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

基本信息

批准号：
10697337
负责人：
EDWARD S BRODKIN
金额：
$ 76.23万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2022-09-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697337
关键词：
Address Adolescence Adolescent Adult Age American Anxiety Anxiety Disorders Attention Attention deficit hyperactivity disorder Auditory Auditory Evoked Potentials Award Behavior Binding 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 biological heterogeneity biomarker performance candidate marker clinic ready cognitive ability cost design detection platform effective therapy efficacy evaluation 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 stability testing symptomatology treatment response white matter

项目摘要

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.

项目概要脑电生理表型分析有望解析自闭症谱系障碍的异质性并能够测试在自闭症谱系障碍的生物学亚组中提出的治疗方法已经相当多了。儿童自闭症谱系障碍表型的非侵入性成像和电生理相关性的进展包括1）延迟听觉诱发反应成分（M50、M100潜伏期）；2）延迟磁由元音对比以及非典型右偏引起的错配场（MMF）3）非典型；伽马带振荡相位同步的发展，与非典型的抑制水平相结合神经递质，GABA；4) 非典型运动振荡活动，特别是运动后 β 反弹（PMBR）我们建议这种电生理特征可以作为分层的生物标志物。根据生物学而不是仅根据行为将患者纳入临床试验然而，人们知之甚少。关于这些候选生物标志物如何成熟到成年这一点很重要，因为有数百万个。我们的初步研究表明，患有自闭症谱系的成年人需要在诊所接受治疗。儿童时期的电生理表型可能会持续到成年（特别是听觉 M50/M100 和 MMF 延迟），而伽玛带相位同步和运动 PMBR 的听觉差异如果童年时期的生物学差异确实存在的话，振荡反应实际上可能会在青春期出现。进入成年期和/或在青春期晚期/成年早期出现一些生物学差异，然后补救的机会和目标也可能持续到成年期。这表明需要进行补救。用于分层（纳入/排除）目的和监测治疗目的的定量生物标志物我们将招募 72 名自闭症青少年/目标参与度以及大脑反应的长期证据。成年人（14-45 岁、48M、24F）和 72 名年龄/性别匹配的典型发育 (TD) 同龄人进入多式联运采用 12 周纵向设计的成像研究，模拟典型的药物试验并建立精确度我们将在后续试验中对每个指标进行估计，以定义间隔变化的分辨率。在目标 1 中，我们将在成人样本中评估群体层面的 ASD 与 TD 歧视。一组 MEG 指标中的每一个，并评估三个扫描会话中受试者内和受试者间的变异性（基线、4 周、12 周）这将确定任何假定药物所需的效应大小。目标 2，我们将使用多模态成像来解决异质性并探索生物学在目标 3 中，我们将使用同时获得的 MEG 和 M50 潜伏期延长的基础。 EEG，以确定所提议的 MEG 措施的 EEG 类似物的功效，以实现类似的组- 自闭症谱系障碍 (ASD) 患者与脑电图 (TD) 患者的水平区分成本更低、更容易执行并且得到广泛应用。最终，本研究的目标将提供关键的信息。回答有关成人自闭症患者电生理生物标志物的关键“临床准备”问题。