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.

Study Overview

• Status: Recruiting
• Conditions: Stress; Prematurity; Infant Development; Language Development
• Intervention / Treatment: Other: Standard Care; Other: Music; Other: Music and parent voice

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 243
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carmina Erdei, MD; Phone Number: 6174620202; Email: cerdei@bwh.harvard.edu
• Study Contact Backup: Name: Isabella J Lawandy; Phone Number: 4014901670; Email: ilawandy@bwh.harvard.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Not yet recruiting
      • Yale New Haven Hospital
      • Contact: Christine Henry; Email: christine.henry@yale.edu
      • Principal Investigator: Angela Montgomery, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Elizabeth Singh, MSN; Phone Number: 5125165360; Email: esingh@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Music; We will create three recordings with increasing complexity for each infant. For each infant developmental stage (32, 34, 36+ weeks PMA), Music Therapists (MTs) in both units will present parents with a curated list of 8-10 musically comparable, familiar lullabies to select from. Songs will be available in different languages reflective of patient diversity, with rhythm, tempo, pitch range/ change, instrumentation, melody, harmony selected drawing on available evidence, including BWH NICU pilot data. Timing: MBI to be administered after regular NICU "care and feeding" times, which are typically considered stressful times for infants. The goal of the intervention will be to provide a calming and relaxing experience to the infant as they "settle" back to sleep after handling times. Music delivery will occur via infant-adapted headphones to facilitate blinding.	Other: Music; Arm 1: Music only; Other Names: Arm 1: Music
Experimental: Music and parent voice; The selected lullabies will be pre-recorded by the MT as described above to include a guitar accompaniment track, and a separate vocal track with the MT singing along, in two separate keys to allow variation for parent voice range and comfort. Parents will be invited to sing along with the recorded track of MT singing, and MT will later remove the MT-voice recording track so only the parent voice will be heard with the guitar in the final recording. Timing: MBI to be administered after regular NICU "care and feeding" times, which are typically considered stressful times for infants. The goal of the intervention will be to provide a calming and relaxing experience to the infant as they "settle" back to sleep after handling times. Music delivery will occur via infant-adapted headphones to facilitate blinding.	Other: Music and parent voice; Arm 2: Music and parent voice; Other Names: Arm 2: Music and parent voice
Active Comparator: Reference/ Standard of care; These are infants recruited in the study who will receive the unit standard of care. They will be listening to the NICU ambient noise via infant-adapted headphones but will not receive any music intervention.	Other: Standard Care; Standard Care; Other Names: Arm 3: Standard Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bayley-4 language performance (SA3 primary outcome)	Study patients Language performance measured on the Bayley-4 at 2 years corrected age	2 years corrected age
Amygdala volume on MRI (SA1a, primary outcome)	Amygdala volume as a proxy of cumulative stress measured on term-equivalent brain MRI	At term-equivalent (~ 3 months of age), 37-41 weeks postmenstrual age (PMA)
Intranetwork connectivity in Salience and Language networks (SA2a, primary outcome)	We will measure the intranetwork connectivity in Salience and Language networks in infants exposed to music and music with parent voice compared those in SC arm at term-equivalent	Term-equivalent (~ 3 months of age), 37-41 weeks postmenstrual age (PMA)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant physiology - oxygen saturation	We will record infant physiologic vital signs (i.e. oxygen saturation) from infants' bedside monitor around each study intervention	From enrollment to term-equivalent 37-41 weeks PMA
Infant physiology - respiratory rate	We will record infant physiologic vital signs (i.e. respiratory rate) from infants' bedside monitor around each study intervention	From enrollment to term-equivalent 37-41 weeks PMA
Infant physiology - heart Rate	We will record infant physiologic vital signs (i.e. heart rate) from infants' bedside monitor around each study intervention	From enrollment to term-equivalent 37-41 weeks PMA
Telomere length	Assess infant premature aging at term-equivalent by measurement of telomere length on blood samples	At enrollment and term-equivalent 37-41 weeks PMA
Neurodevelopmental assessment - cognitive outcomes	Study patients' cognitive performance measured on the Bayley-4 assessment at 2 years corrected age	2 years corrected age
Neurodevelopmental assessment - motor outcomes	Study patients' motor performance measured on the Bayley-4 assessment at 2 years corrected age	2 years corrected age
Neurodevelopmental assessment - child behavior outcomes	Study patients' behavioral performance measured on the Child Behavior Checklist at 2 years corrected age	2 years corrected age
Brain development	Brain development and injury classified using the established Kidokoro scoring system applied to term-equivalent brain MRI	Term-equivalent age - 37-41 weeks PMA
Parent stress	Assessment of parent stress (Parental Stressor Scale) using a standardized survey of families of study infants	From term-equivalent age to 2 years corrected age
Parent anxiety and depression	Assessment of parent anxiety and depression (Hospital Anxiety and Depression Scale) using one standardized survey that provides a combined score	From term-equivalent age to 2 years corrected age
Infant Neurobehavior	We will assess infant neurobehavior using the Hammersmith Neonatal Neurological Examination at term-equivalent age 37-41 weeks PMA	Term-equivalent 37-41 weeks PMA

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Yale New Haven Health System Center for Healthcare Solutions

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2025
• Primary Completion (Estimated): August 30, 2030
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: July 10, 2024
• First Submitted That Met QC Criteria: July 30, 2024
• First Posted (Actual): August 2, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Neurodevelopment; Preterm; Music-based Intervention
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Premature Birth; Health Services Administration; Health Care Quality, Access, and Evaluation; Therapeutics; Quality of Health Care; Complementary Therapies; Quality Indicators, Health Care; Patient Care; Psychotherapy; Behavioral Disciplines and Activities; Rehabilitation; Aftercare; Continuity of Patient Care; Sensory Art Therapies; Standard of Care; Music Therapy
• Other Study ID Numbers: 2024P001561

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No