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.

Co-morbid tics and stereotypies: a systematic literature review.

BACKGROUND: Tics and stereotypies are childhood-onset repetitive behaviours that can pose significant diagnostic challenges in clinical practice. Both tics and stereotypies are characterised by a complex co-morbidity profile, however little is known about the co-occurrence of these hyperkinetic disorders in the same patient population. OBJECTIVE: This review aimed to assess the relationship between tics and stereotypies when these conditions present in co-morbidity. METHODS: We conducted a systematic literature review of original studies on co-morbid tics and stereotypies, according to the standards outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Our literature search identified six studies of suitable sample size (n ≥ 40) presenting data on the association between tics and stereotypies in otherwise typically developing patients. A considerable proportion (23%) of patients diagnosed with stereotypic movement disorder present with co-morbid tics (range 18-43%). Likewise, the prevalence of primary stereotypies is increased in patients with tic disorders such as Tourette syndrome (8%, range 6-12%). DISCUSSION: Tics and stereotypies can often develop in co-morbidity. The association of tics and stereotypies in the same patient has practical implications, in consideration of the different treatment approaches. Future research should focus on the assessment and management of both conditions, particularly in special populations (e.g. patients with pervasive developmental disorders).

Gilles de la Tourette syndrome as a rare co-morbidity of Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (47, XXY) is the most common sex chromosome aneuploidy. In addition to male hypergonadotropic hypogonadism, a wide range of neurodevelopmental disorders, anxiety and affective symptoms have been reported in a substantial proportion of cases. CASE DESCRIPTION: We document the rare case of a 43-year-old man diagnosed with Klinefelter syndrome and co-morbid Gilles de la Tourette syndrome. He presented with multiple motor and vocal tics since adolescence, as well as anxiety and affective symptoms as his main tic-exacerbating factors. Tic severity was rated as marked (Yale Global Tic Severity Scale score of 78/100), and recommendations for the treatment of both tics and psychiatric co-morbidities were formulated. DISCUSSION: Neurodevelopmental tics in the context of Klinefelter syndrome have been previously documented in three cases only. Gilles de la Tourette syndrome is 3-4 times more common in males than females and its etiological factors include multiple genetic components (genetic heterogeneity). Our case report widens the spectrum of neurodevelopmental disorders observed in the context of Klinefelter syndrome and contributes to genetic research on the role of the X chromosome in the pathophysiology of tic disorders.

New-onset functional tics during the COVID-19 pandemic: Clinical characteristics of 105 cases from a single centre.

BACKGROUND AND PURPOSE: The COVID-19 pandemic has been associated amongst other things with a sharp increase in adolescents and young adults presenting acutely with functional tics. Initial reports have suggested clinically relevant differences between functional tics and neurodevelopmental tics seen in primary tic disorders such as Tourette syndrome. We aimed to provide confirmatory findings from the largest single-centre cohort to date. METHODS: In the present study we present data from 105 consecutive patients who developed functional tics during a 3-year period overlapping with the COVID-19 pandemic (April 2020-March 2023). All patients underwent a comprehensive neuropsychiatric assessment at a single specialist centre for tic disorders. RESULTS: Female adolescents and young adults accounted for 69% of our sample. Functional tics had an acute/subacute onset in most cases (75% with a peak of severity within 1 month). We found a disproportionately high frequency of complex movements (81%) and vocalizations (75%). A subset of patients (23%) had a pre-existing primary tic disorder (Tourette syndrome with functional overlay). The most common psychiatric co-morbidities were anxiety (70%) and affective disorders (40%). Moreover, 41% of patients had at least one functional neurological disorder in addition to functional tics. Exposure to tic-related social media content was reported by half of the patients. CONCLUSIONS: Our findings confirm substantial clinical differences between functional tics developed during the pandemic and neurodevelopmental tics. Both patient- and tic-related red flags support the differential diagnostic process and inform ongoing monitoring in the post-pandemic era.

Tourette-like syndrome secondary to Kleefstra syndrome 1 with a de novo microdeletion in the EHMT1 gene.

