Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Pallidal neuronal activity in Gilles de la Tourette syndrome and dystonic patients: A comparative study.

Gilles de la Tourette syndrome (GTS) and dystonia (DYS) are both hyperkinetic movement disorders effectively treated by deep brain stimulation (DBS) of the internal part of the globus pallidus (GPi). In this study, we compared single-neuron activity in the GPi between 18 GTS patients (with an average of 41 cells per patient) and 17 DYS patients (with an average of 54 cells per patient), all of whom underwent bilateral pallidal stimulation surgery, under general anesthesia or while awake at rest. We found no significant differences in GPi neuronal activity characteristics between patients operated on under general anesthesia versus those who were awake, irrespective of their diagnosis (GTS or DYS). We found higher firing rates, firing rate in bursts, pause duration and interspike interval coefficient of variation in GTS patients compared to DYS patients. On the opposite, we found higher number of pauses and bursts frequency in DYS patients. Lastly, we found a higher proportion of GPi oscillatory activities in DYS compared to GTS patients, with predominant activity within the low-frequency band (theta/alpha) in both patient groups. These findings underscore the complex relationship between the different neuronal discharge characteristic such as oscillatory or bursting activity within the GPi in shaping the clinical phenotypes of hyperkinetic disorders. Further research is warranted to deepen our understanding of how neuronal patterns are transmitted within deep brain structures and to develop strategies aimed at normalizing these pathological activities, by refining DBS techniques to enhance treatment efficacy and individual outcomes.

Neural representations of statistical and rule-based predictions in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a disorder characterised by motor and vocal tics, which may represent habitual actions as a result of enhanced learning of associations between stimuli and responses (S-R). In this study, we investigated how adults with GTS and healthy controls (HC) learn two types of regularities in a sequence: statistics (non-adjacent probabilities) and rules (predefined order). Participants completed a visuomotor sequence learning task while EEG was recorded. To understand the neurophysiological underpinnings of these regularities in GTS, multivariate pattern analyses on the temporally decomposed EEG signal as well as sLORETA source localisation method were conducted. We found that people with GTS showed superior statistical learning but comparable rule-based learning compared to HC participants. Adults with GTS had different neural representations for both statistics and rules than HC adults; specifically, adults with GTS maintained the regularity representations longer and had more overlap between them than HCs. Moreover, over different time scales, distinct fronto-parietal structures contribute to statistical learning in the GTS and HC groups. We propose that hyper-learning in GTS is a consequence of the altered sensitivity to encode complex statistics, which might lead to habitual actions.

When the interoceptive and conceptual clash: The case of oppositional phenomenal self-modelling in Tourette syndrome.

Tourette syndrome (TS) has been associated with a rich set of symptoms that are said to be uncomfortable, unwilled, and effortful to manage. Furthermore, tics, the canonical characteristic of TS, are multifaceted, and their onset and maintenance is complex. A formal account that integrates these features of TS symptomatology within a plausible theoretical framework is currently absent from the field. In this paper, we assess the explanatory power of hierarchical generative modelling in accounting for TS symptomatology from the perspective of active inference. We propose a fourfold analysis of sensory, motor, and cognitive phenomena associated with TS. In Section 1, we characterise tics as a form of action aimed at sensory attenuation. In Section 2, we introduce the notion of epistemic ticcing and describe such behaviour as the search for evidence that there is an agent (i.e., self) at the heart of the generative hierarchy. In Section 3, we characterise both epistemic (sensation-free) and nonepistemic (sensational) tics as habitual behaviour. Finally, in Section 4, we propose that ticcing behaviour involves an inevitable conflict between distinguishable aspects of selfhood; namely, between the minimal phenomenal sense of self-which is putatively underwritten by interoceptive inference-and the explicit preferences that constitute the individual's conceptual sense of self. In sum, we aim to provide an empirically informed analysis of TS symptomatology under active inference, revealing a continuity between covert and overt features of the condition.

Comparison of children and adults in deep brain stimulation for Tourette Syndrome: a large-scale multicenter study of 102 cases with long-term follow-up.

