rotation, or in a mixer, where the microarray is mixed by alternating pressure at the pinholes.
After an overnight hybridization, all nonspecific binding is washed off (SDS and SSC).
The microarray is dried and scanned by a machine that uses a laser to excite the dye and measures the emission levels with a detector.
The image is gridded with a template and the intensities of each feature (composed of several pixels) is quantified.
The raw data is normalized; the simplest normalization method is to subtract background intensity and scale so that the total intensities of the features of the two channels are equal, or to use the intensity of a reference gene to calculate the t-value for all of the intensities. More sophisticated methods include z-ratio, loess and lowess regression and RMA (robust multichip analysis) for Affymetrix chips (single-channel, silicon chip, in situ synthesized short oligonucleotides).
== Microarrays and bioinformatics ==
The advent of inexpensive microarray experiments created several specific bioinformatics challenges: the multiple levels of replication in experimental design (Experimental design); the number of platforms and independent groups and data format (Standardization); the statistical treatment of the data (Data analysis); mapping each probe to the mRNA transcript that it measures (Annotation); the sheer volume of data and the ability to share it (Data warehousing).
=== Experimental design ===
Due to the biological complexity of gene expression, the considerations of experimental design that are discussed in the expression profiling article are of critical importance if statistically and biologically valid conclusions are to be drawn from the data.
There are three main elements to consider when designing a microarray experiment. First, replication of the biological samples is essential for drawing conclusions from the experiment. Second, technical replicates (e.g. two RNA samples obtained from each experimental unit) may help to quantitate precision. The biological replicates include independent RNA extractions. Technical replicates may be two aliquots of the same extraction. Third, spots of each cDNA clone or oligonucleotide are present as replicates (at least duplicates) on the microarray slide, to provide a measure of technical precision in each hybridization. It is critical that information about the sample preparation and handling is discussed, in order to help identify the independent units in the experiment and to avoid inflated estimates of statistical significance.
=== Standardization ===
Microarray data is difficult to exchange due to the lack of standardization in platform fabrication, assay protocols, and analysis methods. This presents an interoperability problem in bioinformatics. Various grass-roots open-source projects are trying to ease the exchange and analysis of data produced with non-proprietary chips:
For example, the "Minimum Information About a Microarray Experiment" (MIAME) checklist helps define the level of detail that should exist and is being adopted by many journals as a requirement for the submission of papers incorporating microarray results. But MIAME does not describe the format for the information, so while many formats can support the MIAME requirements, as of 2007 no format permits verification of complete semantic compliance. The "MicroArray Quality Control (MAQC) Project" is being conducted by the US Food and Drug Administration (FDA) to develop standards and quality control metrics which will eventually allow the use of MicroArray data in drug discovery, clinical practice and regulatory decision-making. The MGED Society has developed standards for the representation of gene expression experiment results and relevant annotations.
=== Data analysis ===
Microarray data sets are commonly very large, and analytical precision is influenced by a number of variables. Statistical challenges include taking into account effects of background noise and appropriate normalization of the data. Normalization methods may be suited to specific platforms and, in the case of commercial platforms, the analysis may be proprietary. Algorithms that affect statistical analysis include:
Image analysis: gridding, spot recognition of the scanned image (segmentation algorithm), removal or marking of poor-quality and low-intensity features (called flagging).
Data processing: background subtraction (based on global or local background), determination of spot intensities and intensity ratios, visualisation of data (e.g. see MA plot), and log-transformation of ratios, global or local normalization of intensity ratios, and segmentation into different copy number regions using step detection algorithms.
Class discovery analysis: This analytic approach, sometimes called unsupervised classification or knowledge discovery, tries to identify whether microarrays (objects, patients, mice, etc.) or genes cluster together in groups. Identifying naturally existing groups of objects (microarrays or genes) which cluster together can enable the discovery of new groups that otherwise were not previously known to exist. During knowledge discovery analysis, various unsupervised classification techniques can be employed with DNA microarray data to identify novel clusters (classes) of arrays. This type of approach is not hypothesis-driven, but rather is based on iterative pattern recognition or statistical learning methods to find an "optimal" number of clusters in the data. Examples of unsupervised analyses methods include self-organizing maps, neural gas, k-means cluster analyses, hierarchical cluster analysis, Genomic Signal Processing based clustering and model-based cluster analysis. For some of these methods the user also has to define a distance measure between pairs of objects. Although the Pearson correlation coefficient is usually employed, several other measures have been proposed and evaluated in the literature. The input data used in class discovery analyses are commonly based on lists of genes having high informativeness (low noise) based on low values of the coefficient of variation or high values of Shannon entropy, etc. The determination of the most likely or optimal number of clusters obtained from an unsupervised analysis is called cluster validity. Some commonly used metrics for cluster validity are the silhouette index, Davies-Bouldin index, Dunn's index, or Hubert's
Γ
{\displaystyle \Gamma }
statistic.
Class prediction analysis: This approach, called supervised classification, establishes the basis for developing a predictive model into which future unknown test objects can be input in order to predict the most likely class membership of the test objects. Supervised analysis for class prediction involves use of techniques such as linear regression, k-nearest neighbor, learning vector quantization, decision tree analysis, random forests, naive Bayes, logistic regression, kernel regression, artificial neural networks, support vector machines, mixture of experts, and supervised neural gas. In addition, various metaheuristic methods are employed, such as genetic algorithms, covariance matrix self-adaptation, particle swarm optimization, and ant colony optimization. Input data for class prediction are usually based on filtered lists of genes which are predictive of class, determined using classical hypothesis tests (next section), Gini diversity index, or information gain (entropy).
Hypothesis-driven statistical analysis: Identification of statistically significant changes in gene expression are commonly identified using the t-test, ANOVA, Bayesian method Mann–Whitney test methods tailored to microarray data sets, which take into account multiple comparisons or cluster analysis. These methods assess statistical power based on the variation present in the data and the number of experimental replicates, and can help minimize type I and type II errors in the analyses.
Dimensional reduction: Analysts often reduce the number of dimensions (genes) prior to data analysis. This may involve linear approaches such as principal components analysis (PCA), or non-linear manifold learning (distance metric learning) using kernel PCA, diffusion maps, Laplacian eigenmaps, local linear embedding, locally preserving projections, and Sammon's mapping.
Network-based methods: Statistical methods that take the underlying structure of gene networks into account, representing either associative or causative interactions or dependencies among gene products. Weighted gene co-expression network analysis is widely used for identifying co-expression modules and intramodular hub genes. Modules may corresponds to cell types or pathways. Highly connected intramodular hubs best represent their respective modules.
Microarray data may require further processing aimed at reducing the dimensionality of the data to aid comprehension and more focused analysis. Other methods permit analysis of data consisting of a low number of biological or technical replicates; for example, the Local Pooled Error (LPE) test pools standard deviations of genes with similar expression levels in an effort to compensate for insufficient replication.
=== Annotation ===
The relation between a probe and the mRNA that it is expected to detect is not trivial. Some mRNAs may cross-hybridize probes in the array that are supposed to detect another mRNA. In addition, mRNAs may experience amplification bias that is sequence or molecule-specific. Thirdly, probes that are designed to detect the mRNA of a particular gene may be relying on genomic EST information that is incorrectly associated with that gene.
=== Data warehousing ===
Microarray data was found to be more useful when compared to other similar datasets. The sheer volume of data, specialized formats (such as MIAME), and curation efforts associated with the datasets require specialized databases to store the data. A number of open-source data warehousing solutions, such as InterMine and BioMart, have been created for the specific purpose of integrating diverse biological datasets, and also support analysis.
== Alternative technologies ==
Advances in massively parallel sequencing has led to the development of RNA-Seq technology, that enables a whole transcriptome shotgun approach to characterize and quantify gene expression. Unlike microarrays, which need a reference genome and transcriptome to be available before the microarray itself can be designed, RNA-Seq can also be used for new model organisms whose genome has not been sequenced yet.
== Glossary ==
An array or slide is a collection of features spatially arranged in a two dimensional grid, arranged in columns and rows.
Block or subarray: a group of spots, typically made in one print round; several subarrays/ blocks form an array.
Case/control: an experimental design paradigm especially suited to the two-colour array system, in which a condition chosen as control (such as healthy tissue or state) is compared to an altered condition (such as a diseased tissue or state).
Channel: the fluorescence output recorded in the scanner for an individual fluorophore and can even be ultraviolet.
Dye flip or dye swap or fluor reversal: reciprocal labelling of DNA targets with the two dyes to account for dye bias in experiments.
Scanner: an instrument used to detect and quantify the intensity of fluorescence of spots on a microarray slide, by selectively exciting fluorophores with a laser and measuring the fluorescence with a filter (optics) photomultiplier system.
Spot or feature: a small area on an array slide that contains picomoles of specific DNA samples.
For other relevant terms see:
Glossary of gene expression terms
Protocol (natural sciences)
== See also ==
== References ==
== External links ==
Microarray Animation 1Lec.com
PLoS Biology Primer: Microarray Analysis
Rundown of microarray technology
ArrayMining.net – a free web-server for online microarray analysis
Microarray – How does it work?
PNAS Commentary: Discovery of Principles of Nature from Mathematical Modeling of DNA Microarray Data
DNA microarray virtual experiment | Wikipedia/DNA_microarrays |
The Hodgkin–Huxley model, or conductance-based model, is a mathematical model that describes how action potentials in neurons are initiated and propagated. It is a set of nonlinear differential equations that approximates the electrical engineering characteristics of excitable cells such as neurons and muscle cells. It is a continuous-time dynamical system.
Alan Hodgkin and Andrew Huxley described the model in 1952 to explain the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon. They received the 1963 Nobel Prize in Physiology or Medicine for this work.
== Basic components ==
The typical Hodgkin–Huxley model treats each component of an excitable cell as an electrical element (as shown in the figure). The lipid bilayer is represented as a capacitance (Cm). Voltage-gated ion channels are represented by electrical conductances (gn, where n is the specific ion channel) that depend on both voltage and time. Leak channels are represented by linear conductances (gL). The electrochemical gradients driving the flow of ions are represented by voltage sources (En) whose voltages are determined by the ratio of the intra- and extracellular concentrations of the ionic species of interest. Finally, ion pumps are represented by current sources (Ip). The membrane potential is denoted by Vm.
Mathematically, the current flowing into the capacitance of the lipid bilayer is written as
I
c
=
C
m
d
V
m
d
t
{\displaystyle I_{c}=C_{m}{\frac {{\mathrm {d} }V_{m}}{{\mathrm {d} }t}}}
and the current through a given ion channel is the product of that channel's conductance and the driving potential for the specific ion
I
i
=
g
i
(
V
m
−
V
i
)
{\displaystyle I_{i}={g_{i}}(V_{m}-V_{i})\;}
where
V
i
{\displaystyle V_{i}}
is the reversal potential of the specific ion channel.
Thus, for a cell with sodium and potassium channels, the total current through the membrane is given by:
I
=
C
m
d
V
m
d
t
+
g
K
(
V
m
−
V
K
)
+
g
N
a
(
V
m
−
V
N
a
)
+
g
l
(
V
m
−
V
l
)
{\displaystyle I=C_{m}{\frac {{\mathrm {d} }V_{m}}{{\mathrm {d} }t}}+g_{K}(V_{m}-V_{K})+g_{Na}(V_{m}-V_{Na})+g_{l}(V_{m}-V_{l})}
where I is the total membrane current per unit area, Cm is the membrane capacitance per unit area, gK and gNa are the potassium and sodium conductances per unit area, respectively, VK and VNa are the potassium and sodium reversal potentials, respectively, and gl and Vl are the leak conductance per unit area and leak reversal potential, respectively. The time dependent elements of this equation are Vm, gNa, and gK, where the last two conductances depend explicitly on the membrane voltage (Vm) as well.
== Ionic current characterization ==
In voltage-gated ion channels, the channel conductance is a function of both time and voltage (
g
n
(
t
,
V
)
{\displaystyle g_{n}(t,V)}
in the figure), while in leak channels,
g
l
{\displaystyle g_{l}}
, it is a constant (
g
L
{\displaystyle g_{L}}
in the figure). The current generated by ion pumps is dependent on the ionic species specific to that pump. The following sections will describe these formulations in more detail.
=== Voltage-gated ion channels ===
Using a series of voltage clamp experiments and by varying extracellular sodium and potassium concentrations, Hodgkin and Huxley developed a model in which the properties of an excitable cell are described by a set of four ordinary differential equations. Together with the equation for the total current mentioned above, these are:
I
=
C
m
d
V
m
d
t
+
g
¯
K
n
4
(
V
m
−
V
K
)
+
g
¯
Na
m
3
h
(
V
m
−
V
N
a
)
+
g
¯
l
(
V
m
−
V
l
)
,
{\displaystyle I=C_{m}{\frac {{\mathrm {d} }V_{m}}{{\mathrm {d} }t}}+{\bar {g}}_{\text{K}}n^{4}(V_{m}-V_{K})+{\bar {g}}_{\text{Na}}m^{3}h(V_{m}-V_{Na})+{\bar {g}}_{l}(V_{m}-V_{l}),}
d
n
d
t
=
α
n
(
V
m
)
(
1
−
n
)
−
β
n
(
V
m
)
n
{\displaystyle {\frac {dn}{dt}}=\alpha _{n}(V_{m})(1-n)-\beta _{n}(V_{m})n}
d
m
d
t
=
α
m
(
V
m
)
(
1
−
m
)
−
β
m
(
V
m
)
m
{\displaystyle {\frac {dm}{dt}}=\alpha _{m}(V_{m})(1-m)-\beta _{m}(V_{m})m}
d
h
d
t
=
α
h
(
V
m
)
(
1
−
h
)
−
β
h
(
V
m
)
h
{\displaystyle {\frac {dh}{dt}}=\alpha _{h}(V_{m})(1-h)-\beta _{h}(V_{m})h}
where I is the current per unit area and
α
i
{\displaystyle \alpha _{i}}
and
β
i
{\displaystyle \beta _{i}}
are rate constants for the i-th ion channel, which depend on voltage but not time.
g
¯
n
{\displaystyle {\bar {g}}_{n}}
is the maximal value of the conductance. n, m, and h are dimensionless probabilities between 0 and 1 that are associated with potassium channel subunit activation, sodium channel subunit activation, and sodium channel subunit inactivation, respectively. For instance, given that potassium channels in squid giant axon are made up of four subunits which all need to be in the open state for the channel to allow the passage of potassium ions, the n needs to be raised to the fourth power. For
p
=
(
n
,
m
,
h
)
{\displaystyle p=(n,m,h)}
,
α
p
{\displaystyle \alpha _{p}}
and
β
p
{\displaystyle \beta _{p}}
take the form
α
p
(
V
m
)
=
p
∞
(
V
m
)
/
τ
p
{\displaystyle \alpha _{p}(V_{m})=p_{\infty }(V_{m})/\tau _{p}}
β
p
(
V
m
)
=
(
1
−
p
∞
(
V
m
)
)
/
τ
p
.
{\displaystyle \beta _{p}(V_{m})=(1-p_{\infty }(V_{m}))/\tau _{p}.}
p
∞
{\displaystyle p_{\infty }}
and
(
1
−
p
∞
)
{\displaystyle (1-p_{\infty })}
are the steady state values for activation and inactivation, respectively, and are usually represented by Boltzmann equations as functions of
V
m
{\displaystyle V_{m}}
. In the original paper by Hodgkin and Huxley, the functions
α
{\displaystyle \alpha }
and
β
{\displaystyle \beta }
are given by
α
n
(
V
m
)
=
0.01
(
10
−
V
)
exp
(
10
−
V
10
)
−
1
α
m
(
V
m
)
=
0.1
(
25
−
V
)
exp
(
25
−
V
10
)
−
1
α
h
(
V
m
)
=
0.07
exp
(
−
V
20
)
β
n
(
V
m
)
=
0.125
exp
(
−
V
80
)
β
m
(
V
m
)
=
4
exp
(
−
V
18
)
β
h
(
V
m
)
=
1
exp
(
30
−
V
10
)
+
1
{\displaystyle {\begin{array}{lll}\alpha _{n}(V_{m})={\frac {0.01(10-V)}{\exp {\big (}{\frac {10-V}{10}}{\big )}-1}}&\alpha _{m}(V_{m})={\frac {0.1(25-V)}{\exp {\big (}{\frac {25-V}{10}}{\big )}-1}}&\alpha _{h}(V_{m})=0.07\exp {\bigg (}-{\frac {V}{20}}{\bigg )}\\\beta _{n}(V_{m})=0.125\exp {\bigg (}-{\frac {V}{80}}{\bigg )}&\beta _{m}(V_{m})=4\exp {\bigg (}-{\frac {V}{18}}{\bigg )}&\beta _{h}(V_{m})={\frac {1}{\exp {\big (}{\frac {30-V}{10}}{\big )}+1}}\end{array}}}
where
V
=
V
r
e
s
t
−
V
m
{\displaystyle V=V_{rest}-V_{m}}
denotes the negative depolarization in mV.
In many current software programs
Hodgkin–Huxley type models generalize
α
{\displaystyle \alpha }
and
β
{\displaystyle \beta }
to
A
p
(
V
m
−
B
p
)
exp
(
V
m
−
B
p
C
p
)
−
D
p
{\displaystyle {\frac {A_{p}(V_{m}-B_{p})}{\exp {\big (}{\frac {V_{m}-B_{p}}{C_{p}}}{\big )}-D_{p}}}}
In order to characterize voltage-gated channels, the equations can be fitted to voltage clamp data. For a derivation of the Hodgkin–Huxley equations under voltage-clamp, see. Briefly, when the membrane potential is held at a constant value (i.e., with a voltage clamp), for each value of the membrane potential the nonlinear gating equations reduce to equations of the form:
m
(
t
)
=
m
0
−
[
(
m
0
−
m
∞
)
(
1
−
e
−
t
/
τ
m
)
]
{\displaystyle m(t)=m_{0}-[(m_{0}-m_{\infty })(1-e^{-t/\tau _{m}})]\,}
h
(
t
)
=
h
0
−
[
(
h
0
−
h
∞
)
(
1
−
e
−
t
/
τ
h
)
]
{\displaystyle h(t)=h_{0}-[(h_{0}-h_{\infty })(1-e^{-t/\tau _{h}})]\,}
n
(
t
)
=
n
0
−
[
(
n
0
−
n
∞
)
(
1
−
e
−
t
/
τ
n
)
]
{\displaystyle n(t)=n_{0}-[(n_{0}-n_{\infty })(1-e^{-t/\tau _{n}})]\,}
Thus, for every value of membrane potential
V
m
{\displaystyle V_{m}}
the sodium and potassium currents can be described by
I
N
a
(
t
)
=
g
¯
N
a
m
(
V
m
)
3
h
(
V
m
)
(
V
m
−
E
N
a
)
,
{\displaystyle I_{\mathrm {Na} }(t)={\bar {g}}_{\mathrm {Na} }m(V_{m})^{3}h(V_{m})(V_{m}-E_{\mathrm {Na} }),}
I
K
(
t
)
=
g
¯
K
n
(
V
m
)
4
(
V
m
−
E
K
)
.
{\displaystyle I_{\mathrm {K} }(t)={\bar {g}}_{\mathrm {K} }n(V_{m})^{4}(V_{m}-E_{\mathrm {K} }).}
In order to arrive at the complete solution for a propagated action potential, one must write the current term I on the left-hand side of the first differential equation in terms of V, so that the equation becomes an equation for voltage alone. The relation between I and V can be derived from cable theory and is given by
I
=
a
2
R
∂
2
V
∂
x
2
,
{\displaystyle I={\frac {a}{2R}}{\frac {\partial ^{2}V}{\partial x^{2}}},}
where a is the radius of the axon, R is the specific resistance of the axoplasm, and x is the position along the nerve fiber. Substitution of this expression for I transforms the original set of equations into a set of partial differential equations, because the voltage becomes a function of both x and t.
The Levenberg–Marquardt algorithm is often used to fit these equations to voltage-clamp data.
While the original experiments involved only sodium and potassium channels, the Hodgkin–Huxley model can also be extended to account for other species of ion channels.
=== Leak channels ===
Leak channels account for the natural permeability of the membrane to ions and take the form of the equation for voltage-gated channels, where the conductance
g
l
e
a
k
{\displaystyle g_{leak}}
is a constant. Thus, the leak current due to passive leak ion channels in the Hodgkin-Huxley formalism is
I
l
=
g
l
e
a
k
(
V
−
V
l
e
a
k
)
{\displaystyle I_{l}=g_{leak}(V-V_{leak})}
.
=== Pumps and exchangers ===
The membrane potential depends upon the maintenance of ionic concentration gradients across it. The maintenance of these concentration gradients requires active transport of ionic species. The sodium-potassium and sodium-calcium exchangers are the best known of these. Some of the basic properties of the Na/Ca exchanger have already been well-established: the stoichiometry of exchange is 3 Na+: 1 Ca2+ and the exchanger is electrogenic and voltage-sensitive. The Na/K exchanger has also been described in detail, with a 3 Na+: 2 K+ stoichiometry.
== Mathematical properties ==
The Hodgkin–Huxley model can be thought of as a differential equation system with four state variables,
V
m
(
t
)
,
n
(
t
)
,
m
(
t
)
{\displaystyle V_{m}(t),n(t),m(t)}
, and
h
(
t
)
{\displaystyle h(t)}
, that change with respect to time
t
{\displaystyle t}
. The system is difficult to study because it is a nonlinear system, cannot be solved analytically, and therefore has no closed-form solution. However, there are many numerical methods available to analyze the system. Certain properties and general behaviors, such as limit cycles, can be proven to exist.
=== Center manifold ===
Because there are four state variables, visualizing the path in phase space can be difficult. Usually two variables are chosen, voltage
V
m
(
t
)
{\displaystyle V_{m}(t)}
and the potassium gating variable
n
(
t
)
{\displaystyle n(t)}
, allowing one to visualize the limit cycle. However, one must be careful because this is an ad-hoc method of visualizing the 4-dimensional system. This does not prove the existence of the limit cycle.
A better projection can be constructed from a careful analysis of the Jacobian of the system, evaluated at the equilibrium point. Specifically, the eigenvalues of the Jacobian are indicative of the center manifold's existence. Likewise, the eigenvectors of the Jacobian reveal the center manifold's orientation. The Hodgkin–Huxley model has two negative eigenvalues and two complex eigenvalues with slightly positive real parts. The eigenvectors associated with the two negative eigenvalues will reduce to zero as time t increases. The remaining two complex eigenvectors define the center manifold. In other words, the 4-dimensional system collapses onto a 2-dimensional plane. Any solution starting off the center manifold will decay towards the center manifold. Furthermore, the limit cycle is contained on the center manifold.
=== Bifurcations ===
If the injected current
I
{\displaystyle I}
were used as a bifurcation parameter, then the Hodgkin–Huxley model undergoes a Hopf bifurcation. As with most neuronal models, increasing the injected current will increase the firing rate of the neuron. One consequence of the Hopf bifurcation is that there is a minimum firing rate. This means that either the neuron is not firing at all (corresponding to zero frequency), or firing at the minimum firing rate. Because of the all-or-none principle, there is no smooth increase in action potential amplitude, but rather there is a sudden "jump" in amplitude. The resulting transition is known as a canard.
== Improvements and alternative models ==
The Hodgkin–Huxley model is regarded as one of the great achievements of 20th-century biophysics. Nevertheless, modern Hodgkin–Huxley-type models have been extended in several important ways:
Additional ion channel populations have been incorporated based on experimental data.
The Hodgkin–Huxley model has been modified to incorporate transition state theory and produce thermodynamic Hodgkin–Huxley models.
Models often incorporate highly complex geometries of dendrites and axons, often based on microscopy data.
Conductance-based models similar to Hodgkin–Huxley model incorporate the knowledge about cell types defined by single cell transcriptomics.
Stochastic models of ion-channel behavior, leading to stochastic hybrid systems.
The Poisson–Nernst–Planck (PNP) model is based on a mean-field approximation of ion interactions and continuum descriptions of concentration and electrostatic potential.
Several simplified neuronal models have also been developed (such as the FitzHugh–Nagumo model), facilitating efficient large-scale simulation of groups of neurons, as well as mathematical insight into dynamics of action potential generation.
== See also ==
== References ==
== Further reading ==
== External links ==
Interactive Javascript simulation of the HH model Runs in any HTML5 – capable browser. Allows for changing the parameters of the model and current injection.
Interactive Java applet of the HH model Parameters of the model can be changed as well as excitation parameters and phase space plottings of all the variables is possible.
Direct link to Hodgkin–Huxley model and a Description in BioModels Database
Neural Impulses: The Action Potential In Action by Garrett Neske, The Wolfram Demonstrations Project
Interactive Hodgkin–Huxley model by Shimon Marom, The Wolfram Demonstrations Project
ModelDB A computational neuroscience source code database containing 4 versions (in different simulators) of the original Hodgkin–Huxley model and hundreds of models that apply the Hodgkin–Huxley model to other channels in many electrically excitable cell types.
Several articles about the stochastic version of the model and its link with the original one. | Wikipedia/Neuronal_modeling |
Personality psychology is a branch of psychology that examines personality and its variation among individuals. It aims to show how people are individually different due to psychological forces. Its areas of focus include:
Describing what personality is
Documenting how personalities develop
Explaining the mental processes of personality and how they affect functioning
Providing a framework for understanding individuals
"Personality" is a dynamic and organized set of characteristics possessed by an individual that uniquely influences their environment, cognition, emotions, motivations, and behaviors in various situations. The word personality originates from the Latin persona, which means "mask".
Personality also pertains to the pattern of thoughts, feelings, social adjustments, and behaviors persistently exhibited over time that strongly influences one's expectations, self-perceptions, values, and attitudes. Environmental and situational effects on behaviour are influenced by psychological mechanisms within a person. Personality also predicts human reactions to other people, problems, and stress. Gordon Allport (1937) described two major ways to study personality: the nomothetic and the idiographic. Nomothetic psychology seeks general laws that can be applied to many different people, such as the principle of self-actualization or the trait of extraversion. Idiographic psychology is an attempt to understand the unique aspects of a particular individual.
The study of personality has a broad and varied history in psychology, with an abundance of theoretical traditions. The major theories include dispositional (trait) perspective, psychodynamic, humanistic, biological, behaviorist, evolutionary, and social learning perspective. Many researchers and psychologists do not explicitly identify themselves with a certain perspective and instead take an eclectic approach. Research in this area is empirically driven – such as dimensional models, based on multivariate statistics like factor analysis – or emphasizes theory development, such as that of the psychodynamic theory. There is also a substantial emphasis on the applied field of personality testing. In psychological education and training, the study of the nature of personality and its psychological development is usually reviewed as a prerequisite to courses in abnormal psychology or clinical psychology.
== Philosophical assumptions ==
Many of the ideas conceptualized by historical and modern personality theorists stem from the basic philosophical assumptions they hold. The study of personality is not a purely empirical discipline, as it brings in elements of art, science, and philosophy to draw general conclusions. The following five categories are some of the most fundamental philosophical assumptions on which theorists disagree:
Freedom versus determinism – This is the question of whether humans have control over their own behavior and understand the motives behind it, or if their behavior is causally determined by forces beyond their control. Behavior is categorized as being either unconscious, environmental or biological by various theories.
Heredity (nature) versus environment (nurture) – Personality is thought to be determined largely either by genetics and biology, or by environment and experiences. Contemporary research suggests that most personality traits are based on the joint influence of genetics and environment. One of the forerunners in this arena is C. Robert Cloninger, who pioneered the Temperament and Character model.
Uniqueness versus universality – This question discusses the extent of each human's individuality (uniqueness) or similarity in nature (universality). Gordon Allport, Abraham Maslow, and Carl Rogers were all advocates of the uniqueness of individuals. Behaviorists and cognitive theorists, in contrast, emphasize the importance of universal principles, such as reinforcement and self-efficacy.
Active versus reactive – This question explores whether humans primarily act through individual initiative (active) or through outside stimuli. Traditional behavioral theorists typically believed that humans are passively shaped by their environments, whereas humanistic and cognitive theorists believe that humans play a more active role. Most modern theorists agree that both are important, with aggregate behavior being primarily determined by traits and situational factors being the primary predictor of behavior in the short term.
Optimistic versus pessimistic – Personality theories differ with regard to whether humans are integral in the changing of their own personalities. Theories that place a great deal of emphasis on learning are often more optimistic than those that do not.
== Personality theories ==
=== Type and trait theories ===
Personality type refers to the psychological classification of people into different classes. Personality types are distinguished from personality traits, which come in different degrees. For example, according to type theories, there are two types of people, introverts and extroverts. According to trait theories, introversion and extroversion are part of a continuous dimension with many people in the middle.
Personality is complex; a typical theory of personality contains several propositions or sub-theories, often growing over time as more psychologists explore the theory.
The most widely accepted empirical model of durable, universal personality descriptors is the system of Big Five personality traits: conscientiousness, agreeableness, neuroticism, openness to experience, and extraversion-introversion. It is based on cluster analysis of verbal descriptions in self-reporting surveys. These traits demonstrate considerable genetic heritability.
Perhaps the most ancient attempt at personality psychology is the personality typology outlined by the Indian Buddhist Abhidharma schools. This typology mostly focuses on negative personal traits (greed, hatred, and delusion) and the corresponding positive meditation practices used to counter those traits.
An influential European tradition of psychological types originated in the theoretical work of Carl Jung, specifically in his 1921 book Psychologische Typen (Psychological Types) and William Marston.
Building on the writings and observations of Jung during World War II, Isabel Briggs Myers and her mother, Katharine C. Briggs, delineated personality types by constructing the Myers–Briggs Type Indicator. This model was later used by David Keirsey with a different understanding from Jung, Briggs and Myers.
In the former Soviet Union, Lithuanian Aušra Augustinavičiūtė independently derived a model of personality type from Jung's called socionics. Later on many other tests were developed on this model e.g. Golden, PTI-Pro and JTI.
Theories could also be considered an "approach" to personality or psychology and is generally referred to as a model. The model is an older and more theoretical approach to personality, accepting extroversion and introversion as basic psychological orientations in connection with two pairs of psychological functions:
Perceiving functions: sensing and intuition (trust in concrete, sensory-oriented facts vs. trust in abstract concepts and imagined possibilities)
Judging functions: thinking and feeling (basing decisions primarily on logic vs. deciding based on emotion).
Briggs and Myers also added another personality dimension to their type indicator to measure whether a person prefers to use a judging or perceiving function when interacting with the external world. Therefore, they included questions designed to indicate whether someone wishes to come to conclusions (judgement) or to keep options open (perception).
This personality typology has some aspects of a trait theory: it explains people's behavior in terms of opposite fixed characteristics. In these more traditional models, the sensing/intuition preference is considered the most basic, dividing people into "N" (intuitive) or "S" (sensing) personality types. An "N" is further assumed to be guided either by thinking or feeling and divided into the "NT" (scientist, engineer) or "NF" (author, humanitarian) temperament. An "S", in contrast, is assumed to be guided more by the judgment/perception axis and thus divided into the "SJ" (guardian, traditionalist) or "SP" (performer, artisan) temperament. These four are considered basic, with the other two factors in each case (including always extraversion/introversion) less important. Critics of this traditional view have observed that the types can be quite strongly stereotyped by professions (although neither Myers nor Keirsey engaged in such stereotyping in their type descriptions), and thus may arise more from the need to categorize people for purposes of guiding their career choice. This among other objections led to the emergence of the five-factor view, which is less concerned with behavior under work conditions and more concerned with behavior in personal and emotional circumstances. (The MBTI is not designed to measure the "work self", but rather what Myers and McCaulley called the "shoes-off self.")
Type A and Type B personality theory: During the 1950s, Meyer Friedman and his co-workers defined what they called Type A and Type B behavior patterns. They theorized that intense, hard-driving Type A personalities had a higher risk of coronary disease because they are "stress junkies." Type B people, on the other hand, tended to be relaxed, less competitive, and lower in risk. There was also a Type AB mixed profile.
Health Psychology, a field of study, has been influenced by the Type A and Type B personality theories, which reveal how personality traits can impact cardiovascular health. Type A individuals, known for their competitiveness and urgency, may increase the risk of conditions like high blood pressure and coronary heart disease.
Day and Jreige (2002) investigate the Type A behavior pattern as a mediator in the relationship between job stressors and psychosocial outcomes. Their study, published in the Journal of Occupational Health Psychology, demonstrates that individuals exhibiting Type A characteristics are more susceptible to adverse psychosocial effects, such as increased stress and lower job satisfaction, when exposed to workplace stressors. This research highlights the importance of considering personality traits in managing occupational health.
Eduard Spranger's personality-model, consisting of six (or, by some revisions, 6 +1) basic types of value attitudes, described in his book Types of Men (Lebensformen; Halle (Saale): Niemeyer, 1914; English translation by P. J. W. Pigors - New York: G. E. Stechert Company, 1928).
The Enneagram of Personality, a model of human personality which is principally used as a typology of nine interconnected personality types. It has been criticized as being subject to interpretation, making it difficult to test or validate scientifically.
John L. Holland's RIASEC vocational model, commonly referred to as the Holland Codes, focuses specifically on choice of occupation. It proposes that six personality types lead people to choose their career paths. In this circumplex model, the six types are represented as a hexagon, with adjacent types more closely related than those more distant. The model is widely used in vocational counseling.
=== Psychoanalytical theories ===
Psychoanalytic theories explain human behavior in terms of the interaction of various components of personality. Sigmund Freud was the founder of this school of thought. He drew on the physics of his day (thermodynamics) to coin the term psychodynamics. Based on the idea of converting heat into mechanical energy, Freud proposed psychic energy could be converted into behavior. His theory places central importance on dynamic, unconscious psychological conflicts.
Freud divides human personality into three significant components: the id, ego and super-ego. The id acts according to the pleasure principle, demanding immediate gratification of its needs regardless of external environment; the ego then must emerge in order to realistically meet the wishes and demands of the id in accordance with the outside world, adhering to the reality principle. Finally, the superego (conscience) inculcates moral judgment and societal rules upon the ego, thus forcing the demands of the id to be met not only realistically but morally. The superego is the last function of the personality to develop, and is the embodiment of parental/social ideals established during childhood. According to Freud, personality is based on the dynamic interactions of these three components.
The channeling and release of sexual (libidal) and aggressive energies, which ensues from the "Eros" (sex; instinctual self-preservation) and "Thanatos" (death; instinctual self-annihilation) drives respectively, are major components of his theory. Freud's broad understanding of sexuality included all kinds of pleasurable feelings experienced by the human body.
Freud proposed five psychosexual stages of personality development. He believed adult personality is dependent upon early childhood experiences and largely determined by age five. Fixations that develop during the infantile stage contribute to adult personality and behavior.
One of Sigmund Freud's earlier associates, Alfred Adler, agreed with Freud that early childhood experiences are important to development, and believed birth order may influence personality development. Adler believed that the oldest child was the individual who would set high achievement goals in order to gain attention lost when the younger siblings were born. He believed the middle children were competitive and ambitious. He reasoned that this behavior was motivated by the idea of surpassing the firstborn's achievements. He added, however, that the middle children were often not as concerned about the glory attributed to their behavior. He also believed the youngest would be more dependent and sociable. Adler finished by surmising that an only child loves being the center of attention and matures quickly but in the end fails to become independent.
Heinz Kohut thought similarly to Freud's idea of transference. He used narcissism as a model of how people develop their sense of self. Narcissism is the exaggerated sense of self in which one is believed to exist in order to protect one's low self-esteem and sense of worthlessness. Kohut had a significant impact on the field by extending Freud's theory of narcissism and introducing what he called the 'self-object transferences' of mirroring and idealization. In other words, children need to idealize and emotionally "sink into" and identify with the idealized competence of admired figures such as parents or older siblings. They also need to have their self-worth mirrored by these people. Such experiences allow them to thereby learn the self-soothing and other skills that are necessary for the development of a healthy sense of self.
Another important figure in the world of personality theory is Karen Horney. She is credited with the development of "Feminist Psychology". She disagrees with Freud on some key points, one being that women's personalities are not just a function of "Penis Envy", but that girl children have separate and different psychic lives unrelated to how they feel about their fathers or primary male role models. She talks about three basic Neurotic needs "Basic Anxiety", "Basic Hostility" and "Basic Evil". She posits that to any anxiety an individual experiences they would have one of three approaches, moving toward people, moving away from people or moving against people. It is these three that give us varying personality types and characteristics. She also places a high premium on concepts like Overvaluation of Love and romantic partners.
=== Behaviorist theories ===
Behaviorists explain personality in terms of the effects external stimuli have on behavior. The approaches used to evaluate the behavioral aspect of personality are known as behavioral theories or learning-conditioning theories. These approaches were a radical shift away from Freudian philosophy. One of the major tenets of this concentration of personality psychology is a strong emphasis on scientific thinking and experimentation. This school of thought was developed by B. F. Skinner who put forth a model which emphasized the mutual interaction of the person or "the organism" with its environment. Skinner believed children do bad things because the behavior obtains attention that serves as a reinforcer. For example: a child cries because the child's crying in the past has led to attention. These are the response, and consequences. The response is the child crying, and the attention that child gets is the reinforcing consequence. According to this theory, people's behavior is formed by processes such as operant conditioning. Skinner put forward a "three term contingency model" which helped promote analysis of behavior based on the "Stimulus - Response - Consequence Model" in which the critical question is: "Under which circumstances or antecedent 'stimuli' does the organism engage in a particular behavior or 'response', which in turn produces a particular 'consequence'?"
Richard Herrnstein extended this theory by accounting for attitudes and traits. An attitude develops as the response strength (the tendency to respond) in the presences of a group of stimuli become stable. Rather than describing conditionable traits in non-behavioral language, response strength in a given situation accounts for the environmental portion. Herrnstein also saw traits as having a large genetic or biological component, as do most modern behaviorists.
Ivan Pavlov is another notable influence. He is well known for his classical conditioning experiments involving dogs, which led him to discover the foundation of behaviorism.
=== Social cognitive theories ===
In cognitive theory, behavior is explained as guided by cognitions (e.g. expectations) about the world, especially those about other people. Cognitive theories are theories of personality that emphasize cognitive processes, such as thinking and judging.
Albert Bandura, a social learning theorist suggested the forces of memory and emotions worked in conjunction with environmental influences. Bandura was known mostly for his "Bobo doll experiment". During these experiments, Bandura video taped a college student kicking and verbally abusing a bobo doll. He then showed this video to a class of kindergarten children who were getting ready to go out to play. When they entered the play room, they saw bobo dolls, and some hammers. The people observing these children at play saw a group of children beating the doll. He called this study and his findings observational learning, or modeling.
Early examples of approaches to cognitive style are listed by Baron (1982). These include Witkin's (1965) work on field dependency, Gardner's (1953) discovering people had consistent preference for the number of categories they used to categorize heterogeneous objects, and Block and Petersen's (1955) work on confidence in line discrimination judgments. Baron relates early development of cognitive approaches of personality to ego psychology. More central to this field have been:
Attributional style theory dealing with different ways in which people explain events in their lives. This approach builds upon locus of control, but extends it by stating we also need to consider whether people attribute to stable causes or variable causes, and to global causes or specific causes.
Various scales have been developed to assess both attributional style and locus of control. Locus of control scales include those used by Rotter and later by Duttweiler, the Nowicki and Strickland (1973) Locus of Control Scale for Children and various locus of control scales specifically in the health domain, most famously that of Kenneth Wallston and his colleagues, The Multidimensional Health Locus of Control Scale. Attributional style has been assessed by the Attributional Style Questionnaire, the Expanded Attributional Style Questionnaire, the Attributions Questionnaire, the Real Events Attributional Style Questionnaire and the Attributional Style Assessment Test.
Achievement style theory focuses upon identification of an individual's Locus of Control tendency, such as by Rotter's evaluations, and was found by Cassandra Bolyard Whyte to provide valuable information for improving academic performance of students. Individuals with internal control tendencies are likely to persist to better academic performance levels, presenting an achievement personality, according to Cassandra B. Whyte.
Recognition that the tendency to believe that hard work and persistence often results in attainment of life and academic goals has influenced formal educational and counseling efforts with students of various ages and in various settings since the 1970s research about achievement. Counseling aimed toward encouraging individuals to design ambitious goals and work toward them, with recognition that there are external factors that may impact, often results in the incorporation of a more positive achievement style by students and employees, whatever the setting, to include higher education, workplace, or justice programming.
Walter Mischel (1999) has also defended a cognitive approach to personality. His work refers to "Cognitive Affective Units", and considers factors such as encoding of stimuli, affect, goal-setting, and self-regulatory beliefs. The term "Cognitive Affective Units" shows how his approach considers affect as well as cognition.
Cognitive-Experiential Self-Theory (CEST) is another cognitive personality theory. Developed by Seymour Epstein, CEST argues that humans operate by way of two independent information processing systems: experiential system and rational system. The experiential system is fast and emotion-driven. The rational system is slow and logic-driven. These two systems interact to determine our goals, thoughts, and behavior.
Personal construct psychology (PCP) is a theory of personality developed by the American psychologist George Kelly in the 1950s. Kelly's fundamental view of personality was that people are like naive scientists who see the world through a particular lens, based on their uniquely organized systems of construction, which they use to anticipate events. But because people are naive scientists, they sometimes employ systems for construing the world that are distorted by idiosyncratic experiences not applicable to their current social situation. A system of construction that chronically fails to characterize and/or predict events, and is not appropriately revised to comprehend and predict one's changing social world, is considered to underlie psychopathology (mental disorders.)
From the theory, Kelly derived a psychotherapy approach and also a technique called The Repertory Grid Interview that helped his patients to uncover their own "constructs" with minimal intervention or interpretation by the therapist. The repertory grid was later adapted for various uses within organizations, including decision-making and interpretation of other people's world-views.
=== Humanistic theories ===
Humanistic psychology emphasizes that people have free will and that this plays an active role in determining how they behave. Accordingly, humanistic psychology focuses on subjective experiences of persons as opposed to forced, definitive factors that determine behavior. Abraham Maslow and Carl Rogers were proponents of this view, which is based on the "phenomenal field" theory of Combs and Snygg (1949). Rogers and Maslow were among a group of psychologists that worked together for a decade to produce the Journal of Humanistic Psychology. This journal was primarily focused on viewing individuals as a whole, rather than focusing solely on separate traits and processes within the individual.
Robert W. White wrote the book The Abnormal Personality that became a standard text on abnormal psychology. He also investigated the human need to strive for positive goals like competence and influence, to counterbalance the emphasis of Freud on the pathological elements of personality development.
Maslow spent much of his time studying what he called "self-actualizing persons", those who are "fulfilling themselves and doing the best they are capable of doing". Maslow believes all who are interested in growth move towards self-actualizing (growth, happiness, satisfaction) views. Many of these people demonstrate a trend in dimensions of their personalities. Characteristics of self-actualizers according to Maslow include the four key dimensions:
Awareness – maintaining constant enjoyment and awe of life. These individuals often experienced a "peak experience". He defined a peak experience as an "intensification of any experience to the degree there is a loss or transcendence of self". A peak experience is one in which an individual perceives an expansion of themselves, and detects a unity and meaningfulness in life. Intense concentration on an activity one is involved in, such as running a marathon, may invoke a peak experience.
Reality and problem centered – having a tendency to be concerned with "problems" in surroundings.
Acceptance/Spontaneity – accepting surroundings and what cannot be changed.
Unhostile sense of humor/democratic – do not take kindly to joking about others, which can be viewed as offensive. They have friends of all backgrounds and religions and hold very close friendships.
Maslow and Rogers emphasized a view of the person as an active, creative, experiencing human being who lives in the present and subjectively responds to current perceptions, relationships, and encounters. They disagree with the dark, pessimistic outlook of those in the Freudian psychoanalysis ranks, but rather view humanistic theories as positive and optimistic proposals which stress the tendency of the human personality toward growth and self-actualization. This progressing self will remain the center of its constantly changing world; a world that will help mold the self but not necessarily confine it. Rather, the self has opportunity for maturation based on its encounters with this world. This understanding attempts to reduce the acceptance of hopeless redundancy. Humanistic therapy typically relies on the client for information of the past and its effect on the present, therefore the client dictates the type of guidance the therapist may initiate. This allows for an individualized approach to therapy. Rogers found patients differ in how they respond to other people. Rogers tried to model a particular approach to therapy – he stressed the reflective or empathetic response. This response type takes the client's viewpoint and reflects back their feeling and the context for it. An example of a reflective response would be, "It seems you are feeling anxious about your upcoming marriage". This response type seeks to clarify the therapist's understanding while also encouraging the client to think more deeply and seek to fully understand the feelings they have expressed.
=== Biopsychological theories ===
Biology plays a very important role in the development of personality. The study of the biological level in personality psychology focuses primarily on identifying the role of genetic determinants and how they mold individual personalities. Some of the earliest thinking about possible biological bases of personality grew out of the case of Phineas Gage. In an 1848 accident, a large iron rod was driven through Gage's head, and his personality apparently changed as a result, although descriptions of these psychological changes are usually exaggerated.
In general, patients with brain damage have been difficult to find and study. In the 1990s, researchers began to use electroencephalography (EEG), positron emission tomography (PET), and more recently functional magnetic resonance imaging (fMRI), which is now the most widely used imaging technique to help localize personality traits in the brain. This line of research has led to the developing field of personality neuroscience, which uses neuroscientific methods to study the neural underpinnings of personality traits.
==== Genetic basis of personality ====
Ever since the Human Genome Project allowed for a much more in depth comprehension of genetics, there has been an ongoing controversy involving heritability, personality traits, and environmental vs. genetic influence on personality. The human genome is known to play a role in the development of personality.
Previously, genetic personality studies focused on specific genes correlating to specific personality traits. Today's view of the gene-personality relationship focuses primarily on the activation and expression of genes related to personality and forms part of what is referred to as behavioral genetics. Genes provide numerous options for varying cells to be expressed; however, the environment determines which of these are activated. Many studies have noted this relationship in varying ways in which our bodies can develop, but the interaction between genes and the shaping of our minds and personality is also relevant to this biological relationship.
DNA-environment interactions are important in the development of personality because this relationship determines what part of the DNA code is actually made into proteins that will become part of an individual. While different choices are made available by the genome, in the end, the environment is the ultimate determinant of what becomes activated. Small changes in DNA in individuals are what leads to the uniqueness of every person as well as differences in looks, abilities, brain functioning, and all the factors that culminate to develop a cohesive personality.
Cattell and Eysenck have proposed that genetics have a powerful influence on personality. A large part of the evidence collected linking genetics and the environment to personality have come from twin studies. This "twin method" compares levels of similarity in personality using genetically identical twins. One of the first of these twin studies measured 800 pairs of twins, studied numerous personality traits, and determined that identical twins are most similar in their general abilities. Personality similarities were found to be less related for self-concepts, goals, and interests.
Twin studies have also been important in the creation of the five factor personality model: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Neuroticism and extraversion are the two most widely studied traits. Individuals scoring high in trait extraversion more often display characteristics such as impulsiveness, sociability, and activeness. Individuals scoring high in trait neuroticism are more likely to be moody, anxious, or irritable. Identical twins, however, have higher correlations in personality traits than fraternal twins. One study measuring genetic influence on twins in five different countries found that the correlations for identical twins were .50, while for fraternal they were about .20. It is suggested that heredity and environment interact to determine one's personality.
=== Evolutionary theory ===
Charles Darwin is the founder of the theory of the evolution of the species. The evolutionary approach to personality psychology is based on this theory. This theory examines how individual personality differences are based on natural selection. Through natural selection organisms change over time through adaptation and selection. Traits are developed and certain genes come into expression based on an organism's environment and how these traits aid in an organism's survival and reproduction.
Polymorphisms, such as sex and blood type, are forms of diversity which evolve to benefit a species as a whole. The theory of evolution has wide-ranging implications on personality psychology. Personality viewed through the lens of evolutionary biology places a great deal of emphasis on specific traits that are most likely to aid in survival and reproduction, such as conscientiousness, sociability, emotional stability, and dominance. The social aspects of personality can be seen through an evolutionary perspective. Specific character traits develop and are selected for because they play an important and complex role in the social hierarchy of organisms. Such characteristics of this social hierarchy include the sharing of important resources, family and mating interactions, and the harm or help organisms can bestow upon one another.
=== Drive theories ===
In the 1930s, John Dollard and Neal Elgar Miller met at Yale University, and began an attempt to integrate drives (see Drive theory), into a theory of personality, basing themselves on the work of Clark Hull. They began with the premise that personality could be equated with the habitual responses exhibited by an individual – their habits. From there, they determined that these habitual responses were built on secondary, or acquired drives.
Secondary drives are internal needs directing the behavior of an individual that results from learning. Acquired drives are learned, by and large in the manner described by classical conditioning. When we are in a certain environment and experience a strong response to a stimulus, we internalize cues from the said environment. When we find ourselves in an environment with similar cues, we begin to act in anticipation of a similar stimulus. Thus, we are likely to experience anxiety in an environment with cues similar to one where we have experienced pain or fear – such as the dentist's office.
Secondary drives are built on primary drives, which are biologically driven, and motivate us to act with no prior learning process – such as hunger, thirst or the need for sexual activity. However, secondary drives are thought to represent more specific elaborations of primary drives, behind which the functions of the original primary drive continue to exist. Thus, the primary drives of fear and pain exist behind the acquired drive of anxiety. Secondary drives can be based on multiple primary drives and even in other secondary drives. This is said to give them strength and persistence. Examples include the need for money, which was conceptualized as arising from multiple primary drives such as the drive for food and warmth, as well as from secondary drives such as imitativeness (the drive to do as others do) and anxiety.
Secondary drives vary based on the social conditions under which they were learned – such as culture. Dollard and Miller used the example of food, stating that the primary drive of hunger manifested itself behind the learned secondary drive of an appetite for a specific type of food, which was dependent on the culture of the individual.
Secondary drives are also explicitly social, representing a manner in which we convey our primary drives to others. Indeed, many primary drives are actively repressed by society (such as the sexual drive). Dollard and Miller believed that the acquisition of secondary drives was essential to childhood development. As children develop, they learn not to act on their primary drives, such as hunger but acquire secondary drives through reinforcement. Friedman and Schustack describe an example of such developmental changes, stating that if an infant engaging in an active orientation towards others brings about the fulfillment of primary drives, such as being fed or having their diaper changed, they will develop a secondary drive to pursue similar interactions with others – perhaps leading to an individual being more gregarious. Dollard and Miller's belief in the importance of acquired drives led them to reconceive Sigmund Freud's theory of psychosexual development. They found themselves to be in agreement with the timing Freud used but believed that these periods corresponded to the successful learning of certain secondary drives.
Dollard and Miller gave many examples of how secondary drives impact our habitual responses – and by extension our personalities, including anger, social conformity, imitativeness or anxiety, to name a few. In the case of anxiety, Dollard and Miller note that people who generalize the situation in which they experience the anxiety drive will experience anxiety far more than they should. These people are often anxious all the time, and anxiety becomes part of their personality. This example shows how drive theory can have ties with other theories of personality – many of them look at the trait of neuroticism or emotional stability in people, which is strongly linked to anxiety.
== Personality tests ==
There are two major types of personality tests, projective and objective.
Projective tests assume personality is primarily unconscious and assess individuals by how they respond to an ambiguous stimulus, such as an ink blot. Projective tests have been in use for about 60 years and continue to be used today. Examples of such tests include the Rorschach test and the Thematic Apperception Test.
The Rorschach Test involves showing an individual a series of note cards with ambiguous ink blots on them. The individual being tested is asked to provide interpretations of the blots on the cards by stating everything that the ink blot may resemble based on their personal interpretation. The therapist then analyzes their responses. Rules for scoring the test have been covered in manuals that cover a wide variety of characteristics such as content, originality of response, location of "perceived images" and several other factors. Using these specific scoring methods, the therapist will then attempt to relate test responses to attributes of the individual's personality and their unique characteristics. The idea is that unconscious needs will come out in the person's response, e.g. an aggressive person may see images of destruction.
The Thematic Apperception Test (TAT) involves presenting individuals with vague pictures/scenes and asking them to tell a story based on what they see. Common examples of these "scenes" include images that may suggest family relationships or specific situations, such as a father and son or a man and a woman in a bedroom. Responses are analyzed for common themes. Responses unique to an individual are theoretically meant to indicate underlying thoughts, processes, and potentially conflicts present within the individual. Responses are believed to be directly linked to unconscious motives. There is very little empirical evidence available to support these methods.
Objective tests assume personality is consciously accessible and that it can be measured by self-report questionnaires. Research on psychological assessment has generally found objective tests to be more valid and reliable than projective tests. Critics have pointed to the Forer effect to suggest some of these appear to be more accurate and discriminating than they really are. Issues with these tests include false reporting because there is no way to tell if an individual is answering a question honestly or accurately.
The Myers-Briggs Type Indicator (also known as the MBTI) is self-reporting questionnaire based on Carl Jung's Psychological Types. However, the MBTI modified Jung's theory into their own by disregarding certain processes held in the unconscious mind and the impact these have on personality.
=== Personality theory assessment criteria ===
Verifiability – the theory should be formulated in such a way that the concepts, suggestions and hypotheses involved in it are defined clearly and unambiguously, and logically related to each other.
Heuristic value – to what extent the theory stimulates scientists to conduct further research.
Internal consistency – the theory should be free from internal contradictions.
Economy – the fewer concepts and assumptions required by the theory to explain any phenomenon, the better it is Hjelle, Larry (1992). Personality Theories: Basic Assumptions, Research, and Applications.
Psychology has traditionally defined personality through its behavioral patterns, and more recently with neuroscientific studies of the brain. In recent years, some psychologists have turned to the study of inner experiences for insight into personality as well as individuality. Inner experiences are the thoughts and feelings to an immediate phenomenon. Another term used to define inner experiences is qualia. Being able to understand inner experiences assists in understanding how humans behave, act, and respond. Defining personality using inner experiences has been expanding due to the fact that solely relying on behavioral principles to explain one's character may seem incomplete. Behavioral methods allow the subject to be observed by an observer, whereas with inner experiences the subject is its own observer.
=== Methods measuring inner experience ===
Descriptive experience sampling (DES): Developed by psychologist Russel Hurlburt. This is an idiographic method that is used to help examine inner experiences. This method relies on an introspective technique that allows an individual's inner experiences and characteristics to be described and measured. A beep notifies the subject to record their experience at that exact moment and 24 hours later an interview is given based on all the experiences recorded. DES has been used in subjects that have been diagnosed with schizophrenia and depression. It has also been crucial to studying the inner experiences of those who have been diagnosed with common psychiatric diseases.
Articulated thoughts in stimulated situations (ATSS): ATSS is a paradigm which was created as an alternative to the TA (think aloud) method. This method assumes that people have continuous internal dialogues that can be naturally attended to. ATSS also assesses a person's inner thoughts as they verbalize their cognitions. In this procedure, subjects listen to a scenario via a video or audio player and are asked to imagine that they are in that specific situation. Later, they are asked to articulate their thoughts as they occur in reaction to the playing scenario. This method is useful in studying emotional experience given that the scenarios used can influence specific emotions. Most importantly, the method has contributed to the study of personality. In a study conducted by Rayburn and Davison (2002), subjects' thoughts and empathy toward anti-gay hate crimes were evaluated. The researchers found that participants showed more aggressive intentions towards the offender in scenarios which mimicked hate crimes.
Experimental method: This method is an experimental paradigm used to study human experiences involved in the studies of sensation and perception, learning and memory, motivation, and biological psychology. The experimental psychologist usually deals with intact organisms although studies are often conducted with organisms modified by surgery, radiation, drug treatment, or long-standing deprivations of various kinds or with organisms that naturally present organic abnormalities or emotional disorders. Economists and psychologists have developed a variety of experimental methodologies to elicit and assess individual attitudes where each emotion differs for each individual. The results are then gathered and quantified to conclude if specific experiences have any common factors. This method is used to seek clarity of the experience and remove any biases to help understand the meaning behind the experience to see if it can be generalized. The experimental method does have some complications though. If researchers are manipulating a variable, it's possible this change will affect a different variable, which in turn will change the measured result (not the original manipulated condition), introducing uncertainty. This method, in personality research, often requires deception, so the ethics of experiments are also brought into question.
== See also ==
== References ==
== Further reading ==
Allport, G. W. (1937). Personality: A psychological interpretation. New York: Holt, Rinehart & Winston.
Mischel, Walter (1999-01-01). An Introduction to Personality. John Wiley & Sons Incorporated. ISBN 978-0-470-00552-1. Retrieved 30 April 2012.
Buss, D.M.; Greiling, H. (1999). "Adaptive Individual Differences". Journal of Personality. 67 (2): 209–243. CiteSeerX 10.1.1.387.3246. doi:10.1111/1467-6494.00053.
Lombardo, G.P.; Foschi, R. (2003). "The concept of personality in 19th-century French and 20th-century American psychology". History of Psychology. 6 (2): 123–142. doi:10.1037/1093-4510.6.2.123. PMID 12817602.
Lombardo, G.P.; Foschi, R. (2002). "The European origins of "personality psychology". European Psychologist. 7 (2): 134–145. doi:10.1027//1016-9040.7.2.134.
Engler, Barbara (2008-08-25). Personality Theories: An Introduction. Cengage Learning. ISBN 978-0-547-14834-2. Retrieved 30 April 2012.
John, Oliver P.; Robins, Richard W.; Pervin, Lawrence A. (2010-11-24). Handbook of Personality, Third Edition: Theory and Research. Guilford Press. ISBN 978-1-60918-059-1. Retrieved 30 April 2012.
Hall, Calvin S., and Gardner Lindzey (1957). Theories of Personality. New York: J. Wiley & Sons. xi, 571 p., ill. with diagrams.
Hjelle, Larry A.; Ziegler, Daniel J. (1992-01-01). Personality theories: basic assumptions, research, and applications. McGraw-Hill. ISBN 978-0-07-029079-2. Retrieved 30 April 2012.
Ryckman, Richard M. (2007-03-15). Theories of Personality. Cengage Learning. ISBN 978-0-495-09908-6. Retrieved 30 April 2012.
== External links ==
Northwestern University-led collaboration between personality psychologists worldwide to "attempt to bring information about current personality theory and research to the readers of the World Wide Web"
Psychology, Art of Human Life : Personality
Cambridge University based myPersonality project offering to researchers access to robust database of millions of detailed psycho-demographic profiles
Personality Theories
Personality: Theory & Perspectives – Individual Differences
Holland's Types (PDF)
Murray, Henry A.; Kluckhohn, Clyde (1953). "Personality in Nature, Society, and Culture".
What is Personality Psychology? | Wikipedia/Personality_theory |
In economics, the consumption function describes a relationship between consumption and disposable income. The concept is believed to have been introduced into macroeconomics by John Maynard Keynes in 1936, who used it to develop the notion of a government spending multiplier.
== Details ==
Its simplest form is the linear consumption function used frequently in simple Keynesian models:
C
=
a
+
b
⋅
Y
d
{\displaystyle C=a+b\cdot Y_{d}}
where
a
{\displaystyle a}
is the autonomous consumption that is independent of disposable income; in other words, consumption when disposable income is zero. The term
b
⋅
Y
d
{\displaystyle b\cdot Y_{d}}
is the induced consumption that is influenced by the economy's income level
Y
d
{\displaystyle Y_{d}}
. The parameter
b
{\displaystyle b}
is known as the marginal propensity to consume, i.e. the increase in consumption due to an incremental increase in disposable income, since
∂
C
/
∂
Y
d
=
b
{\displaystyle \partial C/\partial Y_{d}=b}
. Geometrically,
b
{\displaystyle b}
is the slope of the consumption function.
Keynes proposed this model to fit three stylized facts:
People typically spend a part, but not all of their income on consumption, and they save the rest. They typically do not borrow money to spend, or borrow money to save. This fact is modelled by requiring
.
People with higher income save a higher proportion of the income. This is modelled by
C
Y
d
{\displaystyle {\frac {C}{Y_{d}}}}
decreasing with
Y
d
{\displaystyle Y_{d}}
.
People, when deciding how much to save, are insensitive to the interest rate.
By basing his model in how typical households decide how much to save and spend, Keynes was informally using a microfoundation approach to the macroeconomics of saving.
Keynes also took note of the tendency for the marginal propensity to consume to decrease as income increases, i.e.
∂
2
C
/
∂
Y
d
2
<
0
{\displaystyle \partial ^{2}C/\partial Y_{d}^{2}<0}
. If this assumption is to be used, it would result in a nonlinear consumption function with a diminishing slope. Further theories on the shape of the consumption function include James Duesenberry's (1949) relative consumption expenditure, Franco Modigliani and Richard Brumberg's (1954) life-cycle hypothesis, and Milton Friedman's (1957) permanent income hypothesis.
Some new theoretical works following Duesenberry's and based in behavioral economics suggest that a number of behavioural principles can be taken as microeconomic foundations for a behaviorally-based aggregate consumption function.
== See also ==
Aggregate demand
Absolute income hypothesis
Life cycle hypothesis
Measures of national income and output
Permanent income hypothesis
== Notes ==
== Further reading ==
Poindexter, J. Carl (1976). "The Consumption Function". Macroeconomics. Hinsdale: Dryden Press. pp. 113–141. ISBN 0-03-089419-0. (Undergraduate level discussion of the subject.)
Sargent, Thomas J. (1979). "The Consumption Function". Macroeconomic Theory. New York: Academic Press. pp. 298–323. ISBN 0-12-619750-4. (Graduate level discussion of the subject.)
== External links ==
An essay examining the strengths and weaknesses of Keynes's theory of consumption | Wikipedia/Consumption_function |
Consumer culture theory (CCT) is the study of consumption from a social and cultural point of view, as opposed to an economic or psychological one.
CCT does not offer a grand unifying theory but "refers to a family of theoretical perspectives that address the dynamic relationships between consumer actions, the marketplace, and cultural meanings". Reflective of a post-modernist society, CCT views cultural meanings as being numerous and fragmented and hence views culture as an amalgamation of different groups and shared meanings, rather than a homogeneous construct (such as the American culture).
Consumer culture is viewed as "social arrangement in which the relations between lived culture and social resources, between meaningful ways of life and the symbolic and material resources on which they depend, are mediated through markets" and consumers as part of an interconnected system of commercially produced products and images which they use to construct their identity and orient their relationships with others. This evolution underscores the intricate relationship between technology, consumer behavior, and cultural production in contemporary society.
== Methodology ==
There is a widely held misperception by people outside CCT researchers that this field is oriented toward the study of consumption contexts. Memorable study contexts, such as the Harley-Davidson subculture or the Burning Man festival probably fueled this perspective, which is far from the theory development aim of this school of thought. Some academic journals associated with research on consumer culture theory are Journal of Consumer Research, Consumption Markets & Culture, and Marketing Theory.
CCT is often associated with qualitative methodologies, such as interviews, case studies, ethnography, and netnography, because they are suitable to study the experiential, sociological and cultural aspects of consumption. However, CCT researchers use a variety of methods
== Fields of study ==
In 2005, Arnould and Thompson identified four research programs in CCT:
Consumer identity projects, such as Schau & Gilly study on personal web space, which studied how consumers create a coherent self through marketer-produced materials
Marketplace culture. These studies look at consumers as culture producers. Some examples include subcultures of consumption, brand communities, and consumer tribes.
Mass-mediated marketplace ideologies and consumers' interpretive strategies, such as Kozinets study of the Burning Man Festival, which looked at consumer ideologies and identities are influenced by economic and cultural globalisation and how cultural product systems orient consumers toward certain ideologies or identity projects.
Sociohistoric patterning of consumption, such as Holt study which looked at the influence of social capital on consumption choices.
== References == | Wikipedia/Consumer_culture_theory |
Place theory is a theory of hearing that states that our perception of sound depends on where each component frequency produces vibrations along the basilar membrane. By this theory, the pitch of a sound, such as a human voice or a musical tone, is determined by the places where the membrane vibrates, based on frequencies corresponding to the tonotopic organization of the primary auditory neurons.
More generally, schemes that base attributes of auditory perception on the neural firing rate as a function of place are known as rate–place schemes.
The main alternative to the place theory is the temporal theory, also known as timing theory. These theories are closely linked with the volley principle or volley theory, a mechanism by which groups of neurons can encode the timing of a sound waveform. In all cases, neural firing patterns in time determine the perception of pitch. The combination known as the place–volley theory uses both mechanisms in combination, primarily coding low pitches by temporal pattern and high pitches by rate–place patterns. It is now generally believed that there is good evidence for both mechanisms.
The place theory is usually attributed to Hermann Helmholtz, though it was widely believed much earlier.
Experiments to distinguish between place theory and rate theory are difficult to devise, because of the strong correlation: large vibrations with low rate are produced at the apical end of the basilar membrane while large vibrations with high rate are produced at the basal end. The two can be controlled independently using cochlear implants: pulses with a range of rates can be applied via electrodes distributed along the membrane. Experiments using implant recipients showed that, at low stimulation rates, ratings of pitch on a pitch scale were proportional to the log of stimulation rate, but also decreased with distance from the round window. At higher rates, the effect of rate was weaker, but the effect of place was strong.
== References == | Wikipedia/Place_theory |
Music-evoked autobiographical memories (MEAMs) refer to the recollection of personal experiences or past events that are triggered when hearing music or some musical stimulus. While there is a degree of inter-individual variation in music listening patterns and evoked responses, MEAMs are generally triggered in response to a wide variety of music, often popular or classical genres, and are estimated to occur in the range from one to a few times per day, regardless of formal instrumental practice or music lessons. Consistent with the hallmarks of general autobiographical memories, everyday MEAMs similarly exhibit a recency effect, a reminiscence bump (later discussed in the section “The reminiscence bump”), and childhood amnesia, encoding autobiographical knowledge at several levels of specificity and across several common social and situational contexts. The phenomenon of MEAMs has been widely studied in the fields of psychology, neuroscience, and musicology. In recent years, the subject has garnered significant interest from researchers and the general public alike due to music's capacity to evoke vivid, emotional, and episodically rich autobiographical memories.
== History ==
The relationship between music and memory has long been recognized, with music's ability to elicit emotional responses and trigger memories dating back to ancient times. In ancient Graeco-Roman society, for instance, musical memory formed a fundamental part of social, cultural, and political life.
The scientific study of music's deep correlation with autobiographical memories gained prominence in the early 2000s, when the term “music-evoked autobiographical memory” was coined by cognitive neuroscientist Petr Janata and colleagues, who first described the phenomenon in healthy undergraduate students. At this time, Janata conducted a pioneering experiment in which his team developed a novel approach to studying autobiographical memory using a range of popular music. Analyses indicated that 30% of the presented songs evoked autobiographical memories, demonstrating the paradigm's efficacy and justifying its use in subsequent neuroimaging work.
Since Janata's work, numerous studies have contributed to the understanding of MEAMs. Researchers have investigated factors that influence the formation and retrieval of MEAMs, from the characteristics of the music stimulus to its personal relevance, with many contemporary studies citing his work.
== Recording techniques ==
=== fMRI ===
Functional magnetic resonance imaging (fMRI) is a powerful neuroimaging technique that has been instrumental in advancing our understanding of MEAMs. By utilizing fMRI, researchers aim to uncover the neural mechanisms underlying this unique experience and shed light on the intricate interplay between music, memory, and emotions.
In studies exploring MEAMs, participants are typically placed inside an MRI scanner while they listen to music that holds personal significance to them. The fMRI scanner measures the blood oxygen level-dependent (BOLD) signals, which provide an indirect measure of neural activity. Researchers analyze the fMRI data to identify brain regions that exhibit increased activity during MEAM retrieval compared to control conditions. These regions are believed to play crucial roles in memory processing, emotional responses, and self-referential processing.
Beyond fMRI measurements, studies on MEAMs often incorporate additional behavioral measures such as questionnaires or interviews to capture the subjective experience and vividness of the retrieved memories. These measures help validate the connection between music and autobiographical memories and provide a richer understanding of the phenomenon.
Since fMRI measures blood oxygenation level-dependent signals, this showcases an indirect line to neural activity, which can be seen as a limitation to this recording system.
=== EEG ===
Electroencephalography (EEG) has emerged as a valuable tool in the investigation of MEAMs. EEG allows researchers to examine the temporal dynamics of neural activity associated with MEAMs, providing insights into the underlying cognitive and emotional processes.
In studies focusing on MEAMs, participants wear a cap embedded with multiple electrodes that record electrical brain activity. EEG captures the millisecond-level fluctuations in neural oscillations, revealing the brain's real-time response to MEAMs. Researchers analyze the EEG data to identify specific patterns of brain activity, such as event-related potentials (ERPs) and oscillatory activity.
ERPs, derived from averaging the EEG signal time-locked to specific events, offer insights into the brain's response to musical stimuli. In MEAM research, researchers examine ERPs related to memory retrieval processes, such as the P300 component, which reflects attention allocation and memory updating. By comparing ERPs between music-evoked and control conditions, researchers gain insights into the neural mechanisms underlying MEAMs.
Oscillatory activity, as measured by EEG, provides further understanding of the neural dynamics during MEAMs. Researchers investigate changes in frequency bands, such as alpha, beta, and theta, associated with memory processes and emotional responses. For example, enhanced theta activity has been observed during successful memory retrieval, suggesting its involvement in encoding and recollection of music-evoked autobiographical memories.
EEGs have a hard time localizing the signals they receive from the brain which brings forth a limitation of being unable to capture information in a precise manner.
=== Deep learning architecture ===
Deep learning has also been a tool that is used to study MEAMs. Deep learning, a subset of machine learning, involves training neural networks with multiple layers to automatically learn and extract complex patterns from data. In the context of MEAMs, deep learning architectures are used to analyze and model the relationships between music and autobiographical memories, providing valuable insights into the underlying mechanisms.
Researchers employ deep learning architectures, such as convolutional neural networks (CNNs) and recurrent neural networks (RNNs), to process and analyze musical features and associated autobiographical memory data. CNNs excel at capturing spatial patterns and are commonly used to analyze spectrograms or other representations of music. By training CNNs on large datasets of music and associated memory information, researchers can uncover patterns and correlations that may be indicative of MEAMs.
RNNs, on the other hand, are specifically designed to model sequential data and are well-suited for analyzing the temporal aspects of music and memory. Researchers use RNNs to capture the dependencies and dynamics between musical elements and autobiographical memories. By training RNNs on sequences of music and associated memory descriptions, researchers can generate predictions and gain insights into the temporal dynamics of MEAMs.
Deep learning architectures in MEAM research are not limited to CNNs and RNNs alone. Variants such as long short-term memory (LSTM) networks and generative models, such as generative adversarial networks (GANs), are also employed. LSTM networks are capable of capturing long-range dependencies and are particularly useful when modeling the temporal aspects of music-evoked memories. GANs, on the other hand, can generate new music or memory samples based on learned patterns, allowing researchers to explore the generative aspects of MEAMs.
== Memory type ==
In general, musical memory can be split into both explicit and implicit memory systems. “Implicit” memory refers to the unconscious, automatic storage of information, encompassing procedural memories and motor skill learning. In the context of music, implicit memory accounts for the ability to play an instrument or sing a song without consciously bringing into memory how to play it. This differs from explicit memory, a declarative memory consisting of conscious recall of a specific piece of information. Explicit memory can be further split into episodic and semantic memory. Semantic memories are stored general knowledge and facts, accounting for a general sense of familiarity of music. In contrast, episodic memories are memory for the associated context of an event, accounting for the time, place, people, emotions, and personal experiences surrounding a musical experience. By these definitions, MEAMs are typically characterized as an explicit and episodic memory type. The distinct neural activation patterns associated with semantic vs episodic memories, as evidenced by a fMRI study looking into the neural correlates of music memory, helps explain some of the observed characteristics of MEAMs. This is further discussed in the next section “Brain regions involved“.
== Brain regions involved ==
The act of listening to music elicits a wide range of neural responses and engages various cognitive processes, encompassing motor, auditory, emotional, memory, and reward-related functions within the brain. Processing of musical qualities in general such as timbre, tonality, and rhythm are associated with activation in temporal (superior and middle temporal gyri, insula), frontal (superior and middle frontal gyri, cingulate gyrus, precentral gyrus), parietal (inferior parietal gyrus, precuneus, postcentral gyrus), and cerebellar regions. In terms of forming and retrieving MEAMs specifically, the medial prefrontal cortex, encompassing both dorsal and ventral regions, emerges as a central hub. The dorsal MPFC responds to the autobiographical salience of music excerpts and tracks their movements through tonal space. This region exhibited a familiarity effect and showed properties of associating structural aspects of retrieval cues with episodic memories. Additionally, rostral and ventral aspects of the MPFC also exhibited responses related to familiarity, autobiographical salience, and positive valence.
The involvement of prefrontal regions in MEAMs was not limited to the MPFC. Both lateral and medial prefrontal areas showed responses, suggesting the usage of multiple memory retrieval processes to assemble semantic and episodic content into a recollective experience with an affective component. Also, the ventrolateral prefrontal cortex (VLPFC) has been implicated in processing musical structure, integrating musical events into syntactically coherent sequences.
== Retrieval mechanisms ==
=== Involuntary vs voluntary retrieval ===
MEAMs can occur in a variety of settings, both through deliberate and spontaneous recall. There has been some debate in the classification of MEAMs as voluntary or involuntary autobiographical memories. Voluntary autobiographical memories are “personal memories that follow a controlled, strategic retrieval process”. Involuntary autobiographical memories are “memories of personal events that come to mind spontaneously-that is, with no conscious initiation of the retrieval process”. They are considered to be more specific, retrieved significantly faster, and accompanied by a stronger emotional response than voluntary autobiographical memories.
Current research supports the idea that MEAMs aligns more often with the latter memory retrieval mechanism, as MEAMs are similarly more specific, retrieved faster, and are accompanied by greater emotional impact than memories retrieved in silence. A recent diary study also provides support, with a higher proportion of MEAMs being reported by participants to be involuntarily rather than deliberately retrieved. However, as 20% of participants in this study used deliberate recall, involuntary retrieval is not an exclusive feature of MEAMs.
=== Situational context ===
Involuntary memories of past events are context-sensitive, helping to explain the situational context in which MEAMs are most often evoked. Previous evidence demonstrates that involuntary memories are more likely to come back during cognitively undemanding activities, in which our mind is free to wander to thoughts about our past. These types of activities match almost perfectly with those recorded in a diary study, in which MEAMs typically occurred during routine tasks that were non-demanding on attention, such as driving, traveling, housework, and relaxing. This further introduces MEAMs as a form of music-evoked mind-wandering due to the similar type of tasks that are reported to accompany mind-wandering and daydreaming.
=== Memory reactivation through music ===
Eight psychological mechanisms have been proposed that explain how music elicits emotions. These mechanisms include brain stem reflex (arousal or surprise caused by sudden, loud, or dissonant sounds), rhythmic entrainment (increased arousal or social connectedness through synchronization with the music's rhythm), evaluative conditioning (associations formed between music and other stimuli), emotional contagion (induction of emotions expressed in the music), visual imagery (feelings of pleasure or deep relaxation evoked by mental imagery), evocation of episodic memories (MEAMs), aesthetic judgment (such as awe or wonder), and musical expectancy and predictions. Musical expectancies and predictions are particularly relevant as they not only evoke strong emotions but also play a central role in memory processing. When listening to music, expectations based on previous experiences regarding melody, harmony, and rhythm influence our emotional reactions, actions, and musical learning. These cognitive processes associated with music facilitate the retrieval of autobiographical memories.
Music can also evoke memories through specific individual associations. For example, certain songs become connected to specific events, life periods, or relationships. This effect is reinforced by the fact that people tend to revisit their preferred music more often than other cultural products. The likelihood of familiar music evoking memories may be attributed to its ability to activate an associative network of autobiographical memories, leading to spreading activation that facilitates memory retrieval.
Moreover, music plays a significant role in the formation of both social and personal identity. Certain music becomes strongly associated with essential aspects of an individual's identity and can enhance the retrieval of autobiographical memories through increased self-reference or by triggering specific memories that are central to one's identity.
== Autobiographical memory cues ==
Memory cues, or memory aids, are internal patterns of thinking or external stimuli that facilitate the retrieval of stored information. Memory cues have practical applications in various domains, including education, where they aid in processing complex information, as well as in rehabilitation programs to assist individuals with memory impairments. Thus, a primary goal in these efforts is choosing a cue that is memorable across various contexts.
=== Comparison of cues in healthy individuals ===
Music is particularly powerful in comparison to other autobiographical memory cues. Current research attests to its high saliency, with prior work indicating that MEAMs are more episodically rich and contain more perceptual details than face-evoked memories. An explanation for this observation may come from music's ability to evoke autobiographical memories in a more involuntary manner than other cues, which is described further in the previous section “Involuntary vs voluntary retrieval”. MEAMs are also characterized by greater episodic detail, personal significance, social content, and positive emotional response in comparison to television-evoked autobiographical memories. In comparison to food-evoked cues, music evokes significantly more autobiographical memories and a greater proportion of involuntary memories.
=== Comparison of cues in individuals with memory dysfunction ===
There has been a large body of evidence comparing MEAMs to other cues in populations with impaired memory function. In studies with Alzheimer's patients, MEAMs were relatively preserved as opposed to picture-evoked memories, and autobiographical memories generated in silence. In comparison to this silent condition, MEAMs were found to be more self-defining, positive, and recall enhancing.
MEAMs are also believed to be a more effective memory cue than verbal prompts, as demonstrated by results from three patients with acquired brain injury. Recent work provides evidence that both music and photographs are effective cues for individuals with behavioral variant fronto-temporal dementia, while individuals with damage to the ventromedial prefrontal cortex may experience decreased episodic richness of MEAMs.
== Emotion ==
Through its unique ability to deeply resonate with emotions and evoke vivid recollections, music has been shown to significantly enhance the formation and retrieval of personal memories. While aesthetic responses to music can vary across cultures, there is a universal aspect to music-evoked emotions. In fact, the retrieval of MEAMs often leads to an emotional reaction. These emotions can be categorized along three dimensions: valence (unpleasant to pleasant), arousal (low to high), and intensity (weak to strong). A recent study explored the memories and emotions evoked when listening to musical pieces from one's past. Participants were presented with a large set of short musical excerpts, and among the songs that triggered autobiographical memories, the majority elicited strong positive emotions, such as nostalgia. These findings align with previous research, which indicates that recall is enhanced for positively valenced and arousing events. Positive emotions and high arousal levels strengthen the associations between memories, contributing to this memory-enhancing effect. Music has the ability to awaken, arouse, and evoke specific emotions, which in turn modulate and influence various cognitive functions.
Emotions can influence the strength and quantity of MEAMs in two ways. First, the emotional intensity during the formation of a memory can enhance its vividness and consolidation into long-term memory. Second, the emotional experience when listening to music can facilitate the retrieval of memories, especially when the music is associated with a specific emotional experience. In both cases, emotions play a vital role in strengthening the connection between music and memories. It is important to note that the causal relationship between music, emotions, and memories remains a topic of debate, as there may be a reciprocal influence where music triggers emotions that, in turn, activate memories.
== The reminiscence bump ==
The "reminiscence bump" effect, observed in autobiographical memory research, highlights the tendency for older individuals to recall and rate memories from adolescence and early adulthood as more vivid and important. Studies in the realm of music have revealed that songs released during an individual's 10-30-year age range are not only preferred but are also better recognized, evoking heightened emotional responses compared to songs from other periods. Additionally, there is some evidence suggesting that music from the reminiscence bump period may prompt the retrieval of more MEAMs. Furthermore, observations have been made among undergraduate students, where increased recognition, preference, and emotional responses have been observed for music from their parents' reminiscence bump period—a phenomenon referred to as "cascading reminiscence bumps".
== Practical applications ==
=== Alzheimer’s Disease ===
Music-evoked autobiographical memories (MEAMs) have been shown to have great potential for addressing the emotional and cognitive deficits in Alzheimer's disease and other dementias. Studies assessing patient response to silence compared with music for the spontaneous recall of autobiographical memories have demonstrated that not only does music lead to improved memory recollection, but these memories tend to be associated with more positive emotions. A study by Cuddy et al. (2017) showed that MEAMs induced positive reminiscence in both Alzheimer's patients and elderly people, and music having lyrics or being preferred by the participants was not required. Merely pure, somewhat culturally familiar instrumental music was sufficient for MEAMs with a positive bias. This “positivity effect” may underscore the use of music therapy to improve the mood of Alzheimer's patients and reduce the frequency of anxiety and depression. In conjunction with reminiscence therapy, this may be a significant tool for the enhancement of wellbeing and sense of identity and self for Alzheimer's patients.
