The potential for animal models to provide insight into mild traumatic brain injury: Translational challenges and strategies

Shultz, Sandy R.; McDonald, Stuart J.; Haar, Cole Vonder; Meconi, Alicia; Vink, Robert; Donkelaar, Paul; Taneja, Chand; Iverson, Grant L.; Christie, Brian R.

doi:10.1016/j.neubiorev.2016.09.014

Cited by 124 publications

(119 citation statements)

References 224 publications

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“…Maturational brain changes that typify childhood and adolescent development,4, 5, 6 along with significant sex differences in neurological organization and function,7, 8, 9 likely contribute to the heterogeneity in injury outcomes and some of the difficulty associated with determining prognosis. To date, a majority of the animal and human studies that examine mTBI and RmTBI have focused on adult males,10 creating a void in the literature with respect to the female brain and the role of maturation.…”

Section: Introductionmentioning

confidence: 99%

Sex matters: repetitive mild traumatic brain injury in adolescent rats

Wright

O’Brien

Shultz

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWhether sex differences contribute to the heterogeneity of mild traumatic brain injury (mTBI) and repeated mTBI (RmTBI) outcomes in adolescents is unknown. Therefore, this study examined changes in, and differences between, male and female rats following single mTBI and RmTBI.MethodsRats were given a single mTBI, RmTBI (i.e., 3x), or sham injuries. Injuries were administered using a lateral impact model that mimics forces common in human mTBI. After the final injury, rats underwent extensive behavioral testing to examine cognition, motor function, and anxiety‐ and depressive‐like behavior. Postmortem analyses investigated gene expression and structural changes in the brain.ResultsMany of the outcomes exhibited a sex‐dependent response to RmTBI. While all rats given RmTBI had deficits in balance, motor coordination, locomotion, and anxiety‐like behavior, only male rats given RmTBI had short‐term working memory deficits, whereas only females given RmTBI had increased depressive‐like behavior. Volumetric and diffusion weighted MRI analyses found that while RmTBI‐induced atrophy of the prefrontal cortex was greater in female rats, only the male rats exhibited worse white matter integrity in the corpus callosum following RmTBI. Sex‐dependent changes in brain expression of mRNA for glial fibrillary acidic protein, myelin basic protein, and tau protein were also observed following injury.InterpretationThese findings suggest that in adolescent mTBI, sex matters; and future studies incorporating both male and females are warranted to provide a greater understanding of injury prognosis and better inform clinical practice.

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Section: Introductionmentioning

confidence: 99%

Sex matters: repetitive mild traumatic brain injury in adolescent rats

Wright

O’Brien

Shultz

et al. 2017

Ann Clin Transl Neurol

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“…An mTBI is induced by biomechanical forces, and a single mTBI typically results in transient neurological impairment 5. Sustaining repeated mTBI, however, may result in cumulative and persisting neurological deficits,6, 7, 8, 9, 10 and has been associated with increased risk of developing neurodegenerative disease such as chronic traumatic encephalopathy (CTE) 11, 12. Considering the difficulty of mTBI diagnosis and prognosis, and the potential for long‐term sequalae after repeated mTBI, there have been increased research efforts to develop sensitive and objective biomarkers to help guide the clinical management of these injuries 10, 13, 14…”

Section: Introductionmentioning

confidence: 99%

“…For example, previous DWI studies in mTBI patients have been limited by the use of a single broad postinjury time point, lack of appropriate control groups, and may be confounded by other factors (e.g., lifestyle choices such as drug and alcohol use, genetics, selection bias) 10. Animal models allow for the control of experimental parameters, as well as the rigorous characterization and validation of biomarkers in a relatively short time period.…”

