Treatment of Circadian Sleep Disorders with Bright Light

描述（由申请人提供）：光是人体昼夜节律起搏器的主要同步器，对光的反应取决于曝光的时间、数量、强度、持续时间和模式。光刺激相对于昼夜节律相位的定时在现实世界的治疗环境中具有特别重要的实际意义，因为不适当地定时的光暴露可能导致与所期望的相位相反的相位重置响应。在本补助的前几年，我们量化了白色光暴露的时间与相位响应曲线（PRC）中的昼夜节律重置效应之间的关系。这些PRC为设计适当定时的照明方案提供了基础，以在一系列治疗应用中重置昼夜节律起搏器。最近的研究已经证明，在较短（蓝色）波长中具有峰值灵敏度的新型光感受器，而不是视杆细胞和视锥细胞，主要负责介导非图像形成响应，例如昼夜节律相位重置和褪黑激素抑制。这对于使用光来治疗昼夜节律紊乱和其他疾病具有戏剧性的意义。目前的照明是专为视觉明视系统（峰值灵敏度555 nm），使大多数目前的照明不适合优化昼夜节律反应。固态照明的发展将使人们有可能轻松地改变光的光谱组成，从而使光谱可以根据所需的生物效应进行调整。鉴于未来十年将广泛引入家庭和职业环境的固态照明，我们必须了解如何利用这种新技术造福人类健康的基本方面。我们已经提出了一项研究，在这项研究中，我们将系统地评估昼夜节律相移，褪黑激素抑制和警觉性增强对单色光刺激的反应，使用已被证明最大限度地刺激昼夜节律系统的波长（460 nm）。我们将评估对这种最佳光源的相位依赖性响应（目标I）。我们将研究刺激的褪黑激素抑制效应与其急性警觉和表现增强效应之间的关系，以确定这些效应是否是阶段依赖性的（目的II和III），以及警觉和表现增强效应是否与褪黑激素抑制的程度相关（目的II）。我们将研究EEG频率功率分布的变化，以确定对刺激的急性反应是否会在一天中的不同时间对EEG频谱产生差异性影响（目的III）。这项工作的结果将为新的固态照明技术应用于延迟睡眠期障碍，高级睡眠期障碍，轮班工作睡眠障碍，时差，季节性情感障碍，阿尔茨海默病中的“日落”以及与年龄相关的睡眠维持失眠的光疗治疗奠定基础。

DESCRIPTION (provided by applicant): Light is a primary synchronizer of the human circadian pacemaker, with the response to light dependent on the timing, number, intensity, duration, and pattern of exposures. The timing of a light stimulus relative to circadian phase has particularly important practical implications in a real-world therapeutic setting, because inappropriately timed light exposure can cause an opposite phase resetting response to that desired. In prior years of this grant, we quantified the relationship between the timing of white light exposure and its circadian resetting effect in Phase Response Curves (PRC). These PRCs have provided the basis for designing appropriately-timed lighting regimes to reset the circadian pacemaker in a range of therapeutic applications. Recent studies have demonstrated that novel photoreceptors with a peak sensitivity in the shorter (blue) wavelengths, rather than rods and cones, are primarily responsible for mediating non-image forming responses such as circadian phase resetting and melatonin suppression. This has dramatic implications for using light to treat circadian rhythm disorders and other conditions. Current lighting is designed for the visual photopic system (peak sensitivity 555 nm), making most current lighting inappropriate for optimizing circadian responses. The development of solid-state lighting will make it possible to easily alter the spectral composition of light, such that light spectra could be tailored to the desired biological effect. Given that solid- state lighting for home and occupational settings will be introduced widely over the next decade, it is vital that we understand the fundamental aspects of how this new technology can be used to benefit human health. We have proposed a study in which we will systematically assess the circadian phase-shifting, melatonin suppressing, and alertness-enhancing response to a monochromatic light stimulus, using a wavelength (460 nm) that has been shown to maximally stimulate the circadian system. We will assess the phase-dependent response to this optimal light source (Aim I). We will examine the relationship between the melatonin- suppressing effects of the stimulus and its acute alerting and performance-enhancing effects in order to determine whether these effects are phase-dependent (Aims II and III), and whether the alerting and performance-enhancing effects are correlated with the degree of melatonin suppression (Aim II). We will examine changes in the EEG frequency power distribution to determine whether acute responses to the stimulus differentially affect the EEG spectrum at different times of day (Aim III). The results of this work will build the foundation for the application of new solid-state lighting technology for the phototherapy treatment of delayed sleep phase disorder, advanced sleep phase disorder, shift-work sleep disorder, jet lag, seasonal affective disorder, "sundowning" in Alzheimer's Disease, and age-related sleep maintenance insomnia.