Electrical impedance myography

Electrical Impedance Myography, or EIM, is a non-invasive technique that uses the electrical impedance of individual muscles as a diagnostic tool for a number of neuromuscular diseases. Muscle composition changes with disease progression, and EIM measures changes in impedance that occur as a result of disease pathology. To apply the technique, four surface electrodes are placed along the muscle of interest. A minute alternating current is applied across the outer two electrodes, and voltage signals are recorded by the inner electrodes. From these recordings, one can calculate the electrical impedance of the muscle at a given input frequency.

EIM has shown abnormalities in impedance characteristics in several neuromuscular diseases, including amyotrophic lateral sclerosis (ALS), radiculopathy, and inflammatory myopathy. It is currently being used to study spinal muscular atrophy (SMA) as well.

Biological relevance

Interest in electrical impedance dates back to the turn of the 20th century, when physiologist Louis Lapicque postulated an elementary circuit to model membranes of nerve cells. Scientists experimented with variations on this model until 1940, when Kenneth Cole developed a circuit model that accounted for the impedance properties of both cell membranes and intracellular fluid. EIM hinges on a simplified model of muscle tissue as an RC circuit. This model attributes the resistive component of the circuit to the resistance of extracellular and intracellular fluids, and the reactive component to the capacitive effects of cell membranes. The integrity of individual cell membranes has a significant effect on the tissue’s impedance; hence, a muscle’s impedance can be used to measure the tissue’s degradation in disease progression. In neuromuscular disease, muscle fibers can atrophy, become disorganized, or be replaced with fatty tissue. EIM captures these changes in the tissue as a whole by measuring its impedance properties.

In EIM, impedance is separated into resistance and reactance, its real and imaginary components. From this, one can compute the muscle’s phase, which represents the time-shift that a sinusoid undergoes when passing through the muscle. For a given resistance (R) and reactance (X), phase (θ) can be calculated as

$\theta=tan^{-1}\left(\frac{X}{R}\right)$

Of the three impedance factors, phase is studied most often as it eliminates the dependence on muscle size and shape present in both resistance and reactance.

Recently EIM was recognized for its potential as an ALS biomarker (also known as a biological correlate or surrogate endpoint) by Prize4Life, a 501(c)(3) nonprofit organization dedicated to accelerating the discovery of treatments and cures for ALS. The $1M ALS Biomarker Challenge focused on identifying a biomarker precise and reliable enough to cut Phase II drug trials in half. Dr. Seward Rutkove, chief, Division of Neuromuscular Disease, in the Department of Neurology at Beth Israel Deaconess Medical Center and is Associate Professor of Neurology at Harvard Medical School, has published over two dozen papers researching the potential of EIM and was the basis of the Award. It is hoped that EIM as a biomarker will have an impact on both the identification of new and better treatments for neuromuscular disease as well as improvements in patient care.

Muscle anisotropy

Electrical impedance of muscle tissue is anisotropic; current flowing parallel to muscle fibers flows differently than current flowing orthogonally across the fibers. Current flowing orthogonally across a muscle encounters more cell membranes, thus increasing resistance, reactance, and phase values. By taking measurements at different angles with respect to muscle fibers, EIM can be used to determine the anisotropy of a given muscle. Anisotropy tends to be shown either as a graph plotting resistance, reactance, or phase as a function of angle with respect to the direction of muscle fibers or as a ratio of transverse (perpendicular to fibers) measurement to longitudinal measurement (parallel to muscle fibers) of a given impedance factor.

Muscle anisotropy also changes with neuromuscular disease. EIM has shown a difference between anisotropy profiles of neuromuscular disease patients and healthy controls. In addition, EIM can use anisotropy to discriminate between myopathic and neurogenic disease. Different forms of neuromuscular disease have unique anisotropies. Myopathic disease is characterized by decreased anisotropy. Neurogenic disease produces a less predictable anisotropy. The angle of lowest phase may be shifted from the parallel position, and the anisotropy as a whole is often greater than that of a healthy control.

Multifrequency measurements

Both resistance and reactance depend on the input frequency of the signal. Because changes in frequency shift the relative contributions of resistance (fluid) and reactance (membrane) to impedance, multifrequency EIM may allow a more comprehensive assessment of disease. Resistance, reactance, or phase can be plotted as a function of frequency to demonstrate the differences in frequency dependence between healthy and diseased groups. Diseased muscle exhibits an increase in reactance and phase with increasing frequency, while reactance and phase values of healthy muscle increase with frequency until 50-100 kHz, at which point they begin to decrease as a function of frequency. Frequencies ranging from 500 Hz to 2 MHz are used to determine the frequency spectrum for a given muscle.

Measurement systems

EIM has been performed with a number of different impedance analysis devices. Commercially-available systems used for bioimpedance analysis, can be calibrated to measure impedance of individual muscles. A suitable impedance analyzer can also be custom built using a lock-in amplifier to produce the signal and a low-capacitance probe, such as the Tektronix P6243, to record voltages from the surface electrodes.

A hand-held device has also been built to conduct EIM, consisting of HS3 and HS4 oscilloscopes from TiePie Engineering to send and record the signal and a custom-designed wand to apply voltages to the skin. Instead of attaching to an impedance analysis system via surface electrodes, this hand-held array can be placed directly on the subject. The device features an array of electrode plates, which can be selectively activated to perform impedance measurements in arbitrary orientations. The oscilloscopes have been programmed to produce a compound sinusoid signal, which can be used to measure the impedance at multiple frequencies simultaneously via a Fast Fourier transform. Thus, the hand-held device can quickly and easily generate data detailing the anisotropy and frequency dependence of muscle impedance.