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

• 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
• 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

 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（由适用提供）：深脑仿真（DBS）彻底改变了帕金森氏病（PD）的治疗，当副丘脑皮层电路的关键点在长期刺激性刺激性时，对其许多基本电动机迹象观察到了许多基本电动机标志的治疗益处。将近三十年后，这些仿真参数在很大程度上已经消失了，我们对适应帕金森氏症运动标志的发展和发展的基本神经活动的变化的理解不断变化。最近的几种理论表明，多巴胺缺失的层状甲状腺皮质皮质'电路在基底神经节和运动皮质结构之间的功能相互作用改变了同步振荡，并且与运动符号的出现和进展有关。与这些理论一致，已经提出了新型的刺激范式，它可能不仅可以更有效地缓解这些病理变化，而且还会引起理论益处，从而超过了刺激递送。迄今为止，只有有限的研究试图解决这些新型范式的治疗潜力和机制。当前的提案将评估和表征由TASS开发的一种范式，协调的复位（CR）DB，该范式涉及在丘脑下核us（STN）的空间不同区域的随机刺激施加，以便在跨Pallidothalamoportolical Cource中脱离病理神经活性。使用已建立的PD临床前模型，我们将确定CR DBS对单个Parkinsonian电机标志的影响的幅度和时间过程，无论是在DBS期间还是在停用之后，并比较了传统STN DBS期间观察到的更改。此外，我们还将使用植入皮层，丘脑和基本神经节中植入的慢性记录阵列来评估在pallidothothalamoportical Couss遍布与单个帕金森氏菌运动符号的改善的同步振荡性神经元活动的变化。这项研究将洞悉CR和传统DBS的治疗潜力和机制，同时提高我们对pallidothothalamoportical Couce内和跨关键淋巴结点之间神经元活动之间关系的理解，以及帕金森氏症电脑的表现。