Steven Miller

Children born very preterm exhibit neurodevelopmental problems, compared to term-born peers. Math underperformance is particularly evident and is associated with poorer visuospatial skills. Neonatal exposure to repeated invasive procedures during neonatal intensive care unit (NICU) stay that induce pain and stress has been identified as one contributing factor to poorer cognitive performance, but relationships with mathematics achievement have not been studied.Partial least squares correlation (PLSC) analyses were performed to investigate whether:1. Neonatal pain-related stress and clinical factors are related to math skills at age 8 years, and whether: a) maternal education, b) white matter injury, and c) child sex, contribute to the relationship.2. Neonatal pain-related stress and clinical factors are related to functional network activation during visuospatial processing.3. Functional network activation during visuospatial processing is related to math skills.In an ongoing prospective longitudinal cohort study, N=118 (63 male) children born very preterm at 8 years underwent neuropsychological and math skills assessment, and N=75 children also completed a visuospatial mental rotation of hands task. Prospective daily clinical chart review conducted across the NICU stay recorded pain/stress (number of invasive procedures) and clinical factors. No child with major brain injury and/or severe motor, sensory, or cognitive impairments was included. I found that:1. Greater pain/stress exposure was related to poorer math skills, along with morphine, gestational age, ventilation, and infection (τ=80%, p.001). None of maternal education, white matter injury, or child sex contributed to the relationship.2. Greater neonatal pain/stress, morphine, ventilation, SNAP-II, infection, and lower gestational age were then related to increased brain network activation that included the right superior parietal, right lateral occipital, and left inferior temporal cortices (τ=65%, p.001).3. Poorer scores in all math domains were related to increased activation including in the superior parietal and lateral occipital cortices bilaterally and with concomitant decreased activation that included the right inferior parietal cortex (τ=93%, p.001).Overall this study suggests a link via visuospatial processing between math and pain/stress and supports the importance of visuospatial abilities in relation to math performance for children born very preterm.

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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 neonatal pain-related stress (adjusted for clinical factors) deferentially 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, 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 were 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 deferentially 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. 

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