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Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder? | [
"Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects.",
"If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD."
] | [
"Autism spectrum disorders (ASD) often show obsessive repetitive symptoms that are characteristic to obsessive-compulsive disorder (OCD). Aberrant glutamate function has been suggested to a risk for both ASDs and OCD. Considering the common metabolic pathway and recent results from association studies both in OCD and ASDs, a question, whether there is common molecular background in ASDs and OCD, was raised. Ten single nucleotide polymorphisms (SNPs) at 9p24 and 11p12-p13 containing glutamate transporter genes SLC1A1 and SLC1A2 and their neighboring regions in 175 patients with ASDs and 216 controls of Finnish origin were analyzed using real-time-PCR or direct sequencing. The strongest association was detected with rs1340513 in the JMJD2C gene at 9p24.1 (P=0.007; corrected P=0.011) that is the same SNP associated with infantile autism (P=0.0007) in the autism genome project consortium (2007). No association was detected at 11p12-p13 with ASD. Interestingly, the strongest association in OCD has been found at rs301443 (P=0.000067) residing between SLC1A1 and JMJD2C at 9p24.",
"5-Hydroxytryptophan (5-HT(2A)) receptor involvement in alcoholism is suggested by less 5-HT(2A) binding in alcohol preferring rats, association of a 5-HT(2A) receptor gene polymorphism with alcohol dependence and reduced alcohol intake with 5-HT(2A) antagonists. We sought to determine postmortem whether 5-HT(2A) receptors are altered in the prefrontal cortex (PFC) of alcoholics. Brain tissue from 25 alcoholics and 19 controls was collected at autopsy. Diagnosis of DSM-IV alcoholism/abuse and other psychiatric disorders and the determination of family history of alcoholism were made by psychological autopsy. Specific binding to 5-HT(2A) ((3)H-ketanserin) receptors in the PFC was measured by quantitative autoradiography. 5-HT(2A) binding decreased with age [Brodmann areas (BA) 9, 46 gyrus; r = -0.381, -0.334, p < 0.05]. No differences in receptor binding between alcoholics and controls were detected in the gyrus or sulcus of any PFC area examined. Cases (controls or alcoholics) with a family history of alcoholism (n = 23) had less 5-HT(2A) binding throughout PFC than subjects without (n = 21) a family history of alcoholism (p < 0.05). 5-HT(2A) receptor binding in alcoholics without a family history of alcoholism (n = 7) did not differ from controls without a family history of alcoholism (n = 14). There was no association between alcoholism or alcohol rating and genotype. There was an association between genotype and the total amount of (3)H-ketanserin binding in BA46 with the TT genotype having more binding (TT>TC approximately CC).",
"The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first-degree relatives treated for MDD. We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a \"risk-dose effect\" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012).",
"yes. Our results indicate that endogenous 5-HT is involved in the modulation of circular muscle accommodation during the preparatory phase of peristalsis via the activation of 5-HT7 receptors expressed by neurons in addition to smooth muscle cells. Overstimulation of these receptors leading to an exaggerated accommodation of circular muscle might contribute to abdominal symptoms in functional bowel disorders.",
"yes. Single nucleotide polymorphisms in COMT were associated with symptom change in duloxetine-treated patients with MDD. If replicated, the magnitude of the COMT genotype effect is of clinical relevance.",
"yes. The genotype combination DRD4/7 heterozygotes and DAT1/10 homozygotes is a high risk factors in Chilean families for ADHD. Increased density of dopamine transporters in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of studies to understand the functional basis of ADHD.",
"Recent genetic studies have linked serotonin-related genetic polymorphisms with diverse disorders characterized by functional somatic symptoms, including chronic fatigue syndrome, irritable bowel syndrome, and premenstrual dysphoric disorder. We investigated three serotonin-related genetic polymorphisms by screening genomic DNA of 36 temporomandibular disorder (TMD) patients. A significant increase of longer alleles (l and xl) was found in the TMD patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p < 0.01 by chi(2) test and Fisher's exact test).",
"Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10(-4) ). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found.",
"The genetic variations in serotonin-related genes may be associated with antidepressant treatment response in major depressive disorder (MDD). The tryptophan hydroxylase-1 (TPH1) gene and serotonin 5A receptor (HTR5A) gene are known to be involved in serotonin biosynthesis and signal transduction, respectively. The purpose of this study was to investigate a possible interaction between the TPH1 gene and the HTR5A gene in the treatment outcome of escitalopram in MDD. In total, 245 patients diagnosed with MDD were recruited, and their symptoms were evaluated using the 17-item Hamilton Depression Rating scale (HAMD-17). The association between the TPH1 218A/C and HTR5A 12A/T polymorphisms and the clinical outcomes (remission, response and changes in HAMD-17 score) was investigated after 2, 4 and 8 weeks of escitalopram treatment using multiple logistic regression or multiple linear regression analysis. No significant associations of TPH1 or HTR5A gene polymorphisms were observed with either response rate or remission rate at 2, 4 and 8 weeks after escitalopram treatment. In addition, the gene-gene interaction between TPH1 and HTR5A genes was not associated with the treatment outcome.",
"yes. Our data suggest that serotonergic activity may be involved in the development of analgesic overuse in CTTH and that 5-HTTLPR might be one of the genetically contributing factors.",
"Several clinical and genetic studies have focused on the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of various mental disorders. Recent lines of evidence regarding the network hypothesis of treatment outcome point towards the involvement of BDNF variants in the pharmacologic response in mood disorders (MD). Furthermore, there is strong evidence of a role for the serotonergic system in the pathophysiology and treatment of OCD, and upregulation of BDNF has been observed with various classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI). Thus, we hypothesized that the BDNF gene might also be associated with treatment outcome in OCD. We performed a single-marker and haplotype association study of eight tag single nucleotide polymorphisms in the BDNF genomic region and related this to pharmacologic response in a sample of 131 OCD patients. We found an association for a haplotype containing two single nucleotide polymorphisms that have previously been reported to be associated with treatment outcome in MD (rs908867 and rs1491850).",
"yes. These data suggest that arginine vasopressin-induced flank marking may serve as an animal model for screening drugs used in the control of Obsessive Compulsive Disorder.",
"yes. While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.",
"The serotonergic system contributes substantially to the regulation of glucose homeostasis and feeding. 5-HTTLPR is a serotonin transporter (5-HTT) gene-linked polymorphic region that regulates the transcriptional activity of 5-HTT. Our aim was to investigate the possible association of 5-HTTLPR polymorphism with type 2 diabetes mellitus and obesity. Study population consisted of 252 subjects diagnosed with Type 2 DM and 211 non-diabetic subjects, all Caucasians of Greek ethnic origin. Genomic DNA was extracted from peripheral blood and analyzed for 5-HTTLPR polymorphism with a novel PCR protocol. The frequency of SS and SL genotypes of HTTLPR was significantly higher in the diabetic group (77.0%) than in the non-diabetic group (61.6%) (P<0.001). The genetic risk of Type 2 DM for subjects carrying at least one S allele was increased compared to non-diabetic subjects (OR=2.08, 95% CI=1.39-3.12). When subjects were divided according to BMI status, the frequency of S allele carriers was similar in obese and non-obese subjects.",
"Four serotonin-related genes including guanine nucleotide binding protein beta polypeptide 3 (GNB3), 5-hydroxytryptamine receptor 1A (HTR1A; serotonin receptor 1A), 5-hydroxytryptamine receptor 2A (HTR2A; serotonin receptor 2A), and solute carrier family 6 member 4 (SLC6A4; serotonin neurotransmitter transporter) have been suggested to be candidate genes for influencing antidepressant treatment outcome. The aim of this study was to explore whether interaction among these genes could contribute to the pharmacogenomics of short-term antidepressant response in a Taiwanese population with major depressive disorder (MDD). Included in this study were 101 MDD patients who were treated with antidepressants, 35 of whom were rapid responders and 66 non-responders after 2weeks of treatment. We genotyped four single nucleotide polymorphisms (SNPs), including GNB3 rs5443 (C825T), HTR1A rs6295 (C-1019G), HTR2A rs6311 (T102C), and SLC6A4 rs25533, and employed the generalized multifactor dimensionality reduction (GMDR) method to investigate gene-gene interactions. Single-locus analyses showed the GNB3 rs5443 polymorphism to be associated with short-term antidepressant treatment outcome (P-value=0.029). We did not correct for multiple testing in these multiple exploratory analyses. Finally, the GMDR approach identified a significant gene-gene interaction (P-value=0.025) involving GNB3 and HTR2A, as well as a significant 3-locus model (P-value=0.015) among GNB3, HTR2A, and SLC6A4.",
"To determine whether variation in the serotonin transporter gene promoter (5HTTLPR) influences the efficacy of selective serotonin reuptake inhibitors (SSRIs) in generalized social anxiety disorder (GSAD). Consecutive series of N=32 patients with DSM-IV GSAD for whom DNA and standardized outcome data from a 12-week SSRI trial were available. After ensuring that neither clinical response [clinical global impression of change scale (CGI-C)] nor 5HTTLPR genotype was confounded by ethnicity or sex, we determined whether the number of copies (0, 1, or 2) of hi-risk alleles using either the diallelic L-S system or the triallelic La-Lg-S system, predicted response and change in Liebowitz social anxiety scale (LSAS) and brief social phobia scale (BSPS) scores during SSRI treatment. Twenty-one patients (66%) were responders to SSRI (i.e., CGI-C much or very much improved). A trend was seen for a linear association between 5HTTLPR genotype and likelihood of response to SSRI: diallelic classification L/L 7/8 (88%), L/S 12/18 (67%), S/S 2/6 (33%), p=0.051; triallelic classification L'/L' 4/5 (80%), L'/S' 14/19 (74%), S'/S' 3/8 (38%), p=0.093. Reduction in LSAS (and BSPS) scores during SSRI treatment was significantly (p<0.02) associated with 5HTTLPR genotype using either the diallelic or triallelic classification.",
"yes. Lower 5-HT(2A) receptor binding in the PFC of cases with a family history of alcoholism suggests a genetic predisposition to alcoholism. Alcohol abuse by itself did not have a significant effect on PFC 5-HT(2A) binding and as 5-HT(2A) binding in alcoholics is not different from controls and antagonists may be therapeutic, fewer receptors may result in downstream developmental effects on the brain resulting in a predisposition to alcoholism.",
"yes. The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.",
"Bipolar disorder (BD) is associated with a higher risk of suicide and with worse early life stress. A serotonin (5-hydroxytryptamine; 5-HT) transporter-linked polymorphic region (5-HTTLPR) has been shown to influence the relationship between stress and the risk of attempting suicide in the general population, but has not been investigated in BD. We studied 136 inpatients (93 females, 43 males) with a major depressive episode in the course of BD. Early and recent stressful life events were scored on the Social Readjustment Rating Scale (SRRS). Regional gray matter (GM) volumes were analyzed, acquiring T1-weighted images on a 3.0 Tesla scanner. Homozygote l/l patients attempted suicide in a higher proportion than *s carriers. A separate-slopes logistic regression showed a significant effect of 5-HTTLPR on the relationship between stress, depression, and suicide among *s carriers, but not among l/l homozygotes, early stress associated with worse probability of attempting suicide and with earlier age at onset of BD. Exposure to early stress correlated with GM volumes in the right prefrontal cortex (Brodmann area 46) - again, in *s carriers only.",
"Current perspectives on the pathophysiology of schizophrenia direct attention to serotonergic (serotonin, 5-HT) dysregulation in the prodrome or at-risk mental state (ARMS). To study the cerebral 5-HT(2A) receptor (5-HT(2A)R) in the ARMS with [(18)F]altanserin positron emission tomography (PET) and a bolus-infusion paradigm. We quantified the spatial distribution of 5-HT(2A)R binding potential (BP(1)') in never-medicated subjects assigned to early (n = 6) and late (n = 8) prodromal states of schizophrenia relative to healthy controls (n = 21). Five single nucleotide polymorphisms (SNPs) in the 5-HT(2A)R-encoding gene (HTR2A; 13q14-21) were genotyped to control for a potential bias in BP(1)' due to between-group differences in genotype distributions. Group comparisons of partial-volume corrected PET data by statistical parametric mapping and confirmatory volume of interest analysis yielded a dissemination of BP(1)' decreases consistent with increasing levels of risk. An additional decrease in caudate BP(1)' was present in subjects who subsequently converted to first-episode psychosis (n = 5), but absent in non-converters (n = 9). Between-group differences were not confounded by a differential distribution of SNP genotypes.",
"Serotonergic neurotransmission has been implicated in the pathogenesis of both alcohol dependence and mood disorders and may therefore be important in understanding the pathophysiology of comorbid alcohol dependence and major depression. Studies of the association of these disorders with a functional polymorphism in the promoter region of the gene encoding the serotonin transporter protein (locus SLC6A4) have yielded inconsistent results. Because the convergence of these disorders may provide a refined phenotype, we examined the association of serotonin (5-HT) transporter linked polymorphic region (5-HTTLPR) alleles to comorbid alcohol dependence and major depression. A sample of 296 European American and 16 African American patients with comorbid alcohol dependence and major depression was recruited from treatment studies. The control group included 260 European Americans and 43 African Americans; all were screened to exclude the presence of a mood or substance use disorder. DNA isolated from whole blood was polymerase chain reaction-amplified, and genotypes were assigned on the basis of agarose gel size fractionation. The frequency of the short allele in the patient group was in the range of those previously reported for samples with unipolar depression but was significantly more common than among controls (short allele frequency of cases, 45.8%; controls, 39.8%; chi(2)(1) = 4.02; p = 0.045).",
"yes. Behaviors of undercontrol, which occur at increased rates in children of alcoholics, may be genetically influenced through the regulation of the 5-HT transporter. Due to the small sample size and the preliminary nature of our findings, replication is necessary.",
"yes. Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.",
"Schizophrenia patients exhibit impairment in prepulse inhibition (PPI) of the acoustic startle response (ASR), suggesting a sensorimotor gating deficit. The serotonin-2A receptor (5-HT(2A)R) has been implicated in both the pathogenesis of schizophrenia and the PPI deficits of schizophrenia patients. Moreover, both schizophrenia and PPI are thought to be inheritable. We investigated the impact of three 5-HT(2A)R polymorphisms (A-1438G, T102C, H452Y) on PPI in schizophrenia patients. We analyzed the 5-HT(2A)R A-1438G, T102C, and H452Y polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Patients were also examined with the Positive and Negative Syndrome Scale. The 5-HT(2A)R A-1438G and T102C polymorphisms were in complete linkage disequilibrium. Patients carrying the T102C TT and the A-1438G AA allele show significantly higher PPI levels and a faster early habituation compared with all other variants. 5-HT(2A)R A-1438G and T102C genotype explained approximately 11% of the PPI and early habituation variance. In contrast, the 5-HT(2A)R H452Y polymorphism did not affect startle parameters.",
"Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and LG) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. thirty-two healthy volunteers underwent in vivo SERT imaging with [(11)C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and LG-allele carriers tended to show a larger CAR (p=0.07) than LA homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR).",
"yes. Our data supports the hypothesis that 5-HT(3) receptors play an important role in the pathogenesis of CINV. Along with previously identified HTR3 polymorphisms, the HTR3D p.G36A variant could also contribute to facilitating individual risk predictions.",