BACKGROUND: Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. METHODS: This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged < 18 years; n = 34) and adults (aged ≥ 18 years; n = 68). The longitudinal outcomes as tic symptoms were assessed by the YGTSS, and the YBOCS, BDI, and GTS-QOL were evaluated for symptoms of obsessive-compulsive disorder (OCD), depression, and quality of life, respectively. RESULTS: Overall, these included patients who finished a median 60-month follow-up, with no significant difference between children and adults (p = 0.44). Overall, the YGTSS total score showed significant postoperative improvements and further improved with time (improved 45.2%, 51.6%, 55.5%, 55.6%, 57.8%, 61.4% after 6, 12, 24, 36, 48, and ≥ 60 months of follow-up compared to baseline, respectively) in all included patients (all p < 0.05). A significantly higher improvement was revealed in children than adults at ≥ 60 months of follow-up in the YGTSS scores (70.1% vs 55.9%, p = 0.043), and the time to achieve 60% improvement was significantly shorter in the children group (median 6 months vs 12 months, p = 0.013). At the last follow-up, the mean improvements were 45.4%, 48.9%, and 55.9% and 40.3%, 45.4%, and 47.9% in YBOCS, BDI, and GTS-QOL scores for children and adults, respectively, which all significantly improved compared to baseline (all p < 0.05) but without significant differences between these two groups (all p > 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). CONCLUSIONS: DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.

An Online Mindfulness-Based Group Intervention for Tics: A Pilot Randomized Controlled Trial.

BACKGROUND: Current treatments for Tourette syndrome (TS) and persistent tic disorder (PTD) are often insufficiently effective, inaccessible, and frequently associated with adverse events. Thus, we must continue to develop and test effective, accessible, and safe treatment options. OBJECTIVE: We aimed to conduct a pilot randomized controlled trial (RCT) comparing a novel, videoconference-delivered group mindfulness-based intervention for tics (MBIT) to videoconference-delivered group psychoeducation, relaxation, and supportive therapy (PRST) for adults with TS or PTD. METHODS: Thirty-two adults with TS or PTD were randomly assigned to receive 8 weeks of either MBIT or PRST. Tic severity, tic-related impairment, and global improvement were assessed by a trained, independent evaluator who was masked to treatment condition at baseline (week 0), posttreatment (week 9), 1-month follow-up, and 6-month follow-up. All study procedures were conducted online via secure videoconferencing. RESULTS: Twenty-eight participants began treatment and were included in analyses. MBIT, relative to PRST, was associated with a significantly greater decline in tic severity (d = 0.85) and tic-related impairment (d = 0.99) from baseline to posttreatment. Treatment response was significantly higher in MBIT (69%) than in PRST (13%). Neither treatment resulted in serious adverse effects. The durability of treatment outcomes is also reported and discussed. CONCLUSIONS: The results from this pilot RCT suggest that videoconference-delivered group MBIT may be an efficacious, accessible, and safe intervention for adults with tics. Future research is necessary to confirm these preliminary findings. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated Quantification of Eye Tics Using Computer Vision and Deep Learning Techniques.

BACKGROUND: Tourette syndrome (TS) tics are typically quantified using "paper and pencil" rating scales that are susceptible to factors that adversely impact validity. Video-based methods to more objectively quantify tics have been developed but are challenged by reliance on human raters and procedures that are resource intensive. Computer vision approaches that automate detection of atypical movements may be useful to apply to tic quantification. OBJECTIVE: The current proof-of-concept study applied a computer vision approach to train a supervised deep learning algorithm to detect eye tics in video, the most common tic type in patients with TS. METHODS: Videos (N = 54) of 11 adolescent patients with TS were rigorously coded by trained human raters to identify 1.5-second clips depicting "eye tic events" (N = 1775) and "non-tic events" (N = 3680). Clips were encoded into three-dimensional facial landmarks. Supervised deep learning was applied to processed data using random split and disjoint split regimens to simulate model validity under different conditions. RESULTS: Area under receiver operating characteristic curve was 0.89 for the random split regimen, indicating high accuracy in the algorithm's ability to properly classify eye tic vs. non-eye tic movements. Area under receiver operating characteristic curve was 0.74 for the disjoint split regimen, suggesting that algorithm generalizability is more limited when trained on a small patient sample. CONCLUSIONS: The algorithm was successful in detecting eye tics in unseen validation sets. Automated tic detection from video is a promising approach for tic quantification that may have future utility in TS screening, diagnostics, and treatment outcome measurement. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gamified Closed-Loop Intervention Enhances Tic Suppression in Children: A Randomized Trial.

