Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Co-occurrence of attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) is very frequent in the pediatric population as well as the presence of an impairment of the executive functions. The aim of our study was to investigate motor timing, that is, the temporal organization of motor behavior, in a pediatric population of Tourette patients. Thirty-seven Tourette patients (divided in 22 "pure" Tourette patients and 15 with ADHD) were compared with 22 healthy age- and gender-matched subjects. All subjects underwent a neuropsychiatric screening and were tested for their planning and decision-making abilities by using a standardized test, such as Tower of London (ToL). Two experimental paradigms were adopted: finger-tapping test (FTT), a free motor tapping task, and synchronization-continuation task. An accuracy index was calculated as measure of ability of synchronization. We found that "pure" TS as well as TS+ADHD showed lower scores in the FTT for the dominant and non-dominant hands than controls. Moreover, in the synchronization and continuation test, we observed an overall lack of accuracy in both TS groups in the continuation phase for 2,000 ms (supra-second interval), interestingly, with opposite direction of accuracy index. Thus, "pure" TS patients were classified as "behind the beat," whereas, TS+ADHD as "ahead of the beat." The performance in the finger tapping was inversely correlated to ToL total scores and execution time, whereas we did not find any correlation with the accuracy index of the synchronization and continuation test. In conclusion, here, we explored motor timing ability in a childhood cohort of Tourette patients, confirming that patients exhibit an impaired temporal control of motor behavior and these findings may be explained by the common underlying neurobiology of TS and motor timing.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Tourette syndrome is characterized by 'unvoluntary' tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. Although tic suppression in Tourette syndrome also engages the inferior frontal gyrus, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during functional MRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withhold responses to NoGo cues, and decide whether to press or withhold to 'Choose' cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus, thalamus and primary motor cortex. In Tourette syndrome, activity was elevated in the inferior frontal gyrus, insula and basal ganglia, most notably within the right inferior frontal gyrus during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this inferior frontal gyrus hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the pre-supplementary motor area to the caudate nucleus, globus pallidus and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater inferior frontal gyrus engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia.

Genetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS.

Recently, a genome-wide association study has indicated associations between single nucleotide polymorphisms in the Collagen Type XXVII Alpha 1 gene (COL27A1) and Tourette syndrome in several ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of Tourette syndrome, the associations between polymorphisms in COL27A1 and Tourette syndrome were assessed in Chinese trios. PCR-directed sequencing was used to evaluate the genetic contributions of three SNPs in COL27A1(rs4979356, rs4979357 and rs7868992) using haplotype relative risk (HRR) and transmission disequilibrium tests (TDT) with a total of 260 Tourette syndrome trios. The family-based association was significant between Tourette syndrome and rs4979356 (TDT: χ2 = 4.804, P = 0.033; HRR = 1.75, P = 0.002; HHRR = 1.32, P = 0.027), and transmission disequilibrium was suspected for rs4979357 (TDT: χ2 = 3.969, P = 0.053; HRR = 1.84, P = 0.001; HHRR = 1.29, P = 0.044). No statistically significant allele transfer was found for rs7868992 (TDT: χ2 = 2.177, P = 0.158). Although the TDT results did not remain significant after applying the conservative Bonferroni correction (p = 0.005), the significant positive HRR analysis confirmed the possibility of showing transmission disequilibrium, which provides evidence for an involvement of COL27A1in the development of TS. However, these results need to be verified with larger datasets from different populations.

Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Tourette syndrome (TS) is a complex neuropsychiatric disorder with chronic motor and vocal tics. Though the etiology is elusive, strong evidence for a genetic contribution to TS has been established. To date, various chromosomal or genetic alterations have been implicated in its pathogenesis. Recently, the deletion in the arylacetamide deacetylase gene (AADAC) was reported to be associated with TS. To investigate the association between the AADAC gene variants and TS, we conducted genetic analysis of the AADAC gene in 200 Han Chinese patients and 300 ethnicity-matched normal controls. Two variants, including a heterozygous splice-site variant, c.361 + 1G > A (rs762169706), and a missense variant, c.744A > T (p.R248S, rs186388618), were identified in two unrelated patients. The c.361 + 1G > A variant, absent in 300 ethnicity-matched controls, led to the deletion of exon 2 in AADAC mRNA, probably associated with development of TS. The c.744A > T variant, predicted to be damaging, was identified in two normal controls. The findings indicate that the AADAC gene c.361 + 1G > A variant may be a potential candidate factor for TS development, though further investigations are warranted.

