Next generation electrical impedance myography: the virtual muscle biopsy

 描述（由申请人提供）：一种提供肌肉微观状况定量数据的非侵入性方法可以彻底改变神经肌肉疾病患者的管理，从肌萎缩性侧索硬化到肌营养不良。虽然成像技术，如超声和MRI可以提供有用的和重要的措施，总的肌肉大小和存在的水肿或脂肪浸润的肌肉，这些方式提供最少的信息，微观状况的肌肉本身。一种可能接近于“虚拟肌肉活检”的技术方法是电阻抗肌电图（EIM）。长期以来，人们都知道阻抗测量可以间接测量细胞大小、细胞外环境，以及在应用甚高频电流的情况下测量细胞内结构。EIM是一种以肌肉为中心的非侵入性阻抗技术，其最近的发展使这一新目标成为可能。显然，期望非侵入性技术可以实现实际肌肉组织的所有可能性是不合理的，例如免疫组织化学和生化分析。然而，可以获得大量关于肌肉微观状况的定量信息，以帮助初步诊断，更有可能的是，在各种神经肌肉状况的治疗试验期间进行疾病监测。本研究的基本假设是，通过应用多频电阻抗测量结合有限元和电等效电路分析技术，我们可以获得定量信息的肌肉非侵入性的某些微观特征。我们计划通过研究各种小鼠模型来验证这一想法。在我们的第一个目标中，我们将专注于通过建立阻抗参数与不同大小的肌纤维之间的关系来精确测量肌纤维大小，包括来自未成熟动物、药物诱导的肥大和疾病模型的肌纤维。第二个具体目标将集中于通过评估几种模型（包括mdx小鼠、db/db肥胖小鼠和药物诱导的炎症模型）中的低频数据来测量细胞外间隙。在第三个具体目标中，我们将集中于识别细胞内异常，包括异常线粒体含量，糖原异常积累和空泡化。在第四个目标中，我们将利用开发的分析技术来评估研究人员不知情的动物群体。最后，作为我们的研究共享计划的一部分，我们将开发一个在线用户界面，这将有助于确保这项工作的结果被广泛提供给研究人员，包括那些只熟悉电阻抗方法的人。

 DESCRIPTION (provided by applicant): A non-invasive method that provides quantitative data on the microscopic condition of muscle could revolutionize the management of patients with neuromuscular diseases, ranging from amyotrophic lateral sclerosis to muscular dystrophy. While imaging techniques such as ultrasound and MRI can provide useful and important measures of gross muscle size and the presence of edema or fatty infiltration in the muscle, these modalities provide minimal information on the microscopic condition of the muscle itself. One technological approach that could potentially come close to serving as a "virtual muscle biopsy" is electrical impedance myography (EIM). Impedance measurements have long been known to provide indirect measures of cell size, extracellular milieu and, with the application of very high frequency current, intracellular structure. The recent development of EIM, a muscle-focused, non-invasive impedance technique, now makes this new objective possible. Obviously, it is unreasonable to expect that a non-invasive technique can achieve all that is possible with actual muscle tissue, such as immunohistochemistry and biochemical analysis. Yet, it may be possible to obtain a wealth of quantitative information about the microscopic condition of muscle in order to assist with initial diagnosis and, more likely, disease monitoring during therapy trial in a wide variety of neuromuscular conditions. The underlying hypothesis of this research is that by applying multifrequency electrical impedance measurements in conjunction with finite element and electrical equivalent circuit analytic techniques, we can obtain quantitative information on certain microscopic features of muscle non-invasively. We plan to test this idea by studying a variety of mouse models. In our first aim, we will focus on the accurate measurement of muscle fiber size by establishing a relationship between impedance parameters and muscle fibers of varying size, including those from immature animals, drug-induced hypertrophy, and a disease model. The second specific aim will focus on the measurement of the extracellular space by assessment of low-frequency data in several models including the mdx mouse, the db/db obese mouse, and a model of drug-induced inflammation. In the third specific aim, we will focus on identifying intracellular abnormalities, including abnormal mitochondrial content, abnormal accumulations of glycogen, and vacuolization. In the fourth aim, we will utilize the developed analytic techniques to evaluate groups of animals to which the researchers are blinded. Finally, as part of our research sharing plans, we will develop an online user interface that will help ensure that the results of this work are widely available to researchers including those with only a passing familiarity with electrical impedance methodologies.