"yes. Downregulation of 5-HT1A autoreceptor binding by SSRI treatment of major depression is consistent with animal studies. This may be a necessary but insufficient requirement for clinical response to SSRIs. A PET agonist ligand that binds selectively to the high-affinity conformation of this receptor can determine whether SSRIs also cause desensitization of the autoreceptor as reported by some rodent studies and whether that effect may be related to clinical response.",
"yes. The results indicate a partial role for the 5-HT(7) receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.",
"Novelty seeking is a trait that has been consistently associated with problem behaviours. There is evidence for heritability of novelty seeking, but the molecular genetic basis of the trait is still widely unclear. The interaction between polymorphisms of catechol-O-methyltransferase (COMT) and serotonin receptor 2A genes was examined in relation to novelty seeking and its different subscales in healthy Finnish adults. A subsample of 1214 participants derived from a population-based sample was genotyped for the COMT Val158Met (rs4680) and HTR2A T102C (rs6313) genes. Novelty seeking was measured twice, with a 4-year interval, using Cloninger's Temperament and Character Inventory. The interaction between COMT Val158Met and HTR2A T102C polymorphisms was found to be associated with subscale impulsiveness. T/T carriers of HTR2A T102C polymorphism, that also had Met/Met genotype of COMT Val158Met single nucleotide polymorphism, scored significantly higher on impulsiveness than Val allele carriers (P=0.005).",
"yes. These findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.",
"Serotonin (5-HT) plays a complex regulatory role in processes like anxiety, depression, aggression, and impulse control. Due to the large amount of serotonergic receptors, knockout mice offer an important opportunity to investigate the role of specific receptors. The 5-HT(1B) receptor is thought to mediate aggression and impulse control. This was studied here in mice lacking 5-HT(1B) receptors (5-HT(1B) KO). Wild type and 5-HT(1B) KO mice were exposed to several types of entrained and nonentrained stimuli. With telemetry, body temperature, heart rate, and locomotor activity were measured continuously during the different experiments. To nonentrained stimuli like disturbance stress and confrontation with an intruder, 5-HT(1B) KO mice showed exaggerated physiologic and behavioral responses. These mice displayed behavioral disinhibition, measured as increased social interest and aggression to an intruder mouse. However, in response to well-entrained stimuli like daily light transitions, responses were smaller in 5-HT(1B) KO than in wild type mice, suggesting that hyperreactivity is stimulus specific.",
"The serotonin transporter gene (SLC6A4) encodes a trans-membrane protein (5-HTT) that plays an important role in regulating serotonergic neurotransmission, which is known to be involved in many psychiatric disorders. A polymorphism in the transcriptional control region containing long (L) and short (S) variants (5-HTTLPR) as well as alleles of the variable number tandem repeats (VNTR) region were demonstrated. Higher serotonin levels among carriers of the S allele might exhibit increased liability of serotonin-mediated, psychopathology-like anxiety and depression and may impair social skills reflected by harm avoidance. To analyze the data of alcohol-dependent, unrelated German individuals for a significant association between serotonin transporter gene and history of depression as well as TCI scales. We characterized 368 alcohol-dependent participants by TCI and SSAGA/history of depression. HHT and VNTR genes were amplified by polymerase chain reaction. No significant association was found between history of depression and 5-HTTLPR (F=0.42, P=0.65, d.f.=2) as well as between history of depression and VNTR (F=0.24, P=0.91, d.f.=2). As harm avoidance is often associated with history of depression, the TCI was used. Regarding the TCI temperament and character scale scores, no significant association was found between harm avoidance and this genetic variant 5-HTTLPR (F=0.55, P=0.57, d.f.=2), and between harm avoidance and VNTR (F=0.39, P=0.81, d.f.=2). Haplotype analysis showed significant relationship between low level of harm avoidance and haplotype S/12 (chi=7.01, P=0.00). Haplotype analysis of history of depression (chi=2.04, P=0.742) showed no significant result.",
"Obsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminergic neurotransmission. Deep brain stimulation (DBS) targeted at the nucleus accumbens (NAc) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder, but its effect on dopaminergic transmission is unknown. We measured the effects of NAc DBS in 15 patients on the dopamine D2/3 receptor availability in the striatum with [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission computed tomography. We correlated changes in [(123)I]IBZM binding potential (BP) with plasma levels of homovanillic acid (HVA) and clinical symptoms. Acute (1-hour) and chronic (1-year) DBS decreased striatal [(123)I]IBZM BP compared with the nonstimulated condition in the putamen. BP decreases were observed after 1 hour of stimulation, and chronic stimulation was related to concurrent HVA plasma elevations, implying DBS-induced dopamine release. BP decreases in the area directly surrounding the electrodes were significantly correlated with changes in clinical symptoms (45% symptom decrease).",
"Our data provides further evidence that DRD4 VNTR polymorphism is associated with OCD. Furthermore, the presence of the 2R allele was significantly associated with the symmetry dimension. This dimension may represent a more homogeneous subtype of OCD with a genetic etiology.",
"yes. For the first time, we report the evidence that D2 receptor level is significantly associated with glucose metabolism in the same individuals with internet gaming disorder, which indicates that D2/5-HT2A receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects.",
"The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [(11)C]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [(11)C]WAY-100635. Several single nucleotide polymorphisms were associated with [(11)C]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [(11)C]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with (123)I-beta-CIT as ligand.",
"Bariatric surgery is the method of choice in the treatment of morbid obesity. Different genotypes of the serotonin transporter gene (5-HTT) are known to impact the prevalence of psychiatric disorders and the psychosocial state in obese individuals. In this study, we examined the influence of the 5-HTTLPR polymorphism on physiologic and psychosocial measures in morbidly obese women after bariatric surgery. We investigated women 1-5 years after bariatric surgery using a semi-structured interview and the Beck Depression Inventory, the Moorhead-Ardelt Quality of life questionnaire, the NEO-Five Factor Inventory and a Resilience scale. The 5-HTTLPR polymorphism (s/s, s/l, l/l) was genotyped using mouth swabs. The influence of genotype on outcome variables was analyzed by independent t test and analysis of covariance corrected for possible confounders. 64 women were enrolled in this study between January 2004 and September 2009. Significantly lower quality of life and higher depression, neuroticism and resilience scores were found in homozygous s-allele carriers of the 5-HTTLPR polymorphism than in l-allele carriers. Except for neuroticism, other factors (age, education, year of surgery, weight before surgery and method of surgery) did not affect the results. We found no influence of genotype on weight loss, current weight or weight before surgery.",
"Increased dopaminergic activity may play a primary role in psychotic depression. Dopamine beta-hydroxylase (DbetaH) catalyses the key step in biosynthesis of the neurotransmitter noradrenaline from dopamine, and low DbetaH activity is a possible risk factor for developing psychotic depression. An exon 2 polymorphism (DBH*444 g/a) of the DbetaH gene (DBH) is significantly associated with both serum and cerebrospinal fluid levels of DbetaH. We determined the genotype of the DBH*444g/a polymorphism in a cohort of 164 patients with major depression and examined the association of this polymorphism with paranoid ideation, interpersonal sensitivity, and psychoticism on the Hopkins Symptom Checklist. Patients who possessed the A allele were significantly more likely to have higher scores for interpersonal sensitivity and paranoia than patients without the A allele (p =.004 and p =.048, respectively), suggesting that this allele may predispose patients to paranoia in major depression. In addition, we found an association between prolactin levels in men and DBH*444 g/a genotype such that homozygous G individuals displayed significantly higher levels than homozygous A or heterozygote individuals.",
"yes. These results suggest a progressive reduction of cortical 5-HT(2A)R density as a surrogate biological measure of increased risk for schizophrenia, irrespective of conversion. Progressive reductions of subcortical 5-HT(2A)R density could provide an indicator of illness activity and help to predict imminent conversion to schizophrenia. Moreover, our findings substantiate the rationale for establishing a phase-specific psychopharmacological intervention in the ARMS that addresses the serotonergic component of vulnerability to schizophrenia.",
"yes. These results support a dysfunction of 5-HT transmission in anorexia nervosa. This dysfunction does not seem to be related to concomitant depressive or obsessive--compulsive symptoms or to the level of aggressiveness of the patients.",
"We explored the association between the BDNF Val66Met polymorphism and susceptibility to both obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) in the Chinese Han population. Genotyping for the BDNF Val66Met polymorphism was performed in 321 OCD patients and 426 healthy control subjects and case-control association study data were analysed. Additionally, we evaluated the genetic contribution of this variant in 331 TS patients (including 267 TS trios) and 519 controls using the transmission disequilibrium test (TDT) and case-control study. A statistically significant difference was found in the genetic contribution of the BDNF Val66Met polymorphism between both the OCD (χ(2) = 7.50, P = 0.023 by genotype; χ(2) = 6.67, P = 0.01 by allele) and TS (χ(2) = 6.76, P = 0.03 by genotype; χ(2) = 4.27, P = 0.04 by allele), and control groups. TDT and GHRR analysis for TS trios also showed a significant transform disequilibrium of this polymorphism (TDT: χ(2) = 3.96, P = 0.05; HHRR: χ(2) = 4.33 P = 0.04; GHRR: χ(2) = 5.74, P = 0.02; χ(2) = 0.98, P = 0.37). There was also a significant gender trend between patients and controls in female cases for OCD and in male cases for TS.",
"Negative mood states are characterized by both stress hormone dysregulation and serotonergic dysfunction, reflected by altered thalamic serotonin transporter (5-HTT) levels. However, so far, no study examined the individual association between cortisol response and cerebral in vivo 5-HTT levels in patients suffering from negative mood states. The objective of this cross-sectional study was to assess the interrelation of cortisol response, thalamic 5-HTT levels, and anxiety in healthy subjects and two previously published samples of patients with unipolar major depression (UMD) and obsessive-compulsive disorder (OCD), controlling for age, gender, 5-HTT genotype, smoking, and seasonality. Regional 5-HTT levels and cortisol response to dexamethasone-corticotropin (Dex-CRH) challenge were assessed in consecutive samples of medication-free patients suffering from UMD (N = 10) and OCD (N = 10), and 20 healthy volunteers. The intervention used was combined Dex-CRH test and [(11)C]DASB positron emission tomography. The main outcome measures were: 5-HTT binding potential (BP(ND)) in a predefined thalamic ROI, cortisol response defined as the maximum cortisol increase in the combined Dex-CRH-test, and state of anxiety from the state-trait-anxiety inventory. Reduced thalamic 5-HTT BP(ND) was associated with increased cortisol response (r = -0.35, p < 0.05; in patients: r = -0.53, p < 0.01) and with increased state anxiety (r = -0.46, p < 0.01), surviving correction for age, gender, 5-HTT genotype, smoking, and seasonality (p < 0.05). The 5-HTT genotype, on the contrary, was not significantly associated with cortisol response (p = 0.19) or negative mood (p = 0.23).",
"yes. Our results suggest that a decrease in the expression of the serotonin receptor 2c gene may contribute to the pathophysiology of disc herniation. Further research on its involvement is warranted.",
"yes. Absence of 5-HT(1A)R signaling during early stages of brain maturation predisposes an organism to affective dysfunction later in life. Because early-life treatment with WAY-100,635 in Swiss-Webster mice reduced diazepam sensitivity and increased GABA(A)R alpha subunit levels in the prefrontal cortex and hippocampus, our data suggest a putative link between early-life disruption of the serotonergic system and the emergence of increased anxiety and decreased benzodiazepine responsivity at adult age. Moreover, early-life 5-HT(1A) receptor functionality appears to be essential for the development of normal GABA(A)R functionality. This study may have clinical implications for psychoactive drug use during pregnancy and for the pharmacogenetic background of benzodiazepine sensitivity.",
"Decision-making impairment is an important feature of some psychiatric disorders, such as attention-deficit/hyperactivity disorder and substance-use disorders, and is associated with dysfunction of the fronto-subcortical circuit, mainly the orbitofrontal cortex (OFC). Several data reports support significant correlations between decision-making impairment and the serotonin system. Thus, this neurotransmission system may be a major step in some cognitive features, particularly in OCD because serotonin is associated with this disorder. Therefore, the serotonin transporter promoter polymorphism (5-HTTLPR) may be related to the modulation of these cognitive characteristics. In a sample of Caucasian OCD patients, we explored the link between decision-making and the 5-HTTLPR. We used the Iowa Gambling Task (IGT) to measure decision-making in 49 OCD patients, according to the DSM-IV criteria. All patients were submitted to Y-BOCS, BDI, BAI, the Raven Progressive Matrices, the Continuous Performance Task, and the Trail Making Test. We grouped S- and/or Lg-carriers in view of the fact that these act in a nearly dominant way. On IGT, S- and/or Lg-carriers had significantly lower scores on the third, fourth, and fifth blocks. These findings were confirmed after adjusting for clinical and cognitive variables.",
"yes. The Met allele of the COMT gene Val158Met polymorphism is associated with low COMT enzyme activity and high endogenous dopamine synaptic levels in the prefrontal cortex. This leads to a decrease in dopaminergic neurotransmission in nucleus accumbens and a need for an increased activity to stimulate it. Novelty seeking behavior corresponds with this need.",
"Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01).",
"Pharmacological studies indicate a functional interaction between the serotonergic and oxytocinergic system. This study tested for an interaction of the prominent serotonin transporter polymorphism (SLC6A4) and an oxytocin receptor gene variation on individual differences in negative emotionality in healthy Caucasians (n = 750). Participants carrying both the homozygous LL-variant of the serotonin transporter polymorphism and the TT variant of the single nucleotide polymorphism rs2268498 on the oxytocin receptor gene showed lowest scores on the personality dimensions Fear and Sadness of the Affective Neuroscience Personality Scales, as well as on an underlying factor Negative Emotionality.",
"Current models suggest that a variation in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with altered amygdala reactivity not only towards negative but also towards positive stimuli, which has been neglected in the past. This association may possibly convey an elevated vulnerability for psychopathology like abuse, craving, and relapses. Since appetitive conditioning is a crucial mechanism in the pathogenesis of these psychiatric disorders, the identification of specific factors contributing to interindividual variation is important. In the present study (N = 86), an appetitive conditioning paradigm was conducted, in which a neutral stimulus (CS+) was associated with appetitive stimuli, while a second stimulus (CS-) predicted their absence. Subjects were genotyped according to the 5-HTTLPR genotype. As the main result, we report a significant association between the 5-HTTLPR genotype and hemodynamic responses. Individuals with the s-allele displayed elevated conditioned bilateral amygdala activity in contrast to l/l-allele carriers. Further, increased hemodynamic responses in s-allele carriers were also found in the extended emotional network including the orbitofrontal cortex, the thalamus, and the ventral striatum.",
"Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s) in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. w0 e therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs) at the serotonin receptor gene (5HT2A) and the occurrence of the disease. Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing). The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311) and CC genotypes (32%, rs6313), were higher in patients (P<0.05) than in controls. The study also showed presence of G and C alleles in patients. s0 ignificant levels of linkage disequilibrium (LD) were found to exist between the genotype frequencies of rs6311 and rs6313.",