BACKGROUND: Gills de la Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder manifested by motor and vocal tics. Kleefstra syndrome 1 (KS1), a rare genetic disorder, is caused by haploinsufficiency of the EHMT1 gene and is characterized by intellectual disability (ID), childhood hypotonia, and distinctive facial features. Tourette-like syndrome in KS1 has rarely been reported. CASE PRESENTATION: Here we describe a 7-year-old girl presenting involuntary motor and vocal tics, intellectual disability, childhood hypotonia, and dysmorphic craniofacial appearances, as well as comorbidities including attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and self-injurious behavior (SIB). The patient's CNV-seq testing revealed a de novo 320-kb deletion in the 9q34.3 region encompassing the EHMT1 gene. CONCLUSIONS: This is the first case reporting Tourette-like syndrome secondary to KS1 with a de novo microdeletion in the EHMT1 gene. Our case suggests TS with ID and facial anomalies indicate a genetic cause and broadens the phenotypic and genotypic spectrum of both TS and KS1.

Dimensional Assessment of Depression and Anxiety in a Clinical Sample of Adults With Chronic Tic Disorder.

OBJECTIVE: Among adults with Tourette syndrome, depression and anxiety symptoms are widely prevalent and consistently associated with poor quality of life. Important knowledge gaps remain regarding mood and anxiety dimensions of the adult Tourette syndrome phenotype. Taking a dimensional approach, this study sought to determine the prevalence, severity, and clinical correlates of depression and anxiety symptoms in a clinical sample of adults with Tourette syndrome and other chronic tic disorders. METHODS: A retrospective chart review was conducted of all adults with a chronic tic disorder presenting to a tertiary care Tourette syndrome clinic between December 2020 and July 2022. Information extracted during chart review included data from scales administered as part of routine care: Quality of Life in Neurological Disorders (Neuro-QoL) Depression Short Form, Neuro-QoL Anxiety Short Form, Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale, Dimensional Obsessive-Compulsive Scale, and Yale Global Tic Severity Scale. Relationships between variables were examined by conducting between-group, correlation, and multivariable regression analyses. RESULTS: Data from 120 adult patients with a chronic tic disorder (77 men and 43 women) were analyzed. Neuro-QoL Anxiety scores were elevated in 66% of the cohort; Neuro-QoL Depression scores were elevated in 26%. Neuro-QoL Anxiety scores were significantly higher than general population norms, whereas Neuro-QoL Depression scores were not. After adjustment for covariates, depressive and anxiety symptom severity scores were significantly associated with each other and with obsessive-compulsive disorder symptom severity but not with tic severity. Sex-based differences emerged in the analyses. CONCLUSIONS: Among adults with chronic tic disorder, anxiety symptoms were more prevalent and severe than depressive symptoms, co-occurring psychiatric symptoms were more tightly linked with each other than with tic severity, and sex-based differences were evident.

Impact of Tourette Syndrome on Education.

BACKGROUND: Previous studies have shown that Tourette syndrome (TS) has an impact on academic achievements. The aim of this study was to investigate the association between the severity of tics and comorbidities and educational outcomes. METHODS: From 2005 to 2007, 395 participants were included in a large cohort (314 with TS and 81 controls) and the mean age was 12.60 ± 2.64 years. The cohort was re-examined after 4 to 8 years (median 5.6) where n = 276 participants (223 with TS and 53 controls) were included with a mean age of 18.52 ± 2.73 years. At both time points, severity of tics and the presence and severity of psychiatric comorbidity were assessed. Educational achievements were assessed through structured interviews. RESULTS: Children with TS had a lower passing rate at lower secondary and high school compared to healthy controls. More severe vocal tics were associated with fewer passing lower secondary school at a prospective level. At a cross-sectional level, more severe motor tics were associated with fewer passing high school. Tic severity only influenced children with TS without comorbidity. The severity of comorbidity was found to be associated with the educational level at a longitudinal view, but not cross-sectional. CONCLUSION: Overall, children with TS had a lower passing rate at lower secondary school and high school compared to healthy controls. We found that this difference was more likely driven by the severity of comorbidities than tic severity. It is important to be aware of academic achievement in children with TS in order to give them the right support and thereby optimize educational opportunities.

