Compulsive patterns of behaviour in Autism Spectrum Disorder and Obsessive Compulsive Disorder

Compulsivity is a cross-disorder trait underlying phenotypically distinct
psychiatric disorders that emerge in (early) childhood (ASD, OCD), or
adolescence (addiction to substance use). 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 (Chamberlain et al. 2006).
Autism Spectrum Disorders (ASD) are characterized by deficits in (i) reciprocal
social interaction and (ii) communication, and by (iii) restricted, repetitive
and stereotyped patterns of behaviour, interests and activities. ASD have onset
prior to age 3, and a strong persistence over time in childhood, over
adolescence and into adulthood.
Obsessive Compulsive Disorders (OCD) are characterized by repetitive thoughts,
impulses or images (obsessions) and repetitive behaviours or mental acts
(compulsions). It has its onset in late childhood.
Repetitive and compulsive behaviours are core features of both ASD and OCD. In
this study the focus will be on compulsive behaviours across the two different
clinical phenotypes and the developmental links between compulsivity,
impulsivity and addiction.
Compulsivity and the closely associated impulsivity trait are characterized by
behavioural disinhibition maintained by maladaptive fronto-striatal circuits.
Increased activity in the striatal components or decreased activity in the
prefrontal components may result in an increased automatic tendency for
executing impulsive or compulsive behaviours, depending on the sub-component
affected. As to date studies have typically investigated prefrontal and
striatal areas in isolation, we will focus on abnormalities in functional and
anatomical brain connectivity between the various prefrontal components and the
components of the striatum.
Furthermore, glutamatergic imbalance in fronto-striatal regions has been
observed in childhood OCD. This suggests that impaired functioning of both
frontal and striatal areas may be due to a common underlying pathophysiology,
such as dysregulation of glutamatergic mechanisms and glutamatergic genes.
The biological determinants that contribute to the pathogenesis of several
dysfunctions are poorly defined and no well-characterized biomarkers are
available. Therefore, we will also explore potential biomarkers.

The two primary objectives are to test the hypothesis that (1) structural and
functional abnormalities of the fronto-striatal circuits are related to the
development of compulsive and impulsive behaviour in ASD and OCD; and that (2)
the glutamate system a key modulator is in these fronto-striatal circuits.
Secundary exploratory objectives are: identify genetic mechanisms underlying
compulsive behaviours in high risk subjects and controls, and identify
biomarkers for the compulsivity trait.

This study has a mixed cross-sectional longitudinal design with assessments at
two points, three years apart. Measurements will be: MRI (sMRI, fMRI, DTI,
rsMRI), MRS, cognition, and behaviour. These measurements will be standardized
across four centres (Nijmegen, Utrecht, London, Mannheim). We will study the
fronto-striatal circuits by using MRI techniques and study the glutamate system
by using MRS.
In addition to extensive MRI and MRS measures, psychiatric and behavioural
phenotypes will be collected, including measures of (a) rigid and compulsive
patterns of behaviour that are appropriate for these disorders, (b)
impulsivity-related behaviours, and measures of (c) addiction. Serum will be
collected for genetic analyses and for biomarkers.

The proposed study includes an invasive measure, namely the collection of a
blood sample, and a MRI session, both at two time points. This is necessary to
identify biomarkers for clinical outcome of pharmocological treatment and, at
the DNA level, to identify common and rare genetic variants.
Children of 8-12 year will be included in this study, as we are investing the
development of compulsive behaviour of early adolescence. This can only be
achieved by studying children as these patterns of behaviour are developing
over early adolescence.
Participants will undergo an hour scanning session in the MRI scanner. The
session will be divided into two separate days. Degree of anxiety and degree of
pleasure will be permanently monitored and explicitly asked of parents and
children. If children show any resistance the procedure will be stopped
immediately. All centres involved have extensive experience with the type of
research we are proposing in this protocol and there are no special risks
associated with this kind of research. The anticipated scientific merits
justify the proposed study. There will be no therapeutic benefit for the
participants.