The tail-bending maneuver generated by myomeres in zebrafish requires innervation from motor neurons for both the hypaxial and epaxial muscle regions. It has been found that timing/intensity of neurons firing in these two regions varies, respectively. This process is mediated by a circuit that controls motor neuron activation during swimming behaviors, which, in turn, affects force generation. Similar to this idea, one study found that hypaxial and epaxial myomere activation did not always correlate with myomeric fibers closer to the horizontal septum itself. [ 6 ]


Myomeres run vertically and do not undergo folding like in bony fishes. Further, in higher order vertebrates, myomeres are fused and run longitudinally. Myosepta that divides myomeres are completely obsolete in amniotes.


Myomeres also play a role in swimming in adult newts. Specifically, epaxial myomeres located opposite to each other at the same longitudinal site alternate rhythmic contraction. During stepping on the ground, the myomeres of the mid-trunk undergo bursts of contraction that are synchronized in contrast to double bursting patterns (in opposite directions) expressed in the anterior and posterior trunks. [ 7 ]


In salamanders, hypaxial muscles, myomeres, and myosepta run in a straight line mid-laterally to mid-ventrally. Specifically, the orientation of collagen fibers within these myomeres runs mediolateral. It is also theorized that, in salamanders, myosepta increase the amplification of strain of angled muscle fibers. This controls  how myomeres bulge during contraction in what is called the 'bulge control hypothesis'. [ 8 ]


Eel  myomeres are W-shaped and cover the entire body. Within these is a mucosal-like matrix that is a-cellular. Superficial to these myomeres is an epithelial layer.


Salamanders in the genus  Necturus  (mudpuppies) are a salamander species with simply-lain myomeres, unlike the complex nature of bony fishes. [ 9 ]


The myomeres of some  Chondrichthyes , specifically sharks, are W-shaped. Thus, function in Chondrichthyes is similar to that of bony fish, where myomeres contribute to propulsive force for locomotion.


Leptocephalus  myomeres are W-shaped and extend from head all the way to the tail. Distinguishing eels can be done through evaluation of the number of myomeres (European has 112-119 while American has 103–11).


Myotoxins  are small, basic  peptides  found in  snake   venoms  (e.g.  rattlesnakes ) [ 2 ] [ 3 ]  and  lizard  venoms (e.g.  Mexican beaded lizard ). [ 4 ]  This involves a non-enzymatic mechanism that leads to severe  muscle   necrosis . These peptides act very quickly, causing instantaneous  paralysis  to prevent  prey  from escaping and eventually death due to  diaphragmatic  paralysis.


The first myotoxin to be identified and isolated was  crotamine , from the venom of  Crotalus durissus terrificus , a tropical South American rattlesnake, by  Brazilian   scientist   José Moura Gonçalves , in the 1950s. Its biological actions,  molecular structure  and  gene  responsible for its synthesis were all elucidated in the last two decades.


Neuromuscular-blocking drugs , or  Neuromuscular blocking agents  ( NMBAs ), block transmission at the  neuromuscular junction , [ 1 ]  causing  paralysis  of the affected  skeletal muscles . This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.


In clinical use, neuromuscular block is used adjunctively to  anesthesia  to produce  paralysis , firstly to paralyze the vocal cords, and permit  endotracheal intubation , [ 2 ]  and secondly to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles.  Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm),  mechanical ventilation  should be available to maintain adequate  respiration .


This  class  of  medications  helps  to  reduce  patient  movement,  breathing,  or  ventilator  dyssynchrony  and  allows  lower  insufflation  pressures  during  laparoscopy. [ 3 ] [ 4 ]  It has several indications for use in the intense care unit.  It can help reduce hoarseness in voice as well as injury to the vocal cord during intubation. In addition, it plays an important role in facilitating  mechanical ventilation  in patients with poor lung function.


Patients are still aware of pain even after full  conduction block  has occurred; hence,  general anesthetics  and/or  analgesics  must also be given to prevent  anesthesia awareness .


Neuromuscular blocking drugs are often classified into two broad classes:


It is also common to classify them based on their chemical structure.


Suxamethonium  was synthesised by connecting two  acetylcholine   molecules  and has  the same number of heavy  atoms  between methonium heads as  decamethonium .  Just like acetylcholine, succinylcholine, decamethonium and other  polymethylene  chains, of the appropriate length and with two methonium, heads have small  trimethyl   onium  heads and flexible links. They all exhibit a depolarizing block.


Pancuronium ,  vecuronium ,  rocuronium ,  rapacuronium ,  dacuronium ,  malouètine ,  dihydrochandonium ,  dipyrandium ,  pipecuronium ,  chandonium  (HS-310),  HS-342  and other HS- compounds are aminosteroidal agents. They have in  common the  steroid  structural base, which provides a rigid and bulky body. Most of the agents in this category would also be classified as non-depolarizing.


Compounds based on the  tetrahydroisoquinoline  moiety such as  atracurium ,  mivacurium , and  doxacurium  would fall in this category. They have a long and flexible chain between the  onium  heads, except for the double bond of  mivacurium .  D-tubocurarine  and  dimethyltubocurarine  are also in this category. Most of the agents in this category would be classified as non-depolarizing.


Gallamine  is a trisquaternary ether with three ethonium heads attached to a  phenyl  ring through an ether linkage. Many other different structures have been used for their muscle relaxant effect such as  alcuronium  (alloferin),  anatruxonium ,  diadonium ,  fazadinium  (AH8165) and  tropeinium .


In recent years much research has been devoted to new types of quaternary ammonium muscle relaxants. These are asymmetrical diester  isoquinolinium  compounds and bis-benzyltropinium compounds that are bistropinium salts of various  diacids .  These classes have been developed to create  muscle relaxants  that are faster and shorter acting. Both the asymmetric structure of diester isoquinolinium compounds and the acyloxylated benzyl groups on the bisbenzyltropiniums destabilizes them and can lead to spontaneous breakdown and therefore possibly a shorter duration of action. [ 6 ]


These drugs fall into two groups:


A  neuromuscular non-depolarizing agent  is a form of  neuromuscular blocker  that does not depolarize the  motor end plate . [ 8 ]


The quaternary ammonium muscle relaxants belong to this class. Quaternary ammonium muscle relaxants are  quaternary ammonium salts  used as  drugs  for  muscle relaxation , most commonly in  anesthesia . It is necessary to prevent spontaneous movement of muscle during  surgical operations . Muscle relaxants inhibit  neuron  transmission to muscle by blocking the  nicotinic acetylcholine receptor . What they have in common, and is necessary for their effect, is the structural presence of quaternary ammonium groups, usually two. Some of them are found in nature and others are  synthesized  molecules. [ 9 ] [ 5 ]


Below are some more common agents that act as  competitive antagonists  against acetylcholine at the site of postsynaptic acetylcholine receptors.


Tubocurarine , found in  curare  of the South American plant Pareira,  Chondrodendron tomentosum , is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (<5 min) and a long  duration of action  (30 mins). Side-effects include  hypotension , which is partially explained by its effect of increasing  histamine  release, a  vasodilator , [ 10 ]  as well as its effect of blocking  autonomic ganglia . [ 11 ]   It is excreted in the  urine .


This drug needs to block about 70–80% of the ACh receptors for neuromuscular conduction to fail, and hence for effective blockade to occur. At this stage,  end-plate potentials  (EPPs) can still be detected, but are too small to reach the  threshold potential  needed for activation of muscle fiber contraction.


The speed of onset depends on the potency of the drug, greater potency is associated with slower onset of block. Rocuronium, with an ED 95  of 0.3 mg/kg IV has a more rapid onset than Vecuronium with an ED 95  of 0.05mg/kg. [ 12 ]  Steroidal compounds, such as rocuronium and vecuronium, are intermediate-acting drugs while Pancuronium and  pipecuronium  are long-acting drugs. [ 12 ]


(no hypotension) [ 13 ]


In larger clinical dose, some of the blocking agent can access the pore of the ion channel and cause blockage. This weakens neuromuscular transmission and diminishes the effect of  acetylcholinesterase inhibitors  (e.g.  neostigmine ). [ 14 ]  Nondepolarizing NBAs may also block prejunctional sodium channels which interfere with the mobilization of acetylcholine at the nerve ending. [ 14 ]


A  depolarizing neuromuscular blocking agent  is a form of  neuromuscular blocker  that depolarizes the  motor end plate . [ 15 ]  An example is  succinylcholine . Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to  acetylcholine .  However, these agents are more resistant to degradation by  acetylcholinesterase , the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.


There are two phases to the depolarizing block. During phase I ( depolarizing phase ), succinylcholine interacts with nicotinic receptor to open the channel and cause  depolarization  of the  end plate , which later spread to and result in depolarization of adjacent membranes. As a result, there is disorganisation of contraction of muscle motor unit. [ 14 ]  This causes muscular  fasciculations  (muscle twitches) while they are depolarizing the muscle fibers.  Eventually, after sufficient depolarization has occurred, phase II ( desensitizing phase ) sets in and the muscle is no longer responsive to acetylcholine released by the  motoneurons . [ 14 ]  At this point, full neuromuscular block has been achieved. Phase I block effect can be increased by  cholinesterase inhibitors  which further delay the action of metabolism and removal by cholinesterase. [ 14 ]


Under continuous exposure to succinylcholine, the initial end plate depolarization is reduced, and repolarisation process is initiated. [ 14 ]  As a result of the widespread sustained depolarization the synapses ultimately begin  repolarization . Once repolarized, the membrane is still less susceptible to additional depolarization (phase II block). [ 14 ]


The prototypical depolarizing blocking drug is  succinylcholine  (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as  butyrylcholinesterase  in the blood). The patient will experience  fasciculation  due to the depolarisation of muscle neurone fibres and seconds later,  flaccid paralysis  will occur. [ 12 ]  Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group.  Decamethonium  is sometimes, but rarely, used in clinical practice.


It is indicated for rapid sequence intubation.


IV dose 1-1.5mg/kg or 3 to 5 x ED 95


Paralysis occurs in one to two minutes.


Clinical duration of action (time from drug administration to recovery of single twich to 25% of baseline) is 7-12 minutes.


If IV access is unavailable, intramuscular administration 3-4mg/kg. Paralysis occurs at 4 minutes.