"Our study showed that serotonin polymorphism (5-HTTLPR) is strongly associated with violent suicidal behavior in BD patients. If confirmed, our results could be an important step to create a genetic tool for long-term suicide prediction.",
"The 5-hydroxytryptamine 2A receptor, encoded by HTR2A, is a major postsynaptic target for serotonin in the human brain and a therapeutic drug target. Despite hundreds of genetic associations investigating HTR2A polymorphisms in neuropsychiatric disorders and therapies, the role of genetic HTR2A variability in health and disease remains uncertain. To discover and characterize regulatory HTR2A variants, we sequenced whole transcriptomes from 10 human brain regions with massively parallel RNA sequencing and measured allelic expression of multiple HTR2A messenger (m)RNA transcript variants. Following discovery of functional variants, we further characterized their impact on genetic expression in vitro. Three polymorphisms modulate the use of novel alternative exons and untranslated regions (UTRs), changing expression of RNA and protein. The frequent promoter variant rs6311, widely implicated in human neuropsychiatric disorders, decreases usage of an upstream transcription start site encoding a longer 5'UTR with greater translation efficiency. rs76665058, located in an extended 3'UTR and unique to individuals of African descent, modulates allelic HTR2A mRNA expression. The third single nucleotide polymorphism, unannotated and present in only a single subject, directs alternative splicing of exon 2. Targeted analysis of HTR2A in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study reveals associations between functional variants and depression severity or citalopram response.",
"yes. The present findings provide evidence of COMT genetic variations' role in the susceptibility to AD-related psychosis. The observation of a haplotype effect of different polymorphisms within the COMT gene puts emphasis on the usefulness of haplotype analysis in better defining individualized genetic risk profiles in AD.",
"yes. In summary, our results give evidence for a possible common locus for OCD and ASDs at 9p24. We speculate that the area may represent a special candidate region for obsessive repetitive symptoms in ASDs.",
"In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems (DRD4, DRD2, COMT, 5-HTT, OXTR) on attachment security and disorganization. Parenting was assessed using observational rating scales for parental sensitivity (Ainsworth, Bell,&Stayton, 1974), and infant attachment was assessed with the Strange Situation Procedure. We found no consistent additive genetic associations for attachment security and attachment disorganization. However, specific tests revealed evidence for a codominant risk model for COMT Val158Met, consistent across both samples. Children with the Val/Met genotype showed higher disorganization scores (combined effect size d = .22, CI = .10-.34, p<.001). Gene-by-environment interaction effects were not replicable across the two samples.",
"yes. Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.",
"The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia. HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).",
"Patients with childhood-onset obsessive-compulsive disorder or Tourette's syndrome had significantly greater B cell D8/17 expression than comparison subjects despite the absence of documented Sydenham's chorea or rheumatic fever. These findings suggest that D8/17 may serve as a marker for susceptibility among some forms of childhood-onset obsessive-compulsive disorder and Tourette's syndrome, as well as rheumatic fever or Sydenham's chorea.",
"There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L.",
"This study investigates the association of four single nucleotide polymorphisms (SNPs) in the serotonin 2A (5-HT-2A) receptor gene with anger-, aggression- and suicide-related behavior in a total of 566 subjects (203 German suicide attempters and 363 German community-based healthy volunteers). Anger- and aggression-related traits were assessed by using the State Trait Anger Expression Inventory (STAXI) and the Questionnaire for Measuring Factors of Aggression (FAF). Three (rs643627-rs594242-rs6311: A-C-T), two (rs594242-rs6311: C-T) and a single functional (rs6311: T) marker were protective against suicidal behavior. The complementary makers (rs594242-rs6311: G-C and rs6311: C) were associated with increased risk for non-violent (p=0.01; p=0.009 respectively) and impulsive suicidal behavior (p=0.03; p=0.01 respectively). Furthermore, CC-homozygotes for the functional SNP rs6311 reported more anger- (p=0.004) and aggression-related behavior (p=0.011).",
"Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively.",
"yes. These results show that the monoamine oxidase A gene may play an important role in the etiological development of the borderline personality disorder.",
"yes. The results of this study represent the strongest linkage finding for OCD in a primary analysis to date and suggest that chromosome 1p36, and possibly several other genomic regions, may harbor susceptibility loci for OCD. Multiple brain-expressed genes lie under the primary linkage peak (approximately 4 megabases in size). Follow-up studies, including replication in additional samples and targeted sequencing of the areas of interest, are needed to confirm these findings and to identify specific OCD risk variants.",
"Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis. Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction.",
"yes. Our findings suggest an impact of allelic variation in 5-HT(1A) receptor expression on the development of interferon alfa-induced depression during antiviral treatment of chronic hepatitis C. Prediction models of interferon-induced depressive symptoms based on HTR1A variation offer a perspective for an antidepressant selective serotonin reuptake inhibitor prophylaxis in patients genetically at risk for interferon-induced depression.",
"Gene association studies detect an influence of natural variation in the 5-hydroxytryptamine transporter (5-HTT) gene on multiple aspects of individuality in brain function, ranging from personality traits through to susceptibility to psychiatric disorders such as anxiety and depression. The neural substrates of these associations are unknown. Human neuroimaging studies suggest modulation of the amygdala by 5-HTT variation, but this hypothesis is controversial and unresolved, and difficult to investigate further in humans. We used a mouse model in which the 5-HTT is overexpressed throughout the brain and recorded hemodynamic responses (using a novel in vivo voltammetric monitoring method, analogous to blood oxygen level-dependent functional magnetic resonance imaging) and local field potentials during Pavlovian fear conditioning. Increased 5-HTT expression impaired, but did not prevent, fear learning and significantly reduced amygdala hemodynamic responses to aversive cues. Increased 5-HTT expression was also associated with reduced theta oscillations, which were a feature of aversive cue presentation in controls. Moreover, in control mice, but not those with high 5-HTT expression, there was a strong correlation between theta power and the amplitude of the hemodynamic response.",
"yes. We conclude that the HTR to DOI in mice is strongly modulated by 5-HT(2C) receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT(2) receptors.",
"yes. Our findings suggest that PPI and habituation are modulated by 5-HT(2A)R A-1438G and T102C genotype in schizophrenia. Consequently, alterations within brain 5-HT(2A)Rs may contribute to the PPI deficits in schizophrenia.",
"yes. Lower frequency of -759T allele of the 5- HT2C receptor gene was associated with type 2 diabetes but not with obesity in male and female Caucasians. Thus, this polymorphism might constitute a prognostic marker for diabetic risk.",
"yes. The observed interaction effect provides converging evidence from human molecular genetics that serotonergic and oxytocinergic neurotransmission are entwined and play a crucial role for human personality with implications for affective disorders.",
"Serotonergic (5-HT) dysfunction has been implicated in the etiology of both behavioral disinhibition (BD) and negative affect (NA). This work extends our previous finding of relationships between whole blood 5-HT and both BD and NA in pubescent, but not prepubescent, children of alcoholics and continues examination of a hypothesized role of 5-HT dysfunction in alcoholism risk. The long and short (L and S) variants of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) are responsible for differing transcriptional efficiencies in 5-HT uptake. Although associations have been found between the SS 5-HTTLPR genotype and severe alcoholism and neuroticism, recent reports describe relationships between the LL genotype and both low level of response to alcohol and alcoholism diagnosis and a predominance of the LL genotype in early-onset alcoholics. This report is from an ongoing prospective study of the development of risk for alcoholism and other problematic outcomes in a sample of families classified by father's alcoholism subtype. This study examines relationships between 5-HTTLPR genotype and both child BD (Child Behavior Checklist Aggressive Behavior) and NA (Child Behavior Checklist Anxious/Depressed) in offspring from 47 families. Results showed significantly higher levels of BD and NA in the 16 children with the LL genotype than the 46 SS or SL children.",
"yes. Our analysis indicates that variants of two genes modulating monoamine metabolism contribute significantly to OCD susceptibility. Most importantly, an unexpected sexually dimorphic pattern of genetic susceptibility to OCD is revealed and suggests the possibility that profound gender differences in genetic predisposition may exist not only for other OCD susceptibility genes, but for an array of other psychiatric disorders as well.",
"yes. These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.",
"yes. We conclude that variations in the 5-HT-2A gene may modify the phenotype of suicide-, anger-, and aggression-related behavior. Further studies should especially focus on intermediate personality traits in this context.",
"yes. These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the \"therapeutic\" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.",
"yes. The Met allele load of the COMT receptor gene was associated with response to 10 weeks of treatment with citalopram in drug-free or drug-naïve OCD patients.",
"Dysfunctions of serotonergic neurotransmission are supposed to be involved in the pathogenesis of psychiatric disorders such as major depressive disorder (MDD). The concentration of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft is essentially regulated by the 5-HT transporter (5-HTT). A length polymorphism repeat in the 5-HTT promoter region, termed 5-HTTLPR, has been commonly investigated for an association with psychiatric disorders. Genotyping of the 5-HTTLPR is time-consuming and technically challenging. Recently, a two-SNP haplotype was identified that tags the 5-HTTLPR at r(2)=0.775. This allows extraction of 5-HTTLPR genotype information from large genome-wide association study (GWAS) data sets. In the present study we performed haplotype analysis using a German GWAS case-control dataset to test for an association between MDD and the two-SNP tagging haplotype for 5-HTTLPR. We detected a significant association between the TA haplotype (tagging the S-allele of the 5-HTTLPR) and MDD. Our result is consistent with previous findings of an association between the 5-HTTLPR S-allele and MDD.",
"yes. Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment.",
"Family, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD. Eight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated. Haplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5' of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).",
"The pathophysiology of tardive dyskinesia (TD) is not completely understood.Aim. - To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol-o-methyltransferase (COMT) gene polymorphisms. Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects.",
"The dopamine D4 receptor (DRD4) is a promising candidate gene in obsessive compulsive disorder (OCD). A 48-bp variable number of tandem repeats (VNTR) sequence in exon 3 has been studied previously, and alleles containing 2-11 repeats (2R-11R) have been identified. We investigated the association of DRD4 VNTR polymorphism with OCD and its relationship with various clinical parameters (age of onset, gender, family history, co-morbidity, factor-analyzed symptom dimensions and insight). One hundred and seventy three South Indian OCD patients (DSM-IV) recruited from a specialty OCD clinic were evaluated using the Yale-Brown obsessive compulsive scale (YBOCS), YBOCS item-11 for insight, Mini International Neuropsychiatric Interview (MINI) plus, tic disorder subsection of the MINI-KID and Clinical Global Impression scale. 201 healthy controls were evaluated using MINI plus. All subjects were genotyped for the DRD4 VNTR polymorphism. Genotype frequencies did not deviate significantly from the Hardy-Weinberg equilibrium. Case-control association analysis revealed that the 7R allele frequency was significantly greater in OCD patients than controls. This difference was restricted to the women subsample when performing the gender sub-analysis. Among other clinical variables examined, factor 3 (symmetry) was associated with presence of 2R allele. Linear regression analysis confirmed the association of symmetry dimension with the 2R allele (Beta=0.23, t=2.96, p=0.004, CI=0.19-0.95).",
"no. Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD.",
"Excessive worry is associated with a range of psychological disorders. While previous studies have examined genes associated with a range of different anxiety phenotypes, none have explored genes specifically associated with the general tendency to worry. The present study tested associations between trait worry and functional polymorphisms of three candidate genes: the serotonin transporter-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene, the Val66Met region of the brain-derived neurotrophic factor (BDNF) gene, and the Val158Met region of the catechol-O-methyltransferase (COMT) gene. A heterogeneous sample of adult participants (n=173) completed the Penn State Worry Questionnaire (PSWQ) and provided DNA samples for genotyping. Results revealed a significant interaction between 5-HTTLPR and BDNF genotypes predicting levels of worry. Specifically, there was a significant positive association between 5-HTTLPR short alleles and PSWQ scores, but only in BDNF met allele carriers. COMT genotype was not significantly associated levels of worry, nor did COMT interact with 5-HTTLPR or BDNF genotypes to predict PSWQ scores.",
"yes. The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.",
"Serotonin-1B receptor (5-HT1BR) agonist treatment induces obsessive-compulsive disorder (OCD)-like behaviors including locomotor stereotypy, prepulse inhibition deficits, and delayed alternation disruptions, which are selectively prevented by clinically effective OCD treatment. However, the role of 5-HT1BRs in modulating other repetitive behaviors or OCD-like patterns of brain activation remains unclear. We assessed the effects of 5-HT1BR agonism on digging, grooming, and open field behaviors in mice. We also quantified effects on neuronal activation in brain regions overactivated in OCD. Finally, we assessed whether effects of the 5-HT1BR challenge could be blocked by clinically effective, but not ineffective, drug treatments. Mice were tested in open field, dig, and splash tests after acute treatment with saline, 1, 3, 5, or 10 mg/kg RU24969 (5-HT1B/1A agonist). Behavioral effects of RU24969 were also tested following co-treatment with vehicle, 1 mg/kg WAY100635 (5-HT1A antagonist) and 5 or 10 mg/kg GR127935 (5HT1B/D antagonist). Separate mice were behaviorally assessed following chronic pretreatment with vehicle with 10 mg/kg fluoxetine or 20 mg/kg desipramine and acute treatment with saline or 10 mg/kg RU24969. Brains were analyzed for Fos expression in the orbitofrontal cortex, the dorsal striatum, and the cerebellum. RU24969 induced robust locomotor stereotypy and decreased rearing, digging, and grooming. Effects were blocked by GR127935 but not by WAY100635. RU24969 also increased Fos expression in the dorsal striatum. Chronic fluoxetine, but not desipramine, alleviated 5-HT1BR-induced effects.",
"Serotonin 1-A receptors are key regulators of serotonin activity and their dysregulation might be implicated in the emergence of both major depression (MD) and generalized anxiety disorder (GAD). Previous studies have yielded inconclusive results as to whether the 5-HT1A receptor gene (HTR1A) has a role in the aetiology of MD and no study up to date has analysed this polymorphism on either pure MD or MD comorbid with GAD. In this study, 1059 patients taking part in the PREDICT-Gene study were ascertained for Diagnostic and Statistical Manual of Mental Disorders-IV MD and GAD diagnoses using the Composite International Diagnostic Interview and the Primary Care Evaluation of Mental Disorders questionnaire, respectively. They were also genotyped for the C(-1019)G functional polymorphism at the promoter region of HTR1A gene. Genetic variability at HTR1A was significantly associated with MD [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 1.14-2.44; P = 0.008], although this effect disappeared after adjusting for GAD (OR = 1.43; 95% CI = 0.96-2.14; P = 0.080). Similarly, a crude association between C(-1019)G polymorphism and GAD was found (OR = 2.54; 95% CI = 1.28-4.86; P = 0.003), but these results became no longer significant after adjusting for MD (OR = 1.97; 95% CI = 0.99-3.91; P = 0.050). However, a main effect of HTR1A G(-1019) allele on comorbid MD-GAD was found (OR = 3.41; 95% CI = 1.44-8.05; P = 0.005) and it remained robust and statistically significant after adjusting by sex, age and family history of psychological problems (OR = 2.82; 95% CI = 1.18-6.77; P = 0.020).",
