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 脑电生理表型分析有望解析ASD的异质性， 提出的治疗方法在ASD的生物学亚组中更可靠。相关的环境有很多 非侵入性成像和ASD表型的电生理学相关性的进展，在儿童中， 包括1）延迟听觉诱发反应成分（M50，M100潜伏期）; 2）延迟磁刺激成分（M50，M100潜伏期）; 元音对比和非典型偏侧化引起的不匹配场（MMF）; 3）非典型偏侧化 发展的γ波段振荡相位同步，再加上非典型水平的抑制 神经递质，GABA;和4）非典型运动振荡活动，特别是运动后β反弹 （PMBR）。我们已经提出，这种电生理特征可以作为分层的生物标志物， 根据生物学，而不仅仅是行为，将患者纳入临床试验。然而， 这些候选生物标志物是如何成熟到成年的。这很重要，因为有数百万 自闭症谱系的成年人，在诊所需要治疗。我们的初步研究表明， 儿童期的电生理表型可能会持续到成年期（特别是听觉 M50/M100和MMF延迟），而听觉伽马带相位同步和运动PMBR的差异 振荡反应实际上可能在青春期出现。如果儿童的生物学差异确实存在 进入成年和/或一些生物学差异出现在青春期后期/成年早期，那么， 补救的机会和目标也可能持续到成年。这将表明需要一个 用于分层（入选/排除）和监测治疗的定量生物标志物 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/ 成年人（14- 45岁，48 M，24 F）和72名年龄/性别匹配的典型发育（TD）同龄人组成多模态 采用12周纵向设计的成像研究，以模拟典型的药物试验并确定精密度 每个度量的估计值，以定义后续试验中间隔变化的分辨率。创新实施 遵循目标。在目标1中，我们将在成人样本中评估ASD与TD的组水平区分， 每个MEG指标电池，并评估三个扫描会话中的受试者内和受试者间变异性 （基线、4周、12周）。这将确定任何推定药物所需的效应量。在 目的2，我们将使用多模态成像来解决异质性和探测生物学特性。 成人M50潜伏期延长的基础。在目标3中，我们将使用错误获得的MEG， EEG，以确定拟议MEG措施的EEG类似物的功效，以实现类似的组- ASD与TD个体的水平歧视。EEG成本较低，操作简单，并且具有广泛的应用前景。 适用于临床试验实施的可用性。最后，本研究的目的将提供关键的 关于自闭症成人电生理生物标志物的关键“临床准备”问题的答案。