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

描述（由申请人提供）：该奖项将允许候选人在必要的保护时间内专注于原发性全身性肌张力障碍（PGD）的功能MRI （fMRI）研究的发展，并提供一个精通与其研究领域相关的新研究领域的机会。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培养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、以患者为导向的转化研究者。本研究的总体目标是在休息和执行特定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）发展的病理生理基础，以及由于刺激苍白球（GPi）内节导致的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，导致运动控制的进行性丧失，同时保留智力功能。这些患者往往严重残疾，无法照顾自己，对药物治疗的反应往往不佳。世界各地的一些中心，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。尽管越来越多的证据表明PGD是一种有效的治疗方法，可使肌张力障碍运动减少50%，但PGD发展的病理生理基础和DBS改善PGD的机制都尚不清楚。这些研究将为肌张力障碍的病理生理学和深部脑刺激产生其益处的机制提供见解。与正常对照相比，本研究的结果将更清楚地了解PGD中皮层下和皮层结构的激活模式，以及这些激活模式在GPi DBS期间如何随时间变化。激活模式的时间变化将与患者的症状相关联，以阐明其与患者症状学的关系。这些数据不仅将促进肌张力障碍的治疗，而且将为DBS的工作机制提供重要的新数据。这一信息可能对目前正在探索的其他神经和精神疾病的治疗有用。

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.