"yes. Inconclusive findings about the link between OCD and 5-HTTLPR may be better elucidated by studying OCD subgroups that could be more related in some genetic characteristics. Based on our study, low performance on IGT is associated with S- and/or Lg-carriers.",
"Non-selective serotonin (5-HT) receptor agonists like meta-chlorophenylpiperazine and MK-212 have been used to explore the role of 5-HT in obsessive compulsive disorder (OCD). The results of these studies and the findings of autoradiography and neuroimaging studies, pointed to a possible role of the 5-HT1B/1D receptor in the pathophysiology of OCD. Recently the selective 5-HT1B/1D receptor agonist sumatriptan was used to further explore the role of the 5-HT1B/1D receptor in OCD. Equivocal results with respect to the increase of obsessive compulsive symptoms in patients with OCD were reported. In one study a significant increase in plasma growth hormone (GH) concentration was observed, although sumatriptan does not pass the blood-brain barrier. In order to further explore the role of the 5-HT1B/1D receptor in the pathophysiology of OCD, we performed this study, following the same design as Ho Pian et al. (Psychopharmacology 140:365-370). In the present study we performed a randomized, double-blind, placebo-controlled, cross-over design with zolmitriptan (5 mg per os), a selective 5-HT1B/1D receptor agonist with better brain penetrating properties than sumatriptan. We could not detect any changes in obsessive compulsive symptoms, mood, or anxiety levels, although we found a (nonsignificant) increase in plasma GH levels.",
"To determine whether polymorphisms of the dopamine D(2) receptor (DRD2) and catechol-O-methyl-transferase (COMT) receptor genes affect the efficacy of quetiapine addition to citalopram in patients with OCD. Sixty-four drug-free or drug-naïve patients meeting DSM-IV criteria for OCD were randomized to 10 weeks double-blind treatment with citalopram (60 mg/day) with quetiapine (300 -450 mg/day) or with placebo. The change from baseline to endpoint on the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the response to treatment were the primary outcome measures. Response was defined as a 25% decrease in Y-BOCS score. Responders and nonresponders were stratified according to DRD2 TaqI A and COMT Val(158)Met genotypes. No significant differences in genotype distribution or allele frequencies of the COMT or DRD2 receptor were found between responders and nonresponders to citalopram with quetiapine. However, nearly half of responders to citalopram with placebo carried the Met/Met (48%) genotype of the COMT polymorphism compared to none of the nonresponders (χ(2) = 10.06, df = 2, P = 0.007).",
"As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P = 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P = 0.034, odds ratio = 2.26).",
"Obsessive-compulsive disorder (OCD) has a complex etiology involving both genetic and environmental factors. However, the genetic causes of OCD are largely unknown, despite the identification of several promising candidate genes and linkage regions. Our objective was to conduct genetic linkage studies of the type of OCD thought to have the strongest genetic etiology (i.e., childhood-onset OCD), in 33 Caucasian families with ≥2 childhood-onset OCD-affected individuals from the United States (n = 245 individuals with genotype data). Parametric and nonparametric genome-wide linkage analyses were conducted with Morgan and Merlin in these families using a selected panel of single nucleotide repeat polymorphisms from the Illumina 610-Quad Bead Chip. The initial analyses were followed by fine-mapping analyses in genomic regions with initial heterogeneity logarithm of odds (HLOD) scores of ≥2.0. We identified five areas of interest (HLOD score ≥2) on chromosomes 1p36, 2p14, 5q13, 6p25, and 10p13. The strongest result was on chromosome 1p36.33-p36.32 (HLOD = 3.77, suggestive evidence for linkage after fine mapping). At this location, several of the families showed haplotypes co-segregating with OCD.",
"Obsessive-compulsive disorder (OCD) is a common and severe psychiatric illness that affects 1-3% of the population and presents a well-established co-morbidity with major depressive disorder (MDD). Twin and family studies have suggested a genetic component in the etiology of OCD, although the mode of inheritance is unknown. Pharmacotherapy of the disease implicates both serotonergic and dopaminergic pathways. Previously, guided by the 22q11 microdeletion-related psychiatric phenotype, we provided evidence for a sexually dimorphic association between OCD and the gene for catechol-O-methyltransferase (COMT). In this report, we use 110 nuclear OCD families to analyze the inheritance of variants of COMT and monoamine oxidase-A (MAOA), another gene modulating monoamine metabolism. A sample of 110 nuclear OCD families was collected, and lifetime diagnoses were ascertained using the Diagnostic Interview for Genetic Studies (DIGS). DNA was genotyped for functional variants of the COMT and MAO genes, and allele inheritance was examined using the Transmission Disequilibrium Test (TDT) and Haplotype-based Haplotype Relative Risk (HHRR) test. We provide evidence supporting the previously reported sexually dimorphic association between low COMT enzymatic activity and OCD. We also provide evidence for a similar sexually dimorphic association between OCD and an allele of the MAOA gene, previously linked to high MAO-A enzymatic activity. In agreement with the well-established action of MAO-A inhibitors as antidepressants, this association is particularly marked among male OCD probands with co-morbid MDD, who represent more than 50% of our male OCD sample.",
"Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with onset in childhood and is characterized by obsessions (recurrent, intrusive, persistent thoughts, impulses and/or ideas that often cause anxiety or distress) and compulsions (ritualized and stereotypic behaviours or mental acts that are often performed to relieve anxiety or distress associated with obsessions). Although OCD is a heritable disorder, its complex molecular etiology is poorly understood. We combined enrichment analyses and an elaborate literature review of the top-ranked genes emerging from the 2 published genome-wide association studies of OCD and candidate genes implicated through other evidence in order to identify biological processes that, when dysregulated, increase the risk for OCD. The resulting molecular protein landscape was enriched for proteins involved in regulating postsynaptic dendritic spine formation - and hence synaptic plasticity - through insulin-dependent molecular signalling cascades.",
"yes. We report novel 5-HT1BR-induced behaviors and striatal activation that were alleviated only by clinically effective pharmacological OCD treatment. Studying the mechanisms underlying these effects could provide insight into OCD pathophysiology.",
"In the present study, we investigate the association between the 5-HTTLPR polymorphism and executive functions in a sample of patients with obsessive compulsive disorder (OCD). A total of 98 unmedicated patients diagnosed with OCD according to DSM-IV criteria and 80 healthy controls were included in this study. The genotype frequencies of 5-HTTLPR polymorphism were compared in OCD and healthy control groups. The four subgroups of OCD and healthy control participants, determined according to having LaLa genotype (high expressing) or S- and/or Lg alleles (low expressing), were also compared using neuropsychological tests of executive functions. The frequency of SLa genotype of 5-HTTLPR polymorphism was found to be higher in patients with OCD compared with healthy controls. The mean scores of conceptual level responses of the Wisconsin Card Sorting Test (WCST) were significantly lower in the OCD-high-expressing subgroup compared with the low-expressing control group. The mean scores of the number of moves of the Tower of London were found to be significantly higher in the OCD-high-expressing subgroup, compared with the high-expressing subgroup of healthy controls.",
"yes. Based upon these findings, no evidence was found for a specific role of the 5-HT1B/1D receptor in OCD. It should be noted, however, that challenge studies in OCD are difficult to perform. Perhaps in the future better challenge paradigms will make it possible to further explore the role of specific receptor types in OCD.",
"If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD.",
"Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects."
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Are premonitory urges a prerequisite of tic inhibition in Gilles de la Tourette syndrome? | [
"Despite the common notion that premonitory urges facilitate tic inhibition, no studies have investigated this question systematically. We examined the relation of the trait of premonitory urges with tics and tic suppression. We hypothesised that patients with more urges would be more efficient at inhibiting tics. 15 adult (14 men, mean age 32.2±7.9 years) pure Gilles de la Tourette syndrome patients participated. Tic severity was evaluated using the modified Rush Video Scale and by employing the Yale Global Tic Severity Scale. Tic suppressibility was assessed from videos of additional periods where patients were instructed to maximally suppress their tics. Rush score based inhibition potency was synthesised by combining the scores in the two conditions. A measure of pure motor tic inhibition potency was also generated based on the number of motor tics alone. Premonitory urges were assessed by the Premonitory Urge for Tics Scale. All participants reported urges preceding their tics and were able to voluntarily suppress their tics. However, there was no correlation between urge scores and the Rush score based inhibition potency or the pure motor tic inhibition potency. Scores of the Premonitory Urge for Tics Scale correlated with the interference subscale item of the Yale Global Tic Severity Scale.",
"Urges and tic inhibition are not directly related. There seem to exist at least two distinct neurophysiological systems of urge/tic generation and tic control in adult Gilles de la Tourette syndrome patients."
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"To assess whether cortico-cortical inhibition (CCI) induced by paired-pulse transcranial magnetic stimulation (TMS) is influenced by 'preferential' or 'non-preferential' activation of the motor cortex. Paired-pulse TMS (conditioning-test paradigm with interstimulus intervals of 2-5 ms) with a round coil centered over the vertex was performed in 10 normal subjects using opposite current flow directions. The amount of CCI in the opponens pollicis and first dorsal interosseus muscles was determined. When a clockwise current was induced in the brain (side A of the coil uppermost) a 'preferential' activation of the left hemisphere (right hand muscles) was observed, but the suppression of the test response by the conditioning stimulus (i.e. the CCI) was significantly greater in the left hand muscles. The situation was reversed when an anticlockwise current (side B of the coil uppermost) was induced in the brain. These effects occurred independently of the interstimulus interval, or of the absolute conditioning stimulus strength.",
"Certain environmental stimuli are frequently reported as typical triggers of migraine pain. Whether these so-called triggers are independent precipitators of migraine pain or mere symptoms of the premonitory phase of migraine remains to be elucidated. In this retrospective cohort study of 1010 migraine patients of a tertiary headache center we assessed the frequency of common trigger factors, premonitory symptoms and accompanying symptoms as well as basic headache characteristics and demographic data. Premonitory symptoms with an onset of 2 or more hours prior to the headache were present in 38.9% of migraine patients, the most frequent being a tense neck, phonophobia and difficulty concentrating. There was a clear overlap of certain trigger factors and the presence of corresponding premonitory symptoms: flickering or bright light as a trigger was associated with higher frequency of photophobia in the premonitory phase. The same applied to the presence of food craving and osmophobia in the premonitory phase and certain foods or odours as trigger factors.",
"yes. Our results suggest an attentional impulsiveness-related attenuation in response inhibition performance in individuals with BED. This might have been related to increased reward responsiveness and limited resources to activate the prefrontal control network involved in response inhibition. Our results substantiate the importance of neuronal markers for investigating prevention and treatment of obesity, especially in specific subgroups at risk such as BED.",
"Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control.",
"Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon. Fifteen CD patients and 15 age matched control subjects (CS) were asked to perform a rotational movement (RM) to either side as quick as possible immediately after IS perception (a low intensity electrical stimulus to the II finger). In randomly interspersed test trials (25%) a 130 dB SAS was delivered simultaneously with the IS. We recorded RMs in the horizontal plane with a high speed video camera (2.38 ms per frame) in synchronization with the IS. The RM kinematic-parameters (latency, velocity, duration and amplitude) were analyzed using video-editing software and screen protractor. Patients were asked to rate the difficulty of their RMs in a numerical rating scale. In control trials, CD patients executed slower RMs (repeated measures ANOVA, p<0.10(-5)), and reached a smaller final head position angle relative to the midline (p<0.05), than CS. In test trials, SAS improved all RMs in both groups (p<0.10(-14)). In addition, patients were more likely to reach beyond their baseline RM than CS (χ(2), p<0.001) and rated their performance better than in control trials (t-test, p<0.01).",
"Cognitive and attentional deficits in schizophrenia include impairment of the sensorimotor filter as measured by prepulse inhibition (PPI). In this way, the study of animals that naturally present low PPI responses could be a useful approach for screening new antipsychotic drugs. Several pieces of evidence suggest that dopamine and nitric oxide (NO) can modulate PPI but their role in those animals is unknown. The aim of this study was to investigate the role of dopamine and NO in Wistar rats with naturally low PPI response. Male Wistar rats with low PPI responses received an i.p. injection of the antipsychotics haloperidol (0.1, 0.3 or 1mg/kg) or clozapine (0.5, 1.5 or 5mg/kg), the anxiolytic diazepam (1 or 3mg/kg) or the NO synthase (NOS) inhibitors, N(G)- nitro-l-arginine (l-NOARG; 40mg/kg, acutely or sub-chronically) or 7-Nitroindazole (7-NI; 3, 10 or 30mg/kg). All animals were submitted to the PPI test 1h after injection. Striatal and cortical dopamine, DOPAC, and noradrenaline levels of rats with low PPI responses were compared to rats with normal PPI responses. We found increased levels of catecholamines on the striatum and prefrontal cortex of Wistar rats with low PPI. In these animals, both antipsychotics, typical and atypical, and NOS inhibitors significantly increased PPI.",
"Prepulse inhibition of the blink reflex is a robust phenomenon with an interesting physiology and a large potential for clinical applicability. In the study presented here we investigated whether the blink reflex inhibition by a prepulse (BRIP) is influenced by the blink reflex excitability recovery (BRER). The study was undertaken in 20 patients with Parkinson's disease (PD), 20 patients with Huntington's disease (HD) and 20 healthy volunteers. BRER was determined by measuring the size of the response to a test supraorbital nerve stimulus as a percentage of the response to a conditioning stimulus at inter-stimuli intervals of 100-1000 ms. BRIP was determined as the percentage reduction induced in the response to a supraorbital nerve stimulus by either a low intensity auditory click or a weak third finger somatosensory stimulus, applied with a leading interval of 50-110 ms. There was a negative correlation between the percentage BRER and the percentage BRIP (Pearson's correlation coefficient of -0.37). BRER was enhanced in 14 PD patients (70%) and 6 HD patients (30%), while it was depressed in 10 HD patients (50%). BRIP was significantly reduced in 15 PD patients (75%) and 16 HD patients (80%). No significant correlation was found between abnormally enhanced BRER and abnormally reduced BRIP in all patients as a group (chi(2)=2.4;P=0.11). A weak correlation was found in PD patients (P=0.019) and no correlation was observed in HD patients (P=0.8).",
