Abstract
BackgroundEarly exposure to nociceptive events may cause brain structural alterations in preterm neonates, with long-lasting consequences on neurodevelopmental outcome. Little is known on the extent to which early pain may affect brain connectivity. We aim to evaluate brain functional connectivity changes in preterm neonate that underwent multiple invasive procedures during the postnatal period, and to correlate them with the neurodevelopmental outcome at 24 months.MethodsIn this prospective case-control study, we collected information about exposure to painful events during the early postnatal period and resting-state BOLD-fMRI data at term equivalent age from two groups of preterm neonate: 33 subjected to painful procedures during the neonatal intensive care (mean gestational age 27.9 ± 1.8 weeks) and 13 who did not require invasive procedures (average gestational age 31.2 ± 2.1 weeks). A data-driven principal-component-based multivariate pattern analysis (MVPA) was used to investigate the effect of early pain exposure on brain functional connectivity, and the relationship between connectivity changes and neurodevelopmental outcome at 24 months, assessed with Griffiths, Developmental Scale-Revised: 0–2.ResultsEarly pain was associated with decreased functional connectivity between thalami and bilateral somatosensory cortex, and between the right insular cortex and ipsilateral amygdala and hippocampal regions, with a more evident effect in preterm neonate undergoing more invasive procedures. Functional connectivity of the right thalamocortical pathway was related to neuromotor outcome at 24 months (P = 0.003).ConclusionEarly exposure to pain is associated with abnormal functional connectivity of developing networks involved in the modulation of noxious stimuli in preterm neonate, contributing to the neurodevelopmental consequence of preterm birth.
Highlights
The survival rates for preterm infants have improved considerably in recent decades due to the advances in perinatal and neonatal care (Lea et al, 2017)
For the analysis we considered 8 PCA components (C = 8) and we maintained the four principal components that explained most of the variance of the connectivity matrix (Thompson et al, 2016)
We evaluated the relationship between the brain connectivity of regions influenced by early pain exposure and the neurodevelopmental outcome at 24 months of corrected age, extracting connectivity values from the suprathreshold clusters obtained at the previous post hoc seed-to-voxel analysis
Summary
The survival rates for preterm infants have improved considerably in recent decades due to the advances in perinatal and neonatal care (Lea et al, 2017). In the early phases of development, the brain is extremely adaptable to novel sensory information inducing experiencedependent plasticity mechanisms (i.e., adaptive neuroplasticity) and vulnerable to several different insults leading to reactive post-injury neuroplasticity (Ismail et al, 2017). In this regards, it has been recently demonstrated that exposure to nociceptive stimuli at earlier gestational ages may have several effects on the developing brain, with more severe alterations of multiple cerebral structures in extremely preterm neonates exposed to multiple painful procedures (≤28 weeks of gestational age) (Brummelte et al, 2015; Duerden et al, 2018). We aim to evaluate brain functional connectivity changes in preterm neonate that underwent multiple invasive procedures during the postnatal period, and to correlate them with the neurodevelopmental outcome at 24 months
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