Use of succinylcholine infusion or repeated  bolus administration  increase the risk of Phase II block and prolonged paralysis. Phase II block occurs after large doses (>4mg/kg). This occurs when the post-synaptic membrane action potential returns to baseline in spite of the presence of succinylcholine and causes continued activation of nicotinic acetylcholine receptors. [ 12 ]


The main difference is in the reversal of these two types of neuromuscular-blocking drugs.


The  tetanic fade  is the failure of muscles to maintain a fused  tetany  at sufficiently high frequencies of electrical stimulation.


This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug. [ 16 ]


(fade)


(not fade)


Neuromuscular blocking agents exert their effect by modulating the signal transmission in skeletal muscles. An action potential is, in other words, a depolarisation in neurone membrane due to a change in membrane potential greater than the  threshold potential  leads to an electrical impulse generation. The electrical impulse travels along the pre-synaptic neurone axon to synapse with the muscle at the neuromuscular junction (NMJ) to cause muscle contraction. [ 17 ]


When the action potential reaches the axon terminal, it triggers the opening of the  calcium ion gated channels , which causes the influx of Ca 2+ . Ca 2+  will stimulate the release of neurotransmitter in the neurotransmitter containing vesicles by  exocytosis  (vesicle fuses with the pre-synpatic membrane). [ 17 ]


The neurotransmitter, acetylcholine(ACh) binds to the nicotinic receptors on the motor end plate, which is a specialised area of the muscle fibre's post-synaptic membrane. This binding causes the nicotinic receptor channels to open and allow the influx of Na +  into the muscle fibre. [ 17 ]


Fifty percent of the released ACh is hydrolysed by acetylcholinesterase (AChE) and the remaining bind to the nicotinic receptors on the motor end plate. When ACh is degraded by AChE, the receptors are no longer stimulated and the muscle cannot be depolarized. [ 17 ]


If enough Na +  enter the muscle fibre, it causes an increase in the membrane potential from its  resting potential  of -95mV to -50mV (above the threshold potential -55mV) which causes an action potential to spread throughout the fibre. This potential travels along the surface of the  sarcolemma . The sarcolemma is an excitable membrane that surrounds the contractile structures known as  myofibrils  that are located deep in the muscle fibre. For the action potential to reach the myofibrils, the action potential travels along the  transverse tubules  (T-tubules) that connects the sarcolemma and center of the fibre. [ 17 ]


Later, action potential reaches the  sarcoplasmic reticulum  which stores the Ca 2+   needed for muscle contraction and causes Ca 2+  to be released from the sarcoplasmic reticulum. [ 17 ]


Quaternary muscle relaxants bind to the  nicotinic acetylcholine receptor  and inhibit or interfere with the binding and effect of  ACh  to the  receptor . Each  ACh-receptor  has two receptive sites and activation of the receptor requires binding to both of them. Each receptor site is located at one of the two α-subunits of the receptor. Each receptive site has two subsites, an  anionic  site that binds to the  cationic   ammonium  head and a site that binds to the blocking agent by donating a  hydrogen bond . [ 5 ]


Non-depolarizing agents
A decrease in binding of acetylcholine leads to a decrease in its effect and  neuron  transmission to the  muscle  is less likely to occur. It is generally accepted that non-depolarizing agents block by acting as reversible competitive  inhibitors . That is, they bind to the receptor as  antagonists  and that leaves fewer receptors available for acetylcholine to bind. [ 5 ] [ 18 ]


Depolarizing agents
 Depolarizing  agents produce their block by binding to and activating the ACh receptor, at first causing muscle contraction, then paralysis. They bind to the receptor and cause depolarization by opening channels just like acetylcholine does. This causes repetitive excitation that lasts longer than a normal acetylcholine excitation and is most likely explained by the resistance of depolarizing agents to the  enzyme   acetylcholinesterase . The constant depolarization and triggering of the receptors keeps the endplate resistant to activation by acetylcholine. Therefore, a normal neuron transmission to muscle cannot cause contraction of the muscle because the endplate is depolarized and thereby the muscle paralysed. [ 5 ] [ 18 ]


Binding to the  nicotinic receptor
Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), usually span the two receptive sites with one molecule (binding inter-site). Longer congeners must bend when fitting receptive sites.


The greater energy a molecule needs to bend and fit usually results in lower potency. [ 19 ]


Conformational study on  neuromuscular blocking drugs  is relatively new and developing. Traditional  SAR  studies do not specify environmental factors on molecules.  Computer -based conformational searches assume that the molecules are  in vacuo , which is not the case  in vivo . Solvation models take into account the effect of a solvent on the conformation of the molecule. However, no system of solvation can mimic the effect of the complex fluid composition of the body. [ 20 ]


The division of  muscle relaxants  to rigid and non-rigid is at most qualitative. The  energy  required for conformational changes may give a more precise and quantitative picture. Energy required for reducing  onium  head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites. [ 19 ]  Using computers it is possible to calculate the lowest energy state conformer and thus most populated and best representing the molecule. This state is referred to as the global minimum. The global minimum for some simple molecules can be discovered quite easily with certainty. Such as for  decamethonium  the straight line conformer is clearly the lowest energy state. Some molecules, on the other hand, have many rotatable bonds and their global minimum can only be approximated. [ 20 ]


Neuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium. [ 19 ]  Some molecules of decamethonium congeners may bind only to one receptive site. Flexible molecules have a greater chance of fitting receptive sites. However, the most populated conformation may not be the best-fitted one. Very flexible molecules are, in fact, weak neuromuscular inhibitors with flat dose-response curves. On the other hand, stiff or rigid molecules tend to fit well or not at all. If the lowest-energy conformation fits, the compound has high potency because there is a great concentration of molecules close to the lowest-energy conformation. Molecules can be thin but yet rigid. [ 20 ]  Decamethonium for example needs relatively high energy to change the  N - N  distance. [ 19 ]


In general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant shows a  polarizing  or a  depolarizing  effect. [ 6 ]   Cations  must be able to flow through the trans-membrane tube of the  ion-channel  to depolarize the endplate. [ 20 ]  Small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites. [ 6 ]  Large molecules, on the other hand, may bind to both receptive sites and hinder depolarizing cations independent of whether the ion-channel is open or closed below. Having a  lipophilic  surface pointed towards the synapse enhances this effect by repelling cations. The importance of this effect varies between different muscle relaxants and classifying depolarizing from non-depolarizing blocks is a complex issue. The onium heads are usually kept small and the chains connecting the heads usually keep the N-N distance at 10 N or O atoms. Keeping the distance in mind the structure of the chain can vary (double bonded, cyclohexyl, benzyl, etc.) [ 20 ]


Succinylcholine  has a 10- atom  distance between its  N  atoms, like decamethonium. Yet it has been reported that it takes two molecules, as with acetylcholine, to open one  nicotinic ion channel . The conformational explanation for this is that each  acetylcholine  moiety of succinylcholine prefers the  gauche  (bent, cis) state. The attraction between the N and  O  atoms is greater than the onium head repulsion. In this most populated state, the N-N distance is shorter than the optimal distance of  ten carbon atoms and too short to occupy both receptive sites. This similarity between succinyl- and acetyl-choline also explains its acetylcholine-like side-effects. [ 20 ]
Comparing molecular lengths, the pachycurares  dimethyltubocurarine  and d-tubocurarine both are very rigid and measure close to 1.8 nm in total length.  Pancuronium  and  vecuronium  measure 1.9 nm, whereas  pipecuronium  is 2.1 nm. The potency of these compounds follows the same rank of order as their length. Likewise, the leptocurares prefer a similar length. Decamethonium, which measures 2 nm, is the most potent in its category, whereas C11 is slightly too long.  Gallamine  despite having low bulk and rigidity is the most potent in its class, and it measures 1.9 nm. [ 6 ] [ 19 ]  Based on this information one can conclude that the optimum length for neuromuscular blocking agents, depolarizing or not, should be 2 to 2.1 nm. [ 20 ]


The CAR for long-chain bisquaternary tetrahydroisoquinolines like atracurium, cisatracurium, mivacurium, and doxacurium is hard to determine because of their bulky onium heads and large number of rotatable  bonds  and  groups . These agents must follow the same  receptive  topology as others, which means that they do not fit between the receptive sites without bending. [ 19 ]   Mivacurium  for example has a molecular length of 3.6 nm when stretched out, far from the 2 to 2.1 nm optimum. Mivacurium, atracurium, and  doxacurium  have greater N-N distance and molecular length than d-tubocurarine even when bent. To make them fit, they have flexible connections that give their onium heads a chance to position themselves beneficially. This bent N-N scenario probably does not apply to  laudexium  and  decamethylene bisatropium , which prefer a straight conformation. [ 20 ]


It has been concluded that acetylcholine and related compounds must be in the  gauche  (bent) configuration when bound to the nicotinic receptor. [ 21 ]  Beers and Reich's studies on cholinergic receptors in 1970 showed a relationship affecting whether a compound was  muscarinic  or  nicotinic . They showed that the distance from the centre of the quaternary N atom to the  van der Waals  extension of the respective O atom (or an equivalent H-bond acceptor) is a determining factor. If the distance is 0.44 nm, the compound shows muscarinic properties—and if the distance is 0.59 nm, nicotinic properties dominate. [ 22 ] )


Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action / effects relationship data. A  steroid  skeleton was chosen because of its appropriate size and rigidness. Acetylcholine moieties were inserted to increase receptor affinity. Although having many unwanted side-effects, a slow onset of action and recovery rate it was a big success and at the time the most potent  neuromuscular drug  available. Pancuronium and some other neuromuscular blocking agents block  M2-receptors  and therefore affect the  vagus nerve , leading to  hypotension  and  tachycardia . This muscarinic blocking effect is related to the acetylcholine moiety on the A ring on pancuronium. Making the N atom on the A ring tertiary, the ring loses its acetylcholine moiety, and the resulting compound, vecuronium, has nearly 100 times less affinity to muscarin receptors while maintaining its nicotinic affinity and a similar duration of action. Vecuronium is, therefore, free from cardiovascular effects. [ 5 ]  The D ring shows excellent properties validating Beers and Reich's rule with great precision. As a result, vecuronium has the greatest potency and specificity of all mono-quaternary compounds. [ 20 ]


