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BackgroundObsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS.MethodsHere, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation.ResultsWhen tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). Interestingly, the patient’s symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed.ConclusionThis study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment.

Background: Though Gilles de la Tourette's syndrome (GTS) has significant impact on the quality of life of its patients, measures of health-related quality of life (HR-QOL) specific to adolescents and adults with GTS were not developed until recently. The present study provides evidence on the validity of the Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL), the first disease-specific HR-QOL instrument for GTS patients, for the first time in an East Asian sample.Methods: One hundred and two Japanese individuals aged 13 and above with GTS were included in our study. Internal consistency was evaluated using Cronbach's alpha. The 4-factor structure of the GTS-QOL was assessed using confirmatory factor analysis, using goodness of fit indices, factor loadings of each questionnaire item, and covariances between factors. Validity was assessed using interscale correlations. Convergent and discriminate construct validity was evaluated using correlations with other scales such as the 28-item General Health Questionnaire, the Yale Global Tic Severity Scale, and the short version of the Padua Inventory.Results: Scaling assumptions were met. Internal consistency reliability was high, with a Cronbach's alpha of 0.96. Confirmatory factor analysis revealed sufficient factor loadings and goodness of fit. All measures of goodness of fit corroborated the fit of the 4-factor model. Standardized covariances between factors in the confirmatory factor analysis were >0.8. There were significant correlations with other well-validated scales, and thus convergent and discriminate construct validity was sufficient.Conclusion: The GTS-QOL is a valid and reliable instrument to measure disease-specific HR-QOL of GTS patients in Japan.

Introduction: Patients with Gilles de la Tourette syndrome (GTS) may experience blocking tics (BTs) defined as recurrent, brief cessations of motor acts. The aim of this study was to assess the prevalence, age of onset, and clinical correlates of BTs in GTS patients.Materials and Methods: We performed a one-time registration study in a cohort of 195 consecutive GTS patients aged 5–66 years (mean age: 15.0 ± 9.2; 47 females, 24.1%). All patients were personally interviewed and examined.Results: At least one BT occurred at some point in the lifetime of 73 patients (37.4%) with a mean age of onset of 10.4 ± 5.9 years. BTs occurred an average of 4.8 ± 5.3 years after tic onset. The most common BT was cessation of walking (n = 59, 80.8%), followed by speech (n = 19, 26.0%), running (n = 18, 24.7%), and writing (n = 9, 12.3%). Most of the patients (n = 52, 71.2%) reported cessation of only one activity. Clinical associations of BTs included more severe tics, overall greater number of tics, and, to a lesser extent, higher age at evaluation and comorbid obsessive-compulsive disorder.Conclusions: BTs represent complex tics, early and common symptoms of GTS, and are associated with a more severe form of GTS.

Rare inherited variations in multiplex families with Gilles de la Tourette syndrome (GTS) are suggested to play an important role in the genetic etiology of GTS. In order to explore the rare inherited variations with the risk of GTS, whole-exome sequencing (WES) was performed in a family with three affected patients with GTS. Among the five novel rare variations identified by WES, CLCN2 G161S was presented in three patients, but not in four unaffected individuals, and thus co-segregated with GTS. A validation study was also performed in a cohort of Chinses Han population to further examine the identified rare variants. CLCN2 G161S was genotyped in 207 sporadic patients with tic disorder including 111 patients with GTS and 489 healthy controls. Compared with that in controls [allele frequency (AF) = 0], CLCN2 G161S had higher variant AF in patients with tic (AF = 0.00483) and in patients with GTS (0.00900), respectively. However, this variant was absent from the current 1000 Genome databases, and the variant AF is very low in the current public databases including ExAC (AF = 0.00001) and gnomAD (AF = 0.00003). Our results suggest that CLCN2 G161S might play a major role in the genetic etiology of GTS, at least in a Chinese Han population.

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive–compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.

Gilles de la Tourette syndrome is a multifaceted and complex neuropsychiatric disorder. Given that tics as motor phenomena are the defining and cardinal feature of Tourette syndrome, it has long been conceptualized as a motor/movement disorder. However, considering premonitory urges preceding tics, hypersensitivity to external stimuli and abnormalities in sensorimotor integration perceptual processes also seem to be relevant in the pathophysiology of Tourette syndrome. In addition, tic expression depends on attention and tics can, at least partly and transiently, be controlled, so that cognitive processes need to be considered as well. Against this background, explanatory concepts should encompass not only the motor phenomenon tic but also perceptual and cognitive processes. Representing a comprehensive theory of the processing of perceptions and actions paying particular attention to their interdependency and the role of cognitive control, the Theory of Event Coding seems to be a suitable conceptual framework for the understanding of Tourette syndrome. In fact, recent data suggests that addressing the relation between actions (i.e., tics) and perceptions (i.e., sensory phenomena like premonitory urges) in the context of event coding allows to gaining relevant insights into perception-action coding in Tourette syndrome indicating that perception action binding is abnormally strong in this disorder.

Gilles de la Tourette Syndrome is a multifaceted neuropsychiatric disorder typically commencing in childhood and characterized by motor and phonic tics. Its pathophysiology is still incompletely understood. However, there is convincing evidence that structural and functional abnormalities in the basal ganglia, in cortico-striato-thalamo-cortical circuits, and some cortical areas including medial frontal regions and the prefrontal cortex as well as hyperactivity of the dopaminergic system are key findings. Conventional therapeutic approaches in addition to counseling comprise behavioral treatment, particularly habit reversal therapy, oral pharmacotherapy (antipsychotic medication, alpha-2-agonists) and botulinum toxin injections. In treatment-refractory Tourette syndrome, deep brain stimulation, particularly of the internal segment of the globus pallidus, is an option for a small minority of patients. Based on pathophysiological considerations, non-invasive brain stimulation might be a suitable alternative. Repetitive transcranial magnetic stimulation appears particularly attractive. It can lead to longer-lasting alterations of excitability and connectivity in cortical networks and inter-connected regions including the basal ganglia through the induction of neural plasticity. Stimulation of the primary motor and premotor cortex has so far not been shown to be clinically effective. Some studies, though, suggest that the supplementary motor area or the temporo-parietal junction might be more appropriate targets. In this manuscript, we will review the evidence for the usefulness of repetitive transcranial magnetic stimulation and transcranial electric stimulation as treatment options in Tourette syndrome. Based on pathophysiological considerations we will discuss the rational for other approaches of non-invasive brain stimulation including state informed repetitive transcranial magnetic stimulation.

