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• Up through the advent of digitization, quantitative EMG required significant time for acquisition and analysis.
• The EMG laboratory developed a novel technique called multi-motor unit action potential analysis (Nandedkar SD, Barkhaus PE, Charles A: Multi-motor unit action potential analysis [MMA] Muscle Nerve 18:1155-1166, 1995.)
• This technique allowed rapid extraction and analysis of multiple motor unit potentials at a single recording site (3-5 minutes).

Figure 1. Motor unit potentials (MUPs) recorded from one site (center box) where the highlighted box in yellow shows the same MUP in the box to the left where it can be analyzed. The box below it shows an epoch of EMG signal with the highlighted (white) segment that is being analyzed is shown. The far right shows the quantitative analysis of the MUPs (4.1 to 4.4 are highlighted as they are the MUPs displayed in the center box). The far right center box plots outliers and the bottom shows firing rates of the 4 MUPs identified by color and the shaded column shows the segment that has been analyzed.

Figure 2. Display of 18 MUPs from a patient with myopathy. Individual MUPs showing abnormality are highlighted in yellow as well as mean values in table at right..

Selected references:

Nandedkar SD, Barkhaus PE, Charles A: Multi-motor unit action potential analysis (MMA) Muscle Nerve 18:1155-1166, 1995.

Barkhaus PE, Periquet MI, Nandedkar SD: Quantitative electromyography studies in sporadic inclusion body myositis. Muscle Nerve 22:480-87, 1999.

Barkhaus PE, Nandedkar SD: Serial quantitative electrophysiologic studies in sporadic inclusion body myositis. Electromyography & Clinical Neurophysiology, 2007; 47:97-104.

Nandedkar SD, Sheridan C, Bertorini S, Hiner BC, Barkhaus PE: Deep brain stimulator artifact in needle electromyography: Effects and distribution in paraspinal and upper limb muscle. Muscle Nerve 2013; 47:561-565. (n.b. This article was the first article in this journal to have videos as part of the publication.).

Motor Unit Number Indexing (“MUNIX”) is a novel method for estimation of motor units in a muscle. This allows investigators to have a biologic surrogate marker to track motor unit loss in neurogenic processes, specifically amyotrophic lateral sclerosis (ALS). A surface recording is made of the optimized compound muscle action potential (CMAP). The subject then voluntarily activates the muscle at different levels of effort, essentially a surface recorded interference pattern.

Figure 3. Recording of MUNIX: normal subject. Upper left is CMAP. On the right are interference pattern recordings at increasing levels of effort. Their area (surface interference pattern or SIP) is plotted against the “ideal case motor unit count” (ICMUC).

Figure 4. In this patient with amyotrophic lateral sclerosis the amplitude of the compound muscle action potential (CMAP) declines over 12 months (9.1 mV down to 2.9 mV [purple]). The MUNIX value starts at 59 (reduced) and ultimately declines to 8 (dark dashed line). The motor unit size index (MUSIX) shows an increase (successful reinnervation- red dashed line) before ultimately falling (failing reinnervation due to ongoing motor neuron loss). The box at right shows the percent decline over time. Note that MUNIX fell by 86% whereas the CMAP fell to 68% indicating how the reinnervated motor units maintain the CMAP amplitude in patients with slower progression. Unfortunately reinnervation ultimately fails resulting in declines of MUNIX, the CMAP, and MUSIX.

Selected references:

Nandedkar SD, Nandedkar, D, Stålberg EV, Barkhaus PE: Motor Unit Number Index (MUNIX): A new method to study the number of MUs. IEEE Transactions in Biomedical Engineering, 2004; 51(12):2009-2011.

Nandedkar SD, Nandedkar, D, Stålberg EV, Barkhaus PE: Motor Unit Number Index (MUNIX): A new method to study the number of MUs. IEEE Transactions in Biomedical Engineering, 2004; 51(12):2009-2011.

Nandedkar SD, Barkhaus PE, Stålberg EV: Reproducibility of MUNIX in patients with amyotrophic lateral sclerosis. Muscle Nerve 2011; 44: 919-922.

