COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes

Compulsivity and impulsivity are cross-disorder traits that are present across various neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD).

Compulsivity can be defined as the repetitive, irresistible urge to perform certain behaviour, the experience of loss of voluntary control over this intense urge, the diminished ability to delay or inhibit thoughts and behaviours, and the tendency to perform repetitive acts in a habitual or stereotyped manner [1, 2]. Compulsivity is a cross-disorder trait observed in the phenotypically distinct neurodevelopmental disorders ASD and OCD. ASDs have a prevalence of 1.5 % [3, 4] and are characterized by deficits in reciprocal social interaction and communication and by restricted, repetitive and stereotyped patterns of behaviour, interests and activities [5]. OCD, on the other hand, is a relatively common anxiety disorder, characterized by repetitive thoughts, impulses, or images (obsessions), and repetitive behaviours or mental acts (compulsions) that cause marked distress [5]. OCD has its onset in late childhood and is present in about 2.5 % of the adult population [6]. Repetitive behaviours are among the core features of both ASD and OCD, and comparison of symptom characteristics has demonstrated more similarities than differences [7]. In addition to symptom overlap, similar executive function impairments related to inhibiting compulsive behaviours have been reported in first degree relatives of people with ASD and OCD [8]. Compulsivity can be seen as an overarching concept that includes both the failure to resist an impulse, which links it to impulsivity, and maladaptive habitual patterns of behaviours, which relates to addictive behaviour.

Impulsivity is described as a predisposition toward rapid unplanned reactions to internal or external stimuli with diminished regard to the potentially negative consequences of these reactions [2]. Impulsivity is one of the core characteristics of ADHD. ADHD is characterized by clinically significant levels of hyperactivity, impulsivity and/or inattention and is affecting about 5 % of all school-age children world-wide [9, 10]. About 40 % of children with ADHD have comorbid ASD (e.g. [11‐13]). Further, prevalence of OCD in children with ADHD is estimated at 8 %, which is a 2-3 fold increase compared to non-ADHD children [7, 14]. There are strong similarities between the uncontrollable behaviour based on impulsivity (seen in ADHD) and the excessive and unwanted rituals related to compulsivity [15].

Addictive behaviour is characterized by both impulsivity and compulsivity [16]. One shows compulsive drug-seeking, loss of control in limiting this intake, and the emergence of a negative emotional state reflecting a motivational withdrawal syndrome, when access to the drug is prevented. Impulsivity often dominates early stages of addiction, while compulsivity becomes important in later stages. See Fig. 1 for the relation between compulsivity, impulsivity and addictive behaviour in different disorders.

Separate but intercommunicating cortico-striatal circuits seem to be involved in impulsivity and compulsivity [2, 17]. In the impulsive circuit, a striatal component (nucleus accumbens) may drive impulsive behaviours, and a prefrontal component (anterior cingulate (ACC), ventromedial prefrontal cortex) exerts inhibitory control. Similarly, compulsive behaviour may be driven by a striatal component (caudate, putamen), which is controlled by the orbitofrontal cortex (OFC). Increased activity in the striatum and/or decreased activity in the prefrontal cortex (PFC) may alter the functioning of these cortico-striatal circuits and cause impulsive or compulsive disorders, both characterized by deficits in response inhibition. Although, in contrast to impulsivity, compulsivity is considered a maladaptive perseveration of behaviour that does not fall within the range of normal behaviour [15], both patterns of behaviour often co-occur [18, 19].

Compulsivity-related disorders differ in their age of onset. ASD starts very early in life, ADHD in early childhood, and OCD has its onset in late childhood or early adolescence. This variation in onset of impulsivity/compulsivity may be related to variation in the maturation of the fronto-striatal circuits and the role of glutamate within these circuits. Recent theories suggest that striatal brain regions underlying impulsive and compulsive behaviours may show a nonlinear developmental pattern with a peak inflection between 13 and 17 years of age [20]. The prefrontal regions on the other hand, which are important for top-down regulation of (striatum-driven) impulsive and compulsive behaviour, show a more linear pattern of maturation well into young adulthood.

Glutamate is the major excitatory neurotransmitter in the human brain and is critical to the understanding of the top-down control of the prefrontal cortex over the dorsal and ventral striatum [21]. The impulsivity- and compulsivity-related fronto-striatal circuits are notable for their relatively rich glutamatergic receptor density. Glutamate modulates the neural activity and metabolism of these circuits, as is reflected by the effects of glutamate on synapse induction and elimination as well as synaptic transmission via ionotropic and metabotropic glutamate receptors [22]. Indeed, glutamatergic projections from the prefrontal sub-regions to the striatum are already known to play a key role in various compulsive and impulsive behaviours including repetitive behaviours such as stereotypy seen in ASD, impulsivity seen in ADHD, and feelings of loss of control seen in OCD (for a review, see [23]).

The study of genetics offers an opportunity to gather additional evidence for the role of glutamate. Many compulsivity- and impulsivity-related disorders are substantially heritable but genetically very complex, with multiple genetic factors of varying penetrance implicated [10, 24, 25]. A number of candidate genes have been identified, suggesting glutamatergic pathways to operate in ASD, ADHD, and OCD. For example, variation in genes encoding the glutamate transporters SLC1A1, SLC1A2, and SLC1A3 are strong candidate genes for both ASD and OCD [26]. In addition, genes encoding the NMDA receptors GRIN2A and GRIN2B have been implicated in ASD ([27], and GRIN2B has also been associated with ADHD [28] and OCD [29]. While glutamate has an important role in the neurobiology of compulsivity and impulsivity and the related disorders, it is certainly not the only biological substrate involved. For example, we have recently identified central insulin signalling as an additional molecular cascade involved in OCD [30] and neurite outgrowth as a neurodevelopmental process implicated in ADHD [31] and ASD [32]. Genetic variation in such genes is likely to alter their regulation and/or function, leading to changes in the encoded proteins and biological processes contributing to proper cell function. Brain structure and brain function, also highly heritable, may mediate the effects of the variation in genes and proteins on compulsive and impulsive behaviours and related disorders [32, 33]. See Fig. 2 for a representation of this relation between genes, cell functioning, brain and behaviour.

The COMPULS database will offer the unique opportunity to study several key aspects of compulsivity in a large cohort of ASD, ADHD, and OCD patients. By assessing neural and cognitive systems during the critical period of transition from childhood to adolescence across disorders, we can investigate stability and changes of neural systems, which seem to be critical in the development of compulsive behaviour. Integrating data from cognitive, neural, and genetic markers linked to compulsivity can largely increase our understanding of neural mechanisms involved in compulsivity and related disorders. Additionally, by using a dimensional approach of compulsive and impulsive behaviour in several different disorder groups, we can find differing and overlapping deficits, which may explain the high comorbidity rates. At the clinical level, this would provide means for identifying children at risk for poor clinical outcome and provide a basis for the development of better treatment strategies that take into account this dimensional nature of neurodevelopmental disorders. COMPULS will contribute its data to meta- and mega-analyses in international initiatives like the Psychiatric Genomics Consortium [61] and the ENIGMA Consortium [62] and will collaborate with other large international project with a focus on neurodevelopmental disorders (i.e. EU AIMS: http://​www.​eu-aims.​eu/​).

At the more technical and logistic level, the COMPULS database will provide opportunities to thoroughly investigate the effect of acquiring data at different centers on outcome variables during analyses. It can examine which types of data are most sensitive to the effect of multi-centre collection, and can thus provide input for future multi-center studies. It will form an international scientific resource, which may be accessed by other researchers in the field on request.