Two functional groups contribute significantly to  aminosteroidal  neuromuscular blocking potency, it is presumed to enable them to bind the receptor at two points. A bis-quaternary two point arrangement on A and D-ring (binding inter-site) or a D-ring acetylcholine moiety (binding at two points intra-site) are most likely to succeed. A third group can have variable effects. [ 20 ]  The quaternary and acetyl groups on the A and D ring of pipecuronium prevent it from binding intra-site (binding to two points at the same site). Instead, it must bind as bis-quaternary (inter-site). [ 6 ]  These structures are very dissimilar from acetylcholine and free pipecuronium from nicotinic or muscarinic side-effects linked to acetylcholine moiety. Also, they protect the molecule from hydrolysis by cholinesterases, which explain its nature of kidney excretion. The four  methyl-groups  on the quaternary N atoms make it less lipophilic than most aminosteroids. This also affects pipecuroniums metabolism by resisting hepatic uptake, metabolism, and  biliary  excretion. The length of the molecule (2.1 nm, close to ideal) and its rigidness make pipecuronium the most potent and clean one-bulk bis-quaternary. Even though the N-N distance (1.6 nm) is far away from what is considered ideal, its onium heads are well-exposed, and the quaternary groups help to bring together the onium heads to the anionic centers of the receptors without chirality issues. [ 20 ]


Adding more than two onium heads in general does not add to potency. Though the third onium head in gallamine seems to help position the two outside heads near the optimum molecular length, it can interfere unfavorably and gallamine turns out to be a weak muscle relaxant, like all multi-quaternary compounds.
Considering acetylcholine a quaternizing group larger than methyl and an acyl group larger than acetyl would reduce the molecule's potency. The charged N and the  carbonyl  O atoms are distanced from structures they bind to on receptive sites and, thus, decrease potency. The carbonyl O in vecuronium for example is thrust outward to appose the  H-bond  donor of the receptive site. This also helps explain why gallamine, rocuronium, and rapacuronium are of relatively low potency. [ 20 ]
In general, methyl quaternization is optimal for potency but, opposing this rule, the trimethyl derivatives of gallamine are of lower potency than gallamine. The reason for this is that gallamine has a suboptimal N-N distance. Substituting the ethyl groups with methyl groups would make the molecular length also shorter than optimal.  Methoxylation  of tetrahydroisoquinolinium agents seems to improve their potency. How methoxylation improves potency is still unclear.
 Histamine  release is a common attribute of benzylisoquinolinium muscle relaxants. This problem generally decreases with increased potency and smaller doses. The need for larger doses increases the degree of this side-effect. Conformational or structural explanations for histamine release are not clear. [ 20 ]


Metabolism and Hofmann elimination


Deacetylating   vecuronium  at position 3 results in a very active metabolite. [ 23 ]   In the case of  rapacuronium  the 3- deacylated   metabolite  is even more potent than rapacuronium. As long as the D-ring  acetylcholine  moiety is unchanged they retain their muscle relaxing effect.  Mono -quaternary   aminosteroids  produced with  deacylation  in position 17 on the other hand are generally weak muscle relaxants. [ 20 ]  In the development of  atracurium  the main idea was to make use of  Hofmann elimination  of the muscle relaxant  in vivo . When working with bisbenzyl-isoquinolinium types of molecules, inserting proper features into the molecule such as an appropriate  electron  withdrawing group then  Hofmann elimination  should occur at conditions  in vivo . Atracurium, the resulting  molecule , breaks down spontaneously in the body to inactive  compounds  and being especially useful in patients with  kidney  or  liver  failure.  Cis -atracurium  is very similar to atracurium except it is more potent and has a weaker tendency to cause  histamine  release. [ 5 ]


Structure relations to onset time


The effect of structure on the  onset of action  is not very well known except that the time of onset appears inversely related to potency. [ 24 ]  In general  mono -quaternary aminosteroids are faster than  bis -quaternary  compounds, which means they are also of lower potency. A possible explanation for this effect is that drug delivery and receptor binding are of a different timescale. Weaker muscle relaxants are given in larger doses so more molecules in the  central compartment  must diffuse into the  effect compartment , which is the space within the mouth of the receptor, of the body. After delivery to the effect compartment then all  molecules  act quickly. [ 25 ]  Therapeutically this relationship is very inconvenient because low potency, often meaning low specificity can decrease the safety margin thus increasing the chances of  side-effects . In addition, even though low potency usually accelerates  onset of action , it does not guaranty a fast onset.  Gallamine , for example, is weak and slow. When fast onset is necessary then  succinylcholine  or  rocuronium  are usually preferable. [ 20 ]


Elimination


Muscle relaxants  can have very different  metabolic pathways  and it is important that the drug does not accumulate if certain elimination pathways are not active, for example in  kidney  failure.


Administration of neuromuscular blocking agents (NMBA) during  anesthesia  can facilitate  endotracheal intubation . [ 12 ]  This can decrease the incidence of postintubation hoarseness and airway injury. [ 12 ]


Short-acting neuromuscular blocking agents are chosen for endotracheal intubation for short procedures (< 30minutes), and neuromonitoring is required soon after intubation. [ 12 ]  Options include  succinylcholine , rocuronium or vecuronium if  sugammadex  is available for rapid reversal block. [ 12 ]


Any short or intermediate acting neuromuscular blocking agents can be applied for endotracheal intubation for long procedures (≥ 30 minutes). [ 12 ]  Options include succinylcholine, rocuronium, vecuronium,  mivacurium , atracurium and  cisatracurium . [ 12 ]  The choice among these NMBA depends on availability, cost and patient parameters that affect  drug metabolism .


Intraoperative relaxation can be maintained as necessary with additional dose of nondepolarizing NMBA. [ 12 ]


Among all NMBA, Succinylcholine establish the most stable and fastest intubating conditions, thus is considered as the preferred NMBA for rapid sequence induction and intubation (RSII). [ 12 ]  Alternatives for succinylcholine for RSII include high dose rocuronium (1.2mg/kg which is a 4 X ED95 dose), or avoidance of NMBAs with a high dose  remifentanil  intubation. [ 12 ]


Nondepolarizing NMBAs can be used to induce muscle relaxation that improves surgical conditions, including  laparoscopic ,  robotic ,  abdominal  and  thoracic  procedures. [ 12 ]  It can reduce patient movement, muscle tone, breathing or coughing against ventilator and allow lower  insufflation  pressure during laparoscopy. [ 12 ]  Administration of NMBAs should be individualized according to patient’s parameters. However, many operations can be performed without the need to apply any NMBAs as adequate anesthesia during surgery can achieve many of the theoretical benefits of neuromuscular blockage. [ 12 ]


Since these drugs may cause  paralysis  of the  diaphragm , mechanical ventilation should be at hand to provide respiration.


In addition, these drugs may exhibit  cardiovascular  effects, since they are not fully selective for the  nicotinic receptor  and hence may have effects on  muscarinic receptors . [ 11 ]   If nicotinic receptors of the  autonomic ganglia  or  adrenal medulla  are blocked, these drugs may cause autonomic symptoms.  Also, neuromuscular blockers may facilitate  histamine  release, which causes hypotension,  flushing , and tachycardia.


Succinylcholine may also trigger  malignant hyperthermia  in rare cases in patients who may be susceptible.


In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of  potassium  from muscle fibers.  This puts the patient at risk for life-threatening complications, such as  hyperkalemia  and  cardiac arrhythmias . Other effects include  myalgia , increased intragastric pressure, increased intraocular pressure, increased intracranial pressure,  cardiac dysrhythmias  ( bradycardia  is the most common type) and  allergic reactions . [ 12 ]  As a result, it is contraindicated for patients with susceptibility to malignant hyperthermia,  denervating conditions , major burns after 48 hours, and severe hyperkalemia.


For nondepolarizing NMBAs except vecuronium, pipecuronium, doxacurium, cisatracurium, rocuronium and rapacuronium, they produce certain extent of cardiovascular effect. [ 14 ]  Moreover, Tubocurarine can produce  hypotension  effect while Pancuronium can lead to moderate increase in heart rate and small increase in cardiac output with little or no increase in  systemic vascular resistance , which is unique in nondeploarizing NMBAs. [ 14 ]


Certain drugs such as  aminoglycoside  antibiotics and  polymyxin  and some  fluoroquinolones  also have neuromuscular blocking action as their side-effect. [ 26 ]


Some drugs enhance or inhibit the response to NMBAs which require the dosage adjustment guided by monitoring.


In some clinical circumstances,  succinylcholine  may be administered before and after a nondepolarising NMBA or two different nondepolarising NMBAs are administered in sequence. [ 12 ]  Combining different NMBAs can result in different degrees of neuromuscular block and management should be guided with the use of a  neuromuscular function monitor .


The administration of nondepolarising neuromuscular blocking agent has an  antagonistic effect  on the subsequent depolarising block induced by succinylcholine. [ 12 ]  If a nondepolarising NMBA is administered prior to succinycholine, the dose of succinylcholine must be increased.


The administration of succinylcholine on the subsequent administration of a nondepolarising neuromuscular block depends on the drug used. Studies have shown that administration of succinylcholien before a nondepolarising NMBA does not affect the potency of  mivacurium  or  rocuronium . [ 12 ]  But for  vecuronium  and  cisatracurium , it speeds up the onset, increases the potency and prolongs the duration of action. [ 12 ]


Combining two nondepolarising NMBAs of the same chemical class (e.g. rocuronium and vecuronium) produces an additive effect, while combining two nondepolarising NMBAs of different chemical class (e.g. rocuronium and cisatracurium) produces a synergistic response. [ 12 ]


Inhaled anesthetics inhibit nicotinic acetylcholine receptors (nAChRs) and potentiate neuromuscular blockage with nondepolarising NMBAs. [ 12 ]  It depends on the type of  volatile anesthetic  ( desflurane  >  sevoflurane  >  isoflurane  >  nitrous oxide ), the concentration and the duration of exposure. [ 12 ]


Tetracycline ,  aminoglycosides ,  polymyxins  and  clindamycin  potentiate neuromuscular blockage by inhibiting ACh release or  desensitisation  of post-synpatic nAChRs to ACh. [ 12 ]  This interaction happens mostly during maintenance of anesthesia. As antibiotics typically are given after a dose of NMBA, this interaction needs to be considered when re-dosing NMBA. [ 12 ]


Patients receiving chronic treatment are relatively resistance to nondepolarising NMBAs due to the accelerated  clearance . [ 12 ]


Lithium is structurally similar to other cations such as sodium, potassium, magnesium and calcium, this causes lithium to activate potassium channels which inhibit neuromuscular transmission. [ 12 ]  Patients who take lithium can have a prolonged response to both depolarising and nondepolarising NMBAs.