Music plays a direct role in modulating neural pathways to improve memory retrieval. Music can stimulate particular brain regions associated with the processing of memories, and overtime establish new pathways for autobiographical memory retrieval. It has been speculated that activation of the anterior hippocampus by music-evoked emotions and memories may stimulate neurogenesis and neuroplasticity to support the development of alternative pathways and decelerate atrophy of existing ones critical for memory processing and mood. As a result, Alzheimer's patients may show a reduction in memory retrieval time and improved overall performance in autobiographical memory assessments. One study, aiming to measure the effect of music compared with silence on the speed of memory retrieval, found that Alzheimer's patients in the “Music” condition improved their autobiographical memory performance significantly. They retrieved memories nearly twice as fast as subjects under the “Silence” conditions and the MEAMs were additionally more specific, emotional in nature, and had a greater influence on the participants’ mood. Another study by El Haj et al. (2011) concluded that while recall was improved with music versus silence, chosen music had an even more strongly enhancing effect for the memory retrieval of Alzheimer's patients. Familiar music appears to better leverage the evocative power of music for individuals to recall early, emotionally charged memories (generally with a positive bias) and can serve as an outstanding tool for improving the cognitive functioning and mental well-being of Alzheimer's patients. Curating personalized playlists influenced by the patients’ preferences may help induce powerful MEAMs to facilitate the development of memory retrieval pathways.
MEAMs may also improve the social interactions and communications of Alzheimer's patients. The sharing of memories, emotions, and music preferences with caregivers, family members, and friends may foster stronger connections for Alzheimer's patients. Similarly, group music therapy sessions can cultivate a supportive environment between Alzheimer's patients. This is believed to help develop a sense of positive reminiscence and overall well-being for the patients and encourage meaningful engagement with other people.
=== Mental health and depression ===
MEAMs can have a distinct effect on individuals who experience depression. The findings of a study by Sakka et al. (2020) indicate that depressed participants tend to rate their autobiographical memories evoked by music as more negative as opposed to healthy control participants. Though music is usually associated with being a pleasurable and positive activity, music can be a trigger for depressed individuals bringing back unpleasant experiences. These results have several implications when it comes to understanding depression. First, listening to music that evokes negative autobiographical memories can lead to negative health effects for depressed individuals. Second, these individuals may begin to avoid listening to music in general to avoid these negative memories. Last, the tendency of music to evoke negative memories may lead to the use of music for purposeful contemplation over negative experiences, which can be harmful for depressive individuals. These findings allow researchers to understand the ways in which music therapy can be leveraged for these individuals. For example, these findings can allow therapists to make suggestions on how patients can modify the manner in which they listen to music to evoke more positive memories and prevent negative, triggering ones. Using music as therapy for depressed individuals can have both a positive and negative effect. It can benefit these individuals by alleviating symptoms or create an even greater depressive state by triggering negative memories. Due to these findings, when using music as therapy, it appears important to make sure the chosen therapy has positive effects.
MEAMs can also have an effect on the mental health of healthy individuals not experiencing depression through the impact they have on emotion regulation and relationships between individuals. A study by Blais-Rochette et al. (2016) examines how various types of MEAMs can impact the way in which young people suppress or reprise emotions, perceive time, and internalize symptoms regarding their mental health. One notable finding of this study suggests that self-identifying with a MEAM predicts greater self esteem—when one still identifies with their remembered self specifically in a MEAM, they experience greater self esteem than other types of autobiographical memories. The implication of this finding is that music specifically provides an opportunity for the creation of a positive self identity. Another significant finding suggests that the sharing of MEAMs within relationships creates positive emotions and strengthens relationships. This social sharing can lead to an overall greater sense of happiness. Lastly, it is also important to consider that those who tend to scrutinize over the coherence of MEAMs tend to experience more negative emotions. Overall, the experience of MEAMs can encourage social sharing which, in turn, can result in overall happiness and better mental health.
=== Music therapy ===
Music has been shown to have various therapeutic effects. The Neuroscience of Music suggests that involving music in therapy can help children with anxiety, trouble focusing, coping with pain, cancer, and even autism. MEAMs can also be utilized in therapy to benefit all individuals, including those suffering from Alzheimer's, dementia, and mental health related issues. Various studies have demonstrated the benefits of using MEAMs in therapy. For example, a study by Jakubowski et al. 2022 demonstrates how music tends to evoke positive memories despite the valance of the song. Even songs that are negative in valance can bring back positive memories. Researchers suggest these findings can have implications in music therapy as a powerful memory cue. Additionally, as suggested by Jakubowski et al. 2021, these associations between music and autobiographical memories can be utilized in therapeutic practices in order to help people regulate their emotions as well as maintain their sense of self.
=== Effect on relationships ===
MEAMs can play a role in romantic relationships, specifically the way in which couples tend to link songs to their relationships. A study by Harris et al. (2020) investigated the phenomenon in which couples identify their relationship through a certain song. The findings of this study indicate that chosen songs are generally associated with positive emotions and memories. These results support current research on MEAMs, demonstrating music's abilities to elicit strong memories. The shared experience that these defining songs provide may have various beneficial impacts on a couple's relationship, including greater intimacy.
== References == | Wikipedia/Music-evoked_autobiographical_memory |
The temporal theory of hearing, also called frequency theory or timing theory, states that human perception of sound depends on temporal patterns with which neurons respond to sound in the cochlea. Therefore, in this theory, the pitch of a pure tone is determined by the period of neuron firing patterns—either of single neurons, or groups as described by the volley theory. Temporal theory competes with the place theory of hearing, which instead states that pitch is signaled according to the locations of vibrations along the basilar membrane.
Temporal theory was first suggested by August Seebeck.
== Description ==
As the basilar membrane vibrates, each clump of hair cells along its length is deflected in time with the sound components as filtered by basilar membrane tuning for its position. The more intense this vibration is, the more the hair cells are deflected and the more likely they are to cause cochlear nerve firings. Temporal theory supposes that the consistent timing patterns, whether at high or low average firing rate, code for a consistent pitch percept.
== High amplitudes ==
At high sounds levels, nerve fibers whose characteristic frequencies do not exactly match the stimulus still respond, because of the motion induced in larger areas of the basilar membrane by loud sounds. Temporal theory can help explain how we maintain this discrimination. Even when a larger group of nerve fibers are all firing, there is a periodicity to this firing, which corresponds to the periodicity of the stimulus.
== High frequencies ==
Neurons tend to have a maximum firing frequency within the range of frequencies we can hear. To be complete, rate theory must somehow explain how we distinguish pitches above this maximum firing rate. The volley theory, in which groups of neurons cooperate to code the temporal pattern, is an attempt to make the temporal theory more complete, but some frequencies are too high to see any synchrony in the cochlear nerve firings.
=== The random firing solution ===
Beament outlined a potential solution. He noted that in two classic studies individual hair cell neurons did not always fire at the first moment they were able to. Though they would fire in time with the vibrations, the neurons would not fire on every vibration. The number of skipped vibrations was seemingly random. The gaps in the resulting train of neural impulses would then all be integer multiples of the period of vibration. For example, a pure tone of 100 Hz has a period of 10 ms. The corresponding train of impulses would contain gaps of 10 ms, 20 ms, 30 ms, 40 ms, etc. Such a group of gaps can only be generated by a 100 Hz tone. The set of gaps for a sound above the maximum neural firing rate would be similar except it would be missing some of the initial gaps, however it would still uniquely correspond to the frequency. The pitch of a pure tone could then be seen as corresponding to the difference between adjacent gaps.
=== Another solution ===
Research suggests that the perception of pitch depends on both the places and patterns of neuron firings. Place theory may be dominant for higher frequencies. However, it is also suggested that place theory may be dominant for low, resolved frequency harmonics,
and that temporal theory may be dominant for high, unresolved frequency harmonics.
== Experiments to distinguish rate and place effects on pitch perception ==
Experiments to distinguish between place theory and rate theory using subjects with normal hearing are easy to devise, because of the strong correlation between rate and place: large vibrations at a low rate are produced at the apical end of the basilar membrane while large vibrations at a high rate are produced at the basal end. The two stimulus parameters can, however, be controlled independently using cochlear implants: pulses with a range of rates can be applied via different pairs of electrodes distributed along the membrane and subjects can be asked to rate a stimulus on a pitch scale.
Experiments using implant recipients (who had previously had normal hearing) showed that, at stimulation rates below about 500 Hz, ratings on a pitch scale were proportional to the log of stimulation rate, but also decreased with distance from the round window. At higher rates, the effect of rate became weaker, but the effect of place was still strong.
== References == | Wikipedia/Temporal_theory_(hearing) |
Volley theory states that groups of neurons of the auditory system respond to a sound by firing action potentials slightly out of phase with one another so that when combined, a greater frequency of sound can be encoded and sent to the brain to be analyzed. The theory was proposed by Ernest Wever and Charles Bray in 1930 as a supplement to the frequency theory of hearing. It was later discovered that this only occurs in response to sounds ranging from about 500 Hz to 5000 Hz.
== Description ==
The volley theory was explained in depth in Ernest Wever's 1949 book, Theory of Hearing Groups of neurons in the cochlea individually fire at subharmonic frequencies of a sound being heard and collectively phase-lock to match the total frequencies of the sound. The reason for this is that neurons can only fire at a maximum of about 500 Hz but other theories of hearing did not explain for hearing sounds below about 5000 Hz.
=== Harmonic spectrums ===
Sounds are often sums of multiple frequency tones. When these frequencies are whole number multiples of a fundamental frequency they create a harmonic. When groups of auditory neurons are presented with harmonics, each neuron fires at one frequency and when combined, the entire harmonic is encoded into the primary auditory cortex of the brain. This is the basis of volley theory.
=== Phase-locking ===
Phase-locking is known as matching amplitude times to a certain phase of another waveform. In the case of auditory neurons, this means firing an action potential at a certain phase of a stimulus sound being delivered. It has been seen that when being played a pure tone, auditory nerve fibers will fire at the same frequency as the tone. Volley theory suggests that groups of auditory neurons use phase-locking to represent subharmonic frequencies of one harmonic sound. This has been shown in guinea pig and cat models.
In 1980, Don Johnson experimentally revealed phase-locking in the auditory nerve fibers of the adult cat. In the presence of -40 to -100 decibel single tones lasting 15 or 30 seconds, recordings from the auditory nerve fibers showed firing fluctuations in synchrony with the stimulus. Johnson observed that during frequencies below 1000 Hz, two peaks are recorded for every cycle of the stimulus, which had varying phases according to stimulation frequency. This phenomenon was interpreted as the result of a second harmonic, phase-locking to the stimulus waveform. However, at frequencies between about 1000 Hz and 5000 Hz, phase-locking becomes progressively inaccurate and intervals tend to become more random.
=== Pitch perception ===
Pitch is an assigned, perceptual property where a listener orders sound frequencies from low to high. Pitch is hypothesized to be determined by receiving phase-locked input from neuronal axons and combining that information into harmonics. In simple sounds consisting of one frequency, the pitch is equivalent to the frequency. There are two models of pitch perception; a spectral and a temporal. Low frequency sounds evoke the strongest pitches, suggesting that pitch is based on the temporal components of the sound.
Historically, there have been many models of pitch perception. (Terhardt, 1974; Goldstein, 1973; Wightman, 1973). Many consisted of a peripheral spectral-analysis stage and a central periodicity-analysis stage. In his model, Terhardt claims that the spectral-analysis output of complex sounds, specifically low frequency ones, is a learned entity which eventually allows easy identification of the virtual pitch. The volley principle is predominantly seen during the pitch perception of lower frequencies where sounds are often resolved. Goldstein proposed that through phase-locking and temporal frequencies encoded in neuron firing rates, the brain has the itemization of frequencies that can then be used to estimate pitch.
== Discovery and history ==
Throughout the nineteenth century, many theories and concepts of hearing were created. Ernest Wever proposed the volley theory in 1937 with his paper "The Perception of Low Tones and the Resonance-Volley Theory". In this paper, Wever discusses previous theories of hearing and introduces volley theory using support from his own experiments and research. The theory was introduced as a supplement to the frequency theory or temporal theory of hearing, which was in contrast to the place theory of hearing.
=== Place theory ===
The most prominent figure in the creation of the place theory of hearing is Hermann von Helmholtz, who published his finished theory in 1885. Helmholtz claimed that the cochlea contained individual fibers for analyzing each pitch and delivering that information to the brain. Many followers revised and added to Helmholtz's theory and the consensus soon became that high frequency sounds were encoded near the base of the cochlea and that middle frequency sounds were encoded near the apex. Georg von Békésy developed a novel method of dissecting the inner ear and using stroboscopic illumination to observe the basilar membrane move, adding evidence to support the theory.
=== Frequency theory ===
Ideas related to the frequency theory of hearing came about in the late 1800s as a result of the research of many individuals. In 1865, Heinrich Adolf Rinne challenged the place theory; he claimed that it’s not very efficient for complex sounds to be broken into simple sounds then be reconstructed in the brain. Later, Friedrich Voltolini added on by proposing that every auditory hair cell is stimulated by any sound. Correspondingly, William Rutherford provided evidence that this hypothesis was true, allowing greater accuracy of the cochlea. In 1886, Rutherford also proposed that the brain interpreted the vibrations of the hair cells and that the cochlea did no frequency or pitch analysis of the sound. Soon after, Max Friedrich Meyer, among other ideas, theorized that nerves would be excited at the same frequency of the stimulus.
=== Volley theory ===
Of the various theories and notions created by Rinne, Rutherford, and their followers, the frequency theory was born. In general, it claimed that all sounds were encoded to the brain by neurons firing at a rate that mimics the frequency of the sound. However, because humans can hear frequencies up to 20,000 Hz but neurons cannot fire at these rates, the frequency theory had a major flaw. In an effort to combat this fault, Ernest Wever and Charles Bray, in 1930, proposed the volley theory, claiming that multiple neurons could fire in a volley to later combine and equal the frequency of the original sound stimulus. Through more research, it was determined that because phase synchrony is only accurate up to about 1000 Hz, volley theory cannot account for all frequencies at which we hear.
=== Present thoughts ===
Ultimately, as new methods of studying the inner ear came about, a combination of place theory and frequency theory was adopted. Today, it is widely believed that hearing follows the rules of the frequency theory, including volley theory, at frequencies below 1000 Hz and place theory at frequencies above 5000 Hz. For sounds with frequencies between 1000 and 5000 Hz, both theories come into play so the brain can utilize the basilar membrane location and the rate of the impulse.
== Experimental evidence ==
Due to the invasiveness of most hearing related experiments, it is difficult to use human models in the study of the auditory system. However, many findings have been revealed in cats and guinea pigs. Additionally, there are few ways to study the basilar membrane in vivo.
=== Sound Stimuli ===
Many revolutionary concepts regarding hearing and encoding sound in the brain were founded in the late nineteenth and early twentieth centuries. Various tools were used to induce a response in auditory nerves, and that were to be recorded. Experiments by Helmholtz, Wever, and Bray often involved the use of organ pipes, stretched springs, loaded reeds, lamellas, vibrating forks, beats, and interruption tones to create “clicks”, harmonics, or pure tones. Today, electronic oscillators are often used to create sinusoidal or square waves of precise frequencies.
=== Electrophysiology ===
Attempts to electrically record from the auditory nerve began as early as 1896. Electrodes were placed into the auditory nerve of various animal models to give insight on the rate at which the neurons are firing. In a 1930 experiment involving the auditory nerve of a cat, Wever and Bray found that 100–5000 Hz sounds played to the cat produced similar frequency firing in the nerve. This supported the frequency theory and the volley theory.
=== Stroboscopic illumination ===
Pioneered by Georg von Békésy, a method to observe the basilar membrane in action came about in the mid 1900s. Békésy isolated the cochlea from human and animal cadavers and labeled the basilar membrane with silver flakes. This allowed strobe imaging to capture the movement of the membrane as sounds stimulated the hair cells. This led to the solidification of the idea that high frequencies excite the basal end of the cochlea and provided new information that low frequencies excite a large area of the cochlea. This new finding suggested that specialized properties are occurring for high frequency hearing and that low frequencies involve mechanisms explained in the frequency theory.
=== Missing fundamental ===
A fundamental frequency is the lowest frequency of a harmonic. In some cases, sound can have all the frequencies of a harmonic but be missing the fundamental frequency, this is known as missing fundamental. When listening to a sound with a missing fundamental, the human brain still receives information for all frequencies, including the fundamental frequency which does not exist in the sound. This implies that sound is encoded by neurons firing at all frequencies of a harmonic, therefore, the neurons must be locked in some way to result in the hearing of one sound.
=== Hearing loss and deafness ===
Congenital deafness or sensorineural hearing loss is an often used model for the study of the inner ear regarding pitch perception and theories of hearing in general. Frequency analysis of these individuals’ hearing has given insight on common deviations from normal tuning curves, excitation patterns, and frequency discrimination ranges. By applying pure or complex tones, information on pitch perception can be obtained. In 1983, it was shown that subjects with low frequency sensorineural hearing loss demonstrated abnormal psychophysical tuning curves. Changes in the spatial responses in these subjects showed similar pitch judgment abilities when compared to subjects with normal spatial responses. This was especially true regarding low frequency stimuli. These results suggest that the place theory of hearing does not explain pitch perception at low frequencies, but that the temporal (frequency) theory is more likely. This conclusion is due to the finding that when deprived of basilar membrane place information, these patients still demonstrated normal pitch perception. Computer models for pitch perception and loudness perception are often used during hearing studies on acoustically impaired subjects. The combination of this modeling and knowledge of natural hearing allows for better development of hearing aids.
== References == | Wikipedia/Volley_theory |
Hypergraphia is a behavioral condition characterized by the intense desire to write or draw. Forms of hypergraphia can vary in writing style and content. It is a symptom associated with temporal lobe changes in epilepsy and in Geschwind syndrome. Structures that may have an effect on hypergraphia when damaged due to temporal lobe epilepsy are the hippocampus and Wernicke's area. Aside from temporal lobe epilepsy, chemical causes may be responsible for inducing hypergraphia.
== Characteristics ==
=== Writing style ===
American neurologists Stephen Waxman and Norman Geschwind were the first to describe hypergraphia, in the 1970s. The patients they observed displayed highly compulsive detailed writing, sometimes with literary creativity. The patients kept diaries, which some used to meticulously document minute details of their everyday activities, write poetry, or create lists. Case 1 of their study wrote lists of her relatives, her likes and dislikes, and the furniture in her apartment. Beside lists, the patient wrote poetry, often with a moral or philosophical undertone. She described an incident in which she wrote the lyrics of a song she learned when she was 17 several hundred times and another incident in which she felt the urge to write a word over and over again. Another patient wrote aphorisms and certain sentences in repetition.
A patient from a separate study experienced continuous "rhyming in his head" for five years after a seizure and said that he "felt the need to write them down." The patient did not talk in rhyme, nor did he read poetry. Language capacity and mental status were normal for this patient, except for recorded right-temporal spikes on electroencephalograms. This patient had right-hemisphere epilepsy. Functional MRI scans of other studies suggest that rhyming behavior is produced in the left hemisphere, but Mendez proposed that postictal hypoactivity of the right hemisphere may induce a release of writing and rhyming abilities in the left hemisphere.
=== Content ===
In addition to writing in different forms (poetry, books, repetition of one word), hypergraphia patients differ in the complexity of their writings. While some writers (e.g. Alice Flaherty and Dyane Harwood) use their hypergraphia to help them write extensive papers and books, most patients do not write things of substance. Flaherty describes hypergraphia as a result of decreased temporal lobe function which disinhibits frontal lobe idea and language generation, "sometimes at the expense of quality." Patients hospitalized with temporal lobe epilepsy and other disorders causing hypergraphia have written memos and lists (like their favorite songs) and recorded their dreams in extreme length and detail.
There are many accounts of patients writing in nonsensical patterns including writing in a center-seeking spiral starting around the edges of a piece of paper. In one case study, a patient even wrote backward, so that the writing could only be interpreted with the aid of a mirror. Sometimes the writing can consist of scribbles and frantic, random thoughts that are quickly jotted down on paper very frequently. Grammar can be present, but the meaning of these thoughts is generally hard to grasp and the sentences are loose. In some cases, patients write extremely detailed accounts of events that are occurring or descriptions of where they are.
In some cases, hypergraphia can manifest with compulsive drawing. The composer Robert Schumann, during periods of high musical output, also wrote many long letters to his wife Clara; similarly, Vincent van Gogh had much more written correspondence during bouts of intense painting. Many drawings by patients with hypergraphia exhibit repetition and a high level of detail, sometimes mixing both compulsive writing and drawing together.
== Causes ==
Some studies have suggested that hypergraphia is related to bipolar disorder, hypomania, and schizophrenia. Although creative ability was observed in the patients of these studies, signs of creativity were observed, not hypergraphia specifically. Therefore, it is difficult to say with absolute certainty that hypergraphia is a symptom of these psychiatric illnesses because creativity in patients with bipolar disorder, hypomania, or schizophrenia may manifest into something aside from writing. However, other studies have shown significant accounts between hypergraphia and temporal lobe epilepsy and chemical causes.
=== Temporal lobe epilepsy ===
Hypergraphia was first studied as a symptom of temporal lobe epilepsy, a condition of reoccurring seizures caused by excessive neuronal activity, but it is not a common symptom among patients. Less than 10 percent of patients with temporal lobe epilepsy exhibit characteristics of hypergraphia. Temporal lobe epilepsy patients may exhibit irritability, discomfort, or an increasing feeling of dread if their writing activity is disrupted. To elicit such responses when interrupting their writing suggests that hypergraphia is a compulsive condition, resulting in an obsessive motivation to write. A temporal lobe epilepsy may influence frontotemporal connections in such a way that the drive to write is increased in the frontal lobe, beginning with the prefrontal and premotor cortex planning out what to write, and then leading to the motor cortex (located next to the central fissure) executing the physical movement of writing.
Most temporal lobe epilepsy patients who suffer from hypergraphia can write words, but not all may have the capacity to write complete sentences that have meaning.
=== Bipolar disorder ===
The disorder most often associated with high-output writers is bipolar disorder, especially during hypomania. In fact, temporal lobe epilepsy is more likely to produce hypergraphia if it also produces manic symptoms. While depression has been linked to increased writing, it appears that most writers with depression write little while depressed, and high output periods correspond to rebound mood elevation after the end of a depression, or in mixed mood states.
=== Chemicals ===
Drugs that boost mood and energy have been known to induce hypergraphia, possibly by increasing activity in brain networks utilizing one of the body's neurotransmitters, dopamine. Dopamine has been known to decrease latent inhibition, which causes a decrease in the ability to habituate to screen out unexpected stimuli. Low latent inhibition leads to an excessive level of stimulation and could contribute to the onset of hypergraphia and general creativity. This research implies that there is a direct correlation between the levels of dopamine between neuronal synapses and the level of creativity exhibited by the patient. Dopamine agonists increase the levels of dopamine between synapses which results in higher levels of creativity, and the opposite is true for dopamine antagonists.
In one case study, a patient taking donepezil reported an elevation in mood and energy levels which led to hypergraphia and other excessive forms of speech (such as singing). Six other cases of patients taking donepezil and experiencing mania have been previously reported. These patients also had cases of dementia, cognitive impairment from a cerebral aneurysm, bipolar I disorder, and/or depression. Researchers are unsure why donepezil can induce mania and hypergraphia. It could potentially result from an increase in acetylcholine levels, which would have an effect on the other neurotransmitters in the brain.
== Pathophysiology ==
Several regions of the brain are involved in the act of written composition. Handwriting depends on the superior parietal cortex, and motor control areas in the frontal lobe and cerebellum. An area of the frontal lobe that is especially active is Exner's area, located in the premotor cortex. Writing creatively and generating ideas, on the other hand, activates multiple sites in the limbic system and cerebral cortex, including the left inferior frontal gyrus (BA 45) and the left temporal pole (BA 38). Lesions to Wernicke's area (in the left temporal lobe) can increase speech output, which can sometimes manifest itself in writing. In one study, patients with hippocampal atrophy showed signs of having Geschwind syndrome, including hypergraphia. While epilepsy-induced hypergraphia is usually lateralized to the left cerebral hemisphere in the language areas, hypergraphia associated with lesions and other brain damage usually occurs in the right cerebral hemisphere. Lesions to the right side of the brain usually cause hypergraphia because they can disinhibit language function on the left side of the brain. Hypergraphia has also been known to be caused by right hemisphere strokes and tumors.
== Society and culture ==
Hypergraphia was one of the central issues in the 1999 trial of Alvin Ridley for the imprisonment and murder of his wife Virginia Ridley. The mysterious woman, who had died in bed of apparent suffocation, had remained secluded in her home for 27 years in the small town of Ringgold, Georgia, United States. Her 10,000-page journal, which provided abundant evidence that she suffered from epilepsy and had remained housebound of her own will, was instrumental in the acquittal of her husband.
In 1969, Isaac Asimov said "I am a compulsive writer". Other artistic figures reported to have been affected by hypergraphia include Vincent van Gogh, Fyodor Dostoevsky, and Robert Burns. Alice in Wonderland author Lewis Carroll is also said to have had the condition, having written more than 98,000 letters in various formats throughout his life. Some were written backward, in rebus, and in patterns, as with "The Mouse's Tale" in Alice.
Eleanor Alice Burford, whose pen-names included Jean Plaidy, Victoria Holt, Philippa Carr, Eleanor Burford, Elbur Ford, Kathleen Kellow, Anna Percival, and Ellalice Tate, described herself as a compulsive writer.
Naomi Mitchison, often called a doyenne of Scottish literature, writing over 90 books of historical and science fiction, travel writing and autobiography, has been described as a compulsive writer.
== See also ==
Automatic writing
Free writing
Graphomania
== References ==
== Further reading ==
Flaherty, Alice Weaver (2004). The Midnight Disease: The Drive to Write, Writer's Block, and the Creative Brain. Houghton Mifflin Harcourt. ISBN 0-618-23065-3.
Pickover, C. A. (1999). Strange brains and genius: The secret lives of eccentric scientists and madmen. New York: William Morrow. ISBN 0-688-16894-9
Schachter, S. C., Holmes, G. L., & Kasteleijn-Nolst Trenité, D. (2008). Behavioral aspects of epilepsy: Principles and practice. New York: Demos. ISBN 1-933864-04-4 | Wikipedia/Hypergraphia |
Reproducibility, closely related to replicability and repeatability, is a major principle underpinning the scientific method. For the findings of a study to be reproducible means that results obtained by an experiment or an observational study or in a statistical analysis of a data set should be achieved again with a high degree of reliability when the study is replicated. There are different kinds of replication but typically replication studies involve different researchers using the same methodology. Only after one or several such successful replications should a result be recognized as scientific knowledge.
== Types of reproducibility ==
There are different kinds of replication studies, each serving a unique role in scientific validation:
Direct replication – the exact experiment or study is repeated under the same conditions to verify the original findings.
Conceptual replication – a study tests the same hypothesis but uses a different methodology, materials, or population to see if the results hold in different contexts.
Computational reproducibility – in data science and computational research, reproducibility requires making all datasets, code, and algorithms openly available so others can replicate the analysis and obtain the same results.
== Importance of reproducibility ==
Reproducibility serves several critical purposes in science:
Verification of results – confirms that findings are not due to random chance or errors.
Building trust in research – scientists, policymakers, and the public rely on reproducible studies to make informed decisions.
Advancing knowledge – establishes a strong foundation for future research by validating existing theories.
Avoiding bias and fraud – helps detect false positives, publication bias, and data manipulation that could mislead the scientific community.
Many studies fail reproducibility tests, leading to what is known as the replication crisis in fields like psychology, medicine, and social sciences.
Some key challenges include:
Insufficient data sharing – many researchers do not make raw data, code, or methodology openly available, making replication difficult.
Small sample sizes – studies with limited sample sizes may show results that do not generalize to larger populations.
Publication bias – journals tend to publish positive findings rather than null or negative results, leading to an incomplete scientific record.
Complex experimental conditions – in some cases, small variations in laboratory settings, equipment, or researcher expertise can affect outcomes, making exact replication difficult.
== Real-world applications of reproducibility ==
Medical research – reproducibility ensures that clinical trials and drug effectiveness studies produce reliable results before treatments reach the public.
AI and machine learning – scientists emphasize reproducibility in AI by requiring open-source models and datasets to validate algorithm performance.
Climate science – climate models must be reproducible across different datasets and simulations to ensure accurate predictions of global warming.
Pharmaceutical development – drug discovery relies on reproducing experiments across multiple labs to ensure safety and efficacy.
== Improving reproducibility in science ==
To enhance reproducibility, researchers and institutions can adopt several best practices:
Open data and code – making datasets and computational methods publicly available ensures that others can verify results.
Registered reports – some scientific journals now accept studies based on pre-registered research plans, reducing bias.
Standardized methods – using well-documented, standardized experimental protocols helps ensure consistent results.
Independent replication studies – funding agencies and journals should prioritize replication studies to strengthen scientific integrity.
With a narrower scope, reproducibility has been defined in computational sciences as having the following quality: the results should be documented by making all data and code available in such a way that the computations can be executed again with identical results.
In recent decades, there has been a rising concern that many published scientific results fail the test of reproducibility, evoking a reproducibility or replication crisis.
== History ==
The first to stress the importance of reproducibility in science was the Anglo-Irish chemist Robert Boyle, in England in the 17th century. Boyle's air pump was designed to generate and study vacuum, which at the time was a very controversial concept. Indeed, distinguished philosophers such as René Descartes and Thomas Hobbes denied the very possibility of vacuum existence. Historians of science Steven Shapin and Simon Schaffer, in their 1985 book Leviathan and the Air-Pump, describe the debate between Boyle and Hobbes, ostensibly over the nature of vacuum, as fundamentally an argument about how useful knowledge should be gained. Boyle, a pioneer of the experimental method, maintained that the foundations of knowledge should be constituted by experimentally produced facts, which can be made believable to a scientific community by their reproducibility. By repeating the same experiment over and over again, Boyle argued, the certainty of fact will emerge.
The air pump, which in the 17th century was a complicated and expensive apparatus to build, also led to one of the first documented disputes over the reproducibility of a particular scientific phenomenon. In the 1660s, the Dutch scientist Christiaan Huygens built his own air pump in Amsterdam, the first one outside the direct management of Boyle and his assistant at the time Robert Hooke. Huygens reported an effect he termed "anomalous suspension", in which water appeared to levitate in a glass jar inside his air pump (in fact suspended over an air bubble), but Boyle and Hooke could not replicate this phenomenon in their own pumps. As Shapin and Schaffer describe, "it became clear that unless the phenomenon could be produced in England with one of the two pumps available, then no one in England would accept the claims Huygens had made, or his competence in working the pump". Huygens was finally invited to England in 1663, and under his personal guidance Hooke was able to replicate anomalous suspension of water. Following this Huygens was elected a Foreign Member of the Royal Society. However, Shapin and Schaffer also note that "the accomplishment of replication was dependent on contingent acts of judgment. One cannot write down a formula saying when replication was or was not achieved".
The philosopher of science Karl Popper noted briefly in his famous 1934 book The Logic of Scientific Discovery that "non-reproducible single occurrences are of no significance to science". The statistician Ronald Fisher wrote in his 1935 book The Design of Experiments, which set the foundations for the modern scientific practice of hypothesis testing and statistical significance, that "we may say that a phenomenon is experimentally demonstrable when we know how to conduct an experiment which will rarely fail to give us statistically significant results". Such assertions express a common dogma in modern science that reproducibility is a necessary condition (although not necessarily sufficient) for establishing a scientific fact, and in practice for establishing scientific authority in any field of knowledge. However, as noted above by Shapin and Schaffer, this dogma is not well-formulated quantitatively, such as statistical significance for instance, and therefore it is not explicitly established how many times must a fact be replicated to be considered reproducible.
== Terminology ==
Replicability and repeatability are related terms broadly or loosely synonymous with reproducibility (for example, among the general public), but they are often usefully differentiated in more precise senses, as follows.
Two major steps are naturally distinguished in connection with reproducibility of experimental or observational studies: when new data are obtained in the attempt to achieve it, the term replicability is often used, and the new study is a replication or replicate of the original one. Obtaining the same results when analyzing the data set of the original study again with the same procedures, many authors use the term reproducibility in a narrow, technical sense coming from its use in computational research. Repeatability is related to the repetition of the experiment within the same study by the same researchers. Reproducibility in the original, wide sense is only acknowledged if a replication performed by an independent researcher team is successful.
The terms reproducibility and replicability sometimes appear even in the scientific literature with reversed meaning, as different research fields settled on their own definitions for the same terms.
== Measures of reproducibility and repeatability ==
In chemistry, the terms reproducibility and repeatability are used with a specific quantitative meaning. In inter-laboratory experiments, a concentration or other quantity of a chemical substance is measured repeatedly in different laboratories to assess the variability of the measurements. Then, the standard deviation of the difference between two values obtained within the same laboratory is called repeatability. The standard deviation for the difference between two measurement from different laboratories is called reproducibility.
These measures are related to the more general concept of variance components in metrology.
== Reproducible research ==
=== Reproducible research method ===
The term reproducible research refers to the idea that scientific results should be documented in such a way that their deduction is fully transparent. This requires a detailed description of the methods used to obtain the data
and making the full dataset and the code to calculate the results easily accessible.
This is the essential part of open science.
To make any research project computationally reproducible, general practice involves all data and files being clearly separated, labelled, and documented. All operations should be fully documented and automated as much as practicable, avoiding manual intervention where feasible. The workflow should be designed as a sequence of smaller steps that are combined so that the intermediate outputs from one step directly feed as inputs into the next step. Version control should be used as it lets the history of the project be easily reviewed and allows for the documenting and tracking of changes in a transparent manner.
A basic workflow for reproducible research involves data acquisition, data processing and data analysis. Data acquisition primarily consists of obtaining primary data from a primary source such as surveys, field observations, experimental research, or obtaining data from an existing source. Data processing involves the processing and review of the raw data collected in the first stage, and includes data entry, data manipulation and filtering and may be done using software. The data should be digitized and prepared for data analysis. Data may be analysed with the use of software to interpret or visualise statistics or data to produce the desired results of the research such as quantitative results including figures and tables. The use of software and automation enhances the reproducibility of research methods.
There are systems that facilitate such documentation, like the R Markdown language
or the Jupyter notebook.
The Open Science Framework provides a platform and useful tools to support reproducible research.
=== Reproducible research in practice ===
Psychology has seen a renewal of internal concerns about irreproducible results (see the entry on replicability crisis for empirical results on success rates of replications). Researchers showed in a 2006 study that, of 141 authors of a publication from the American Psychological Association (APA) empirical articles, 103 (73%) did not respond with their data over a six-month period. In a follow-up study published in 2015, it was found that 246 out of 394 contacted authors of papers in APA journals did not share their data upon request (62%). In a 2012 paper, it was suggested that researchers should publish data along with their works, and a dataset was released alongside as a demonstration. In 2017, an article published in Scientific Data suggested that this may not be sufficient and that the whole analysis context should be disclosed.
In economics, concerns have been raised in relation to the credibility and reliability of published research. In other sciences, reproducibility is regarded as fundamental and is often a prerequisite to research being published, however in economic sciences it is not seen as a priority of the greatest importance. Most peer-reviewed economic journals do not take any substantive measures to ensure that published results are reproducible, however, the top economics journals have been moving to adopt mandatory data and code archives. There is low or no incentives for researchers to share their data, and authors would have to bear the costs of compiling data into reusable forms. Economic research is often not reproducible as only a portion of journals have adequate disclosure policies for datasets and program code, and even if they do, authors frequently do not comply with them or they are not enforced by the publisher. A Study of 599 articles published in 37 peer-reviewed journals revealed that while some journals have achieved significant compliance rates, significant portion have only partially complied, or not complied at all. On an article level, the average compliance rate was 47.5%; and on a journal level, the average compliance rate was 38%, ranging from 13% to 99%.
A 2018 study published in the journal PLOS ONE found that 14.4% of a sample of public health statistics researchers had shared their data or code or both.
There have been initiatives to improve reporting and hence reproducibility in the medical literature for many years, beginning with the CONSORT initiative, which is now part of a wider initiative, the EQUATOR Network.
This group has recently turned its attention to how better reporting might reduce waste in research, especially biomedical research.
Reproducible research is key to new discoveries in pharmacology. A Phase I discovery will be followed by Phase II reproductions as a drug develops towards commercial production. In recent decades Phase II success has fallen from 28% to 18%. A 2011 study found that 65% of medical studies were inconsistent when re-tested, and only 6% were completely reproducible.
Some efforts have been made to increase replicability beyond the social and biomedical sciences. Studies in the humanities tend to rely more on expertise and hermeneutics which may make replicability more difficult. Nonetheless, some efforts have been made to call for more transparency and documentation in the humanities.
== Noteworthy irreproducible results ==
Hideyo Noguchi became famous for correctly identifying the bacterial agent of syphilis, but also claimed that he could culture this agent in his laboratory. Nobody else has been able to produce this latter result.
In March 1989, University of Utah chemists Stanley Pons and Martin Fleischmann reported the production of excess heat that could only be explained by a nuclear process ("cold fusion"). The report was astounding given the simplicity of the equipment: it was essentially an electrolysis cell containing heavy water and a palladium cathode which rapidly absorbed the deuterium produced during electrolysis. The news media reported on the experiments widely, and it was a front-page item on many newspapers around the world (see science by press conference). Over the next several months others tried to replicate the experiment, but were unsuccessful.
Nikola Tesla claimed as early as 1899 to have used a high frequency current to light gas-filled lamps from over 25 miles (40 km) away without using wires. In 1904 he built Wardenclyffe Tower on Long Island to demonstrate means to send and receive power without connecting wires. The facility was never fully operational and was not completed due to economic problems, so no attempt to reproduce his first result was ever carried out.
Other examples which contrary evidence has refuted the original claim:
N-rays, a hypothesized form of radiation subsequently found to be illusory
Polywater, a hypothesized polymerized form of water found to be just water with common contaminations
Stimulus-triggered acquisition of pluripotency, revealed to be the result of fraud
GFAJ-1, a bacterium that could purportedly incorporate arsenic into its DNA in place of phosphorus
MMR vaccine controversy — a study in The Lancet claiming the MMR vaccine caused autism was revealed to be fraudulent
Schön scandal — semiconductor "breakthroughs" revealed to be fraudulent
Power posing — a social psychology phenomenon that went viral after being the subject of a very popular TED talk, but was unable to be replicated in dozens of studies
== See also ==
== References ==
== Further reading ==
Timmer, John (October 2006). "Scientists on Science: Reproducibility". Ars Technica.
Saey, Tina Hesman (January 2015). "Is redoing scientific research the best way to find truth? During replication attempts, too many studies fail to pass muster". Science News. "Science is not irrevocably broken, [epidemiologist John Ioannidis] asserts. It just needs some improvements. "Despite the fact that I've published papers with pretty depressive titles, I'm actually an optimist," Ioannidis says. "I find no other investment of a society that is better placed than science.""
== External links ==
Transparency and Openness Promotion Guidelines from the Center for Open Science
Guidelines for Evaluating and Expressing the Uncertainty of NIST Measurement Results of the National Institute of Standards and Technology
Reproducible papers with artifacts by the CTuning foundation
ReproducibleResearch.net | Wikipedia/Replication_(scientific_method) |
Layered graph drawing or hierarchical graph drawing is a type of graph drawing in which the vertices of a directed graph are drawn in horizontal rows or layers with the edges generally directed downwards. It is also known as Sugiyama-style graph drawing after Kozo Sugiyama, who first developed this drawing style.
The ideal form for a layered drawing would be an upward planar drawing, in which all edges are oriented in a consistent direction and no pairs of edges cross. However, graphs often contain cycles, minimizing the number of inconsistently oriented edges is NP-hard, and minimizing the number of crossings is also NP-hard; so, layered graph drawing systems typically apply a sequence of heuristics that reduce these types of flaws in the drawing without guaranteeing to find a drawing with the minimum number of flaws.
== Layout algorithm ==
The construction of a layered graph drawing proceeds in a sequence of steps:
If the input graph is not already a directed acyclic graph, a set of edges is identified the reversal of which will make it acyclic. Finding the smallest possible set of edges is the NP-complete feedback arc set problem, so often greedy heuristics are used here in place of exact optimization algorithms. The exact solution to this problem can be formulated using integer programming. Alternatively, if the number of reversed edges is very small, these edges can be found by a fixed-parameter-tractable algorithm.
The vertices of the directed acyclic graph resulting from the first step are assigned to layers, such that each edge goes from a higher layer to a lower layer. The goals of this stage are to simultaneously produce a small number of layers, few edges that span large numbers of layers, and a balanced assignment of vertices to layers. For instance, by Mirsky's theorem, assigning vertices by layers according to the length of the longest path starting from each vertex produces an assignment with the minimum possible number of layers. The Coffman–Graham algorithm may be used to find a layering with a predetermined limit on the number of vertices per layer and approximately minimizing the number of layers subject to that constraint. Minimizing the width of the widest layer is NP-hard but may be solved by branch-and-cut or approximated heuristically. Alternatively, the problem of minimizing the total number of layers spanned by the edges (without any limits on the number of vertices per layer) may be solved using linear programming. Integer programming procedures, although more time-consuming, may be used to combine edge length minimization with limits on the number of vertices per level.
Edges that span multiple layers are replaced by paths of dummy vertices so that, after this step, each edge in the expanded graph connects two vertices on adjacent layers of the drawing.
As an optional step, a layer of edge concentrator vertices (or confluent junctions) may be imposed between two existing vertex layers, reducing the edge density by replacing complete bipartite subgraphs by stars through these edge concentrators.
The vertices within each layer are permuted in an attempt to reduce the number of crossings among the edges connecting it to the previous layer. Finding the minimum number of crossings or finding a maximum crossing-free set of edges is NP-complete, even when ordering a single layer at a time in this way, so again it is typical to resort to heuristics, such as placing each vertex at a position determined by finding the average or median of the positions of its neighbors on the previous level and then swapping adjacent pairs as long as that improves the number of crossings. Alternatively, the ordering of the vertices in one layer at a time may be chosen using an algorithm that is fixed-parameter tractable in the number of crossings between it and the previous layer.
Each vertex is assigned a coordinate within its layer, consistent with the permutation calculated in the previous step. Considerations in this step include placing dummy nodes on a line between their two neighbors to prevent unnecessary bends, and placing each vertex in a centered position with respect to its neighbors. Sugiyama's original work proposed a quadratic programming formulation of this step; a later method of Brandes and Köpf takes linear time and guarantees at most two bends per edge.
The edges reversed in the first step of the algorithm are returned to their original orientations, the dummy vertices are removed from the graph and the vertices and edges are drawn. To avoid intersections between vertices and edges, edges that span multiple layers of the drawing may be drawn as polygonal chains or spline curves passing through each of the positions assigned to the dummy vertices along the edge.
== Implementations ==
In its simplest form, layered graph drawing algorithms may require O(mn) time in graphs with n vertices and m edges, because of the large number of dummy vertices that may be created. However, for some variants of the algorithm, it is possible to simulate the effect of the dummy vertices without actually constructing them explicitly, leading to a near-linear time implementation.
The "dot" tool in Graphviz produces layered drawings. A layered graph drawing algorithm is also included in Microsoft Automatic Graph Layout and in Tulip.
== Variations ==
Although typically drawn with vertices in rows and edges proceeding from top to bottom, layered graph drawing algorithms may instead be drawn with vertices in columns and edges proceeding from left to right. The same algorithmic framework has also been applied to radial layouts in which the graphs are arranged in concentric circles around some starting node and to three-dimensional layered drawings of graphs.
In layered graph drawings with many long edges, edge clutter may be reduced by grouping sets of edges into bundles and routing them together through the same set of dummy vertices. Similarly, for drawings with many edges crossing between pairs of consecutive layers, the edges in maximal bipartite subgraphs may be grouped into confluent bundles.
Drawings in which the vertices are arranged in layers may be constructed by algorithms that do not follow Sugiyama's framework. For instance, it is possible to tell whether an undirected graph has a drawing with at most k crossings, using h layers, in an amount of time that is polynomial for any fixed choice of k and h, using the fact that the graphs that have drawings of this type have bounded pathwidth.
For layered drawings of concept lattices, a hybrid approach combining Sugiyama's framework with additive methods (in which each vertex represents a set and the position of the vertex is a sum of vectors representing elements in the set) may be used. In this hybrid approach, the vertex permutation and coordinate assignment phases of the algorithm are replaced by a single phase in which the horizontal position of each vertex is chosen as a sum of scalars representing the elements for that vertex.
Layered graph drawing methods have also been used to provide an initial placement for force-directed graph drawing algorithms.
== References == | Wikipedia/Layered_graph_drawing |
Problem structuring methods (PSMs) are a group of techniques used to model or to map the nature or structure of a situation or state of affairs that some people want to change. PSMs are usually used by a group of people in collaboration (rather than by a solitary individual) to create a consensus about, or at least to facilitate negotiations about, what needs to change. Some widely adopted PSMs include
soft systems methodology
the strategic choice approach
strategic options development and analysis (SODA)
Unlike some problem solving methods that assume that all the relevant issues and constraints and goals that constitute the problem are defined in advance or are uncontroversial, PSMs assume that there is no single uncontested representation of what constitutes the problem.
PSMs are mostly used with groups of people, but PSMs have also influenced the coaching and counseling of individuals.
== History ==
The term "problem structuring methods" as a label for these techniques began to be used in the 1980s in the field of operations research, especially after the publication of the book Rational Analysis for a Problematic World: Problem Structuring Methods for Complexity, Uncertainty and Conflict. Some of the methods that came to be called PSMs had been in use since the 1960s.
Thinkers who later came to be recognized as significant early contributors to the theory and practice of PSMs include:
Horst Rittel and Melvin M. Webber
Russell L. Ackoff
Peter Checkland
Colin Eden and Fran Ackermann
Robert L. Flood and Michael C. Jackson
Jonathan Rosenhead and John Mingers
== Types of situations that call for PSMs ==
In discussions of problem structuring methods, it is common to distinguish between two different types of situations that could be considered to be problems. Rittel and Webber's distinction between tame problems and wicked problems (Rittel & Webber 1973) is a well known example of such types. The following table lists similar (but not exactly equivalent) distinctions made by a number of thinkers between two types of "problem" situations, which can be seen as a continuum between a left and right extreme:
Tame problems (or puzzles or technical challenges) have relatively precise, straightforward formulations that are often amenable to solution with some predetermined technical fix or algorithm. It is clear when these situations have changed in such a way that the problem can be called solved.
Wicked problems (or messes or adaptive challenges) have multiple interacting issues with multiple stakeholders and uncertainties and no definitive formulation. These situations are complex and have no stopping rule and no ultimate test of a solution.
PSMs were developed for situations that tend toward the wicked or "soft" side, when methods are needed that assist argumentation about, or that generate mutual understanding of multiple perspectives on, a complex situation. Other problem solving methods are better suited to situations toward the tame or "hard" side where a reliable and optimal solution is needed to a problem that can be clearly and uncontroversially defined.
== Characteristics ==
Problem structuring methods constitute a family of approaches that have differing purposes and techniques, and many of them had been developed independently before people began to notice their family resemblance. Several scholars have noted the common and divergent characteristics among PSMs.
Eden and Ackermann identified four characteristics that problem structuring methods have in common:
The methods focus on creating "a model that is populated with data that is specific to the problem situation". These cause–effect models can be analyzed (albeit in different ways by different methods), and the models are intended to facilitate conversation and negotiation between the participants.
The methods seek to increase the overall productivity of group processes. Productivity includes creating better agreements that are more likely to be implemented, and realizing (to the extent possible in the given situation) ideals such as communicative rationality and procedural justice.
The methods emphasize that the facilitation of effective group processes requires some attention to, and open conversation about, power and politics within and between organizations. Power and politics can become especially important when major change is being proposed.
The methods provide techniques and skills for facilitation of group processes, and they appreciate that such techniques and skills are essential for effective sensemaking, systems modeling, and participative decision-making. People who use PSMs must pay attention to what group facilitators call process skills (guiding interactions between people through nonlinear applications of the methods) and content skills (helping people build sufficiently comprehensive models of the given situation).
Rosenhead provided another list of common characteristics of PSMs, formulated in a more prescriptive style:
Seek solutions which satisfice on separate dimensions rather than seeking an optimal decision on a single dimension.
Integrate hard and soft (quantitative and qualitative) data with social judgments.
Produce models that are as transparent as possible to and that clarify conflicts of interpretation, rather than hiding conflicts behind neutral technical language.
Consider people to be agents actively involved in the decision-making process, rather than as passive objects to be modeled or ignored.
Facilitate the problem structuring process from the bottom-up as much as possible, not only top-down from formal organizational leadership.
Aim to preserve options in the face of unavoidable uncertainty, rather than to base decisions on a prediction of the future.
An early literature review of problem structuring proposed grouping the texts reviewed into "four streams of thought" that describe some major differences between methods:
the checklist stream, which is step-by-step technical problem solving (not problem structuring as it came to be defined in PSMs, so this stream does not apply to PSMs),
the definition stream, which is primarily modeling of relationships between variables, as described by Ackoff and others,
the science research stream which emphasizes doing field research and gathering quantitative data, and
the people stream, which "regards the definition of problems as a function of people's perceptions" as described by Checkland, Eden, and others.
=== Compared to large group methods ===
Mingers and Rosenhead have noted that there are similarities and differences between PSMs and large group methods such as Future Search, Open Space Technology, and others. PSMs and large group methods both bring people together to talk about, and to share different perspectives on, a situation or state of affairs that some people want to change. However, PSMs always focus on creating a sufficiently rigorous conceptual model or cognitive map of the situation, whereas large group methods do not necessarily emphasize modeling, and PSMs are not necessarily used with large groups of people.
=== Compared to participatory rural appraisal ===
There is significant overlap or shared characteristics between PSMs and some of the techniques used in participatory rural appraisal (PRA). Mingers and Rosenhead pointed out that in situations where people have low literacy, the nonliterate (oral and visual) techniques developed in PRA would be a necessary complement to PSMs, and the approaches to modeling in PSMs could be (and have been) used by practitioners of PRA.
== Applications ==
In 2004, Mingers and Rosenhead published a literature review of papers that had been published in scholarly journals and that reported practical applications of PSMs. Their literature survey covered the period up to 1998, which was "relatively early in the development of interest in PSMs", and categorized 51 reported applications under the following application areas: general organizational applications; information systems; technology, resources, planning; health services; and general research. Examples of applications reported included: designing a parliamentary briefing system, modeling the San Francisco Zoo, developing a business strategy and information system strategy, planning livestock management in Nepal, regional planning in South Africa, modeling hospital outpatient services, and eliciting knowledge about pesticides.
== Technology and software ==
PSMs are a general methodology and are not necessarily dependent on electronic information technology, but PSMs do rely on some kind of shared display of the models that participants are developing. The shared display could be flip charts, a large whiteboard, Post-it notes on the meeting room walls, and/or a personal computer connected to a video projector. After PSMs have been used in a group work session, it is normal for a record of the session's display to be shared with participants and with other relevant people.
Software programs for supporting problem structuring include Banxia Decision Explorer and Group Explorer, which implement cognitive mapping for strategic options development and analysis (SODA), and Compendium, which implements IBIS for dialogue mapping and related methods; a similar program is called Wisdom. Such software can serve a variety of functions, such as simple technical assistance to the group facilitator during a single event, or more long-term online group decision support systems.
Some practitioners prefer not to use computers during group work sessions because of the effect they have on group dynamics, but such use of computers is standard in some PSMs such as SODA and dialogue mapping, in which computer display of models or maps is intended to guide conversation in the most efficient way.
In some situations additional software that is not used only for PSMs may be incorporated into the problem structuring process; examples include spreadsheet modeling, system dynamics software or geographic information systems. Some practitioners, who have focused on building system dynamics simulation models with groups of people, have called their work group model building (GMB) and have concluded "that GMB is another PSM". GMB has also been used in combination with SODA.
== See also ==
== Notes ==
== References ==
== Further reading == | Wikipedia/Problem_structuring_methods |
Graphic communication as the name suggests is communication using graphic elements. These elements include symbols such as glyphs and icons, images such as drawings and photographs, and can include the passive contributions of substrate, colour and surroundings. It is the process of creating, producing, and distributing material incorporating words and images to convey data, concepts, and emotions.
The field of graphics communications encompasses all phases of the graphic communications processes from origination of the idea (design, layout, and typography) through reproduction, finishing and distribution of two- or three-dimensional products or electronic transmission.
== Overview ==
Graphic Communications focuses on the technical aspects of producing and distributing items of visual communication. This includes technical aspects associated with the production of tangible items such as books, magazines and packaging, as well as digital items such as e-newsletters, interactive apps, websites, video and virtual reality applications.
Graphic communication involves the use of visual material to relate ideas such as drawings, photographs, slides, and sketches. The drawings of plans and refinements and a rough map sketched to show the way could be considered graphical communication.
Graphic Design focuses on development of concepts and creation of visuals. This includes instruction regarding elements and principles of design, typography, image editing, web and video production, etc.
Any medium that uses a graphics to aid in conveying a message, instruction, or an idea is involved in graphical communication. One of the most widely used forms of graphical communication is the drawing.
== History ==
In the prehistoric period, communication was done visually and aurally and involved touching, either delicately or forcefully, as well as movements and gestures. The earliest graphics known to anthropologists studying prehistoric periods are cave paintings and markings on boulders, bone, ivory, and antlers, which were created during the Upper Paleolithic period from 40,000 to 10,000 B.C. or earlier. Many of these played a major role in geometry. They used graphics to represent their mathematical theories such as the Circle Theorem and the Pythagorean theorem.
== Graphic communication topics ==
=== Graphics ===
Graphics are visual presentations on some surface, such as a wall, canvas, computer screen, paper, or stone to brand, inform, illustrate, or entertain. Examples are photographs, drawings, line art, graphs, diagrams, typography, numbers, symbols, geometric designs, maps, engineering drawings, or other images. Graphics often combine text, illustration, and color. Graphic design may consist of the deliberate selection, creation, or arrangement of typography alone, as in a brochure, flier, poster, web site, or book without any other element. Clarity or effective communication may be the objective, association with other cultural elements may be sought, or merely, the creation of a distinctive style.
Graphics can be functional or artistic. The latter can be a recorded version, such as a photograph, or an interpretation by a scientist to highlight essential features, or an artist, in which case the distinction with imaginary graphics may become blurred.
=== Communication ===
Communication is the process whereby information is imparted by a sender to a receiver via a medium. It requires that all parties have an area of communicative commonality. There are auditory means, such as speaking, singing and sometimes tone of voice, and nonverbal, physical means, such as body language, sign language, paralanguage, touch, eye contact, by using writing. Communication is defined as a process by which we assign and convey meaning in an attempt to create shared understanding. This process requires a vast repertoire of skills in intrapersonal and interpersonal processing, listening, observing, speaking, questioning, analyzing, and evaluating. If you use these processes it is developmental and transfers to all areas of life: home, school, community, work, and beyond. It is through communication that collaboration and cooperation occur.
=== Visual communication ===
Visual communication as the name suggests is communication through visual aid. It is the conveyance of ideas and information in forms that can be read or looked upon. Primarily associated with two dimensional images, it includes: signs, typography, drawing, graphic design, illustration, colour and electronic resources. It solely relies on vision. It is a form of communication with visual effect. It explores the idea that a visual message with text has a greater power to inform, educate or persuade a person. It is communication by presenting information through Visual form. The evaluation of a good visual design is based on measuring comprehension by the audience, not on aesthetic or artistic preference. There are no universally agreed-upon principles of beauty and ugliness. There exists a variety of ways to present information visually, like gestures, body languages, video and TV. Here, focus is on the presentation of text, pictures, diagrams, photos, et cetera, integrated on a computer display. The term visual presentation is used to refer to the actual presentation of information. Recent research in the field has focused on web design and graphically oriented usability. Graphic designers use methods of visual communication in their professional practice.
=== Communication design ===
Communication design is a mixed discipline between design and information-development which is concerned with how intermission such as printed, crafted, electronic media or presentations communicate with people. A communication design approach is not only concerned with developing the message aside from the aesthetics in media, but also with creating new media channels to ensure the message reaches the target audience. Communication design seeks to attract, inspire, create desires and motivate the people to respond to messages, with a view to making a favorable impact to the bottom line of the commissioning body, which can be either to build a brand, move sales, or for humanitarian purposes. Its process involves strategic business thinking, utilizing market research, creativity, and problem-solving.
=== Graphic design ===
The term graphic design can refer to a number of artistic and professional disciplines which focus on visual communication and presentation. Various methods are used to create and combine symbols, images and/or words to create a visual representation of ideas and messages. A graphic designer may use typography, visual arts and page layout techniques to produce the final result. Graphic design often refers to both the process (designing) by which the communication is created and the products (designs) which are generated.
Common uses of graphic design include magazines, advertisements, product packaging and web design. For example, a product package might include a logo or other artwork, organized text and pure design elements such as shapes and color which unify the piece. Composition is one of the most important features of graphic design especially when using pre-existing materials or diverse elements.
=== Graphical representation ===
The term representation, according to O'Shaughnessy and Stadler (2005), can carry a range of meanings and interpretations. In literary theory representation is commonly defined in 3 ways.
To look like or resemble
To stand in for something or someone
To present a second time to re-present
Representation, according to Mitchell (1995), began with early literary theory in the ideas of Plato and Aristotle, and has evolved into a significant component of language, Saussurian and communication studies. Aristotle discusses representation in 3 ways:
The object: The symbol being represented.
Manner: The way the symbol is represented.
Means: The material that is used to represent it.
The means of literary representation is language. The means of graphical representation are graphics. Graphical representation of data is one of the most commonly used modes of presentation.
The purpose of graphical communication is transfer message or information to the receiver in effective way. When professional organizations prepare reports, they usually use the mode of graphical presentations.
== See also ==
Related subjects
Graphicacy
Technical
Related experts
Stuart Bailey
Rosemary Sassoon
Michael Twyman
Gerard Unger
Related organizations
American Institute of Graphic Arts
High School of Graphic Communication Arts
== References == | Wikipedia/Graphic_communication |
A method for pruning dense networks to highlight key links
== Rationale ==
Relationships among a set of elements are often represented as a square matrix with entries representing the relations between all pairs of the elements. Relations such as distances, dissimilarities, similarities, relatedness, correlations, co-occurrences, conditional probabilities, etc., can be represented by such matrices. Such data can also be represented as networks with weighted links between the elements. Such matrices and networks are extremely dense and are not easily apprehended without some form of data reduction or pruning.
A pathfinder network results from applying a pruning method that removes weaker links from a (usually dense) network according to the lengths of alternative paths (see below). It is used as a psychometric scaling method based on graph theory and used in the study of expertise, education, knowledge acquisition, mental models, and knowledge engineering. It is also employed in generating communication networks, software debugging, visualizing scientific citation patterns, information retrieval, and other forms of data visualization. Pathfinder networks are potentially applicable to any problem addressed by network theory.
== Overview ==
Network pruning aims to highlight the more important links between elements represented in a network. It helps to simplify the collection of connections involved which is valuable in data visualization and in comprehending essential relations among the elements represented in the network.
Several psychometric scaling methods start from pairwise data and yield structures revealing the underlying organization of the data. Data clustering and multidimensional scaling are two such methods. Network scaling represents another method based on graph theory. Pathfinder networks are derived from matrices of data for pairs of entities. Because the algorithm uses distances, similarity data are inverted to yield dissimilarities for the computations.
In the pathfinder network, the entities correspond to the nodes of the generated network, and the links in the network are determined by the patterns of proximities. For example, if the proximities are similarities, links will generally connect nodes of high similarity. When proximities are distances or dissimilarities, links will connect the shorter distances. The links in the network will be undirected if the proximities are symmetrical for every pair of entities. Symmetrical proximities mean that the order of the entities is not important, so the proximity of i and j is the same as the proximity of j and i for all pairs i,j. If the proximities are not symmetrical for every pair, the links will be directed.
== Algorithm ==
The pathfinder algorithm uses two parameters.
The
q
{\displaystyle q}
parameter constrains the number of indirect proximities examined in generating the network.
q
{\displaystyle q}
is an integer between
2
{\displaystyle 2}
and
n
−
1
{\displaystyle n-1}
, inclusive where
n
{\displaystyle n}
is the number of nodes or items. Shortest paths can have no more than
q
{\displaystyle q}
links. When
q
=
n
−
1
{\displaystyle q=n-1}
, all possible paths are included.
The
r
{\displaystyle r}
parameter defines the metric used for computing the distance of paths (cf. the Minkowski distance).
r
{\displaystyle r}
is a real number between
1
{\displaystyle 1}
and
∞
{\displaystyle \infty }
, inclusive.
Path distance
d
p
{\displaystyle d_{p}}
is computed as:
d
p
=
(
∑
i
=
1
k
l
i
r
)
1
/
r
{\displaystyle d_{p}=(\sum _{i=1}^{k}l_{i}^{r})^{1/r}}
, where
l
i
{\displaystyle l_{i}}
is the distance of the
i
t
h
{\displaystyle ith}
link in the path and
2
≤
k
≤
q
{\displaystyle 2\leq k\leq q}
. For
r
=
1
{\displaystyle r=1}
,
d
p
{\displaystyle d_{p}}
is simply the sum of the distances of the links in the path. For
r
=
∞
{\displaystyle r=\infty }
,
d
p
{\displaystyle d_{p}}
is the maximum of the distances of the links in the path because
lim
r
→
∞
d
p
=
max
i
=
1
k
l
i
{\displaystyle \lim _{r\rightarrow \infty }d_{p}=\max _{i=1}^{k}l_{i}}
. A link is pruned if its distance is greater than the minimum distance of paths between the nodes connected by the link. Efficient methods for finding minimum distances include the Floyd–Warshall algorithm (for
q
=
n
−
1
{\displaystyle q=n-1}
) and Dijkstra's algorithm (for any value of
q
{\displaystyle q}
).
A network generated with particular values of
q
{\displaystyle q}
and
r
{\displaystyle r}
is called a
P
F
N
e
t
(
q
,
r
)
{\displaystyle PFNet(q,r)}
. Both of the parameters have the effect of decreasing the number of links in the network as their values are increased. The network with the minimum number of links is obtained when
q
=
n
−
1
{\displaystyle q=n-1}
and
r
=
∞
{\displaystyle r=\infty }
, i.e.,
P
F
N
e
t
(
n
−
1
,
∞
)
{\displaystyle PFNet(n-1,\infty )}
.
With ordinal-scale data (see level of measurement), the
r
{\displaystyle r}
parameter should be
∞
{\displaystyle \infty }
because the same
P
F
N
e
t
{\displaystyle PFNet}
would result from any positive monotonic transformation of the proximity data. Other values of
r
{\displaystyle r}
require data measured on a ratio scale. The
q
{\displaystyle q}
parameter can be varied to yield the desired number of links in the network or to focus on more local relations with smaller values of
q
{\displaystyle q}
.
Essentially, pathfinder networks preserve the shortest possible paths given the data. Therefore, links are eliminated when they are not on shortest paths. The
P
F
N
e
t
(
n
−
1
,
∞
)
{\displaystyle PFNet(n-1,\infty )}
will be the minimum spanning tree for the links defined by the proximity data if a unique minimum spanning tree exists. In general, the
P
F
N
e
t
(
n
−
1
,
∞
)
{\displaystyle PFNet(n-1,\infty )}
includes all of the links in any minimum spanning tree.
== Example ==
Here is an example of an undirected pathfinder network derived from average ratings of a group of biology graduate students. The students rated the relatedness of all pairs of the terms shown, and the mean rating for each pair was computed. The solid blue links are the
P
F
N
e
t
(
n
−
1
,
∞
)
{\displaystyle PFNet(n-1,\infty )}
(labeled "both" in the figure). The dotted red links are added in the
P
F
N
e
t
(
2
,
∞
)
{\displaystyle PFNet(2,\infty )}
. For the added links, there are no 2-link paths shorter than the link distance but there is at least one shorter path with more than two links in the data. A minimal spanning tree would have 24 links so the 26 links in
P
F
N
e
t
(
n
−
1
,
∞
)
{\displaystyle PFNet(n-1,\infty )}
implies that there is more than one minimum spanning tree. There are two cycles present so there are tied distances in the set of links in the cycle. Breaking each cycle would require removing one of the tied links in each cycle.
== References ==
== Other Information ==
Further information on pathfinder networks and several examples of the application of PFnets to a variety of problems can be found in the references.
The 1990 book is out of print. A zipped copy of pdf chapters can be downloaded.
The 1989 chapter in the Bower book is an article summarizing pathfinder networks and some applications. pdf
Three papers describing fast implementations of pathfinder networks:
Guerrero-Bote, V.; Zapico-Alonso, F.; Esinosa-Calvo, M.; Gomez-Crisostomo, R.; Moya-Anegon, F. (2006). "Binary pathfinder: An improvement to the pathfinder algorithm". Information Processing and Management. 42 (6): 1484–1490. CiteSeerX 10.1.1.378.5375. doi:10.1016/j.ipm.2006.03.015.
Quirin, A; Cordón, O; Santamaría, J; Vargas-Quesada, B; Moya-Anegón, F (2008). "A new variant of the Pathfinder algorithm to generate large visual science maps in cubic time". Information Processing and Management. 44 (4): 1611–1623. doi:10.1016/j.ipm.2007.09.005.
Quirin, A.; Cordón, O.; Guerrero-Bote, V. P.; Vargas-Quesada, B.; Moya-Anegón, F. (2008). "A Quick MST-based Algorithm to Obtain Pathfinder Networks". Journal of the American Society for Information Science and Technology. 59 (12): 1912–1924. CiteSeerX 10.1.1.331.1548. doi:10.1002/asi.20904.
(The two variants by Quirin et al. are significantly faster. While the former can be applied with
q
=
2
{\displaystyle q=2}
or
q
=
n
−
1
{\displaystyle q=n-1}
and any value for
r
{\displaystyle r}
, the latter can only be applied in cases where
q
=
n
−
1
{\displaystyle q=n-1}
and
r
=
∞
{\displaystyle r=\infty }
.)
== External links ==
Extensive list of papers relating to Pathfinder
Pathfinder Software Download Site
Implementation of the original, Binary, Fast and MST variants of the algorithm in C
Comparison table between the different variants | Wikipedia/Pathfinder_network |
A model is an informative representation of an object, person, or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin modulus, 'a measure'.
Models can be divided into physical models (e.g. a ship model or a fashion model) and abstract models (e.g. a set of mathematical equations describing the workings of the atmosphere for the purpose of weather forecasting). Abstract or conceptual models are central to philosophy of science.
In scholarly research and applied science, a model should not be confused with a theory: while a model seeks only to represent reality with the purpose of better understanding or predicting the world, a theory is more ambitious in that it claims to be an explanation of reality.
== Types of model ==
=== Model in specific contexts ===
As a noun, model has specific meanings in certain fields, derived from its original meaning of "structural design or layout":
Model (art), a person posing for an artist, e.g. a 15th-century criminal representing the biblical Judas in Leonardo da Vinci's painting The Last Supper
Model (person), a person who serves as a template for others to copy, as in a role model, often in the context of advertising commercial products; e.g. the first fashion model, Marie Vernet Worth in 1853, wife of designer Charles Frederick Worth.
Model (product), a particular design of a product as displayed in a catalogue or show room (e.g. Ford Model T, an early car model)
Model (organism) a non-human species that is studied to understand biological phenomena in other organisms, e.g. a guinea pig starved of vitamin C to study scurvy, an experiment that would be immoral to conduct on a person
Model (mimicry), a species that is mimicked by another species
Model (logic), a structure (a set of items, such as natural numbers 1, 2, 3,..., along with mathematical operations such as addition and multiplication, and relations, such as
<
{\displaystyle <}
) that satisfies a given system of axioms (basic truisms), i.e. that satisfies the statements of a given theory
Model (CGI), a mathematical representation of any surface of an object in three dimensions via specialized software
Model (MVC), the information-representing internal component of a software, as distinct from its user interface
=== Physical model ===
A physical model (most commonly referred to simply as a model but in this context distinguished from a conceptual model) is a smaller or larger physical representation of an object, person or system. The object being modelled may be small (e.g., an atom) or large (e.g., the Solar System) or life-size (e.g., a fashion model displaying clothes for similarly-built potential customers).
The geometry of the model and the object it represents are often similar in the sense that one is a rescaling of the other. However, in many cases the similarity is only approximate or even intentionally distorted. Sometimes the distortion is systematic, e.g., a fixed scale horizontally and a larger fixed scale vertically when modelling topography to enhance a region's mountains.
An architectural model permits visualization of internal relationships within the structure or external relationships of the structure to the environment. Another use is as a toy.
Instrumented physical models are an effective way of investigating fluid flows for engineering design. Physical models are often coupled with computational fluid dynamics models to optimize the design of equipment and processes. This includes external flow such as around buildings, vehicles, people, or hydraulic structures. Wind tunnel and water tunnel testing is often used for these design efforts. Instrumented physical models can also examine internal flows, for the design of ductwork systems, pollution control equipment, food processing machines, and mixing vessels. Transparent flow models are used in this case to observe the detailed flow phenomenon. These models are scaled in terms of both geometry and important forces, for example, using Froude number or Reynolds number scaling (see Similitude). In the pre-computer era, the UK economy was modelled with the hydraulic model MONIAC, to predict for example the effect of tax rises on employment.
=== Conceptual model ===
A conceptual model is a theoretical representation of a system, e.g. a set of mathematical equations attempting to describe the workings of the atmosphere for the purpose of weather forecasting. It consists of concepts used to help understand or simulate a subject the model represents.
Abstract or conceptual models are central to philosophy of science, as almost every scientific theory effectively embeds some kind of model of the physical or human sphere. In some sense, a physical model "is always the reification of some conceptual model; the conceptual model is conceived ahead as the blueprint of the physical one", which is then constructed as conceived. Thus, the term refers to models that are formed after a conceptualization or generalization process.
=== Examples ===
Conceptual model (computer science), an agreed representation of entities and their relationships, to assist in developing software
Economic model, a theoretical construct representing economic processes
Language model, a probabilistic model of a natural language, used for speech recognition, language generation, and information retrieval
Large language models are artificial neural networks used for generative artificial intelligence (AI), e.g. ChatGPT
Mathematical model, a description of a system using mathematical concepts and language
Statistical model, a mathematical model that usually specifies the relationship between one or more random variables and other non-random variables
Model (CGI), a mathematical representation of any surface of an object in three dimensions via specialized software
Medical model, a proposed "set of procedures in which all doctors are trained"
Mental model, in psychology, an internal representation of external reality
Model (logic), a set along with a collection of finitary operations, and relations that are defined on it, satisfying a given collection of axioms
Model (MVC), information-representing component of a software, distinct from the user interface (the "view"), both linked by the "controller" component, in the context of the model–view–controller software design
Model act, a law drafted centrally to be disseminated and proposed for enactment in multiple independent legislatures
Standard model (disambiguation)
== Properties of models, according to general model theory ==
According to Herbert Stachowiak, a model is characterized by at least three properties:
1. Mapping
A model always is a model of something—it is an image or representation of some natural or artificial, existing or imagined original, where this original itself could be a model.
2. Reduction
In general, a model will not include all attributes that describe the original but only those that appear relevant to the model's creator or user.
3. Pragmatism
A model does not relate unambiguously to its original. It is intended to work as a replacement for the original
a) for certain subjects (for whom?)
b) within a certain time range (when?)
c) restricted to certain conceptual or physical actions (what for?).
For example, a street map is a model of the actual streets in a city (mapping), showing the course of the streets while leaving out, say, traffic signs and road markings (reduction), made for pedestrians and vehicle drivers for the purpose of finding one's way in the city (pragmatism).
Additional properties have been proposed, like extension and distortion as well as validity. The American philosopher Michael Weisberg differentiates between concrete and mathematical models and proposes computer simulations (computational models) as their own class of models.
== Uses of models ==
According to Bruce Edmonds, there are at least 5 general uses for models:
Prediction: reliably anticipating unknown data, including data within the domain of the training data (interpolation), and outside the domain (extrapolation)
Explanation: establishing plausible chains of causality by proposing mechanisms that can explain patterns seen in data
Theoretical exposition: discovering or proposing new hypotheses, or refuting existing hypotheses about the behaviour of the system being modelled
Description: representing important aspects of the system being modelled
Illustration: communicating an idea or explanation
== See also ==
== References ==
== External links ==
Media related to Physical models at Wikimedia Commons | Wikipedia/Models |
Object–role modeling (ORM) is used to model the semantics of a universe of discourse. ORM is often used for data modeling and software engineering.
An object–role model uses graphical symbols that are based on first order predicate logic and set theory to enable the modeler to create an unambiguous definition of an arbitrary universe of discourse. Attribute free, the predicates of an ORM Model lend themselves to the analysis and design of graph database models in as much as ORM was originally conceived to benefit relational database design.
The term "object–role model" was coined in the 1970s and ORM based tools have been used for more than 30 years – principally for data modeling. More recently ORM has been used to model business rules, XML-Schemas, data warehouses, requirements engineering and web forms.
== History ==
The roots of ORM can be traced to research into semantic modeling for information systems in Europe during the 1970s. There were many pioneers and this short summary does not by any means mention them all. An early contribution came in 1973 when Michael Senko wrote about "data structuring" in the IBM Systems Journal. In 1974 Jean-Raymond Abrial contributed an article about "Data Semantics". In June 1975, Eckhard Falkenberg's doctoral thesis was published and in 1976 one of Falkenberg's papers mentions the term "object–role model".
G.M. Nijssen made fundamental contributions by introducing the "circle-box" notation for object types and roles, and by formulating the first version of the conceptual schema design procedure. Robert Meersman extended the approach by adding subtyping, and introducing the first truly conceptual query language.
Object role modeling also evolved from the Natural language Information Analysis Method, a methodology that was initially developed by the academic researcher, G.M. Nijssen in the Netherlands (Europe) in the mid-1970s and his research team at the Control Data Corporation Research Laboratory in Belgium, and later at the University of Queensland, Australia in the 1980s. The acronym NIAM originally stood for "Nijssen's Information Analysis Methodology", and later generalised to "Natural language Information Analysis Methodology" and Binary Relationship Modeling since G. M. Nijssen was only one of many people involved in the development of the method.
In 1989, Terry Halpin completed his PhD thesis on ORM, providing the first full formalization of the approach and incorporating several extensions.
Also in 1989, Terry Halpin and G.M. Nijssen co-authored the book "Conceptual Schema and Relational Database Design" and several joint papers, providing the first formalization of object–role modeling.
A graphical NIAM design tool which included the ability to generate database-creation scripts for Oracle, DB2 and DBQ was developed in the early 1990s in Paris. It was originally named Genesys and was marketed successfully in France and later Canada. It could also handle ER diagram design. It was ported to SCO Unix, SunOs, DEC 3151's and Windows 3.0 platforms, and was later migrated to succeeding Microsoft operating systems, utilising XVT for cross operating system graphical portability. The tool was renamed OORIANE and is currently being used for large data warehouse and SOA projects.
Also evolving from NIAM is "Fully Communication Oriented Information Modeling" FCO-IM (1992). It distinguishes itself from traditional ORM in that it takes a strict communication-oriented perspective. Rather than attempting to model the domain and its essential concepts, it models the communication in this domain (universe of discourse). Another important difference is that it does this on instance level, deriving type level and object/fact level during analysis.
Another recent development is the use of ORM in combination with standardised relation types with associated roles and a standard machine-readable dictionary and taxonomy of concepts as are provided in the Gellish English dictionary. Standardisation of relation types (fact types), roles and concepts enables increased possibilities for model integration and model reuse.
== Concepts ==
=== Facts ===
Object–role models are based on elementary facts, and expressed in diagrams that can be verbalised into natural language. A fact is a proposition such as "John Smith was hired on 5 January 1995" or "Mary Jones was hired on 3 March 2010".
With ORM, propositions such as these, are abstracted into "fact types" for example "Person was hired on Date" and the individual propositions are regarded as sample data. The difference between a "fact" and an "elementary fact" is that an elementary fact cannot be simplified without loss of meaning. This "fact-based" approach facilitates modeling, transforming, and querying information from any domain.
=== Attribute-free ===
ORM is attribute-free: unlike models in the entity–relationship (ER) and Unified Modeling Language (UML) methods, ORM treats all elementary facts as relationships and so treats decisions for grouping facts into structures (e.g. attribute-based entity types, classes, relation schemes, XML schemas) as implementation concerns irrelevant to semantics. By avoiding attributes, ORM improves semantic stability and enables verbalization into natural language.
=== Fact-based modeling ===
Fact-based modeling includes procedures for mapping facts to attribute-based structures, such as those of ER or UML.
Fact-based textual representations are based on formal subsets of native languages. ORM proponents argue that ORM models are easier to understand by people without a technical education. For example, proponents argue that object–role models are easier to understand than declarative languages such as Object Constraint Language (OCL) and other graphical languages such as UML class models. Fact-based graphical notations are more expressive than those of ER and UML. An object–role model can be automatically mapped to relational and deductive databases (such as datalog).
=== ORM 2 graphical notation ===
ORM2 is the latest generation of object–role modeling. The main objectives for the ORM 2 graphical notation are:
More compact display of ORM models without compromising clarity
Improved internationalization (e.g. avoid English language symbols)
Simplified drawing rules to facilitate creation of a graphical editor
Extended use of views for selectively displaying/suppressing detail
Support for new features (e.g. role path delineation, closure aspects, modalities)
=== Design procedure ===
System development typically involves several stages such as: feasibility study; requirements analysis; conceptual design of data and operations; logical design; external design; prototyping; internal design and implementation; testing and validation; and maintenance. The seven steps of the conceptual schema design procedure are:
Transform familiar information examples into elementary facts, and apply quality checks
Draw the fact types, and apply a population check
Check for entity types that should be combined, and note any arithmetic derivations
Add uniqueness constraints, and check arity of fact types
Add mandatory role constraints, and check for logical derivations
Add value, set comparison and subtyping constraints
Add other constraints and perform final checks
ORM's conceptual schema design procedure (CSDP) focuses on the analysis and design of data.
== See also ==
Concept map
Conceptual schema
Enhanced entity–relationship model (EER)
Information flow diagram
Ontology double articulation
Ontology engineering
Relational algebra
Three-schema approach
== References ==
== Further reading ==
Halpin, Terry (1989), Conceptual Schema and Relational Database Design, Sydney: Prentice Hall, ISBN 978-0-13-167263-5
Rossi, Matti; Siau, Keng (April 2001), Information Modeling in the New Millennium, IGI Global, ISBN 978-1-878289-77-3
Halpin, Terry; Evans, Ken; Hallock, Pat; Maclean, Bill (September 2003), Database Modeling with Microsoft Visio for Enterprise Architects, Morgan Kaufmann, ISBN 978-1-55860-919-8
Halpin, Terry; Morgan, Tony (March 2008), Information Modeling and Relational Databases: From Conceptual Analysis to Logical Design (2nd ed.), Morgan Kaufmann, ISBN 978-0-12-373568-3
== External links == | Wikipedia/Object-role_modeling |
The picture theory of language, also known as the picture theory of meaning, is a theory of linguistic reference and meaning articulated by Ludwig Wittgenstein in the Tractatus Logico-Philosophicus. Wittgenstein suggested that a meaningful proposition pictured a state of affairs or atomic fact. Wittgenstein compared the concept of logical pictures (German: Bilder) with spatial pictures. The picture theory of language is considered a correspondence theory of truth.
Wittgenstein claims there is an unbridgeable gap between what can be expressed in language and what can only be expressed in non-verbal ways. The picture theory of meaning states that statements are meaningful if, and only if, they can be defined or pictured in the real world.
Wittgenstein's later investigations laid out in the First Part of Philosophical Investigations refuted and replaced his earlier picture-based theory with a use theory of meaning. However, the second psychology-focused Part of Philosophical Investigations employs the concept as a metaphor for human psychology.
== See also ==
Early Wittgenstein
Truth-conditional semantics
== References == | Wikipedia/Picture_theory_of_language |
Mental Models is a book published by Lawrence Erlbaum Associates, Inc., in 1983 ISBN 0-89859-242-9. It was edited by Dedre Gentner and Albert L. Stevens, both employees of Bolt, Beranek and Newman, Inc. at the time. It appeared at about the same time as a book by the same name by Philip Johnson-Laird. According to the acknowledgment of the book, it resulted from a workshop on mental models held at the University of California, San Diego in October 1980, that was jointly sponsored by the Office of Naval Research and the Sloan Foundation.
== Chapters ==
Some Observations on Mental Models — Donald A. Norman, UCSD
Dr. Norman describes the properties of mental models — that they can be contradictory, incomplete, superstitious, erroneous, and unstable, varying in time. So the job of system designers is to help users form an accurate and useful mental model of a system. And the job of researchers is to set up experiments to learn to understand actual mental models, even though they may be messy and incomplete.
