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。 在此应用中，我们将集中精力研究病理性高频振荡（pHFO），我们认为这反映了癫痫发生和癫痫发生的基础神经元紊乱。 涟漪振荡（人80- 150 Hz，大鼠100-200 Hz）发生在正常海马和海马旁结构，但不发生在齿状回。 快速波动（FR）（人类150-500 Hz，大鼠200-500 Hz）是唯一发生在能够产生自发性癫痫发作的内侧颞叶结构（包括齿状回）中的病理事件。 在致痫齿状回也可记录到病理性波动。 这两种类型的pHFO可以在自发性癫痫发作发生前几天到几周的癫痫发生过程中检测到，也存在于自发性癫痫发作的开始。 我们推测，癫痫性脑损伤导致神经元重组，包括增加兴奋性的小团体内的相互联系的主要神经元的病理同步的特定类别的生理和/或形态异常的中间神经元。 我们将使用pHFO来解决这一假设与三个紧密结合的子项目，旨在阐明这些致癫痫场电位的神经元基板。 在MTLE患者和这种病症的实验动物模型中进行的体外和体内实验被提出来：i）鉴定和表征在pHFO期间激活的主要神经元和中间神经元的亚类; ii）检查特定神经元的消融或刺激对pHFO产生的影响; iii）绘制内侧颞叶边缘结构内pHFO产生区域之间的时空关系;和iv）通过检查回路断开对pHFO和癫痫发作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和癫痫发作产生的基础网络将提供新的目标，为未来的治疗方法，预防癫痫，和新的诊断策略。

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.