Clinical Research Program for the Partial Epilepsies

描述（由申请人提供）：加州大学洛杉矶分校临床神经生理学项目（CNP）由一组临床和基础神经科学家组成，他们已经合作多年，对内侧颞叶癫痫（MTLE）的基本机制进行了多学科研究。CNP目前是NIH资助的第43个年头，并继续利用癫痫手术设施提供的独特机会，对MTLE患者和这种疾病的实验动物模型进行平行、重复、侵入性研究。有了这个应用，我们将把我们的努力集中在病理性高频振荡（pHFO）上，我们认为这反映了癫痫致痫性和癫痫发生的基本神经紊乱。波纹振荡（人类80-150Hz，大鼠100- 200hz）发生在正常海马和海马旁结构中，而不是齿状体。快速波纹（FR）（人类150-500赫兹，大鼠200-500赫兹）是一种独特的病理事件，发生在能够产生自发癫痫发作的内侧颞叶结构中，包括齿状回。病理性波纹也可记录在致痫性齿状回。两种类型的pHFO均可在癫痫发生前数天至数周内检测到，也可在自发性癫痫发作开始时出现。我们假设，癫痫性脑损伤导致神经元重组，包括在小群相互连接的主要神经元中增加兴奋性，这些神经元在病理上与特定类别的生理和/或形态异常的中间神经元同步。我们将使用pHFO来解决这一假设，三个紧密结合的子项目旨在阐明这些致痫场电位的神经元基质。提出了MTLE患者的体外和体内实验以及该疾病的实验动物模型：i)鉴定和表征pHFO期间激活的主要神经元和中间神经元亚类；ii)检查消融或刺激特定神经元对pHFO生成的影响；iii)绘制内侧颞叶边缘结构内pHFO产生区域的时空关系；iv)通过检查电路断开对pHFO和癫痫发作产生的影响，确定系统相互作用的重要性。我们预计，鉴定特定的神经元底物和表征pHFO和癫痫发生的网络将为未来治疗和预防癫痫的方法提供新的靶点，以及新的诊断策略。

DESCRIPTION (provided by applicant): The UCLA Clinical Neurophysiology Program Project (CNP) consists of multidisciplinary investigations into the fundamental mechanisms of mesial temporal lobe epilepsy (MTLE) by a team of clinical and basic neuroscientists who have been working together for a number of years. The CNP is currently in its 43rd year of NIH funding, and has continued to take advantage of the unique opportunities offered by an epilepsy surgery facility to carry out parallel, reiterative, invasive research on patients with MTLE and on experimental animal models of this disorder. With this application, we will focus our efforts on pathological high frequency oscillations (pHFO), which we believe reflect the fundamental neuronal disturbances underlying epileptogenicity and epileptogenesis. Ripple oscillations (human 80-150Hz, rat 100-200 Hz) occur in normal hippocampus and parahippocampal structures but not dentate gyms. Fast Ripples (FR) (human 150-500, rat 200-500 Hz) are pathological events uniquely occurring in mesial temporal structures capable of generating spontaneous seizures, including the dentate gyrus. Pathological Ripples can also be recorded in the epileptogenic dentate gyrus. Both types of pHFO can be detected during epileptogenesis days to weeks before spontaneous seizures occur, and also are present at the initiation of spontaneous seizures. We hypothesize that epileptogenic cerebral injuries result in neuronal reorganization consisting of increased excitability within small groups of interconnected principal neurons which are pathologically synchronized by specific classes of physiologically and/or morphologically, abnormal interneurons. We will use pHFO to address this hypothesis with three tightly integrated subprojects designed to elucidate the neuronal substrates of these epileptogenic field potentials. In vitro and in vivo experiments in patients with MTLE and experimental animal models of this condition are proposed to: i) identify and characterize the principal neurons and subclasses of interneurons activated during pHFO; ii) examine the effects of ablation or stimulation of specific neurons on pHFO generation; iii) map the temporospatial relationships among pHFO generating areas within mesial temporal limbic structures; and iv) establish the importance of systems interactions by examining the effects of circuit disconnection on pHFO and seizure generation. We anticipate that identification of the specific neuronal substrates and characterization of the networks underlying pHFO and seizure generation will provide novel targets for future approaches to treatment, and prevention of epilepsy, and new strategies for diagnosis.