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

慢性局灶性和弥漫性创伤性脑损伤：癫痫发生和进行性功能障碍的机制

• 批准号: 10490256
• 负责人: John Allen Wolf
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490256
• 关键词: Address; Algorithms; Animal Model; Animals; Antiepileptic Agents; Area; Autopsy; Axon; Behavior; Behavioral; Behavioral Mechanisms; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Chronic; Complex; Cortical Contusions; Data; Deafferentation procedure; Detection; Development; Diffuse; Electrodes; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Family suidae; Functional disorder; Future; Generalized Epilepsy; Goals; Hippocampus (Brain); Image; Implant; Incidence; Injury; Intervention; Investigation; Laboratories; Lead; Location; Measures; Military Personnel; Modeling; Monitor; Nerve Degeneration; Neurologic; Neurons; Outcome; Partial Epilepsies; Pathologic; Pathology; Pathway interactions; Phenotype; Population; Post-Traumatic Epilepsy; Pre-Clinical Model; Predictive Value; Pregnancy; Procedures; Process; Prognosis; Prognostic Marker; Resistance; Rodent Model; Seizures; Serum; Sleep; Sleep disturbances; Temporal Lobe Epilepsy; Therapeutic; Time; Trauma; Traumatic Brain Injury; Veterans; awake; axon injury; behavioral outcome; cognitive task; controlled cortical impact; injured; mild traumatic brain injury; neurobehavioral; neuroimaging; neuropathology; neurophysiology; predictive modeling; prevent; prognostication; rational design; risk stratification; therapeutic development; therapy design; therapy development; white matter

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.

军事创伤性脑损伤 (TBI) 很复杂，通常涉及弥漫性和多灶性成分，和/或 重复性 TBI。虽然退伍军人 TBI 后癫痫的高发病率是众所周知的，但 PTE 往往具有耐药性 标准抗癫痫治疗。此外，从创伤到创伤转变的机制 损伤情况尚不清楚，这使得新治疗方法的开发具有挑战性。但孕育期较长 损伤和癫痫发作（癫痫发生）使这一过程成为有吸引力的干预目标。由于 由于过度兴奋性网络定位在癫痫发生中的关键作用，我们提出大型动物模型 （猪）具有环脑和复杂的白质通路可能是模拟这些损伤的唯一方法 准确地表型和癫痫发生。因此，我们将利用我们的大型动物临床前大脑模型 损伤诱发癫痫发生，以研究导致癫痫发作的潜在机制 PTE，并研究重复性 TBI 是否也会诱发这些网络状态。早期癫痫样活动， 轴突和神经胶质病理学的血液生物标志物以及白质成像将用于评估其预测 预测和风险分层的价值。这种大型动物 TBI 模型的独特组合， 电生理学、神经病理学和生物标志物将使我们能够解决以下问题的基本机制： 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 可以更好地理解创伤导致的病理和神经生理机制 至癫痫。此外，了解这一进展对清醒行为和机制的影响 潜在的睡眠障碍是治疗患有 PTE 相关慢性功能障碍的退伍军人的重要问题。 因此，我们将描述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。我们还将检查睡眠和行为功能障碍相关的进展 与 TBI 诱发癫痫发生，并比较 PTE 的生物标志物（血液、睡眠、神经影像、早期 电生理学）和电生理学结果来开发 VA 中 PTE 发展的预测因子 人口。我们还将把慢性死后神经病理学与电图特征和 行为结果，以便对未来治疗的进展产生机械理解 发展。为了实现这些目标，我们将局灶性损伤模型 (CCI) 与重复性损伤模型进行比较。 矢状损伤，以评估 PTE 的长期发展和过度兴奋。我们会长期 用皮层和海马电极植入损伤后的猪，并表征癫痫发生和 癫痫发作持续 9 个月至 1 年。将使用视频脑电图对猪进行长期监测，并将 使用以下方法评估癫痫发生的进展以及部分性和全身性癫痫的发展 使用既定程序将专家评估和癫痫检测算法相结合 实验室。在此期间，我们将收集这些动物的血清、睡眠数据、成像和电生理学数据 时间课程。此外，将使用洞板任务评估猪的神经和行为缺陷 我们在实验室开发的。这些是实验室的既定程序，CCI 损伤已导致许多人发生 PTE。猪受伤后一年内将受到监测，并进行评估 结合使用以下方法来研究癫痫发生的进展以及部分性和全身性癫痫的发展 专家评估和癫痫检测算法。将进行尸检神经病理学检查，以便 将慢性神经退行性变和海马神经病理学与结果进行比较 电生理学以及血液生物标志物。因此，本提案将比较两种语言的 PTE 成绩 大型动物 TBI 模型（局灶性和重复性 mTBI），为机械性脑损伤提供了一个转化平台 调查和治疗开发，以使患有 PTE 的退伍军人受益，并开发 尚未发展为 PTE 的 TBI 患者的预后标志物。