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“推”（或其相位重置），使用DC刺激在其周期期间的“关键”时间交付。传统的AC刺激脉冲不适合于此目的。被推入“零空间”的振荡被消除，但“有限幅度”的相位重置（相位延迟或提前）是常见的。这种现象的存在已令人信服地证明在神经元和轴突的准备。阴极或阳极去极化块和最近描述的“延迟反应”的单一阴极脉冲传递到人类癫痫皮层，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，癫痫发作可能会持续延迟，阻断或消灭，但也沉淀，使用直流电刺激，作为一个功能时，在周期中，他们被交付。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DC（单相）脉冲自动（响应于癫痫发作检测）并直接递送到已经用局部青霉素致癫痫的兔中的离散皮质区域; 2.经颅连续DC刺激3-MPA诱导的大鼠全身性癫痫发作;和，3。单次直流电脉冲输送至致痫皮质的组织学效应，目前尚无相关文献。将使用高精度DC放大器记录皮层电活动，因为与癫痫发作相关的DC振荡的长时间常数（几秒到几分钟）提供了系统和彻底扫描其“相空间”的独特机会，增加了定位“零空间”的概率。“这项研究的潜在贡献将是实质性的：1。它将提供深入了解的现象，在神经元同步性疾病，如癫痫和运动障碍的病理生理学中起着重要作用; 2。它将为开发成功的治疗方法提供科学依据; 3.它将改善这些疾病患者的生活质量，在癫痫的情况下，它可以减少每年43亿美元的护理费用。在控制致命性心律失常方面取得的重大进展部分归因于心脏病专家将相位重置用作研究和治疗工具。

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.