Sertraline  and  amitriptyline  inhibit  butyrylcholinesterase  and cause prolonged  paralysis . [ 12 ]  Mivacurium causes prolonged paralysis for patients chronically taking sertraline. [ 12 ]


LAs  may enhance the effects of depolarisation and nondepolarising NMBAs through pre and post-synaptic interactions at the NMJ. [ 12 ]  It may result in blood levels high enough to potentiate NMBA-induced neuromuscular block. [ 12 ]  Epidurally administered  levobupivacaine  and  mepivacaine  potentiate  amino-steroidal NMBAs  and delay recovery from neuromuscular blockade. [ 12 ]


Methods for estimating the degree of neuromuscular block include valuation of muscular response to stimuli from surface electrodes, such as in the  train-of-four  test, wherein four such stimuli are given in rapid succession. With no neuromuscular blockade, the resultant muscle contractions are of equal strength, but gradually decrease in case of neuromuscular blockade. [ 27 ]  It is recommended during use of continuous-infusion neuromuscular blocking agents in  intensive care . [ 28 ]


The effect of non-depolarizing neuromuscular-blocking drugs may be reversed with  acetylcholinesterase inhibitors ,  neostigmine , and  edrophonium , as commonly used examples. Of these, edrophonium has a faster onset of action than neostigmine, but it is unreliable when used to antagonize deep neuromuscular block. [ 29 ]  Acetylcholinesterase inhibitors increase the amount of acetylcholine in the neuromuscular junction, so a prerequisite for their effect is that the neuromuscular block is not complete, because in case every acetylcholine receptor is blocked then it does not matter how much acetylcholine is present.


Sugammadex  is a newer drug for reversing neuromuscular block by  rocuronium  and vecuronium in  general anaesthesia . It is the first  selective relaxant binding agent  (SRBA). [ 30 ]


Curare  is a crude  extract  from certain South American plants in the genera  Strychnos  and  Chondrodendron , originally brought to Europe by explorers such as  Walter Raleigh [ 31 ]   Edward Bancroft , a chemist and physician in the 16th century brought samples of crude curare from  South America  back to the Old-World. The effect of curare was experimented with by  Sir Benjamin Brodie  when he injected small animals with  curare , and found that the animals stopped breathing but could be kept alive by inflating their lungs with  bellows . This observation led to the conclusion that curare can paralyse the respiratory muscles. It was also experimented by  Charles Waterton  in 1814 when he injected three donkeys with curare. The first donkey was injected in the shoulder and died afterward. The second donkey had a  tourniquet  applied to the foreleg and was injected distal to the tourniquet. The donkey lived while the tourniquet was in place but died after it was removed. The third donkey after injected with curare appeared to be dead but was resuscitated using bellows. Charles Waterton's experiment confirmed the paralytic effect of curare.


It was known in the 19th century to have a  paralysing effect , due in part to the studies of scientists like  Claude Bernard . [ 32 ]   D-tubocurarine  a  mono -quaternary  alkaloid  was isolated from  Chondrodendron tomentosum  in 1942, and it was shown to be the major constituent in curare responsible for producing the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the  neuromuscular junction . The isolation of tubocurarine and its marketing as the drug  Intocostrin  led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two  quaternary ammonium  heads. [ 9 ] [ 33 ]


Neurologist  Walter Freeman  learned about curare and suggested to  Richard Gill , a patient suffering from  multiple sclerosis , that he try using it. Gill brought 25 pounds of raw curare from Ecuador. The raw curare was then given to  Squibb and Sons  to derive an effective antidote to curare. In 1942, Wintersteiner and Dutcher (two scientists working for Squibb and Sons) isolated the alkaloid  d-tubocurarine . Soon after, they developed a preparation of curare called  Intocostrin .


At the same time in Montreal,  Harold Randall Griffith  and his resident Enid Johnson at the Homeopathic Hospital administered curare to a young patient undergoing  appendectomy . This was the first use of NMBA as muscle relaxant in anesthesia.


The 1940s, 1950s and 1960s saw the rapid development of several synthetic NMBA.  Gallamine  was the first synthetic NMBA used clinically. Further research led to the development of  synthesized  molecules with different curariform effects, depending on the distance between the  quaternary ammonium  groups. One of the synthesized  bis -quaternaries was  decamethonium  a 10- carbon   bis -quaternary compound. Following research with decamethonium, scientists developed  suxamethonium , which is a double acetylcholine molecule that was connected at the  acetyl  end. The discovery and development of suxamethonium lead to a  Nobel Prize in medicine  in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the  muscle  before block. Also, tubocurarine effects were known to be reversible by  acetylcholinesterase inhibitors , whereas decamethonium and suxamethonium block were not reversible. [ 9 ] [ 5 ]


Another compound  malouétine  that was a  bis -quaternary steroid was isolated from the plant  Malouetia bequaertiana  and showed curariform activity. This led to the synthetic drug  pancuronium , a  bis -quaternary steroid, and subsequently other drugs that had better pharmacological properties. [ 9 ] [ 34 ]  Research on these molecules helped improve understanding of the  physiology  of  neurons  and  receptors .


Gallamine triethiodide  is originally developed for preventing muscle contractions during surgical procedures. However, it is no longer marketed in the United States according to the  FDA orange book .


A  nuclear bag fiber  is a type of  intrafusal muscle fiber  that lies in the center of a  muscle spindle . [ 1 ]  Each has many  nuclei  concentrated in bags and they cause excitation of the  primary sensory fibers . [ 2 ]


There are two kinds of bag fibers based upon contraction speed and motor innervation.


Both bag types extend beyond the spindle capsule.


These sense dynamic length of the muscle. They are sensitive to length and velocity.


This  neuroscience  article is a  stub . You can help Wikipedia by  expanding it .


A  nuclear chain fiber  is a specialized  sensory   organ  contained within a  muscle .  Nuclear chain fibers are  intrafusal fibers  that, along with  nuclear bag fibers , make up the  muscle spindle  responsible for the detection of changes in muscle length.


There are 3–9  nuclear chain fibers  per muscle spindle that are half the size of the  nuclear bag fibers . Their nuclei are aligned in a chain and they excite the secondary nerve. [ clarification needed ]  They are static, whereas the nuclear bag fibers are dynamic in comparison. [ clarification needed ]   The name "nuclear chain" refers to the structure of the central region of the fiber, where the sensory axons wrap around the  intrafusal fibers .


The secondary nerve association involves an efferent and afferent pathway that measure the stress and strain placed on the muscle (usually the  extrafusal fibers  connected from the muscle portion to a bone).  The afferent pathway resembles a spring wrapping around the nuclear chain fiber and connecting to one of its ends away from the bone.  Again, depending on the stress and strain the muscles sustains, this afferent and efferent coordination will measure the "stretch of the spring" and communicate the results to the  central nervous system .


A similar structure attaching one end to muscle and the other end to a tendon is known as a  Golgi tendon organ .  However, Golgi tendon organs differ from nuclear chain and  nuclear bag fibers  in that they are considered  in series  rather than  in parallel  to the muscle fibers.


As  intrafusal muscle fibers ,  nuclear chain fibers  are innervated by both  sensory afferents  and  motor efferents .  The afferent innervation is via  type Ia sensory fibers  and  type II sensory fibers . These project to the  nucleus proprius  in the  dorsal horn  of the  spinal cord .  Efferent innervation is via  static γ motor neurons .  Stimulation of γ neurons causes the nuclear chain to shorten along with the  extrafusal muscle fibers .  This shortening allows the nuclear chain fiber to be sensitive to changes in  length while its corresponding muscle is contracted.


List of distinct cell types in the adult human body


Orthotics  ( Greek :  Ορθός ,  romanized :  ortho ,  lit.   'to straighten, to align') is a  medical specialty  that focuses on the design and application of  orthoses , sometimes known as braces, calipers, or splints. [ 1 ]  An  orthosis  is "an externally applied device used to influence the structural and functional characteristics of the  neuromuscular  and  skeletal systems ." [ 2 ]   Orthotists  are medical professionals who specialize in designing orthotic devices such as braces or foot orthoses.


Orthotic devices are classified into four areas of the body according to the international classification system (ICS): [ 2 ]  orthotics of the  lower extremities , orthotics of the  upper extremities , orthotics for the  trunk , and orthotics for the head. Orthoses are also classified by function: paralysis orthoses and relief orthoses. [ 3 ]


Under the  International Standard  terminology, orthoses are classified by an acronym describing the anatomical joints they support. [ 2 ]  Some examples include KAFO, or knee-ankle-foot orthoses, which span the knee, ankle, and foot; TLSO, or thoracic-lumbar-sacral orthoses, supporting the  thoracic ,  lumbar  and   sacral  regions of the  spine . The use of the International Standard is promoted to reduce the widespread variation in the description of orthoses, which is often a barrier to interpreting research studies. [ 4 ]


The transition from an orthosis to a  prosthesis  can be fluid. An example is compensating for a leg length discrepancy, equivalent to replacing a missing part of a limb. Another example is the replacement of the forefoot after a forefoot  amputation . This treatment is often made from a combination of a prosthesis to replace the forefoot and an orthosis to replace the lost muscular function (ortho prosthesis). [ citation needed ]


An orthotist is a specialist responsible for the customising, manufacture, and repair of orthotic devices (orthoses). [ 5 ]  The manufacture of modern orthoses requires both artistic skills in modeling body shapes and manual skills in processing traditional and innovative materials—  CAD / CAM ,  CNC machines  and  3D printing  are involved in orthotic manufacture. [ 6 ]  Orthotics also combines knowledge of anatomy and physiology,  pathophysiology ,  biomechanics  and engineering. [ 7 ]


In the United States, while orthotists require a prescription from a licensed healthcare provider, physical therapists are not legally authorized to prescribe orthoses. In the U.K., orthotists will often accept referrals from doctors or other healthcare professionals for orthotic assessment without requiring a prescription. [ 8 ]


Orthoses are offered as:


Both custom-fabricated products and semi-finished products are used in long-term care and are manufactured or adapted by the orthotist or by trained orthopedic technicians according to the prescription. In many countries the physician or clinician defines the functional deviations in his prescription, e.g. paralysis ( paresis ) of the calf muscles ( M. Triceps Surae ) and derives the indication from this, e.g. orthotic to restore safety when standing and walking after a  stroke . The orthotist creates another detailed physical examination and compares it with the prescription from the physician. The orthotist describes the configuration of the orthosis, which shows which orthotic functions are required to compensate for the functional deviation of the neuromuscular or skeletal system and which functional elements must be integrated into the orthosis for this. Ideally, the necessary orthotic functions and the functional elements to be integrated are discussed in an interdisciplinary team between physician,  physical therapist , orthotist and patient.


