Project 2: Pharmacological Probing of Sleep Physiology in Autism

项目2：项目摘要/摘要 自闭症谱系障碍(ASD)是一种以社会交往为特征的神经发育障碍 缺陷、感觉异常和受限/重复行为(RRB)。睡眠中断通常被描述为 作为儿童和青少年ASD最沉重的症状之一，其发生率高达80%。 动物研究表明，睡眠在突触网络结构的可塑性中起着重要作用， 突触强度的动态平衡再平衡以及记忆的重演和巩固。在人类身上， 睡眠障碍会损害认知和情感，这是有据可查的。事实上，家长报告已经发现 ASD患者睡眠不足会加剧核心症状的严重性，RRB增加为 以及社会沟通障碍的恶化。因此，增加我们对睡眠的理解 ASD的生理和改善睡眠对潜在的干预措施的发展至关重要，这些干预措施可能 有利于自闭症的核心特征以及相关行为。虽然人们对 ASD的神经生物学，目前已进行了有限的研究来阐明睡眠的神经生物学。 骚乱。最近的研究提供了证据表明，患有自闭症的儿童总睡眠时间较短 时间，较大的慢波睡眠百分比，和少得多的快速眼动(REM)睡眠百分比。 然而，尽管ASD的睡眠异常的发现是一致的，但有限的研究检查了 药物化合物对睡眠生理学的影响。关键的是，缺乏调查。 评估催眠剂对睡眠结构的生物影响。拟议项目的目标是 进行一系列先导试验，以调查三种不同机制的催眠剂的效果 苯海拉明、唑吡坦和亚消炎痛对自闭症儿童和青少年睡眠结构的影响 8-17年)。苯海拉明是一种具有很强催眠作用的抗组胺能药物。唑吡坦是 一种非苯二氮类伽马氨基丁酸-GABA受体激动剂药物，其作用是镇静和 催眠药。Suvorexant是一种选择性的双重增食欲素受体拮抗剂，用于治疗睡眠开始 困难和/或睡眠维护。我们将使用随机、双盲、交叉、安慰剂对照的8- 周设计考察3种催眠化合物对睡眠生理和昼夜节律的影响 通过多导睡眠图、动作图、皮质醇和褪黑素唾液水平进行评估。这些措施将是 在随机化前、第4周和第8周获得。睡眠测量将包括慢波睡眠，非 快速眼动睡眠、快速眼动睡眠、睡眠效率、睡眠开始后醒来和睡眠延迟。我们还将比较 三种药物对睡眠参数、昼夜节律和睡眠质量的影响。最后，我们将研究 这些措施与ASD临床特征变化的关系，包括RRB，Social 沟通障碍及相关行为，包括易怒和多动症。

Project 2: Project Summary/Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits, sensory abnormalities, and restricted/repetitive behaviors (RRB). Disrupted sleep is usually described as the one of the most burdensome symptoms in children and adolescents with ASD with rate of up to 80%. Animal studies demonstrate that sleep plays important roles in structural plasticity of synaptic networks, homeostatic rebalancing of synaptic strengths and the replay and consolidation of memories. In humans, sleep disruption is well documented to impair cognition and affect. In fact, parent reports have found insufficient sleep in individuals with ASD to exacerbate the severity of core symptoms, with increased RRB as well as worsening of social communication deficits. Therefore, increasing our understanding of sleep physiology and improving sleep in ASD is critical for the potential development of interventions that could benefit core autism features as well as in associated behaviors. While there is increased interest in the neurobiology of ASD, limited research has been conducted to elucidate the neurobiology of sleep disturbances. Recent investigations have provided evidence that children with ASD had shorter total sleep time, greater slow-wave sleep percentage, and much less rapid eye movement (REM) sleep percentage. However, despite the consistent findings of sleep abnormalities in ASD, limited studies have examined the effectiveness of pharmacological compounds on sleep physiology. Critically, there is a lack of investigations assessing the biologic effects of hypnotic agents on sleep architecture. The goal of the proposed project is to conduct a series of pilot trials to investigate the effect of three sleep-inducing agents with different mechanisms (diphenhydramine, zolpidem, and suvorexant) on sleep architecture in children and adolescents with ASD (age range 8-17 years). Diphenhydramine is an anti-histaminergic agent with strong hypnotic properties. Zolpidem is a nonbenzodiazepine Gamma Aminobutyric Acid-GABAa receptor agonist drug which acts as a sedative and hypnotic. Suvorexant is a selective, dual orexin receptor antagonist used for the treatment of sleep onset difficulties and/or sleep maintenance. We will use a randomized double-blind crossover placebo-controlled 8- week design to examine the effect of the 3 hypnotic compounds on sleep physiology and circadian rhythm as assessed by polysomnography, actigraphy, cortisol and melatonin saliva levels. These measures will be obtained before randomization, at week 4, and at week 8. Sleep measures will include slow wave sleep, Non- REM sleep, REM sleep, sleep efficiency, wake after sleep onset, and sleep latency. We will also compare the effect of the three agents on sleep parameters, circadian rhythm, and sleep quality. Finally, we will examine the relationship between these measures and changes in the clinical features of ASD, including RRB, social communication deficits and associated behaviors, including irritability and hyperactivity.