Advanced MRI analysis to detect white matter brain injury in growth restricted newborn lambs

Abstract

Background: Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased risk of adverse neurodevelopment and neuromorbidity. Current imaging techniques, including conventional magnetic resonance imaging (MRI), are not sensitive enough to detect subtle structural abnormalities in the FGR brain. We examined whether advanced MRI analysis techniques have the capacity to detect brain injury (particularly white matter injury) caused by chronic hypoxia-induced fetal growth restriction in newborn preterm lambs. Methods: Surgery was undertaken in twin bearing pregnant ewes at 88–90 days gestation (term = 150 days) to induce FGR in one fetus. At 127 days gestation (~32 weeks human brain development), FGR and control (appropriate for gestational age, AGA) lambs were delivered by caesarean section, intubated and ventilated. Conventional and advanced brain imaging was conducted within the first two hours of life using a 3T MRI scanner. T1-weighted (T1w) and T2-weighted (T2w) structural imaging, magnetic resonance spectroscopy (MRS), and diffusion MRI (dMRI) data were acquired. Diffusion tensor imaging (DTI) modelling and analysis of dMRI data included the following regions of interest (ROIs): subcortical white matter, periventricular white matter, cerebellum, hippocampus, corpus callosum and thalamus. Fixel-based analysis of 3-tissue constrained spherical deconvolution (CSD) of the dMRI data was performed and compared between FGR and AGA lambs. Lambs were euthanised immediately after the scans and brain histology performed in the regions of interest to correlate with imaging. Results: FGR and AGA lamb (body weight, mean (SD): 2.2(0.5) vs. 3.3(0.3) kg, p = .002) MRI brain scans were analysed. There were no statistically significant differences observed between the groups in conventional T1w, T2w or MRS brain data. Mean, axial and radial diffusivity, and fractional anisotropy indices obtained from DTI modelling also did not show any statistically significant differences between groups in the ROIs. Fixel-based analysis of 3-tissue CSD, however, did reveal a decrease in fibre cross-section (FC, p < .05) but not in fibre density (FD) or combined fibre density and cross-section (FDC) in FGR vs. AGA lamb brains. The specific tracts that showed a decrease in FC were in the regions of the periventricular white matter, hippocampus and cerebellar white matter, and were supported by histological evidence of white matter hypomyelination and disorganisation in corresponding FGR lamb brain regions. Conclusions: The neuropathology associated with FGR in neonatal preterm lambs is subtle and imaging detection may require advanced MRI and tract-based analysis techniques. Fixel-based analysis of 3-tissue CSD demonstrates that the preterm neonatal FGR brain shows evidence of macrostructural (cross-sectional) deficits in white matter subsequent to altered antenatal development. These findings can inform analysis of similar brain pathology in neonatal infants.