PROJECT SUMMARY In the prior work we have extended our multimodal magnetoencephalography (MEG) and magnetic resonance imaging (MRI) approaches and have shown that it is possible to model, or predict, the latency of the auditory evoked neuromagnetic field component, the M50, occurring approximately 50-100ms post stimulus in children, but delayed in ASD, and measured by magnetoencephalography (MEG), by using diffusion magnetic resonance imaging (dMRI) to quantify the microstructure of the auditory pathway white matter (in particular the thalamocortical acoustic radiations). While this approach accounted for more than 50% of the variance in typically developing controls, it was confounded by heterogeneity in a cohort of ~100children with autism spectrum disorder (ASD). However, this actually allowed identification of a sub-population of children with ASD whose M50 responses appeared as “outliers” to the TD model (i.e. “unpredictably long M50’s); interestingly, these children showed significantly lower levels of gamma-aminobutyric acid (GABA) estimated by advance magnetic resonance spectroscopy (MRS) than their ASD peers whose latencies were consistent with the TD model. Identification of this group has significant implications for treatment/intervention by identifying a biological basis for stratification (sub-population definition) and thus a putative biological target for intervention (as well as a means of defining an inclusion criterion for selecting that therapy). The present proposal extends this work to the scientifically and societally critical group of children with ASD with severe language and cognitive impairments, who are under-included in imaging research, but whose vital participation is made possible by a combined behavioral and technical protocol we have recently developed, called MEG-PLAN, and its MRI analog: MRI-PLAN. To ascertain the clinical and behavioral implications of delayed M50 brain responses, we also recruit children with mixed etiology intellectual and developmental disability (IDD), but not autism, and seek to identify the relative associations of language impairment, cognitive impairment and ASD diagnosis to the M50 latency delay and to investigate the biophysical underpinnings of these association with multimodal MEG, MRI and MRS. We also extend beyond examination of auditory response timing to probes of auditory and language neuronal circuitry via. oscillatory responses also detected by MEG and examine their relation to GABA levels as well as to clinical language assessment. Taken together, this proposal focuses on several levels of stratification to combat the formidable heterogeneity observed in ASD and, critically, employs state of the art multimodal methodologies, made feasible by the MEG-PLAN and MRI-PLAN protocols, in severely-impaired children with ASD (conventionally not included in such research) to assess generalization of observations across the broad autism spectrum.