Phase resetting using DC stimulation for seizure blockage

描述（由申请人提供）：生物振荡器，其中神经元是一个特殊的类别，产生具有特征频率和相位的振荡。这些振荡可以从拓扑学的角度来研究，以确定区域（“零空间”），它们可以被“推”到其中（或它们的相位重置），使用在其周期中的“关键”时间提供的直流刺激。传统的交流刺激脉冲不适用于此目的。被推入“零空间”的振荡被湮灭，但“有限量级”的相位重置（相位延迟或提前）是一种常见现象。这种现象的存在已经在神经元和轴突的制备中得到了令人信服的证明。阴极或阳极去极化阻滞和最近描述的对单个阴极脉冲的“延迟反应”传递到人类致癫痫皮质，实际上可能是相位重置的例子。我们实验室的初步结果表明，使用直流电刺激，癫痫发作可能会持续延迟、阻断或消失，但也会沉淀，这是它们在周期中何时传递的函数。本提案将研究相位重置作为控制异常振荡（如癫痫发作）的工具，使用：1。单个DC（单相）脉冲自动传递（响应癫痫检测），直接传递到局部用青霉素致痫的家兔的离散皮质区域；2. 经颅连续直流电刺激对3- mpa致大鼠全面性癫痫发作的影响, 3。单次直流电脉冲对致痫皮质的组织病理学影响，目前尚无文献报道。皮层电活动将用高精度直流放大器记录，因为与癫痫发作相关的直流振荡的长时间常数（几秒到几分钟）提供了一个独特的机会，系统地彻底扫描它们的“相空间”，增加了定位“零空间”的可能性。本研究的潜在贡献将是实质性的：1。它将提供对在癫痫和运动障碍等神经元同步障碍的病理生理学中起基本作用的现象的见解；2. 它将为开发成功的疗法提供科学依据；3. 它将改善这些疾病患者的生活质量，就癫痫而言，它可能会使每年的护理费用减少43亿美元。在控制致命性心律失常方面取得的重大进展部分归功于心脏病学家将相重置作为一种调查和治疗工具的使用。

DESCRIPTION (provided by applicant): Biological oscillators, of which neurons are a special class, generate oscillations with characteristic frequencies and phases. These oscillations can be investigated from a topological perspective to identify regions ("null spaces") into which they can be "pushed" (or their phases reset), using DC stimuli delivered at a "critical" time during their cycle. Conventional AC stimulation pulses are unsuitable for this purpose. Oscillations pushed into the "null space" are annihilated, but phase resetting of "finite magnitude" (phase delays or advances) are a common occurrence. The existence of this phenomenon has been convincingly demonstrated in neuronal and axonal preparations. The cathodal or anodal depolarization blocks and the recently described "delayed responses" to single cathodal pulses delivered to human epileptogenic cortex, may in fact be examples of phase resetting. Preliminary results in our lab suggest that seizure onset may be consistently delayed, blocked or annihilated, but also precipitated, using DC stimulation, as a function of when in the cycle they are delivered. This proposal will investigate phase resetting as a tool for control of abnormal oscillations such as seizures, using: 1. Single DC (monophasic) pulses delivered automatically (in response to seizure detections) and directly to a discrete cortical region in rabbits that has been made epileptogenic with topical penicillin; 2. Transcranial continuous DC stimulation of rats with 3-MPA-induced generalized seizures; and, 3. Histopathologic effects of single DC pulses delivered to epileptogenic cortex, for which there is no literature. Electrical cortical activity will be recorded with high-precision DC amplifiers, since the long time constant of DC oscillations associated with seizures (several seconds to minutes) provide a unique opportunity to systematically and thoroughly scan their "phase space", increasing the probability of locating the "null space." The potential contributions of this study will be substantive: 1. It will provide insight into a phenomenon that plays a fundamental role in the pathophysiology of disorders of neuronal synchronization such as epilepsy and movement disorders; 2. It will provide scientific bases for developing successful therapies; 3. It will improve quality of life of those with these disorders and in the case of epilepsy it may decrease annual costs of care by $4.3B. The significant advances made in the control of fatal arrhythmias are in part attributable to the use by cardiologists of phase resetting as an investigative and therapeutic tool.