Disrupted Nighttime Sleep (DNS) in Pediatric Narcolepsy

摘要 该提案将支持这项研究，并进一步培养Kiran Maski博士作为一名医生科学家， 睡眠神经学马斯基博士的长期目标是研究夜间睡眠的神经生理学， 儿童嗜睡症及其与该疾病常见的认知和心理共病的关系， 识别潜在的睡眠神经生理学诊断和预测生物标志物，并开发和测试睡眠- 减少儿童发作性睡病患者疾病负担的特殊治疗。为了实现这些目标，A 培训计划侧重于（1）研究睡眠动力学的分析技能，（2）认知和 行为神经科学和睡眠-觉醒生理学，（3）纵向和临床试验设计， 促进罕见疾病研究的建议，以补充马斯基博士在儿童神经学的背景， 安眠药这项培训将通过正式的课程，动手培训，和多- 与世界知名的睡眠-觉醒神经生理学专家（托马斯·斯卡梅尔博士）进行学科指导， 认知神经科学（Robert Stickgold博士）。具有以下方面专门知识的其他顾问和合作者： 数学建模、统计学、行为科学和利用远程视听的研究方法 技术将丰富Maski博士的培训和拟议的研究。培训将在以下背景下进行： 哈佛医学院、哈佛T.H.波士顿公共卫生学院 儿童医院这项研究计划旨在验证扰乱夜间睡眠的核心假设 (DNS)在小儿发作性睡病1型（NT1）是一种特定的和动态的形式的睡眠病理，损害 睡眠中正常的情绪和记忆过程。为了验证这一假设，我们提出了三个 互补但独立的目标。在目标1中，我们进行了一项横断面研究，以定义DNS， 与其他睡眠障碍和对照组相比，儿童NT1的独特指标。在目标2中，我们研究变化 在儿童NT1队列中使用翻译分析方法进行DNS。最后，在目标3中，我们研究 未使用药物的儿童NT1患者、使用药物的儿童NT1患者之间的睡眠结构预测变化 已建立的羟丁酸钠疗法（一种治疗DNS的镇静药物）和健康的年龄匹配对照组， 确定睡眠片段对记忆巩固和睡眠后情绪过程的直接影响。 公共卫生：大量证据将睡眠与认知和情绪过程联系起来。然而，人们对 儿童神经系统疾病中发生的特定病理性睡眠变化及其作用 在认知和心理共病的发展中起作用。这项建议旨在 提供新的分析方法来表征神经系统疾病（如嗜睡症）的睡眠病理学特征， 新的方法，显示睡眠中断的直接认知和心理影响，并形成 睡眠特异性治疗策略的基础，以减少神经系统疾病的疾病负担。

ABSTRACT The proposal will support the research and further Dr. Kiran Maski's training as a physician-scientist in sleep neurology. Dr. Maski's long-term objectives are to examine the neurophysiology of nocturnal sleep in pediatric narcolepsy and its relationship to cognitive and psychological co-morbidities common to this disease, to identify potential sleep neurophysiological diagnostic and predictive biomarkers, and develop and test sleep- specific treatments to reduce disease burden of pediatric narcolepsy patients. To achieve these goals, a training plan focused on (1) analytic skills to study sleep dynamics, (2) fundamental knowledge in cognitive and behavioral neuroscience and sleep-wake physiology, (3) longitudinal and clinical trial research design to facilitate rare disease research is proposed to complement Dr. Maski's background in child neurology and sleep medicine. This training will be accomplished through formal coursework, hands on training, and multi- disciplinary mentorship with world-renown experts in sleep-wake neurophysiology (Dr. Thomas Scammell) and cognitive neuroscience (Dr. Robert Stickgold). Additional consultants and collaborators with expertise in mathematical modeling, statistics, behavioral science, and research methodology utilizing remote audiovisual technology will enrich Dr. Maski's training and proposed research. This training will occur in the context of the rich scholarly environment of Harvard Medical School, Harvard T.H. Chan School of Public Health and Boston Children's Hospital. The research plan is devised to test the central hypothesis that disrupted nighttime sleep (DNS) in pediatric narcolepsy type 1 (NT1) is a specific and dynamic form of sleep pathology that impairs normal emotional and memory processes that occur during sleep. To test this hypothesis, we propose three complimentary but independent aims. In Aim 1, we conduct a cross-sectional study to define DNS with measures unique to pediatric NT1 compared to other sleep disorders and controls. In Aim 2, we study changes in DNS using translational analytic methods within a pediatric NT1 cohort. Lastly, in Aim 3, we investigate predicted changes to sleep architecture between drug-free pediatric NT1 patients, pediatric NT1 patients on established sodium oxybate therapy (a sedating drug that treats DNS) and healthy, aged-matched controls to determine direct effects of sleep fragmentation on memory consolidation and post-sleep emotional processes. Public Health: Substantial evidence links sleep with cognitive and emotional processes. Yet , little is known of the specific pathologic sleep changes that occur in pediatric neurologic diseases and the role this pathology plays in the development of burdensome cognitive and psychological co-morbidities. This proposal serves to provide new analytic methods to characterize sleep pathology in neurological diseases like narcolepsy, test novel methods that show direct cognitive and psychological effects of sleep disruption, and forms the foundation for sleep-specific treatment strategies to reduce disease burden in neurological diseases.