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Periodic Report Summary 3 - TACTICS (Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes)

Project Context and Objectives:
The overall objective of TACTICS is to identify, over a 5-year period, the neural, genetic and molecular factors involved in the pathogenesis of compulsivity in (i) normally developing children and adolescents, (ii) high risk samples, i.e. children and adolescents with attention-deficit hyperactivity disorders (ADHD), and (iii) children and adolescents with specific disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorders (OCD), impulse control disorders (ICD) and behavioural addictions. Compulsivity is defined as the repetitive, irresistible urge to perform a behaviour, the experience of loss of voluntary control over this intense urge, the diminished ability to delay or inhibit thoughts or behaviours, and the tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity-related disorders (ADHD, ASD, OCD, ICD, Substance Use Disorder and behavioural addictions) have a high prevalence (together affecting more than 10% of youth) and are associated with an enormous burden for patients and their families and society in general. TACTICS takes a developmental neuroscience perspective at these disorders, applies a dimensional and cross-disorder framework, and in particular examines structure and function of the fronto-striatal circuits and the modelating role of glutamate therein.

The specific objectives for the reporting period are:

(WP1) Further MR imaging profiling of the rat quinpirole model of compulsivity and further phenotypic and MRI characterisation of dysregulated insulin signalling in a Type II diabetes mouse model (the TALLYHO mouse) as a potential new model of compulsivity.

(WP2) Characterize developmental changes in a) morphometry, b) white matter integrity, and c) functional connectivity in the fronto-striatal circuit from the juvenile to adolescent phase in an appropriate rodent model of compulsivity, as determined in WP1, with similar neuroimaging protocols as in WP4, and analysis tools as in WP7. Identify effects of memantine as a promising therapeutic drug, as selected in WP1, on functional activation of the fronto-striatal system in rats with compulsive behavior.

(WP3). Examine the relationship between variation in glutamate measured by Magnetic Resonance Spectroscopy and symptom severity within, and across, each clinical phenotype (ASD, OCD, controls)

(WP4) To collect a new cohort of children with ASD, OCD and controls (N=180) to replicate common neural, neurocognitive and genetic mechanisms underlying compulsive behaviors across different clinical phenotypes in a longitudinal design, to identify disease-modifying factors (OCD, ASD) of these neural, neurocognitive and genetic mechanisms, to replicate high-risk profiles and/or biomarkers for the compulsivity trait.

(WP5) Identification of new candidate genes for compulsive behavior from the results of genome-wide association studies (GWAS) and integration of the findings from these studies with data available from the GWAS of the Obsessive Compulsive Foundation Genetics Collaborative (>2000 OCD cases) and the Psychiatric GWAS Consortium (PGC).

(WP6) Selection of glutamatergic medication for clinical studies and perform proof-of-concept randomized clinical trials in clinical populations of children and adolescents with compulsivity disorders (OCD, ASD) to document efficacy and safety of glutamatergic medications.

(WP7) Develop Bayesian machine learning techniques for robust feature selection and marker relevance determination for individual, single source, prediction tasks (Task 1). Apply the developed approach to data gathered in WP1 and existing data in NeuroIMAGE and BIG (Task 2).

(WP8) Increase the visibility of TACTICS by reaching out to the scientific community, industry, patient organisations and other interested or potential stakeholders.

(WP9) Ensure that the studies will be conducted in according to the highest ethical standards, i.e. in compliance with European Directive 86/609/EEC, the Recommendation 2007/526/65/EC, ICH Good Clinical Practice (GCP), Declaration of Helsinki and the legal regulations of the European Union, national legislations and local animal use and medical ethical committees.

(WP10) Ensure the proper functioning of the project and foster collaboration and results.

Project Results:
WP1. Work has been completed in six animal models of compulsivity. Phenotypic data on the seventh animal model, the SLITRK5 -/- mouse model reported in the literature could not be reproduced. As an alternative we will investigate the role of another impulsivity associated gene ANK3, and determine if it also has a compulsive phenotype.

Results. The effects of memantine and riluzole were not very robust across animal models, gender and experimental manipulations. Therefore, these animal experiments do not support a major role for glutamate involvement in the pathophysiology of compulsivity. The link between insulin signalling and compulsivity has been validated in vivo: (i) compulsive phenotype of the type II diabetes TALLYHO mouse in reversal learning, appetitive extinction and spontaneous alternation and (ii) reduction of compulsive checking induced by quinpirole by the anti-diabetic drug metformin. We identified a number of genetic substrates for further investigation validation including KCNQ1, MEIS2, IGFR1/2 (insulin pathway) and 4 novel microRNAs. A conditional knockout mouse of KCNQ1 within brain is currently being produced at GenOway.

WP2. The quinpirole OCD model has been chosen for all MR studies. The model has been adapted to focus on the development of OCD at juvenile/adolescent age. Animals developed OCD-like checking behavior which agrees with results in WP1 and findings in the literature for adults.

Results. The white matter integrity of the internal capsule and corpus callosum was different (i.e. higher FA values) in animals which developed OCD as compared to controls. The functional connectivity between interhemispheric prefrontal cortical areas and interhemispheric striatal areas decreased during development in OCD animals. This was not observed in controls. Memantine injection resulted in brain activation responses in prefrontal areas in control adolescent animals. This effect was not observed in age-matched OCD animals. Memantine did not induce activation responses in striatal areas in adolescent OCD and control animals.

