Testing the causal role of orbitofrontal cortex in human compulsive behavior: a non-invasive brain stimulation study

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，是强迫症的核心特征- 强迫症（OC）谱系障碍，但出现在非常广泛的心理状况。实验结果表明，目标导向的行为无法克服通过反复练习和短期的痛苦减轻而“印入”的习惯性行为。在OC患者中，这种“习惯假说”得到了行为数据的支持，这些数据表明OC患者即使在其功能价值被否定后也难以克服习惯，并且在灵活的目标导向认知标记中表现出缺陷。会聚神经影像学证据表明皮质-纹状体-丘脑-皮质（CSTC）回路异常。然而，将CSTC功能和神经认知障碍与强迫行为联系起来的人类研究受到相关设计的限制（例如，横截面组比较），留下关键的未解决的问题有关的因果机制，在人类的强迫行为。相比之下，最近在OC行为的动物模型的进展，允许前所未有的实验操作的目标脑回路，并提供了令人信服的证据，眶额皮质（OFC）在强迫行为的因果关系的作用。光遗传学研究已经确定，激活眶额皮质（OFC）通路会诱导小鼠的强迫性梳理行为，而破坏类似区域的活动会阻止大鼠的习惯形成和表达。然而，OFC在促进目标导向行为中起着同样关键的作用，并且OFC抑制同样可以破坏目标导向行为，而OFC的光遗传学激活可以减少条件性梳理。这就留下了一个问题，即如何最好地将动物的工作转化为人类的工作，具体来说，人类的哪种调节方向将有助于在服务于目标的过程中使平衡朝着“习惯超越”的能力倾斜。这是第一次，我们建议将动物模型转换回人类研究，并使用实验操作来测试人类中的平行因果关系。在该实验中，70名具有慢性强迫行为的个体将被随机化以接受两种形式的非侵入性脑刺激之一的单次会话，所述非侵入性脑刺激针对OFC-预期增强OFC的间歇Theta爆发刺激（TBS），或预期去增强OFC的连续TBS。大脑调节将与超越临床相关习惯（过度学习的电击避免行为）的实践相结合。我们的目标是：1）通过在脑调制的急性窗口期间检查OFC活性和CSTC连接的急性标志物来验证iTBS与cTBS对OFC功能的不同急性作用; 2）通过检查TBS对习惯和强迫脆弱性以及灵活的目标导向认知的标记的持久影响，描绘出一个因果转换模型，将OFC的实验调制与人类强迫行为脆弱性的标记联系起来-在TBS后90分钟和1周测量-以及个体之间行为，认知和神经标记物之间的关系。作为机械干预发展的先驱，我们将阐明OFC在人类强迫脆弱性中的因果作用，为未来的转化研究假设和新疗法的开发提供信息。

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. However, the OFC plays an equally critical role in promoting goal-directed behavior, and OFC inhibition can likewise disrupt goal-directed behavior, while optogenetic activation of OFC can reduce conditioned grooming. This leaves open the question of how best to translate animal work to humans, and specifically, which direction of modulation in humans would help tip the balance towards a capacity for `habit override' in the service of goals. For the first time, we propose to translate animal models back to human studies and use experimental manipulation to test parallel causality in humans. In this experiment, 70 individuals with chronic compulsive behaviors will be randomized to receive a single session of one of two forms of non-invasive brain stimulation targeting the OFC—intermittent Theta Burst Stimulation (TBS) expected to potentiate the OFC, or continuous TBS, expected to de-potentiate the OFC. Brain modulation will be coupled with practice in overriding a clinically relevant habit (an overlearned shock avoidance behavior). We aim to: 1) Verify differential acute effects of iTBS vs. cTBS on OFC function by examining acute markers of OFC activity and CSTC connectivity during the acute window of brain modulation; 2) Delineate a causal translational model linking experimental modulation of OFC to markers of compulsive behavior vulnerability in humans by examining enduring effects of TBS on markers of habit and compulsion vulnerability and flexible goal-directed cognition—measured at both 90min and 1-week post-TBS—and relationships between behavioral, cognitive, and neural markers across individuals. As a precursor to mechanistic intervention development, we will clarify the OFC's causal role in compulsion vulnerability in humans, informing future translational research hypotheses and development of novel treatments.