Background: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental condition characterized by motor and vocal tics. The underlying etiology remains largely unknown, and GTS is considered as a complex multifactorial disorder associated with effects of several genes in combination with environmental factors. The inner mitochondrial membrane peptidase, subunit 2 (IMMP2L) has been suggested as one of the susceptibility genes for GTS, and IMMP2L-deficient mouse and human cells show increased levels of mitochondrial oxidative stress and altered cell fate programming. Hence, a potential involvement of IMMP2L-induced mitochondrial dysfunction in GTS pathology is yet to be elucidated. To address this, we investigated mitochondrial function in a group of GTS patients with intragenic IMMP2L deletions and compared with GTS without IMMP2L deletions and healthy controls.Methods: Mitochondrial function in fibroblasts from GTS patients and non-GTS parents (with and without IMMP2L deletions) compared to healthy controls were evaluated by measuring mitochondrial superoxide production, mitochondrial membrane potential, mitochondrial mass, and mitochondrial respiration. In addition, we evaluated apoptosis and senescence.Results: None of the mitochondrial parameters assessed in this study were significantly distinctive when comparing GTS patients with and without IMMP2L deletions against healthy controls or parents with or without IMMP2L deletions, and we did not observe altered cell programming.Conclusion: This study suggests that IMMP2L deletions do not lead to a substantial general mitochondrial dysfunction in GTS fibroblasts. Assessing a large cohort of controls and patients of similar age and gender would possibly reveal small differences in mitochondrial function. However, it is possible that IMMP2L variants affect mitochondrial function during specific instances of stress stimuli or in brain regions suggested to be affected in GTS.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by motor and vocal tics. There are several hypotheses as to the cause of the disease. One of which suggests that the immune system is involved in the pathophysiology of GTS. Here, we present a 40-year-old female patient with a typical history and clinical presentation of GTS with tics and psychiatric comorbidities, in whom positive oligoclonal bands (OCBs) type 2 in cerebral spinal fluid (CSF) were detected in an earlier study. At that time point, all other investigations were unremarkable (including neurological examination and cMRI), but 2 years later, she presented with further neurological symptoms including tetraparesis mostly affecting the left limbs, distal hypesthesia and paresthesia, and dyspnea. Since further examinations (including EMG, MRI, CSF, virological, and bacteriological tests, as well as autoimmune-encephalitis antibodies) revealed normal results, based on clinical presentation, the diagnosis of Guillain-Barré-like immune-mediated neuropathy was made and treatment with intravenous immunoglobulins (IVIg) (30 g/day for 5 days) was initiated resulting in complete remission of immune-mediated neuropathy. Based on the “immune hypothesis” of GTS, we were interested in whether in this patient positive CSF OCBs might serve as a biomarker for treatment response of tics and additional GTS-related psychiatric symptoms to IVIg, and therefore assessed tics, premonitory urges, and psychiatric comorbidities before and several times after the IVIg treatment. However, even though immune-mediated neuropathy resolved after treatment, tics, premonitory urges, and comorbidities remained unchanged. Thus, this case study suggests that treatment with IVIg is not effective in the treatment of GTS—even in a patient with intrathecal antibody synthesis as expressed by CSF isolated OCBs.

BackgroundGilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder of unknown etiology, although a major role of genetic factors has been established. Cannabis-based medicines may alleviate GTS-associated tics and variants of CNR1 gene encoding central cannabinoid receptor (CB1) are believed to be a risk factor for the development of some neurodevelopmental diseases. Our aim was to test the association of selected CNR1 gene variants with GTS.Material and MethodsThe cohort of GTS cases comprised 262 unrelated patients aged 3–53 years (mean age: 18.3 ± 9.1 years; 204 males (77.9%), 126 (48.1%) adults defined as ≥18 years). As a control group we enrolled 279 unrelated, ethnically and gender matched individuals with no diagnosed mental, neurological or general disorder, aged 13–54 years (mean age: 22.5 ± 3.0 years; 200 males, (74.1%). Both study and control groups were selected from Polish population, which is ethnically homogenous subgroup of Caucasian population. Four single nucleotide polymorphisms (SNPs) in CNR1 were selected: rs2023239, rs2180619, rs806379, and rs1049353 based on minor allele frequency in general population >15%. These variants were genotyped using a real-time quantitative polymerase chain reaction system (TaqMan SNP genotyping assay).ResultsWe found significant association of GTS clinical phenotype with rs2023239 variant. Minor allele C and CT+CC genotypes were found significantly more often in GTS patients compared to controls (17.4 vs 11.1%, p=0.003 and 32.8 vs 20.4%, p=0.001, respectively), and the difference remained significant after correction for multiple testing. C allele of rs2023239 polymorphism of the CNR1 gene was associated with the occurrence of tics. There were no statistically significant associations for rs806379, rs1049353 or rs2180619 variants.ConclusionOur findings suggest that C allele of rs2023239 polymorphism of the CNR1 gene is a risk factor of GTS in Polish population. The variant can be potentially associated with abnormal endocannabinoid transmission, which is suspected to be one of the causes of GTS.

