Targeted Pathway Activation for PosturalInstability and Gait Disorder in Parkinson'sDisease

帕金森病姿势不稳定和步态障碍的靶向通路激活

• 批准号: 10666621
• 负责人: SCOTT E COOPER
• 金额: $ 74.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666621
• 关键词: Affect; Agreement; Anatomy; Basal Ganglia; Bradykinesia; Brain imaging; Bypass; Cell Nucleus; Clinical; Complex; Computer Models; Consumption; Coupled; Data; Data Set; Deep Brain Stimulation; Diffusion Magnetic Resonance Imaging; Effectiveness; Efferent Pathways; Electric Stimulation; Electrodes; Environment; Equilibrium; Experimental Designs; Failure; Fiber; Gait; Gait abnormality; Globus Pallidus; Goals; High Resolution Computed Tomography; Hour; Image; Institution; Intervention Studies; Investigation; Laboratories; Lesion; Location; MRI Scans; Magnetic Resonance Imaging; Measures; Modeling; Morphologic artifacts; Motor; Neural Pathways; Neurodegenerative Disorders; Operative Surgical Procedures; Parkinson Disease; Pars Interna; Pathway interactions; Patients; Pharmaceutical Preparations; Postoperative Period; Process; Quality of life; Research; STN stimulation; Safety; Sample Size; Structure; Structure of subthalamic nucleus; Symptoms; Techniques; Testing; Therapeutic; Time; Work; X-Ray Computed Tomography; associated symptom; deep field survey; design; disability; disabling symptom; functional status; home test; improved; individual patient; innovation; interest; machine learning method; motor impairment; motor symptom; neural; neuroimaging; non-motor symptom; novel; novel therapeutic intervention; particle; phase I trial; posture instability; programs; prospective; reduce symptoms; response; success; tool; tractography

Project Summary and Abstract Parkinson's disease (PD) symptoms of postural instability and gait disorder (PIGD) cause profound disability and are inadequately treated by current therapies. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and Globus Pallidus (GP) is effective for PIGD, but not nearly as much as for other PD symptoms e.g. bradykinesia and rigidity. Standard DBS optimization relies on assessing changes in symptoms each time stimulation changes, a very time consuming process. PIGD changes slowly in response to changes in stimulation. Hence, DBS is normally optimized to quicker- responding symptoms, which may be why DBS works better for symptoms other than PIGD. The goal of DBS optimization is to affect neural target structures which best ameliorate symptoms. Different target structures may ameliorate different symptoms. While bradykinesia and rigidity are thought to respond to stimulation of the subthalamopallidal projection, PIGD is thought to involve other structures, especially pedunculopontine nucleus (PPN). PPN afferents and efferents, passing through or near STN & GP may therefore be more effective stimulation targets for PIGD. New directional DBS electrodes, coupled with high field strength MRI imaging and patient-specific computational models, now enable more selective targeting of these pathways. We hypothesize that targeting the ascending PPN efferent pathway will increase the effectiveness of DBS on PIGD, whereas targeting the descending pallidofugal pathway, by inhibiting PPN, will decrease its effectiveness for PIGD. We will compare effects on gait, postural instability, bradykinesia, and rigidity, of DBS targeting pedunculopallidal and pallidopeduncular pathways, directly, as well as subthalamopallidal pathway directly, pallidosubthalamic pathway directly, and pallidopeduncular pathway indirectly (by targeting inhibitory afferents to GP pars interna GPi). Preoperative 7 Tesla structural and diffusion-weighted MRI scans and postoperative high-resolution CT scans will determine electrode location and orientation, relative to nuclei and fiber tracts. Patient-specific models from these imaging datasets will estimate percent activation of each fiber tract, and a novel particle swarm optimization will design stimulation settings maximizing the difference in activation between pathways being compared. Aims 1 (STN) & 2 (GP) compare settings in a single- session, within-subjects experimental design. Aim 3 compares settings with much longer wash- in/ out intervals, and will also collect data between laboratory testing sessions using measures of functional status and quality of life. This project will comprehensively investigate how DBS can be tailored on a patient-specific basis to treat disabling symptoms of PIGD.

项目概要和摘要 帕金森病（PD）的姿势不稳定和步态障碍（PIGD）症状引起了深刻的 残疾，目前的治疗方法无法充分治疗。脑深部电刺激（DBS） 丘脑底核（subthalamic nucleus，简称NNNA）和苍白球（Globus Pallidus，简称GP）对PIGD有效，但不如 其他PD症状，如运动迟缓和僵硬。标准DBS优化依赖于评估 每次刺激变化时症状都会发生变化，这是一个非常耗时的过程。PIGD变化 缓慢地响应刺激的变化。因此，DBS通常被优化为更快- 这可能是DBS比PIGD更好地治疗其他症状的原因。目标 DBS优化的目的是影响最能改善症状的神经靶结构。不同 靶向结构可以改善不同的症状。虽然运动迟缓和僵硬被认为 PIGD对丘脑底苍白球投射的刺激有反应，PIGD被认为涉及其他神经元。 结构，特别是脚桥核（PPN）。PPN传入和传出，通过 因此，PIGD的刺激靶点可能更有效。 新的定向DBS电极，结合高场强MRI成像和患者特异性 计算机模型，现在能够更有选择性地靶向这些途径。我们假设 靶向上行PPN传出通路将增加DBS对PIGD的有效性， 而通过抑制PPN，靶向下行的苍白球分离途径， PIGD的功效。 我们将比较DBS对步态、姿势不稳、运动迟缓和僵硬的影响 直接靶向脚苍白球和苍白球脚通路，以及丘脑下苍白球通路 直接途径、直接途径和直接途径 间接地（通过靶向抑制性传入至GP内部GPi）。术前7特斯拉 结构和扩散加权MRI扫描以及术后高分辨率CT扫描将 确定电极相对于细胞核和纤维束的位置和方向。患者特异 来自这些成像数据集的模型将估计每个纤维束的激活百分比， 新的粒子群优化将设计刺激设置， 比较途径之间的激活。目标1（ESTA）和2（GP）比较设置在一个单一的- 会话，受试者内实验设计。目标3比较设置与更长的洗入/ 间隔，并将收集实验室测试会话之间的数据，使用的措施， 功能状态和生活质量。本项目将全面研究DBS如何能够 根据患者的具体情况量身定制，以治疗PIGD的致残症状。