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Background There is clear evidence that tic disorders (TDs) are associated with psychosocial stress as well as emotional and behavioral problems. Studies have shown that individuals with TDs have higher acute physiological stress responses to external, single stressors (as reflected by saliva cortisol). The aim of the present study was to examine a physiological marker of longer-term stress (as reflected by hair cortisol concentration) in children and adolescents with TDs and unaffected siblings of individuals with TDs. Methods Two samples of a European cohort were included in this study. In the COURSE sample, 412 children and adolescents aged 3–16 years with a chronic TD including Tourette syndrome according to DSM IV-TR criteria were included. The ONSET sample included 131 3–10 years old siblings of individuals with TDs, who themselves had no tics. Differences in hair cortisol concentration (HCC) between the two samples were examined. Within the COURSE sample, relations of HCC with tic severity and perceived psychosocial stress as well as potential effects and interaction effects of comorbid emotional and behavioral problems and psychotropic medication on HCC were investigated. Results There were no differences in HCC between the two samples. In participants with TDs, there were no associations between HCC and tic severity or perceived psychosocial stress. No main effects of sex, psychotropic medication status and comorbid emotional and behavioral problems on HCC were found in participants with TDs. Conclusion A link between HCC and TDs is not supported by the present results.

In 2011 a working group of the European Society for the Study of Tourette Syndrome (ESSTS) has developed the first European assessment guidelines for Tourette syndrome (TS). Now, we present an updated version 2.0 of these European clinical guidelines for Tourette syndrome and other tic disorders, part I: assessment. Therefore, the available literature has been thoroughly screened, supplemented with national guidelines across countries and discussions among ESSTS experts. Diagnostic changes between DSM-IV and DSM-5 classifications were taken into account and new information has been added regarding differential diagnoses, with an emphasis on functional movement disorders in both children and adults. Further, recommendations regarding rating scales to evaluate tics, comorbidities, and neuropsychological status are provided. Finally, results from a recently performed survey among ESSTS members on assessment in TS are described. We acknowledge that the Yale Global Tic Severity Scale (YGTSS) is still the gold standard for assessing tics. Recommendations are provided for scales for the assessment of tics and psychiatric comorbidities in patients with TS not only in routine clinical practice, but also in the context of clinical research. Furthermore, assessments supporting the differential diagnosis process are given as well as tests to analyse cognitive abilities, emotional functions and motor skills.

Tic disorders have a strong male predominance, with a male-to-female ratio of 4:1 in Tourette syndrome (TS) and 2:1 in persistent tic disorders. In other neurodevelopmental conditions, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), the disparity in sex distribution has been partially related to differences in symptom presentation between males and females. In tic disorders, however, little research has been conducted on this topic, probably due to the limited access to large samples with a significant proportion of females. The aim of this study was to describe sex differences in the clinical presentation of tic disorders in children and adolescents in one of the largest pediatric samples with TS/persistent tic disorders (n = 709, 23.3% females) recruited as part of the European Multicenter Tics in Children Study (EMTICS). Validated measures assessed the severity of tics and comorbid psychiatric symptoms. Using mixed-effect models, we found that sex had a significant influence on the severity of tics, ADHD symptoms, ASD symptoms, and emotional problems. Males had more severe symptoms than females, except for emotional problems. We also observed a statistically significant interaction between sex and age on the severity of tics and compulsions, with females showing higher symptom severity with increasing age than males. These findings indicate that the clinical presentation of TS/persistent tic disorders varies with sex. Males seem to exhibit a more noticeable pattern of clinical symptoms at a younger age that may contribute to their earlier detection in comparison to females.

The error-related negativity (ERN) is an event-related potential component indexing processes of performance monitoring during simple stimulus-response tasks: the ERN is typically enhanced for error processing and conflicting response representations. Investigations in healthy participants and different patient groups have linked the ERN to the dopamine system and to prefrontal information processing. As in patients with Tourette Syndrome (TS) both dopamine release and prefrontal information processing are impaired, we hypothesized that performance monitoring would be altered, which was investigated with magnetencephalography (MEG). We examined performance monitoring in TS patients by assessing the magnetic equivalent of the ERN (mERN). The mERN was investigated in tic-free trials of eight adult, unmedicated TS patients without clinically significant comorbidity and ten matched healthy controls while performing a Go/NoGo task in selected frontocentral channels. The analysis of the response-related amplitudes of the event-related magnetic field showed that TS patients, in contrast to controls, did not show earlier amplitude modulation (between 70 and 105 ms after response onset) depending on response type (errors or correct responses). In both groups significant mERN amplitudes in the time-window between 105 and 160 ms after response onset were detected thus pointing at only later error processing in TS patients. In TS patients, early error-related processing might be affected by an enhanced motor control triggered by a conflict between the targeted high task performance and tic suppression. TS patients seem to tend to initially process all responses as erroneous responses.

