Longitudinal, Multiparametric MRI Assessment of repetitive mild TBI in rats

Abstract

Repetitive mild traumatic brain injury (mTBI) has long term health effects and may result in the development of neurodegenerative or neuropsychiatric disorders. Histology shows axonal and dendritic beading, synaptic atrophy, vasodilation and gliosis occuring within hours/days post-mTBI. However, current neuroimaging techniques are unable to detect the early effects of repetitive mTBI. Consequently, mTBI brain scans are normal appearing and inconclusive. Hence, neuroimaging markers capable of detecting subtle microstructural and functional alterations are needed. We present results from longitudinal, multiparametric magnetic resonance imaging (MRI) assessment of repetitive mTBI in rats. We employ advanced in-vivo diffusion MRI (dMRI) to probe brain microstructural alterations, perfusion MRI to assess cerebral blood flow (CBF), close to the injury site, and proton MR spectroscopy to assess metabolic alterations in the ipsilateral cerebral cortex. High resolution anatomical scans were also acquired. In agreement with clinical observations, anatomical scans of rats were normal appearing even after repeated mTBI. Throughout, significance is regarded as p<0.05 post false discovery rate correction. dMRI revealed significant microstructural remodelling in ipsilateral hippocampus (reduced radial kurtosis), may be due to axonal/dendritic beading, demyelination, synaptic atrophy and edema. Consistent with prior reports of reduced cell/fiber density in mTBI, we find significantly increased mean diffusivity in ipsilateral corpus callosum. We also find significantly decreased glutathione (GSH) and increased total Choline (tCho) following second and third mTBI (vs baseline), also reported in clinical mTBI cohorts. Reduced GSH suggests oxidative stress and increase in tCho indicate cell damage/repair. CBF did not change significantly, however, high variability in CBF following the second and third mTBI suggest increased variability in CBF likely due to tissue hypoxia and oxidative stress. Oxidative stress may affect capillary blood flow by disturbing pericyte capillary contraction. Around 40% of pericytes retract after mTBI causing pericyte depletion and white matter dysfunction as suggested by dMRI findings. Multiparametric MRI detects meaningful mTBI-induced alterations otherwise undetectable with conventional MRI. Similar strategies may provide useful information to aid diagnosis of human mTBI.