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Natalia Szejko,1– 4 Kirsten R Müller-Vahl2 1Division of Neurocritical Care, Department of Neurology, Yale University, New Haven, CT, USA; 2Clinic of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany; 3Department of Neurology, Medical University of Warsaw, Warsaw, Poland; 4Department of Bioethics, Medical University of Warsaw, Warsaw, PolandCorrespondence: Natalia SzejkoDivision of Neurocritical Care, Department of Neurology, Yale University, 15 Lock Street, New Haven, CT, USAEmail natalia.szejko@yale.eduAbstract: Tourette syndrome (TS) is characterized by the presence of vocal and motor tics with an onset in childhood. In almost 80% of patients psychiatric comorbidities coexist, particularly, attention deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) or behavior (OCB), depression, anxiety, rage attacks, and self-injurious behaviour (SIB). In this review, we discuss current state of the art regarding diagnosis and assessment of tics and OCD in patients with TS as well as challenges related to differential diagnosis between tics and OCD-related phenomena based on a systematic literature search. While in most cases clinical symptoms can be easily classified as either tics or OCB/OCD, some phenomena lay on the frontier between tics and compulsions/obsessions. For example, compulsions may resemble tics and, vice versa, sequences of motor tics may be misdiagnosed as compulsions. Accordingly, the terms “compulsive tics” and “cognitive tics” have been introduced. The most common and typical OCD symptom in patients with TS are “just right” phenomena, which also may show an overlap with tics, since patients may perform tics repeatedly until this feeling is achieved. Similarly, repetitive behaviors in patients with TS may manifest in a more “tic-like” or a more “OCD-like” type. Furthermore, SIB shows similarities with both tics and OCD. Until today, it is unclear how to classify this symptom best, although from most recent research a closer relationship between SIB and tics is suggested. In this review, in addition, we illustrate differences of the clinical spectrum of OCD in patients with TS compared to those with “pure OCD” without tics. To assess tics, the revised version of the Yale Global Tic Severity Scale (YGTSS-R) should be used, while for the assessment of OCD, the Yale Brown Obsessive Compulsive Disorder Scale (Y-BOCS) is recommended. Finally, we briefly summarize treatment strategies for tics and OCB/OCD in patients with TS.Keywords: Tourette syndrome, obsessive-compulsive disorder, obsessive-compulsive behavior, comorbidities, tics

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.

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity., Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined., Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects., Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Cannabinoids, including tetrahydrocannabinol and cannabidiol, are the most important active constituents of the cannabis plant. Over recent years, cannabinoid-based medicines (CBMs) have become increasingly available to patients in many countries, both as pharmaceutical products and as herbal cannabis (marijuana). While there seems to be a demand for multiple cannabinoid-based therapeutic products, specifically for symptomatic amelioration in chronic diseases, therapeutic effects of different CBMs have only been directly compared in a few clinical studies. The survey presented here was performed by the International Association for Cannabinoid Medicines (IACM), and is meant to contribute to the understanding of cannabinoid-based medicine by asking patients who used cannabis or cannabinoids detailed questions about their experiences with different methods of intake. The survey was completed by 953 participants from 31 countries, making this the largest international survey on a wide variety of users of cannabinoid-based medicine performed so far. In general, herbal non-pharmaceutical CBMs received higher appreciation scores by participants than pharmaceutical products containing cannabinoids. However, the number of patients who reported experience with pharmaceutical products was low, limiting conclusions on preferences. Nevertheless, the reported data may be useful for further development of safe and effective medications based on cannabis and single cannabinoids.

The endogenous cannabinoid system was first described in 1988. There are two specific receptors, the CB2-receptor, located in the lymphatic system (spleen, lymphocytes), and the CB1-receptor occurring predominantly in the central nervous system. The CB1-receptor shows a distinct distribution in the CNS with a very high density in the cerebellum, the basal ganglia and in the hippocampus. In 1992 endogenous ligands of the cannabinoid system were discovered for the first time (e.g. anandamide and 2-arachidonylglycerol). The physiological role of these arachidonic acid derivates is still unclear. Implications of these recent discoveries for the Gilles de la Tourette syndrome, ischaemic brain lesions, schizophrenic psychoses and opiate drug dependence are described. A dysregulation in the endogenous cannabinoid/anandamide system could possibly play an import role in the etiology of Gilles de la Tourette syndrome and schizophrenic psychoses; administration of cannabinoids affects the symptoms of the Gilles de la Tourette syndrome positively, whereas cannabinoids probably have rather negative effects in schizophrenic psychoses. In ischaemic brain lesions cannabinoids seem to have a neuroprotective effect; they appear to minimize the extent of a lesion by reduction of glutamate release. Additionally the meaning of the endogenous cannabinoid system for the development of opioid drug dependency is discussed and interactions between the endogenous opioid system and the endogenous cannabainoid system are pointed out. This is of interest since it could be shown in animal experiments that the absence of CB1 receptors reduces the positive reinforcement of opiate administration.