Abstract
BackgroundNeonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown. MethodsFrom birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were reared in room-air (20.9% O2). Longitudinal MRI (Diffusion Tensor Imaging and T2-mapping) was performed on P14 and P28 and retinal and brain tissue were examined for histopathological changes. Long-term neurodevelopment was assessed on P20 and P27. ResultsMean, radial and axial diffusivity were higher in white matter of IHH versus controls at P14 (p < 0.04), while fractional anisotropy (FA) was lower in the hippocampal fimbria and tended to be lower in corpus callosum (p = 0.08) and external capsule (p = 0.05). White matter diffusivity in IHH was similar to controls at P28. Higher cortical vessel density (p = 0.005) was observed at P14. Cortical and thalamic T2-relaxation time and mean diffusivity were higher in the IHH group at P14 (p ≤ 0.03), and albumin leakage was present at P28. Rats in the IHH group ran for a longer time on a Rotarod than the control group (p ≤ 0.005). Pups with lower bodyweight had more severe MRI alterations and albumin leakage.ConclusionIHH led to subtle reversible changes in brain white matter diffusivity, grey matter water content and vascular density. However, alterations in blood-brain barrier permeability may point to long-term effects. The changes seen after IHH exposure were more severe in animals with lower bodyweight and future studies should aim at exploring possible interactions between IHH and growth restriction.
Highlights
Preterm born infants may be subject to pathological conditions in several organ systems like retinopathy of prematurity (ROP) and preterm encephalopathy
Hyperoxia due to treatment combined with hypoxia due to apnoea is common in the sick premature child, and clinicians question whether such unphysiological oxygen levels will affect long-term brain development [7]
At P28 there was no difference in white matter diffusivity of the corpus callosum between intermittent hyperoxia-hypoxia (IHH) and controls, but there was a significant increase in fractional anisotropy (FA) (p = 0.03) and decrease in radial (p = 0.008) and mean (p = 0.009) diffusivity from postnatal day 14 (P14) to P28 in the IHH group (Table 2)
Summary
Preterm born infants may be subject to pathological conditions in several organ systems like retinopathy of prematurity (ROP) and preterm encephalopathy. Paucity of endothelial pericyte [18] and astrocyte coverage [19] in the germinal matrix of preterm born infants, a predilection site for intraventricular haemorrhage, indicates fragile vasculature Vascularization of both the retina [20] and brain [21] occur in parallel to the brain growth spurt from gestational week 20 until term in humans and from birth until postnatal day 14 (P14) in the rat, a species that at birth is comparable to a very preterm human infant [22]. Exposure of neonatal rats to a profile of intermittent hyperoxia-hypoxia (IHH) that cause ROP may induce a parallel disruption of neural and vascular tissue in the brain with ensuing white and grey matter injury To investigate this hypothesis we conducted a study of longterm brain development in rats exposed to IHH from birth until P14. Outcome was evaluated with multimodal in vivo magnetic resonance imaging (MRI) combined with neurodevelopmental testing and detailed immunohistochemical studies of bloodbrain barrier (BBB) permeability and vascular density
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