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）是复杂的，通常涉及弥漫性和多灶性成分，和/或 反复性脑外伤虽然退伍军人TBI后癫痫的高发病率是众所周知的， 标准的抗癫痫药物此外，从创伤到创伤的转变的潜在机制， 损伤尚不清楚，这使得新的治疗方法的开发具有挑战性。然而， 损伤和癫痫发作发展（癫痫发生）使该过程成为有吸引力的干预目标。由于 高兴奋性网络定位在癫痫发生中的关键作用，我们提出了一个大型动物模型， (pig)脑回和复杂的白色物质通路可能是模拟这些损伤的唯一方法 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， 损伤诱导的癫痫发生，以研究有助于向癫痫过渡的潜在机制。 PTE，并调查是否重复TBI也可以诱导这些网络状态。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色物质成像将用于评估其预测性 预后和危险分层的价值。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 创伤后癫痫发生以及发展PTE发展的预测模型。我们的分析将 允许更好地理解创伤导致的病理和神经生理机制， 到癫痫。此外，了解这种进展对清醒行为和机制的影响， 潜在的睡眠中断是治疗患有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研究睡眠和行为功能障碍的进展， 与TBI诱导的癫痫发生，并比较PTE的生物标志物（血液，睡眠，神经影像学，早期 电生理学）与电生理学结果，以开发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相关联， 行为结果，以便对未来治疗的进展进行机械理解 发展为了实现这些目标，我们将比较局灶性损伤模型（CCI）与重复， 矢状面损伤，以评估PTE和过度兴奋的长期发展。我们将长期 在猪受伤后植入皮质和海马电极，并描述癫痫发生的特征， 癫痫发作进展超过9个月至1年。将使用视频EEG对猪进行长期监测， 评估癫痫发生的进展以及部分性和全身性癫痫的发展， 专家评估和癫痫发作检测算法的组合，使用 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。 时间进程此外，猪将使用洞板任务评估神经和行为缺陷 我们在实验室里开发的。这些都是实验室的既定程序，CCI 受伤导致PTE的人数很多。猪将在受伤后监测长达一年，并将评估 癫痫发生的进展以及部分性和全身性癫痫的发展， 专家评估和癫痫发作检测算法。将进行死后神经病理学检查， 比较慢性神经退行性变和海马神经病理学与 电生理学以及血液生物标志物。因此，本提案将比较两种情况下的PTE结果 大型动物TBI模型（局灶性和重复性mTBI），导致机制的翻译平台 调查和治疗的发展，以造福那些退伍军人患有PTE，并制定 TBI患者尚未发展为PTE的预后标志物。