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的恐惧。 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。取得重大进展 将恐惧条件反射和灭绝数据转化到人类大脑中， 加深了我们对创伤后应激障碍心理病理学的理解然而，主动回避的机制 几乎没有在人类大脑中进行过检查，特别是在适应不良反应的背景下， PTSD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）来检查神经元的行为。 主动回避和恐惧消退学习的相关性，并探索消退如何调节 有和没有PTSD诊断的参与者的主动回避反应， 磁共振成像（fMRI）。PTSD精神病理学涉及功能障碍的边缘-额叶活动 包括腹内侧前额叶皮质（vmPFC）、海马（HPC）和杏仁核。研究 啮齿类动物的回避和一些健康人的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解威胁反应。参与者（健康 创伤暴露的对照组和诊断为创伤后应激障碍的患者）将接受新的（经验证的）两个- 日CAAP。在第一天，参与者将接受巴甫洛夫恐惧条件反射，然后立即进行积极的 回避条件反射阶段通过按下按钮来避免电击发生 但不会终止条件刺激（CS）。巴甫洛夫恐惧消退学习（按钮移除;否） 可以避免）。在第2天，将测试消退学习的回忆。开始前 在回忆测试中，参与者将获得一笔小额捐赠，并被告知这笔钱可以用于 用来支付回忆测试中的电击回避第一个目标是识别活动的神经相关物， 回避第二个目的是研究CS+终止后的激活，其指示从 避免休克。第三个目的是研究注意-回避迁移的神经相关因素。的 拟议的研究预计将提供一个更全面的机制的理解， 创伤后应激障碍的精神病理学，并减少啮齿动物文献和人类神经影像学之间的差距， 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.