Testing the causal role of orbitofrontal cortex in human compulsive behavior: a non-invasive brain stimulation study

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Project Summary. Compulsive behaviors, or unwanted, repetitive behaviors aimed at reducing distress, are a core feature of obsessive- compulsive (OC) spectrum disorders, but appear across a very broad spectrum of psychological conditions. Compulsions suggest a failure of goal-directed behavior to override habitual behaviors “stamped in” through repeated practice and short-term distress reduction. In OC patients, this “habit hypothesis” is supported by behavioral data suggesting OC patients struggle to override habits even after their functional value has been negated and show deficits in markers of flexible goal-directed cognition. Convergent neuroimaging evidence suggests abnormalities in a cortico-striato-thalamo-cortical (CSTC) circuit. However, human studies linking CSTC function and neurocognitive disruptions to compulsive behaviors have been limited by a correlational design (e.g., cross-sectional group comparisons), leaving critical unresolved questions regarding the causal mechanisms of compulsive behaviors in humans. By contrast, recent advances in animal models of OC behavior have allowed unprecedented experimental manipulation of targeted brain circuits and provide compelling evidence for a causal role of the orbitofrontal cortex (OFC) in compulsive behavior. Optogenetic studies have established that activating an orbitofrontal cortex (OFC) pathway induces compulsive grooming behavior in mice, while disrupting activity in a similar region blocked habit formation and expression in rats. However, the OFC plays an equally critical role in promoting goal-directed behavior, and OFC inhibition can likewise disrupt goal-directed behavior, while optogenetic activation of OFC can reduce conditioned grooming. This leaves open the question of how best to translate animal work to humans, and specifically, which direction of modulation in humans would help tip the balance towards a capacity for `habit override' in the service of goals. For the first time, we propose to translate animal models back to human studies and use experimental manipulation to test parallel causality in humans. In this experiment, 70 individuals with chronic compulsive behaviors will be randomized to receive a single session of one of two forms of non-invasive brain stimulation targeting the OFC—intermittent Theta Burst Stimulation (TBS) expected to potentiate the OFC, or continuous TBS, expected to de-potentiate the OFC. Brain modulation will be coupled with practice in overriding a clinically relevant habit (an overlearned shock avoidance behavior). We aim to: 1) Verify differential acute effects of iTBS vs. cTBS on OFC function by examining acute markers of OFC activity and CSTC connectivity during the acute window of brain modulation; 2) Delineate a causal translational model linking experimental modulation of OFC to markers of compulsive behavior vulnerability in humans by examining enduring effects of TBS on markers of habit and compulsion vulnerability and flexible goal-directed cognition—measured at both 90min and 1-week post-TBS—and relationships between behavioral, cognitive, and neural markers across individuals. As a precursor to mechanistic intervention development, we will clarify the OFC's causal role in compulsion vulnerability in humans, informing future translational research hypotheses and development of novel treatments.