Abstract
Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to pain-related stress (adjusted for clinical factors and genotype) differentially impacts regional structures within the limbic system and thalamus, and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (<32 weeks GA) followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years. Hippocampal subfields and white matter tracts, thalamus and amygdala were automatically segmented using the MAGeT Brain algorithm. The relationship between those subcortical brain volumes (adjusted for total brain volume) and neonatal invasive procedures, gestational age (GA), illness severity, postnatal infection, days of mechanical ventilation, number of surgeries, morphine exposure, and genotype (COMT, SLC6A4, and BDNF) was examined using constrained principal component analysis. We found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala. After controlling for clinical risk factors and total brain volume, greater neonatal invasive procedures was associated with lower volumes in the amygdala and thalamus (p = 0.0001) and an interaction with COMT genotype predicted smaller hippocampal subregional volume (p = 0.0001). More surgeries, days of ventilation, and lower GA were also related to smaller volumes in various subcortical regions (p < 0.002). These reduced volumes were in turn differentially related to poorer cognitive, visual-motor and behavioral outcomes. Our findings highlight the complexity that interplays when examining how exposure to early-life stress may impact brain development both at the structural and functional level, and provide new insight on possible novel avenues of research to discover brain-protective treatments to improve the care of children born preterm.
Highlights
Children born very preterm [24–32 weeks gestational age (GA)] are at risk for cognitive, emotional and behavior problems, persisting to adulthood (e.g., Anderson et al, 2003; Grunau et al, 2004; Doyle and Anderson, 2010; Linsell et al, 2018)
We examined in school-age children born very preterm whether the extent of exposure to procedural pain/stress in the neonatal intensive care unit (NICU), acting directly and/or through genetic interaction with COMT, brain-derived neurotrophic factor (BDNF), 5HTTLPR, is associated with development of subcortical structures in the limbic system and the basal ganglia, after accounting for clinical factors associated with prematurity
We found that greater exposure to neonatal pain/stress was associated with smaller regional volumes in the limbic system and basal ganglia at age 8 years, after accounting for clinical factors associated with prematurity
Summary
Children born very preterm [24–32 weeks gestational age (GA)] are at risk for cognitive, emotional and behavior problems, persisting to adulthood (e.g., Anderson et al, 2003; Grunau et al, 2004; Doyle and Anderson, 2010; Linsell et al, 2018). Very preterm infants are exposed to developmentally unexpected environmental stress in the neonatal intensive care unit (NICU) during a critical period of rapid brain development and programming of stress systems. These infants undergo about 10 noxious procedures per day (Simons et al, 2003; Carbajal et al, 2008; Johnston et al, 2011; Roofthooft et al, 2014). We recently found in infants born very preterm that thalamic volume, metabolism and structural maturation, were related to greater exposure to neonatal pain-related stress (Duerden et al, 2018; Schneider et al, 2018), and in turn, associated with poorer cognitive and motor outcomes (Duerden et al, 2018). The relationship between neonatal pain/stress exposure and the structures adjacent to thalamus, including the limbic system and basal ganglia, have not been examined
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