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MECHANISMS OF EPILEPTOGENESIS

癫痫发生机制

基本信息

批准号：
6322237
负责人：
EDWARD H BERTRAM
金额：
$ 5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-02-01 至 2002-11-30
项目状态：
已结题

项目摘要

Epilepsy is a chronic neurological condition that affects about 1% of the population in the United States. Although it is usually readily treatable with medications, about 25-30% of epileptic patients continue to experience recurrent seizures in spite of multiple drug therapy. A very common form of difficult to control human epilepsy is the mesial temporal lope epilepsy syndrome, which involves limbic structures such as the hippocampus, entorhinal cortex and amygdala. Understanding the pathophysiological basis for this condition is essential for the development of improved treatments. Human studies have suggested that the process of seizure initiation may involve multiple sites. In these situations the seizures often begin simultaneously at several of the limbic sites. These observations raise the possibility that seizure onset may be triggered in part through a subcortical mechanism that has input to multiple limbic structures. Testing this idea has not been possible until recently with the development of several new rat models of limbic epilepsy that have similarities to the human condition. These limbic epilepsy models are characterized by spontaneous seizures as well as limbic pathology and seizure physiology on EEG that are morphologically similar to the human condition (mesial temporal lobe epilepsy). Work completed or nearing completion has suggested that all of the limbic sites demonstrated to participate in seizure onset have hyperexcitable responses to stimulation. More importantly, we have recently discovered that the midline thalamic nuclei have significant excitatory input to these areas (amygdala, hippocampus and entorhinal cortex). We have also found that the midline thalamic nuclei participate in, and may regulate, the seizure activity in the limbic system. These observations suggest that these thalamic regions may have an important role in seizure initiation and modulation. In this project we propose to evaluate the role of the midline thalamic nuclei in limbic seizures and epilepsy to answer the following questions: 1) What role does the midline thalamic nuclei play in limbic seizures and epilepsy to answer the following questions: 2) How are the interactions between the midline thalamic nuclei and its limbic targets altered in limbic epilepsy? 3) How is the physiology of the midline thalamic nuclei changed in chronic limbic epilepsy? These experiments will combine in vitro and in vivo physiology of several rat models of limbic seizures, including chronic limbic seizures, to examine these issues, which are the first steps to understanding the role of this region in limbic epilepsy. These results will provide new insights into the network changes and basis for these conditions.

癫痫是一种慢性神经疾病，在美国约有1%的人口受到影响。虽然癫痫通常很容易用药物治疗，但大约25%-30%的癫痫患者尽管接受了多种药物治疗，仍继续经历反复发作。人类难以控制的癫痫的一种非常常见的形式是内侧颞叶癫痫综合征，它涉及到边缘结构，如海马体、内嗅觉皮质和杏仁核。了解这种情况的病理生理学基础对于改进治疗方法的发展是至关重要的。人体研究表明，癫痫发作的启动过程可能涉及多个部位。在这种情况下，癫痫发作往往同时在几个边缘部位开始。这些观察结果提出了癫痫发作可能部分通过皮质下机制触发的可能性，该机制与多个边缘结构有关。直到最近，随着几种与人类情况相似的新的边缘癫痫大鼠模型的发展，测试这一想法才成为可能。这些边缘癫痫模型的特点是自发性癫痫发作以及边缘病理和EEG上与人类相似的形态特征(内侧颞叶癫痫)。已完成或接近完成的研究表明，所有参与癫痫发作的边缘部位对刺激都有过度兴奋的反应。更重要的是，我们最近发现丘脑中线核团对这些区域(杏仁核、海马体和内嗅皮层)有显著的兴奋性输入。我们还发现丘脑中线核团参与并可能调节边缘系统的癫痫发作活动。这些观察结果表明，这些丘脑区域可能在癫痫发作的启动和调制中起着重要作用。在本项目中，我们建议评估丘脑中线核团在边缘癫痫和癫痫中的作用，以回答以下问题：1)丘脑中线核团在边缘癫痫和癫痫中起什么作用？2)在边缘癫痫中，丘脑中线核与其边缘靶点之间的相互作用是如何改变的？3)在慢性边缘癫痫中，丘脑中线核的生理学是如何改变的？这些实验将结合包括慢性边缘癫痫在内的几种边缘癫痫大鼠模型的体外和体内生理学来研究这些问题，这是了解该区域在边缘癫痫中所起作用的第一步。这些结果将为网络变化和这些情况的基础提供新的见解。