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 -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.

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

“…Studies designed to investigate the contribution of such stressors to the long-term effects of PTB are difficult, because of the presence of multiple confounders such as illness severity or length of the NICU stay. Nevertheless, studies which have attempted to correct for various confounders have shown that the number of painful procedures experienced associates with alterations in brain development [15][16][17] suggesting that some stressors may indeed have long term consequences.…”

Self‐reported mental health and cortisol activity at 27‐28 years of age in individuals born with very low birthweight

“…It is plausible that the plasticity of the infant brain is even more vulnerable to the exposure to illness and the environment in neonatal intensive care. Neonatal pain‐related stress in very preterm infants is associated with altered brain cortical thickness at school age and has been shown to contribute to slower growth of thalamus associated with poorer cognitive and motor outcome at 3 years of age . An association has been found between neonatal pain‐related stress and hair cortisol in preterm boys at school age, suggesting the early programming effect downregulating the HPA axis response to psychosocial stress in preterm children several years after prenatal and postnatal stressors had been terminated .…”

Atypical neuromagnetic resting activity associated with thalamic volume and cognitive outcome in very preterm children

“…Disruption in this developmental process might cause neural apoptosis [Anand et al, 2007;Dührsen et al, 2013] and altered development of thalamocortical axons [Dean et al, 2013;Molnar and Rutherford, 2013]. Moreover, very preterm infants present abnormal myelinization and fractional anisotropy in gray and white matter areas [Dubois et al, 2008;Eaton-Rosen et al, 2015], decreased cortical and subcortical gray matter volume [Dubois et al, 2008;Eaton-Rosen et al, 2015], decreased cortical and subcortical gray matter volume Chau et al, 2019], thalamocortical alterations [Ball et al, 2012;Cai et al, 2017] and pain-induced volume reduction of white matter and subcortical gray matter [Brummelte et al, 2012;Duerden et al, 2018]. These structural alterations persist into school age [Hohmeister et al, 2010;Lax et al, 2013] and adulthood [Menegaux et al, 2017;Nosarti et al, 2014] and are associated with lower IQ [Breeman et al, 2017;Nosarti et al, 2014].…”