Optimizing coordinated reset deep brain stimulation for Parkinson's disease

项目摘要/摘要 帕金森氏病(PD)是一种神经退行性疾病，全球有600-700万人患病。传统型 高频等时脑深部电刺激是治疗相关运动体征的有效方法。 和警察在一起。然而，临床结果在不同中心和不同患者的中心内是不同的。不良反应 当DBS导联放置在次优位置时，可能会导致电流扩散到意外的大脑区域， 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，它具有以下潜力 克服传统DBS的局限性。通过交替以突发模式提供较低强度的刺激 在DBS导线的不同触点上，CR DBS与较小的电流分布相关联，从而减少 不良反应的发生率以及停药后持续数天至数周的运动体征的改善 刺激，即结转效应。尽管CR DBS的有效性已在临床前和临床前两个阶段得到证明 和临床研究，提供最大残留效应的CR参数的选择 很有挑战性。还必须确定CR DBS的最佳目标。使用受试者内部的拟议研究 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)的DBS，以及(3)特征 皮质和皮质下神经元活动的变化与其疗效有关。非人类 将使用帕金森病的灵长类动物模型，每只动物在STN和GPI内植入DBS导联，并在 在初级运动、背前运动和背外侧前额叶皮质上放置密度较高的犹他州阵列。 将进行客观和定量的运动评估，以衡量急性和遗留的影响 不同周期和不同目标(STN和GPI)的CR DBS。中心假设是 根据受试者不同的病理生理指标，CR-DBS的治疗效果最好 与帕金森病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 有益于运动体征，并引起显著更长的遗留效应。我们预测马达的改进 CR DBS诱导的DBS将与皮质内和皮质间同步神经元活动减少相关 和基底节-丘脑皮质(BGTC)环路的皮质下结点。这项研究的结果将 为基于受试者特定生物标志物的CR-DBS周期频率的选择提供了一种省时的方法 BGTC回路中的活动，确定CR DBS的最佳目标，并加深我们对 CR DBS治疗作用机制(S)。这项研究的结果将大大推进 开发CR DBS治疗帕金森病，将改善临床结果，延长电池寿命和 减少副作用，提高接受DBS治疗的PD患者的生活质量。

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.