Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates

Abstract

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 N-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.SIGNIFICANCE STATEMENT 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.

Keywords: DTI; MRI; MRS; critical period; pain; preterm.

Figure 1.

Timeline of study procedures.

Figure 2.

Late skin-breaking procedures were not significantly associated with variations in thalamic volumetric development at term equivalent age and were not dependent on neonates' prior exposure to early skin-breaking procedures (p = 0.35). Estimated marginal means of thalamic volumes adjusting for male sex, GA at birth, DOL at scan, days of intubation, morphine dose, midazolam dose, dexamethasone dose, and total cerebral volume. Error bars are the SE of the estimated marginal means.

Figure 3.

Extremely preterm neonates exposed to high early skin breaks demonstrate slower (a) macrostructural (β = −211.81, p = 0.04) and (b) metabolic thalamic growth (β = −0.06, p < 0.0001) and (c) microstructural development of posterior white matter (β = −0.02, p = 0.02) across early and term-equivalent age scans. Late skin breaks were not associated with delays in macrostructural (β = 9.4, p = 0.9), metabolic (β = −0.006, p = 0.5), and microstructural development (β = 0.007, p = 0.5). Boxes represent the estimated marginal means of high/low early/late skin breaks fixed at the values for sex, birth GA, DOL at scan, total morphine dose, midazolam dose, dexamethasone dose, days of mechanical ventilation, and total cerebral volume (volume analysis only) in three separate models. Error bars are the SE of the estimated marginal means.

Figure 4.

Volume loss in the lateral thalamus is associated with a greater number of early skin-breaking procedures (t₍₁₅₂₎ = −5.9, p < 0.001, corrected). Left, DBM t-statistic map overlaid on a template MRI developed from the T1-weighted images collected at the early-in life time point (median PMA: 32 weeks). t Values reflect regional reductions in volume associated with the number of early skin-breaking procedures (birth–Scan 1). Right, Scatterplot of the relative increase and decrease values associated with early skin breaking procedures (birth–Scan1).