In 2018, the World Health Organization reported 15 million (>1 in 10) preterm births with rising annual rates. 50% of preterm infants suffer from neurodevelopmental impairments, and all preterm infants experience high volumes of painful procedures as part of medical care. Preterm music intervention shows immediate physiologic improvements in heart rate and oxygen saturation, as well as improved physiologic responses to pain. What remains unknown is how music impacts preterm brain maturation, neurodevelopment, and pain responses in preterm infants. 

We propose a R61 project to explore biological mechanisms of music based intervention (MBI) on preterm brain maturation and neurodevelopment using electroencephalography (EEG) and event related potentials (ERPs). EEG captures electrical potential oscillations of the brain which yields valuable information about brain function. Serial EEGs can track brain maturation in preterm infants. ERPs quantify electrical brain potentials changes time-locked with a stimulus. ERPs at 1 month corrected age test recognition memory function and cognitive processing and offers another objective measure to study the early effects of the MBI’s on neurodevelopment. 

The R61 will also explore the behavioral processes underlying effects of MBI on pain using EEG and the premature infant pain profile (PIPP). In preterm infants, central EEG amplitudes change when time-locked to a painful stimulus and PIPP scores scale pain responses with painful procedures. Specific recorded lullabies with simple arpeggiated accompaniment will be played for 6 weeks in a small randomized, blinded, controlled study of 50 medically stable 30 week preterms. Exploratory R61 findings will be assessed by specific Go/NoGo milestones that provide insight into the effects of MBI on biological mechanisms underlying neurodevelopment and behavioral processes underlying pain. 

By achieving one of the Go/NoGo milestones, the proposal progresses to the R33 proof of concept pilot clinical trial with an additional 100 randomized subjects that will assess two primary outcomes measures: 

1. MBI effects on Late Neurodevelopment using Bayley’s III neurodevelopmental testing at 6 month corrected age, and 

2. Cumulative effects of MBI on Pain Response using longitudinal comparisons of baseline PIPP scores and final PIPP scores after 4 weeks of MBI. 

Secondary measures would explore more nuanced aspects of neurodevelopment: 

1. MBI effects on brain maturation with expanded analyses of EEG-sleep components; 

2. repeat ERP analysis at 6 months corrected age with expanded memory and cognitive testing (additional mismatch negativity paradigms); and pain response: 

3. MBI effects on pain related EEG responses with comparative analyses of central EEG amplitude changes to the frontal, parietal, temporal, and occipital lobes. 

This project addresses the following public health concerns:

1. high rates of neurodevelopmental impairments from preterm birth and 

2. detrimental neurodevelopmental sequelae as a result of current preterm pain management regimens. 

We will initiate a two phased pilot clinical trial (randomized, double blinded, controlled) to support mechanistic research on the effects of music based intervention on neurodevelopment and pain response in preterm infants, with the second phase, as a proof of concept clinical trial evaluating the effects of music based intervention on late neurodevelopment and the cumulative effects of music on pain response. 

The public health relevance of this study is to provide groundbreaking results on effects of music based intervention in preterm infant health to inform future strategies on music research, given that music intervention is low risk, minimally invasive with a high potential health impact.