Phenomenology and the Evolution of Intuition — Andrea diSessa, MIT
Surrogates and Mappings: Two Kinds of Conceptual Models for Interactive Devices — Richard M. Young, Medical Research Council, Applied Psychology Unit, Cambridge, England
Qualitative Reasoning About Space and Motion — Kenneth D. Forbus, MIT
The Role of Problem Representation in Physics — Jill H. Larkin, Carnegie Mellon University
Flowing Waters or Teeming Crowds:Mental Models of Electricity — Dedre Gentner, Bolt Beranek and Newman, and Donald R. Gentner, UCSD
Human Reasoning About a Simple Physical System — Michael D. Williams, Xerox PARC, James D. Hollan, and Albert L. Stevens, Bolt Beranek and Newman
Assumptions and Ambiguities in Mechanistic Mental Models — Johan de Kleer and John Seely Brown, Xerox PARC
Understanding Micronesian Navigation — Edwin Hutchins, Navy Personnel Research and Development Center
Conceptual Entities — James G. Greeno, University of Pittsburgh
Using the Method of Fibres in Mecho to Calculate Radii of Gyration — Alan Bundy, University of Edinburgh
When Heat and Temperature Were One — Marianne Wiser and Susan Carey, MIT
Naive Theories of Motion — Michael McCloskey, Johns Hopkins University
A Conceptual Model Discussed by Galileo and Used Intuitively by Physics Students — John Clement, University of Massachusetts Amherst
== Reception ==
Upon release, Mental Models received reviews from journals such as American Anthropologist. The American Journal of Psychology reviewed the work, stating that it would be of interest to "those who are concerned with what is new in cognitive science". Instructional Science also wrote a review, writing "Mental Models succeeds as an introduction to the vigorous, multidisciplinary attack on the ethereal problems surrounding knowledge representation. Whether mental models will prove their mettle in the earthly settings of instructional applications remains an open question."
== References ==
== External links ==
Preview at Google Books | Wikipedia/Mental_Models_(Gentner-Stevens_book) |
The mental model theory of reasoning was developed by Philip Johnson-Laird and Ruth M.J. Byrne (Johnson-Laird and Byrne, 1991). It has been applied to the main domains of deductive inference including relational inferences such as spatial and temporal deductions; propositional inferences, such as conditional, disjunctive and negation deductions; quantified inferences such as syllogisms; and meta-deductive inferences.
Ongoing research on mental models and reasoning has led the theory to be extended to account for probabilistic inference (e.g., Johnson-Laird, 2006) and counterfactual thinking (Byrne, 2005).
== See also ==
Mental model § Mental models and reasoning
Psychology of reasoning
== References ==
Byrne, R.M.J. (2005). The Rational Imagination: How People Create Alternatives to Reality. Cambridge, M.A.: MIT Press.
Johnson-Laird, P.N. (2006). How We Reason. New York: Oxford University Press.
Johnson-Laird, P.N., & Byrne, R.M.J. (1991). Deduction. Hillsdale, NJ: Lawrence Erlbaum Associates. | Wikipedia/Mental_model_theory_of_reasoning |
Clinical psychology is an integration of human science, behavioral science, theory, and clinical knowledge for the purpose of understanding, preventing, and relieving psychologically-based distress or dysfunction and to promote subjective well-being and personal development. Central to its practice are psychological assessment, clinical formulation, and psychotherapy, although clinical psychologists also engage in research, teaching, consultation, forensic testimony, and program development and administration. In many countries, clinical psychology is a regulated mental health profession.
The field is generally considered to have begun in 1896 with the opening of the first psychological clinic at the University of Pennsylvania by Lightner Witmer. In the first half of the 20th century, clinical psychology was focused on psychological assessment, with little attention given to treatment. This changed after the 1940s when World War II resulted in the need for a large increase in the number of trained clinicians. Since that time, three main educational models have developed in the US—the PhD Clinical Science model (heavily focused on research), the PhD science-practitioner model (integrating scientific research and practice), and the PsyD practitioner-scholar model (focusing on clinical theory and practice). In the UK and Ireland, the Clinical Psychology Doctorate falls between the latter two of these models, whilst in much of mainland Europe, the training is at the master's level and predominantly psychotherapeutic. Clinical psychologists are expert in providing psychotherapy, and generally train within four primary theoretical orientations—psychodynamic, humanistic, cognitive behavioral therapy (CBT), and systems or family therapy.
Clinical psychology is different from psychiatry. Although practitioners in both fields are experts in mental health, clinical psychologists are experts in psychological assessment including neuropsychological and psychometric assessment and treat mental disorders primarily through psychotherapy. Currently, only seven US states, Louisiana, New Mexico, Illinois, Iowa, Idaho, Colorado and Utah (being the most recent state) allow clinical psychologists with advanced specialty training to prescribe psychotropic medications. Psychiatrists are medical doctors who specialize in the treatment of mental disorders via a variety of methods, e.g., diagnostic assessment, psychotherapy, psychoactive medications, and medical procedures such as electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS).
== History ==
The earliest recorded approaches to assess and treat mental distress were a combination of religious, magical, and/or medical perspectives. In the early 19th century, one approach to study mental conditions and behavior was using phrenology, the study of personality by examining the shape of the skull. Other popular treatments at that time included the study of the shape of the face (physiognomy) and Mesmer's treatment for mental conditions using magnets (mesmerism). Spiritualism and Phineas Quimby's "mental healing" were also popular.
While the scientific community eventually came to reject all of these methods for treating mental illness, academic psychologists also were not concerned with serious forms of mental illness. The study of mental illness was already being done in the developing fields of psychiatry and neurology within the asylum movement. It was not until the end of the 19th century, around the time when Sigmund Freud was first developing his "talking cure" in Vienna, that the first scientific application of clinical psychology began.
=== Early clinical psychology ===
By the second half of the 1800s, the scientific study of psychology was becoming well established in university laboratories. Although there were a few scattered voices calling for applied psychology, the general field looked down upon this idea and insisted on "pure" science as the only respectable practice. This changed when Lightner Witmer (1867–1956), a past student of Wundt and head of the psychology department at the University of Pennsylvania, agreed to treat a young boy who had trouble with spelling. His successful treatment was soon to lead to Witmer's opening of the first psychological clinic at Penn in 1896, dedicated to helping children with learning disabilities. Ten years later in 1907, Witmer was to found the first journal of this new field, The Psychological Clinic, where he coined the term "clinical psychology", defined as "the study of individuals, by observation or experimentation, with the intention of promoting change". The field was slow to follow Witmer's example, but by 1914, there were 26 similar clinics in the US.
Even as clinical psychology was growing, working with issues of serious mental distress remained the domain of psychiatrists and neurologists. However, clinical psychologists continued to make inroads into this area due to their increasing skill at psychological assessment. Psychologists' reputation as assessment experts became solidified during World War I with the development of two intelligence tests, Army Alpha and Army Beta (testing verbal and nonverbal skills, respectively), which could be used with large groups of recruits. Due in large part to the success of these tests, assessment was to become the core discipline of clinical psychology for the next quarter-century, when another war would propel the field into treatment.
=== Early professional organizations ===
The field began to organize under the name "clinical psychology" in 1917 with the founding of the American Association of Clinical Psychology. This only lasted until 1919, after which the American Psychological Association (founded by G. Stanley Hall in 1892) developed a section on Clinical Psychology, which offered certification until 1927. Growth in the field was slow for the next few years when various unconnected psychological organizations came together as the American Association of Applied Psychology in 1930, which would act as the primary forum for psychologists until after World War II when the APA reorganized. In 1945, the APA created what is now called Division 12, the Society for Clinical Psychology, which remains a leading organization in the field. Psychological societies and associations in other English-speaking countries developed similar divisions, including in Britain, Canada, Australia, and New Zealand.
=== World War II and the integration of treatment ===
When World War II broke out, the military once again called upon clinical psychologists. As soldiers began to return from combat, psychologists started to notice symptoms of psychological trauma labeled "shell shock" (eventually to be termed post-traumatic stress disorder) that were best treated as soon as possible. Because physicians (including psychiatrists) were over-extended in treating bodily injuries, psychologists were called to help treat this condition. At the same time, female psychologists (who were excluded from the war effort) formed the National Council of Women Psychologists with the purpose of helping communities deal with the stresses of war and giving young mothers advice on child rearing. After the war, the Veterans Administration in the US made an enormous investment to set up programs to train doctoral-level clinical psychologists to help treat the thousands of veterans needing care. As a consequence, the US went from having no formal university programs in clinical psychology in 1946 to over half of all PhDs in psychology in 1950 being awarded in clinical psychology.
WWII helped bring dramatic changes to clinical psychology, not just in America but internationally as well. Graduate education in psychology began adding psychotherapy to the science and research focus based on the 1947 scientist-practitioner model, known today as the Boulder Model, for PhD programs in clinical psychology. Clinical psychology in Britain developed much like in the US after WWII, specifically within the context of the National Health Service with qualifications, standards, and salaries managed by the British Psychological Society.
=== Development of the Doctor of Psychology degree ===
By the 1960s, psychotherapy had become embedded within clinical psychology, but for many, the PhD educational model did not offer the necessary training for those interested in practice rather than research. There was a growing argument that said the field of psychology in the US had developed to a degree warranting explicit training in clinical practice. The concept of a practice-oriented degree was debated in 1965 and narrowly gained approval for a pilot program at the University of Illinois starting in 1968. Several other similar programs were instituted soon after, and in 1973, at the Vail Conference on Professional Training in Psychology, the practitioner–scholar model of clinical psychology—or Vail Model—resulting in the Doctor of Psychology (PsyD) degree was recognized. Although training would continue to include research skills and a scientific understanding of psychology, the intent would be to produce highly trained professionals, similar to programs in medicine, dentistry, and law. The first program explicitly based on the PsyD model was instituted at Rutgers University. Today, about half of all American graduate students in clinical psychology are enrolled in PsyD programs.
=== A changing profession ===
Since the 1970s, clinical psychology has continued growing into a robust profession and academic field of study. Although the exact number of practicing clinical psychologists is unknown, it is estimated that between 1974 and 1990, the number in the US grew from 20,000 to 63,000. Clinical psychologists continue to be experts in assessment and psychotherapy while expanding their focus to address issues of gerontology, sports, and the criminal justice system to name a few. One important field is health psychology, the fastest-growing employment setting for clinical psychologists in the past decade. Other major changes include the impact of managed care on mental health care; an increasing realization of the importance of knowledge relating to multicultural and diverse populations; and emerging privileges to prescribe psychotropic medication.
== Professional practice ==
Clinical psychologists engage in a wide range of activities. Some focus solely on research into the assessment, treatment, or cause of mental illness and related conditions. Some teach, whether in a medical school or hospital setting, or in an academic department (e.g., psychology department) at an institution of higher education. The majority of clinical psychologists engage in some form of clinical practice, with professional services including psychological assessment, provision of psychotherapy, development and administration of clinical programs, and forensics (e.g., providing expert testimony in a legal proceeding).
In clinical practice, clinical psychologists may work with individuals, couples, families, or groups in a variety of settings, including private practices, hospitals, mental health organizations, schools, businesses, and non-profit agencies. Clinical psychologists who provide clinical services may also choose to specialize. Some specializations are codified and credentialed by regulatory agencies within the country of practice. In the United States, such specializations are credentialed by the American Board of Professional Psychology (ABPP).
== Training and certification to practice ==
Clinical psychologists study a generalist program in psychology plus postgraduate training and/or clinical placement and supervision. The length of training differs across the world, ranging from four years plus post-Bachelors supervised practice to a doctorate of three to six years which combines clinical placement. The practice of clinical psychology requires a license in the United States, Canada, the United Kingdom, and many other countries.
=== US and Canada ===
In the US, about half of all clinical psychology graduate students are being trained in PhD programs—a model that emphasizes research—with the other half in PsyD programs, which has more focus on practice (similar to professional degrees for medicine and law). Both models are accredited by the American Psychological Association and many other English-speaking psychological societies. A smaller number of schools offer accredited programs in clinical psychology resulting in a master's degree, which usually takes two to three years post-Bachelors.
Although each of the US states is somewhat different in terms of requirements and licenses, there are three common elements:
Graduation from an accredited school with the appropriate degree
Completion of supervised clinical experience or internship
Passing a written examination and, in some states, an oral examination
All U.S. state and Canadian province licensing boards are members of the Association of State and Provincial Psychology Boards (ASPPB), which created and maintains the Examination for Professional Practice in Psychology (EPPP). Many states require other examinations in addition to the EPPP, such as a jurisprudence (i.e. mental health law) examination and/or an oral examination. Most states also require a certain number of continuing education credits per year in order to renew a license, which can be obtained through various means, such as taking audited classes and attending approved workshops. Clinical psychologists require the psychologist license to practice, although other mental health provider licenses can be obtained with a master's degree, such as Marriage and Family Therapist (MFT), Licensed Professional Counselor (LPC), and Licensed Psychological Associate (LPA).
=== UK ===
In the UK, clinical psychologists undertake a Doctor of Clinical Psychology (DClinPsych), which is a practitioner doctorate with both clinical and research components. This is a three-year full-time salaried program sponsored by the National Health Service (NHS) and based in universities and the NHS. Entry into these programs is highly competitive and requires at least a three-year undergraduate degree in psychology plus some form of experience, usually in either the NHS as an assistant psychologist or in academia as a research assistant. It is not unusual for applicants to apply several times before being accepted onto a training course as only about one-fifth of applicants are accepted each year. These clinical psychology doctoral degrees are accredited by the British Psychological Society and the Health Professions Council (HPC). The HPC is the statutory regulator for practitioner psychologists in the UK. Those who successfully complete clinical psychology doctoral degrees are eligible to apply for registration with the HPC as a clinical psychologist.
In the UK, registration as a clinical psychologist with the Health Professions Council (HPC) is necessary. The HPC is the statutory regulator for practitioner psychologists in the UK. In the UK the following titles are restricted by law "registered psychologist" and "practitioner psychologist"; in addition, the specialist title "clinical psychologist" is also restricted by law.
=== Pakistan ===
In Pakistan, training is through institutions like University of Management and Technology, University of the Punjab, University of Central Punjab, Fatima Jinnah Women's University, National University of Medical Sciences. Some psychological associations are The Pakistan Psychological Association(PPA), Pakistan Association of Clinical Psychologists(PACP), Pakistan Psychological Association(PPA) and Pakistan Psychological Society(PPS).
== Assessment ==
An important area of expertise for many clinical psychologists is psychological assessment, and there are indications that as many as 91% of psychologists engage in this core clinical practice. Such evaluation is usually done in service to gaining insight into and forming hypothesis about psychological or behavioral problems. As such, the results of such assessments are usually used to create generalized impressions (rather than diagnosis) in service to informing treatment planning. Methods include formal testing measures, interviews, reviewing records, clinical observation, and physical examination.
=== Measurement domains ===
There exist hundreds of various assessment tools, although only a few have been shown to have both high validity (i.e., test actually measures what it claims to measure) and reliability (i.e., consistency). Many psychological assessment measures are restricted for use by those with advanced training in mental health. For instance, Pearson (one of the many companies with rights and protection of psychological assessment tools) separates who can administer, interpret, and report on certain tests. Anybody is able to access Qualification Level A tests. Those who intend to use assessment tools at Qualification Level B must hold a master's degree in psychology, education, speech language pathology, occupational therapy, social work, counseling, or in a field closely related to the intended use of the assessment, and formal training in the ethical administration, scoring, and interpretation of clinical assessments. Those with access to Qualification C (highest level) assessment measures must hold a doctorate degree in psychology, education, or a closely related field with formal training in the ethical administration, scoring, and interpretation of clinical assessments related to the intended use of the assessment.
Psychological measures generally fall within one of several categories, including the following:
Intelligence & achievement tests – These tests are designed to measure certain specific kinds of cognitive functioning (often referred to as IQ) in comparison to a norming group. These tests, such as the WISC-IV and the WAIS, attempt to measure such traits as general knowledge, verbal skill, memory, attention span, logical reasoning, and visual/spatial perception. Several tests have been shown to predict accurately certain kinds of performance, especially scholastic. Other tests in this category include the WRAML and the WIAT.
Personality tests – Tests of personality aim to describe patterns of behavior, thoughts, and feelings. They generally fall within two categories: objective and projective. Objective measures, such as the MMPI, are based on restricted answers—such as yes/no, true/false, or a rating scale—which allow for the computation of scores that can be compared to a normative group. Projective tests, such as the Rorschach inkblot test, allow for open-ended answers, often based on ambiguous stimuli. Other commonly used personality assessment measures include the PAI and the NEO
Neuropsychological tests – Neuropsychological tests consist of specifically designed tasks used to measure psychological functions known to be linked to a particular brain structure or pathway. They are typically used to assess impairment after an injury or illness known to affect neurocognitive functioning, or when used in research, to contrast neuropsychological abilities across experimental groups.
Diagnostic Measurement Tools – Clinical psychologists are able to diagnose psychological disorders and related disorders found in the DSM-5 and ICD-10. Many assessment tests have been developed to complement the clinicians clinical observation and other assessment activities. Some of these include the SCID-IV, the MINI, as well as some specific to certain psychological disorders such as the CAPS-5 for trauma, the ASEBA, and the K-SADS for affective and Schizophrenia in children.
Clinical observation – Clinical psychologists are also trained to gather data by observing behavior. The clinical interview is a vital part of the assessment, even when using other formalized tools, which can employ either a structured or unstructured format. Such assessment looks at certain areas, such as general appearance and behavior, mood and affects, perception, comprehension, orientation, insight, memory, and content of the communication. One psychiatric example of a formal interview is the mental status examination, which is often used in psychiatry as a screening tool for treatment or further testing.
=== Diagnosis ===
Psychological assessment usually includes determining a mental disorder diagnosis. Many countries use the International Statistical Classification of Diseases and Related Health Problems (ICD-10 or ICD-11) while the US most often uses the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Both are nosological systems that largely assume categorical disorders diagnosed through the application of sets of criteria including symptoms and signs.
Several new models are being discussed, including a "dimensional model" based on empirically validated models of human differences (such as the five factor model of personality) and a "psychosocial model", which would take changing, intersubjective states into greater account. The proponents of these models claim that they would offer greater diagnostic flexibility and clinical utility without depending on the medical concept of illness. However, they also admit that these models are not yet robust enough to gain widespread use, and should continue to be developed.
=== Clinical v. mechanical prediction ===
Clinical assessment can be characterized as a prediction problem where the purpose of assessment is to make inferences (predictions) about past, present, or future behavior. For example, many therapy decisions are made on the basis of what a clinician expects will help a patient make therapeutic gains. Once observations have been collected (e.g., psychological testing results, diagnostic impressions, clinical history, X-ray, etc.), there are two mutually exclusive ways to combine those sources of information to arrive at a decision, diagnosis, or prediction. One way is to combine the data in an algorithmic, or "mechanical" fashion. Mechanical prediction methods are simply a mode of combination of data to arrive at a decision/prediction of behavior (e.g., treatment response). The mechanical prediction does not preclude any type of data from being combined; it can incorporate clinical judgments, properly coded, in the algorithm. The defining characteristic is that, once the data to be combined is given, the mechanical approach will make a prediction that is 100% reliable. That is, it will make exactly the same prediction for exactly the same data every time. Clinical prediction, on the other hand, does not guarantee this, as it depends on the decision-making processes of the clinician making the judgment, their current state of mind, and knowledge base.
What has come to be called the "clinical versus statistical prediction" debate was first described in detail in 1954 by Paul Meehl, where he explored the claim that mechanical (formal, algorithmic) methods of data combination could outperform clinical (e.g., subjective, informal, "in the clinician's head") methods when such combinations are used to arrive at a prediction of behavior. Meehl concluded that mechanical modes of combination performed as well or better than clinical modes. Subsequent meta-analyses of studies that directly compare mechanical and clinical predictions have borne out Meehl's 1954 conclusions. A 2009 survey of practicing clinical psychologists found that clinicians almost exclusively use their clinical judgment to make behavioral predictions for their patients, including diagnosis and prognosis.
== Intervention ==
Psychotherapy involves a formal relationship between professional and client—usually an individual, couple, family, or small group—that employs a set of procedures intended to form a therapeutic alliance, explore the nature of psychological problems, and encourage new ways of thinking, feeling, or behaving.
Clinicians have a wide range of individual interventions to draw from, often guided by their training—for example, a cognitive behavioral therapy (CBT) clinician might use worksheets to record distressing cognitions, a psychoanalyst might encourage free association, while a psychologist trained in Gestalt techniques might focus on immediate interactions between client and therapist. Clinical psychologists generally seek to base their work on research evidence and outcome studies as well as on trained clinical judgment. Although there are literally dozens of recognized therapeutic orientations, their differences can often be categorized on two dimensions: insight vs. action and in-session vs. out-session.
Insight – emphasis is on gaining a greater understanding of the motivations underlying one's thoughts and feelings (e.g. psychodynamic therapy)
Action – focus is on making changes in how one thinks and acts (e.g. solution focused therapy, cognitive behavioral therapy)
In-session – interventions center on the here-and-now interaction between client and therapist (e.g. humanistic therapy, Gestalt therapy)
Out-session – a large portion of therapeutic work is intended to happen outside of session (e.g. bibliotherapy, rational emotive behavior therapy)
The methods used are also different in regards to the population being served as well as the context and nature of the problem. Therapy will look very different between, say, a traumatized child, a depressed but high-functioning adult, a group of people recovering from substance dependence, and a ward of the state suffering from terrifying delusions. Other elements that play a critical role in the process of psychotherapy include the environment, culture, age, cognitive functioning, motivation, and duration (i.e. brief or long-term therapy).
=== Four main schools ===
Many clinical psychologists are integrative or eclectic and draw from the evidence base across different models of therapy in an integrative way, rather than using a single specific model.
In the UK, clinical psychologists have to show competence in at least two models of therapy, including CBT, to gain their doctorate. The British Psychological Society Division of Clinical Psychology has been vocal about the need to follow the evidence base rather than being wedded to a single model of therapy.
In the US, intervention applications and research are dominated in training and practice by essentially four major schools of practice: psychodynamic, humanism, behavioral/cognitive behavioral, and systems or family therapy.
==== Psychodynamic ====
The psychodynamic perspective developed out of the psychoanalysis of Sigmund Freud. The core object of psychoanalysis is to make the unconscious conscious—to make the client aware of his or her own primal drives (namely those relating to sex and aggression) and the various defenses used to keep them in check. The essential tools of the psychoanalytic process are the use of free association and an examination of the client's transference towards the therapist, defined as the tendency to take unconscious thoughts or emotions about a significant person (e.g. a parent) and "transfer" them onto another person. Major variations on Freudian psychoanalysis practiced today include self psychology, ego psychology, and object relations theory. These general orientations now fall under the umbrella term psychodynamic psychology, with common themes including examination of transference and defenses, an appreciation of the power of the unconscious, and a focus on how early developments in childhood have shaped the client's current psychological state.
==== Humanistic/Experiential ====
Humanistic psychology was developed in the 1950s in reaction to both behaviorism and psychoanalysis, largely due to the person-centered therapy of Carl Rogers (often referred to as Rogerian Therapy) and existential psychology developed by Viktor Frankl and Rollo May. Rogers believed that a client needed only three things from a clinician to experience therapeutic improvement—congruence, unconditional positive regard, and empathetic understanding. By using phenomenology, intersubjectivity and first-person categories, the humanistic approach seeks to get a glimpse of the whole person and not just the fragmented parts of the personality. This aspect of holism links up with another common aim of humanistic practice in clinical psychology, which is to seek an integration of the whole person, also called self-actualization. From 1980, Hans-Werner Gessmann integrated the ideas of humanistic psychology into group psychotherapy as humanistic psychodrama. According to humanistic thinking, each individual person already has inbuilt potentials and resources that might help them to build a stronger personality and self-concept. The mission of the humanistic psychologist is to help the individual employ these resources via the therapeutic relationship.
Emotion focused therapy/Emotionally focused therapy (EFT), not to be confused with Emotional Freedom Techniques, was initially informed by humanistic–phenomenological and Gestalt theories of therapy. "Emotion Focused Therapy can be defined as the practice of therapy informed by an understanding of the role of emotion in psychotherapeutic change. EFT is founded on a close and careful analysis of the meanings and contributions of emotion to human experience and change in psychotherapy. This focus leads therapist and client toward strategies that promotes the awareness, acceptance, expression, utilization, regulation, and transformation of emotion as well as corrective emotional experience with the therapist. The goals of EFT are strengthening the self, regulating affect, and creating new meaning". Similarly to some Psychodynamic therapy approaches, EFT pulls heavily from attachment theory. Pioneers of EFT are Les Greenberg and Sue Johnson. EFT is often used in therapy with individuals, and may be especially useful for couples therapy. Founded in 1998, Sue Johnson and others lead the International Centre for Excellence in Emotion Focused Therapy (ICEEFT) where clinicians can find EFT training internationally. EFT is also a commonly chosen modality to treat clinically diagnosable trauma.
==== Behavioral and cognitive behavioral ====
Cognitive behavioral therapy (CBT) developed from the combination of cognitive therapy and rational emotive behavior therapy, both of which grew out of cognitive psychology and behaviorism. CBT is based on the theory that how we think (cognition), how we feel (emotion), and how we act (behavior) are related and interact together in complex ways. In this perspective, certain dysfunctional ways of interpreting and appraising the world (often through schemas or beliefs) can contribute to emotional distress or result in behavioral problems. The object of many cognitive behavioral therapies is to discover and identify the biased, dysfunctional ways of relating or reacting and through different methodologies help clients transcend these in ways that will lead to increased well-being. There are many techniques used, such as systematic desensitization, socratic questioning, and keeping a cognition observation log. Modified approaches that fall into the category of CBT have also developed, including dialectic behavior therapy and mindfulness-based cognitive therapy.
Behavior therapy is a rich tradition. It is well researched with a strong evidence base. Its roots are in behaviorism. In behavior therapy, environmental events predict the way we think and feel. Our behavior sets up conditions for the environment to feedback back on it. Sometimes the feedback leads the behavior to increase- reinforcement and sometimes the behavior decreases- punishment. Oftentimes behavior therapists are called applied behavior analysts or behavioral health counselors. They have studied many areas from developmental disabilities to depression and anxiety disorders. In the area of mental health and addictions a recent article looked at APA's list for well established and promising practices and found a considerable number of them based on the principles of operant and respondent conditioning. Multiple assessment techniques have come from this approach including functional analysis (psychology), which has found a strong focus in the school system. In addition, multiple intervention programs have come from this tradition including community reinforcement approach for treating addictions, acceptance and commitment therapy, functional analytic psychotherapy, including dialectic behavior therapy and behavioral activation. In addition, specific techniques such as contingency management and exposure therapy have come from this tradition.
==== Systems or family therapy ====
Systems or family therapy works with couples and families, and emphasizes family relationships as an important factor in psychological health. The central focus tends to be on interpersonal dynamics, especially in terms of how change in one person will affect the entire system. Therapy is therefore conducted with as many significant members of the "system" as possible. Goals can include improving communication, establishing healthy roles, creating alternative narratives, and addressing problematic behaviors.
=== Other therapeutic perspectives ===
There exist dozens of recognized schools or orientations of psychotherapy—the list below represents a few influential orientations not given above. Although they all have some typical set of techniques practitioners employ, they are generally better known for providing a framework of theory and philosophy that guides a therapist in his or her working with a client.
Existential – Existential psychotherapy postulates that people are largely free to choose who we are and how we interpret and interact with the world. It intends to help the client find deeper meaning in life and to accept responsibility for living. As such, it addresses fundamental issues of life, such as death, aloneness, and freedom. The therapist emphasizes the client's ability to be self-aware, freely make choices in the present, establish personal identity and social relationships, create meaning, and cope with the natural anxiety of living.
Gestalt – Gestalt therapy was primarily founded by Fritz Perls in the 1950s. This therapy is perhaps best known for using techniques designed to increase self-awareness, the best-known perhaps being the "empty chair technique." Such techniques are intended to explore resistance to "authentic contact", resolve internal conflicts, and help the client complete "unfinished business".
Postmodern – Postmodern psychology says that the experience of reality is a subjective construction built upon language, social context, and history, with no essential truths. Since "mental illness" and "mental health" are not recognized as objective, definable realities, the postmodern psychologist instead sees the goal of therapy strictly as something constructed by the client and therapist. Forms of postmodern psychotherapy include narrative therapy, solution-focused therapy, and coherence therapy.
Transpersonal – The transpersonal perspective places a stronger focus on the spiritual facet of human experience. It is not a set of techniques so much as a willingness to help a client explore spirituality and/or transcendent states of consciousness. Transpersonal psychology is concerned with helping clients achieve their highest potential.
Multiculturalism – Although the theoretical foundations of psychology are rooted in European culture, there is a growing recognition that there exist profound differences between various ethnic and social groups and that systems of psychotherapy need to take those differences into greater consideration. Further, the generations following immigrant migration will have some combination of two or more cultures—with aspects coming from the parents and from the surrounding society—and this process of acculturation can play a strong role in therapy (and might itself be the presenting problem). Culture influences ideas about change, help-seeking, locus of control, authority, and the importance of the individual versus the group, all of which can potentially clash with certain givens in mainstream psychotherapeutic theory and practice. As such, there is a growing movement to integrate knowledge of various cultural groups in order to inform therapeutic practice in a more culturally sensitive and effective way.
Feminism – Feminist therapy is an orientation arising from the disparity between the origin of most psychological theories (which have male authors) and the majority of people seeking counseling being female. It focuses on societal, cultural, and political causes and solutions to issues faced in the counseling process. It openly encourages the client to participate in the world in a more social and political way.
Positive psychology – Positive psychology is the scientific study of human happiness and well-being, which started to gain momentum in 1998 due to the call of Martin Seligman, then president of the APA. The history of psychology shows that the field has been primarily dedicated to addressing mental illness rather than mental wellness. Applied positive psychology's main focus, therefore, is to increase one's positive experience of life and ability to flourish by promoting such things as optimism about the future, a sense of flow in the present, and personal traits like courage, perseverance, and altruism. There is now preliminary empirical evidence to show that by promoting Seligman's three components of happiness—positive emotion (the pleasant life), engagement (the engaged life), and meaning (the meaningful life)—positive therapy can decrease clinical depression.
Community psychology approaches are often used for psychological prevention of harm and clinical intervention.
=== Integration ===
In the last couple of decades, there has been a growing movement to integrate the various therapeutic approaches, especially with an increased understanding of cultural, gender, spiritual, and sexual-orientation issues. Clinical psychologists are beginning to look at the various strengths and weaknesses of each orientation while also working with related fields, such as neuroscience, behavioural genetics, evolutionary biology, and psychopharmacology. The result is a growing practice of eclecticism, with psychologists learning various systems and the most efficacious methods of therapy with the intent to provide the best solution for any given problem.
== Professional ethics ==
The field of clinical psychology in most countries is strongly regulated by a code of ethics. In the US, professional ethics are largely defined by the APA Code of Conduct, which is often used by states to define licensing requirements. The APA Code generally sets a higher standard than that which is required by law as it is designed to guide responsible behavior, the protection of clients, and the improvement of individuals, organizations, and society. The Code is applicable to all psychologists in both research and applied fields.
The APA Code is based on five principles: Beneficence and Nonmaleficence, Fidelity and Responsibility, Integrity, Justice, and Respect for People's Rights and Dignity. Detailed elements address how to resolve ethical issues, competence, human relations, privacy and confidentiality, advertising, record keeping, fees, training, research, publication, assessment, and therapy.
The Canadian Psychological Association ethical code principle's are: Respect for the Dignity of Persons and Peoples, Responsible Caring, Integrity in Relationships, and Responsibility to Society. It is considered very similar to the APA's Code.
In the UK the British Psychological Society has published a Code of Conduct and Ethics for clinical psychologists. This has four key areas: Respect, Competence, Responsibility and Integrity. Other European professional organizations have similar codes of conduct and ethics.
The Asian Federation for Psychotherapy published a code of ethics in 2008 with the following principles: Beneficence, Responsibility, Integrity, Justices, and Respect. Similar to the APA code, it provides detailed instructions for the conduct of psychologists, specifically psychotherapists. Russia, India, Iran, Kazakhstan, China, Malaysia, and Japan are member countries.
The National Latina/o Psychological Association adopted their current ethical guidelines in 2018, stating that "the traditional Eurocentric foundations in mainstream psychology have provided culturally bound knowledge about worldviews, ways of living, and cultural practices." Their principles are: Respect and Responsibility, Ethical Dilemmas, Ethical Decision-Making and Legal Responsibility, Consultation, Justice and Advocacy, Self-Awareness and Social-Consciousness, Action and Accountability, Training and Creating Infrastructure, and Mentorship.
== Comparison with other mental health professions ==
=== Psychiatry ===
Although clinical psychologists and psychiatrists can be said to share a same fundamental aim—the alleviation of mental distress—their training, outlook, and methodologies are often quite different. Perhaps the most significant difference is that psychiatrists are licensed physicians. As such, psychiatrists often use the medical model to assess psychological problems (i.e., those they treat are seen as patients with an illness) and can use psychotropic medications as a method of addressing the illness—although some also employ psychotherapy as well. Psychiatrists are able to conduct physical examinations, order and interpret laboratory tests and EEGs, and may order brain imaging studies such as computed tomography (CT or CAT), MRI, and PET scanning. Conversely, clinical psychologists conduct specialist assessment and psychometric testing. Such assessments and tests would not normally only be administered and interpreted by psychologists due to their advanced training in psychometric assessment. Standard clinical psychologists also usually possess more advanced training and specialist knowledge in psychosocial development and psychological therapies.
Clinical psychologists generally do not prescribe medication, although there is a movement for psychologists to have prescribing privileges. These medical privileges require additional training and education. To date, medical psychologists (prescribing psychologists) may prescribe psychotropic medications in Colorado, Guam, Iowa, Idaho, Illinois, New Mexico, Louisiana, the Public Health Service, the Indian Health Service, and the United States Military. In contrast, psychiatrists are legally authorized to prescribe psychotropic medications in all states of the U.S. and in all provinces of Canada. However, psychiatrists are not usually involved in psychometric assessment.
In education, clinical psychologists attend a graduate institution and have a Doctor of Philosophy (Ph.D.) or a Doctor of Psychology (Psy.D.) degree, usually following both an undergraduate and master's degree in Psychology or a related discipline. Conversely, psychiatrists complete their studies at a medical school and hold a medical degree (M.D.), Bachelor of Medicine, Bachelor of Surgery (with additional post-graduate training), or an osteopathic degree and the (D.O.) which is only available in the United States.
Due to their scientist-practitioner model of training, clinical psychologists have more advanced research knowledge and skills, including advanced training in statistics, compared with standard psychiatric training.
=== Counseling psychology ===
Counseling psychologists undergo the same level of rigor in study and use many of the same interventions and tools as clinical psychologists, including psychotherapy and assessment. Traditionally, counseling psychologists helped people with what might be considered normal or moderate psychological problems—such as the feelings of anxiety or sadness resulting from major life changes or events. However, that distinction has faded over time, and of the counseling psychologists who do not go into academia (which does not involve treatment or diagnosis), the majority of counseling psychologists treat mental illness alongside clinical psychologists. Many counseling psychologists also receive specialized training in career assessment, group therapy, and relationship counseling.
Counseling psychology as a field values multiculturalism and social advocacy, often stimulating research in multicultural issues. There are fewer counseling psychology graduate programs than those for clinical psychology and they are more often housed in departments of education rather than psychology. Counseling psychologists tend to be more frequently employed in university counseling centers compared to hospitals and private practice for clinical psychologists. However, counseling and clinical psychologists can be employed in a variety of settings, with a large degree of overlap (prisons, colleges, community mental health, non-profits, corporations, private practice, hospitals and Veterans Affairs).
=== School psychology ===
School psychologists are primarily concerned with the academic, social, and emotional well-being of children and adolescents within a scholastic environment. In the UK, they are known as "educational psychologists". Like clinical (and counseling) psychologists, school psychologists with doctoral degrees are eligible for licensure as health service psychologists, and many work in private practice. Unlike clinical psychologists, they receive much more training in education, child development and behavior, and the psychology of learning. Common degrees include the Educational Specialist Degree (EdS), Doctor of Philosophy (PhD), and Doctor of Education (EdD).
Traditional job roles for school psychologists employed in school settings have focused mainly on assessment of students to determine their eligibility for special education services in schools, and on consultation with teachers and other school professionals to design and carry out interventions on behalf of students. Other major roles also include offering individual and group therapy with children and their families, designing prevention programs (e.g. for reducing dropout), evaluating school programs, and working with teachers and administrators to help maximize teaching efficacy, both in the classroom and systemically.
=== Clinical social work ===
Social workers provide a variety of services, generally concerned with social problems, their causes, and their solutions. With specific training, clinical social workers may also provide psychological counseling (in the US and Canada), in addition to more traditional social work.
=== Occupational therapy ===
Occupational therapy—often abbreviated OT—is the "use of productive or creative activity in the treatment or rehabilitation of physically, cognitively, or emotionally disabled people." Most commonly, occupational therapists work with people with disabilities to enable them to maximize their skills and abilities. Occupational therapy practitioners are skilled professionals whose education includes the study of human growth and development with specific emphasis on the physical, emotional, psychological, sociocultural, cognitive and environmental components of illness and injury. They commonly work alongside clinical psychologists in settings such as inpatient and outpatient mental health, pain management clinics, eating disorder clinics, and child development services. OT's use support groups, individual counseling sessions, and activity-based approaches to address psychiatric symptoms and maximize functioning in life activities.
== Criticisms and controversies ==
Clinical psychology is a diverse field and there have been recurring tensions over the degree to which clinical practice should be limited to treatments supported by empirical research. Despite some evidence showing that all the major therapeutic orientations are about of equal effectiveness, there remains much debate about the efficacy of various forms of treatment in use in clinical psychology.
== See also ==
== References ==
== External links ==
American Academy of Clinical Psychology
American Association for Marriage and Family Therapy Archived 2019-05-30 at the Wayback Machine
American Board of Professional Psychology
Annual Review of Clinical Psychology Archived 2009-01-20 at the Wayback Machine
APA Society of Clinical Psychology (Division 12)
Association of State and Provincial Psychology Boards (ASPPB) Archived 2017-10-09 at the Wayback Machine
NAMI: National Alliance on Mental Illness
National Institute of Mental Health | Wikipedia/Clinical_psychologist |
Sexual orientation is an enduring pattern of romantic or sexual attraction (or a combination of these) to persons of the opposite sex or gender, the same sex or gender, or to both sexes or more than one gender, or none of the aforementioned at all. The ultimate causes and mechanisms of sexual orientation development in humans remain unclear and many theories are speculative and controversial. However, advances in neuroscience explain and illustrate characteristics linked to sexual orientation. Studies have explored structural neural-correlates, functional and/or cognitive relationships, and developmental theories relating to sexual orientation in humans.
== Developmental neurobiology ==
Many theories concerning the development of sexual orientation involve fetal neural development, with proposed models illustrating prenatal hormone exposure, maternal immunity, and developmental instability. Other proposed factors include genetic control of sexual orientation. No conclusive evidence has been shown that environmental or learned effects are responsible for the development of non-heterosexual orientation.
As of 2005, sexual dimorphisms in the brain and behavior among vertebrates were accounted for by the influence of gonadal steroidal androgens as demonstrated in animal models over the prior few decades. The prenatal androgen model of homosexuality describes the neuro-developmental effects of fetal exposure to these hormones. In 1985, Geschwind and Galaburda proposed that homosexual men are exposed to high androgen levels early in development and proposed that temporal and local variations in androgen exposure to a fetus's developing brain is a factor in the pathways determining homosexuality. This led scientists to look for somatic markers for prenatal hormonal exposure that could be easily, and non-invasively, explored in otherwise endocrinologically normal populations. Various somatic markers (including 2D:4D finger ratios, auditory evoked potentials, fingerprint patterns and eye-blink patterns) have since been found to show variation based on sexual orientation in healthy adult individuals.
Other evidence supporting the role of testosterone and prenatal hormones in sexual orientation development include observations of male subjects with cloacal exstrophy who were sex-assigned as female during birth only later to declare themselves male. This supports the theory that the prenatal testosterone surge is crucial for gender identity development. Additionally, females whose mothers were exposed to diethylstilbestrol (DES) during pregnancy show higher rates of bi- and homosexuality.
Variations in the hypothalamus may have some influence on sexual orientation. Studies show that factors such as cell number and size of various nuclei in the hypothalamus may impact one's sexual orientation.
== Brain structure ==
Multiple areas of the human brain have been found to display structural differences associated with sexual orientation. Several of these can be found in the hypothalamus, particularly the sexually dimorphic nucleus of the preoptic area (SDN-POA) in mammals. Researchers have shown that the SDN-POA aides in sex-dimorphic mating behavior in some mammals, which is representative of human sexual orientation. In humans, its equivalent is the interstitial nucleus of the anterior hypothalamus (INAH-3), which has demonstrated size differences between heterosexual and homosexual men in early post-mortem studies. There are also other POA-like brain structures in the human brain which differ between sexual orientations, such as the suprachiasmatic nucleus and the anterior hypothalamus have similarly shown structural variations linked to sexual orientation. Using meta-analysis of neuroimaging, researchers have concluded that these areas are linked to sexual preferences in humans, which would explain why they may differ based on sexual orientation.
Neuroimaging studies have also identified differences in other brain regions. Meta-analyses suggest that areas involved in emotional processing and sexual arousal, such as the thalamus and amygdala, exhibit distinct patterns between heterosexual and homosexual individuals. Another area of the brain which demonstrates sexual orientation differentiation is the thalamus, which is a structure involved in sexual arousal and reward. Earlier research found that the thalamus tends to be larger in heterosexual individuals compared to homosexual individuals. The placement of connections in the amygdala have been demonstrated to differ between heterosexual and homosexual individuals. The posterior cingulate cortex, a part of the occipital lobe, the region of the brain that processes visual information, has also been demonstrated to have differences based on sexual orientation.
Additionally, hemispheric connectivity differs by sexual orientation: the anterior commissure was reported to be wider and the corpus callosum larger in homosexual men than in heterosexual men.
Some areas of the brain which researchers looked at but did not find differences in structure between sexualities are the temporal cortex, hippocampus and putamen.
Multiple neuroimaging studies have reported structural brain differences associated with sexual orientation. Early research by LeVay (1991) found that the third interstitial nucleus of the anterior hypothalamus (INAH-3) was significantly smaller in homosexual men compared to heterosexual men, though methodological limitations and small sample sizes limited conclusions.
Subsequent studies using MRI techniques observed variations in hemispheric asymmetry and amygdala connectivity patterns, suggesting that homosexual men exhibit brain structural and functional patterns more similar to heterosexual women, and vice versa for homosexual women.
A 2020 study by Wang et al. examined cortical thickness, surface area, and gray matter volume in 29 gay men, 29 straight men, 17 gay women, and 17 straight women. The results showed complex interactive effects of biological sex and sexual orientation. Notably, gay men exhibited increased cortical thickness in regions such as the right anterior cingulate cortex (ACC), superior frontal gyrus, and precuneus when compared to both heterosexual men and women. In contrast, straight women displayed "female-typical" cortical thickness in parietal regions. Also, gay men demonstrated a mixture of sex-atypical (cross-sex) characteristics in midline brain areas (ACC, frontal cortex) alongside some sex-typical patterns. The study also emphasized differences in the left inferior frontal gyrus and temporal lobes, suggesting these regions may play a critical role in the sexual differentiation of the human brain.
Functional neuroimaging studies have examined whether sexual orientation is associated with differences in brain activation patterns during cognitive tasks known to show sex differences. Folkierska-Żukowska et al. (2020) investigated mental rotation ability, confirming established sex differences in parietal and frontal regions, with men showing greater parietal activation and women greater frontal activation. Among gay men, the results indicated variability linked to childhood gender nonconformity. Subgroups of gay men with gender-nonconforming histories displayed partial cross-sex shifts in brain activation, while others did not. The study suggested the presence of subgroup variation within sexual orientation categories, with functional differences emerging primarily in specific sub-populations.
While some studies have reported subtle neuroanatomical and functional differences related to sexual orientation, others have urged caution in interpreting these findings. A systematic review by Frigerio et al. (2021) emphasized that most neuroimaging features of homosexual individuals resembled those of same-sex heterosexuals rather than opposite-sex individuals. The review noted that reported effects were often inconsistent, small in size, and frequently failed replication. For example, Kranz et al. (2014) found that sex differences in white-matter microstructure persisted after adjusting for sexual orientation. These findings have led some researchers to argue that evidence for orientation-linked brain structure is limited and that any real effects may be confined to subtle network-level patterns detectable only in larger, more powered studies.
A 2021 voxel-based morphometry MRI study involving approximately 500 adults identified focal gray matter volume differences associated with sexual orientation. Votinov et al. reported that heterosexual men exhibited larger thalamic volumes than homosexual men, while homosexual women had larger putamen volumes than heterosexual women. Additionally, volume differences were noted in the precentral gyrus. The study concluded that sexual orientation is "reflected in brain structure characteristics" in a sex-specific manner.
A large-scale imaging and genetics study conducted by Abe et al. (2021) analyzed brain MRI and genetic data from 18,645 individuals through the UK Biobank project. Using a data-driven partial least squares (PLS) approach, the study found that brain features typically distinguishing male and female participants were attenuated in non-heterosexual individuals. Specifically, non-heterosexual women exhibited brain-activation and structural patterns shifted toward male-typical profiles. Additionally, higher polygenic scores for same-sex sexual behavior were associated with increased volume in occipital and temporo-occipital cortices. The authors concluded that the study provided multivariate neuroanatomical correlates of same-sex sexual behavior, suggesting a potential biological basis for sexual orientation.
More recently, a 2022 study by Clemens et al. utilized resting-state functional magnetic resonance imaging (fMRI) combined with machine learning techniques to examine patterns of intrinsic functional connectivity (FC) in relation to sexual orientation. The study involved 86 adult participants and demonstrated that a classifier trained on FC data could predict participants’ sexual orientation with approximately 92% accuracy, a rate significantly above chance. Key brain regions contributing to this classification included the precentral gyrus, precuneus, and prefrontal cortex, among others. The study highlighted that patterns of connectivity within distributed brain networks, rather than isolated brain structures, carry information associated with sexual orientation. In contrast, analyses based solely on gray matter volumes achieved a lower predictive accuracy of approximately 62%.
== Fraternal birth order effect ==
Neuroscience has been implicated in the study of birth order and male sexual orientation. A significant volume of research has found that the more older brothers a man has from the same mother, the greater the probability he will have a homosexual orientation. Estimates indicate that there is a 33–48% increase in chances of homosexuality in a male child with each older brother, and the effect is not observed in those with older adoptive or step-brothers, indicative of a prenatal biological mechanism. Ray Blanchard and Anthony Bogaert discovered the association in the 1990s, and named it the fraternal birth order (FBO) effect. The mechanism by which the effect is believed to operate states that a mother develops an immune response against a substance important in male fetal development during pregnancy, and that this immune effect becomes increasingly likely with each male fetus gestated by the mother. This immune effect is thought to cause an alteration in (some) later born males' prenatal brain development. The target of the immune response are molecules (specifically Y-linked proteins, which are thought to play a role in fetal brain sex-differentiation) on the surface of male fetal brain cells, including in sites of the anterior hypothalamus (which has been linked to sexual orientation in other research). Antibodies produced during the immune response are thought to cross the placental barrier and enter the fetal compartment where they bind to the Y-linked molecules and thus alter their role in sexual differentiation, leading some males to be attracted to men as opposed to women. Biochemical evidence to support this hypothesis was identified in 2017, finding mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than other samples of women, including mothers of heterosexual sons.
The effect does not mean that all or most sons will be gay after several male pregnancies, but rather, the odds of having a gay son increase from approximately 2% for the firstborn son, to 4% for the second, 6% for the third and so on. Scientists have estimated that 15–29% of gay men owe their sexual orientation to this effect, but the number may be higher, as prior miscarriages and terminations of male pregnancies may have exposed their mothers to Y-linked antigens. In addition, the effect is nullified in left-handed men. As it is contingent on handedness and handedness is a prenatally determined trait, it further attributes the effect to be biological, rather than psychosocial. The fraternal birth order effect does not apply to the development of female homosexuality. Blanchard does not believe the same antibody response would cause homosexuality in firstborn gay sons – instead, they may owe their orientation to genes, prenatal hormones and other maternal immune responses which also influence fetal brain development.
The few studies which have not observed a correlation between gay men and birth order have generally been criticized for methodological errors and sampling methods. J. Michael Bailey has said that no plausible hypothesis other than a maternal immune response has been identified.
== Research directions ==
As of 2005, research directions included:
finding markers for sex steroid levels in the brains of fetuses that highlight features of early neuro-development leading to certain sexual orientations
determine the precise neural circuitry underlying direction of sexual preference
use animal models to explore genetic and developmental factors that influence sexual orientation
further population studies, genetic studies, and serological markers to clarify and definitively determine the effect of maternal immunity
performing neuroimaging studies to quantify sexual-orientation-related differences in structure and function in vivo
carrying out neurochemical studies to investigate the roles of sex steroids upon neural circuitry involved in sexual attraction
Since the early 2000s, research in this area has expanded considerably. Key recent developments include a shift towards larger, data-driven studies using multivariate analyses and machine learning techniques. Notably, the UK Biobank imaging-genetics project has combined brain MRI, polygenic risk scores, and multivariate statistical approaches in large population samples to investigate neuroanatomical correlates of same-sex sexual behavior.
Another trend has been a reevaluation of binary models of brain "sex" and "gender". Several contemporary studies have emphasized the importance of considering gender identity, social context, and environmental stressors rather than focusing solely on anatomical dimorphism. One commentary published in 2025 noted that decades of male-versus-female brain research had not fully delivered on early expectations, and called for greater attention to how factors such as stigma and stress influence brain development.
Additionally, whole-brain network analyses and pattern classifiers have been increasingly applied to neuroimaging data. Recent studies suggest that orientation-related patterns may be more accurately detected through distributed network connectivity rather than isolated regional volume or thickness differences alone.
Recent research directions also emphasize greater inclusivity and intersectionality. Compared to early work, contemporary studies aim to include a wider range of identities. Analyses of the literature indicate that, although LGBTQ-related neuroscience studies increased during the 2010s, they remained unevenly distributed: approximately 32% focused on gay men and 24% on transgender people, while lesbians and bisexual individuals were notably underrepresented. New initiatives call for broadening samples and considering variables such as ethnicity, gender expression, and minority stress. This reflects a broader shift toward more diverse, representative studies and an intersectional lens in neuroimaging research.
The field has also adopted a more cautious approach regarding interpretation and reproducibility. Scholars in the 2020s have openly questioned whether robust, replicable brain correlates of sexual orientation will emerge, given historical replication difficulties. Some researchers also express concern about the ethical implications of attempting to "explain" sexual orientation through neuroscience. As a result, recent studies increasingly emphasize effect sizes, confidence intervals, and transparency in reporting, while systematic reviews and meta-analyses frequently highlight limitations and call for careful, nuanced interpretation of findings.
== See also ==
Biology and sexual orientation
Neuroanatomy of intimacy
Neuroscience of sex differences
Heterosexuality
Homosexuality and psychology
== References == | Wikipedia/Neuroscience_and_sexual_orientation |
Large-scale brain networks (also known as intrinsic brain networks) are collections of widespread brain regions showing functional connectivity by statistical analysis of the fMRI BOLD signal or other recording methods such as EEG, PET and MEG. An emerging paradigm in neuroscience is that cognitive tasks are performed not by individual brain regions working in isolation but by networks consisting of several discrete brain regions that are said to be "functionally connected". Functional connectivity networks may be found using algorithms such as cluster analysis, spatial independent component analysis (ICA), seed based, and others. Synchronized brain regions may also be identified using long-range synchronization of the EEG, MEG, or other dynamic brain signals.
The set of identified brain areas that are linked together in a large-scale network varies with cognitive function. When the cognitive state is not explicit (i.e., the subject is at "rest"), the large-scale brain network is a resting state network (RSN). As a physical system with graph-like properties, a large-scale brain network has both nodes and edges and cannot be identified simply by the co-activation of brain areas. In recent decades, the analysis of brain networks was made feasible by advances in imaging techniques as well as new tools from graph theory and dynamical systems.
The Organization for Human Brain Mapping has created the Workgroup for HArmonized Taxonomy of NETworks (WHATNET) group to work towards a consensus regarding network nomenclature. WHATNET conducted a survey in 2021 which showed a large degree of agreement about the name and topography of three networks: the "somato network", the "default network" and the "visual network", while other networks had less agreement. Several issues make the work of creating a common atlas for networks difficult: some of these issues are the variability of spatial and time scales, variability across individuals, and the dynamic nature of some networks.
Some large-scale brain networks are identified by their function and provide a coherent framework for understanding cognition by offering a neural model of how different cognitive functions emerge when different sets of brain regions join together as self-organized coalitions. The number and composition of the coalitions will vary with the algorithm and parameters used to identify them. In one model, there is only the default mode network and the task-positive network, but most current analyses show several networks, from a small handful to 17. The most common and stable networks are enumerated below. The regions participating in a functional network may be dynamically reconfigured.
Disruptions in activity in various networks have been implicated in neuropsychiatric disorders such as depression, Alzheimer's, autism spectrum disorder, schizophrenia, ADHD and bipolar disorder.
== Commonly identified networks ==
Because brain networks can be identified at various different resolutions and with various different neurobiological properties, there is currently no universal atlas of brain networks that fits all circumstances. Uddin, Yeo, and Spreng proposed in 2019 that the following six networks should be defined as core networks based on converging evidences from multiple studies to facilitate communication between researchers.
=== Default mode (medial frontoparietal) ===
The default mode network is active when an individual is awake and at rest. It preferentially activates when individuals focus on internally-oriented tasks such as daydreaming, envisioning the future, retrieving memories, and theory of mind. It is negatively correlated with brain systems that focus on external visual signals. It is the most widely researched network.
=== Salience (midcingulo-insular) ===
The salience network consists of several structures, including the anterior (bilateral) insula, dorsal anterior cingulate cortex, and three subcortical structures which are the ventral striatum, substantia nigra/ventral tegmental region. It plays the key role of monitoring the salience of external inputs and internal brain events. Specifically, it aids in directing attention by identifying important biological and cognitive events.
This network includes the ventral attention network, which primarily includes the temporoparietal junction and the ventral frontal cortex of the right hemisphere. These areas respond when behaviorally relevant stimuli occur unexpectedly. The ventral attention network is inhibited during focused attention in which top-down processing is being used, such as when visually searching for something. This response may prevent goal-driven attention from being distracted by non-relevant stimuli. It becomes active again when the target or relevant information about the target is found.
=== Attention (dorsal frontoparietal) ===
This network is involved in the voluntary, top-down deployment of attention. Within the dorsal attention network, the intraparietal sulcus and frontal eye fields influence the visual areas of the brain. These influencing factors allow for the orientation of attention.
=== Control (lateral frontoparietal) ===
This network initiates and modulates cognitive control and comprises 18 sub-regions of the brain. There is a strong correlation between fluid intelligence and the involvement of the fronto-parietal network with other networks.
Versions of this network have also been called the central executive (or executive control) network and the cognitive control network.
=== Sensorimotor or somatomotor (pericentral) ===
This network processes somatosensory information and coordinates motion. The auditory cortex may be included.
=== Visual (occipital) ===
This network handles visual information processing.
== Other networks ==
Different methods and data have identified several other brain networks, many of which greatly overlap or are subsets of more well-characterized core networks.
Limbic
Auditory
Right/left executive
Cerebellar
Spatial attention
Language
Lateral visual
Temporal
Visual perception/imagery
== See also ==
Complex network
Neural network (biology)
== References == | Wikipedia/Large-scale_brain_networks |
The NeuroGenderings Network is an international group of researchers in neuroscience and gender studies. Members of the network study how the complexities of social norms, varied life experiences, details of laboratory conditions and biology interact to affect the results of neuroscientific research. Working under the label of "neurofeminism", they aim to critically analyze how the field of neuroscience operates, and to build an understanding of brain and gender that goes beyond gender essentialism while still treating the brain as fundamentally material. Its founding was part of a period of increased interest and activity in interdisciplinary research connecting neuroscience and the social sciences.
== History ==
The group, comprising scholars who specialized in feminism, queer theory and gender studies, formed to tackle "neurosexism" as defined by Cordelia Fine in her 2010 book Delusions of Gender: "uncritical biases in [neuroscientific] research and public perception, and their societal impacts on an individual, structural, and symbolic level." Research can suffer from neurosexism by failing to include the social factors and expectations that shape sex differences, which possibly leads to making inferences based on flawed data.
By contrast, the network members advocate "neurofeminism", aiming to critically evaluate heteronormative assumptions of contemporary brain research and examine the impact and cultural significance of neuroscientific research on society's views about gender. This includes placing greater emphasis on neuroplasticity rather than biological determinism.
=== Conferences ===
In March 2010, the first conference – NeuroGenderings: Critical Studies of the Sexed Brain – was held in Uppsala, Sweden. Organisers Anelis Kaiser and Isabelle Dussauge described its long terms goals "to elaborate a new conceptual approach of the relation between gender and the brain, one that could help to head gender theorists and neuroscientists to an innovative interdisciplinary place, far away from social and biological determinisms but still engaging with the materiality of the brain." The NeuroGenderings Network was established at this event, with the group's first results published in a special issue of the journal Neuroethics.
Further conferences have since been held on a biennial basis: NeuroCultures — NeuroGenderings II, September 2012 at the University of Vienna's physics department; NeuroGenderings III – The First International Dissensus Conference on Brain and Gender, May 2014 in Lausanne, Switzerland; and NeuroGenderings IV in March 2016, at Barnard College, New York City.
== Members ==
The members of the NeuroGenderings Network are:
== Bibliography ==
Books
Fine, Cordelia (2010). Delusions of gender: how our minds, society, and neurosexism create difference. New York: W.W. Norton. ISBN 9780393068382.
Bluhm, Robyn; Maibom, Heidi Lene; Jaap Jacobson, Anne (2012). Neurofeminism: issues at the intersection of feminist theory and cognitive science. New York: Palgrave Macmillan. ISBN 9780230296732. Also available to view by chapter online.
Schmitz, Sigrid; Höppner, Grit, eds. (2014). Gendered neurocultures: feminist and queer perspectives on current brain discourses. challenge GENDER, 2. Wien: Zaglossus. ISBN 9783902902122.
Rippon, Gina (2019). Gender and Our Brains: How New Neuroscience Explodes the Myths of the Male and Female Minds. New York: Knopf Doubleday. ISBN 9781524747039.
Book chapters
Kaiser, Anelis (2010). "Sex/Gender and neuroscience: focusing on current research". In Blomqvist, Martha; Ehnsmyr, Ester (eds.). Never mind the gap! Gendering science in transgressive encounters. Uppsala Sweden: Skrifter från Centrum för genusvetenskap. University Printers. pp. 189–210. ISBN 9789197818636.
Schmitz, Sigrid (2014). "Sex, gender, and the brain – biological determinism versus socio-cultural constructivism". In Klinge, Ineke; Wiesemann, Claudia (eds.). Sex and gender in biomedicine: theories, methodologies, results. Akron, Ohio: University Of Akron Press. pp. 57–76. ISBN 9781935603689.
Kaiser, Anelis; Dussauge, Isabelle (2014). "Re-queering the brain". In Bluhm, Robyn; Japp Jacobson, Anne; Maibom, Heidi Lene (eds.). Neurofeminism: issues at the intersection of feminist theory and cognitive science. Hampshire New York: Palgrave Macmillan. pp. 121–144. ISBN 9781349333929.
Kraus, Cynthia (2016), "What is the feminist critique of neuroscience? A call for dissensus studies", in de Vos, Jan; Pluth, Ed, eds. (2016). Neuroscience and critique: exploring the limits of the neurological turn. London New York: Routledge. pp. 100–116. ISBN 9781138887350.
Journal articles
Hyde, Janet Shibley (September 2005). "The gender similarities hypothesis". American Psychologist. 60 (6): 581–592. CiteSeerX 10.1.1.374.1723. doi:10.1037/0003-066X.60.6.581. PMID 16173891.
Nash, Alison; Grossi, Giordana (2007). "Picking Barbie™'s brain: inherent sex differences in scientific ability?". Journal of Interdisciplinary Feminist Thought. 2 (1): 5. Pdf.
Schmitz, Sigrid; Höppner, Grit (25 July 2014). "Neurofeminism and feminist neurosciences: a critical review of contemporary brain research". Frontiers in Human Neuroscience. 8 (article 546): 546. doi:10.3389/fnhum.2014.00546. PMC 4111126. PMID 25120450.
Roy, Deboleena (Spring 2016). "Neuroscience and feminist theory: a new directions essay". Signs. 41 (3): 531–552. doi:10.1086/684266. S2CID 146995854.
Opposing publications
Below is a list of works which cause the network concern due to their "neurodeterminist notions of a ‘sexed brain’ [which] are being transported into public discourse [..] without reflecting the biases in empirical work."
Pease, Allan; Pease, Barbara (2001). Why men don't listen & women can't read maps. Sydney, NSW: Pease International. ISBN 9780957810815.
Cahill, Larry (October 1, 2012). "His brain, her brain". Scientific American. 292 (5): 22–29. PMID 15882020.
Cahill, Larry (January–February 2017). "An issue whose time has come (editorial)". Journal of Neuroscience Research. 95 (1–2): 12–13. doi:10.1002/jnr.23972. PMID 27870429.
Brizendine, Louann (2009). The female brain. London: Bantham. ISBN 9781407039510.
Brizendine, Louann (2011). The male brain. Edinburgh: Harmony. ISBN 9780767927543.
Gray, John (2004). Men are from Mars, women are from Venus: the classic guide to understanding the opposite sex. New York: HarperCollins Publishers. ISBN 9780060574215.
== See also ==
Feminist movements and ideologies
Gender essentialism
Heteronormativity
Neuroscience of sex differences
Neurogender
Neuroqueer theory
== References ==
== External links ==
Official website | Wikipedia/The_NeuroGenderings_Network |
Psychological Science, the flagship journal of the Association for Psychological Science, is a monthly, peer-reviewed scientific journal published by SAGE Publications. The journal publishes research articles, short reports, and research reports covering all aspects of psychology. Its editor-in-chief is Simine Vazire (University of Melbourne).
== Past editors ==
The following persons have been editors-in-chief:
Patricia Bauer (Emory University) (2020–2023)
Stephen Lindsay, University of Victoria (2015–2019)
Eric Eich, University of British Columbia (2012–2015)
Robert V. Kail, Purdue University (2007–2012)
James E. Cutting, Cornell University (2003–2007)
Sam Glucksberg, Princeton University (1999–2003)
John F. Kihlstrom, University of California, Berkeley
William Kaye Estes, Indiana University
== References == | Wikipedia/Psychological_Science |
Tensor network theory is a theory of brain function (particularly that of the cerebellum) that provides a mathematical model of the transformation of sensory space-time coordinates into motor coordinates and vice versa by cerebellar neuronal networks. The theory was developed by Andras Pellionisz and Rodolfo Llinas in the 1980s as a geometrization of brain function (especially of the central nervous system) using tensors.
== History ==
=== Geometrization movement of the mid-20th century ===
The mid-20th century saw a concerted movement to quantify and provide geometric models for various fields of science, including biology and physics. The geometrization of biology began in the 1950s in an effort to reduce concepts and principles of biology down into concepts of geometry similar to what was done in physics in the decades before. In fact, much of the geometrization that took place in the field of biology took its cues from the geometrization of contemporary physics. One major achievement in general relativity was the geometrization of gravitation. This allowed the trajectories of objects to be modeled as geodesic curves (or optimal paths) in a Riemannian space manifold. During the 1980s, the field of theoretical physics also witnessed an outburst of geometrization activity in parallel with the development of the Unified Field Theory, the Theory of Everything, and the similar Grand Unified Theory, all of which attempted to explain connections between known physical phenomena.
The geometrization of biology in parallel with the geometrization of physics covered a multitude of fields, including populations, disease outbreaks, and evolution, and continues to be an active field of research even today. By developing geometric models of populations and disease outbreaks, it is possible to predict the extent of the epidemic and allow public health officials and medical professionals to control disease outbreaks and better prepare for future epidemics. Likewise, there is work being done to develop geometric models for the evolutionary process of species in order to study the process of evolution, the space of morphological properties, the diversity of forms and spontaneous changes and mutations.
=== Geometrization of the brain and tensor network theory ===
Around the same time as all of the developments in the geometrization of biology and physics, some headway was made in the geometrization of neuroscience. At the time, it became more and more necessary for brain functions to be quantified in order to study them more rigorously. Much of the progress can be attributed to the work of Pellionisz and Llinas and their associates who developed the tensor network theory in order to give researchers a means to quantify and model central nervous system activities.
In 1980, Pellionisz and Llinas introduced their tensor network theory to describe the behavior of the cerebellum in transforming afferent sensory inputs into efferent motor outputs. They proposed that intrinsic multidimensional central nervous system space could be described and modeled by an extrinsic network of tensors that together describe the behavior of the central nervous system. By treating the brain as a "geometrical object" and assuming that (1) neuronal network activity is vectorial and (2) that the networks themselves are organized tensorially, brain function could be quantified and described simply as a network of tensors.
Sensory input = covariant tensor
Motor output = contravariant tensor
Cerebellar neuronal network = metric tensor that transforms the sensory input into the motor output
== Example ==
=== Vestibulo-ocular reflex ===
In 1986, Pellionisz described the geometrization of the "three-neuron vestibulo-ocular reflex arc" in a cat using tensor network theory. The "three-neuron vestibulo-ocular reflex arc" is named for the three neuron circuit the arc comprises. Sensory input into the vestibular system (angular acceleration of the head) is first received by the primary vestibular neurons which subsequently synapse onto secondary vestibular neurons. These secondary neurons carry out much of the signal processing and produce the efferent signal heading for the oculomotor neurons. Prior to the publishing of this paper, there had been no quantitative model to describe this "classic example of a basic sensorimotor transformation in the central nervous system" which is precisely what tensor network theory had been developed to model.
Here, Pellionisz described the analysis of the sensory input into the vestibular canals as the covariant vector component of tensor network theory. Likewise, the synthesized motor response (reflexive eye movement) is described as the contravariant vector component of the theory. By calculating the neuronal network transformations between the sensory input into the vestibular system and the subsequent motor response, a metric tensor representing the neuronal network was calculated.
The resulting metric tensor allowed for accurate predictions of the neuronal connections between the three intrinsically orthogonal vestibular canals and the six extraocular muscles that control the movement of the eye.
== Applications ==
=== Neural Networks and Artificial Intelligence ===
Neural networks modeled after the activities of the central nervous system have allowed researchers to solve problems impossible to solve by other means. Artificial neural networks are now being applied in various applications to further research in other fields.
One notable non-biological application of the tensor network theory was the simulated automated landing of a damaged F-15 fighter jet on one wing using a "Transputer parallel computer neural network". The fighter jet's sensors fed information into the flight computer which in turn transformed that information into commands to control the plane's wing-flaps and ailerons to achieve a stable touchdown. This was synonymous to sensory inputs from the body being transformed into motor outputs by the cerebellum. The flight computer's calculations and behavior was modeled as a metric tensor taking the covariant sensor readings and transforming it into contravariant commands to control aircraft hardware.
== References ==
== External links ==
Andras Pellionisz Google Scholar page Page | Wikipedia/Tensor_network_theory |
Neuroscience and intelligence refers to the various neurological factors that are partly responsible for the variation of intelligence within species or between different species. A large amount of research in this area has been focused on the neural basis of human intelligence. Historic approaches to studying the neuroscience of intelligence consisted of correlating external head parameters, for example head circumference, to intelligence. Post-mortem measures of brain weight and brain volume have also been used. More recent methodologies focus on examining correlates of intelligence within the living brain using techniques such as magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), positron emission tomography and other non-invasive measures of brain structure and activity.
Researchers have been able to identify correlates of intelligence within the brain and its functioning. These include overall brain volume, grey matter volume, white matter volume, white matter integrity, cortical thickness and neural efficiency.
Analyses of the parameters of intellectual systems, patterns of their emergence and evolution, distinctive features, and the constants and limits of their structures and functions made it possible to measure and compare the capacity of communications (~100 m/s), to quantify the number of components in intellectual systems (~1011 neurons), and to calculate the number of successful links responsible for cooperation (~1014 synapses).
Although the evidence base for our understanding of the neural basis of human intelligence has increased greatly over the past 30 years, even more research is needed to fully understand it.
The neural basis of intelligence has also been examined in animals such as primates, cetaceans, and rodents.
== Humans ==
=== Brain volume ===
One of the main methods used to establish a relationship between intelligence and the brain is to use measures of brain volume. The earliest attempts at estimating brain volume were done using measures of external head parameters, such as head circumference as a proxy for brain size. More recent methodologies employed to study this relationship include post-mortem measures of brain weight and volume. These have their own limitations and strengths. The advent of MRI as a non-invasive highly-accurate measure of living brain structure and function (using fMRI) made this the pre-dominant and preferred method for measuring brain volume.
Overall, larger brain size and volume is associated with better cognitive functioning and higher intelligence. The specific regions that show the most robust correlation between volume and intelligence are the frontal, temporal and parietal lobes of the brain. A large number of studies have been conducted with uniformly positive correlations, leading to the generally safe conclusion that larger brains predict greater intelligence. In healthy adults, the correlation of total brain volume and IQ is approximately 0.4 when high-quality tests are used. A large scale study (n = 29k) using the UK Biobank found a correlation of .275. The strength of this relationship did not depend on sex, contradicting some earlier studies. A study using a sibling-design in two medium sized samples found evidence of causality with an effect size of .19. This study design rules out confounders that vary between families, but not those that vary within families.
Less is known about variation on scales less than total brain volume. A meta-analytic review by McDaniel found that the correlation between intelligence and in vivo brain size was larger for females (0.40) than for males (0.25). The same study also found that the correlation between brain size and Intelligence increased with age, with children showing smaller correlations. It has been suggested that the link between larger brain volumes and higher intelligence is related to variation in specific brain regions: a whole-brain measure would under-estimate these links. For functions more specific than general intelligence, regional effects may be more important. For instance evidence suggests that in adolescents learning new words, vocabulary growth is associated with gray matter density in bilateral posterior supramarginal gyri. Small studies have shown transient changes in gray-matter associated with developing a new physical skill (juggling) occipito-temporal cortex
Brain volume is not a perfect account of intelligence: the relationship explains a modest amount of variance in intelligence – 12% to 36% of the variance. The amount of variance explained by brain volume may also depend on the type of intelligence measured. Up to 36% of variance in verbal intelligence can be explained by brain volume, while only approximately 10% of variance in visuospatial intelligence can be explained by brain volume. A 2015 study by researcher Stuart J. Ritchie found that brain size explained 12% of the variance in intelligence among individuals. These caveats imply that there are other major factors influencing how intelligent an individual is apart from brain size. In a large meta-analysis consisting of 88 studies Pietschnig et al. (2015) estimated the correlation between brain volume and intelligence to be about correlation coefficient of 0.24 which equates to 6% variance. Taking into account measurement quality, and sample type and IQ-range, the meta-analytic association of brain volume in appears to be ~ .4 in normal adults. Researcher Jakob Pietschnig argued that the strength of the positive association of brain volume and IQ remains robust, but has been overestimated in the literature. He has stated that "It is tempting to interpret this association in the context of human cognitive evolution and species differences in brain size and cognitive ability, we show that it is not warranted to interpret brain size as an isomorphic proxy of human intelligence differences".
=== Grey matter ===
Grey matter has been examined as a potential biological foundation for differences in intelligence. Similarly to brain volume, global grey matter volume is positively associated with intelligence. More specifically, higher intelligence has been associated with larger cortical grey matter in the prefrontal and posterior temporal cortex in adults. Furthermore, both verbal and nonverbal intelligence have been shown to be positively correlated with grey matter volume across the parietal, temporal and occipital lobes in young healthy adults, implying that intelligence is associated with a wide variety of structures within the brain.
There appear to be sex differences between the relationship of grey matter to intelligence between men and women. Men appear to show more intelligence to grey matter correlations in the frontal and parietal lobes, while the strongest correlations between intelligence and grey matter in women can be found in the frontal lobes and Broca's area. However, these differences do not seem to impact overall Intelligence, implying that the same cognitive ability levels can be attained in different ways.
One specific methodology used to study grey matter correlates of intelligence in areas of the brain is known as voxel-based morphometry (VBM). VBM allows researchers to specify areas of interest with great spatial resolution, allowing the examination of grey matter areas correlated with intelligence with greater special resolution. VBM has been used to correlate grey matter positively with intelligence in the frontal, temporal, parietal, and occipital lobes in healthy adults. VBM has also been used to show that grey matter volume in the medial region of the prefrontal cortex and the dorsomedial prefrontal cortex correlate positively with intelligence in a group of 55 healthy adults. VBM has also been successfully used to establish a positive correlation between grey matter volumes in the anterior cingulate and intelligence in children aged 5 to 18 years old.
Grey matter has also been shown to positively correlate with intelligence in children. Reis and colleagues have found that grey matter in the prefrontal cortex contributes most robustly to variance in Intelligence in children between 5 and 17, while subcortical grey matter is related to intelligence to a lesser extent. Frangou and colleagues examined the relationship between grey matter and intelligence in children and young adults aged between 12 and 21, and found that grey matter in the orbitofrontal cortex, cingulate gyrus, cerebellum and thalamus was positively correlated to intelligence, while grey matter in the caudate nucleus is negatively correlated with intelligence. However, the relationship between grey matter volume and intelligence only develops over time, as no significant positive relationship can be found between grey matter volume and intelligence in children under 11.
An underlying caveat to research into the relationship of grey matter volume and intelligence is demonstrated by the hypothesis of neural efficiency. The findings that more intelligent individuals are more efficient at using their neurons might indicate that the correlation of grey matter to intelligence reflects selective elimination of unused synapses, and thus a better brain circuitry.
=== White matter ===
Similar to grey matter, white matter has been shown to correlate positively with intelligence in humans. White matter consists mainly of myelinated neuronal axons, responsible for delivering signals between neurons. The pinkish-white color of white matter is actually a result of these myelin sheaths that electrically insulate neurons that are transmitting signals to other neurons. White matter connects different regions of grey matter in the cerebrum together. These interconnections make transport more seamless and allow us to perform tasks easier. Significant correlations between intelligence and the corpus callosum have been found, as larger callosal areas have been positively correlated with cognitive performance. However, there appear to be differences in importance for white matter between verbal and nonverbal intelligence, as although both verbal and nonverbal measures of intelligence correlate positively with the size of the corpus callosum, the correlation for intelligence and corpus callosum size was larger (.47) for nonverbal measures than that for verbal measures (.18). Anatomical mesh-based geometrical modelling has also shown positive correlations between the thickness of the corpus callosum and Intelligence in healthy adults.
White matter integrity has also been found to be related to intelligence. White matter tract integrity is important for information processing speed, and therefore reduced white matter integrity is related to lower intelligence. The effect of white matter integrity is mediate entirely through information processing speed. These findings indicate that the brain is structurally interconnected and that axonal fibres are integrally important for fast information process, and thus general intelligence.
Contradicting the findings described above, VBM failed to find a relationship between the corpus callosum and intelligence in healthy adults. This contradiction can be viewed to signify that the relationship between white matter volume and intelligence is not as robust as that of grey matter and intelligence.
=== Cortical thickness ===
Cortical thickness has also been found to correlate positively with intelligence in humans. However, the rate of growth of cortical thickness is also related to intelligence. In early childhood, cortical thickness displays a negative correlation with intelligence, while by late childhood this correlation has shifted to a positive one. More intelligent children were found to develop cortical thickness more steadily and over longer periods of time than less bright children. Studies have found cortical thickness to explain 5% in the variance of intelligence among individuals. In a study conducted to find associations between cortical thickness and general intelligence between different groups of people, sex did not play a role in intelligence. Although it is hard to pin intelligence on age based on cortical thickness due to different socioeconomic circumstances and education levels, older subjects (17 - 24) tended to have less variances in terms of intelligence than when compared to younger subjects (19 - 17).
=== Cortical convolution ===
The folding of the brain’s surface, known as cortical convolution, has become more pronounced throughout human evolution. It has been suggested that this increased folding serves as a neurological foundation for some of the brain’s most unique cognitive functions. As a result, the extent of cortical convolution may play a role in shaping individual intelligence within the human species.
An analysis published in 2019 found the contours of 677 children and adolescent (mean age 12.72 years) brains had a genetic correlation of almost 1 between IQ and surface area of the supramarginal gyrus on the left side of the brain.
=== Neural efficiency ===
The neural efficiency hypothesis postulates that more intelligent individuals display less activation in the brain during cognitive tasks, as measured by Glucose metabolism. A small sample of participants (N=8) displayed negative correlations between intelligence and absolute regional metabolic rates ranging from -0.48 to -0.84, as measured by PET scans, indicating that brighter individuals were more effective processors of information, as they use less energy. According to an extensive review by Neubauer & Fink a large number of studies (N=27) have confirmed this finding using methods such as PET scans, EEG and fMRI.
fMRI and EEG studies have revealed that task difficulty is an important factor affecting neural efficiency. More intelligent individuals display neural efficiency only when faced with tasks of subjectively easy to moderate difficulty, while no neural efficiency can be found during difficult tasks. In fact, more able individuals appear to invest more cortical resources in tasks of high difficulty. This appears to be especially true for the Prefrontal Cortex, as individuals with higher intelligence displayed increased activation of this area during difficult tasks compared to individuals with lower intelligence. It has been proposed that the main reason for the neural efficiency phenomenon could be that individuals with high intelligence are better at blocking out interfering information than individuals with low intelligence.
=== Further research ===
Some scientists prefer to look at more qualitative variables to relate to the size of measurable regions of known function, for example relating the size of the primary visual cortex to its corresponding functions, that of visual performance.
In a study of the head growth of 633 term-born children from the Avon Longitudinal Study of Parents and Children cohort, it was shown that prenatal growth and growth during infancy were associated with subsequent IQ. The study’s conclusion was that the brain volume a child achieves by the age of 1 year helps determine later intelligence. Growth in brain volume after infancy may not compensate for poorer earlier growth.
There is an association between IQ and myopia. One suggested explanation is that one or several pleiotropic gene(s) affect the size of the neocortex part of the brain and eyes simultaneously.
==== Parieto-frontal integration theory ====
In 2007, Behavioral and Brain Sciences published a target article that put forth a biological model of intelligence based on 37 peer-reviewed neuroimaging studies (Jung & Haier, 2007). Their review of a wealth of data from functional imaging (functional magnetic resonance imaging and positron emission tomography) and structural imaging (diffusion MRI, voxel-based morphometry, in vivo magnetic resonance spectroscopy) argues that human intelligence arises from a distributed and integrated neural network comprising brain regions in the frontal and parietal lobes.
A recent lesion mapping study conducted by Barbey and colleagues provides evidence to support the P-FIT theory of intelligence.
Brain injuries at an early age isolated to one side of the brain typically results in relatively spared intellectual function and with IQ in the normal range.
== Primates ==
=== Brain size ===
Another theory of brain size in vertebrates is that it may relate to social rather than mechanical skills. Cortical size relates directly to pair-bonding lifestyle and among primates, cerebral cortex size varies directly with the demands of living in a large complex social network. Compared to other mammals, primates have significantly larger brain sizes. Additionally, most primates are found to be polygynandrous, having many social relationships with others. Although inconclusive, some studies have shown that this polygynandrous statue correlates to brain size.
Intelligence in chimpanzees has been found to be related to brain size, grey matter volume, and cortical thickness, as in humans.
== Health ==
Several environmental factors related to health can lead to significant cognitive impairment, particularly if they occur during pregnancy and childhood when the brain is growing and the blood–brain barrier is less effective. Developed nations have implemented several health policies regarding nutrients and toxins known to influence cognitive function. These include laws requiring fortification of certain food products and laws establishing safe levels of pollutants (e.g. lead, mercury, and organochlorides). Comprehensive policy recommendations targeting reduction of cognitive impairment in children have been proposed.
== See also ==
== References ==
== External links ==
Neuroscience for Kids
Deary, I. J.; Penke, L.; Johnson, W. (2010). "The neuroscience of human intelligence differences" (PDF). Nature Reviews Neuroscience. 11 (3): 201–211. doi:10.1038/nrn2793. hdl:20.500.11820/9b11fac3-47d0-424c-9d1c-fe6f9ff2ecac. PMID 20145623. S2CID 5136934.
Jeremy R. Gray, Psychology Department, Yale University, and Paul M. Thompson, Laboratory of Nero Imaging, Department of Neurology, University of California, Los Angeles School of Medicine (June 2004). "Neurobiology of Intelligence: Science and Ethics" (PDF). Nature Publishing Group, Volume 5. Archived from the original (PDF) on September 3, 2006. Retrieved August 6, 2006.{{cite web}}: CS1 maint: multiple names: authors list (link) | Wikipedia/Neuroscience_and_intelligence |
A neural network, also called a neuronal network, is an interconnected population of neurons (typically containing multiple neural circuits). Biological neural networks are studied to understand the organization and functioning of nervous systems.