"yes. As is seen in several childhood conditions, such as cerebral palsy and autism, lower SES is a risk factor for Tourette syndrome/chronic tics. Potential explanations include differential exposure to environmental risk factors or parental psychopathology as a measure of an increased genetic risk leading to decreased parental SES.",
"Preliminary studies suggested that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa L., might be effective in the treatment of Tourette syndrome (TS). This study was performed to investigate for the first time under controlled conditions, over a longer-term treatment period, whether THC is effective and safe in reducing tics in TS. In this randomized, double-blind, placebo-controlled study, 24 patients with TS, according to DSM-III-R criteria, were treated over a 6-week period with up to 10 mg/day of THC. Tics were rated at 6 visits (visit 1, baseline; visits 2-4, during treatment period; visits 5-6, after withdrawal of medication) using the Tourette Syndrome Clinical Global Impressions scale (TS-CGI), the Shapiro Tourette-Syndrome Severity Scale (STSSS), the Yale Global Tic Severity Scale (YGTSS), the self-rated Tourette Syndrome Symptom List (TSSL), and a videotape-based rating scale. Seven patients dropped out of the study or had to be excluded, but only 1 due to side effects. Using the TS-CGI, STSSS, YGTSS, and video rating scale, we found a significant difference (p <.05) or a trend toward a significant difference (p <.10) between THC and placebo groups at visits 2, 3, and/or 4. Using the TSSL at 10 treatment days (between days 16 and 41) there was a significant difference (p <.05) between both groups. ANOVA as well demonstrated a significant difference (p =.037). No serious adverse effects occurred.",
"yes. Schizophrenic patients show increased predictive saccadic activity, but no qualitative changes in predictive saccades. Since prediction itself was not disturbed, the patients' deficit rather lies in the suppression or gating of anticipatory saccades than in their generation. This may be explained by a selective dysfunction of the basal ganglia oculomotor loop. As predictive hand movements were unimpaired, the problems in eye-hand coordination as expressed by a longer initiation time of hand movements relative to saccades are a direct consequence of impaired predictive saccadic behaviour.",
"The tryptophan hydroxylase 1 gene (TPH1) catalyzes the formation of 5-hydroxytryptophan, a precursor to the neurotransmitter serotonin. Variations in the gene encoding this enzyme may underlie difficulties in impulse control; however, the proximate relationship between risk alleles for polymorphisms in the TPH1 gene and the neural correlates of response inhibition remain poorly understood. The present study examined the relationship of 2 single nucleotide polymorphisms in the TPH1 gene (rs1799913 and rs4537731) to prefrontal cortex (PFC) activation on a response inhibition task. Evoked hemodynamic oxygenation in the PFC was measured in 30 unrelated healthy adult women using 16-channel continuous-wave functional near-infrared spectroscopy while they completed a manual go/no-go task. TPH1 alleles showed no association with demographic characteristics, general intelligence, impulsive personality traits, or accuracy and response latency indices on the go/no-go task. Participants carrying the risk alleles, however, showed less activity primarily in bilateral inferior frontal gyri and medial PFC under conditions of response inhibition.",
"Impairment in initiating movements in PD might be related to executive dysfunction associated with abnormal proactive inhibitory control, a pivotal mechanism consisting in gating movement initiation in uncertain contexts. Testing this hypothesis on the basis of direct neural-based evidence. Twelve PD patients on antiparkinsonian medication and fifteen matched healthy controls performed a simple reaction time task during event-related functional MRI scanning. For all subjects, the level of activation of SMA was found to predict RT on a trial-by-trial basis. The increase in movement initiation latency observed in PD patients with regard to controls was associated with pre-stimulus BOLD increases within several nodes of the proactive inhibitory network (caudate nucleus, precuneus, thalamus).",
"Based on a variety of empirical evidence obtained within the theoretical framework of embodiment theory, we considered it likely that motor disorders in Tourette's syndrome (TS) would have emotional consequences for TS patients. However, previous research using emotional facial categorization tasks suggests that these consequences are limited to TS patients with obsessive-compulsive behaviors (OCB). These studies used long stimulus presentations which allowed the participants to categorize the different emotional facial expressions (EFEs) on the basis of a perceptual analysis that might potentially hide a lack of emotional feeling for certain emotions. In order to reduce this perceptual bias, we used a rapid visual presentation procedure. Using this new experimental method, we revealed different and surprising impairments on several EFEs in TS patients compared to matched healthy control participants. Moreover, a spatial frequency analysis of the visual signal processed by the patients suggests that these impairments may be located at a cortical level.",
"Dopaminergic drugs are the mainstay of treatment for restless legs syndrome (RLS). We analyzed the frequency and clinical characteristics of impulse control disorders (ICD) in patients with RLS on transdermal rotigotine treatment. Retrospective case series at a university movement disorder clinic (n = 28, 17 women). Symptoms of ICD were assessed via detailed history taking and scoring with the Zurich Screening Questionnaire for ICD (ZICD) prior to and after initiation of treatment. None of the patients had a history of ICD prior to treatment. Baseline mean scores for patients who did (8.0 ± 2.5) and did not (6.2 ± 2.7) develop ICD under treatment did not differ. Six male patients (21%) developed various symptoms of ICD (mean ZICD scores 20.7 ± 10.2) on rotigotine treatment (mean dose: 3.8 mg/d), including binge eating, hypersexuality, compulsive shopping, pathological gambling, and punding, equaling a prevalence rate of 21%. Also in the non-ICD group, ZICD scores increased (7.5 ± 2.8).",
"Current information processing models propose that heightened attention bias for sex-related threats (eg, pain) and lowered automatic incentive processes (\"wanting\") may play an important role in the impairment of sexual arousal and the development of sexual dysfunctions such as genitopelvic pain/penetration disorder (GPPPD). Differential threat and incentive processing may also help explain the stronger persistence of coital avoidance in women with vaginismus compared to women with dyspareunia. As the first aim, we tested if women with GPPPD show (1) heightened attention for pain and sex, and (2) heightened threat and lower incentive associations with sexual penetration. Second, we examined whether the stronger persistence of coital avoidance in vaginismus vs dyspareunia might be explained by a stronger attentional bias or more dysfunctional automatic threat/incentive associations. Women with lifelong vaginismus (n = 37), dyspareunia (n = 29), and a no-symptoms comparison group (n = 51) completed a visual search task to assess attentional bias, and single target implicit-association tests to measure automatic sex-threat and sex-wanting associations. There were no group differences in attentional bias or automatic associations. Correlational analysis showed that slowed detection of sex stimuli and stronger automatic threat associations were related to lowered sexual arousal.",
"The phasic inhibition index (PII) is the rate of the simultaneous occurrence of rapid eye movement bursts (RBs) and phasic chin muscle activity (PCMA) during rapid eye movement sleep (REMS). PII is low insofar as physiologically occurring REM-related phasic inhibition acts on chin muscles. Previously we found that PII was significantly higher in patients with infantile spasms (ISs) who had a recurrence of convulsions than in patients with ISs who exhibited no recurrence. We aimed to predict the response of patients with ISs to conventional anticonvulsants (AEDs) by means of REMS components including PII, expecting to facilitate avoidance of potentially hazardous hormonal therapy. REMS, recorded before the beginning of any medication, was retrospectively examined in 15 patients with ISs. The patients were classified into two groups according to the response to initial treatment with conventional AEDs. Conventional AEDs were enough to control the spasms in six good responders (GRs), whereas further hormonal therapy was required in nine poor responders (PRs) to control the spasms. The amount of REMS was significantly lower in patients with ISs than in controls. GRs had less REMS than did PRs, although no significant difference was observed. Although the frequencies of RB and PCMA showed no significant differences among GRs, PRs, and controls, the average PII value in PRs (12.6+/-3.4; mean+/-SD) was significantly (p < 0.001) higher than that in GRs (6.1+/-1.7).",
"yes. This finding adds further evidence to the concept that PS-on neurons of the SLD generating PS are of small size and glutamatergic in nature. By means of their descending projections to medullary and/or spinal glycinergic/GABAergic premotoneurons, they may be especially important for the induction of muscle atonia during PS, a disturbed phenomenon in narcolepsy and REM sleep behavior disorder.",
"yes. Our data show that 5-ALA does not compromise the derivation of TICs. It also reveals that the margin contains TICs, which are phenotypically different from those isolated from the corresponding mass.",
"Prepulse inhibition (PPI) of the startle response is a measure of the inhibitory function and time-linked information processing by which a weak sensory stimulus (the prepulse) inhibits the startle response caused by a sudden intense stimulus. We attempted to clarify the neuronal circuits underlying the control of PPI of the startle reflex in mice. c-Fos immunohistochemistry was used to detect neurons activated by startle pulse and/or prepulse trials. Behavioural pharmacology and tracing studies were also conducted. The lateral globus pallidus (LGP) was activated by prepulses. Activation of the caudal pontine reticular nucleus (PnC) evoked by the startle pulses was inhibited under PPI conditions. Double-immunostaining revealed that c-Fos-positive cells in the LGP following prepulse trials were GABAergic neurons. Bilateral microinjections of lidocaine into the LGP resulted in an impairment of PPI. Fluoro-gold infusion into the PnC and the pedunculopontine tegmental nucleus (PPTg) retrogradely labeled neurons in the PPTg and LGP, respectively. Microinjections of phaclofen into the PPTg significantly impaired PPI.",
"yes. Since behavioral inhibition but not intrinsic alertness or motor memory was improved by so-tDCS, our results suggest that lateral prefrontal slow oscillations during sleep might play a specific role for executive functioning in ADHD.",
"To examine the influence of psychiatric comorbidity on response and relapse rates in children and adolescents treated with paroxetine for obsessive-compulsive disorder (OCD). Patients responding following 16 weeks of treatment (phase I) were randomized to continued paroxetine or to placebo for 16 additional weeks (phase II). OCD response (phase I) and relapse (phase II) criteria were based on the Clinical Global Impression-Improvement Scale and the Children's Yale-Brown Obsessive Compulsive Scale. The presence of OCD and other psychiatric disorders was ascertained using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview. At entry, 193 of 335 (57.6%) patients had at least one psychiatric disorder in addition to OCD, and 102 of 335 (30.4%) had multiple other disorders. Although the response rate to paroxetine in the overall population was high (71%), the response rates in patients with comorbid attention deficit hyperactivity disorder, tic disorder, or oppositional defiant disorder (56%, 53%, and 39%, respectively) were significantly less than in patients with OCD only (75%) (intent-to-treat population, last observation carried forward analysis, p<0.05). Psychiatric comorbidity was associated with a greater rate of relapse in the total patient population (46% for one or more comorbid disorders [p = 0.04] and 56% for two or more comorbid disorders [p<0.05] vs. 32% for no comorbidity).",
"yes. These results demonstrate that alcoholics exhibit a basic prepotent response inhibition deficit, which is enhanced when the response to be suppressed is related to alcohol. We discuss clinical and theoretical implications of these findings.",
"Schizophrenia is associated with high rates of cigarette smoking and deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. However, the relationship between PPI deficits and smoking status is unclear. We examined whether smoking status modifies PPI deficits in schizophrenia. We studied PPI as a function of smoking status and schizophrenia diagnosis in four groups using a cross-sectional design: Smokers with schizophrenia (SS; n=14), non-smokers with schizophrenia (SNS; n=15), control smokers (CS; n=11), and control non-smokers (CNS; n=10). PPI in smokers was recorded under conditions of smoking satiation, and smoking status was verified biochemically. The Diagnosis x Smoking Status x Prepulse Interval interaction was significant (F(11,140)=5.01, p<0.001). At all prepulse to pulse intervals (PPTPIs; 30, 60 and 120 ms), we found that SNS had reductions (~50%; p<0.01) in PPI compared to CNS. However, when SS were compared to CS under conditions of smoking satiation, SS had comparable levels of PPI to CS, and significantly higher levels of PPI than SNS.",
"Imaging studies of patients with Tourette's syndrome (TS) across different cohorts have shown alterations in gray and white matter in areas associated with the cortico-striato-thalamic-cortical (CSTC) pathways; however, no consistent findings have subsequently established a clear indication of the pathophysiology of TS. This study was designed to investigate changes in gray and white matter in medication-free children with TS in the CSTC areas. With MRI, 24 children with TS and 18 healthy controls were analyzed using three complementary methods.",
"no. Results do not support the hypothesis that PANDAS and Tourette syndrome are secondary to antineuronal antibodies. Longitudinal studies are required to determine whether autoantibodies correlate with fluctuations in clinical activity.",
"It has been hypothesized that Sydenham's chorea, a major manifestation of rheumatic fever, may provide a medical model for obsessive-compulsive disorder and associated conditions, such as Tourette's syndrome. Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to this complication of group A streptococcal infection. The authors investigated whether D8/17 expression is greater than normal in some forms of obsessive-compulsive disorder and Tourette's syndrome. By immunofluorescence techniques, 31 patients with childhood-onset obsessive-compulsive disorder and/or Tourette's syndrome or chronic tic disorder and 21 healthy comparison subjects were evaluated for percentage of D8/17-positive B cells. None had rheumatic fever or Sydenham's chorea. Levels of antineuronal antibodies and streptococcal antibodies were also determined. The average percentage of B cells expressing the D8/17 antigen was significantly higher in the patients (mean = 22%, SD = 5%) than in the comparison subjects (mean = 9%, SD = 2%). When classified categorically, all patients but only one comparison subject were D8/17 positive. No difference between groups in the presence of antineuronal antibodies or high streptococcal titers was found.",
"In a subgroup of patients with obsessive-compulsive disorder (OCD), motor soft signs, tics and other movement disorders can be observed, indicating a special pathogenetic involvement of basal ganglia. The main objective of this study was to verify the hypothesis that such motor dysfunction characterises a subgroup of OCD patients with poor treatment response. For assessing even subtle motor dysfunction, a new method for kinematical analysis of hand movements has been applied. We examined the performance of 45 in-patients who met the DSM-IV criteria for OCD before and under therapy (sertraline and behaviour therapy) using a digitising tablet and kinematical analysis of simple handwriting and drawing movements. All subjects wrote a sentence, their signature and letter sequences. Moreover, they drew circles under different conditions. Three kinematical parameters (stroke duration, variation coefficient of peak velocity, stroke length) were calculated to quantify hand-motor performance. Prior to therapy, non-responders wrote with significantly smaller amplitudes than responders. Additionally, non-responders drew significantly larger circles with the non-dominant hand at baseline, as compared to responders. Disturbances of handwriting were more frequent in non-responders than in responders.",
"yes. The findings of a decreased SEV in PMS patients could be due to poor sleep and consequently increased sedation, but might also indicate that gamma-aminobutyric acidergic inhibition is different in patients with premenstrual syndrome.",