Neuwirth C, Barkhaus PE, Burkhardt C, Castro J, Czell D, de Carvalho M, Nandedkar S, Stålberg E, Weber M: Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis. Clin Neurophysiol 2017 Mar;128(3):495-500 PMID: 28043769 01/04/2017

Nandedkar SD, Barkhaus PE, Stålberg EV, Neuwirth C, Weber M: Motor Unit Number Index (MUNIX): Guidelines for Recording Signals and Their Analysis. Muscle Nerve 2018; 58(3):374-380. doi: 10.1002/mus.26099. PMID: 29427557

Alix JJP, Neuwirth C, Gelder L, Burkhardt C, Castro J, Carvalho M, Gawel M, Goedee S, Grosskreutz J, Lenglet T, Moglia C, Omer T, Schrooten M, Nandedkar S, Stålberg E, Barkhaus PE, Furtula J, van Dijk JP, Baldinger R, Costa J, Otto M, Sandberg A, Weber M: Assessment of the reliability of the motor unit size index (MUSIX) in single subject “round robin” and muliti-centre settings. Clinical Neurophysiology 2019 May;130(5):666-674. doi: 10.1016/j.clinph.2019.01.020. PMID: 30870802

Primary investigators are Paul E. Barkhaus, MD, and Sanjeev D. Nandedkar, PhD. This research has involved a number of projects over the past 25 years. Recordings are made from control subjects or those with neuromuscular disorders to address research questions in various aspects of the CMAP and how it is influenced by recording techniques. Recordings are made in a standard conventional manner or modified in order to further refine a standard technique. All studies meet the requirements of the 91九色视频 Human Studies Committee. Most recordings are made with commercially available electromyograph systems.

Selected references:

Barkhaus PE, Nandedkar SD: Recording characteristics of the surface EMG electrodes. Muscle Nerve 17:1317-23, 1994.

Barkhaus PE, Collins MI, Nandedkar SD: Influence of the surface EMG electrode on the compound muscle action potential. Electromyography & Clinical Neurophysiology, 2006; 46:235-239.

Barkhaus PE, Kincaid JC, Nandedkar SD: CMAP amplitude drop at the knee in tibial motor conduction studies. Muscle Nerve 2011; 44:776-782.

Nandedkar SD, Barkhaus PE: Contribution of reference electrode to the compound muscle action potential. Muscle Nerve 2007;36:87-92.

Nandedkar SD, Barkhaus PE: Tibial nerve F wave recordings. Muscle Nerve 2015 Apr 3: PMID 25847109. 04/08/2015.

Nandedkar SD, Barkhaus PE: Influence of reference (E2) electrode position on the compound muscle action potential (CMAP). Clinical Neurophysiology 2020:131(1):160-166.

Primary investigators are Paul E. Barkhaus, MD, and Sanjeev D. Nandedkar, PhD. “Normal” or “Reference values (RV)” are required to interpret results of electrodiagnostic procedures. Ideally each laboratory should develop their own RVs. This is not possible due to the time constraints and lack of resources. We have developed a method called Extrapolated Reference Value (E-Ref) that analyzes the patient data to derive RV. It requires data from 500+ patients. When the RV depend on patient demographic data, e.g. age and height, the multi-variable E-Ref approach (MeRef) gives RV as regression equations. RVs based on such equations can increase the specificity of the test.

Selected references:

Nandedkar SD, Sanders DB, Hobson-Smith L, Barkhaus PE, Stålberg EV: Extrapolated Reference Values (E-Ref): Theory, Algorithm, and Results in Patients & Control Subjects. Muscle Nerve 2017 Feb 09 PMID: 28181271 02/10/2017

Nandedkar SD, Stålberg E, Barkhaus PE: MeRef: Multi-Variate Extrapolated Reference Values in Motor Nerve Conduction Studies. Muscle & Nerve 2021: in press.

Drs. Nandedkar and Barkhaus have collaborated on several educational pieces in clinical neurophysiology including multi-media books online as well as peer-reviewed journal articles. The latter include a challenge to current concepts in anodal block in routine nerve conduction studies and proposing stricter standards in digital recordings.

References:

Barkhaus PE: . Hopewell Junction, NY, CASA Engineering, 1997. (Book on multi-media CD-ROM/DVD) (last accessed 02/10/2021)

Barkhaus PE, Nandedkar SD: . Hopewell Junction, NY, CASA Engineering, 1998. (Book on multi-media DVD) (last accessed 02/10/2021)

Barkhaus PE, Nandedkar SD: . Hopewell Junction, NY, CASA Engineering, 2007. (Book on multi-media DVD) (last accessed 02/10/2021)

Barkhaus PE, Nandedkar SD: . In: Nandedkar SD (ed) Essential EMG series. Hopewell Junction, NY, CASA Engineering, 2018. (Book on multi-media DVD) (last accessed 02/10/2021)

Nandedkar SD, Barkhaus PE, Stålberg EV: Experiment for teaching virtual cathode in nerve conduction studies. Muscle Nerve 2021; in press.