All orthoses that affect the foot, the ankle joint, the lower leg, the knee joint, the thigh or the hip joint belong to the category of orthoses for the lower extremities. [ 2 ]


Paralysis  orthoses are used for partial or complete paralysis, as well as complete functional failure of muscles or muscle groups, or incomplete paralysis ( paresis ). They are intended to correct or improve functional limitations or to replace functions that have been lost as a result of the paralysis. Functional leg length differences caused by paralysis can be compensated for by using orthosis. [ 9 ]


For the quality and function of a paralysis orthosis, it is important that the orthotic shell is in total-contact  with the patient's leg to create an optimal fit, which is why a custom-made orthotic is often preferred. As reducing the weight of an orthosis significantly lessens the energy needed to walk with it, the use of light weight and highly resilient materials such as  carbon fiber ,  titanium  and  aluminum  is indispensable for the manufacture of a custom-made orthosis. [ 10 ]


The production of a custom-made orthotic also allows the integration of orthotic joints, which means the dynamics of the orthotic can be matched exactly with the pivot points of the patient's anatomical joints. As a result, the dynamics of the orthosis take place exactly where dictated by the patient's anatomy. Since the dynamics of the orthosis are executed via the orthotic joints, it is possible to manufacture the orthotic shells as stable and torsion-resistant, which is necessary for the quality and function of the orthosis. The orthosis thus offers the necessary stability to regain the security that has been lost due to paralysis when standing and walking. [ 11 ]


In addition, an orthosis can be individually configured through the use of orthosis joints. In this way, the combination of the orthotic joints and the adjustability of the functional elements can be adjusted to compensate for any existing functional deviations that have resulted from the muscle weakness. [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ] [ 17 ]  The goal of a high-quality orthotic fitting is to adjust the functional elements so precisely that the orthosis provides the necessary support while restricting the dynamics of the lower extremities as little as possible to preserve the remaining functionality of the muscles. [ 11 ]


In the case of paralysis due to disease or injury to the spinal/peripheral nervous system, a  physical examination  is needed to determine the strength levels of the affected leg's six major muscle groups and the orthosis's necessary functions.


According to Vladimir Janda, a muscle function test is carried out to determine strength levels. [ 18 ]  The degree of paralysis is given for each muscle group on a scale from 0 to 5, with the value 0 indicating complete paralysis (0%) and the value 5 indicating normal strength (100%). The values between 0 and 5 indicate a percentage reduction in muscle function. All strength levels below five are called  muscle weakness .


The combination of strength levels of the muscle groups determines the type of orthosis (AFO or KAFO) and the functional elements necessary to compensate for restrictions caused by the reduced muscular strength levels. [ medical citation needed ]


Paralysis may be caused by injury to the spinal or peripheral nervous system after  spinal cord injury , or by diseases such as  spina bifida ,  poliomyelitis  and  Charcot-Marie-Tooth disease . In these patients, knowledge of the strength levels of the large muscle groups is necessary to configure the orthotic  for the necessary functions. [ medical citation needed ]


Paralysis caused by diseases or injuries to the central nervous system (e.g.  cerebral palsy ,  traumatic brain injury ,  stroke , and  multiple sclerosis ) can cause incorrect motor impulses that often result in clearly visible deviations in gait. [ 19 ] [ 20 ]  The usefulness of muscle strength tests is therefore limited, as even with high degrees of strength, disturbances to the gait pattern can occur due to the incorrect control of the central nervous system.


In  ambulatory  patients with paralysis due to  cerebral palsy  or  traumatic brain injury ,  the gait pattern is analysed as part of the  physical examination  in order to determine the necessary functions of an orthosis. [ 21 ] [ 22 ]


One way of classifying gait is according to the "Amsterdam Gait Classification", which describes five gait types. To assess the gait pattern, the patient is viewed directly, or via a video recording, from the side of the leg being assessed. At the point when the leg is   mid-stance  the knee angle and the contact of the foot with the ground are assessed. [ 21 ]  The five gait types are:


Patients with paralysis due to cerebral palsy or traumatic brain injury are usually treated with an ankle-foot orthosis (AFO). Although in these patients the muscles are not paralyzed but being sent the wrong impulses from the brain, the functional elements used in the orthotics are the same for both groups. The compensatory gait is an unconscious reaction to the lack of security when standing or walking that usually worsens with increasing age; [ 20 ]  if the right functional elements are integrated into the orthosis to counter this, and maintain physiological mobility, the right motor impulses are sent to create new cerebral connections. [ 23 ]  The goal of an orthotic is the best possible approximation of the physiological gait pattern. [ 24 ]


In the case of paralysis after a  stroke , rapid care with an orthosis is necessary. Often areas of the brain are affected that contain "programs" for controlling the musculoskeletal system. [ 25 ] [ 26 ] [ 27 ]  With the help of an orthosis, physiological standing and walking can be relearned, preventing long term health consequences caused by an abnormal gait pattern. [ 28 ]  According to Vladimir Janda, when configuring the orthotic it is important to understand that the muscle groups are not paralyzed, but are controlled by the brain with wrong impulses, and this is why a muscle function test can lead to incorrect results when assessing the ability to stand and walk. [ citation needed ]


An important basic requirement for regaining the ability to walk is that the patient trains early on to stand on both legs safely and well balanced. An orthosis with functional elements to support balance and safety when standing and walking can be integrated into physical therapy from the first standing exercises, and this makes the work of mobilizing the patient at an early stage easier. With the right functional elements that maintain physiological mobility and provide security when standing and walking, the necessary motor impulses to create new cerebral connections can occur. [ 23 ]  Clinical studies confirm the importance of orthoses in stroke rehabilitation. [ 29 ]


Patients with paralysis after a stroke are often treated with an ankle-foot orthosis (AFO), as after a stroke stumbling can occur if only the  dorsiflexors  are supplied with incorrect impulses from the central nervous system. This can lead to insufficient foot lifting during swing phase of walking, and in these cases, an orthosis that only has functional elements to support the dorsiflexors can be helpful. Such an orthosis is also called drop foot orthosis. When configuring a foot lifter orthosis, adjustable functional elements for setting the resistance can be included, which make it possible to adapt the passive lowering of the forefoot (plantar flexion) to the  eccentric work  of the dorsal flexors during loading response. [ 12 ] [ 13 ]


In cases where the muscle group of the  plantar flexors  is supplied with wrong impulses from the central nervous system, which leads to uncertainty when standing and walking, an unconscious compensatory gait can occur. [ 20 ]  When configuring an orthosis functional elements that can restore safety when standing and walking must be used in these cases; a foot lifter orthosis is not suitable as it only compensates for the functional deviations caused by weakness of the dorsiflexors.


Patients with paralysis after stroke who are able to walk have the option of analysing the gait pattern in order to determine the optimal function of an orthosis. One way of assessing is the classification according to the "N.A.P. Gait Classification", which is a physiotherapeutic treatment concept. [ 30 ]  According to this classification, the gait pattern is assessed in the mid-stance phase and described as one of four possible gait types.


This assessment is a two step process; in the first step, the patient is viewed from the side of the leg to be assessed, either directly or via a video recording. In gait type 1 the knee angle is hyperextended, while in type 2, the knee angle is flexed. In the second step, the patient is viewed from the front to determine if the foot is  inverted , if it is the letter "a" is added to the gait. This is associated with a  varus deformity  of the knee. If instead the patient stands on the inner edge of the foot (eversion), which is associated with a  valgus deformity  of the knee, the letter "b" is added to the gait type. Patients are thus classified as gait types 1a, 1b, 2a or 2b. The goal of orthotic fitting for patients who are able to walk is the best possible approximation of the physiological gait pattern. [ medical citation needed ]


In the case of paralysis due to  multiple sclerosis , the degree of strength of the six major muscle groups of the affected leg should be determined as part of the  physical examination  in order to determine the necessary functions of an orthosis, just as in the case of diseases or injuries to the spinal/peripheral nervous system. However, patients with multiple sclerosis may experience muscular fatigue as well. The fatigue can be more or less pronounced and, depending on the severity, can lead to considerable restrictions in everyday life. Persistent stress, such as from walking, causes a deterioration in muscle function and has a significant effect on the spatial and temporal parameters of walking, for example by significantly reducing the cadence and walking speed. [ 31 ] [ 32 ] [ 33 ]  Fatigue can be measured as  muscle weakness . When determining the strength levels of the six major muscle groups as part of the patient's medical history, fatigue can be taken into account by using a standardized six-minute walking test. [ 34 ]  According to Vladimir Janda the muscle function test is carried out in combination with the six-minute walk test in the following steps:


This sequence of muscle function test and six-minute walk test is used to determine whether muscular fatigue can be induced. If the test reveals muscular fatigue, the strength levels and measured fatigue should be included in the planning of an orthosis, and when determining the functional elements. [ medical citation needed ]


Paralysis of the dorsiflexors  –  weakness  of the  dorsiflexors  results in a  drop foot . The patient's foot cannot be sufficiently lifted during the swing phase while walking, as the necessary concentric work of the dorsiflexors can not be activated. [ 35 ]  There is a risk of stumbling, and the patient cannot influence the shock absorption when walking (gait phase, loading response), as the  eccentric work  of the dorsiflexors is limited. [ 35 ]  After initial heel contact the forefoot either slaps too quickly on the floor via the heel rocker, which creates an audible noise, or the foot does touch the floor with forefoot first, which disrupts gait development. [ 36 ] : 178–181  [ 37 ] : 44–45, 50–54 and 126  [ 38 ]


Paralysis of the plantar flexors  – If the  plantar flexors  are weak, the muscles of the forefoot lever are either inadequately activated or not activated at all. The patient has no balance when standing and has to support themself with aids such as  crutches . The forefoot lever required for energy-saving walking in the gait phases from mid-stance to pre-swing cannot be activated by the plantar flexors. This leads to excessive dorsiflexion in the ankle joint in terminal stance and a loss of energy while walking. The center of gravity of the body lowers towards the end of the stance phase and the knee of the contralateral leg is flexed excessively. With each step, the center of gravity must be raised above the leg by straightening the excessively flexed knee. Since the plantar flexors originate above the knee joint, they also have a knee-extension effect in the stance phase. [ 36 ] : 177–210  [ 37 ] : 72  [ 38 ]


