The pathogenesis of compulsivity

Scientists are investigating the neural, genetic and molecular factors involved in the pathogenesis of compulsivity under the aegis of the project TACTICS (Translational adolescent and childhood therapeutic interventions in compulsive syndromes).

Researchers will identify relevant changes in the structure and function of the brain as well as determine the modulating role of glutamate signalling. In addition, the efficacy of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine, will be assessed.

Compulsivity refers to conditions such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), impulse control disorders and behavioural addictions.

TACTICS discovered potential players in compulsivity, including genetic substrates such as KCNQ1, IGFR1/2 (insulin pathway) and four novel microRNAs that need further validation. They are currently producing a conditional knockout mouse model of KCNQ1 within the brain to conduct more studies.

Systematic reviews of studies on ASD, ADHD and OCD patients suggest that neurodevelopmental changes in the frontostriatal glutamatergic circuits in the brain occur across their lifespan. However, results from tests on four animal models of compulsivity did not indicate that glutamate is a major player in the pathophysiology of compulsivity.

In parallel, researchers established standard operating procedures for their longitudinal observational study on patients with OCD and ASD and obtained necessary ethical approvals. This study will measure glutamate to assess how glutamate signalling affects compulsive and impulsive behaviours across different clinical phenotypes.

Another major undertaking is the analysis of several data sets from cohorts such as NEUROIMAGE and BIG. For this purpose, TACTICS developed Bayesian machine-learning techniques to ensure robust feature selection and marker relevance determination. Data collection is ongoing with preliminary results linking particular changes in brain matter with specific conditions such as ASD and ADHD. Genotyping revealed five previously unknown genetic variants that affect brain structure in the basal ganglia region.

TACTICS activities have already led to over 15 papers. By project-end, study outcomes will provide novel insight into the genes and signalling mechanisms associated with compulsivity or impulsivity. These could then be therapeutically targeted to alleviate the socioeconomic burden of such disorders and improve patients' quality of life.