The Impact of Music Medicine on Preterm Brain Development and Behavior

The Impact of Music Medicine on Preterm Brain Development and Behavior - A Two-Center Randomized Controlled Trial "The Lullaby Study"

The investigators are conducting a two-site randomized control trial with the aim of defining the impact of music (M) without or with parent voice (MPV) on very preterm infants' acute and cumulative stress, intranetwork connectivity on term brain MRI, and language and other neurodevelopmental outcomes at two years corrected age. This is based on the hypothesis that infants in MPV arm are expected to experience the greatest benefit compared with infants receiving standard care.

Preterm birth remains the leading cause of death for children under five. For survivors, it also accounts for high morbidity and substantial physical, psychosocial, emotional, and financial burden for individuals, families, and communities. The impairments span over multiple domains, with language difficulties affecting about half of surviving children. Evidence indicates that preterm birth has significant impacts on long-term functioning, yet primary prevention of preterm birth is presently not feasible. It is therefore imperative to prioritize early interventions to mitigate these adverse long-term effects on child and family outcomes.

Very preterm (VP) infants, i.e., those born below 32 weeks gestational age (GA) typically spend 2-4 months hospitalized in the Neonatal Intensive Care Unit (NICU) before reaching term-equivalent age (TEA). During this time, the preterm brain nearly quadruples in volume and is highly sensitive to both positive and negative environmental experiences. Yet, during this period, VP infants must also receive life-saving intensive medical care in the sensory-atypical environment of the NICU. From an auditory perspective, this atypical environment comprises loud equipment sounds at volumes far exceeding recommended levels, silence, and a paucity of human interaction. One domain of neurosensory experience is the auditory environment, comprised predominantly of non-meaningful, high-frequency/ high decibel equipment sounds, and silence. The deprivation of VP infants from enriching auditory experiences (parental voice, infant-directed language) combined with the constant influx of high frequency/high decibel sounds (alarms and electronic noise) can induce chronic stress and negatively impact auditory and other areas of cortical development.

For preterm infants who have not yet reached term-equivalent age (TEA), the NICU hospitalization is a critical window for developmental adaptability to experience during a highly sensitive period of brain development. There are two key pathways whereby music and voice therapy in the VP infant are thought to have benefit - stress reduction and auditory enrichment. Recent work indicates that music therapy may reduce the immediate stress experienced by VP infants, with evidence emerging on its impact to improve neurodevelopmental outcomes. Prior studies have been limited due to small size, variability of music exposures, inconsistent study design and outcome measures. Further, most studies explored exposure-outcome associations, without mechanistic investigation. One study showed improved white matter maturation in acoustic radiations, larger amygdala volumes, and enhanced functional connectivity brain magnetic resonance imaging (MRI) after early music exposures. These suggests that early music exposure may enhance auditory cortex development and reduce stress (amygdala) in VP infants.

While small studies inform these hypotheses, a large, randomized trial is necessary to test them more rigorously. Our own center's pilot study demonstrated that a music condition with low, repetitive, and rhythmically consistent entrainment stimulus was associated with improved physiologic state after the exposure. Based on these data, the investigators plan to further develop an individualized intervention encompassing evidence-based musical elements onto which parental voice will be carefully layered. The aim of this proposal is to conduct a randomized trial to determine the effects of a protocolized music-based intervention (MBI) with and without parental voice on stress reduction, early brain structure and function, and neurodevelopmental outcomes.

The investigators propose to address this knowledge gap in a large, two-center randomized controlled trial (RCT), employing a novel MBI tailored based on available preliminary data and inclusive of musical and non-musical elements to facilitate parent engagement, with comprehensive evaluation of relevant clinical, neuroimaging, and neurodevelopmental outcomes of VP infants up to two years of age. The impact of this work will be two-fold: this proposal will 1) generate rigorous evidence to specifically support the integration of music medicine as a therapeutic approach for VP infants in the NICU, and 2) strengthen the evidence base for neurosensory interventions for hospitalized infants, which will shift the framework of care in the NICU by leveraging developmental care interventions to optimize the outcomes of VP infants.

Inclusion Criteria:

• Very preterm infants born between 24+0 and 30+6 weeks' gestational age (GA) from 2 level III NICUs (Brigham and Women's Hospital, Boston, MA and Yale New Haven, CT)
• Infants who are medically stable per the clinical care team

Exclusion Criteria:

• Infants with major genetic or congenital anomalies known to be associated with developmental delay
• Infants with severe brain injury (such as intraparenchymal hemorrhage, severe white matter injury)
• Infants who are severely ill infants for whom MBI is not feasible
• Infants of parents who cannot complete questionnaires in English or Spanish.