Abstract
BackgroundAltered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.Methods42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.ResultsAfter correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.ConclusionsIn very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.
Highlights
Altered brain development is evident in children born very preterm (24–32 weeks gestational age) in early infancy [1,2,3] and at school-age [4,5], including reduced gray and white matter volumes in infancy, childhood and adolescence [6,7,8,9,10], compared to term-born peers
Two children with periventricular leukomalacia (PVL) and/or intraventricular hemorrhage (IVH) grade 3 or 4 on neonatal ultrasound and confirmed on magnetic resonance (MR) at age 7 years were excluded, and three left handed children were excluded to eliminate the effect of handedness on cortical thickness asymmetries [33,34]
Since child age may contribute to variations in cortical development [11], we performed correlations between age at MR scan and cortical thickness and no statistically significant associations were found, after Bonferroni correction for multiple comparisons
Summary
Altered brain development is evident in children born very preterm (24–32 weeks gestational age) in early infancy [1,2,3] and at school-age [4,5], including reduced gray and white matter volumes in infancy, childhood and adolescence [6,7,8,9,10], compared to term-born peers. Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age
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