Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response.

震颤回路的功能成像和治疗反应机制。

• 批准号: 8286203
• 负责人: Fatta B Nahab
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286203
• 关键词: Activities of Daily Living; Acute; Address; Adrenergic Antagonists; Adverse effects; Affect; Age; American; Animal Model; Anticonvulsants; Attention; Benzodiazepines; Biological Markers; Biological Neural Networks; Blood flow; Brain; Brain Stem; Brain region; Cerebellum; Characteristics; Clinical Management; Cues; DNA; Data; Data Set; Deep Brain Stimulation; Development; Devices; Diagnostic; Disease; Dose; Drug Delivery Systems; Essential Tremor; Ethanol; Face; Frequencies; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Generations; Genomics; Goals; Harmaline; Head; Human; Image; Image Analysis; Individual; Inferior; Kinetics; Knowledge; Laboratories; Lead; Leg; Maps; Medulla oblongata olive; Methods; Morbidity - disease rate; Olives - dietary; Operative Surgical Procedures; Outcome; Participant; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Physiology; Positioning Attribute; Positron-Emission Tomography; Prevalence; Productivity; Propranolol; Public Health; Quality of life; Red nucleus structure; Rest; Sampling; Severities; Site; Source; Structure; Tablets; Testing; Thalamic structure; Treatment outcome; Tremor; Voice; Work; age group; alcohol effect; arm; base; blood oxygen level dependent; data acquisition; design; disability; drug development; effective therapy; experience; imaging modality; improved; neuroimaging; neuromechanism; novel; novel strategies; regional difference; relating to nervous system; response; therapeutic development; treatment response

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.

描述（由申请人提供）：基本震颤（ET）是最常见的震颤障碍，目前影响约290万美国人，并导致残疾和降低75％的病例生活质量。 ET的病理生理学知之甚少，由于所有研究表明小脑的活性增加（包括模仿对照中的震颤），而ET的动物模型使用Harmaline和一项人类PET研究暗示了大脑的下橄榄核。 我们实验室有证据表明，与对照组相比，使用静止状态功能磁共振成像（RS-FMRI）可用于表征ET中异常的震颤神经网络，而没有与先前的基于任务的方法相关的性能相关的混杂。使用这些数据，我们计划使用更灵敏的自相关方法来表征患者和对照组中的全脑连接性。目的是确定震颤的来源，该震颤的源头可以在休息期间保持活跃。 当前的ET诊断标准需要存在姿势和/或动力学震颤，这被认为是相同震颤振荡器的不同表现。基于我们实验室的几种证据，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大影响。首先，患者比另一个震颤的震颤量不成比例。其次，治疗可能会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，不同的连通性模式导致每种震颤子类型的产生。我们计划检验以下假设：姿势和动力学震颤是通过不同的神经机制产生的。 ET的处理重点是各种机制的药理剂（例如B阻滞剂，抗惊厥药，苯二氮卓类药物）和对VIM丘脑的大脑刺激很少。尽管有用于治疗ET的药物的各种药物，但只有约50％的患者从特定药物中受益。此外，对震颤的作用机制通常不知道。了解各种震颤剂的作用机制对于未来的药物开发至关重要。在该提案中，我们计划研究乙醇（目前可用的最有效的震颤抑制剂）和普萘洛尔（具有证明功效和未知作用机制的非特异性B-肾上腺素能阻止者）对震颤神经网络的影响。 本提案中的目标和方法对于进一步了解ET病理生理学，表型变异性以及治疗策略的发展至关重要。虽然提出的方法代表了从传统的神经影像学方法的转变，但我们的初步工作证明了我们执行每个组件的能力。解决这些当前障碍将使人们更好地了解ET生理学，表型变异性和治疗机制，以减少残疾和改善生活质量的最终目标。