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

描述(申请人提供)：智力优势：脑深部刺激(DBS)是治疗帕金森氏病(PD)的一种非常有前途的疗法。然而，大多数患者并没有从DBS中获得完全的治疗益处，因为它对电极位置的治疗效果至关重要，电极位置是丘脑下核(STN)背外侧后感觉运动亚单位(STN)的“甜蜜点”。皮成在一家中心接受培训，在那里，70%的星展患者获得了完全的治疗益处，进步如此显著，以至于他们不再需要任何帕金森病药物。即使在学术中心，这种疗效也是不典型的，因为DBS电极的放置不标准化、科学化或系统化。我们建议为STN构建一个神经建模、评估和控制框架，这将使一种新的手术工具的开发成为可能，该工具将标准化DBS的放置：术中自动闭环式DBS定位系统。这项变革性技术的发展需要：1)“甜蜜点”的神经生理学特征。在帕金森氏病患者中，微电极记录将测量STN神经元在距离“甜蜜点”不同距离和从“甜蜜点”内部的单个单位放电活动(动作电位)。点过程模型将从这些数据中估计出来，并将捕捉外部(例如行为)和内在(本地神经网络活动)因素与STN尖峰活动之间的复杂随机关系。原则性的推理方法将确认“甜蜜点”的存在并表征其电生理特性；而基于计算电导的模拟将阐明“甜蜜点”生理基础下的离子机制。2)STN DBS神经网络估计与控制算法的构建。信号处理和控制将从STN尖峰活动中获得一个健壮的特征集，它将可靠地预测电极的位置，然后将电极引导到最佳位置。这个变革性的项目需要拥有神经外科、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，星展银行本地化的自动化在很大程度上仍未得到开发，使我们有机会引领这一下一代技术的科学发展。更广泛的影响：由于成本的原因，全世界接受DBS治疗的PD患者不到10%。自动化手术植入，避免复杂的术后DBS编程，而不是最优的电极放置，将降低成本，从而增加患者的接近率。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。郑志刚的星展银行患者表示，他们已经恢复到帕金森病前的状态，不仅是他们的生活，还有他们的家人的生活，他们长期以来一直被一种令人衰弱的慢性病过程所劫持。我们的建议试图将这些好处外推到更大的帕金森病人群。更重要的是，DBS是一种新的手术程序，对未来的许多神经和精神适应症具有很大的希望。一项提高DBS目标保真度和有效性的技术将有可能改善全球数百万患者及其家人的生活。这一项目将被纳入私人投资机构内务部和附属部门的课程。高年级、本科生和研究生阶段的信号处理和神经元棘波建模课程将从我们的建议中受益。还将开发和提供研究生级别的现代控制理论课程，以及神经系统的应用。神经解剖学和神经生理学的传统课程将通过我们的提案对生理学、解剖学和功能之间的关系的见解而得到加强。PI还计划通过提供具有代表性的稀有神经生理学数据和分析代码样本来接触学术界。培育完成后，这样一个数据库将为世界各地的研究人员提供一个平台，以对软件算法进行基准测试，为将处理神经信号的新硬件平台优化模拟和数字组件，并对DBS的机制产生更完整的理解。皮成与包括星展硬件制造商美敦力在内的行业公司有着深厚的关系。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.