Exposure and Response Prevention: Evaluation of Tic Severity Over Time for Children and Adolescents with Tourette Syndrome and Chronic Tic Disorders.

Tourette syndrome and chronic tic disorders are characterized by the presence of tics. Different behavioral therapies have shown to be efficacious for treating tics in children and adolescents, but Exposure and Response Prevention (ERP) is a less researched method. However, ERP is a method often used in the clinical setting. Therefore, the present study evaluated the severity of tics over time from beginning of ERP to follow-up approximately 1 year after last training session.In total, 116 patients treated with ERP face to face or ERP via web-based videoconferencing were included. The primary outcome measure was tic severity measured with the Danish version of the Yale Global Tic Severity Scale.The results showed that tic severity decreased during ERP and lasted in the follow-up period, with a statistically higher decrease in the group with patients who completed ERP as planned and the group that stopped earlier than planned because of reduction in tics, compared with those who dropped out due to lack of motivation (p < 0.001).The study concludes that ERP seems to have an immediate and a long-term effect on severity of tics, especially in those who complete the program or those who discontinue earlier due to good results.

Biomarkers of tic severity in children with Tourette syndrome: Motor cortex inhibition measured with transcranial magnetic stimulation.

AIM: To compare transcranial magnetic stimulation (TMS)-derived measures of primary motor cortex (M1) physiology between children with and without Tourette syndrome, and to dimensionally analyze TMS measures with Tourette syndrome-related symptom severity. METHOD: We used a cross-sectional experimental design. Sixty 8- to 12-year-old children participated (30 with Tourette syndrome: three females, mean age 10 years 10 months, standard deviation [SD] 1 year 3 months; 30 typically developing children: seven females, mean age 10 years 7 months, SD 1 year 3 months). In the group with Tourette syndrome, 15 (one female, mean age 10 years 11 months, SD 1 year 3 months) had comorbid attention-deficit/hyperactivity disorder (ADHD), rated with the Conners, Third Edition and the parent-reported ADHD rating scales. Tic severity was rated with the Yale Global Tic Severity Scale and urge severity with the Individualized Premonitory Urge for Tics Scale. M1 short-interval cortical inhibition (SICI) and intracortical facilitation were compared between diagnostic groups and, within the group with Tourette syndrome, correlated with symptom severity using linear mixed-effects models for repeated measures. RESULTS: Accounting for ADHD, we found no difference in SICI or intracortical facilitation in those with Tourette syndrome versus typically developing children (p > 0.1). In the group with Tourette syndrome, reduced M1 SICI predicted greater total (p = 0.012) and global (p = 0.002) tic severity. There were no associations with urge severity (p > 0.5). INTERPRETATION: Reduced M1 SICI is robustly associated with increased tic, but not urge, severity. WHAT THIS PAPER ADDS: Increased tic severity is associated with reduced motor cortex short-interval cortical inhibition (SICI). Children with Tourette syndrome with increased urge severity also show increased tic severity. However, reduced motor cortex SICI is associated with tic, but not urge, severity.

Symptoms compatible with long COVID in an Italian pediatric cohort of Tourette patients with and without SARS­CoV­2 infection: a short-term follow-up assessment.

