Effgen Gwen B, Morrison Barclay
Department of Biomedical Engineering, Columbia University , New York, New York.
J Neurotrauma. 2017 Feb 15;34(4):914-924. doi: 10.1089/neu.2016.4477. Epub 2016 May 16.
Clinical studies suggest that repeat exposures to mild traumatic brain injury (mTBI) or concussion, such as sports-related mTBI, result in verbal, memory, and motor deficits that can progressively worsen and take longer for recovery with each additional concussion. Pre-clinical studies suggest that mild mechanical injury of the brain can initiate a period of heightened vulnerability during which the brain is more susceptible to a subsequent mild injury. It is unknown how long this period of heightened vulnerability lasts and, as a result, appropriate return-to-play guidelines for athletes who have sustained sports-related mTBI could be better clarified. To better understand this pathology and define the duration of heightened vulnerability to subsequent exposure, we employed a well-defined stretch injury model to mechanically stimulate organotypic hippocampal slice cultures (OHSCs) and evaluated both electrophysiological and pathological markers of injury. We found that an initial mild stretch initiated a period of heightened vulnerability to a subsequent stretch that lasted at least 24 h. Two mild stretch injuries delivered 24 h apart significantly increased tissue injury, including cell death, damage to dendrites, increased nitrite production, astrogliosis, and loss of long-term potentiation (LTP). Cell loss, dendrite damage, and nitrite production were not significantly increased when the inter-injury interval was increased to 72 h; however, LTP deficits and astrogliosis persisted. An interval of 144 h was sufficient to prevent the detrimental effects of repetitive stretch. Improved understanding of the brain's response to repetitive mTBI in vitro may aid in translational studies, informing rest periods for the injured athlete.
临床研究表明，反复暴露于轻度创伤性脑损伤（mTBI）或脑震荡，如与运动相关的mTBI，会导致言语、记忆和运动功能缺陷，这些缺陷可能会逐渐恶化，且每次额外的脑震荡后恢复时间会更长。临床前研究表明，大脑的轻度机械损伤会引发一段易损性增强的时期，在此期间大脑更容易受到随后的轻度损伤。目前尚不清楚这段易损性增强的时期会持续多久，因此，对于遭受与运动相关mTBI的运动员，合适的重返比赛指南可以得到更好的明确。为了更好地理解这种病理状况并确定对后续暴露的易损性增强的持续时间，我们采用了一种定义明确的拉伸损伤模型来机械刺激器官型海马切片培养物（OHSCs），并评估损伤的电生理和病理标志物。我们发现，最初的轻度拉伸引发了一段对随后拉伸的易损性增强时期，该时期至少持续24小时。相隔24小时进行的两次轻度拉伸损伤显著增加了组织损伤，包括细胞死亡、树突损伤、亚硝酸盐生成增加、星形胶质细胞增生以及长时程增强（LTP）丧失。当损伤间隔增加到72小时时，细胞损失、树突损伤和亚硝酸盐生成没有显著增加；然而，LTP缺陷和星形胶质细胞增生仍然存在。144小时的间隔足以防止重复性拉伸的有害影响。对大脑在体外对重复性mTBI的反应有更好的理解可能有助于转化研究，为受伤运动员的休息时间提供参考。