BACKGROUND: Gamification of behavioral intervention for tic disorders (TDs) potentially enhances compliance and offers key clinical advantages. By delivering immediate positive feedback upon tic-suppression, games may counteract negative reinforcement, which presumably contribute to tic consolidation by relieving uncomfortable premonitory urges. OBJECTIVES: We developed a gamified protocol (XTics), which leverages this potential by combining gamified tic-triggering with immediate feedback, and evaluated its clinical value in enhancing tic suppression. METHODS: XTics encompasses two conditions: Immediate and Contingent Reward (ICR), where game progression is contingent upon successful tic suppression, and Delayed Reward (DR), where game events' outcomes are random. Employing a randomized crossover design, 35 participants (aged 7-15 years) underwent daily gaming sessions over a week per condition. Improvements in our primary measures, including the inter-tic interval (ITI) and tic severity assessment by blinded evaluators (Yale Global Tic Severity-Total Tic Score [YGTSS-TTS], Rush), and parents (Parent Tic Questionnaire [PTQ]), were compared between ICR and DR, and assessed across conditions for the 4-week protocol. RESULTS: No participant voluntarily left the study before completing its two-phase protocol. As expected, ITI showed significantly larger improvement (Z = 4.19, P = 2.85 × 10-5) after ICR (1442 ± 2250%) versus DR (242 ± 493%) training, increasing at a higher pace (t(67) = 3.15, P = 0.0025). Similarly, Rush tic severity scores reduced more post-ICR versus DR (t(47) = 3.47, P = 0.002). We observed a clinically significant reduction of 25.69 ± 23.39% in YGTSS-TTS following a f4-week protocol including both conditions. Parent-reported tic severity decreased by 42.99 ± 31.69% from baseline to 3 months post-treatment. CONCLUSIONS: The combination of gamified tic-triggering with immediate and contingent rewards demonstrates a promising approach for enhancing treatment efficacy in TDs, boosting traditional therapeutic methods. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebrospinal fluid findings in patients with obsessive-compulsive disorder, Tourette syndrome, and PANDAS: A systematic literature review.

BACKGROUND: Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS. METHODS: A systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool. RESULTS: Meta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies. CONCLUSIONS: This systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

Impact of movie and video game elements on tic manifestation in children.

BACKGROUND AND PURPOSE: Children in developed countries spend a significant portion of their waking hours engaging with audiovisual content and video games. The impact of media consumption on children's health and well-being has been widely studied, including its effects on tic disorders. Previous studies have shown that tic frequency can both increase and decrease during activities like gaming and television watching, resulting in mixed findings. METHODS: To better understand the impact of audiovisual media on tics, we conducted a fine-grained tic manifestation analysis. We focused on the effects of the impact of a movie scene with suspensful elements and a video game designed to heighten anticipation, thought to stimulate phasic and striatal dopamine release. We closely monitored tic frequency throuhghout these experiences based on moment-to-moment tic annotation. The study included 20 participants (19 males aged 7-16) diagnosed with tic disorders (Yale Global Tic Severity Scale≥8), and we tested the replicability of our findings with an independent group of 36 children (15 females, aged 7-15) with tic disorders. RESULTS: During film viewing, we observed significant synchronization in the temporal tic patterns of various individuals despite diversity in their tic profiles. Furthermore, employing a video game developed for our study, we found that tic frequency increases during anticipation of a pending reward. This finding was replicated in a second experiment with an independent cohort. CONCLUSIONS: Our results indicate that tic frequency is affected by media elements in the short-term, and call for further investigation of the long-term impacts of exposure to such tic triggers.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

