Circadian and Ultradian Cortisol Rhythms in Chronic Sleep Continuity Disturbance

摘要 大约30%-50%的美国人口每年经历急性睡眠连续性障碍(即失眠) 每年，约有10%的人口报告长期失眠。慢性失眠(CI) 与严重的日间损害有关，是多发性精神疾病和 医学上的障碍。鉴于CI的流行和后果，必须确定使其永久化的因素 这种紊乱。脑梗塞的神经生物学基础的主要候选者之一是下丘脑-垂体-肾上腺 (HPA)轴失调，具体地说，皮质醇能张力的改变。皮质醇分泌模式显示出这两种模式 一个昼夜节律和一个极端的节奏。超长脉冲(即，每隔60-120分钟)被假设为 参与维持白天的清醒状态，可能与抑制清醒状态有关 夜间(即脉搏的抑制促进睡眠的巩固)。当皮质醇脉冲自然出现时 在瞬间唤醒的情况下，我们假设这些脉冲可以成为CI中的条件现象 使个体倾向于唤醒和/或体验长时间的夜间唤醒。皮质醇增加 白天的脉搏也是可以预期的，因为保持清醒所需的努力增加了， 反过来，这些增加的脉搏可能会进一步调节夜间皮质醇脉冲的异常出现。 科学目的是(1)评估与睡眠质量好的受试者相比，CI受试者是否表现出更高的睡眠质量 超短波皮质醇在白天和/或夜间的脉动性，以及(2)量化超短波之间的联系 皮质醇分泌和与自发从睡眠中唤醒相关的指标(即，定时、频率、持续时间， 和觉醒的脑电频谱分布)。拟议的研究将作为受试者之间的研究进行 设计：在实验室连续两晚对20名CI患者和20名睡眠良好者进行检查 (第一晚是放映之夜)。在实验室里，每10分钟就会采集一次血液样本，持续24小时，然后睡觉 会被多项生理记录仪记录下来。对昼夜节律和超常方面的精细描绘 皮质醇分泌可能有助于更好地了解慢性失眠的病因，治疗失眠的疗效 已建立的治疗方法，以及潜在的新治疗方法的开发。培训计划 包括三大主题领域的教育活动：(1)一般技能(即，专业、 道德和研究培训活动)，(2)与以下方面有关的原则、做法和方法问题 神经内分泌学，以及(3)与行为睡眠有关的原则、实践和方法学问题 药物和安眠药。培训计划以申请者在抑郁症相关领域的背景为基础 睡眠研究和压力生理学，并提供必要的神经内分泌学、行为学培训 睡眠药物，以及睡眠药物，以进一步探索和记录HPA轴的任何关联 夜间持续清醒的异常现象。教学方法包括常规的一对一 辅导、定向阅读、课程作业、迷你奖学金、基于实验室的培训和会议/研讨会。

ABSTRACT Approximately 30-50% of the US population experiences acute sleep continuity disturbance (i.e., insomnia) per annum, and approximately 10% of the population report chronic levels of insomnia. Chronic insomnia (CI) is associated with significant daytime impairment and is a substantial risk factor for multiple psychiatric and medical disorders. Given CI's prevalence and consequences, it is essential to identify factors that perpetuate this disorder. One of the leading candidates for the neurobiological basis of CI is hypothalamic-pituitary-adrenal (HPA) axis dysregulation, specifically, alterations in cortisolinergic tone. Cortisol secretory patterns exhibit both a circadian and an ultradian rhythm. Ultradian pulses (i.e., every 60-120 minutes) are hypothesized to be involved in the maintenance of wakefulness during the day and may be related to the inhibition of wakefulness at night (i.e., the inhibition of pulses promotes the consolidation of sleep). While cortisol pulses naturally occur with transient awakenings, we hypothesize that these pulses can become a conditioned phenomenon in CI that predisposes the individual to awaken and/or experience prolonged nocturnal awakenings. Increased cortisol pulses during the day may also be expected because of the increased effort required to maintain wakefulness, and in turn, these increased pulses may further condition the aberrant occurrence of cortisol pulses at night. The scientific aims are (1) to evaluate whether subjects with CI, as compared to good sleepers, exhibit greater ultradian cortisol pulsatility during the day and/or at night, and (2) to quantify the association between ultradian cortisol secretion and metrics related to spontaneous awakenings from sleep (i.e., timing, frequency, duration, and EEG spectral profile of the awakenings). The proposed study will be conducted as a between-subjects design, examining 20 individuals with CI and 20 good sleepers during two consecutive nights in the laboratory (Night 1 is a screening night). While in the lab, blood will be sampled every 10 minutes for 24 hours and sleep will be polysomographically recorded. A refined delineation of both the circadian and ultradian aspects of cortisol secretion may allow for a better understanding of the etiology of chronic insomnia, the efficacy of established treatments, and potentially the development of new therapeutic approaches. The training plan includes educational activities that encompass three broad topic areas: (1) general skills (i.e., professional, ethics, and research training activities), (2) principles and practice and methodology issues related to neuroendocrinology, and (3) principles and practice and methodology issues related to behavioral sleep medicine and sleep medicine. The training plan builds upon the applicant's background in depression-related sleep research and stress physiology and provides the necessary training in neuroendocrinology, behavioral sleep medicine, and sleep medicine to further explore and document any association of HPA-axis abnormalities with persistent wakefulness at night. The pedagogic approach includes routine one-on-one mentorship, directed readings, course work, mini-fellowships, lab-based trainings, and conferences/workshops.