Introduction: Major symptoms of Gilles de la Tourette syndrome (GTS) are tics, but in 90% of cases, psychiatric comorbidities occur. Self-harm behaviors (SHBs) could result from deliberate action and unintentional injury from tics.Methods: We examined 165 consecutive GTS patients aged 5 to 50 years (75.8% males). The median duration of GTS was 14 years (interquartile range, 9–22 years). The patients were evaluated for GTS and comorbid mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Self-harm behavior was diagnosed during the interview. To determine a direct relationship between SHB and clinical variables, we conducted two analyses, at the time of evaluation and lifetime. We also compared the group of children and adults with SHB. We also tried to distinguish between deliberate (non–tic-related SHB) and accidental (tic-related SHB).Results: Lifetime SHB was reported by 65 patients (39.4%), and in 55 of the cases, it was present at the time of evaluation. The age at the onset of SHB was reported in 55 of the cases (84.6%), and the median was 10 years (interquartile range, 7–13 years). In 30 of the patients (46.2%), SHB was evaluated as mild; in 26 (40%), as moderate; and in only 9 cases (13.9%), as severe. In the multivariable analysis for the predictor of lifetime SHB, attention-deficit/hyperactivity disorder (p = 0.016) and obsessive-compulsive disorder (OCD; p = 0.042) were determined as risk factors, while for current SHB, only tic severity (p < 0.0001) was statistically significant. When comparing predictors of SHB for children and adults, tic severity was determined as predictor for lifetime SHB in children (p < 0.0001), while the anxiety disorder was associated with lifetime SHB in adults (p = 0.05). Similarly, tic severity was a predictor of current SHB in the children group (p = 0.001), but this was not confirmed for adults. The group of patients with tic-related and non–tic-related SHB did not differ.Conclusions: Self-harm behavior appears mostly in children and adolescents and rarely begins in adulthood. Self-harm behavior is associated mainly with tic severity, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder. Clinical correlates of SHB are age related and differ at different points of life. Tic severity is the main factor associated with SHB in children. In the adult group, anxiety disorder and other psychiatric comorbidities may play the most important role.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p-value = 5.8x10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with encoded protein of SLIT and WNT genes guiding the growth cone towards its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a cohort of 240 Danish GTS patients and 1007 healthy controls. Our results did not reveal an association (OR= 1.363; p-value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p-value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis.

Gilles de la Tourette Syndrome (GTS) is characterised by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared aetiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No.316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex aetiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared aetiology between GTS, OCD and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and twelve PhD candidates pursue the project. Our ultimate aims are to elucidate the complex aetiology and neurobiological underpinnings of GTS, translate research findings into clinical applications and establish Pan-European infrastructure for the study of GTS and associated disorders.

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

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and vocal tics. Adult-onset cases are rare and may be due to “reactivation” of childhood tics, or secondary to psychiatric or genetic diseases, or due to central nervous system lesions of different etiologies. Late-onset psychogenic motor/vocal tics resembling GTS have been described. Neurophysiology may serve to differentiate organic from functional GTS. Altered blink reflex pre-pulse inhibition (BR-PPI), blink reflex excitability recovery (BR-ERC), and short-interval intracortical inhibition (SICI) have been described in GTS. We report a 48-years-old male, who developed numerous motor/vocal tics 2 months after sustaining non-commotional craniofacial trauma in a car accident. Both his father and brother had died earlier in car crashes. He presented with blepharospasm-like forced lid closure, forceful lip pursing, noisy suction movements, and deep moaning sounds, occurring in variable combinations, without warning symptoms or internal “urge.” Tics showed low distractibility and these increased with attention. Standard magnetic resonance imaging, electroencephalography, and evoked potentials were unremarkable. Neuropsychology diagnosed moderately impaired intellect, attention, and executive functions. Psychiatric assessment revealed somatization disorder and generalized anxiety. BR-PPI was unremarkable, while BR-ERC was enhanced, even showing facilitation at short intervals. SICI was markedly reduced at 1 and 3 ms and intracortical facilitation (ICF) was enhanced at 10 ms. The patient fulfilled Fahn and Williams' diagnostic criteria for a psychogenic movement disorder. Neurophysiology, however, documented hyperexcitability of motor cortex and brainstem. We suggest that—similar to what has been reported in psychogenic dystonia—a pre-existing predisposition may have led to the functional hyperkinetic disorder in response to severe psychic stress.

Introduction: Stimulus-bound tics (SBTs) belong to stimulus-induced behaviors and are defined as tics that occur in response to internal or external stimuli. The aim of the study was to assess the prevalence and associations of SBTs with other stimulus-triggered behaviors, premonitory urges and stimulus sensitization in Gilles de la Tourette syndrome (GTS).Methods: We performed a prospective, one-registration study in a cohort of 140 consecutive patients with GTS. Duration of GTS was 10.6 ± 8.7 years (range: 0–39 years). SBTs were diagnosed during the interview.Results: SBTs occurred at some point in the lifetime of 20.7% of patients. The presence of SBTs in adults was four times as frequent as in children (35.5% vs. 9.0%) with the most frequent onset in adolescence (58.8%) and adulthood (29.4%). These tics started 9.1 ± 4.7 years after the onset of tics. One stimulus and mental stimulus preceded tics most frequently, 44.8 and 33.3%, respectively. There was no established pattern of tics triggered by stimuli. Multivariate logistic regression analysis showed significant associations of SBTs with age at evaluation, tic severity, and palilalia but not with any co-morbid psychiatric disorders. 80% of patients showed at least one stimulus-triggered behavior. Premonitory urges and stimulus sensitization were reported by 60.0 and 40.7% of patients, respectively. No significant correlations between SBTs, premonitory urges and stimulus sensitization were found.Conclusion: SBTs are a part of the tic spectrum and should be taken into account by clinicians who deal with GTS patients. These tics fall at the tic end of the continuum of stimulus-induced behaviors.

