Sleep reactivity as a novel mechanism in Shift Work Disorder

项目概要/摘要 所有基本的24小时操作（例如，第一反应者，医院服务）依靠夜班工人谁放弃 夜间睡眠工作。轮班工人占劳动力的20%，有1500万人经常上夜班。 大多数人不适应颠倒的睡眠-觉醒时间表，导致轮班工作障碍（SWD），其特征是 过度嗜睡和/或失眠伴睡眠不足。此外，由于夜班对安全至关重要- 由于社署的运作敏感，发生灾难性意外的风险，令社署对公众健康和安全构成威胁。那里 在将轮班工作研究转化为有效的社会福利署治疗方法的临床转化方面仍然存在关键差距。一个间隙 缺乏对SWD大样本临床研究的机制研究，以探索相关的治疗靶点。作为 这样的治疗主要集中在症状管理（例如，保持警觉的兴奋剂 催眠药物（用于睡眠）。症状管理本身留下了潜在的机制 其可继续引起无数急性和长期问题和发病率。解决 这个差距，这一建议的总体目标是阐明关键和新的机制，推动社会福利署。我们 长期目标是开发一种治疗方法，识别并靶向适当的潜在机制， SWD.我们的试验数据表明，除了昼夜节律失调（即，身体和身体之间的不匹配 时钟和睡眠-工作时间表），SWD中的一个新的和关键的机制是睡眠反应性。睡眠 反应性是睡眠容易被环境刺激和紧张性刺激破坏的特征。我们的试点数据在一个 横断面样本表明，睡眠反应预测持续的SWD症状，即使在减少 昼夜节律失调我们还表明，睡眠反应可以减少与认知行为疗法 （CBT）。然而，睡眠反应性还没有被实验性地从昼夜节律失调中分离出来， 社署的独立因果机制。这项研究是至关重要的，因为它将证明， 治疗应该针对睡眠反应性，而不依赖于昼夜节律失调。为此，我们提出了一个 两步机械随机对照试验在SWD分层的高和低睡眠反应（N=150）： 第一步使用定时强光照射探测昼夜节律失调，第二步减少睡眠 认知行为疗法的反应。我们的中心假设是， 与睡眠反应性低的SWD的昼夜节律重新调整成比例;然而，失眠（目的1） 和嗜睡（目标2）的症状将持续存在，即使在实验后， 减少昼夜节律失调。在那些尽管昼夜节律降低但症状持续的患者中， 如果不对准，进一步降低CBT的睡眠反应性将导致症状的减少（目的3&4）。 完成后，这项研究的结果将建立睡眠反应作为一种新的因果机制， 社署将告知未来的精确医学方法，以治疗这种高度流行和治疗不足的疾病。

Project Summary/Abstract All essential 24-hr operations (e.g., first responders, hospital services) rely on nightshift workers who forgo nocturnal sleep for work. Shift workers comprise 20% of the workforce, with 15 million regularly working nights. Most do not adapt to the inverted sleep-wake schedule, resulting in shift work disorder (SWD) characterized by excessive sleepiness and/or insomnia with sleep loss. Furthermore, because nightshifts are critical to safety- sensitive operations, the risk for catastrophic accidents makes SWD a threat to public health and safety. There remain critical gaps in the clinical translation of shift work research into validated treatments for SWD. One gap is a lack of mechanistic research in large clinical samples of SWD that probe pertinent treatment targets. As such, treatments have predominantly focused on symptom management (e.g., stimulants to maintain alertness and hypnotic medications for sleep). Symptom management alone leaves the underlying mechanisms unabated which can continue to cause a myriad of acute and long-term problems and morbidities. To address this gap, the overall objective of this proposal is to elucidate critical and novel mechanisms driving SWD. Our long-term goal is to develop a treatment that identifies and targets the appropriate underlying mechanisms in SWD. Our pilot data indicates that in addition to circadian misalignment (i.e., a mismatch between the body- clock and the sleep-work schedule), one novel and critical mechanism in SWD is sleep reactivity. Sleep reactivity is a trait where sleep is easily disrupted by environmental stimuli and stressors. Our pilot data in a cross-sectional sample suggests that sleep reactivity predicts persistent SWD symptoms even after reducing circadian misalignment. We also show that sleep reactivity can be reduced with Cognitive Behavioral Therapy (CBT). However, sleep reactivity has not been experimentally disassociated from circadian misalignment as an independent causal mechanism of SWD. This research is critical because it would demonstrate that SWD treatment should target sleep reactivity independently from circadian misalignment. To do this, we propose a two-step mechanistic randomized controlled trial in SWD stratified by high and low sleep reactivity (N=150): the first step probes circadian misalignment using timed bright light exposure, and the second step reduces sleep reactivity with Cognitive Behavioral Therapy. Our central hypothesis is that symptoms of SWD will reduce proportionately with circadian realignment in SWD with low sleep reactivity; however, both insomnia (Aim 1) and sleepiness (Aim 2) symptoms will persist in SWD with high sleep reactivity even after experimental reduction of circadian misalignment. In those with persistent symptoms despite reduced circadian misalignment, further reducing sleep reactivity with CBT would result in reductions in symptoms (Aims 3 & 4). Upon completion, results from this study will have established sleep reactivity as a novel causal mechanism of SWD to be inform future precision medicine approaches for this highly prevalent and undertreated disorder.