Chronic physiologic and behavior changes induced by novel STN DBS patterns for PD

PD 新型 STN DBS 模式引起的慢性生理和行为变化

基本信息

批准号：
9248110
负责人：
KENNETH B BAKER
金额：
$ 48.58万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-23 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248110
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Acute Address Algorithms Animal Model Animals Basal Ganglia Behavioral Biological Markers Bradykinesia Brain Brain region Chronic Coupling Cues Data Deep Brain Stimulation Development Dopamine Dose Electric Stimulation Event Evolution Experimental Designs Frequencies Future Gait Globus Pallidus Goals Health High Frequency Oscillation Hour Implant Individual Infection Life Location Long-Term Effects Modeling Motor Motor Cortex Movement Nodal Operative Surgical Procedures Parkinson Disease Parkinsonian Disorders Patients Pattern Performance Pharmaceutical Preparations Phase Physiologic pulse Physiological Pre-Clinical Model Randomized Recurrence Rest Risk Schedule Stimulus Structure Structure of subthalamic nucleus System Task Performances Testing Thalamic structure Therapeutic Therapeutic Effect Time Translations Tremor base behavior change cost design improved insight kinematics motor symptom nonhuman primate novel novel strategies pre-clinical relating to nervous system theories

项目摘要

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has revolutionized the treatment of Parkinson's disease (PD), with therapeutic benefit observed for many of its cardinal motor signs when key nodal points of the pallidothalamocortical circuit are chronically stimulated using high-frequency, isochronal electrical pulses. Almost three decades later, these stimulation parameters have largely gone unchanged despite significant advances in our understanding of the changes in underlying neural activity that accompany the development and progression of parkinsonian motor signs. Several recent theories suggest that the development of synchronized oscillations within the dopamine- depleted pallidothalamocortical 'motor' circuit alter functional interactions between the basal ganglia and motor cortical structures, and are associated with the emergence and progression of motor signs. In line with these theories, novel stimulation paradigms have been proposed that may not only be more effective at mitigating these pathological changes but also induce therapeutic benefit that outlasts stimulus delivery. To date, only a limited number of studies have attempted to address the therapeutic potential and mechanisms of these novel paradigms. The current proposal will evaluate and characterize one such paradigm, coordinated reset (CR) DBS developed by Tass, which involves the application of randomized bursts of stimulation across spatially distinct regions of the subthalamic nucleus (STN) in order to desynchronize pathological neural activity across the pallidothalamocortical circuit. Using an established preclinical model of PD, we will determine the magnitude and time course of CR DBS' effects on individual parkinsonian motor signs, both during DBS and following its discontinuation, and compare those to changes observed during traditional STN DBS. In addition, we will use chronic recording arrays implanted in the cortex, thalamus and basal ganglia to assess the changes synchronized oscillatory neural activity that occur across the pallidothalamocortical circuit coincident with improvements in individual parkinsonian motor signs. This study will provide insight into the therapeutic potential and mechanisms of CR and traditional DBS while improving our understanding of the relationship between neural activity within and across key nodal points of the pallidothalamocortical circuit and the manifestation of parkinsonian motor signs.

描述（由申请人提供）：深部脑刺激 (DBS) 彻底改变了帕金森病 (PD) 的治疗方法，当使用高频长期刺激苍白球丘脑皮质回路的关键节点时，可观察到其许多主要运动体征的治疗效果近三十年后，尽管我们对伴随帕金森病运动体征的发展和进展的潜在神经活动变化的理解取得了重大进展，但这些刺激参数基本上没有变化。最近的一些理论表明，多巴胺耗尽的苍白丘脑皮质“运动”回路内同步振荡的发展改变了基底神经节和运动皮质结构之间的功能相互作用，并且与运动体征的出现和进展相关。已经提出了新的刺激范例，它们不仅可以更有效地减轻这些病理变化，而且可以产生比刺激传递更持久的治疗效果，迄今为止，只有有限数量的研究试图解决治疗问题。目前的提案将评估和描述一种这样的范例，即 Tass 开发的协调重置（CR）DBS，其中涉及在丘脑底核（STN）的空间不同区域应用随机突发刺激。为了使整个苍白丘脑皮层回路的病理性神经活动去同步化，我们将使用已建立的 PD 临床前模型来确定 CR DBS 对个体帕金森运动体征的影响程度和时间过程，两者均在 DBS 期间。并将其与传统 STN DBS 期间观察到的变化进行比较。此外，我们将使用植入皮质、丘脑和基底神经节的慢性记录阵列来评估与苍白球丘脑皮质回路同步的振荡神经活动的变化。这项研究将深入了解 CR 和传统 DBS 的治疗潜力和机制，同时增进我们对关键节点内和关键节点间神经活动之间关系的理解。苍白球丘脑皮质回路和帕金森运动体征的表现。