Circadian influence on fear extinction resulting from prolonged exposure therapy for PTSD

昼夜节律对 PTSD 长期暴露疗法引起的恐惧消退的影响

• 批准号: 10619526
• 负责人: Edward F. Pace-Schott
• 金额: $ 22.22万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619526
• 关键词: Adopted; Aftercare; Age; Anxiety; Anxiety Disorders; Area Under Curve; Clinical; Clinical Trials; Collection; DSM-V; Development; Diagnosis; Disease; Disease remission; Distress; Electromyography; Exclusion; Extinction; Face; Female; Fright; Galvanic Skin Response; Glucocorticoids; Healthcare; Healthcare Systems; Heart Rate; Home; Hour; Hydrocortisone; Imagery; Individual; Intake; Intervention; Investigational Therapies; Learning; Manuals; Measures; Mediating; Memory; Mental Health Services; National Institute of Mental Health; Neurocognitive; Outcome; Outcome Measure; Panic Disorder; Participant; Phobias; Physiology; Post-Traumatic Stress Disorders; Protocols documentation; Psychophysiology; Questionnaires; Randomized; Reporting; Research; Research Personnel; Salivary; Sampling; Schedule; Severities; Sleep; Social Anxiety Disorder; Spiders; Symptoms; Testing; Time; Trauma; Treatment Efficacy; Treatment outcome; Wrist; actigraphy; analog; arm; base; circadian; clinical outcome measures; cognitive reappraisal; conditioned fear; design; diaries; fear memory; improved; indexing; inter-individual variation; learning extinction; male; prevent; randomized, clinical trials; reduce symptoms; response; sleep quality; social stressor; trial comparing

Fear extinction learning and memory are the neurocognitive bases of exposure therapies for anxiety- and trauma-related disorders, including prolonged exposure therapy (PE) for posttraumatic stress disorder (PTSD). Proposed research will examine time-of-day effects on extinction produced during PE for PTSD. Using an experimental paradigm in healthy individuals, we reported that extinction is better learned and generalized in the morning than evening. Our team also showed that exposure therapy for panic disorder is more efficacious when provided in the morning, and that higher endogenous cortisol levels mediate this effect. Thus a possible mechanism underlying this morning advantage is enhanced extinction learning by the morning circadian acrophase of endogenous cortisol. This Exploratory/Developmental mechanistic randomized clinical trial (RCT) will apply these findings to test the hypothesis that PE for PTSD delivered in the morning will show greater effects on fear memory extinction (target mechanism) and PTSD symptoms (clinical outcome), compared to PE delivered in the late afternoon. PE is an established, efficacious, manualized 10-session treatment. This RCT will compare 20 individuals treated with PE beginning within 2 hours of awakening (i.e., between 07:00- 10:00) to 20 treated at 16:00 or later. Participants will complete at-home exposures at the same time of day as PE sessions. Fear memory extinction, the primary mechanistic outcome, will be measured using a validated composite index for psychophysiological reactivity to trauma recall during script-driven imagery (SDI-PR). SDI- PR combines skin conductance, heart rate, and facial electromyography measures. The primary clinical outcome will be PTSD severity on the Clinician-Administered PTSD Scale (CAPS-5). SDI and CAPS-5 will occur at pre-, mid-, and post-treatment. Secondary mechanistic (peak subjective units of distress; SUDS) and clinical (PTSD Checklist for DSM-5) measures will be obtained at each PE session. Extinction learning will be operationalized as decreased SDI-PR across the 3 assessment time points and decreased SUDS across the 8 PE sessions that include imaginal exposure. Endogenous salivary cortisol levels, obtained immediately before each PE session and normalized using diurnal cortisol profiles, will be tested as a mechanism contributing to time of day effects on mechanistic and clinical outcome measures. Sleep quality will be assessed using wrist actigraphy and daily sleep diaries throughout treatment. We hypothesize that: (1) Morning, compared to late- afternoon, PE sessions will produce greater declines in mechanistic and clinical outcomes. (2) Higher cortisol levels measured at the previous PE session will be associated with greater session-to-session change in secondary mechanistic and clinical outcomes. (3) Better sleep quality will be associated with greater declines in mechanistic and clinical outcomes. Confirmation of hypotheses would suggest adopting strategic scheduling of PE to maximize clinical outcome, an easily implemented and inexpensive health care strategy.

恐惧消退学习和记忆是焦虑和恐惧暴露疗法的神经认知基础 创伤相关疾病，包括针对创伤后应激障碍 (PTSD) 的长期暴露疗法 (PE)。 拟议的研究将检查一天中的时间对创伤后应激障碍 (PTSD) 运动期间产生的消退的影响。使用 在健康个体的实验范式中，我们报告说，灭绝在以下情况中得到了更好的学习和推广 早上比晚上。我们的团队还表明，暴露疗法对恐慌症更有效 当早上提供时，较高的内源性皮质醇水平会介导这种作用。因此一个可能的 早晨优势的潜在机制是早晨昼夜节律增强的消退学习 内源性皮质醇的顶相。这项探索性/发展机制随机临床试验 (RCT) 将应用这些发现来检验以下假设：早上进行的针对 PTSD 的体育锻炼会显示出更好的效果 与相比，对恐惧记忆消退（目标机制）和 PTSD 症状（临床结果）的影响 PE于下午晚些时候交付。 PE 是一种成熟、有效、手动的 10 次治疗。这 RCT 将比较 20 名在醒来后 2 小时内（即 07:00 至 10:00) 至 20 16:00 或更晚接受治疗。参与者将在一天中的同一时间完成在家暴露 体育课。恐惧记忆消退是主要的机制结果，将使用经过验证的方法来测量 脚本驱动意象（SDI-PR）期间对创伤回忆的心理生理反应的综合指数。 SDI- PR 结合了皮肤电导、心率和面部肌电图测量。主要临床 结果将是临床医生管理的 PTSD 量表 (CAPS-5) 上的 PTSD 严重程度。 SDI 和 CAPS-5 将 发生在治疗前、治疗中、治疗后。次要机制（痛苦主观峰值单位；SUDS）和 临床（DSM-5 的 PTSD 检查表）测量将在每次 PE 课程中获得。灭绝学习将是 通过在 3 个评估时间点上减少 SDI-PR 并在 8 个评估时间点上减少 SUDS 来实施 体育课程包括想象暴露。内源性唾液皮质醇水平，在之前立即获得 每次体育训练并使用昼夜皮质醇分布进行标准化，将作为一种机制进行测试，以促进 一天中的时间对机械和临床结果测量的影响。将通过手腕评估睡眠质量 治疗期间的体动记录仪和每日睡眠日记。我们假设：（1）早上，与晚间相比 下午，体育课将导致机械和临床结果出现更大的下降。 (2)皮质醇较高 前一次 PE 会话中测得的水平将与会话之间更大的变化相关 次要机制和临床结果。 (3) 睡眠质量越好，下降幅度越大 机械和临床结果。假设的确认将建议采用战略调度 PE 旨在最大限度地提高临床效果，这是一种易于实施且廉价的医疗保健策略。