Optimizing coordinated reset deep brain stimulation for Parkinson's disease

项目总结/摘要 帕金森病（PD）是一种神经退行性疾病，影响全球600 - 700万人。传统 高频等时脑深部电刺激（DBS）是治疗相关运动体征的有效方法 PD的。然而，临床结果在不同中心和不同患者的中心内各不相同。不利影响 当DBS电极导线放置在次优位置时， 限制了临床获益。协调复位（CR）DBS是一种有前途的新型DBS方法， 克服了传统DBS的局限性。通过交替以突发模式递送的较低强度刺激 在DBS电极导线的不同触点上，CR DBS与较小的电流扩散相关，从而降低了 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改善 刺激，即携带效应。尽管CR DBS的有效性已在临床前和临床试验中得到证实， 和临床研究，选择CR参数，提供最大的遗留效应， 挑战性还必须确定CR DBS的最佳靶点。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 DBS的效果， 丘脑底核（subthalamic nucleus，DBS）和苍白球内段（internal segment of the globus pallidus，GPi）的DBS，以及（3）表征 皮层和皮层下神经元活动的变化与其治疗效果有关。非人 PD的灵长类动物模型将用于在MRI和GPi中植入DBS电极导线的每只动物， 密度犹他州阵列放置在初级运动，背侧前运动和背外侧前额叶皮质。 将进行客观和定量的运动评估，以测量 具有不同周期率和不同靶点的CR DBS（SPECT和GPi）。核心假设是， 当周期率基于受试者特定的病理生理学时，CR DBS的治疗效果最大 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 运动体征的益处，并诱导显著更长的残留效应。我们预测， 由CR DBS诱导的脑缺血将与皮质内和皮质间同步神经元活动的减少相关 以及基底神经节-丘脑皮质（BGTC）回路中的皮质下节点。这项研究的结果将 根据受试者特异性生物标志物，为选择CR DBS周期率提供了一种时间效率高的方法 BGTC回路中的活动，确定CR DBS的最佳目标，并增强我们对 CR DBS治疗效果的潜在机制。研究结果将大大促进 开发用于治疗PD的CR DBS，这将改善临床结局，延长电池寿命， 导致更少的副作用，从而提高接受DBS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.