Tsetsos, Fotis et al., Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS., This research is co-financed by Greece and the European Union (European Social Fund—ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Reinforcement of Postdoctoral Researchers - 2nd Cycle” (MIS-5033021), implemented by the State Scholarships Foundation (IKY). L.K.D. was supported by grants from the National Institutes of Health including U54MD010722-04, R01NS102371, R01MH113362, U01HG009086, R01MH118223, DP2HD98859, R01DC16977, R01NS105746, R56MH120736, R21HG010652, and RM1HG009034.

Background: Children with Tourette syndrome (TS) often have comorbid disorders, particularly attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). While subtle premorbid symptoms have been described in various psychiatric disorders, the presence of clinical precursors that may exist before the onset of tics is unknown. This longitudinal study aimed to find clinical precursors of tics by assessing a range of clinical characteristics prior to tic onset in comparison with children without onset of tics.Methods: A sample of 187 3- to 10-year-old first-degree unaffected relatives of children with TS were followed up to 7 years in the European Multicentre Tics in Children Study (EMTICS). We investigated whether clinical characteristics assessed at baseline predicted tic onset, comparing 126 children without tic onset to 61 children who developed tics. We used the least absolute shrinkage and selection operator (LASSO) method, a penalised logistic regression approach. We also explored sex differences and repeated our analyses in an age- and sex-matched subsample.Results: Children with tic onset were more frequently male (beta = -0.36), had higher baseline severity of conduct problems (beta = 0.23), autism spectrum disorder symptoms (ASD; beta = 0.08), compulsions (beta = 0.02) and emotional problems (beta = 0.03) compared to children without tic onset. Conduct and ASD problems were male-specific predictors, whereas severity of compulsions and oppositional (beta = 0.39) and emotional problems were female-specific predictors.Conclusion: This study supports the presence of clinical precursors prior to tic onset and highlights the need of sex-specific monitoring of children at risk of developing tics. This may aid in the earlier detection of tics, particularly in females. We moreover found that tics most often persisted one year after tic onset, in contrast to the common belief that tics are mostly transient.

SUMMARY We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk., In Brief Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis., Graphical Abstract

The EMTICS collaborative group: Anastasiou, Zacharias; Apter, Alan; Baglioni, Valentina; Bartolini, Erika; Benaroya-Milshtein, Noa; Bodmer, Benjamin; Bognar, Emese; Burger', Bianka; Buttiglione, Maura; Cardona, Francesco; Vela, Marta Correa; Creti, Roberta; Dietrich, Andrea; Debes, Nanette M.; Efstratiou, Androulla; Ferro, Maria Cristina; Fremer, Carolin; Garcia-Delgar, Blanca; Gariup, Maria; Georgitsi, Marianthi; Gulisano, Mariangela; Hagen, Annelieke; Hagstrom, Julie; Hedderly, Tammy J.; Heyman, Isobel; Hoekstra, Pieter J.; Huyser, Chaim; Imperi, Monica; Karagiannidis, Iordanis; Laviola, Giovanni; Macri, Simone; Madruga-Garrido, Marcos; Margarit, Immaculada; Marotta, Anna; Martino, Davide; Meier, Ute C.; Mir, Pablo; Mo, Natalie; More, Astrid; Mueller-Vahl, Kirsten; Muenchau, Alexander; Nagy, Peter; Neri, Valeria; Openneer, Thafra J. C.; Orefici, Graziella; Paschou, Peristera; Pellico, Alessandra; Petruzzelli, Onofrio; Porcelli, Cesare; Redondo, Marina; Rizzo, Renata; Roazzi, Paolo; Roessner, Veit; Ruhrman, Daphna; Schnell, Jaana M. L.; Schrag, Anette; Schutze, Gregor A.; Schwarz, Markus J.; Silvestri, Paola Rosaria; Skov, Liselotte; Steinberg, Tamar; Stober, Sara; Tallon, Marco; Tarnok, Zsanett, In Tourette Syndrome (TS) a role for autoantibodies directed against neuronal proteins has long been suspected, but so far results are still inconsistent. The aim of this study was to look for antibodies to specific or undefined neuronal proteins that could be involved in the aetiology of the disease. Sera from children with Tourette Syndrome or another chronic tic disorder (TS/TD), collected as part of the longitudinal European Multicenter Tics in Children Study, were investigated. Participants included 30 siblings of patients with TS/TD prior to developing tics (preclinical stage) and the same children after the first tic onset (onset), and 158 patients in the chronic phase undergoing an acute relapse (exacerbation). Presence of antibodies binding to rodent brain tissue was assessed by immunohistology on rat brain sections and by immunofluorescent staining of live hippocampal neurons. Live cell-based assays were used to screen for antibodies to NMDAR, CASPR2, LGI1, AMPAR and GABAAR. Immunohistology indicated evidence of antibodies reactive with brain tissue, binding mainly to the hippocampus, the basal ganglia or the cerebellum in 26/218 (12%), with 8% of the preclinical or onset sera binding to the dentate gyrus/CA3 region or cerebellum. Only two individuals (one pre-clinical, one chronic) had antibodies binding the NMDAR and the binding was only weakly positive. No other specific antibodies were detected. Despite some immunoreactivity towards neuronal antigens on brain tissue, this was not mirrored by antibodies binding to live neurons, suggesting the presence of non-specific antibodies or those that bind non-pathogenic intracellular epitopes. NMDAR or the other neuronal surface antibodies tested were very infrequent in these patients. The evidence for pathogenic antibodies that could be causative of TS is weak.