Closely related are artificial neural networks, machine learning models inspired by biological neural networks. They consist of artificial neurons, which are mathematical functions that are designed to be analogous to the mechanisms used by neural circuits.
== Overview ==
A biological neural network is composed of a group of chemically connected or functionally associated neurons. A single neuron may be connected to many other neurons and the total number of neurons and connections in a network may be extensive. Connections, called synapses, are usually formed from axons to dendrites, though dendrodendritic synapses and other connections are possible. Apart from electrical signalling, there are other forms of signalling that arise from neurotransmitter diffusion.
Artificial intelligence, cognitive modelling, and artificial neural networks are information processing paradigms inspired by how biological neural systems process data. Artificial intelligence and cognitive modelling try to simulate some properties of biological neural networks. In the artificial intelligence field, artificial neural networks have been applied successfully to speech recognition, image analysis and adaptive control, in order to construct software agents (in computer and video games) or autonomous robots.
Neural network theory has served to identify better how the neurons in the brain function and provide the basis for efforts to create artificial intelligence.
== History ==
The preliminary theoretical base for contemporary neural networks was independently proposed by Alexander Bain (1873) and William James (1890). In their work, both thoughts and body activity resulted from interactions among neurons within the brain.
For Bain, every activity led to the firing of a certain set of neurons. When activities were repeated, the connections between those neurons strengthened. According to his theory, this repetition was what led to the formation of memory. The general scientific community at the time was skeptical of Bain's theory because it required what appeared to be an inordinate number of neural connections within the brain. It is now apparent that the brain is exceedingly complex and that the same brain “wiring” can handle multiple problems and inputs.
James' theory was similar to Bain's; however, he suggested that memories and actions resulted from electrical currents flowing among the neurons in the brain. His model, by focusing on the flow of electrical currents, did not require individual neural connections for each memory or action.
C. S. Sherrington (1898) conducted experiments to test James' theory. He ran electrical currents down the spinal cords of rats. However, instead of demonstrating an increase in electrical current as projected by James, Sherrington found that the electrical current strength decreased as the testing continued over time. Importantly, this work led to the discovery of the concept of habituation.
McCulloch and Pitts (1943) also created a computational model for neural networks based on mathematics and algorithms. They called this model threshold logic. These early models paved the way for neural network research to split into two distinct approaches. One approach focused on biological processes in the brain and the other focused on the application of neural networks to artificial intelligence.
The parallel distributed processing of the mid-1980s became popular under the name connectionism. The text by Rumelhart and McClelland (1986) provided a full exposition on the use of connectionism in computers to simulate neural processes.
Artificial neural networks, as used in artificial intelligence, have traditionally been viewed as simplified models of neural processing in the brain, even though the relation between this model and brain biological architecture is debated, as it is not clear to what degree artificial neural networks mirror brain function.
== Neuroscience ==
Theoretical and computational neuroscience is the field concerned with the analysis and computational modeling of biological neural systems.
Since neural systems are intimately related to cognitive processes and behaviour, the field is closely related to cognitive and behavioural modeling.
The aim of the field is to create models of biological neural systems in order to understand how biological systems work. To gain this understanding, neuroscientists strive to make a link between observed biological processes (data), biologically plausible mechanisms for neural processing and learning (neural network models) and theory (statistical learning theory and information theory).
=== Types of models ===
Many models are used; defined at different levels of abstraction, and modeling different aspects of neural systems. They range from models of the short-term behaviour of individual neurons, through models of the dynamics of neural circuitry arising from interactions between individual neurons, to models of behaviour arising from abstract neural modules that represent complete subsystems. These include models of the long-term and short-term plasticity of neural systems and their relation to learning and memory, from the individual neuron to the system level.
=== Connectivity ===
In August 2020 scientists reported that bi-directional connections, or added appropriate feedback connections, can accelerate and improve communication between and in modular neural networks of the brain's cerebral cortex and lower the threshold for their successful communication. They showed that adding feedback connections between a resonance pair can support successful propagation of a single pulse packet throughout the entire network. The connectivity of a neural network stems from its biological structures and is usually challenging to map out experimentally. Scientists used a variety of statistical tools to infer the connectivity of a network based on the observed neuronal activities, i.e., spike trains. Recent research has shown that statistically inferred neuronal connections in subsampled neural networks strongly correlate with spike train covariances, providing deeper insights into the structure of neural circuits and their computational properties.
== Recent improvements ==
While initially research had been concerned mostly with the electrical characteristics of neurons, a particularly important part of the investigation in recent years has been the exploration of the role of neuromodulators such as dopamine, acetylcholine, and serotonin on behaviour and learning.
Biophysical models, such as BCM theory, have been important in understanding mechanisms for synaptic plasticity, and have had applications in both computer science and neuroscience.
== See also ==
Adaptive resonance theory
Biological cybernetics
Cognitive architecture
Cognitive science
Connectomics
Cultured neuronal networks
Parallel constraint satisfaction processes
Wood Wide Web
== References == | Wikipedia/Neuronal_networks |
The soliton hypothesis in neuroscience is a model that claims to explain how action potentials are initiated and conducted along axons based on a thermodynamic theory of nerve pulse propagation. It proposes that the signals travel along the cell's membrane in the form of certain kinds of solitary sound (or density) pulses that can be modeled as solitons. The model is proposed as an alternative to the Hodgkin–Huxley model in which action potentials: voltage-gated ion channels in the membrane open and allow sodium ions to enter the cell (inward current). The resulting decrease in membrane potential opens nearby voltage-gated sodium channels, thus propagating the action potential. The transmembrane potential is restored by delayed opening of potassium channels. Soliton hypothesis proponents assert that energy is mainly conserved during propagation except dissipation losses; Measured temperature changes are completely inconsistent with the Hodgkin-Huxley model.
The soliton model (and sound waves in general) depends on adiabatic propagation in which the energy provided at the source of excitation is carried adiabatically through the medium, i.e. plasma membrane. The measurement of a temperature pulse and the claimed absence of heat release during an action potential were the basis of the proposal that nerve impulses are an adiabatic phenomenon much like sound waves. Synaptically evoked action potentials in the electric organ of the electric eel are associated with substantial positive (only) heat production followed by active cooling to ambient temperature. In the garfish olfactory nerve, the action potential is associated with a biphasic temperature change; however, there is a net production of heat. These published results are inconsistent with the Hodgkin-Huxley Model and the authors interpret their work in terms of that model: The initial sodium current releases heat as the membrane capacitance is discharged; heat is absorbed during recharge of the membrane capacitance as potassium ions move with their concentration gradient but against the membrane potential. This mechanism is called the "Condenser Theory". Additional heat may be generated by membrane configuration changes driven by the changes in membrane potential. An increase in entropy during depolarization would release heat; entropy increase during repolarization would absorb heat. However, any such entropic contributions are incompatible with Hodgkin and Huxley model
== History ==
Ichiji Tasaki pioneered a thermodynamic approach to the phenomenon of nerve pulse propagation which identified several phenomena that were not included in the Hodgkin–Huxley model. Along with measuring various non-electrical components of a nerve impulse, Tasaki investigated the physical chemistry of phase transitions in nerve fibers and its importance for nerve pulse propagation. Based on Tasaki's work, Konrad Kaufman proposed sound waves as a physical basis for nerve pulse propagation in an unpublished manuscript. The basic idea at the core of the soliton model is the balancing of intrinsic dispersion of the two dimensional sound waves in the membrane by nonlinear elastic properties near a phase transition. The initial impulse can acquire a stable shape under such circumstances, in general known as a solitary wave. Solitons are the simplest solution of the set of nonlinear wave equations governing such phenomenon and were applied to model nerve impulse in 2005 by Thomas Heimburg and Andrew D. Jackson, both at the Niels Bohr Institute of the University of Copenhagen. Heimburg heads the institute's Membrane Biophysics Group. The biological physics group of Matthias Schneider has studied propagation of two-dimensional sound waves in lipid interfaces and their possible role in biological signalling
== Justification ==
The model starts with the observation that cell membranes always have a freezing point (the temperature below which the consistency changes from fluid to gel-like) only slightly below the organism's body temperature, and this allows for the propagation of solitons. An action potential traveling along a mixed nerve results in a slight increase in temperature followed by a decrease in temperature. Soliton model proponents claim that no net heat is released during the overall pulse and that the observed temperature changes are inconsistent with the Hodgkin-Huxley model. However, this is untrue: the Hodgkin Huxley model predicts a biphasic release and absorption of heat. In addition, the action potential causes a slight local thickening of the membrane and a force acting outwards; this effect is not predicted by the Hodgkin–Huxley model but does not contradict it, either.
The soliton model attempts to explain the electrical currents associated with the action potential as follows: the traveling soliton locally changes density and thickness of the membrane, and since the membrane contains many charged and polar substances, this will result in an electrical effect, akin to piezoelectricity. Indeed, such nonlinear sound waves have now been shown to exist at lipid interfaces that show superficial similarity to action potentials (electro-opto-mechanical coupling, velocities, biphasic pulse shape, threshold for excitation etc.). Furthermore, the waves remain localized in the membrane and do not spread out in the surrounding due to an impedance mismatch.
== Formalism ==
The soliton representing the action potential of nerves is the solution of the partial differential equation
∂
2
Δ
ρ
∂
t
2
=
∂
∂
x
[
(
c
0
2
+
p
Δ
ρ
+
q
Δ
ρ
2
)
∂
Δ
ρ
∂
x
]
−
h
∂
4
Δ
ρ
∂
x
4
,
{\displaystyle {\frac {\partial ^{2}\Delta \rho }{\partial t^{2}}}={\frac {\partial }{\partial x}}\left[\left(c_{0}^{2}+p\Delta \rho +q\Delta \rho ^{2}\right){\frac {\partial \Delta \rho }{\partial x}}\right]-h{\frac {\partial ^{4}\Delta \rho }{\partial x^{4}}},}
where t is time and x is the position along the nerve axon. Δρ is the change in membrane density under the influence of the action potential, c0 is the sound velocity of the nerve membrane, p and q describe the nature of the phase transition and thereby the nonlinearity of the elastic constants of the nerve membrane. The parameters c0, p and q are dictated by the thermodynamic properties of the nerve membrane and cannot be adjusted freely. They have to be determined experimentally. The parameter h describes the frequency dependence of the sound velocity of the membrane (dispersion relation). The above equation does not contain any fit parameters. It is formally related to the Boussinesq approximation for solitons in water canals. The solutions of the above equation possess a limiting maximum amplitude and a minimum propagation velocity that is similar to the pulse velocity in myelinated nerves. Under restrictive assumptions, there exist periodic solutions that display hyperpolarization and refractory periods.
== Role of ion channels ==
Advocates of the soliton model claim that it explains several aspects of the action potential, which are not explained by the Hodgkin–Huxley model. Since it is of thermodynamic nature it does not address the properties of single macromolecules like ion channel proteins on a molecular scale. It is rather assumed that their properties are implicitly contained in the macroscopic thermodynamic properties of the nerve membranes. The soliton model predicts membrane current fluctuations during the action potential. These currents are of similar appearance as those reported for ion channel proteins. They are thought to be caused by lipid membrane pores spontaneously generated by the thermal fluctuations. Such thermal fluctuations explain the specific ionic selectivity or the specific time-course of the response to voltage changes on the basis of their effect on the macroscopic susceptibilities of the system.
== Application to anesthesia ==
The authors claim that their model explains the previously obscure mode of action of numerous anesthetics. The Meyer–Overton observation holds that the strength of a wide variety of chemically diverse anesthetics is proportional to their lipid solubility, suggesting that they do not act by binding to specific proteins such as ion channels but instead by dissolving in and changing the properties of the lipid membrane. Dissolving substances in the membrane lowers the membrane's freezing point, and the resulting larger difference between body temperature and freezing point inhibits the propagation of solitons. By increasing pressure, lowering pH or lowering temperature, this difference can be restored back to normal, which should cancel the action of anesthetics: this is indeed observed. The amount of pressure needed to cancel the action of an anesthetic of a given lipid solubility can be computed from the soliton model and agrees reasonably well with experimental observations.
== Differences between model predictions and experimental observations ==
The following is a list of some of the disagreements between experimental observations and the "soliton model":
Antidromic invasion of soma from axon
An action potential initiated anywhere on an axon will travel in an antidromic (backward) direction to the neuron soma (cell body) without loss of amplitude and produce a full-amplitude action potential in the soma. As the membrane area of the soma is orders of magnitude larger than the area of the axon, conservation of energy requires that an adiabatic mechanical wave decrease in amplitude. Since the absence of heat production is one of the claimed justifications of the 'soliton model', this is particularly difficult to explain within that model.
Persistence of action potential over wide temperature range
An important assumption of the soliton model is the presence of a phase transition near the ambient temperature of the axon ("Formalism", above). Then, rapid change of temperature away from the phase transition temperature would necessarily cause large changes in the action potential. Below the phase transition temperature, the soliton wave would not be possible. Yet, action potentials are present at 0 °C. The time course is slowed in a manner predicted by the measured opening and closing kinetics of the Hodgkin-Huxley ion channels.
Collisions
Nerve impulses traveling in opposite directions annihilate each other on collision. On the other hand, mechanical waves do not annihilate but pass through each other. Soliton model proponents have attempted to show that action potentials can pass through a collision; however, collision annihilation of orthodromic and antidromic action potentials is a routinely observed phenomenon in neuroscience laboratories and are the basis of a standard technique for identification of neurons. Solitons pass each other on collision (Figure--"Collision of Solitons"), solitary waves in general can pass, annihilate or bounce of each other and solitons are only a special case of such solitary waves.
Ionic currents under voltage clamp
The voltage clamp, used by Hodgkin and Huxley (1952) (Hodgkin-Huxley Model) to experimentally dissect the action potential in the squid giant axon, uses electronic feedback to measure the current necessary to hold membrane voltage constant at a commanded value. A silver wire, inserted into the interior of the axon, forces a constant membrane voltage along the length of the axon. Under these circumstances, there is no possibility of a traveling 'soliton'. Any thermodynamic changes are very different from those resulting from an action potential. Yet, the measured currents accurately reproduce the action potential.
Single channel currents
The patch clamp technique isolates a microscopic patch of membrane on the tip of a glass pipette. It is then possible to record currents from single ionic channels. There is no possibility of propagating solitons or thermodynamic changes. Yet, the properties of these channels (temporal response to voltage jumps, ionic selectivity) accurately predict the properties of the macroscopic currents measured under conventional voltage clamp.
Selective ionic conductivity
The current underlying the action potential depolarization is selective for sodium. Repolarization depends on a selective potassium current. These currents have very specific responses to voltage changes which quantitatively explain the action potential. Substitution of non-permeable ions for sodium abolishes the action potential. The 'soliton model' cannot explain either the ionic selectivity or the responses to voltage changes.
Pharmacology
The drug tetrodotoxin (TTX) blocks action potentials at extremely low concentrations. The site of action of TTX on the sodium channel has been identified. Dendrotoxins block the potassium channels. These drugs produce quantitatively predictable changes in the action potential. The 'soliton model' provides no explanation for these pharmacological effects.
== Action waves ==
A recent theoretical model, proposed by Ahmed El Hady and Benjamin Machta, proposes that there is a mechanical surface wave which co-propagates with the electrical action potential. These surface waves are called "action waves". In the El Hady–Machta's model, these co-propagating waves are driven by voltage changes across the membrane caused by the action potential.
== See also ==
Biological neuron models
Hodgkin–Huxley model
Vector soliton
== Sources ==
Federico Faraci (2013) "The 60th anniversary of the Hodgkin-Huxley model: a critical assessment from a historical and modeler’s viewpoint"
Revathi Appali, Ursula van Rienen, Thomas Heimburg (2012) "A comparison of the Hodgkin-Huxley model and the Soliton theory for the Action Potential in Nerves "
Action Waves in the Brain, The Guardian, 1 May 2015.
Ichiji Tasaki (1982) "Physiology and Electrochemistry of Nerve Fibers"
Konrad Kaufman (1989) "Action Potentials and Electrochemical Coupling in the Macroscopic Chiral Phospholipid Membrane".
Andersen, Jackson and Heimburg"Towards a thermodynamic theory of nerve pulse propagation"
Pradip Das; W.H. Schwarz (4 November 1994). "Solitons in cell membrane". Physical Review E. 51 (4): 3588–3612. Bibcode:1995PhRvE..51.3588D. doi:10.1103/PhysRevE.51.3588. PMID 9963042.
Revisiting the mechanics of the action potential, Princeton University Journal watch, 1 April 2015.
On the (sound) track of anesthetics, Eurekalert, according to a press release University of Copenhagen, 6 March 2007
Kaare Græsbøll (2006). "Function of Nerves — Action of Anesthetics" (PDF). Gamma. 143. Archived from the original (PDF) on 2016-03-03. Retrieved 2007-03-11. An elementary introduction.
Solitary acoustic waves observed to propagate at a lipid membrane interface, Phys.org June 20, 2014
== References == | Wikipedia/Soliton_model_in_neuroscience |
Evolutionary biology, in particular the understanding of how organisms evolve through natural selection, is an area of science with many practical applications. Creationists often claim that the theory of evolution lacks any practical applications; however, this claim has been refuted by scientists.
== Wider biology ==
The evolutionary approach is key to much current research in biology that does not set out to study evolution per se, especially in organismal biology and ecology. For example, evolutionary thinking is key to life history theory. Annotation of genes and their function relies heavily on comparative, that is evolutionary, approaches. The field of evolutionary developmental biology investigates how developmental processes work by using the comparative method to determine how they evolved.
== Artificial selection ==
A major technological application of evolution is artificial selection, which is the intentional selection of certain traits in a population of organisms. Humans have used artificial selection for thousands of years in the domestication of plants and animals. More recently, such selection has become a vital part of genetic engineering, with selectable markers such as antibiotic resistance genes being used to manipulate DNA in molecular biology. It is also possible to use repeated rounds of mutation and selection to evolve proteins with particular properties, such as modified enzymes or new antibodies, in a process called directed evolution.
== Medicine ==
Antibiotic resistance can be a result of point mutations in the pathogen genome at a rate of about 1 in 108 per chromosomal replication. The antibiotic action against the pathogen can be seen as an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will result in a fully resistant colony.
Understanding the changes that have occurred during organism's evolution can reveal the genes needed to construct parts of the body, genes which may be involved in human genetic disorders. For example, the Mexican tetra is an albino cavefish that lost its eyesight during evolution. Breeding together different populations of this blind fish produced some offspring with functional eyes, since different mutations had occurred in the isolated populations that had evolved in different caves. This helped identify genes required for vision and pigmentation, such as crystallins and the melanocortin 1 receptor. Similarly, comparing the genome of the Antarctic icefish, which lacks red blood cells, to close relatives such as the Antarctic rockcod revealed genes needed to make these blood cells.
== Computer science ==
As evolution can produce highly optimised processes and networks, it has many applications in computer science. Here, simulations of evolution using evolutionary algorithms and artificial life started with the work of Nils Aall Barricelli in the 1960s, and was extended by Alex Fraser, who published a series of papers on simulation of artificial selection. Artificial evolution became a widely recognised optimisation method as a result of the work of Ingo Rechenberg in the 1960s and early 1970s, who used evolution strategies to solve complex engineering problems. Genetic algorithms in particular became popular through the writing of John Holland. As academic interest grew, dramatic increases in the power of computers allowed practical applications, including the automatic evolution of computer programs. Evolutionary algorithms are now used to solve multi-dimensional problems more efficiently than software produced by human designers, and also to optimise the design of systems.
== References == | Wikipedia/Applications_of_evolution |
Many scientists and philosophers of science have described evolution as fact and theory, a phrase which was used as the title of an article by paleontologist Stephen Jay Gould in 1981. He describes fact in science as meaning data, not known with absolute certainty but "confirmed to such a degree that it would be perverse to withhold provisional assent". A scientific theory is a well-substantiated explanation of such facts. The facts of evolution come from observational evidence of current processes, from imperfections in organisms recording historical common descent, and from transitions in the fossil record. Theories of evolution provide a provisional explanation for these facts.
Each of the words evolution, fact and theory has several meanings in different contexts. In biology, evolution refers to observed changes in organisms over successive generations, to their descent from a common ancestor, and at a technical level to a change in gene frequency over time; it can also refer to explanatory theories (such as Charles Darwin's theory of natural selection) which explain the mechanisms of evolution. To a scientist, fact can describe a repeatable observation capable of great consensus; it can refer to something that is so well established that nobody in a community disagrees with it; and it can also refer to the truth or falsity of a proposition. To the public, theory can mean an opinion or conjecture (e.g., "it's only a theory"), but among scientists it has a much stronger connotation of "well-substantiated explanation". With this number of choices, people can often talk past each other, and meanings become the subject of linguistic analysis.
Evidence for evolution continues to be accumulated and tested. The scientific literature includes statements by evolutionary biologists and philosophers of science demonstrating some of the different perspectives on evolution as fact and theory.
== Evolution, fact and theory ==
Evolution has been described as "fact and theory"; "fact, not theory"; "only a theory, not a fact"; "multiple theories, not fact"; and "neither fact, nor theory." The disagreements among these statements, however, have more to do with the meaning of words than the substantial issues and this controversy is discussed below.
=== Evolution ===
Professor of biology Jerry Coyne sums up biological evolution succinctly:
Life on Earth evolved gradually beginning with one primitive species – perhaps a self-replicating molecule – that lived more than 3.5 billion years ago; it then branched out over time, throwing off many new and diverse species; and the mechanism for most (but not all) of evolutionary change is natural selection.
This shows the breadth and scope of the issue, incorporating the scientific fields of zoology, botany, genetics, geology, and paleontology, among many others.
But the central core of evolution is generally defined as changes in trait or gene frequency in a population of organisms from one generation to the next. This has been dubbed the standard genetic definition of evolution. Natural selection is only one of several mechanisms in the theory of evolutionary change that explains how organisms historically adapt to changing environments. The principles of heredity were re-discovered in 1900, after Darwin's death, in Gregor Mendel's research on the inheritance of simple trait variations in peas. Subsequent work into genetics, mutation, paleontology, and developmental biology expanded the applicability and scope of Darwin's original theory.
According to Douglas J. Futuyma:
Biological evolution may be slight or substantial; it embraces everything from slight changes in the proportion of different alleles within a population (such as those determining blood types) to the successive alterations that led from the earliest proto-organism to snails, bees, giraffes, and dandelions.
The word evolution in a broad sense refers to processes of change, from stellar evolution to changes in language. In biology, the meaning is more specific: heritable changes which accumulate over generations of a population. Individual organisms do not evolve in their lifetimes, but variations in the genes they inherit can become more or less common in the population of organisms. Any changes during the lifetime of organisms which are not inherited by their offspring are not part of biological evolution.
To Keith Stewart Thomson, the word evolution has at least three distinct meanings:
The general sense of change over time.
All life forms have descended with modifications from ancestors in a process of common descent.
The cause or mechanisms of these process of change, that are examined and explained by evolutionary theories.
Thomson remarks: "Change over time is a fact, and descent from common ancestors is based on such unassailable logic that we act as though it is a fact. Natural selection provides the outline of an explanatory theory."
Biologists consider it to be a scientific fact that evolution has occurred in that modern organisms differ from past forms, and evolution is still occurring with discernible differences between organisms and their descendants. There is such strong quantitative support for the second that scientists regard common descent as being as factual as the understanding that in the Solar System the Earth orbits the Sun, although the examination of the fundamentals of these processes is still in progress. There are several theories about the mechanisms of evolution, and there are still active debates about specific mechanisms.
There is a fourth meaning for the word evolution that is not used by biologists today. In 1857, the philosopher Herbert Spencer defined it as "change from the homogeneous to the heterogeneous." He claimed (before Darwin) that this was "settled beyond dispute" for organic evolution and applied it to the evolution of star systems, geology and human society. Even Spencer by 1865 was admitting that his definition was imperfect, but it remained popular throughout the nineteenth century before declining under the criticisms of William James and others.
=== Fact ===
The word fact is often used by scientists to refer to experimental or empirical data or objective verifiable observations. Fact is also used in a wider sense to mean any theory for which there is overwhelming evidence. According to Douglas J. Futuyma,
A fact is a hypothesis that is so firmly supported by evidence that we assume it is true, and act as if it were true.
In the sense that evolution is overwhelmingly validated by the evidence, it is a fact. It is frequently said to be a fact in the same way as the Earth's revolution around the Sun is a fact. The following quotation from Hermann Joseph Muller's article, "One Hundred Years Without Darwinism Are Enough", explains the point.
There is no sharp line between speculation, hypothesis, theory, principle, and fact, but only a difference along a sliding scale, in the degree of probability of the idea. When we say a thing is a fact, then, we only mean that its probability is an extremely high one: so high that we are not bothered by doubt about it and are ready to act accordingly. Now in this use of the term fact, the only proper one, evolution is a fact.
The National Academy of Sciences (U.S.) makes a similar point:
Scientists most often use the word "fact" to describe an observation. But scientists can also use fact to mean something that has been tested or observed so many times that there is no longer a compelling reason to keep testing or looking for examples. The occurrence of evolution in this sense is a fact. Scientists no longer question whether descent with modification occurred because the evidence supporting the idea is so strong.
Stephen Jay Gould also points out that "Darwin continually emphasized the difference between his two great and separate accomplishments: establishing the fact of evolution, and proposing a theory – natural selection – to explain the mechanism of evolution." These two aspects are frequently confused. Scientists continue to argue about particular explanations or mechanisms at work in specific instances of evolution – but the fact that evolution has occurred, and is still occurring, is undisputed.
A common misconception is that evolution cannot be reliably observed because it all happened millions of years ago and the science therefore is not dependent on facts (in the initial sense above). However, both Darwin and Alfred Russel Wallace, the co-founders of the theory, and all subsequent biologists depend primarily on observations of living organisms; Darwin concentrated largely on the breeding of domesticated animals whereas Wallace started from the biogeographical distribution of species in the Amazon and Malay Archipelago. In the early twentieth century, population genetics had centre stage, and more recently DNA has become the main focus of observation and experimentation.
Philosophers of science argue that we do not know mind-independent empirical truths with absolute certainty: even direct observations may be "theory laden" and depend on assumptions about our senses and the measuring instruments used. In this sense all facts are provisional.
=== Theory ===
The scientific definition of the word theory is different from the definition of the word in colloquial use. In the vernacular, theory can refer to guesswork, a simple conjecture, an opinion, or a speculation that does not have to be based on facts and need not be framed for making testable predictions.
In science, however, the meaning of theory is more rigorous. A scientific theory is "a well-substantiated explanation of some aspect of the natural world that can incorporate facts, laws, inferences, and tested hypotheses." Theories are formed from hypotheses that have been subjected repeatedly to tests of evidence which attempt to disprove or falsify them. In the case of evolution through natural selection, Darwin conceived the hypothesis c. 1839, and made a first draft of the concept three years later in 1842. He discussed this widely with many of his intellectual companions, and conducted further research in the background to his other writings and work. After years of development, he finally published his evidence and theory in On the Origin of Species in 1859.
Similar to the term "theory of evolution", the word "theory" is also evident in the names given for other scientific theories, as in "atom theory", "germ theory of diseases" or "cell theory". The "theory of evolution" is actually a network of theories that created the research program of biology.
Specifically Darwin, for example, proposed five separate theories in his original formulation, which included mechanistic explanations for:
populations changing over generations
gradual change
speciation
natural selection
common descent
Since Darwin, evolution has become a well-supported body of interconnected statements that explains numerous empirical observations in the natural world. Evolutionary theories continue to generate testable predictions and explanations about living and fossilized organisms.
Phylogenetic theory is an example of evolutionary theory. It is based on the evolutionary premise of an ancestral descendant sequence of genes, populations, or species. Individuals that evolve are linked together through historical and genealogical ties. Evolutionary trees are hypotheses that are inferred through the practice of phylogenetic theory. They depict relations among individuals that can speciate and diverge from one another. The evolutionary process of speciation creates groups that are linked by a common ancestor and all its descendants. Species inherit traits, which are then passed on to descendants. Evolutionary biologists use systematic methods and test phylogenetic theory to observe and explain changes in and among species over time. These methods include the collection, measurement, observation, and mapping of traits onto evolutionary trees. Phylogenetic theory is used to test the independent distributions of traits and their various forms to provide explanations of observed patterns in relation to their evolutionary history and biology. The neutral theory of molecular evolution is used to study evolution as a null model against which tests for natural selection can be applied.
== Evolution as theory and fact in the literature ==
The following sections provide specific quotable references from evolutionary biologists and philosophers of science demonstrating some of the different perspectives on evolution as fact and theory.
=== Evolution as fact ===
American zoologist and paleontologist George Gaylord Simpson stated that "Darwin ... finally and definitely established evolution as a fact."
Hermann Joseph Muller wrote, "So enormous, ramifying, and consistent has the evidence for evolution become that if anyone could now disprove it, I should have my conception of the orderliness of the universe so shaken as to lead me to doubt even my own existence. If you like, then, I will grant you that in an absolute sense evolution is not a fact, or rather, that it is no more a fact than that you are hearing or reading these words."
Kenneth R. Miller writes, "evolution is as much a fact as anything we know in science."
Ernst Mayr observed, "The basic theory of evolution has been confirmed so completely that most modern biologists consider evolution simply a fact. How else except by the word evolution can we designate the sequence of faunas and floras in precisely dated geological strata? And evolutionary change is also simply a fact owing to the changes in the content of gene pools from generation to generation."
=== Evolution as fact and theory ===
Fact is commonly used to refer to the observable changes in organisms' traits over generations while the word theory is reserved for the mechanisms that cause these changes:
Writing in 1930, biologist Julian Huxley entitled the third book of the wide-ranging series The Science of Life, which dealt with the fossil record and the evidence of plant and animal structures, The Incontrovertible Fact of Evolution. He also says "Natural Selection ... is not a theory, but a fact. But does it ... suffice to account for the whole spectacle of Evolution? ... There we come to speculative matter, to theories." But he concludes that "the broad positions of Darwinism re-emerge from a scrutiny of the most exacting sort essentially unchanged." In 1932, a portion of the book was republished under the title Evolution, Fact and Theory.
Stephen Jay Gould writes, "... evolution is a theory. It is also a fact. And facts and theories are different things, not rungs in a hierarchy of increasing certainty. Facts are the world's data. Theories are structures of ideas that explain and interpret facts. Facts do not go away when scientists debate rival theories to explain them. Einstein's theory of gravitation replaced Newton's, but apples did not suspend themselves in mid-air, pending the outcome. And humans evolved from apelike ancestors whether they did so by Darwin's proposed mechanism or by some other, yet to be discovered."
Similarly, biologist Richard Lenski says, "Scientific understanding requires both facts and theories that can explain those facts in a coherent manner. Evolution, in this context, is both a fact and a theory. It is an incontrovertible fact that organisms have changed, or evolved, during the history of life on Earth. And biologists have identified and investigated mechanisms that can explain the major patterns of change."
Biologist T. Ryan Gregory notes, "biologists rarely make reference to 'the theory of evolution,' referring instead simply to 'evolution' (i.e., the fact of descent with modification) or 'evolutionary theory' (i.e., the increasingly sophisticated body of explanations for the fact of evolution). That evolution is a theory in the proper scientific sense means that there is both a fact of evolution to be explained and a well-supported mechanistic framework to account for it."
=== Evolution as fact and not theory ===
Other commentators – focusing on the changes in species over generations and in some cases common ancestry – have stressed, in order to emphasize the weight of supporting evidence, that evolution is a fact, arguing that the use of the term "theory" is not useful:
Richard Lewontin wrote, "It is time for students of the evolutionary process, especially those who have been misquoted and used by the creationists, to state clearly that evolution is fact, not theory."
Douglas J. Futuyma writes in Evolutionary Biology (1998), "The statement that organisms have descended with modifications from common ancestors – the historical reality of evolution – is not a theory. It is a fact, as fully as the fact of the earth's revolution about the sun."
Richard Dawkins says, "One thing all real scientists agree upon is the fact of evolution itself. It is a fact that we are cousins of gorillas, kangaroos, starfish, and bacteria. Evolution is as much a fact as the heat of the sun. It is not a theory, and for pity's sake, let's stop confusing the philosophically naive by calling it so. Evolution is a fact."
Neil Campbell wrote in his 1990 biology textbook, "Today, nearly all biologists acknowledge that evolution is a fact. The term theory is no longer appropriate except when referring to the various models that attempt to explain how life evolves ... it is important to understand that the current questions about how life evolves in no way implies any disagreement over the fact of evolution."
=== Evolution as a collection of theories, not fact ===
The curator at the Natural History Museum of Los Angeles County, Kirk J. Fitzhugh writes that scientists must be cautious to "carefully and correctly" describe the nature of scientific investigation at a time when evolutionary biology is under attack from creationists and proponents of intelligent design. Fitzhugh writes that while facts are states of being in nature, theories represent efforts to connect those states of being by causal relationships:
"Evolution" cannot be both a theory and a fact. Theories are concepts stating cause–effect relations. Regardless of one's certainty as to the utility of a theory to provide understanding, it would be epistemically incorrect to assert any theory as also being a fact, given that theories are not objects to be discerned by their state of being.
Fitzhugh recognizes that the "theory" versus "fact" debate is one of semantics. He nevertheless contends that referring to evolution as a "fact" is technically incorrect and distracts from the primary "goal of science, which is to continually acquire causal understanding through the critical evaluation of our theories and hypotheses." Fitzhugh concludes that the "certainty" of evolution "provides no basis for elevating any evolutionary theory or hypothesis to the level of fact."
Dr William C. Robertson Archived 2018-01-03 at the Wayback Machine writing for National Science Teachers Association writes, "I have heard too many scientists claim that evolution is a fact, often in retort to the claim that it is just a theory. Evolution isn't a fact. Rather than claiming so, I think scientists would be better served to agree that evolution is a theory and then proceed to explain what a theory is – a coherent explanation that undergoes constant testing and often revision over a period of time."
== Related concepts and terminology ==
"Proof" of a theory has different meanings in science. Proof exists in formal sciences, such as a mathematical proof where symbolic expressions can represent precise arguments and scientific laws having precise definitions of the terms and outcomes . Proof has other meanings as it descends from its Latin roots (provable, probable, probare L.) meaning 'to test'. In this sense a proof is an inference to the best or most parsimonious explanation through a publicly verifiable demonstration (a test) of the factual (i.e., observed) and causal evidence from carefully controlled experiments. Stephen Jay Gould argued that Darwin's research, for example, pointed to the coordination of so many pieces of evidence that no other configuration other than his theory could offer a conceivable causal explanation of the facts. In this way natural selection and common ancestry has been proven. "The classical proof is the improvement of crops and livestock through artificial selection." Natural selection and other evolutionary theories are also represented in various mathematical proofs, such as the Price equation. To remain consistent with the philosophy of science, however, advancement of theory is only achieved through disproofs of hypotheses.
"Models" are part of the scientific or inferential "tool-kit" that are constructed out of preexistent theory. Model-based science uses idealized structures or mathematical expressions to strategically create simpler representations of complex worldly systems. Models are designed to resemble the relevant aspects of hypothetical relations in the target systems under investigation.
"Validation" is a demonstration that a model within its domain of applicability possesses a satisfactory range of accuracy consistent with the intended application of the model." Models are used in simulation research. For example, evolutionary phylogeneticists run simulations to model the tree like branching process of lineages over time. In turn, this is used to understand the theory of phylogenetics and the methods used to test for relations among genes, species, or other evolutionary units.
== See also ==
== References ==
== Bibliography ==
== Further reading ==
Branch, Glenn; Mead, Louise (July 2008). "'Theory' in Theory and Practice". Evolution: Education and Outreach. 1 (3): 287–289. doi:10.1007/s12052-008-0056-5. ISSN 1936-6426.
Dobzhansky, Theodosius (March 1973). "Nothing in Biology Makes Sense Except in the Light of Evolution". The American Biology Teacher. 35 (3): 125–129. CiteSeerX 10.1.1.324.2891. doi:10.2307/4444260. ISSN 0002-7685. JSTOR 4444260. S2CID 207358177.
Lewis, Ralph W. (Winter 1987–1988). "Theory and the Fact of Evolution" (PDF). Creation/Evolution Journal. 8 (22): 34–37. ISSN 0738-6001. Retrieved 2015-01-21.
National Academy of Sciences; Institute of Medicine (2008). Science, Evolution, and Creationism. Washington, D.C.: National Academies Press. ISBN 978-0-309-10586-6. LCCN 2007015904. OCLC 123539346. Retrieved 2015-01-19.
== External links ==
"Evolving Ideas: Isn't Evolution Just a Theory?". Evolution Library (Web resource). Evolution. Boston, MA: WGBH Educational Foundation; Clear Blue Sky Productions, Inc. 2001. OCLC 48165595. Retrieved 2015-01-21. Video requires QuickTime or RealPlayer plugin for viewing.
Isaak, Mark, ed. (September 7, 2006). "Index to Creationist Claims: Claim CB910: No new species have been observed". TalkOrigins Archive. Houston, TX: The TalkOrigins Foundation, Inc. Retrieved 2015-01-21. Response to the claim that no examples of speciation have been observed.
"Is Evolution a Theory or a Fact?". Evolution Resources from the National Academies. Washington, D.C.: National Academy of Sciences. Retrieved 2015-01-21.
Howard, Jules (2016-02-05). "Do whales have nipples? Why discussing evolution in schools can occasionally be tricky". the Guardian. Retrieved 2016-02-05.
"How Do We Know What Is True?" (animated video; 2:52)) | Wikipedia/Evolution_as_fact_and_theory |
Animal welfare science is the scientific study of the welfare of animals as pets, in zoos, laboratories, on farms and in the wild. Although animal welfare has been of great concern for many thousands of years in religion and culture, the investigation of animal welfare using rigorous scientific methods is a relatively recent development. The world's first Professor of Animal Welfare Science, Donald Broom, was appointed by Cambridge University (UK) in 1986.
== Historical legislation and guidelines ==
Early legislation which formed the impetus for assessing animal welfare and the subsequent development of animal welfare science include the Ireland Parliament (Thomas Wentworth) "An Act against Plowing by the Tayle, and pulling the Wooll off living Sheep", 1635, and the Massachusetts Colony (Nathaniel Ward) "Off the Bruite Creatures" Liberty 92 and 93 in the "Massachusetts Body of Liberties" of 1641.
Richard Martin's act, the "Cruel Treatment of Cattle Act 1822" is often considered to be the precursor of modern relevant legislation. One of the first national laws to protect animals was the UK "Cruelty to Animals Act 1835" followed by the "Protection of Animals Act 1911". In the US it was many years until there was a National law to protect animals—the "Animal Welfare Act of 1966"—although there were a number of states that passed anti-cruelty laws between 1828 and 1898. In India, animals are protected by the "Prevention of Cruelty to Animals Act, 1960". In the UK, the "Animal Welfare Act 2006" consolidated many different forms of animal welfare legislation.
Animal welfare science can be considered as the assessment of welfare. The first publication to include the term "assessment" appears to be a 1965 appendix by William Homan Thorpe entitled The assessment of pain and distress in animals. This was followed 20 years later by a highly influential paper on assessing pain and distress in laboratory animals by Morton and Griffiths.
== Methods of assessment ==
Animal welfare science uses a variety of behavioural or physiological measures or indicators. Integrated approaches to assess animal welfare include risk analysis and semantic modelling of animal welfare.
=== Animal behaviour ===
Occurrence of abnormal behaviours (e.g. stereotypies, feather pecking, tail-biting, facial expressions)
Departure from ethogram of ancestral precursors
Intra-specific variations in behavioural welfare indices
Behaviour of captive animals upon release in a natural environment
Preference studies
Motivation studies
Cognitive bias in animals studies
Self selection of anxiolytics
Effects of frustration
=== Animal physiology ===
Heart rate
Heart rate variability
Corticosteroids in plasma, saliva, urine, faeces, hair, feathers and eggs
Immune function
Neurobiology
Eggshell quality
Thermography including eye surface temperature
== Organisations ==
Organisations interested in animal welfare science were set up before the subject became recognised as a science. The Royal Society for the Prevention of Cruelty to Animals (RSPCA) was founded in 1824 by a group of twenty-two reformers led by Richard Martin MP (who would thereby earn the nickname Humanity Dick), William Wilberforce MP and the Reverend Arthur Broome. The Universities Federation for Animal Welfare (UFAW) history can be traced to the founding in 1926 of the University of London Animal Welfare Society (ULAWS) by Major Charles Hume. The name was changed to the Universities Federation for Animal Welfare in 1938, reflecting the increasingly wide range of people and institutions involved.
More recent organisations involved in animal welfare science include the Scientists Center for Animal Welfare (SCAW) and university departments specialising in this branch of science including the Animal Welfare and Anthrozoology Center at Cambridge University, the Animal Welfare Science Centre at The University of Melbourne in Australia and the Animal Welfare Science and Bioethics Centre at Massey University in New Zealand.
Although not limited to animal welfare science, many members of the International Society for Applied Ethology work and publish research in this subject.
== Journals, articles and books ==
Veterinary journals carrying articles on animal welfare have been published for many years, for example, the Veterinary Record has been published weekly since 1888. Peer-reviewed scientific journals have been launched more recently, e.g. Applied Animal Behaviour Science in 1974, Animal Welfare in 1992, the Journal of Applied Animal Welfare Science in 1998, and Frontiers in Veterinary Science—Animal Behavior and Welfare in 2014.
Many books on animal welfare science have been written, for example those by Professor Marian Stamp Dawkins, Professor David Fraser, Michael Appleby, Barry Hughes and Joy Mench, John Webster, and David Mellor et al.
== Teaching ==
In 2011 in an article on the history of animal welfare science, Donald Broom wrote "The numbers of animal welfare scientists is increasing rapidly. The subject is now being taught in all European countries and the number of university courses on animal welfare in Brazil has increased from one to over 60 in 15 years. The diversity of animal welfare science is increasing and the expansion is likely to continue. The decision by the American Veterinary Medical Association to promote the teaching of the subject in all American veterinary schools will have a substantial effect."
== See also ==
Animal welfare
Animal consciousness
Fish welfare at slaughter
Pain in amphibians
Pain in animals
Pain in crustaceans
Pain in fish
Pain in invertebrates
Welfare biology
Wild animal suffering
== References ==
== Further references ==
Broom, D.M. (1991). "Animal welfare: concepts and measurement". Journal of Animal Science. 69 (10): 4167–75. doi:10.2527/1991.69104167x. PMID 1778832.
Huntingford FA, Adams C, Braithwaite VA, Kadri S, Pottinger TG, Sandøe P, Turnbull JF (2006). "Review paper: Current issues in fish welfare" (PDF). Journal of Fish Biology. 68 (2): 332–372. doi:10.1111/j.0022-1112.2006.001046.x. S2CID 84511123.
Kirkwood James K (2013). "Wild animal welfare". Animal Welfare. 22: 147–48. doi:10.7120/09627286.22.1.147. | Wikipedia/Animal_welfare_science |
Phylogenetic comparative methods (PCMs) use information on the historical relationships of lineages (phylogenies) to test evolutionary hypotheses. The comparative method has a long history in evolutionary biology; indeed, Charles Darwin used differences and similarities between species as a major source of evidence in The Origin of Species. However, the fact that closely related lineages share many traits and trait combinations as a result of the process of descent with modification means that lineages are not independent. This realization inspired the development of explicitly phylogenetic comparative methods. Initially, these methods were primarily developed to control for phylogenetic history when testing for adaptation; however, in recent years the use of the term has broadened to include any use of phylogenies in statistical tests. Although most studies that employ PCMs focus on extant organisms, many methods can also be applied to extinct taxa and can incorporate information from the fossil record.
PCMs can generally be divided into two types of approaches: those that infer the evolutionary history of some character (phenotypic or genetic) across a phylogeny and those that infer the process of evolutionary branching itself (diversification rates), though there are some approaches that do both simultaneously. Typically the tree that is used in conjunction with PCMs has been estimated independently (see computational phylogenetics) such that both the relationships between lineages and the length of branches separating them is assumed to be known.
== Applications ==
Phylogenetic comparative approaches can complement other ways of studying adaptation, such as studying natural populations, experimental studies, and mathematical models. Interspecific comparisons allow researchers to assess the generality of evolutionary phenomena by considering independent evolutionary events. Such an approach is particularly useful when there is little or no variation within species. And because they can be used to explicitly model evolutionary processes occurring over very long time periods, they can provide insight into macroevolutionary questions, once the exclusive domain of paleontology.
Phylogenetic comparative methods are commonly applied to such questions as:
What is the slope of an allometric scaling relationship?
→ Example: how does brain mass vary in relation to body mass?
Do different clades of organisms differ with respect to some phenotypic trait?
→ Example: do canids have larger hearts than felids?
Do groups of species that share a behavioral or ecological feature (e.g., social system, diet) differ in average phenotype?
→ Example: do carnivores have larger home ranges than herbivores?
What was the ancestral state of a trait?
→ Example: where did endothermy evolve in the lineage that led to mammals?
→ Example: where, when, and why did placentas and viviparity evolve?
Does a trait exhibit significant phylogenetic signal in a particular group of organisms? Do certain types of traits tend to "follow phylogeny" more than others?
→ Example: are behavioral traits more labile during evolution?
Do species differences in life history traits trade-off, as in the so-called fast-slow continuum?
→ Example: why do small-bodied species have shorter life spans than their larger relatives?
== Phylogenetically independent contrasts ==
Felsenstein proposed the first general statistical method in 1985 for incorporating phylogenetic information, i.e., the first that could use any arbitrary topology (branching order) and a specified set of branch lengths. The method is now recognized as an algorithm that implements a special case of what are termed phylogenetic generalized least-squares models. The logic of the method is to use phylogenetic information (and an assumed Brownian motion like model of trait evolution) to transform the original tip data (mean values for a set of species) into values that are statistically independent and identically distributed.
The algorithm involves computing values at internal nodes as an intermediate step, but they are generally not used for inferences by themselves. An exception occurs for the basal (root) node, which can be interpreted as an estimate of the ancestral value for the entire tree (assuming that no directional evolutionary trends [e.g., Cope's rule] have occurred) or as a phylogenetically weighted estimate of the mean for the entire set of tip species (terminal taxa). The value at the root is equivalent to that obtained from the "squared-change parsimony" algorithm and is also the maximum likelihood estimate under Brownian motion. The independent contrasts algebra can also be used to compute a standard error or confidence interval.
== Phylogenetic generalized least squares (PGLS) ==
Probably the most commonly used PCM is phylogenetic generalized least squares (PGLS). This approach is used to test whether there is a relationship between two (or more) variables while accounting for the fact that lineage are not independent. The method is a special case of generalized least squares (GLS) and as such the PGLS estimator is also unbiased, consistent, efficient, and asymptotically normal. In many statistical situations where GLS (or, ordinary least squares [OLS]) is used residual errors ε are assumed to be independent and identically distributed random variables that are assumed to be normal
ε
∣
X
∼
N
(
0
,
σ
2
I
n
)
.
{\displaystyle \varepsilon \mid X\sim {\mathcal {N}}(0,\sigma ^{2}I_{n}).}
whereas in PGLS the errors are assumed to be distributed as
ε
∣
X
∼
N
(
0
,
V
)
.
{\displaystyle \varepsilon \mid X\sim {\mathcal {N}}(0,\mathbf {V} ).}
where V is a matrix of expected variance and covariance of the residuals given an evolutionary model and a phylogenetic tree. Therefore, it is the structure of residuals and not the variables themselves that show phylogenetic signal. This has long been a source of confusion in the scientific literature. A number of models have been proposed for the structure of V such as Brownian motion Ornstein-Uhlenbeck, and Pagel's λ model. (When a Brownian motion model is used, PGLS is identical to the independent contrasts estimator.). In PGLS, the parameters of the evolutionary model are typically co-estimated with the regression parameters.
PGLS can only be applied to questions where the dependent variable is continuously distributed; however, the phylogenetic tree can also be incorporated into the residual distribution of generalized linear models, making it possible to generalize the approach to a broader set of distributions for the response.
== Phylogenetically informed Monte Carlo computer simulations ==
Martins and Garland proposed in 1991 that one way to account for phylogenetic relations when conducting statistical analyses was to use computer simulations to create many data sets that are consistent with the null hypothesis under test (e.g., no correlation between two traits, no difference between two ecologically defined groups of species) but that mimic evolution along the relevant phylogenetic tree. If such data sets (typically 1,000 or more) are analyzed with the same statistical procedure that is used to analyze a real data set, then results for the simulated data sets can be used to create phylogenetically correct (or "PC") null distributions of the test statistic (e.g., a correlation coefficient, t, F). Such simulation approaches can also be combined with such methods as phylogenetically independent contrasts or PGLS (see above).
== See also ==
== References ==
== Further reading ==
== External links ==
Adaptation and the comparative method online lecture, with worked example of phylogenetically independent contrasts and mastery quiz
List of phylogeny programs
Phylocomm
Phylogenetic Tools for Comparative Biology
Phylogeny of Sleep website
Tree of Life
=== Journals ===
American Naturalist
Behavioral Ecology
Ecology
Evolution
Evolutionary Ecology Research
Functional Ecology
Journal of Evolutionary Biology
Philosophical Transactions of the Royal Society of London B
Physiological and Biochemical Zoology
Systematic Biology
=== Software packages (incomplete list) ===
Analyses of Phylogenetics and Evolution
BayesTraits
Comparative Analysis by Independent Contrasts
COMPARE
Felsenstein's List
Mesquite PDAP:PDTree for Mesquite
mvMorph
ouch: Ornstein-Uhlenbeck for Comparative Hypotheses
PDAP: Phenotypic Diversity Analysis Programs
Phylocom
Phylogenetic Regression
PHYSIG
=== Laboratories === | Wikipedia/Phylogenetic_comparative_methods |
Analysis of Functional NeuroImages (AFNI) is an open-source environment for processing and displaying functional MRI data—a technique for mapping human brain activity.
AFNI is an agglomeration of programs that can be used interactively or flexibly assembled for batch processing using shell script. The term AFNI refers both to the entire suite and to a particular interactive program often used for visualization. AFNI is actively developed by the NIMH Scientific and Statistical Computing Core and its capabilities are continually expanding.
AFNI runs under many Unix-like operating systems that provide X11 and Motif libraries, including IRIX, Solaris, Linux, FreeBSD and OS X. Precompiled binaries are available for some platforms. AFNI is available for research use under the GNU General Public License, the included SVM-light component is non-commercial and non-distributable. AFNI now comprises over 300,000 lines of C source code, and a skilled C programmer can add interactive and batch functions to AFNI with relative ease.
== History and development ==
AFNI was originally developed at the Medical College of Wisconsin beginning in 1994, largely by Robert W. Cox. Cox brought development to the NIH in 2001 and development continues at the NIMH Scientific and Statistical Computing Core. In a 1995 paper describing the rationale for development of the software, Cox wrote of fMRI data: "The volume of data gathered is very large, and it is essential that easy-to-use tools for visualization and analysis of 3D activation maps be available for neuroscience investigators." Since then, AFNI has become one of the more commonly used analysis tools in fMRI research, alongside SPM and FSL.
Although AFNI initially required extensive shell scripting to execute tasks, pre-made batch scripts and improvements to the graphical user interface (GUI) have since made it possible to generate analyses with less user scripting.
== Features ==
=== Visualization ===
One of AFNI's initial offerings improved the approach to transforming scans of individual brains onto a shared standardized space. Since each person's individual brain is unique in size and shape, comparing across a number of brains requires warping (rotating, scaling, etc.) individual brains into a standard shape. Unfortunately, functional MRI data at the time of AFNI's development was too low resolution for effective transformations. Instead, researchers use the higher resolution anatomical brain scans, often acquired at the beginning of an imaging session.
AFNI allows researchers to overlay a functional image to the anatomical, providing tools for aligning the two into the same space. Processes engaged to warp an individual anatomical scan to standard space are then applied also to the functional scan, improving the transformation process.
Another feature available in AFNI is the SUMA tool, developed by Ziad Saad. This tool allows users to project the 2D data onto a 3D cortical surface map. In this way researchers can view activation patterns while more easily taking into account physical cortical features like gyri.
=== Image Pre-processing ===
"afni_proc.py" is a pre-made script that will run fMRI data from a single subject through a series of pre-processing steps, starting with the raw data. The default settings will perform the following pre-processing steps and finish with a basic regression analysis:
Slice timing: Each 3D brain image is composed of multiple 2D images, "slices". Although acquired at approximately the same time, up to several seconds could separate the first slice acquired from the last. Through interpolation, the slices are aligned to the same time point. Generally, any introduced noise from interpolation errors is thought to be outweighed by improvements in signal.
Motion correction: Head movements can create sources of error in the analysis. Each 3D acquisition in a scan is collected on a 3D grid, with each small cube of grid space, "voxel", representing a single image intensity value. Ideally, voxels will always represent the same part of the brain in each acquisition, rather than vary from one 3D image to the next. To correct small motion artifacts, AFNI's motion correction tool employs a linear least squares algorithm that attempts to align each 3D image acquired to the first image acquired in the scan.
Smoothing: To account for random noise in the image, a smoothing kernel is applied. While smoothing can increase the signal-to-noise ratio of the image, it reduces image resolution.
Mask: Removes any non-brain areas, such as skull, from the fMRI image.
Scale: Scale each voxel so that changes in intensity represent percentage of signal change over the course of the scan. The default sets the mean of each voxel equal to 100.
== See also ==
National Institute of Mental Health
Neuroimaging
Statistical parametric mapping
== References ==
== External links ==
Official website
NIMH Scientific and Statistical Computing Core | Wikipedia/Analysis_of_Functional_NeuroImages |
Functional integration is the study of how brain regions work together to process information and effect responses. Though functional integration frequently relies on anatomic knowledge of the connections between brain areas, the emphasis is on how large clusters of neurons – numbering in the thousands or millions – fire together under various stimuli. The large datasets required for such a whole-scale picture of brain function have motivated the development of several novel and general methods for the statistical analysis of interdependence, such as dynamic causal modelling and statistical linear parametric mapping. These datasets are typically gathered in human subjects by non-invasive methods such as EEG/MEG, fMRI, or PET. The results can be of clinical value by helping to identify the regions responsible for psychiatric disorders, as well as to assess how different activities or lifestyles affect the functioning of the brain.
== Imaging techniques ==
A study's choice of imaging modality depends on the desired spatial and temporal resolution. fMRI and PET offer relatively high spatial resolution, with voxel dimensions on the order of a few millimeters, but their relatively low sampling rate hinders the observation of rapid and transient interactions between distant regions of the brain. These temporal limitations are overcome by MEG, but at the cost of only detecting signals from much larger clusters of neurons.
=== fMRI ===
Functional magnetic resonance imaging (fMRI) is a form of MRI that is most frequently used to take advantage of a difference in magnetism between oxy- and deoxyhemoglobin to assess blood flow to different parts of the brain. Typical sampling rates for fMRI images are in the tenths of seconds.
=== MEG ===
Magnetoencephalography (MEG) is an imaging modality that uses very sensitive magnetometers to measure the magnetic fields resulting from ionic currents flowing through neurons in the brain. High-quality MEG machines allow for sub-millisecond sampling rates.
=== PET ===
PET works by introducing a radiolabeled biologically active molecule. The choice of molecule dictates what is visualized: by using a radiolabeled analog of glucose, for example, one can obtain an image whose intensity distribution indicates metabolic activity. PET scanners offer sampling rates in the tenths of seconds.
=== Multimodal imaging ===
Multimodal imaging frequently consists of the coupling of an electrophysiologic measurement technique, such as EEG or MEG, with a hemodynamic one such as fMRI or PET. While the intention is to use the strengths and limitations of each to complement the other, current approaches suffer from experimental limitations. Some previous work has focused on attempting to use the high spatial resolution of fMRI to determine the (spatial) origin of EEG/MEG signals, so that in future work this spatial information could be extracted from a unimodal EEG/MEG signal. While some studies have seen success in correlating signal origins between modalities to within a few millimeters, the results have not been uniformly positive. Another current limitation is the actual experimental setup: taking measurements using both modalities at once yields inferior signals, but the alternative of measuring each modality separately is confounded by trial-to-trial variability.
== Modes of analysis ==
In functional integration, there is a distinction drawn between functional connectivity, and effective connectivity. Two brain regions are said to be functionally connected if there is a high correlation between the times that the two are firing, though this does not imply causality. Effective connectivity, on the other hand, is a description of the causal relationship between various brain regions.
While statistical assessment of the functional connectivity of multiple brain regions is non-trivial, determining the causality of which brain regions influence which to fire is much thornier, and requires solutions to ill-posed optimization problems.
=== Dynamic causal modelling ===
Dynamic causal modeling (DCM) is a Bayesian method for deducing the structure of a neural system based on the observed hemodynamic (fMRI) or electrophysiologic (EEG/MEG) signal. The first step is to make a prediction as to the relationships between the brain regions of interest, and formulate a system of ordinary differential equations describing the causal relationship between them, although many parameters (and relationships) will be initially unknown. Using previous results on how neural activity is known to translate into fMRI or EEG signals, one can take the measured signal and determine the likelihood that model parameters have particular values. The elucidated model can then be used to predict relationships between the considered brain regions under different conditions. A key factor to consider during the design of neuroimaging experiments involving DCM is the relationship between the timing of tasks or stimuli presented to the subject and the ability of DCM to determine the underlying relationships between brain regions, which is partially determined by the temporal resolution of the imaging modality in use.
=== Statistical parametric mapping ===
Statistical parametric mapping (SPM) is a method for determining whether the activation of a particular brain region changes between experimental conditions, stimuli, or over time. The essential idea is simple, and consists of two major steps: first, one performs a univariate statistical test on each individual voxel between each experimental condition. Second, one analyzes the clustering of the voxels that show statistically significant differences, and determines which brain regions exhibit different levels of activation under different experimental conditions.
There is great flexibility in the choice of statistical test (and thus the questions that an experiment can be designed to answer), and common choices include the Student's t test or linear regression. An important consideration with SPM, however, is that the large number of comparisons requires one to control the false positive rate with a more stringent significance threshold. This can be done either by modifying the initial statistical test to decrease the α value so as to make it harder for a particular voxel to exhibit a significant difference (e.g., Bonferroni correction), or by modifying the clustering analysis in the second step by only considering a brain region's activation to be significant if it contains a certain number of voxels that exhibit a statistical difference (see random field theory).
=== Voxel-based morphometry ===
Voxel-based morphometry (VBM) is a method that allows one to measure brain tissue composition differences between subjects. To do so, one must first register all images to a standard coordinate system, by mapping them to a reference image. This is done by use of an affine transformation that minimizes the sum-of-squares intensity difference between the experimental image and the reference. Once this is done, the proportion of grey or white matter in a voxel can be determined by intensity. This allows one to compare the tissue composition of corresponding brain regions between different subjects.
== Applications ==
The ability to visualize whole-brain activity is frequently used in comparing brain function during various sorts of tasks or tests of skill, as well as in comparing brain structure and function between different groups of people.
=== Changes in resting-state brain activation ===
Many previous fMRI studies have seen that spontaneous activation of functionally connected brain regions occurs during the resting state, even in the absence of any sort of stimulation or activity. Human subjects presented with a visual learning task exhibit changes in functional connectivity in the resting state for up to 24 hours and dynamic functional connectivity studies have even shown changes in functional connectivity during a single scan. By taking fMRI scans of subjects before and after the learning task, as well as on the following day, it was shown that the activity had caused a resting-state change in hippocampal activity. Dynamic causal modeling revealed that the hippocampus also exhibited a new level of effective connectivity with the striatum, though there was no learning-related change in any visual area. Combining fMRI with DCM on subjects performing a learning task allows one to delineate which brain systems are involved in various sorts of learning, whether implicit or explicit, and document for long these tasks lead to changes in resting-state brain activation.
=== IQ estimation ===
Voxel-based morphometric measurements of grey matter localization in the brain can be used to predict components of IQ. A set of 35 teenagers were tested for IQ and were fMRI scanned over the course of 3.5 years, and had their IQ predicted by the level of grey matter localization. This study was well-conducted, but studies of this sort frequently suffer from "double-dipping," where a single dataset is used both to identify the brain regions of interest and to develop a predictive model, which leads to overtraining of the model and an absence of real predictive power.
The study authors avoided double-dipping by using a "leave-one-out" methodology, that involves building a predictive model for each of the n members of a sample based on data from the other n-1 members. This ensures that the model is independent of the subject whose IQ is being predicted, and resulted in a model capable of explaining 53% of the change in verbal IQ as a function of grey matter density in the left motor cortex. The study also observed the previously reported phenomenon that a ranking of young subjects by IQ does not stay constant as the subjects age, which confounds any measurement of the efficacy of educational programs.
These studies can be cross-validated by attempting to locate and assess patients with lesions or other damage in the identified brain region, and examining whether they exhibit functional deficits relative to the population. This methodology would be hindered by the lack of a "before" baseline measurement, however.
=== Phonological loop ===
The phonological loop is a component of working memory that stores a small set of words that can be maintained indefinitely if not distracted. The concept was proposed by the psychologists Alan Baddeley and Graham Hitch to explain how phrases or sentences can be internalized and used to direct action.
By using statistical parametric mapping to assess differences in cerebral blood flow between participants performing two different tasks, Paulescu et al. were able to identify the storage of the phonological loop as in the supramarginal gyrii. Human subjects were first split into a control and experimental group. The control group was presented with letters in a language they did not understand, and non-linguistic visual diagrams. The experimental group was tasked with two activities: the first activity was to remember a string of letters, and was intended activate all elements of the phonological loop. The second activity asked participants to assess whether given phrases rhymed, and was intended to only activate certain sub-systems involved in vocalization, but specifically not the phonological storage.
By comparing the first experimental task to the second, as well as to the control group, the study authors observed that the brain region most significantly activated by the task requiring phonological storage was the supramarginal gyrii. This result was backed up by previous literature observations of functional deficits in patients with damage in this area.
Though this study was able to precisely localize a specific function anatomically and the methods of functional integration and imaging are of great value in determining the brain regions involved in certain information processing tasks, the low-level neural circuitry that gives rise to these phenomena remains mysterious.
=== Psychiatric disorders ===
Although fMRI studies of people with schizophrenia and bipolar disorder have yielded some insight into the changes in effective connectivity caused by these diseases, a comprehensive understanding of the functional remodelling that occurs has not yet been achieved.
Montague et al. note that the almost "unreasonable effectiveness of psychotropic medication" has somewhat stymied progress in this field, and advocate for a large-scale "computational phenotyping" of psychiatric patients. Neuroimaging studies of large numbers of these patients could yield brain activation markers for specific psychiatric illnesses, and also aid in the development of therapeutics and animal models. While a true baseline of brain function in psychiatric patients is near-impossible to obtain, reference values can still be measured by comparing images gathered from patients before and after treatment.
== References ==
== Further reading ==
Büchel, C. (2003). Virginia Ng; Gareth J. Barker; Talma Hendler (eds.). The Importance of Connectivity for Brain Function. Proceedings of the NATO Advanced Research Workshop on Psychiatric Neuroimaging, 29 September-1 October 2002, Chiavari, Italy --T.p. verso. Amsterdam; Washington, DC: IOS Press. pp. 55–59. ISBN 9781586033446. OCLC 52820961. {{cite book}}: |work= ignored (help)
Friston, Karl J. (2004). Kenneth Hugdahl; Richard J Davidson (eds.). Characterizing Functional Asymmetries with Brain Mapping. Bradford Books Series. Cambridge, Mass: MIT Press. pp. 161–186. ISBN 9780262083096. OCLC 645171270. {{cite book}}: |work= ignored (help)
Friston, K. J. (Karl J.) (2007). Statistical parametric mapping : the analysis of functional brain image. Amsterdam; Boston: Elsevier/Academic Press. ISBN 978-0-12-372560-8. OCLC 254457654.
== External links ==
Scholarpedia article on Functional imaging | Wikipedia/Functional_integration_(neurobiology) |
Dynamic causal modeling (DCM) is a framework for specifying models, fitting them to data and comparing their evidence using Bayesian model comparison. It uses nonlinear state-space models in continuous time, specified using stochastic or ordinary differential equations. DCM was initially developed for testing hypotheses about neural dynamics. In this setting, differential equations describe the interaction of neural populations, which directly or indirectly give rise to functional neuroimaging data e.g., functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG) or electroencephalography (EEG). Parameters in these models quantify the directed influences or effective connectivity among neuronal populations, which are estimated from the data using Bayesian statistical methods.
== Procedure ==
DCM is typically used to estimate the coupling among brain regions and the changes in coupling due to experimental changes (e.g., time or context). A model of interacting neural populations is specified, with a level of biological detail dependent on the hypotheses and available data. This is coupled with a forward model describing how neural activity gives rise to measured responses. Estimating the generative model identifies the parameters (e.g. connection strengths) from the observed data. Bayesian model comparison is used to compare models based on their evidence, which can then be characterised in terms of parameters.
DCM studies typically involve the following stages:
Experimental design. Specific hypotheses are formulated and an experiment is conducted.
Data preparation. The acquired data are pre-processed (e.g., to select relevant data features and remove confounds).
Model specification. One or more forward models (DCMs) are specified for each dataset.
Model estimation. The model(s) are fitted to the data to determine their evidence and parameters.
Model comparison. The evidence for each model is used for Bayesian Model Comparison (at the single-subject level or at the group level) to select the best model(s). Bayesian model averaging (BMA) is used to compute a weighted average of parameter estimates over different models.
The key stages are briefly reviewed below.
== Experimental design ==
Functional neuroimaging experiments are typically either task-based or examine brain activity at rest (resting state). In task-based experiments, brain responses are evoked by known deterministic inputs (experimentally controlled stimuli). These experimental variables can change neural activity through direct influences on specific brain regions, such as evoked potentials in the early visual cortex, or via a modulation of coupling among neural populations; for example, the influence of attention. These two types of input - driving and modulatory - are parameterized separately in DCM. To enable efficient estimation of driving and modulatory effects, a 2x2 factorial experimental design is often used - with one factor serving as the driving input and the other as the modulatory input.
Resting state experiments have no experimental manipulations within the period of the neuroimaging recording. Instead, hypotheses are tested about the coupling of endogenous fluctuations in neuronal activity, or in the differences in connectivity between sessions or subjects. The DCM framework includes models and procedures for analysing resting state data, described in the next section.
== Model specification ==
All models in DCM have the following basic form:
z
˙
=
f
(
z
,
u
,
θ
(
n
)
)
y
=
g
(
z
,
θ
(
h
)
)
+
ϵ
{\displaystyle {\begin{aligned}{\dot {z}}&=f(z,u,\theta ^{(n)})\\y&=g(z,\theta ^{(h)})+\epsilon \end{aligned}}}
The first equality describes the change in neural activity
z
{\displaystyle z}
with respect to time (i.e.
z
˙
{\displaystyle {\dot {z}}}
), which cannot be directly observed using non-invasive functional imaging modalities. The evolution of neural activity over time is controlled by a neural function
f
{\displaystyle f}
with parameters
θ
(
n
)
{\displaystyle \theta ^{(n)}}
and experimental inputs
u
{\displaystyle u}
. The neural activity in turn causes the timeseries
y
{\displaystyle y}
(second equality), which are generated via an observation function
g
{\displaystyle g}
with parameters
θ
(
h
)
{\displaystyle \theta ^{(h)}}
. Additive observation noise
ϵ
{\displaystyle \epsilon }
completes the observation model. Usually, the neural parameters
θ
(
n
)
{\displaystyle \theta ^{(n)}}
are of key interest, which for example represent connection strengths that may change under different experimental conditions.
Specifying a DCM requires selecting a neural model
f
{\displaystyle f}
and observation model
g
{\displaystyle g}
and setting appropriate priors over the parameters; e.g. selecting which connections should be switched on or off.
=== Functional MRI ===
The neural model in DCM for fMRI is a Taylor approximation that captures the gross causal influences between brain regions and their change due to experimental inputs (see picture). This is coupled with a detailed biophysical model of the generation of the blood oxygen level dependent (BOLD) response and the MRI signal, based on the Balloon model of Buxton et al., which was supplemented with a model of neurovascular coupling. Additions to the neural model have included interactions between excitatory and inhibitory neural populations and non-linear influences of neural populations on the coupling between other populations.
DCM for resting state studies was first introduced in Stochastic DCM, which estimates both neural fluctuations and connectivity parameters in the time domain, using Generalized Filtering. A more efficient scheme for resting state data was subsequently introduced which operates in the frequency domain, called DCM for Cross-Spectral Density (CSD). Both of these can be applied to large-scale brain networks by constraining the connectivity parameters based on the functional connectivity. Another recent development for resting state analysis is Regression DCM implemented in the Tapas software collection (see Software implementations). Regression DCM operates in the frequency domain, but linearizes the model under certain simplifications, such as having a fixed (canonical) haemodynamic response function. The enables rapid estimation of large-scale brain networks.
=== EEG / MEG ===
DCM for EEG and MEG data use more biologically detailed neural models than fMRI, due to the higher temporal resolution of these measurement techniques. These can be classed into physiological models, which recapitulate neural circuitry, and phenomenological models, which focus on reproducing particular data features. The physiological models can be further subdivided into two classes. Conductance-based models derive from the equivalent circuit representation of the cell membrane developed by Hodgkin and Huxley in the 1950s. Convolution models were introduced by Wilson & Cowan and Freeman in the 1970s and involve a convolution of pre-synaptic input by a synaptic kernel function. Some of the specific models used in DCM are as follows:
Physiological models:
Convolution models:
DCM for evoked responses (DCM for ERP). This is a biologically plausible neural mass model, extending earlier work by Jansen and Rit. It emulates the activity of a cortical area using three neuronal sub-populations (see picture), each of which rests on two operators. The first operator transforms the pre-synaptic firing rate into a Post-Synaptic Potential (PSP), by convolving pre-synaptic input with a synaptic response function (kernel). The second operator, a sigmoid function, transforms the membrane potential into a firing rate of action potentials.
DCM for LFP (Local Field Potentials). Extends DCM for ERP by adding the effects of specific ion channels on spike generation.
Canonical Microcircuit (CMC). Used to address hypotheses about laminar-specific ascending and descending connections in the brain, which underpin the predictive coding account of functional brain architectures. The single pyramidal cell population from DCM for ERP is split into deep and superficial populations (see picture). A version of the CMC has been applied to model multi-modal MEG and fMRI data.
Neural Field Model (NFM). Extends the models above into the spatial domain, modelling continuous changes in current across the cortical sheet.
Conductance models:
Neural Mass Model (NMM) and Mean-field model (MFM). These have the same arrangement of neural populations as DCM for ERP, above, but are based on the Morris-Lecar model of the barnacle muscle fibre, which in turn derives from the Hodgin and Huxley model of the giant squid axon. They enable inference about ligand-gated excitatory (Na+) and inhibitory (Cl-) ion flow, mediated through fast glutamatergic and GABAergic receptors. Whereas DCM for fMRI and the convolution models represent the activity of each neural population by a single number - its mean activity - the conductance models include the full density (probability distribution) of activity within the population. The 'mean-field assumption' used in the MFM version of the model assumes the density of one population's activity depends only on the mean of another. A subsequent extension added voltage-gated NMDA ion channels.
Phenomenological models:
DCM for phase coupling. Models the interaction of brain regions as Weakly Coupled Oscillators (WCOs), in which the rate of change of phase of one oscillator is related to the phase differences between itself and other oscillators.
== Model estimation ==
Model inversion or estimation is implemented in DCM using variational Bayes under the Laplace assumption. This provides two useful quantities: the log marginal likelihood or model evidence
ln
p
(
y
|
m
)
{\displaystyle \ln {p(y|m)}}
is the probability of observing of the data under a given model. Generally, this cannot be calculated explicitly and is approximated by a quantity called the negative variational free energy
F
{\displaystyle F}
, referred to in machine learning as the Evidence Lower Bound (ELBO). Hypotheses are tested by comparing the evidence for different models based on their free energy, a procedure called Bayesian model comparison.
Model estimation also provides estimates of the parameters
p
(
θ
|
y
)
{\displaystyle p(\theta |y)}
, for example connection strengths, which maximise the free energy. Where models differ only in their priors, Bayesian Model Reduction can be used to derive the evidence and parameters of nested or reduced models analytically and efficiently.
== Model comparison ==
Neuroimaging studies typically investigate effects that are conserved at the group level, or which differ between subjects. There are two predominant approaches for group-level analysis: random effects Bayesian Model Selection (BMS) and Parametric Empirical Bayes (PEB). Random Effects BMS posits that subjects differ in terms of which model generated their data - e.g. drawing a random subject from the population, there might be a 25% chance that their brain is structured like model 1 and a 75% chance that it is structured like model 2. The analysis pipeline for the BMS approach procedure follows a series of steps:
Specify and estimate multiple DCMs per subject, where each DCM (or set of DCMs) embodies a hypothesis.
Perform Random Effects BMS to estimate the proportion of subjects whose data were generated by each model
Calculate the average connectivity parameters across models using Bayesian Model Averaging. This average is weighted by the posterior probability for each model, meaning that models with greater probability contribute more to the average than models with lower probability.
Alternatively, Parametric Empirical Bayes (PEB) can be used, which specifies a hierarchical model over parameters (e.g., connection strengths). It eschews the notion of different models at the level of individual subjects, and assumes that people differ in the (parametric) strength of connections. The PEB approach models distinct sources of variability in connection strengths across subjects using fixed effects and between-subject variability (random effects). The PEB procedure is as follows:
Specify a single 'full' DCM per subject, which contains all the parameters of interest.
Specify a Bayesian General Linear Model (GLM) to model the parameters (the full posterior density) from all subjects at the group level.
Test hypotheses by comparing the full group-level model to reduced group-level models where certain combinations of connections have been switched off.
== Validation ==
Developments in DCM have been validated using different approaches:
Face validity establishes whether the parameters of a model can be recovered from simulated data. This is usually performed alongside the development of each new model (E.g.).
Construct validity assesses consistency with other analytical methods. For example, DCM has been compared with Structural Equation Modelling and other neurobiological computational models.
Predictive validity assesses the ability to predict known or expected effects. This has included testing against iEEG / EEG / stimulation and against known pharmacological treatments.
== Limitations / drawbacks ==
DCM is a hypothesis-driven approach for investigating the interactions among pre-defined regions of interest. It is not ideally suited for exploratory analyses. Although methods have been implemented for automatically searching over reduced models (Bayesian Model Reduction) and for modelling large-scale brain networks, these methods require an explicit specification of model space. In neuroimaging, approaches such as psychophysiological interaction (PPI) analysis may be more appropriate for exploratory use; especially for discovering key nodes for subsequent DCM analysis.
The variational Bayesian methods used for model estimation in DCM are based on the Laplace assumption, which treats the posterior over parameters as Gaussian. This approximation can fail in the context of highly non-linear models, where local minima may preclude the free energy from serving as a tight bound on log model evidence. Sampling approaches provide the gold standard; however, they are time-consuming and have typically been used to validate the variational approximations in DCM.
== Software implementations ==
DCM is implemented in the Statistical Parametric Mapping software package, which serves as the canonical or reference implementation (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). It has been re-implemented and developed in the Tapas software collection (https://www.tnu.ethz.ch/en/software/tapas.html Archived 2019-02-03 at the Wayback Machine) and the VBA toolbox (https://mbb-team.github.io/VBA-toolbox/).
== References ==
== Further reading ==
Dynamic Causal Modelling on Scholarpedia
Understanding DCM: ten simple rules for the clinician
Neural masses and fields in dynamic causal modeling | Wikipedia/Dynamic_causal_modelling |
In mathematics, the Backus–Gilbert method, also known as the optimally localized average (OLA) method is named for its discoverers, geophysicists George E. Backus and James Freeman Gilbert. It is a regularization method for obtaining meaningful solutions to ill-posed inverse problems. Where other regularization methods, such as the frequently used Tikhonov regularization method, seek to impose smoothness constraints on the solution, Backus–Gilbert instead seeks to impose stability constraints, so that the solution would vary as little as possible if the input data were resampled multiple times. In practice, and to the extent that is justified by the data, smoothness results from this.
Given a data array X, the basic Backus-Gilbert inverse is:
H
θ
=
C
−
1
G
θ
G
θ
T
C
−
1
G
θ
{\displaystyle \mathbf {H} _{\theta }={\frac {\mathbf {C} ^{-1}\mathbf {G} _{\theta }}{\mathbf {G} _{\theta }^{T}\mathbf {C} ^{-1}\mathbf {G} _{\theta }}}}
where C is the covariance matrix of the data, and Gθ is an a priori constraint representing the source θ for which a solution is sought. Regularization is implemented by "whitening" the covariance matrix:
C
′
=
C
+
λ
I
{\displaystyle \mathbf {C} '=\mathbf {C} +\lambda \mathbf {I} }
with C′ replacing C in the equation for Hθ. Then,
H
θ
T
X
{\displaystyle \mathbf {H} _{\theta }^{T}\mathbf {X} }
is an estimate of the activity of the source θ.
== References ==
Backus, G.E., and Gilbert, F. 1968, "The Resolving power of Gross Earth Data", Geophysical Journal of the Royal Astronomical Society, vol. 16, pp. 169–205.
Backus, G.E., and Gilbert, F. 1970, "Uniqueness in the Inversion of inaccurate Gross Earth Data", Philosophical Transactions of the Royal Society of London A, vol. 266, pp. 123–192.
Press, WH; Teukolsky, SA; Vetterling, WT; Flannery, BP (2007). "Section 19.6. Backus–Gilbert Method". Numerical Recipes (3rd ed.). Cambridge University Press. ISBN 978-0-521-88068-8. Archived from the original on 2011-08-11. Retrieved 2011-08-17. | Wikipedia/Backus–Gilbert_method |
Temporal resolution (TR) refers to the discrete resolution of a measurement with respect to time. It is defined as the amount of time needed to revisit and acquire data for exactly the same location. When applied to remote sensing, this amount of time is influenced by the sensor platform's orbital characteristics and the features of the sensor itself. The temporal resolution is low when the revisiting delay is high and vice-versa. Temporal resolution is typically expressed in days.
== Physics ==
Often there is a trade-off between the temporal resolution of a measurement and its spatial resolution, due to Heisenberg's uncertainty principle. In some contexts, such as particle physics, this trade-off can be attributed to the finite speed of light and the fact that it takes a certain period of time for the photons carrying information to reach the observer. In this time, the system might have undergone changes itself. Thus, the longer the light has to travel, the lower the temporal resolution.
== Technology ==
=== Computing ===
In another context, there is often a tradeoff between temporal resolution and computer storage. A transducer may be able to record data every millisecond, but available storage may not allow this, and in the case of 4D PET imaging the resolution may be limited to several minutes.
=== Electronic displays ===
In some applications, temporal resolution may instead be equated to the sampling period, or its inverse, the refresh rate, or update frequency in Hertz, of a TV, for example.
The temporal resolution is distinct from temporal uncertainty. This would be analogous to conflating image resolution with optical resolution. One is discrete, the other, continuous.
The temporal resolution is a resolution somewhat the 'time' dual to the 'space' resolution of an image. In a similar way, the sample rate is equivalent to the pixel pitch on a display screen, whereas the optical resolution of a display screen is equivalent to temporal uncertainty.
Note that both this form of image space and time resolutions are orthogonal to measurement resolution, even though space and time are also orthogonal to each other. Both an image or an oscilloscope capture can have a signal-to-noise ratio, since both also have measurement resolution.
=== Oscilloscopy ===
An oscilloscope is the temporal equivalent of a microscope, and it is limited by temporal uncertainty the same way a microscope is limited by optical resolution. A digital sampling oscilloscope has also a limitation analogous to image resolution, which is the sample rate. A non-digital non-sampling oscilloscope is still limited by temporal uncertainty.
The temporal uncertainty can be related to the maximum frequency of continuous signal the oscilloscope could respond to, called the bandwidth and given in Hertz. But for oscilloscopes, this figure is not the temporal resolution. To reduce confusion, oscilloscope manufacturers use 'Sa/s' instead of 'Hz' to specify the temporal resolution.
Two cases for oscilloscopes exist: either the probe settling time is much shorter than the real time sampling rate, or it is much larger. The case where the settling time is the same as the sampling time is usually undesirable in an oscilloscope. It is more typical to prefer a larger ratio either way, or if not, to be somewhat longer than two sample periods.
In the case where it is much longer, the most typical case, it dominates the temporal resolution. The shape of the response during the settling time also has as strong effect on the temporal resolution. For this reason probe leads usually offer an arrangement to 'compensate' the leads to alter the trade off between minimal settling time, and minimal overshoot.
