The Impact of Music Medicine on Preterm Brain Development and Behavior

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.