Sensitization of Human Circadian Responses to Light

描述（由申请人提供）：睡眠障碍影响35-40%的成年人，导致生活质量下降，发病率，死亡率增加，以及汽车和职业事故的风险。昼夜节律睡眠障碍形成了一种独特的睡眠障碍，其特征是睡眠时间和昼夜节律起搏器之间的不一致。虽然光疗可以有效地治疗昼夜节律睡眠障碍，但有许多实际的局限性。光是影响和调节日常生物节律的环境中最强大的信号。众所周知，光照强度、持续时间和光照时间都会影响昼夜节律系统的反应。虽然曾经认为这些反应是通过视觉系统介导的，但现在已经知道存在一个由内在光敏视网膜神经节细胞（ipRGCs）组成的网络，介导对光的昼夜节律反应。其他新的研究表明，最近的光照历史会影响人类对光的昼夜节律反应。这些最近的发现对利用光治疗昼夜节律障碍具有重要意义，包括延迟和提前睡眠阶段障碍、轮班工作睡眠障碍和时差，它们也可能与利用光治疗季节性情感障碍有关。到目前为止，很少有人关注这种光处理前的光照射时间或强度。我们现在有证据表明，人类的昼夜节律系统可以在长时间暴露在光线下变得不敏感，也有证据表明，它可以通过事先暴露在昏暗的光线下而变得对光敏感。这些最近的发现表明，在光处理之前使昼夜节律系统敏感的光处理方案将比目前使用的光处理方案更有效。我们提出的研究将检查在标准化光处理之前，四种不同时间的昏暗光敏化对人类昼夜节律系统的影响。这些结果将在一项随机交叉设计研究的受试者中进行比较，在该研究中，每个健康受试者将接受对照治疗和事先进行微光致敏的光治疗。我们还将包括一组延迟睡眠阶段障碍患者，以在目标患者人群中测试这些机制。我们的研究结果将为理解昼夜节律光感受系统的新知识如何用于改进昼夜节律障碍并提供更好的治疗选择提供重要的一步。

DESCRIPTION (provided by applicant): Sleep disorders affect 35-40% of adults, resulting in diminished quality of life, and increased morbidity, mortality, and risk of automobile and occupational accidents. Circadian rhythm sleep disorders form a distinct class of sleep disorders characterized by misalignment between the timing of sleep and the circadian pacemaker. While light therapy can be an effective treatment of circadian rhythm sleep disorders, there are numerous practical limitations. Light is the most powerful signal from the environment that influences and regulates daily biological rhythms. It is well-established that the irradiance, duration, and timing of light exposure all affect the response of the circadian system. While it was once thought that these responses were mediated through the visual system, it is now known that there is a network of intrinsically photosensitive retinal ganglion cells (ipRGCs) that mediate circadian responses to light. Other new studies have demonstrated that recent light exposure history affects the circadian response to light in humans. These recent findings have important implications for the use of light to treat circadian rhythm disorders, including delayed and advanced sleep phase disorders, shift work sleep disorder, and jet lag, and they may also have relevance for the use of light to treat seasonal affective disorder. Up to now, little attention has been paid to the duration or intensity of light exposure prior to such light treatments. We now have evidence that the human circadian system can become desensitized to light during long exposures and evidence that it can be sensitized to light by prior exposure to dim light. These recent findings suggest that light treatment protocols that sensitize the circadian system prior to the light treatment will be more effective than those currently in use. The studies we propose will examine the effect on the human circadian system of four different durations of dim-light sensitization prior to a standardized light treatment. These results will be compared within subjects in a randomized cross-over design study in which each healthy subject will receive a control treatment and a light treatment with prior dim-light sensitization. We will also include one group of delayed sleep phase disorder patients to test these mechanisms in the target patient population. Our findings will provide an important step in understanding how new knowledge about the circadian photoreceptive system can be used to refine and provide better treatment options for circadian rhythm disorders. PUBLIC HEALTH RELEVANCE: Circadian rhythm disorders are a class of sleep disorders characterized by misalignment between the timing of sleep and the circadian pacemaker. Light therapy can effectively treat these disorders, but the intensity and duration of light exposure required to do so has limited its practical use. Here we will test how pre exposure to dim light can enhance the response of the circadian system to light therapy, resulting in shorter treatments that have greater practical application.