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: 10264883
• 负责人: Rebecca Price
• 金额: $ 56.81万
• 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/10264883
• 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.

项目摘要。强迫性行为，或不想要的，旨在减少痛苦的重复行为，是一个核心特征 强迫症（OC）谱系障碍，但出现在一个非常广泛的心理条件。 这表明目标导向的行为失败，无法超越通过反复的“烙印”形成的习惯行为。 实践和短期的痛苦减少。在OC患者中，这种“习惯假设”得到了行为数据的支持 这表明OC患者即使在他们的功能价值被否定后也难以克服习惯，并在以下方面表现出缺陷： 灵活的目标导向认知的标志。神经影像学证据表明大脑皮层- 纹状体-丘脑-皮质（CSTC）回路。然而，将CSTC功能与神经认知障碍联系起来的人类研究 强迫性行为受到相关设计的限制（例如，横截面组比较）， 关于人类强迫行为的因果机制的关键未解决的问题。相比之下，最近 OC行为的动物模型的进步使得对目标大脑进行前所未有的实验操作成为可能 回路并为眶额皮质（OFC）在强迫行为中的因果作用提供了令人信服的证据。 光遗传学研究已经证实，激活眶额皮层（OFC）通路会诱导强迫性梳理 行为，而在大鼠中破坏类似区域的活动则会阻止习惯的形成和表达。 一致地，我们从R21资助的翻译研究中的初步发现表明， 人类患者（通过连续Theta Burst刺激; cTBS）可能导致抵抗特定免疫刺激的能力提高。 立即和1周随访时的强迫行为。然而，关键的问题仍然是关于翻译， 动物对人类工作的因果机制，特别是“习惯”中的协同行为训练 在TBS后的机会窗口中递送的“覆盖”可以提供关键的上下文操纵，其提示 在为目标服务的过程中，平衡到一种超越习惯的能力。 在这个实验中，200名患有慢性强迫行为的个体将被随机化，以完成一次单独的访问 涉及两个连续间隔的cTBS块，这会产生长达2小时的OFC去电位窗口18 -20，或假手术 汤匙在完全交叉（2x2）设计中，在TBS后的机会窗口期间，参与者将完成我们先前的 开发了基于计算机的“习惯超越”任务或训练任务的假变体。我们的目标是：1）验证急性效应 通过检查急性窗期间OFC活性和CSTC连接的急性标志物， 2）测试cTBS对行为的功效是否被同时的“习惯覆盖”放大 通过检查TBS和习惯超越训练对习惯和强迫标记的相互作用进行训练 脆弱性和灵活的目标导向的认知-立即和1周后TBS测量。探索性测试 将专注于个体之间的神经和行为结果之间的关系。作为机械化的先驱 干预的发展，我们将澄清的背景神经认知条件，适度的眶额皮层的作用， 强迫脆弱性，通知综合理论模型和新的治疗方法的发展。