A multiscale tissue assessment in a rat model of mild traumatic brain injury.

Diffusion tensor imaging (DTI) has demonstrated the potential to assess the pathophysiology of mild traumatic brain injury (mTBI) but correlations of DTI findings and pathological changes in mTBI are unclear. We evaluated the potential of ex vivo DTI to detect tissue damage in a mild mTBI rat model by exploiting multiscale imaging methods, histology and scanning micro-X-ray diffraction (SµXRD) 35 days after sham-operation (n = 2) or mTBI (n = 3). There were changes in DTI parameters rostral to the injury site. When examined by histology and SµXRD, there was evidence of axonal damage, reduced myelin density, gliosis, and ultrastructural alterations in myelin that were ongoing at the experimental time point of 35 days postinjury. We assessed the relationship between the 3 imaging modalities by multiple linear regression analysis. In this analysis, DTI and histological parameters were moderately related, whereas SµXRD parameters correlated weakly with DTI and histology. These findings suggest that while DTI appears to distinguish tissue changes at the microstructural level related to the loss of myelinated axons and gliosis, its ability to visualize alterations in myelin ultrastructure is limited. The use of several imaging techniques represents a novel approach to reveal tissue damage and provides new insights into mTBI detection.

Histopathological modeling of status epilepticus-induced brain damage based on in vivo diffusion tensor imaging in rats.

Non-invasive magnetic resonance imaging (MRI) methods have proved useful in the diagnosis and prognosis of neurodegenerative diseases. However, the interpretation of imaging outcomes in terms of tissue pathology is still challenging. This study goes beyond the current interpretation of in vivo diffusion tensor imaging (DTI) by constructing multivariate models of quantitative tissue microstructure in status epilepticus (SE)-induced brain damage. We performed in vivo DTI and histology in rats at 79 days after SE and control animals. The analyses focused on the corpus callosum, hippocampal subfield CA3b, and layers V and VI of the parietal cortex. Comparison between control and SE rats indicated that a combination of microstructural tissue changes occurring after SE, such as cellularity, organization of myelinated axons, and/or morphology of astrocytes, affect DTI parameters. Subsequently, we constructed a multivariate regression model for explaining and predicting histological parameters based on DTI. The model revealed that DTI predicted well the organization of myelinated axons (cross-validated R = 0.876) and astrocyte processes (cross-validated R = 0.909) and possessed a predictive value for cell density (CD) (cross-validated R = 0.489). However, the morphology of astrocytes (cross-validated R > 0.05) was not well predicted. The inclusion of parameters from CA3b was necessary for modeling histopathology. Moreover, the multivariate DTI model explained better histological parameters than any univariate model. In conclusion, we demonstrate that combining several analytical and statistical tools can help interpret imaging outcomes to microstructural tissue changes, opening new avenues to improve the non-invasive diagnosis and prognosis of brain tissue damage.

Microstructural Tissue Changes in a Rat Model of Mild Traumatic Brain Injury.

Our study investigates the potential of diffusion MRI (dMRI), including diffusion tensor imaging (DTI), fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI), to detect microstructural tissue abnormalities in rats after mild traumatic brain injury (mTBI). The brains of sham-operated and mTBI rats 35 days after lateral fluid percussion injury were imaged ex vivo in a 11.7-T scanner. Voxel-based analyses of DTI-, fixel- and NODDI-based metrics detected extensive tissue changes in directly affected brain areas close to the primary injury, and more importantly, also in distal areas connected to primary injury and indirectly affected by the secondary injury mechanisms. Histology revealed ongoing axonal abnormalities and inflammation, 35 days after the injury, in the brain areas highlighted in the group analyses. Fractional anisotropy (FA), fiber density (FD) and fiber density and fiber bundle cross-section (FDC) showed similar pattern of significant areas throughout the brain; however, FA showed more significant voxels in gray matter areas, while FD and FDC in white matter areas, and orientation dispersion index (ODI) in areas most damage based on histology. Region-of-interest (ROI)-based analyses on dMRI maps and histology in selected brain regions revealed that the changes in MRI parameters could be attributed to both alterations in myelinated fiber bundles and increased cellularity. This study demonstrates that the combination of dMRI methods can provide a more complete insight into the microstructural alterations in white and gray matter after mTBI, which may aid diagnosis and prognosis following a mild brain injury.

In Vivo Diffusion Tensor Imaging in Acute and Subacute Phases of Mild Traumatic Brain Injury in Rats.

Mild traumatic brain injury (mTBI) is the most common form of TBI with 10-25% of the patients experiencing long-lasting symptoms. The potential of diffusion tensor imaging (DTI) for evaluating microstructural damage after TBI is widely recognized, but the interpretation of DTI changes and their relationship with the underlying tissue damage is unclear. We studied how both axonal damage and gliosis contribute to DTI alterations after mTBI. We induced mTBI using the lateral fluid percussion (LFP) injury model in adult male Sprague Dawley rats and scanned them at 3 and 28 d post-mTBI. To characterize the DTI findings in the tissue, we assessed the histology by performing structure tensor (ST)-based analysis and cell counting on myelin-stained and Nissl-stained sections, respectively. In particular, we studied the contribution of two tissue components, myelinated axons and cellularity, to the DTI changes. Fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD) were decreased in both white and gray matter areas in the acute phase post-mTBI, mainly at the primary lesion site. In the subacute phase, FA and AD were decreased in the white matter, external capsule, corpus callosum, and internal capsule. Our quantitative histologic assessment revealed axonal damage and gliosis throughout the brain in both white and gray matter, consistent with the FA and AD changes. Our findings suggest that the usefulness of in vivo DTI is limited in its detection of secondary damage distal to the primary lesion, while at the lesion site, DTI detected progressive microstructural damage in the white and gray matter after mTBI.