If it is much shorter, the oscilloscope may be prone to aliasing from radio frequency interference, but this can be removed by repeatedly sampling a repetitive signal and averaging the results together. If the relationship between the 'trigger' time and the sample clock can be controlled with greater accuracy than the sampling time, then it is possible to make a measurement of a repetitive waveform with much higher temporal resolution than the sample period by upsampling each record before averaging. In this case the temporal uncertainty may be limited by clock jitter.
== See also ==
High-motion
== References == | Wikipedia/Temporal_resolution |
Anatomy (from Ancient Greek ἀνατομή (anatomḗ) 'dissection') is the branch of morphology concerned with the study of the internal structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having its beginnings in prehistoric times. Anatomy is inherently tied to developmental biology, embryology, comparative anatomy, evolutionary biology, and phylogeny, as these are the processes by which anatomy is generated, both over immediate and long-term timescales. Anatomy and physiology, which study the structure and function of organisms and their parts respectively, make a natural pair of related disciplines, and are often studied together. Human anatomy is one of the essential basic sciences that are applied in medicine, and is often studied alongside physiology.
Anatomy is a complex and dynamic field that is constantly evolving as discoveries are made. In recent years, there has been a significant increase in the use of advanced imaging techniques, such as MRI and CT scans, which allow for more detailed and accurate visualizations of the body's structures.
The discipline of anatomy is divided into macroscopic and microscopic parts. Macroscopic anatomy, or gross anatomy, is the examination of an animal's body parts using unaided eyesight. Gross anatomy also includes the branch of superficial anatomy. Microscopic anatomy involves the use of optical instruments in the study of the tissues of various structures, known as histology, and also in the study of cells.
The history of anatomy is characterized by a progressive understanding of the functions of the organs and structures of the human body. Methods have also improved dramatically, advancing from the examination of animals by dissection of carcasses and cadavers (corpses) to 20th-century medical imaging techniques, including X-ray, ultrasound, and magnetic resonance imaging.
== Etymology and definition ==
Derived from the Greek ἀνατομή anatomē "dissection" (from ἀνατέμνω anatémnō "I cut up, cut open" from ἀνά aná "up", and τέμνω témnō "I cut"), anatomy is the scientific study of the structure of organisms including their systems, organs and tissues. It includes the appearance and position of the various parts, the materials from which they are composed, and their relationships with other parts. Anatomy is quite distinct from physiology and biochemistry, which deal respectively with the functions of those parts and the chemical processes involved. For example, an anatomist is concerned with the shape, size, position, structure, blood supply and innervation of an organ such as the liver; while a physiologist is interested in the production of bile, the role of the liver in nutrition and the regulation of bodily functions.
The discipline of anatomy can be subdivided into a number of branches, including gross or macroscopic anatomy and microscopic anatomy. Gross anatomy is the study of structures large enough to be seen with the naked eye, and also includes superficial anatomy or surface anatomy, the study by sight of the external body features. Microscopic anatomy is the study of structures on a microscopic scale, along with histology (the study of tissues), and embryology (the study of an organism in its immature condition). Regional anatomy is the study of the interrelationships of all of the structures in a specific body region, such as the abdomen. In contrast, systemic anatomy is the study of the structures that make up a discrete body system—that is, a group of structures that work together to perform a unique body function, such as the digestive system.
Anatomy can be studied using both invasive and non-invasive methods with the goal of obtaining information about the structure and organization of organs and systems. Methods used include dissection, in which a body is opened and its organs studied, and endoscopy, in which a video camera-equipped instrument is inserted through a small incision in the body wall and used to explore the internal organs and other structures. Angiography using X-rays or magnetic resonance angiography are methods to visualize blood vessels.
The term "anatomy" is commonly taken to refer to human anatomy. However, substantially similar structures and tissues are found throughout the rest of the animal kingdom, and the term also includes the anatomy of other animals. The term zootomy is also sometimes used to specifically refer to non-human animals. The structure and tissues of plants are of a dissimilar nature and they are studied in plant anatomy.
== Animal tissues ==
The kingdom Animalia contains multicellular organisms that are heterotrophic and motile (although some have secondarily adopted a sessile lifestyle). Most animals have bodies differentiated into separate tissues and these animals are also known as eumetazoans. They have an internal digestive chamber, with one or two openings; the gametes are produced in multicellular sex organs, and the zygotes include a blastula stage in their embryonic development. Metazoans do not include the sponges, which have undifferentiated cells.
Unlike plant cells, animal cells have neither a cell wall nor chloroplasts. Vacuoles, when present, are more in number and much smaller than those in the plant cell. The body tissues are composed of numerous types of cells, including those found in muscles, nerves and skin. Each typically has a cell membrane formed of phospholipids, cytoplasm and a nucleus. All of the different cells of an animal are derived from the embryonic germ layers. Those simpler invertebrates which are formed from two germ layers of ectoderm and endoderm are called diploblastic and the more developed animals whose structures and organs are formed from three germ layers are called triploblastic. All of a triploblastic animal's tissues and organs are derived from the three germ layers of the embryo, the ectoderm, mesoderm and endoderm.
Animal tissues can be grouped into four basic types: connective, epithelial, muscle and nervous tissue.
=== Connective tissue ===
Connective tissues are fibrous and made up of cells scattered among inorganic material called the extracellular matrix. Often called fascia (from the Latin "fascia," meaning "band" or "bandage"), connective tissues give shape to organs and holds them in place. The main types are loose connective tissue, adipose tissue, fibrous connective tissue, cartilage and bone. The extracellular matrix contains proteins, the chief and most abundant of which is collagen. Collagen plays a major part in organizing and maintaining tissues. The matrix can be modified to form a skeleton to support or protect the body. An exoskeleton is a thickened, rigid cuticle which is stiffened by mineralization, as in crustaceans or by the cross-linking of its proteins as in insects. An endoskeleton is internal and present in all developed animals, as well as in many of those less developed.
=== Epithelium ===
Epithelial tissue is composed of closely packed cells, bound to each other by cell adhesion molecules, with little intercellular space. Epithelial cells can be squamous (flat), cuboidal or columnar and rest on a basal lamina, the upper layer of the basement membrane, the lower layer is the reticular lamina lying next to the connective tissue in the extracellular matrix secreted by the epithelial cells. There are many different types of epithelium, modified to suit a particular function. In the respiratory tract there is a type of ciliated epithelial lining; in the small intestine there are microvilli on the epithelial lining and in the large intestine there are intestinal villi. Skin consists of an outer layer of keratinized stratified squamous epithelium that covers the exterior of the vertebrate body. Keratinocytes make up to 95% of the cells in the skin. The epithelial cells on the external surface of the body typically secrete an extracellular matrix in the form of a cuticle. In simple animals this may just be a coat of glycoproteins. In more advanced animals, many glands are formed of epithelial cells.
=== Muscle tissue ===
Muscle cells (myocytes) form the active contractile tissue of the body. Muscle tissue functions to produce force and cause motion, either locomotion or movement within internal organs. Muscle is formed of contractile filaments and is separated into three main types; smooth muscle, skeletal muscle and cardiac muscle. Smooth muscle has no striations when examined microscopically. It contracts slowly but maintains contractibility over a wide range of stretch lengths. It is found in such organs as sea anemone tentacles and the body wall of sea cucumbers. Skeletal muscle contracts rapidly but has a limited range of extension. It is found in the movement of appendages and jaws. Obliquely striated muscle is intermediate between the other two. The filaments are staggered and this is the type of muscle found in earthworms that can extend slowly or make rapid contractions. In higher animals striated muscles occur in bundles attached to bone to provide movement and are often arranged in antagonistic sets. Smooth muscle is found in the walls of the uterus, bladder, intestines, stomach, oesophagus, respiratory airways, and blood vessels. Cardiac muscle is found only in the heart, allowing it to contract and pump blood round the body.
=== Nervous tissue ===
Nervous tissue is composed of many nerve cells known as neurons which transmit information. In some slow-moving radially symmetrical marine animals such as ctenophores and cnidarians (including sea anemones and jellyfish), the nerves form a nerve net, but in most animals they are organized longitudinally into bundles. In simple animals, receptor neurons in the body wall cause a local reaction to a stimulus. In more complex animals, specialized receptor cells such as chemoreceptors and photoreceptors are found in groups and send messages along neural networks to other parts of the organism. Neurons can be connected together in ganglia. In higher animals, specialized receptors are the basis of sense organs and there is a central nervous system (brain and spinal cord) and a peripheral nervous system. The latter consists of sensory nerves that transmit information from sense organs and motor nerves that influence target organs. The peripheral nervous system is divided into the somatic nervous system which conveys sensation and controls voluntary muscle, and the autonomic nervous system which involuntarily controls smooth muscle, certain glands and internal organs, including the stomach.
== Vertebrate anatomy ==
All vertebrates have a similar basic body plan and at some point in their lives, mostly in the embryonic stage, share the major chordate characteristics: a stiffening rod, the notochord; a dorsal hollow tube of nervous material, the neural tube; pharyngeal arches; and a tail posterior to the anus. The spinal cord is protected by the vertebral column and is above the notochord, and the gastrointestinal tract is below it. Nervous tissue is derived from the ectoderm, connective tissues are derived from mesoderm, and gut is derived from the endoderm. At the posterior end is a tail which continues the spinal cord and vertebrae but not the gut. The mouth is found at the anterior end of the animal, and the anus at the base of the tail. The defining characteristic of a vertebrate is the vertebral column, formed in the development of the segmented series of vertebrae. In most vertebrates the notochord becomes the nucleus pulposus of the intervertebral discs. However, a few vertebrates, such as the sturgeon and the coelacanth, retain the notochord into adulthood. Jawed vertebrates are typified by paired appendages, fins or legs, which may be secondarily lost. The limbs of vertebrates are considered to be homologous because the same underlying skeletal structure was inherited from their last common ancestor. This is one of the arguments put forward by Charles Darwin to support his theory of evolution.
=== Fish anatomy ===
The body of a fish is divided into a head, trunk and tail, although the divisions between the three are not always externally visible. The skeleton, which forms the support structure inside the fish, is either made of cartilage, in cartilaginous fish, or bone in bony fish. The main skeletal element is the vertebral column, composed of articulating vertebrae which are lightweight yet strong. The ribs attach to the spine and there are no limbs or limb girdles. The main external features of the fish, the fins, are composed of either bony or soft spines called rays, which with the exception of the caudal fins, have no direct connection with the spine. They are supported by the muscles which compose the main part of the trunk. The heart has two chambers and pumps the blood through the respiratory surfaces of the gills and on round the body in a single circulatory loop. The eyes are adapted for seeing underwater and have only local vision. There is an inner ear but no external or middle ear. Low frequency vibrations are detected by the lateral line system of sense organs that run along the length of the sides of fish, and these respond to nearby movements and to changes in water pressure.
Sharks and rays are basal fish with numerous primitive anatomical features similar to those of ancient fish, including skeletons composed of cartilage. Their bodies tend to be dorso-ventrally flattened, they usually have five pairs of gill slits and a large mouth set on the underside of the head. The dermis is covered with separate dermal placoid scales. They have a cloaca into which the urinary and genital passages open, but not a swim bladder. Cartilaginous fish produce a small number of large, yolky eggs. Some species are ovoviviparous and the young develop internally but others are oviparous and the larvae develop externally in egg cases.
The bony fish lineage shows more derived anatomical traits, often with major evolutionary changes from the features of ancient fish. They have a bony skeleton, are generally laterally flattened, have five pairs of gills protected by an operculum, and a mouth at or near the tip of the snout. The dermis is covered with overlapping scales. Bony fish have a swim bladder which helps them maintain a constant depth in the water column, but not a cloaca. They mostly spawn a large number of small eggs with little yolk which they broadcast into the water column.
=== Amphibian anatomy ===
Amphibians are a class of animals comprising frogs, salamanders and caecilians. They are tetrapods, but the caecilians and a few species of salamander have either no limbs or their limbs are much reduced in size. Their main bones are hollow and lightweight and are fully ossified and the vertebrae interlock with each other and have articular processes. Their ribs are usually short and may be fused to the vertebrae. Their skulls are mostly broad and short, and are often incompletely ossified. Their skin contains little keratin and lacks scales, but contains many mucous glands and in some species, poison glands. The hearts of amphibians have three chambers, two atria and one ventricle. They have a urinary bladder and nitrogenous waste products are excreted primarily as urea. Amphibians breathe by means of buccal pumping, a pump action in which air is first drawn into the buccopharyngeal region through the nostrils. These are then closed and the air is forced into the lungs by contraction of the throat. They supplement this with gas exchange through the skin which needs to be kept moist.
In frogs the pelvic girdle is robust and the hind legs are much longer and stronger than the forelimbs. The feet have four or five digits and the toes are often webbed for swimming or have suction pads for climbing. Frogs have large eyes and no tail. Salamanders resemble lizards in appearance; their short legs project sideways, the belly is close to or in contact with the ground and they have a long tail. Caecilians superficially resemble earthworms and are limbless. They burrow by means of zones of muscle contractions which move along the body and they swim by undulating their body from side to side.
=== Reptile anatomy ===
Reptiles are a class of animals comprising turtles, tuataras, lizards, snakes and crocodiles. They are tetrapods, but the snakes and a few species of lizard either have no limbs or their limbs are much reduced in size. Their bones are better ossified and their skeletons stronger than those of amphibians. The teeth are conical and mostly uniform in size. The surface cells of the epidermis are modified into horny scales which create a waterproof layer. Reptiles are unable to use their skin for respiration as do amphibians and have a more efficient respiratory system drawing air into their lungs by expanding their chest walls. The heart resembles that of the amphibian but there is a septum which more completely separates the oxygenated and deoxygenated bloodstreams. The reproductive system has evolved for internal fertilization, with a copulatory organ present in most species. The eggs are surrounded by amniotic membranes which prevents them from drying out and are laid on land, or develop internally in some species. The bladder is small as nitrogenous waste is excreted as uric acid.
Turtles are notable for their protective shells. They have an inflexible trunk encased in a horny carapace above and a plastron below. These are formed from bony plates embedded in the dermis which are overlain by horny ones and are partially fused with the ribs and spine. The neck is long and flexible and the head and the legs can be drawn back inside the shell. Turtles are vegetarians and the typical reptile teeth have been replaced by sharp, horny plates. In aquatic species, the front legs are modified into flippers.
Tuataras superficially resemble lizards but the lineages diverged in the Triassic period. There is one living species, Sphenodon punctatus. The skull has two openings (fenestrae) on either side and the jaw is rigidly attached to the skull. There is one row of teeth in the lower jaw and this fits between the two rows in the upper jaw when the animal chews. The teeth are merely projections of bony material from the jaw and eventually wear down. The brain and heart are more primitive than those of other reptiles, and the lungs have a single chamber and lack bronchi. The tuatara has a well-developed parietal eye on its forehead.
Lizards have skulls with only one fenestra on each side, the lower bar of bone below the second fenestra having been lost. This results in the jaws being less rigidly attached which allows the mouth to open wider. Lizards are mostly quadrupeds, with the trunk held off the ground by short, sideways-facing legs, but a few species have no limbs and resemble snakes. Lizards have moveable eyelids, eardrums are present and some species have a central parietal eye.
Snakes are closely related to lizards, having branched off from a common ancestral lineage during the Cretaceous period, and they share many of the same features. The skeleton consists of a skull, a hyoid bone, spine and ribs though a few species retain a vestige of the pelvis and rear limbs in the form of pelvic spurs. The bar under the second fenestra has also been lost and the jaws have extreme flexibility allowing the snake to swallow its prey whole. Snakes lack moveable eyelids, the eyes being covered by transparent "spectacle" scales. They do not have eardrums but can detect ground vibrations through the bones of their skull. Their forked tongues are used as organs of taste and smell and some species have sensory pits on their heads enabling them to locate warm-blooded prey.
Crocodilians are large, low-slung aquatic reptiles with long snouts and large numbers of teeth. The head and trunk are dorso-ventrally flattened and the tail is laterally compressed. It undulates from side to side to force the animal through the water when swimming. The tough keratinized scales provide body armour and some are fused to the skull. The nostrils, eyes and ears are elevated above the top of the flat head enabling them to remain above the surface of the water when the animal is floating. Valves seal the nostrils and ears when it is submerged. Unlike other reptiles, crocodilians have hearts with four chambers allowing complete separation of oxygenated and deoxygenated blood.
=== Bird anatomy ===
Birds are tetrapods but though their hind limbs are used for walking or hopping, their front limbs are wings covered with feathers and adapted for flight. Birds are endothermic, have a high metabolic rate, a light skeletal system and powerful muscles. The long bones are thin, hollow and very light. Air sac extensions from the lungs occupy the centre of some bones. The sternum is wide and usually has a keel and the caudal vertebrae are fused. There are no teeth and the narrow jaws are adapted into a horn-covered beak. The eyes are relatively large, particularly in nocturnal species such as owls. They face forwards in predators and sideways in ducks.
The feathers are outgrowths of the epidermis and are found in localized bands from where they fan out over the skin. Large flight feathers are found on the wings and tail, contour feathers cover the bird's surface and fine down occurs on young birds and under the contour feathers of water birds. The only cutaneous gland is the single uropygial gland near the base of the tail. This produces an oily secretion that waterproofs the feathers when the bird preens. There are scales on the legs, feet and claws on the tips of the toes.
=== Mammal anatomy ===
Mammals are a diverse class of animals, mostly terrestrial but some are aquatic and others have evolved flapping or gliding flight. They mostly have four limbs, but some aquatic mammals have no limbs or limbs modified into fins, and the forelimbs of bats are modified into wings. The legs of most mammals are situated below the trunk, which is held well clear of the ground. The bones of mammals are well ossified and their teeth, which are usually differentiated, are coated in a layer of prismatic enamel. The teeth are shed once (milk teeth) during the animal's lifetime or not at all, as is the case in cetaceans. Mammals have three bones in the middle ear and a cochlea in the inner ear. They are clothed in hair and their skin contains glands which secrete sweat. Some of these glands are specialized as mammary glands, producing milk to feed the young. Mammals breathe with lungs and have a muscular diaphragm separating the thorax from the abdomen which helps them draw air into the lungs. The mammalian heart has four chambers, and oxygenated and deoxygenated blood are kept entirely separate. Nitrogenous waste is excreted primarily as urea.
Mammals are amniotes, and most are viviparous, giving birth to live young. Exceptions to this are the egg-laying monotremes, the platypus and the echidnas of Australia. Most other mammals have a placenta through which the developing foetus obtains nourishment, but in marsupials, the foetal stage is very short and the immature young is born and finds its way to its mother's pouch where it latches on to a teat and completes its development.
==== Human anatomy ====
Humans have the overall body plan of a mammal. Humans have a head, neck, trunk (which includes the thorax and abdomen), two arms and hands, and two legs and feet.
Generally, students of certain biological sciences, paramedics, prosthetists and orthotists, physiotherapists, occupational therapists, nurses, podiatrists, and medical students learn gross anatomy and microscopic anatomy from anatomical models, skeletons, textbooks, diagrams, photographs, lectures and tutorials and in addition, medical students generally also learn gross anatomy through practical experience of dissection and inspection of cadavers. The study of microscopic anatomy (or histology) can be aided by practical experience examining histological preparations (or slides) under a microscope.
Human anatomy, physiology and biochemistry are complementary basic medical sciences, which are generally taught to medical students in their first year at medical school. Human anatomy can be taught regionally or systemically; that is, respectively, studying anatomy by bodily regions such as the head and chest, or studying by specific systems, such as the nervous or respiratory systems. The major anatomy textbook, Gray's Anatomy, has been reorganized from a systems format to a regional format, in line with modern teaching methods. A thorough working knowledge of anatomy is required by physicians, especially surgeons and doctors working in some diagnostic specialties, such as histopathology and radiology.
Academic anatomists are usually employed by universities, medical schools or teaching hospitals. They are often involved in teaching anatomy, and research into certain systems, organs, tissues or cells.
== Invertebrate anatomy ==
Invertebrates constitute a vast array of living organisms ranging from the simplest unicellular eukaryotes such as Paramecium to such complex multicellular animals as the octopus, lobster and dragonfly. They constitute about 95% of the animal species. By definition, none of these creatures has a backbone. The cells of single-cell protozoans have the same basic structure as those of multicellular animals but some parts are specialized into the equivalent of tissues and organs. Locomotion is often provided by cilia or flagella or may proceed via the advance of pseudopodia, food may be gathered by phagocytosis, energy needs may be supplied by photosynthesis and the cell may be supported by an endoskeleton or an exoskeleton. Some protozoans can form multicellular colonies.
Metazoans are a multicellular organism, with different groups of cells serving different functions. The most basic types of metazoan tissues are epithelium and connective tissue, both of which are present in nearly all invertebrates. The outer surface of the epidermis is normally formed of epithelial cells and secretes an extracellular matrix which provides support to the organism. An endoskeleton derived from the mesoderm is present in echinoderms, sponges and some cephalopods. Exoskeletons are derived from the epidermis and is composed of chitin in arthropods (insects, spiders, ticks, shrimps, crabs, lobsters). Calcium carbonate constitutes the shells of molluscs, brachiopods and some tube-building polychaete worms and silica forms the exoskeleton of the microscopic diatoms and radiolaria. Other invertebrates may have no rigid structures but the epidermis may secrete a variety of surface coatings such as the pinacoderm of sponges, the gelatinous cuticle of cnidarians (polyps, sea anemones, jellyfish) and the collagenous cuticle of annelids. The outer epithelial layer may include cells of several types including sensory cells, gland cells and stinging cells. There may also be protrusions such as microvilli, cilia, bristles, spines and tubercles.
Marcello Malpighi, the father of microscopical anatomy, discovered that plants had tubules similar to those he saw in insects like the silk worm. He observed that when a ring-like portion of bark was removed on a trunk a swelling occurred in the tissues above the ring, and he unmistakably interpreted this as growth stimulated by food coming down from the leaves, and being captured above the ring.
=== Arthropod anatomy ===
Arthropods comprise the largest phylum of invertebrates in the animal kingdom with over a million known species.
Insects possess segmented bodies supported by a hard-jointed outer covering, the exoskeleton, made mostly of chitin. The segments of the body are organized into three distinct parts, a head, a thorax and an abdomen. The head typically bears a pair of sensory antennae, a pair of compound eyes, one to three simple eyes (ocelli) and three sets of modified appendages that form the mouthparts. The thorax has three pairs of segmented legs, one pair each for the three segments that compose the thorax and one or two pairs of wings. The abdomen is composed of eleven segments, some of which may be fused and houses the digestive, respiratory, excretory and reproductive systems. There is considerable variation between species and many adaptations to the body parts, especially wings, legs, antennae and mouthparts.
Spiders a class of arachnids have four pairs of legs; a body of two segments—a cephalothorax and an abdomen. Spiders have no wings and no antennae. They have mouthparts called chelicerae which are often connected to venom glands as most spiders are venomous. They have a second pair of appendages called pedipalps attached to the cephalothorax. These have similar segmentation to the legs and function as taste and smell organs. At the end of each male pedipalp is a spoon-shaped cymbium that acts to support the copulatory organ.
== Other branches of anatomy ==
Surface anatomy is important as the study of anatomical landmarks that can be readily seen from the exterior contours of the body. It enables medics and veterinarians to gauge the position and anatomy of the associated deeper structures. Superficial is a directional term that indicates that structures are located relatively close to the surface of the body.
Comparative anatomy relates to the comparison of anatomical structures (both gross and microscopic) in different animals.
Artistic anatomy relates to anatomic studies of body proportions for artistic reasons.
== History ==
=== Ancient ===
In 1600 BCE, the Edwin Smith Papyrus, an Ancient Egyptian medical text, described the heart and its vessels, as well as the brain and its meninges and cerebrospinal fluid, and the liver, spleen, kidneys, uterus and bladder. It showed the blood vessels diverging from the heart. The Ebers Papyrus (c. 1550 BCE) features a "treatise on the heart", with vessels carrying all the body's fluids to or from every member of the body.
Ancient Greek anatomy and physiology underwent great changes and advances throughout the early medieval world. Over time, this medical practice expanded due to a continually developing understanding of the functions of organs and structures in the body. Phenomenal anatomical observations of the human body were made, which contributed to the understanding of the brain, eye, liver, reproductive organs, and nervous system.
The Hellenistic Egyptian city of Alexandria was the stepping-stone for Greek anatomy and physiology. Alexandria not only housed the biggest library for medical records and books of the liberal arts in the world during the time of the Greeks but was also home to many medical practitioners and philosophers. Great patronage of the arts and sciences from the Ptolemaic dynasty of Egypt helped raise Alexandria up, further rivalling other Greek states' cultural and scientific achievements.
Some of the most striking advances in early anatomy and physiology took place in Hellenistic Alexandria. Two of the most famous anatomists and physiologists of the third century were Herophilus and Erasistratus. These two physicians helped pioneer human dissection for medical research, using the cadavers of condemned criminals, which was considered taboo until the Renaissance—Herophilus was recognized as the first person to perform systematic dissections. Herophilus became known for his anatomical works, making impressive contributions to many branches of anatomy and many other aspects of medicine. Some of the works included classifying the system of the pulse, the discovery that human arteries had thicker walls than veins, and that the atria were parts of the heart. Herophilus's knowledge of the human body has provided vital input towards understanding the brain, eye, liver, reproductive organs, and nervous system and characterizing the course of the disease. Erasistratus accurately described the structure of the brain, including the cavities and membranes, and made a distinction between its cerebrum and cerebellum During his study in Alexandria, Erasistratus was particularly concerned with studies of the circulatory and nervous systems. He could distinguish the human body's sensory and motor nerves and believed air entered the lungs and heart, which was then carried throughout the body. His distinction between the arteries and veins—the arteries carrying the air through the body, while the veins carry the blood from the heart was a great anatomical discovery. Erasistratus was also responsible for naming and describing the function of the epiglottis and the heart's valves, including the tricuspid. During the third century, Greek physicians were able to differentiate nerves from blood vessels and tendons and to realize that the nerves convey neural impulses. It was Herophilus who made the point that damage to motor nerves induced paralysis. Herophilus named the meninges and ventricles in the brain, appreciated the division between cerebellum and cerebrum and recognized that the brain was the "seat of intellect" and not a "cooling chamber" as propounded by Aristotle Herophilus is also credited with describing the optic, oculomotor, motor division of the trigeminal, facial, vestibulocochlear and hypoglossal nerves.
Incredible feats were made during the third century BCE in both the digestive and reproductive systems. Herophilus discovered and described not only the salivary glands but also the small intestine and liver. He showed that the uterus is a hollow organ and described the ovaries and uterine tubes. He recognized that spermatozoa were produced by the testes and was the first to identify the prostate gland.
The anatomy of the muscles and skeleton is described in the Hippocratic Corpus, an Ancient Greek medical work written by unknown authors. Aristotle described vertebrate anatomy based on animal dissection. Praxagoras identified the difference between arteries and veins. Also in the 4th century BCE, Herophilos and Erasistratus produced more accurate anatomical descriptions based on vivisection of criminals in Alexandria during the Ptolemaic period.
In the 2nd century, Galen of Pergamum, an anatomist, clinician, writer, and philosopher, wrote the final and highly influential anatomy treatise of ancient times. He compiled existing knowledge and studied anatomy through the dissection of animals. He was one of the first experimental physiologists through his vivisection experiments on animals. Galen's drawings, based mostly on dog anatomy, became effectively the only anatomical textbook for the next thousand years. His work was known to Renaissance doctors only through Islamic Golden Age medicine until it was translated from Greek sometime in the 15th century.
=== Medieval to early modern ===
Anatomy developed little from classical times until the sixteenth century; as the historian Marie Boas writes, "Progress in anatomy before the sixteenth century is as mysteriously slow as its development after 1500 is startlingly rapid".: 120–121 Between 1275 and 1326, the anatomists Mondino de Luzzi, Alessandro Achillini and Antonio Benivieni at Bologna carried out the first systematic human dissections since ancient times. Mondino's Anatomy of 1316 was the first textbook in the medieval rediscovery of human anatomy. It describes the body in the order followed in Mondino's dissections, starting with the abdomen, thorax, head, and limbs. It was the standard anatomy textbook for the next century.
Leonardo da Vinci (1452–1519) was trained in anatomy by Andrea del Verrocchio. He made use of his anatomical knowledge in his artwork, making many sketches of skeletal structures, muscles and organs of humans and other vertebrates that he dissected.
Andreas Vesalius (1514–1564), professor of anatomy at the University of Padua, is considered the founder of modern human anatomy. Originally from Brabant, Vesalius published the influential book De humani corporis fabrica ("the structure of the human body"), a large format book in seven volumes, in 1543. The accurate and intricately detailed illustrations, often in allegorical poses against Italianate landscapes, are thought to have been made by the artist Jan van Calcar, a pupil of Titian.
In England, anatomy was the subject of the first public lectures given in any science; these were provided by the Company of Barbers and Surgeons in the 16th century, joined in 1583 by the Lumleian lectures in surgery at the Royal College of Physicians.
=== Late modern ===
Medical schools began to be set up in the United States towards the end of the 18th century. Classes in anatomy needed a continual stream of cadavers for dissection, and these were difficult to obtain. Philadelphia, Baltimore, and New York were all renowned for body snatching activity as criminals raided graveyards at night, removing newly buried corpses from their coffins. A similar problem existed in Britain where demand for bodies became so great that grave-raiding and even anatomy murder were practised to obtain cadavers. Some graveyards were, in consequence, protected with watchtowers. The practice was halted in Britain by the Anatomy Act of 1832, while in the United States, similar legislation was enacted after the physician William S. Forbes of Jefferson Medical College was found guilty in 1882 of "complicity with resurrectionists in the despoliation of graves in Lebanon Cemetery".
The teaching of anatomy in Britain was transformed by Sir John Struthers, Regius Professor of Anatomy at the University of Aberdeen from 1863 to 1889. He was responsible for setting up the system of three years of "pre-clinical" academic teaching in the sciences underlying medicine, including especially anatomy. This system lasted until the reform of medical training in 1993 and 2003. As well as teaching, he collected many vertebrate skeletons for his museum of comparative anatomy, published over 70 research papers, and became famous for his public dissection of the Tay Whale. From 1822 the Royal College of Surgeons regulated the teaching of anatomy in medical schools. Medical museums provided examples in comparative anatomy, and were often used in teaching. Ignaz Semmelweis investigated puerperal fever and he discovered how it was caused. He noticed that the frequently fatal fever occurred more often in mothers examined by medical students than by midwives. The students went from the dissecting room to the hospital ward and examined women in childbirth. Semmelweis showed that when the trainees washed their hands in chlorinated lime before each clinical examination, the incidence of puerperal fever among the mothers could be reduced dramatically.
Before the modern medical era, the primary means for studying the internal structures of the body were dissection of the dead and inspection, palpation, and auscultation of the living. The advent of microscopy opened up an understanding of the building blocks that constituted living tissues. Technical advances in the development of achromatic lenses increased the resolving power of the microscope, and around 1839, Matthias Jakob Schleiden and Theodor Schwann identified that cells were the fundamental unit of organization of all living things. The study of small structures involved passing light through them, and the microtome was invented to provide sufficiently thin slices of tissue to examine. Staining techniques using artificial dyes were established to help distinguish between different tissue types. Advances in the fields of histology and cytology began in the late 19th century along with advances in surgical techniques allowing for the painless and safe removal of biopsy specimens. The invention of the electron microscope brought a significant advance in resolution power and allowed research into the ultrastructure of cells and the organelles and other structures within them. About the same time, in the 1950s, the use of X-ray diffraction for studying the crystal structures of proteins, nucleic acids, and other biological molecules gave rise to a new field of molecular anatomy.
Equally important advances have occurred in non-invasive techniques for examining the body's interior structures. X-rays can be passed through the body and used in medical radiography and fluoroscopy to differentiate interior structures that have varying degrees of opaqueness. Magnetic resonance imaging, computed tomography, and ultrasound imaging have all enabled the examination of internal structures in unprecedented detail to a degree far beyond the imagination of earlier generations.
== See also ==
Anatomical model
Bibliography of biology § Anatomy
Outline of human anatomy
Plastination
Evelyn tables
Anatomy portal
== References ==
== External links ==
Anatomy, In Our Time. BBC Radio 4. Melvyn Bragg with guests Ruth Richardson, Andrew Cunningham and Harold Ellis.
"Anatomy of the Human Body". 20th edition. 1918. Henry Gray
Parsons, Frederick Gymer (1911). "Anatomy" . Encyclopædia Britannica. Vol. 1 (11th ed.). pp. 920–943.
Anatomia Collection: anatomical plates 1522 to 1867 (digitized books and images)
Lyman, Henry Munson. The Book of Health (1898). Science History Institute Digital Collections Archived 2 February 2019 at the Wayback Machine.
Gunther von Hagens True Anatomy for New Ways of Teaching.
== Sources ==
This article incorporates text from a free content work. Licensed under CC BY 4.0. Text taken from Openstax Anatomy and Physiology, J. Gordon Betts et al, Openstax. | Wikipedia/anatomy |
Basic research, also called pure research, fundamental research, basic science, or pure science, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenomena. In contrast, applied research uses scientific theories to develop technology or techniques, which can be used to intervene and alter natural or other phenomena. Though often driven simply by curiosity, basic research often fuels the technological innovations of applied science. The two aims are often practiced simultaneously in coordinated research and development.
In addition to innovations, basic research serves to provide insights and public support of nature, possibly improving conservation efforts. Technological innovations may influence engineering concepts, such as the beak of a kingfisher influencing the design of a high-speed bullet train.
== Overview ==
Basic research advances fundamental knowledge about the world. It focuses on creating and refuting or supporting theories that explain observed phenomena. Pure research is the source of most new scientific ideas and ways of thinking about the world. It can be exploratory, descriptive, or explanatory; however, explanatory research is the most common.
Basic research generates new ideas, principles, and theories, which may not be immediately utilized but nonetheless form the basis of progress and development in different fields. Today's computers, for example, could not exist without research in pure mathematics conducted over a century ago, for which there was no known practical application at the time. Basic research rarely helps practitioners directly with their everyday concerns; nevertheless, it stimulates new ways of thinking that have the potential to revolutionize and dramatically improve how practitioners deal with a problem in the future.
== By country ==
In the United States, basic research is funded mainly by the federal government and done mainly at universities and institutes. As government funding has diminished in the 2010s, however, private funding is increasingly important.
== Basic versus applied science ==
Applied science focuses on the development of technology and techniques. In contrast, basic science develops scientific knowledge and predictions, principally in natural sciences but also in other empirical sciences, which are used as the scientific foundation for applied science. Basic science develops and establishes information to predict phenomena and perhaps to understand nature, whereas applied science uses portions of basic science to develop interventions via technology or technique to alter events or outcomes. Applied and basic sciences can interface closely in research and development. The interface between basic research and applied research has been studied by the National Science Foundation. A worker in basic scientific research is motivated by a driving curiosity about the unknown. When his explorations yield new knowledge, he experiences the satisfaction of those who first attain the summit of a mountain or the upper reaches of a river flowing through unmapped territory. Discovery of truth and understanding of nature are his objectives. His professional standing among his fellows depends upon the originality and soundness of his work. Creativeness in science is of a cloth with that of the poet or painter.It conducted a study in which it traced the relationship between basic scientific research efforts and the development of major innovations, such as oral contraceptives and videotape recorders. This study found that basic research played a key role in the development in all of the innovations. The number of basic science research that assisted in the production of a given innovation peaked between 20 and 30 years before the innovation itself. While most innovation takes the form of applied science and most innovation occurs in the private sector, basic research is a necessary precursor to almost all applied science and associated instances of innovation. Roughly 76% of basic research is conducted by universities.
A distinction can be made between basic science and disciplines such as medicine and technology. They can be grouped as STM (science, technology, and medicine; not to be confused with STEM [science, technology, engineering, and mathematics]) or STS (science, technology, and society). These groups are interrelated and influence each other, although they may differ in the specifics such as methods and standards.
The Nobel Prize mixes basic with applied sciences for its award in Physiology or Medicine. In contrast, the Royal Society of London awards distinguish natural science from applied science.
== See also ==
Blue skies research
Hard and soft science
Metascience
Normative science
Physics
Precautionary principle
Pure mathematics
Pure Chemistry
== References ==
== Further reading ==
Levy, David M. (2002). "Research and Development". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563 | Wikipedia/Basic_sciences |
Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, origin, evolution, and distribution of life. Central to biology are five fundamental themes: the cell as the basic unit of life, genes and heredity as the basis of inheritance, evolution as the driver of biological diversity, energy transformation for sustaining life processes, and the maintenance of internal stability (homeostasis).
Biology examines life across multiple levels of organization, from molecules and cells to organisms, populations, and ecosystems. Subdisciplines include molecular biology, physiology, ecology, evolutionary biology, developmental biology, and systematics, among others. Each of these fields applies a range of methods to investigate biological phenomena, including observation, experimentation, and mathematical modeling. Modern biology is grounded in the theory of evolution by natural selection, first articulated by Charles Darwin, and in the molecular understanding of genes encoded in DNA. The discovery of the structure of DNA and advances in molecular genetics have transformed many areas of biology, leading to applications in medicine, agriculture, biotechnology, and environmental science.
Life on Earth is believed to have originated over 3.7 billion years ago. Today, it includes a vast diversity of organisms—from single-celled archaea and bacteria to complex multicellular plants, fungi, and animals. Biologists classify organisms based on shared characteristics and evolutionary relationships, using taxonomic and phylogenetic frameworks. These organisms interact with each other and with their environments in ecosystems, where they play roles in energy flow and nutrient cycling. As a constantly evolving field, biology incorporates new discoveries and technologies that enhance the understanding of life and its processes, while contributing to solutions for challenges such as disease, climate change, and biodiversity loss.
== Etymology ==
From Greek bios, life, (from Proto-Indo-European root *gwei-, to live) and logy, study of. The compound was coined in 1800 by Karl Friedrich Burdach and in 1802 used by both German naturalist Gottfried Reinhold Treviranus and Jean-Baptiste Lamarck.
== History ==
The earliest of roots of science, which included medicine, can be traced to ancient Egypt and Mesopotamia in around 3000 to 1200 BCE. Their contributions shaped ancient Greek natural philosophy. Ancient Greek philosophers such as Aristotle (384–322 BCE) contributed extensively to the development of biological knowledge. He explored biological causation and the diversity of life. His successor, Theophrastus, began the scientific study of plants. Scholars of the medieval Islamic world who wrote on biology included al-Jahiz (781–869), Al-Dīnawarī (828–896), who wrote on botany, and Rhazes (865–925) who wrote on anatomy and physiology. Medicine was especially well studied by Islamic scholars working in Greek philosopher traditions, while natural history drew heavily on Aristotelian thought.
Biology began to quickly develop with Anton van Leeuwenhoek's dramatic improvement of the microscope. It was then that scholars discovered spermatozoa, bacteria, infusoria and the diversity of microscopic life. Investigations by Jan Swammerdam led to new interest in entomology and helped to develop techniques of microscopic dissection and staining. Advances in microscopy had a profound impact on biological thinking. In the early 19th century, biologists pointed to the central importance of the cell. In 1838, Schleiden and Schwann began promoting the now universal ideas that (1) the basic unit of organisms is the cell and (2) that individual cells have all the characteristics of life, although they opposed the idea that (3) all cells come from the division of other cells, continuing to support spontaneous generation. However, Robert Remak and Rudolf Virchow were able to reify the third tenet, and by the 1860s most biologists accepted all three tenets which consolidated into cell theory.
Meanwhile, taxonomy and classification became the focus of natural historians. Carl Linnaeus published a basic taxonomy for the natural world in 1735, and in the 1750s introduced scientific names for all his species. Georges-Louis Leclerc, Comte de Buffon, treated species as artificial categories and living forms as malleable—even suggesting the possibility of common descent.
Serious evolutionary thinking originated with the works of Jean-Baptiste Lamarck, who presented a coherent theory of evolution. The British naturalist Charles Darwin, combining the biogeographical approach of Humboldt, the uniformitarian geology of Lyell, Malthus's writings on population growth, and his own morphological expertise and extensive natural observations, forged a more successful evolutionary theory based on natural selection; similar reasoning and evidence led Alfred Russel Wallace to independently reach the same conclusions.
The basis for modern genetics began with the work of Gregor Mendel in 1865. This outlined the principles of biological inheritance. However, the significance of his work was not realized until the early 20th century when evolution became a unified theory as the modern synthesis reconciled Darwinian evolution with classical genetics. In the 1940s and early 1950s, a series of experiments by Alfred Hershey and Martha Chase pointed to DNA as the component of chromosomes that held the trait-carrying units that had become known as genes. A focus on new kinds of model organisms such as viruses and bacteria, along with the discovery of the double-helical structure of DNA by James Watson and Francis Crick in 1953, marked the transition to the era of molecular genetics. From the 1950s onwards, biology has been vastly extended in the molecular domain. The genetic code was cracked by Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg after DNA was understood to contain codons. The Human Genome Project was launched in 1990 to map the human genome.
== Chemical basis ==
=== Atoms and molecules ===
All organisms are made up of chemical elements; oxygen, carbon, hydrogen, and nitrogen account for most (96%) of the mass of all organisms, with calcium, phosphorus, sulfur, sodium, chlorine, and magnesium constituting essentially all the remainder. Different elements can combine to form compounds such as water, which is fundamental to life. Biochemistry is the study of chemical processes within and relating to living organisms. Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including molecular synthesis, modification, mechanisms, and interactions.
=== Water ===
Life arose from the Earth's first ocean, which formed some 3.8 billion years ago. Since then, water continues to be the most abundant molecule in every organism. Water is important to life because it is an effective solvent, capable of dissolving solutes such as sodium and chloride ions or other small molecules to form an aqueous solution. Once dissolved in water, these solutes are more likely to come in contact with one another and therefore take part in chemical reactions that sustain life. In terms of its molecular structure, water is a small polar molecule with a bent shape formed by the polar covalent bonds of two hydrogen (H) atoms to one oxygen (O) atom (H2O). Because the O–H bonds are polar, the oxygen atom has a slight negative charge and the two hydrogen atoms have a slight positive charge. This polar property of water allows it to attract other water molecules via hydrogen bonds, which makes water cohesive. Surface tension results from the cohesive force due to the attraction between molecules at the surface of the liquid. Water is also adhesive as it is able to adhere to the surface of any polar or charged non-water molecules. Water is denser as a liquid than it is as a solid (or ice). This unique property of water allows ice to float above liquid water such as ponds, lakes, and oceans, thereby insulating the liquid below from the cold air above. Water has the capacity to absorb energy, giving it a higher specific heat capacity than other solvents such as ethanol. Thus, a large amount of energy is needed to break the hydrogen bonds between water molecules to convert liquid water into water vapor. As a molecule, water is not completely stable as each water molecule continuously dissociates into hydrogen and hydroxyl ions before reforming into a water molecule again. In pure water, the number of hydrogen ions balances (or equals) the number of hydroxyl ions, resulting in a pH that is neutral.
=== Organic compounds ===
Organic compounds are molecules that contain carbon bonded to another element such as hydrogen. With the exception of water, nearly all the molecules that make up each organism contain carbon. Carbon can form covalent bonds with up to four other atoms, enabling it to form diverse, large, and complex molecules. For example, a single carbon atom can form four single covalent bonds such as in methane, two double covalent bonds such as in carbon dioxide (CO2), or a triple covalent bond such as in carbon monoxide (CO). Moreover, carbon can form very long chains of interconnecting carbon–carbon bonds such as octane or ring-like structures such as glucose.
The simplest form of an organic molecule is the hydrocarbon, which is a large family of organic compounds that are composed of hydrogen atoms bonded to a chain of carbon atoms. A hydrocarbon backbone can be substituted by other elements such as oxygen (O), hydrogen (H), phosphorus (P), and sulfur (S), which can change the chemical behavior of that compound. Groups of atoms that contain these elements (O-, H-, P-, and S-) and are bonded to a central carbon atom or skeleton are called functional groups. There are six prominent functional groups that can be found in organisms: amino group, carboxyl group, carbonyl group, hydroxyl group, phosphate group, and sulfhydryl group.
In 1953, the Miller–Urey experiment showed that organic compounds could be synthesized abiotically within a closed system mimicking the conditions of early Earth, thus suggesting that complex organic molecules could have arisen spontaneously in early Earth (see abiogenesis).
=== Macromolecules ===
Macromolecules are large molecules made up of smaller subunits or monomers. Monomers include sugars, amino acids, and nucleotides. Carbohydrates include monomers and polymers of sugars.
Lipids are the only class of macromolecules that are not made up of polymers. They include steroids, phospholipids, and fats, largely nonpolar and hydrophobic (water-repelling) substances.
Proteins are the most diverse of the macromolecules. They include enzymes, transport proteins, large signaling molecules, antibodies, and structural proteins. The basic unit (or monomer) of a protein is an amino acid. Twenty amino acids are used in proteins.
Nucleic acids are polymers of nucleotides. Their function is to store, transmit, and express hereditary information.
== Cells ==
Cell theory states that cells are the fundamental units of life, that all living things are composed of one or more cells, and that all cells arise from preexisting cells through cell division. Most cells are very small, with diameters ranging from 1 to 100 micrometers and are therefore only visible under a light or electron microscope. There are generally two types of cells: eukaryotic cells, which contain a nucleus, and prokaryotic cells, which do not. Prokaryotes are single-celled organisms such as bacteria, whereas eukaryotes can be single-celled or multicellular. In multicellular organisms, every cell in the organism's body is derived ultimately from a single cell in a fertilized egg.
=== Cell structure ===
Every cell is enclosed within a cell membrane that separates its cytoplasm from the extracellular space. A cell membrane consists of a lipid bilayer, including cholesterols that sit between phospholipids to maintain their fluidity at various temperatures. Cell membranes are semipermeable, allowing small molecules such as oxygen, carbon dioxide, and water to pass through while restricting the movement of larger molecules and charged particles such as ions. Cell membranes also contain membrane proteins, including integral membrane proteins that go across the membrane serving as membrane transporters, and peripheral proteins that loosely attach to the outer side of the cell membrane, acting as enzymes shaping the cell. Cell membranes are involved in various cellular processes such as cell adhesion, storing electrical energy, and cell signalling and serve as the attachment surface for several extracellular structures such as a cell wall, glycocalyx, and cytoskeleton.
Within the cytoplasm of a cell, there are many biomolecules such as proteins and nucleic acids. In addition to biomolecules, eukaryotic cells have specialized structures called organelles that have their own lipid bilayers or are spatially units. These organelles include the cell nucleus, which contains most of the cell's DNA, or mitochondria, which generate adenosine triphosphate (ATP) to power cellular processes. Other organelles such as endoplasmic reticulum and Golgi apparatus play a role in the synthesis and packaging of proteins, respectively. Biomolecules such as proteins can be engulfed by lysosomes, another specialized organelle. Plant cells have additional organelles that distinguish them from animal cells such as a cell wall that provides support for the plant cell, chloroplasts that harvest sunlight energy to produce sugar, and vacuoles that provide storage and structural support as well as being involved in reproduction and breakdown of plant seeds. Eukaryotic cells also have cytoskeleton that is made up of microtubules, intermediate filaments, and microfilaments, all of which provide support for the cell and are involved in the movement of the cell and its organelles. In terms of their structural composition, the microtubules are made up of tubulin (e.g., α-tubulin and β-tubulin) whereas intermediate filaments are made up of fibrous proteins. Microfilaments are made up of actin molecules that interact with other strands of proteins.
=== Metabolism ===
All cells require energy to sustain cellular processes. Metabolism is the set of chemical reactions in an organism. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; the conversion of food/fuel to monomer building blocks; and the elimination of metabolic wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolic reactions may be categorized as catabolic—the breaking down of compounds (for example, the breaking down of glucose to pyruvate by cellular respiration); or anabolic—the building up (synthesis) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy. The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts—they allow a reaction to proceed more rapidly without being consumed by it—by reducing the amount of activation energy needed to convert reactants into products. Enzymes also allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.
=== Cellular respiration ===
Cellular respiration is a set of metabolic reactions and processes that take place in cells to convert chemical energy from nutrients into adenosine triphosphate (ATP), and then release waste products. The reactions involved in respiration are catabolic reactions, which break large molecules into smaller ones, releasing energy. Respiration is one of the key ways a cell releases chemical energy to fuel cellular activity. The overall reaction occurs in a series of biochemical steps, some of which are redox reactions. Although cellular respiration is technically a combustion reaction, it clearly does not resemble one when it occurs in a cell because of the slow, controlled release of energy from the series of reactions.
Sugar in the form of glucose is the main nutrient used by animal and plant cells in respiration. Cellular respiration involving oxygen is called aerobic respiration, which has four stages: glycolysis, citric acid cycle (or Krebs cycle), electron transport chain, and oxidative phosphorylation. Glycolysis is a metabolic process that occurs in the cytoplasm whereby glucose is converted into two pyruvates, with two net molecules of ATP being produced at the same time. Each pyruvate is then oxidized into acetyl-CoA by the pyruvate dehydrogenase complex, which also generates NADH and carbon dioxide. Acetyl-CoA enters the citric acid cycle, which takes places inside the mitochondrial matrix. At the end of the cycle, the total yield from 1 glucose (or 2 pyruvates) is 6 NADH, 2 FADH2, and 2 ATP molecules. Finally, the next stage is oxidative phosphorylation, which in eukaryotes, occurs in the mitochondrial cristae. Oxidative phosphorylation comprises the electron transport chain, which is a series of four protein complexes that transfer electrons from one complex to another, thereby releasing energy from NADH and FADH2 that is coupled to the pumping of protons (hydrogen ions) across the inner mitochondrial membrane (chemiosmosis), which generates a proton motive force. Energy from the proton motive force drives the enzyme ATP synthase to synthesize more ATPs by phosphorylating ADPs. The transfer of electrons terminates with molecular oxygen being the final electron acceptor.
If oxygen were not present, pyruvate would not be metabolized by cellular respiration but undergoes a process of fermentation. The pyruvate is not transported into the mitochondrion but remains in the cytoplasm, where it is converted to waste products that may be removed from the cell. This serves the purpose of oxidizing the electron carriers so that they can perform glycolysis again and removing the excess pyruvate. Fermentation oxidizes NADH to NAD+ so it can be re-used in glycolysis. In the absence of oxygen, fermentation prevents the buildup of NADH in the cytoplasm and provides NAD+ for glycolysis. This waste product varies depending on the organism. In skeletal muscles, the waste product is lactic acid. This type of fermentation is called lactic acid fermentation. In strenuous exercise, when energy demands exceed energy supply, the respiratory chain cannot process all of the hydrogen atoms joined by NADH. During anaerobic glycolysis, NAD+ regenerates when pairs of hydrogen combine with pyruvate to form lactate. Lactate formation is catalyzed by lactate dehydrogenase in a reversible reaction. Lactate can also be used as an indirect precursor for liver glycogen. During recovery, when oxygen becomes available, NAD+ attaches to hydrogen from lactate to form ATP. In yeast, the waste products are ethanol and carbon dioxide. This type of fermentation is known as alcoholic or ethanol fermentation. The ATP generated in this process is made by substrate-level phosphorylation, which does not require oxygen.
=== Photosynthesis ===
Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that can later be released to fuel the organism's metabolic activities via cellular respiration. This chemical energy is stored in carbohydrate molecules, such as sugars, which are synthesized from carbon dioxide and water. In most cases, oxygen is released as a waste product. Most plants, algae, and cyanobacteria perform photosynthesis, which is largely responsible for producing and maintaining the oxygen content of the Earth's atmosphere, and supplies most of the energy necessary for life on Earth.
Photosynthesis has four stages: Light absorption, electron transport, ATP synthesis, and carbon fixation. Light absorption is the initial step of photosynthesis whereby light energy is absorbed by chlorophyll pigments attached to proteins in the thylakoid membranes. The absorbed light energy is used to remove electrons from a donor (water) to a primary electron acceptor, a quinone designated as Q. In the second stage, electrons move from the quinone primary electron acceptor through a series of electron carriers until they reach a final electron acceptor, which is usually the oxidized form of NADP+, which is reduced to NADPH, a process that takes place in a protein complex called photosystem I (PSI). The transport of electrons is coupled to the movement of protons (or hydrogen) from the stroma to the thylakoid membrane, which forms a pH gradient across the membrane as hydrogen becomes more concentrated in the lumen than in the stroma. This is analogous to the proton-motive force generated across the inner mitochondrial membrane in aerobic respiration.
During the third stage of photosynthesis, the movement of protons down their concentration gradients from the thylakoid lumen to the stroma through the ATP synthase is coupled to the synthesis of ATP by that same ATP synthase. The NADPH and ATPs generated by the light-dependent reactions in the second and third stages, respectively, provide the energy and electrons to drive the synthesis of glucose by fixing atmospheric carbon dioxide into existing organic carbon compounds, such as ribulose bisphosphate (RuBP) in a sequence of light-independent (or dark) reactions called the Calvin cycle.
=== Cell signaling ===
Cell signaling (or communication) is the ability of cells to receive, process, and transmit signals with its environment and with itself. Signals can be non-chemical such as light, electrical impulses, and heat, or chemical signals (or ligands) that interact with receptors, which can be found embedded in the cell membrane of another cell or located deep inside a cell. There are generally four types of chemical signals: autocrine, paracrine, juxtacrine, and hormones. In autocrine signaling, the ligand affects the same cell that releases it. Tumor cells, for example, can reproduce uncontrollably because they release signals that initiate their own self-division. In paracrine signaling, the ligand diffuses to nearby cells and affects them. For example, brain cells called neurons release ligands called neurotransmitters that diffuse across a synaptic cleft to bind with a receptor on an adjacent cell such as another neuron or muscle cell. In juxtacrine signaling, there is direct contact between the signaling and responding cells. Finally, hormones are ligands that travel through the circulatory systems of animals or vascular systems of plants to reach their target cells. Once a ligand binds with a receptor, it can influence the behavior of another cell, depending on the type of receptor. For instance, neurotransmitters that bind with an inotropic receptor can alter the excitability of a target cell. Other types of receptors include protein kinase receptors (e.g., receptor for the hormone insulin) and G protein-coupled receptors. Activation of G protein-coupled receptors can initiate second messenger cascades. The process by which a chemical or physical signal is transmitted through a cell as a series of molecular events is called signal transduction.
=== Cell cycle ===
The cell cycle is a series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and the subsequent partitioning of its cytoplasm into two daughter cells in a process called cell division. In eukaryotes (i.e., animal, plant, fungal, and protist cells), there are two distinct types of cell division: mitosis and meiosis. Mitosis is part of the cell cycle, in which replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis (division of the nucleus) is preceded by the S stage of interphase (during which the DNA is replicated) and is often followed by telophase and cytokinesis; which divides the cytoplasm, organelles and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the mitotic phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. The cell cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed. After cell division, each of the daughter cells begin the interphase of a new cycle. In contrast to mitosis, meiosis results in four haploid daughter cells by undergoing one round of DNA replication followed by two divisions. Homologous chromosomes are separated in the first division (meiosis I), and sister chromatids are separated in the second division (meiosis II). Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.
Prokaryotes (i.e., archaea and bacteria) can also undergo cell division (or binary fission). Unlike the processes of mitosis and meiosis in eukaryotes, binary fission in prokaryotes takes place without the formation of a spindle apparatus on the cell. Before binary fission, DNA in the bacterium is tightly coiled. After it has uncoiled and duplicated, it is pulled to the separate poles of the bacterium as it increases the size to prepare for splitting. Growth of a new cell wall begins to separate the bacterium (triggered by FtsZ polymerization and "Z-ring" formation). The new cell wall (septum) fully develops, resulting in the complete split of the bacterium. The new daughter cells have tightly coiled DNA rods, ribosomes, and plasmids.
=== Sexual reproduction and meiosis ===
Meiosis is a central feature of sexual reproduction in eukaryotes, and the most fundamental function of meiosis appears to be conservation of the integrity of the genome that is passed on to progeny by parents. Two aspects of sexual reproduction, meiotic recombination and outcrossing, are likely maintained respectively by the adaptive advantages of recombinational repair of genomic DNA damage and genetic complementation which masks the expression of deleterious recessive mutations.
The beneficial effect of genetic complementation, derived from outcrossing (cross-fertilization) is also referred to as hybrid vigor or heterosis. Charles Darwin in his 1878 book The Effects of Cross and Self-Fertilization in the Vegetable Kingdom at the start of chapter XII noted “The first and most important of the conclusions which may be drawn from the observations given in this volume, is that generally cross-fertilisation is beneficial and self-fertilisation often injurious, at least with the plants on which I experimented.” Genetic variation, often produced as a byproduct of sexual reproduction, may provide long-term advantages to those sexual lineages that engage in outcrossing.
== Genetics ==
=== Inheritance ===
Genetics is the scientific study of inheritance. Mendelian inheritance, specifically, is the process by which genes and traits are passed on from parents to offspring. It has several principles. The first is that genetic characteristics, alleles, are discrete and have alternate forms (e.g., purple vs. white or tall vs. dwarf), each inherited from one of two parents. Based on the law of dominance and uniformity, which states that some alleles are dominant while others are recessive; an organism with at least one dominant allele will display the phenotype of that dominant allele. During gamete formation, the alleles for each gene segregate, so that each gamete carries only one allele for each gene. Heterozygotic individuals produce gametes with an equal frequency of two alleles. Finally, the law of independent assortment, states that genes of different traits can segregate independently during the formation of gametes, i.e., genes are unlinked. An exception to this rule would include traits that are sex-linked. Test crosses can be performed to experimentally determine the underlying genotype of an organism with a dominant phenotype. A Punnett square can be used to predict the results of a test cross. The chromosome theory of inheritance, which states that genes are found on chromosomes, was supported by Thomas Morgans's experiments with fruit flies, which established the sex linkage between eye color and sex in these insects.
=== Genes and DNA ===
A gene is a unit of heredity that corresponds to a region of deoxyribonucleic acid (DNA) that carries genetic information that controls form or function of an organism. DNA is composed of two polynucleotide chains that coil around each other to form a double helix. It is found as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell is collectively known as its genome. In eukaryotes, DNA is mainly in the cell nucleus. In prokaryotes, the DNA is held within the nucleoid. The genetic information is held within genes, and the complete assemblage in an organism is called its genotype.
DNA replication is a semiconservative process whereby each strand serves as a template for a new strand of DNA. Mutations are heritable changes in DNA. They can arise spontaneously as a result of replication errors that were not corrected by proofreading or can be induced by an environmental mutagen such as a chemical (e.g., nitrous acid, benzopyrene) or radiation (e.g., x-ray, gamma ray, ultraviolet radiation, particles emitted by unstable isotopes). Mutations can lead to phenotypic effects such as loss-of-function, gain-of-function, and conditional mutations.
Some mutations are beneficial, as they are a source of genetic variation for evolution. Others are harmful if they were to result in a loss of function of genes needed for survival.
=== Gene expression ===
Gene expression is the molecular process by which a genotype encoded in DNA gives rise to an observable phenotype in the proteins of an organism's body. This process is summarized by the central dogma of molecular biology, which was formulated by Francis Crick in 1958. According to the Central Dogma, genetic information flows from DNA to RNA to protein. There are two gene expression processes: transcription (DNA to RNA) and translation (RNA to protein).
=== Gene regulation ===
The regulation of gene expression by environmental factors and during different stages of development can occur at each step of the process such as transcription, RNA splicing, translation, and post-translational modification of a protein. Gene expression can be influenced by positive or negative regulation, depending on which of the two types of regulatory proteins called transcription factors bind to the DNA sequence close to or at a promoter. A cluster of genes that share the same promoter is called an operon, found mainly in prokaryotes and some lower eukaryotes (e.g., Caenorhabditis elegans). In positive regulation of gene expression, the activator is the transcription factor that stimulates transcription when it binds to the sequence near or at the promoter. Negative regulation occurs when another transcription factor called a repressor binds to a DNA sequence called an operator, which is part of an operon, to prevent transcription. Repressors can be inhibited by compounds called inducers (e.g., allolactose), thereby allowing transcription to occur. Specific genes that can be activated by inducers are called inducible genes, in contrast to constitutive genes that are almost constantly active. In contrast to both, structural genes encode proteins that are not involved in gene regulation. In addition to regulatory events involving the promoter, gene expression can also be regulated by epigenetic changes to chromatin, which is a complex of DNA and protein found in eukaryotic cells.
=== Genes, development, and evolution ===
Development is the process by which a multicellular organism (plant or animal) goes through a series of changes, starting from a single cell, and taking on various forms that are characteristic of its life cycle. There are four key processes that underlie development: Determination, differentiation, morphogenesis, and growth. Determination sets the developmental fate of a cell, which becomes more restrictive during development. Differentiation is the process by which specialized cells arise from less specialized cells such as stem cells. Stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. Cellular differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals, which are largely due to highly controlled modifications in gene expression and epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Thus, different cells can have very different physical characteristics despite having the same genome. Morphogenesis, or the development of body form, is the result of spatial differences in gene expression. A small fraction of the genes in an organism's genome called the developmental-genetic toolkit control the development of that organism. These toolkit genes are highly conserved among phyla, meaning that they are ancient and very similar in widely separated groups of animals. Differences in deployment of toolkit genes affect the body plan and the number, identity, and pattern of body parts. Among the most important toolkit genes are the Hox genes. Hox genes determine where repeating parts, such as the many vertebrae of snakes, will grow in a developing embryo or larva.
== Evolution ==
=== Evolutionary processes ===
Evolution is a central organizing concept in biology. It is the change in heritable characteristics of populations over successive generations. In artificial selection, animals were selectively bred for specific traits.
Given that traits are inherited, populations contain a varied mix of traits, and reproduction is able to increase any population, Darwin argued that in the natural world, it was nature that played the role of humans in selecting for specific traits. Darwin inferred that individuals who possessed heritable traits better adapted to their environments are more likely to survive and produce more offspring than other individuals. He further inferred that this would lead to the accumulation of favorable traits over successive generations, thereby increasing the match between the organisms and their environment.
=== Speciation ===
A species is a group of organisms that mate with one another and speciation is the process by which one lineage splits into two lineages as a result of having evolved independently from each other. For speciation to occur, there has to be reproductive isolation. Reproductive isolation can result from incompatibilities between genes as described by Bateson–Dobzhansky–Muller model. Reproductive isolation also tends to increase with genetic divergence. Speciation can occur when there are physical barriers that divide an ancestral species, a process known as allopatric speciation.
=== Phylogeny ===
A phylogeny is an evolutionary history of a specific group of organisms or their genes. It can be represented using a phylogenetic tree, a diagram showing lines of descent among organisms or their genes. Each line drawn on the time axis of a tree represents a lineage of descendants of a particular species or population. When a lineage divides into two, it is represented as a fork or split on the phylogenetic tree. Phylogenetic trees are the basis for comparing and grouping different species. Different species that share a feature inherited from a common ancestor are described as having homologous features (or synapomorphy). Phylogeny provides the basis of biological classification. This classification system is rank-based, with the highest rank being the domain followed by kingdom, phylum, class, order, family, genus, and species. All organisms can be classified as belonging to one of three domains: Archaea (originally Archaebacteria), Bacteria (originally eubacteria), or Eukarya (includes the fungi, plant, and animal kingdoms).
=== History of life ===
The history of life on Earth traces how organisms have evolved from the earliest emergence of life to present day. Earth formed about 4.5 billion years ago and all life on Earth, both living and extinct, descended from a last universal common ancestor that lived about 3.5 billion years ago. Geologists have developed a geologic time scale that divides the history of the Earth into major divisions, starting with four eons (Hadean, Archean, Proterozoic, and Phanerozoic), the first three of which are collectively known as the Precambrian, which lasted approximately 4 billion years. Each eon can be divided into eras, with the Phanerozoic eon that began 539 million years ago being subdivided into Paleozoic, Mesozoic, and Cenozoic eras. These three eras together comprise eleven periods (Cambrian, Ordovician, Silurian, Devonian, Carboniferous, Permian, Triassic, Jurassic, Cretaceous, Tertiary, and Quaternary).
The similarities among all known present-day species indicate that they have diverged through the process of evolution from their common ancestor. Biologists regard the ubiquity of the genetic code as evidence of universal common descent for all bacteria, archaea, and eukaryotes. Microbial mats of coexisting bacteria and archaea were the dominant form of life in the early Archean eon and many of the major steps in early evolution are thought to have taken place in this environment. The earliest evidence of eukaryotes dates from 1.85 billion years ago, and while they may have been present earlier, their diversification accelerated when they started using oxygen in their metabolism. Later, around 1.7 billion years ago, multicellular organisms began to appear, with differentiated cells performing specialised functions.
Algae-like multicellular land plants are dated back to about 1 billion years ago, although evidence suggests that microorganisms formed the earliest terrestrial ecosystems, at least 2.7 billion years ago. Microorganisms are thought to have paved the way for the inception of land plants in the Ordovician period. Land plants were so successful that they are thought to have contributed to the Late Devonian extinction event.
Ediacara biota appear during the Ediacaran period, while vertebrates, along with most other modern phyla originated about 525 million years ago during the Cambrian explosion. During the Permian period, synapsids, including the ancestors of mammals, dominated the land, but most of this group became extinct in the Permian–Triassic extinction event 252 million years ago. During the recovery from this catastrophe, archosaurs became the most abundant land vertebrates; one archosaur group, the dinosaurs, dominated the Jurassic and Cretaceous periods. After the Cretaceous–Paleogene extinction event 66 million years ago killed off the non-avian dinosaurs, mammals increased rapidly in size and diversity. Such mass extinctions may have accelerated evolution by providing opportunities for new groups of organisms to diversify.
== Diversity ==
=== Bacteria and Archaea ===
Bacteria are a type of cell that constitute a large domain of prokaryotic microorganisms. Typically a few micrometers in length, bacteria have a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, and are present in most of its habitats. Bacteria inhabit soil, water, acidic hot springs, radioactive waste, and the deep biosphere of the Earth's crust. Bacteria also live in symbiotic and parasitic relationships with plants and animals. Most bacteria have not been characterised, and only about 27 percent of the bacterial phyla have species that can be grown in the laboratory.
Archaea constitute the other domain of prokaryotic cells and were initially classified as bacteria, receiving the name archaebacteria (in the Archaebacteria kingdom), a term that has fallen out of use. Archaeal cells have unique properties separating them from the other two domains, Bacteria and Eukaryota. Archaea are further divided into multiple recognized phyla. Archaea and bacteria are generally similar in size and shape, although a few archaea have very different shapes, such as the flat and square cells of Haloquadratum walsbyi. Despite this morphological similarity to bacteria, archaea possess genes and several metabolic pathways that are more closely related to those of eukaryotes, notably for the enzymes involved in transcription and translation. Other aspects of archaeal biochemistry are unique, such as their reliance on ether lipids in their cell membranes, including archaeols. Archaea use more energy sources than eukaryotes: these range from organic compounds, such as sugars, to ammonia, metal ions or even hydrogen gas. Salt-tolerant archaea (the Haloarchaea) use sunlight as an energy source, and other species of archaea fix carbon, but unlike plants and cyanobacteria, no known species of archaea does both. Archaea reproduce asexually by binary fission, fragmentation, or budding; unlike bacteria, no known species of Archaea form endospores.
The first observed archaea were extremophiles, living in extreme environments, such as hot springs and salt lakes with no other organisms. Improved molecular detection tools led to the discovery of archaea in almost every habitat, including soil, oceans, and marshlands. Archaea are particularly numerous in the oceans, and the archaea in plankton may be one of the most abundant groups of organisms on the planet.
Archaea are a major part of Earth's life. They are part of the microbiota of all organisms. In the human microbiome, they are important in the gut, mouth, and on the skin. Their morphological, metabolic, and geographical diversity permits them to play multiple ecological roles: carbon fixation; nitrogen cycling; organic compound turnover; and maintaining microbial symbiotic and syntrophic communities, for example.
=== Eukaryotes ===
Eukaryotes are hypothesized to have split from archaea, which was followed by their endosymbioses with bacteria (or symbiogenesis) that gave rise to mitochondria and chloroplasts, both of which are now part of modern-day eukaryotic cells. The major lineages of eukaryotes diversified in the Precambrian about 1.5 billion years ago and can be classified into eight major clades: alveolates, excavates, stramenopiles, plants, rhizarians, amoebozoans, fungi, and animals. Five of these clades are collectively known as protists, which are mostly microscopic eukaryotic organisms that are not plants, fungi, or animals. While it is likely that protists share a common ancestor (the last eukaryotic common ancestor), protists by themselves do not constitute a separate clade as some protists may be more closely related to plants, fungi, or animals than they are to other protists. Like groupings such as algae, invertebrates, or protozoans, the protist grouping is not a formal taxonomic group but is used for convenience. Most protists are unicellular; these are called microbial eukaryotes.
Plants are mainly multicellular organisms, predominantly photosynthetic eukaryotes of the kingdom Plantae, which would exclude fungi and some algae. Plant cells were derived by endosymbiosis of a cyanobacterium into an early eukaryote about one billion years ago, which gave rise to chloroplasts. The first several clades that emerged following primary endosymbiosis were aquatic and most of the aquatic photosynthetic eukaryotic organisms are collectively described as algae, which is a term of convenience as not all algae are closely related. Algae comprise several distinct clades such as glaucophytes, which are microscopic freshwater algae that may have resembled in form to the early unicellular ancestor of Plantae. Unlike glaucophytes, the other algal clades such as red and green algae are multicellular. Green algae comprise three major clades: chlorophytes, coleochaetophytes, and stoneworts.
Fungi are eukaryotes that digest foods outside their bodies, secreting digestive enzymes that break down large food molecules before absorbing them through their cell membranes. Many fungi are also saprobes, feeding on dead organic matter, making them important decomposers in ecological systems.
Animals are multicellular eukaryotes. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and grow from a hollow sphere of cells, the blastula, during embryonic development. Over 1.5 million living animal species have been described—of which around 1 million are insects—but it has been estimated there are over 7 million animal species in total. They have complex interactions with each other and their environments, forming intricate food webs.
=== Viruses ===
Viruses are submicroscopic infectious agents that replicate inside the cells of organisms. Viruses infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea. More than 6,000 virus species have been described in detail. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity.
The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids—pieces of DNA that can move between cells—while others may have evolved from bacteria. In evolution, viruses are an important means of horizontal gene transfer, which increases genetic diversity in a way analogous to sexual reproduction. Because viruses possess some but not all characteristics of life, they have been described as "organisms at the edge of life", and as self-replicators.
== Ecology ==
Ecology is the study of the distribution and abundance of life, the interaction between organisms and their environment.
=== Ecosystems ===
The community of living (biotic) organisms in conjunction with the nonliving (abiotic) components (e.g., water, light, radiation, temperature, humidity, atmosphere, acidity, and soil) of their environment is called an ecosystem. These biotic and abiotic components are linked together through nutrient cycles and energy flows. Energy from the sun enters the system through photosynthesis and is incorporated into plant tissue. By feeding on plants and on one another, animals move matter and energy through the system. They also influence the quantity of plant and microbial biomass present. By breaking down dead organic matter, decomposers release carbon back to the atmosphere and facilitate nutrient cycling by converting nutrients stored in dead biomass back to a form that can be readily used by plants and other microbes.
=== Populations ===
A population is the group of organisms of the same species that occupies an area and reproduce from generation to generation. Population size can be estimated by multiplying population density by the area or volume. The carrying capacity of an environment is the maximum population size of a species that can be sustained by that specific environment, given the food, habitat, water, and other resources that are available. The carrying capacity of a population can be affected by changing environmental conditions such as changes in the availability of resources and the cost of maintaining them. In human populations, new technologies such as the Green revolution have helped increase the Earth's carrying capacity for humans over time, which has stymied the attempted predictions of impending population decline, the most famous of which was by Thomas Malthus in the 18th century.
=== Communities ===
A community is a group of populations of species occupying the same geographical area at the same time. A biological interaction is the effect that a pair of organisms living together in a community have on each other. They can be either of the same species (intraspecific interactions), or of different species (interspecific interactions). These effects may be short-term, like pollination and predation, or long-term; both often strongly influence the evolution of the species involved. A long-term interaction is called a symbiosis. Symbioses range from mutualism, beneficial to both partners, to competition, harmful to both partners. Every species participates as a consumer, resource, or both in consumer–resource interactions, which form the core of food chains or food webs. There are different trophic levels within any food web, with the lowest level being the primary producers (or autotrophs) such as plants and algae that convert energy and inorganic material into organic compounds, which can then be used by the rest of the community. At the next level are the heterotrophs, which are the species that obtain energy by breaking apart organic compounds from other organisms. Heterotrophs that consume plants are primary consumers (or herbivores) whereas heterotrophs that consume herbivores are secondary consumers (or carnivores). And those that eat secondary consumers are tertiary consumers and so on. Omnivorous heterotrophs are able to consume at multiple levels. Finally, there are decomposers that feed on the waste products or dead bodies of organisms.
On average, the total amount of energy incorporated into the biomass of a trophic level per unit of time is about one-tenth of the energy of the trophic level that it consumes. Waste and dead material used by decomposers as well as heat lost from metabolism make up the other ninety percent of energy that is not consumed by the next trophic level.
=== Biosphere ===
In the global ecosystem or biosphere, matter exists as different interacting compartments, which can be biotic or abiotic as well as accessible or inaccessible, depending on their forms and locations. For example, matter from terrestrial autotrophs are both biotic and accessible to other organisms whereas the matter in rocks and minerals are abiotic and inaccessible. A biogeochemical cycle is a pathway by which specific elements of matter are turned over or moved through the biotic (biosphere) and the abiotic (lithosphere, atmosphere, and hydrosphere) compartments of Earth. There are biogeochemical cycles for nitrogen, carbon, and water.
=== Conservation ===
Conservation biology is the study of the conservation of Earth's biodiversity with the aim of protecting species, their habitats, and ecosystems from excessive rates of extinction and the erosion of biotic interactions. It is concerned with factors that influence the maintenance, loss, and restoration of biodiversity and the science of sustaining evolutionary processes that engender genetic, population, species, and ecosystem diversity. The concern stems from estimates suggesting that up to 50% of all species on the planet will disappear within the next 50 years, which has contributed to poverty, starvation, and will reset the course of evolution on this planet. Biodiversity affects the functioning of ecosystems, which provide a variety of services upon which people depend. Conservation biologists research and educate on the trends of biodiversity loss, species extinctions, and the negative effect these are having on our capabilities to sustain the well-being of human society. Organizations and citizens are responding to the current biodiversity crisis through conservation action plans that direct research, monitoring, and education programs that engage concerns at local through global scales.
== See also ==
== References ==
== Further reading ==
== External links ==
OSU's Phylocode
Biology Online – Wiki Dictionary
MIT video lecture series on biology
OneZoom Tree of Life
Journal of the History of Biology (springer.com)
Journal links
PLOS ONE
PLOS Biology A peer-reviewed, open-access journal published by the Public Library of Science
Current Biology: General journal publishing original research from all areas of biology
Biology Letters: A high-impact Royal Society journal publishing peer-reviewed biology papers of general interest
Science: Internationally renowned AAAS science journal – see sections of the life sciences
International Journal of Biological Sciences: A biological journal publishing significant peer-reviewed scientific papers
Perspectives in Biology and Medicine: An interdisciplinary scholarly journal publishing essays of broad relevance | Wikipedia/Biological_sciences |
An anatomical model is a three-dimensional representation of human or animal anatomy, used for medical and biological education. From the 16th to the 19th century, the most prominent models were made from wax. These techniques were developed partly from a shortage of cadavers due to religious objections to their use by anatomists. The use of these models declined with the use of cadavers in modern medical instruction. Digital anatomical models have been created by scanning microscopically sliced human bodies.
== The evolution of materials and models ==
=== Paper ===
Books with anatomical illustrations were extended by innovations such as flaps. The oldest anatomical work of this kind was produced by Heinrich Vogtherr in 1538. Andreas Vesalius published De Humani Corporis Fabrica (“On the fabric of the human body”) and the Epitome in 1543. The Epitome, allowed students to cut parts of the illustrations to produce their own layered anatomical model. Johann Remmelin produced a flap book Catoptrum Microcosmicum in 1619.
=== Wax ===
Among the earliest anatomical models was the Écorché made by Ludovico Cardi around 1600. This was widely copied and became a model and inspiration for further anatomical models. By the end of the 17th century the first anatomical wax models were produced by artists like Gaetano Giulio Zumbo collaborating with the anatomist Guillaume Desnoues. The growth of anatomical instruction and medical education in Italy led to more work on models. Noted artist included Giovanni Manzolini and his wife Anna Morandi working in Bologna which became a centre for the development of the art. Joseph Towne (1808–1879) was one of the few who attempted similar work in England. In the 19th century reclining models of women meant for medical instruction came to be called "Venuses" after Venus de Medici, typically showing a fetus in position. Other Italian artists included Clemente Susini (1754–1814), Ercole Lelli (1702–1766), Giuseppe Astorri (1795–1852), and Francesco Calenzuoli (1796–1829). In Germany Rudolf Weisker began an Institute for Wax Modelling (Institut für Wachsbildnerei) in Leipzig. These developed wax models beyond humans into the zoological domain. Gustav Zeiller (1826-1904) worked with the anatomists Carl Bogislaus Reichert, Johannes Müller, Friedrich Theodor von Frerichs, or Emil Du Bois-Reymond while his brother Paul Zeiller (1820–1893) worked with Michael Erd in Munich. Paul Zeiller and his wife Franziska also protested the use of dissections in anatomical teaching. Wax models went into decline at the end of the 19th century.
The model may show the anatomy partially dissected, or have removable parts allowing the student to remove and inspect the modelled body parts. Some models may have changeable genital inserts and other interchangeable parts which permit a unisex model to represent an individual of either sex.
=== Digital ===
One of the first computational models was through the ADAM project. Although 3D computer models of anatomy now exist as an alternative, physical anatomical models still have advantages in providing insight into anatomy.
== See also ==
Anatomy
Visible Human Project
Comparative anatomy
Mannequin § Medical education
== References ==
== External links ==
Media related to Anatomical models at Wikimedia Commons | Wikipedia/Anatomical_model |
Echidnas (), sometimes known as spiny anteaters, are quill-covered monotremes (egg-laying mammals) belonging to the family Tachyglossidae , living in Australia and New Guinea. The four extant species of echidnas and the platypus are the only living mammals that lay eggs and the only surviving members of the order Monotremata. The diet of some species consists of ants and termites, but they are not closely related to the American true anteaters or to hedgehogs. Their young are called puggles.
Echidnas evolved between 20 and 50 million years ago, descending from a platypus-like monotreme. This ancestor was aquatic, but echidnas adapted to life on land, where a single individual can move seven tons of soil each year, making them important for the environment.
== Etymology ==
Echidnas are possibly named after Echidna, a creature from Greek mythology who was half-woman, half-snake, as the animal was perceived to have qualities of both mammals and reptiles.
An alternative explanation is a confusion with Ancient Greek: ἐχῖνος, romanized: ekhînos, lit. 'hedgehog, sea urchin'.
== Physical characteristics ==
Echidnas are medium-sized, solitary mammals covered with coarse hair and spines. The spines are modified hairs and are made of keratin, the same fibrous protein that makes up fur, claws, nails, and horn sheaths in animals.
Superficially, they resemble the anteaters of South America and other spiny mammals such as hedgehogs and porcupines. They are usually black or brown in coloration. There have been several reports of albino echidnas with pink eyes and white spines. They have elongated and slender snouts, or proboscises, that function as both mouth and nose, and which have electrosensors to find earthworms, termites, ants, and other burrowing prey. This is similar to the platypus, which has 40,000 electroreceptors on its bill, but the long-beaked echidna has only 2,000, while the short-beaked echidna, which lives in a drier environment, has no more than 400 at the tip of its snout.
Echidnas have short, strong limbs with large claws, and are powerful diggers. Their hind claws are elongated and curved backwards to aid in digging. Echidnas have tiny mouths and toothless jaws, and feed by tearing open soft logs, anthills and the like, and licking off prey with their long, sticky tongues. The ears are slits on the sides of their heads under the spines. The external ear is created by a large cartilaginous funnel, deep in the muscle. At 33 °C (91.4 °F), echidnas also possess the second-lowest active body temperature of all mammals, behind the platypus.
Despite their appearance, echidnas are capable swimmers, as they evolved from platypus-like ancestors. When swimming, they expose their snout and some of their spines, and are known to journey to water to bathe.
The first European drawing of an echidna was made in Adventure Bay, Tasmania by HMS Providence's third lieutenant George Tobin during William Bligh's second breadfruit voyage.
== Diet ==
The short-beaked echidna's diet consists mostly of ants and termites, while the Zaglossus (long-beaked) species typically eat worms and insect larvae. The tongues of long-beaked echidnas have sharp, tiny spines that help them capture their prey. They have no teeth, so they break down their food by grinding it between the bottoms of their mouths and their tongues. Echidnas' faeces are 7 cm (3 in) long and are cylindrical in shape; they are usually broken and unrounded, and composed largely of dirt and ant-hill material.
