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EMTICS Report Summary

Project ID: 278367
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 3 - EMTICS (European Multicentre Tics in Children Studies)

Project Context and Objectives:
The European Multicentre Tics in Children Studies (EMTICS) undertake pre-clinical and cohort studies that address susceptibility factors for paediatric and adolescent tic disorders, with a particular focus on comorbid obsessive-compulsive symptomatology, from clinical, epidemiological, genetic, microbiological and immunological angles.
Tic disorders are common, childhood-onset neuropsychiatric conditions and are characterised by the presence of multiple sudden, rapid, recurrent, and non-rhythmic movements (motor tics) and/or utterances (vocal tics). Tics and their associated neuropsychiatric symptoms have been found to negatively impact the quality of life as well as social and academic functioning and lifetime achievements of patients. On top of that, tic symptoms are extremely troubling to family members of affected individuals, and the entire family is often in need of care and counselling. Apart from tics, many individuals with tic disorders experience additional neurobehavioral problems such as inattention, hyperactivity and impulsivity, and obsessive-compulsive symptoms (recurrent and persistent intrusive thoughts, impulses or images and/or repetitive behaviours or mental acts).
The cellular and molecular basis of tic disorders is not well understood and their aetiology is still incompletely known. Based on pharmacological and neuroimaging data, attention has focused on frontal-cortical-striatal circuitry and dopaminergic neurotransmission underlying the control of motor, cognitive and emotional functioning, although the exact mechanisms leading to a derangement of these regulatory pathways remain elusive. In addition, other neurotransmitter systems, e.g. glutamatergic, gamma-aminobutyric acid (GABA)-ergic, serotonergic and cholinergic systems, may also play a role in the pathogenesis of the core features of tic disorders.
EMTICS aims to elucidate the complex aetiology of the onset and clinical course of chronic tic disorders and associated obsessive-compulsive symptoms, through disentangling the interplay between environmental factors and genetic background; translate research findings into clinical applications by developing disease prediction models and investigating a treatment strategy; and will establish a Pan-European infrastructure for the study of tic disorders. We hypothesise that the onset and/or exacerbation of tic and comorbid obsessive-compulsive disorders is associated with increased preceding occurrence of Group A beta-haemolytic Streptococcus (GAS) infections of specific molecular subtypes, and that this association is based on genetic susceptibility factors and mediated through immunological mechanisms related to psychosocial stress and immunological factors in host and GAS strains. Large-scale cohort studies involve affected patients (COURSE stud; N=719) and at-risk first-degree relatives (ONSET; N=263) within an integrated, multidisciplinary research strategy. Treatment effects of active surveillance and standardized antibiotic treatment of GAS colonisation, thus addressing one of the main environmental factors involved (GAS infections), are being evaluated. Our approach will result in the identification of genetic and environmental susceptibility factors and will greatly contribute to a better understanding of the underlying mechanisms of tic disorders, with a focus on elucidating the role of autoimmunity. Our consortium has brought together the highest expertise in the field of tic disorders across Europe in academia and industry, including a number of SMEs and a professional management company.