Section: Introductionmentioning

confidence: 99%

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

Wortman

Meconi

Neale

et al. 2018

Ann Clin Transl Neurol

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ObjectiveMild traumatic brain injury (mTBI) is a serious health concern in the adolescent population. Repeated mTBI may result in more pronounced deficits, and has been associated with long‐term neurological consequences including neurodegeneration. As such, there is a critical need for the development of objective mTBI biomarkers to help guide medical management. Diffusion‐weighted imaging (DWI) is an advanced magnetic resonance imaging (MRI) technique that may detect brain abnormalities after mTBI. Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported DTI changes in mTBI patients. Furthermore, new DWI methods (e.g., track‐weighted imaging; TWI) are being developed that may also be sensitive to mTBIs, but remain to be comprehensively studied.MethodsThis study utilized the Awake Closed Head Injury (ACHI) model of mTBI to investigate changes in DTI and TWI following repeated mTBI in adolescent male and female rats. A total of four ACHI impacts, two/day over two consecutive days, were delivered beginning on postnatal day 25. At 1 day and 7 days postinjury, rats were euthanized and brains were collected for DWI analyses.ResultsRats given repeated mTBI displayed changes in fractional anisotropy and radial diffusivity (i.e., DTI measures), as well as track density (i.e., TWI).InterpretationThese findings are consistent with initial DTI findings in mTBI patients, suggest that TWI may complement DTI, support the utility of DWI measures as biomarkers in mTBI, and further validate the ACHI rat model of mTBI.

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“…Using the mouse central fluid percussion injury (cFPI) model of mild TBI to induce diffuse axonal injury, we have previously reported that the optic nerve reveals a predilection for diffuse axonal injury based on identification of scattered axonal swellings as well as disconnected axonal segments (Wang et al, 2011). Distinct from other modes of optic nerve injury such as cutting, crushing, or stretching, the cFPI model induces only scattered DAI pathology with the sparing of a large fraction of axons, closely approximating the situation found in most cases of concussion and mild TBI (Marklund, 2016; Maxwell et al, 2015; Shultz et al, 2016) . In the experiments described here, we utilize this model to evaluate the downstream changes evoked by injury of the optic nerve and conduct analysis of deafferentation as well as potential reorganization of retinogeniculate axon projections to the dorsal lateral geniculate nucleus (dLGN), a critical structure in the formed vision pathway of mouse.…”

Section: Introductionmentioning

confidence: 70%

Adaptive reorganization of retinogeniculate axon terminals in dorsal lateral geniculate nucleus following experimental mild traumatic brain injury

Patel

Jurgens

Krahe

et al. 2017

Experimental Neurology

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The pathologic process in traumatic brain injury marked by delayed axonal loss, known as diffuse axonal injury (DAI), leads to partial deafferentation of neurons downstream of injured axons. This process is linked to persistent visual dysfunction following mild traumatic brain injury (mTBI), however, examination of deafferentation in humans is impossible with current technology. To investigate potential reorganization in the visual system following mTBI, we utilized the central fluid percussion injury (cFPI) mouse model of mTBI. We report that in the optic nerve of adult male C57BL/6J mice, axonal projections of retinal ganglion cells (RGC) to their downstream thalamic target, dorsal lateral geniculate nucleus (dLGN), undergo DAI followed by scattered, widespread axon terminals loss within the dLGN at 4 days post-injury. However, at 10 days post-injury, significant reorganization of RGC axon terminals was found, suggestive of an adaptive neuroplastic response. While these changes persisted at 20 days post-injury, the RGC axon terminal distribution did not recovery fully to sham-injury levels. Our studies also revealed that following DAI, the segregation of axon terminals from ipsilateral and contralateral eye projections remained consistent with normal adult mouse distribution. Lastly, our examination of the shell and core of dLGN suggested that different RGC subpopulations may vary in their susceptibility to injury or in their contribution to reorganization following injury. Collectively, these findings support the premise that subcortical axon terminal reorganization may contribute to recovery following mTBI, and that different neural phenotypes may vary in their contribution to this reorganization despite exposure to the same injury.

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The potential for animal models to provide insight into mild traumatic brain injury: Translational challenges and strategies

Cited by 124 publications

References 224 publications

Sex matters: repetitive mild traumatic brain injury in adolescent rats

Sex matters: repetitive mild traumatic brain injury in adolescent rats

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

Adaptive reorganization of retinogeniculate axon terminals in dorsal lateral geniculate nucleus following experimental mild traumatic brain injury

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