Repeated Mild Traumatic Brain Injury Results in Long-Term White-Matter Disruption

Abstract

Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI.

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

“…Overall, we demonstrated that mTBI can lead to long-term alterations in WM microstructural integrity distal to the injury site at the AC in the developing brain, where repeated injury exacerbates abnormalities, similar to adult TBI [16]. Such increases in FA, in view of the significantly reduced RD and unaltered AD, clearly report WM microstructural disruption and suggest potential myelin-based dysregulation of microstructural integrity, as RD is often associated with myelin changes whereas AD is associated with axonal injuries [35, 64].…”

“…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].…”

“…LFB staining was performed as previously described with a few modifications [16]. The mounted slides were thawed to room temperature for 1 h, and then treated with a 0.1% LFB staining solution (Solvent Blue 38 in 95% alcohol and 0.5% acetic acid) overnight at 56°C.…”

“…Furthermore, repeated (r)mTBI in adults is known to aggravate mTBI outcomes, with subacute and long-term exacerbation of cognitive, motor, sensory, and affective functions [13, 14] as well as damage to myelin and axonal structures [15, 16] as demonstrated in animal models. However, there is a disproportionate paucity of pediatric mTBI research in preclinical models for translation to the human condition.…”

“…Advanced magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) can provide unique insights into WM microstructural pathology [31-33]. We and others have reported the ability to noninvasively detect myelin and axon pathology using DTI [16, 34]. DTI reports several metrics: fractional anisotropy (FA) measures the directionality of water diffusion; axonal diffusivity (AD) evaluates diffusion parallel to the fibers ( λ // ); radial diffusivity (RD) examines diffusion perpendicular to fibers ( λ ⊥ ); and the apparent diffusion coefficient (ADC) or mean diffusivity provides information on bulk water mobility within tissues.…”