Dataset Information

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

ABSTRACT:

Background

Following one mild traumatic brain injury (mTBI), there is a window of vulnerability during which subsequent mTBIs can cause substantially exacerbated impairments. Currently, there are no known methods to monitor, shorten or mitigate this window.

Methods

To characterize a preclinical model of this window of vulnerability, we first gave male and female mice one or two high-depth or low-depth mTBIs separated by 1, 7, or 14 days. We assessed brain white matter integrity using silver staining within the corpus callosum and optic tracts, as well as behavioural performance on the Y-maze test and visual cliff test.

Results

The injuries resulted in windows of white matter vulnerability longer than 2 weeks but produced no behavioural impairments. Notably, this window duration is substantially longer than those reported in any previous preclinical vulnerability study, despite our injury model likely being milder than the ones used in those studies. We also found that sex and impact depth differentially influenced white matter integrity in different white matter regions.

Conclusions

These results suggest that the experimental window of vulnerability following mTBI may be longer than previously reported. Additionally, this work highlights the value of including white matter damage, sex, and replicable injury models for the study of post-mTBI vulnerability and establishes important groundwork for the investigation of potential vulnerability mechanisms, biomarkers, and therapies.

SUBMITTER: Velayudhan PS

PROVIDER: S-EPMC9290236 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

Velayudhan Prashanth S PS Mak Jordan J JJ Gazdzinski Lisa M LM Wheeler Anne L AL

BMC neuroscience 20220718 1

<h4>Background</h4>Following one mild traumatic brain injury (mTBI), there is a window of vulnerability during which subsequent mTBIs can cause substantially exacerbated impairments. Currently, there are no known methods to monitor, shorten or mitigate this window.<h4>Methods</h4>To characterize a preclinical model of this window of vulnerability, we first gave male and female mice one or two high-depth or low-depth mTBIs separated by 1, 7, or 14 days. We assessed brain white matter integrity us ...[more]

PMID: 35850624

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Project description:Blast-related traumatic brain injury (TBI) has been a common injury among returning troops due to the widespread use of improvised explosive devices in the Iraq and Afghanistan Wars. As most of the TBIs sustained are in the mild range, brain changes may not be detected by standard clinical imaging techniques such as CT. Furthermore, the functional significance of these types of injuries is currently being debated. However, accumulating evidence suggests that diffusion tensor imaging (DTI) is sensitive to subtle white matter abnormalities and may be especially useful in detecting mild TBI (mTBI). The primary aim of this study was to use DTI to characterize the nature of white matter abnormalities following blast-related mTBI, and in particular, examine the extent to which mTBI-related white matter abnormalities are region-specific or spatially heterogeneous. In addition, we examined whether mTBI with loss of consciousness (LOC) was associated with more extensive white matter abnormality than mTBI without LOC, as well as the potential moderating effect of number of blast exposures. A second aim was to examine the relationship between white matter integrity and neurocognitive function. Finally, a third aim was to examine the contribution of PTSD symptom severity to observed white matter alterations. One hundred fourteen OEF/OIF veterans underwent DTI and neuropsychological examination and were divided into three groups including a control group, blast-related mTBI without LOC (mTBI - LOC) group, and blast-related mTBI with LOC (mTBI + LOC) group. Hierarchical regression models were used to examine the extent to which mTBI and PTSD predicted white matter abnormalities using two approaches: 1) a region-specific analysis and 2) a measure of spatial heterogeneity. Neurocognitive composite scores were calculated for executive functions, attention, memory, and psychomotor speed. Results showed that blast-related mTBI + LOC was associated with greater odds of having spatially heterogeneous white matter abnormalities. Region-specific reduction in fractional anisotropy (FA) in the left retrolenticular part of the internal capsule was observed in the mTBI + LOC group as the number of blast exposures increased. A mediation analysis revealed that mTBI + LOC indirectly influenced verbal memory performance through its effect on white matter integrity. PTSD was not associated with spatially heterogeneous white matter abnormalities. However, there was a suggestion that at higher levels of PTSD symptom severity, LOC was associated with reduced FA in the left retrolenticular part of the internal capsule. These results support postmortem reports of diffuse axonal injury following mTBI and suggest that injuries with LOC involvement may be particularly detrimental to white matter integrity. Furthermore, these results suggest that LOC-associated white matter abnormalities in turn influence neurocognitive function.

Dataset Information

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

Background

Methods

Results

Conclusions

Publications

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury.

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