Barkhaus PE, Nandedkar SD: Atypical fibrillation and fasciculation potentials: an exercise in waveform identification and analysis. Muscle Nerve 2021; in press.

Title: Systematic analysis of molecular pathways implicated in amyotrophic lateral sclerosis
Source: Advancing a Healthier Wisconsin
Role: Collaborator/Clinical Investigators: Dr. Barkhaus and Dr. Fee
Dates: July 1, 2015– present

Title: MT-1186-A01: A Phase 3, Multi-center, Open-label, Safety Study of Oral Edaravone Administered over 48 Weeks in Subjects With Amyotrophic Lateral Sclerosis (ALS)
Source: Mitsubishi Tanabe Pharma Development America, Inc
Role: Dr. Fee site PI, Dr. Barkhaus/Dr. Shirilla Sub-I
Dates: February 2020–present, closed to enrollment

Title: MT-1186-A02: A Phase 3, Multi-center, Open-label, Safety Study of Oral Edaravone Administered over 48 Weeks in Subjects with Amyotrophic Lateral Sclerosis (ALS)
Source: Mitsubishi Tanabe Pharma Development America, Inc
Role: Dr. Fee site PI, Dr. Shirilla Sub-I
Dates: August 2020–present, not open to enrollment yet

Title: Radicava ®/Edaravone Findings in Biomarkers From ALS (REFINE)
Source: Mitsubishi Tanabe Pharma Development America, Inc
Role: Dr. Fee, site PI, Dr. Shirilla Sub-I
Dates: Dec 2019–present

Title: HEALEY ALS Platform Trial
Description: The primary objective of this study is to evaluate the efficacy of multiple investigational products as compared to placebo on ALS disease progression.
Source: Healey Center for ALS at Mass General
Role: Dr. Fee site PI, Dr. Shirilla Sub-I
Dates: Jan 2021–present

Jeremy M. Sheffner, Merit E. Cudkowicz, Orla Hardiman, Bettina M. Cockroft, Jacqueline behalf of the VITALITY-ALS Study Group (includes Fee D). . Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019.

Babu S, Macklin EA, Jackson K, Simpson E, Mahoney K, Yu H, Walker J, Simmons Z, David W, Barkhaus PE et al: Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2020; 21:15-23.

Seminary ER, Santarriaga S, Wheeler L, Mejaki M, Abrudan J, Demos W, Zimmerman M, Urrutia R, Fee D, Barkhaus PE, Ebert AD: . Cells 2020, 9(3), 571.

Sheffner J, Andrews J, Genge A, Jackson C, Lechtzin N, Miller T, Cockroft B, Meng L, Wei J, Wolff A, Malik F, Bodkin C, Brooks B, Caress J, Dionne A, Fee D, Goutman S, Goyal N, Hardiman O, Hayat G, Heiman-patterson T, Heitzman D, Henderson R, Johnston W, Karam C, Kiernan M, Kolb S, Korngut L, Ladha S, Matte G, Mora J, Needham M, Oskarsson B, Pattee G, Pioro E, Pulley M, Quann D, Rezania K, Schellenberg K, Schults D, Shoessmith C, Simmons Z, Statland J, Sultan S, Swenson A, Van Den Berg L, Vu T, Vucic S, Weiss M, Whyte-Rayson A, Wymer J, Zinman L, Rudnicki S. CY5022 Writing Group. A Phase 2 Double-Blind, Randomized, Dose-Ranging Study of Relsesemtiv in Patients with ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. ePub Sept 2020

Collaborative work in ALS with Melinda Kavanaugh, PhD on children and youths as caregivers in ALS:

Kavanaugh MS. Cho CC, Howard M, Fee D, Barkhaus PE: U.S. data on children and youth caregivers in Amyotrophic Lateral Sclerosis. Neurology 2020; 94:e1452-e1459.

Kavanaugh MS. Cho Y, Fee D, Barkhaus PE: Skill, confidence and support: Conceptual elements of a child/ youth training program in ALS (Y Care). Neurodegenerative Disease Management, 2020; Aug 4. doi: 10.2217/nmt-2020-0004.