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

恐惧消退、学习和记忆是暴露疗法治疗焦虑的神经认知基础--以及 创伤相关障碍，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的PE过程中产生的灭绝的影响。使用 在健康个体的实验范式中，我们报告了更好地学习和推广灭绝 早晨比傍晚要好。我们的团队还表明，暴露疗法对恐慌症更有效 当在早上提供时，较高的内源性皮质醇水平介导了这种效果。因此，一个可能的 这种早晨优势背后的机制是通过早晨的昼夜节律增强灭绝学习 内源性皮质醇的顶期。这项探索性/发展性机制随机临床试验(RCT) 我将应用这些发现来检验这样的假设，即早上分娩的创伤后应激障碍患者的PE将显示出更大的 对恐惧记忆消退(靶机制)和创伤后应激障碍症状(临床结果)的影响 PE是在下午晚些时候交付的。PE是一种公认的、有效的、手动的10次治疗。这 RCT将比较20名在觉醒后2小时内开始接受PE治疗的人(即07：00- 10：00)至20：00或更晚于16：00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，这是主要的机制结果，将使用经过验证的 脚本驱动表象中创伤回忆的心理生理反应综合指数(SDI-PR)。SDI- PR结合了皮肤电导、心率和面部肌电测量。初级临床 结果将是临床医生管理的创伤后应激障碍量表(CAPS-5)上的创伤后应激障碍严重程度。SDI和CAPS-5将 发生在治疗前、治疗中和治疗后。次级机械(最大主观痛苦单位；SODS)和 临床(DSM-5创伤后应激障碍检查表)措施将在每次PE会议上获得。灭绝学习将是 在3个评估时间点上降低了SDI-PR，在8个时间点上减少了SOD 体育课，包括想象中的暴露。内源性唾液皮质醇水平 将测试每个PE会话并使用每日皮质醇曲线进行归一化，作为促进 一天中的时间对机械性和临床结果测量的影响。睡眠质量将使用腕部进行评估 在整个治疗过程中进行动作记录和日常睡眠日记。我们假设：(1)早晨与晚些时候相比- 下午，体育课将导致机械性和临床结果的更大下降。(2)皮质醇含量较高 在上一次PE会话中测量的级别将与更大的会话间变化相关联 继发性机制和临床结果。(3)更好的睡眠质量将与更大的下降相关 在机制和临床结果上。假设的确认将建议采用战略调度 最大限度地提高临床疗效，这是一种易于实施且成本低廉的保健策略。

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.