Like all mammals, echidnas feed their young on milk, which contains various factors to sustain their growth and development.
== Habitat ==
Echidnas do not tolerate extreme temperatures; they shelter from harsh weather in caves and rock crevices. Echidnas are found in forests and woodlands, hiding under vegetation, roots or piles of debris. They sometimes use the burrows (both abandoned and in use) of animals such as rabbits and wombats. Individual echidnas have large, mutually overlapping territories.
== Anatomy ==
Echidnas and platypuses are the only egg-laying mammals, the monotremes.
The average lifespan of an echidna in the wild is estimated at 14–16 years. Fully grown females can weigh about 4.5 kilograms (9.9 lb), the males 33% larger, at about 6 kilograms (13 lb). Though the internal reproductive organs differ, both sexes possess an identical single cloaca opening for urination, defecation, and mating.
Male echidnas have non-venomous spurs on the hind feet, similar to the venomous male platypus.
Due to their low metabolism and accompanying stress resistance, echidnas are long-lived for their size; the longest recorded lifespan for a captive echidna is 50 years, with anecdotal accounts of wild individuals reaching 45 years.
The echidna's brain is half neocortex, compared to 80% of a human brain. Contrary to previous research, the echidna does enter REM sleep, but only in a comfortable temperature around 25 °C (77 °F). At lower or higher temperatures of 15 °C (59 °F) and 28 °C (82 °F), REM sleep is suppressed.
== Reproduction ==
The female lays a single soft-shelled, leathery egg 22 days after mating, and deposits it directly into her pouch. An egg weighs 1.5 to 2 grams (0.05 to 0.07 oz) and is about 1.4 centimetres (0.55 in) long. While hatching, the baby echidna opens the leather shell with a reptile-like egg tooth. Hatching takes place after 10 days of gestation; the young echidna, called a puggle, born larval and fetus-like, then sucks milk from the pores of the two milk patches (monotremes have no teats) and remains in the pouch for 45 to 55 days, at which time it starts to develop spines. The mother digs a nursery burrow and deposits the young, returning every five days to suckle it until it is weaned at seven months. Puggles will stay within their mother's den for up to a year before leaving.Male echidnas have a four-headed penis. During mating, the heads on one side "shut down" and do not grow in size; the other two are used to release semen into the female's two-branched reproductive tract. Each time it copulates, it alternates heads in sets of two. When not in use, the penis is retracted inside a preputial sac in the cloaca. The male echidna's penis is 7 centimetres (2.8 in) long when erect, and its shaft is covered with penile spines. These may be used to induce ovulation in the female.
It is a challenge to study the echidna in its natural habitat, and they show no interest in mating while in captivity. Prior to 2007, no one had ever seen an echidna ejaculate. There have been previous attempts, trying to force the echidna to ejaculate through the use of electrically stimulated ejaculation in order to obtain semen samples but this has only resulted in the penis swelling.
Breeding season begins in late June and extends through September. During mating season, a female may be followed by a line or "train" of up to ten males, the youngest trailing last, and some males switching between lines.
== Threats ==
Echidnas are very timid. When frightened, they attempt to partially bury themselves and curl into a ball similar to a hedgehog. Strong front arms allow echidnas to dig in and hold fast against a predator pulling them from the hole.
Their many predators include feral cats, foxes, domestic dogs, and goannas. Snakes pose a large threat when they slither into echidna burrows and prey on the spineless young puggles.
They are easily stressed and injured by handling. Some ways to help echidnas include picking up litter, causing less pollution, planting vegetation for shelter, supervising pets, reporting hurt echidnas, and leaving them undisturbed.
In June 2024, scientists reported a first-of-its-kind encounter when they witnessed a tiger shark regurgitating a whole echidna off the cost of an island near Australia. Sharks are known to eat a wide range of animals, and occasionally objects, according to a news release by the researchers from James Cook University in North Queensland who also noted that sharks had previously been observed eating rocks for no apparent reason.
== Evolution ==
The divergence between oviparous (egg-laying) and viviparous (offspring develop internally) mammals is believed to date to the Triassic period. Most findings from genetics studies (especially of nuclear genes) are in agreement with the paleontological dating, but some other evidence, like mitochondrial DNA, give slightly different dates.
Molecular clock data suggest echidnas split from platypuses between 19 and 48 million years ago, so that platypus-like fossils dating back to over 112.5 million years ago represent basal forms, rather than close relatives of the modern platypus. This would imply that echidnas evolved from water-foraging ancestors that returned to land living, which put them in competition with marsupials. Although extant monotremes lack adult teeth (platypuses have teeth only as juveniles), many extinct monotreme species have been identified based on the morphology of their teeth. Of the eight genes involved in tooth development, four have been lost in both platypus and echidna, indicating that the loss of teeth occurred before the echidna-platypus split.
Further evidence of water-foraging ancestors can be found in some of the echidna's anatomy, including hydrodynamic streamlining, dorsally projecting hind limbs acting as rudders, and locomotion founded on hypertrophied humeral long-axis rotation, which provides an efficient swimming stroke.
Oviparous reproduction in monotremes may give them an advantage over marsupials in some environments. Their observed adaptive radiation contradicts the assumption that monotremes are frozen in morphological and molecular evolution.
It has been suggested that echidnas originally evolved in New Guinea when it was isolated from Australia and from marsupials. This would explain their rarity in the fossil record, their abundance in present times in New Guinea, and their original adaptation to terrestrial niches, presumably without competition from marsupials.
== Taxonomy ==
Echidnas are a small clade with two extant genera and four species. The genus Zaglossus includes three extant and two fossil species, with only one extant species from the genus Tachyglossus.
=== Zaglossus ===
The three living Zaglossus species are endemic to New Guinea. They are rare and are hunted for food. They forage in leaf litter on the forest floor, eating earthworms and insects. The species are
Western long-beaked echidna (Z. bruijni), of the highland forests;
Sir David's long-beaked echidna (Z. attenboroughi), discovered by Western science in 1961 (described in 1998) and preferring a still higher habitat;
Eastern long-beaked echidna (Z. bartoni), of which four distinct subspecies have been identified.
=== Tachyglossus ===
The short-beaked echidna (Tachyglossus aculeatus) is found in southern, southeast and northeast New Guinea, and also occurs in almost all Australian environments, from the snow-clad Australian Alps to the deep deserts of the Outback, essentially anywhere ants and termites are available. It is smaller than the Zaglossus species, and it has longer hair.
Despite the similar dietary habits and methods of consumption to those of an anteater, there is no evidence supporting the idea that echidna-like monotremes have been myrmecophagic (ant or termite-eating) since the Cretaceous. The fossil evidence of invertebrate-feeding bandicoots and rat-kangaroos, from around the time of the platypus–echidna divergence and pre-dating Tachyglossus, show evidence that echidnas expanded into new ecospace despite competition from marsupials.
Additionally, extinct echidnas continue to be described by taxonomists;
=== Megalibgwilia ===
The genus Megalibgwilia is known only from fossils:
M. owenii from Late Pleistocene sites in Australia;
M. robusta from Pliocene sites in Australia.
=== Murrayglossus ===
The genus Murrayglossus is known only from fossils:
M. hacketti (previously classified in the genus Zaglossus) from Pleistocene of Western Australia.
== As food ==
The Kunwinjku people of Western Arnhem Land (Australia) call the echidna ngarrbek, and regard it as a prized food and "good medicine". The echidna is hunted at night, gutted, and filled with hot stones and mandak (Persoonia falcata) leaves. According to Larrakia elders Una Thompson and Stephanie Thompson Nganjmirra, once captured, an echidna is carried attached to the wrist like a thick bangle.
== In popular culture ==
The echidna appears on the reverse of the Australian five-cent coin.
An echidna named Millie was one of the three official mascots for the 2000 Summer Olympics in Sydney.
The Sonic the Hedgehog franchise features a race of anthropomorphic echidnas, the most prominent being Knuckles.
== See also ==
List of mammal genera
List of recently extinct mammals
List of prehistoric mammals
== Notes ==
== References ==
== Bibliography ==
Ronald M. Nowak (1999), Walker's Mammals of the World (6th ed.), Baltimore: Johns Hopkins University Press, ISBN 0-8018-5789-9, LCCN 98023686
== External links ==
Stewart, Doug (April 2003). "The Enigma of the Echidna". National Wildlife. Retrieved 3 February 2017.
Parker, J. (1 June 2000). "Echidna Love Trains". ABC Science. Australian Broadcasting Corporation.
Rismiller, Peggy (2005). "Echidna research, Kangaroo island". Pelican Lagoon Research & Wildlife Centre. Archived from the original on 21 February 2015. Retrieved 15 July 2012.
"Tachyglossidae". NCBI Taxonomy Browser. 9259. | Wikipedia/Echidna |
Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain.
The vertebrates make up the subphylum Vertebrata with some 65,000 species, by far the largest ranked grouping in the phylum Chordata. The vertebrates include mammals, birds, amphibians, and various classes of fish and reptiles. The fish include the jawless Agnatha, and the jawed Gnathostomata. The jawed fish include both the cartilaginous fish and the bony fish. Bony fish include the lobe-finned fish, which gave rise to the tetrapods, the animals with four limbs. Despite their success, vertebrates still only make up less than five percent of all described animal species.
The first vertebrates appeared in the Cambrian explosion some 518 million years ago. Jawed vertebrates evolved in the Ordovician, followed by bony fishes in the Devonian. The first amphibians appeared on land in the Carboniferous. During the Triassic, mammals and dinosaurs appeared, the latter giving rise to birds in the Jurassic. Extant species are roughly equally divided between fishes of all kinds, and tetrapods. Populations of many species have been in steep decline since 1970 because of land-use change, overexploitation of natural resources, climate change, pollution and the impact of invasive species.
== Characteristics ==
=== Unique features ===
Vertebrates belong to Chordata, a phylum characterised by five synapomorphies (unique characteristics): namely a notochord, a hollow nerve cord along the back, an endostyle (often as a thyroid gland), and pharyngeal gills arranged in pairs. Vertebrates share these characteristics with other chordates.
Vertebrates are distinguished from all other animals, including other chordates, by multiple synapomorphies: namely the vertebral column, skull of bone or cartilage, large brain divided into 3 or more sections, a muscular heart with multiple chambers; an inner ear with semicircular canals; sense organs including eyes, ears, and nose; and digestive organs including intestine, liver, pancreas, and stomach.
=== Physical ===
Vertebrates (and other chordates) belong to the Bilateria, a group of animals with mirror symmetrical bodies. They move, typically by swimming, using muscles along the back, supported by a strong but flexible skeletal structure, the spine or vertebral column. The name 'vertebrate' derives from the Latin vertebratus, 'jointed', from vertebra, 'joint', in turn from Latin vertere, 'to turn'.
As embryos, vertebrates still have a notochord; as adults, all but the jawless fishes have a vertebral column, made of bone or cartilage, instead. Vertebrate embryos have pharyngeal arches; in adult fish, these support the gills, while in adult tetrapods they develop into other structures.
In the embryo, a layer of cells along the back folds and fuses into a hollow neural tube. This develops into the spinal cord, and at its front end, the brain. The brain receives information about the world through nerves which carry signals from sense organs in the skin and body. Because the ancestors of vertebrates usually moved forwards, the front of the body encountered stimuli before the rest of the body, favouring cephalisation, the evolution of a head containing sense organs and a brain to process the sensory information.
Vertebrates have a tubular gut that extends from the mouth to the anus. The vertebral column typically continues beyond the anus to form an elongated tail.
The ancestral vertebrates, and most extant species, are aquatic and carry out gas exchange in their gills. The gills are finely-branched structures which bring the blood close to the water. They are positioned just behind the head, supported by cartilaginous or bony branchial arches. In jawed vertebrates, the first gill arch pair evolved into the jaws. In amphibians and some primitive bony fishes, the larvae have external gills, branching off from the gill arches. Oxygen is carried from the gills to the body in the blood, and carbon dioxide is returned to the gills, in a closed circulatory system driven by a chambered heart. The tetrapods have lost the gills of their fish ancestors; they have adapted the swim bladder (that fish use for buoyancy) into lungs to breathe air, and the circulatory system is adapted accordingly. At the same time, they adapted the bony fins of the lobe-finned fishes into two pairs of walking legs, carrying the weight of the body via the shoulder and pelvic girdles.
Vertebrates vary in size from the smallest frog species such as Brachycephalus pulex, with a minimum adult snout–vent length of 6.45 millimetres (0.254 in) to the blue whale, at up to 33 m (108 ft) and weighing some 150 tonnes.
=== Molecular ===
Molecular markers known as conserved signature indels in protein sequences have been identified and provide distinguishing criteria for the vertebrate subphylum. Five molecular markers are exclusively shared by all vertebrates and reliably distinguish them from all other animals; these include protein synthesis elongation factor-2, eukaryotic translation initiation factor 3, adenosine kinase and a protein related to ubiquitin carboxyl-terminal hydrolase). A specific relationship between vertebrates and tunicates is supported by two molecular markers, the proteins Rrp44 (associated with the exosome complex) and serine C-palmitoyltransferase. These are exclusively shared by species from these two subphyla, but not by cephalochordates.
== Evolutionary history ==
=== Cambrian explosion: first vertebrates ===
Vertebrates originated during the Cambrian explosion at the start of the Paleozoic, which saw a rise in animal diversity. The earliest known vertebrates belong to the Chengjiang biota and lived about 518 million years ago. These include Haikouichthys, Myllokunmingia, Zhongjianichthys, and probably Yunnanozoon. Unlike other Cambrian animals, these groups had the basic vertebrate body plan: a notochord, rudimentary vertebrae, and a well-defined head and tail, but lacked jaws. A vertebrate group of uncertain phylogeny, small eel-like conodonts, are known from microfossils of their paired tooth segments from the late Cambrian to the end of the Triassic. Zoologists have debated whether teeth mineralized first, given the hard teeth of the soft-bodied conodonts, and then bones, or vice versa, but it seems that the mineralized skeleton came first.
=== Paleozoic: from fish to amphibians ===
The first jawed vertebrates may have appeared in the late Ordovician (~445 mya) and became common in the Devonian period, often known as the "Age of Fishes". The two groups of bony fishes, Actinopterygii and Sarcopterygii, evolved and became common. By the middle of the Devonian, a lineage of sarcopterygii with both gills and air-breathing lungs adapted to life in swampy pools used their muscular paired fins to propel themselves on land. The fins, already possessing bones and joints, evolved into two pairs of walking legs. These established themselves as amphibians, terrestrial tetrapods, in the next geological period, the Carboniferous. A group of vertebrates, the amniotes, with membranes around the embryo allowing it to survive on dry land, branched from amphibious tetrapods in the Carboniferous.
=== Mesozoic: from reptiles to mammals and birds ===
At the onset of the Mesozoic, all larger vertebrate groups were devastated after the largest mass extinction in earth history. The following recovery phase saw the emergence of many new vertebrate groups that are still around today, and this time has been described as the origin of modern ecosystems. On the continents, the ancestors of modern lissamphibians, turtles, crocodilians, lizards, and mammals appeared, as well as dinosaurs, which gave rise to birds later in the Mesozoic. In the seas, various groups of marine reptiles evolved, as did new groups of fish. At the end of the Mesozoic, another extinction event extirpated dinosaurs (other than birds) and many other vertebrate groups.
=== Cenozoic: Age of Mammals ===
The Cenozoic, the current era, is sometimes called the "Age of Mammals", because of the dominance of the terrestrial environment by that group. Placental mammals have predominantly occupied the Northern Hemisphere, with marsupial mammals in the Southern Hemisphere.
== Approaches to classification ==
=== Taxonomic history ===
In 1811, Jean-Baptiste Lamarck defined the vertebrates as a taxonomic group, a phylum distinct from the invertebrates he was studying. He described them as consisting of four classes, namely fish, reptiles, birds, and mammals, but treated the cephalochordates and tunicates as molluscs. In 1866, Ernst Haeckel called both his "Craniata" (vertebrates) and his "Acrania" (cephalochordates) "Vertebrata". In 1877, Ray Lankester grouped the Craniates, cephalochordates, and "Urochordates (tunicates) as "Vertebrata". In 1880–1881, Francis Maitland Balfour placed the Vertebrata as a subphylum within the Chordates. In 2018, Naoki Irie and colleagues proposed making Vertebrata a full phylum.
=== Traditional taxonomy ===
Conventional evolutionary taxonomy groups extant vertebrates into seven classes based on traditional interpretations of gross anatomical and physiological traits. The commonly held classification lists three classes of fish and four of tetrapods. This ignores some of the natural relationships between the groupings. For example, the birds derive from a group of reptiles, so "Reptilia" excluding "Aves" is not a natural grouping; it is described as paraphyletic.
Subphylum Vertebrata
Class Agnatha (jawless fishes, paraphyletic)
Class Chondrichthyes (cartilaginous fishes)
Class Osteichthyes (bony fishes, paraphyletic)
Class Amphibia (traditional amphibians, paraphyletic)
Class Reptilia (reptiles, paraphyletic)
Class Aves (birds)
Class Mammalia (mammals)
In addition to these, there are two classes of extinct armoured fishes, Placodermi and Acanthodii, both paraphyletic.
Other ways of classifying the vertebrates have been devised, particularly with emphasis on the phylogeny of early amphibians and reptiles. An example based on work by M.J. Benton in 2004 is given here († = extinct):
Subphylum Vertebrata
Infraphylum "Agnatha" (lampreys and other jawless fishes)
Superclass †Anaspidomorphi (anaspids and relatives)
Class †Anaspida (anaspids)
Superclass Cyclostomata (cyclostomes)
Class Myxini (hagfish)
Class Petromyzontida (lampreys)
Class †Cephalaspidomorphi (cephalaspidomorphs)
Class †Conodonta (conodonts)
Class †Pteraspidomorpha (pteraspidomorphs)
Class †Thelodonti (thelodonts)
Infraphylum Gnathostomata (vertebrates with jaws)
Class †"Placodermi" (extinct armoured fishes)
Class Chondrichthyes (cartilaginous fishes)
Class †"Acanthodii" (extinct spiny "sharks")
Superclass "Osteichthyes" (bony fishes)
Class Actinopterygii (ray-finned bony fishes)
Class "Sarcopterygii" (lobe-finned fishes, cladistically including the tetrapods)
Superclass Tetrapoda (four-limbed vertebrates)
Class "Amphibia" (amphibians, some ancestral to the amniotes)—now a paraphyletic group
Class Synapsida (mammals and their extinct relatives)
Class Sauropsida (reptiles and birds)
Incertae sedis
Genus †Nuucichthys
Genus †Palaeospondylus
While this traditional taxonomy is orderly, most of the groups are paraphyletic, meaning that the structure does not accurately reflect the natural evolved grouping. For instance, descendants of the first reptiles include modern reptiles, mammals and birds; the agnathans have given rise to the jawed vertebrates; the bony fishes have given rise to the land vertebrates; a group of amphibians, the labyrinthodonts, have given rise to the reptiles (traditionally including the mammal-like synapsids), which in turn have given rise to the mammals and birds. Most scientists working with vertebrates use a classification based purely on phylogeny, organized by their known evolutionary history.
=== External phylogeny ===
The closest relatives of vertebrates have been debated over the years. It was once thought that the Cephalochordata was the sister taxon to Vertebrata. This group, Notochordata, was taken to be sister to the Tunicata. Since 2006, analysis has shown that the tunicates + vertebrates form a clade, the Olfactores, with Cephalochordata as its sister (the Olfactores hypothesis), as shown in the following phylogenetic tree.
=== Internal phylogeny ===
The internal phylogeny of the vertebrates is shown in the below tree.
The placement of hagfishes within the vertebrates has been controversial. Their lack of proper vertebrae (among other characteristics of jawless lampreys and jawed vertebrates) led authors of phylogenetic analyses based on morphology to place them outside Vertebrata. Molecular data however indicates that they are vertebrates, being most closely related to lampreys. An older view is that they are a sister group of vertebrates in the common taxon of Craniata. In 2019, Tetsuto Miyashita and colleagues reconciled the two types of analysis, supporting the Cyclostomata hypothesis using only morphological data.
== Diversity ==
=== Species by group ===
Described and extant vertebrate species are split roughly evenly but non-phylogenetically between non-tetrapod "fish" and tetrapods. The following table lists the number of described extant species for each vertebrate class as estimated in the IUCN Red List of Threatened Species, 2014.3. Paraphyletic groups are shown in quotation marks.
The IUCN estimates that 1,305,075 extant invertebrate species have been described, which means that less than 5% of the described animal species in the world are vertebrates.
=== Population trends ===
The Living Planet Index, following 16,704 populations of 4,005 species of vertebrates, shows a decline of 60% between 1970 and 2014. Since 1970, freshwater species declined 83%, and tropical populations in South and Central America declined 89%. The authors note that "An average trend in population change is not an average of total numbers of animals lost." According to WWF, this could lead to a sixth major extinction event. The five main causes of biodiversity loss are land-use change, overexploitation of natural resources, climate change, pollution and invasive species.
== Notes ==
== See also ==
Marine vertebrate – Marine animals with a vertebrate column
Taxonomy of the vertebrates (Young, 1962) – Classification of spine-possessing animals according to some authorities
== References ==
== Bibliography ==
Kardong, Kenneth V. (1998). Vertebrates: Comparative Anatomy, Function, Evolution (second ed.). USA: McGraw-Hill. pp. 747 pp. ISBN 978-0-697-28654-3.
"Vertebrata". Integrated Taxonomic Information System. Retrieved 6 August 2007.
== External links ==
Tree of Life
Tunicates and not cephalochordates are the closest living relatives of vertebrates
Vertebrate Pests chapter in United States Environmental Protection Agency and University of Florida/Institute of Food and Agricultural Sciences National Public Health Pesticide Applicator Training Manual
The Vertebrates
The Origin of Vertebrates Marc W. Kirschner, iBioSeminars, 2008. | Wikipedia/Vertebrate_anatomy |
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three months. Early in the course of CKD, patients are usually asymptomatic, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include (in chronological order) high blood pressure (often related to activation of the renin–angiotensin system), bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization. CKD can lead to end-stage kidney failure requiring kidney dialysis or kidney transplantation.
Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Risk factors include a family history of chronic kidney disease. Diagnosis is by blood tests to measure the estimated glomerular filtration rate (eGFR), and a urine test to measure albumin. Ultrasound or kidney biopsy may be performed to determine the underlying cause. Several severity-based staging systems are in use.
Testing people with risk factors (case-finding) is recommended. Initial treatments may include medications to lower blood pressure, blood sugar, and cholesterol. Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are generally first-line agents for blood pressure control, as they slow progression of the kidney disease and the risk of heart disease. Loop diuretics may be used to control edema and, if needed, to further lower blood pressure. NSAIDs should be avoided. Other recommended measures include staying active, and "to adopt healthy and diverse diets with a higher consumption of plant-based foods compared to animal-based foods and a lower consumption of ultraprocessed foods." Plant-based diets are feasible and are associated with improved intermediate outcomes and biomarkers. An example of a general, healthy diet, suitable for people with CKD who do not require restrictions, is the Canada Food Guide Diet. People with CKD who require dietary restrictions or who have other specific nutritional problems should be referred to a dietitian. Treatments for anemia and bone disease may also be required. Severe disease requires hemodialysis, peritoneal dialysis, or a kidney transplant for survival.
Chronic kidney disease affected 753 million people globally in 2016 (417 million females and 336 million males.) In 2015, it caused 1.2 million deaths, up from 409,000 in 1990. The causes that contribute to the greatest number of deaths are high blood pressure at 550,000, followed by diabetes at 418,000, and glomerulonephritis at 238,000.
== Signs and symptoms ==
CKD is initially without symptoms and is usually detected on routine screening blood work by either an increase in serum creatinine, or protein in the urine. As the kidney function decreases, more unpleasant symptoms may emerge:
Blood pressure is increased due to fluid overload and the production of vasoactive hormones created by the kidney via the renin-angiotensin system, increasing the risk of developing hypertension and heart failure. People with CKD are more likely than the general population to develop atherosclerosis with consequent cardiovascular disease, an effect that may be at least partly mediated by uremic toxins. People with both CKD and cardiovascular disease have significantly worse prognoses than those with only cardiovascular disease.
Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic concentration, urea is excreted in eccrine sweat at high concentrations and crystallizes on the skin as the sweat evaporates ("uremic frost").
Potassium accumulates in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20–25 mL/min/1.73 m2, when the kidneys have decreased ability to excrete potassium. Hyperkalemia in CKD can be exacerbated by acidemia (triggering the cells to release potassium into the bloodstream to neutralize the acid) and from lack of insulin.
Fluid overload symptoms may range from mild edema to life-threatening pulmonary edema.
Hyperphosphatemia results from poor phosphate elimination in the kidney, and contributes to increased cardiovascular risk by causing vascular calcification. Circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the kidney capacity for phosphate excretion declines, which may contribute to left ventricular hypertrophy and increased mortality in people with CKD .
Hypocalcemia results from 1,25 dihydroxyvitamin D3 deficiency (caused by high FGF-23 and reduced kidney mass) and the skeletal resistance to the calcemic action of parathyroid hormone. Osteocytes are responsible for the increased production of FGF-23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D3). Later, this progresses to secondary hyperparathyroidism, kidney osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.
Changes in mineral and bone metabolism that may cause 1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; 2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (kidney osteodystrophy); and 3) vascular or other soft-tissue calcification. CKD–mineral and bone disorders have been associated with poor outcomes.
Metabolic acidosis may result from decreased capacity to generate enough ammonia from the cells of the proximal tubule. Acidemia affects the function of enzymes and increases the excitability of cardiac and neuronal membranes by the promotion of hyperkalemia.
Anemia is common and is especially prevalent in those requiring hemodialysis. It is multifactorial in cause but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression. Hypoproliferative anemia occurs due to inadequate production of erythropoietin by the kidneys.
In later stages, cachexia may develop, leading to unintentional weight loss, muscle wasting, weakness, and anorexia.
Cognitive decline in patients experiencing CKD is an emerging symptom revealed in research literature. Research suggests that patients with CKD face a 35–40% higher likelihood of cognitive decline and or dementia. This relation is dependent on the severity of CKD in each patient; although emerging literature indicates that patients at all stages of CKD will have a higher risk of developing these cognitive issues.
Sexual dysfunction is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. Most women have trouble with sexual arousal, and painful menstruation and problems with performing and enjoying sex are common.
== Causes ==
The most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis. About one of five adults with hypertension and one of three adults with diabetes have CKD. If the cause is unknown, it is called idiopathic.
=== By anatomical location ===
Vascular disease includes large-vessel disease such as bilateral kidney artery stenosis and small-vessel disease such as ischemic nephropathy, hemolytic–uremic syndrome, and vasculitis.
Glomerular disease comprises a diverse group and is classified into:
Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
Secondary glomerular disease such as diabetic nephropathy and lupus nephritis
Tubulointerstitial disease includes drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy
Obstructive nephropathy, as exemplified by bilateral kidney stones and benign prostatic hyperplasia of the prostate gland; rarely, pinworms infecting the kidney can cause obstructive nephropathy.
=== Other ===
Genetic congenital disease such as polycystic kidney disease or 17q12 microdeletion syndrome.
Mesoamerican nephropathy, is "a new form of kidney disease that could be called agricultural nephropathy". A high and so-far unexplained number of new cases of CKD, referred to as the Mesoamerican nephropathy, has been noted among male workers in Central America, mainly in sugarcane fields in the lowlands of El Salvador and Nicaragua. Heat stress from long hours of piece-rate work at high average temperatures of about 36 °C (96 °F) is suspected, as are agricultural chemicals
Chronic lead exposure
== Diagnosis ==
Diagnosis of CKD is largely based on history, examination, and urine dipstick combined with the measurement of the serum creatinine level. Differentiating CKD from acute kidney injury (AKI) is important because AKI can be reversible. One diagnostic clue that helps differentiate CKD from AKI is a gradual rise in serum creatinine (over several months or years) as opposed to a sudden increase in the serum creatinine (several days to weeks). In many people with CKD, previous kidney disease or other underlying diseases are already known. A significant number present with CKD of unknown cause.
=== Screening ===
Screening those who have neither symptoms nor risk factors for CKD is not recommended. Those who should be screened include: those with hypertension or history of cardiovascular disease, those with diabetes or marked obesity, those aged > 60 years, subjects with African American ancestry, those with a history of kidney disease in the past, and subjects who have relatives who had kidney disease requiring dialysis.
Screening should include calculation of the estimated GFR (eGFR) from the serum creatinine level, and measurement of urine albumin-to-creatinine ratio (ACR) in a first-morning urine specimen (this reflects the amount of a protein called albumin in the urine), as well as a urine dipstick screen for hematuria.
The GFR is derived from the serum creatinine and is proportional to 1/creatinine, i.e. it is a reciprocal relationship; the higher the creatinine, the lower the GFR. It reflects one aspect of kidney function, how efficiently the glomeruli – the filtering units – work. The normal GFR is >90 ml/min. The units of creatinine vary from country to country, but since the glomeruli comprise <5% of the mass of the kidney, the GFR does not indicate all aspects of kidney health and function. This can be done by combining the GFR level with the clinical assessment of the person, including fluid status, and measuring the levels of hemoglobin, potassium, phosphate, and parathyroid hormone.
=== Ultrasound ===
Kidney ultrasonography is useful for diagnostic and prognostic purposes in chronic kidney disease. Whether the underlying pathologic change is glomerular sclerosis, tubular atrophy, interstitial fibrosis, or inflammation, the result is often increased echogenicity of the cortex. The echogenicity of the kidney should be related to the echogenicity of the liver or the spleen. Moreover, decreased kidney size and cortical thinning are often seen especially when the disease progresses. However, kidney size correlates to height, and short persons tend to have small kidneys; thus, kidney size as the only parameter is unreliable.
=== Additional imaging ===
Additional tests may include nuclear medicine MAG3 scan to confirm blood flow and establish the differential function between the two kidneys. Dimercaptosuccinic acid (DMSA) scans are also used in kidney imaging; with both MAG3 and DMSA being used chelated with the radioactive element technetium-99.
=== Stages ===
A glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 is considered normal without chronic kidney disease if there is no kidney damage present.
Kidney damage is defined as signs of damage seen in blood, urine, or imaging studies which include lab albumin/creatinine ratio (ACR) ≥ 30. All people with a GFR <60 mL/min/1.73 m2 for 3 months are defined as having chronic kidney disease.
Protein in the urine is regarded as an independent marker for the worsening of kidney function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if protein loss is significant.
Stage 1: Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m2) and persistent albuminuria. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
Stage 2: Mild reduction in GFR (60–89 mL/min/1.73 m2) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies.
Stage 3: Moderate reduction in GFR (30–59 mL/min/1.73 m2):. British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral.
Stage 4: Severe reduction in GFR (15–29 mL/min/1.73 m2) Preparation for kidney replacement therapy.
Stage 5: Established kidney failure (GFR <15 mL/min/1.73 m2), permanent kidney replacement therapy, or end-stage kidney disease.
The term "non-dialysis-dependent chronic kidney disease" (NDD-CKD) is a designation used to encompass the status of those persons with an established CKD who do not yet require the life-supporting treatments for kidney failure known as kidney replacement therapy (RRT, including maintenance dialysis or kidney transplantation). The condition of individuals with CKD, who require either of the two types of kidney replacement therapy (dialysis or transplant), is referred to as end-stage kidney disease (ESKD). Hence, the start of the ESKD is practically the irreversible conclusion of the NDD-CKD. Even though the NDD-CKD status refers to the status of persons with earlier stages of CKD (stages 1 to 4), people with advanced stages of CKD (stage 5), who have not yet started kidney replacement therapy, are also referred to as NDD-CKD.
== Management ==
Chronic kidney disease (CKD) is a serious condition often linked to diabetes and high blood pressure. There is no cure, but a combination of lifestyle changes and medications can help slow its progression. This might include a plant-dominant diet with less protein and salt, medications to control blood pressure and sugar, and potentially newer anti-inflammatory drugs. Doctors may also focus on managing heart disease risk, preventing infections, and avoiding further kidney damage. While dialysis may eventually be needed, a gradual transition can help preserve remaining kidney function. More research is ongoing to improve CKD management and patient outcomes.
=== Blood pressure ===
Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor antagonists (ARBs) are recommended as first-line agents since they have been found to slow the decline of kidney function, relative to a more rapid decline in those not on one of these agents. They have also been found to reduce the risk of major cardiovascular events such as myocardial infarction, stroke, heart failure, and death from cardiovascular disease when compared to placebo in individuals with CKD. ACEIs may be superior to ARBs for protection against progression to kidney failure and death from any cause in those with CKD. Aggressive blood pressure lowering decreases people's risk of death.
=== Other measures ===
Aggressive treatment of high blood lipids is recommended.
A low-protein, low-salt diet may result in slower progression of CKD and reduction in proteinuria as well as controlling symptoms of advanced CKD to delay dialysis start. A tailored low-protein diet, designed for low acidity, may help prevent damage to kidneys for people with CKD. Additionally, controlling salt ingestion helps to decrease the incidence of coronary heart disease, lowering blood pressure and reducing albuminuria.
Anemia – A target hemoglobin level of 100–120 g/L is recommended; raising hemoglobin levels to the normal range has not been found to be of benefit.
Guidelines recommend treatment with parenteral iron prior to treatment with erythropoietin.
Replacement of erythropoietin is often necessary in people with advanced disease.
It is unclear if androgens improve anemia.
Calcitriol is recommended for vitamin D deficiency and control of metabolic bone disease.
Phosphate binders are used to control the serum phosphate levels, which are usually elevated in advanced chronic kidney disease.
Phosphodiesterase-5 inhibitors and zinc may improve sexual dysfunction in men.
=== Lifestyle interventions ===
==== Weight loss ====
Obesity may have a negative impact in CKD, increasing the risk of disease progression to ESKD or kidney failure compared to controls with healthy weight, and when in advanced stages also may hinder people's eligibility to kidney transplantation. For example, the consumption of high calorie and high fructose beverages can make an individual "60% more likely to develop CKD".
Weight management interventions in overweight and obese adults with CKD include lifestyle interventions (dietary changes, physical activity/exercise, or behavioural strategies), pharmacological (used to reduce absorption or suppress appetite) and surgical interventions. Any of these can help people with CKD lose weight, however, it is not known if they can also prevent death or cardiovascular events like heart complications or stroke. It is recommended that weight management interventions should be individualised, according to a thorough patients' assessment regarding clinical condition, motivations, and preferences.
==== Dietary salt intake ====
High dietary sodium intake may increase the risk of hypertension and cardiovascular disease. The effect of dietary restriction of salt in foods has been investigated in people with chronic kidney disease. For people with CKD, including those on dialysis, reduced salt intake may help to lower both systolic and diastolic blood pressure, as well as albuminuria. Some people may experience low blood pressure and associated symptoms, such as dizziness, with lower salt intake. The effect of salt restriction on extracellular fluid, oedema, and total body weight reduction is unknown.
EHealth interventions may improve dietary sodium intake and fluid management for people with CKD.
==== Omega-3 supplementation ====
In people with CKD who require hemodialysis, there is a risk that vascular blockage due to clotting, may prevent dialysis therapy from being possible. Even though Omega-3 fatty acids contribute to the production of eicosanoid molecules that reduce clotting, it does not have any impact on the prevention of vascular blockage in people with CKD.
==== Protein supplementation ====
Regular consumption of oral protein-based nutritional supplements may increase serum albumin levels slightly in people with CKD, especially among those requiring hemodialysis or who are malnourished. Prealbumin level and mid-arm muscle circumference may also be increased following supplementation. Despite possible improvement in these indicators of nutritional status, it is not certain that protein supplements affect the quality of life, life expectancy, inflammation, or body composition.
==== Iron supplementation ====
Intravenous (IV) iron therapy may help more than oral iron supplements in reaching target hemoglobin levels. However, allergic reactions may also be more likely following IV-iron therapy.
=== Sleep ===
Individuals with CKD have an increased prevalence of sleep apnea compared to the general population (both obstructive sleep apnea and central sleep apnea). The presence of sleep apnea in CKD has been associated with an increased risk of cardiovascular events and mortality.
People with CKD also experience sleep disorders, thus unable to get quality sleep. There are several strategies that could help, such as relaxation techniques, exercise, and medication. Exercise may be helpful with sleep regulation and may decrease fatigue and depression in people with CKD. However, none of these options have been proven to be effective in the treatment of sleep disorders. This means that it is unknown what is the best guidance to improve sleep quality in this population.
=== Referral to a nephrologist ===
Guidelines for referral to a nephrologist vary between countries. Most agree that nephrology referral is required by Stage 4 CKD (when eGFR/1.73m2 is less than 30 mL/min; or decreasing by more than 3 mL/min/year).
It may also be useful at an earlier stage (e.g. CKD3) when urine albumin-to-creatinine ratio is more than 30 mg/mmol, when blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular disorder or secondary disease amenable to a specific treatment. Other benefits of early nephrology referral include proper education regarding options for kidney replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those people with chronic kidney disease opting for future hemodialysis.
=== Renal replacement therapy ===
At stage 5 CKD, kidney replacement therapy is usually required, in the form of either dialysis or a kidney transplant.
In CKD numerous uremic toxins accumulate in the blood. Even when ESKD (largely synonymous with CKD5) is treated with dialysis, the toxin levels do not go back to normal as dialysis is not that efficient. Similarly, after a kidney transplant, the levels may not go back to normal as the transplanted kidney may not work 100%. If it does, the creatinine level is often normal. The toxins show various cytotoxic activities in the serum and have different molecular weights, and some of them are bound to other proteins, primarily to albumin. Uremic toxins are classified into three groups as small water-soluble solutes, middle molecular-weight solutes, and protein-bound solutes. Hemodialysis with high-flux dialysis membrane, long or frequent treatment, and increased blood/dialysate flow has improved removal of water-soluble small molecular weight uremic toxins. Middle molecular weight molecules are removed more effectively with hemodialysis using a high-flux membrane, hemodiafiltration, and hemofiltration. However, conventional dialysis treatment is limited in its ability to remove protein-bound uremic toxins.
== Prognosis ==
CKD increases the risk of cardiovascular disease, and people with CKD often have other risk factors for heart disease, such as high blood lipids. The most common cause of death in people with CKD is cardiovascular disease rather than kidney failure.
Chronic kidney disease results in worse all-cause mortality (the overall death rate) which increases as kidney function decreases. The leading cause of death in chronic kidney disease is cardiovascular disease, regardless of whether there is progression to stage 5.
While kidney replacement therapies can maintain people indefinitely and prolong life, the quality of life is negatively affected. Kidney transplantation increases the survival of people with stage 5 CKD when compared to other options; however, it is associated with an increased short-term mortality due to complications of the surgery. Transplantation aside, high-intensity home hemodialysis appears to be associated with improved survival and a greater quality of life, when compared to the conventional three-times-a-week hemodialysis and peritoneal dialysis.
People with ESKD are at increased overall risk for cancer. This risk is particularly high in younger people and gradually diminishes with age. Medical specialty professional organizations recommend that physicians do not perform routine cancer screening in people with limited life expectancies due to ESKD because the evidence does not show that such tests lead to improved outcomes.
In children, growth failure is a common complication of CKD. Children with CKD will be shorter than 97% of children the same age and sex. This can be treated with additional nutritional support or medication such as growth hormone.
=== Survival without dialysis ===
Survival rates of CKD are generally longer with dialysis than without (having only conservative kidney management). However, from the age of 80 and in elderly patients with comorbidities there is no difference in survival between the two groups. Quality of life might be better for people without dialysis.
People who had decided against dialysis treatment when reaching end-stage chronic kidney disease could survive several years and experience improvements in their mental well-being in addition to sustained physical well-being and overall quality of life until late in their illness course. However, use of acute care services in these cases is common, and the intensity of end-of-life care is highly variable among people opting out of dialysis.
== High prevalence of CKD in some areas ==
High Prevalence of Chronic Kidney Disease in Certain Regions
Overview
Chronic kidney disease (CKD) is a growing global health problem, affecting over 10% of the world's population—more than 800 million people. While CKD is prevalent worldwide, certain regions and communities experience exceptionally high rates, often due to a combination of traditional and unique risk factors.
Regional Hotspots and Prevalence
In India, the Uddanam region of Andhra Pradesh has reported a CKD prevalence of 18.2%, which is 3–4 times higher than most other areas in India and comparable to global hotspots like Sri Lanka and Central America. Notably, a significant proportion of CKD cases here are of unknown cause (CKDu), not linked to common risk factors like diabetes or hypertension.
In Thailand, the overall CKD prevalence was found to be 17.5%, with certain rural areas reaching as high as 22.2%.
Globally, the estimated prevalence of CKD is about 13.4%.
Risk Factors and Contributing Causes
Traditional risk factors include diabetes, hypertension, obesity, and aging, which are rapidly increasing in low- and middle-income countries (LMICs).
Environmental and occupational exposures, such as toxins, heat stress, and possibly contaminated water, are suspected contributors in CKD hotspots like Uddanam, Sri Lanka, and Central America, though the exact causes often remain unclear.
Limited access to healthcare, high poverty rates, and underfunded health systems exacerbate the problem, leading to late diagnosis and high mortality.
Public Health Impact
CKD is a leading cause of morbidity and mortality, particularly in regions with high prevalence and limited treatment options.
The financial burden of CKD is substantial, especially where access to dialysis and transplantation is limited.
Dr Y.Sreehari created new word 'CKDum'. That means Chronic Kidney Disease Un Conclusive etiology and Mystery Un Conclusive:
A. Un conclusive etiology means, No BP or Diabetis, no any other risk factors.
B. Mystery Un Conclusive means:
1.No causes of Environmental (Toxins,Heavy Metals: Exposure to cadmium, arsenic, lead, and fluoride through drinking water or soil).
2.No Pesticides and Herbicides,No Chronic exposure to glyphosate, organophosphates and other agrochemicals used in farming.
3.No Heat Stress and Dehydration.
4.No Prolonged physical labor in hot, humid climates.
5.No Contaminated Water Sources
6.No Hard water with high fluoride, silica, and sodium content.
7.No Groundwater contamination.
8.No Poor nutrition.
9.No Use of NSAIDs (Painkillers)
2. Dr Y. Sreehari is a physician, and belongs to Visakhapatnam, chairman of Dr Sreehari hospitals.
3. The world has a crores of Villages. 'X' is a world average prevalence CKD . So as per probability, chance, like lottery chances,have some villages may be more than world average prevalence 'X'
5. If we count the top 10 villages with high CKDum prevalence , any 10 villages must be in top position.
6.Probability Theory and CKDum:
Probability theory governs the likelihood of events in large populations. In the context of CKDum, we can model its prevalence using a binomial distribution, which describes the number of occurrences of an event (e.g., CKDum cases) in a fixed number of trials (e.g., individuals in a village). Let’s denote:
p = the global average prevalence of CKDum (a subset of X, estimated to be lower, e.g., 1–2% in high-risk rural populations []).
n = the population of a village.
k = the number of CKDum cases in the village.
The probability of observing k cases in a village of size n is given by the binomial probability formula:
P(k)=(nk)pk(1−p)n−kP(k) = \binom{n}{k} p^k (1-p)^{n-k}P(k)=(kn)pk(1−p)n−k
where (nk)\binom{n}{k}(kn) is the binomial coefficient, representing the number of ways to choose k cases from n individuals.
In a world with millions of villages, the law of large numbers suggests that most villages will have CKDum prevalence close to p. However, the central limit theorem implies that, due to random variation, some villages will exhibit prevalence significantly higher or lower than p. This is analogous to a lottery, where a small number of tickets (villages) win the "prize" of unusually high prevalence by chance alone.
7.The Top 10 Villages: A Statistical Inevitability:Dr. Sreehari posits that if we rank villages worldwide by CKDum prevalence, the top 10 will inevitably show rates far above the global average, purely due to statistical chance.
This can be understood through extreme value theory, which studies the behavior of the tails of probability distributions. In a large sample (e.g., millions of villages), the maximum values of CKDum prevalence are expected to be significantly higher than the mean.
For example, suppose p = 0.02 (2% prevalence) and a village has n = 1000 residents. The expected number of CKDum cases is n⋅p=20n \cdot p = 20n⋅p=20. However, the standard deviation of the binomial distribution is:
σ=n⋅p⋅(1−p)=1000⋅0.02⋅0.98≈4.43\sigma = \sqrt{n \cdot p \cdot (1-p)} = \sqrt{1000 \cdot 0.02 \cdot 0.98} \approx 4.43σ=n⋅p⋅(1−p)=1000⋅0.02⋅0.98≈4.43
Using a normal approximation, the probability of observing, say, 50 or more cases (5% prevalence, 2.5 times the expected value) can be calculated using the z-score:
z=50−204.43≈6.77z = \frac{50 - 20}{4.43} \approx 6.77z=4.4350−20≈6.77
The probability of z≥6.77z \geq 6.77z≥6.77 is extremely small (on the order of 10−1110^{-11}10−11), but with millions of villages globally, the expected number of such outliers becomes non-negligible. For instance, with 10 million villages worldwide, we expect:
10,000,000⋅P(z≥6.77)≈a small but positive number of villages10,000,000 \cdot P(z \geq 6.77) \approx \text{a small but positive number of villages}10,000,000⋅P(z≥6.77)≈a small but positive number of villages
Thus, it is statistically inevitable that some villages will have CKDum prevalence far exceeding the global average, even without specific causal factors.
Global Applicability: With millions of villages worldwide, Dr. Sreehari’s framework applies universally. Whether in Sri Lanka, India, or Central America, the lottery-like distribution of CKDum explains why certain communities are disproportionately affected.
Conclusion: The CKDum Mystery Solved
Dr. Y. Sreehari’s innovative application of probability theory offers a compelling resolution to the CKDum mystery.
...
== Epidemiology ==
About one in ten people have chronic kidney disease. In Canada 1.9 to 2.3 million people were estimated to have CKD in 2008. CKD affected an estimated 13.9% of U.S. adults aged 18 years and older in the period from 2017 to 2020. In 2007 8.8% of the population of Great Britain and Northern Ireland had symptomatic CKD.
Chronic kidney disease was the cause of 956,000 deaths globally in 2013, up from 409,000 deaths in 1990.
=== Chronic kidney disease of unknown aetiology ===
The cause of chronic kidney disease is sometimes unknown; it is referred to as chronic kidney disease of unknown aetiology (CKDu). As of 2020 a rapidly progressive chronic kidney disease, unexplained by diabetes and hypertension, had increased dramatically in prevalence over a few decades in several regions in Central America and Mexico, a CKDu referred to as the Mesoamerican nephropathy (MeN). It was estimated in 2013 that at least 20,000 men had died prematurely, some in their 20s and 30s; a figure of 40,000 per year was estimated in 2020. In some affected areas CKD mortality was five times the national rate. MeN primarily affects men working as sugarcane labourers. The cause is unknown, but in 2020 the science found a clearer connection between heavy labour in high temperatures and incidence of CKDu; improvements such as regular access to water, rest and shade, can significantly decrease the potential CKDu incidence. CKDu also affects people in Sri Lanka where it is the eighth largest cause of in-hospital mortality.
=== Race ===
African, Hispanic, and South Asian (particularly those from Pakistan, Sri Lanka, Bangladesh, and India) populations are at high risk of developing CKD. Africans are at greater risk due to the number of people affected with hypertension among them. As an example, 37% of ESKD cases in African Americans can be attributed to high blood pressure, compared with 19% among Caucasians. Treatment efficacy also differs between racial groups. Administration of antihypertensive drugs generally halts disease progression in white populations but has little effect in slowing kidney disease among black people, and additional treatment such as bicarbonate therapy is often required. While lower socioeconomic status contributes to the number of people affected with CKD, differences in the number of people affected by CKD are still evident between Africans and Whites when controlling for environmental factors.
Although CKD of unknown etiology was first documented among sugar cane workers in Costa Rica in the 1970s, it may well have affected plantation laborers since the introduction of sugar cane farming to the Caribbean in the 1600s. In colonial times the death records of slaves on sugar plantations were much higher than for slaves forced into other labor.
==== Denial of care ====
Denial of care in chronic kidney disease treatment and management is a significant issue for minority populations. This can be due to healthcare provider prejudice, structural barriers, and health insurance coverage disparities. Healthcare provider biases can lead to under-treatment, misdiagnosis, or delayed diagnosis. Structural barriers, such as lack of insurance and limited healthcare facilities, hinder access to timely care. Furthermore, health insurance coverage disparities, with minority populations lacking adequate coverage, contribute to these disparities. Denial of care worsens health outcomes and perpetuates existing health inequities.
==== Race-based kidney function metric ====
Race-based kidney function metrics, particularly normalizing creatinine, pose ethical challenges in diagnosing and managing chronic kidney disease (CKD). While certain racial and ethnic groups are at higher risk, using race as a reference range may reinforce stereotypes and perpetuate health disparities. This approach fails to account for the complex interplay of genetic, environmental, and social factors influencing kidney function. Depending solely on race-based metrics may lead to misdiagnosis or underdiagnosis in minority populations. Alternative approaches that consider socioeconomic status, environmental exposures, and genetic vulnerability, are needed to accurately assess kidney function and address CKD care disparities.
== Society and culture ==
=== Organisations ===
The International Society of Nephrology is an international body representing specialists in kidney diseases.
==== United States ====
The National Kidney Foundation is a national organization representing people with chronic kidney diseases and professionals who treat kidney diseases.
The American Kidney Fund is a national nonprofit organization providing treatment-related financial assistance to one of every five people undergoing dialysis each year.
The Renal Support Network is a nonprofit, patient-focused, patient-run organization that provides non-medical services to those affected by CKD.
The American Association of Kidney Patients is a nonprofit, patient-centric group focused on improving the health and well-being of CKD and people undergoing dialysis .
The Renal Physicians Association is an association representing nephrology professionals.
==== United Kingdom ====
It was said to be costing the National Health Service about £1.5 billion a year in 2020.
Kidney Care UK and The UK National Kidney Federation represent people with chronic kidney disease. The Renal Association represents Kidney physicians and works closely with the National Service Framework for kidney disease.
==== Australia ====
Kidney Health Australia serves that country.
== Other animals ==
=== Dogs ===
The incidence rate of CKD in dogs was 15.8 cases per 10,000 dog years at risk. The mortality rate of CKD was 9.7 deaths per 10,000 dog years at risk. (Rates developed from a population of 600,000 insured Swedish dogs; one dog year at risk is one dog at risk for one year). The breeds with the highest rates were the Bernese mountain dog, miniature schnauzer, and boxer. The Swedish elkhound, Siberian husky and Finnish spitz were the breeds with the lowest rates.
=== Cats ===
Cats with chronic kidney disease may have a buildup of waste products usually removed by the kidneys. They may appear lethargic, unkempt, and lose weight, and may have hypertension. The disease can prevent appropriate concentration of urine, causing cats to urinate in greater volumes and drink more water to compensate. Loss of important proteins and vitamins through urine may cause abnormal metabolism and loss of appetite. The buildup of acids within the blood can result in acidosis, which can lead to anemia (which can sometimes be indicated by pink or whitish gums, but by no means does the presence of normal colored gums guarantee that anemia is not present or developing), and lethargy.
== Research ==
As of 2019 several compounds are in development for the treatment of CKD. These include the angiotensin receptor blocker (ARB) olmesartan medoxomil; and sulodexide, a mixture of low molecular weight heparin and dermatan sulfate.
== References ==
== External links ==
Dialysis Complications of Chronic Renal Failure at eMedicine
Chronic Renal Failure Information Archived 2013-03-15 at the Wayback Machine from Great Ormond Street Hospital
Note also the External resources links in the table below. | Wikipedia/Chronic_kidney_disease |
Fluorescein angiography (FA), fluorescent angiography (FAG), or fundus fluorescein angiography (FFA) is a technique for examining the circulation of the retina and choroid (parts of the fundus) using a fluorescent dye and a specialized camera. Sodium fluorescein is added into the systemic circulation, the retina is illuminated with blue-green light at a wavelength of 490 nanometers, and an angiogram is obtained by photographing the fluorescent green light that is emitted by the dye. The fluorescein is administered intravenously in intravenous fluorescein angiography (IVFA) and orally in oral fluorescein angiography (OFA). The test is a dye tracing method.
The fluorescein dye also reappears in the patient urine, causing the urine to appear darker, and sometimes orange. It can also cause discolouration of the saliva.
Fluorescein angiography is one of several health care applications of this dye, all of which have a risk of severe adverse effects. See fluorescein safety in health care applications. Fluorescein angiography does not involve the use of ionizing radiation.
Fluorescein angiography was pioneered by German ophthalmologist Achim Wessing, who published his findings in 1969.
== Equipment ==
Exciter filter: Allows only blue light to illuminate the retina. Depending on the specific filter, the excitation wavelength hitting the retina will be between 465 and 490 nm. Most only allow light through at a wavelength of 490 nm.
Barrier filter: Allows only yellow-green light (from the fluorescence) to reach the camera. Both filters are interference bandpass filters, which means they block out all light except that at a specific wavelength. The barrier filter only allows light with a wavelength of 525 nm, but depending on the filter it can be anywhere from 520 to 530 nm.
Fundus camera, either digital or with camera body containing black and white, or slide positive film.
== Technique ==
Baseline color and black and white red-free filtered images are taken prior to injection. The black and white images are filtered red-free (a green filter) to increase contrast and often gives a better image of the fundus than the color image.
A 6-second bolus injection of 2-5 cc of sodium fluorescein into a vein in the retina
Local injection
A series of black-and-white or digital photographs are taken of the retina before and after the fluorescein reaches the retinal circulation (approximately 10 seconds after injection). The early images allow for the recognition of autofluorescence of the retinal tissues. Photos are taken approximately once every second for about 20 seconds, then less often. A delayed image is obtained at 5 and 10 minutes. Some doctors like to see a 15-minute image as well.
A filter is placed in the camera so only the fluorescent, yellow-green light (530 nm) is recorded. The camera may however pick up signals from pseudofluorescence or autofluorescence. In pseudofluorescence, non-fluorescent light is imaged. This occurs when blue light reflected from the retina passes through the filter. This is generally a problem with older filters, and annual replacement of these filters is recommended. In autofluorescence, fluorescence from the eye occurs without injection of the dye. This may be seen with optic nerve head drusen, astrocytic hamartoma, or calcific scarring.
Black-and-white photos give better contrast than color photos, which aren't necessary because the filter transmits only one color of light.
== Normal circulatory filling ==
times are approximate
0 seconds – injection of fluorescein
9.5 sec – posterior ciliary arteries
10 sec – choroidal flush (or "pre-arterial phase")
10–12 sec – retinal arterial stage
13 sec – capillary transition stage
14–15 sec – early venous stage (or "laminar stage", "arterial-venous stage")
16–17 sec – venous stage
18–20 sec – late venous stage
5 minutes – late staining
Fluorescein enters the ocular circulation from the internal carotid artery via the ophthalmic artery. The ophthalmic artery supplies the choroid via the short posterior ciliary arteries and the retina via the central retinal artery, but the route to the choroid is typically less circuitous than the route to the retina. This accounts for the short delay between the "choroidal flush" and retinal filling.
== Pathologic findings ==
Pathologic changes are recognized by the detection of either hyperfluorescence or hypofluorescence.
Causes of hyperfluorescence:
window/transmission (filling) defects
leaking defects (i.e. capillary leakage, aneurysm, neovascularization)
pooling defects
staining
abnormal vasculature
Causes of hypofluorescence:
blocking defect (i.e. blood)
filling defect (capillary nonperfusion/blockage)
Fluorescein angiography is used by physicians specializing in the treatment of eye diseases (ophthalmologists) to evaluate the vasculature of the retina, choroid, optic disc, and iris. Among the common groups of ophthalmologic disease, fluorescein angiography can detect diabetic retinopathy (neovascularization), vein occlusions, retinal artery occlusions, edema of the optic disc, and tumors. Additionally, the transit time (the period between injection of the dye and when it appears in the examined blood vessels) can provide an objective measurement of the rate of blood flow through the imaged blood vessels.
== See also ==
Fundus photography
Laser Doppler imaging
== References ==
=== Additional references ===
Gisbert, Gisbert Richard; Gisele Soubrane; Lawrence Y. Yannuzzi (1998). Fluorescein angiography: textbook and atlas (2nd rev. and expanded ed.). Stuttgart: Thieme. ISBN 0-86577-712-8.
Kanski, Jack J. (2003). Clinical ophthalmology: a systematic approach (5. ed.). Edinburgh: Butterworth-Heinemann. ISBN 978-0750655415.
Manfred Spitznas: Understanding fluorescein angiography = Fluoreszeinangiografie verstehen. (German, English, Spanish) Springer, Berlin/Heidelberg/New York 2006, ISBN 978-3-540-30060-1.
Achim Wessing (1969). Fluorescein angiography of the retina.Textbook and atlas. Saint Louis: Mosby, ISBN 978-0801653889 | Wikipedia/Fluorescein_angiography |
Pulmonary angiography (or pulmonary arteriography,conventional pulmonary angiography, selective pulmonary angiography) is a medical fluoroscopic procedure used to visualize the pulmonary arteries and much less frequently, the pulmonary veins. It is a minimally invasive procedure performed most frequently by an interventional radiologist or interventional cardiologist to visualise the arteries of the lungs.
== Uses ==
Pulmonary angiography is useful as the confirmation test where the non-invasive imaging such as CT pulmonary angiography is inconclusive on determining the presence of pulmonary embolism. The accuracy of pulmonary angiography may be higher than clinical examination, arterial blood gas results, and ventilation/perfusion scan. Pulmonary angiography is also used to confirm chronic thromboembolic pulmonary hypertension (CTEPH) and provides a platform for balloon pulmonary angioplasty to treat the disease.
CT pulmonary angiography has nearly entirely replaced conventional pulmonary angiography in common practice as it is less invasive, faster, safer, and provides most of the same diagnostic information with the added benefit of visualizing the lung tissue as well as other structures. Nevertheless, it is still used in cases where CT angiography is nondiagnostic.
== Procedure ==
Types of catheters that can be used are pigtail catheters and balloon occlusion catheters. Tip of the catheter is advanced through the inferior vena cava, right atrium, right ventricle, right ventricular outflow tract, pulmonary trunk, and the tip is parked in the left pulmonary artery.
== History ==
Conventional pulmonary angiography was first performed in 1931 by Portuguese angiography pioneers Lopo de Carvalho, Egas Moniz and colleagues. Robb and Steinberg described pulmonary angiography by infusion of peripheral radiocontrast.
== References ==
== External links ==
"Pulmonary angiography" @ MedlinePlus Medical Encyclopedia | Wikipedia/Pulmonary_angiography |
Carbon dioxide angiography is a diagnostic radiographic technique in which a carbon dioxide (CO2) based contrast medium is used - unlike traditional angiography where the contrast medium normally used is iodine based – to see and study the body vessels. Since CO2 is a non-radio-opaque contrast medium, angiographic procedures need to be performed in digital subtraction angiography (DSA).
== History ==
The use of carbon dioxide as a contrast agent goes back to 1920s when the gas was used to visualize retroperitoneal structures. In the 1950s and early 1960s, CO2 was injected intravenously to delineate the right atrium for the detection of pericardial effusion. This imaging technique developed from animal and clinical studies which demonstrated that CO2 was safe and well tolerated with venous injections. In the early 1970s, Dr. Hawkins and Dr. Cho started using and studying CO2 as a contrast agent also for peripheral vascular imaging and intervention. With the advent of digital subtraction angiography (DSA) technique in 1980s, CO2 has evolved into a safe and useful alternative contrast agent in both arteriography and venography. Because of its lack of renal toxicity and allergic potential, CO2 is a preferred contrast agent in patients with renal failure or iodinated contrast medium allergy, and particularly in patients who require large volumes of contrast medium for complex endovascular procedures.
== Technique ==
CO2 angiography is intended only for peripheral procedures. In case of procedures in the arterious system it is allowed to inject CO2 only below the diaphragm; while in the venous system it can also be investigated supradiaphragmatic, provided that the cerebral vessels are excluded. Taking this aspect into consideration, the practical approach follows that of the iodinated contrast procedures. The contrast injection can be carried out, similarly, both with manual devices and with automatic injectors (Automated Carbon Dioxide Angiography, ACDA).
== Properties ==
Being naturally present in the human body, CO2 is the only 100% biocompatible contrast agent, meaning no adverse reactions, such as allergy, nephrotoxicity, and hepatotoxicity.
Carbon dioxide is a negative contrast medium and it has a low radiopacity (while iodinated contrast media are defined as positive contrast media due to their high radiopacity). Contrast is caused by the different X-ray absorption coefficients between the tissue and the contrast agent. In the vascular imaging results produced using CO2, vessels look brighter rather than the surrounding tissues, because the contrast medium absorbs less X-ray radiations rather an iodine-based contrast medium, where the vessel are displayed in black.
The CO2 does not mix with blood. At atmospheric pressure CO2 is in gaseous form and, when it comes out from the catheter, it forms a train of bubbles which displaces blood, causing a transient ischemia, in relation to the bloodstream (systolic pressure). When added together by DSA “stacking” software, the result is a composite diagnostic image of the frames.
Carbon dioxide is highly soluble, allowing multiple injections without a maximum dosage (per procedure, while it is 100 mL per injection by the literature), but, in case of multiple injections, should be considered and adequate time interval between them, so to allow the gas to be expelled from the body. Compared with the oxygen, the most present gaseous substance in the body, CO2 is more than 20 times more soluble, meaning the possibility of injecting high quantities in the body.
High compressibility and explosive delivery. More pressure is exerted to the gas, more its density increases, resulting in a decrease in gas volume and an increase in gas pressure. The effusion of the gas from the catheter orifice into a state of lower pressure, such as a blood vessel, leads to a sudden increase in the volume of the gas - the “explosive delivery” or “jet effect” - which could lead to an excessive stress in vessels walls. To avoid this, immediately prior to the injection of CO2, a flush is performed, injecting small amounts of CO2 to reduce gas compression and guarantee gas delivery at a steady flow rate.
CO2 is 400 times less viscous than iodinated contrast medium, allowing its injection through devices with a very little inner lumen, as microcatheters, or, even, with other devices inserted in the catheter, as guidewires, balloons or as in atherectomy procedures. The low viscosity of CO2 makes it easy to pass through small vessels, visualizing tight stenosis, collaterals, small bleedings and endoleaks in AAA procedures.
Expulsion: Once dissolved in the plasma, CO2 is transported to the lungs and removed in a single pass by the alveoli, favoring the possibility of performing multiple injections without complications (in healthy patients, meaning no severe COPD or significant POF, especially in presence of pulmonary embolism).
Buoyancy is defined as the tendency of a body to float when submerged into a fluid. CO2 is lighter than blood and, therefore, floats above the bloodstream. The main advantage is represented by the simplicity of filling the more superficial (in transverse plane) vessels of the body, conversely the main disadvantage consists in a less ease of filling the deeper ones.
== Side effects ==
Pins and needles/burning sensation, nausea and temporary discomfort are possible sensations during CO2 angiography, mainly because the transient ischemia caused by the CO2 bubbles flowing in the bloodstream. CO2 is also neurotoxic, so brain injections should be avoided. The most feared complication for intravascular use is air embolism, which can result in stroke, myocardial infarction, paralysis, amputation, or death, although this risk across all patients is less than 1%. A large amount of CO2 trapped in the pulmonary artery or right side of the heart (only of concern during venography) obstructs venous return resulting in bradycardia and hypotension. The patient should be rotated into a left lateral decubitus position if this happens to attempt to separate the CO2 into a gas layer floating "on top of" and no longer interfering with the flow of the liquid and solid components of blood (vapor lock). Therefore, having a delivery system, which prevents air room diffusion, is a necessary safety measure for the patients.
== References == | Wikipedia/Carbon_dioxide_angiography |
Laser surgery is a type of surgery that cuts tissue using a laser in contrast to using a scalpel.
Soft-tissue laser surgery is used in a variety of applications in humans (general surgery, neurosurgery, ENT, dentistry, orthodontics, and oral and maxillofacial surgery) as well as veterinary surgical fields. The primary uses of lasers in soft tissue surgery are to cut, ablate, vaporize, and coagulate. There are several different laser wavelengths used in soft tissue surgery. Different laser wavelengths and device settings (such as pulse duration and power) produce different effects on the tissue. Some commonly used lasers types in soft tissue surgery include erbium, diode, and CO2. Erbium lasers are excellent cutters, but provide minimal hemostasis. Diode lasers (hot tip) provide excellent hemostasis, but are slow cutters. CO2 lasers are both efficient at cutting and coagulating. Laser surgery is commonly used on the eye. Techniques used include LASIK, which is used to correct near and far-sightedness in vision, and photorefractive keratectomy, a procedure which permanently reshapes the cornea using an excimer laser to remove a small amount of the human tissue.
== Effects ==
Photochemical effect: clinically referred to as photodynamic therapy. Photosensitizer (photophrin II) is administered which is taken up by the tumor tissue and later irradiated by laser light resulting in highly toxic substances with resultant necrosis of the tumor. Photodynamic therapy is used in palliation of oesophageal and bronchial carcinoma and ablation of mucosal cancers of Gastrointestinal tract and urinary bladder.
Photoablative effect: Used in eye surgeries like band keratoplasty, and endartectomy of peripheral blood vessels.
Photothermal effect: this property is used for endoscopic control of bleeding e.g. Bleeding peptic ulcers, oesophageal varices
Photomechanical effect: used in intraluminal lithotripsy
== Equipment ==
Surgical laser systems, sometimes called "laser scalpels", are differentiated not only by the wavelength, but also by the light delivery system: flexible fiber or articulated arm, as well as by other factors.
Types of surgical lasers include carbon dioxide, argon, Nd:YAG laser, and potassium titanyl phosphate. CO2 lasers were the dominant soft-tissue surgical lasers as of 2010.
== Applications ==
=== Dermatology and plastic surgery ===
A range of lasers such as erbium, dye, Q switch lasers, and CO2 are used to treat various skin conditions including scars, vascular and pigmented lesions, and for photorejuvenation. The laser surgery for dermatology often bypasses the skin surface. The principle of laser surgery for dermatologic problems is based on SPTL (selective photothermolysis). The laser beam penetrates the skin until it encounters chromophore which absorbs the laser beam. After absorption of the laser beam, heat is generated to induce coagulation, necrosis of the targeted tissue, this results in the removal of unwanted tissue by laser surgery.
Laser resurfacing is a technique in which covalent bonds of a material are dissolved by a laser, a technique invented by aesthetic plastic surgeon Thomas L. Roberts, III using CO2 lasers in the 1990s.
Lasers are also used for laser-assisted lipectomy.
=== Eye surgery ===
Various types of laser surgery are used to treat refractive error. LASIK, in which a knife is used to cut a flap in the cornea, and a laser is used to reshape the layers underneath, is used to treat refractive error. IntraLASIK is a variant in which the flap is also cut with a laser. In photorefractive keratectomy (PRK, LASEK), the cornea is reshaped without first cutting a flap. In laser thermal keratoplasty, a ring of concentric burns is made in the cornea, which causes its surface to steepen, allowing better near vision. ReLEx SMILE is the latest advancement in laser vision correction technology. In SMILE surgery, ZEISS VisuMax femtosecond laser is used to make a small incision and to create a pre-calculated mini lens tissue (or lenticule) inside the cornea.
Lasers are also used to treat non-refractive conditions, such as phototherapeutic keratectomy (PTK) in which opacities and surface irregularities are removed from the cornea and laser coagulation in which a laser is used to cauterize blood vessels in the eye, to treat various conditions. Lasers can be used to repair tears in the retina.
=== Endovascular surgery ===
Laser endarterectomy is a technique in which an entire atheromatous plaque in the artery is excised. Other applications include laser assisted angioplasties and laser-assisted vascular anastomosis.
=== Foot and ankle surgery ===
Lasers are used to treat several disorders in foot and ankle surgery. They are used to remove benign and malignant tumors, treat bunions, debride ulcers and burns, excise epidermal nevi, blue rubber bleb nevi, and keloids, and the removal of hypertrophic scars and tattoos.
A carbon dioxide laser (CO2) is used in surgery to treat onychocryptosis (ingrown nails), onychauxis (club nails), onychogryposis (rams horn nail), and onychomycosis (fungus nail).
=== Gastro-intestinal tract ===
Peptic ulcer disease and oesophageal varices - Laser photoablation is done.
Coagulation of vascular malformations of stomach, duodenum, and colon.
Lasers can be effectively used to treat early gastric cancers provided they are less than 4 cm and without lymph node involvement. Lasers are also used in treating oral submucous fibrosis.
Palliative laser therapy is given in advanced oesophageal cancers with obstruction of lumen. Recanalisation of the lumen is done which allows the patient to resume a soft diet and maintain hydration.
Ablative laser therapy is used in advanced colorectal cancers to relieve obstruction and to control bleeding.
Laser surgery used in hemorrhoidectomy, and is a relatively popular and non-invasive method of hemorrhoid removal.
Laser-assisted liver resections have been done using carbon dioxide and Nd:YAG lasers.
The ablation of liver tumors can be achieved by selective photovaporization of the tumor.
Endoscopic laser lithotripsy is a safer modality compared to electrohydraulic lithotripsy.
=== Oral and dental surgery ===
The CO2 laser is used in oral and dental surgery for virtually all soft-tissue procedures, such as gingivectomies, vestibuloplasties, frenectomies, and operculectomies. The CO2 10,600 nm wavelength is safe around implants as it is reflected by titanium, and thus has been gaining popularity in the field of periodontology. The laser may also be effective in treating peri-implantitis.
=== Spine surgery ===
Laser spine surgery first began seeing clinical use in the 1980s and was primarily used within discectomy to treat lumbar disc disease under the notion that heating a bulging disc vaporized enough tissue to relieve pressure on the nerves and help alleviate pain.
Since that time, laser spine surgery has become one of the most marketed forms of minimally invasive spine surgery, despite the fact that it has never been studied in a controlled clinical trial to determine its effectiveness apart from disc decompression. Evidence-based data surrounding the use of lasers in spine surgery is limited and its safety and efficacy were poorly understood as of 2017.
=== Thoracic surgery ===
In thoracic surgery, surgical laser applications are most often used to remove pulmonary metastases and tumors of different primary localizations. Other areas of application are surgical sectioning of the parenchyma, anatomic segmental resections, removal of tumors from the thoracic wall and abrasion of the pleura parietalis. Since the introduction of surgical lasers, the amount of potentially surgically resectable pulmonary nodules has significantly increased. Compared to laser surgery, other conventional surgical methods such as segmental or wedge resections with surgical stapling will normally lead to a bigger loss of lung tissue, especially in patients with multiple pulmonary nodules methods.
Other advantages of laser surgery compared to conventional methods are that it leads to an improved postoperative lung function and that it gives the additional possibility to histologically analyze the removed material which would otherwise be destroyed through radiation or heat.
=== Hard tissues ===
Lasers are used to cut or ablate bones and teeth in dentistry.
=== Other surgery ===
The CO2 laser is also used in gynecology, genitourinary, general surgery, otorhinolaryngology, orthopedic, and neurosurgery.
== References == | Wikipedia/Laser_surgery |
Sclerotherapy (the word reflects the Greek skleros, meaning hard)
is a procedure used to treat blood vessel malformations (vascular malformations) and also malformations of the lymphatic system. A medication is injected into the vessels, which makes them shrink. It is used for children and young adults with vascular or lymphatic malformations. In adults, sclerotherapy is often used to treat spider veins, smaller varicose veins, hemorrhoids, and hydroceles.
Sclerotherapy is one method for the treatment of spider veins, varicose veins (which are also often treated with surgery, radiofrequency, and laser ablation), and venous malformations. In ultrasound-guided sclerotherapy, ultrasound is used to visualize the underlying vein so the physician can deliver and monitor the injection. Sclerotherapy often takes place under ultrasound guidance after venous abnormalities have been diagnosed with duplex ultrasound. Sclerotherapy under ultrasound guidance and using microfoam sclerosants has been shown to be effective in controlling reflux from the sapheno-femoral and sapheno-popliteal junctions. However, some authors believe that sclerotherapy is not suitable for veins with reflux from the greater or lesser saphenous junction, or for veins with axial reflux. This is due to the emergence of more effective technologies, including laser ablation and radiofrequency, which have demonstrated superior efficacy to sclerotherapy for treatment of these veins.
== Historical aspects ==
Sclerotherapy has been used in the treatment of spider veins and occasionally varicose veins for over 150 years. Like varicose vein surgery, sclerotherapy techniques have evolved during that time. Modern techniques including ultrasonographic guidance and foam sclerotherapy are the latest developments in this evolution.
The first reported attempt at sclerotherapy was by D Zollikofer in Switzerland in 1682, who injected an acid into a vein to induce thrombus formation. Both Debout and Cassaignaic reported success in treating varicose veins by injecting perchlorate of iron in 1853. Desgranges in 1854 cured 16 cases of varicose veins by injecting iodine and tannin into the veins. This was approximately 12 years after the probable advent of great saphenous vein stripping in 1844 by Madelung. However, due to high rates of side-effects with the drugs used at the time, sclerotherapy had been practically abandoned by 1894. With the improvements in surgical techniques and anaesthetics over that time, stripping became the treatment of choice.
Work continued on alternative sclerosants in the early 20th century. During that time carbolic acid and perchlorate of mercury were tried and whilst these showed some effect in obliterating varicose veins, side-effects also caused them to be abandoned. Prof. Sicard and other French doctors developed the use of sodium carbonate and then sodium salicylate during and after the First World War. Quinine was also used with some effect during the early 20th century. At the time of Coppleson's book in 1929, he was advocating the use of sodium salicylate or quinine as the best choices of sclerosant.
Further work on improving the technique and development of safer more effective sclerosants continued through the 1940s and 1950s. Of particular importance was the development of sodium tetradecyl sulfate (STS) in 1946, a product still widely used to this day. George Fegan in the 1960s reported treating over 13,000 patients with sclerotherapy, significantly advancing the technique by focussing on fibrosis of the vein rather than thrombosis, concentrating on controlling significant points of reflux and emphasizing the importance of compression of the treated leg. The procedure became medically accepted in mainland Europe during that time. However, it was poorly understood or accepted in England or the United States, a situation that continues to this day amongst some sections of the medical community.
The next major development in the evolution of sclerotherapy was the advent of duplex ultrasonography in the 1980s and its incorporation into the practise of sclerotherapy later that decade. Knight was an early advocate of this new procedure and presented it at several conferences in Europe and the United States. Thibault's article was the first on this topic to be published in a peer-reviewed journal.
The work of Cabrera and Monfreaux in utilising foam sclerotherapy along with Tessari's "3-way tap method" of foam production further revolutionised the treatment of larger varicose veins with sclerotherapy. This has now been further modified by Whiteley and Patel to use 3 non-silicone syringes for more long lasting foam.
== Methods ==
Injecting the unwanted veins with a sclerosing solution causes the target vein to immediately shrink, and then dissolve over a period of weeks as the body naturally absorbs the treated vein. The initial "shrinkage" is caused by spasm of the muscular layer of the vein wall. The sclerosing solution damages the vein wall, causing inflammation and gradual scarring ("sclerosis") over the following weeks. The sclerosis is caused by an increase in fibroblasts in the cell wall which causes contraction of the vein. The process requires carefully assessing the strength of the sclerosing solution so it is strong enough to cause a clinically significant effect in the target vein without causing excessive damage to surrounding tissues. Sclerotherapy is a non-invasive procedure taking only about 10 minutes to perform. The downtime is minimal, in comparison to an invasive varicose vein surgery.
Sclerotherapy is the "gold standard" and is preferred over laser for eliminating large spider veins telangiectasias. [Telangiectasia is a condition in which broken or widened small blood vessels that sit near the surface of the skin or mucous membranes create visible], and smaller varicose leg veins. Unlike a laser, the sclerosing solution additionally closes the reticular veins also known as feeder veins under the skin that are causing the spider veins to form, thereby making a recurrence of the spider veins in the treated area less likely. Multiple injections of dilute sclerosant are injected into the abnormal surface veins of the involved leg. The patient's leg is then compressed with either stockings or bandages that they wear usually for one week after treatment. Patients are also encouraged to walk regularly during that time. It is common practice for the patient to require at least two treatment sessions separated by several weeks to significantly improve the appearance of their leg veins.
Sclerotherapy can also be performed using microfoam sclerosants under ultrasound guidance to treat larger varicose veins, including the great and small saphenous veins. After a map of the patient's varicose veins is created using ultrasound, these veins are injected whilst real-time monitoring of the injections is undertaken, also using ultrasound. The sclerosant can be observed entering the vein, and further injections performed so that all the abnormal veins are treated. Follow-up ultrasound scans are used to confirm closure of the treated veins and any residual varicose veins can be identified and treated.
== Foam sclerotherapy ==
Foam sclerotherapy is a technique that involves injecting "foamed sclerosant drugs" within a blood vessel using a pair of syringes – one with sclerosant in it and one with gas (originally air). The original Tessari method has now been modified by the Whiteley-Patel modification which uses 3 syringes, all of which are silicone-free. The sclerosant drugs (sodium tetradecyl sulfate, bleomycin or polidocanol) are mixed with air or a physiological gas (carbon dioxide) in a syringe or by using mechanical pumps. This increases the surface area of the drug. The foam sclerosant drug is more efficacious than the liquid one in causing sclerosis (thickening of the vessel wall and sealing off the blood flow), for it does not mix with the blood in the vessel and in fact displaces it, thus avoiding dilution of the drug and causing maximal sclerosant action. It is therefore useful for longer and larger veins. Experts in foam sclerotherapy have created “tooth paste” like thick foam for their injections, which has revolutionized the non-surgical treatment of varicose veins and venous malformations, including Klippel–Trénaunay syndrome.
== Bleomycin electrosclerotherapy ==
Bleomycin electrosclerotherapy consists of locally delivering the sclerosant bleomycin and applying short high voltage electrical pulses to the area to be treated, resulting in a local and temporary increased permeability of the cell membranes, increasing the intracellular concentration of bleomycin by a factor of up to several thousand. Preclinical studies also indicated that electroporation in combination with bleomycin impaired the barrier function of the endothelium by interacting with the organization of the cytoskeleton and the integrity of the junctions. This can lead to extravasation, interstitial edema and a desired collapse of the vascular structures.
The procedure has been researched as electrochemotherapy of skin tumors since the early 1990s and was first used in 2017 for vascular malformations. Initial reports indicated that the use of bleomycin in combination with reversible electroporation can potentially enhance the sclerotherapy effect. A retrospective study of 17 patients with venous malformations who did not respond to previous invasive therapies showed an average decrease in lesion volume measured on MRI images of 86% with clinical improvement in all patients after an average of 3.7 months and 1.12 sessions per patient, with a reduced dose of bleomycin and a reduced number of sessions compared to standard bleomycin sclerotherapy
== Clinical evaluations ==
A study by Kanter and Thibault in 1996 reported a 76% success rate at 24 months in treating saphenofemoral junction and great saphenous vein incompetence with STS 3% solution. Padbury and Benveniste found that ultrasound guided sclerotherapy was effective in controlling reflux in the small saphenous vein. Barrett et al. found that microfoam ultrasound guided sclerotherapy was "effective in treating all sizes of varicose veins with high patient satisfaction and improvement in quality of life".
A Cochrane Collaboration review of the medical literature concluded that "the evidence supports the current place of sclerotherapy in modern clinical practice, which is usually limited to treatment of recurrent varicose veins following surgery and thread veins." A second Cochrane Collaboration review comparing surgery to sclerotherapy concluded that sclerotherapy has greater benefits than surgery in the short term but surgery has greater benefits in the longer term. Sclerotherapy was better than surgery in terms of treatment success, complication rate and cost at one year, but surgery was better after five years. However, the evidence was not of very good quality and more research is needed.
A Health Technology Assessment found that sclerotherapy provided less benefit than surgery, but is likely to provide a small benefit in varicose veins without reflux from the sapheno-femoral or sapheno-popliteal junctions. It did not study the relative benefits of surgery and sclerotherapy in varicose veins with junctional reflux.
The European Consensus Meeting on Foam Sclerotherapy in 2003 concluded that "Foam sclerotherapy allows a skilled practitioner to treat larger veins including saphenous trunks". A second European Consensus Meeting on Foam Sclerotherapy in 2006 has now been published.
== Complications ==
Complications, while rare, include venous thromboembolism, visual disturbances, allergic reaction, thrombophlebitis, skin necrosis, and hyperpigmentation or a red treatment area.
If the sclerosant is injected properly into the vein, there is no damage to the surrounding skin, but if it is injected outside the vein, tissue necrosis and scarring can result. Skin necrosis, whilst rare, can be cosmetically "potentially devastating", and may take months to heal. It is very rare when small amounts of dilute (<0.25%) sodium tetradecyl sulfate (STS) is used, but has been seen when higher concentrations (3%) are used. Blanching of the skin often occurs when STS is injected into arterioles (small artery branches). Telangiectatic matting, or the development of tiny red vessels, is unpredictable and usually must be treated with repeat sclerotherapy or laser.
