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: 8193794
• 负责人: Fatta B Nahab
• 金额: $ 33.1万
• 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/8193794
• 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. PUBLIC HEALTH RELEVANCE: Essential tremor (ET) is the most common tremor disorder currently affecting ~ 2.9 million Americans of all ages, and is estimated to have a prevalence of 4.1 million by 2025. Of those affected, 75% experience significant morbidity in productivity, quality of life and activities of daily living. This proposal addresses this critical public health challenge using novel approaches to: 1) identify its neural correlates (aim 1), characterize the phenotypic spectrum of this disorder (aim 2), and elucidate the mechanisms of treatment with the goal of developing more targeted and effective therapies (aim 3).

描述（由申请人提供）：原发性震颤 (ET) 是最常见的震颤疾病，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。人们对 ET 的病理生理学知之甚少，震颤的来源仍然存在争议，因为所有研究都显示小脑活动增加（包括对照中的模拟震颤），而使用骆驼蓬碱的 ET 动物模型和单个人类 PET 研究表明，脑干中的下橄榄核有关。 我们实验室的证据表明，与对照组相比，使用静息态功能磁共振成像 (rs-fMRI) 有助于表征 ET 中的异常震颤神经网络，并且不会出现与先前基于任务的方法相关的与表现相关的混淆。利用这些数据，我们计划使用更灵敏的自相关方法来表征患者和对照组的全脑连接。目标是确定震颤的来源，假设震颤在休息期间仍然活跃。 目前的 ET 诊断标准要求存在姿势性和/或动力性震颤，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，这一长期存在的假设可能是不正确的，并且对于理解 ET 病理生理学和治疗具有重大意义。首先，患者出现的一种震颤亚型的数量可能多于另一种震颤亚型。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。我们计划检验姿势和运动性震颤是通过不同的神经机制产生的假设。 ET 的治疗侧重于各种机制的药物（例如 b 阻滞剂、抗惊厥药、苯二氮卓类药物），很少使用 Vim 丘脑深部脑刺激。尽管用于治疗 ET 的药物种类繁多，但只有约 50% 的患者从特定药物中受益。此外，对震颤的作用机制尚不清楚。了解各种震颤抑制剂的作用机制对于未来的药物开发至关重要。在本提案中，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β-肾上腺素能阻滞剂，其功效已被证实，但作用机制未知）对震颤神经网络的影响。 该提案中的目标和方法对于进一步了解 ET 病理生理学、表型变异和治疗策略的制定至关重要。虽然所提出的方法代表了传统神经影像方法的转变，但我们的初步工作证明了我们执行每个组件的能力。解决当前的这些障碍将有助于更好地了解 ET 生理学、表型变异和治疗机制，最终目标是减少残疾和提高生活质量。 公共卫生相关性：特发性震颤 (ET) 是最常见的震颤疾病，目前影响约 290 万各个年龄段的美国人，预计到 2025 年患病率将达到 410 万。在受影响的人中，75% 的人在生产力、生活质量和日常生活活动方面出现显着的发病率。该提案使用新颖的方法解决这一关键的公共卫生挑战：1）确定其神经相关性（目标 1），描述这种疾病的表型谱（目标 2），并阐明治疗机制，以开发更有针对性和更有效的疗法（目标 3）。