PROJECT SUMMARY / ABSTRACT Very preterm survivors continue to experience high rates of neurodevelopmental impairment (up to ~60%) after discharge from the neonatal intensive care unit (NICU). These impairments lead to significant burden for individuals, communities, and society, as translate to high rates of special education in school, social and mental health difficulties, and reduced employment potential in adulthood. As primary prevention of preterm birth is presently infeasible, it is imperative to prioritize early interventions to mitigate adverse long-term effects of very preterm birth on child and family outcomes. One critical window for intervention is the third trimester of gestation, during which the preterm brain volume quadruples in size and is highly sensitive to positive and negative environmental experiences. This is a time very preterm infants spend in the NICU, frequently exposed to atypical sensory experiences (loud alarms, noise, pain) and a paucity of human interaction. Enriching experiences in the NICU during this key period can lead to exponential downstream effects on infant neurodevelopment. Music- based interventions (MBI) have been recently studied as enriching interventions for hospitalized infants. However, evidence from existing studies lacks rigor due to small sample sizes, study design limitations (mostly observational), and outcomes focused on short-term associations without mechanistic investigation and long- term follow-up. To fill this gap, we propose a rigorous, two-center randomized controlled trial (RCT), employing a novel MBI tailored based on preliminary data and inclusive of evidence-based musical elements with layered parent voice to facilitate engagement. The MBI will be delivered on average 5 days/week between 32-40 weeks gestation (or discharge), followed by comprehensive evaluation of relevant clinical, neuroimaging, and neurodevelopmental outcomes during the NICU stay and up to 2 years of age. Outcomes will include assessment of acute (physiologic and behavioral) and cumulative stress (amygdala volume on term-equivalent brain magnetic resonance imaging [MRI] and telomere length) in the NICU, intranetwork connectivity in key networks (language and salience) on term MRI along with investigation of other relevant regions of interest and internetwork connectivity, and comprehensive neurodevelopmental assessment of language, cognition, behavior, social emotional, and family functioning at 2 years' corrected age. Our overarching goal is to improve long-term neuro-developmental outcomes of very preterm infants through leveraging music medicine as an evidence-based innovation in the NICU. This work has the potential to benefit over 63,000 very preterm infants born each year in the U.S. and many more worldwide.

PROJECT NARRATIVE This study will test the delivery of a tailored music intervention as an evidence-based therapeutic approach for very preterm infants hospitalized in the Neonatal Intensive Care Unit (NICU) during a critical period of brain development. We will test the effects of the intervention on acute and cumulative stress during the NICU stay, relevant measures of regional brain volumes (amygdala) and intranetwork connectivity (language and salience networks), and a range of neurodevelopmental outcomes, with a primary outcome of language performance at 2 years corrected age. The overall goal is to establish music medicine as an evidence-based innovative therapy in the neonatal intensive care unit that improve long-term neurodevelopmental outcomes for the ~63,000 very preterm infants born each year in the U.S. and many more worldwide.