Project 2: Pharmacological Probing of Sleep Physiology in Autism

项目2：自闭症睡眠生理学的药理学探索

• 批准号: 10531475
• 负责人: ANTONIO HARDAN
• 金额: $ 38.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531475
• 关键词: Adolescent; Affect; Age; Aggressive behavior; Agonist; Animals; Anxiety; Attention; Behavior; Behavioral; Biological; Caregivers; Child; Circadian Rhythms; Clinical; Diphenhydramine; Double-Blind Method; Drowsiness; Effectiveness; Equilibrium; Goals; Histamine; Histamine Agents; Human; Hydrocortisone; Hyperactivity; Impaired cognition; Investigation; Learning; Link; Maintenance; Measures; Melatonin; Moods; Neurobiology; Neurodevelopmental Disorder; Neurotransmitters; Parents; Pharmaceutical Preparations; Pharmacology; Phase; Physiology; Pilot Projects; Placebo Control; Placebos; Play; Polysomnography; Prevalence; Property; Questionnaires; REM Sleep; Randomized; Reporting; Research; Role; Saliva; Sensory; Series; Severities; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep Initiation and Maintenance Disorders; Sleep disturbances; Slow-Wave Sleep; Symptoms; Synapses; Synaptic plasticity; Testing; Time; Wakefulness; Youth; actigraphy; adolescent with autism spectrum disorder; aged; antagonist; associated symptom; autism spectrum disorder; autistic children; design; developmental disease; gamma-Aminobutyric Acid; hypnotic; hypocretin; improved; inattention; individuals with autism spectrum disorder; interest; memory consolidation; neurobiological mechanism; non rapid eye movement; peer; pilot trial; receptor; recruit; repetitive behavior; sedative; sleep abnormalities; sleep behavior; sleep onset; sleep physiology; sleep quality; social communication; therapy development; zolpidem

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.

项目2：项目概要/摘要 自闭症谱系障碍是一种以社会交往为特征的神经发育障碍 缺陷，感觉异常和限制/重复行为（RRB）。睡眠中断通常被描述为 是儿童和青少年ASD患者最常见的症状之一，患病率高达80%。 动物研究表明，睡眠在突触网络的结构可塑性中起着重要作用， 突触强度的稳态再平衡以及记忆的重放和巩固。在人类中， 睡眠中断会损害认知和情感。事实上，家长报告发现， ASD患者睡眠不足，加重核心症状的严重程度，RRB增加， 以及社会沟通缺陷的恶化。因此，增加我们对睡眠的了解 生理学和改善ASD的睡眠对于潜在的干预措施的发展至关重要， 有益于核心自闭症特征以及相关行为。虽然人们对这一问题的兴趣越来越大， ASD的神经生物学，有限的研究已经进行，以阐明睡眠的神经生物学 干扰.最近的调查提供的证据表明，患有ASD的儿童的总睡眠时间较短 时间，更大的慢波睡眠百分比，以及更少的快速眼动（REM）睡眠百分比。 然而，尽管ASD睡眠异常的发现一致，但有限的研究已经检查了 药理学化合物对睡眠生理学的有效性。关键的是， 评估催眠药物对睡眠结构的生物学效应。拟议项目的目标是 进行一系列的试验，以研究三种不同机制的睡眠诱导剂的效果 （苯海拉明、唑吡坦和苏沃雷生）对ASD儿童和青少年（年龄 8-17岁）。苯海拉明是一种抗组胺药，具有很强的催眠作用。唑吡坦是 一种非苯并二氮杂 * γ-氨基丁酸-GABA α受体激动剂药物，其用作镇静剂， 催眠。苏沃雷生是一种选择性的双重食欲素受体拮抗剂，用于治疗睡眠发作 困难和/或睡眠维持。我们将使用随机双盲交叉安慰剂对照的8- 一周的设计，以检查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、活动记录仪、皮质醇和褪黑激素唾液水平进行评估。这些措施将 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，入睡后觉醒，睡眠潜伏期。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临床特征变化之间的关系，包括RRB、社会 沟通缺陷和相关行为，包括易怒和多动。