Manipulating multisite endogenous brain rhythms disrupts epileptic seizures

 描述（由申请人提供）：癫痫是最常见的神经系统疾病之一，困扰着300多万美国人。 作为癫痫特征的反复发作有时可以通过药物治疗来预防;然而，超过三分之一的癫痫患者不能通过抗癫痫药物或其他现有药物得到充分帮助。 治疗 本文所述研究的目的是建立在该研究团队在使用大脑多个部位的内源性神经同步的实时动态分析和大脑回路的计算分析以闭合反馈回路方面的重大成功的基础上，以产生比目前更有效的刺激方案。 available. 目前使用脑深部电刺激（DBS）治疗癫痫的大多数方法都涉及对刺激模式的先验选择，这些刺激模式与潜在的脑动力学关系不大，并且总体上产生了不可预测的结果。 简单地将电刺激应用于大脑而不考虑大脑电生理学的及时动态状态提供了一种“击中或错过”的治疗形式，这大大降低了DBS成功的可能性。 这里描述的研究旨在提供一套更清晰、更有效的刺激方案，允许对大脑内的活动进行靶向治疗调节。 这一点尤其重要，因为癫痫发作在人类患者中演变的动力学可能差异很大。 本提案中描述的研究的最终目标是进一步开发这种新型且可能更有效的药物难治性癫痫患者治疗方法。 本研究建议的主要焦点是DBS的主要电生理效应在于其调节整个大脑神经元同步性的能力。 实验将使用复杂的非线性数学分析，以获得实时的关键动态信息，这些信息将用于构建控制算法， 通过在癫痫大鼠中长期植入电极的新型多位点电刺激来破坏大脑中的癫痫发作进展。 相关脑回路的计算建模将用于帮助破译DBS抗癫痫效应背后的机制。 此外，该团队对人类癫痫发作动力学的初步分析表明，这种行为也存在于人类癫痫患者中。 在理解复杂的非线性过程和控制这种活动的最新进展提供了一个宝贵的机会，进一步应用这些原则对操纵病变的脑电活动。 这些技术有可能为难治性癫痫提供有效的治疗，即使潜在的癫痫发作动力学和病因不同，也适用于不同的癫痫患者。 这种治疗可以为美国超过一百万人提供巨大的好处，他们目前没有令人满意的疗法来治疗这些破坏性的、有时甚至是危险的病理性大脑状态。

 DESCRIPTION (provided by applicant): Epilepsy is one of the most common neurological diseases, afflicting over 3 million Americans. The recurrent seizures that characterize epilepsy can sometimes be prevented with pharmaceutical treatment; however, over a third of all epilepsy patients cannot be sufficiently helped by antiepileptic drugs or other currently available therapies. The objective of the research described here is to build upon this research team's significant successes in using real-time dynamical analysis of endogenous neural synchrony at multiple sites in the brain and computational analysis of brain circuitry to close the feedback loop in order to produce stimulation protocols with significantly better efficacy than is currently available. Most current approaches that use deep brain stimulation (DBS) to treat epilepsy involve a priori selection of stimulation patterns that bear little relationship to the underlying brain dynamics and have produced unpredictable results overall. Simple application of electrical stimulation to the brain without regard to the timely dynamic state of brain electrophysiology provides a "hit-or-miss" form of treatment that greatly reduces the probability that DBS can be successful. The research described here seeks to provide a much clearer and more efficacious set of stimulation protocols that would permit targeted therapeutic modulation of activity within the brain. This is especially important since the dynamics by which seizures evolve in human patients can greatly vary. The ultimate goal of the research described in this proposal is to further develop this novel and potentially much more effective treatment for drug-refractory epilepsy patients. The primary focus of this research proposal is that a major electrophysiological effect of DBS lay in its ability to modulate neuronal synchrony throughout the brain. Experiments will use complex nonlinear mathematical analysis to derive critical dynamical information in real-time that will be used to construct control algorithms for delivering novel multisite electrical stimulation through chronic implanted electrodes in epileptic rats to disrupt seizure progression in the brain. Computational modeling of the relevant brain circuitry will be used to assist in deciphering the mechanisms behind the anti- seizure effects of DBS. Furthermore, preliminary analysis of human seizure dynamics by this team has shown evidence that such behavior is also present in human epileptic patients. Recent advances in understanding complex nonlinear processes and in controlling such activity have provided an invaluable opportunity to further apply these principles toward manipulation of diseased electrical activity in the brain. These techniques have the potential to provide an effective treatment for intractable epilepsy that would be adaptable to different epilepsy patients even if underlying seizure dynamics and etiologies differ. Such a treatment could provide huge benefits to the more than one million people in the United States who currently have no satisfactory therapy to treat these disruptive and sometimes dangerous pathological brain states.