Subcortical brain volumes in neonatal hypoxic-ischemic encephalopathy

Background: Hypoxic ischemic encephalopathy (HIE) is a severe brain injury impacting term-born neonates. Despite treatment with therapeutic hypothermia (TH), HIE is associated with myriad adverse developmental outcomes suggesting the involvement of subcortical structures, including the thalamus and basal ganglia, which may be vulnerable to perinatal asphyxia, particularly during the acute period. Aims: 1) To examine subcortical macrostructure in the first few days of life in neonates with HIE compared to age- and sex-matched healthy neonates. 2) To determine whether subcortical volumetric maturation is associated with HIE severity. Methods: A cohort of 28 neonates (19 males [67.9%], median gestational age [GA]=38.6 weeks, interquartile range [IQR]=36.8-39.6) with HIE (mild=4, moderate=21, severe=3 based on Sarnat Staging) were scanned with MRI within the first four days of life (median postmenstrual age [PMA]=39.2, IQR=37.6-40.3), with the majority of scans occurring in the post-cooling period (n=23[82%]). The control group included 28 healthy neonates matched for GA, birth weight and PMA at the scan. Subcortical volumes (thalamus, basal ganglia, hippocampus, cerebellum) were automatically extracted from T1-weighted images. General linear models assessed between-group differences in subcortical volumes, adjusting for sex, GA, PMA, and total cerebral volumes. Within-group analyses evaluated the association between subcortical volumes and HIE severity. Results: Neonates with HIE had significantly smaller bilateral thalamic, basal ganglia and right hippocampal and cerebellar volumes compared to healthy neonates (all, p<0.02). Within the HIE group, milder HIE severity was associated with smaller volumes of the left and right basal ganglia (both, p<0.007) and the left hippocampus and thalamus (both, p<0.04) when adjusting for TH, days of mechanical ventilation and other clinical and demographic factors. Conclusions: Consistent with findings from childhood survivors of HIE, newborns with HIE, scanned with MRI within the first days of life, had smaller subcortical volumes impacting sensory and motor regions, including the thalamus, basal ganglia and cerebellum compared to healthy newborns. Additionally, HIE severity was associated with subcortical volumes, particularly impacting the basal ganglia, suggesting these regions may be important brain-based biomarkers in newborns impacted by the hypoxic-ischaemic injury. Findings suggest that despite advances in neonatal care, HIE is associated with significant alterations in brain macrostructure.