FMRI Study of the Effects of DBS in Primary Generalized Dystonia (K23)

描述(由申请者提供)：该奖项将给予候选人必要的保护时间，以专注于发展初级泛发性肌无力(PGD)的功能磁共振(FMRI)研究，并提供机会精通与其研究领域相关的新研究领域。在导师的指导下，候选人将在纵向临床研究和功能磁共振技术方面发展独立的研究技能和能力。这种有指导的培训经验将使他在接下来的几年里成为一名独立的、以患者为导向的翻译调查员。这项研究的总体目标是在休息和执行特定的感觉和运动任务时使用功能磁共振成像，旨在阐明原发性全身性肌张力障碍(PGD)发生的病理生理学基础，以及由于刺激苍白球(GPI)内段而导致的与PGD症状改善相关的变化。PGD是一种始于儿童和年轻人的疾病，会导致运动控制的进行性丧失，同时保留智力功能。患者往往严重残疾，无法照顾自己，对药物治疗往往反应不佳。世界各地的精选中心，包括我们自己的中心，现在都在使用深部脑刺激(DBS)来治疗肌张力障碍。虽然越来越多的证据表明，它是一种有效的治疗方法，可以减少50%的肌张力障碍运动，但PGD发生的病理生理学基础以及DBS改善其作用的机制尚不清楚。这些研究将为肌张力障碍的病理生理学和脑深部刺激产生益处的机制提供洞察力。这项研究的结果将使我们更清楚地了解与正常对照组相比，PGD患者皮质下和皮质结构中的激活模式，以及这些激活模式是如何在GPI DBS期间随时间变化的。激活模式的时间变化将与患者的症状相关联，以澄清它们与患者症状的关系。这些数据不仅将推进肌张力障碍的治疗，还将为DBS的工作机制提供重要的新数据。这些信息可能对DBS正在探索的其他神经和精神障碍的治疗有用。

DESCRIPTION (provided by applicant): This Award will allow the candidate the protected time necessary to focus his efforts on the development of functional MRI (fMRI) research in Primary Generalized Dystonia (PGD) and provide an opportunity to become well-versed in new areas of study relevant to his research field. Under the guidance of his mentors, the candidate will develop independent research skills and abilities in longitudinal clinical investigations and functional magnetic resonance techniques. This mentored training experience will lead to his establishment as an independent, patient-oriented translational investigator in the following years. The overall goal of this study is to use fMRI both at rest and during the performance of specific sensory and motor tasks designed to clarify the pathophysiological basis underlying the development of primary generalized dystonia (PGD), and the changes that occur associated with the symptomatic improvement in PGD as a result of stimulation in the internal segment of the globus pallidus (GPi). PGD is a disorder that begins in children and young adults, and leads to progressive loss of motor control, while sparing intellectual function. The patients are often significantly disabled and unable to care for themselves and often do not respond well to medical therapy. Select centers around the world, including our own, are now using deep brain stimulation (DBS) to treat dystonia. Although it has increasingly been demonstrated as an effective therapy with > 50% reduction in dystonic movements, neither the pathophysiological basis underlying the development of PGD nor the mechanism underlying its improvement with DBS is known. These studies will provide insight into both the pathophysiology of dystonia, and the mechanism by which deep brain stimulation produces its benefit. The results of this study will provide a more clear understanding of the activation patterns in subcortical and cortical structures in PGD compared to normal controls and how these activation patterns are changed over time during GPi DBS. The temporal changes in activation patterns will be correlated with the patients' symptoms to clarify their relationship to the patients' symptomatology. These data will not only advance the treatment of dystonia but will also provide important new data regarding the mechanism by which DBS works. This information may be useful for the treatment of other neurologic and psychiatric disorders for which DBS is now being explored.