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。相对于昼夜节律阶段的光刺激时间在现实世界的治疗环境中具有特别重要的实际意义，因为不适当的光照射时间可能导致与期望相反的阶段重置反应。在这项资助的前几年，我们在相位响应曲线（PRC）中量化了白光照射时间与其昼夜节律重置效应之间的关系。这些prc为在一系列治疗应用中设计适当的定时照明制度来重置昼夜节律起搏器提供了基础。最近的研究表明，具有较短（蓝色）波长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反应，如昼夜节律相位重置和褪黑激素抑制。这对利用光治疗昼夜节律紊乱和其他疾病具有重大意义。当前的照明是为视觉感光系统设计的（峰值灵敏度为555nm），使得大多数当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能够轻易地改变光的光谱组成，从而使光谱能够适应所需的生物效应。考虑到家用和职业场所的固态照明将在未来十年被广泛引入，我们了解这项新技术如何用于造福人类健康的基本方面是至关重要的。我们提出了一项研究，在这项研究中，我们将系统地评估对单色光刺激的昼夜节律相移、褪黑激素抑制和警觉性增强反应，使用的波长（460 nm）已被证明能最大限度地刺激昼夜节律系统。我们将评估对该最佳光源的相位相关响应（Aim I）。我们将研究刺激的褪黑激素抑制效应与其急性警觉性和表现增强效应之间的关系，以确定这些效应是否具有相位依赖性（Aims II和III），以及警觉性和表现增强效应是否与褪黑激素抑制程度相关（Aim II）。我们将研究脑电图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不同时间对脑电图谱产生不同的影响（Aim III）。本研究结果将为新型固态照明技术在光疗治疗延迟睡眠阶段障碍、晚期睡眠阶段障碍、倒班睡眠障碍、时差反应、季节性情感障碍、阿尔茨海默病“日落症”、年龄相关性睡眠维持性失眠等方面的应用奠定基础。

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.