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.

项目摘要长时间暴露（PE）治疗是创伤后应激障碍（PTSD）的选择。尽管它的有效性，大量个人不会从中受益，也不会在完成之前退出所有会议。这是发现方法提高体育效率以提高PE效率的重要性的重要性患有PTSD的人的生活质量。现在广泛认为扩展学习范式基础研究中使用的是有用的实验室类似物。在健康对照方面的研究表明升高的雌激素水平通过促进其巩固而受益于扩展学习，从而增强其稍后对其进行测试时，请回想一下。这也反映出大脑区域的激活变化恐惧扩展网络，包括杏仁核，背扣带回皮层（DACC）和腹膜前额叶皮层（VMPFC）。雌二醇（E2）给药是否可以调节激活仍然未知口服避孕（OC）用户的恐惧扩展网络以及E2剂量可以产生最佳结果。当前研究的R61阶段旨在确定两种E2剂量（安慰剂（PLC），2mg或4mg）中的哪个可以最好地通过OC暴露于恐惧的恐惧中，可以最好地吸引健康女性的恐惧扩展网络调理和扩展协议。功能fMRI（粗体信号）和心理生理学措施（皮肤电导响应 - SCR）将用于测试以下假设：1）E2给药将增强扩展召回（由下scr索引）以剂量反应方式； 2）E2给药将增加VMPFC 并以剂量反应方式降低DACC和杏仁核激活。一旦最佳E2 已经确定了剂量，R33阶段将检查E2给药（相对于PLC）在与PTSD症状重大症状的OC使用者中的5个PE会议的结合。参与者会暴露于PE之前和之后的恐惧条件和扩展方案。大胆的信号，SCR和症状严重程度将在治疗之前和之后使用以检验这些假设：1）在延长召回期间，两组将在相对于pE时显示较低的SCR，而E2+PE组显示出强大的效果。 2）在VMPFC中，灭绝引起的激活将较高，而DACC和杏仁核的激活将更高相对于Pre-PE，E2+PE组显示出强大的作用。 3）扩展之间的信息流在治疗后，节点将改善（通过动态 - 果实建模索引），对E2+PE产生更强的影响团体。 4）在E2+PE组中，相对于PLC+PE组的PTSD症状严重程度将较低治疗以及3个月和6个月的随访评估。 5）减少PTSD症状将相关在扩展召回期间观察到大胆和SCR变化。我们的发现将阐明中立为基于恐惧的症状提供有效暴露治疗的机制，并将揭示E2如何成为提高基于扩展疗法（例如PE）的效率的辅助功能。