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

确定联合雌激素和长期暴露疗法减少 PTSD 症状的神经机制

基本信息

批准号：
10003444
负责人：
Mohammed R Milad
金额：
$ 151.49万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-05 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10003444
关键词：
Aftercare Amygdaloid structure Anterior Area Brain Brain region Development Dorsal Dose Double-Blind Method Drops Drug Kinetics Estradiol Estrogens Ethinyl Estradiol Exhibits Exposure to Extinction (Psychology)Female Fright Functional Magnetic Resonance Imaging Galvanic Skin Response Impairment Individual Intervention Laboratories Learning Measures Mediating Modeling Neurons Oral Contraceptives Outcome Participant Pathologic Pharmaceutical Preparations Phase Physiological Placebos Post-Traumatic Stress Disorders Prefrontal Cortex Protocols documentation Psychophysiology Quality of life Randomized Rodent Severities Signal Transduction Symptoms Testing Woman analog base blood oxygen level dependent causal model cingulate cortex clinically significant conditioned fear falls follow up assessment improved indexing learning extinction memory recall neuromechanism pill placebo group reduce symptoms relating to nervous system response symptom treatment trauma exposure treatment choice

项目摘要

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.

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。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这强调了寻找提高体育锻炼功效的方法以改善的重要性。患有创伤后应激障碍 (PTSD) 的个体的生活质量现在已被广泛接受。健康对照研究表明，基础研究中使用的 PE 是有用的实验室类似物。雌激素水平升高有利于消除学习，促进其巩固，从而增强其稍后进行测试时回忆起来，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) 和腹内侧目前尚不清楚雌二醇 (E2) 是否可以调节前额皮质 (vmPFC) 的激活。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消除记忆（以较低的 SCR 为索引）；2) E2 给药将增加 vmPFC；一旦达到最佳 E2，就会以剂量反应方式减少 dACC 和杏仁核的激活。剂量已确定，R33 阶段将检查 E2 给药（相对于 Plc）对与具有明显 PTSD 症状的 OC 用户的 5 次体育课程一起进行。在 PE 之前和之后暴露于恐惧调节和消退方案。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，两组在术后的 SCR 均较低，其中 E2+PE 组的效果最强 2)。消退诱导的激活在 vmPFC 中较高，在 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）消退之间的信息流。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 4) 相对于 Plc+PE 组，E2+PE 组的 PTSD 症状严重程度较低。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。在消退回忆过程中观察到 BOLD 和 SCR 的变化，我们的研究结果将阐明神经元的变化。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。