"Obsessive-compulsive (OC) symptoms and repetitive negative thinking (RNT) are associated with poor inhibitory control. Sleep disruptions may partially mediate these relations and/or act as a \"second hit\" to individuals with OC symptoms and RNT. Models including habitual (past month) hours slept and bedtimes were tested. We employed a go/no-go task that allowed us to examine the relation between sleep and inhibition with various task contingencies. Sixty-seven unselected individuals were recruited from the participant pool at a public university. Bias-corrected bootstrap estimates did not show that sleep disruption mediated the relation between OC symptoms and response inhibition nor the relation between RNT and response inhibition. Multiple linear regression analyses found significant interactions between hours slept and OC symptom severity and between RNT and hours slept to predict poor response inhibition. Hours slept significantly negatively predicted commission errors when OC symptoms and RNT levels were relatively heightened but not when OC symptoms and RNT levels were relatively low. These effects were present in blocks where task contingencies were designed to shape a no-go bias. No significant relations were found with habitual bedtimes.",
"The magnitude of the startle eyeblink response is reduced if the startle eliciting stimulus is shortly preceded by another stimulus. There is evidence that schizophrenia patients exhibit impairments in this so-called prepulse inhibition. Our study investigated whether prepulse inhibition is affected by neuroleptic drug treatment as is suggested by animal research. Prepulse inhibition was tested in five unmedicated and 20 medicated inpatients with schizophrenia, and 12 normal controls. The unmedicated schizophrenia patients showed a strong impairment of sensorimotor gating as indexed by the absence of prepulse inhibition. By contrast, the medicated patients showed a pronounced prepulse inhibition that did not differ from that of the normal controls. There was a substantial covariation between the rated severity of the positive syndrome and the amount of prepulse inhibition--i.e., the patients whose positive symptoms were rated as more severe showed less prepulse inhibition.",
"yes. The decreased flash-lag illusion and lower electroencephalography background frequency in more bradykinetic PD patients provides support for disturbed visuomotor anticipations, putatively caused by reduced, sub-cortically mediated, network efficiency. This suggests a link between anticipation in early-stage visual motion processing and motor preparation.",
"Cocaine dependence has been associated with blunted dopamine and norepinephrine signaling, but it is unknown if recreational cocaine use is also associated with alterations of catecholamine systems. Prepulse inhibition (PPI) of the acoustic startle response-a measure of sensorimotor gating-is highly sensitive for manipulations of the catecholamine system. Therefore, we investigated whether relatively pure recreational users (RCU) and dependent cocaine users (DCU) display alterations of PPI, startle reactivity, and habituation. Moreover, the influences of methylenedioxymethamphetamine and cannabis co-use, craving, and attention-deficit/hyperactivity disorder (ADHD) symptoms on startle measures were examined. In 64 RCU, 29 DCU, and 66 stimulant-naïve control subjects, PPI of acoustic startle response, startle reactivity, habituation, ADHD symptoms, and cocaine craving were assessed. Drug use of all participants was controlled by hair and urine toxicologies. Both RCU and DCU showed increased PPI in comparison with control participants (Cohen's d=.38 and d=.67, respectively), while RCU and DCU did not differ in PPI measures (d=.12). No significant group differences were found in startle reactivity or habituation measures. In cocaine users, PPI was positively correlated with cumulative cocaine dose used, craving for cocaine, and ADHD symptoms. Users with a diagnosis of ADHD and strong craving symptoms displayed the highest PPI levels compared with control subjects (d=.78).",
"Tonic inhibition index (TII) and phasic inhibition index (PII) were proposed as indices for evaluating the degree of two types of motor inhibition activity during rapid eye movement (REM) sleep. In the present study, therefore, six healthy men underwent two consecutive all-night polysomnography, and reproducibility of TII and PII was evaluated. TII was 0.85+/-0.07 (mean+/-SD) on the first night and 0.88+/-0.08 on the second; and PII was 3.4+/-2.1 on the first night and 4.9+/-1.8 on the second. Neither TII nor PII was significantly different between the two nights.",
"Impulsivity is a multifaceted personality construct associated with numerous psychiatric disorders. Recent research has characterized four facets of impulsivity: \"urgency\" (the tendency to act rashly especially in the context of distress or cravings); \"lack of premeditation\" (not envisaging the consequences of actions); \"lack of perseverance\" (not staying focused on a task); and \"sensation seeking\" (engaging in exciting activities). Urgency is particularly associated with clinical populations and problematic disinhibited behavior. We used magnetic resonance spectroscopy to measure concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the dorsolateral prefrontal cortex (DLPFC) in two cohorts of 12 and 13 participants. We find that variation in trait urgency in healthy men correlates with GABA concentration in the DLPFC. The result was replicated in an independent cohort. More GABA predicted lower urgency scores, consistent with a role in self-control for GABA-mediated inhibitory mechanisms in DLPFC.",
"Obsessive-compulsive disorder (OCD) has been associated with impairments in stop-signal inhibition, a measure of motor response suppression. The study used a novel paradigm to examine both thought suppression and response inhibition in OCD, where the modulatory effects of stimuli relevant to OCD could also be assessed. Additionally, the study compared inhibitory impairments in OCD patients with and without co-morbid depression, as depression is the major co-morbidity of OCD. Volitional response suppression and unintentional thought suppression to emotive and neutral stimuli were examined using a novel thought stop-signal task. The thought stop-signal task was administered to non-depressed OCD patients, depressed OCD patients and healthy controls (n=20 per group). Motor inhibition impairments were evident in OCD patients, while motor response performance did not differ between patients and controls. Switching to a new response but not motor inhibition was affected by stimulus relevance in OCD patients. Additionally, unintentional thought suppression as measured by repetition priming was intact. OCD patients with and without depression did not differ on any task performance measures, though there were significant differences in all self-reported measures.",
"The purpose of this study was to assess the effect of type and dose of serotonin reuptake inhibitors (SRIs) on treatment outcome in quetiapine addition trials for obsessive-compulsive disorder. Results from all available, double blind, placebo-controlled quetiapine addition trials were pooled. Treatment outcome was assessed in a sample of 102 patients by change from baseline to end point on the Yale-Brown obsessive-compulsive scale (Y-BOCS). Quetiapine addition was superior with a mean Y-BOCS decrease of 6.8 +/- 6.7 compared with placebo with a decrease of 3.9 +/- 6.5 points. Patients with the lowest SRI dose showed the largest decrease on the Y-BOCS (11.6 +/- 7.7) compared with patients with the median dose (6.1 +/- 6.1) and highest dose (5.9 +/- 6.4).",
"Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or 'gate' irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding cognitive information processing deficits such as slowed processing speed. Parkinson's disease is characterised by the degeneration of the midbrain dopaminergic system and is associated with cognitive dysfunction, including slowed information processing. Although sensorimotor processes in Parkinson's disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I-FP-CIT-SPECT scanning, in patients with Parkinson's disease. 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. Patients with a higher level of prepulse inhibition performed better on cognitive measures tapping attention and processing speed than patients with a lower level of prepulse inhibition. Furthermore, there were significant correlations between prepulse inhibition and 123I-FP-CIT uptake in the striatum.",
"These results suggest that P50 and antisaccade performance reflects a common endophenotype and that prepulse inhibition identifies a separate endophenotype reflecting different neurobiological substrate(s) in subjects with schizotypal personality disorder. This pattern may generalize to schizophrenia spectrum disorder patients.",
"yes. Higher BIS-11 scores in all domains of impulsivity [i.e., motor, attentional, and lack of planning] corroborated previous findings described in patients with JME. On the other hand, BIS-11 could not demonstrate problem solving and inhibitory control deficits related to impulsive behavior, which were described in patients with TLE. Other behavioral measures may be more sensitive to some aspects of impulsivity in TLE. Our results reinforce the concept that distinct epileptic syndromes require different neuropsychological approaches, especially considering a complex construct such as impulsivity.",
"yes. Low levels of prepotent response inhibition are associated with worse response to treatment with methylphenidate. Prepotent response inhibition may be an intermediate phenotypical predictor of treatment outcome.",
"We studied the comorbid behavioural and mood problems in children with non-psychiatric Tourette's syndrome (TS) and their relationship with severity of tic disorder. Sixty-nine TS children and 69 healthy controls were assessed by Child Behavior Checklist (CBCL) and Yale Global Tic Severity Scale (YGTSS). The relationships between behavioural problems and severity of tic symptoms were analysed statistically by comparison, correlation and multiple linear regression. Tourette's syndrome patients scored significantly lower (p<0.01) on the CBCL competency subscales and total score, and higher on all behavioural problem subscales and total score (p<0.01). Expectedly, the TS children had lower social competence than normal children. Among the TS children, the severity of tic symptoms is positively correlated with the severity of overall impairment in school and social competence. When the behavioural and mood problems commonly associated with TS were studied in detail, we found that delinquent behaviour, thought problems, attention problems, aggressive behaviour and externalizing are positively correlated with severity of tic symptoms.",
"Tourette syndrome (TS) is characterized by the presence of tics and is often accompanied by other symptoms, like attention deficit hyperactive disorder (ADHD), obsessive-compulsive disorder. The presenting symptoms are supposed to be tics. Onset is usually around school age. Early diagnosis of TS is important in order to provide patients with the necessary support as early as possible. We examined the diagnostic process via a systematic interview in 314 children with TS. Median age at onset of symptoms was 3.0 years. In 40.1%, tics were the presenting clinically meaningful symptoms; in the other cases it was an associated symptom, like ADHD symptoms, obsessive-compulsive behavior, or behavioral problems. Median age of tic onset was 5.5 years. If TS presented with an accompanying symptom, the median age of onset was earlier (0-3.5 years). The mean age at the time of diagnosis was 8.9 years. The median delay from onset of the presenting symptoms until diagnosis was 5.3 years and the delay from onset of tics until diagnosis 2.8 years.",
"yes. These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use.",
"The familial nature of obsessive-compulsive disorder (OCD) has been previously demonstrated. The identification of candidate symptoms such as age at onset may help to disentangle the clinical and genetic heterogeneity of the disorder. In this study, the specificity of early-onset OCD was investigated, focusing on the effect of gender, comorbid conditions and familial risk of tics and OCD by studying a population consisting exclusively of patients with early-onset OCD. One hundred and forty-four patients having OCD were recruited in the study (108 early-onset probands and 36 late-onset probands). The early-onset probands and 199 of their first-degree relatives were investigated using structured interviews and questionnaires. This sample of early onset was mainly composed of children and adolescents (74 children and adolescents and 34 adults). The average age of onset of OCD is 9.98+/-3.2 years. Forty-four per cent of the probands have a comorbid tic disorder. The age-corrected morbid risk among the first-degree relatives is 17% for OCD and 12% for tics. Morbid risk for OCD and tics was independent of the presence of tics in probands. Only 32.6% of the probands have a positive family history of OCD.",
"yes. Repetitive paired-pulses allow selective induction of corticospinal inhibition or facilitation, but do not enhance the transient improvement of finger motility induced by conventional single-pulse rTMS.",
"yes. Under these experimental conditions, schizophrenia-linked deficits in prepulse inhibition detected with a relatively strong prepulse are correlated with both positive and negative symptoms of schizophrenia. The level of correlation, while significant in this cohort, is not as robust as that in previous reports linking prepulse inhibition deficits with other measures, such as thought disorder. Future work should probably focus on the relationship of prepulse inhibition deficits to measures such as thought disorder rather than positive and negative symptoms.",
"no. These results suggest that effects of atypical antipsychotics on prepulse inhibition may not be evident when patients with schizophrenia are acutely symptomatic, and do not directly influence prepulse inhibition.",
"Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels. Effects of the GR antagonists ORG34517 (5-45 mg/kg by mouth [PO]) and mifepristone (5-45 mg/kg PO) and the CRF(1) receptor antagonists CP154,526 (20-80 mg/kg intraperitoneally [IP]) and DMP695 (2.5-40.0 mg/kg IP) on prepulse inhibition (PPI) of the acoustic startle response were studied in mice overexpressing CRF and in their wild-type littermates. In addition, PPI was measured in both genotypes 2 weeks after adrenalectomy with or without exogenous corticosterone administration via subcutaneous pellet implant (20 mg corticosterone). ORG34517 and mifepristone did not influence perturbation of PPI in mice overexpressing CRF; reducing corticosterone levels by adrenalectomy likewise did not improve PPI. Further, elevation in corticosterone levels by pellet implantation did not disrupt PPI in wild-type mice. Conversely, both CRF(1) receptor antagonists, CP154,526 (40-80 mg/kg IP) and DMP695 (40 mg/kg IP), significantly restored PPI in CRF-overexpressing mice.",
"In Gilles de la Tourette syndrome (GTS) an immunopathogenic influence of autoantibodies is suspected. In familial GTS a disruption of the contactin-associated protein 2 gene (CNTNAP2), coding for the contactin-associated protein 2 (CASPR2), has been reported. Autoantibodies against CASPR2 are associated with other movement disorders like Morvan's syndrome. In addition, positive oligoclonal bands (OCB) in cerebrospinal fluid (CSF) have been found in more than a third of GTS patients, indicating a pathological intrathecal immunoglobulin synthesis. These findings drove the hypothesis that CASPR2 antibodies are involved in GTS. In this cross sectional study, 51 patients with GTS were examined for CASPR2 and other autoantibodies. We used indirect immunofluorescence or enzyme-linked visualization in cell-based assays on tissue sections from cerebellum (rat and monkey), hippocampus (rat), and immunoblots for the detection of specific or any other autoantibodies. Serum samples from 51 GTS patients, mean age 35.0 ± 13.1 y, were analyzed. In none of the 51 GTS sera CASPR2 antibodies were detectable. Neither had we found any other specific autoantibodies (LGI1, NMDAR, AMPA1, AMPA/2 or GABAB1/B2). An anti-nuclear pattern of immunoreactivity was observed in 7/51 (14 %) samples. In these patients an immunoblot analysis was used to rule out antibodies directed against well-defined intracellular target antigens. A specific anti-neuronal binding pattern could not be seen in any of the tissue sections.",
"Altered sensory processing in interstitial cystitis/painful bladder syndrome cases may result from a deficiency of the central nervous system to adequately filter incoming visceral afferent information. We used prepulse inhibition as an operational measure of sensorimotor gating to examine early pre-attentive stages of information processing in females with interstitial cystitis/painful bladder syndrome and healthy controls. We assessed prepulse inhibition in 14 female patients with interstitial cystitis/painful bladder syndrome and 17 healthy controls at 60 and 120-millisecond prepulse-to-startle stimulus intervals. We evaluated group differences in prepulse inhibition, and relationships between prepulse inhibition, neuroticism and acute stress ratings. Patients showed significantly decreased prepulse inhibition at 60 and 120-millisecond prepulse intervals. The prepulse inhibition deficit was related to acute stress ratings in the patients. However, increased neuroticism appeared to mitigate the prepulse inhibition deficit in those with interstitial cystitis/painful bladder syndrome, possibly reflecting greater vigilance.",