Background: Obsessive compulsive disorder (OCD) and Gilles de la Tourette syndrome (GTS) are neurodevelopmental disorders characterized by difficulties in controlling intrusive thoughts (obsessions) and undesired actions (tics), respectively. Both conditions have been associated with abnormal inhibition but a tangible deficit of inhibitory control abilities is controversial in GTS. Methods: Here, we examined a 25 years-old male patient with severe OCD symptoms and a mild form of GTS, where impairments in motor control were central. Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) to elicit motor-evoked potentials (MEPs) during four experimental sessions, allowing us to assess the excitability of motor intracortical circuitry at rest as well as the degree of MEP suppression during action preparation, a phenomenon thought to regulate movement initiation. Results: When tested for the first time, the patient presented a decent level of MEP suppression during action preparation, but he exhibited a lack of intracortical inhibition at rest, as evidenced by reduced short-interval intracortical inhibition (SICI) and longinterval intracortical inhibition (LICI). Interestingly, the patient’s symptomatology drastically improved over the course of the sessions (reduced obsessions and tics), coinciding with feedback given on his good motor control abilities. These changes were reflected in the TMS measurements, with a significant strengthening of intracortical inhibition (SICI and LICI more pronounced than previously) and a more selective tuning of MEPs during action preparation; MEPs became even more suppressed, or selectively facilitated depending on the behavioral condition in which they we probed. Conclusion: This study highlights the importance of better understanding motor inhibitory mechanisms in neurodevelopmental disorders and suggests a biofeedback approach as a potential novel treatment. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette Syndrome (GTS) is characterized by motor and vocal tics, as well as associated comorbid conditions including obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), depression, and anxiety which are present in a substantial number of patients. Although randomized controlled trials including a large number of patients are still missing, aripiprazole is currently considered as a first choice drug for the treatment of tics. The aim of this study was to further investigate efficacy and safety of aripiprazole in a group of drug-free, adult patients. Specifically, we investigated the influence of aripiprazole on tic severity, comorbidities, premonitory urge (PU), and quality of life (QoL). Moreover we were interested in the factors that influence a patient’s decision in electing for-or against- pharmacological treatment. In this prospective uncontrolled open-label study, we included 44 patients and used a number of rating scales to assess tic severity, PU, comorbidities, and QoL at baseline and during treatment with aripiprazole. 18 out of 44 patients decided for undergoing treatment for their tics with aripiprazole and completed follow-up assessments after 4-6 weeks. Our major findings were (1) aripiprazole resulted in significant reduction of tics, but did not affect PU; (2) aripiprazole significantly improved OCD and showed a trend towards improvement of other comorbidities including depression, anxiety and ADHD; (3) neither severity of tics, nor PU or QoL influenced patients’ decisions for or against treatment of tics with aripiprazole; instead patients with comorbid OCD tended to decide in favor of, while patients with comorbid ADHD tended to decide against tic treatment; (4) most frequently reported adverse effects were sleeping problems; (5) patients’ QoL was mostly impaired by comorbid depression. Our results suggest that aripiprazole may improve associated comorbid conditions in addition to tics in patients with GTS. It can be hypothesized that these beneficial effects are related to aripiprazole’s adaptive pharmacological profile, which exhibits an influence on the dopaminergic as well as a number of other neurotransmitter systems. For the first time, our data provide evidence that patients’ decision making process for or against medical treatment is influenced by other factors than tic severity and QoL.

Background: Gilles de la Tourette syndrome (TS) is a complex neuropsychiatric disorder defined by the presence of motor and phonic tics, but often associated with psychiatric comorbidities. The main objective of this study was to explore the clinical presentation and comorbidities of TS. Method: We analyzed clinical data obtained from a large sample (n=1032; 529 children and 503 adults) of patients with tic disorders from one single German TS center assessed by one investigator. Data was collected with the help of an expert-reviewed semi-structured interview, designed to assess tic severity and certain comorbidities. Group comparisons were carried out via independent sample t-tests and chi-square tests.Results: The main findings of the study are: (1) tic severity is associated with the presence of premonitory urges (PU), copro-, echo-, and paliphenomena and the number of comorbidities, but not age at tic onset; it is higher in patients with comorbid obsessive-compulsive disorder (OCD) than in patients with comorbid attention deficit/hyperactivity disorder (ADHD). (2) PU were found to be highly associated with not just right experiences and to emerge much earlier than previously thought alongside with the ability to suppress tics (PU in >60% and suppressibility in >75% at age 8-10 years). (3) Self-injurious behavior (SIB) is highly associated with complex motor tics and coprophenomena, but not with OCD/ obsessive-compulsive behavior (OCB). While comorbid ADHD is associated with a lower ability to suppress tics, comorbid depression is associated with sleeping problems.Discussion: Our results demonstrate that tic severity is not influenced by age at onset. From our data, it is suggested that PU represent a specific type of not just right experience that is not a prerequisite for tic suppression. Comorbid ADHD reduces patients’ ability of successful tic suppression. Our data suggest that SIB belongs to the coprophenomena spectrum and hence should be conceptualized as a complex tic rather than a compulsion. Finally, this study strongly supports the hypothesis that TS+OCD is a more severe form of TS and that comorbid OCD/OCB, depression, and anxiety belong to the TS spectrum, while ADHD should be better conceptualized as a separate problem.

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson’s disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with implanted DBS worldwide, have delayed regulatory agency approval (e.g. FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry.

