Peripheral nerve and muscle disorders that produce weakness and dysfunction taken as a whole are relatively common and include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), muscular dystrophy, and even the generalized condition of sarcopenia, or muscle deterioration in the elderly. Given a variety of discoveries in basic science, a plethora of new therapies is reaching the stage of pre-clinical and clinical testing. In order to test the efficacy of these drugs, effective, sensitive biomarkers are needed both for early disease identification and for following disease progression. One technique that has the promise of serving as an effective biomarker is electrical impedance myography (EIM). In this technique, a minute electrical current is applied to a muscle via surface electrodes and the resulting surface voltages measured. From these data, the tissue's resistance and reactance are obtained, providing structural and compositional information on the health of the underlying muscle. Several human clinical studies are demonstrating the potential power of EIM. However, in order for EIM to reach its full potential, an improved understanding of the relationship between EIM and underlying muscle pathology is still needed. In the past 4 years since the initiation of grant R01-055099, we have made substantial in-roads in that direction, exploring impedance alterations in two basic rat disease models, while also developing a set of experimental and analytic tools. In this renewal, we plan to continue to this work, expanding our studies into new and relevant models of neuromuscular disease, further refining the science and technology of EIM. Our broad hypothesis is that alterations in surface EIM data reflect the inherent electrical material properties of muscle, and that these properties are directly impacted by muscle pathology. We plan to test this by studying mouse models of four distinct neuromuscular disorders and comparing data across them and within them as the disorders progress. In addition to EIM data, behavioral, electrophysiological, and histological data will be collected.
In Specific Aim 1, we will study EIM in the SOD1 G93A model of ALS as an example of a progressive motor neuron disorder.
In Specific Aim 2, we will study EIM in the recently developed FVBn C/C mouse model of SMA, a disease characterized by both primary and secondary muscle degeneration.
In Specific Aim 3, we will study EIM in the MDx mouse model of Duchenne muscular dystrophy, in which there are marked structural and compositional changes in muscle. And in Specific Aim 4, we will study EIM in the aged mouse model sarcopenia, a condition in which a combination of disuse and fibrotic change renders the muscle weak. As part of this work we will also apply a number of innovations, including refined measuring and analytic techniques, such as EIM assessment of contraction and anisotropic measurement and finite element modeling of electrical current flow. With the successful completion of this research, we will have greatly expanded our tools to effectively apply and interpret EIM in both pre-clinical animal studies and human clinical research.

Public Health Relevance

Electrical impedance myography (EIM) is a new, non-invasive tool for the evaluation of muscle that can serve as an effective method for neuromuscular disease assessment. This study will evaluate EIM changes in several animal models of neuromuscular disease, with the goal of improving our ability to measure and interpret EIM data. With the completion of this work, it will be possible to utilize EIM more effectively in both pre-clinical animal studies and human clinical trials, in order to help speed the search and discovery of effective therapies for a variety of neuromuscular diseases, ranging from amyotrophic lateral sclerosis to muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055099-07
Application #
8415877
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Porter, John D
Project Start
2006-04-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
7
Fiscal Year
2013
Total Cost
$367,304
Indirect Cost
$156,210
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Sanchez, Benjamin; Rutkove, Seward B (2017) Electrical Impedance Myography and Its Applications in Neuromuscular Disorders. Neurotherapeutics 14:107-118
Sanchez, Benjamin; Iyer, Shama R; Li, Jia et al. (2017) Non-invasive assessment of muscle injury in healthy and dystrophic animals with electrical impedance myography. Muscle Nerve 56:E85-E94
Hakim, Chady H; Mijailovic, Alex; Lessa, Thais B et al. (2017) Non-invasive evaluation of muscle disease in the canine model of Duchenne muscular dystrophy by electrical impedance myography. PLoS One 12:e0173557
Li, Jia; Yim, Sung; Pacheck, Adam et al. (2016) Electrical Impedance Myography to Detect the Effects of Electrical Muscle Stimulation in Wild Type and Mdx Mice. PLoS One 11:e0151415
Sanchez, Benjamin; Li, Jia; Geisbush, Tom et al. (2016) Impedance Alterations in Healthy and Diseased Mice During Electrically Induced Muscle Contraction. IEEE Trans Biomed Eng 63:1602-12
Arnold, W; McGovern, Vicki L; Sanchez, Benjamin et al. (2016) The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy. Neurobiol Dis 87:116-23
Pacheck, Adam; Mijailovic, Alex; Yim, Sung et al. (2016) Tongue electrical impedance in amyotrophic lateral sclerosis modeled using the finite element method. Clin Neurophysiol 127:1886-90
Rutkove, Seward B; Wu, Jim S; Zaidman, Craig et al. (2016) Loss of electrical anisotropy is an unrecognized feature of dystrophic muscle that may serve as a convenient index of disease status. Clin Neurophysiol 127:3546-3551
Li, Jia; Pacheck, Adam; Sanchez, Benjamin et al. (2016) Single and modeled multifrequency electrical impedance myography parameters and their relationship to force production in the ALS SOD1G93A mouse. Amyotroph Lateral Scler Frontotemporal Degener 17:397-403
Wu, Jim S; Li, Jia; Greenman, Robert L et al. (2015) Assessment of aged mdx mice by electrical impedance myography and magnetic resonance imaging. Muscle Nerve 52:598-604

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