Efficacy of cannabis-based medicine in the treatment of Tourette syndrome: a systematic review and meta-analysis.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. It is a condition that affects between 0.3% and 0.7% of children, and its pathophysiology remains largely elusive. TS is associated with structural and functional alterations in corticostriatal circuits and neurochemical imbalances. Even though TS is currently incurable, there are established treatment options available, including behavioral therapy and neuroleptics. The use of cannabis-based medicine for tic management is an emerging therapeutic strategy, although its efficacy is still under investigation. It is hypothesized to interact with the endogenous cannabinoid system, but further research is required to ascertain its safety and effectiveness in TS. AIM: In our systematic review and meta-analysis, we aim to assess the effectiveness of cannabis-based medicine in the treatment of TS. METHODS: We searched PubMed, Cochrane, Scopus, and Web of Sciences until February 2024. We included clinical trials and cohort studies investigating the efficacy of cannabis-based medicine in the treatment of TS. Data extraction focused on baseline characteristics of the included studies and efficacy outcomes, including scores on the Yale Global Tic Severity Scale (YGTSS), Premonitory Urge for Tics Scale (PUTS), and Yale-Brown Obsessive Compulsive Scale (Y-BOCS). We conducted the meta-analysis using Review Manager version 5.4. software. We compared the measurements before and after drug intake using mean difference (MD) and 95% confidence interval (CI). RESULTS: In total, 357 articles were identified for screening, with nine studies included in the systematic review and 3 in the meta-analysis. These studies involved 401 adult patients with TS treated with cannabis. YGTSS revealed a significant reduction in total scores (MD = -23.71, 95% CI [-43.86 to -3.55], P = 0.02), PUTS revealed a significant decrease in scores (MD = -5.36, 95% CI [-8.46 to -2.27], P = 0.0007), and Y-BOCS revealed no significant difference in score reduction (MD = -6.22, 95% CI [-12.68 to 0.23], P = 0.06). CONCLUSION: The current study indicates promising and potentially effective outcomes with the use of cannabis-based medicine in mitigating the severity of tics and premonitory urges. However, there is a need for larger, placebo-controlled studies with more representative samples to validate these findings.

What distinguishes patients with mass social media-induced illness presenting with Tourette-like behavior from those with Tourette syndrome? Results of a prospective cohort study.

Since 2019, a global increase in patients presenting with functional Tourette-like behaviors (FTB) has been observed. This has been related to the exposure of tic-related content in social media, although other factors seem to further fuel this phenomenon. Recently, we, therefore, proposed the term mass social media-induced illness (MSMI) as, in our opinion, this phenomenon constitutes a new type of mass sociogenic illness (MSI) that is in contrast to all recent outbreaks spread solely via social media. In accordance with this hypothesis, we were able to identify the host of the German YouTube channel "Gewitter im Kopf" ("Thunderstorm in the brain") as the initial virtual index case. The purpose of this paper is to present clinical characteristics of a sample of 32 patients diagnosed with MSMI-FTB compared to a large sample of patients with Tourette syndrome (TS) and other chronic tic disorders (CTD) (n = 1032) from the same center in Germany indicating clinical factors helpful to distinguish between tics in TS/CTD and MSMI-FTB. Our main findings were: in patients with MSMI-FTB compared to those with TS/CTD we found (i) a significantly higher age at onset, (ii) a significantly higher rate of females, (iii) a significantly higher rate of obscene and socially inappropriate symptoms, (iv) a significantly lower rate of comorbid ADHD, and (v) a significantly lower rate of OCD/OCB. In contrast, rates of comorbid anxiety and depression as well as reported frequencies of premonitory urges/sensations and suppressibility of symptoms did not differ between groups.

Structural hyperconnectivity of the subthalamic area with limbic cortices underpins anxiety and impulsivity in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics, which is often associated with psychiatric comorbidities. Dysfunction of basal ganglia pathways might account for the wide spectrum of symptoms in TS patients. Although psychiatric symptoms may be related to limbic networks, the specific contribution of different limbic structures remains unclear. We used tractography to investigate cortical connectivity with the striatal area (caudate, putamen, core and shell of the nucleus accumbens), the subthalamic nucleus (STN), and the adjacent medial subthalamic region (MSR) in 58 TS patients and 35 healthy volunteers. 82% of TS patients showed psychiatric comorbidities, with significantly higher levels of anxiety and impulsivity compared to controls. Tractography analysis revealed significantly increased limbic cortical connectivity of the left MSR with the entorhinal (BA34), insular (BA48), and temporal (BA38) cortices in TS patients compared to controls. Furthermore, we found that left insular-STN connectivity was positively correlated with impulsivity scores for all subjects and with anxiety scores for all subjects, particularly for TS. Our study highlights a heterogenous modification of limbic structure connectivity in TS, with specific abnormalities found for the subthalamic area. Abnormal connectivity with the insular cortex might underpin the higher level of impulsivity and anxiety observed in TS.

From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Nutrient intake and food selectivity in children with Tourette syndrome.

