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，或旨在减少痛苦的不受欢迎的重复行为，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疾病。强迫症表明，目标导向的行为未能超越通过反复练习和短期痛苦缓解而形成的习惯性行为。在OC患者中，这一“习惯假说”得到了行为学数据的支持，这些数据表明，OC患者即使在其功能价值被否定并显示出灵活的目标导向认知标记的缺陷后，也难以超越习惯。聚合的神经影像证据提示皮质-纹状体-丘脑-皮质(CSTC)环路异常。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一直受到相关设计的限制(例如，横断面小组比较)，留下了关于人类强迫行为的因果机制的关键问题。相比之下，最近在OC行为的动物模型上取得的进展，使得对靶向大脑回路的前所未有的实验操作成为可能，并为眶前皮质(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，激活眼眶前额叶皮质(OFC)通路可以诱导小鼠的强迫梳理行为，而扰乱类似区域的活动则会阻止大鼠习惯的形成和表达。然而，OFC在促进目标定向行为方面起着同样重要的作用，OFC抑制同样可以扰乱目标定向行为，而OFC的光基因激活可以减少条件性梳理。这就留下了一个悬而未决的问题，那就是如何最好地将动物的工作转化为人类，具体地说，人类的哪个调制方向将有助于扭转平衡，使其能够在为目标服务的过程中实现“习惯优先”。我们首次提议将动物模型转化为人类研究，并使用实验操作来测试人类的平行因果关系。在这项实验中，70名有慢性强迫行为的人将被随机分配接受两种形式的非侵入性脑刺激中的一种，目标是OFC--间歇性Theta Burst刺激(TBS)，预计会增强OFC，或连续TBS，预计会降低OFC。大脑调节将与克服临床相关习惯(过度学习的电击避免行为)的练习相结合。我们的目标是：1)通过在大脑调制的急性窗口中检测OFC活动和CSTC连通性的急性标记物，验证ITBS和CTBS对OFC功能的不同急性影响；2)通过检测TBS对习惯和强迫易损性标记物和灵活的目标定向认知的持久影响-在TBS后90分钟和1周测量-以及行为、认知和神经标记物之间的关系，描绘一个因果转换模型，将OFC的实验调节与人类强迫行为易损性的标记物联系起来。作为机械性干预发展的先导，我们将阐明OFC在人类强迫易损性中的因果作用，为未来的翻译研究假设和新治疗方法的开发提供信息。

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.