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

项目摘要 长时间暴露(PE)疗法是治疗创伤后应激障碍(PTSD)的首选方法。尽管 它的有效性，相当数量的人将不会受益于它或可能在完成 所有会话。这强调了发现提高体育效果的方法的重要性，以便改进 创伤后应激障碍患者的生活质量。现在人们普遍认为，灭绝学习范式 在基础研究中使用的是有用的PE的实验室类似物。对健康对照的研究表明 雌激素水平的升高有利于灭绝学习，因为它促进了灭绝学习的巩固，从而增强了 回想一下以后进行测试时的情况。这也反映在形成的大脑区域的激活变化上 恐惧消退网络，包括杏仁核、背侧前扣带回(DACC)和腹内侧 前额叶皮质(VmPFC)。雌二醇(E_2)是否能调节这种激活尚不清楚。 了解口服避孕药(OC)使用者的恐惧消退网络，以及哪种剂量的E2效果最好。 目前研究的R61阶段将旨在确定两种E2剂量中的哪一种(安慰剂(Plc)、2 mg或4 mg) 在使用OC的健康女性中，通过让她们暴露在经过验证的恐惧中，可以最好地利用恐惧消退网络 条件反射和消亡方案。功能磁共振成像(BOLD信号)和心理生理测量(皮肤 电导响应(SCR)将用来检验以下假设：1)服用雌二醇会增强 消退回忆(以较低的Scr为指标)呈剂量-反应关系；2)给予E2会增加vmPFC 并以剂量-反应方式减少回忆过程中dACC和杏仁核的激活。一旦最优的E2 剂量已确定，R33阶段将检查E2给药(相对于Plc)的影响 对有明显创伤后应激障碍症状的OC使用者进行5次体育训练。参与者将是 暴露在体育前后的恐惧条件和消退程序中。粗体信号、SCR以及 治疗前后将使用症状严重程度来检验这些假说：1)在消亡回忆过程中， 两组患者术后血肌酐均低于术前，其中以E2组效果最好。2) 在POST后，消退诱导的激活在vmPFC中较高，而在dACC和杏仁核中较低 相对于PE前，以E2 PE组作用最强。3)物种灭绝之间的信息流 治疗后结节将得到改善(以动态因果模型为指标)，在E2 PE中效果更强 一群人。4)E2 PE组的创伤后应激障碍症状严重程度低于Plc PE组 治疗，以及3个月和6个月的随访评估。5)创伤后应激障碍症状的减少与 在灭绝回忆过程中观察到了粗体和SCR的变化。我们的发现将阐明神经 有效治疗基于恐惧的症状的暴露治疗的潜在机制，并将揭示E2如何 作为一种辅助手段，以提高基于灭绝的疗法的疗效，如PE。

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.