Pathophysiology-based approaches to deep brain stimulation for Parkinson's disease

摘要(项目1) 帕金森氏病(PD)是一种进行性神经退行性疾病，全球有1000多万人患有帕金森氏病。 很宽。它可以是一种衰弱的疾病，尽管几十年来一直在研究，但在基础 作为其发育基础的丘脑皮质神经节(BGTC)回路仍在争论中。脑深部刺激 丘脑底核(STN)和苍白球内侧核(GPI)是一种非常有效的治疗方法 然而，对于许多帕金森病患者来说，结果是高度可变的，可能与认知有关 在一些患者中出现妥协。为了推进DBS治疗帕金森病，我们需要更深入地了解当地 以及全网络电路动力学及其与运动体征和认知功能的关系。这 了解将为优化STN和GPI DBS提供理论基础，目标是 STN和GPI，以及根据患者的运动体征和认知特征开发针对患者的DBS。 这项研究的目的是促进我们对BGTC(皮质下-皮质)和 皮质-皮质环路在帕金森病发生发展中的作用，DBS和L-多巴的变化，以及 利用这一认识来推进当前的DBS治疗方法并开发新的治疗方法。我们会 在更广泛的BGTC中定义同步振荡、一致性和连通性之间的关系 环路(STN、GPI、感觉、运动、前运动和前额叶背外侧皮质)对PD运动发育的影响 体征定义了它们在运动表现(SA1，2)、认知功能(SA1，2，3)和相应的变化中的作用 与DBS、L-多巴和DBS+L-多巴(SA2)。通过定义静态连接模式的强度和方向 在移动过程中，我们将确定BGTC网络中各个电路的角色，并定义其 各自在运动表现和认知功能中的作用为未来的发展铺平了道路 利用这种理解的DBS的优化算法(SA1，2，3，4)。通过将学位关联起来 对于多个单细胞之间的一致性和局部场势(LFP)活动，我们还将推进我们的 了解峰时相锁定在运动体征发育中的作用。通过高分辨率 成像技术和分割分析我们将在STN和GPI中定义DBS的最佳位置 (SA2，3，4)将运动和认知结果与生物标记物活动和导联位置关联起来，导致患者- 根据每个患者的表型和特征开发特定的DBS和自动编程算法 引线位置。建议的目标将使用定向DBS导线、多个独立电流进行 帕金森病患者的受控(MICC)设备、高分辨率成像和电生理记录 患者术后接受微电极标测的皮层脑电(ECoG)阵列(SA1，3) 使用ECoG阵列和外置导线(SA2，3)，并遵循DBS参数的优化(SA4)。

ABSTRACT (Project 1) Parkinson’s disease (PD) is a progressive neurodegenerative disease affecting over 10 million people world- wide. It can be a debilitating disorder and although studied for decades the physiological changes in the basal ganglia thalamocortical (BGTC) circuit that underlie its development remain under debate. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) has been a highly effective therapy for many patients with PD, however, the results have been highly variable and may be associated with cognitive compromise in some patients. To advance DBS therapies for PD we require a deeper understanding of the local and network-wide circuit dynamics and their relationship to motor signs and cognitive function. This understanding will provide the rationale for optimizing STN and GPi DBS, targeting specific regions within the STN and GPi, and development of patient-specific DBS based on the patients’ motor signs and cognitive profile. The goals of this study are to advance our understanding of the role of BGTC (subcortical-cortical) and cortical-cortical circuits in the development of PD, the changes that occur with DBS and L-dopa, and to use this understanding to advance current and develop new DBS approaches for its treatment. We will define the relationship between synchronized oscillations, coherence and connectivity within the broader BGTC circuit (STN, GPi, sensory, motor, premotor and dorsolateral prefrontal cortices) to the development of PD motor signs, define their role in motor performance (SA1,2), cognitive function (SA1,2,3), and corresponding changes with DBS, L-dopa and DBS+L-dopa (SA2). By defining the strength and direction of connectivity patterns at rest and during movement we will characterize the role of individual circuits within the BGTC network and define their respective roles in motor performance and cognitive function paving the way for future development of optimization algorithms for DBS that take advantage of this understanding (SA1,2,3,4). By correlating the degree of coherence between multiple single cells and local field potential (LFP) activity we will also advance our understanding of the role of spike-phase locking to the development of motor signs. Through high resolution imaging techniques and parcellation analyses we will define the optimal site for DBS within the STN and GPi (SA2,3,4) correlating motor and cognitive outcomes to biomarker activity and lead location, leading to patient- specific DBS and development of automated programming algorithms based on each patient’s phenotype and lead location. The proposed aims will be conducted using directional DBS leads, multiple independent current controlled (MICC) devices, high resolution imaging and electrophysiological recordings in PD patients with electrocorticography (ECoG) arrays undergoing microelectrode mapping (SA1,3), postoperatively in patients with ECoG arrays and externalized leads (SA2,3), and following optimization of DBS parameters (SA4).