Morning Light Treatment for Traumatic Stress: the Role of Amygdala Reactivity

摘要 暴露在创伤中会导致创伤后应激障碍(PTSD)、抑郁和焦虑。虽然 创伤应激有治疗方法，许多人未能接受治疗或仍有症状，尽管 治疗。创伤性应激需要针对潜在的病理机制进行新的治疗 并提供一个安全和可接受的替代方案。晨光作为一种新型的非侵入性、 创伤应激的低风险治疗。晨间强光疗法已被证明可以减轻抑郁症， 焦虑和创伤后应激障碍症状(包括我们自己的飞行员数据)。然而，目前还没有研究探索这种疗法 强光治疗创伤应激的机制。视网膜昼夜节律光感受器将光传输到 大脑，包括直接投射到杏仁核。健康对照组，进行为期3周的晨间强光治疗 杏仁核对情绪面孔fMRI任务的反应性降低。杏仁核对负面暗示的反应性与 创伤应激症状，并在成功治疗后减少。因此，早晨的强光治疗可以 通过减少杏仁核的反应性来减少创伤应激。使用跨诊断方法，我们将注册 受试者在过去5年中经历过A级创伤，并表现出显著的情绪和 唤醒症状。我们将使用市面上出售的ReTimer®强光设备，该设备可优化 治疗用光波长。将对治疗依从性进行客观评估。在R61阶段，66名受试者 将被随机分成3种不同剂量的4周晨光：15分钟、30分钟或1小时/天。 杏仁核的反应性(用fmri情绪面孔任务探测)将在3个时间点进行评估：基线，2 周，和4周。我们将测试每日晨光持续时间之间的剂量-反应关系 脉搏和杏仁核反应性从基线到2周和4周的变化。R61目标(目标交战)： 在每日晨光脉冲持续时间和减少之间建立显著的剂量反应关系 从第2周和/或第4周的杏仁核反应性基线开始。早晨的强光必须诱导有意义的 杏仁核反应性降低(d≥0.5)，继续进行R33(进行/不进行标准)。在R33阶段，122 受试者将被随机分配到明亮的(活跃的)和昏暗的(可信的和生物上无效的安慰剂)晨光中， 最佳治疗持续时间来自R61阶段(每天早晨光脉冲的最小持续时间 引起杏仁核反应性中d≥0.5%的最早有意义的降低)。R33目标1(功能结果)： 确定晨光与暗光(安慰剂)治疗对创伤应激症状的影响 标准和跨诊断的临床措施。R33目标2：建立杏仁核反应性的改变 创伤应激症状改善的预测因子。这个项目将是第一个建立解剖联系的项目 视网膜昼夜节律光感受器和杏仁核之间的关系转化为临床上有意义的变化 采用晨光疗法治疗杏仁核反应性。本课题的研究将为下一步的开发奠定基础 晨光疗法作为治疗创伤应激的新方法。

ABSTRACT Exposure to trauma can lead to posttraumatic stress disorder (PTSD), depression and anxiety. Although therapies exist for traumatic stress, many individuals fail to receive treatment or remain symptomatic despite treatment. New treatments are needed for traumatic stress that target underlying mechanisms of the pathology and offer a safe and acceptable alternative. Morning bright light has good potential as a novel non-invasive, low risk treatment for traumatic stress. Morning bright light treatment has been shown to reduce depression, anxiety, and PTSD symptoms (including our own pilot data). However, no studies are exploring the therapeutic mechanisms of bright light treatment for traumatic stress. Retinal circadian photoreceptors transmit light to the brain, including direct projections to the amygdala. In healthy controls, a 3-week morning bright light treatment reduced amygdala reactivity to an emotional faces fMRI task. Amygdala reactivity to negative cues is linked to traumatic stress symptoms, and reduces after successful treatment. Thus, morning bright light treatment may reduce traumatic stress by reducing amygdala reactivity. Using a transdiagnostic approach, we will enroll subjects who have experienced a criterion A trauma in the past 5 years and display significant mood and arousal symptoms. We will use the commercially available Retimer® bright light device, which optimizes the therapeutic light wavelength. Treatment adherence will be objectively assessed. In the R61 phase, 66 subjects will be randomized to 4 weeks of bright morning light at 3 different doses: 15 min or 30 min or 1 hour/day. Amygdala reactivity (probed with fMRI emotional faces task) will be assessed at 3 time points: baseline, 2 weeks, and 4 weeks. We will test for a dose-response relationship between duration of daily morning light pulse and change in amygdala reactivity from baseline to 2 and 4 weeks. R61 Aim (Target Engagement): establish a significant dose response relationship between duration of daily morning light pulse and reduction from baseline in amygdala reactivity at week 2 and/or week 4. Morning bright light must induce a meaningful reduction (d≥0.5) in amygdala reactivity to proceed to the R33 (the go/no-go criteria). In the R33 phase, 122 subjects will be randomized to bright (active) vs. dim (credible and biologically inactive placebo) morning light, with optimal treatment duration derived from the R61 phase (minimal duration of daily morning light pulse that elicits the earliest meaningful reduction of d≥0.5 in amygdala reactivity). R33 Aim 1 (Functional Outcomes): establish the effect of morning bright vs. dim (placebo) light treatment on traumatic stress symptoms using standard and transdiagnostic clinical measures. R33 Aim 2: establish change in amygdala reactivity as a predictor of traumatic stress symptom improvement. This project will be the first to establish if anatomical links between the retinal circadian photoreceptors and amygdala translate into clinically meaningful changes in amygdala reactivity using morning bright light therapy. This research will lay the foundation for developing morning bright light treatment as a novel treatment for traumatic stress.