Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response.

特发性震颤（ET）是最常见的震颤性疾病，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的病理生理学知之甚少，震颤的来源仍然存在争议，因为所有研究均显示小脑活动增加（包括对照组中的模拟震颤），而使用harmonic的ET动物模型和单一人类PET研究涉及脑干中的下橄榄核。 有证据表明，从我们的实验室，使用静息态功能磁共振成像（rs-fMRI）是有用的特征异常震颤神经网络与对照组相比，在ET，没有性能相关的混淆与以前的任务为基础的方法。利用这些数据，我们计划使用更敏感的自相关方法来表征患者和对照组的全脑连接。目标是确定震颤的来源，假设震颤在休息期间保持活跃。 目前的ET诊断标准要求存在姿势性和/或运动性震颤，这被认为是同一震颤振荡器的不同表现。基于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病理生理学和治疗具有重要意义。首先，患者可以呈现与另一种震颤亚型不成比例的量。其次，治疗可以不成比例地改善一种亚型。最后，我们实验室使用基于任务的fMRI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。我们计划测试的假设，姿势和动力震颤是通过不同的神经机制产生的。 ET的治疗集中于各种机制的药理学药物（例如，b受体阻滞剂、抗惊厥药、苯二氮卓类），很少对Vim丘脑进行脑深部刺激。尽管用于治疗ET的药物种类繁多，但只有约50%的患者从特定药物中获益。此外，对震颤的作用机制通常还不清楚。了解各种震颤抑制剂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（目前最有效的震颤抑制剂）和普萘洛尔（一种非特异性B-肾上腺素能阻滞剂，具有已证实的疗效和未知的作用机制）对震颤神经网络的影响。 该建议的目标和方法对于进一步理解ET的病理生理学、表型变异和治疗策略的发展至关重要。虽然所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导致更好地了解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.