Circadian and Ultradian Cortisol Rhythms in Chronic Sleep Continuity Disturbance

摘要 大约30-50%的美国人口经历急性睡眠连续性障碍（即，失眠症） 每年，大约10%的人口报告患有慢性失眠症。慢性失眠（CI） 与显著的日间损害相关，是多种精神疾病的重要风险因素， 医学疾病鉴于CI的流行和后果，必须确定使CI持续存在的因素。 这种混乱。下丘脑-垂体-肾上腺是脑梗死的神经生物学基础之一 (HPA)轴失调，特别是皮质醇能张力的改变。皮质醇分泌模式表现为 昼夜节律和超昼夜节律。超日脉冲（即，每隔60-120分钟）被假设为 参与维持白天的觉醒，可能与抑制觉醒有关 在晚上（即，脉冲的抑制促进睡眠的巩固）。当皮质醇脉冲自然发生时 对于短暂的觉醒，我们假设这些脉冲可以成为CI中的条件现象， 使个体倾向于觉醒和/或经历长时间的夜间觉醒。皮质醇增加 白天的脉搏也是可以预期的，因为需要增加努力来保持清醒， 反过来，这些增加的脉冲可能进一步调节夜间皮质醇脉冲的异常发生。 科学目的是（1）评估与睡眠良好者相比，CI受试者是否表现出更大的 在白天和/或晚上的超昼夜皮质醇脉动，和（2）量化超昼夜皮质醇脉动之间的关联， 皮质醇分泌和与从睡眠中自发唤醒有关的度量（即，定时，频率，持续时间， 和觉醒的EEG频谱轮廓）。拟定研究将作为受试者间研究进行 设计，在实验室中连续两个晚上对20名CI患者和20名睡眠良好者进行检查 （第一天晚上是放映日）。而在实验室里，血液将采样每10分钟为24小时和睡眠 会被多导生理记录下来一个精确的昼夜节律和超昼夜方面的描绘， 皮质醇的分泌可以让我们更好地了解慢性失眠的病因， 已建立的治疗方法，并可能开发新的治疗方法。培训计划 包括包含三个广泛主题领域的教育活动：（1）一般技能（即，专业， （2）与下列方面有关的原则、做法和方法问题： 神经内分泌学，以及（3）与行为睡眠相关的原则、实践和方法论问题 药物和睡眠药物。该培训计划建立在申请人的背景，在抑郁症相关的 睡眠研究和压力生理学，并提供必要的培训，神经内分泌学，行为 睡眠医学和睡眠医学，以进一步探索和记录HPA轴的任何关联 异常，夜间持续失眠。教学方法包括常规的一对一 导师制、指导性阅读、课程工作、小型奖学金、实验室培训和会议/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.