Diffusion indices alteration in major white matter tracts of children with tic disorder using TRACULA.

BACKGROUND: Tic disorder is a neuropsychiatric disorder characterized by involuntary movements or vocalizations. Previous studies utilizing diffusion-weighted imaging to explore white-matter alterations in tic disorders have reported inconsistent results regarding the affected tracts. We aimed to address this gap by employing a novel tractography technique for more detailed analysis. METHODS: We analyzed MRI data from 23 children with tic disorders and 23 healthy controls using TRActs Constrained by UnderLying Anatomy (TRACULA), an advanced automated probabilistic tractography method. We examined fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity, and mean diffusivity in 42 specific significant white matter tracts. RESULTS: Our findings revealed notable differences in the children with tic disorders compared to the control group. Specifically, there was a significant reduction in FA in the parietal part and splenium of the corpus callosum and the left corticospinal tract. Increased RD was observed in the temporal and splenium areas of the corpus callosum, the left corticospinal tract, and the left acoustic radiation. A higher mean diffusivity was also noted in the left middle longitudinal fasciculus. A significant correlation emerged between the severity of motor symptoms, measured by the Yale Global Tic Severity Scale, and FA in the parietal part of the corpus callosum, as well as RD in the left acoustic radiation. CONCLUSION: These results indicate a pattern of reduced interhemispheric connectivity in the corpus callosum, aligning with previous studies and novel findings in the diffusion indices changes in the left corticospinal tract, left acoustic radiation, and left middle longitudinal fasciculus. Tic disorders might involve structural abnormalities in key white matter tracts, offering new insights into their pathogenesis.

Transcranial sonography of subcortical structures in tic/tourette disorder.

Functional neuroimaging studies demonstrate disinhibition of the cortico-striatal-thalamo-cortical circuit. However, structural imaging studies revealed conflicting results, some suggesting smaller volumes of the caudate nucleus (CN) in children with Gilles de la Tourette syndrome (TS). Here we wanted to find out whether transcranial sonography (TCS) detects alterations of raphe nuclei, substantia nigra, lenticular nucleus (LN), or CN in children with Tic disorder or TS (TIC/TS).The study included 25 treatment-naive children (age: 12.2 ± 2.5 years) with a DSM-V based diagnosis of Tic disorder or TS (10 subjects), without other psychiatric or neurologic diagnosis, and 25 healthy controls (age: 12.17 ± 2.57 years), matched for age and sex. Parental rating of behavioral, emotional abnormalities, somatic complaints and social competencies of the participants were assessed using the Child Behavior Check List (CBCL/4-18R). TCS of deep brain structures was conducted through the preauricular acoustic bone windows using a 2.5-MHz phased-array ultrasound system. Fisher's exact test and Mann-Whitney-U test were used for comparisons between TIC/TS patients and healthy volunteers. The number of participants with hyperechogenic area of left CN in the TIC/TS sample was increased, compared to the healthy control group. TIC/TS patients with hyperechogenic CN showed an increased occurrence of thought- and obsessive-compulsive problems. This TCS study revealed pathologic structural changes in CN, its higher occurrence in TIC/TS compared to healthy controls and the relation to comorbidity of thought problems. Further research should focus on the molecular cause of these alterations, probably the disturbed iron metabolism.

Aberrant Functional Connectivity of the Salience Network in Adult Patients with Tic Disorders: A Resting-State fMRI Study.

