White Matter Changes Caused by Mild Traumatic Brain Injury in Mice Evaluated Using Neurite Orientation Dispersion and Density Imaging

Mild traumatic brain injury (mTBI) is common and can lead to persistent cognitive and behavioral symptoms. Although diffusion tensor imaging (DTI) has demonstrated some sensitivity to changes in white matter following mTBI, recent studies have suggested that more complex geometric models of diffusion, including the neurite orientation dispersion and density imaging (NODDI) model, may be more sensitive and specific. Here, we evaluate microstructural changes in white matter following mTBI using DTI and NODDI in a mouse model, and compare the time course of these changes to behavioral impairment and recovery. We also assess volumetric changes for a comprehensive picture of the structural alterations in the brain and histological staining to identify cellular changes that may contribute to the differences detected in the imaging data. Increased orientation dispersion index (ODI) was observed in the optic tracts of mTBI mice compared with shams. Changes in fractional anisotropy (FA) were not statistically significant. Volume deficits were detected in the optic tract as well as in several gray matter regions: the lateral geniculate nuclei of the thalamus, the entorhinal cortex, and the superior colliculi. Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) staining was increased in the optic tracts of mTBI brains, and this staining correlated with ODI values. A transient impairment in working memory was observed, which resolved by 6 weeks, whereas increased ODI, GFAP, and Iba1 persisted to 18 weeks post-injury. We conclude that the optic tracts are particularly vulnerable to damage from the closed-skull impact model used in this study, and that ODI may be a more sensitive metric to this damage than FA. Differences in ODI and in histological measures of astrogliosis, neuroinflammation, and axonal degeneration persist beyond behavioral impairment in this model.