Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response.

描述（由申请人提供）：特发性震颤（ET）是最常见的震颤障碍，目前影响约290万美国人，75%的病例导致残疾和生活质量下降。ET的病理生理学尚不清楚，震颤的来源仍然存在争议，因为所有的研究都显示小脑活动增加（包括对照组的模拟震颤），而使用正电子碱的ET动物模型和单个人类PET研究暗示脑干的下橄榄核。我们实验室的证据表明，与对照组相比，静息状态功能磁共振成像（rs-fMRI）的使用有助于表征ET中的异常震颤神经网络，而不存在与先前基于任务的方法相关的性能相关混淆。利用这些数据，我们计划使用一种更敏感的自相关方法来表征患者和对照组的全脑连接。目的是确定震颤的来源，假设震颤在休息时仍保持活跃。目前的ET诊断标准要求存在体位性和/或动态性震颤，这被认为是同一震颤振荡器的不同表现。根据我们实验室的几条证据，这种长期存在的假设可能是不正确的，并且对理解ET的病理生理和治疗具有重要意义。首先，患者表现出的一种震颤亚型比另一种震颤亚型的数量不成比例。其次，治疗可以不成比例地改善一种亚型。最后，我们的实验室使用基于任务的功能磁共振成像方法的证据表明，不同的连接模式导致每种震颤亚型的产生。我们计划测试姿势性和动态性震颤是通过不同的神经机制产生的假设。ET的治疗主要集中在各种机制的药理学药物（如b受体阻滞剂、抗惊厥药、苯二氮卓类药物）和很少对Vim丘脑进行深部脑刺激。尽管用于治疗ET的药物种类繁多，但只有约50%的患者受益于特定的药物。此外，对震颤的作用机制尚不清楚。了解各种震颤抑制药物的作用机制对未来的药物开发至关重要。在这个提议中，我们计划研究乙醇（目前可用的最有效的震颤抑制剂）和心得安（一种非特异性b-肾上腺素能阻滞剂，已被证实有效，作用机制未知）对震颤神经网络的影响。本研究的目标和方法对于进一步了解ET的病理生理、表型变异性和制定治疗策略至关重要。虽然提出的方法代表了传统神经成像方法的转变，但我们的初步工作证明了我们执行每个组件的能力。解决这些目前的障碍将有助于更好地理解ET生理学、表型变异性和治疗机制，最终目标是减少残疾和提高生活质量。

DESCRIPTION (provided by applicant): Essential Tremor (ET) is the most common tremor disorder, currently affecting an estimated 2.9 million Americans and leading to disability and decreased quality of life in 75% of cases. The pathophysiology of ET is poorly understood, with the source of the tremor remaining controversial since all studies show increased activity in the cerebellum (including mimicked tremor in controls), while animal models of ET using harmaline and a single human PET study implicate the inferior olivary nucleus in the brainstem. There is evidence from our laboratory that the use of resting-state functional magnetic resonance imaging (rs-fMRI) is useful for characterizing the aberrant tremor neural network in ET compared with controls, without the performance-related confounds associated with prior task-based methods. Using this data, we plan to use a more sensitive autocorrelation method to characterize whole-brain connectivity in patients and controls. The goal is to identify the source of the tremor, which is hypothesized to remain active during rest. Current ET diagnostic criteria require the presence of postural and/or kinetic tremor, which are assumed to be different manifestations of the same tremor oscillator. This long-standing assumption may be incorrect based on several lines of evidence from our laboratory, and has major implications for understanding ET pathophysiology and treatment. First, patients can present with disproportionate amounts of one tremor subtype than the other. Second, treatments can disproportionately improve one subtype. Lastly, evidence from our lab using task-based fMRI methods suggests different connectivity patterns lead to the generation of each tremor subtype. We plan to test the hypothesis that postural and kinetic tremors are generated through different neural mechanisms. Treatment of ET focuses on pharmacological agents of various mechanisms (e.g. b-blockers, anticonvulsants, benzodiazepines) and rarely deep brain stimulation of the Vim thalamus. Despite the assortment of agents used to treat ET, only ~50% of patients benefit from a particular agent. Furthermore, the mechanisms of action on tremor are not generally known. Understanding the mechanisms of action of various tremor-suppressing agents is critical for future drug development. In this proposal, we plan to study the effects of ethanol (the most efficacious tremor-suppressant currently available) and propranolol (a non-specific b- adrenergic blocker with proven efficacy and unknown mechanism of action) on the tremor neural network. The goals and methods in this proposal are critical to the further understanding of ET pathophysiology, phenotypic variability, and development of therapeutic strategies. While the proposed methods represent a shift from traditional neuroimaging methods, our preliminary work demonstrates our ability to carry out each component. Addressing these current barriers will lead to a better understanding of ET physiology, phenotypic variability and treatment mechanisms with the ultimate goal of reducing disability and improving quality of life.