Neurostimulation of the Nucleus Basalis of Meynert for the cognitive-motor syndrome in Parkinson's disease

认知能力下降开始于帕金森氏病(PD)的早期阶段，并在75%的人中进展为痴呆症 十年后患帕金森病的人。多巴胺能药物和脑深部刺激(DBS)提供长期的 帕金森病患者主要运动症状的改善，但认知能力下降在很大程度上仍未得到解决 不治疗，尽管在痴呆症发生之前有很长的潜在干预窗口。临床前证据 提示Meynert基底核(NBM)的间歇性DBS具有稳定的潜能 胆碱能系统的恶化及其对认知和认知运动功能的负面影响 轻度认知障碍和帕金森病患者。我们建议应用成功的三个预测因素 运动(多巴胺能)DBS到认知运动(胆碱能)DBS的结果：1)选择特征良好的DBS 痴呆症前的候选者2)优化靶点选择、导联位置和组织体积 激活(VTA)，以及3)使用间歇性神经刺激模式。我们将利用UG3阶段来建立 一种新的靶向NBM用于DBS的方法的可行性 刺激技术，与波士顿科学公司及其基于研究的Chronos软件合作，用于 这是人类研究中的第一个。我们将在#年首次获得使用Chronos的调查设备豁免 人类受试者和一种新的DBS靶点(即NBM纤维束)。仅在成功完成UG3之后 与项目这些方面相关的里程碑，然后我们将过渡到研究的UH3阶段，该阶段将 包括一项小型试点临床试验，调查STN和STN联合应用的安全性、耐受性和效果 间歇性NBM DBS。10名帕金森病患者至少在一个领域有认知障碍，但没有 有痴呆者，将接受STN+NBM DBS植入。以中央前部为靶点的垂直入路 将在5名参与者中使用NBM区域和一种针对外侧传出纤维束的新的侧向入路 NBM的流出将用于其他5名参与者。参赛者将获得标准高频 连续刺激STN和间歇性刺激NBM(60赫兹，开启20秒，关闭40秒/分钟)1小时/天。 行为和认知测量将在长达两年的时间内每6次测量一次，主要结果为 12个月。一项独立的科学成果将使用氟代脱氧葡萄糖(FDG)正电子发射断层扫描 (PET)评估持续或间歇刺激NBM对皮质血流量和血糖的影响 新陈代谢。

Cognitive decline begins in early stages of Parkinson’s disease (PD) and progresses to dementia in 75% of people with PD after ten years. Dopaminergic medication and deep brain stimulation (DBS) provide long-term improvement of cardinal motor symptoms in PD, but cognitive decline remains largely unaddressed and untreated, despite a long window for potential intervention before dementia occurs. Pre-clinical evidence indicates that intermittent DBS of the Nucleus Basalis of Meynert (NBM) offers the potential to stabilize deterioration of the cholinergic system and its negative impact on cognitive and cognitive-motor function in individuals with mild cognitive impairment and PD. We propose to apply the three predictors of a successful outcome for motor (dopaminergic) DBS to cognitive-motor (cholinergic) DBS: 1) select well-characterized candidates before the stage of dementia 2) optimize target selection, lead location, and volume of tissue activated (VTA), and 3) use intermittent neurostimulation patterns. We will utilize the UG3 phase to establish the feasibility of a novel approach to target the NBM for DBS via tractography modeling and translate novel patterned stimulation technology, in partnership with Boston Scientific and their research based Chronos software, for a first in human study. We will obtain an Investigational Device Exemption to use Chronos for the first time in human subjects and in a novel DBS target (i.e., NBM fiber bundles). Only after successful completion of the UG3 milestones related to these aspects of the project will we then transition to the UH3 phase of the study which will consist of a small pilot clinical trial investigating the safety, tolerability, and effect of combined STN and intermittent NBM DBS. Ten individuals with PD with cognitive impairment in at least one domain, but who do not have dementia, will undergo implantation of STN + NBM DBS. A vertical approach targeting the central anterior NBM region will be used in 5 participants, and a novel lateral approach targeting the lateral efferent fiber bundle outflow of the NBM will be used in the other 5 participants. Participants will receive standard high-frequency continuous STN stimulation and 1 hour/day of intermittent (60 Hz, 20 sec on, 40 sec off/minute) NBM stimulation. Behavioral and cognitive measures will be measured every 6 for up to two years with the primary outcomes at 12 months. An independent scientific outcome will use fluorodeoxyglucose (FDG)-positron emission tomography (PET) to assess the effect of continuous or intermittent NBM stimulation on cortical blood flow and glucose metabolism.