Most complications occur due to an intense inflammatory reaction to the sclerotherapy agent in the area surrounding the injected vein. In addition, there are systemic complications that are now becoming increasingly understood. These occur when the sclerosant travels through the veins to the heart, lung and brain. A recent report attributed a stroke to foam treatment, although this involved the injection of an unusually large amount of foam.
More recent reports have shown that bubbles from even a small amount of sclerosant foam injected into the veins quickly appear in the heart, lung and brain. The significance of this is not fully understood at this point and large studies show that foam sclerotherapy is safe. Sclerotherapy is fully FDA approved in the USA.
Contraindications include: bed rest, severe systemic diseases, poor patient understanding, needle phobia, short life expectancy, late stage cancer, known allergy to the sclerosing agent, and treatment with tamoxifen.
== See also ==
Pleurodesis
CLaCS, a treatment using a transdermal laser and sclerotherapy
== References ==
== External links ==
Management of venous malformations in Klippel–Trenaunay syndrome with ultrasound-guided foam sclerotherapy
Information about Lymphatic Malformations and the use of sclerotherapy to treat them from Children's Hospital, Seattle
Ultrasound video of a sclerotherapy taking place
Video of Sclerotherapeutic procedure
The American Vein and Lymphatic Society is an Association of venous disease providers who practice sclerotherapy and other venous modalities.
Bleomycin Electrosclerotherapy of Vascular Malformations #YiiRS2021 by Prof. Walter A. Wohlgemuth (Video)
Bleomycin ElectroScleroTherapy (BEST) - Compendium Vascular Anomalies | Wikipedia/Sclerotherapy |
Impedance cardiography (ICG) is a non-invasive technology measuring total electrical conductivity of the thorax and its changes in time to process continuously a number of cardiodynamic parameters, such as stroke volume (SV), heart rate (HR), cardiac output (CO), ventricular ejection time (VET), pre-ejection period and used to detect the impedance changes caused by a high-frequency, low magnitude current flowing through the thorax between additional two pairs of electrodes located outside of the measured segment. The sensing electrodes also detect the ECG signal, which is used as a timing clock of the system.
== Introduction ==
Impedance cardiography (ICG), also referred to as electrical impedance plethysmography (EIP) or Thoracic Electrical Bioimpedance (TEB) has been researched since the 1940s. NASA helped develop the technology in the 1960s. The use of impedance cardiography in psychophysiological research was pioneered by the publication of an article by Miller and Horvath in 1978. Subsequently, the recommendations of Miller and Horvath were confirmed by a standards group in 1990. A comprehensive list of references is available at ICG Publications. With ICG, the placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate cardiodynamic parameters.
== Process ==
Four pairs of electrodes are placed at the neck and the diaphragm level, delineating the thorax
High frequency, low magnitude current is transmitted through the chest in a direction parallel with the spine from the set of outside pairs
Current seeks path of least resistance: the blood filled aorta (the systolic phase signal) and both vena cava superior and inferior (the diastolic phase signal, mostly related to respiration)
The inside pairs, placed at the anatomic landmarks delineating thorax, sense the impedance signals and the ECG signal
ICG measures the baseline impedance (resistance) to this current
With each heartbeat, blood volume and velocity in the aorta change
ICG measures the corresponding change in impedance and its timing
ICG attributes the changes in impedance to (a) the volumetric expansion of the aorta (this is the main difference between ICG and electrical cardiometry) and (b) to the blood velocity-caused alignment of erythrocytes as a function of blood velocity
ICG uses the baseline and changes in impedance to measure and calculate hemodynamic parameters
== Hemodynamics ==
Hemodynamics is a subchapter of cardiovascular physiology, which is concerned with the forces generated by the heart and the resulting motion of blood through the cardiovascular system. These forces demonstrate themselves to the clinician as paired values of blood flow and blood pressure measured simultaneously at the output node of the left heart.
Hemodynamics is a fluidic counterpart to the Ohm's law in electronics: pressure is equivalent to voltage, flow to current, vascular resistance to electrical resistance and myocardial work to power.
The relationship between the instantaneous values of aortic blood pressure and blood flow through the aortic valve over one heartbeat interval and their mean values are depicted in Fig.1. Their instantaneous values may be used in research; in clinical practice, their mean values, MAP and SV, are adequate.
=== Blood flow parameters ===
Systemic (global) blood flow parameters are (a) the blood flow per heartbeat, the Stroke Volume, SV [ml/beat], and (b) the blood flow per minute, the Cardiac Output, CO [l/min].
There is clear relationship between these blood flow parameters:
CO[l/min] = (SV[ml] × HR[bpm])/1000 {Eq.1}
where HR is the Heart Rate frequency (beats per minute, bpm).
Since the normal value of CO is proportional to body mass it has to perfuse, one "normal" value of SV and CO for all adults cannot exist. All blood flow parameters have to be indexed. The accepted convention is to index them by the Body Surface Area, BSA [m2], by DuBois & DuBois Formula, a function of height and weight:
BSA[m2] = W0.425[kg] × H0.725[cm] × 0.007184 {Eq.2}
The resulting indexed parameters are Stroke Index, SI (ml/beat/m2) defined as
SI[ml/beat/m2] = SV[ml]/BSA[m2] {Eq.3}
and Cardiac Index, CI (l/min/m2), defined as
CI[l/min/m2] = CO[l/min]/BSA[m2] {Eq.4}
These indexed blood flow parameters exhibit typical ranges:
For the Stroke Index: 35 < SItypical < 65 ml/beat/m2; for the Cardiac Index: 2.8 < CItypical < 4.2 l/min/m2.
Eq.1 for indexed parameters then changes to
CI[l/min/m2] = (SI[ml/beat/m2] × HR[bpm])/1000 {Eq.1a}
=== Oxygen transport ===
The primary function of the cardiovascular system is transport of oxygen: blood is the vehicle, oxygen is the cargo. The task of the healthy cardiovascular system is to provide adequate perfusion to all organs and to maintain a dynamic equilibrium between oxygen demand and oxygen delivery. In a healthy person, the cardiovascular system always increases blood flow in response to increased oxygen demand. In a hemodynamically compromised person, when the system is unable to satisfy increased oxygen demand, the blood flow to organs lower on the oxygen delivery priority list is reduced and these organs may, eventually, fail. Digestive disorders, male impotence, tiredness, sleepwalking, environmental temperature intolerance, are classic examples of a low-flow-state, resulting in reduced blood flow.
=== Modulators ===
SI variability and MAP variability are accomplished through activity of hemodynamic modulators.
The conventional cardiovascular physiology terms for the hemodynamic modulators are preload, contractility and afterload. They deal with (a) the inertial filling forces of blood return into the atrium (preload), which stretch the myocardial fibers, thus storing energy in them, (b) the force by which the heart muscle fibers shorten thus releasing the energy stored in them in order to expel part of blood in the ventricle into the vasculature (contractility), and (c) the forces the pump has to overcome in order to deliver a bolus of blood into the aorta per each contraction (afterload).
The level of preload is currently assessed either from the PAOP (pulmonary artery occluded pressure) in a catheterized patient, or from EDI (end-diastolic index) by use of ultrasound. Contractility is not routinely assessed; quite often inotropy and contractility are interchanged as equal terms. Afterload is assessed from the SVRI value.
Rather than using the terms preload, contractility and afterload, the preferential terminology and methodology in per-beat hemodynamics is to use the terms for actual hemodynamic modulating tools, which either the body utilizes or the clinician has in his toolbox to control the hemodynamic state:
The preload and the Frank-Starling (mechanically)-induced level of contractility is modulated by variation of intravascular volume (volume expansion or volume reduction/diuresis).
Pharmacological modulation of contractility is performed with cardioactive inotropic agents (positive or negative inotropes) being present in the blood stream and affecting the rate of contraction of myocardial fibers.
The afterload is modulated by varying the caliber of sphincters at the input and output of each organ, thus the vascular resistance, with the vasoactive pharmacological agents (vasoconstrictors or vasodilators and/or ACE Inhibitors and/or ARBs)(ACE = Angiotensin-converting-enzyme; ARB = Angiotensin-receptor-blocker). Afterload also increases with increasing blood viscosity, however, with the exception of extremely hemodiluted or hemoconcentrated patients, this parameter is not routinely considered in clinical practice.
With the exception of volume expansion, which can be accomplished only by physical means (intravenous or oral intake of fluids), all other hemodynamic modulating tools are pharmacological, cardioactive or vasoactive agents.
The measurement of CI and its derivatives allow clinicians to make timely patient assessment, diagnosis, prognosis, and treatment decisions. It has been well established that both trained and untrained physicians alike are unable to estimate cardiac output through physical assessment alone.
=== Invasive monitoring ===
Clinical measurement of cardiac output has been available since the 1970s. However, this blood flow measurement is highly invasive, utilizing a flow-directed, thermodilution catheter (also known as the Swan-Ganz catheter), which represents significant risks to the patient. In addition, this technique is costly (several hundred dollars per procedure) and requires a skilled physician and a sterile environment for catheter insertion. As a result, it has been used only in very narrow strata (less than 2%) of critically ill and high-risk patients in whom the knowledge of blood flow and oxygen transport outweighed the risks of the method. In the United States, it is estimated that at least two million pulmonary artery catheter monitoring procedures are performed annually, most often in peri-operative cardiac and vascular surgical patients, decompensated heart failure, multi-organ failure, and trauma.
=== Noninvasive monitoring ===
In theory, a noninvasive way to monitor hemodynamics would provide exceptional clinical value because data similar to invasive hemodynamic monitoring methods could be obtained with much lower cost and no risk. While noninvasive hemodynamic monitoring can be used in patients who previously required an invasive procedure, the largest impact can be made in patients and care environments where invasive hemodynamic monitoring was neither possible nor worth the risk or cost. Because of its safety and low cost, the applicability of vital hemodynamic measurements could be extended to significantly more patients, including outpatients with chronic diseases. ICG has even been used in extreme conditions such as outer space and a Mt. Everest expedition. Heart failure, hypertension, pacemaker, and dyspnea patients are four conditions in which outpatient noninvasive hemodynamic monitoring can play an important role in the assessment, diagnosis, prognosis, and treatment. Some studies have shown ICG cardiac output is accurate, while other studies have shown it is inaccurate. Use of ICG has been shown to improve blood pressure control in resistant hypertension when used by both specialists and general practitioners. ICG has also been shown to predict worsening status in heart failure.
== ICG Parameters ==
The electrical and impedance signals are processed to determine fiducial points, which are then utilized to measure and calculate hemodynamic parameters, such as cardiac output, stroke volume, systemic vascular resistance, thoracic fluid content, acceleration index, and systolic time ratio.
== References ==
== External links ==
http://bomed.us/teb.html Archived 2016-07-03 at the Wayback Machine | Wikipedia/Impedance_phlebography |
Digital subtraction angiography (DSA) is a fluoroscopy technique used in interventional radiology to clearly visualize blood vessels in a bony or dense soft tissue environment. Images are produced using contrast medium by subtracting a "pre-contrast image" or mask from subsequent images, once the contrast medium has been introduced into a structure. Hence the term "digital subtraction angiography. Subtraction angiography was first described in 1935 and in English sources in 1962 as a manual technique. Digital technology made DSA practical starting in the 1970s.
== Procedure ==
=== DSA and fluoroscopy ===
In traditional angiography, images are acquired by exposing an area of interest with time-controlled x-rays while injecting a contrast medium into the blood vessels. The image obtained includes the blood vessels, together with all overlying and underlying structures. The images are useful for determining anatomical position and variations, but unhelpful for visualizing blood vessels accurately.
In order to remove the distracting structures to see the vessels better, first a mask image is acquired. The mask image is simply an image of the same area before the contrast is administered. The radiological equipment used to capture this is usually an X-ray image intensifier, which then keeps producing images of the same area at a set rate (1 to 7.5 frames per second). Each subsequent image gets the original "mask" image subtracted out. (Mathematically, the incoming image is divided by the mask image) The radiologist controls how much contrast media is injected and for how long. Smaller structures require less contrast to fill the vessel than others. Images produced appear with a very pale grey background, which produces a high contrast to the blood vessels, which appear a very dark grey.
=== Intravenous digital subtraction angiography ===
Intravenous digital subtraction angiography (IV-DSA) is a form of angiography which was first developed in the late 1970s.
IV-DSA is a computer technique that compares an X-ray image of a region of the body before and after radiopaque iodine based dye has been injected intravenously into the body. Tissues and blood vessels on the first image are digitally subtracted from the second image, leaving a clear picture of the artery which can then be studied independently and in isolation from the rest of the body.
Some limited studies have indicated that IV-DSA is not suitable for patients with diabetes or kidney failure because the dye load is significantly higher than that used in arteriography. However, IV-DSA has been used successfully to study the vessels of the brain and heart and has helped detect carotid artery obstruction and to map patterns of cerebral blood flow. It also helps detect and diagnose lesions in the carotid arteries, a potential cause of strokes.
IV-DSA has also been useful in assessing patients prior to surgery and after coronary artery bypass surgery and some transplant operations.
== Applications ==
DSA is primarily used to image blood vessels. It is useful in the diagnosis and treatment of arterial and venous occlusions, including carotid artery stenosis, pulmonary embolisms, and acute limb ischaemia; arterial stenosis, which is particularly useful for potential kidney donors in detecting renal artery stenosis (DSA is the gold standard investigation for renal artery stenosis); cerebral aneurysms and arteriovenous malformations (AVM).
== The future ==
DSA is done less routinely in imaging departments. It is being replaced by computed tomography angiography (CTA), which can produce 3D images through a test which is less invasive and stressful for the patient, and magnetic resonance angiography (MRA), which avoids X-rays and nephrotoxic contrast agents.
== See also ==
Angiography
Computed tomography angiography (CTA)
Contrast medium
Peripheral artery disease
X-ray image intensifier
Digital variance angiography (DVA)
== References ==
== Further reading ==
Anagnostakos, Nicholas Peter; Tortora, Gerard J. (1990). Principles of Anatomy and Physiology. San Francisco: Harper & Row. ISBN 0-06-046694-4. | Wikipedia/Digital_subtraction_angiography |
Microangiography ( MY-kroh-AN-jee-OG-rə-fee) is a type of angiography that consists of the radiography of small blood or lymphatic vessels of an organ. While most other types of angiography cannot produce images of vessels smaller than 200 μm in diameter, microangiography does just that. A microangiographic image is the result of injection of a contrast medium into either the blood or the lymphatic system and, then, enlargement of the resulting radiograph. Thus, an image is obtained in which there is contrast between vessel and surrounding tissue. It is often used in order to detect microvascular lesions in organs. But, it has been suggested that microangiography can also be used to detect tumors through visualization of tumor-induced small blood vessels. This is because tumor growths require vascularization before they can develop more rapidly. A few of the commonly used types are fluorescent, silicone rubber, and synchrotron radiation microangiography.
== Common types ==
=== Fluorescent microangiography ===
Also known as FMA, fluorescent microangiography is used to visualize and quantify changes in microvasculature. It is different from other types of microangiography in that a fluorescent marker or contrast medium is used instead of something else. Fluorescein and indocyanine green are often used for this purpose.
=== Laser Doppler holography ===
Computational imaging with lasers, ultrahigh-speed cameras, commodity graphics cards, and state-of-the-art statistical filtering algorithms, emerges as a competitive alternative to dye angiographies. This class of non-invasive microangiography techniques can be advantageously applied to the eye fundus to reveal endoluminal blood flow profiles in the retina and choroid. Laser Doppler imaging by holography provides high-contrast visualization of local blood flow in choroidal vessels in humans, with a spatial resolution comparable to state-of-the-art indocyanine green angiography.
=== Silicone rubber microangiography ===
This type of microangiography produces a three-dimensional image that depicts the distribution of vasculature in a tissue. It is commonly used to determine changes in microvasculature.
=== Synchrotron radiation microangiography ===
This type of microangiography uses monochromatic synchrotron radiation and a high-definition video system to provide an image of small collateral arteries with a diameter less than 100 μm.
== See also ==
Computed Tomography Angiography
Intravenous digital subtraction angiography
== References == | Wikipedia/Microangiography |
Open aortic surgery (OAS), also known as open aortic repair (OAR), describes a technique whereby an abdominal, thoracic or retroperitoneal surgical incision is used to visualize and control the aorta for purposes of treatment, usually by the replacement of the affected segment with a prosthetic graft. OAS is used to treat aneurysms of the abdominal and thoracic aorta, aortic dissection, acute aortic syndrome, and aortic ruptures. Aortobifemoral bypass is also used to treat atherosclerotic disease of the abdominal aorta below the level of the renal arteries. In 2003, OAS was surpassed by endovascular aneurysm repair (EVAR) as the most common technique for repairing abdominal aortic aneurysms in the United States.
Depending on the extent of the aorta repaired, an open aortic operation may be called an Infrarenal aortic repair, a Thoracic aortic repair, or a Thoracoabdominal aortic repair. A thoracoabdominal aortic repair is a more extensive operation than either an isolated infrarenal or thoracic aortic repair.
OAS is distinct from aortic valve repair and aortic valve replacement, as OAS describes surgery of the aorta, rather than of the heart valves. When the aortic valve is diseased in addition to the ascending aorta, the Bentall procedure is used to treat the entire aortic root. An axillary-bifemoral bypass is another type of vascular bypass used to treat aortic pathology, however it is not true open aortic surgery as it reconstructs the flow of blood to the legs from the arm, rather than in the native location of the aorta.
== Medical uses ==
Open aortic surgery (OAS) is used to treat patients with aortic aneurysms greater than 5.5 cm in diameter, to treat aortic rupture of an aneurysm any size, to treat aortic dissections, and to treat acute aortic syndrome. It is used to treat infrarenal aneurysms, as well as juxta- and pararenal aneurysm, thoracic and thoracoabdominal aneurysms, and also non-aneurysmal aortic pathology. Disease of the aorta proximal to the left subclavian artery in the chest lies within the specialty of cardiac surgery, and is treated via procedures such as the valve-sparing aortic root replacement.
== Open repair versus endovascular repair ==
Prior to the advent of endovascular aneurysm repair (EVAR), OAS was the only surgical treatment available for aortic aneurysms. The shift away from open aortic surgery towards endovascular surgery since 2003 has been driven by worse perioperative mortality associated with OAS, particularly in patients in relatively frail health. Unlike endovascular repair, there are no strict anatomic contra-indications to open repair; Rather, open repair is viewed as the fall back option for patients with unfavorable anatomy for endovascular repair. The main drawback of open repair is the larger physiologic demand of the operation, which is associated with increased rates of short term mortality in most studies.
OAR is still preferred to EVAR at some institutions and by some patients as it may be more durable than EVAR, and does not require post-operative surveillance CT scans.
Patients younger than 50 years with descending and thoracoabdominal aortic aneurysm have low surgical risks, and open repairs can be performed with excellent short-term and durable long-term results. Open surgical repairs should be considered initially in younger patients requiring descending and thoracoabdominal aortic aneurysm repairs. Heritable thoracic aortic disease (HTAD) warrants closer postoperative surveillance.
OAS is sometimes required for patients who have previously undergone EVAR but need further treatment, such as for degeneration of the EVAR seal zones leading to continued aneurysm growth. OAS is also sometimes required in cases of EVAR graft infection where the stent graft is removed to treat the infection.
== Technique ==
Open surgery typically involves exposure of the dilated portion of the aorta and insertion of a synthetic (Dacron or Gore-Tex) graft (tube). Once the graft is sewn into the proximal (toward the patient's head - and more specifically, towards their aortic valve) and distal (toward the patient's foot) portions of the aorta, the aneurysmal sac is closed around the graft.
The aorta and its branching arteries are cross-clamped during open surgery. This can lead to inadequate blood supply to the spinal cord, resulting in paraplegia, when repairing thoracic aneurysms. A 2004 systematic review and meta analysis found that cerebrospinal fluid drainage (CFSD), when performed in experienced centers, reduces the risk of ischemic spinal cord injury by increasing the perfusion pressure to the spinal cord. A 2012 Cochrane systematic review noted that further research regarding the effectiveness of CFSD for preventing a spinal cord injury is required.
=== Approach ===
The infrarenal aorta can be approached via a transabdominal midline or paramedian incision, or via a retroperitoneal approach.
The paravisceral and thoracic aorta are approached via a left-sided posteriolateral thoracotomy incision in approximately the 9th intercostal space. For a thoracoabdominal aortic aneurysm, this approach can be extended to a median or paramedian abdominal incision to allow access to the iliac arteries.
=== Sequential aortic clamping ===
At medical centers with a high volume of open aortic surgery, the fastest option for open aortic surgery was sequential aortic clamping or "clamp-and-sew", whereby the aorta was clamped proximally and distally to the diseased segment, and a graft sewn into the intervening segment. This technique leaves the branches of the aorta un-perfused during the time it takes to sew in the graft, potentially increasing the risk of ischemia to the organs which derive their arterial supply from the clamped segment. Critics of this technique advocate intra-operative aortic perfusion. In infrarenal aneurysms, the relative tolerance of the lower extremities to ischemia allows surgeons to clamp distally with low risk of ill effect.
=== Techniques to limit ischemia ===
A number of techniques exist for maintaining perfusion to the viscera and spinal cord during open thoracoabdominal aortic aneurysm repair, including left heart bypass, balloon perfusion catheter placement in the visceral arteries, selective spinal drainage and cold crystalloid renal perfusion. There is limited evidence supporting these techniques.
=== Graft configuration ===
In OAS for infra-renal aneurysms, the abdominal aorta is anastomosed preferentially to the main limb of a tube or bifurcated graft in an end-to-end fashion to minimize turbulent flow at the proximal anastomosis. If normal aorta exists superior to the iliac bifurcation, a tube graft can be sewn distally to that normal aorta. If the distal aorta is diseased, a bifurcated graft can be used in an aorto-billiac or aorto-bifemoral configuration. If visceral vessels are involved in the diseased aortic segment, a branched graft can be used with branches sewn directly to visceral vessels, or the visceral vessels can be separately revascularized.
=== Reimplantation of the inferior mesenteric artery ===
Because of collateral blood flow from the superior mesenteric artery (SMA) via the marginal artery, the inferior mesenteric artery usually does not have to be reimplanted into the aortic graft when performing an open abdominal aortic aneurysm repair.
== Risks and complications ==
OAS is widely recognized as having higher rates of perioperative morbidity and mortality than endovascular procedures for comparable segments of the aorta. For example, in infrarenal aneurysms, perioperative mortality with endovascular surgery is approximately 0.5%, against 3% with open repair.
Besides the risk of death, other risks and complications with OAS depend on the segment of aorta involved, and may include renal failure, spinal cord ischemia leading to paralysis, buttock claudication, ischemic colitis, embolization leading to acute limb ischemia, infection, and bleeding. Development of spinal cord injury is associated with increased
perioperative mortality after the complex aortic repair.
Aortic graft infections occur in 1-5% of aortic prosthetic placements. It can result in limb amputation, pseudo-aneurysm formation, septic emboli, aorto-enteric fistulae, septic shock and death. The most frequently involved pathogens are Staphylococcus aureus, and coagulase-negative staphylococci, followed by Enterobacterales and uncommon bacteria. In case of gut involvement also fungi may play a role. For patients unable to undergo major surgery, the outcome of conservative approach remains uncertain but usually provides for life-long suppressive antibiotic therapy. In selected cases an attempt of stopping antibiotic treatment after 3-6 months can be done.
== Recovery after OAS ==
Recovery time after OAS is substantial. Immediately following surgery, patients can expect to spend 1–3 days in the intensive care unit, followed by 4–10 days on the hospital ward. After discharge, patients will take 3–6 months to fully recover their energy and return to their pre-operative daily activities. However, enhanced recovery after surgery (ERAS) protocols can improve recovery following surgery.
Open repair for thoracoabdominal aneurysms requires a very large incision that cuts through muscles and sometimes bones making recovery very difficult and painful for the patient. Intraoperative intercostal nerve cryoanalgesia has been used during procedure to help reduce pain after TAAA.
== History ==
The history of aortic surgery dates back to Greek surgeon Antyllus, who first performed surgeries for various aneurysms in the second century CE. Many advancements of OAS have been developed in the past century.
In 1955, cardiovascular surgeons, Drs. Michael DeBakey and Denton Cooley performed the first replacement of a thoracic aneurysm with a homograft. In 1958, they began using the Dacron graft, resulting in a revolution for surgeons in the surgical repair of aortic aneurysms. DeBakey was first to perform cardiopulmonary bypass to repair the ascending aorta, using antegrade perfusion of the brachiocephalic artery.
By the mid-1960s, at Baylor College of Medicine, DeBakey’s group began performing surgery on thoracoabdominal aortic aneurysms (TAAA), which presented formidable surgical challenges, often fraught with serious complications, such as paraplegia, paraparesis and renal failure. DeBakey protégé and vascular Surgeon, E. Stanley Crawford, in particular, began dedicating most of his time to TAAAs. In 1986, he classified TAAA open surgery cases into four types: Extent I, extending from the left subclavian artery to just below the renal artery; Extent II, from the left subclavian to below the renal artery; Extent III, from the sixth intercostal space to below the renal artery; and Extent IV, from the twelfth intercostal space to the iliac bifurcation (i.e. total abdominal).
In 1992, another classification, Extent V, characterized by Hazim J. Safi, MD, identified aneurysmal disease extending from the sixth intercostal space to above the renal arteries. Safi's group used experimental animal models for a prospective study on the use distal aortic perfusion, cerebrospinal fluid drainage, moderate hypothermia and sequential clamping to decrease in the incidence of neurological deficit. In 1994, they presented their experiences, showing that the incidence for Extent I and II dropped from 25% to 5%. This marked a new era for protecting the spinal cord, brain, kidneys, heart and lungs during OAS on TAAA.
== Progress and future challenges ==
Postoperative paraplegia and paraparesis have been the scourge of thoracoabdominal aortic repair since the inception of the procedure. However, with evolving surgical strategies, identification of predictors, and use of various adjuncts over the years, the incidence of spinal cord injury after thoracic/thoracoabdominal aortic repair has declined. Embracing a multimodality approach offers a good insight into combating this grave complication
== See also ==
Aortic valve repair
== References == | Wikipedia/Open_aortic_surgery |
Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.
== Expression pattern ==
First discovered in 1979, EpCAM was initially described as a dominant surface antigen on human colon carcinoma. Because of its prevalence on many carcinomas, it has been "discovered" many different times. EpCAM therefore has many aliases the most notable of which include TACSTD1 (tumor-associated calcium signal transducer 1), CD326 (cluster of differentiation 326), and the 17-1A antigen.
EpCAM expression is not limited to human colon carcinomas; in fact, EpCAM is expressed in a variety of human epithelial tissues, carcinomas, and progenitor and stem cells. However, EpCAM is not found in non-epithelial cells or cancers of non-epithelial origin. EpCAM is expressed on the basolateral membrane of all simple (especially glandular), pseudo-stratified, and transitional epithelia. In contrast, normal squamous stratified epithelia are negative for EpCAM. The level of expression may differ significantly between the individual tissue types. In the gastrointestinal tract, the gastric epithelium expresses very low levels of EpCAM. Expression levels are substantially higher in small intestine, and in colon EpCAM is probably expressed at the highest levels among all epithelial cell types.
EpCAM is frequently upregulated in carcinomas but is not expressed in cancers of non-epithelial origin. In cancer cells, EpCAM is expressed in a dispersed pattern across the cell membrane. However, EpCAM expression in carcinomas is often heterogeneous; some cells in a tumor have more EpCAM than other cells in the same tumor.
Squamous carcinomas often express EpCAM whereas normal squamous cells do not express EpCAM. EpCAM expression differs between different types of renal cell carcinomas, and EpCAM expression increases during development of androgen resistance in prostate cancer. All of this points towards the utility of EpCAM as a diagnostic tool for various cancers.
== Structure ==
Although it is identified as a cell adhesion molecule, EpCAM does not structurally resemble any of the four major families of cell adhesion molecules, namely cadherins, integrins, selectins, and members of the immunoglobulin super-family.
EpCAM is a glycosylated, 30- to 40-kDa type I membrane protein. The sequence of the EpCAM molecule predicts the presence of three potential N-linked glycosylation sites. It is composed of 314 amino acids. EpCAM consists of an extracellular domain (242 amino acids) with epidermal growth factor (EGF)- and thyroglobulin repeat-like domains, a single transmembrane domain (23 amino acids), and a short intracellular domain (26 amino acids). The extracellular domain is sometimes referred to as EpEX, and the intracellular domain is sometimes referred to as EpICD.
== Function ==
The exact function of EpCAM is currently being elucidated, but EpCAM appears to play many different roles.
=== Cell adhesion ===
EpCAM was first found to play a role in homotypic cell adhesion. This means that EpCAM on the surface of one cell binds to the EpCAM on a neighboring cell thereby holding the cells together. The adhesions mediated by EpCAM are relatively weak, as compared to some other adhesion molecules, such as classic cadherins.
EpICD is required for EpCAM to mediate intercellular adhesion; EpCAM mediates intercellular adhesion and associates with the actin cytoskeleton via EpICD.
EpCAM has a negative impact on cadherin-mediated adhesions. Overexpression of EpCAM does not alter overall total cellular level of cadherins but rather decreases the association of the cadherin/catenin complex in the cytoskeleton. As EpCAM expression increases, the total amount of α-catenin decreases, whereas cellular β-catenin levels remain constant.
The homotypic adhesive activity has been questioned, as a variety of in vivo and in vitro biochemical experiments have failed to detect trans-interactions. EpCAM pro-adhesive activity could be explained by alternative models, based on its ability to regulate PKC signalling and myosin activity.
Recently, it has been discovered that EpCAM contributes to the maintenance of tight junctions.
Active proliferation in a number of epithelial tissues is associated with increased or de novo EpCAM expression. This is especially evident in tissues that normally reveal no or low levels of EpCAM expression, such as squamous epithelium. The level of EpCAM expression correlates with the proliferative activity of intestinal cells, and inversely correlates with their differentiation.
=== Role in cancer ===
EpCAM can be cleaved which lends the molecule oncogenic potential. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with the proteins FHL2, β-catenin, and Lef inside the nucleus. This complex then binds to DNA and promotes the transcription of various genes. Targets of upregulation include c-myc, e-fabp, and cyclins A & E. This has the effect of promoting tumor growth. Additionally, EpEX that has been cleaved can stimulate the cleavage of additional EpCAM molecules resulting in a positive feedback loop. The amount of β-catenin in the nucleus can modulate the expression level of EpCAM.
EpCAM may also play a role in epithelial mesenchymal transition (EMT) in tumors, although its exact effects are poorly understood. Its ability to suppress E-cadherin suggests that EpCAM would promote EMT and tumor metastasis, but its homotypic cell adhesion properties can counteract its ability to suppress E-cadherin. Results from different studies are often conflicting. In one study, for example, silencing of EpCAM with short interfering RNA (siRNA) led to a reduction of proliferation, migration, and invasion of breast cancer cells in vitro supporting the role of EpCAM in promoting EMT. In another study, cells undergoing EMT were found to downregulate EpCAM. In one study, epithelial tumors were often strongly positive for EpCAM, but mesenchymal tumors showed only occasional and weak positivity. It has been suggested that EpCAM expression is downregulated during EMT but then upregulated once the metastasis reaches its future tumor site.
== Clinical significance ==
=== Target for immunotherapy ===
It has been speculated that since EpCAM in normal epithelia is expressed mostly on the basolateral membrane, it would be much less accessible to antibodies than EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface. In addition to being overexpressed in many carcinomas, EpCAM is expressed in cancer stem cells, making EpCAM an attractive target for immunotherapy. However, the heterogeneous expression of EpCAM in carcinomas and the fact that EpCAM is not tumor-specific (i.e., it is found in normal epithelium) raise concerns that immunotherapy directed towards EpCAM could have severe side effects. As the role of EpCAM in cancer cell signaling is better understood, EpCAM signaling rather than EpCAM itself may be a target for therapeutic intervention.
Edrecolomab, catumaxomab, nofetumomab and other monoclonal antibodies are designed to bind to it.
=== Histopathology ===
EpCAM is often overexpressed in certain carcinomas, including in breast cancer, colon cancer and basal cell carcinoma of the skin. The diagnosis of such conditions can therefore be assisted by immunohistochemistry using BerEp4, which is an antibody to EpCAM.
=== Genetic disorders ===
A problem in EpCAM can indirectly cause Lynch syndrome, a genetic disorder that leads to increased risk of cancer. Deletion of a portion of the 3' end of the EpCAM gene causes epigenetic inactivation of the MSH2 gene by hypermethylating the promoter region of the MSH2 gene.
Mutations in EpCAM have also been associated with congenital tufting enteropathy which causes intractable diarrhea in newborn children.
== References ==
== External links ==
FAQs on HNPCC Archived 15 August 2007 at the Wayback Machine from the National Institute of Health
GeneReviews/NCBI/NIH/UW entry on Lynch syndrome
TACSTD1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Epithelial_cell_adhesion_molecule |
Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.
== Forms, domains and homophilic binding ==
NCAM is a glycoprotein of Immunoglobulin (Ig) superfamily.
At least 27 alternatively spliced NCAM mRNAs are produced, giving a wide diversity of NCAM isoforms. The three main isoforms of NCAM vary only in their cytoplasmic domain:
NCAM-120kDa (GPI anchored)
NCAM-140kDa (short cytoplasmic domain)
NCAM-180kDa (long cytoplasmic domain)
The extracellular domain of NCAM consists of five immunoglobulin-like (Ig) domains followed by two fibronectin type III (FNIII) domains. The different domains of NCAM have been shown to have different roles, with the Ig domains being involved in homophilic binding to NCAM, and the FNIII domains being involved signalling leading to neurite outgrowth.
Homophilic binding occurs between NCAM molecules on opposing surfaces (trans-) and NCAM molecules on the same surface (cis-)1. There is much controversy as to how exactly NCAM homophilic binding is arranged both in trans- and cis-. Current models suggest trans- homophilic binding occurs between two NCAM molecules binding antiparallel between all five Ig domains or just IgI and IgII. cis- homophilic binding is thought to occur by interactions between both IgI and IgII, and IgI and IgIII, forming a higher order NCAM multimer. Both cis- and trans- NCAM homophilic binding have been shown to be important in NCAM “activation” leading to neurite outgrowth.
== Minor exons ==
Another layer of complexity is created by the insertion of other "minor" exons in the NCAM transcript. The two most notable are:
the VASE (VAriable domain Spliced Exon) exon which is thought to correlate with an inhibition of the neurite outgrowth promoting properties of NCAM.
the MSD (Muscle Specific Domain), which is thought to play a positive role in myoblast fusion. In skeletal muscle it is found in all three NCAM isoforms, increasing their MW, giving NCAM-125, NCAM-145, and NCAM-185 isoforms, but is most commonly found in the NCAM-125 isoform.
== Posttranslational modification ==
NCAM exhibits glycoforms as it can be posttranslationally modified by the addition of polysialic acid (PSA) to the fifth Ig domain, which is thought to abrogate its homophilic binding properties and can lead to reduced cell adhesion important in cell migration and invasion. PSA has been shown to be critical in learning and memory. Removal of PSA from NCAM by the enzyme endoneuraminidase (EndoN) has been shown to abolish long-term potentiation (LTP) and long-term depression (LTD).
== Expression in normal cells ==
The neural cell adhesion molecule NCAM1 appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis.
Later in development, NCAM1 (CD56) expression is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle.
== Function ==
NCAM is thought to signal to induce neurite outgrowth via the fibroblast growth factor receptor (FGFR) and act upon the p59Fyn signaling pathway.
In nerves, NCAM1 regulates homophilic (like-like) interactions between neurons and between neurons and muscle; it associates with fibroblast growth factor receptor (FGFR) and stimulates tyrosine kinase activity of receptor to induce neurite outgrowth. When neural crest cells stop making N-CAM and N-cadherin, and start displaying integrin receptors, cells separate and migrate.
During hematopoiesis, CD56 is the prototypic marker of NK cells, also present on subset of CD4+ T cells and CD8+ T cells.
In cell adhesion, CD56 contributes to cell-cell adhesion or cell-matrix adhesion during embryonic development.
== Pathology ==
In anatomic pathology, pathologists make use of CD56 immunohistochemistry to recognize certain tumors.
Normal cells that stain positively for CD56 include NK cells, activated T cells, the brain and cerebellum, and neuroendocrine tissues.
Tumors that are CD56-positive are myeloma, myeloid leukemia, neuroendocrine tumors, Wilms' tumor, neuroblastoma, extranodal NK/T-cell lymphoma, nasal type, pancreatic acinar cell carcinoma, pheochromocytoma, paraganglioma, small cell lung carcinoma, and the Ewing's sarcoma family of tumors.
=== Cancer ===
A member of the NCAM superfamily, NCAM2 gene has been observed progressively downregulated in human papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, NCAM2 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression.
=== Alzheimer's disease ===
NCAM2 is found in lower levels in hippocampal synapses of Alzheimer's disease sufferers and is found to be broken down by beta-amyloid.
=== Rabies ===
NCAM has been identified as one of the target proteins for the rabies virus, allowing entry into the cell.
== Anti-NCAM therapy ==
NCAM has been used as a target molecule for experimental antibody-based immunotherapy. Successful radio-immunolocalisation of metastases was demonstrated after giving injections of NCAM-binding 123J-UJ13a or 131J-UJ13a radio-immunoconjugates to children with neuroblastoma. Patients with small cell lung cancer were treated with the anti-NCAM immunotoxin huN901-DM1 in two different clinical studies, revealing acceptable toxicity and signs of clinical response.
== References ==
== External links ==
Neural+Cell+Adhesion+Molecule at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Neural_cell_adhesion_molecule |
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes. Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. LFA-1 belongs to the integrin superfamily of adhesion molecules.
== Structure ==
LFA-1 is a heterodimeric glycoprotein with non-covalently linked subunits. LFA-1 has two subunits designated as the alpha subunit and beta subunit. The alpha subunit was named aL in 1983. The alpha subunit is designated CD11a; and the beta subunit, unique to leukocytes, is beta-2 or CD18. The ICAM binding site is on the alpha subunit. The general binding region of the alpha subunit is the I-domain. Due to the presence of a divalent cation site in the I-domain, the specific binding site is often referred to as the metal-ion dependent adhesion site (MIDAS).
== Activation ==
In an inactive state, LFA-1 rests in a bent conformation and has a low affinity for ICAM binding. This bent conformation conceals the MIDAS. Chemokines stimulate the activation process of LFA-1. The activation process begins with the activation of Rap1, an intracellular g-protein. Rap1 assists in breaking the constraint between the alpha and beta subunits of LFA-1. This induces an intermediate extended conformation. The conformational change stimulates a recruitment of proteins to form an activation complex. The activation complex further destabilizes the alpha and beta subunits. Chemokines also stimulate an I-like domain on the beta subunit, which causes the MIDAS site on the beta subunit to bind to glutamate on the I domain of the alpha subunit. This binding process causes the beta subunit to pull down the alpha 7 helix of the I domain, exposing and opening up the MIDAS site on the alpha subunit for binding. This causes LFA-1 to undergo a conformational change to the fully extended conformation. The process of activating LFA-1 is known as inside out signaling, which causes LFA-1 to shift from low affinity to high affinity by opening the ligand-binding site.
== Discovery ==
Early discovery of cellular adhesion molecules involved the use of monoclonal antibodies to inhibit cellular adhesion processes. The antigen that bound to the monoclonal antibodies was identified as an important molecule in cellular recognition processes. These experiments yielded the protein name “integrin” as a description of the proteins' integral role in cellular adhesion processes and the transmembrane association between the extracellular matrix and the cytoskeleton. LFA-1, a leukocyte integrin, was first discovered by Timothy Springer in mice in the 1980s.
== Leukocyte Adhesion Deficiency (LAD) ==
Leukocyte adhesion deficiency is an immunodeficiency caused by the absence of key adhesion surface proteins, including LFA-1. LAD is a genetic defect caused by autosomal recessive genes. The deficiency causes ineffective migration and phagocytosis for impacted leukocytes. Patients with LAD also have poorly functioning neutrophils. LAD1, a subtype of LAD, is caused by a lack of integrins that contain the beta subunit, including LFA-1. LAD1 is characterized by recurring bacterial infection, delayed (>30 days) separation of umbilical cord, ineffective wound healing and pus formation, and granulocytosis. LAD1 is caused by low expression of CD11 and CD18. CD18 is found on chromosome 21 and CD11 is found on chromosome 16.
== See also ==
Leukocyte adhesion deficiency
Lifitegrast, a drug that blocks LFA-1 from binding to ICAM-1
== References ==
== Further reading ==
== External links ==
LFA-1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ITGAL ITGB2 Info with links in the Cell Migration Gateway | Wikipedia/Lymphocyte_function-associated_antigen_1 |
Myelin protein zero (MPZ), also Myelin protein P0, is a single membrane glycoprotein which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease.
== Structure ==
In humans, the gene that encodes myelin protein zero is located on chromosome 1 near the Duffy locus or the Duffy antigen/chemokine receptor. The gene is about 7,000 bases long and is divided into 6 exons. In total, myelin protein zero is 219 amino acids long and has many basic amino acid residues.
Myelin protein zero consists of an extracellular N-terminal domain (amino acids 1–124), a single transmembrane region (125–150), and a smaller positively charged intracellular region (151–219). Its cytoplasmic domain is highly positively charged but presumably does not fold into a globular structure. The extracellular domain is structurally similar to the immunoglobulin domain and therefore the protein is considered as belonging to immunoglobulin superfamily.
Besides existing as a monomer, myelin protein zero is also known to form dimers and tetramers with other myelin protein zero molecules in vertebrates.
== Function ==
The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. Myelin protein zero, absent in the central nervous system, is a major component of the myelin sheath in peripheral nerves. Mutations that disrupt the function of myelin protein zero can lead to less expression of myelin and degeneration of myelin sheath in the peripheral nervous system. Currently, myelin protein zero expression is postulated to be produced by signals from the axon. However, more details about the regulation of myelin protein zero are unknown.
It is postulated that myelin protein zero is a structural element in the formation and stabilization of peripheral nerve myelin. Myelin protein zero is also hypothesized to serve as a cell adhesion molecule, holding multiple layers of myelin together. When a myelinating cell wraps its membrane around an axon multiple times, generating multiple layers of myelin, myelin protein zero helps keep these sheets compact by serving as a "glue" that keeps the layers of myelin together. It does so by holding its characteristic coil structure together by the electrostatic interactions of its positively charged intracellular domain with acidic lipids in the cytoplasmic face of the opposite bilayer. and by interaction between hydrophobic globular 'heads' of adjacent extracellular domains.
Myelin protein zero's function is similar to the function of other proteins with immunoglobin domains like polyimmunoglobin and T4 protein. These proteins function as binding and adhesion molecules and participate in homotypic interactions, or interactions that involve two similar proteins. Myelin protein zero holds together the myelin sheath by participating in homotypic interactions with other myelin protein zero proteins. Myelin protein zero's extracellular domain binds to the myelin sphingolipid membrane and holds together myelin layers using homotypic interactions with other myelin protein zero extracellular domains, and with extracellular tryptophan residues interacting with the membrane.
Myelin protein zero has also been demonstrated to interact with other proteins like peripheral myelin protein 22. However, at this point the purpose of these interactions has not yet been determined.
== Associations with neuropathy ==
Mutations in myelin protein zero are known to cause myelin degeneration and neuropathy. Mutations that reduce myelin protein zero's adhesion function or its ability to participate in homeotypic interactions with other myelin protein zero proteins are thought to cause neuropathy. Mutations to myelin protein zero can lead to issues with the development of myelin early on in life or myelin degeneration on the axon later on in life. Some mutations can cause neuropathy in infancy like Derjerine-Sottas disease while other mutations can cause neuropathy within the first two decades of life like Charcot-Marie-Tooth disease. Adding a charged amino acid or changing a cysteine residue in the extracellular membrane can lead to neuropathy onset early on. Truncating the cytoplasmic domain or changing the tertiary structure of myelin protein zero can also result in neuropathy because the cytoplasmic domain has been demonstrated to be necessary for homotypic interactions.
== References ==
== Further reading ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 1
GeneReviews/NCBI/NIH/UW entry on Charcot-Marie-Tooth Neuropathy Type 2
Myelin+protein+zero at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P25189 (Myelin protein P0) at the PDBe-KB. | Wikipedia/Myelin_protein_zero |
In biochemistry and medicine, glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a transmembrane receptor for fibrinogen and von Willebrand factor, and aids platelet activation. The complex is formed via calcium-dependent association of gpIIb and gpIIIa, a required step in normal platelet aggregation and endothelial adherence. Platelet activation by ADP (blocked by clopidogrel) leads to the aforementioned conformational change in platelet gpIIb/IIIa receptors that induces binding to fibrinogen. The gpIIb/IIIa receptor is a target of several drugs including abciximab, eptifibatide, and tirofiban.
== gpIIb/IIIa complex formation ==
Once platelets are activated, granules secrete clotting mediators, including both ADP and TXA2. These then bind their respective receptors on platelet surfaces, in both an autocrine and paracrine fashion (binds both itself and other platelets). The binding of these receptors result in a cascade of events resulting in an increase in intracellular calcium (e.g. via Gq receptor activation leading to Ca2+ release from platelet endoplasmic reticulum Ca2+ stores, which may activate Protein Kinase C). Hence, this calcium increase triggers the calcium-dependent association of gpIIb and gpIIIa to form the activated membrane receptor complex gpIIb/IIIa, which is capable of binding fibrinogen (factor I), resulting in many platelets "sticking together" as they may connect to the same strands of fibrinogen, resulting in a clot. The coagulation cascade then follows to stabilize the clot, as thrombin (factor IIa) converts the soluble fibrinogen into insoluble fibrin strands. These strands are then cross-linked by factor XIII to form a stabilized blood clot.
== Pathology ==
Defects in glycoprotein IIb/IIIa cause Glanzmann's thrombasthenia.
Autoantibodies against IIb/IIIa can be produced in immune thrombocytopenic purpura.
== Medicine ==
Glycoprotein IIb/IIIa inhibitors like abciximab can be used to prevent blood clots in an effort to decrease the risk of heart attack or stroke.
== See also ==
Glycoprotein IIb/IIIa inhibitors
== References ==
== External links ==
Glycoproteins+IIb-IIIa at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Glycoprotein_IIb/IIIa |
L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200 to 220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.
Mutations in the L1 protein are the cause of L1 syndrome, sometimes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).
== Tissue and cellular distribution ==
L1 protein is located all over the nervous system on the surface of neurons. It is placed along the cellular membrane so that one end of the protein remains inside the nerve cell while the other end stays on the outer surface of the neurone. This position allows the protein to activate chemical signals which spread through the neurone.
There are a wide variety of cells which express the protein L1, not only neuronal cells but also some non-neuronal ones. Cells which are known nowadays to express the protein L1 are: immature oligodendrocytes and Schwann cells, which are non-neuronal cells that provide support and protection for neurons and form myelin; T cells which are lymphocytes involved in cell-mediated immunity; other types of lymphocytes such as B cells and Monocytes. It is also expressed in intestinal epithelial progenitor cells, cerebellum neurons such as Cerebellum granule cell and Purkinje cells. Finally, it is expressed in multiple tumor cells for example Melanoma and lung carcinoma cells.
L1CAM is also frequently used as a marker of Extracellular Vesicles (EVs) originating from neuronal cells, although its presence specifically on neuron-derived EVs is debatable.
== Gene ==
The human L1CAM gene is found in X chromosome regions that are implicated in different neuromuscular diseases, and near the one associated with mental retardation. The L1CAM gene is located in the long arm of X chromosome in Xq28 position.
== Structure ==
The L1 cell adhesion molecule (L1CAM) is a cell surface glycoprotein found in humans (and other forms of life as mice, for example) which has a 1253 amino acid protein sequence. The extracellular portion is formed of six immunoglobulin domains followed by five fibronectin type III domains which are connected to a small intracellular domain by a transmembrane helix. The human protein is very similar to the one that is found in mice (they are 92% identical at amino acid level, this enabling the scientists to study its structure. There are other CAM proteins like Ng-CAM (found in chicken) which has lower similarities to the human one (they are 40% identical at the amino acid level). The comparative of the sequences from human, mouse, chick and Drosophila and its good conservation, indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 probably are functionally important.
== Function ==
L1 is an important protein for the development of the nervous system affecting both cell adhesion and motility.
=== Cell adhesion ===
L1 has a static function as a cell adhesion molecule which connects different cells. It is involved in the adhesion between neurons and in the growth and association of neurites called neurite fasciculation.
=== Cell motility ===
Motility promoting functions are related to the regulation of the movement of nerve cells during neural development. L1 is present in developing neurons and plays an important role in guiding new neurons into the correct positions and helping axons grow and make connections with other neurons. L1 is also involved in synaptic plasticity, which is the ability of synapses to strengthen or weaken, and it also plays a role in regeneration after trauma.
Some studies have proved that L1 has a role in tumor growth, tumor cell invasion, metastasis of melanoma, ovarian and colon cancer due to an overexpression of the protein L1 that improves cell motion of the malignant cells.
The domains of this protein promote homophilic interactions, where adhesion molecules on one cell interact with identical molecules on the other cell. And also heterophilic interactions, where an adhesion molecule on one cell works as a receptor that connects with a different molecule on the other cell. These interactions promote cell adhesion and regulation of signal transduction.
In addition, L1 participates in myelination processes, which are involved in the proliferation of myelin through the nervous system (specifically the progressive myelination of nerve axon fibers), by mediating the elongation of Schwann cells along the axon.
=== Nervous system ===
L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on Schwann cells and interactions among epithelial cells of intestinal crypts. As a consequence, mutations in the L1CAM gene cause the Nervous System to malfunction. The main disorders linked to this mutation are known by the acronym CRASH or can be also referred as L1 syndrome. This includes disorders such as HSAS, MASA syndrome, agenesis of the corpus callosum and spastic paraplegia. Lower limb spasticity, mental retardation, hydrocephalus and flexion deformity of the thumbs are some of the symptoms expressed mostly in male individuals who suffer from this condition. Although the pathological mechanisms leading to L1 syndrome are still unknown, about 200 mutations of the L1CAM gene have been identified and then associated with the syndrom. These mutations mostly affect structurally important key residues in the extracellular region of L1 causing alterations in the protein binding properties, which correlate to the impairment of neuronal physiological mechanisms such as cell adhesion or specific interacting with other molecules. Ankyrin interaction with L1CAM is an example of a protein binding that fails in CRASH patients due to a mutation that causes leucine and histidine to replace serine and tyrosine respectively, in the SFIGQY motif, where ankyrin should be bound in the L1CAM family cytoplasmic terminus. Ankyrin-L1CAM interaction is involved in the growth cone initiation, consequently, a failure in this interaction causes neurites to not reach synaptic target.
Furthermore, evidence shows there is a correlation between fetal alcohol spectrum disorder and L1 protein since ethanol inhibits L1-mediated adhesion and neurite outgrowth. Hirschsprung's disease has also been linked to a L1CAM malfunction.
== Transcription and synthesis ==
The gene that regulates L1CAM transcription is found in chromosome X. The L1CAM gene is 24,657 bp in length, and is made up of 28 exons. The alternative splicing of this gene leads to multiple transcript variants (there are 7 different transcripts of the gene), including some that have an alternate exon that is considered to be specific to neurons. L1 transcription is known to take place in human fetal brain and in neuroblastoma and retinoblastoma cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204. Two forms of L1 can be found in humans, with the difference that one has a 12-bp cytoplasmic segment and the other lacks of it. The regulation of L1CAM expression in transcription is not fully comprehended. Two sites were verified in endometrial carcinoma cell lines and seem to be used in a specific manner depending on the cell type. There are two transcription beginning sites, located in two different exons (in front of a non-translated exon 0 and next to the first protein-coding exon 1). SLUG (SNAI2), a transcription factor, upregulates the expression of L1CAM.
== Sequences and different isoforms ==
L1CAM has three different isoforms, that differ in their amino acid sequency, because of alternative splicing (a process that allows obtaining different mRNA mature molecules from one primary transcript of mRNA). L1CAM isoform 1 is known as the canonical sequence. The main difference between them is where they can be found, for example, the full-length isoform (isoform 1), is the one usually found in neural cells, while the short one or nonneural isoform (isoform 2), is predominant in the other cell types.
== Interactions ==
L1 (protein) has been shown to interact with NUMB.
=== Ig-like domain interactions ===
L1CAM is capable of folding into a horseshoe configuration by the establishment of homophilic interactions within Ig-like domains of the same protein (the first and the second Ig motifs folding back onto the 4th and 3rd motifs). This conformation is essential for L1CAM being able to interact with other molecules and subsequently performing some of its most important functions.
Ig-like domains are implicated in many homophilic interactions with other L1CAM proteins located in adjacent cells. L1CAM molecules interact via the Ig (1-4)-like domains, allowing cell to cell adhesion. They are also important in the formation of heterophilic interactions with NCAM, TAG-1, F11 and receptor tyrosine kinases (specially during the development of the nervous system).
The six Ig motif of the L1 protein contains an Arg-Gly-Asp sequence which allows binding with diverse surface cell integrins. This interaction leads to a signaling cascade which activates focal adhesion kinases (FAK) which are then converted to its active state and form the FAK/SRC complex. The latest functions as an activator of mitogen-activated protein kinases. Another function derived from integrin binding is the activation of NF-κB which results in making cells more motile and invasive.
=== Fibronectin domain interactions ===
Fibronectin domains of L1 protein are also capable of binding cell surface integrins. They interact with fibroblast growth factor receptor 1, which suggests it may be linked to the modulating of neuronal differentiation.
=== Cytoplasmic tail interactions ===
The most important binding partners of the cytoplasmic tail of L1 proteins are ankyrins. The interaction is held in high-affinity binding sites located within the so-called “ank repeats” also known as membrane-binding domains. This interaction allows L1 protein connect with the cell's cytoskeleton. Also, L1 protein cytoplasmic tail can bind adaptor 2 (ADP), a key component of clathrin mediated endocytosis.
The fact this region contains some phosphorylation sites suggests L1 may be subject to regulation by kinases.
== Implications in cancer metastasis ==
L1CAM protein expression is normally restricted to neurons. However, it has been noticed there's L1CAM overexpression in all types of cancer cells, which has been associated with poor prognosis, tumor progression and metastasis. This up-regulation may not be necessarily associated with mutations in L1 transcription factors. It has been seen this protein plays a key role in inflammatory reactions as the ones taking place in the tissue surrounding a tumor. This could explain why this protein gets suddenly overproduced in tumor cells. L1CAM's diverse functions make tumor cells more aggressive and resistant. Their migratory and motility related functions may result key in cell epithelial–mesenchymal transition (EMT) allowing cells to lose cell to cell static junctions and apico-basal polarity leading to them becoming migratory and independent. Also, its capacity to form adhesive interactions within different cell types may result in an advantage for tumor cells when it comes to co-opt and invade the surrounding tissues or capillaries.
Once tumor cells become anchorage-independent and migratory, due to L1 up-regulation, they leave the tissue where they belong and migrate through the capillaries to other organs. One frequent destination of tumor cells is the brain. So to settle in the brain, tumor cells have to succeed in crossing the blood brain barrier (BBB) where they get exposed to the plasmin secreted by astrocytes. Plasmin breaks L1CAM and inhibits the malignant cell's migrating powers. However, recent studies have noted these cancer cells overproduce anti-PA serpins, which are the usual inhibitors of plasmin, allowing them to cross the BBB and succeed in metastasis.
== Possible therapies involving L1CAM ==
Because L1CAM is considered to be a key factor in metastasis, it has been suggested that blocking this protein may inhibit cancer cells migration and tumor progression. Antibody therapy directed against L1CAM in mice models of cancer block tumor growth but enhance EMT. Liposome-encapsulated small interfering RNA has also proved to be an effective inhibitor for L1CAM expression as its function is to degrade a specific range of mRNA base pairs (in this case, the ones encoding for L1CAM sequence of amino acids) after transcription, so that the protein cannot be synthetised. Nevertheless, these possible therapies involving L1CAM as a target in human cancer are still in preclinical research.
== References ==
== Further reading ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on L1 Syndrome
L1+Cell+Adhesion+Molecule at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Atlas of genetics and cytogenetics in oncology and haematology: http://atlasgeneticsoncology.org/Genes/L1CAMID44110chXq28.html | Wikipedia/L1_(protein) |
Occupational cardiovascular diseases (CVD) are diseases of the heart or blood vessels caused by working conditions, making them a form of occupational illness. These diseases include coronary heart disease, stroke, cardiomyopathy, arrhythmia, and heart valve or heart chamber problems. Cardiovascular disease is the leading cause of death in the United States and worldwide. In the United States, cardiovascular diseases account for one out of four deaths. The 6th International Conference on Work Environment and Cardiovascular Diseases found that within the working age population about 10-20% of cardiovascular disease deaths can be attributed to work. Ten workplace stressors and risk factors (shift work, long work hours, low job control, low job security, high job demand, work-family imbalance, low work social support, low organizational justice, unemployment, and no health insurance) were estimated to be associated with 120,000 U.S. deaths each year and account for 5-8% of health care costs.
Research related to the association between work and cardiovascular disease is on-going. Links have been established between cardiovascular disease risk and occupational exposure to chemicals, noise, psychosocial stressors, physical activity, and certain workplace organization factors. Additionally, work-related risk factors for cardiovascular disease may also increase the risk of other cardiovascular disease risk factors such as hypertension, diabetes, obesity, unhealthy diet, leisure-time physical inactivity, and excessive alcohol use. Work may also increase risk of depression, burnout, sleeping problems, and physiological and cardiorespiratory stress mechanisms in the body which may also affect the risk for cardiovascular disease.
== United States trends in cardiovascular disease and the impact of work ==
Age-adjusted cardiovascular disease death rates in the U.S. are no longer declining, as they previously had been since the 1960s. Cardiovascular disease death rates are increasing in older (45–64 years) working-age people. In fact, death rates from all causes have been increasing since about 2012 in working-age people (25–64 years), primarily due to increases in drug (mainly opioid) overdoses, alcohol abuse, suicides, and chronic diseases, such as cardiovascular diseases, hypertension and diabetes. Between 2000-2015, the cardiovascular disease mortality gap between the U.S. and other wealthy countries has widened. These trends are occurring despite improvements in the medical treatment of cardiovascular diseases. Primary prevention of cardiovascular diseases, including workplace health promotion, is key to reducing death rates.
Related explanations for cardiovascular disease trends are increases in the prevalence of other stress-related (including work-related stress) conditions, obesity, diabetes, metabolic syndrome, and short sleeping hours. The age-adjusted prevalence of hypertension increased in the U.S. between 1988-2010 and increased again between 2010-2018 for most gender-race groups. Mental health disorders, including depression and anxiety, are increasing globally and in the U.S.
A 2021 National Academy of Sciences report points out that "social, economic, and cultural changes that have undermined economic security, intergenerational mobility, and social support networks can adversely affect cardiometabolic health through stress-mediated biological pathways and reduced access to care".
Recent research indicates working conditions that may be contributing to the cardiovascular disease trends in the U.S. include,
increases in
annual working hours
job stressors, such as low job control, job strain, and work-family conflict
income inequality
precarious employment (such as temporary or contract work) that involves inadequate pay, job insecurity, changes in working-time arrangements, loss of workers' rights and protections, lack of collective organization (such as unionization)
decreases in
union membership
social mobility (movement of people upward or downward in society through job status, education level, income, etc.)
work intensification through new technology and "lean production" techniques
== Work-related risk factors for cardiovascular disease ==
Psychosocial work stressors
High job demands combined with low control (known as job strain)
High work efforts combined with low work rewards (known as effort-reward imbalance)
Bullying and violence
Low social support at work
Lack of opportunities for personal development
Job insecurity
Frequent stimulation of the sympathetic nervous system
Non-standard shift work (such as night or rotating shifts)
Long work hours (55 or more hours per week)
Occupational exposure to loud noise
Occupational exposure to ionizing radiation
Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life.
Occupational exposure to chemicals
Chemicals are used in many workplaces. Workers can be exposed to chemicals by breathing them in, eating or drinking contaminated food and drinks, or absorbing them through the skin.
A 2017 Swedish government report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminum or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD (dioxin) or asbestos.
Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxy acids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke.
According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week.
== Occupations at higher risk for cardiovascular disease ==
First responders, including firefighters and police officers
NFL Players
Professional drivers, including long-haul truck drivers
Food and drink preparatory workers
Fishery workers
Cargo workers
Civil engineer workers
Plant and machine operators and assemblers
=== Occupational cardiovascular disease in firefighters ===
Given the many hazards present during career firefighting, firefighters are at a greater risk for occupational cardiovascular disease. CVD is the leading cause of death in firefighters, and accounts for 45% of on-duty deaths. About 90% of CVD in firefighters is attributed to coronary heart disease. Other researchers have found that blood plasma volume decreases after just minutes of firefighting which increases blood pressure and causes the heart to work harder to distribute blood systemically. Firefighting has also shown to increase arterial stiffness and overall cardiovascular strain. In a study by Barger, et al., a positive screening for a sleep disorder increased the odds a firefighter would also have cardiovascular disease (OR = 2.37, 95% CI 1.54-3.66, p < 0.0001).
==== CVD risk factors in firefighting ====
Sleep disorders and partial sleep deprivation
Shiftwork and frequently disrupted sleep
Dehydration
Heat stress from environmental, metabolic work, and heavy PPE
Physical workload - Long sedentary periods followed by strenuous physical workload
Sympathetic activation ("fight or flight response") due to noise, low visibility work conditions, and danger
Inadequate leisure time physical activity
Unhealthy eating habits
Smoke exposure - gases and ultrafine particulates
Occupational stress due to stressful or traumatic experiences
== Prevention of occupational cardiovascular disease ==
=== Primary Prevention ===
Common programs to reduce CVD risk have been worksite-based health promotion, wellness, or stress management. However, rigorous research has suggested small effects of such programs. Organizational and workplace interventions have been effective in reducing sources of stress at work. Other strategies for reducing work stressors include legislative and regulatory-level interventions with examples including laws providing for better nurse-patient staffing ratios, bans on mandatory overtime, paid sick days, paid family leave or retail worker schedule predictability (see case studies on-line, Healthy Work Campaign, 2021). However, such legislative interventions are rarely evaluated and thus are typically not included in review articles.
The 7th International Conference on Work Environment and Cardiovascular Diseases emphasized the need to bridge the gap between knowledge and preventive interventions at the workplace, to reduce cardiovascular diseases, through effective collaboration between health operators involved in prevention of CVD. The NIOSH Total Worker Health Program conveys the innovative concept that only holistic interventions at the workplace which reduce both work-related and life-style risk factors, may be effective to prevent CVDs. As examples, the interactions between job strain and sedentarism at work as well as the findings that the relations of job strain and CVD incidence is more pronounced among salaried workers (white and blue collars) are crucial in the perspectives to convey "the right preventive interventions to the right people".
Unfortunately, no organizational intervention studies have been carried out to prevent CVD at work, and few to prevent CVD risk factors, such as hypertension. The following are three examples of organizational interventions to reduce blood pressure, which provided some evidence of their effectiveness:
A small Swedish study found that systolic blood pressure increased among workers on a traditional auto assembly line but did not increase during a work shift among auto assembly workers in a flexible team-based work organization.
Another small Swedish study looked at the impact of a set of interventions in Stockholm, including separate bus lanes; a bus priority traffic signal system; passenger peninsulas; reducing illegally parked cars; and electronic information systems for passengers. The intervention was effective in reducing self-reported workload, job hassles, systolic blood pressure, heart rate and distress after work among bus drivers. However, no significant change was seen for diastolic blood pressure, fatigue, or psychosomatic symptoms.
A program among white-collar workers at a Quebec insurance services agency included surveys, focus groups, and meetings at work to "diagnose" problems and suggest changes in policies and procedures. Managers made decisions about changes, specific to each department over 17–24 months. There were joint union-management committees in four of nine intervention departments. Examples of changes to policies and procedures were: regular employee/manager meetings on routine matters; group meetings with managers; organizational restructuring to reduce workload; slowing down changes in work processes and computer software to allow for better adaptation; more flexible work hours; and career and skills development. Follow-up at 30-months showed lower psychological distress, and lower job demands, and higher co-worker support and respect/esteem, although no change in low job control, supervisor support or reward, in the intervention group compared to the control group. blood pressure and hypertension significantly decreased in the intervention group with no change in the control group.
== See also ==
Occupational hazard
Chemical hazard
Psychosocial hazard
== References == | Wikipedia/Occupational_cardiovascular_disease |
The dynamic-maturational model of attachment and adaptation (DMM) is a biopsychosocial model describing the effect attachment relationships can have on human development and functioning. It is especially focused on the effects of relationships between children and parents and between reproductive couples. It developed initially from attachment theory as developed by John Bowlby and Mary Ainsworth, and incorporated many other theories into a comprehensive model of adaptation to life's many dangers. The DMM was initially created by developmental psychologist Patricia McKinsey Crittenden and her colleagues including David DiLalla, Angelika Claussen, Andrea Landini, Steve Farnfield, and Susan Spieker.
A main tenet of the DMM is that exposure to danger drives neural development and adaptation to promote survival. Danger includes relationship danger. In DMM-attachment theory, when a person needs protection or comfort from danger from a person with whom they have a protective relationship, the nature of the relationship generates relation-specific self-protective strategies. These are patterns of behavior which include the underlying neural processing. The DMM protective strategies describe aspects of the parent–child relationship, romantic relationships, and to a degree, relationships between patients/clients and long-term helping professionals.
== History ==
Out of the development of attachment theory, British psychiatrist John Bowlby coalesced a coherent theory and is generally credited with creating the foundation for modern attachment theory. Mary Ainsworth, an American-Canadian psychologist, started working with Bowlby in 1950. Ainsworth completed her doctoral thesis in 1940 under William Blatz, who had developed security theory, a precursor to attachment theory. Blatz believed the core nature of the relationship between a (to use his colloquial terms) mother and child involved the development of a trusted and secure relationship to function as a safe base for a child's need to explore. This set an initial foundation for the developing theory of attachment as involving a two-pattern model, security vs insecurity, centered on safety and play.
However, throughout the 1950s, both Ainsworth and Bowlby began developing a three-pattern model centered on danger and survival. In the 1960s, Ainsworth developed the first scientific method to assess attachment, called the strange situation. The results of her assessments confirmed a three-pattern model. Staying with a secure vs insecure framework, Ainsworth identified one secure pattern and two completely different insecure patterns. She labeled these with the letters A, B, C, with B representing the secure pattern.
Ainsworth's graduate students, including Mary Main and Patricia "Pat" Crittenden, made important developments to attachment science and theory. Both Main and Crittenden realized that the criteria Ainsworth was using did not allow for the attachment classification of a significant number of children. Main initially described most of this group as being disorganized, unable to organize an attachment strategy to help them meet their attachment system needs for safety. Main and Solomon later redefined disorganized attachment. Decades of research were dedicated to exploring the concept of disorganized attachment, but ultimately the concept proved almost completely unhelpful.
Crittenden studied under Ainsworth in the 1980s, ten years after Main. Because Crittenden initially focused on danger and saw the attachment system as promoting survival, she rejected the idea that a significant portion of children could fail to organize an attachment strategy to survive. Thus, she looked for other explanations about the apparent shortcomings in Ainsworth's initial model. As she did, she expanded the A, B, C patterns of attachment, and with the help of Andrea Landini they organized the patterns into what eventually became the DMM.
She also started her work after John Bowlby wrote the third book in his Attachment and Loss trilogy in 1980, Loss: Sadness and Depression. In Chapter 4 of that book, Bowlby outlined his view that attachment was intimately connected with information processing and the defensive exclusion of information to survive psychological danger. He argued that common psychological defense mechanisms were actually efforts to keep certain types of unwanted information out of one's mind during experiences and while considering issues and making decisions. Crittenden centered her work on how humans develop self-protective strategies and patterns of information processing in the context of danger.
In a sense, Crittenden began where Bowlby and Ainsworth left off. While moving away from some of the older concepts such as secure vs insecure and internal working models, she kept and refined the three-pattern model. The DMM continues to evolve and Fonagy describes it as ″the most clinically sophisticated model that attachment theory has to offer at the present time.″: ii
== DMM-attachment ==
=== Basic definition of DMM-attachment ===
Attachment describes a system which involves a person's need to be protected from danger, and comforted especially after exposure to danger, and a relationship with an attachment figure who can provide protection from danger and comfort. As a system centered on survival, it also involves a person's need to increase reproductive opportunities and protect progeny.
Particularly when the attachment system involves a caregiver and child, the relational interactions associated with attachment needs shapes neural development and emotional and biological regulation processes in children. Thus, a child's relational environment, and parenting environment, has lifelong impacts.
An attachment figure for children may be one or both parents or other close caregiver, and for adults a romantic partner. An attachment figure is someone to whom a person is most likely to turn to under stress. That person may be a stronger, wiser, and trusted (even if not always safe or protective) person. An attachment-influencing relationship has the qualities of being affectively charged and involving the regulation or dysregulation of emotions. It also involves protecting a person from being forced to handle something outside their developmental ability (their zone of proximal development). An optimal attachment figure is sensitively attuned and responsive to the person's communications and needs and encourages curiosity and the exploration of new information.
Helping professionals, clergy, lawyers, probation officers, teachers, club leaders, friends and other people may function as an auxiliary attachment figure, or transitional attachment figure (TAF), to help people get through a difficult experience.
Danger can be objective (deep water, cliff edges, snakes) or subjective and relevant to only particular attachment patterns. For people who tend to use self-protective A-strategies, danger can include aggressive or dismissive parental responses, not doing the right thing, doing the wrong thing, expressing feelings especially if negative, relying on others to meet needs, and being in conflict. For people who tend to use self-protective C-strategies, danger can include an inconsistent or lack of parental response, not expressing and satisfying feelings especially if negative, following someone else's rules which don't satisfy feelings, compromising, relying on the self to meet needs, and not being in conflict or a struggle.
=== DMM contributions to the development of attachment theory ===
Crittenden and colleagues have advanced attachment knowledge in numerous ways. Crittenden and Landini describe many of these in their 2011 book Assessing Adult Attachment: A Dynamic-Maturational Approach to Discourse Analysis.
Focus on danger: The DMM focus on danger, rather than safety, orients an understanding of the attachment system in a way that is practical and useful for understanding response to threat and conflict. Bowlby focused on danger, but other subsequent models changed the focus to safety. The DMM focus on danger is consistent with other biopsychosocial models, such as the polyvagal theory which describes opposing nervous system features which activate in contexts of safety or danger.
Clarification of terminology: The DMM avoids older attachment terms such as secure vs insecure, attachment categories and measures, attachment disorders, disorganized attachment, internal working models, and top level terms such as avoidant and ambivalent. It uses terms such as pathways of development instead of developmental trajectories.
Development of lifespan attachment assessments: Crittenden and colleagues developed a comprehensive lifespan set of attachment assessments (described below), and enhanced existing assessments. Since theory leads scientific inquiry, and scientific findings add to theory, DMM assessments contributed to more detailed theory.
Maturational and changeable: DMM-attachment recognizes that humans are able to utilize more and more sophisticated self-protective attachment strategies as they age. Hence, attachment patterns can become increasingly complex with age. Infants begin with instinctive strategies such as smiling and reaching, and through behavioral learning develop an increasing array of ways to gain protection from danger from their caregivers. Thought and communication patterns are eventually added to a person's available strategies. People can change their primary strategy, add additional strategies, and reorganize from an A-C strategy to a B strategy.
Strategies: Strategies are the ways people get their needs met. Self-protective strategies are not diagnoses or mental health disorders. The strategies may be quite functional in certain types of relationships, and dysfunctional in other relationships if not adjusted. Selecting a specific response in a specific situation is not necessarily dictated by a strategy preference, it is situation and context driven, which Crittenden describes as a dispositional representation (DR). Crittenden expanded and more finely defined attachment strategies (or patterns), as noted below.
Detailed strategies: The DMM described known behaviors with more specificity, identified new attachment behaviors, and new attachment patterns.
Compulsive compliance was first identified in 1988, and was added into the DMM patterns as A4 in 1992. It describes a child's adaptation to a harsh or controlling parent by learning to inhibit behavior disagreeable to the parent and compulsively engaging in behaviors which please the parent, but may be boring or harmful to the child.
False positive affect (FPA) describes the use of inappropriate positive affect when negative affect would be more appropriate. An example is overbright smiling or laughing in the context of present danger or while experiencing pain. Victoria Climbié is considered a good case example. At age eight she was murdered by caregiver abuse and neglect. Her physical scars and other signs of abuse were seen by multiple professionals and agencies, including doctors, nurses, social workers, and clergy, who all failed to recognize the extreme danger she was in. At the same time, she was described by a number of people as happy, friendly, "twirling up and down the ward", "had the most beautiful smile that lit up the room", and "you could beat her and she wouldn't cry... she could take the beatings and pain like anything." In the ABC+D model, this behavior is theorized as a marker of disorganized attachment.
Shame is identified by adult attachment interviews (below) conducted with the DMM method as a particularly sensitive emotion in A-patterns. Shame is defined as having an intrapersonal quality involving the fear of failing to meet an external standard, often too high a standard, set by others, along with self-blame and over-attribution of responsibility.
Adaptive and strategic function of behavior: Attachment behaviors and communication styles are developed through adaptation to danger and function to promote survival in a given relationship.
Every DMM-attachment pattern involves both adaptive and maladaptive behaviors. A person using B3 "balanced" strategies may fail to predict danger or access a self-protective strategy and end up being harmed. A person using A-strategies may focus on cooperating and avoiding conflict to the exclusion of protecting their children or financial interests. A person using C-strategies may focus on satisfying their own feelings to the exclusion of cooperation and conflict resolution even to the detriment of their children or financial interests.
Individual behaviors can be seen in all attachment strategies, but serve different functions. For example, bright smiling can serve several self-protective purposes. In A-strategies it can function to hide pain and take attention away from in-the-moment negative experiences. In C-strategies it can function to disarm prior or following aggression.
Dimensional: Strategies are described as dimensional rather than categorical. As demonstrated on the DMM circumplex, they range from exposing people to more and more risk (moving down the outside of the circumplex), and more or more intensity (moving from the center of the circumplex to the outer rim). The DMM eschews the terms secure and insecure, although it is used in various DMM literature.
=== DMM foundations and support ===
The DMM has and continues to incorporate all relevant disciplines. It incorporates all the disciplines Bowlby utilized, including psychoanalytic, ethology, systems psychology, evolutionary biology, cognitive information processing, and cognitive neurosciences. It incorporates all the disciplines Ainsworth utilized, including naturalistic observation, and empirical grounding of attachment theory. DMM additions include genetics, epigenetics, neurobiology, sociology, developmental psychology, Piaget's theory of cognitive development, Erikson's stages of psychosocial development, behavioral learning theory, social learning theory, theory of mind, cognitive psychology, Vygotsky's zone of proximal development, Vygotsky and Bronfenbrenner's social ecological model, transactional theory, family systems theory, polyvagal theory, mindfulness theory, and functional somatic syndrome theory.
The DMM is supported by the International Association for the Study of Attachment (IASA). The Family Relations Institute (FRI) is the primary organization teaching DMM theory and assessments. The attachment studies programme at University of Roehampton, U.K., includes the DMM and some of its assessments, as does the Barnard Center for Infant Mental Health and Development at the University of Washington in Seattle.
IASA maintains a list of publications describing the DMM. There are over 500 such publications.
== DMM attachment patterns ==
DMM attachment patterns can viewed several different ways.
In its simplest form, the DMM offers a 3-part model using Ainsworth's basic A, B, C patterns.
Some populations of clients tend to be heavily oriented to either a cognitive or affective information processing pattern, such as clinical populations. In these contexts, the DMM offers a basic 2-part model.
The DMM circumplex graphically depicts 22 adult patterns. There are some sub-patterns, such as A3- (compulsive attending) and A4- (compulsive performance), and A and C patterns can be combined, such as A4/C5-6 or A3-4/C2. In the table below, the cognitive A and affective C-patterns are arranged from the middle out, where the patterns in the middle (B1-5, A1-2 and C1-2) represent the least at risk patterns (lower number in the classification) to most at risk (higher number). The B1-2 patterns are somewhat cognitively organized, the B4-5 patterns are somewhat affectively organized. The A1-2 and C1-2 patterns are not considered "insecure," rather normal strategies involving only slight transformations of information.
The DMM can be used as a 4-part model (or a multi-part model depending on its application), as demonstrated in the left and right columns in the table above. The odd-numbered strategies share elements in common which differ from the even-numbered strategies.
Odd-numbered A-patterns (A1-7) tend to focus on idealizing others while even-numbered A-patterns (A2-8) tend to focus on negating the self.: 42 In relations with important authorities, the higher odd-numbered A-patterns can involve compulsive caretaking and the even-numbered A-patterns compulsive compliance.
C-patterns organize self-protective strategies around feelings. Odd-numbered C-patterns focus on feelings of anger, increasing in intensity in the higher numbers. Even-numbered patterns focus on desire for comfort and fear, with increasing intensity of fear in the higher numbers.: 43 Higher C-odd patterns can involve obsessive coercion. Higher C-even patterns can involve increasing amounts of rage which may escape notice because of simultaneous exaggeration of innocence and vulnerability.: 195–196
The odd-even split can also be seen from diagonal corners to reflect the opposite functioning of similar elements. The odd-numbered A-strategies in the upper left quadrant (A1-7) all involve some sort of tendency to focus care outward to the needs of others, which differs from the C2-8 patterns which tend to focus care inward to the emotions of the self. The even-numbered A-patterns (A2-8) patterns all involve some sort of tendency to express anger inward to the self, whereas the C1-7 patterns tend to express anger outward toward objects or others.
As noted above, the self-protective strategy patterns are adaptive, and dimensional rather than categorical. For example, a person may primarily utilize C1 strategies to manage danger, but on occasion use higher forms of C strategies such as C3, C4, or C5. This could result from exposure to higher forms of danger or be a response to unresolved trauma or loss.
All the attachment strategies can be impacted by a variety of additional factors, such as unresolved trauma, unresolved loss, depression, and family triangulation.
== Information processing and transformation ==
The DMM is fundamentally an information processing model, and self-protective attachment strategies develop around two primary sources of information available to humans: cognitive and affective.
Cognitive information is described as temporally sequenced, as illustrated with "if/then" statements. Affective information is described as being emotionally intense experiences. Attachment A-strategies tend to emphasize cognitive information and de-emphasize or exclude affective information. Attachment C-strategies do the opposite, emphasizing affective information and de-emphasizing or excluding cognitive information. Attachment B-strategies tend to blend both types of information as they process experiences in the world, although they can emphasize one or the other.
Crittenden describes information processing as involving four main steps:
Perceive the information, or not;
Interpret the information in some way, or not;
Select response of some sort, or not; and
Implement behavior of some sort, or not.
An example involves a child who is feeling a strong emotion:
Will the parent perceive their child's emotion?
If so, will they interpret it as the child needing help to process the emotion, or as the child being weak, overly-needy, or interrupting what they are doing?
Will the parent consider selecting a response, and if so which one?
Will the parent implement a response, or get distracted or decide to ignore their child's emotional experience?
=== Transformation of information ===
At each stage of information processing, information is transformed as it is converted from what it is, to a representation of what it is in the mind. A test result, a smile, and divorce papers, come to mean something in the mind through a neural process. The DMM currently identifies seven ways information can be transformed, each of which represents increased transformation: true, erroneous, distorted, omitted, falsified, denied, delusional.
A parent's processing of information about a child's strong negative emotion, continuing with that example, could be seen as:
True, and provide information which helps the parent ease the child's distress.
Erroneous, over- or under-interpreted, such that a parental response might be non-productive, such as giving too much or not enough attention to the distress.
Distorted, where some portion of the information is emphasized and the other de-emphasized, such as acknowledging the distress but emphasizing that it will go away on its own when it won't easily do so.
Omitted, so that some portion of the information is discarded, such as the reason for the distress.
Falsified, where the emotion is changed from one thing to another, such as distressed to hungry.
Denied, where the emotion is actively avoided.
Delusional, where new and incorrect information is created to replace the true information, such as thinking the child is laughing or is signaling a desire to play.
=== Memory systems ===
DMM assessments look for memory system function as described by memory researchers such as Endel Tulving and Daniel Schacter. Eight memory systems assessed by the DMM method are body talk, somatic, procedural, semantic, imaged, connotative, episodic, and reflective integration.
