. 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. Convergently, our preliminary findings from an R21-funded translational study suggest that de-potentiating the OFC in human patients (via continuous Theta Burst Stimulation; cTBS) may lead to improved capacity to resist idiographic compulsions, both immediately and at 1-week follow-up. However, critical questions remain regarding the translation of causal mechanisms in animal work to humans, and specifically, whether synergistic behavioral training in `habit override', delivered in a post-TBS window-of-opportunity, might provide a critical contextual manipulation that tips the balance towards a capacity for habit override in the service of goals. In this experiment, 200 individuals with chronic compulsive behaviors will be randomized to complete a single visit involving two serially spaced blocks of cTBS, which creates up to a 2-hour window18-20 of OFC depotentiation, or sham TBS. In a fully crossed (2x2) design, during a post-TBS window of opportunity, participants will complete our previously developed computer-based `habit override' task or a sham variant of the training task.
We aim to: 1) Verify acute effects of cTBS on OFC function by examining acute markers of OFC activity and CSTC connectivity during the acute window of brain modulation; 2) Test whether the efficacy of cTBS on behavior is amplified by simultaneous `habit override' training by examining interacting effects of TBS and habit override training on markers of habit and compulsion vulnerability and flexible goal-directed cognition?measured both immediately and 1-week post-TBS. Exploratory tests will focus on relationships between neural and behavioral outcomes across individuals. As a precursor to mechanistic intervention development, we will clarify the contextual neurocognitive conditions that moderate the OFC's role in compulsion vulnerability, informing integrative theoretical models and the development of novel treatments.

Public Health Relevance

This project seeks to identify causal neural mechanisms underlying unwanted, repetitive behaviors (compulsions). Using non-invasive brain stimulation, with or without coupled practice in a computer-based `habit override' task, we will modulate activity in a target brain region and measure effects on compulsive behaviors and related measures. This work could ultimately lead to the ability to treat compulsions more effectively by synergistically targeting the regions of the brain and the specific cognitive processes that can help to overcome compulsions.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Mcmullen, David
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University of Pittsburgh
Schools of Medicine
United States
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