WP3. MRS spectra were collected for 143 out of 163 participants. Because of issues with spectral quality or image segmentation, spectra were included from 133 subjects for the anterior cingulate cortex (ACC) and for 114 subjects for the striatum.

Results: A group difference was found for corrected glutamate levels in the ACC, while including gender, medication status and scanner site as covariates. Post-hoc tests showed higher glutamate in the ACC of the ASD & OCD groups combined compared with control subjects. There was no significant difference in glutamate levels between the two disorder groups. In smaller groups of medication naïve subjects and comorbidity-free subjects, this difference in glutamate levels was still found. Dimensional analysis showed a positive correlation between ACC glutamate levels and compulsivity measured with the Repetitive Behaviour Scale (RBS), but not with the RBS total score.

WP4. We have completed collection of wave-1 of a new cohort of patients with ASD, OCD and controls, and continued analyses of the NeuroIMAGE data set.

Results: Smokers in contrast to non-smokers lacked the expected lower connectivity between the anterior putamen and ACC during inhibition in smokers. Inattention and hyperactivity/impulsivity symptom scores (but not categorical ADHD case-control differences) were associated with increases in functional connectivity in the networks of posterior putamen and ventral caudate.
We could not corroborate previous evidence for functional connectivity alterations between key reward processing regions in adolescents and young adults with ADHD.
The glutamate gene-set revealed association to severity of hyperactivity/impulsivity and autism symptoms.

WP5. We integrated findings from various GWAS studies on OCD, andperformed a large international analysis of subcortical brain regions altered in ADHD based on the ENIGMA-ADHD Working Group.

Results. Rigidity trait in the population is associated with risk genes for clinical ASD, especially the MET gene. Patients with ADHD have smaller volumes in several compulsivity-associated subcortical brain regions.

WP6. Memantine was selected for further piloting in clinical studies. A medical-ethics protocol has been submitted to ethics committees and approved in 2 sites (2 other sites pending). Lundbeck has provided memantine and matching placebo tablets, and has become a partner of the TACTICS consortium.

WP7. We have developed Bayesian machine learning techniques for robust feature selection and marker relevance determination for individual, single source, prediction tasks, and applied these algorithms on existing datasets. Inattention appears to be driving severity of hyperactivity and impulsivity.

WP8. We have more than 15 papers published/submitted, given several lectures on TACTICS related topics, published a video paper presenting our signal attenuation model, and organized a TACTICS symposium at the ECNP congress in Amsterdam 2015, and will have lectures on TACTICS results at the Eunethydis meeting on ADHD in Berlin 2016.

WP9. Ethics approval has been obtained for all animal studies and human studies, except that approval for the medication study in WP6 is pending in 2 sites.

WP10 is going according to plan. Six-monthly face-to-face meetings have been organised as planned and monthly telephone conferences are held with all WP leaders (Steering Committee). Two amendments have been filed in the last period. The third periodic report was prepared and submitted in time.

Potential Impact:
WP1. We will further characterize the ANK3 model, and conditional knockout mouse of KCNQ1 when is has been produced at GenOway. The profiling of novel microRNAs within tissue from the rat signal attenuation task and the proteomic analysis in brain tissue from the orbitofrontal cortex and striatum of the rat quinpirole will provide more insights in the relevance of new compulsivity/impulsivity genes.

WP2. Further examination of the effects of Memantine on the neural correlates of compulsivity in the rat models will add to more clarity of the involvement of glutamate in modulating the function and structure of the fronstriatal circuits and will be matched with data from the human studies in WP3, WP4 and WP6.

WP3 - WP4. The initial cross-sectional and later longitudinal analysis of cognitive and multiple domain MRI data of patients with ASD, OCD, ADHD, TS and controls will provide us with a very comprehensive picture of the neural and cognitive correlates of compulsivity across disorders, and across age and gender.

WP5. Together with WP1, we will further investigate the link between insulin signalling and compulsivity, and validate the involvement of insulin signalling in compulsivity. We will further continue bioinformatics analysis and genetic network building, and conduct imaging-genetic analysis within the context of the large international consortia as ENIGMA and the Psychiatric GWAS Consortium. This will provide more insight into already known and new genes involved in compulsivity and their cognitive and neural mechanisms.

WP6. The placebo-controlled proof of concept study with Memantine in patients with OCD and ASD with MRI assessment pre- and posttreatment will provide with data that allow evaluating the clinical significance of glutamatergic interventions in modulating the neural basis of compulsivity across disorders, and deciding on strategies for further phase-III studies. The adding of Lundbeck to the TACTICS consortium together with the spin-out company SENSA will facilitate further clinical development of Memantine, pending positive evaluations.

WP7. We expect further application of Bayesian machine learning techniques on the animal and human data-sets of TACTICS to contribute to developing biomarkers for compulsivity, impulsivity and (risk for) addiction. The biomarkers will need to be validated in independent datasets for use in future clinical medication studies.

Overall, TACTICS is expected to provide with a very thorough animal-hum integrated view on the role of the frontostriatial circuits in compulsivity disorders (ASD, OCD, ADHD and Tourette syndrome), and the general and disorder-specific modulating role of glutamate thereby. In addition, TACTICS will provide us with several new genetic leads and mechanisms (among which the insuline pathway) that underline compulsivity and its related clinical disorders.

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