Paralysis of the knee extensors  – if the  knee extensors  are weak, there is an increased risk of falling when walking, as between loading response to the mid-stance the knee extensors control knee flexion inadequately, or not at all. To control the knee, the patient develops compensatory mechanisms that lead to an incorrect gait pattern, for example by exaggerated activation of the plantar flexors, leading into hyperextension of the knee, or when initial contact is with the forefoot and not the heel in order to prevent the knee-flexing effect of the heel rocker. [ 36 ] : 222, 226  [ 37 ] : 132, 143, 148–149  [ 38 ]


Paralysis of the knee flexors  – if the knee flexors are weak, it is more difficult to flex the knee in pre-swing. [ 36 ] : 220  [ 37 ] : 154  [ 38 ]


Paralysis of the hip flexors  – if the hip flexors are weak, it is more difficult to flex the knee in pre-swing. [ 36 ] : 221  [ 37 ] : 154  [ 38 ]


Paralysis of the hip extensors  – the  hip extensors  help control of the knee against unwanted flexion when walking between loading response and mid-stance. [ 36 ] : 216–17  [ 37 ] : 45–46  [ 38 ]


The functional elements of an orthosis ensure the flexion and extension movements of the ankle, knee and  hip joints. They correct and control the movements and secure the joints against undesired incorrect movements, and help avoid falls when standing or walking. [ citation needed ]


Functional elements in paralysis of the dorsiflexors  – if the  dorsiflexors  are weak, an orthosis should lift the forefoot during the swing phase in order to reduce the risk of the patient stumbling. An orthosis that has only one functional element for lifting the forefoot in order to compensate for a weakness in the dorsiflexors is also known as a drop foot orthosis. An AFO of the drop foot orthosis type is therefore not suitable for the care of patients with weakness in other muscle groups, as these patients require additional functional elements to be taken into account. Initial contact with the heel should be achieved by lifting the foot through the orthosis, and if the dorsiflexors are very weak, control of the rapid drop of the forefoot should be taken over by dynamic functional elements that allow for adjustable resistance of  plantar flexion . Orthoses should be adapted to the functional deviation of the dorsiflexors in order to correct the shock absorption of the heel rocker lever during loading response, but should not block plantar flexion of the ankle joint as this leads to excessive flexion in the knee and hip and an increase in the energy needed for walking. This is why static functional elements are not recommended when there are newer technical alternatives. [ 12 ] [ 36 ] : 105  [ 37 ] : 134  [ 38 ]


Functional elements in paralysis of the plantar flexors  – in order to compensate for a  weakness  of the  plantar flexors , the orthosis has to transfer large forces that the strong muscle group would otherwise take over. These forces are transmitted in a similar way to a ski boot during downhill skiing via the functional elements of the foot part, ankle joint and lower leg shell. Dynamic functional elements are preferable for the ankle joint as static functional elements would completely block the dorsiflexion, which would have to be compensated for by the upper body, resulting in an increased energy cost when walking. [ 15 ]  The functional element's resistance to protect against unwanted dorsiflexion should be able to be adapted according to the weakness of the plantar flexors. In the case of very weak plantar flexors, the functional element's resistance against undesired dorsiflexion must be very high in order to compensate for the functional deviations this causes. [ 39 ] [ 16 ]  Adjustable functional elements allow the resistance to be adjusted exactly to the weakness of the muscle, and scientific studies recommend adjustable resistance in patients with paralysis or weakness of the plantar flexors. [ 13 ] [ 14 ]


Functional elements in paralysis of knee extensors and hip extensors  – in the case of weak  knee extensors  or  hip extensors , the orthosis must take over the stability and stance phase control when walking. Different knee-securing functional elements are needed depending on the weakness of these muscles. In order to compensate for functional deviations with slightly weakness of these muscle groups, a free moving mechanical knee joint with the mechanical pivot point behind the anatomical knee pivot point can be sufficient. In the case of significant weakness, knee flexion when walking must be controlled by functional elements that mechanically secure the knee joint during the early stance phases between loading response and mid stance. Stance phase control knee joints which lock the knee in the early stance phases and release it for knee flexion during the swing phase can be used here, with these joints, a natural gait pattern can be achieved despite mechanically securing against unwanted knee flexion. In these cases, locked knee joints are often used, and while they have a good safety function, the knee joint remains mechanically locked during the swing phase while walking. Patients with locked knee joints have to manage the swing phase with a stiff leg, which only works if the patient develops compensatory mechanisms, such as by raising the body's center of gravity in the swing phase ( Duchenne  limping) or by swinging the orthotic leg to the side ( circumduction ). Stance phase control knee joints and locked joints can both be mechanically "unlocked" so the knee can be flexed to sit down. [ 17 ]


AFO is the abbreviation for ankle-foot orthoses, which is the English name for an orthosis that spans the ankle and foot. [ 2 ]  In the treatment of paralyzed patients, they are mainly used when there is a  weakness  of the  dorsiflexors  or  plantar flexors . [ 40 ] [ 41 ]


Through the use of modern materials, such as carbon fibers and  aramid  fibers, and new knowledge about processing these materials into composite materials, the weight of orthotics has been reduced significantly. In addition to the weight reduction, these materials and technologies have created the possibility of making some areas of an orthosis so rigid that it can take over the forces of the weakened muscles (e.g. the connection from the ankle joint to the frontal contact surface on the shin), while at the same time leaving areas requiring less support very flexible (e.g. the flexible part of the forefoot). [ 42 ]


It is now possible to combine the required rigidity of the orthotic shells with the dynamics in the ankle, [ 43 ]  with this, other new technologies, and the possibility of producing lightweight but rigid orthoses, new demands have been made of orthotics: [ 44 ] [ 45 ]


A custom-made AFO can compensate for functional deviations of muscle groups, it should be configured according to the patient data through a function and load calculation so that it meets the functional and load requirements. In calculating or configuring an AFO, variants are optimally matched to individual requirements for the functional elements of the ankle joint, for the stiffness of the foot shell, and for the shape of the lower leg shell. The size of these components is selected by matching their resilience to the load data. [ medical citation needed ]


An ankle joint based on new technology is the connection between the foot shell and the lower leg shell and at the same time contains all the necessary adjustable functional elements of an AFO. [ clarification needed ]


Depending on the combination of the degree of paralysis of the  dorsiflexors  or  plantar flexors , different functional elements to compensate for their weakness can be integrated into the ankle joint; if both muscle groups are affected, the elements should be integrated into one orthotic joint. The necessary dynamics and resistance to movements in the ankle can be adapted via adjustable functional elements in the ankle joint of the orthosis, which allows it to compensate for muscle weaknesses, provide safety when standing and walking, and still allow as much mobility as possible. For example, adjustable spring units with pre-compression can enable an exact adaptation of both static and dynamic resistance to the measured degree of muscle weakness. Studies show the positive effects of these new technologies. [ 12 ] [ 14 ] [ 15 ] [ 39 ] [ 16 ]  It is of great advantage if the resistances for these two functional elements can be set separately. [ 13 ]


An AFO with functional elements to compensate for a weakness of the  plantar flexors  can also be used for slight weakness of the knee-securing muscle groups, the  knee extensors  and the  hip extensors . [ medical citation needed ]


A drop foot orthosis is an AFO that only has one functional element for lifting the forefoot in order to compensate for a weakness in the dorsiflexors. [ 46 ]  If other muscle groups, such as the plantar flexors, are weak, additional functional elements must be taken into account, making a drop foot orthosis unsuitable for patients with weakness in other muscle groups.


In 2006, before these new technologies were available, the  International Committee of the Red Cross  published in its 2006 Manufacturing Guidelines for Ankle-Foot Orthoses, with the aim of providing people with disabilities worldwide standardized processes for the production of high-quality, modern, durable and economical devices. [ 47 ]


Because new technologies are not widely used, AFOs are often made from polypropylene-based plastic, mostly in the shape of a continuous "L" shape, with the upright part behind the calf and the lower part under the foot, however, this only offers the rigidity of the material. AFOs made of polypropylene are still called "DAFO" (dynamic ankle-foot orthosis), "SAFO" (solid ankle-foot orthosis) or "Hinged AFO". DAFOs are not stable enough to transfer the high forces required to balance the weak plantar flexors when standing and walking, and SAFOs block the mobility of the ankle joint. A "Hinged AFO"  only allowed for the compensation that could be achieved with the orthotic joints of the time, for example, they commonly block plantar flexion, as the joints cannot simultaneously transmit the large forces that are required to compensate for muscle deviations while also  offering the necessary dynamics. [ medical citation needed ]


While there was a multitude of AFOs with differing designs in clinical practice, there was also a clear lack of details regarding the design and the materials used for manufacture, leading Eddison and  Chockalingam  to call for a new standardization of the terminology. [ 48 ] [ 49 ]  With a focus on caring for children with cerebral palsy there is a recommendation to investigate the potential for gait pattern improvement via the design and manufacture of orthotics made of polypropylene. [ 50 ]  On the other hand, integrating orthotic joints with modern functional elements into the  production of older technologies using polypropylene is unusual because the orthotic shells made of polypropylene either could not transfer the high forces or would be too soft. [ medical citation needed ]


New studies now show the better possibilities for improving the gait pattern through the new technologies. [ 12 ] [ 15 ] [ 39 ] [ 16 ] [ 13 ]


The International Committee of the Red Cross published its manufacturing guidelines for ankle–foot orthoses in 2006, and, unfortunately, today's terminologies are still based those guidelines and therefore require a particularly high level of explanation. [ 47 ]  The intent was to provide standardized procedures for the manufacture of high-quality modern, durable and economical devices to people with disabilities throughout the world. However, with the new technologies available, the main types mentioned are in need of revision today.


plus the body parts included in the orthosis fitting: ankle and foot, English abbreviation: AFO for ankle-foot orthoses


"SAFO"


Rigid AFO [ 47 ]


"DAFO"


Flexible AFO [ 47 ]


"Hinged-AFO"


"Hinged" simply means a flexible connection between the two parts of the orthosis. The joint itself does not offer any further functional elements.


