Neurochemical closed-loop controller for smart DBS

描述(申请人提供)：深部脑刺激(DBS)是FDA批准的一种公认的治疗晚期帕金森病(PD)和震颤的方法。此外，已经建立了针对肌张力障碍和强迫症的人道主义设备豁免，并且正在对抑郁症和癫痫进行研究。尽管这是一种非常成功的治疗方法，但该领域仍然存在许多挑战。这些挑战之一是在寻找治疗临床结果时必须尝试大量的手术靶点、刺激设置和电极配置。神经状态、电极位置、脑移位、组织包裹和刺激参数等多种因素都会影响DBS的临床结果。因此，迫切需要星展银行系统能够补偿其中一些不可控因素。例如，通过使用大脑的动态环境来指导电极放置和刺激编程，从而产生可以针对个别患者和症状量身定做的DBS系统。对负责调节关键治疗神经活动的电活性神经化学物质的表征将使我们能够使用实时神经递质浓度测量来确定这些电极放置的最佳位置，以及在电极被植入后确定最佳刺激参数。我们建议通过表征刺激STN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。在目标1中，我们将建立一种廉价的动物模型，用于研究麻醉健康猪丘脑底核DBS诱发的纹状体多巴胺释放的急性特征。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种闭环控制器，用于调节健康麻醉的非人类灵长类动物(NHP)的多巴胺浓度。最后，在目标3中，我们将使用PD的NHP模型来开发一个神经化学介导的闭环式DBS系统，以在动态环境中实现持续的治疗反应。表征DBS诱发的多巴胺的神经化学动力学是了解DBS潜在机制的重要一步。未来，建立在这里提出的系统基础上的闭环系统将减少通过DBS规划和药物调整的形式进行频繁的临床干预的需要。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影响，并将为扩大可以用DBS治疗的神经和精神疾病提供理论基础。

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.