Tic disorders (TD) are characterized by the presence of motor and/or vocal tics. Common neurophysiological frameworks suggest dysregulations of the cortico-striatal-thalamo-cortical (CSTC) brain circuit that controls movement execution. Besides common tics, there are other "non-tic" symptoms that are primarily related to sensory perception, sensorimotor integration, attention, and social cognition. The existence of these symptoms, the sensory tic triggers, and the modifying effect of attention and cognitive control mechanisms on tics may indicate the salience network's (SN) involvement in the neurophysiology of TD. Resting-state functional MRI measurements were performed in 26 participants with TD and 25 healthy controls (HC). The group differences in resting-state functional connectivity patterns were measured based on seed-to-voxel connectivity analyses. Compared to HC, patients with TD exhibited altered connectivity between the core regions of the SN (insula, anterior cingulate cortex, and temporoparietal junction) and sensory, associative, and motor-related cortices. Furthermore, connectivity changes were observed in relation to the severity of tics in the TD group. The SN, particularly the insula, is likely to be an important site of dysregulation in TD. Our results provide evidence for large-scale neural deviations in TD beyond the CSTC pathologies. These findings may be relevant for developing treatment targets.

Rapid Compensation for Noisy Voluntary Movements in Adults with Primary Tic Disorders.

BACKGROUND: It has been proposed that tics and premonitory urges in primary tic disorders (PTD), like Tourette syndrome, are a manifestation of sensorimotor noise. However, patients with tics show no obvious movement imprecision in everyday life. One reason could be that patients have strategies to compensate for noise that disrupts performance (ie, noise that is task-relevant). OBJECTIVES: Our goal was to unmask effects of elevated sensorimotor noise on the variability of voluntary movements in patients with PTD. METHODS: We tested 30 adult patients with PTD (23 male) and 30 matched controls in a reaching task designed to unmask latent noise. Subjects reached to targets whose shape allowed for variability either in movement direction or extent. This enabled us to decompose variability into task-relevant versus less task-relevant components, where the latter should be less affected by compensatory strategies than the former. In alternating blocks, the task-relevant target dimension switched, allowing us to explore the temporal dynamics with which participants adjusted movement variability to changes in task demands. RESULTS: Both groups accurately reached to targets, and adjusted movement precision based on target shape. However, when task-relevant dimensions of the target changed, patients initially produced movements that were more variable than controls, before regaining precision after several reaches. This effect persisted across repeated changes in the task-relevant dimension across the experiment, and therefore did not reflect an effect of novelty, or differences in learning. CONCLUSIONS: Our results suggest that patients with PTD generate noisier voluntary movements compared with controls, but rapidly compensate according to current task demands. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Symptom Severity and Health Impacts of Functional Tic-Like Behaviors in Youth.

BACKGROUND: We performed this study to improve understanding of the relationship between functional tic-like behaviors (FTLBs) and quality of life, loneliness, family functioning, anxiety, depression, and suicidality. METHOD: This cross-sectional study assessed self-reported quality of life, disability, loneliness, depression, anxiety, family functioning, tic severity, and suicide risk in age- and birth-sex matched youth with FTLBs, Tourette syndrome (TS), and neurotypical controls. We performed specific subanalyses comparing individuals with FTLBs who identified as transgender/gender diverse (TGD) with cisgender individuals. RESULTS: Eighty-two youth participated (age range 11 to 25, 90% female at birth), including 35 with FTLBs, 22 with TS, and 25 neurotypical controls. A significantly higher proportion of participants with FTLB identified as TGD (15 of 35) than TS (two of 22) and neurotypical control (three of 25) participants. Compared with neurotypical controls, individuals with FTLBs had significantly lower quality of life, greater disability, loneliness, social phobia, anxiety symptoms, depressive symptoms, and suicidality. Compared with individuals with TS, individuals with FTLBs had more school/work absences due to tics, had more depressive symptoms, were more likely to be at high risk for suicidality, and had disability in self-care and life activity domains. There were no significant differences between cisgender and TGD participants with FTLB in any of the domains assessed. CONCLUSIONS: Youth with FTLB have unique health care needs and associations with anxiety, depression, sex, and gender.

Testing the specificity of phenomenological criteria for functional tic-like behaviours in youth with Tourette syndrome.