Background: Though Gilles de la Tourette's syndrome (GTS) has significant impact on the quality of life of its patients, measures of health-related quality of life (HR-QOL) specific to adolescents and adults with GTS were not developed until recently. The present study provides evidence on the validity of the Gilles de la Tourette Syndrome-Quality of Life Scale (GTS-QOL), the first disease-specific HR-QOL instrument for GTS patients, for the first time in an East Asian sample. Methods: One hundred and two Japanese individuals aged 13 and above with GTS were included in our study. Internal consistency was evaluated using Cronbach's alpha. The 4-factor structure of the GTS-QOL was assessed using confirmatory factor analysis, using goodness of fit indices, factor loadings of each questionnaire item, and covariances between factors. Validity was assessed using interscale correlations. Convergent and discriminate construct validity was evaluated using correlations with other scales such as the 28-item General Health Questionnaire, the Yale Global Tic Severity Scale, and the short version of the Padua Inventory. Results: Scaling assumptions were met. Internal consistency reliability was high, with a Cronbach's alpha of 0.96. Confirmatory factor analysis revealed sufficient factor loadings and goodness of fit. All measures of goodness of fit corroborated the fit of the 4-factor model. Standardized covariances between factors in the confirmatory factor analysis were >0.8. There were significant correlations with other well-validated scales, and thus convergent and discriminate construct validity was sufficient. Conclusion: The GTS-QOL is a valid and reliable instrument to measure disease-specific HR-QOL of GTS patients in Japan. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome is a multifaceted and complex neuropsychiatric disorder. Given that tics as motor phenomena are the defining and cardinal feature of Tourette syndrome, it has long been conceptualized as a motor/movement disorder. However, considering premonitory urges preceding tics, hypersensitivity to external stimuli and abnormalities in sensorimotor integration perceptual processes also seem to be relevant in the pathophysiology of Tourette syndrome. In addition, tic expression depends on attention and tics can, at least partly and transiently, be controlled, so that cognitive processes need to be considered as well. Against this background, explanatory concepts should encompass not only the motor phenomenon tic but also perceptual and cognitive processes. Representing a comprehensive theory of the processing of perceptions and actions paying particular attention to their interdependency and the role of cognitive control, the Theory of Event Coding seems to be a suitable conceptual framework for the understanding of Tourette syndrome. In fact, recent data suggests that addressing the relation between actions (i.e., tics) and perceptions (i.e., sensory phenomena like premonitory urges) in the context of event coding allows to gaining relevant insights into perception-action coding in Tourette syndrome indicating that perception action binding is abnormally strong in this disorder. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Gilles de la Tourette syndrome (GTS) may experience blocking tics (BTs) defined as recurrent, brief cessations of motor acts. The aim of this study was to assess the prevalence, age of onset, and clinical correlates of BTs in GTS patients. Materials and Methods: We performed a one-time registration study in a cohort of 195 consecutive GTS patients aged 5–66 years (mean age: 15.0 ± 9.2; 47 females, 24.1%). All patients were personally interviewed and examined. Results: At least one BT occurred at some point in the lifetime of 73 patients (37.4%) with a mean age of onset of 10.4 ± 5.9 years. BTs occurred an average of 4.8 ± 5.3 years after tic onset. The most common BT was cessation of walking (n = 59, 80.8%), followed by speech (n = 19, 26.0%), running (n = 18, 24.7%), and writing (n = 9, 12.3%). Most of the patients (n = 52, 71.2%) reported cessation of only one activity. Clinical associations of BTs included more severe tics, overall greater number of tics, and, to a lesser extent, higher age at evaluation and comorbid obsessive-compulsive disorder. Conclusions: BTs represent complex tics, early and common symptoms of GTS, and are associated with a more severe form of GTS. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive–compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS. [ABSTRACT FROM AUTHOR]

Rare inherited variations in multiplex families with Gilles de la Tourette syndrome (GTS) are suggested to play an important role in the genetic etiology of GTS. In order to explore the rare inherited variations with the risk of GTS, whole-exome sequencing (WES) was performed in a family with three affected patients with GTS. Among the five novel rare variations identified by WES, CLCN2 G161S was presented in three patients, but not in four unaffected individuals, and thus co-segregated with GTS. A validation study was also performed in a cohort of Chinses Han population to further examine the identified rare variants. CLCN2 G161S was genotyped in 207 sporadic patients with tic disorder including 111 patients with GTS and 489 healthy controls. Compared with that in controls [allele frequency (AF) = 0], CLCN2 G161S had higher variant AF in patients with tic (AF = 0.00483) and in patients with GTS (0.00900), respectively. However, this variant was absent from the current 1000 Genome databases, and the variant AF is very low in the current public databases including ExAC (AF = 0.00001) and gnomAD (AF = 0.00003). Our results suggest that CLCN2 G161S might play a major role in the genetic etiology of GTS, at least in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette Syndrome is a multifaceted neuropsychiatric disorder typically commencing in childhood and characterized by motor and phonic tics. Its pathophysiology is still incompletely understood. However, there is convincing evidence that structural and functional abnormalities in the basal ganglia, in cortico-striato-thalamo-cortical circuits, and some cortical areas including medial frontal regions and the prefrontal cortex as well as hyperactivity of the dopaminergic system are key findings. Conventional therapeutic approaches in addition to counseling comprise behavioral treatment, particularly habit reversal therapy, oral pharmacotherapy (antipsychotic medication, alpha-2-agonists) and botulinum toxin injections. In treatment-refractory Tourette syndrome, deep brain stimulation, particularly of the internal segment of the globus pallidus, is an option for a small minority of patients. Based on pathophysiological considerations, non-invasive brain stimulation might be a suitable alternative. Repetitive transcranial magnetic stimulation appears particularly attractive. It can lead to longer-lasting alterations of excitability and connectivity in cortical networks and inter-connected regions including the basal ganglia through the induction of neural plasticity. Stimulation of the primary motor and premotor cortex has so far not been shown to be clinically effective. Some studies, though, suggest that the supplementary motor area or the temporo-parietal junction might be more appropriate targets. In this manuscript, we will review the evidence for the usefulness of repetitive transcranial magnetic stimulation and transcranial electric stimulation as treatment options in Tourette syndrome. Based on pathophysiological considerations we will discuss the rational for other approaches of non-invasive brain stimulation including state informed repetitive transcranial magnetic stimulation. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by motor and vocal tics. There are several hypotheses as to the cause of the disease. One of which suggests that the immune system is involved in the pathophysiology of GTS. Here, we present a 40-year-old female patient with a typical history and clinical presentation of GTS with tics and psychiatric comorbidities, in whom positive oligoclonal bands (OCBs) type 2 in cerebral spinal fluid (CSF) were detected in an earlier study. At that time point, all other investigations were unremarkable (including neurological examination and cMRI), but 2 years later, she presented with further neurological symptoms including tetraparesis mostly affecting the left limbs, distal hypesthesia and paresthesia, and dyspnea. Since further examinations (including EMG, MRI, CSF, virological, and bacteriological tests, as well as autoimmune-encephalitis antibodies) revealed normal results, based on clinical presentation, the diagnosis of Guillain-Barré-like immune-mediated neuropathy was made and treatment with intravenous immunoglobulins (IVIg) (30 g/day for 5 days) was initiated resulting in complete remission of immune-mediated neuropathy. Based on the "immune hypothesis" of GTS, we were interested in whether in this patient positive CSF OCBs might serve as a biomarker for treatment response of tics and additional GTS-related psychiatric symptoms to IVIg, and therefore assessed tics, premonitory urges, and psychiatric comorbidities before and several times after the IVIg treatment. However, even though immune-mediated neuropathy resolved after treatment, tics, premonitory urges, and comorbidities remained unchanged. Thus, this case study suggests that treatment with IVIg is not effective in the treatment of GTS—even in a patient with intrathecal antibody synthesis as expressed by CSF isolated OCBs. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome, OCD, neurodevelomental disorders, tic discorder, Asia - Pacific The findings indicate that aversive tic-associated somatosensory experiences do not facilitate tic suppression but the awareness of when the tic will occur prior to them experiencing the tic was correlated with the ability to suppress tics. Keywords: Gilles de la Tourette syndrome; OCD; neurodevelomental disorders; tic discorder; Asia - Pacific EN Gilles de la Tourette syndrome OCD neurodevelomental disorders tic discorder Asia - Pacific N.PAG N.PAG 3 05/03/21 20210412 NES 210412 Gilles de la Tourette Syndrome (GTS) is a neurodevelopmental disorder characterized by the presence of multiple motor and one or more vocal tics of more than one-year duration ([1]). [Extracted from the article]

