Identifying neural mechanisms of PTSD symptom reduction induced by combined estrogen and prolonged exposure therapy

项目概要 长时间暴露（PE）疗法是创伤后应激障碍（PTSD）的首选治疗方法。尽管 其功效，相当多的人不会从中受益，或者可能在完成之前退出 所有会议。这凸显了寻找增强体育锻炼功效的方法的重要性，以改善 患有创伤后应激障碍 (PTSD) 的人的生活质量。现在人们普遍认为灭绝学习范式 基础研究中使用的 PE 是有用的实验室类似物。健康对照研究表明 雌激素水平升高有利于消除学习，促进其巩固，从而增强其 回忆一下稍后测试时的情况。这也反映在大脑区域激活的变化上 恐惧消退网络，包括杏仁核、背侧前扣带皮层 (dACC) 和腹内侧 前额皮质（vmPFC）。目前尚不清楚雌二醇 (E2) 给药是否可以调节激活 口服避孕药 (OC) 使用者的恐惧消退网络以及哪种 E2 剂量可以产生最佳效果。 当前研究的 R61 阶段旨在确定两种 E2 剂量中的哪一种（安慰剂 (Plc)、2mg 或 4mg） 通过让使用 OC 的健康女性接触经过验证的恐惧，可以最好地参与她们的恐惧消退网络 调节和消退协议。功能性 fMRI（BOLD 信号）和心理生理学测量（皮肤 电导响应 – SCR）将用于测试以下假设：1）E2 管理将增强 以剂量反应方式进行灭绝回忆（以较低的 SCR 为索引）； 2) E2管理将增加vmPFC 并以剂量反应方式减少回忆过程中 dACC 和杏仁核的激活。一旦最优E2 剂量已确定，R33 阶段将检查 E2 给药（相对于 Plc）的影响 与有明显 PTSD 症状的 OC 用户女性一起进行 5 次体育锻炼。参加者将是 在PE之前和之后暴露于恐惧调节和消退方案。 BOLD 信号、SCR 以及 将在治疗前后使用症状严重程度来检验这些假设：1）在消退回忆期间， 相对于 PE 前，两组在 PE 后均表现出较低的 SCR，其中 E2 PE 组表现出最强的效果。 2） 消退诱导的激活在 vmPFC 中较高，而 dACC 和杏仁核中较低。 相对于PE前，E2 PE组表现出最强的效果。 3）灭绝之间的信息流 节点将改善后续治疗（以动态因果模型为索引），在 E2 PE 中效果更强 组。 4) 相对于 Plc PE 组，E2 PE 组的 PTSD 症状严重程度较低，如下 治疗以及 3 个月和 6 个月的随访评估。 5) PTSD 症状的减轻与此相关 在灭绝回忆期间观察到 BOLD 和 SCR 变化。我们的研究结果将阐明神经 针对基于恐惧的症状进行有效暴露治疗的机制，并将揭示 E2 如何能够 可以作为增强基于消除的疗法（例如 PE）疗效的辅助手段。

Project Summary Prolonged-exposure (PE) therapy is the treatment of choice for posttraumatic stress disorder (PTSD). Despite its efficacy, a significant number of individuals will not benefit from it or might drop out before the completion of all sessions. This underlies the importance of findings ways to enhance the efficacy of PE in order to improve the life quality of individuals suffering from PTSD. It is now widely accepted that extinction learning paradigms used in fundamental studies are useful laboratory analogs to PE. Studies in healthy controls have suggested that elevated estrogen levels benefit extinction learning by promoting its consolidation and thus enhancing its recall when tested later for it. This is also being reflected by changes in the activation of brain regions forming the fear extinction network, including the amygdala, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC). It is still unknown whether estradiol (E2) administration can modulate the activation of the fear extinction network in oral contraceptive (OC) users and which E2 dose could yield the best results. The R61 phase of the current study will aim to establish which of two E2 doses (placebo (Plc), 2mg or 4mg) can best engage the fear extinction network in healthy women using OC by exposing them to a validated fear conditioning and extinction protocol. Functional fMRI (BOLD signal) and psychophysiological measures (skin conductance responses – SCR) will be used to test the following hypotheses: 1) E2 administration will enhance extinction recall (indexed by lower SCR) in a dose-response manner; 2) E2 administration will increase vmPFC and decrease dACC and amygdala activations during recall in a dose-response manner. Once the optimal E2 dose has been identified, the R33 phase will examine the impact of E2 administration (relative to Plc) in conjunction with 5 PE sessions in OC users women having significant symptoms of PTSD. Participants will be exposed to the fear conditioning and extinction protocol before and after PE. BOLD signal, SCR as well as symptom severity will be used before and after treatment to test these hypotheses: 1) During extinction recall, both groups will show lower SCR at post- relative to pre-PE, with E2+PE group showing the strongest effect. 2) Extinction-induced activations will be higher in the vmPFC and lower in the dACC and amygdala in post relative to pre-PE, with E2+PE group showing the strongest effect. 3) Information flow between the extinction nodes will improve following therapy (indexed by dynamic-causal modeling), with stronger effects in the E2+PE group. 4) PTSD symptom severity will be lower in the E2+PE group relative to the Plc+PE group following treatment, as well as at the 3 and 6-month follow-up assessments. 5) PTSD symptom reduction will correlate with BOLD and SCR changes observed during extinction recall. Our findings will elucidate the neural mechanisms underlying effective exposure treatment for fear-based symptoms, and will reveal how E2 could be an adjunct to enhance the efficacy of extinction-based therapies such as PE.