Neurochemical closed-loop controller for smart DBS

描述（由申请人提供）：深部脑刺激（DBS）是FDA批准的治疗晚期帕金森病（PD）和震颤的成熟疗法。此外，已确定对肌张力障碍和强迫症的人道主义装置豁免，并正在对抑郁症和癫痫进行研究。尽管这是一种非常成功的疗法，但该领域仍存在许多挑战。其中一个挑战是大量的手术靶点、刺激设置和电极配置，这些都是在寻找治疗临床结果时必须尝试的。神经状态、电极放置、脑移位、组织包封、刺激参数等多种因素均可影响DBS的临床效果。因此，迫切需要能够补偿这些不可控因素的DBS系统。例如，通过使用大脑的动态环境来指导电极的放置和刺激程序，从而产生一个可以针对个体患者和症状量身定制的DBS系统。表征负责调节关键治疗性神经活动的电活性神经化学物质将使我们能够使用实时神经递质浓度测量来确定电极放置的最佳位置，以及确定电极植入后的最佳刺激参数。我们建议通过表征STN刺激引起的纹状体多巴胺反应来研究DBS的神经化学动力学。我们还建议利用这些反应来开发一个调节多巴胺浓度的闭环系统。在Aim 1中，我们将开发一种廉价的动物模型，用于麻醉健康猪丘脑下核（STN） DBS诱发纹状体多巴胺释放的急性表征。在目标2中，我们将使用使用较便宜的猪模型开发的技术来开发一个闭环控制器，用于调节健康麻醉的非人灵长类动物（NHP）的多巴胺浓度。最后，在Aim 3中，我们将使用PD的NHP模型来开发一种神经化学介导的闭环DBS系统，以在动态环境中持续治疗反应。DBS诱发多巴胺的神经化学动力学表征是了解DBS潜在机制的重要一步。在未来，基于本文提出的系统构建的闭环系统将减少以DBS编程和药物调整的形式进行频繁临床干预的需要。毫无疑问，这项技术将对治疗神经和精神疾病的基础和临床神经科学方法产生深远的影响，并将为扩展可以用DBS治疗的神经和精神疾病提供理论依据。

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) is a well-established therapy approved by the FDA for the treatment of advanced Parkinson's disease (PD) and tremor. Additionally, humanitarian device exemptions for dystonia and obsessive-compulsive disorder have been established and studies are underway for depression and epilepsy. Although a highly successful therapy, there remain many challenges to the field. One of such challenges is the large number of surgical targets, stimulation settings, and electrode configurations that have to be attempted in the search for therapeutic clinical outcomes. A wide range of factors such as neurologic state, electrode placement, brain shift, tissue encapsulation, and stimulation parameters can affect the clinical outcomes of DBS. As such, there is a critical need for DBS systems that can compensate for some of these uncontrollable factors. For example, by using the brain's dynamic environment to guide electrode placement and stimulation programming, thereby resulting in a DBS system that can be tailored to individual patients and symptoms. Characterization of electroactive neurochemicals in charge of modulating critical therapeutic neural activity will allow us to use real-time neurotransmitter concentration measurements to identify these optimal locations for electrode placement, as well as to identify optimal stimulation parameters after the electrode has been implanted. We propose to study the neurochemical dynamics of DBS by characterizing striatal dopamine responses evoked by STN stimulation. We also propose using these responses to develop a closed-loop system for modulating dopamine concentration. In Aim 1, we will develop an inexpensive animal model for acute characterization of striatal dopamine release evoked by DBS of the subthalamic nucleus (STN) in anesthetized healthy pigs. In Aim 2, we will use techniques developed using the less-expensive pig model to develop a closed-loop controller for modulating dopamine concentration in healthy anesthetized non-human primates (NHP). Finally, in Aim 3, we will use a NHP model of PD to develop a neurochemically-mediated closed-loop DBS system for sustained therapeutic response in a dynamic environment. Characterization of the neurochemical dynamics of dopamine evoked by DBS represents an important step forward toward understanding the underlying mechanisms of DBS. In the future, closed-loop systems building on the system proposed here will reduce the need for frequent clinical interventions in the form of DBS programming and medication adjustments. Undoubtedly, this technology will have a profound impact on both basic and clinical neuroscience approaches to the treatment of neurologic and psychiatric disease, and will provide the rationale for expanding the neurologic and psychiatric conditions that can be treated with DBS.