Reinforcement Learning and Obsessive-compulsive Disorder: Exploring the Role of the Orbitofrontal Cortex

INTRODUCTION:

Obsessive-compulsive disorder (OCD) is the fourth most common psychiatric disorder, characterized by recurrent and intrusive obsessive thoughts and/or compulsions that are distressing, time-consuming , and a cause of significant impairment. OCD has a lifetime prevalence of 1-3%, and is associated with a reduced life expectancy due to natural and unnatural causes. Current treatments, based on a combination of pharmacotherapy and psychotherapy, are ineffective in at least 50% of cases, with rTMS of the prefrontal cortex having recently received FDA clearance as an adjunctive treatment. Yet, OCD pathophysiology remains largely unknown , and it is expected that a better understanding of OCD 's biological mechanisms would contribute to a better prevention and treatment of the disorder.

Current neurobiological models for the disorder highlight the role of cortico-striatal-thalamo-cortical (CSTC) loops and hyperactivity of the orbitofrontal cortex (OFC), and it has been hypothesized that corticostriatal dysfunction in OCD may occur as an end-consequence of immune and inflammatory dysregulation that leads to structural and functional changes in these circuits. This pathophysiological mechanism was first proposed based on the association between group A β-hemolytic streptococcal (GAS) infection and the abrupt onset of OCD in children, described by Swedo and colleagues (1998) as a distinctive nosologic entity named Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS). This post-infectious neuropsychiatric syndrome was hypothesized to occur due to a cross-reaction between anti-streptococcal antibodies and the basal ganglia, causing CSTC circuit dysfunction. In addition to GAS, other pathogens have since been suggested as contributing to the development of OCD, albeit no definitive causal associations have been established. Interestingly, childhood adversity, an environmental risk factor for OCD, has also been associated with chronic immune dysfunction in adulthood, namely with increased C-reactive protein, interleukin-6, and tumor necrosis factor (TNF)-α, as well as with increased volume of the right OFC in adult patients with OCD.

While the specific psychopathological consequences of OFC dysfunction in OCD remain unclear, in recent years research in rodents has shown that the OFC, particularly the lateral OFC, is crucial in controlling transitions between automatic, repetitive stimulus-response behaviors (such as habitual behavior in operant-learning tasks, or model-free RL), and behaviors that reflect the acquisition, by the agent, of a predictive model of the consequences of each action (such as goal-directed behavior, or model-based RL). Evidence suggests that patients with OCD may have an abnormal bias towards habitual behavior during operant learning tasks, with subjects having a higher difficulty in developing model-based reinforcement learning strategies. This bias has been proposed to favor the emergence of ritualized compulsive behaviors typical of OCD, and is regarded as a marker of corticostriatal dysfunction that is central to the disorder's pathophysiology.

In this case-control study, the investigators propose an integrative experimental approach to test if structural, functional , and metabolic changes in corticostriatal circuits of patients with OCD correlate with performance in an RL task, as well as with peripheral blood markers of immune dysfunction and early-life environmental risk factors previously implicated in the disorder (e.g., infectious insults and childhood adversities).