Objectives: Children with Tourette syndrome (TS) have been shown to exhibit high levels of food selectivity; however, its association with nutritional status has yet to be explored. The current study explored macro and micronutrient intake and food selectivity among children with and without TS, using 24-hour dietary recall and the Child Eating Behaviour Questionnaire.Method: Parents of 43 children diagnosed with TS and 38 age-matched children without a clinical diagnosis completed an online 24-hour food diary.Results: Fifty-eight per cent of children with TS were identified as falling outside of the healthy BMI range (underweight = 24.2%; overweight = 27.3%; obese = 6.1%). Children with TS also consumed fewer portions of fruit and vegetables along with meeting the daily reference nutrient intake guidelines significantly less often for vitamins B3, B6 and C, selenium and phosphorus compared to children without TS.Conclusions: Understanding the nutritional risk of children with TS relative to other children is important to clinicians and health care professionals who oversee nutritional inspection in primary care, and caregivers who are worried about the impact of limited or restricted diets.

The psychometric properties of Chinese version of the Gilles de la Tourette syndrome-quality of life scale (GTS-QOL) for children and adolescents.

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a persistent neurological disorder that profoundly affects the quality of life for afflicted individuals, however, tailored health-related quality of life (QOL) measures for Chinese pediatric GTS patients are lacking. This pioneering study aims to develop a QOL scale for Chinese children with GTS. METHODS: A cohort of 1,121 children (aged 6-16 years) diagnosed with GTS participated in scale development. Internal consistency was evaluated using Cronbach's alpha. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed to assess the factor structure of the GTS-QOL-Chinese, examining goodness-of-fit indices, factor loadings of individual items, and covariances between factors. Validity was determined through interscale correlations and comparisons with external measures to establish convergent and discriminant validity. RESULTS: Following reliability and validity analyses, a Chinese version of the 24-item GTS-specific quality of life scale was conclusively established, encompassing five subscales (psychological, compulsive, cognitive, physical, social). The scale demonstrated high internal consistency with a Cronbach's alpha coefficient of 0.93, and validity was substantiated through interscale correlations ranging from 0.46 to 0.68. EFA identified five factors, explaining 61.26% of the total variation. CFA further confirmed the scale's robustness, with all goodness-of-fit indicators meeting acceptable criteria (AGFI = 0.86, PCFI = 0.78, GFI = 0.89, CFI = 0.89, RMSEA = 0.07, SRMR = 0.06). CONCLUSIONS: The Chinese version of the GTS-QOL scale has exhibits robust reliability and validity and is valuable for assessing the quality of life of Chinese children and adolescents with GTS. This scale may assist in tailoring interventions and improving patient care.

Identification of immune traits associated with neurodevelopmental disorders by two-sample Mendelian randomization analysis.

BACKGROUND: One of the main causes of health-related issues in children is neurodevelopmental disorders (NDDs), which include attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette syndrome (TS). Nonetheless, there is relatively little prior research looking at the link between immunological inflammation and NDDs. Our work uses a two-sample Mendelian Randomization (MR) approach to provide a thorough evaluation of the causal effects of immune traits on ADHD, ASD, and TS. METHODS: As exposures, 731 immunological traits' genetic associations were chosen, and the outcomes were genome-wide association data for ADHD, ASD, and TS. The inverse-variance weighted (IVW), weighted median (WM), and MR-Egger methods were used to conduct MR analysis. The results' robustness, heterogeneity, and horizontal pleiotropy were confirmed using extensive sensitivity analysis. RESULTS: With single-nucleotide polymorphisms serving as instruments and false discovery rate (FDR) correction applied, the study found that significantly higher expression of CD62L on CD62L+ myeloid DC (IVW, OR: 0.926, 95% CI 0.896~0.958, P = 9.42 × 10-6, FDR = 0.007) and suggestively higher absolute cell count (AC) of CD28 + DN (CD4-CD8-) (IVW, OR: 0.852, 95% CI = 0.780 ∼ 0.932, P-value = 4.65 × 10-4, FDR = 0.170) was associated with a lower risk of ADHD. There was no pleiotropy, and the causal relationships were strong according to sensitivity, leave-one-out, and MR-Steiger directionality tests. For ASD and TS, no harmful or protective immune traits were observed. CONCLUSIONS: The results of the study lend credence to the theory that deficiency in CD62L on CD62L+ myeloid DC and CD28 + DN (CD4-CD8) AC may contribute to the onset of ADHD.