Traumatic Brain Injury Results in Cellular, Structural and Functional Changes Resembling Motor Neuron Disease

Abstract

Traumatic brain injury (TBI) has been suggested to increase the risk of amyotrophic lateral sclerosis (ALS). However, this link remains controversial and as such, here we performed experimental moderate TBI in rats and assessed for the presence of ALS-like pathological and functional abnormalities at both 1 and 12 weeks post-injury. Serial in-vivo magnetic resonance imaging (MRI) demonstrated that rats given a TBI had progressive atrophy of the motor cortices and degeneration of the corticospinal tracts compared with sham-injured rats. Immunofluorescence analyses revealed a progressive reduction in neurons, as well as increased phosphorylated transactive response DNA-binding protein 43 (TDP-43) and cytoplasmic TDP-43, in the motor cortex of rats given a TBI. Rats given a TBI also had fewer spinal cord motor neurons, increased expression of muscle atrophy markers, and altered muscle fiber contractile properties compared with sham-injured rats at 12 weeks, but not 1 week, post-injury. All of these changes occurred in the presence of persisting motor deficits. These findings resemble some of the pathological and functional abnormalities common in ALS and support the notion that TBI can result in a progressive neurodegenerative disease process pathologically bearing similarities to a motor neuron disease.

Neurodegeneration and Sensorimotor Deficits in the Mouse Model of Traumatic Brain Injury

“…Our result agrees with previous studies that demonstrates progressive brain atrophy and sensorimotor deficits in rodent model of traumatic brain injury [38][39][40][41]. The parietal lobes and their related circuitry are particularly more vulnerable to traumatic damage; hence executive dysfunction is prevalent [42,43].…”

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury

“…It should also be noted that our MRI study was conducted on ex vivo brain samples, which somewhat limits the clinical relevance of the findings. However, both the scan time (i.e., 2 h) and the DWI sequences that were used are appropriate for future in vivo studies 23, 31, 57. As our current study only investigated rats given repeated mTBI, future in vivo studies could investigate the effects of a single mTBI using serial MRI at different postinjury times.…”

“…However, both the scan time (i.e., 2 h) and the DWI sequences that were used are appropriate for future in vivo studies. 23,31,57 As our current study only investigated rats given repeated mTBI, future in vivo studies could investigate the effects of a single mTBI using serial MRI at different postinjury times. Such investigations would provide important information related to diagnosis and recovery/cerebral vulnerability after a single mTBI.…”

“…Fiber orientation distributions (FODs) were computed using constrained spherical deconvolution with an average response function and a study template constructed using symmetric diffeomorphic registration 30. To avoid biasing, the study template to any one group, templates were first constructed for each group (i.e., sham Day 1 postinjury, sham Day 7 postinjury, repeat mTBI Day 1 postinjury, and repeat mTBI Day 7 postinjury) and then combined to create the study template 23, 24, 31…”

“…30 To avoid biasing, the study template to any one group, templates were first constructed for each group (i.e., sham Day 1 postinjury, sham Day 7 postinjury, repeat mTBI Day 1 postinjury, and repeat mTBI Day 7 postinjury) and then combined to create the study template. 23,24,31 DTI metrics including FA, radial diffusivity (RD), and axial diffusivity (AD) were generated for each subject and transformed into study-specific template space using MRtrix. For TWI, tractograms were generated for each rat using the iFOD2 algorithm and registered to the study-specific FOD template.…”