Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and -acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development. Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.

Increasing burden of WMI is associated with worse motor outcomes at 30 months for infants with critical congenital heart disease, whereas no adverse association was seen between small strokes and outcome. These results support the utility of neonatal brain magnetic resonance imaging in this population to aid in predicting later outcomes and the importance of ND follow-up beyond 1 year of age.

The predictive value of frontal lobe WMI volume highlights the importance of lesion location when considering the neurodevelopmental significance of WMI. Frontal lobe lesions are of particular concern.

In preterm neonates, greater energy and enteral feeding during the first 2 weeks of life predicted more robust brain growth and accelerated WM maturation. The long-lasting effect of early nutrition on neurodevelopment may be mediated by enhanced brain growth. Optimizing nutrition in preterm neonates may represent a potential avenue to mitigate the adverse brain health consequences of critical illness.

Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.

Our objectives were to determine whether procedural pain and glucose exposure are associated with altered structural and functional brain development differently in preterm males and females, and neurodevelopment at 18-month corrected age. Fifty-one very preterm neonates (22 males; median [interquartile range] gestational age 27.6 [2.0] weeks) underwent 3 serial scans including T1-weighted and resting-state functional magnetic resonance imaging (MRI) at median postmenstrual weeks: 29.4, 31.9, and 41.1. Thalamus, basal ganglia, and total brain volumes were segmented. Functional resting-state MRI data were extracted from the independent-components maps. Pain was operationalized as the total number of neonatal intensive care unit-administered invasive procedures. Neurodevelopmental outcomes at 18-month corrected age were assessed with the Bayley Scales of Infant Development, second edition. Generalized estimating equations assessed the association of pain and glucose exposure with brain structural and functional development. More invasive procedures were independently associated with slower growth of thalamic (P < 0.001), basal ganglia (P = 0.028), and total brain volumes (P = 0.001), particularly in females. Similar relationships were observed between glucose exposure and brain volumes. Functional connectivity between thalamus and sensorimotor cortices was negatively associated with number of invasive procedures. Greater procedural pain and higher glucose exposure were related to poorer neurodevelopmental outcomes. These findings suggest that structural and functional brain development is vulnerable to procedural pain. Glucose used for analgesia does not appear to mitigate the adverse impact of pain on brain development. The vulnerability of brain development in females towards early pain is distinct from other neonatal morbidities. The link between pain and glucose with neurodevelopment suggests that these factors have long-lasting impact.

WMI in term neonates with CHD occurs in a characteristic topology. The spatial distribution of WMI in term neonates with CHD reflects the expected maturation of pre-oligodendrocytes such that the central regions are less vulnerable than in the preterm neonates.

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