Optimizing coordinated reset deep brain stimulation for Parkinson's disease

优化帕金森病的协调重置深部脑刺激

• 批准号: 10267675
• 负责人: Jing Wang
• 金额: $ 62.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267675
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acute; Advanced Development; Adverse effects; Affect; Animals; Area; Basal Ganglia; Behavioral; Biological Markers; Brain; Clinical; Clinical Research; Consumption; Data; Deep Brain Stimulation; Development; Dorsal; Effectiveness; Evaluation; Experimental Designs; Frequencies; Future; Globus Pallidus; Goals; Healthcare Systems; Hour; Implant; Incidence; Lead; Life; MPTP non-human primate; Measures; Modeling; Motor; Movement; Neurodegenerative Disorders; Neurons; Nodal; Operative Surgical Procedures; Outcome; Parkinson Disease; Parkinsonian Disorders; Patient Care; Patients; Pattern; Prefrontal Cortex; Probability; Quality of life; Research; Rest; Site; Structure; Structure of subthalamic nucleus; Testing; Therapeutic; Therapeutic Effect; Time; Translations; Utah; Work; base; density; effective therapy; human subject; improved; motor disorder; motor function improvement; motor symptom; neurotransmission; nonhuman primate; novel; novel strategies; preclinical study; relating to nervous system; side effect; specific biomarkers; therapeutically effective

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder affecting 6-7 million people worldwide. Traditional high frequency, isochronal deep brain stimulation (DBS) is an effective treatment for the motor signs associated with PD. Clinical outcomes, however, vary across centers and within centers across patients. Adverse effects can be induced by “current-spread” to unintended brain areas when the DBS lead is sub-optimally placed which limits clinical benefits. Coordinated reset (CR) DBS is a promising novel DBS approach that has the potential to overcome the limitations of traditional DBS. By alternating lower intensity stimulation delivered in a burst pattern across different contacts of the DBS lead, CR DBS is associated with less current spread, thus reducing the incidence of adverse effects, and improvement in motor signs that persist for days to weeks after cessation of stimulation, i.e. carryover effect. Although the effectiveness of CR DBS has been demonstrated in both preclinical and clinical studies, the selection of CR parameters that provide the greatest carryover effect has been challenging. The optimal target for CR DBS must also be identified. The proposed study using a within-subject experimental design will 1) optimize the critical parameter (cycle rate) of CR DBS, (2) compare the effect of CR DBS in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi), and (3) characterize the changes in cortical and subcortical neuronal activities associated with its therapeutic effect. The nonhuman primate model of PD will be used with each animal implanted with DBS leads in the STN and GPi and high- density Utah arrays placed over the primary motor, dorsal premotor and dorsolateral prefrontal cortices. Objective and quantitative motor assessments will be performed to measure the acute and carryover effect of CR DBS with different cycle rates and in different targets (STN and GPi). The central hypothesis is that the therapeutic effect of CR DBS is greatest when the cycle rate is based on subject-specific pathophysiological biomarkers associated with the PD state. We further hypothesize that CR DBS in GPi will provide greater acute benefits in motor signs and induce significantly longer carryover effects. We predict that motor improvements induced by CR DBS will correlate with a reduction in synchronized neuronal activity within and across cortical and subcortical nodal points in the basal-ganglia-thalamocortical (BGTC) circuit. The results of this study will provide a time efficient approach for the selection of CR DBS cycle rate based on subject-specific biomarker activity in the BGTC circuit, identify the optimal target for CR DBS and enhance our understanding of the mechanism(s) underlying the therapeutic effect of CR DBS. Results of the study will significantly advance the development of CR DBS for the treatment of PD that will enhance clinical outcomes, prolong battery life and induce fewer side effects leading to higher quality of life for PD patients undergoing DBS.

项目概要/摘要 帕金森病 (PD) 是一种神经退行性疾病，影响全球 6-700 万人。传统的 高频等时深部脑刺激 (DBS) 是治疗相关运动症状的有效方法 与PD。然而，不同中心以及中心内不同患者的临床结果各不相同。不良反应 当 DBS 导线放置得不理想时，可能会因“电流扩散”到非预期的大脑区域而引起 限制了临床益处。协调重置 (CR) DBS 是一种很有前途的新型 DBS 方法，有潜力 克服传统DBS的局限性。通过以突发模式交替提供较低强度的刺激 在 DBS 引线的不同触点上，CR DBS 与较小的电流分布相关，从而减少了 不良反应的发生率以及停止后持续数天至数周的运动体征的改善 刺激，即残留效应。尽管 CR DBS 的有效性已在临床前和临床前研究中得到证实。 和临床研究中，提供最大残留效应的 CR 参数的选择已被 具有挑战性的。还必须确定 CR DBS 的最佳目标。拟议的研究使用受试者内 实验设计将1）优化CR DBS的关键参数（循环率），（2）比较CR的效果 丘脑底核 (STN) 和苍白球内段 (GPi) 中的 DBS，以及 (3) 表征 与其治疗效果相关的皮质和皮质下神经元活动的变化。非人类 将使用 PD 灵长类动物模型，每只动物在 STN 和 GPi 中植入 DBS 导线，并且高 密度犹他阵列放置在初级运动、背侧前运动和背外侧前额叶皮质上。 将进行客观和定量的运动评估，以测量急性和残留效应 具有不同循环速率和不同目标（STN 和 GPi）的 CR DBS。中心假设是 当循环率基于受试者特定的病理生理学时，CR DBS 的治疗效果最佳 与 PD 状态相关的生物标志物。我们进一步假设 GPi 中的 CR DBS 将提供更大的急性 对运动体征有好处，并引起显着更长的残留效应。我们预测电机的改进 CR DBS 诱导的神经元同步活动与皮质内和皮质间同步神经元活动的减少相关 和基底神经节丘脑皮质（BGTC）回路中的皮质下节点。这项研究的结果将 提供一种基于受试者特定生物标志物选择 CR DBS 循环速率的省时方法 BGTC 回路中的活动，确定 CR DBS 的最佳目标并增强我们对 CR DBS 治疗效果的机制。研究结果将显着推进 开发用于治疗 PD 的 CR DBS，将提高临床结果、延长电池寿命和 引起较少的副作用，从而提高接受 DBS 的 PD 患者的生活质量。