Globus pallidus interna (GPi) is an effective deep brain stimulation site for the treatment of Tourette syndrome (TS), and plays a crucial role in the pathophysiology of TS. To investigate the functional network feature of GPi in TS patients, we retrospectively studied 24 boys with 'pure' TS and 32 age-/education-matched healthy boys by resting state functional magnetic resonance images. Amplitude of low-frequency fluctuation (ALFF) and functional connectivity were used to estimate the local activity in GPi and its functional coordinate with the whole brain regions, respectively. We found decreased ALFF in patients' bilateral GPi, which was also negatively correlated with clinical symptoms. Functional connectivity analysis indicated abnormal regions within motor and motor-control networks in patients (inferior part of sensorimotor area, cerebellum, prefrontal cortex, cingulate gyrus, caudate nucleus, and brain stem). Transcranial magnetic stimulation sites defined by previous studies ("hand knob" area, premotor area, and supplementary motor area) did not show significantly different functional connectivity with GPi between groups. In summary, this study characterized the disrupted functional network of GPi and provided potential regions-of-interest for further basic and clinical studies on TS.

Background: Several lines of evidence support the hypothesis of an autoimmune origin of Gilles de la Tourette-Syndrome (GTS). Accordingly, in a recent study we detected positive oligoclonal bands (OCB) in cerebrospinal fluid (CSF) in >30% of adult patients indicating an intrathecal antibody synthesis. However, until today no corresponding antibodies could be identified. The aims of this study were to replicate our findings of positive OCB in an independent sample and to detect CSF autoantibodies. Methods: In this prospective study, 20 adult patients with GTS (male: female = 18:2, median age 36.1 years ± 14.34 SD) were included. All patients were thoroughly clinically characterized. Magnetic Resonance Imaging (MRI) and CSF standard measurements were performed. Isoelectric focusing on polyacrylamide gels with silver staining was used to detect OCB. To examine specific and unspecified autoantibodies, we used transfected Human Embryonic Kidney (HEK) cells expressing different surface antigens (NMDA-, CASPR2-, LGI1-, AMPA-, or GABAB1/B), indirect immunofluorescence on different brain tissue sections, and enzyme-linked visualization. Additionally, we differentiated Glioma stem cells SY5Y (human neuroblastoma) using retinoic acid and astrocytes (rat). Results: CSF analyses showed positive OCB (type 2) in 4/20 patients (20%). Using transfected HEK cells we did not find specific surface-autoantibodies. Immunohistochemistry on tissue-sections, SY5Y Glioma stem-cells, and astrocytes showed no specific binding patterns either. Conclusions: Our results corroborate previous findings and demonstrate positive OCB in a substantial number of patients with GTS (prevalence in healthy controls: 5%). Although this is the largest study investigating CSF autoantibodies in GTS using several techniques, we failed to detect any specific or unspecified autoantibodies.

Food avoidant behaviours are common concerns amongst individuals with Tourette syndrome, with high levels of food selectivity reported in children and food neophobia and avoidant restrictive eating behaviours in adults. However, less is known about food approach behaviours. The current study aimed to explore differences in food approach and food avoidant eating behaviours in children with Tourette syndrome (TS) and their relationship to caregiver mealtime actions. Thirty-seven caregivers of children with Tourette syndrome were compared with children with Autism Spectrum Disorders, children with Attention-Deficit/Hyperactivity Disorder and a control group. Caregivers completed the Child Eating Behaviour Questionnaire and Parent Mealtime Action Scale-Revised. Caregiver-reported findings revealed that children with Tourette syndrome exhibited more food approach behaviours, specifically greater food responsiveness, emotional overeating and desire to drink, compared to controls. Children from the three neurodiverse groups had similar levels of emotional overeating and food selectivity, which were all significantly higher than the control group. Positive persuasion was uniquely identified as a mealtime strategy adopted by caregivers of children with Tourette syndrome. The results suggest that children with Tourette syndrome are at more risk of showing a broader array of food difficulties than previously reported, including food avoidant and approach behaviours. It is encouraged that clinicians monitor eating behaviour in appointments with children with Tourette syndrome.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region. To identify the risk gene within the region we studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. We genotyped eight markers across the gene and observed biased transmission of haplotypes from parents to probands in this sample. We then tested these markers in an independent sample of 242 nuclear families with ADHD and found the same haplotype was significantly over transmitted to ADHD probands. Screening of the coding region of KCNJ5 in 48 probands with TS did not identify any variation that could explain the association of the haplotype. We also genotyped two microsatellite markers, one in the promoter and the other in the 3' region and found no evidence for association for either marker for TS, however, we found significant evidence for association with the 3' repeat and ADHD. A small gene (c11orf45) of unknown function lies within the first intron of KCNJ5 that is transcribed in the opposite orientation and this gene may regulate the expression of KCNJ5. We studied the correlation of the expression of KCNJ5 and the antisense transcript in brain tissues from control individuals and found that the antisense transcript and the short KCNJ5 isoform are co-expressed in three brain regions. The results of this study indicate that KCNJ5 is associated with TS and ADHD in our samples, however, the functional variant(s) remain to be identified.

