Experimental Manipulation of OFC Function and Behavioral Context: Towards an Integrative Translational Model of Compulsive Behaviors

OFC 功能和行为背景的实验操作：建立强迫行为的综合转化模型

• 批准号: 10452669
• 负责人: Rebecca Price
• 金额: $ 57.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452669
• 关键词: Acute; Animal Model; Animals; Anxiety; Area; Back; Behavior; Behavioral; Biological; Brain; Brain region; Chemosensitization; Chronic; Cognition; Compulsive Behavior; Computers; Coupled; Data; Disease; Distress; Dose; Equilibrium; Etiology; Exhibits; Failure; Functional disorder; Funding; Future; Glutamates; Goals; Grooming; Habits; Homosynaptic Depression; Hour; Human; Individual; Laboratories; Lead; Learning; Link; Literature; Measures; Mediating; Modeling; Mus; Neurocognitive; Obsessive compulsive behavior; Participant; Pathway interactions; Patient Self-Report; Patients; Plant Roots; Protocols documentation; Randomized; Rattus; Rest; Role; Selective Serotonin Reuptake Inhibitor; Services; Shock; Symptoms; Testing; Theoretical model; Time; Training; Transcranial magnetic stimulation; Translating; Translations; Uncertainty; Variant; Ventral Striatum; Visit; Work; arm; base; behavioral outcome; brain behavior; clinically relevant; clinically significant; cognitive process; cognitive testing; comparison group; compulsion; cost; design; eating pathology; experimental study; flexibility; follow-up; improved; indexing; model development; neuroimaging; neuromechanism; neuroregulation; noninvasive brain stimulation; novel; optogenetics; psychologic; recruit; relating to nervous system; repetitive behavior; response; skills; substance use; therapy development; time use; tool; translational model; translational study

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.

项目总结。强迫行为，或者说是为了减轻痛苦而做的不必要的重复行为，是一个核心特征