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

项目摘要 特发性震颤（ET）是成人最常见的运动障碍，其症状严重， 致残，仅通过药物治疗仅略有改善。震颤控制有了很大的改善， 使用脑深部刺激（DBS）到丘脑的腹中间核（Vim），沿着丘脑的腹中间核的节点沿着丘脑的腹中间核的节点， ET中从小脑齿状核到对侧红细胞的异常节律输出回路 通过齿状核-红核-丘脑束（DRTt）连接到核和皮质。扩散成像的最新进展导致 纤维束成像技术的发展，其中纤维束的结构连接，如DRTt 可以举例说明，然后，如我们所示，在DBS手术期间直接靶向，以获得出色的临床效果。 尽管有这种新的靶向方法和初始震颤改善，但是， 进行性步态共济失调和多年慢性刺激后疗效减弱等效应表明， 对特发性震颤的病理学了解甚少这种对网络的不完全了解 慢性刺激对ET的影响是一个主要的障碍，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。 静息态功能磁共振成像（restingstatefunctionalMRI，rsfMRI）是研究脑功能连接的有力工具 在不同的大脑区域之间，并改进了ET作为一种基于网络的疾病的想法， 运动回路，包括顶叶视觉处理皮层;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水平的影响。我们 中心假设是DRTt的结构和功能连接与临床 对DBS的反应呈时间依赖性。为了实现这一假设，我们将招募新的ET患者， 已经接受DBS并额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，我们试图通过使用以下公式来定义DRTt的结构连接性： 纤维束成像方法，并比较与临床反应和/或共济失调相关的扩散率随时间的变化 副作用在目标2中，我们试图通过使用连续获得的rsfMRI来检测DBS引起的功能网络变化 在ON/OFF状态下，我们将跟踪随着时间的推移改变的连接变化的演变。在目标3中，我们寻求 通过使用术中皮质电描记术确认目标1和2中确定的震颤皮质介质 在DBS期间。这种使用新型靶向技术和DBS系列成像的创新组合 各州将促进我们对DBS的更大网络响应的理解，这对于开发更多 特异性刺激纤维，以改善ET的反应并避免副作用。

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.