BACKGROUND: Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder with a worldwide prevalence of about 0.3-1% of the population. During the pandemic caused by SARS-CoV-2 infection, the impact on the mental health of children and adolescents was very important. The persistence of symptoms in the post-acute phase of the disease has been termed Long COVID. The neuropsychiatric symptoms seem to be the most common impairment in children and adolescents with long COVID. OBJECTIVES: Considering the impact of pandemic on mental health, in this study we analyzed the long-term effects of SARS-CoV-2 infection in children and adolescents affected by TS. METHODS: We conducted an online questionnaire covering socio-demographic and clinical data among 158 patients affected by TS or chronic tic disorders (CTD), of which 78 participants reported a positive SARS-CoV-2 infection. Data were collected to investigate tic severity and both the comorbidities, as well as lockdown-related changes to daily life activities and, in case of infection of SARS-CoV-2, possible symptoms of acute infection and long COVID. Markers of systemic inflammation including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, iron, electrolytes, white blood cell counts, platelet cell counts levels, markers of liver, kidney and thyroid function were analyzed. First, all patients were screened with the Schedule for affective disorders and Schizophrenia for School age children-present and lifetime (Kiddie-SADS-PL) to rule out primary psychiatric disorders considered as criteria of exclusion. Then, all patients were clinically assessed at baseline (T0), and after three months (T1) through the administration of Yale Global Tic Severity Rating Scale (YGTSS), Multidimensional Anxiety Scale for Children (MASC), Child Depression Inventory (CDI) and Child Behavior Checklist (CBCL). RESULTS: Among the cohort of TS patients that contracted SARS-CoV-2 infection, 84.6% (n = 66) experienced any acute symptoms, and long COVID symptoms occurred in 38.5% (n = 30). A worsening of clinical symptoms of tics and eventually associated comorbidities occurred in 34.6% (n = 27) of TS patients that contracted SARS-CoV-2 infection. TS patients with or without SARS-CoV-2 infection showed an increase in the severity of tics and also behavioral, depressive and anxious symptoms. Instead, this increase was more evident in patients who contracted the infection than in patients who did not contract it. CONCLUSIONS: SARS-CoV-2 infection may have a role in the increase of tics and associated comorbidities in TS patients. Despite of these preliminary results, further investigations are necessary to improve knowledge about the acute and long-term impact of SARS-CoV-2 in TS patients.

Obsessive-Compulsive Disorder, PANDAS, and Tourette Syndrome: Immuno-inflammatory Disorders.

In the last years, much focus has been given to the possible role of inflammatory and immunologic alterations in the pathophysiology of obsessive-compulsive disorder (OCD) and some related conditions, such as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and Tourette syndrome (TS). Although the matter is intriguing, the available data are still controversial and/or limited. Therefore, the aim of this chapter was at reviewing and commenting on the literature on possible dysfunctions of inflammatory and immune system processes in OCD, PANDAS, and TS.This narrative review was carried out through searching PubMed and Google Scholar for English language papers from January 1985 to December 31, 2021.The data gathered up to now would suggest that the mechanisms involved might be heterogeneous according to the age of the patients and the disorder examined. Indeed, PANDAS seem more related to infections triggering autoimmunity not necessarily following group A beta-hemolytic streptococcal (GABHS) infection, as supposed in the past. Autoimmunity seems also important in TS, if coupled with an individual vulnerability that can be genetic and/or environmental. The data in adult OCD, albeit scattered and sometimes obtained in small samples of patients, would indicate that immune system and inflammatory processes are involved in the pathophysiology of the disorder. However, it is still unclear to conclude whether they are primary or secondary phenomena.In conclusion, taken together, the current findings pave that way towards novel and promising domains to explore the pathophysiology of OCD and related disorders, as well towards the development of innovative therapeutic strategy beyond current pharmacological paradigms.

The Severity and Neural Correlates of Premonitory Urge in Tourette Syndrome: A Systematic Review and Meta-Analysis.

INTRODUCTION: Premonitory urge (PU) is an aversive bodily sensation that signals the onset of tic disorder.To our knowledge, PU typically precedes the appearance of tic symptoms, and both age and tic severity are correlated with PU. However, inconsistent findings have also been reported. Hence, we conducted a meta-analysis to examine the relationship among premonitory symptoms, patient age and the severity of tic symptoms, as well as to summarize the research on the neural underpinnings of PU in Tourette syndrome (TS). METHODS: We conducted a literature search of relevant studies published between December 2005 and April 2022 using databases such as PubMed, Elsevier, PsycINFO, and Web of Science. Our analysis was carried out using R software with the assistance of the "meta" and "metafor" packages. RESULTS: Our meta-analysis included 22 studies with a total of 1236 tic disorder patients. The mean Premonitory Urge for Tics Scale (PUTS) score was 20.17, with a 95% confidence interval of [18.14, 21.68]. Through meta-regression, we found that age and tic severity play important moderating roles in PU severity (p < 0.0001). Neuroimaging studies suggest that PU is related to the insula, prefrontal cortex (PFC), anterior cingulate cortex (ACC), and supplementary motor area (SMA), regardless of the structural or functional level. CONCLUSIONS: Our meta-analysis confirmed the positive relationship between the severity of tics and PU and identified age as a significant factor influencing PU. The neural mechanisms underlying PU remain largely unknown, but evidence suggests that the insula, PFC, ACC, and SMA are related regions.

