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

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 适应不良的回避行为。创伤后应激障碍的临床前模型已经对大脑进行了大量研究 恐惧抑制和主动回避学习的机制。在以下方面取得了重大进展 将恐惧条件作用和消退数据转化为人脑及其影响是有帮助的 进一步加深我们对创伤后应激障碍精神病理学的理解。然而，主动回避的机制有 在人脑中几乎没有被研究过，特别是在适应不良反应的背景下，如 创伤后应激障碍的案例。本申请中提出的研究旨在开始填补这一科学空白。 我们将使用一种新的条件反射和主动回避范式(CAAP)来检查神经 主动回避和恐惧消退学习的相关性，并探索消退是如何调节的 功能性创伤后应激障碍患者与非创伤后应激障碍患者的主动回避反应 磁共振成像(FMRI)。创伤后应激障碍的精神病理学涉及边缘-额叶活动障碍 包括腹内侧额前皮质(VmPFC)、海马体(HPC)和杏仁核。的研究 啮齿类动物的回避和健康人的一些功能磁共振研究表明，vmPFC和纹状体 通过切换恐惧和回避反应的表达来调节威胁反应。参与者(健康) 有创伤暴露的对照组和被诊断为创伤后应激障碍的患者)将接受新的(经验证的)两项- DAY CAAP。在第一天，参与者将接受巴甫洛夫恐惧条件反射，紧随其后的是积极的 回避条件反射阶段。通过按下按钮来防止电击的发生，即可实现避震 但不会终止条件刺激(CS)。巴甫洛夫式的恐惧消退学习(扣子取下；否 可能的避免)将随之而来。在第二天，将测试对灭绝学习的回忆。在开始之前 回忆测试，参与者将获得一小笔货币捐赠，并被告知这笔钱可能是 用于支付召回测试期间的避震费用。第一个目标是确定活跃的神经关联 回避。第二个目标是研究CS+终止后的激活，该激活索引从 避免了震惊。第三个目标是检验从灭绝到回避转移的神经关联。这个 拟议的研究可望提供更全面的机制理解 创伤后应激障碍的精神病理学和缩小啮齿动物文献与人类神经影像之间的差距 回避研究。

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.