Project Results:
EMTICS has now been running for 54 months. In the past period, recruitment for the clinical cohort studies ONSET and COURSE has been finalised, while recruitment for TREATMENT is still ongoing at all involved clinical sites. The treatment trial investigates the effectiveness of antibiotics (compared to placebo) in a randomised controlled trial of children with tics, who have proven to be actual GAS carriers. A core element of EMTICS is the detection of Group A β-Haemolytic Streptococcus (GAS) from carriers with low bacterial density. We validated two microbiological methods that are now used by the clinical centres to isolate GAS.
All clinical data of the cohort studies and the treatment study are continuously being entered into an effective online electronic data capture system. The data system fully protects research participants’ confidentiality. Biobank specimens are currently being collected to be shipped to the various laboratories within EMTICS according to standard operational procedures at a later stage. Our clinical studies fully comply with EU medical-ethical regulations and those of participating countries; and have designed appropriate Informed Consent (parent/guardian) and assent (children/adolescents) procedures. In the next 12 months the genetic, laboratory and clinical data will finally become available, which will allow us to answer our research objectives.
Considerable progress has already been made with an animal model that investigates the hypothesis that repeated exposure to GAS may constitute a vulnerability factor in TS. We exposed developing SJL male mice to four injections with a GAS homogenate and evaluated their neurobehavioral phenotype. In accordance with our predictions, GAS-exposed mice showed increased repetitive and perseverative behaviours, and reduced concentrations of serotonin in the prefrontal cortex of the brain. They also showed remarkable elevations in lactate (an indicator of inflammation) in the prefrontal cortex, a brain area linked to perseverative responding, impulse control, and sensorimotor gating. The presence of active inflammatory processes was further substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon; this profile was not observed in control mice. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behaviour, and result in behavioural and neurological abnormalities.
In an independent set of studies, we investigated the consequences of neonatal exposure to experimental paradigms mimicking environmental stress. We first replicated the data obtained in the previous experiment and then showed that developmental stress interacts with GAS administration in the regulation of the resulting phenotype. A third set of preclinical experiments demonstrated that the administration of pharmacological compounds targeting the endocannabinoid system may reduce the exhibition of TS-like symptoms in mice. This study has been conducted on four different mouse strains, thus demonstrating that the effects of the endocannabinoid agonists generalise to a variable population and do not reflect a strain-specific idiosyncrasy.

Potential Impact:
EMTICS will lead to significant innovations in the field of childhood-onset psychiatry, shed light into the aetiology and pathology of Tourette Syndrome (TS) and related disorders (e.g., Obsessive-Compulsive Disorder [OCD],) and contribute to improved therapies and increased quality of life for affected individuals and their families. Our approach will result in the identification of genetic and environmental susceptibility factors and will contribute to a better understanding of the underlying mechanisms of tic disorders with and without co-occurring paediatric OCD. Through multi-modal combined behavioural and systems neuroscience studies in representative subgroups of children with TS and well defined comorbid disorders EMTICS aims at delineating intermediate phenotypes, which will represent both a pre-requisite for the understanding of consequences of genetic and environmental susceptibility factors at a system level and a means to define susceptibility factors within these system networks. Our project will also enable targeted prevention and health care management strategies to prevent TS and OCD, and new therapies in the form of the appropriate use of antibiotic prophylaxis. This may ultimately enable disease prevention or significant decrease in the incidence of tic disorders and OCD.
As one of the objectives, EMTICS intends to verify if and how a GAS infection can stimulate the onset and/or exacerbation of symptoms in patients with TS. The description of the GAS genetic structure and virulence characteristics isolated from patients with TS, at-risk patients and controls will give a more robust evidence of the involvement of GAS and, possibly of particular bacterial clones, in TS pathology.
A demonstration that GAS can be an environmental trigger of TS can help design new strategies for prevention and therapy, through antibiotic treatment, and offer new possibilities for the prevention and control of the symptomatology. New validated protocols may become available to paediatricians and neuropsychiatrists as supplemental intervention policies in treating TS in the case of GAS colonised children. The results of our treatment trial would further unravel the role of GAS colonisation in the pathogenesis of tic disorders. Results would foster a more evidence-based antibiotic treatment for clinical practice; promote a more appropriate use of antibiotics in patients with tics; promote a decrease in the use of symptomatic psychotropic drugs in patients with tics; establish protocols of active surveillance and treatment in populations at risk for developing tics. The results of panel of responses to GAS antigens of high risk children who do versus those who do not develop tics might be used to develop a prognostic test.
To consider the role of non-streptococcal bacterial, as well as viral, and other microbial infections as potential environmental risk factors for TS/OCD, different specific antibody titres will be determined. The specific pathogen-related responses of the innate and adaptive immune systems will be identified on the level of the cellular immune system, of cytokines and soluble cytokine receptors, and of specific cross-reacting antibodies against neuronal targets. The tryptophan/kynurenine metabolism, which is the link between immune changes and neurotransmitter functions, will be determined in order to detect early neurochemical changes after infection but before the development of tics. This will give us information about the inflammatory response and possible molecular structures for the development of therapeutic targets.
Furthermore, data obtained from the EMTICS projects will provide the basis of building up the first European TS database. Our research activities, therefore, will provide the basis (I) for further genetic analyses, (II) for the characterisation of predictors, (III) and for improved treatment strategies and social support in order to minimise socioeconomic costs of the disease.

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