Background: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder of unknown etiology, although a major role of genetic factors has been established. Cannabis-based medicines may alleviate GTS-associated tics and variants of CNR1 gene encoding central cannabinoid receptor (CB1) are believed to be a risk factor for the development of some neurodevelopmental diseases. Our aim was to test the association of selected CNR1 gene variants with GTS. Material and Methods: The cohort of GTS cases comprised 262 unrelated patients aged 3–53 years (mean age: 18.3 ± 9.1 years; 204 males (77.9%), 126 (48.1%) adults defined as ≥18 years). As a control group we enrolled 279 unrelated, ethnically and gender matched individuals with no diagnosed mental, neurological or general disorder, aged 13–54 years (mean age: 22.5 ± 3.0 years; 200 males, (74.1%). Both study and control groups were selected from Polish population, which is ethnically homogenous subgroup of Caucasian population. Four single nucleotide polymorphisms (SNPs) in CNR1 were selected: rs2023239, rs2180619, rs806379, and rs1049353 based on minor allele frequency in general population >15%. These variants were genotyped using a real-time quantitative polymerase chain reaction system (TaqMan SNP genotyping assay). Results: We found significant association of GTS clinical phenotype with rs2023239 variant. Minor allele C and CT+CC genotypes were found significantly more often in GTS patients compared to controls (17.4 vs 11.1%, p=0.003 and 32.8 vs 20.4%, p=0.001, respectively), and the difference remained significant after correction for multiple testing. C allele of rs2023239 polymorphism of the CNR1 gene was associated with the occurrence of tics. There were no statistically significant associations for rs806379, rs1049353 or rs2180619 variants. Conclusion: Our findings suggest that C allele of rs2023239 polymorphism of the CNR1 gene is a risk factor of GTS in Polish population. The variant can be potentially associated with abnormal endocannabinoid transmission, which is suspected to be one of the causes of GTS. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette syndrome (TS) is a neuropsychiatric neurodevelopmental disorder with the cardinal clinical features of motor and phonic tics. Clinical phenomenology can be complex since, besides tics, there are other features including premonitory urges preceding tics, pali-, echo-, and coprophenomena, hypersensitivity to external stimuli, and symptom dependency on stress, attention, and other less well-defined factors. Also, the rate of comorbidities, particularly attention deficit hyperactivity disorder and obsessive-compulsive disorder, is high. Mirroring the complexities of the clinical course and phenomenology, pathophysiological findings are very diverse, and etiology is disputed. It has become clear, though, that abnormalities in the basal ganglia and their connections with cortical areas are key for the understanding of the pathophysiology and as regards etiology, genetic factors are crucial. Against this background, both adequate clinical management of TS and TS-related research require multidisciplinary preferably international cooperation in larger groups or networks to address the multiple facets of this disorder and yield valid and useful data. In particular, large numbers of patients are needed for brain imaging and genetic studies. To meet these requirements, a number of networks and groups in the field of TS have developed over the years creating an efficient, lively, and supportive international research community. In this review, we will provide an overview of these groups and networks.

Introduction: Major symptoms of Gilles de la Tourette syndrome (GTS) are tics, but in 90% of cases, psychiatric comorbidities occur. Self-harm behaviors (SHBs) could result from deliberate action and unintentional injury from tics. Methods: We examined 165 consecutive GTS patients aged 5 to 50 years (75.8% males). The median duration of GTS was 14 years (interquartile range, 9–22 years). The patients were evaluated for GTS and comorbid mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Self-harm behavior was diagnosed during the interview. To determine a direct relationship between SHB and clinical variables, we conducted two analyses, at the time of evaluation and lifetime. We also compared the group of children and adults with SHB. We also tried to distinguish between deliberate (non–tic-related SHB) and accidental (tic-related SHB). Results: Lifetime SHB was reported by 65 patients (39.4%), and in 55 of the cases, it was present at the time of evaluation. The age at the onset of SHB was reported in 55 of the cases (84.6%), and the median was 10 years (interquartile range, 7–13 years). In 30 of the patients (46.2%), SHB was evaluated as mild; in 26 (40%), as moderate; and in only 9 cases (13.9%), as severe. In the multivariable analysis for the predictor of lifetime SHB, attention-deficit/hyperactivity disorder (p = 0.016) and obsessive-compulsive disorder (OCD; p = 0.042) were determined as risk factors, while for current SHB, only tic severity (p < 0.0001) was statistically significant. When comparing predictors of SHB for children and adults, tic severity was determined as predictor for lifetime SHB in children (p < 0.0001), while the anxiety disorder was associated with lifetime SHB in adults (p = 0.05). Similarly, tic severity was a predictor of current SHB in the children group (p = 0.001), but this was not confirmed for adults. The group of patients with tic-related and non–tic-related SHB did not differ. Conclusions: Self-harm behavior appears mostly in children and adolescents and rarely begins in adulthood. Self-harm behavior is associated mainly with tic severity, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder. Clinical correlates of SHB are age related and differ at different points of life. Tic severity is the main factor associated with SHB in children. In the adult group, anxiety disorder and other psychiatric comorbidities may play the most important role. [ABSTRACT FROM AUTHOR]

