1 Brain Trauma Neuroprotection and Neurorestoration Branch, Walter Reed Army Institute of Research , Silver Spring, Maryland.
2 Behavioral Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
J Neurotrauma. 2017 Oct 1;34(19):2768-2789. doi: 10.1089/neu.2016.4679. Epub 2017 May 24.
Closed-head concussive injury is one of the most common causes of traumatic brain injury (TBI). Isolated concussions frequently produce acute neurological impairments, and individuals typically recover spontaneously within a short time frame. In contrast, brain injuries resulting from multiple concussions can result in cumulative damage and elevated risk of developing chronic brain pathologies. Increased attention has focused on identification of diagnostic markers that can prognostically serve as indices of brain health after injury, revealing the temporal profile of vulnerability to a second insult. Such markers may demarcate adequate recovery periods before concussed patients can return to required activities. We developed a noninvasive closed-head impact model that captures the hallmark symptoms of concussion in the absence of gross tissue damage. Animals were subjected to single or repeated concussive impact and examined using a battery of neurological, vestibular, sensorimotor, and molecular metrics. A single concussion induced transient, but marked, acute neurological impairment, gait alterations, neuronal death, and increased glial fibrillary acidic protein (GFAP) expression in brain tissue. As expected, repeated concussions exacerbated sensorimotor dysfunction, prolonged gait abnormalities, induced neuroinflammation, and upregulated GFAP and tau. These animals also exhibited chronic functional neurological impairments with sustained astrogliosis and white matter thinning. Acute changes in molecular signatures correlated with behavioral impairments, whereas increased times to regaining consciousness and balance impairments were associated with higher GFAP and neuroinflammation. Overall, behavioral consequences of either single or repeated concussive impact injuries appeared to resolve more quickly than the underlying molecular, metabolic, and neuropathological abnormalities. This observation, which is supported by similar studies in other mTBI models, underscores the critical need to develop more objective prognostic measures for guiding return-to-play decisions.
闭合性颅脑损伤是外伤性脑损伤（TBI）最常见的原因之一。单纯性脑震荡常导致急性神经功能障碍，个体通常在短时间内自发恢复。相比之下，多次脑震荡导致的脑损伤可能导致累积性损伤，并增加慢性脑病理发生的风险。人们越来越关注识别能够作为损伤后脑健康预后指标的诊断标志物，揭示了对第二次损伤易感性的时间特征。这些标志物可以在脑震荡患者恢复到所需活动之前，确定足够的恢复时间。我们开发了一种非侵入性的闭合性颅脑冲击模型，该模型可在无明显组织损伤的情况下捕获脑震荡的标志性症状。动物接受单次或重复脑震荡冲击，并使用一系列神经学、前庭、感觉运动和分子指标进行检查。单次脑震荡导致短暂但明显的急性神经功能障碍、步态改变、神经元死亡和脑组织中胶质纤维酸性蛋白（GFAP）表达增加。正如预期的那样，重复脑震荡加剧了感觉运动功能障碍，延长了步态异常，引起神经炎症，并上调了 GFAP 和 tau。这些动物还表现出慢性功能性神经损伤，伴有持续的星形胶质细胞增生和白质变薄。分子特征的急性变化与行为损伤相关，而恢复意识和平衡损伤所需的时间增加与更高的 GFAP 和神经炎症相关。总的来说，单次或重复脑震荡冲击损伤的行为后果似乎比潜在的分子、代谢和神经病理学异常更快地得到解决。这一观察结果得到了其他 mTBI 模型中类似研究的支持，强调了迫切需要开发更客观的预后指标来指导重返赛场的决策。
