Blast and Blunt Mechanisms for Mild-TBI Induce Differing Outcomes

描述（由申请人提供）： 退伍军人事务部卫生系统为从冲突中返回的退伍军人提供全面的卫生保健。自目前伊拉克和阿富汗冲突开始以来，美国退伍军人的爆炸性创伤性脑损伤（TBI）的发病率大幅上升。在以往军事冲突中受伤的退伍军人主要表现为局灶性损伤，而在目前的冲突中受伤的大多数是爆炸引起的，具有多灶性和多创伤性。虽然冲击波TBI的结果与头部撞击导致的TBI（汽车碰撞和福尔斯摔倒期间通常持续的情况）非常相似，但慢性结果可能不同。这可能表明退伍军人事务部临床医生需要在治疗和康复方面区分爆炸性和钝性TBI。这两个机制之间的结果差异尚未明确界定。拟议的研究将纳入TBI的冲击和钝性创伤机制的体内啮齿动物损伤模型，以描述两种水平的轻度TBI（即，脑震荡）。钝性创伤装置通过头部的纯冠状面旋转加速度诱导TBI。冲击伤装置使用由压缩驱动的激波管产生的冲击超压波诱导TBI。现有的模型是在我们的实验室中开发的，并且在不需要侵入性手术的情况下诱导可重复和可恢复的轻度TBI的能力方面是独特的。初步测试表明，100%的生存率没有颈椎损伤的头部旋转或多发性创伤通常与爆炸伤。实验方案将使Sprague道利大鼠暴露于两个水平的冲击或旋转损伤（轻度和重度脑震荡），总共五个实验损伤组（包括对照组）。旋转TBI的幅度将通过控制峰值头部旋转加速度来调制。通过控制峰值冲击波超压来调节冲击波TBI的大小。使用无意识时间将两种机制之间的损伤水平等同，其中轻度冲击波和轻度旋转TBI的平均无意识时间相等，而重度冲击波和重度旋转TBI的平均无意识时间相等。损伤后评估将包括许多明确定义的测试，以确定顺行性遗忘和空间学习缺陷、逆行性遗忘、神经运动缺陷、焦虑相关行为和攻击、粘着行为（即，情绪/抑郁）、脑水肿和神经元、神经胶质或白色物质病理学。评估将在受伤后2至60天的多个时间点进行。总共需要五个损伤后评估亚组，以避免不同评估和时间点的混淆影响。因此，在拟议的研究过程中，将使用总共25个独立的组（5个实验损伤组乘以5个损伤后评估亚组）。使用文献中报告的评估数据进行的统计分析确定，需要15只大鼠的样本量才能确定两个治疗组之间结局的1.5倍或更大差异（95%置信度）。拟议的研究将在四年内进行，最初的重点是确定严重爆炸和严重旋转TBI之间的差异。初步统计分析将在拟议的研究过程中进行。在每组所有15只大鼠完成之前，等待统计学显著结果，其他组（例如，中度或超重度）可以添加到方案中。这项研究将产生基础科学数据，为临床文化的变化提供基础，并为爆炸和钝性TBI启动定制和更有效的治疗和康复方案。

DESCRIPTION (provided by applicant): ABSTRACT The Department of Veteran's Affairs Health System provides comprehensive health care for veterans returning from conflicts. The incidence of blast traumatic brain injury (TBI) for U.S. veterans has risen considerably since the beginning of the current conflicts in Iraq and Afghanistan. Where injured veterans from previous military conflicts demonstrated primarily focal injuries, a majority of injuries sustained in the current conflicts are blast-induced and are multifocal and polytraumatic in nature. While outcomes from blast TBI are acutely similar to TBI resulting from head impact, a condition commonly sustained during automotive collisions and falls, chronic outcomes may be different. This may indicate a need for Veteran's Affairs clinicians to distinguish between blast and blunt TBI in terms of treatment and rehabilitation. Differences in outcomes between the two mechanisms have not been well defined. The proposed research will incorporate in vivo rodent injury models for blast and blunt trauma mechanisms of TBI to delineate differences in acute, subacute, and chronic outcomes following two levels of mild TBI (i.e., concussion). The blunt trauma injury device induces TBI through pure coronal plane rotational acceleration of the head. The blast injury device induces TBI using a blast overpressure wave created using a compression-driven shock tube. The existing models were developed in our laboratory and are unique in their ability to induce repeatable and recoverable mild TBI without the requirement for invasive surgery. Preliminary testing has demonstrated 100% survivability without cervical spine injury from head rotation or polytrauma typically associated with blast injury. The experimental protocol will expose Sprague Dawley rats to two levels of blast or rotational injury (mild and severe concussion), for a total of five experimental injury groups (including controls). Magnitude of rotational TBI will be modulated by controlling peak head rotational acceleration. Magnitude of blast TBI will be modulated by controlling peak blast overpressure. Injury levels will be equated between the two mechanisms using unconscious times, wherein mean unconscious times will be equal for mild blast and mild rotational TBI and equal for severe blast and severe rotational TBI. Post-injury assessments will incorporate a number of well defined tests to determine the level of anterograde amnesia and spatial learning deficits, retro-grade amnesia, neuromotor deficits, anxiety-related behavior and aggression, adhedonic behavior (i.e., emotionality/depression), brain edema, and neuronal, glial, or white matter pathology. Assessments will be conducted at multiple time points between two and sixty days post-injury. A total of five post-injury assessment sub-groups will be required to avoid confounding effects of different assessments and time points. Therefore, a total of 25 independent groups will be used during the course of the proposed research (five experimental injury groups times five post-injury assessment sub-groups). Statistical analysis using assessment data reported in literature determined a sample size of 15 rats will be required to determine a 1.5-fold or larger difference in the outcome between two treatment groups with 95% confidence. The proposed research will be conducted over a four-year period, with an initial focus on identifying differences between severe blast and severe rotational TBI. Preliminary statistical analyses will be conducted during the course of the proposed research. Pending statistically significant outcomes prior to the completion of all 15 rats per group, other groups (e.g., moderate or super-severe) may be added to the protocol. This research will generate basic science data that will provide the foundation for changes in clinical culture and initiate custom and more effective treatment and rehabilitation protocols for blast and blunt TBI.