Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma

皮质创伤引发癫痫发生的内在机制和突触机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to understand why cerebral cortical trauma often leads to paroxysmal activity. Within 24 hours following head injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often initiate epileptogenesis the subthreshold processes that lead to spontaneous, recurring seizures and ultimately to epilepsy. We propose to study the electrophysiological features of trauma- induced epileptogenesis in chronic experiments in vivo, in vitro and with computational models that will be developed in close contact with the experiments. The primary hypothesis for the cause of epileptogenesis that we will test is that trauma-related chronic blockade of activity may activate homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory conductances). Under the abnormal conditions found in traumatized cortex, this may create an unstable balance that leads to paroxysmal seizures. Multisite local field potential recordings (up to 64 channels) will be used to test the hypothesis that invasive brain trauma creates heterogeneous under- and overexcited cortical areas and that interaction of these areas increases the likelihood of seizure occurrence. Direct evidence for the role of homeostatic plasticity in the epileptogenesis will be obtained by measuring changes in minis, synaptic responsiveness, axonal arborization, intrinsic cellular properties, and multisite focal field potentials. Measurement will be performed over the medium-term (days) and long-term (weeks). In vivo electrophysiological semichronic and chronic experiments, in vitro experiments from chronically deafferented cortical slices as well as morphological studies will be performed at Laval University (Canada). Data from studying the conditions that increase the likelihood of seizure development after brain trauma will be studied using Independent Component Analysis (ICA) at the Salk Institute and will be incorporated into Hodgkin-Huxley type models of cortical neurons and networks at the UC Riverside. The goal of the computational models is to explore the interplay between all of the changes that occur in the cortex in vivo during epileptogenesis and to make predictions for interventions that could prevent seizures. The design of these interventions will be based on approaches that could be further developed to treat humans with trauma-induced epilepsy in clinical settings. PUBLIC HEALTH RELEVANCE: Within 24 hours up to 80% of patients with penetrating head wounds display clinical seizures. Following the Vietnam and Croatia wars, approximately 50% of patients with penetrating cranial wounds developed epilepsy characterized by recurring seizures 10-15 years later. Understanding and preventing epileptogenesis is a central problem in epilepsy research.
描述(由申请人提供):本研究的目的是了解为什么大脑皮质创伤往往导致阵发性活动。在头部损伤后24小时内,高达80%的穿透伤患者显示临床癫痫发作。这种急性发作通常会引发癫痫发生,即导致自发性、复发性发作并最终导致癫痫的阈下过程。我们建议在体内、体外慢性实验中研究创伤诱导癫痫发生的电生理特征,并使用将与实验密切联系开发的计算模型。我们将检验的癫痫发生原因的主要假设是,创伤相关的慢性活动阻滞可能激活稳态可塑性机制,该机制上调去极化影响(如兴奋性内在和突触电导)并下调超极化影响(如抑制性电导)。在创伤皮质中发现的异常条件下,这可能会产生不稳定的平衡,导致阵发性癫痫发作。多部位局部场电位记录(最多64个通道)将用于检验以下假设:侵入性脑创伤会产生异质性兴奋不足和过度兴奋皮质区,这些区域的相互作用会增加癫痫发作发生的可能性。内稳态可塑性在癫痫发生中的作用的直接证据将通过测量minis,突触反应,轴突分支,内在细胞特性和多位点局灶场电位的变化来获得。将在中期(天)和长期(周)进行测量。将在拉瓦尔大学(加拿大)进行体内电生理学半慢性和慢性实验、慢性去传入皮质切片的体外实验以及形态学研究。来自研究增加脑创伤后癫痫发作发展可能性的条件的数据将在索尔克研究所使用独立成分分析(伊卡)进行研究,并将纳入加州大学滨江的皮质神经元和网络的霍奇金-赫胥黎型模型。计算模型的目标是探索癫痫发生过程中体内皮质中发生的所有变化之间的相互作用,并预测可以预防癫痫发作的干预措施。这些干预措施的设计将基于可以进一步开发的方法,以在临床环境中治疗创伤诱导的癫痫。公共卫生相关性:在24小时内,高达80%的头部穿透伤患者显示临床癫痫发作。在越南和克罗地亚战争之后,大约50%的颅骨穿透伤患者在10-15年后发生癫痫,其特征是复发性癫痫发作。了解和预防癫痫发生是癫痫研究的中心问题。

项目成果

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TERRENCE J SEJNOWSKI其他文献

TERRENCE J SEJNOWSKI的其他文献

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{{ truncateString('TERRENCE J SEJNOWSKI', 18)}}的其他基金

DDALAB: Identifying Latent States from Neural Recordings with Nonlinear Causal Analysis
DDALAB:通过非线性因果分析从神经记录中识别潜在状态
  • 批准号:
    10643212
  • 财政年份:
    2023
  • 资助金额:
    $ 38.58万
  • 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
  • 批准号:
    10229375
  • 财政年份:
    2018
  • 资助金额:
    $ 38.58万
  • 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
  • 批准号:
    9789979
  • 财政年份:
    2018
  • 资助金额:
    $ 38.58万
  • 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
  • 批准号:
    10468022
  • 财政年份:
    2018
  • 资助金额:
    $ 38.58万
  • 项目类别:
Nonlinear Causal Analysis of Neural Signals
神经信号的非线性因果分析
  • 批准号:
    9789882
  • 财政年份:
    2018
  • 资助金额:
    $ 38.58万
  • 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
  • 批准号:
    9597206
  • 财政年份:
    2018
  • 资助金额:
    $ 38.58万
  • 项目类别:
Cell Modeling
细胞建模
  • 批准号:
    10228748
  • 财政年份:
    2012
  • 资助金额:
    $ 38.58万
  • 项目类别:
SIMULATION NEUROTRANSMITTER DIFFUSION IN CEREBELLAR GLOMERULI
模拟小脑肾小球中的神经递质扩散
  • 批准号:
    7956214
  • 财政年份:
    2009
  • 资助金额:
    $ 38.58万
  • 项目类别:
Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma
皮质创伤引发癫痫发生的内在机制和突触机制
  • 批准号:
    8318223
  • 财政年份:
    2009
  • 资助金额:
    $ 38.58万
  • 项目类别:
Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma
皮质创伤引发癫痫发生的内在机制和突触机制
  • 批准号:
    7654250
  • 财政年份:
    2009
  • 资助金额:
    $ 38.58万
  • 项目类别:

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