Abstract
Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain.
Highlights
Even in the absence of severe comorbidities, very preterm (VPT) infants need long-lasting hospitalization in the Neonatal Intensive Care Units (NICU) [1] and are at risk for altered socio-emotional development [2]
We extended previous research assessing the potential links between SLC6A4 CpG-specific methylation and brain volumes at term equivalent age (TEA)
The goodness of the model was assessed separately for each region of interest (ROI) according to: non-significant chisquare statistic; comparative fit index (CFI) and Tucker-Lewis index (TLI) close to .95 [34]; Root Mean Squared Error of Approximation (RMSEA) smaller than .05; Square Residual Root Mean (SRMR) smaller than .08 [35]; non-significant p value associated with the CI of RMSEA [36]
Summary
Even in the absence of severe comorbidities, very preterm (VPT) infants (gestational age at birth < 32 weeks) need long-lasting hospitalization in the Neonatal Intensive Care Units (NICU) [1] and are at risk for altered socio-emotional development [2]. During NICU stay, VPT infants are exposed to life-saving yet invasive interventions including mechanical ventilation and painful skin-breaking procedures These sources of NICU-related stress have been found to contribute to VPTs’ socio-emotional development during infancy [3, 4] and childhood [5, 6]. Using data from a longitudinal research study, we examined potential links between early NICU stress exposure and socio-emotional development at 12 months corrected age (CA) in VPT children, assessing both epigenetic variations (i.e., serotonin transporter gene (SLC6A4) methylation [9]) and brain growth (i.e., anterior temporal lobe volume [10, 11]). Through a path analysis, we speculatively tested the hypothesis that an altered ATL volume might mediate the association between early NICU-related SLC6A4 epigenetic alterations (i.e., increased CpG methylation) and socio-emotional development at 12 months CA
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