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

基本信息

批准号：
10452669
负责人：
Rebecca Price
金额：
$ 57.47万
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：
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/10452669
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

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. 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。旨在减少困扰的强迫行为或不必要的重复行为是核心特征强迫症（OC）谱系障碍，但出现在非常广泛的心理状况中。强迫表明，目标指导行为未能通过重复“盖章”覆盖习惯行为练习和短期遇险。在OC患者中，这种“习惯假说”得到了行为数据的支持提示OC患者即使否定了其功能价值后，也很难覆盖习惯灵活目标定向认知的标记。趋同的神经影像学证据表明，皮质的异常纹状体 - 甲状腺皮质（CSTC）电路。但是，将CSTC功能和神经认知破坏联系起来的人类研究强迫行为受到相关设计的限制（例如，横截面比较），离开关于人类强迫行为的因果机制的关键尚未解决的问题。相比之下，最近 OC行为动物模型的进步允许对靶向大脑进行空前的实验操纵电路并提供了令人信服的证据，证明了轨道额皮层（OFC）在强迫行为中的因果作用。光遗传学研究已经确定激活眶额皮层（OFC）途径会引起强迫层修饰小鼠的行为，同时破坏了类似区域的活动，阻止了大鼠的习惯形成和表达。趋于地，我们从R21资助的翻译研究中的初步发现表明，将OFC置于OFC中人类患者（通过连续的theta爆发刺激； CTB）可能会提高抵抗幻想的能力强迫，无论是立即和1周的随访。但是，关于翻译的关键问题仍然存在动物工作中的因果机制向人类，特别是在习惯上的协同行为训练是否在TBS后的商业窗口中交付的覆盖'可能会提供一个关键的上下文操作，以提示平衡具有养成目标的习惯能力。在该实验中，将有200个具有慢性强迫行为的人进行随机分配以完成一次访问涉及两个串行间隔的CTB块，这些块最高可达2小时的窗口18-20 OFC沉积或假 TBS。在完全交叉的（2x2）设计中，在TBS后的机会之窗中，参与者将完成我们以前的开发了基于计算机的“习惯覆盖”任务或训练任务的假变体。我们的目标是：1）验证急性效果通过检查急性窗口中OFC活性和CSTC连接性的急性标记，CTB的OFC功能大脑调节； 2）测试CTB对行为的效率是否通过简单的“习惯覆盖”来扩大通过检查TBS的相互作用和习惯覆盖培训对习惯和强迫的标记的培训脆弱性和灵活的目标定向认知 - 立即和1周的TBS进行测量。探索性测试将重点关注个体的神经和行为结果之间的关系。作为机械的先驱干预开发，我们将阐明上下文的神经认知状况，使OFC在强迫脆弱性，为综合的理论模型和新疗法的发展提供了信息。