Project Summary Human cognition is a product of vastly complex interactions between different cellular networks that continues to elude a mechanistic link to neurobiology. Our understanding of the brain basis for cognition has benefitted from studying human conditions in which cognitive disability is linked to single gene mutations that disrupt healthy cortical development early in life. One such condition is Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 that presents a variety of clinical symptoms including transient autistic-like behavioral deficits, severe cognitive impairments, and abnormal scalp electrophysiology (EEG) activity. However, it is unclear how abnormal cellular network formation gives rise to reported patient EEG abnormalities and associated cognitive disability. Our understanding is severely limited by a fundamental lack of knowledge of any convergent mechanisms relating gene mutations and cortical activity in the developing human brain to cognition within the same individual. This proposal aims to test the hypothesis that there is a convergent mechanism for aberrant cortical activity and cognitive disability housed in the patient transcriptome that can be identified across electrophysiological scales, ranging from in vitro brain organoid electrophysiology to non-invasive human EEG. By using RTT as a genetic model for human neurodevelopment, this proposal aims to leverage multimodal brain data from the same individual to advance our understanding of the neurobiological mechanisms underlying cognition in health and disease. To do so, this proposal will identify biomarkers of cortical function via parallel in vivo and in vitro analytical approaches relating electrophysiological and genetic features to cognitive ability and disease severity. This research will use state-of-the-art analytical tools to parameterize electrophysiological periodic and aperiodic features of scalp EEG from RTT and healthy participants and correlate them to genetic and electrophysiological features of brain organoids derived from the same human participants’ induced pluripotent stem cells. Project findings will define novel electrophysiological and molecular biomarkers for cognitive ability across brain data modalities. These results are expected to have a positive impact in the development of preclinical models of neurodevelopmental disorders as they will provide a strong evidence-based proof of principle for using human-derived tissue cultures to test potential new, personalized therapies in a safe and high-throughput manner.