Clinical Research Program for the Partial Epilepsies

描述(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学家组成，他们共同工作多年，对内侧颞叶癫痫(MTLE)的基本机制进行了多学科的研究。CNP目前处于NIH资助的第43个年头，并继续利用癫痫手术机构提供的独特机会，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。通过这一应用，我们将把重点放在病理性高频振荡(PHFO)上，我们认为它反映了致痫和癫痫发生的基本神经元障碍。波纹振荡(人80-150赫兹，大鼠100-200赫兹)发生在正常的海马区和海马区旁结构中，但不存在齿状回。快速波纹(FR)(人150-500，大鼠200-500赫兹)是唯一发生在包括齿状回在内的近侧颞叶结构中能够产生自发性癫痫发作的病理事件。致痫的齿状回也可记录到病理性波纹。这两种类型的PHFO都可以在自发性癫痫发作前几天到几周的癫痫发作期间检测到，也可以在自发性癫痫发作开始时检测到。我们假设致痫脑损伤导致神经元重组，包括由特定类型的生理和/或形态异常的中间神经元在病理上同步的小群相互连接的主神经元内兴奋性的增加。我们将使用PHFO通过三个紧密结合的子项目来解决这一假设，这些子项目旨在阐明这些致痫区域电位的神经元底物。在体外和活体实验中，MTLE患者和这种情况的实验动物模型被提出：i)确定和表征PHFO期间激活的主要神经元和中间神经元的亚类；ii)研究特定神经元的消融或刺激对PHFO产生的影响；iii)定位近侧颞缘结构内PHFO产生区域之间的时空关系；以及iv)通过检测回路断开对PHFO和癫痫产生的影响来确定系统相互作用的重要性。我们预计，识别特定的神经元底物和表征PHFO和癫痫发生的潜在网络将为未来治疗和预防癫痫的方法提供新的靶点，并为诊断提供新的策略。

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.