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.
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.
