Electrical impedance myography and a little MUNE Seward

Electrical impedance myography (and a little MUNE) Seward B. Rutkove, MD Beth Israel Deaconess Medical Center Harvard Medical School

Disclosures 1. Consultant and equity in Convergence Medical Devices, Inc. 2. Consulting for Neuralstem, Inc. , 3. Two patent applications in electrical impedance 4. Grant funding from NIH, ALSA Association, the Spinal Muscular Atrophy Foundation, and NASA.

Electrical impedance testing? • The assessment of characteristics of a material by measuring changes to an applied electrical current • Used in forestry, metallurgy, geology

But also in humans… • Whole body bioimpedance analysis – Total body water/fat • Electrical impedance tomography – Imaging • Electrical impedance mammography (also EIM) – Breast cancer detection • Electrical impedance dermography

Electrical impedance myography The broad hypothesis: Alterations in composition and structure of muscle with disease will impact the electrical impedance of muscle in unique and reproducible ways.

Different disorders, different pathologies Normal Myopathy/Dystrophy Neurogenic Disuse Atrophy

Electrical impedance in healthy muscle Current Generator Voltmeter Applied electrical current Measured voltage amplitude is proportional to muscle resistance (R) Tissue reactance (X), related to capacitance, causes shift in timing Measured voltage

Electrical impedance in diseased muscle Current Generator Voltmeter Applied electrical current Increased tissue Resistance (R) causes higher amplitude voltage From neuromuscular. wustl. edu Reduced tissue Reactance (X) causes reduced shift in timing Measured voltage Phase will decrease Phase = arctan(X/R)

Off-the-shelf bioimpedance devices Useful, but limited • Single Frequency • Multifrequency

Instrumentation: Past and Present 2001 2005 2009

On the animal front

Phase (degrees) Resistance (ohms) Reactance (ohms) What we measure

Raw muscle data • Gives us the capability of relating surface data to intrinsic muscle data and vice versa • Measure muscle conductivity and permittivity

Conductivity and permittivity plots Ahad et al, 2009

Repeatability Adhesive electrodes-humans Healthy ALS CMD system-humans Rats Mice

Current Data? – ALS – SMA – DMD – Sarcopenia – Nerve injury (radiculopathy, crush models) – AMN

Follow-up ALSA-funded study • Patient visits approximately 3 months apart (a total of 5 visits over 1 year) • 8 Sites involved, 60 patients • EIM measurements performed on • Biceps, wrist extensors, abductor pollicis brevis, quadriceps, and tibialis anterior • Intra-session repeatability on biceps • Also performed handheld dynamometry, ALSFRS, MUNE • Major EIM outcome measure: – Rate of decline in 50 k. Hz phase

Results: In patient terms for 6 month trial Assuming 6 month, placebo-controlled trial, 3 measurements, 20% treatment effect, p < 0. 05, one-sided

Neuralstem study Glass et al, 2012, Stem Cells

ALS Rat Data: Measuring Disease Progression 16 animals followed from pre-symptomatic to death Advanced Early Advanced Wang et al, 2011

SOD 1 g 93 a ALS rat data Wang et al, 2011

As a biomarker in spinal muscular atrophy • Natural history study of EIM in SMA, funded by SMA Foundation – Collaborative effort with Children’s Hospital Boston, Dr. Basil Darras – 28 SMA children mean age 9. 6 years, followed for mean of 16 months – 20 Normal children enrolled, mean age 9. 8 years, followed for mean of 17 months – Mainly Type 2 and Type 3 children

SMA Multifrequency Data

SMA cross-sectional data Type 2 Type 3 healthy

SMA in older kids: no active motor neuron loss, but no muscle growth either Healthy kids SMA P = 0. 018 From Rutkove et al, 2012

Primary muscle disease Tarulli et al, 2006

Preliminary DMD data:

Quantitative Ultrasound and EIM in DMD (QED) • Funded by NIH/NIAMS fall 2011 • Basil Darras, MD: Co-PI • Enrolling 35 healthy kids and 35 with DMD and follow over 2 years • Frequent measurements early on; less frequent later • Started recruiting in March; about 17 DMD boys and 15 healthy boys already recruited

Sarcopenia Quadriceps Tibialis anterior From Aaron et al, 2006

EIM in 4 healthy older subjects over a several year period Two subjects overlap Quadriceps From Aaron et al, 2006

And sensitive to improvement too… • Improvement in EIM data upon returning to normal activity after recovery from ankle fracture Mean Value Closed circles, upon partial or full recovery Open circles, immediately after injury Lower limit of normal From Tarulli et al, 2009

Hind Limb Suspension studies in rats and mice: A model for assessing sarcopenia and disuse

EIM phase declines and recovers with hind limb suspension N = 45

Relationship between phase and muscle fiber size

What does it mean? • Is correlation sufficient? • How do we an answer the question? – Animal models? – Tissue culture studies? – Single cell studies?

Thanks • Physicists and Engineers • • Carl Shiffman, Ph. D Ronald Aaron, Ph. D Joel Dawson, Ph. D Jacob White, Ph. D • Physician researchers • • • Andrew Tarulli, MD Basil Darras, MD Pushpa Narayanaswami, MD Jeremy Shefner, MD, Ph. D Ted Burns, MD (also for wine) Mary Bouxsein, Ph. D Jonathan Bean, MD Jonathan Glass, MD Eva Feldman, MD, Ph. D Jim Caress, MD Michael Benatar, MD • Research Staff • • • Mohammad Ahad, Ph. D Jia Li, Ph. D Lucy Wang Phil Mongiovi Minhee Sung Mina Jafarpoor Lindsay Garmirian Anne Chin Andrew Spieker • Convergence Medical Devices • • Jose Bohorquez, Ph. D Mike Rinehart, Ph. D Neil Lupton, Ph. D Laura Freeman, RN

Funding R 01 NS 055099; R 01 AR 060850; K 24 NS 060951