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.

项目摘要和摘要 帕金森病(PD)姿势不稳和步态障碍(PIGD)的症状导致 残疾，目前的疗法没有得到充分的治疗。脑深部刺激(DBS) 丘脑底核(STN)和苍白球(GP)对PIGD有效，但不如 用于其他帕金森病症状，如运动迟缓和僵硬。标准的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 缓慢地对刺激的变化做出反应。因此，DBS通常会进行优化，以更快地- 有反应的症状，这可能是为什么DBS对PIGD以外的症状更有效。目标是 DBS优化的目的是影响最能改善症状的神经靶点结构。不同 靶结构可能会改善不同的症状。而运动迟缓和僵硬被认为是 对丘脑下丘脑投射的刺激作出反应，PIGD被认为涉及其他 结构，尤其是桥脚核(PPN)。PPN传入和传出，通过 因此，STN和GP附近可能是PIGD更有效的刺激靶点。 新的定向DBS电极，结合高场强MRI成像和患者特定的 计算模型，现在可以更有选择性地瞄准这些通路。我们假设 靶向PPN上行传出通路将增加DBS治疗PIGD的有效性， 然而，通过抑制PPN，靶向苍白球下行通路，将降低其 对PIGD的有效性。 我们将比较DBS对步态、姿势不稳定、运动迟缓和僵硬的影响 直接靶向足叶和苍白球通路，以及丘脑底核 直接通路、直接苍白球下丘脑通路和苍白球双侧通路 间接地(通过靶向GP内侧部GPI的抑制性传入)。术前7特斯拉 结构和弥散加权MRI扫描和术后高分辨率CT扫描将 确定电极相对于细胞核和纤维束的位置和方向。特定于患者 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，并且 新颖的粒子群优化算法将设计激励设置，以最大化 被比较的通路之间的激活。AIMS 1(STN)和2(GP)比较单个- 课程，受试者内实验设计。目标3比较的设置与更长的洗入/ 还将在实验室测试期间使用以下措施收集数据 功能状态和生活质量。该项目将全面调查星展银行如何 根据患者的具体情况量身定做，以治疗PIGD的致残症状。