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

• 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
• 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

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 延长暴露（PE）疗法是创伤后应激障碍（PTSD）的治疗选择。尽管 由于它的功效，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。这强调了研究方法的重要性，以提高体育的功效，以改善 PTSD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实验室类似于PE。对健康对照的研究表明， 雌激素水平升高有利于消退学习，促进其巩固，从而提高其 这也反映在大脑区域的激活变化中， 恐惧消退网络，包括杏仁核，背侧前扣带皮层（dACC）和腹内侧 前额叶皮层（vmPFC）。雌二醇（E2）给药是否能调节激活仍不清楚 口服避孕药（OC）使用者的恐惧消退网络，以及E2剂量可以产生最佳效果。 本研究的R61阶段旨在确定两种E2剂量（安慰剂（Plc），2 mg或4 mg）中的哪一种 在使用OC的健康女性中，通过将她们暴露于有效的恐惧中， 调节和消退方案。功能性磁共振成像（BOLD信号）和心理生理测量（皮肤 电导反应（SCR）将用于测试以下假设：1）E2给药将增强 消退回忆（以较低的SCR为索引）呈剂量反应方式; 2）E2给药将增加vmPFC 并以剂量-反应方式降低回忆过程中dACC和杏仁核的激活。一旦最佳E2 剂量已经确定，R33阶段将检查E2给药（相对于Plc）对 与5个PE会议在OC用户妇女有显着的PTSD症状。参与者将被 在PE之前和之后暴露于恐惧条件反射和消退方案。BOLD信号、SCR以及 在治疗之前和之后将使用症状严重性来检验这些假设：1）在消退回忆期间， 相对于PE前，两组在PE后均显示较低的SCR，其中E2+PE组显示最强的效果。（二） 灭绝诱导的激活在后额叶皮层中较高，在后额叶皮层中较低。 相对于PE前，E2+PE组显示出最强的效果。3)灭绝之间的信息流 治疗后节点将改善（通过动态因果模型索引），在E2+PE中效果更强 组4)E2+PE组的PTSD症状严重程度低于Plc+PE组， 治疗以及3个月和6个月随访评估时。5)创伤后应激障碍症状的减轻 在灭绝回忆期间观察到BOLD和SCR的变化。我们的发现将阐明 有效暴露治疗基于恐惧的症状的机制，并将揭示E2如何 作为辅助手段，以增强基于预防的治疗（如PE）的疗效。