"Craving or the \"urge to consume\" is a characteristic of bulimic eating disorders and addictions. Dysfunction of the dorsolateral prefrontal cortex (DLPFC) is associated with craving. We investigated whether stimulation of the DLPFC reduces food craving in people with a bulimic-type eating disorder. Thirty-eight people with bulimic-type eating disorders were randomly allocated to receive one session of real or sham high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC in a double-blind procedure. Outcome measures included self-reported food craving immediately after the stimulation session and frequency of bingeing over a 24-hour follow-up period. Compared with sham control, real rTMS was associated with decreased self-reported urge to eat and fewer binge-eating episodes over the 24 hours following stimulation.",
"yes. These results provide physiological data consistent with impaired control of proactive inhibition over motor initiation in PD. Patients would be locked into a mode of control maintaining anticipated inhibition over willed movements even when the situation does not require action restraint. The functional and neurochemical bases of brain activity associated with executive settings need to be addressed thoroughly in future studies to better understand disabling symptoms that have few therapeutic options like akinesia.",
"no. The results negate that CASPR2 antibodies play a role in the pathogenesis of Tourette syndrome and do not support the assumption that anti-neuronal antibodies are involved.",
"Prepulse inhibition (PPI) of the startle reflex is modulated by a complex neural network. Prepulse inhibition impairments are found at all stages of schizophrenia. Previous magnetic resonance imaging (MRI) studies suggest that brain correlates of PPI differ between patients with schizophrenia and healthy controls; however, these studies included only patients with chronic illness and medicated patients. Our aim was to examine the structural brain correlates of PPI in antipsychotic-naive patients with first-episode schizophrenia. We performed acoustic PPI assessment and structural MRI (1.5 and 3 T) in men with first-episode schizophrenia and age-matched controls. Voxel-based morphometry was used to investigate the association between PPI and grey matter volumes. We included 27 patients and 38 controls in the study. Patients had lower PPI than controls. The brain areas in which PPI and grey matter volume correlated did not differ between the groups. Independent of group, PPI was significantly and positively associated with regional grey matter volume in the right superior parietal cortex. Prepulse inhibition and grey matter volume associations were also observed in the left rostral dorsal premotor cortex, the right presupplementary motor area and the anterior medial superior frontal gyrus bilaterally. Follow-up analyses suggested that the rostral dorsal premotor cortex and presupplementary motor area correlations were driven predominantly by the controls.",
"yes. Our study demonstrated a low remission rate for TS in a cohort of psychiatric and non-psychiatric patients seen in a movement disorder clinic after the offending agents were completely withdrawn. Such a finding has significant prognostic implications. It is possible that limitations of the retrospective design may have resulted in an underestimation. There is a clear need for prospective, multicenter, clinical trials in populations that can be safely withdrawn from dopamine receptor blocking agents so that true remission rates can be measured.",
"Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 × 10(-4) ). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found.",
"Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D1 and D2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain-dependent. Conversely, the role of D1 receptors in the regulation of PPI across different rat strains remains unclear. We tested the effects of selective D1 and D2 receptor agonists and antagonists on the startle reflex and PPI of Sprague-Dawley, Wistar and Long-Evans rats. In contrast with Sprague-Dawley and Wistar rats, the full D1 receptor agonist SKF82958 elicited significant PPI deficits in Long-Evans rats, an effect sensitive to the selective D1 antagonist SCH23390.",
"yes. Patients with schizophrenia demonstrate abnormal brain responses to rTMS applied to the premotor cortex that appear to relate to reduced motor cortical inhibition.",
"yes. Fine motor skill deficits may be a predictor of future tic severity and global psychosocial function in children with TS. We hypothesize that performance on the Purdue Pegboard test may serve as a useful endophenotype in the study of TS and provide a rough measure of the degree of basal ganglia dysfunction present in TS patients.",
"yes. This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.",
"yes. In ET, antagonist muscle responses to a torque pulse are similar to that in CbT. However, benefit from thalamic stimulation did not alter these EMG responses; therefore, suppression of tremor must be caused by mechanisms other than the re-establishment of normal agonist-antagonist timing.",
"To identify heritable symptom-based subtypes of Tourette syndrome (TS). Forty-nine motor and phonic tics were examined in 3,494 individuals (1,191 TS probands and 2,303 first-degree relatives). Item-level exploratory factor and latent class analyses (LCA) were used to identify tic-based subtypes. Heritabilities of the subtypes were estimated, and associations with clinical characteristics were examined. A 6-factor exploratory factor analysis model provided the best fit, which paralleled the somatotopic representation of the basal ganglia, distinguished simple from complex tics, and separated out socially disinhibited and compulsive tics. The 5-class LCA model best distinguished among the following groups: unaffected, simple tics, intermediate tics without social disinhibition, intermediate with social disinhibition, and high rates of all tic types. Across models, a phenotype characterized by high rates of social disinhibition emerged. This phenotype was associated with increased odds of comorbid psychiatric disorders, in particular, obsessive-compulsive disorder and attention-deficit/hyperactivity disorder, earlier age at TS onset, and increased tic severity. The heritability estimate for this phenotype based on the LCA was 0.53 (SE 0.08, p 1.7 × 10(-18)).",
"yes. Our results suggest that the level of prepulse inhibition is related to the efficiency of information processing in Parkinson's disease, and to the density of dopamine transporters in the striatum.",
"Although there is considerable support for the relationship between impulsivity and alcohol dependence, little is known about the impact of neurocognitive aspects of impulsivity on treatment outcome. The aim of this study was to prospectively investigate the impact of neurocognitive impulsivity at treatment onset on treatment completion. Forty-three alcohol-dependent patients entering inpatient treatment for alcohol dependence completed neurocognitive measures of impulsivity at the beginning of treatment. Assessments included prototypical measures of impulsive action (Go/No-go task [GNG] and Stop Signal Task [SST]) and impulsive choice (Delay Discounting Test [DDT], and Iowa Gambling Task). According to treatment outcomes, patients were divided into a patient group with regular treatment completion (e.g., with planned discharges, and without relapse during treatment) or irregular treatment course (e.g., premature and unplanned termination of treatment, \"dropout,\" and/or relapse). Results show that, relative to patients completing treatment in a regular fashion (regular treatment completers [RTC]; 67%), those with an irregular course of treatment (relapse and/or dropout) (irregular treatment completers [ITC]; 33%) had significantly poorer GNG response inhibition performance (p = 0.011), and showed a trend toward greater delay discounting (DDT; p = 0.052) at treatment onset. Additional logistic regression analyses identified poor GNG response inhibition performance as a significant predictor for an irregular treatment course (GNG: p = 0.021; DDT: p = 0.067), particularly for relapse (GNG: p = 0.023).",
"yes. Our findings extend current theories on the role of 5HT in behavioural inhibition by showing that reductions in serotonin lead to increased behavioural vigour only if there is a motivational drive to inhibit behaviour at baseline.",
"Doses of MPH based on the typical clinical titration procedure did not produce significantly more tics than the placebo in children with or without preexisting (mild to moderate) tics.",
"yes. Impulse control disorders are prevalent in patients with carcinoid syndrome. The serotonin production by the tumor possibly decreases the tryptophan pool in the cerebrospinal fluid, which is the essential substrate for the production of brain serotonin as a pivotal neurotransmitter.",
"To determine whether typical clinical doses of methylphenidate (MPH) cause tics or exacerbate preexisting mild to moderate tics. Ninety-one children with attention-deficit hyperactivity disorder, with and without comorbid tics (excluding severe tics and Tourette's syndrome), were randomly assigned to receive MPH or a placebo in a 1-year prospective study. The target dose was titrated to balance behavior change and side effects. Parents and teachers were the observers. Crossover from the placebo to MPH was common because of poor behavioral response. One MPH-treated subject dropped out; the final MPH group had 72 subjects; the placebo group, 18. The average dose of MPH was 0.5 mg/kg twice daily. Clinically significant tics developed in 19.6% of the subjects without preexisting tics receiving MPH and in 16.7% of those receiving the placebo (Fisher exact test, p = .59, not significant; relative risk = 1.17, confidence interval = 0.31-4.40). Deterioration of tics was observed in 33% of subjects with preexisting tics receiving MPH and in 33% of those receiving the placebo (Fisher exact test, p = .70, not significant; relative risk = 1.0, confidence interval = 0.40-1.85).",
"We have previously proposed that the therapeutic effect of transdermal nicotine in Tourette's syndrome may involve nicotinic receptor inactivation resulting from a prolonged continuous exposure to nicotine. In vitro studies with nicotine and preliminary positive experience with mecamylamine (Inversine), a nicotinic receptor antagonist, in the clinical treatment of Tourette's syndrome patients, further supports the receptor inactivation hypothesis. We retrospectively documented an unexpected therapeutic response to mecamylamine (2.5-7.5 mg/day) in two Tourette's syndrome patients who were subsequently found to have comorbid bipolar disorder as defined by DSM-IV criteria. In patient 1, the mood-stabilizing effect of mecamylamine was noticed by the patient during the course of mecamylamine treatment and brought to our attention, whereas for patient 2, manic symptoms were only apparent clinically following cessation of mecamylamine treatment.",
"In an earlier study comparing obsessive-compulsive disorder (OCD) patients to psychiatrically screened normals, we found lowered motor evoked potential (MEP) threshold to transcranial magnetic stimulation (TMS) and decreased intracortical inhibition in OCD. We sought to determine whether this pattern was specific to OCD. We measured the threshold and amplitude of MEPs to single and paired (subthreshold-suprathreshold; 3, 4, 10, 15 msec intervals) TMS in 46 healthy volunteers (23 women, 23 men) who were given the NEO-PI-R personality inventory. Nineteen of the men also received cognitive and motor tests. The paired-pulse conditioned/unconditioned MEP amplitude ratios correlated with Neuroticism (N), a stable measure of trait-level anxiety and other negative emotions, in the whole sample (r = 0.48; p = 0.0006), and in the men (r = 0.63; p = 0.0009). There were no other significant correlations.",
"Despite strong evidence that the pathophysiology of Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia and cortical frontal areas, findings from in vivo imaging studies have provided conflicting results. In this study we used whole brain diffusion tensor imaging (DTI) to investigate the microstructural integrity of white matter pathways and brain tissue in 19 unmedicated, adult, male patients with TS \"only\" (without comorbid psychiatric disorders) and 20 age- and sex-matched control subjects. Compared to normal controls, TS patients showed a decrease in the fractional anisotropy index (FA) bilaterally in the medial frontal gyrus, the pars opercularis of the left inferior frontal gyrus, the middle occipital gyrus, the right cingulate gyrus, and the medial premotor cortex. Increased apparent diffusion coefficient (ADC) maps were detected in the left cingulate gyrus, prefrontal areas, left precentral gyrus, and left putamen. There was a negative correlation between tic severity and FA values in the left superior frontal gyrus, medial frontal gyrus bilaterally, cingulate gyrus bilaterally, and ventral posterior lateral nucleus of the right thalamus, and a positive correlation in the body of the corpus callosum, left thalamus, right superior temporal gyrus, and left parahippocampal gyrus. There was also a positive correlation between regional ADC values and tic severity in the left cingulate gyrus, putamen bilaterally, medial frontal gyrus bilaterally, left precentral gyrus, and ventral anterior nucleus of the left thalamus.",
"The present study does not support a strong relationship between streptococcal infections and neuropsychiatric syndromes such as obsessive-compulsive disorder and Tourette syndrome. However, it is possible that a weak association (or a stronger association in a small susceptible subpopulation) was not detected due to nondifferential misclassification of exposure and limited statistical power. The data are consistent with previous reports of greater rates of diagnosis of Tourette syndrome or tics in white populations.",
"yes. As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary.",
"The goals of this prospective longitudinal study were to monitor levels of psychosocial stress in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared to healthy control subjects and to examine the relationship between measures of psychosocial stress and fluctuations in tic, obsessive-compulsive (OC), and depressive symptom severity. Consecutive ratings of tic, OC and depressive symptom severity were obtained for 45 cases and 41 matched healthy control subjects over a two-year period. Measures of psychosocial stress included youth self-report, parental report, and clinician ratings of long-term contextual threat. Structural equation modeling for unbalanced repeated measures was used to assess the temporal sequence of psychosocial stress with the severity of tic, OC and depressive symptoms. Subjects with TS and OCD experienced significantly more psychosocial stress than did the controls. Estimates of psychosocial stress were predictive of future depressive symptoms. Current levels of psychosocial stress were also a significant predictor of future OC symptom severity, but not vice versa. Current OC symptom severity was a predictor of future depressive symptom severity, but not vice versa. Current levels of psychosocial stress and depression were independent predictors of future tic severity, even after controlling for the effect of advancing chronological age.",
"Most children with Tourette's syndrome (TS) experience a significant decline in tic symptoms during adolescence. Currently no clinical measures have been identified that can predict whose tic symptoms will persist into adulthood. Patients with TS have deficits on neuropsychological tests involving fine-motor coordination and visual-motor integration. We seek to determine if these neuropsychological tests are useful in predicting future symptom severity. Thirty-two children, aged 8-14, with TS underwent clinical evaluation and a focused neuropsychological testing battery consisting of the Purdue Pegboard, Beery Visual-Motor Integration (VMI) Test and the Rey-Osterreith Complex Figure Task (RCFT). A follow-up clinical assessment was performed on these children an average of 7.5 years later. Ordinal logistic regression analysis was used to correlate neuropsychological testing at Time 1 with tic severity, OCD severity and global psychosocial functioning at Time 2. Poor performance with the dominant hand on the Purdue Pegboard test predicted worse adulthood tic severity and correlated with tic severity at the time of childhood assessment. Poor performance on the VMI and Purdue Pegboard tests (both dominant and non-dominant hand) also predicted worse adulthood global psychosocial functioning. None of the neuropsychological tests were useful in predicting the future course of OCD symptoms in TS patients.",
"Patients with childhood-onset obsessive-compulsive disorder or Tourette's syndrome had significantly greater B cell D8/17 expression than comparison subjects despite the absence of documented Sydenham's chorea or rheumatic fever. These findings suggest that D8/17 may serve as a marker for susceptibility among some forms of childhood-onset obsessive-compulsive disorder and Tourette's syndrome, as well as rheumatic fever or Sydenham's chorea.",
