Motor unit number estimation (MUNE)
- Clifton L Gooch, MD
Clifton L Gooch, MD
- Professor and Chair, Department of Neurology
- University of South Florida
- Robert Henderson, MD
Robert Henderson, MD
- Director of Neurology
- Royal Brisbane & Women's Hospital
Electrophysiologic testing of nerve and muscle function has played a critical role in the diagnosis of neuromuscular disease for over half a century. Advances in computer technology and technical refinements have enabled the development of more sophisticated electrodiagnostic methods, which are providing information on the motor nerve and its function in health and disease. Motor unit number estimation (MUNE) is a technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. In addition, MUNE methods provide a means of measuring motor unit size, enabling tracking of both loss of motor units and the compensatory phenomenon of collateral reinnervation. MUNE is used most often in neuromuscular disorders such as amyotrophic lateral sclerosis and spinal muscular atrophy.
BASIC PRINCIPLES OF MOTOR NERVE FUNCTION
The peripheral nerve is a collection of individual fibers, or axons, bundled together in much the same fashion as individual telephone lines within a telephone cable. Most peripheral nerves are mixed nerves, containing both sensory axons (carrying information from peripheral sensory receptors to the sensory ganglions) and motor axons (carrying commands for muscle contraction from the spinal cord to the muscle). Routine nerve conduction studies (NCS) can selectively test both the sensory axons (sensory NCS) and motor axons (motor NCS). Sensory NCS enable relatively selective stimulation and recording of sensory action potentials in a peripheral nerve, but, although they are a critical part of routine electrodiagnosis, they have little relevance to the assessment of motor function.
Each spinal motor neuron and the axon it supplies, with all of its branches and their innervated muscle fibers, is known as a motor unit. When the healthy motor axon is depolarized, all of its branches and muscle fibers are activated in an all-or-none fashion. Most peripheral nerves contain hundreds of motor axons, each of which supplies a small percentage of the total number of muscle fibers within a muscle. For full contraction of that muscle and full strength, all of the motor units in that muscle must be activated together. When minimal force is needed for a delicate task, only one or a few motor units are activated.
PHYSIOLOGIC MEASURES OF MOTOR NERVE FUNCTION
During standard motor nerve conduction studies (NCS), bipolar electrodes at the skin surface stimulate the nerve strongly enough to activate all of the motor axons within it, resulting in full depolarization and contraction of the muscle, which corresponds with activation of all of its motor units and component muscle fibers. The electrical impulse generated by this muscle activity is recorded by electrodes placed over the muscle on the skin surface. In a healthy muscle, all the motor units and all their muscle fibers are activated simultaneously during this test, generating the compound motor action potential (CMAP), which is the maximum motor response. The amplitude of the CMAP corresponds to the total number of motor units and muscle fibers activated. The time required for transmission from the stimulation site to the recording site and generation of a waveform is measured, and the conduction velocity can be calculated.
- Ives CT, Doherty TJ. Intra- and inter-rater reliability of motor unit number estimation and quantitative motor unit analysis in the upper trapezius. Clin Neurophysiol 2012; 123:200.
- Bromberg MB. Updating motor unit number estimation (MUNE). Clin Neurophysiol 2007; 118:1.
- Galea V, Fehlings D, Kirsch S, McComas A. Depletion and sizes of motor units in spinal muscular atrophy. Muscle Nerve 2001; 24:1168.
- Gooch CL, Doherty TJ, Chan KM, et al. Motor unit number estimation: a technology and literature review. Muscle Nerve 2014; 50:884.
- van Dijk JP, Blok JH, Lapatki BG, et al. Motor unit number estimation using high-density surface electromyography. Clin Neurophysiol 2008; 119:33.
- McComas AJ, Fawcett PR, Campbell MJ, Sica RE. Electrophysiological estimation of the number of motor units within a human muscle. J Neurol Neurosurg Psychiatry 1971; 34:121.
- Brown WF. A method for estimating the number of motor units in thenar muscles and the changes in motor unit count with ageing. J Neurol Neurosurg Psychiatry 1972; 35:845.
- Defaria CR, Toyonaga K. Motor unit estimation in a muscle supplied by the radial nerve. J Neurol Neurosurg Psychiatry 1978; 41:794.
- Sica RE, McComas AJ, Upton AR, Longmire D. Motor unit estimations in small muscles of the hand. J Neurol Neurosurg Psychiatry 1974; 37:55.
- Brown WF, Milner-Brown HS. Some electrical properties of motor units and their effects on the methods of estimating motor unit numbers. J Neurol Neurosurg Psychiatry 1976; 39:249.
- Feasby TE, Brown WF. Variation of motor unit size in the human extensor digitorum brevis and thenar muscles. J Neurol Neurosurg Psychiatry 1974; 37:916.
