Abstract
We have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.
Highlights
Traumatic brain injury (TBI) was defined in a 2010 position statement as an alteration in brain function, or other evidence of brain pathology caused by an external force [70]
The mouse model of Repetitive mild traumatic brain injury (rmTBI) described in this paper is exceedingly mild as judged by the kinematic measurements made at the time of injury and by the transient nature of the inflammation that the injury triggered
It is possible that rmTBI as used here was not as mild as the kinematic measurements suggest and that differences in the ratios of white matter to gray matter or in the geometries of the brain and skull or in the presence of cortical gyri between mice and humans confound our ability to scale TBIs appropriately between humans and mice [31, 79]
Summary
Traumatic brain injury (TBI) was defined in a 2010 position statement as an alteration in brain function, or other evidence of brain pathology caused by an external force [70]. A GCS score of 13–15 is considered a mild TBI (mTBI) while a GCS score of 9–12 is considered moderate and a GCS score of 8 or less is considered severe TBI. The importance of repetitive mTBIs (rmTBIs) is underscored by the finding that a history of rmTBIs is associated with an increased risk of developing chronic traumatic encephalopathy (CTE) [68, 69, 102] and of dementia [4, 28, 72, 81]. The association of a history of mTBI with the later development of dementia and the recognition that many patients with mTBI have symptoms that persist for months or years [3] raises the question: just how mild are mTBIs?
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