Abstract
Mild traumatic brain injury (mTBI) is highly prevalent but lacks both research tools with adequate sensitivity to detect cellular alterations that accompany mild injury and pre-clinical models that are able to robustly mimic hallmark features of human TBI. To address these related challenges, high-resolution diffusion tensor MRI (DTI) analysis was performed in a model of mild TBI in the ferret – a species that, unlike rodents, share with humans a gyrencephalic cortex and high white matter (WM) volume. A set of DTI image analysis tools were optimized and implemented to explore key features of DTI alterations in ex vivo adult male ferret brains (n = 26), evaluated 1 day to 16 weeks after mild controlled cortical impact (CCI). Using template-based ROI analysis, lesion overlay mapping and DTI-driven tensor-based morphometry (D-TBM) significant differences in DTI and morphometric values were found and their dependence on time after injury evaluated. These observations were also qualitatively compared with immunohistochemistry staining of neurons, astrocytes, and microglia in the same tissue. Focal DTI abnormalities including reduced cortical diffusivity were apparent in 12/13 injured brains with greatest lesion extent found acutely following CCI by ROI overlay maps and reduced WM FA in the chronic period was observed near to the CCI site (ANOVA for FA in focal WM: time after CCI p = 0.046, brain hemisphere p = 0.0012) often in regions without other prominent MRI abnormalities. Global abnormalities were also detected, especially for WM regions, which demonstrated reduced diffusivity (ANOVA for Trace: time after CCI p = 0.007) and atrophy that appeared to become more extensive and bilateral with longer time after injury (ANOVA for D-TBM Log of the Jacobian values: time after CCI p = 0.007). The findings of this study extend earlier work in rodent models especially by evaluation of focal WM abnormalities that are not influenced by partial volume effects in the ferret. There is also substantial overlap between DTI and morphometric findings in this model and those from human studies of mTBI implying that the combination of DTI tools with a human-similar model system can provide an advantageous and informative approach for mTBI research.
Highlights
As the adverse consequences of mild traumatic brain injury become increasingly evident in humans (Carroll et al, 2014; Levin and Diaz-Arrastia, 2015), there is a need to develop human-relevant model systems to study mTBI as well as more sensitive diagnostic markers that can be applied at both the bench and bedside
Mild cortical impact (CCI) induced in several diffusion tensor MRI (DTI) and morphometric changes in the ferret brain including prominent focal abnormalities and subtle, widespread changes in DTI values and local volume
Decreased Anisotropy Changes in anisotropy were often, but not always, evident by eye in the affected lobe and 13/13 brains were found to have a region of reduced fractional anisotropy (FA) detectable using lateralized difference maps and corresponded with reactivity of the white matter (WM) astrocytes and microglia (Figure 2)
Summary
As the adverse consequences of mild traumatic brain injury (mTBI) become increasingly evident in humans (Carroll et al, 2014; Levin and Diaz-Arrastia, 2015), there is a need to develop human-relevant model systems to study mTBI as well as more sensitive diagnostic markers that can be applied at both the bench and bedside. While conventional non-invasive imaging by CT and MRI are commonly used for moderate and severe TBI (Duhaime et al, 2010), they do not provide robust markers of brain alterations after mTBI and there is urgency to develop quantitative imaging methods better able to detect particular features of neuropathology Among these methods, diffusion tensor MRI (DTI) has been shown to enable detection of abnormal brain tissue by its sensitivity to the microscale tissue environment, which can be dramatically changed in the presence of cellular alterations and physiologic change. Histologic evidence from mTBI in swine indicates high levels of DAI pathology despite low severity of the injury (Browne et al, 2011) and recent findings from ferrets demonstrate chronic widespread WM gliosis after mTBI (Schwerin et al, 2017)
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