AFO with Tamarack Flexure Joint


"Posterior Leaf Spring"


Spring made from flexible material behind (posterior) the ankle


A DAFO often also known as "Posterior Leaf Spring"


FR for Floor reaction


"FRAFO"


Designation is misleading as other orthoses also have this function


Plus further descriptions, such as:
 - ventral shell with torsionally rigid reinforcement to focus the dynamics on the ankle joint
 - dynamic ankle joint with precompressed spring elements to control plantarflexion and dorsiflexion


KAFO is the abbreviation for knee-ankle-foot orthoses, which spans the knee, ankle and foot. [ 51 ]  In the treatment of paralyzed patients, a KAFO is used when there is a  weakness  of the knee  or hip extensors. [ 17 ] [ 40 ] [ 41 ]  They have two orthotic joints: an ankle joint between the foot and lower leg shells and a knee joint between the lower leg and thigh shells. [ citation needed ]


KAFOs can be roughly divided into three variants, depending on whether the mechanical knee joint is: locked, unlocked or locked and unlocked. [ medical citation needed ]


KAFO with locked knee joint -  The mechanical knee joint is locked both when standing and also when walking (in both the stance and swing phases) in order to achieve the necessary stability. To sit, the user can unlock the knee joint. When walking with a locked knee joint it is difficult for the user to swing the leg forward and, in order to not stumble, the leg must be swung forward and out in a circular arc (circumduction) or the hip must be raised unnaturally to swing the stiff leg. Each of these incorrect gait patterns can lead to secondary diseases in the bone and muscle system, and such compensatory movement patterns lead to increased energy consumption when walking. The film  Forrest Gump  impressively shows how the main character  Forrest Gump  is additionally hindered in his urge to move by such orthoses. [ relevant? ]  For centuries, KAFOs were built with mechanical knee joints that stiffened the knee of the paralyzed leg, and even today, such orthotic fittings are still common. Typical designations for a KAFO with a locked knee joint include "KAFO with Swiss lock" or "KAFO with drop lock lock". [ medical citation needed ]


KAFO with unlocked knee joint -  An unlocked knee joint can move freely both when standing and when walking, both in the stance phase and in the swing phase. In order for the leg to swing through without stumbling, knee flexion of approximately 60° is allowed; the user does not need to unlock the knee joint to sit. As a KAFO with an unlocked knee joint can provide only minor compensation for paralysis-related issues while standing and walking, an orthotic knee joint with a rearward displacement of the pivot point can be installed in order to increase safety. However, even with this, a KAFO with a non-locked knee joint should only be used in cases of minor paralysis of the knee and hip extensors. With more severe paralysis and low levels of strength in these muscle groups, there is a significant risk of falling. A typical designation for a KAFO with a unlocked knee joint is, among other things, "KAFO with knee joint for movement control". [ medical citation needed ]


KAFO with locked and unlocked knee joint -  The mechanical knee joint of a KAFO with locked and unlocked knee joint is locked when walking in the stance phase, [ 52 ]  providing the necessary stability and security for the user. The knee joint is then automatically unlocked in the swing phase, allowing the leg to be swung through without stumbling. In order to be able to walk efficiently, without stumbling, and without compensating mechanisms, the joint should allow  knee flexion of approximately 60° in the swing phase. The first promising developments of automatic knee joints, or stance phase locking knee joints, emerged in the 1990s. In the beginning there were automatic mechanical constructions that took over the locking and unlocking, now [ when? ]  automatic electromechanical and automatic  electrohydraulic  systems are available that make standing and walking safer and more comfortable. Various terms are used for a KAFO with a locked and unlocked knee joint. Typical designations are "KAFO with automatic knee joint" or "KAFO with stance phase control knee joint". In scientific articles, the English term Stance Control Orthoses SCO is often used, but as this term differs from the ICS classification, one of the first two terms is preferable.


Different functional elements to compensate for weakness of the  dorsiflexors  or  plantar flexors  can be integrated into the ankle joint of the orthosis depending on the degree of paralysis of the two muscle groups. It is of great advantage if the resistances for these two functional elements can be set separately. [ 13 ]  The functional elements to compensate for paralysis of the knee-securing muscle groups of the  knee  and  hip extensors  are integrated into the knee joint of the orthosis via knee-securing functional elements. A KAFO can use a variety of combinations of different variants in the stiffness of the foot shell, the different variants of the functional elements of a dynamic ankle joint, the variants in the shape of the lower leg shell, and the functional elements of a knee joint to compensate for the user's limitations. [ 41 ]


HKAFO is the abbreviation for hip-knee-ankle-foot orthoses; which is the English name for an orthosis that spans the hip, the knee, the ankle and the foot. [ 51 ]  In the treatment of paralyzed patients, a HKAFO is used when there is a  weakness  of the pelvic stabilizing trunk muscles. [ 41 ]


Relief Orthoses are used when there is degeneration to a joint (from "wear and tear" for example) or after an injury such as a torn ligament. [ 53 ]  Relief orthoses are also used after operations such as operations on the joint ligaments, other bony, muscular structures, or after a complete replacement of a joint. [ 54 ] [ 55 ]


Relief orthosis may also be used to: [ citation needed ]


A custom-made ankle/foot orthosis can be used for the treatment of patients with foot ulcers, it is a rigid L-shaped support member with a rigid anterior support shell on an articulated hinge. The plantar portion of the L-shaped member has at least one ulcer-protecting hollow to allow the user to transfer their weight away from the ulcer to facilitate treatment. The anterior support shell is designed with a lateral hinged attachment to take advantage of the medial tibial flare structure to enhance the weight-bearing properties of the orthosis. A flexible, polyethylene hinge attaches the support shell to the L-shaped member and straps securely attach the anterior support shell to the user's lower leg. [ 56 ]


Foot orthoses (commonly called  orthotics ) are devices inserted into shoes to provide support for the foot by redistributing  ground reaction forces  acting on the foot joints while standing, walking or running. They may be either pre-moulded (also called pre-fabricated) or custom made according to a cast or impression of the foot. They are used by everyone from athletes to the elderly to accommodate biomechanical deformities and a variety of soft tissue conditions. Foot orthoses are effective at reducing pain for people with painful  high-arched feet , and may be effective for people with  rheumatoid arthritis ,  plantar fasciitis , first  metatarsophalangeal  (MTP) joint pain [ 57 ]  or  hallux valgus  (bunions). For children with  juvenile idiopathic arthritis  (JIA) custom-made and pre-fabricated foot orthoses may also reduce foot pain. [ 58 ]  Foot orthoses may also be used in conjunction with properly fitted orthopedic footwear in the prevention of  diabetic foot ulcers . [ 59 ] [ 60 ]  A real-time weight bearing orthotic can be created using a neutral position casting device and the Vertical Foot Alignment System VFAS. [ citation needed ]


An AFO can also be used to immobilize the ankle and lower leg in the presence of arthritis or a fracture. Ankle–foot orthoses are the most commonly used orthoses, making up about 26% of all orthoses provided in the United States. [ 61 ]  According to a review of Medicare payments from 2001 to 2006, the base cost of an AFO was about $500 to $700. [ 62 ]


A knee orthosis (KO) or knee brace extends above and below the knee joint and is generally worn to support or align the knee. In the case of diseases causing neurological or muscular impairment of muscles surrounding the knee, a KO can prevent flexion, extension, or instability of the knee. If the ligaments or cartilage of the knee are affected, a KO can provide stabilization to the knee by replacing their functions. For instance, knee braces can be used to relieve pressure from diseases such as  arthritis  or  osteoarthritis  by realigning the knee joint. In this way a KO may help reduce osteoarthritis pain, [ 63 ]  however, there is no clear evidence about the most effective orthosis or the best approach to rehabilitation. [ 64 ]  A knee brace is not meant to treat an injury or disease on its own, but is used as a component of treatment along with drugs, physical therapy and possibly surgery. When used properly, a knee brace may help an individual to stay active by enhancing the position and movement of the knee or reducing pain. [ medical citation needed ]


Prophylactic braces are used primarily by athletes participating in contact sports. Evidence indicates that prophylactic knee braces, like the ones football linemen wear that are often rigid with a knee hinge, are ineffective in reducing anterior cruciate ligament tears, but may be helpful in resisting medial and lateral collateral ligament tears. [ 65 ]


Functional braces are designed for use by people who have already experienced a knee injury and need support while recovering from it, or to help people who have pain associated with arthritis. They are intended to reduce the rotation of the knee, support stability, reduce the chance of hyperextension, and increase the agility and strength of the knee. The majority of these are made of elastic. They are the least expensive of all braces and are easily found in a variety of sizes. [ medical citation needed ]


Rehabilitation braces are used to limit the movement of the knee in both medial and lateral directions, these braces often have an adjustable range of motion, and can be used to limit flexion and extension following ACL reconstruction. They are primarily used after injury or surgery to immobilize the leg and are larger in size than other braces, due to their function.


A soft brace, sometimes called soft support or a bandage, belong to the field of orthoses and are supposed to protect the joints from excessive loads.
Soft braces are also classified according to regions of the body. In sport, bandages are used to protect bones and joints, and prevent and protect injuries. [ 66 ]  Bandages should also allow  proprioception . They mostly consist of textiles, some of which have supportive elements. The supporting functions are low compared to paralysis and relief orthoses, though they are sometimes used  prophylactically  or to optimize performance in sport. [ 67 ]  At present, the scientific literature does not provide sufficient high quality research to allow for strong conclusions on their effectiveness and cost-effectiveness. [ 68 ]


Upper-limb (or upper extremity) orthoses are mechanical or electromechanical devices applied externally to the arm, or segments of it, in order to restore or improve function or structural characteristics of the arm segments enclosed in the device. In general, musculoskeletal problems that may be alleviated by the use of upper limb orthoses include those resulting from trauma [ 69 ]  or disease (arthritis for example). They may also benefit individuals who have a neurological impairment from a stroke, spinal cord injury, or peripheral neuropathy. [ citation needed ]


Scoliosis , a condition describing an abnormal curvature of the spine, may in certain cases be treated with spinal orthoses, [ 70 ]  such as the  Milwaukee brace ,  Boston brace ,  Charleston bending brace , or  Providence brace . As scoliosis most commonly develops in adolescent females who are undergoing their  adolescent growth spurt , compliance is hampered by patient concerns about appearance and movement restrictions caused by the brace. [ citation needed ]


Spinal orthoses may also be used in the treatment of spinal fractures. A Jewett brace, for instance, may be used to aid healing of an anterior  wedge fracture  involving the T10 to L3 vertebrae, and a body jacket may be used to stabilize more involved fractures of the spine. There are several types of orthoses for managing cervical spine pathology. [ 71 ]  The halo brace is the most restrictive cervical thoracic orthosis in use; it is used to immobilize the cervical spine, usually following fracture, and was developed by Vernon L. Nickel at  Rancho Los Amigos National Rehabilitation Center  in 1955. [ 72 ]


Helmets  such as a cranial molding orthoses is an example of orthoses for the head. [ 73 ]  These devices are often suggested for infants with  positional plagiocephaly . [ 74 ] [ 75 ]


A  pennate  or  pinnate muscle  (also called a  penniform muscle ) is a type of  skeletal muscle  with  fascicles  that attach obliquely (in a slanting position) to its tendon. This type of muscle generally allows higher force production but a smaller range of motion. [ 1 ] [ 2 ]
When a muscle contracts and shortens, the  pennation angle  increases. [ 3 ]


The term "pennate" comes from the Latin  pinnātus  ("feathered, winged"), from  pinna  ("feather, wing").


