Neural correlates of active avoidance learning and their interactions with fear extinction mechanisms in PTSD patients

PTSD患者主动回避学习的神经相关性及其与恐惧消退机制的相互作用

• 批准号: 10640184
• 负责人: Mohammed R Milad
• 金额: $ 66.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-11 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640184
• 关键词: Amygdaloid structure; Area; Avoidance Learning; Brain; Characteristics; Color; Conditioned Stimulus; Control Groups; Corpus striatum structure; Data; Data Reporting; Decision Making; Diagnosis; Dorsal; Endowment; Experimental Designs; Extinction; Fright; Functional Magnetic Resonance Imaging; Future; Hippocampus; Human; Impairment; Learning; Light; Literature; Measures; Mediating; Methods; Modeling; Nucleus Accumbens; Participant; Patients; Phase; Play; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prefrontal Cortex; Price; Probability; Psychopathology; Research; Rewards; Rodent; Role; Shock; Signal Transduction; Stimulus; Symptoms; Testing; Training; Translating; Translations; Ventral Tegmental Area; avoidance behavior; conditioned fear; conditioning; cost; design; experience; experimental study; indexing; learning extinction; neural; neural correlate; neuroimaging; neuromechanism; neuropathology; novel; prevent; random forest; response; success; trauma exposure; willingness to pay

Project Summary Primary characteristics of posttraumatic stress disorder (PTSD) include persistent fears and excessive maladaptive avoidance behaviors. Preclinical models of PTSD have heavily investigated the brain mechanisms of fear inhibition and active avoidance learning. Significant progress has been made in translating fear conditioning and extinction data into the human brain and their implications have helped further our understanding of PTSD psychopathology. The mechanisms of active avoidance, however, have scarcely been examined in the human brain, especially within the context of maladaptive responses as in the case of PTSD. The studies proposed in this application are designed to begin to fill this scientific gap. We will use a novel conditioning and active avoidance paradigm (CAAP) to examine the neural correlates of active avoidance and fear extinction learning and explore how extinction modulates active avoidance responses in participants with and without a PTSD diagnosis using functional magnetic resonance imaging (fMRI). PTSD psychopathology involves dysfunctional limbic-frontal activity including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala. Studies of avoidance in rodents and a few fMRI studies in healthy humans suggest that the vmPFC and striatum mediate threat response by toggling the expression of fear vs. avoidance responses. Participants (healthy controls with trauma exposure, and patients diagnosed with PTSD) will undergo the novel (validated) two- day CAAP. On day 1, participants will undergo Pavlovian fear conditioning, immediately followed by an active avoidance conditioning phase. Avoidance is achieved by pressing a button to prevent a shock from occurring but will not terminate the conditioned stimulus (CS). Pavlovian fear extinction learning (button removed; no avoidance possible) will follow. On day 2, recall of extinction learning will be tested. Before the start of the recall test, participants will receive a small monetary endowment and will be told that this money could be used to pay for shock avoidance during the recall test. The first aim is to Identify neural correlates of active avoidance. The second aim is to study activations after the CS+ terminates that index the relief from the avoided shock. The third aim is to examine neural correlates of extinction-to-avoidance transfer. The proposed studies are expected to provide a more integrated mechanistic understanding of the psychopathology of PTSD and reduce the gap between the rodent literature and human neuroimaging in avoidance research.

项目摘要 创伤后应激障碍（PTSD）的主要特征包括持续的恐惧和过度 适应不良的避免行为。 PTSD的临床前模型已经大量研究了大脑 恐惧抑制和积极回避学习的机制。已经取得了重大进展 将恐惧调节和灭绝数据转化为人脑及其含义有所帮助 进一步，我们对PTSD心理病理学的理解。但是，主动回避的机制具有 几乎没有在人脑中进行检查，尤其是在适应不良反应的背景下 PTSD的情况。本应用程序中提出的研究旨在开始填补这一科学差距。 我们将使用新颖的调理和主动回避范式（CAAP）检查神经 主动回避和恐惧灭绝学习的相关性并探索灭绝如何调节 使用功能的参与者有或没有PTSD诊断的参与者的主动回避响应 磁共振成像（fMRI）。 PTSD心理病理学涉及功能失调的边缘额外活动 包括腹侧前额叶皮层（VMPFC），海马（HPC）和杏仁核。研究 在健康人类中避免啮齿动物和一些fMRI研究表明VMPFC和纹状体 通过切换恐惧与回避反应的表达来调节威胁反应。参与者（健康 暴露创伤的对照和被诊断为PTSD的患者将接受新颖（经过验证的）两种 日尾。在第1天，参与者将接受帕夫洛维亚恐惧调节，然后立即进行活跃 回避调节阶段。通过按下按钮来防止发生冲击，可以避免避免 但不会终止条件刺激（CS）。帕夫洛维亚恐惧灭绝学习（删除按钮；否 可能会避免）。在第2天，将测试灭绝学习的召回。在开始之前 召回测试，参与者将收到一个少量的货币捐赠，并被告知这笔钱可能是 用于在召回测试期间支付避免冲击的费用。第一个目的是确定主动的神经相关性 避免。第二个目的是在CS+终止后研究激活，从 避免了冲击。第三个目的是检查灭绝与避免转移的神经相关性。这 预计拟议的研究将对对 PTSD的心理病理学，并减少啮齿动物文献与人类神经影像学之间的差距 回避研究。