Group-based comprehensive behavioral intervention for tics (CBIT) for adults with Tourette syndrome or chronic tic disorders: A pilot study.

Comprehensive behavioral intervention for tics (CBIT) administered individually is an effective treatment for tics. However, the effectiveness of CBIT administered in groups for adults with Tourette syndrome and chronic tic disorders has not been investigated yet. This pilot study examined the effectiveness of group-based CBIT with respect to reduction of tic severity and tic-related impairment, as well as improvement of tic-related quality of life. Data from 26 patients were included in the intention-to-treat analyses. The Yale Global Tic Severity Scale was used to assess total tic severity and tic-related impairment. The Gilles de la Tourette - Quality of Life Scale was used to assess tic-related quality of life. These measures were administered at three points in time: at pretreatment, posttreatment, and 1-year follow-up. The results showed a significant reduction of total tic severity from pretreatment to 1-year follow-up, with larges effect sizes. Tic-related impairment and tic-related quality of life also improved significantly, although the effect sizes were smaller. Motor tics showed a stronger reduction than vocal tics. Additional analysis revealed that all change was achieved during treatment and that this effect was maintained from posttreatment to 1-year follow-up. The results of this study indicate that group-based CBIT is a promising treatment for tics.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

Insomnia in Tourette Syndrome and Chronic Tic Disorder.

BACKGROUND: Insomnia is common in Tourette syndrome (TS) and chronic tic disorder (CTD), but precise prevalence estimates are lacking. OBJECTIVE: In this Swedish register-based cohort study, we estimated the prevalence of insomnia in TS/CTD and quantified the magnitude of this association, accounting for familial confounders and relevant somatic and psychiatric comorbidities. METHODS: Of 10,444,702 individuals living in Sweden during the period from 1997 to 2013, 5877 had a diagnosis of TS/CTD and were compared to unexposed individuals from the general population on the presence of insomnia using logistic regression models. RESULTS: Individuals with TS/CTD had a period prevalence of insomnia of 32.16%, compared to 13.70% of the unexposed population. This translated into a 6.7-fold increased likelihood of insomnia in TS/CTD (odds ratio adjusted [aOR] for sex, birth year, birth country, and somatic disorders = 6.74; 95% confidence interval [CI], 6.37-7.15). A full sibling comparison, designed to adjust for shared familial factors, attenuated the estimates (aOR = 5.41; 95% CI, 4.65-6.30). When individuals with attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders were excluded, the association was also attenuated, whereas exclusion of other psychiatric comorbidities had minimal impact. Having persistent TS/CTD, comorbid ADHD, and taking ADHD medication greatly increased the likelihood of insomnia. CONCLUSIONS: Insomnia is significantly associated with TS/CTD, independently from somatic disorders, familial factors or psychiatric comorbidities, although familial factors, neurodevelopmental comorbidities, and ADHD/ADHD medication may explain part of the association. Insomnia should be routinely assessed and managed in TS/CTD, particularly in chronic patients and in those with comorbid ADHD. Other sleep disorders require further study. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine-2 receptor antibody encephalitis presenting as pure tongue-biting in a tourette syndrome patient: a case report.

