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: 10710035
• 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/10710035
• 关键词: Address; Algorithms; Animal Model; Animals; Antiepileptic Agents; Area; Autopsy; Axon; Behavior; Behavioral; 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; 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; epileptiform; inhibitory neuron; 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，通常涉及弥漫和多焦点成分和/或 重复的TBI。虽然在退伍军人中TBI之后的癫痫发病率很高，但PTE通常具有抗性 进行标准的抗癫痫疗法。另外，从创伤到过渡到的机制 伤害尚不清楚，使新的治疗发展具有挑战性。但是，妊娠期很长 损伤和癫痫发育（癫痫发生）使这一过程成为干预的有吸引力的目标。由于 过度兴奋性在癫痫发生中网络定位的关键作用，我们提出了一个大动物模型 （猪）具有术语脑大脑和复杂的白质途径可能是建模这些损伤的唯一方法 表型和癫痫生成准确。因此，我们将利用我们大型动物的大脑临床前模型 损伤诱导的癫痫发生，以研究导致过渡到过渡的潜在机制 PTE，并研究重复性TBI是否也可以诱导这些网络状态。早期癫痫样活动， 将利用轴突和神经胶质病理学以及白质成像的血液生物标志物评估其预测性 预后和风险分层的价值。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的基本机制 创伤后的癫痫发生以及开发PTE发展的预测模型。我们的分析会 允许对创伤引导的病理和神经生理机制有更深入的了解 癫痫。另外，了解这种进展对唤醒行为和机制的影响 潜在的睡眠中断是治疗与PTE相关的慢性功能障碍的退伍军人的重要问题。 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，重复损伤。我们还将检查睡眠和行为功能障碍相关的进展 TBI诱导癫痫发生，并比较PTE的生物标志物（血液，睡眠，神经影像，早期 电生理学）具有电生理结果，以开发VA中PTE发展的预测因子 人口。我们还将将慢性验尸神经病理学与电视表征和 行为结果是为了发展对未来治疗进展的机械理解 发展。为了实现这些目标，我们将将局灶性伤害模型（CCI）与重复性， 矢状损伤是为了评估PTE和过度兴奋性的长期发展。我们会长期以来 皮质和海马电极受伤后的植入猪，并表征癫痫发生和 癫痫发作超过9个月至1年。猪将使用视频EEG长期监测，并且将是 评估了使用A的癫痫生成进展以及部分和广义癫痫的发展 专家评估和癫痫发作检测算法的结合，使用既定程序 实验室。在此期间，我们将为这些动物收集血清，睡眠数据，成像和电生理学 时间课程。此外，将使用孔板任务评估猪的神经和行为缺陷 我们在实验室中发展了。这些是在实验室和CCI中建立的程序 受伤导致了一个人数。受伤后一年后，猪将受到监测，并将评估 癫痫生成的进展以及局部和广泛癫痫的发展，结合 专家评估和癫痫发作算法。验尸神经病理学将进行 比较慢性神经退行性变性和海马神经病理学与结果 电生理学以及血液生物标志物。因此，该提案将比较两者中的PTE结果 大型动物TBI模型（焦点和重复的MTBI），导致了机械的转化平台 调查和治疗性开发，以使患有PTE的退伍军人受益，并发展 TBI尚未发展PTE的人的预后标记。

项目成果

Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs.

• DOI: 10.1111/bpa.12953
• 发表时间: 2021-09
• 期刊: Brain pathology (Zurich, Switzerland)
• 作者: Grovola MR;Paleologos N;Brown DP;Tran N;Wofford KL;Harris JP;Browne KD;Shewokis PA;Wolf JA;Cullen DK;Duda JE
• 通讯作者: Duda JE

Hippocampal interneuronal dysfunction and hyperexcitability in a porcine model of concussion.

• DOI: 10.1038/s42003-023-05491-w
• 发表时间: 2023-11-09
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Ulyanova, Alexandra V;Adam, Christopher D;Cottone, Carlo;Maheshwari, Nikhil;Grovola, Michael R;Fruchet, Oceane E;Alamar, Jami;Koch, Paul F;Johnson, Victoria E;Cullen, D Kacy;Wolf, John A
• 通讯作者: Wolf, John A