Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits

Abstract

Background: Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits.

Methods: Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment.

Results: We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months.

Conclusions: These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.

Keywords: Autism spectrum disorder; Brain development; Cerebellum; Early-life pain; Language development; Motor development; Neonatal intensive care unit; Neurodevelopment; Prematurity; fMRI.