Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor after successful Deep Brain Stimulation to the dentato-rubro-thalamic tract

阐明对齿状红丘脑束成功进行深部脑刺激后特发性震颤结构和功能连接变化的暂时性

• 批准号: 10487557
• 负责人: ALBERT J FENOY
• 金额: --
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487557
• 关键词: Acute; Adult; Ataxia; Atlases; Axon; Biological Markers; Blood flow; Brain; Brain region; Cell Nucleus; Cerebellum; Chronic; Clinical; Contralateral; Deep Brain Stimulation; Dentate nucleus; Development; Diffuse; Diffusion; Disease; Electrocorticogram; Electrophysiology (science); Essential Tremor; Evolution; Exhibits; Failure; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gait Ataxia; Goals; Image; Implant; Individual; Knowledge; Lesion; Limb Ataxia; Maps; Mediator of activation protein; Metabolic; Methodology; Methods; Modeling; Motor; Motor Cortex; Movement Disorders; Network-based; Operative Surgical Procedures; Output; Pacemakers; Paresthesia; Parietal; Parietal Lobe; Pathology; Pathway interactions; Patient Selection; Patients; Periodicity; Pharmaceutical Preparations; Positron-Emission Tomography; Red nucleus structure; Rest; Role; Symptoms; Techniques; Thalamic structure; Therapeutic; Therapeutic Intervention; Time; Travel; Tremor; Work; base; clinical effect; effective therapy; imaging modality; improved; innovation; insight; novel; prospective; recruit; response; serial imaging; side effect; theories; tool; tractography; treatment response; treatment strategy; visual motor

Project Summary The symptoms of Essential Tremor (ET), the most common movement disorder in adults, are seriously disabling and are only marginally improved by medication alone. Tremor control has improved greatly with the use of deep brain stimulation (DBS) to the ventrointermediate nucleus (Vim) of the thalamus, a node along a circuit of abnormal rhythmic output in ET that travels from the cerebellar dentate nucleus to the contralateral red nucleus and cortex via the dentato-rubro-thalamic tract (DRTt). Recent advances in diffusion imaging have led to the development of tractography techniques where the structural connectivity of fiber tracts such as the DRTt can be illustrated and then, as we have shown, directly targeted during DBS surgery for excellent clinical effect. Despite such novel targeting methodology and initial tremor improvement, however, the development of side effects such as progressive gait ataxia and waning efficacy after years of chronic stimulation points to the fact that the pathology of essential tremor is poorly understood. Such incomplete knowledge of the network effects of chronic stimulation in ET is a major barrier that needs to be overcome through understanding the dysfunction and modulation of the connectivity of the cerebellar-thalamic-cortical (CTC) network over time. Resting state functional MRI (rsfMRI) has emerged as a powerful tool to explore the functional connectivity between different brain regions and has improved the idea of ET as a network-based disease not confined to the motor circuit, including parietal visuomotor processing cortices; however, comparisons pre- and post- DBS have not been performed. The use of positron emission tomography (PET) has correlated ataxic side effect with cerebellar metabolic changes after chronic DBS; however, associated changes seen with rsfMRI are unknown. Our long-term goal is to understand how stimulation of the DRTt causes network-level effects over time. Our central hypothesis is that structural and functional connectivity of the DRTt correlates with clinical response to DBS in a time-dependent fashion. In pursuit of this hypothesis, we will recruit new ET patients already undergoing DBS and additionally perform imaging analysis to elucidate the effects of stimulation and define DRTt connectivity. In Aim 1, we seek to define the structural connectivity of the DRTt by using tractography methods and compare over time diffusivity changes correlated with clinical response and/or ataxic side effect. In Aim 2, we seek to detect functional network changes due to DBS by using rsfMRI obtained serially in ON/OFF states, where we will track the evolution of altered connectivity changes over time. In Aim 3, we seek to confirm the cortical mediators of tremor identified in Aims 1 and 2 by use of intraoperative electrocorticography during DBS. This innovative combination of using a novel targeting technique and serial imaging across DBS states will advance our understanding of the larger network response to DBS, which is essential to develop more specific stimulation of fibers to improve response and avoid side effects in ET.

项目概要 特发性震颤 (ET) 是成人最常见的运动障碍，其症状非常严重 致残，并且仅通过药物治疗只能略微改善。震颤控制有了很大改善 使用深部脑刺激 (DBS) 刺激丘脑的腹中间核 (Vim)，丘脑的一个节点 ET 中异常节律输出的回路，从小脑齿状核传播到对侧红细胞 通过齿状红丘脑束 (DRTt) 进入细胞核和皮质。扩散成像的最新进展已导致 纤维束成像技术的发展，其中纤维束的结构连通性，如 DRTt 可以进行说明，然后，正如我们所展示的，在 DBS 手术期间直接靶向，以获得优异的临床效果。 尽管有如此新颖的瞄准方法和初始震颤的改善，但是，侧面的发展 进行性步态共济失调和多年慢性刺激后功效减弱等影响表明了这一事实 人们对特发性震颤的病理学知之甚少。对网络的了解如此不全面 慢性刺激对 ET 的影响是一个主要障碍，需要通过了解 随着时间的推移，小脑-丘脑-皮质（CTC）网络的连接功能障碍和调节。 静息态功能 MRI (rsfMRI) 已成为探索功能连接的强大工具 不同大脑区域之间的联系，并改进了 ET 作为一种基于网络的疾病的观念，而不仅限于 运动回路，包括顶叶视觉运动处理皮层；然而，DBS 前后的比较 尚未执行。正电子发射断层扫描 (PET) 的使用与共济失调副作用相关 慢性 DBS 后小脑代谢变化；然而，rsfMRI 观察到的相关变化尚不清楚。 我们的长期目标是了解 DRTt 的刺激如何随着时间的推移引起网络层面的影响。我们的 中心假设是 DRTt 的结构和功能连接与临床相关 以时间相关的方式对 DBS 做出反应。为了实现这一假设，我们将招募新的 ET 患者 已经接受 DBS 并另外进行成像分析以阐明刺激的影响 并定义 DRTt 连接。在目标 1 中，我们寻求通过使用来定义 DRTt 的结构连通性 纤维束成像方法并比较随时间的扩散率变化与临床反应和/或共济失调的相关性 副作用。在目标 2 中，我们寻求通过使用连续获得的 rsfMRI 来检测 DBS 引起的功能网络变化 在开/关状态下，我们将跟踪连接变化随时间的演变。在目标 3 中，我们寻求 通过术中皮质电图确认目标 1 和 2 中确定的震颤的皮质介质 在星展银行期间。这种创新的组合使用了一种新颖的靶向技术和整个 DBS 的串行成像 各州将加深我们对星展银行更大网络响应的理解，这对于开发更多 对纤维进行特定刺激，以改善 ET 的反应并避免副作用。