Antiepileptogenesis by Transcranial Magnetic Stimulation

经颅磁刺激抗癫痫发生

• 批准号: 7209565
• 负责人: Alexander Rotenberg
• 金额: $ 17.33万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209565
• 关键词: Acute; Affect; Animal Model; Animals; Anticonvulsants; Antiepileptogenic; Attention; Brain; Cell Death; Chronic; Chronic Phase; Clinical; Collection; Condition; DNA Fragmentation; Daily; Data; Doctor of Medicine; Doctor of Philosophy; Down-Regulation; Electric Stimulation; Electroencephalography; Electromagnetics; Epilepsy; Epileptogenesis; Evaluation; Event; FOS gene; Frequencies; Future; Glutamate Receptor; Goals; Hippocampus (Brain); Human; In Situ; In Vitro; Injection of therapeutic agent; Interneurons; Investigation; Isoxazoles; Label; Lead; Literature; Long-Term Depression; Long-Term Potentiation; Methods; Modality; Modeling; Molecular Mechanisms of Action; Monitor; N-Methylaspartate; Neuronal Injury; Neurons; Numbers; Painless; Pathologic; Patients; Peripheral Nerve Stimulation; Phase; Physiologic pulse; Physiology; Process; Property; Propionic Acids; Propionic acid; Protein Dephosphorylation; Protocols documentation; Pulse taking; Pyramidal Cells; Range; Rattus; Recurrence; Research; Role; Seizures; Slice; Staging; Status Epilepticus; Stimulus; Surface; Synapses; Testing; Therapeutic; Training; Transcranial magnetic stimulation; United States Food and Drug Administration; Week; Work; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; brain tissue; cell injury; in vivo; kainate; magnetic field; mossy fiber; neuropsychiatry; novel therapeutics; prevent; prophylactic; receptor; repetitive transcranial magnetic stimulation; research study; tool

DESCRIPTION (provided by applicant): Status epilepticus (SE) is often the triggering event for epileptogenesis, a sequence of neuronal changes that lead to abnormal excitation and ultimately to epilepsy. Epileptogenesis is dependent in large part on lasting enhancement of excitatory synaptic strength that is similar to the long-term potentiation (LTP) seen with experimental high frequency repetitive neuronal stimulation. In this regard, we propose to investigate the anti-epileptogenic potential of transcranial magnetic stimulation (IMS), a noninvasive method for repetitive neuronal activation that is coming to attention as a new therapeutic tool in epilepsy. The attractive properties of TMS are its ability to 1) terminate seizures and to 2) produce a lasting decrease in synaptic strength. The latter effect may be similar to the long-term depression (LTD) that is LTP's inhibitory counterpart. Accordingly, our overall hypothesis is that the anticonvulsive and LTD-like effects of low frequency repetitive (rTMS) can interfere with SE-triggered epileptogenesis and prevent the expression of epilepsy. TMS is based on the principle of electromagnetic induction where intracranial stimulating currents are generated by a strong extracranial magnetic field. TMS is safe, painless and inexpensive. Its anticonvulsive capacity is demonstrated in a small number of human trials showing a reduction seizure frequency reduction in epileptic patients treated with rTMS. However, its mechanism of action is poorly understood. Therefore, this developing field would benefit from animal model research for elucidation of basic TMS physiology, and for evaluation of its therapeutic potential. We recently developed methods for simultaneous TMS and electroencephalography (EEG) in seizing rats, and identified new potent anti-convulsive effect. We now propose to use the rat kainate (KA) SE model to test the capacity of TMS to 1) stop SE and prevent the seizure-associate neuronal injury, and 2) prevent SE-triggered epileptogenesis. Further, to evaluate the TMS-related cellular and molecular mechanisms of action, we will test whether low frequency rTMS can induce LTD by extending our methods to in vitro hippocampal slice recording. To achieve these overall goals, we will extend our studies to include in vitro and ex vivo hippocampal slice recordings.

描述（由申请人提供）：癫痫持续状态（SE）通常是癫痫发生的触发事件，是一系列神经元变化导致异常兴奋并最终导致癫痫。癫痫发生在很大程度上依赖于兴奋性突触强度的持续增强，这类似于实验中高频重复神经元刺激的长期增强（LTP）。在这方面，我们建议研究经颅磁刺激（IMS）的抗癫痫潜能，这是一种非侵入性的重复神经元激活方法，作为一种新的治疗癫痫的工具而受到关注。TMS最吸引人的特性是它能够1)终止癫痫发作，2)使突触强度持续下降。后一种效应可能类似于LTP的抑制性对应物长期抑郁（LTD）。因此，我们的总体假设是，低频重复（rTMS）的抗惊厥和ltd样作用可以干扰se触发的癫痫发生并阻止癫痫的表达。经颅磁刺激是基于电磁感应原理，其中颅内刺激电流是由强颅外磁场产生的。经颅磁刺激是安全、无痛和廉价的。它的抗惊厥能力在少数人体试验中得到证实，在接受rTMS治疗的癫痫患者中，癫痫发作频率降低。然而，其作用机制尚不清楚。因此，这一发展中的领域将受益于动物模型研究，以阐明基本的经颅磁刺激生理学，并评估其治疗潜力。近年来，我们开发了癫痫大鼠同时进行TMS和脑电图（EEG）的方法，并发现了新的有效的抗惊厥作用。我们现在建议使用大鼠kainate (KA) SE模型来测试TMS对1)阻止SE和预防癫痫相关神经元损伤的能力，以及2)预防SE引发的癫痫发生的能力。此外，为了评估tms相关的细胞和分子作用机制，我们将通过将我们的方法扩展到体外海马切片记录来测试低频rTMS是否可以诱导LTD。为了实现这些总体目标，我们将扩展我们的研究，包括体外和离体海马切片记录。