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：项目摘要/摘要 自闭症谱系障碍（ASD）是一种具有社会交流为特征的神经发育障碍 缺陷，感觉异常和受限/重复行为（RRB）。通常描述睡眠干扰 作为ASD的儿童和青少年最繁重的症状之一，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， 突触优势的稳态重新平衡以及记忆的重播和巩固。在人类中 睡眠中断有充分的文献记载，以损害认知和影响。实际上，父母报告发现 ASD患者的睡眠不足无法加剧核心症状的严重程度，RRB增加为 以及社会沟通不足的恶化。因此，增加我们对睡眠的理解 生理学和改善ASD的睡眠对于可能的潜在开发干预措施至关重要 受益核心自闭症特征以及相关行为。虽然对 ASD的神经生物学，有限的研究是为了阐明睡眠的神经生物学 干扰。最近的调查提供了证据，表明患有ASD的儿童的睡眠时间较短 时间，慢波睡眠百分比以及更少的眼睛运动（REM）睡眠百分比。 然而，尽管ASD中睡眠异常的发现一致，但有限的研究研究了 药理化合物对睡眠生理学的有效性。至关重要的是，缺乏调查 评估催眠剂对睡眠结构的生物学作用。拟议项目的目标是 进行一系列试验试验，以研究具有不同机制的三种诱导睡眠剂的作用 （二苯胺，Zolpidem和Suvorexant）在患有ASD的儿童和青少年的睡眠结构上（年龄 范围8 - 17年）。二苯胺是一种具有强催眠特性的抗激素能。 Zolpidem是 一种非苯二氮卓类γ氨基丁酸-GABAA受体激动剂，可作为镇静剂和 催眠。 Suvorexant是用于治疗睡眠开始的选择性的双重OREXIN受体拮抗剂 困难和/或睡眠维护。我们将使用随机的双盲跨界安慰剂对照8-- 每周设计以检查3种催眠化合物对睡眠生理和昼夜节律的影响 通过多摄取术，动力学，皮质醇和褪黑激素唾液水平进行评估。这些措施将是 在随机分组之前，在第4周和第8周获得。睡眠度量将包括慢波睡眠，非 - REM睡眠，REM睡眠，睡眠效率，睡眠发作后醒来以及睡眠潜伏期。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临床特征的变化之间的关系，包括RRB，社会 沟通不足和相关行为，包括烦躁和多动症。