Next generation electrical impedance myography: the virtual muscle biopsy

 描述(申请人提供)：一种非侵入性的方法可以提供肌肉微观状况的定量数据，可以彻底改变从肌萎缩侧索硬化症到肌肉营养不良等神经肌肉疾病患者的治疗。虽然超声和核磁共振等成像技术可以提供有用和重要的测量肌肉大小和肌肉中是否存在水肿或脂肪渗透的指标，但这些方法提供的关于肌肉本身的微观状况的信息很少。一种有可能成为“虚拟肌肉活组织检查”的技术方法是电阻抗肌层摄影术(EIM)。长期以来，阻抗测量一直被认为是提供细胞大小、细胞外环境以及在施加甚高频电流的情况下细胞内结构的间接测量。EIM是一种专注于肌肉的非侵入性阻抗技术，它的最新发展使这一新的目标成为可能。显然，期望一种非侵入性技术可以实现实际肌肉组织所能实现的所有功能，如免疫组织化学和生化分析，是不合理的。然而，在各种神经肌肉疾病的治疗试验中，有可能获得关于肌肉微观状况的丰富的定量信息，以帮助进行初步诊断，更有可能的是，有助于疾病监测。这项研究的基本假设是，通过应用多频电阻抗测量，结合有限元和电气等效电路分析技术，我们可以非侵入性地获得肌肉某些微观特征的定量信息。我们计划通过研究各种老鼠模型来测试这一想法。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肉纤维之间的关系来精确测量肌肉纤维大小，包括来自未成熟动物、药物诱导的肥大的肌肉纤维和疾病模型的肌肉纤维。第二个具体目标将集中在通过评估几个模型中的低频数据来测量细胞外空间，这些模型包括mdx小鼠、db/db肥胖小鼠和药物诱导的炎症模型。在第三个具体目标中，我们将重点识别细胞内的异常，包括线粒体含量异常、糖原异常堆积和空泡化。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对其视而不见的动物群体。最后，作为我们研究共享计划的一部分，我们将开发一个在线用户界面，以帮助确保这项工作的结果广泛提供给研究人员，包括那些只对电阻抗方法略有熟悉的研究人员。

 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.