Circadian Constrained Schedule Optimization for Maximal Performance

描述（由申请人提供）：提出使用数学模型来设计睡眠-觉醒和对策时间表以提高绩效。跨越多个时区的旅行导致环境时间线索和睡眠-觉醒时间表与内源性昼夜节律系统的正常相位关系不同步。昼夜节律失调会导致神经行为表现不佳，睡眠效率下降，以及胃肠道活动和激素释放等生理信号的不恰当时间。频繁和反复的跨子午线旅行与长期认知缺陷有关，实验中暴露于重复时间表变化的啮齿动物死亡率增加。减少短期昼夜节律、睡眠-觉醒和性能问题的一种方法是使用昼夜节律起搏器的数学模型来设计快速改变昼夜节律起搏器以适应新时间表的对策。该方法包括设计干预措施的“前沿”数学和计算机科学方法，将对抗措施的最佳放置算法与新颖的进度表示模式相结合。我们的初步结果表明，快速的昼夜节律再同步和由此带来的神经行为表现的改善，即使在睡眠-觉醒时间表发生中等到较大的变化后，也可以迅速实现。关键的时间表设计输入是内源性昼夜节律周期长度、期望的睡眠-觉醒时间表、干预时间、背景光水平和对抗强度。提出了一种新的时间表表示，作为一种促进时间表设计，模拟研究和实验设计的机制，以显着减少设计适当干预的时间。所提出的方法对设计时差，倒班工作和非24小时时间表有直接影响，包括在极端环境下的时间表，如太空，海底或极地地区。拟议的研究符合国家普通医学科学研究所的几个目标，包括使用生物信息学和计算生物学来确定缓解时差和轮班工作对包括行为在内的多器官系统的影响的干预措施。建议的培训旨在将数学，计算和昼夜节律/睡眠研究方法整合到一个共同的框架中，并满足NIGMS在不同领域界面培养准备充分的科学家的目标。

DESCRIPTION (provided by applicant): The use of mathematical models to design sleep-wake and countermeasure schedules for improved performance is proposed. Travel across multiple time zones results in desynchronization of environmental time cues and the sleep-wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. The approach includes "cutting-edge" mathematical and computer science methods for designing interventions that combine an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. Our preliminary results demonstrate that rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep-wake schedule, length of intervention, background light level, and countermeasure strength. A new schedule representation is proposed as a mechanism that facilitates schedule design, simulation studies, and experiment design to significantly decrease the amount of time to design an appropriate intervention. The proposed methods have direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar-regions. The proposed research meets several objectives of the National Institute of General Medical Sciences including the use of bioinformatics and computational biology to determine interventions that alleviate the effects of jetlag and shift-work on multiple-organ systems including behavior. The proposed training aims to integrate mathematical, computational, and circadian/sleep research methods into a common framework and meets the aim of NIGMS to train well-prepared scientists at the interface of different fields. PUBLIC HEALTH RELEVANCE: This work could affect the millions of people yearly who must work and sleep at time at which their circadian system is promoting the opposite behavior: this includes people experiencing jet lag or who must work night or rotating shifts. This desynchrony between internal circadian clock time and external environmental time affects 5 billion passengers who travel by air yearly, and 20% of global industrial employees who are shift workers, including 4.5 million international transport workers, and 1.4 million US military personnel who are often expected to work optimally despite changes in their schedule. The ultimate goal of this research is to make a set of mathematical, computational, and software tools that allow knowledge derived from circadian and sleep research to be used by non-professionals.