"Tourette syndrome (TS) is characterized by a wide phenotypic polymorphism and this heterogeneity is due partly to the association with several neuropsychiatry disorders. These comorbidities are showed in the 90% of TS cases. The aim of this transversal study is to analyze the presence and prevalence of different psychopathological conditions that could be expressed with tic disorder (TD) and specifically in TS. We examined a sample of 102 patients, between 7 and 17.6 years old, with a diagnosis DSM-IV-TR of TD, using the self-report SAFA. Different correlations between these comorbidities and clinical variables are also analyzed. Our data underlined most of all a prevalence of anxiety disorders in the 31.4% of our patients with TD, of depression in the 27.44%, and of somatization symptoms in the 22.54%.",
"To summarize the current data suggesting that Gilles de la Tourette syndrome (GTS) is inherited and genetic. The extant literature on family studies, segregation analyses, candidate genes studies and linkage studies of GTS was reviewed and summarized.",
"yes. Although originally devised to assess urges to tic in young patients with TS, the PUTS demonstrated good psychometric properties in a large sample of adults recruited at specialist TS clinics. This instrument is therefore recommended for use across the life span as a valid and reliable self-report measure of sensory experiences accompanying tic expression.",
"yes. Our results confirm prior studies suggesting that tics are caused by alterations in prefrontal areas, thalamus and putamen, while changes in the cingulate gyrus seem to reflect secondary compensatory mechanisms. Due to the study design, influences from comorbidities, gender, medication and age can be excluded.",
"A causal relationship of common streptococcal infections and childhood neuropsychiatric disorders has been postulated. To test the hypothesis of an increased rate of streptococcal infections preceding the onset of neuropsychiatric disorders. Case-control study of a large primary care database comparing the rate of possible streptococcal infections in patients aged 2-25 years with obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and tics with that in controls matched for age, gender, and practice (20 per case). We also examined the influence of sociodemographic factors. There was no overall increased risk of prior possible streptococcal infection in patients with a diagnosis of OCD, TS, or tics. Subgroup analysis showed that patients with OCD had a slightly higher risk than controls of having had possible streptococcal infections without prescription of antibiotics in the 2 years prior to the onset of OCD (odds ratio 2.59, 95% confidence interval 1.18, 5.69; p = 0.02). Cases with TS or tics were not more likely to come from more affluent or urban areas, but more cases lived in areas with a greater proportion of white population (p value for trend = 0.05).",
"yes. Caudate volumes in children with Tourette syndrome predict the severity of tic and obsessive-compulsive symptoms in early adulthood. This study provides compelling evidence that morphologic disturbances of the caudate nucleus within cortico-striatal-thalamo-cortical circuits are central to the persistence of both tics and obsessive-compulsive symptoms into adulthood.",
"yes. We suggest that clonidine's effect on inhibitory as opposed to excitatory learning could be related to reduced noradrenergic activity. In terms of clinical implications for TS, impaired conditioned inhibition could reduce the ability of susceptible individuals to learn to control tics in the presence of associative triggers.",
"Prior research has indicated a number of neuropsychological deficits in patients with OCD consistent with the cortico-striato-thalamo-cortical model of the disorder. Response inhibition (RI), defined as the inability to inhibit a prepotent response, has been identified as a possible candidate endophenotype for OCD. However, the results from previous studies of RI in OCD patients have been mixed, suggesting the possibility that some OCD dimensions may be associated with deficits in RI while others may not. The present study aimed to examine RI using a Go/No-Go (GNG) task in two OCD symptom dimensions, one of which, scrupulosity, has never been subject to neuropsychological investigation. A total of 63 individuals, consisting of scrupulous OCD (n = 26), contamination OCD (n = 18) and non-psychiatric controls (n = 19) completed study measures. Controlling for depression symptoms, no significant performance differences were found between the groups on the GNG test, indicating no deficits in RI among contamination or scrupulous OCD. Results are consistent with several prior studies of RI in OCD that found no differences as compared to non-psychiatric controls, especially on GNG tests, and with more recent suggestions that RI may not constitute a clinical significant impaired domain in OCD.",
"The D1CT-7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic-like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT-7 mice to two critical components of TS pathophysiology: the exacerbation of tic-like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics. D1CT-7 and wild-type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic-like behaviours and other spontaneous responses were measured. SC-exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS-related behaviours, including open-field locomotion, novel object exploration and social interaction and compared with non-confined counterparts. SC produced a marked increase in corticosterone concentrations in both D1CT-7 and WT mice. In D1CT-7, but not WT mice, SC exacerbated tic-like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT-7 mice. Both tic-like behaviours and PPI impairments in SC-exposed D1CT-7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism.",
"Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics. Deficient motor inhibition underlying tics is one of the main hypotheses in its pathophysiology. Therefore the question arises whether this supposed deficient motor inhibition affects also voluntary movements. Despite severe motor tics, different personalities who suffer from Tourette perform successfully as neurosurgeon, pilot or professional basketball player. For the investigation of fine motor skills we conducted a motor performance test battery in an adult Tourette sample and an age matched group of healthy controls. The Tourette patients showed a significant lower performance in the categories steadiness of both hands and aiming of the right hand in comparison to the healthy controls. A comparison of patients' subgroup without comorbidities or medication and healthy controls revealed a significant difference in the category steadiness of the right hand.",
"yes. Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area.",
"Several measures of motor cortex excitability are abnormal in Gilles de la Tourette syndrome (GTS). However, it is not clear whether these represent abnormalities of specific pathways or reflect a more widespread reduction of motor cortex excitability. Their significance for the clinical phenotype is also unknown. We measured motor thresholds, input-output (I/O) curves, short interval intracortical inhibition (SICI), and cortical silent period (SP) with transcranial magnetic stimulation in 20 untreated GTS patients (12 uncomplicated, 4 with comorbid attention-deficit/hyperactivity disorder, 4 with comorbid obsessive-compulsive disorder) and 24 healthy subjects. Tics were rated with standard clinical scales and detailed video analysis. Thresholds did not differ between groups. At rest, patients had shallower I/O curve slopes, despite their tics, and reduced SICI. Slopes were equal during voluntary muscle activation, as was the SP duration. Resting I/O slopes correlated, in uncomplicated GTS patients, most strongly to ratings of complex tics, hand and finger tics, and vocal tics, with shallower slopes predicting fewer tics. In complicated patients, good correlations were seen with neck/shoulder tics and vocal tics.",
"We examined the inhibition of stimulus-stimulus associations (formally 'conditioned inhibition') in Tourette syndrome (TS). The present study used video game style conditioned inhibition procedures suitable for children and adolescents. We tested 15 participants with a clinical diagnosis of TS in the absence of co-morbid attention deficit hyperactivity disorder and compared them with 19 typically developing age and sex matched controls (both groups aged 10-20 years). All children were tested for inhibition by summation test using two test stimuli in each of two conditioned inhibition tasks. TS participants showed overall normal inhibition of stimulus-stimulus associations, and there was no correlation between inhibitory learning scores and symptom severity ratings. However, there was a clear reduction in conditioned inhibition in 7 TS participants medicated with clonidine. There was no significant effect of medication on excitatory learning of the stimulus-stimulus associations.",
"Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy.",
"yes. The observed relationship between severity of premonitory urges and interoceptive awareness suggests that interoception might be involved in self-reported premonitory urges in GTS. High levels of interoceptive awareness might reflect a self-attentive capacity to perceive urges.",
"Tics in Gilles de la Tourette syndrome (GTS) are repetitive patterned movements, resembling spontaneous motor behaviour, but escaping voluntary control. Previous studies hypothesised relations between structural alterations in prefrontal cortex of GTS adults and tic severity using voxel-based morphometry (VBM), but could not demonstrate a significant association. The relation between prefrontal cortex structure and tic inhibition has not been investigated. Here, we used VBM to examine 14 GTS adults without associated comorbidities, and 15 healthy controls. We related structural alterations in GTS to clinical measures of tic severity and tic control. Grey matter volumes in the right inferior frontal gyrus and the left frontal pole were reduced in patients relative to healthy controls. These changes were not related to tic severity and tic inhibition.",
"yes. In adults with TS, there is no tic rebound after voluntary tic suppression. Patients also reported no rebound, but erroneously felt a tic reduction in the later course of the study. This misjudgement as well as patients' often reported (mis-)belief of a tic rebound may be caused by overall difficulties in reliable tic rating. Premonitory urges remained unchanged during tic suppression. Tic suppression was not influenced by attention deficits. Premonitory urges are no prerequisite of tic suppression.",
"While in clinical interviews the vast majority of patients with Tourette syndrome (TS) report about a tic rebound after voluntary tic suppression, in recent studies in children no paradoxical tic increase could be found. We hypothesized that in adult patients there is a tic rebound after tic suppression. We investigated the tic severity, premonitory urges and influence of attention deficit hyperactivity disorder (ADHD) before, during and after tic suppression in 22 adult patients with TS using both an objective video tic rating and subjective patient ratings for tics and premonitory urges. According to the video rating, tic suppression resulted in a significant tic reduction, but no rebound. Patients also reported no tic rebound. They erroneously believed in an absolute tic reduction 20 and 30 min after suppression, but paradoxically felt no relative tic change. Premonitory urges remained unchanged. There was no correlation between premonitory urges and tic severity. The potency for tic inhibition did not correlate with premonitory urges and tic severity. ADHD did not influence tic inhibition.",
"Patients with Tourette syndrome (TS) often report characteristic sensory experiences, also called premonitory urges (PUs), which precede tic expression and have high diagnostic relevance. This study investigated the usefulness of a scale developed and validated in children and adolescents-the Premonitory Urge for Tics Scale (PUTS, Woods et al., 2005 [13])-for the assessment of PUs in adult patients with TS. Standard statistical methods were applied to test the psychometric properties of the PUTS in 102 adult TS outpatients recruited from two specialist clinics in the United Kingdom. The PUTS showed good acceptability and endorsement rates, with evenly distributed scores and low floor and ceiling effects. Item-total correlations were moderate to strong; PUTS total scores were significantly correlated with quantitative measures of TS severity. The PUTS showed excellent internal consistency reliability (Cronbach's alpha=0.85) and Spearman's correlations demonstrated satisfactory convergent and discriminant validity.",
"Urges and tic inhibition are not directly related. There seem to exist at least two distinct neurophysiological systems of urge/tic generation and tic control in adult Gilles de la Tourette syndrome patients.",
"A contribution of aberrant interoceptive awareness to the perception of premonitory urges in Gilles de la Tourette syndrome (GTS) has been hypothesized. We assessed interoceptive awareness in 19 adults with GTS and 25 age-matched healthy controls using the heartbeat counting task. We also used multiple regression to explore whether the severity of premonitory urges was predicted by interoceptive awareness or severity of tics and obsessive-compulsive symptoms. We observed lower interoceptive awareness in GTS compared with controls. Interoceptive awareness was the strongest predictor of premonitory urges in GTS, with greater interoceptive awareness being associated with more urges. Greater tic severity was also associated with higher rates of premonitory urges.",
"Despite the common notion that premonitory urges facilitate tic inhibition, no studies have investigated this question systematically. We examined the relation of the trait of premonitory urges with tics and tic suppression. We hypothesised that patients with more urges would be more efficient at inhibiting tics. 15 adult (14 men, mean age 32.2±7.9 years) pure Gilles de la Tourette syndrome patients participated. Tic severity was evaluated using the modified Rush Video Scale and by employing the Yale Global Tic Severity Scale. Tic suppressibility was assessed from videos of additional periods where patients were instructed to maximally suppress their tics. Rush score based inhibition potency was synthesised by combining the scores in the two conditions. A measure of pure motor tic inhibition potency was also generated based on the number of motor tics alone. Premonitory urges were assessed by the Premonitory Urge for Tics Scale. All participants reported urges preceding their tics and were able to voluntarily suppress their tics. However, there was no correlation between urge scores and the Rush score based inhibition potency or the pure motor tic inhibition potency. Scores of the Premonitory Urge for Tics Scale correlated with the interference subscale item of the Yale Global Tic Severity Scale."
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Does deep brain stimulation induce striatal dopamine release in obsessive-compulsive disorder? | ["Obsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminer(...TRUNCATED) | ["Whereas apathy is known as a common consequence of subthalamic nucleus deep brain stimulation in P(...TRUNCATED) | 0 |
"Does behavior therapy augment response of patients with obsessive-compulsive disorder responding to(...TRUNCATED) | ["In many patients with obsessive-compulsive disorder (OCD), residual symptoms persist despite a cli(...TRUNCATED) | ["yes. Cognitive-behavioral therapy can alleviate psychological symptoms in elderly patients with an(...TRUNCATED) | 0 |
"Are stressful life events at onset of obsessive-compulsive disorder associated with a distinct clin(...TRUNCATED) | ["Environmental stressors are considered to play an important role in the triggering of mental disor(...TRUNCATED) | ["Traumatic exposure may modulate the expression of impulsive behavioral dispositions and change the(...TRUNCATED) | 0 |
"Are obsessive-compulsive tendencies and undermined confidence related to reliance on proxies for in(...TRUNCATED) | ["We have previously hypothesized that obsessive-compulsive (OC) tendencies are associated with a ge(...TRUNCATED) | ["yes. The present data suggest that high anxiety predisposes rats to lose control over cocaine-but (...TRUNCATED) | 0 |
Impulsivity in anxiety disorder patients: is it related to comorbid cyclothymia? | ["The relationship between anxiety and impulsivity is controversial and not well explored. In a prev(...TRUNCATED) | ["The inferior frontal cortical (IFC)-striatal network plays an integral role in response inhibition(...TRUNCATED) | 0 |
Does genome-wide linkage analysis of obsessive-compulsive disorder implicate chromosome 1p36? | ["Obsessive-compulsive disorder (OCD) has a complex etiology involving both genetic and environmenta(...TRUNCATED) | ["yes. The genetic regions 3q26-27 and 2q34-37 might contain susceptibility genes for CHD. Linkage t(...TRUNCATED) | 0 |
"Are obsessive compulsive symptoms associated with better functioning independently of cognition in (...TRUNCATED) | ["Although the relationship of obsessive-compulsive symptoms (OCSs) with both cognition and social f(...TRUNCATED) | ["Psychosis is hypothesized to occur on a spectrum between psychotic disorders and healthy individua(...TRUNCATED) | 0 |
"B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder a(...TRUNCATED) | ["It has been hypothesized that Sydenham's chorea, a major manifestation of rheumatic fever, may pro(...TRUNCATED) | ["To evaluate associations between attention-deficit/hyperactivity disorder (ADHD) and comorbid psyc(...TRUNCATED) | 0 |
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