Aberrant oscillatory activity has been hypothesized to play a role in the pathophysiology of Tourette's syndrome (TS). Deep brain stimulation (DBS) has recently been established as an effective treatment for severe TS. Modulation of symptom-specific oscillations may underlie the mechanism of action of DBS and could be used for adaptive neuromodulation to improve therapeutic efficacy. The objective of this study was to demonstrate a pathophysiological association of pallidal and thalamic local field potentials (LFPs) with TS.Nine medication-refractory TS patients were included in the study. Intracerebral LFPs were recorded simultaneously from bilateral pallidal and thalamic DBS electrodes. Spectral and temporal dynamics of pallidal and thalamic oscillations were characterized and correlated with preoperative Yale Global Tic Severity Scale (YGTSS) scores.Peaks of activity in the theta (3-12Hz) and beta (13-35Hz) were present in pallidal and thalamic recordings from all patients (3 women/6 men; mean age, 29.8 years) and coupled through coherence across targets. Presence of prolonged theta bursts in both targets was associated with preoperative motor tic severity. Total preoperative YGTSS scores (mean, 38.1) were correlated with pallidal and thalamic LFP activity using multivariable linear regression (R² = 0.96; p = 0.02).Our findings suggest that pallidothalamic oscillations may be implicated in the pathophysiology of TS. Furthermore, our results highlight the utility of multisite and -spectral oscillatory features in severely affected patients for future identification and clinical use of oscillatory physiomarkers for adaptive stimulation in TS. Ann Neurol 2018;84:505-514.

Inhibitory oscillatory mechanisms subserving tic compensation have been put forward in Tourette syndrome. Modulation of the beta rhythm (15-25 Hz) as the well-established oscillatory movement execution-inhibition indicator was tested during a cognitive-motor task in patients with Tourette syndrome.Performing a Go/NoGo task, 12 patients with Tourette syndrome and 12 matched controls were recorded using whole-head magnetoencephalography.Compared to healthy participants, patients showed less beta suppression in the sensorimotor area and enhanced beta power in parieto-occipital brain regions contralaterally to the response hand. Average beta power and power gain correlated negatively with tic severity.Increased motor inhibitory as well as visuomotor attentional processes are likely to subserve tic compensation. Correlational results suggest that stronger inhibitory compensation accompanies less tic severity.

