Developing electrophysiological markers for clinical trials in autistic adults

开发用于成人自闭症临床试验的电生理标志物

• 批准号: 10583662
• 负责人: EDWARD S BRODKIN
• 金额: $ 78.74万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583662
• 关键词: Address; Adolescence; Adolescent; Adult; Age; American; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Auditory; Auditory Evoked Potentials; Award; Behavior; Biological; Biological Assay; Biological Markers; Biology; Brain; Child; Childhood; Clinic; Clinical; Clinical Trials; Clinical assessments; Collaborations; Conduct Clinical Trials; Coupled; Data; Development; Diffusion Magnetic Resonance Imaging; Dimensions; Discrimination; Electrodes; Electroencephalography; Electrophysiology (science); Environment; Exclusion; Female; Future; Glutamates; Heterogeneity; Individual Differences; Intervention; Laboratories; Language; Longevity; Magnetic Resonance Spectroscopy; Magnetism; Magnetoencephalography; Measures; Menstrual cycle; Modeling; Monitor; Motor; Movement; Multimodal Imaging; Neurotransmitters; Participant; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Publications; Readiness; Research; Resolution; Sampling; Scanning; Sensory; Severities; Stratification; Subgroup; Symptoms; Techniques; Technology; Testing; adolescent with autism spectrum disorder; adult with autism spectrum disorder; analog; autism spectrum disorder; autistic children; base; biological heterogeneity; biomarker performance; candidate marker; cognitive ability; cost; design; detection platform; early adolescence; effective therapy; emerging adult; gamma-Aminobutyric Acid; imaging study; indexing; individuals with autism spectrum disorder; longitudinal design; multimodality; neurophysiology; non-invasive imaging; patient stratification; peer; recruit; remediation; response; sex; symptomatology; treatment response; white matter

Project Summary Brain electrophysiological phenotyping holds promise for parsing heterogeneity in ASD and enabling testing of proposed treatments more reliably in biologically-based subgroups of ASD. There have been considerable advances in the non-invasive imaging and electrophysiologic correlates of phenotypes in ASD, in children, including 1) delayed auditory evoked response components (M50, M100 latency); 2) delayed magnetic mismatch fields (MMF) elicited by vowel contrasts as well as atypical rightward lateralization; 3) atypical development of gamma-band oscillatory phase synchrony, coupled to atypical levels of inhibitory neurotransmitter, GABA; and 4) atypical motor oscillatory activity, particularly the post-movement beta rebound (PMBR). We have suggested that such electrophysiological signatures might serve as biomarkers in stratifying patients for inclusion in clinical trials according to biology, rather than behavior alone. However, little is known about how these candidate biomarkers mature into adulthood. This is important because there are millions of adults on the autism spectrum, presenting in clinic in need of treatment. Our preliminary studies suggest that there might be persistence of childhood electrophysiological phenotypes into adulthood (in particular, auditory M50/M100 and MMF delays), while differences in auditory gamma band phase synchrony and motor PMBR oscillatory responses may in fact emerge during adolescence. If indeed childhood biological differences persist into adulthood and/or some biological differences emerge in late adolescence/ early adulthood, then the opportunity and target for remediation may also persist in adulthood. This would indicate the need for a quantitative biomarker for both stratification (inclusion/exclusion) purposes but also for monitoring treatment target engagement, as well as longer term evidence of brain response. We will recruit 72 autistic adolescents/ adults (14-45yrs, 48M, 24F) and 72 age-/sex-matched typically developing (TD) peers into a multimodal imaging study with a 12-week longitudinal design to mimic a typical pharmaceutical trial and establish precision estimates for each metric to define the resolution of interval change in subsequent trials. We will carry out the following Aims. In Aim 1, we will evaluate, in a sample of adults, the group level ASD vs TD discrimination of each of a battery of MEG metrics and assess intra- and inter-subject variability over three scan sessions (baseline, 4weeks, 12weeks). This will establish the effect size required of any putative pharmaceutical. In Aim 2, we will use multimodal imaging to address heterogeneity and probe the biological underpinnings of M50 latency prolongation in adults. In Aim 3, we will use simultaneously-acquired MEG and EEG, to determine the efficacy of EEG analogs of the proposed MEG measures to achieve similar group- level discrimination of individuals with ASD vs TD. EEG is lower-cost, simpler to perform and has widespread availability appropriate for clinical trial conduct. In culmination, the aims of this study will provide pivotal answers to critical “clinical readiness” questions about electrophysiological biomarkers in autistic adults.

项目摘要 脑电生理表型有望在ASD中解析异质性并实现测试 提出的治疗在基于生物学的ASD亚组中更可靠。有很多 ASD，儿童中表型的非侵入性成像和电生理相关性的进展， 包括1）延迟听觉诱发的响应组件（M50，M100延迟）； 2）延迟磁性 不匹配场（MMF）由元音对比以及非典型的向右侧向化引起； 3）非典型 γ波段振荡阶段同步的发展，耦合到非典型抑制水平 神经递质GABA； 4）非典型运动振荡活动，尤其是运动后β反弹 （PMBR）。我们已经提出，这种电生理特征可能是分层的生物标志物 根据生物学而不是单独行为纳入临床试验的患者。但是，鲜为人知 关于这些候选生物标志物如何成年。这很重要，因为有数百万 自闭症谱系上的成年人，在需要治疗的诊所中呈现。我们的初步研究表明 儿童期电生理表型可能会持续到成年（尤其是听觉 M50/M100和MMF延迟），而听觉伽马频段同步和电动机PMBR的差异 实际上，在青少年期间可能会出现振荡反应。如果确实确实存在着童年的生物学差异 到成年和/或某些生物学差异在青少年晚期/成年早期出现，然后 补救的机会和目标也可能会在成年中持续存在。这将表明需要 定量生物标志物，用于两个分层（包含/排除）目的，也用于监测治疗 目标参与以及大脑反应的长期证据。我们将招募72名自闭症青少年/ 成人（14-45yrs，48m，24f）和72岁的年龄/性别匹配通常发展为多模式 成像研究具有为期12周的纵向设计，以模仿典型的药物试验和建立精度 每个度量标准的估计值以定义后续试验中间隔变化的分辨率。我们将执行 以下目标。在AIM 1中，我们将在成年人样本中评估小组级别ASD与TD的歧视 三个扫描过程中的每一个MEG指标和评估内和受试者间可变性 （基线，4周，12周）。这将确定任何推定药物所需的效果大小。 AIM 2，我们将使用多模式成像来解决异质性并探测生物学 成人M50潜伏期延长的基础。在AIM 3中，我们将使用简单的MEG和 脑电图，确定所提出的MEG测量值的脑电图类似物的效率，以实现相似的组 ASD与TD的个体的水平歧视。脑电图较低成本，更易于执行，并且具有宽度 适用于临床试验的可用性。在高潮中，这项研究的目的将提供关键 关于加速成年人电生理生物标志物的关键“临床准备”问题的答案。