Ultrashort (msec) Light Exposure as a Countermeasure to Circadian Desynchrony

描述（由申请人提供）：昼夜节律不同步是一种内部生物钟与人们试图保持的社会时间表不一致时发生的现象。这种情况在很多情况下都会出现，包括倒班工作和喷气式飞机旅行。它会导致显著的病理生理变化，包括睡眠、认知、新陈代谢、免疫功能和心脏功能的有害变化，而这反过来又会导致肥胖、癌症风险和工作场所事故的增加。昼夜节律不同步也自然发生在延迟睡眠阶段障碍（DSPD）中，这是许多青少年和年轻人的一种情况，社会压力加剧了这种情况，导致个人将睡眠时间推迟，而醒来时间保持不变。DSPD导致工作和学习成绩显著下降，并与包括肥胖和抑郁在内的各种疾病有关。昼夜节律不同步最容易通过几个小时的强光照射来治疗。然而，这并不总是可能的，我们对光的特征以及它如何影响昼夜节律起搏器缺乏完全的了解，限制了我们设计更好的昼夜节律不同步对策的能力。本应用程序的目的是研究光如何影响昼夜节律的基本生理学，以及光如何影响夜间的警觉性，以及在睡眠期间改变昼夜节律的新机制。具体来说，我们将检验这样一个假设，即当受试者在夜间清醒时暴露在超短（毫秒）光脉冲下，光能够同步人体昼夜节律系统并提高警觉性，这是由主观和客观测量确定的。在另一项实验中，实验对象将在夜间睡觉时暴露在超短脉冲光下。在这个实验中，我们打算检验这样一个假设，即这种刺激不仅会穿透闭合的眼睑，使昼夜节律系统同步，而且不会干扰睡眠。为了检验这些假设，年轻、健康的受试者将被带到一个专门设计的人类昼夜节律实验室，并暴露在不同的光线下。我们在这项研究中引入了一种新的方案，将研究停留时间从标准的一周减少到两天。在大大减少受试者负担和研究成本的同时，我们能够保持人类昼夜节律系统的高保真度测量。我们还将通过各种技术来检查警觉性，包括性能跟踪和脑电图活动检查。这项实验的结果不仅将从根本上改变我们对光如何影响人类昼夜节律起搏器的看法，而且还将导致直接的、可测试的治疗昼夜节律不同步的方法。它也可能使我们更好地了解光对其他下丘脑影响功能的影响，包括情绪和内分泌功能。

DESCRIPTION (provided by applicant): Circadian desynchrony is a phenomenon that occurs when the internal circadian clock is misaligned with the social schedule that one tries to keep. This arises volitionally in a variety of circumstances, including shift work and jet travel. It leads to significant pathophysiology including deleterious changes in sleep, cognition, metabolism, immune function, and cardiac function, which in turn can lead to, among other things, increases in obesity, cancer risk, and workplace accidents. Circadian desynchrony also occurs naturally in delayed sleep phase disorder (DSPD), a condition in many adolescents and young adults that is compounded by social pressures and causes individuals to shift their sleep time later while their wake time remains fixed. DSPD leads to significant decline in workplace and academic performance and has been linked to a variety of disorders including obesity and depression. Circadian desynchrony is most readily treated by hours of administration of bright light. This, however, is not always possible and our lack of complete understanding of the characteristics of light and how it influences the circadian pacemaker limit our ability to design better countermeasures to circadian desynchrony. It is the purpose of this application to examine the basic physiology of how light influences circadian timing, as well as how light impacts alertness at night and a novel mechanism by which to change circadian timing during sleep. Specifically, we will examine the hypothesis that when subjects are exposed, while awake at night, to ultrashort (millisecond) pulses of light, the light is able to both synchronize the human circadian system and improve alertness, as determined by both subjective and objective measures. In a separate experiment, subjects will be exposed to ultrashort pulses of light at night while they sleep. In that experiment, we intend to examine the hypothesis that this stimulus will not only penetrate the closed eyelid and synchronize the circadian system, but that it will do so without disrupting sleep. In order to examine these hypotheses, young, healthy subjects will be brought into a specially designed human circadian laboratory and exposed to different regimens of light. We introduce in this study a novel protocol that reduces the study length of stay from the standard week to just two days. While greatly reducing subject burden and study costs, we are able to maintain high fidelity measurements of the human circadian system. We will also examine alertness through a variety of techniques including performance tracking and examination of electroencephalographic activity. Results from this experiment will not only fundamentally change the manner in which we think about how light affects the human circadian pacemaker, but it will also lead to direct, testable therapeutics for the treatment of circadian desynchrony. It may also lead to a better understanding of the impact of light on other hypothalamic- influenced functions including mood and endocrine function.