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

项目摘要。强迫行为，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，但出现在非常广泛的心理疾病。 强迫症表明，目标导向的行为未能超越通过重复而形成的习惯性行为 练习和短期减少痛苦。在OC患者中，这种“习惯假说”得到了行为数据的支持 提示OC患者即使在其功能价值被否定并显示出功能缺陷后，仍难以克服习惯 灵活的目标导向认知的标志。趋同的神经影像证据显示大脑皮质有异常- 纹状体-丘脑-皮质(CSTC)回路。然而，将CSTC功能和神经认知障碍联系起来的人体研究 强迫行为受到相关设计的限制(例如，横断面分组比较)，留下 关于人类强迫行为的因果机制的关键悬而未决的问题。相比之下，最近 OC行为的动物模型的进展使得对靶向大脑的前所未有的实验操作成为可能 并提供令人信服的证据，证明眼眶前额叶皮质(OFC)在强迫行为中起因果作用。 光遗传学研究已经证实，激活眼眶额叶皮质(OFC)通路可以诱导强迫性梳理 小鼠的行为，而类似区域的干扰活动阻止了大鼠习惯的形成和表达。 一致地，我们来自R21资助的翻译研究的初步发现表明，在 人类患者(通过持续的Theta Burst刺激；CTB)可能会提高抵抗特定疾病的能力 强迫症，包括即刻和一周后的随访。然而，关于翻译的关键问题仍然存在。 动物中的因果机制对人类起作用，具体地说，是否在习惯上协同行为训练 在TBS后的机会之窗中提供的覆盖可能提供一种关键的上下文操作，提示 在服务于目标的过程中，平衡习惯，克服习惯。 在这项实验中，200名有慢性强迫行为的人将被随机安排完成一次访问 涉及两个连续间隔的CTB块，这创建了长达2小时的OFC去增强窗口18-20，或假窗口 TBS。在完全交叉(2x2)设计中，在TBS后的机会窗口期间，参与者将完成之前的 开发了基于计算机的“习惯克服”任务或训练任务的假变种。我们的目标是：1)验证急性影响 通过检测急性窗口期OFC活动和CSTC连接性的急性标记物，观察四氯化碳对OFC功能的影响 2)测试四氯化碳对行为的功效是否被同时的“习惯超越”放大。 TBS与习惯超越训练对习惯和强迫指标影响的交互作用研究 脆弱性和灵活的目标导向认知--在TBS后立即和一周后测量。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。作为机械论的先驱 干预发展，我们将阐明语境神经认知条件，调节OFC的作用 强迫易感性，告知综合理论模型和开发新的治疗方法。

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.