Bi-directional changes in fractional anisotropy after experiment TBI: Disorganization and reorganization?

Abstract

The current dogma to explain the extent of injury related changes following rodent controlled cortical impact (CCI) injury is a focal injury with limited axonal pathology. However, there is in fact good, published histologic evidence to suggest that axonal injury is far more widespread in this model than generally thought. One possibility that might help to explain this is the often-used region-of-interest data analysis approach taken by experimental traumatic brain injury (TBI) diffusion tensor imaging (DTI) or histologic studies that might miss more widespread damage, when compared to the whole brain, statistically robust method of tract based analysis used more routinely in clinical research. To determine the extent of DTI changes in this model, we acquired in vivo DTI data before and at 1 and 4 weeks after CCI injury in 17 adult, male rats and analyzed parametric maps of fractional anisotropy (FA), axial, radial and mean diffusivity (AD, RD, MD), tensor mode (MO), and fiber tract density (FTD) using tract based spatial statistics. Contusion volume was used as a surrogate marker of injury severity and as a covariate for investigating severity dependence of the data. Mean fiber tract length was also computed from seeds in the cortical spinal tract regions. In parallel experiments (n=3–5/group) we investigated corpus callosum neurofilaments and demyelination using immunohistochemistry (IHC) at 3 days and 6 weeks, callosal tract patency using dual-label retrograde tract-tracing at 5 weeks, and the contribution of gliosis to DTI parameter maps using GFAP IHC at 4 weeks post-injury. The data show widespread ipsilateral regions of significantly reduced FA at 1 week post-injury, driven by temporally changing values of AD, RD and MD that persist to 4 weeks. Demyelination, retrograde label tract loss, and reductions in MO (tract degeneration) and FTD were shown to underpin these data. Significant FA increases occurred in subcortical and corticospinal tract regions that were spatially distinct from regions of FA decrease, grossly affected gliotic areas and from MO changes. However, there was good spatial correspondence between regions of increased FA and areas of increased FTD and mean fiber length. We discuss these widespread changes in DTI parameters in terms of axonal degeneration and potential reorganization, with reference to a resting state fMRI companion paper (Harris et al, 2016, Exp. Neurol.227:124–138) that demonstrated altered functional connectivity data acquired from the same rats used in this study.

Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging, Histopathology, and Behavior

“…52 CCI in rats produces a cortical contusion lesion along with pathology in a widespread distribution of white matter tracts and corresponds with bidirectional changes in FA. 14 In this report, FA was reduced in the corpus callosum, but was increased in subcortical white matter as well as in some white matter tracts. Therefore, reduced FA was predicted to reflect fiber disorganization versus reorganization and/or higher fiber density in tracts with increased FA.…”

“…10–13 FA values depend on fiber topography among brain regions and the time post-injury, for example, acute, subacute, or chronic stage. 14–17 FA changes in relationship to changes in diffusivity parallel (axial) and transverse (radial) to fibers. These parameters are influenced by complex signal generated by multiple tissue features, including axon internal elements, myelination, cellularity, and extracellular elements.…”

“…These parameters are influenced by complex signal generated by multiple tissue features, including axon internal elements, myelination, cellularity, and extracellular elements. 14, 18 Increased FA early post-injury may occur with reduced radial diffusivity, which has been attributed to decreased water content in myelin or extracellular space, 19 or with increased axial diffusivity, which may be associated with increased fiber track density or gliosis. 14 Several studies have observed reduced FA in white matter in patients post-mTBI, which, in experimental models, has corresponded with demyelination and axon damage.…”

“…14, 18 Increased FA early post-injury may occur with reduced radial diffusivity, which has been attributed to decreased water content in myelin or extracellular space, 19 or with increased axial diffusivity, which may be associated with increased fiber track density or gliosis. 14 Several studies have observed reduced FA in white matter in patients post-mTBI, which, in experimental models, has corresponded with demyelination and axon damage. 10–14,18,20 Advancing DTI for clinical diagnosis and as a predictive outcome measure will require extended longitudinal studies and a comprehensive understanding of the correlation between abnormal tissue components and imaging results.…”

Repeated Pediatric Concussions Evoke Long-Term Oligodendrocyte and White Matter Microstructural Dysregulation Distant from the Injury

“…Changes in WM characteristics, such as myelin integrity [16, 37, 70], axonal responses [16, 70], and fiber organization [71], contribute to WM microstructure and likely alter DTI findings. Furthermore, the potential effects of the ongoing development of WM should not be overlooked [26].…”