BACKGROUND AND PURPOSE: The aim was to test the specificity of phenomenological criteria for functional tic-like behaviours (FTLBs). The European Society for the Study of Tourette Syndrome (ESSTS) criteria for the diagnosis of FTLBs include three major criteria: age at symptom onset ≥12 years, rapid evolution of symptoms and specific phenomenology. METHODS: Children and adolescents with primary tic disorders have been included in a Registry in Calgary, Canada, since 2017. Using the Yale Global Tic Severity Scale, the proportion of youth with primary tic disorders who met specific phenomenological criteria for FTLBs at first visit was assessed: (1) having ≥1 specific complex motor tic commonly seen in FTLBs, including complex arm/hand movements, self-injurious behaviour, blocking, copropraxia; (2) having ≥1 specific complex phonic tic commonly seen in FTLBs, including saying words, phrases, disinhibited speech, coprolalia; (3) having a greater number of complex tics than simple tics. Children seen for the first time between 2017 and 2019 and between 2021 and 2023 were analysed separately. RESULTS: Of 156 participants included between 2017 and 2019, high specificity (94.2%) of the age at onset criterion (≥12 years) and of having at least two complex motor behaviours and one complex phonic behaviour at first visit (96.2%) was observed. Some of the complex motor tics had lower specificity. The specificity of the FTLB diagnostic criterion of having more complex tics than simple tics was 89.7%. There was no significant difference in specificity of the criteria for children seen for the first time between 2017 and 2019 and between 2021 and 2023 (n = 149). CONCLUSION: This information supports the use of the ESSTS criteria for FTLBs in clinical practice.

Rotational plane-wise analysis of angular movement of neck motor tics in Tourette's syndrome.

Motor tics are sudden, rapid, recurrent, non-rhythmic movements. There is a lack of quantitative assessment methods for the motor tics despite severe neck complications. We aimed to provide an improved quantitative method for neck tic assessment in motor tic disorders. We recorded neck motor tics in patients with motor tic disorders and voluntary neck movements in healthy controls. The maximum peak angular velocities and angular accelerations were calculated. Motor tics were assessed in three orthogonal planes (yaw, pitch, and roll) separately, and compared between the patients with motor tic disorders and controls. Correlations between the maximum angular velocities/accelerations and tic counts were also assessed. In the pitch plane, motor tics of the patients showed higher angular velocities/accelerations than voluntary movements of the controls. Angular acceleration in the yaw, and roll planes showed positive correlations with tic count. Some of the observed tics were comparable to the movements experienced in contact sports. Our findings may aid in the identification of populations at a high risk for severe neck complications among motor tic disorder patients.

Sensory hypersensitivity in Tourette syndrome: A review.

Tourette syndrome (TS) is a neurodevelopmental disorder defined by tics, but most patients also experience bothersome sensory phenomena, in the form of premonitory urges and/or sensory hypersensitivity. Whereas premonitory urges are temporally paired with tics, sensory hypersensitivity is a constant, heightened awareness of external and/or internal stimuli. The intensity of sensory hypersensitivity does not strongly correlate with the severity of tics or premonitory urges, suggesting it is a dissociable clinical phenomenon. At least 80% of TS patients report subjectively enhanced perception of various sensory stimuli. These same patients demonstrate normal static detection thresholds. However, individuals with TS habituate abnormally to repetitive stimuli, indicating incapacity to appropriately filter redundant sensory input, i.e. impaired sensory gating. Physiologic support for this hypothesis is provided by abnormal pre-pulse inhibition (PPI) and event-related potential (ERP) investigations. Preclinical data implicates parvalbumin-positive (PV+) interneuron dysfunction in altered sensory gating in TS and other neurodevelopment disorders. Studies probing TS sensory hypersensitivity must methodically account for comorbid psychiatric conditions, namely obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), as these entities appear to involve pathophysiologic processes shared with TS. The presence of psychiatric comorbidities in TS is associated with even more profound sensory processing dysfunction. A deepened understanding of TS sensory hypersensitivity will afford novel insights into disease mechanisms, clinical phenotype, and therapeutic management.

Brain functional connectivity in chronic tic disorders and Gilles de la Tourette syndrome.

