CRCNS: Collaborative Research: Model-Based Control of Spreading Depression

描述（由申请人提供）：该CRCNS申请源自当前DAAD（Deutscher Akademischer Austausch Dienst，德国学术交流服务）资助中在柏林技术大学和宾夕法尼亚州立大学之间进行的题为“神经系统中扩散去极化的反馈控制：理论和实验”的工作。这个CRCNS提案的设计，以及所有的初步数据，都是在德国教师和博士生来到宾夕法尼亚州立大学的过程中产生的，以及协同合作的努力，以建立扩散性抑郁症反馈控制的可行性。扩散性抑郁（SD）是一种缓慢传播的大脑戏剧性去极化，是偏头痛初始先兆的生理基础。提出了以下假设：SD可以表示在计算模型的基础神经元生物物理学，因此可以使用基于模型的控制策略进行控制。该项目首先使用切向二维视觉皮层啮齿动物脑切片开发实验制剂。SD是由灌注液钾扰动触发的，并且SD使用灵敏的CCD照相机成像，所述CCD照相机检测与来自细胞肿胀的折射率变化相关联的固有光学成像信号。一个基于模型的策略，类似于使用在自主机器人，如机身自动着陆器。硬件和软件控制系统实时获取光学图像，将其与SD模型融合，重建潜在的生理过程，计算所需的控制，并调制电场以调制SD。神经元室和离子流的生物病理学精确模型以及反映波传播动力学的简化模型都将用作观察和控制模型。智力优势：这将是第一个基于模型的神经网络控制的实验演示。类似的工程策略已经彻底改变了先进的机器人技术，从计算神经科学与控制工程的融合中学到的基础知识将在神经元调制的其他领域具有广泛的适应性。此外，这将是第一个基于模型的生理机制控制的基础上的动态疾病的大脑-偏头痛的先兆。控制模型将进一步作为探针，以增加对SD机制的理解。该团队在执行该项目所需的学科范围内有着丰富的记录：神经生理学，实验和理论物理学，计算神经科学，控制理论和神经工程。提案中所列的初步工作表明，鉴于所要求的资源，这一项目是可行的。更广泛的影响：将计算神经科学模型与现代基于模型的控制理论相结合，将为观察大脑活动的转换范式奠定基础，并为控制大脑中的病理过程提供更优化的技术。将形成一个跨学科的德美教育合作，在那里训练的研究生（和PI）将协同工作在计算神经科学，控制理论，实验神经生理学和控制系统工程之间的接口。项目执行人在培训和指导妇女和代表性不足的少数民族方面有着良好的记录，他们将尽一切努力为该项目的指导机会寻找这样的受训人员。作为一个合作伙伴关系，PI预计，在控制SD中所学到的东西可能会为患有严重偏头痛发作和顽固性偏头痛的人提供一套可测试的偏头痛电控制策略。此外，基于该CRCNS，相同的科学和工程将适用于体外（例如Schiff等人，2007年）和体内（例如Sunderam等人，2009年）系统中振荡波和节律的调制。他们计划广泛传播数据管理计划中所述的算法和硬件设计。

DESCRIPTION (provided by applicant): This CRCNS application derives from work performed in a current DAAD (Deutscher Akademischer Austausch Dienst, German Academic Exchange Service) Grant between the Technical University of Berlin and Penn State University entitled: "Feedback control of spreading depolarizations in neural systems: Theory and Experiments". The design of this CRCNS proposal, and all preliminary data, were generated during the course of German Faculty and PhD students coming to Penn State University, and the synergistic collaborative efforts to establish the feasibility of feedback control of spreading depression. Spreading depression (SD) is a dramatic depolarization of brain that propagates slowly and is the physiological underpinning of the initial aura in migraines. The following hypothesis is posed: SD can be represented in computational models of the underlying neuronal biophysics, and can therefore be controlled using model-based control strategies. The project starts by developing an experimental preparation using a tangential 2-dimensional visual cortex rodent brain slice. SD is triggered with a perfusate potassium perturbation, and SD is imaged using a sensitive CCD camera that detects the intrinsic optical imaging signal associated with index of refraction changes from cellular swelling. A model-based strategy similar to that used in autonomous robotics such as airframe autolanders is employed. A hardware and software control system takes the optical image in real-time, fuses it with a model of SD, reconstructs the underlying physiological processes, calculates needed control, and modulates an electrical field to modulate SD. Both biophysically accurate models of the neuronal compartments and ion flows, and reduced models that reflect the dynamics of the wave propagation, will be used as observation and control models. Intellectual merit: This will be the first experimental demonstration of model-based control of a neuronal network. Similar engineering strategies have revolutionized advanced robotics, and the fundamentals learned from a fusion of computational neuroscience with control engineering will have wide ranging adaptations in other areas of neuronal modulation. Furthermore, this will be the first model-based control of a physiological mechanism that underlies a dynamical disease of the brain - migraine auras. The control models will further serve as probes to gain increased understanding of the mechanisms of SD. The team assembled has a substantial track record in the range of disciplines required to carry out this project: neurophysiology, experimental and theoretical physics, computational neuroscience, control theory and neural engineering. The preliminary work shown in the proposal suggests that this project is feasible given the resources requested. Broader impact: Fusing computational neuroscience models with modern model-based control theory will lay the foundation for a transformational paradigm for the observation of activity within the brain, as well as access to a more optimal technology for the control of pathological processes in the brain. A transdisciplinary German-American educational collaboration will be formed where the graduate students trained (and the PIs) will synergistically work together within the interface between computational neuroscience, control theory, experimental neurophysiology, and control system engineering. The PIs have a track record in training and mentoring women and underrepresented minorities, and they will make every effort to seek such trainees for the mentoring opportunities of this project. As a collaborative partnership, the PIs anticipate that what is learned in controlling SD may provide a set of testable strategies for electrical control of migraines in people who suffer from severe migraine attacks and are pharmacologically intractable. Furthermore, based upon this CRCNS, the same science and engineering will be applicable to the modulation of oscillatory waves and rhythms in both in vitro (e.g. Schiff et al 2007) and in vivo (e.g. Sunderam et al 2009) systems. They plan to widely disseminate the algorithms and hardware design developed as described in the Data Management Plan.