Tourette syndrome (TS) is a heritable disorder characterized by tics that are decreased in some patients by treatment with alpha adrenergic agonists and dopamine receptor blockers. Thus, this study examines the relationship between catecholamine gene expression in blood and tic severity. TS diagnosis was confirmed using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria and tic severity measured using the Yale Global Tic Severity Scale (YGTSS) for 26 un-medicated subjects with TS. Whole blood was collected and Ribonucleic acid (RNA) processed on Affymetrix Human Exon 1.0 ST arrays. An Analysis of Covariance (ANCOVA) identified 3627 genes correlated with tic severity (p<0.05). Searches of Medical Subject Headings, Gene Ontology, Allen Mouse Brain Atlas, and PubMed determined genes associated with catecholamines and located in the basal ganglia. Using GeneCards, PubMed, and manual curation, seven genes associated with TS were further examined: DRD2, HRH3, MAOB, BDNF, SNAP25, SLC6A4, and SLC22A3. These genes are highly associated with TS and have also been implicated in other movement disorders, Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD). Correlation of gene expression in peripheral blood with tic severity may allow inferences about catecholamine pathway dysfunction in TS subjects. Findings built on previous work suggest that at least some genes expressed peripherally are relevant for central nervous system (CNS) pathology in the brain of individuals with TS.

Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS.

The exact pathophysiology of TS is still elusive. Previous studies have identified default mode networks (DMN) abnormalities in patients with TS. However, these literatures investigated the neural activity during the tic suppression, not a true resting-state. Therefore, this study aimed to reveal the neural mechanism of Tourette's syndrome (TS) from the perspective of topological organization and functional connectivity within the DMN by electroencephalography (EEG) in resting-state.

Gilles de la Tourette syndrome is a childhood-onset syndrome characterized by the presence and persistence of motor and vocal tics. A dysfunction of cortico-striato-pallido-thalamo-cortical networks in this syndrome has been supported by convergent data from neuro-pathological, electrophysiological as well as structural and functional neuroimaging studies. Here, we addressed the question of structural integration of cortico-striato-pallido-thalamo-cortical networks in Gilles de la Tourette syndrome. We specifically tested the hypothesis that deviant brain development in Gilles de la Tourette syndrome could affect structural connectivity within the input and output basal ganglia structures and thalamus. To this aim, we acquired data on 49 adult patients and 28 gender and age-matched control subjects on a 3 T magnetic resonance imaging scanner. We used and further implemented streamline probabilistic tractography algorithms that allowed us to quantify the structural integration of cortico-striato-pallido-thalamo-cortical networks. To further investigate the microstructure of white matter in patients with Gilles de la Tourette syndrome, we also evaluated fractional anisotropy and radial diffusivity in these pathways, which are both sensitive to axonal package and to myelin ensheathment. In patients with Gilles de la Tourette syndrome compared to control subjects, we found white matter abnormalities in neuronal pathways connecting the cerebral cortex, the basal ganglia and the thalamus. Specifically, striatum and thalamus had abnormally enhanced structural connectivity with primary motor and sensory cortices, as well as paracentral lobule, supplementary motor area and parietal cortices. This enhanced connectivity of motor cortex positively correlated with severity of tics measured by the Yale Global Tics Severity Scale and was not influenced by current medication status, age or gender of patients. Independently of the severity of tics, lateral and medial orbito-frontal cortex, inferior frontal, temporo-parietal junction, medial temporal and frontal pole also had enhanced structural connectivity with the striatum and thalamus in patients with Gilles de la Tourette syndrome. In addition, the cortico-striatal pathways were characterized by elevated fractional anisotropy and diminished radial diffusivity, suggesting microstructural axonal abnormalities of white matter in Gilles de la Tourette syndrome. These changes were more prominent in females with Gilles de la Tourette syndrome compared to males and were not related to the current medication status. Taken together, our data showed widespread structural abnormalities in cortico-striato-pallido-thalamic white matter pathways in patients with Gilles de la Tourette, which likely result from abnormal brain development in this syndrome.

Tourette syndrome (TS) is a childhood-onset neuro-developmental disorder and the genetic factors play an important role in its etiology. As pericentrin (PCNT) binds to disruption-in-schizophrenia 1 (DISC1) and is a risk factor for many mental illnesses, we aimed to investigate the effect of PCNT on TS in the Chinese Han population.

Little is known about the brain's functional organization during resting-state in children with Tourette syndrome (TS). We aimed to investigate this with a specific focus on the role of comorbid attention-deficit/hyperactivity disorder (ADHD). We applied graph theoretical analysis to resting-state functional magnetic resonance imaging data of 109 8-to-12-year-old children with TS (n = 46), ADHD without tics (n = 23), and healthy controls (n = 40). First, we compared these three groups, and in a second comparison four groups, distinguishing TS with (TS + ADHD, n = 19) and without comorbid ADHD (TS-ADHD, n = 27). Weighted brain graphs were constructed for both comparisons to investigate global efficiency, local efficiency, and clustering coefficient per acquired network. Local efficiency and clustering coefficient were significantly lower in children with TS-ADHD in the default mode network compared with healthy controls, and in the frontoparietal network compared with ADHD; we also found associations with higher tic severity. Our study supports a different functional brain network organization in children with TS-ADHD, compared with healthy controls and children with ADHD.