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

Introduction: Stimulus-bound tics (SBTs) belong to stimulus-induced behaviors and are defined as tics that occur in response to internal or external stimuli. The aim of the study was to assess the prevalence and associations of SBTs with other stimulus-triggered behaviors, premonitory urges and stimulus sensitization in Gilles de la Tourette syndrome (GTS). Methods: We performed a prospective, one-registration study in a cohort of 140 consecutive patients with GTS. Duration of GTS was 10.6 ± 8.7 years (range: 0-39 years). SBTs were diagnosed during the interview. Results: SBTs occurred at some point in the lifetime of 20.7% of patients. The presence of SBTs in adults was four times as frequent as in children (35.5% vs. 9.0%) with the most frequent onset in adolescence (58.8%) and adulthood (29.4%). These tics started 9.1 ± 4.7 years after the onset of tics. One stimulus and mental stimulus preceded tics most frequently, 44.8 and 33.3%, respectively. There was no established pattern of tics triggered by stimuli. Multivariate logistic regression analysis showed significant associations of SBTs with age at evaluation, tic severity, and palilalia but not with any co-morbid psychiatric disorders. 80% of patients showed at least one stimulus-triggered behavior. Premonitory urges and stimulus sensitization were reported by 60.0 and 40.7% of patients, respectively. No significant correlations between SBTs, premonitory urges and stimulus sensitization were found. Conclusion: SBTs are a part of the tic spectrum and should be taken into account by clinicians who deal with GTS patients. These tics fall at the tic end of the continuum of stimulus-induced behaviors. [ABSTRACT FROM AUTHOR]

Novel methods of neural stimulation are transforming the management of hyperkinetic movement disorders. In this review the diversity of approach available is showcased. We first describe the most commonly used features that can be extracted from oscillatory activity of the central nervous system, and how these can be combined with an expanding range of non-invasive and invasive brain stimulation techniques. We then shift our focus to the periphery using tremor and Tourette's syndrome to illustrate the utility of peripheral biomarkers and interventions. Finally, we discuss current innovations which are changing the landscape of stimulation strategy by integrating technological advances and the use of machine learning to drive optimization.

The existing therapeutic strategies of Tourette syndrome (TS) do not lead to sufficient improvement in a significant number of patients. Recently published studies show that paying attention to tics increases whereas directing attention away decreases tic frequency. The aim of the present case series in three patients with TS was to investigate the effect of attention training technique (ATT) on TS symptoms. ATT is a technique derived from metacognitive therapy that aims on training patients to consciously (re-)focus their attention away from themselves. Friedman’s chi-square test indicated a trend regarding the reduction of tic frequency and tic severity and a significant reduction of positive metacognitions from pre-baseline to follow-up. Reliable Change Indices (RCIs) are given for each measure and patient. Given the small number of patients, further studies including randomized controlled trials appear warranted.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p-value = 5.8 × 10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of SLIT and WNT genes guiding the growth cone toward its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a Danish cohort of 240 GTS patients and 1006 healthy controls. Our results did not reveal an association (OR = 1.363; p-value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from the GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p-value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Gilles de la Tourette syndrome (TS) is a complex neuropsychiatric disorder defined by the presence of motor and phonic tics, but often associated with psychiatric comorbidities. The main objective of this study was to explore the clinical presentation and comorbidities of TS. Method: We analyzed clinical data obtained from a large sample (n = 1032; 529 children and 503 adults) of patients with tic disorders from one single German TS center assessed by one investigator. Data was collected with the help of an expert-reviewed semi-structured interview, designed to assess tic severity and certain comorbidities. Group comparisons were carried out via independent sample t-tests and chi-square tests. Results: The main findings of the study are: (1) tic severity is associated with the presence of premonitory urges (PU), copro-, echo-, and paliphenomena and the number of comorbidities, but not age at tic onset; it is higher in patients with comorbid obsessive-compulsive disorder (OCD) than in patients with comorbid attention deficit/hyperactivity disorder (ADHD). (2) PU were found to be highly associated with “not just right experiences” and to emerge much earlier than previously thought alongside with the ability to suppress tics (PU in >60% and suppressibility in >75% at age 8–10 years). (3) Self-injurious behavior (SIB) is highly associated with complex motor tics and coprophenomena, but not with OCD/obsessive-compulsive behavior (OCB). While comorbid ADHD is associated with a lower ability to suppress tics, comorbid depression is associated with sleeping problems. Discussion: Our results demonstrate that tic severity is not influenced by age at onset. From our data, it is suggested that PU represent a specific type of “not just right experience” that is not a prerequisite for tic suppression. Comorbid ADHD reduces patients’ ability of successful tic suppression. Our data suggest that SIB belongs to the coprophenomena spectrum and hence should be conceptualized as a complex tic rather than a compulsion. Finally, this study strongly supports the hypothesis that TS+OCD is a more severe form of TS and that comorbid OCD/OCB, depression, and anxiety belong to the TS spectrum, while ADHD should be better conceptualized as a separate problem. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette Syndrome (GTS) is characterized by motor and vocal tics, as well as associated comorbid conditions including obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), depression, and anxiety which are present in a substantial number of patients. Although randomized controlled trials including a large number of patients are still missing, aripiprazole is currently considered as a first choice drug for the treatment of tics. The aim of this study was to further investigate efficacy and safety of aripiprazole in a group of drug-free, adult patients. Specifically, we investigated the influence of aripiprazole on tic severity, comorbidities, premonitory urge (PU), and quality of life (QoL). Moreover, we were interested in the factors that influence a patient’s decision in electing for-or against- pharmacological treatment. In this prospective uncontrolled open-label study, we included 44 patients and used a number of rating scales to assess tic severity, PU, comorbidities, and QoL at baseline and during treatment with aripiprazole. Eighteen out of fortyfour patients decided for undergoing treatment for their tics with aripiprazole and completed follow-up assessments after 4–6 weeks. Our major findings were (1) aripiprazole resulted in significant reduction of tics, but did not affect PU; (2) aripiprazole significantly improved OCD and showed a trend toward improvement of other comorbidities including depression, anxiety, and ADHD; (3) neither severity of tics, nor PU or QoL influenced patients’ decisions for or against treatment of tics with aripiprazole; instead patients with comorbid OCD tended to decide in favor of, while patients with comorbid ADHD tended to decide against tic treatment; (4) most frequently reported adverse effects were sleeping problems; (5) patients’ QoL was mostly impaired by comorbid depression. Our results suggest that aripiprazole may improve associated comorbid conditions in addition to tics in patients with GTS. It can be hypothesized that these beneficial effects are related to aripiprazole’s adaptive pharmacological profile, which exhibits an influence on the dopaminergic as well as a number of other neurotransmitter systems. For the first time, our data provide evidence that patients’ decision making process for or against medical treatment is influenced by other factors than tic severity and QoL. [ABSTRACT FROM AUTHOR]

