Obsessive-Compulsive Disorder (OCD) is a disabling illness that typically begins in childhood and persists into adulthood. Neuroimaging studies suggest anatomical and functional disturbances of frontostriatal circuits in OCD but few studies have assessed the functioning of these circuits in pediatric (child-onset) OCD which is likely a distinct OCD subtype, coinciding with developmental changes in the function and structure of the prefrontal cortex. We hypothesize that dysfunction in overlapping frontostriatal circuits contributes to OCD by impairing control over intrusive thoughts (obsessions) and repetitive behaviors (compulsions) and diminishing the capacity to process rewards. An over-reliance on the earlier developing striatum then allows compulsions to become habits. In this R21, we will use fMRI to assess the functioning of these circuits in 30 unmedicated children with OCD (ages 6-12) compared to 30 age-matched healthy controls. The functioning of dorsal frontostriatal control systems will be assessed using the well-validated Simon task. Functioning of the dorsal striatum and ventral frontostriatal circuits that support habit learning and reward processing will be assessed using a novel fMRI paradigm directly analogous to tasks used to define the neural bases of reward-based learning systems in rodents, tailored to a virtual reality environment within the MRI scanner. This paradigm provides a translational neuroscience approach to the study of brain function in OCD. We will also assess functional connectivity in dorsal and ventral frontostriatal circuits in the same children, and determine whether disturbances in these overlapping circuits are associated with OCD symptom severity. Identification of dysfunction in either of these circuits in OCD will support future longitudinal study of their neurodevelopmental trajectories in OCD. Our long-term goal is to identify a distinct pattern of brain abnormalities tht underlies OCD and to develop novel treatments that target these abnormalities directly. By validating the use of specific fMRI paradigms to examine potential brain mechanisms underlying OCD, this R21 application is a first step in this direction and consistent with the NIMH strategic plan to promote brain discovery.
We propose to investigate the functioning of overlapping frontostriatal circuits in children with Obsessive- Compulsive Disorder (OCD). Identification of dysfunction in these circuits will not only foster a better understanding of OCD pathophysiology, but also enable future studies to examine the onset and progression (e.g., a longitudinal study of neurodevelopment in people at risk for OCD) and to develop novel treatments that target these circuits directly.
