Association between brain structural network efficiency at term-equivalent age and early development of cerebral palsy in very preterm infants

Julia E Kline, Weihong Yuan, Karen Harpster, Mekibib Altaye, Nehal A Parikh, Julia E Kline, Weihong Yuan, Karen Harpster, Mekibib Altaye, Nehal A Parikh

Abstract

Very preterm infants (born at less than 32 weeks gestational age) are at high risk for serious motor impairments, including cerebral palsy (CP). The brain network changes that antecede the early development of CP in infants are not well characterized, and a better understanding may suggest new strategies for risk-stratification at term, which could lead to earlier access to therapies. Graph theoretical methods applied to diffusion MRI-derived brain connectomes may help quantify the organization and information transfer capacity of the preterm brain with greater nuance than overt structural or regional microstructural changes. Our aim was to shed light on the pathophysiology of early CP development, before the occurrence of early intervention therapies and other environmental confounders, to help identify the best early biomarkers of CP risk in VPT infants. In a cohort of 395 very preterm infants, we extracted cortical morphometrics and brain volumes from structural MRI and also applied graph theoretical methods to diffusion MRI connectomes, both acquired at term-equivalent age. Metrics from graph network analysis, especially global efficiency, strength values of the major sensorimotor tracts, and local efficiency of the motor nodes and novel non-motor regions were strongly inversely related to early CP diagnosis. These measures remained significantly associated with CP after correction for common risk factors of motor development, suggesting that metrics of brain network efficiency at term may be sensitive biomarkers for early CP detection. We demonstrate for the first time that in VPT infants, early CP diagnosis is anteceded by decreased brain network segregation in numerous nodes, including motor regions commonly-associated with CP and also novel regions that may partially explain the high rate of cognitive impairments concomitant with CP diagnosis. These advanced MRI biomarkers may help identify the highest risk infants by term-equivalent age, facilitating earlier interventions that are informed by early pathophysiological changes.

Keywords: Biomarkers Abbreviations: very preterm (VPT); Cerebral palsy; Diffusion MRI; General Movements Assessment (GMA); Hammersmith Infant Neurological Examination (HINE); Infant; Magnetic resonance imaging; Premature; White matter; bronchopulmonary dysplasia (BPD), fractional anisotropy (FA); cerebral palsy (CP); developing human connectome project (dHCP); gestational age (GA); global efficiency (Eg(lob)); local efficiency (E(loc)), clustering coefficient (CC); retinopathy of prematurity (ROP).

Copyright © 2021. Published by Elsevier Inc.

Figures

Fig. 1.
Fig. 1.
Alignment (3rd column) of the 122-region JHU atlas (2nd column) with diffusion space tractography (1st column) for a female very preterm infant, born at a gestational age of 31.86 weeks. From here, we calculated the mean fractional anisotropy for all streamlines connecting each regional pair as a 122 × 122 symmetrical matrix.
Fig. 2.
Fig. 2.
Brain templates in sagittal, coronal, and axial orientations (left to right) demonstrating regional brain volumes significantly associated with the early diagnosis of cerebral palsy (CP) when correcting for postmenstrual age only (top row) and all covariates of interest (bottom row). Red volumes are positively associated with early CP (ventricles); blue volumes are negatively associated with early CP; light blue = thalamus (top and bottom); dark blue = deep nuclear gray matter (top and bottom) and brainstem (top); gray/white volumes are not significant.
Fig. 3.
Fig. 3.
Nodes in which local efficiency was negatively associated with early CP diagnosis correcting for PMA, GA, sex, BPD, ROP, and maternal magnesium therapy and adjusting for FDR.
Fig. 4.
Fig. 4.
Nodes in which clustering coefficient was negatively associated with early CP diagnosis correcting for PMA, GA, sex, BPD, ROP, and maternal magnesium therapy and adjusting for FDR.
Fig. 5.
Fig. 5.
Nodes in which strength was negatively associated with early CP diagnosis, correcting for PMA, GA, sex, BPD, ROP, and maternal magnesium therapy and adjusting for FDR.

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