In skeletal muscle tissue, 10-100  endomysium -sheathed  muscle fibers  are organized into  perimysium -wrapped bundles known as  fascicles . Each muscle is composed of a number of fascicles grouped together by a sleeve of connective tissue, known as an  epimysium . In a pennate muscle,  aponeuroses  run along each side of the muscle and attach to the tendon. The fascicles attach to the aponeuroses and form an angle (the pennation angle) to the load axis of the muscle. If all the fascicles are on the same side of the tendon, the pennate muscle is called  unipennate  (Fig. 1A). Examples of this include certain muscles in the  hand . If there are fascicles on both sides of the central tendon, the pennate muscle is called  bipennate  (Fig. 1B). The  rectus femoris , a large muscle in the  quadriceps , is typical. If the central tendon branches within a pennate muscle, the muscle is called multipennate (Fig. 1C), as seen in the  deltoid muscle  in the  shoulder .


One advantage of pennate muscles is that more muscle fibers can be packed in parallel, thus allowing the muscle to produce more force, although the fiber angle to the direction of action means that the maximum force in that direction is somewhat less than the maximum force in the fiber direction. [ 4 ] [ 5 ]
The muscle cross sectional area (blue line in figure 1, also known as anatomical cross section area, or ACSA) does not accurately represent the number of muscle fibers in the muscle. A better estimate is provided by the total area of the cross sections perpendicular to the muscle fibers (green lines in figure 1). This measure is known as the physiological cross sectional area (PCSA), and is commonly calculated and defined by the following formula (an alternative definition is provided in the  main article ): [ 6 ] [ 7 ] [ 8 ]


where ρ is the density of the muscle:


PCSA increases with pennation angle, and with muscle length. In a pennate muscle, PCSA is always larger than ACSA. In a non-pennate muscle, it coincides with ACSA.


The total force exerted by the fibers along their oblique direction is proportional to PCSA. If the  specific tension  of the muscle fibers is known (force exerted by the fibers per unit of PCSA), it can be computed as follows: [ 9 ]


However, only a component of that force can be used to pull the tendon in the desired direction. This component, which is the true  muscle force  (also called  tendon force [ 8 ] ), is exerted along the direction of action of the muscle: [ 8 ]


The other component, orthogonal to the direction of action of the muscle (Orthogonal force = Total force × sinΦ) is not exerted on the tendon, but simply squeezes the muscle, by pulling its aponeuroses toward each other.


Notice that, although it is practically convenient to compute PCSA based on volume or mass and fiber length, PCSA (and therefore the total fiber force, which is proportional to PCSA) is not proportional to muscle mass or fiber length alone. Namely, the maximum ( tetanic ) force of a muscle fiber simply depends on its thickness (cross-section area) and  type . By no means it depends on its mass or length alone. For instance, when muscle mass increases due to  physical development  during childhood, this may be only due to an increase in length of the muscle fibers, with no change in fiber thickness (PCSA) or fiber type. In this case, an increase in mass does not produce an increase in force.


In a pennate muscle, as a consequence of their arrangement, fibers are shorter than they would be if they ran from one end of the muscle to the other. This implies that each fiber is composed of a smaller number  N  of  sarcomeres  in series. Moreover, the larger the pennation angle is, the shorter are the fibers.


The speed at which a muscle fiber can shorten is partly determined by the length of the muscle fiber (i.e., by  N ). Thus, a muscle with a large pennation angle will contract more slowly than a similar muscle with a smaller pennation angle.


Architectural gear ratio, also called anatomical gear ratio, (AGR) is a feature of pennate muscle defined by the ratio between the longitudinal strain of the muscle and  muscle fiber  strain. It is sometimes also defined as the ratio between muscle- shortening  velocity and fiber-shortening velocity: [ 10 ]


where ε x  = longitudinal strain (or muscle-shortening velocity) and ε f  is fiber strain (or fiber-shortening velocity). [ 10 ]


It was originally thought that the distance between aponeuroses did not change during the contraction of a pennate muscle, [ 5 ]  thus requiring the fibers to rotate as they shorten.  However, recent work has shown this is false, and that the degree of fiber angle change varies under different loading conditions. This dynamic gearing automatically shifts in order to produce either maximal velocity under low loads or maximal force under high loads. [ 10 ] [ 11 ]


Perimysium  is a  sheath  of  dense irregular connective tissue  that groups  muscle  fibers into bundles (anywhere between 10 and 100 or more) or  fascicles .


Studies of muscle physiology suggest that the perimysium plays a role in  transmitting lateral contractile movements . This hypothesis is strongly supported in one exhibition of the existence of "perimysial junctional plates" in  ungulate   flexor carpi radialis  muscles. [ 1 ]  The overall comprehensive organization of the perimysium  collagen  network, as well as its continuity and disparateness, however, have still not been observed and described thoroughly everywhere within the muscle. Found to have type I, III, VI, and XII collagen.


In  muscle   physiology ,  physiological cross-sectional area  (PCSA) is the area of the cross section of a  muscle  perpendicular to its fibers, generally at its largest point. It is typically used to describe the contraction properties of  pennate muscles . [ 1 ]  It is not the same as the anatomical cross-sectional area (ACSA), which is the area of the crossection of a muscle perpendicular to its longitudinal axis. In a non-pennate muscle the fibers are parallel to the longitudinal axis, and therefore PCSA and ACSA coincide.


One advantage of pennate muscles is that more muscle fibers can be packed in parallel, thus allowing the muscle to produce more force, although the fiber angle to the direction of action means that the maximum force in that direction is somewhat less than the maximum force in the fiber direction. [ 2 ] [ 3 ]


The muscle cross-sectional area (blue line in figure 1, also known as anatomical cross-section area, or ACSA) does not accurately represent the number of muscle fibers in the muscle. A better estimate is provided by the total area of the cross-sections perpendicular to the muscle fibers (green lines in figure 1). This measure is known as the physiological cross-sectional area (PCSA), and is commonly calculated and defined by the following formula, developed in 1975 by Alexander and Vernon: [ 4 ] [ 5 ] [ 6 ]


The total force exerted by the fibers in their oblique direction is proportional to PCSA. If the  specific tension  of the muscle fibers is known (force exerted by the fibers per unit of PCSA), it can be computed as follows: [ 7 ]


However, only a component of that force can be used to pull the tendon in the desired direction. This component, which is the true  muscle force  (also called  tendon force [ 6 ] ), is exerted along the direction of action of the muscle: [ 6 ]


Sometimes, the increase in mass is associated with an increase in thickness. Only in this case it will have some effect on fiber force, but this effect will be proportional to the increase in thickness, not to the increase in mass. For instance, in some stages of physical development, the increase in mass may be due to both an increase in PCSA and in fiber length. Even in this case, muscle force does not increase as much as muscle mass does, because the mass increase is partly produced by a variation in fiber length, and fiber length has no effect on muscle force.


In 1982 a different definition of PCSA, herein denoted PCSA 2 , to facilitate comparison with the previous definition, was introduced by Sacks & Roy: [ 7 ]


The comparison shows that


in a pennate muscle, since

 cos

 Φ

 {\displaystyle \cos \Phi }

  is always smaller than 1, PCSA 2  is always smaller than PCSA. Hence, it cannot be described as the total area of the cross-sections perpendicular to the muscle fibers (green lines in figure 1). It can be interpreted two ways:


This implies that, in a muscle such as that in figure 1A, PCSA 2  coincides with ACSA. The disadvantage of this definition is its more complex interpretation, its advantage is that muscle force can be computed more directly:


Currently, some authors keep using the original definition of PCSA, [ 5 ] [ 6 ]  probably because of its intuitively appealing geometrical interpretation (figure 1).


The  posterior chain  is a group of muscles on the posterior of the body. Examples of these muscles include the  hamstrings , [ 1 ]  the  gluteus maximus , [ 1 ]   erector spinae [ 1 ]  muscle group,  trapezius , and posterior  deltoids .


The primary exercises for developing the posterior chain are the  Olympic lifts ,  squats , [ 1 ]   good-mornings ,  bent-over rows ,  deadlifts , [ 1 ]   pull-ups  and  hyperextensions . The common denominator among many of these movements is a focus on hip extension, excluding bent-over rows and pull ups. Working on hamstrings is also important.


Preflexes  are the latent capacities in the  musculoskeletal system  that auto-stabilize movements through the use of the  nonlinear   visco-elastic  properties of  muscles  when they  contract . [ 1 ] [ 2 ]  The term "preflex" for such a zero-delay, intrinsic feedback loop was coined by Loeb. [ 3 ]  Unlike stabilization methods using  neurons , such as  reflexes  and  higher brain control , a preflex happens with minimal time delay; however, it only stabilizes the main movements of the musculoskeletal system. [ citation needed ]


Muscles possess nonlinear visco-elastic properties when they contract. [ 4 ] [ 5 ] [ 6 ]  This property can autocorrect movements when a muscle is forced to change its length, and at a velocity different from that with which it was originally commanded. Such automatic correction is useful when a commanded action is perturbated, for example, if a step goes into a hole as this causes the foot to unexpectedly stretch down. The nonlinear visco-elastic properties of muscles interact with these perturbation induced velocity and length differences such that they  counteract directly, as they happen, the effects upon the body of the perturbation.
Part of the resistance to perturbation is passive, by means of the nonlinear increase in passive tension and joint torques produced by muscular and other soft tissues. [ 4 ]  Tissue prestress is a preflexive property that constitutes a basal level of passive tension which, due to its presence in antagonistic tissues of a joint, increases joint passive stiffness and stability. [ 7 ]