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

基本信息

批准号：
10698075
负责人：
ANTONIO HARDAN
金额：
$ 38.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10698075
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 Equilibrium Goals Histamine Histamine Agents Human Hydrocortisone Hyperactivity Impaired cognition Investigation Learning Link Maintenance Measures Melatonin Moods Neurobiology Neurodevelopmental Disorder Neurotransmitters Parents Pharmaceutical Preparations Phase 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 drug action effectiveness evaluation gamma-Aminobutyric Acid hypnotic hypocretin improvement on sleep inattention individuals with autism spectrum disorder interest memory consolidation neurobiological mechanism non rapid eye movement peer pharmacologic pilot trial receptor recruit repetitive behavior sedative sleep abnormalities sleep behavior sleep onset sleep physiology sleep quality social communication therapy development zolpidem

项目摘要

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：项目总结/摘要自闭症谱系障碍（ASD）是一种以社交沟通为特征的神经发育障碍缺陷、感觉异常和限制/重复行为（RRB）。通常描述睡眠中断是自闭症儿童和青少年中最严重的症状之一，发病率高达 80%。动物研究表明，睡眠在突触网络的结构可塑性中发挥着重要作用，突触强度的稳态再平衡以及记忆的重放和巩固。在人类中，有充分证据表明，睡眠中断会损害认知和情感。事实上，家长报告发现自闭症谱系障碍 (ASD) 患者睡眠不足会加剧核心症状的严重程度，RRB 增加以及社交沟通缺陷的恶化。因此，加深我们对睡眠的认识生理学和改善自闭症谱系障碍患者的睡眠对于干预措施的潜在发展至关重要有益于自闭症的核心特征以及相关行为。虽然人们对自闭症谱系障碍的神经生物学，已进行有限的研究来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自闭症谱系障碍的儿童的总睡眠时间较短时间，更高的慢波睡眠百分比，以及更少的快速眼动 (REM) 睡眠百分比。然而，尽管自闭症谱系障碍患者的睡眠异常得到了一致的发现，但有限的研究对自闭症谱系障碍的睡眠异常进行了检验。药理学化合物对睡眠生理学的有效性。关键是缺乏调查评估催眠药对睡眠结构的生物效应。拟议项目的目标是进行一系列试点试验，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 Suvorexant）对自闭症谱系障碍 (ASD) 儿童和青少年睡眠结构的影响（年龄范围 8-17 岁）。苯海拉明是一种抗组胺药，具有很强的催眠作用。唑吡坦是一种非苯二氮卓类 γ 氨基丁酸-GABAa 受体激动剂药物，可作为镇静剂和催眠的。 Suvorexant 是一种选择性双重食欲素受体拮抗剂，用于治疗入睡困难和/或睡眠维持。我们将使用随机双盲交叉安慰剂对照 8- 周设计旨在检查 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、体动记录仪、皮质醇和褪黑激素唾液水平进行评估。这些措施将在随机分组前、第 4 周和第 8 周获得。睡眠测量将包括慢波睡眠、非睡眠快速眼动睡眠、快速眼动睡眠、睡眠效率、入睡后觉醒和睡眠潜伏期。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，我们将检查这些措施与 ASD 临床特征（包括 RRB、社会特征）变化之间的关系沟通缺陷和相关行为，包括烦躁和多动。