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

测试眶额皮质在人类强迫行为中的因果作用：一项非侵入性脑刺激研究

基本信息

批准号：
9292806
负责人：
Rebecca Price
金额：
$ 22.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-20 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292806
关键词：
Acute Animal Model Animals Anxiety Back Behavior Behavioral Biological Neural Networks Brain Brain region Chemosensitization Chronic Cognition Cognitive Compulsive Behavior Computers Coupled Data Development Disease Distress Dose Down-Regulation Equilibrium Etiology Exhibits Failure Functional disorder Future Glutamates Goals Grooming Habits Homosynaptic Depression Human Individual Laboratories Lead Learning Link Literature Measures Mediating Modeling Mus Neurocognitive Neuropsychological Tests Obsessive compulsive behavior Outcome Participant Pathway interactions Patient Self-Report Patients Placebo Control Play Protocols documentation Randomized Rattus Rest Role Selective Serotonin Reuptake Inhibitor Services Shock Substance Addiction Symptoms Testing Time Transcranial magnetic stimulation Translating Translational Research Translations Treatment Cost Uncertainty Ventral Striatum Withdrawal Work avoidance behavior base clinically relevant comparison group compulsion cost design eating pathology experimental study flexibility hedonic indexing neural model neuroimaging neuromechanism novel optogenetics psychologic relating to nervous system repetitive behavior response reward processing skills theories therapy development

项目摘要

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.

项目摘要。旨在减少困扰的强迫行为或不必要的重复行为，是强迫症的核心特征强迫性（OC）谱系障碍，但出现在非常广泛的心理状况中。强迫表明，目标指导行为未能通过反复的练习和短期遇险减少来覆盖习惯行为。在OC患者中，这种“习惯假说”得到了行为数据的支持，表明OC患者即使否定了其功能价值，并在灵活目标定向认知的标记中显示了定义。收敛性神经影像学证据表明，皮质 - 纹状体 - 甲状腺皮质（CSTC）电路异常。 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, 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强迫行为中的轨道额皮层（OFC）。光遗传学研究已经确定，激活眶额皮层（OFC）途径会引起小鼠的强迫层饰行，同时破坏了相似区域的活性阻碍了大鼠的习惯形成和表达。但是，OFC在促进目标指导行为中起同样至关重要的作用，而OFC抑制也可以破坏目标指导的行为，而OFC的光遗传学激活可以减少条件修饰。这留下了一个问题，即如何最好地将动物作品转化为人类，具体来说，人类的调制方向将有助于平衡在为目标服务方面的“习惯覆盖”能力。我们第一次提议将动物模型转换回人类研究，并使用实验操纵来测试人类的平行休闲性。在该实验中，将有70名具有慢性强迫行为的个体随机分配，以接收针对OFC的两种形式的非侵入性脑刺激之一 - 靶向OFC的theta爆发刺激（TBS），预计会潜在OFC或连续的TBS，预计将使OFC脱离功能。脑部调节将与练习相结合，以覆盖临床相关的习惯（过度避免冲击行为）。我们的目的是：1）通过检查脑调节急性窗口中OFC活性和CSTC连接性的急性标记来验证ITB与CTB对OFC功能的差异急性效应； 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 neuronal markers across individuals.作为机械干预开发的先驱，我们将阐明OFC在人类强迫脆弱性中的因果作用，从而为未来的翻译研究假设和新疗法的发展提供信息。