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

梅纳特基底核神经刺激治疗帕金森病认知运动综合征

• 批准号: 10686249
• 负责人: Helen Bronte-Stewart
• 金额: $ 109.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686249
• 关键词: 3-Dimensional; Anterior; Atrophic; Attention; Basal Nucleus of Meynert; Behavioral; Blood Glucose; Blood flow; Boston; Calibration; Clinical Research; Clinical Trials; Cognition; Cognitive; Computer software; Data Set; Deep Brain Stimulation; Dementia; Dementia with Lewy Bodies; Deterioration; Devices; Diffusion; Electrodes; Fiber; Frequencies; Future; Globus Pallidus; Goals; Growth Factor; Hour; Impaired cognition; Impairment; Implant; Individual; Intervention; Lateral; Lead; Link; Location; Measures; Modeling; Motor; Neurosurgeon; Operative Surgical Procedures; Outcome; Parkinson Disease; Participant; Pattern; Performance; Persons; Pharmaceutical Preparations; Phase; Play; Research; Role; STN stimulation; Safety; Source; Structure; Structure of subthalamic nucleus; Syndrome; System; Technology; Testing; Therapeutic; Time; Tissues; Translating; Visuospatial; Work; cholinergic; cognitive impairment in Parkinson' s; density; evidence base; executive function; first-in-human; fluorodeoxyglucose positron emission tomography; glucose metabolism; high standard; human study; human subject; implantation; improved; lead optimization; mild cognitive impairment; motor control; motor impairment; motor symptom; nerve supply; novel; novel strategies; open data; pre-clinical; preclinical study; primary outcome; randomized, clinical trials; reconstruction; technology development; tractography

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.

认知能力下降开始于帕金森病（PD）的早期阶段，75%的患者进展为痴呆症。 十年后的PD多巴胺能药物和脑深部电刺激（DBS）提供了长期的 PD患者的主要运动症状得到改善，但认知功能下降在很大程度上仍未得到解决， 未经治疗，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 表明Meynert基底核（NBM）的间歇性DBS提供了稳定 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PD患者。我们建议应用成功的三个预测因素， 运动（多巴胺能）DBS与认知运动（胆碱能）DBS的结局：1）选择特征良好的 2）优化靶点选择、电极导线位置和组织体积 激活（VTA），和3）使用间歇性神经刺激模式。我们将利用UG 3阶段建立 一种通过纤维束成像建模靶向NBM进行DBS的新方法的可行性， 刺激技术，与波士顿科学公司及其基于Chronos软件的研究合作， 首先是人类研究。我们将获得一项研究器械豁免，以便在年首次使用Chronos。 人类受试者和新的DBS靶（即，NBM纤维束）。只有在成功完成UG 3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UH 3阶段， 包括一个小型的试点临床试验，研究联合使用的安全性，耐受性和效果。 间歇性NBM DBS。10名PD患者在至少一个领域有认知障碍，但没有 患有痴呆症，将接受脑电刺激+ NBM DBS植入术。以中央前部为目标的垂直入路 5名参与者将使用NBM区域，并采用针对外侧传出纤维束的新型外侧入路 NBM的流出将用于其他5名参与者。参与者将获得标准的高频 连续的NBM刺激和1小时/天的间歇性（60 Hz，20秒开启，40秒关闭/分钟）NBM刺激。 行为和认知测量将每6年进行一次，持续长达两年，主要结局为 12个月一个独立的科学成果将使用氟脱氧葡萄糖（FDG）-正电子发射断层扫描 (PET)评估连续或间歇性NBM刺激对皮质血流量和葡萄糖的影响 新陈代谢.

项目成果

Bradykinesia and Its Progression Are Related to Interhemispheric Beta Coherence.

运动迟缓及其进展与半球间 Beta 相干性有关。

• DOI: 10.1002/ana.26605
• 发表时间: 2023
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Wilkins,KevinB;Kehnemouyi,YasmineM;Petrucci,MatthewN;Anderson,RossW;Parker,JordanE;Trager,MeganH;Neuville,RauminS;Koop,MandyM;Velisar,Anca;Blumenfeld,Zack;Quinn,EmmaJ;Bronte-Stewart,HelenM
• 通讯作者: Bronte-Stewart,HelenM

Unraveling the complexities of programming neural adaptive deep brain stimulation in Parkinson's disease.

• DOI: 10.3389/fnhum.2023.1310393
• 发表时间: 2023
• 期刊: FRONTIERS IN HUMAN NEUROSCIENCE
• 影响因子: 2.9
• 作者: Wilkins, Kevin B.;Melbourne, Jillian A.;Akella, Pranav;Bronte-Stewart, Helen M.
• 通讯作者: Bronte-Stewart, Helen M.

No laughing white matter: Reduced integrity of the cortical cholinergic pathways in Parkinson's disease-related cognitive impairment.

• DOI: 10.1016/j.nbd.2023.106243
• 发表时间: 2023-09
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Crockett, Rachel A.;Wilkins, Kevin B.;Aditham, Sudeep;Bronte-Stewart, Helen M.
• 通讯作者: Bronte-Stewart, Helen M.

The digital signature of emergent tremor in Parkinson's disease.

帕金森病紧急震颤的数字签名。

• DOI: 10.21203/rs.3.rs-3467667/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Bronte-Stewart,Helen;Gala,Aryaman;Wilkins,Kevin;Pettruci,Matthew;Kehnemouyi,Yasmine;Velisar,Anca;Trager,Megan
• 通讯作者: Trager,Megan