As with information processing, attachment patterns can involve the use, or bias of, various memory systems as sources of information. Attachment A-strategies tend to utilize information from procedural and semantic memory systems, and de-emphasize or exclude information from imaged and connotative systems. Attachment C-strategies do the opposite and emphasize information from imaged and connotative systems and de-emphasize or exclude information from procedural and semantic systems. Attachment B-strategies tend to have better access to all memory systems. Each attachment pattern has its own strength in various circumstances where different memory systems may be advantageous.
== DMM attachment assessments ==
Attachment measures, or assessments, assess the self-protective strategy of a person. In infancy and early childhood, it is assessed with respect to specific attachment figures whereas beginning in the school years a generalized strategy is assessed. Assessments generally use a video-recorded interaction or an audio-recorded interview. In observed assessments behavior is assessed, and with interviews the discourse, or manner of speech, is primarily assessed. Crittenden and others have modified existing attachment assessments and developed others to create a range of DMM assessments intended to cover the lifespan. Assessments generally assess individuals, caregivers (usually parents) and/or children, and can assess non-primary caregivers such as close grandparents and foster parents. DMM assessments can be used for research, clinically, forensically, and personally.
Some DMM assessments are considered valid and reliable, and others are still in a development and validation phase which generally takes at least 10 years. IASA considers an assessment valid and reliable if it has a minimum of five published studies supporting it, including studies that the author of the assessment did not author, and that address several of the following:
Concurrent validity
Longitudinal validity
Face validity
Predictive validity
Clinical utility
IASA's Family Court Protocol requires that assessments in a development phase should not be used forensically, particularly in court cases where children and parents could lose access to each other. IASA also argues that individual assessments are only reliable if the assessor (coder) is qualified by having passed a standardized reliability test and maintained their qualification.
=== Infant Care-Index (ICI) ===
The ICI consists of a 3-minute interaction of a caregiver and child (a 2-person, or dyadic, relationship) aged from birth to 15 months. The ICI assesses interaction, not attachment (which does not develop until 9–11 months of age). The ICI assesses a dyad's interpersonal functioning under non-threatening play conditions and clusters dyads as sensitive to good enough, at mild risk of parenting difficulties, or at high risk of parenting difficulties, including infant neglect and maltreatment. It was developed by Crittenden with input from Ainsworth and Bowlby. The ICI is considered a valid and reliable assessment and has more than 60 published studies.
=== Strange Situation Procedure (SSP) ===
The SSP is the classic assessment of attachment developed by Ainsworth. Almost all other assessments of attachment are validated against it. The SSP consists of eight episodes over 21–23 minutes. Unlike the ICI which assesses only dyadic synchrony under the favorable condition of play, the SSP uses threat to elicit the infant's pattern of attachment. Threat, or relationship danger, comes in several forms such as the stranger coming into the observation room with parent and child (episode 3), the parent leaving the child in the room with the stranger (episode 4), the parent later leaving the child in the room alone (episode 6), and the stranger re-entering the room without the parent (episode 7). The parent returns and the stranger leaves in the eighth and final episode. The infant's behavior on the parent's return is the primary basis for classification into one of three major strategies, labeled A, B, and C.
The SSP was developed for 11-month-old infants. It has been used for older infants, but, as infants age, their tolerance for separation increases and the behavioral markers defined by Ainsworth fit less well, resulting in higher proportions of infants classified as secure, including maltreated infants. In the DMM, this problem was resolved by limiting the age range to 11–15 months, and developing, with Ainsworth's assistance, an alternating A/C classification and pre-compulsive and pre-coercive patterns. These include A1-2 or C1-2 patterns, and clear evidence for A+ or C+ patterns (which involves more intense use of self-protective strategies). These expansions of the Ainsworth categories have been associated with maltreated infants and infants of depressed mothers.
=== Preschool Assessment of Attachment (PAA) ===
The PAA is a version of Mary Ainsworth's Strange Situation Procedure (SSP), adapted to 2–5-year-old children. It assesses the child's self-protective strategies used with the adult involved in the assessment. It also uses a video recorded 8-segment process over a structured 21–23 minute adult-child interaction. The PAA is valid and reliable, with more than 30 studies using it.
=== School-age Assessment of Attachment (SAA) ===
The SAA involves an audio recorded interview which is transcribed and analyzed with discourse analysis techniques, for children aged 6–13 years. In the assessment, a child is given story cards which represent increasing levels of danger, and they are asked to make up a story that describes what is depicted on the card, and then, if they had any similar experience in their life, asked a series of exploratory questions. It assesses the child's generalized attachment pattern, self-protective strategies, pattern of information processing, level and type of risk, and possible unresolved trauma and loss. It was initially developed in 1997 by Crittenden, has been tested in eight research studies, and is considered to provide discriminate validity. The SAA was the subject of a special section of Clinical Child Psychology and Psychiatry in July 2017.
=== Adult Attachment Interview (AAI) ===
The AAI is considered one of the most comprehensive attachment assessments, and is well validated. It was initially created by Carol George and Nancy Kaplan in, and later developed with Mary Main in 1985. Crittenden and Landini slightly modified it with DMM theory in 2011. It assesses self-protective attachment strategies, patterns of information processing, a possible unresolved trauma and loss which distort behavior and information processing, an over-riding condition which causes information distortion such as depression and triangulation in childhood, memory system usage, and reflective function. The assessment involves asking a person a series of structured questions, transcribing the audio recording, and applying a complex set of discourse analysis techniques. The interview takes 60–90 minutes, and it can take hours or days to analyze. Learning to code reliably generally takes several years.
The coding manual for the DMM-AAI is Assessing Adult Attachment: A Dynamic-Maturational Approach to Discourse Analysis (2011) and is publicly available.
=== DMM Assessments undergoing the validation process ===
The following assessments have not been validated with three or more studies and are not considered by IASA to be acceptable for use forensically under their Family Court Protocol.
==== Toddler Care-Index (TCI) ====
The TCI video records a 5-minute interaction of a caregiver and child aged from 15 to 72 months. It assesses the general attachment characteristics of a specific dyad, such as mother and child or father and child. The TCI is considered a useful assessment, but has not been validated by research. It was developed by Crittenden.
==== Transition to Adulthood Attachment Interview (TAAI) ====
The TAAI is a modified version of the AAI for adolescents aged about 14–25 years old. It was modified from the AAI by Crittenden in 2005 and 2020.
==== Meaning of the Child interview (MotC) ====
The MotC is an interview of a parent which is transcribed and assessed with discourse analysis techniques similar to the AAI. The MotC assesses a parent's general pattern of caregiving, sensitivity and level of responsiveness to their child, the degree and forms of control a parent may utilize, and self-reflective function (mentalization). It examines how caregiving is shaped by a parent's pattern of attachment and need for self protection. In a validation study, the way parents talked about their children in the MotC was found to predict how they behaved with their child in a CARE-Index video. The MotC has also been used to research the parent–child relationships of parent of autistic children. It was developed by Ben Grey and Steve Farnfield in 2011, and uses DMM theory and methods.
==== Child Attachment and Play Assessment (CAPA) ====
The CAPA assesses the attachment and exploration systems of children aged 7–11. It uses an interview process similar to the SAA. The CAPA currently has one published validation study demonstrating convergence with other attachment procedures. It was developed by Steve Farnfield, and uses DMM theory and methods.
== Applications ==
=== DMM Integrative Treatment ===
DMM concepts have been used to develop DMM specific treatment interventions for mental health, family, and criminal problems. The DMM has been applied to models of psychotherapy, attachment narrative therapy, family therapy, and criminal behavior.
DMM integrative treatment can include a focus on how information is processed and transformed, especially in response to danger. It can include DMM concepts such as adaptations to relational danger (for both individuals and families), developmental processes and learned patterns of information processing.
DMM Integrative treatment involves five principles;
Define problems in terms of response to danger.
The professional acts as a transitional attachment figure.
Explore the family's past and present responses to danger.
Work progressively and recursively with the family.
Practice reflective integration with the client as a form of teaching reflective integration.
DMM Family Functional Formulation (DMM FFF) describes a comprehensive approach to a wide array of mental health problems. Crittenden and colleagues argue that psychological diagnosis and systems psychology have proven substantially ineffective in treating a wide array of mental health problems. A clinical formulation, which is a broad-based analysis and explanation of the problem, is an alternative approach. Crittenden argues the DMM can contribute to a more effective case formulation when the entire family is consulted and understood using DMM assessments.
=== Law ===
The DMM and its methods are useful for discourse and argument analysis, client counseling, understanding shortcomings in client and witness memory recall, forensic purposes, criminal justice, probation, and conflict management. At its heart, attachment theory describes the conflict of contradictory information and needs, and information processing and decision making using biased information.
Because information processing involves the defensive exclusion and inclusion of information, it can affect how people make decisions and communicate. The DMM-AAI discourse analysis method is specifically designed to "understand the meanings behind unclear communication, distorted communication and dysfunctional behavior".
DMM attachment assessments can be used in court cases and forensically if done by a trained and reliable coder. The IASA Family Court Protocol is designed to promote attachment information in a way that is as comprehensive and reliable as attachment assessments can allow, and which also supplements other information about individuals, family members, and family systems. FRI's Family Functional Formula is a comprehensive and valuable, if expensive, method to assess a family system.
DMM perspectives on attachment and information processing are useful for understanding neglectful and harmful parenting,
domestic violence
and criminal behavior.
=== Medicine – somatic symptoms ===
Kozlowska argues that functional somatic symptoms are impacted by disrupted or chronically challenged attachment relationships. The DMM assessment method, especially for children, specifically identifies and assesses nonverbal communications and somatic expressions. Two large studies, which Kozlowska relied on, found a strong association between low quality attachment relationships and functional somatic symptoms later in life. Kozlowska's own research showed children with functional neurological disorders (FND) almost universally used higher attachment strategies (A3-4, A5-6, C3-4, and C5-6).
=== Occupational therapy ===
Occupational therapists can apply the DMM directly, and in conjunction with other modalities. Kozlowska describes incorporating occupational therapy with pediatric medicine, hypnosis, physiotherapy, neurology, and DMM-Attachment theory. Occupational therapists can increase a child's day-to-day functioning and manage emotional arousal. They can also address Functional Neurological Disorder (FND), which she found almost always involved children's use of higher DMM self-protective strategies. DMM theory helps integrate different modalities around the concepts of protection from danger, the impact of interpersonal relationships and family environments, and the use of transitional attachment figures.
Meredith, using non-DMM attachment assessments designed for research rather than clinical purposes, has found associations between pain, sensory processing and distress and adult attachment patterns. She argues that occupational therapists are in a good, if not unique position to utilize attachment theory to guide interventions. Kozlowska uses DMM theory to specifically guide assessment and intervention.
In a University of Roehampton dissertation paper, Gounaridis describes a successful pilot project combining a sensory integration approach, a DMM-attachment assessment (CAPA), and vagal tone measurements as described by the polyvagal theory.
In an Arizona State University dissertation paper, Taggart described how occupational therapists can use Éadaoin Bhreathnach's Sensory Attachment Intervention (SAI) approach, which is informed by the DMM, together with trauma and polyvagal theory informed perspectives, to help children improve emotional expression.
=== Psychotherapy ===
The DMM is not necessarily a therapy model, rather it provides a framework to better understand clients, improve communication, and assist with selecting appropriate therapy models. It can help therapists:
Assess or formulate the client's self-protective attachment strategies;
Identify response to dangers from the past and in the present;
Focus the therapeutic alliance around the concept of being a transitional attachment figure;
Determine how the client functions interpersonally (including with the therapist);
Identify a client's patterns of information processing and information bias;
Identify failures of self-protective strategies which lead to psychological and/or somatic problems;
Be mindful to practice reflective integration for its own value and for modeling;
Help clients build a coherent narrative of their experiences.
Attachment Centred Therapy (ACT) provides a model for adult psychotherapy. It uses the DMM, the DMM-AAI, and incorporates other models such as an attachment-based modification of Maslow's hierarchy of needs and rational emotive behavior therapy. ACT seeks to help patients reprogram and reorganize their unconscious mind, reorganize their attachment strategies, and create healthier narratives about difficult life experiences.
For therapists using a family systems approach, it can help identify self-protective strategies between the parents, between each child and parent, and between children, to provide more insight into the functioning of the family system. It can help therapists avoid blame and reframe negative emotions to honesty and more appropriate contexts. It can help a therapist move a client's strong negative emotions such as anger and a desire for revenge to softer and more manageable emotions such as sadness and vulnerability. Play therapy, the polyvagal theory, and DMM theory were combined in Hadiprodjo's doctoral thesis. Combining the DMM with the Assessment of Parent-Child Interactions (ACPI, a music theory-based assessment), can allow the application of music theory to understand family attunement and nonverbal communication in the context of self-relevant dangers within a family context. The DMM has been used in a public service context, and informs therapists how to be a safe base and improve the therapeutic alliance.
The DMM provides insight into various mental health issues, such as working with emotions, adolescent challenges, trauma and neurobiological impacts, PTSD, ADHD, autism, borderline personality disorder, avoidant personality disorder, eating disorders, conversion disorders, somatic/factitious/fabricated illnesses, shutdown states in children, drug addiction, psychopathy, child abuse, sex abuse, effects of institutionalization, and depression. It offers an alternate view of personality disorders.
=== Research ===
The DMM theory and assessment methods are useful for conducting attachment assessments. Because there are DMM assessments to cover the lifespan, they can be used to assess an individual and a family system. The DMM approach appears to provide more precise results with populations of people whose childhood involved adverse childhood experiences or parents who consistently used cold, inconsistent, harsh or controlling parenting techniques or engaged in parental conflict or failed to protect or comfort their children. It appears that between the DMM and Berkeley assessment methods, the DMM method can better delineate between secure and insecure attachment classifications, and also the quantity of A, C, and mixed AC patterns. This is likely because the DMM is focused on a person's response to danger and fear, and describes the attachment system's primary purpose as being to organize self-protective responses.
== Comparison to other attachment models ==
Ainsworth developed the ABC model in the 1960s and 1970s. It was the foundation for the ABC+D (sometimes called Berkeley) model and the DMM.
The newer ABC+D and DMM models both describe the attachment system, use Ainsworth's basic ABC patterns, and use the SSP and AAI attachment assessments. Both models reject the single-person focus of psychiatric models such as the DSM and ICD, instead focusing on how a parent-child (dyadic) relationship affects each person, and that childhood attachment patterns represent a child's best attempt to deal with the caregiving environment. Both find the most effective attachment-informed interventions in family problems is to focus on improving sensitivity of the child's primary caretaker. Both are based on principles of human development.
Ainsworth's ABC model ultimately described 9 subcategories, A1, A2, B1, B2, B3, B4, B5, C1, and C2. The newer models went on to identify additional basic subcategories, 24 in the adult version of the ABC+D model and 29 in the DMM, and each describe additional AC combinations.
While they both describe the effect of the attachment system on information processing and memory function, and both describe the impacts of trauma and loss, the DMM provides more focus and detail on these elements. The DMM utilizes more memory systems and considers more types of trauma. In the ABC+D model meaning is assigned to behavior, whereas the DMM looks for the function of behavior to define its meaning.
The ABC+D model has historically focused on safety, attachment security vs insecurity, is categorical, describes linear developmental trajectories, describes attachment with different concepts and terms for children and adults, and uses Bowlby's "internal working model" concept. The DMM is focused on danger, focuses on risk instead of security-insecurity, is dimensional, describes potentially branching developmental pathways, describes the maturational development of self-protective strategies, and describes neurobiological systems and processes.
Landa and Duschinsky offer a theory about the historical development of both models to provide an explanation about why and how they differ. The ABC+D model initially relied on normative (average) research populations. Initial DMM research utilized both normative and maltreated populations, so it had a richer data set to work from. Each model also makes different foundational assumptions. The DMM (and others) assumes, as did Bowlby and Ainsworth, that a primary purpose of the attachment system for children is to maintain the attachment figure's availability. In the ABC+D model, as defined by Mary Main and Judith Solomon, the purpose is to maintain proximity. (Not all attachment theorists who use the ABC+D model use the same definitions as Mary Main. Increasingly, they use terms and definitions identical, or nearly so, to Crittenden's.)
The DMM rejects the concept of disorganized attachment, instead arguing that people can organize a response to almost all forms of danger, even if the response is increased aggression or ignoring physical and psychological pain. Granqvist and 42 other attachment experts, including Mary Main, agreed that the concept of disorganized attachment, as understood in 2017, has little or no utility, and may not be used clinically or forensically.
The ABC+D model was widely accepted by the research community from about 1990–2017, although Main was calling for caution in the use of disorganized attachment in clinical and forensic settings by at least 2011. In 2018 van IJzendoorn et al. pointed out the replication crisis of ABC+D-based attachment assessments, and called for the ABC+D attachment community to revisit its foundations.
== Criticisms ==
After Granqvist, and 42 other authors (2017), clearly identified the limits and misapplication of the disorganized attachment category, Van IJzendoorn, et al., and Crittenden and Spieker exchanged a series of comments and criticisms about the ABC+D and DMM attachment models in the November/December 2018 issue of Infant Mental Health Journal. Van IJzendoorn criticized the DMM for having too many classifications, 29 basic patterns, compared to the ABC+D model (which has 24). While conceding that assessments using the ABC+D attachment model cannot be used forensically, he argued neither could DMM assessments since they did not meet the "beyond a reasonable doubt" standard required in court. However, "more likely than not" is the correct standard in civil (non-criminal) court cases. Van IJzendoorn argued DMM assessments lack validity as much as ABC+D assessments do, which Crittenden (and others) dispute. Van IJzendoorn found fault with Crittenden's position that the DMM is still developing. Crittenden responded that a complex and transdisciplinary model of human development must always continue to add new information and develop.
Forslund and 68 other authors subsequently discussed the use of attachment assessments in court proceedings. They described limitations and the appropriate use of assessments using the ABC+D model. Some authors argued they could never be used in court proceedings, and some argued they could. However, the article, while making side references to Crittenden, did not clarify that it was only addressing the problems of assessments using the ABC+D model.
Other people echo Van IJzendoorn's point about complexity in terms of becoming a reliable coder and being able to use a DMM-assessment to testify forensically about a particular person's self-protective strategies in a particular context, or for a family assessment using the DMM Family Functional Formulation method. The PAA and SAA can take a year or more to learn The AAI can take several years. In fact, there are few people in the world who can use DMM-assessments forensically, particularly under the requirements of IASA's Family Court Protocol. (Neither IASA nor FRI list any available forensic coders on their websites as of November 2021.)
David Pocock found the DMM useful, and powerful, and at the same raising the risk of reductionism and reification. The DMM attempts to make it clear that people are not reduced to "a C3" or "an A4", instead they are described as using strategies from those patterns. Reification involves making something abstract concrete, turning an attachment strategy used in one situation into what completely defines the person. He echoes common concerns that attachment, and the DMM in particular, is such a powerful model it is potentially easy to fall into the use of counterproductive shortcuts.
== References ==
== Bibliography ==
=== Introductory reading materials ===
Atkins, Louise, (2020), Why Attachment Matters: Dynamic Maturational Model (DMM) of attachment theory, medium.com.
Crittenden, Patricia M. (2002), Attachment, information processing, and psychiatric disorder, World Psychiatry, 1:2.
Crittenden, Patricia. M. (2006). A dynamic-maturational model of attachment. Australian and New Zealand Journal of Family Therapy, 27, 105–115.
Farnfield, Steve, Holmes, Paul (2014). The Routledge Handbook of Attachment: Assessment. London: Routledge.
Hautamäki, Airi (Ed.), (2014). The Dynamic-Maturational Model of Attachment and Adaptation – Theory and Practice. University of Helsinki, SSKH, Skrifter, 37.
Purnell, C. (2010). Childhood trauma and adult attachment, Healthcare Counselling and Psychotherapy Journal, 10, 1–7.
Spieker, Susan J. and Crittenden, Patricia M. (2018), Can attachment inform decision making in child protection and forensic settings?. Infant Mental Health Journal, 39: 625–641. doi:10.1002/imhj.21746
=== Advanced reading materials ===
Baldoni, Franco, Minghetti, Mattia, Craparo, Giuseppe, Facondini, Elisa, Cena, Loredana, & Schimmenti, Adriano (2018). Comparing Main, Goldwyn, and Hesse (Berkeley) and Crittenden (DMM) coding systems for classifying Adult Attachment Interview transcripts: an empirical report, Attachment and Human Development, 20:4, 423–438, DOI: 10.1080/14616734.2017.1421979.
Crittenden, Patricia M. (2016). Raising parents: Attachment, representation, and treatment, 2nd edition. London: Routledge.
Crittenden, Patricia M., Dallos, Rudi, Landini, Andrea, & Kozlowska, Kasia (2014). Attachment and family therapy. London: Open University Press.
Crittenden, Patricia M., & Landini, Andrea (2011). Assessing Adult Attachment: A Dynamic-Maturational Method of Discourse Analysis. New York: Norton.
Crittenden, Patricia M. & Newman, Louise (2010). Comparing models of borderline personality disorder: Mothers' experience, self-protective strategies, and dispositional representations. Clinical Child Psychology and Psychiatry, 15,433-452.
Crittenden, Patricia M., Robson, Katrina, Tooby, Alison, Fleming, Charles (2017), Are mothers' protective attachment strategies related to their children's strategies? Clinical Child Psychology and Psychiatry, 22:3, 358-377 (Note: this article uses three DMM attachment assessments, the PAA, SAA, and AAI, and offers a comprehensive and longitudinal review of attachment strategies in mother-child pairs.)
Kozlowska, Kasia; Scher, Stephen; Helgeland, Helene (2020). Functional Somatic Symptoms in Children and Adolescents: A Stress-System Approach to Assessment and Treatment, Palgrave Macmillan. PDF and Kindle versions available free as open access textbook.
Landa, Sophie & Duschinsky, Robbie (2013) Letters from Ainsworth: Contesting the "Organization" of Attachment. Journal of the Canadian Academy of Child & Adolescent Psychiatry. 22, 172–177.
Landa, Sophie, & Duschinsky, Robbie (2013). Crittenden's dynamic–maturational model of attachment and adaptation. Review of General Psychology, 17, 326–338. doi:10.1037/a0032102
Strathearn, Lane, Fonagy, Peter, Amico, Janet A., & Montague, P. Read (2009). Adult attachment predicts mother's brain and peripheral oxytocin response to infant cues. Neuropsychopharmacology, 34, 2655–66. | Wikipedia/Dynamic-maturational_model_of_attachment_and_adaptation |
Polyvagal theory (PVT) is a collection of proposed evolutionary, neuroscientific, and psychological constructs pertaining to the role of the vagus nerve in emotion regulation, social connection and fear response. The theory was introduced in 1994 by Stephen Porges. There is consensus among experts that the assumptions of the polyvagal theory are untenable.
PVT is popular among some clinical practitioners and patients, but it is not endorsed by current social neuroscience.
Polyvagal theory takes its name from the vagus nerve, a cranial nerve that forms the primary component of the parasympathetic nervous system. The traditional view of the autonomic nervous system presents a two-part system: the sympathetic nervous system, which is more activating ("fight or flight"), and the parasympathetic nervous system, which supports health, growth, and restoration ("rest and digest"). Polyvagal theory views the parasympathetic nervous system as being split into two distinct branches: a "ventral vagal system" which supports social engagement, and a "dorsal vagal system" which supports immobilisation behaviours, both "rest and digest" and defensive immobilisation or "shutdown". This "social engagement system" is a hybrid state of activation and calming that plays a role in the ability to socially engage.
== Theory ==
The vagus, or tenth cranial nerve, is a primary component of the autonomic nervous system, which operates the internal organs. It transmits parasympathetic signals to and from the heart, lungs, and digestive tract. The vagal system is claimed to be inhibitory of primal instincts by being part of the parasympathetic nervous system, in opposition to the sympathetic-adrenal system, involved in mobilization behaviors.
Polyvagal theory was developed in 1994 by Porges, who at the time was director of the Brain-Body Center at the University of Illinois at Chicago. It focuses on the structure and function of the two efferent branches of the vagus cranial nerve, which originate from the medulla. Each branch is claimed to be associated with a different adaptive behavioral strategy; the ventral branches more restful in nature and the dorsal ones more active in nature.
According to the theory, three organizational principles can be distinguished:
Hierarchy: The autonomic nervous system reacts in three reaction patterns, which are activated in a specific order.
Neuroception: In contrast to perception, it is here a cognition without awareness, triggered by a stimulus such as danger.
Co-regulation: The need to feel safe enough to allow oneself to be in relationships, which is difficult for traumatized people.
Porges describes the three neural circuits as regulators for reactive behavior. His findings were taken into account by some theorists of childhood trauma, with related techniques used by trauma therapists such as Bessel van der Kolk, Peter A. Levine and Marianne Bentzen.
=== Anatomical hypothesis ===
Polyvagal theory combines ideas from evolutionary biology and neurology, to claim that autonomic reactions have adapted to the phylogenetic development of neural circuits. It claims that the sympathetic nervous system, and two distinct branches of the parasympathetic nervous system, are phylogenetically ordered and activated for responses. The branches of the vagal nerve are claimed to serve different evolutionary stress responses in mammals: the more primitive branch is said to elicit immobilization behaviors (e.g., feigning death), whereas the more evolved branch is said to be linked to social communication and self-soothing behaviors. These functions are claimed to follow a phylogenetic hierarchy, where the most primitive systems are activated only when the more evolved functions fail.
According to the theory, these neural pathways regulate autonomic states and the expression of emotional and social behaviour. It claims that in mammals, facial expressions are connected to internal physical reactions, such as cardiac and digestive changes, and in general physiological state dictates the range of behaviour and psychological experience.
Claims about the nature of stress, emotion, and social behaviour, are traditionally studied via peripheral indices of arousal such as heart rate, cortisol level and skin conductance. Polyvagal theory champions the measurement of vagal tone as a new index of stress vulnerability and reactivity, including in populations with affective disorders.
=== Proposed dorsal vagal complex (DVC) ===
The dorsal branch of the vagus nerve originates in the dorsal motor nucleus and is postulated by polyvagal theory to be the phylogenetically older branch. This branch is unmyelinated and exists in most vertebrates. Polyvagal theory calls this the "vegetative vagus" because it sees it as being associated with primal survival strategies of primitive vertebrates, reptiles, and amphibians. Under certain conditions, these animals "freeze" when threatened, conserving their metabolic resources. This draws on the simplifying claims of the triune brain theory which are no longer considered accurate due to the many exceptions to this rule (see Triune brain § Status of the model).
The DVC provides primary control of subdiaphragmatic visceral organs, such as the digestive tract. Under normal conditions, the DVC maintains regulation of these digestive processes. However, prolonged disinhibition can be lethal for mammals, as it results in apnea and bradycardia.
=== Proposed ventral vagal complex (VVC) ===
With increased neural complexity as seen in mammals (due to phylogenetic development) there is said to have evolved a more sophisticated system to enrich behavioral and affective responses to an increasingly complex environment. The ventral branch of the vagus originates in the nucleus ambiguus and is myelinated to provide more speed in responding. Polyvagal theory calls this the "smart vagus" because it associates it with the regulation of sympathetic "fight or flight" behaviors by way of social affiliative behaviors. These behaviors are said to include social communication and self-soothing and calming. In other words, this branch of the vagus is said to inhibit or disinhibit defensive limbic circuits, depending on the situation. Note: Attributing defensive behaviours purely to the limbic system is an oversimplification, as these are triggered by perceived threats, thus requiring an interplay of brain areas performing sensory integration, memory, and semantic knowledge with the limbic system to be elicited. Similarly, the regulation of emotions requires a complex interplay of higher cognitive areas with limbic ones.
The vagus nerve mediates the control of supradiaphragmatic visceral organs, such as the esophagus, bronchi, pharynx, and larynx. It also exerts an important influence on the heart. When vagal tone to the heart’s pacemaker is high, a baseline or resting heart rate is produced. In other words, the vagus acts as a restraint, or brake, limiting heart rate. However, when vagal tone is removed, there is little inhibition to the pacemaker, and according to polyvagal theory, rapid mobilization ("fight/flight") can be activated in times of stress, but without having to engage the sympathetic-adrenal system, as activation comes at a severe biological cost. Note: While the vagus nerve's role in downregulating the heart rate is well-established, the notion that a fight-or-flight response can be triggered without engaging the sympathetic nervous system is not substantiated by any evidence.
=== Vagal tone as a marker of stress ===
In order to maintain homeostasis, the central nervous system responds constantly, via neural feedback, to environmental cues. Stressful events disrupt the rhythmic structure of autonomic states, and subsequently, behaviors. Since the vagus plays such an integral role in the peripheral nervous system via regulation of heart rate, Porges suggests that the amplitude of respiratory sinus arrhythmia (RSA) is a good index of parasympathetic nervous system activity via the cardiac vagus. That is, RSA is proposed as a measurable, noninvasive way to see how the vagus modulates heart rate activity in response to stress. If true, this method could be useful to measure individual differences in stress reactivity.
RSA is the widely used measure of the amplitude of heart rate rhythm associated with the rate of spontaneous breathing. Research has shown that amplitude of RSA is an accurate indicator of the efferent influence of the vagus on the heart. Since inhibitory effects of the VVC branch of the vagus allow for a wide range of adaptive, prosocial behaviors, it has been theorized that individuals with greater vagal tone are able to exhibit a greater range of such behaviors. On the other hand, decreased vagal tone is associated with illnesses and medical complications that compromise the CNS. These complications may reduce one's capacity to respond to stress appropriately.
==== Clinical applications in the human fetus ====
Healthy human fetuses have high variability in heart rate, which is mediated by the vagus. On the other hand, heart rate decelerations, which are also mediated by the vagus, are a sign of fetal distress. More specifically, prolonged withdrawal of vagal influence on the heart creates a physiological vulnerability to the influence of the dorsal vagal complex, which in turn produces bradycardia (very low heart rate). However, the onset of this deceleration is commonly preceded by transitory tachycardia, which is reflective of the immediate effects of ventral vagal complex withdrawal.
== Reception ==
In a 2023 review of the literature, Paul Grossman lists five premises of polyvagal theory and states that "there is broad consensus among experts [...] that each basic physiological assumption of the polyvagal theory is untenable. Much of the existing evidence, upon which these consensuses are grounded, strongly indicates that the underlying polyvagal hypotheses have been falsified."
Although proponents like Bessel van der Kolk praise the theory's explanatory power, Grossman considers the theory an unnecessary and unsubstantiated conflict imposed on the public dialogue.
=== Neuroscientific claims ===
Neuhuber and Berthoud (2022) state that polyvagal theory's "basic phylogenetic and functional-anatomical tenets do not withstand closer scrutiny". They argue that polyvagal theory incorrectly portrays the role of the different vagal nuclei in mediating the freeze response. According to their analysis, the evidence "does not support a role of the 'dorsal vagal complex' in freezing as proposed by the PVT" and the dorsal vagal complex "should not be linked to passive defensive behavior".
Regarding the proposed "ventral vagal complex", they state that "the PVT, by construeing a 'new ventral vagal complex' encompassing the entire branchiomotor column ascribed to the vagus much more than it actually can serve." They see it as "misleading to propose that brainstem branchiomotor ('source') nuclei 'communicate directly with the visceromotor portion of the nucleus ambiguus'", and conclude that the relevant networks "should not be termed 'ventral vagal complex'. This terminology may insinuate that the vagus is a "prime mover". This not the case [...]".
Taylor, Wang & Leite (2022) similarly regard it as "invalid to refer to this as a 'vagal system' or to postulate the existence of a 'smart vagus'."
=== Evolutionary claims ===
Grossman and Taylor (2007) argue that there is no evidence that the dorsal motor nucleus (DMN) is an evolutionarily more primitive center of the brainstem parasympathetic system than the nucleus ambiguus (NA), and review evidence to the contrary.
A more recent paper by Monteiro et al. (2018) finding myelinated vagus nerve fibers of lungfish leading from the nucleus ambiguus to the heart also indicates that polyvagal theory’s hypothesis that the nucleus ambiguus is unique to mammals is incorrect. They state that "the mechanisms [Porges] identifies as solely mammalian are undeniably present in the lungfish that sits at the evolutionary base of the air-breathing vertebrates."
Grossman (2023) concurs, stating that "the polyvagal notion that the ventral vagal area is unique to mammals is opposed by years of evidence" and that the "findings, as a whole, firmly and consistently contradict the polyvagal hypotheses that propose the [dorsal vagal motor nucleus] as the “source nucleus” of unmyelinated pathways and the [nucleus ambiguus] as the “source nucleus” of myelinated pathways in mammals".
Results reviewed by Taylor, Leite and Skovgaard (2010) also "refute the proposition that centrally controlled cardiorespiratory coupling is restricted to mammals, as propounded by the polyvagal theory of Porges".
In Taylor, Wang & Leite's 2022 review, the evidence for the presence of cardio-respiratory interactions similar to respiratory sinus arrhythmia (RSA) and their potential purpose in blood oxygenation in many vertebrate species (both air- and water-breathing) leads them to conclude that RSA may be a relic of older cardio-respiratory systems, contrary to polyvagal assumptions.
The dichotomy between asocial reptiles and social mammals subscribed to by polyvagal theory has been contested. Doody, Burghardt & Dinets consider several ways of assessing and classifying animal sociality and state that "Porges’ dichotomy is incorrect. While many mammals (particularly humans) may show more complex social behavior than reptiles, there is considerable overlap in social tendencies between the two groups. The labels ‘social’ and ‘asocial’ are too crude to have utility in a comparative framework of social behavior and should not be used to describe taxa". Listing examples of social behavior in reptiles and other non-mammal vertebrates, they observe that "PT appears to rest upon 20th century folk interpretation of vertebrate evolutionary biology rather than on current scientific understanding of it."
=== Claims regarding cardiac functioning ===
Polyvagal theory proposes a relationship between RSA responses and forms of psychopathology, but a meta-analysis finds the empirical evidence to be inconclusive.
According to Grossman and Taylor, the existing research indicates that respiratory sinus arrhythmia is not a reliable marker of vagal tone, since it is subject to both respiratory variables and sympathetic (beta-adrenergic) influences in addition to vagal influences. In addition, they argue that the results of Porges' 2003 study on two species of lizard was flawed due to incorrect measurements of heart rate variability.
Reviewing more recent evidence, Paul Grossman again finds RSA not "a direct measure of cardiac vagal tone" due to confounding factors. In addition, he concludes that contrary to polyvagal claims "there is no credible evidence that the [dorsal vagal motor nucleus] plays any role in massive bradycardia", and that it "appears to have almost no effect upon vagal heart rate responses".
=== Scientific standards ===
In a 2021 publication, Porges stated that "the theory was not proposed to be either 'proven' or 'falsified', rather to be informed by research and modified". Falsifiability is a central tenet of the scientific method.
== See also ==
== References ==
== Further reading ==
Ulrich F. Lanius, Sandra L. Paulsen, Frank M. Corrigan: Neurobiology and Treatment of Traumatic Dissociation: Towards an Embodied Self. Springer Publishing Co., 2014
Porges, S. W. (2006). "The Polyvagal Perspective". Biological Psychology. 74 (2): 116–143. doi:10.1016/j.biopsycho.2006.06.009. PMC 1868418. PMID 17049418. (Review).
Holly Bridges: Reframe Your Thinking Around Autism: How the Polyvagal Theory and Brain Plasticity Help Us Make Sense of Autism ISBN 978-1849056724 Jessica Kingsley Publishers. 2015
Robert Bright: The Polyvagal Theory: The Simplified Guide to Understanding the Autonomic Nervous System and the Healing Power of the Vagus Nerve – Learn to Manage Emotional Stress and PTSD Through Neurobiology. White Publishing, Ltd., 2020, ISBN 978-1801119689
== External links ==
The Polyvagal Theory – www.wam.umd.edu
After 20 years of "polyvagal" hypotheses, is there any direct evidence for the first 3 premises that form the foundation of the polyvagal conjectures? Paul Grossman, University Hospital of Basle, Switzerland, on ResearchGate, with references and some discussion starting January 2016
Dunning, Brian (25 January 2022). "Skeptoid #816: The Dark Side of Polyvagal Theory". Skeptoid. | Wikipedia/Polyvagal_theory |
The medical model of disability, or medical model, is based in a biomedical perception of disability. This model links a disability diagnosis to an individual's physical body. The model supposes that a disability may reduce the individual's quality of life and aims to correct or diminish the disability with medical intervention. It is often contrasted with the social model of disability.
The medical model focuses on curing or managing illness or disability. By extension, the medical model supposes a compassionate or just society invests resources in health care and related services in an attempt to cure or manage disabilities medically. This is in an aim to expand or improve functioning, and to allow disabled people to lead a more "normal" life. The medical profession's responsibility and potential in this area is seen as central.
== History ==
Before the introduction of the biomedical model, patients relaying their narratives to the doctors was paramount. Through these narratives and developing an intimate relationship with the patients, the doctors would develop treatment plans in a time when diagnostic and treatment options were limited. This could particularly be illustrated with aristocratic doctors treating the elite during the 17th and 18th century.
In 1980, the World Health Organization (WHO) introduced a framework for working with disability, publishing the "International Classification of Impairments, Disabilities and Handicaps". The framework proposed to approach disability by using the terms Impairment, Handicap and Disability:
Impairment
A loss or abnormality of physical bodily structure or function, of logic-psychic origin, or physiological or anatomical origin.
Disability
Any limitation or function loss deriving from impairment that prevents the performance of an activity in the time lapse considered normal for a human being.
Handicap
The disadvantaged condition deriving from impairment or disability limiting a person performing a role considered normal in respect of age, sex and social and cultural factors.
=== Components and usage ===
While personal narrative is present in interpersonal interactions, and particularly dominant in Western Culture, personal narrative during interactions with medical personnel is reduced to relaying information about specific symptoms of the disability to medical professionals. The medical professionals then interpret the information provided about the disability by the patient to determine a diagnosis, which likely will be linked to biological causes. Medical professionals now define what is "normal" and what is "abnormal" in terms of biology and disability.
In some countries, the medical model of disability has influenced legislation and policy pertaining to persons with disabilities on a national level.
The International Classification of Functioning, Disability and Health (ICF), published in 2001, defines disability as an umbrella term for impairments, activity limitations and participation restrictions. Disability is the interaction between individuals with a health condition (such as cerebral palsy, Down syndrome and depression) and personal and environmental factors (such as negative attitudes, inaccessible transportation and public buildings, and limited social supports).
The altered language and words used show a marked change in emphasis from talking in terms of disease or impairment to talking in terms of levels of health and functioning. It takes into account the social aspects of disability and does not see disability only as a 'medical' or 'biological' dysfunction. That change is consistent with widespread acceptance of the social model of disability.
== Criticism ==
The medical model focuses on individual intervention and treatment as the proper approach to disability. Emphasis is placed on the biological expression of disability rather than on the systems and structures that can inhibit the lives of people with disabilities. Under the medical model, disabled bodies are defined as something to be corrected, changed, or cured. Terminology used can perpetuate negative labels such as deviant, pathological, and defective, thus, best understood in medical terms. The history and future of disability are severely constricted, focusing solely on medical implications and can overlook social constructions contributing to the experience of disability. Alternatively, the social model presents disability less as an objective fact of the body and mind, and positions it in terms of social relations and barriers that an individual may face in social settings.
The medical model of disability can influence the factors within the creation of medical or disability aides, such as creating aides reminiscent of hospital settings and institutions which can be traumatic to some who have spent an extended period of time there, or which solely reflect the function of hospital aides but not necessarily the function of an aide outside of these contexts.
Among advocates of disability rights, who tend to subscribe to the social model instead, the medical model of disability is often cited as the basis of an unintended social degradation of disabled people (otherwise known as ableism). Resources are seen as excessively misdirected towards an almost-exclusively medical focus when those same resources could potentially be used towards things like universal design and societal inclusionary practices. This includes the monetary and societal costs and benefits of various interventions, be they medical, surgical, social or occupational, from prosthetics, drug-based and other cures, and medical tests such as genetic screening or preimplantation genetic diagnosis. According to disability rights advocates, the medical model of disability is used to justify large investment in these procedures, technologies and research, when adaptation of the disabled person's environment could potentially be more beneficial to the society at large, as well as financially cheaper and physically more attainable.
Also, some disability rights groups see the medical model of disability as a civil rights issue and criticize charitable organizations or medical initiatives that use it in their portrayal of disabled people, because it promotes a pitiable, essentially negative, largely disempowered image of people with disabilities rather than casting disability as a political, social and environmental problem (see also the political slogan "Piss On Pity").
== See also ==
Cure
Medical model of autism
Medicalization
Models of deafness
Neurodiversity
== References ==
== External links ==
The Open University: Making your teaching inclusive: The Medical Model | Wikipedia/Medical_model_of_disability |
Moral treatment was an approach to mental disorder based on humane psychosocial care or moral discipline that emerged in the 18th century and came to the fore for much of the 19th century, deriving partly from psychiatry or psychology and partly from religious or moral concerns. The movement is particularly associated with reform and development of the asylum system in Western Europe at that time. It fell into decline as a distinct method by the 20th century, however, due to overcrowding and misuse of asylums and the predominance of biomedical methods. The movement is widely seen as influencing certain areas of psychiatric practice up to the present day. The approach has been praised for freeing sufferers from shackles and barbaric physical treatments, instead considering such things as emotions and social interactions, but has also been criticised for blaming or oppressing individuals according to the standards of a particular social class or religion.
== Context ==
Moral treatment developed in the context of the Enlightenment and its focus on social welfare and individual rights. At the start of the 18th century, the "insane" were typically viewed as wild animals who had lost their reason. They were not held morally responsible but were subject to scorn and ridicule by the public, sometimes kept in madhouses in appalling conditions, often in chains and neglected for years or subject to numerous torturous "treatments" including whipping, beating, bloodletting, shocking, starvation, irritant chemicals, and isolation. There were some attempts to argue for more psychological understanding and therapeutic environments. For example, in England John Locke popularized the idea that there is a degree of madness in most people because emotions can cause people to incorrectly associate ideas and perceptions, and William Battie suggested a more psychological approach, but conditions generally remained poor. The treatment of King George III also led to increased optimism about the possibility of therapeutic interventions.
== Early development ==
=== Italy ===
Under the Enlightened concern of Grand Duke Pietro Leopoldo in Florence, Italian physician Vincenzo Chiarugi instituted humanitarian reforms. Between 1785 and 1788 he managed to outlaw chains as a means of restraint at the Santa Dorotea hospital, building on prior attempts made there since the 1750s. From 1788 at the newly renovated St. Bonifacio Hospital he did the same, and led the development of new rules establishing a more humane regime.
=== France ===
The ex-patient Jean-Baptiste Pussin and his wife Margueritte, and the physician Philippe Pinel (1745–1826), are also recognized as the first instigators of more humane conditions in asylums. From the early 1780s, Pussin had been in charge of the mental hospital division of the La Bicêtre, an asylum in Paris for male patients. From the mid-1780s, Pinel was publishing articles on links between emotions, social conditions and insanity. In 1792 (formally recorded in 1793), Pinel became the chief physician at the Bicetre. Pussin showed Pinel how really knowing the patients meant they could be managed with sympathy and kindness as well as authority and control. In 1797, Pussin first freed patients of their chains and banned physical punishment, although straitjackets could be used instead. Patients were allowed to move freely about the hospital grounds, and eventually dark dungeons were replaced with sunny, well-ventilated rooms. Pussin and Pinel's approach was seen as remarkably successful and they later brought similar reforms to a mental hospital in Paris for female patients, La Salpetrière. Pinel's student and successor, Jean Esquirol (1772–1840), went on to help establish 10 new mental hospitals that operated on the same principles. There was an emphasis on the selection and supervision of attendants in order to establish a suitable setting to facilitate psychological work, and particularly on the employment of ex-patients as they were thought most likely to refrain from inhumane treatment while being able to stand up to pleading, menaces, or complaining.
Pinel used the term "traitement moral" for the new approach. At that time "moral", in French and internationally, had a mixed meaning of either psychological/emotional (mental) or moral (ethical). Pinel distanced himself from the more religious work that was developed by the Tukes, and in fact considered that excessive religiosity could be harmful. He sometimes took a moral stance himself, however, as to what he considered to be mentally healthy and socially appropriate.
=== England ===
English Quaker William Tuke (1732–1822) independently led the development of a radical new type of institution in northern England, following the death of a fellow Quaker in a local asylum in 1790. In 1796, with the help of fellow Quakers and others, he founded the York Retreat, where eventually about 30 patients lived as part of a small community in a quiet country house and engaged in a combination of rest, talk, and manual work. Rejecting medical theories and techniques, the efforts of the York Retreat centered around minimizing restraints and cultivating rationality and moral strength. The entire Tuke family became known as founders of moral treatment. They created a family-style ethos and patients performed chores to give them a sense of contribution. There was a daily routine of both work and leisure time. If patients behaved well, they were rewarded; if they behaved poorly, there was some minimal use of restraints or instilling of fear. The patients were told that treatment depended on their conduct. In this sense, the patient's moral autonomy was recognized. William Tuke's grandson, Samuel Tuke, published an influential work in the early 19th century on the methods of the retreat; Pinel's Treatise on Insanity had by then been published, and Samuel Tuke translated his term as "moral treatment".
=== Scotland ===
A very different background to the moral approach may be discerned in Scotland. Interest in mental illness was a feature of the Edinburgh medical school in the eighteenth century, with influential teachers including William Cullen (1710–1790) and Robert Whytt (1714–1766) emphasising the clinical importance of psychiatric disorders. In 1816, the phrenologist Johann Spurzheim (1776–1832) visited Edinburgh and lectured on his craniological and phrenological concepts, arousing considerable hostility, not least from the theologically doctrinaire Church of Scotland. Some of the medical students, however, notably William A.F. Browne (1805–1885), responded very positively to this materialist conception of the nervous system and, by implication, of mental disorder. George Combe (1788–1858), an Edinburgh solicitor, became an unrivalled exponent of phrenological thinking, and his brother, Andrew Combe (1797–1847), who was later appointed a physician to Queen Victoria, wrote a phrenological treatise entitled Observations on Mental Derangement (1831). George and Andrew Combe exerted a rather dictatorial authority over the Edinburgh Phrenological Society, and in the mid-1820s manipulated the de facto expulsion of the Christian phrenologists.
This tradition of medical materialism found a ready partner in the Lamarckian biology purveyed by the naturalist Robert Edmond Grant (1793–1874) who exercised a striking influence on the young Charles Darwin during his time as a medical student in Edinburgh in 1826/1827. William Browne advanced his own versions of evolutionary phrenology at influential meetings of the Edinburgh Phrenological Society, the Royal Medical Society and the Plinian Society. Later, as superintendent of Sunnyside Royal Hospital (the Montrose Asylum) from 1834 to 1838, and, more extravagantly, at the Crichton Royal in Dumfries from 1838 to 1859, Browne implemented his general approach of moral management, indicating a clinical sensitivity to the social groupings, shifting symptom patterns, dreams and art-works of the patients in his care. Browne summarised his moral approach to asylum management in his book (actually the transcripts of five public lectures) which he entitled What Asylums Were, Are, and Ought To Be. His achievements with this style of psychiatric practice were rewarded with his appointment as a Commissioner in Lunacy for Scotland, and by his election to the Presidency of the Medico-Psychological Association in 1866. Browne's eldest surviving son, James Crichton-Browne (1840–1938), did much to extend his father's work in psychiatry, and, on 29 February 1924, he delivered a remarkable lecture The Story of the Brain, in which he recorded a generous appreciation of the role of the phrenologists in the early foundations of psychiatric thought and practice.
=== United States ===
A key figure in the early spread of moral treatment in the United States was Benjamin Rush (1745–1813), an eminent physician at Pennsylvania Hospital. He limited his practice to mental illness and developed innovative, humane approaches to treatment. He required that the hospital hire intelligent and sensitive attendants to work closely with patients, reading and talking to them and taking them on regular walks. He also suggested that it would be therapeutic for doctors to give small gifts to their patients every so often. However, Rush's treatment methods included bloodletting (bleeding), purging, hot and cold baths, mercury, and strapping patients to spinning boards and "tranquilizer" chairs.
A Boston schoolteacher, Dorothea Dix (1802–1887), also helped make humane care a public and a political concern in the US. On a restorative trip to England for a year, she met Samuel Tuke. In 1841 she visited a local prison to teach Sunday school and was shocked at the conditions for the inmates and the treatment of those with mental illnesses. She began to investigate and crusaded on the issue in Massachusetts and all over the country. She supported the moral treatment model of care. She spoke to many state legislatures about the horrible sights she had witnessed at the prisons and called for reform. Dix fought for new laws and greater government funding to improve the treatment of people with mental disorders from 1841 until 1881, and personally helped establish 32 state hospitals that were to offer moral treatment. Many asylums were built according to the so-called Kirkbride Plan.
== Consequences ==
The moral treatment movement was initially opposed by those in the mental health profession. By the mid-19th century, however, many psychologists had adopted the strategy. They became advocates of moral treatment, but argued that since the mentally ill often had separate physical/organic problems, medical approaches were also necessary. Making this argument stick has been described as an important step in the profession's eventual success at securing a monopoly on the treatment of "lunacy".
The moral treatment movement had a huge influence on asylum construction and practice. Many countries were introducing legislation requiring local authorities to provide asylums for the local population, and they were increasingly designed and run along moral treatment lines. Additional "non-restraint movements" also developed. There was great belief in the curability of mental disorders, particularly in the US, and statistics were reported showing high recovery rates. They were later much criticized, particularly for not differentiating between new admissions and re-admissions (i.e. those who hadn't really achieved a sustained recovery). It has been noted, however, that the cure statistics showed a decline from the 1830s onwards, particularly sharply in the second half of the century, which has been linked to the dream of small, curative asylums giving way to large, centralized, overcrowded asylums.
There was also criticism from some ex-patients and their allies. By the mid-19th century in England, the Alleged Lunatics' Friend Society was proclaiming that the new moral treatment was a form of social repression achieved "by mildness and coaxing, and by solitary confinement"; that its implication that the "alleged lunatics" needed re-educating meant it treated them as if they were children incapable of making their own decisions; and that it failed to properly inform people of their rights or involve them in discussion about their treatment. The Society was suspicious of the tranquility of the asylums, suggesting that patients were simply being crushed and then discharged to live a "milk sop" (meek) existence in society.
In the context of industrialization, public asylums expanded in size and number. Bound up in this was the development of the profession of psychiatry, able to expand with large numbers of inmates collected together. By the end of the 19th century and into the 20th, these large out-of-town asylums had become overcrowded, misused, isolated and run-down. The therapeutic principles had often been neglected along with the patients. Moral management techniques had turned into mindless institutional routines within an authoritarian structure. Consideration of costs quickly overrode ideals. There was compromise over decoration—no longer a homey, family atmosphere but drab and minimalist. There was an emphasis on security, custody, high walls, closed doors, shutting people off from society, and physical restraint was often used. It is well documented that there was very little therapeutic activity, and medics were little more than administrators who seldom attended to patients and mainly then for other, somatic, problems. Any hope of moral treatment or a family atmosphere was "obliterated". In 1827 the average number of asylum inmates in Britain was 166; by 1930 it was 1221. The relative proportion of the public officially diagnosed as insane grew.
Although the Retreat had been based on a non-medical approach and environment, medically based reformers emulating it spoke of "patients" and "hospitals". Asylum "nurses" and attendants, once valued as a core part of providing good holistic care, were often scapegoated for the failures of the system. Towards the end of the 19th century, somatic theories, pessimism in prognosis, and custodialism had returned. Theories of hereditary degeneracy and eugenics took over, and in the 20th century the concepts of mental hygiene and mental health developed. From the mid 20th century, however, a process of antipsychiatry and deinstitutionalization occurred in many countries in the West, and asylums in many areas were gradually replaced with more local community mental health services.
In the 1960s, Michel Foucault renewed the argument that moral treatment had really been a new form of moral oppression, replacing physical oppression, and his arguments were widely adopted within the antipsychiatry movement. Foucault was interested in ideas of "the other" and how society defines normalcy by defining the abnormal and its relationship to the normal. A patient in the asylum had to go through four moral syntheses: silence, recognition in the mirror, perpetual judgment, and the apotheosis of the medical personage. The mad were ignored and verbally isolated. They were made to see madness in others and then in themselves until they felt guilt and remorse. The doctor, despite his lack of medical knowledge about the underlying processes, had all powers of authority and defined insanity. Thus Foucault argues that the "moral" asylum is "not a free realm of observation, diagnosis, and therapeutics; it is a juridical space where one is accused, judged, and condemned." Foucault's reassessment was succeeded by a more balanced view, recognizing that the manipulation and ambiguous "kindness" of Tuke and Pinel may have been preferable to the harsh coercion and physical "treatments" of previous generations, while aware of moral treatment's less benevolent aspects and its potential to deteriorate into repression.
The moral treatment movement is widely seen as influencing psychiatric practice up to the present day, including specifically therapeutic communities (although they were intended to be less repressive); occupational therapy and Soteria houses. The Recovery model is said to have echoes of the concept of moral treatment.
== See also ==
Erwadi fire incident
Humane treatment of the mentally ill
Moral insanity
The Retreat, the first institution to implement moral treatment
Testimony of equality describing actions of the Quakers towards equality
== References == | Wikipedia/Moral_Treatment |
Over time, the approach to cerebral palsy management has shifted away from narrow attempts to fix individual physical problems – such as spasticity in a particular limb – to making such treatments part of a larger goal of maximizing the person's independence and community engagement.: 886 Much of childhood therapy is aimed at improving gait and walking. Approximately 60% of people with CP are able to walk independently or with aids at adulthood. However, the evidence base for the effectiveness of intervention programs reflecting the philosophy of independence has not yet caught up: effective interventions for body structures and functions have a strong evidence base, but evidence is lacking for effective interventions targeted toward participation, environment, or personal factors. There is also no good evidence to show that an intervention that is effective at the body-specific level will result in an improvement at the activity level, or vice versa. Although such cross-over benefit might happen, not enough high-quality studies have been done to demonstrate it.
Because cerebral palsy has "varying severity and complexity" across the lifespan, it can be considered a collection of conditions for management purposes. A multidisciplinary approach for cerebral palsy management is recommended, focusing on "maximising individual function, choice and independence" in line with the International Classification of Functioning, Disability and Health's goals. The team may include a paediatrician, a health visitor, a social worker, a physiotherapist, an orthotist, a speech and language therapist, an occupational therapist, a teacher specialising in helping children with visual impairment, an educational psychologist, an orthopaedic surgeon, a neurologist and a neurosurgeon.
Various forms of therapy are available to people living with cerebral palsy as well as caregivers and parents. Treatment may include one or more of the following: physical therapy; occupational therapy; speech therapy; water therapy; drugs to control seizures, alleviate pain, or relax muscle spasms (e.g. benzodiazepines); surgery to correct anatomical abnormalities or release tight muscles; braces and other orthotic devices; rolling walkers; and communication aids such as computers with attached voice synthesisers. A Cochrane review published in 2004 found a trend toward benefit of speech and language therapy for children with cerebral palsy, but noted the need for high quality research. A 2013 systematic review found that many of the therapies used to treat CP have no good evidence base; the treatments with the best evidence are medications (anticonvulsants, botulinum toxin, bisphosphonates, diazepam), therapy (bimanual training, casting, constraint-induced movement therapy, context-focused therapy, fitness training, goal-directed training, hip surveillance, home programmes, occupational therapy after botulinum toxin, pressure care) and surgery (selective dorsal rhizotomy).
== Lifestyle ==
Physical activity is recommended for people with cerebral palsy, particularly in terms of cardiorespiratory endurance, muscle strengthening and reduction of sedentary behaviour. Participating in physical activity can supplement or replace some forms of therapy. It has been argued that people with cerebral palsy need to maintain a higher level of fitness than the general population to offset loss of functionality as they age. Access to exercise can often depend on the caregivers' perception of whether it will benefit the person with CP, or barriers in the community. Accommodations in the environment and context has been identified as important when sustaining exercise participation in adults with cerebral palsy. There has been increasing interest in maintaining muscle strength through the lifespan of a person with CP. Aerobic capacity is not routinely assessed in people with cerebral palsy in a rehabilitation context, but Wingate tests have been advocated for use. Behavioural change methods have been used to promote physical activity among young people with cerebral palsy, but there is no significant evidence for these working. It is difficult to sustain behavioural change in terms of increasing physical activity of children with CP. Even though exercise is commonly recommended, there is only a small amount of evidence saying that aerobic exercise is good for gross motor function in children. Exercise can increase wellness in those with cerebral palsy. With regards to sports, the amount of exercise advised should be unique to the demands of the sport in question, the effect of the individual's condition on performance, and the potential to cause worsening of the condition. It is recommended, to encourage integrating moderate to vigorous exercise, including the use of a motor-assisted elliptical trainer. This is thought to improve fitness and the functioning.
Function gait training in children and young adults with cerebral palsy improves their ability to walk. There is evidence that antigravity treadmill training may improve the gait and balance of those children with diplegic cerebral palsy, it may also reduce risk of falls in these children.
Hippo therapy, or therapeutic horseback riding, is a physical therapy treatment strategy that uses equine movement. Evidence suggests that those with CP can benefit from symmetry of trunk movement. It is common for horses to sway, so those on them constantly have to adjust their posture. The symmetric, rhythmic, and consistent input that horseback riding provides helps with postural improvement. During horseback riding, a locomotor impulse is sent up the back of the horse. This impulse is then interpreted by the riders body, and it allows for regulation of mediolateral and anteroposterior postural sway, adaptation to new environments, anticipatory and feedback postural control and better use of multi sensory posture and movement related inputs (Keon et al., 2011).
A normal vaccination schedule should be adhered to, as preventable diseases may take away energy that a person with CP would normally use in day-to-day life.
== Therapy ==
Physiotherapy (also known as physical therapy) programs are designed to encourage the patient to build a strength base for improved gait and volitional movement, together with stretching programs to limit contractures. Physiotherapists can teach parents how to position and handle their child for activities of daily living. The need for lifelong physiotherapy for muscle tone, bone structure and preventing joint dislocation has been debated in terms of the costs and benefits of such therapy. Children may find long-term physical therapy boring. Physiotherapy exercises are designed to improve balance, postural control, gait, and assist with mobility and transferring the person with CP, for example from a wheelchair to a bed.
Speech therapy helps control the muscles of the mouth and jaw, and helps improve communication. Just as CP can affect the way a person moves their arms and legs, it can also affect the way they move their mouth, face and head. This can make it hard for the person to breathe; talk clearly; and bite, chew and swallow food. Speech therapy often starts before a child begins school and continues throughout the school years.
Biofeedback is a therapy in which people learn how to control their affected muscles. Biofeedback therapy has been found to significantly improve gait in children with cerebral palsy. Mirror therapy has been used to improve hand function and was found to be "generally effective in enhancing muscle strength, motor speed, muscle activity, and the accuracy of both hands". Second-generation mirror therapy, which includes the use of robotics or virtual reality, has been developed since the 2000s, however the evidence supporting this is of low quality.
Massage therapy is designed to help relax tense muscles, strengthen muscles, and keep joints flexible.
Gait analysis is often used to describe gait abnormalities in children. Gait training has been shown to improve walking speed in children and young adults with cerebral palsy.
Occupational therapy helps adults and children maximise their function, adapt to their limitations and live as independently as possible. A family-centred philosophy is used with children who have CP. Occupational therapists work closely with families in order to address their concerns and priorities for their child. Family-centered care is a paradigm that is often used with families with a child with CP. A review of how parents facilitate their child's participation found that parents typically "enable and support performance of meaningful activities" and "enable, change and use the environment", but that there is little written on parents' needs.
CP commonly causes hemiplegia. Those with hemiplegia have limited use of the limbs on one side of the body, and have normal use of the limbs on the other side. People with hemiplegia often adapt by ignoring the limited limbs, and performing nearly all activities with the unaffected limbs, which can lead to increased problems with muscle tone, motor control and range of motion. An emerging technique called constraint-induced movement therapy (CIMT) is designed to address this. In CIMT, the unaffected limbs are constrained, forcing the individual to learn to use the affected limbs. CIMT promotes increased motor function due to structural plasticity in the brain. As of 2007 there was limited, preliminary evidence that CIMT is effective, but more study is needed before it can be recommended with confidence. CIMT, modified CIMT, and forced use are three movement therapies that have been examined. CIMT is defined as "restraint of the unaffected upper limb ..., with more than three hours of therapy per day ... and is provided for at least two consecutive weeks". Children with hemiplegic cerebral palsy often have sensory impairments as well as motor deficits. CIMT has been shown to be an effective OT intervention to improve proprioception and sensory processing. CIMT has also been found to improve postural symmetry during functional tasks in individuals with CP.
Modified CIMT (mCIMT) is defined as "restraint of the unaffected upper limb and less than three hours per day of therapy provided to the affected limb". Forced use is when "restraint of the unaffected upper limb is applied but no additional treatment of the affected upper limb is provided". A review concluded that there is a positive trend favoring all three aforementioned therapies.
A comparison of bimanual training (BIT) and CIMT found that there was no significant difference between the two in terms of effects. However, bimanual training may be more able to be integrated into a child's daily life, because the goals in bimanual training are more functional. CIMT has some advantages, such as therapists being able to solely focus on the affected arm, and the child having no choice but to use the affected arm in their activities of daily life as their unaffected arm is constrained. In bimanual training, the child may continue to use the unaffected arm to compensate if their therapist or parent does not remind them to use both hands.
However, there is only some benefit from therapy. Treatment is usually symptomatic and focuses on helping the person to develop as many motor skills as possible or to learn how to compensate for the lack of them. Nonspeaking people with CP are often successful availing themselves of augmentative and alternative communication (AAC).
Therapeutic tests for assessing balance do not appear to have good evidence for their reliability and responsiveness. The tests with the strongest evidence are the Trunk Control Measurement Scale and the Level of Sitting Scale (when measuring the ability to maintain balance), Timed Up and Go test (when measuring the ability to achieve balance), and the Segmental Assessment of Trunk Control (when restoring balance).
Certain countries practice intensive physical therapy, but obtaining reliable data on its medium and long-term effectiveness is challenging.
== Assistive technology ==
Assistive technology is commonly used to promote the independence of people with disabilities. Commonly used technologies for people with cerebral palsy can include patient lifts, electric wheelchairs, orthotics, seating systems, mealtime aids (such as large-handled cutlery and slip-resistant mats), mobility aids, standing frames, non-motorised wheelchairs, augmentative and alternative communication and speech-generating devices. Scope has identified 3D printing as an area of promise in being able to print customised orthotics on-demand.
Orthotic devices such as ankle-foot orthoses (AFOs) are often prescribed to achieve the following objectives: correct and/or prevent deformity, provide a base of support, facilitate training in skills, and improve the efficiency of gait. The available evidence suggests that orthoses can have positive effects on all temporal and spatial parameters of gait, i.e. velocity, cadence, step length, stride length, single and double support. AFOs have also been found to reduce energy expenditure. Often children with CP require orthoses, such as casts and splints, to correct or prevent joint abnormalities, stabilize joints, prevent unwanted movement, allow desired movement, and prevent permanent muscle shortening. Orthoses may also make it easier to dress or to maintain hygiene. Lower limb splinting is specifically beneficial in providing a base of support and facilitating walking. It is equally important that the child be able to carry out daily activities and prevent joint deformities.
Children with CP have difficulties with mobility and posture. Occupational therapists often assess and prescribe seating equipment and wheelchairs. An appropriate wheelchair will stabilize the body so the child can use their arms for other activities. Wheelchairs therefore enhance independence.
Accessible housing may assist some people with cerebral palsy, particularly wheelchair users.
Assistive technologies used during sleep to position the body to prevent painful hip migration are called 'sleep positioning systems'. Studies on their effectiveness are of poor quality.
== Medication ==
Various oral and injectable medication have been used to treat cerebral palsy and its associated comorbid conditions. They include botulinum toxin, benzodiazepines, baclofen, dantrolene, tizanidine, cyclobenzaprine, and phenol.
Botulinum toxin injections are given into muscles that are spastic or sometimes dystonic, the aim being to reduce the muscle hypertonus that can be painful. A reduction in muscle tone can also facilitate bracing and the use of orthotics. Both lower extremity and upper extremity muscles are injected. Botulinum toxin is focal treatment, meaning that a limited number of muscles can be injected at the same time. The effect of the toxin is reversible and a reinjection may be needed every 4–6 months. In children it decreases spasticity and improve range of motion and thus has become commonly used. Botulin toxin has been used in CP treatment for around two decades and can be recommended for children above the age of two. Two systematic reviews published in 2010 and 2020 found that there is high level evidence in the use of botulinum toxin as an add on therapy to occupational therapy among other physical therapies modalities in order to manage spasticity in the arms of children with cerebral palsy. However, there is no strong research associated with the use of botulinum toxin in the management of spasticity in the legs or improving gait compared to casting. More evidence related to the frequency and dosage of injections as it relates to long-term outcomes is needed in order to support or refute the use of botulinum toxin in the management of lower limb spasticity in children with cerebral palsy. Dosages of botulinum toxin have been based on expert opinion rather than evidence-based practices. The dosages recommended have recently been reduced to reduce severe side-effects including becoming sensitive to the botulin toxin and developing an allergic response. Higher risks have been noted with children who are at level IV and V on the GMFCS.
Drooling is often treated with botulinum toxin A, benztropine or anticholinergics (e.g. glycopyrrolate). A review on the treatment of sialorrhea in children with cerebral palsy found that it was not possible to tell whether these interventions worked or were safe. Anticholinergics may contribute to constipation.
Bisphosphonates are used to treat osteoporosis in adults. Osteoporosis is common in children with cerebral palsy, and non-oral bisphosphonates have been used to treat children with a very low bone mass density and a medical history of fragility fracture.
Oral baclofen or diazepam is used to reduce spasticity which results in pain, muscle spasms or functional disability. Baclofen is used for a long-term effect and works at the spinal level. Diazepam is fast-acting. Baclofen may also be administerd intrathecally.
Trihexyphenidyl is often prescribed for dystonia. However, a 2018 Cochrane review (one study met inclusion criteria) on the use of trihexyphenidyl for dystonia found insufficient evidence of its effectiveness.
Sometimes, medication used to manage physical aspects of CP can have effects on the person's mental health, or medications used to manage mental health can affect motor function.
Epilepsy that co-occurs with cerebral palsy is often drug-resistant.
== Orthopaedic surgery ==
Deformities in cerebral palsy children are inherently known for being Multiplane i.e. occurring in more than one plane such as transverse plane through which rotation occurs and sagittal plane through which flexion/extension of joint occurs. Furthermore, deformities in cerebral palsy children are characteristically multilevel i.e. occurring at simultaneously at more than one joint. This adds to the complexity of orthopedic management of cerebral palsy children. Thus, multilevel orthopedic surgery is the mainstay of orthopedic management. Multilevel orthopedic surgery may include soft tissue as tendon lengthening or transfer and/or bony surgery as corrective bone osteotomies. Multilevel orthopedic surgery is usually performed in one anesthetic sitting. This allows for the institution of one postoperative rehabilitation protocol and reduces hospital admission rates.
Orthopaedic surgery is widely used to correct fixed deformities and improve the functional capacity and gait pattern of children with CP. Dynamic deformities such as ankle equinus and hip adduction deformity leading to subluxation are usually managed conservatively with exercises; serial casting and botulinum toxin type A injections. This main goal of these conservative measures is to impede or prevent the happening of fixed or static joint deformities. Once joint contractures- fixed deformities - develop or joint subluxation or dislocation occurs, surgical treatment could become mandatory. It is of paramount importance to delay the age at which orthopaedic surgical intervention becomes necessary as surgery early in life carries a greater risk of deformity recurrence especially in cases of ankle equines. Additionally, unjustified lengthening of the tendon Achilles is fraught with risk of over lengthening and subsequent gait deterioration namely crouch gait.
In general, orthopaedic surgery for children with CP consists of tendon releases, lengthening, transposition and corrective osteotomies. For example, fixed/static ankle equinus is usually managed by gastrocnemius-soleus aponeurotic lengthening or tendon Achilles lengthening. Hip subluxation/dislocation is usually managed by adductor musculature release with or without a psoas tendon release together with femoral and pelvic osteotomies. This aims at hip joint containment and preservation. In the event that hip joint dislocation becomes longstanding and painful in elder children or adolescence, hip salvage surgery may be an option to reduce pain help nursing and improve sitting balance. A variety of surgical procedures are included under hip salvage namely valgization osteotomy and femoral head resection. Total hip arthroplasty is recommended for those with a mature skeleton, who are also likely less severely impaired. Because CP is widely heterogeneous in its presentation, surgery should be considered on a case-by-case basis.
Orthopaedic surgery usually involves one or a combination of:
Orthopaedic surgery as mentioned above involves releasing tight muscles and fixed joint contractures, and corrective osteotomies conducted basically to restore sagittal and rotational malalignment of bones. Orthopedic surgery is most often performed on the hips, knees, hamstrings, and ankles. For example, hip adductor release, musculotendinous lengthening for equinus gait, femoral derotational osteotomy, and knee extension osteotomy are commonly practiced. Less commonly, this surgery may be used for people with stiffness of their elbows, wrists, hands, and fingers.
== Other surgeries ==
The insertion of a baclofen pump usually during the stages while a person is a young adult. This is usually placed in the left abdomen. It is a pump that is connected to the spinal cord, whereby it releases doses of baclofen to alleviate continuous muscle flexion. Baclofen is a muscle relaxant and is often given by mouth to people to help counter the effects of spasticity, although this has the side effect of sedating the individual. The pump can be adjusted if muscle tone is worse at certain times of the day or night. The baclofen pump is most appropriate for individuals with chronic, severe stiffness or uncontrolled muscle movement throughout the body. There is a small amount of evidence that baclofen pumps are effective in the short term.
Cutting nerves on the limbs most affected by movements and spasms. This procedure, called a rhizotomy ("rhizo" meaning root and "tomy" meaning "a cutting of" from the Greek suffix tomia), reduces spasms and allows more flexibility and control of the affected limbs and joints.
Tracheotomy
Dental surgery
Diagnostic endoscopy
Nissen fundoplication
Other surgical procedures are available to try to help with other problems. Those who have serious difficulties with eating may undergo a procedure called a gastrostomy: a hole is cut through the belly skin and into the stomach to allow for a feeding tube. There is no good evidence about the effectiveness or safety of gastrostomy. Gastrostomies are associated with a lower life expectancy, this is probably due to underlying problems with swallowing rather than the procedure itself.
== Others ==
Whole-body vibration might improve speed, gross motor function and femur bone density in children with cerebral palsy.
Aquatic therapy or hydrotherapy are commonly used therapies for children with CP, but evidence for their effectiveness is mixed. Potential benefits of aquatic therapy is that children might find it more interesting than exercising on land, and they can try different kinds of movement such as jumping or skipping with less impact on their joints. Due to the principles of water, buoyancy allows for optimal joint positioning, which enables the execution of these activities as well as walking exercises for children with CP experiencing mild mobility constraint. Buoyancy enables children with moderate to severe mobility impairments to maneuver and exercise in water more freely than they can on land. While aquatic exercise is feasible and has low risk of adverse effects, the dose required to make a difference to gross motor skills is unclear. Research suggests that the dose required may vary depending on age. A systematic review investigating the effects of aquatic therapy showed that children around 9-10 years old showed significant improvements in gross motor function, whereas older children did not. Although still unclear, these findings suggest that older children may require longer aquatic therapy interventions in order to improve their skills and prevent decline.
Hip surveillance is the term for monitoring a child with CP who is at risk of hip dislocation to try to prevent dislocation from happening. The modern definition of cerebral palsy includes secondary skeletal effects on the child. The Gross Motor Function Classification System is a good indicator of hip issues, and more commonly occurs in children with spastic tetraplegia or spastic quadriplegia, but it is difficult to tell what type of CP a child has at the age where hip displacement might first become an issue (sometimes at 2 years old, but more commonly between 3 and 4 years old). Children are assessed for the risk of hip displacement using radiography.
Music therapy has been used in CP to motivate or relax children, or used as auditory feedback. Playing percussion instruments has been used as part of groupwork in therapy. Piano lessons may be beneficial in CP rehabilitation, however more research is needed.
While there is great interest in using video game rehabilitation with children with cerebral palsy, it is difficult to compare outcomes between studies, and therefore to reach evidence-based conclusions on its effectiveness. Because video gaming is popular, it may help children's motivation to continue with the therapy. There is moderate evidence for improvements with balance and motor skills in children and teens, but it is not recommended as an effective therapy.
Service dogs may be used to assist people who have seizures as part of their CP.
Yoga has been used by carers as part of the physical therapies for children to assist in developing basic motor skills.
There is evidence around using multi-modal and physical interventions to improve general cognitive functioning in people with CP.
== Alternative therapy ==
There has not been much research into the use of alternative medicine to treat cerebral palsy. Acupuncture has been used as a treatment for cerebral palsy since at least the 1980s, but as of 2009, there have been no Cochrane reviews of the effectiveness of acupuncture in the management of cerebral palsy. In Traditional Chinese Medicine, cerebral palsy is often covered in the traditional diagnosis of "5 delayed syndrome". Dolphin-assisted therapy, Adeli suits, and hyperbaric oxygen therapy have been criticised as being alternative medicine and contrary to the practice of evidence-based medicine.
Hyperbaric oxygen therapy (HBOT), in which pressurised oxygen is inhaled inside a hyperbaric chamber, has been studied under the theory that improving oxygen availability to damaged brain cells can reactivate some of them to function normally. HBOT results in no significant difference from that of pressurised room air, however, and some children undergoing HBOT may experience adverse events such as seizures and the need for ear pressure equalisation tubes.
Patterning is a controversial form of alternative therapy for people with CP. The method is promoted by The Institutes for the Achievement of Human Potential (IAHP), a Philadelphia nonprofit organisation, but has been criticised by the American Academy of Pediatrics.
Conductive education (CE) was developed in Hungary from 1945 based on the work of András Pető. It is a unified system of rehabilitation for people with neurological disorders including cerebral palsy, Parkinson's disease and multiple sclerosis, amongst other conditions. It is theorised to improve mobility, self-esteem, stamina and independence as well as daily living skills and social skills. The conductor is the professional who delivers CE in partnership with parents and children. Skills learned during CE should be applied to everyday life and can help to develop age-appropriate cognitive, social and emotional skills. It is available at specialised centres.
Reviews disagree on the usefulness of therapy with horses – one found there was a positive effect on large scale motor function and another found that there was no evidence of improvements.
Occupational therapists may use neuro-developmental techniques to promote normal movement and posture and to inhibit abnormal movement and posture. Specific techniques include joint compression and stretching to provide sensory-motor input and to guide motor output. Neurodevelopmental treatment, despite being commonly used as a therapy for children with CP, has not been found to have strong evidence for its use. It has been suggested that rhythmic auditory stimulation may be more effective in improving gait than NDT techniques.
== Occupational therapy ==
Occupational Therapy (OT) enables individuals with cerebral palsy to participate in activities of daily living that are meaningful to them. A family-centred philosophy is used with children who have CP. Occupational therapists work closely with families in order to address their concerns and priorities for their child. Occupational therapists may address issues relating to sensory, cognitive, or motor impairments resulting from CP that affect the child's participation in self-care, productivity, or leisure. Parent counselling is also an important aspect of occupational therapy treatment with regard to optimizing the parent's skills in caring for and playing with their child to support improvement of their child's abilities to do things. The occupational therapist typically assesses the child to identify abilities and difficulties, and environmental conditions, such as physical and cultural influences, that affect participation in daily activities. Occupational therapists may also recommend changes to the play space, changes to the structure of the room or building, and seating and positioning techniques to allow the child to play and learn effectively.
=== Effect of sensory and perceptual impairments ===
Children with CP may experience decreased sensation or a limited understanding of how the brain interprets what it sees. Occupational therapists may plan and implement sensory-perceptual-motor (SPM) training for children with CP who have sensory impairments so that they learn to take in, understand, plan and produce organized behaviour. The SPM training improves the daily, functional abilities of people with CP. Occupational therapists may also use verbal instructions and supplementary visual input, such as visual cues, to help children with CP learn and carry out activities.
For children with CP with limited movement and sensation, the risk of pressure sores increases. Pressure sores often occur on bony parts of the body. For example, pressure sores may occur when a child has limited feeling and movement of their lower body and uses a wheelchair; the tailbone bears weight when seated and can become vulnerable to pressure sores. The occupational therapist can educate the child, family, and caregivers about how to prevent pressure sores by monitoring the skin for areas of irritation, changing positions frequently, or using a tilt-in-space wheelchair.
=== Effect of cognitive and perceptual impairments ===
OT can address cognitive and perceptual disabilities, especially of the visual-motor area. For children with CP who have difficulty remembering the order and organization of self-care tasks in the morning, an occupational therapist can construct a morning routine schedule with reminders. An occupational therapist may analyze the steps involved in a task to break down an activity into simpler tasks. For example, dressing can be broken down into smaller, manageable steps. This can be done by having a caregiver lay out the clothing in order so the child knows what needs to be put on first.
=== Effect of motor impairments ===
The effect of motor impairments is significant for children with CP because it affects the ability to walk, propel a wheelchair, maintain hygiene, access the community and interact with other people. Occupational therapists address motor impairments in a variety of ways and makes use of various techniques, depending on the child's needs and goals. The occupational therapist may help the child with gross motor rehabilitation, or whole body and limb movements, through repetitive activities. If the child has muscle weakness, progressive resistance exercises can improve muscular strength and endurance. Fine motor rehabilitation, or small, specific movements, such as threading the eye of a needle, can be implemented to improve finger movement and control.
For children with difficulties speaking, an occupational therapist may liaise with a speech therapist, carry out assessments, provide education and prescribe adaptive equipment. Adaptive equipment may include picture boards to help with communication and computers that respond to voice.
Occupational therapists can help the child promote use of a neglected arm through techniques such as constraint-induced movement therapy (CIMT), which forces use of the unused arm by placing the other arm in a sling, cast or oversized mitt.
Another OT technique that may be used is neuromuscular facilitation techniques, which involves physically moving and stretching the muscles to improve function so that the child can participate in activities.
Spasticity is a common problem experienced by people with cerebral palsy. It can cause pain and loss of sleep, impair function in activities of daily living, and cause unnecessary complications. Spasticity is measured with the Ashworth scale. Occupational therapy targeting spasticity aims to lengthen the overactive muscles. Some people with cerebral palsy use spasticity to compensate for muscle weakness, and so reducing spasticity can reduce function.
=== OT role with factors influencing participation ===
Barriers to participation for children with CP include difficulty accessing the community. This includes difficulty accessing buildings and using transportation. Occupational therapists may work with developers to ensure new homes are accessible to all people. Also, occupational therapists often help people apply for government and non-profit funding to provide assistive devices, such as special computer programs or wheelchairs, to children with CP. Availability of transportation services can be limited for children with CP because of many factors, such as difficulties fitting wheelchairs into vehicles and dependency on public transit schedules. Therefore, the occupational therapists may also be involved in education and referral regarding accessible vehicles and funding.
Occupational therapists address the community and environmental factors that affect participation in leisure activities by educating children with CP, their families, and others on available options and adaptive ways to engage in leisure activities of interest. Prejudice of others toward disability can also be a barrier to participation for children with CP with respect to leisure activities. One way occupational therapists can address this barrier is to teach the child to educate others on CP – thus reducing stigma and enhancing participation. Finally, occupational therapists take children's preferences into consideration in terms of cosmetic appearance when prescribing or fabricating adaptive equipment and splints. This is important as appearance may affect the child's compliance with assistive devices, as well as their self-confidence, which may impact participation. In addition to providing dedicated occupational therapy to such children, some non-profit organizations viz. Spastic Society of Gurgaon are providing comprehensive assistance which includes designing of child specific assisting devices to such children for making their lives more meaningful by enabling them to be self-reliant to the best possible extent.
== Research ==
Most research into cerebral palsy covers children and adolescents. Stem cell therapy, and other cell-based therapies are being studied as a treatment. A potential treatment for some forms of cerebral palsy may be deep brain stimulation.As of 2016 it is thought that research in genetics and genomics, teratology, and developmental neuroscience is going to yield greater understanding of cerebral palsy. Genetic testing may help find the etiology or comorbidities for types of cerebral palsy which could help in clarifying the classification systems for cerebral palsy. In addition, experimenting with combinations of therapies may result in additional benefits. A 2016 review which looked at research gaps in cerebral palsy identified neuroplasticity as an "underresearched opportunity for treating CP".
== Defining functional independence ==
Despite the transition in philosophy from treating individual body problems to treating the person with CP holistically, it has remained difficult to define what functional independence is. The Functional Independence Measure is sometimes used to describe people with CP.
== See also ==
Autism therapies
Disease management (health)
Management of depression
Neuropsychiatry
Neurorehabilitation
Salutogenesis
Quality of life (healthcare)
== References ==
== Further reading ==
== External links == | Wikipedia/Occupational_therapy_in_the_management_of_cerebral_palsy |
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