Developing electrophysiological markers for clinical trials in autistic adults

点击翻译按钮获取中文摘要

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.