CRCNS: Hitting the spot: Optimizing Placement of Deep Brain Stimulation Electrode

描述（由申请人提供）：智力优势：脑深部电刺激（DBS）是一种非常有前途的帕金森病（PD）治疗方法。然而，大多数患者并没有从DBS中获得充分的治疗益处，这是由于DBS的治疗效果对电极位置的关键依赖性，电极位置是丘脑下核（sub-thalamic nucleus，DBS）背外侧后感觉运动亚单位中的“最佳点”。PI Cheng在一家中心接受培训，70%的DBS患者获得了充分的治疗益处，改善如此显著，以至于他们不再需要任何PD药物。即使在学术中心，这种疗效也是不典型的，因为DBS电极放置不标准、不科学或不系统。我们建议为STN构建一个神经建模、估计和控制框架，这将能够开发一种新的手术工具，使DBS放置标准化：自动化术中闭环DBS定位系统。这种变革性技术的发展需要：1）“甜蜜点”的神经生理学表征。在帕金森病患者中，微电极记录将测量单个单位尖峰活动（动作电位）的突触神经元在不同的距离“甜蜜点”，并从它。点过程模型将估计从这些数据，并将捕捉复杂的随机关系之间的外在（如行为）和内在（局部神经网络活动）的因素和突触尖峰活动。原则推理方法将确认“甜蜜点”的存在，并表征其电生理特性;基于计算电导的建模将阐明“甜蜜点”生理学背后的离子机制。2)神经网络估计和控制算法的构建。信号处理和控制将从脉冲尖峰活动中导出稳健的特征集，其将可靠地预测电极的位置，然后将电极引导到最佳点。这个变革性的项目需要在神经外科、神经生理学、神经信号处理、估计和建模以及控制理论方面具有专业知识的医生、科学家、数学家和工程师之间的合作。由于这些原因，DBS本地化的自动化在很大程度上尚未开发，这使我们有机会领导下一代技术的科学发展。更广泛的影响：由于成本，全球不到10%的PD患者接受DBS。自动化手术植入和避免复杂的术后DBS程控（电极放置不佳）将降低成本，从而增加患者入路。然而，更大的社会影响将来自DBS疗效的改善，这将改变PD患者的生活。郑博士的DBS患者表示，他们已经恢复到PD前的状态，不仅是他们的生活，而且他们的家庭成员的生活，长期以来一直被衰弱的慢性疾病过程所挟持，已经回到他们身边。我们的建议试图将这些益处外推到更大的PD人群中。更重要的是，DBS是一种新兴的手术，对许多未来的神经和精神适应症有很大的希望。一项提高DBS靶向保真度和疗效的技术将有可能改善全球数百万患者及其家属的生活。这一项目将纳入公共教育机构的家庭和附属部门的课程。在高年级本科生和研究生水平的信号处理和神经元尖峰建模课程将从我们的建议中获益。一个研究生水平的现代控制理论课程与神经系统的应用也将开发和提供。传统的神经解剖学和神经生理学课程将通过我们对生理学，解剖学和功能之间关系的见解而得到加强。PI还计划通过提供稀有神经生理学数据和分析代码的代表性样本来接触学术界。当培养时，这样的数据库将为世界各地的研究人员提供一个平台，以基准测试软件算法，优化用于处理神经信号的新硬件平台的模拟和数字组件，并更全面地了解DBS的机制。PI Cheng与包括DBS硬件制造商Medtronic在内的行业公司建立了牢固的关系。我们将利用这一点来加快我们概念的开发和测试。因此，我们的项目的结果可能会对DBS系统的设计产生重大影响。

DESCRIPTION (provided by applicant): Intellectual Merit: Deep brain stimulation (DBS) is a highly promising therapy for Parkinson's disease (PD). Yet most patients do not get full therapeutic benefit from DBS due to its critical dependence on electrode location, a "sweet spot" in the dorsolateral posterior sensorimotor subunit of the sub-thalamic nucleus (STN), for therapeutic efficacy. PI Cheng was trained at a center where 70% of DBS patients obtained full therapeutic benefit, improving so markedly that they no longer require any PD medications. Such efficacy is atypical even in academic centers because DBS electrode placement is not standardized, scientific, or systematic. We propose to construct a neural modeling, estimation and control framework for STN, which will enable the development of a new surgical tool that will standardize DBS placement: an automated intraoperative closed-loop DBS localization system. Development of this transformative technology requires: 1) neurophysiologic characterization of the "sweet spot". In PD patients, microelectrode recordings will measure single unit spiking activity (action potentials) of STN neurons at different distances from the "sweet spot" and from within it. Point process models will be estimated from this data and will capture complex stochastic relationships between extrinsic (e.g. behavior) and intrinsic (local neural network activity) factors and STN spiking activity. Principled inferential methods will confirm the "sweet spot's" existence and characterize its electrophysiological properties; and computational conductance-based modeling will elucidate the ionic mechanisms underlying the "sweet spot's" physiology. 2) construction of neural estimation and control algorithms for STN DBS. Signal processing and control will derive a robust feature set from STN spiking activity which will reliably predict where the electrode is and will then guide the electrode to the sweet spot. This transformative project requires collaborations between physicians, scientists, mathematicians and engineers with expertise in neurosurgery, neurophysiology, neural signal processing, estimation and modeling, and control theory. For these reasons automation of DBS localization remains largely untapped, giving us the opportunity to lead the scientific development of this next-generation technology. Broader Impact: Due to cost, less than 10% of PD patients worldwide receive DBS. Automating surgical implantation and obviating complex postoperative DBS programming from suboptimal electrode placement would decrease cost, and thus increase patient access. Even greater societal impact, however, would come from improved DBS efficacy, which is life-changing for PD patients. DBS patients of Dr. Cheng have stated that they have been returned to their pre-PD status, and that not just their lives but also the lives of their family members, so long held hostage by a debilitating chronic disease process, have been returned to them. Our proposal attempts to extrapolate these benefits to the larger PD population. Even more importantly, DBS is a nascent procedure holding great promise for many future neurological and psychiatric indications. A technology that improves DBS targeting fidelity and efficacy would hold the potential to improve the lives of millions of patients and their families worldwide. This project will be integrated into curricula in the home and affiliated departments of the PIs. Coursework for signal processing and neuronal spike modeling in the senior undergraduate and graduate levels will gain from our proposal. A graduate level modern control theory course with applications to neural systems will also be developed and offered. Traditional courses in neuroanatomy and neurophysiology will be enhanced by our proposal's insights into the relationships between physiology, anatomy, and function. The PIs also plan to reach out to the academic community by providing representative samples of rare neurophysiological data and analysis code. When cultivated, such a database will provide a platform for investigators around the world to benchmark software algorithms, optimize analog and digital components for new hardware platforms that will process neural signals, and develop a more complete understanding of the mechanisms of DBS. PI Cheng has strong relationships with industry companies including Medtronic, the manufacturer of DBS hardware. We will leverage this to expedite the development and testing of our concept. Our project's outcome may thus have a substantial impact on how DBS systems are designed.