The pathophysiology of chronic tic disorder (cTD) and Gilles de la Tourette syndrome (GTS) is characterized by the dysfunction of both motor and non - motor cortico - striatal - thalamo - cortical (CSTC) circuitries, which leads to tic release and comorbids. A role of fronto - parietal network (FPN) connectivity breakdown has been postulated for tic pathogenesis, given that the FPN entertain connections with limbic, paralimbic, and CSTC networks. Our study was aimed at characterizing the FPN functional connectivity in cTD and GTS in order to assess the role of its deterioration in tic severity and the degree of comorbids. We recorded scalp EEG during resting state in patients with cTD and GTS. The eLORETA current source densities were analyzed, and the lagged phase synchronization (LPS) was calculated to estimate nonlinear functional connectivity between cortical areas. We found that the FPN functional connectivity in delta band was more detrimental in more severe GTS patients. Also, the sensorimotor functional connectivity in beta2 band was stronger in more severe cTD and GTS patients. FPN functional connectivity deterioration correlated with comorbids presence and severity in patients with GTS. Our data suggest that a FPN disconnection may contribute to the motoric symptomatology and comorbid severity in GTS, whereas sensorimotor disconnection may contribute to tic severity in cTD and GTS. Although preliminary, our study points out a differently disturbed brain connectivity between patients with cTD and GTS. This may serve as diagnostic marker and potentially interesting base to develop pharmacological and noninvasive neuromodulation trials aimed at reducing tic symptomatology.

Deep slow nasal respiration with tight lip closure for immediate attenuation of severe tics.

BACKGROUND: Severe intractable tics, which are associated with Tourette syndrome and chronic tic disorder (TS/CTD), severely affect the quality of life. Common less-invasive treatments are often unable to attenuate tics with deep brain stimulation currently being the only effective treatment. We aimed to assess the anti-tic effect of deep slow nasal respiration with tight lip closure using patients with TS/CTD. METHODS: We retrospectively analyzed 10 consecutive patients (9 men, 1 woman; 23-41 years old). We instructed the patients to perform the procedure for 120 s and to obtain a video recording of before and during the procedure. The videos were used to count tics and determine lip competency or incompetency. The counted tics were rated using the modified Rush Video Rating Scale. RESULTS: Compared with before the procedure, there were significantly lower frequencies of motor and phonic tics, as well as video scored, during the procedure. Eight patients presented with lip incompetency before the procedure and none after the procedure (P = 0.041). There were no side effects associated with the procedure. CONCLUSION: Our findings indicate that deep slow nasal respiration with tight lip closure ameliorates tics in patients with TS/CTD. In accordance with our results, lip opening and oral breathing could be causes of tics, in addition to heritability. Therefore, this novel procedure could improve tics. Furthermore, our findings could contribute toward the development of tic treatments and elucidate their pathophysiology regarding the reward system, hypersensitivity, autonomic nerves, and nasal airway.

Exploring circannual rhythms and chronotype effect in patients with Obsessive-Compulsive Tic Disorder (OCTD): A pilot study.

BACKGROUND: The aim of this study was to test, through a chronobiologic approach, the existence of a significant circannual rhythm of tics and obsessive-compulsive symptoms in patients with Obsessive-Compulsive Tic Disorder (OCTD). The chronotype effect on tics and OC symptoms during seasons was also studied. METHODS: Patients with a diagnosis of OCTD (N = 37; mean age = 18.78 ± 8.61) underwent four clinical evaluations: Winter (WIN), Spring (SPR), Summer (SUM) and Autumn (AUT). Tics were evaluated through Yale Global Tic Severity Scale (YGTSS) and OC symptoms through Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Patients' chronotype was assessed by the Horne-Ostberg morningness-eveningness questionnaire (MEQ), which categorizes subjects according to the individuals'chronotype, being morning-type, evening-type, and neither-type. RESULTS: A statistically significant circannual rhythm was observed for OC symptoms (p = 0.007), with the acrophase occurring between AUT and WIN. Y-BOCS differed along the year (p = 0.0003 and η2p = 0.40) with lower results in SUM compared to WIN (p < 0.05) and AUT (p < 0.01). Tics displayed no circannual rhythm and YGTSS scores were comparable among seasons. Patients were classified as 15 morning-types (40.5%) 15 neither-types (40.5%) and 7 evening-types (19.0%). YGTSS data were similar for all chronotypes while Y-BOCS results were greater during SUM in evening-types than morning-type patients (p < 0.05; 15.7 ± 5.2 vs 3.4 ± 6.0). LIMITATIONS: It is essential to investigate the existence of tics and OC symptoms circannual rhythms over the course of more than one year with a larger sample. CONCLUSIONS: OC symptoms displayed a significant circannual rhythm and were influenced by patients' chronotype. On the contrary, tics resulted similar among seasons and chronotypes.

