PROJECT SUMMARY This mentored career development proposal will 1) generate a novel multimodal arousal-based objective biomarker of cognitive, social, and sensory outcomes in infants with DS and 2) establish Dr. Rebecca Grzadzinski as an independent clinical researcher in behavioral and neurobiological characteristics of infants with DS. The overarching hypothesis is that atypical arousal patterns in early life influence how an infant with DS interacts with, samples from, and learns within a multisensory environment. Building upon neurobiological findings in typical and neurodevelopmental disorders, we hypothesize that 1) social arousal is associated with parent- reported social skills as well as amygdala volume, 2) non-social arousal is associated with parent-reported sensory reactivity and occipital volumes, and 3) habituation to stimuli is associated with estimates of cognitive ability and frontal lobe volumes. By identifying these arousal patterns in real-time in response to specific, well- controlled stimuli, we can begin to develop novel early interventions that are tailored to the infant's unique arousal profile. Linking arousal dynamics with underlying neurobiology not only validates the constructs but also provides targets for dissection in preclinical models of DS. This proposal is an unprecedented and time-sensitive opportunity to capitalize on the largest longitudinally followed sample of infants with DS with robust behavioral and neurobiological phenotyping. The foundation of this work leverages the ongoing data collection pipeline of infants with DS from 6 to 24 months of age within the multi-site, longitudinal Infant Brain Imaging Study (IBIS; PI: Piven; R01MH118362; PI: Botteron; R01HD088125-01A1). With the support of this proposal, stimuli designed to elicit arousal-based responses will be added to the standard IBIS battery. Parent report and direct assessment measures will be extracted from the IBIS database and arousal biometrics will be linked with concurrent and longitudinal metrics of cognitive, social, and sensory behaviors in infants with DS. Dr. Grzadzinski has assembled an expert mentorship team, including Drs. Piven (Director of IBIS) and Hazlett (UNC Site PI), who will mentor her during completion of this project and ensure she has access to all the IBIS resources necessary to bring this project to fruition. Drs. Lynch, Rodriguez-Romaguera, and Vora complete her mentorship team by adding methodological, translational, and clinical expertise needed to guide Dr. Grzadzinski toward independence. This project is a groundbreaking opportunity to validate early arousal biomarkers of cognitive, social, and sensory outcomes in infants with DS and ultimately guide early intervention and preclinical research in DS. This proposal aligns with the NIH INCLUDE Project Research Plan to collect deep phenotyping data on individuals with DS by linking with existing cohorts and will position Dr. Grzadzinski to be a highly successful independent clinical researcher dedicated to improving the lives of individuals with DS and their families.

PROJECT NARRATIVE Individuals with Down syndrome (DS) have heterogeneous developmental outcomes and varying support needs which impact quality of life and contribute to significant family stress and financial burden. Identification of objective early markers, with robust neurobiological underpinnings, of specific cognitive, social, and sensory outcomes is key for advancing and tailoring early interventions for DS. This series of testable experiments described in this proposal will yield physiological biometrics of arousal that are objective, present in infancy, and provide clinically actionable targets for treatment in early life to ultimately lead to improved functional outcomes for those with DS.