The classification of tic disorders has been revised in the new fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The previously expressed suggestion to categorize tic disorders within the "Anxiety and Obsessive Compulsive Disorders" was not implemented. The section "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence" was revised and renamed as "Neurodevelopmental Disorders." Tic disorders are classified there as movement disorders. Most of the changes are distinct improvements from both a clinical and a scientific perspective. For example, by removing the adjective "stereotype," the definition of tics is more precise and unified. Also, the new time-oriented criteria are more practical in the clinical setting, e.g., the exclusion criterion of a tic-free interval more than 3 months given for chronic tic disorders has been deleted. The renamings from "Transient" to "Provisional Tic Disorder" as well as from "Chronic" to "Persistent Tic Disorder" are welcome changes from a clinical perspective. Overall, the revision of the criteria is an important step towards providing more clarity and feasibility. However, the revised classification of tic disorders is still based only on clinical experience and not on evidence. Future studies should show whether the revised and improved criteria truly provide the optimal classification.In der neu erschienenen, fünften Ausgabe des Diagnostic and Statistical Manual of Mental Disorders (DSM-5) wurde die Klassifikation von Tic-Störungen überarbeitet. Der im Vorfeld geäußerte Vorschlag, Tic-Störungen bei «Angst- und Zwangsstörungen» einzuordnen, hat sich nicht durchsetzen können. Der Abschnitt «Störungen, die gewöhnlich zuerst im Kleinkindalter, in der Kindheit oder Adoleszenz diagnostiziert werden», wurde überarbeitet und in «Entwicklungsstörungen» (Neurodevelopmental Disorders) umbenannt. Tic-Störungen wurden dort unter der Überschrift «Bewegungsstörungen» eingruppiert. Die meisten Änderungen stellen sowohl aus klinischer als auch aus wissenschaftlicher Sicht eine eindeutige Verbesserung dar. So ist die Definition von Tics durch das Entfernen des Adjektivs «stereotyp» präziser und wurde vereinheitlicht. Die nun mehr gültigen Zeitkriterien sind im klinischen Alltag praktikabler: z. B. wurde das Ausschlusskriterium eines tic-freien Intervalls von mehr als drei Monaten bei persistierenden (chronischen) Tic-Störungen ersatzlos gestrichen. Sowohl die Umbenennung von «vorübergehender» in «vorläufige Tic-Störung» als auch von «chronischer» in «persistierende Tic-Störung» sind aus klinischer Sicht zu begrüßen. Insgesamt ist mit der Überarbeitung der Kriterien ein wichtiger Schritt hin zu mehr Klarheit und Praktikabilität gelungen. Allerdings orientiert sich auch die nun in revidierter Fassung vorliegende Klassifikation von Tic-Störungen weiterhin ausschließlich an klinischen Merkmalen, ohne dass es hierfür eine wissenschaftliche Evidenz gibt. Zukünftige Studien werden zeigen müssen, ob dies dauerhaft gerechtfertigt ist.

Brain imaging has shown altered corpus callosum (CC) morphology in patients with Gilles de la Tourette syndrome (GTS). Yet it is unclear whether these morphological changes are associated with altered interhemispheric interactions. Here, we combined transcranial magnetic stimulation (TMS) with diffusion tensor magnetic resonance imaging (DTI) to explore functional and structural interhemispheric connections between the left and right motor hand areas. We studied 14 unmedicated GTS patients without psychiatric comorbidity (2 women, mean age 35.5 years) and 15 healthy volunteers (3 women, mean age 35 years). Left-to-right and right-to-left interhemispheric inhibitions (IHIs) were measured in hand muscles with TMS. In 13 GTS patients and all healthy controls, we measured fractional anisotropy (FA) with DTI to examine the relation between functional measures of interhemispheric connectivity as derived by TMS and structural properties of the CC region that carries fibers interconnecting both motor cortices. In GTS patients, left-to-right IHI was weaker than right-to-left IHI. Left-to-right IHI in GTS patients was also reduced compared with healthy controls. Voxel-based morphometric analysis revealed that FA in the motor region of the CC did not differ between groups. However, there was a significant interaction between groups and the relation between regional FA and left-to-right IHI in the motor region of the CC. A negative linear relation between FA and left-to-right IHI was present in control subjects but not in patients. Our combined TMS-DTI approach demonstrates abnormal functional interhemispheric connectivity in GTS accompanied by an altered structure-function relationship in the motor CC.

To investigate the health-related quality of life (HrQoL) of adult patients with Gilles de la Tourette's syndrome (GTS) in Germany. HrQoL was evaluated in 200 adult patients with GTS (Mean age: 34.9 +/- 11.8 years). Patients were recruited from three outpatient departments in Germany and completed a semi-structured, self-rating interview. HrQoL was measured using the EQ-5D. Depression was assessed using the Beck's depression inventory (BDI) and clinical symptoms using the Yale Tourette syndrome symptom list (TSSL) and the Shapiro Tourette-syndrome severity scale (STSSS). Multivariate regression analyses were performed to identify independent predictors of HrQoL. Patients with GTS proved to have a worse HrQoL than a sample from the general German population. The domains most affected were anxiety/depression (57.1%), followed by pain/discomfort (47.5%), usual activities (38.4%), mobility (14%), and self-care (6.6%). The mean EQ-5D visual analog scale (EQ-VAS) was 65.4 +/- 21.9. The patients had a mean BDI score of 12.3 +/- 9.9, which was considerably worse compared to a healthy group who had a score of 6.45 +/- 5.2. The mean STSSS value was 3.2 +/- 1.1. In multivariate analyses, depressive symptoms contributed considerably, whereas the severity of symptoms as well as age only contributed minimally to HrQoL in the model (R(2) = 0.54). HrQoL is considerably reduced in adult patients with GTS. The main independent factors for determining HrQoL were depression, severity of symptoms, and age. Although, treatment of tics is important, co-morbidities such as depression should be diagnosed and treated vigorously.