A Review on Functional Analyses of Tics.

Tic disorders are characterized by a class of responses assumed to be neurobiological in origin. Still, several studies have shown that tic frequency can be influenced by antecedent environmental events and social consequences. Prior reviews have summarized the effects of environmental events but have not examined relations between tic diagnosis, behavioral deficits (e.g., intellectual disability), tic topography, and the consequences observed to maintain tics. These variables might be important when attempting to predict or identify relevant consequences. A more thorough understanding of the variables that maintain and give rise to tics might also be useful in predicting responsiveness to treatment and intervention refinement. We reviewed and summarized results from the 13 attempts to experimentally identify maintaining consequences for tics (i.e., functional analyses) that have been published to date. We examined patterns of functions across tic diagnoses (i.e., Tourette's syndrome or not), communication impairments (i.e., an intellectual disability or reported language difficulty), and tic topography. Results suggested that individuals with Tourette's syndrome and those without communication impairments are more likely to have functional analysis outcomes consistent with automatic reinforcement, but exceptions in both directions highlight the utility of functional analysis in treating tics.

Inhibition-related differences between tic-free and tic-related obsessive-compulsive disorder: evidence from the N2 and P3.

Tic-related OCD (obsessive-compulsive disorder) was introduced as an OCD subtype in the DSM-5 based mainly on family and clinical data that showed differences between OCD in dependence of accompanying tics. Little is known, however, regarding neurocognitive differences between subtypes. We used the stop-signal task to examine whether differences exist in response inhibition between OCD patients without tics (n = 21), patients with tic-related OCD (n = 12), and 21 healthy controls. The groups were carefully matched for gender, age and level of education. The stop-signal reaction time (SSRT) and inhibition-related N2 and P3 were used to examine behavioral and neural correlates of response inhibition and inhibition-related processes. In the SSRT, no difference was found between groups. P3 amplitude was larger in tic-free compared to tic-related OCD and healthy controls. No group differences were found in the N2 amplitude. For tic-related OCD, SSRT data indicate intact response inhibition, and P3 data indicate intact neural aftereffects of inhibition like the evaluation of the outcome. This is similar to what is found in patients with TD and may, thus, be interpreted as a support for shared mechanisms in relation to TD. In OCD, alterations in P3 amplitude indicate hyperactivity in the evaluation of the outcome of the inhibition process. This is in line with hyperactivity generally found in performance monitoring in OCD.

The spectrum of involuntary vocalizations in humans: A video atlas.

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sensory dysregulation in tic disorders is associated with executive dysfunction and comorbidities.

