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 帕金森氏病（PD）姿势不稳定和步态障碍（PIGD）的症状引起了深刻的 残疾，受到当前疗法的治疗不足。大脑刺激（DB） 丘脑下核（STN）和Globus pallidus（GP）对PIGD有效，但不高 对于其他PD症状，例如Bradykinesia和刚性。标准DBS优化依赖于评估 每次刺激变化时，症状的变化，这是一个非常耗时的过程。猪变化 缓慢响应刺激变化。因此，DB通常优化为快速 反应症状，这可能就是为什么DBS在PIGD以外的其他症状方面更好的原因。目标 DB的优化是为了影响最佳减轻症状的神经靶标结构。不同的 目标结构可能会改善不同的症状。虽然心动过难和刚性被认为 应对刺激亚丘脑的刺激，猪被认为涉及其他 结构，特别是花梗核（PPN）。 PPN的传入和竞争者，通过 因此，在STN和GP附近可能是PIGD的更有效刺激靶标。 新的定向DBS电极，结合高场强MRI成像和患者特异性 计算模型，现在可以实现这些途径的更多选择性靶向。我们假设这一点 靶向上升的PPN传出途径将提高DBS对PIGD的有效性， 而通过抑制PPN来靶向下降的pallidofugal途径，将减少 猪的有效性。 我们将比较DBS对步态，姿势不稳定性，Bradykinesia和刚度的影响 直接靶向靶向拟孔胶质和苍白球的途径 直接的途径，直接的胶囊丘脑途径和pallidopeduncular途径 间接（通过将抑制传入靶向GP Pars Interna GPI）。术前7特斯拉 结构和扩散加权的MRI扫描和术后高分辨率CT扫描将会 确定相对于核和纤维区域的电极位置和方向。特定于患者 这些成像数据集中的模型将估计每条纤维的激活百分比，并且 新颖的粒子群优化将设计刺激设置，以最大化 比较途径之间的激活。 AIMS 1（STN）和2（GP）比较单一的设置 会话，受试者内实验设计。 AIM 3将设置与更长的清洗范围进行比较。 间隔，还将使用实验室测试会话之间的数据 功能状况和生活质量。该项目将全面研究DBS如何 以特定于患者的基础来量身定制，以治疗猪的残疾症状。