Chronic Focal and Diffuse Traumatic Brain Injury: Mechanisms Underlying Epileptogenesis and Progressive Dysfunction

军事创伤性脑损伤(TBI)是复杂的，通常涉及弥漫性和多灶性成分，和/或 重复性脑损伤。虽然众所周知，退伍军人脑外伤后癫痫的发生率很高，但PTE往往具有抵抗力 到标准的抗癫痫疗法。此外，从创伤过渡到 受伤情况尚不清楚，这使得新的治疗方法的开发具有挑战性。然而，漫长的妊娠期 损伤和癫痫的发展(癫痫的发生)使这一过程成为一个有吸引力的干预目标。由于 高兴奋性的网络定位在癫痫发生中的关键作用，我们提出了一个大动物模型 (猪)具有脑回回和复杂的白质通路，可能是模拟这些损伤的唯一方法 准确的表型和癫痫的发生。因此，我们将利用我们的大型动物临床前脑模型 损伤导致癫痫的发生，以调查导致向 PTE，并研究重复的TBI是否也能诱导这些网络状态。早期癫痫样活动， 轴突和神经胶质病理的血液生物标记物和白质成像将被用来评估它们的预测性。 对预后和危险分层的价值。这种独特的大型动物脑外伤模型的组合， 电生理学、神经病理学和生物标记物将使我们能够解决 研究创伤后癫痫的发生，以及开发PTE发展的预测模型。我们的分析将 能够更好地理解创伤导致的病理和神经生理机制 致癫痫。此外，了解这一过程对觉醒行为和机制的影响 潜在的睡眠障碍是治疗退伍军人PTE相关慢性功能障碍的重要问题。 因此，我们将表征和验证受控皮质撞击损伤的PTE模型，并与 弥漫性重复性损伤。我们还将研究与睡眠和行为障碍相关的进展 与脑外伤诱发癫痫，比较PTE的生物标志物(血液、睡眠、神经影像、早期 电生理学)结合电生理学结果开发预测VA PTE发展的指标 人口。我们还将将慢性死后神经病理与电信号特征和 行为结果，以发展对未来治疗进展的机械性理解 发展。为了实现这些目标，我们将比较局灶性损伤模型(CCI)和重复性、 以评估矢状面损伤对PTE远期发展及兴奋性的影响。我们将长期 将损伤后的猪植入皮质和海马区电极，并研究癫痫的发生和 癫痫发作进展超过9个月至1年。将使用视频脑电波对猪进行长期监测，并将 评估癫痫发生的进展和部分性和全面性癫痫的发展 结合专家评估和癫痫检测算法，使用在 实验室。在此期间，我们将收集这些动物的血清、睡眠数据、成像和电生理。 时间航向。此外，还将使用孔板任务评估猪的神经和行为缺陷。 这是我们在实验室里研发出来的。这些都是实验室的既定程序，CCI 伤病已经导致了一些人的PTE。猪将在受伤后接受长达一年的监测，并将接受评估 部分和全身性癫痫联合应用的癫痫发生和发展进展 专家评估和癫痫检测算法。将进行死后神经病理学检查，以便 慢性神经退行性变和海马神经病理结果的比较 电生理学，以及血液生物标志物。因此，该提案将在两个方面比较PTE的结果 大动物颅脑损伤模型(焦点和重复性mTBI)，为机械学提供了一个平移平台 研究和治疗进展，以造福于患有PTE的退伍军人，并发展 对于那些尚未发展为PTE的脑外伤患者，预后标志物。

Military traumatic brain injury (TBI) is complex, often involving both diffuse and multi-focal components, and/or repetitive TBI. While the high incidence of epilepsy following TBI in Veterans is well known, PTE is often resistant to standard anti-epileptic therapeutics. In addition, the mechanisms underlying the transition from trauma to injury are unclear, making new treatment development challenging. However, the long gestation period between injury and seizure development (epileptogenesis) make this process an attractive target for intervention. Due to the key role of network localization of hyperexcitability in epileptogenesis, we propose that a large animal model (pig) with a gyrencephalic brain and complex white matter pathways may be the only way to model these injury phenotypes and epileptogenesis accurately. We will therefore utilize our large animal pre-clinical model of brain injury induced epileptogenesis in order to investigate the underlying mechanisms contributing to the transition to PTE, and investigate whether repetitive TBI can also induce these network states. Early epileptiform activity, blood biomarkers of axonal and glial pathology, and white matter imaging will be utilized to assess their predictive value for prognosis and risk stratification. This unique combination of large animal TBI models, electrophysiology, neuropathology and biomarkers will allow us to address the fundamental mechanisms of epileptogenesis following trauma as well as develop predictive models of PTE development. Our analyses will allow for greater understanding of the pathological and neurophysiological mechanisms whereby trauma leads to epilepsy. In addition, an understanding of the effects of this progression on waking behavior and mechanisms underlying sleep disruption are important questions for treating Veterans with PTE related chronic dysfunction. We will therefore characterize and validate a PTE model of controlled cortical impact injury and compare with diffuse, repetitive injury. We will also examine the progression of sleep and behavioral dysfunction associated with TBI induced epileptogenesis, and compare biomarkers for PTE (blood, sleep, neuroimaging, early electrophysiology) with electrophysiological outcomes to develop predictors of PTE development in the VA population. We will also correlate chronic post-mortem neuropathology with electrographic characterization and behavioral outcomes in order to develop mechanistic understanding of progression for future treatment development. In order to carry out these goals, we will compare a focal injury model (CCI) with the repetitive, sagittal injury in order to assess the long-term development of PTE and hyperexcitability. We will chronically implant pigs following injury with cortical and hippocampal electrodes, and characterize epileptogenesis and seizure progression over 9 months to 1 year. Pigs will be monitored chronically using video-EEG and will be assessed for progression of epileptogenesis and development of partial and generalized epilepsy using a combination of expert assessment and seizure detection algorithms using established procedures in the laboratory. We will collect blood serum, sleep data, imaging, and electrophysiology for these animals during this time course. In addition, pigs will be assessed for neurological and behavioral deficits using a hole-board task that we have developed in our laboratory. These are established procedures in the laboratory, and the CCI injury has led to PTE in a number. Pigs will be monitored up to a year post injury and will be assessed for progression of epileptogenesis and development of partial and generalized epilepsy using a combination of expert assessment and seizure detection algorithms. Post-mortem neuropathology will be performed in order to compare the chronic neurodegeneration and hippocampal neuropathology with the outcomes of the electrophysiology, as well as the blood biomarkers. This proposal will therefore compare PTE outcomes in two large animal TBI models (focal and repetitive mTBI), leading to a translational platform for mechanistic investigation and therapeutic development in order to benefit those Veterans suffering from PTE, and to develop prognostic markers for those with TBI yet to develop PTE.