BACKGROUND: Tics are conceptualized as a sensorimotor phenomenon with a premonitory urge typically described by patients. As observed in other neurodevelopmental disorders, we have observed sensory dysregulation symptoms, such as tactile hypersensitivity to clothing, in children with tic disorders; however, formal clinical research in this area is limited. OBJECTIVE: To define the presence of sensory dysregulation symptoms in tic disorders, and their clinical associations. METHODS: Prevalence of sensory dysregulation in 102 children with tic disorders was compared to 61 age- and sex-matched healthy controls. Sensory dysregulation, executive function, and quality of life data were obtained through the Short Sensory Profile-2, Sensory Profile-2, Sensory Processing Measure, Behaviour Rating Inventory of Executive Function-2, and Strength and Difficulties Questionnaire and Pediatric Quality of Life Inventory. Tics were assessed with the Yale Global Tic Severity Scale. RESULTS: Children with tics, in the presence of comorbidity, had elevated sensory dysregulation compared to healthy controls (P < 0.001). There was a positive correlation between sensory dysregulation and global executive difficulties in children with tics and comorbidity (n = 87; rho = 0.716; P < 0.001) and a negative correlation of sensory dysregulation with quality of life (n = 87; rho = -0.595; P < 0.001). In children with tics, there was an association between sensory dysregulation and number of comorbidities (P < 0.001). CONCLUSION: In the presence of comorbidity, children with tic disorders have broad sensory dysregulation symptoms beyond the premonitory urge. There was a statistically significant association between sensory dysregulation and executive function difficulties and the presence of neurodevelopmental and psychiatric comorbidity. Sensory dysregulation can be considered neurodevelopmental symptoms, providing insight into the neurobiology of tics and opportunities for therapeutic intervention. © 2019 International Parkinson and Movement Disorder Society.

Neural activation and connectivity during cued eye blinks in Chronic Tic Disorders.

OBJECTIVE: The pathophysiology of Chronic Tic Disorders (CTDs), including Tourette Syndrome, remains poorly understood. The goal of this study was to compare neural activity and connectivity during a voluntary movement (VM) paradigm that involved cued eye blinks among children with and without CTDs. Using the precise temporal resolution of electroencephalography (EEG), we used the timing and location of cortical source resolved spectral power activation and connectivity to map component processes such as visual attention, cue detection, blink regulation and response monitoring. We hypothesized that neural activation and connectivity during the cued eye blink paradigm would be significantly different in regions typically associated with effortful control of eye blinks, such as frontal, premotor, parietal, and occipital cortices between children with and without CTD. METHOD: Participants were 40 children (23 with CTD, 17 age-matched Healthy Control [HC]), between the ages of 8-12 (mean age = 9.5) years old. All participants underwent phenotypic assessment including diagnostic interviews, behavior rating scales and 128-channel EEG recording. Upon presentation of a cue every 3 s, children were instructed to make an exaggerated blink. RESULTS: Behaviorally, the groups did not differ in blink number, latency, or ERP amplitude. Within source resolved clusters located in left dorsolateral prefrontal cortex, posterior cingulate, and supplemental motor area, children with CTD exhibited higher gamma band spectral power relative to controls. In addition, significant diagnostic group differences in theta, alpha, and beta band power in inferior parietal cortex emerged. Spectral power differences were significantly associated with clinical characteristics such as tic severity and premonitory urge strength. After calculating dipole density for 76 anatomical regions, the CTD and HC groups had 70% overlap of top regions with the highest dipole density, suggesting that similar cortical networks were used across groups to carry out the VM. The CTD group exhibited significant information flow increase and dysregulation relative to the HC group, particularly from occipital to frontal regions. CONCLUSION: Children with CTD exhibit abnormally high levels of neural activation and dysregulated connectivity among networks used for regulation and effortful control of voluntary eye blinks.

Controversies Surrounding the Pathophysiology of Tics.

Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations (phonic productions) that are commonly present in children and are required symptoms for the diagnosis of Tourette syndrome. Despite their frequency, the underlying pathophysiology of tics/Tourette syndrome remains unknown. In this review, we discuss a variety of controversies surrounding the pathophysiology of tics, including the following: Are tics voluntary or involuntary? What is the role of the premonitory urge? Are tics due to excess excitatory or deficient inhibition? Is it time to adopt the contemporary version of the cortico-basal ganglia-thalamocortical (CBGTC) circuit? and Do we know the primary abnormal neurotransmitter in Tourette syndrome? Data from convergent clinical and animal model studies support complex interactions among the various CBGTC sites and neurotransmitters. Advances are being made; however, numerous pathophysiologic questions persist.