MRI investigation of orientation-dependent changes in microstructure and function in a mouse model of mild traumatic brain injury

While neuroimaging studies have revealed notable white matter damage following mild traumatic brain injury (mTBI), the specific tracts and brain regions affected vary widely across studies. Here, we explored whether the spatial orientation of white matter tracts influences susceptibility to repeated mTBI, predicting that tracts oriented orthogonal to the axis of rotation of the head during impact (within the plane of rotation) would exhibit the most damage. Using a model of repeated rotational mTBI in mice, we acquired advanced diffusion MRI (diffusional kurtosis imaging using oscillating gradient encoding) and resting-state functional MRI (fMRI) data at baseline and 1-week post-injury. Consistent with our prediction, while both diffusivity and diffusional kurtosis decreased in the white matter of injured mice, only diffusional kurtosis revealed microstructural changes confined to tracts oriented orthogonal to the right-left axis of rotation. In addition, both region and subregion analyses showed functional connectivity (FC) deficits between regions connected via tracts running orthogonal to the rotation axis. The orientation-dependent changes in imaging metrics were validated by histopathological analyses. Females showed greater microstructural changes than males using diffusion MRI following injury, while no sex differences were detected by fMRI. Interestingly, the region-specific and subregion-specific FC analyses showed overlapping but non-identical changes in FC suggesting the utility of using both coarse and fine levels of brain parcellation for FC analyses in mTBI. These findings suggest that mTBI imaging studies may benefit from the consideration that damage after mTBI will predominate in tracts that are oriented orthogonal to the axis of rotation produced by the impact and that diffusivity and diffusional kurtosis as well as region and subregion-specific fMRI analyses can detect these changes.