BACKGROUND: Tourette syndrome (TS) is a neuropsychiatric disorder characterized by repetitive and patterned tics. Its onset correlates with dysfunctions in immunological activation and neurotransmitters. Autoimmune movement disorders such as dopamine-2 receptor antibody encephalitis (D2R encephalitis) may go undiagnosed in TS patients seeking medical help for tic symptoms only. Here, we present a clinical case of D2R encephalitis in a TS patient. CASE PRESENTATION: A 13-year-old boy with a history of TS presented with acute tongue-biting without positive neurologic examination or auxiliary examination results, except for a weakly positive finding for D2R antibodies in the serum sample. He was initially diagnosed with possible D2R encephalitis, but the influence of TS could not be ruled out. In addition to psychotropics, we administered immunotherapy early based on clinical characteristics, and his symptoms were ameliorated significantly. During the follow-up, he was diagnosed with definite D2R encephalitis, and the dosage of psychotropics was further adjusted for fluctuating symptoms. CONCLUSIONS: Our case suggests that clinicians should discern D2R encephalitis in TS patients when tics are the primary symptoms. Administering immunotherapy early, according to clinical characteristics, may benefit the patient. Moreover, the features of premonitory urges could help evaluate the state of TS.

Comprehensive behavioural intervention for tics: a neurophysiological intervention.

BACKGROUND: Gilles de la Tourette Syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterised by motor and vocal tics. While Comprehensive Behavioural Intervention for Tics (CBIT) is an effective, non-pharmacological treatment for patients with GTS, the underlying neurophysiological basis of this intervention has not been investigated. METHODS: To investigate the clinical effectiveness of CBIT in reducing tic severity in young people with GTS and explore neurophysiological mechanisms associated with clinical change. RESULTS: There was a significant overall improvement in tic severity of large effect size. The Cortical Silent Period (CSP) to motor evoked potential (MEP) ratio (CSP/MEP ratio) increased after the intervention with a small effect size. Other neurophysiological measures of inhibition were not significantly related to the change in tic severity. CONCLUSIONS: Alongside significant clinical improvements, these results suggest a role for motor cortical Gamma-aminobutyric acid (GABA)-ergic inhibitory circuitry in the neurophysiological changes underlying CBIT treatment. These findings need to be replicated in larger studies using control samples.

Group behavioral interventions for tics and comorbid symptoms in children with chronic tic disorders.

Exposure and Response Prevention (ERP), Habit Reversal Training (HRT) and Comprehensive Behavioral Intervention for Tics (CBIT) are effective in reducing tic severity. ERP and HRT have recently gained primary support in a group setting, while CBIT has not been examined similarly. We compared the efficacy of group-CBIT to group-Educational Intervention for Tics (group-EIT) for tics and comorbid symptoms. Children with Tourette Syndrome (TS) or Chronic Tic Disorder (CTD) were randomized to group-CBIT or group-EIT. Tics and comorbid symptoms were assessed in forty-six children pre- and postintervention, and 3-month later. Yale Global Tic Severity Scale (YGTSS) Motor tic severity decreased following both interventions, and was maintained at follow-up for group-CBIT only. The Parent Tic Questionnaire (PTQ) showed significant decrease in total and motor tic severity following group-CBIT only, a gain maintained three months later. YGTSS impairment score decreased following both interventions and was maintained at follow-up. YGTSS vocal tic severity score increased following both interventions, and then decreased significantly at follow up. Co-morbid symptoms including anxiety, behavioral problems, and aggressive behavior decreased following both interventions. Children with behavioral problems benefitted less while children with higher intellectual ability benefit more from intervention. Both group interventions showed efficacy in reducing tic impairment and comorbid symptoms. Group-CBIT was superior to group-EIT in reducing motor tic severity at 3-month follow-up, showing an advantage for tic-focused treatment. Based on the PTQ, group-CBIT was superior to group-EIT in reducing motor, vocal, and total tic scores, a gain maintained three months later. Clinical trial registry information-Group Intervention for Children with Chronic Tics Syndrome: CBIT vs Psychoeducational Intervention URL: http://clinicaltrials.gov , Identifier: NCT02407951, http://www.controlled-trials.com ).

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment.

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.