Gilles de la Tourette Syndrome (TS) is a childhood-onset neurodevelopmental disorder that is characterized by multiple motor and phonic tics. It has a complex etiology with multiple genes likely interacting with environmental factors to lead to the onset of symptoms. The genetic basis of the disorder remains elusive;however, multiple resources and large-scale projects are coming together, launching a new era in the field and bringing us on the verge of discovery. The large-scale efforts outlined in this report, are complementary and represent a range of different approaches to the study of disorders with complex inheritance. The Tourette Syndrome Association International Consortium for Genetics (TSAICG) has focused on large families, parent-proband trios and cases for large case-control designs such as genomewide association studies (GWAS), copy number variation (CNV) scans and exome/genome sequencing. TIC Genetics targets rare, large effect size mutations in simplex trios and multigenerational families. The European Multicentre Tics in Children Study (EMTICS) seeks to elucidate gene-environment interactions including the involvement of infection and immune mechanisms in TS etiology. Finally, TS-EUROTRAIN, a Marie Curie Initial Training Network, aims to act as a platform to unify large-scale projects in the field and to educate the next generation of experts. Importantly, these complementary large-scale efforts are joining forces to uncover the full range of genetic variation and environmental risk factors for TS, holding great promise for indentifying definitive TS susceptibility genes and shedding light into the complex pathophysiology of this disorder.

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson's disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with DBS worldwide, have delayed regulatory agency approval (e.g., FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry. [ABSTRACT FROM AUTHOR]

Context: Tic disorders (TD) are characterized by the presence of non-voluntary contractions of functionally related groups of skeletal muscles in one or multiple body parts. Patients with body-focused repetitive behaviors (BFRB) present frequent and repetitive behaviors, such as nail biting or hair pulling. TD and BFRB can be treated with a cognitive-behavioral therapy (CBT) that regulates the excessive amount of sensorimotor activation and muscular tension. Our CBT, which is called the cognitive-psychophysiological therapy (CoPs), targets motor execution and inhibition, and it was reported to modify brain activity in TD. However, psychophysiological effects of therapy are still poorly understood in TD and BFRB patients. Our goals were to compare the event-related potentials (ERP) of TD and BFRB patients to control participants, and to investigate the effects of the CoPs therapy on the P200, N200 and P300 components during a motor and non-motor oddball task.Method: ERP components were compared in 26 TD patients, 27 BFRB patients and 27 control participants. ERP were obtained from 63 EEG electrodes during two oddball tasks. In the non-motor task, participants had to count rare stimuli. In the motor task, participants had to respond with a left or right button press for rare and frequent stimuli, respectively. ERP measures were recorded before and after therapy in both patients groups.Results: CoPs therapy improved symptoms similarly in both clinical groups. Before therapy, TD and BFRB patients had lower P300 oddball effect during the non-motor task, in comparison with controls participants. An increase in the P300 oddball effect was observed post therapy. This increase was distributed over the whole cortex in BFRB patients, but localized in the parietal area in TD patients.Discussion: These results suggest a modification of neural processes following CoPs therapy in TD and BFRB patients. CoPs therapy seems to impact patients’ attentional processes and context updating capacities in working memory (i.e. P300 component). Our results are consistent with a possible role of the prefrontal cortex and corpus callosum in mediating inter-hemispheric interference in TD.

Animals often behave repetitively and predictably. These repetitive behaviors can have a component that is learned and ingrained as habits, which can be evolutionarily advantageous as they reduce cognitive load and the expenditure of attentional resources. Repetitive behaviors can also be conscious and deliberate, and may occur in the absence of habit formation, typically when they are a feature of normal development in children, or neuropsychiatric disorders. They can be considered pathological when they interfere with social relationships and daily activities. For instance, people affected by obsessivecompulsive disorder, autism spectrum disorder, Huntington's disease and Gilles de la Tourette syndrome can display a wide range of symptoms like compulsive, stereotyped and ritualistic behaviors. The striatum nucleus of the basal ganglia is proposed to act as a master regulator of these repetitive behaviors through its circuit connections with sensorimotor, associative, and limbic areas of the cortex. However, the precise mechanisms within the striatum, detailing its compartmental organization, cellular specificity, and the intricacies of its downstream connections, remain an area of active research. In this review, we summarize evidence across multiple scales, including circuitlevel, cellular, and molecular dimensions, to elucidate the striatal mechanisms underpinning repetitive behaviors and offer perspectives on the implicated disorders. We consider the close relationship between behavioral output and transcriptional changes, and thereby structural and circuit alterations, including those occurring through epigenetic processes. [ABSTRACT FROM AUTHOR]