- Milner-Brown HS, Brown WF. New methods of estimating the number of motor units in a muscle. J Neurol Neurosurg Psychiatry 1976; 39:258.
- Ballantyne JP, Hansen S. New method for the estimation of the number of motor units in a muscle. 2. Duchenne, limb-girdle and facioscapulohumeral, and myotonic muscular dystrophies. J Neurol Neurosurg Psychiatry 1974; 37:1195.
- Ballantyne JP, Hansen S. A new method for the estimation of the number of motor units in a muscle. I. Control subjects and patients with myasthenia gravis. J Neurol Neurosurg Psychiatry 1974; 37:907.
- Hansen S, Ballantyne JP. Axonal dysfunction in the neuropathy of diabetes mellitus: a quantitative electrophysiological study. J Neurol Neurosurg Psychiatry 1977; 40:555.
- Kadrie HA, Yates SK, Milner-Brown HS, Brown WF. Multiple point electrical stimulation of ulnar and median nerves. J Neurol Neurosurg Psychiatry 1976; 39:973.
- Doherty TJ, Brown WF. The estimated numbers and relative sizes of thenar motor units as selected by multiple point stimulation in young and older adults. Muscle Nerve 1993; 16:355.
- Goyal N, Salameh JS, Baldassari LE, David WS. Added sampling improves reproducibility of multipoint motor unit estimates. Muscle Nerve 2010; 41:114.
- Wang FC, Delwaide PJ. Number and relative size of thenar motor units estimated by an adapted multiple point stimulation method. Muscle Nerve 1995; 18:969.
- Felice KJ. Thenar motor unit number estimates using the multiple point stimulation technique: reproducibility studies in ALS patients and normal subjects. Muscle Nerve 1995; 18:1412.
- Shefner JM, Watson ML, Simionescu L, et al. Multipoint incremental motor unit number estimation as an outcome measure in ALS. Neurology 2011; 77:235.
- Daube JR. Estimating the number of motor units in a muscle. J Clin Neurophysiol 1995; 12:585.
- Abstracts of free communications: American Association of Electromyography and Diagnosis. San Diego, California, October 7-8, 1988. Muscle Nerve 1988; 11:957.
- Shefner JM, Jillapalli D, Bradshaw DY. Reducing intersubject variability in motor unit number estimation. Muscle Nerve 1999; 22:1457.
- Jillapalli D, Shefner JM. Single motor unit variability with threshold stimulation in patients with amyotrophic lateral sclerosis and normal subjects. Muscle Nerve 2004; 30:578.
- Lomen-Hoerth C, Olney RK. Comparison of multiple point and statistical motor unit number estimation. Muscle Nerve 2000; 23:1525.
- Olney RK, Yuen EC, Engstrom JW. Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis. Muscle Nerve 2000; 23:193.
- Blok JH, van Dijk JP, Drenthen J, et al. Size does matter: the influence of motor unit potential size on statistical motor unit number estimates in healthy subjects. Clin Neurophysiol 2010; 121:1772.
- Shefner JM, Cudkowicz ME, Zhang H, et al. Revised statistical motor unit number estimation in the Celecoxib/ALS trial. Muscle Nerve 2007; 35:228.
- Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor unit number estimation--a Bayesian approach. Biometrics 2006; 62:1235.
- Henderson RD, Ridall PG, Hutchinson NM, et al. Bayesian statistical MUNE method. Muscle Nerve 2007; 36:206.
- Nandedkar SD, Nandedkar DS, Barkhaus PE, Stalberg EV. Motor unit number index (MUNIX). IEEE Trans Biomed Eng 2004; 51:2209.
- Nandedkar SD, Barkhaus PE, Stålberg EV. Motor unit number index (MUNIX): principle, method, and findings in healthy subjects and in patients with motor neuron disease. Muscle Nerve 2010; 42:798.
- Neuwirth C, Nandedkar S, Stålberg E, et al. Motor Unit Number Index (MUNIX): a novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers. Clin Neurophysiol 2011; 122:1867.
- Ahn SW, Kim SH, Kim JE, et al. Reproducibility of the motor unit number index (MUNIX) in normal controls and amyotrophic lateral sclerosis patients. Muscle Nerve 2010; 42:808.
- Furtula J, Johnsen B, Christensen PB, et al. MUNIX and incremental stimulation MUNE in ALS patients and control subjects. Clin Neurophysiol 2013; 124:610.
- Eisen A, Karpati G, Carpenter S, Danon J. The motor unit profile of the rat soleus in experimental myopathy and reinnervation. Neurology 1974; 24:878.
- Peyronnard JM, Lamarre Y. Electrophysiological and anatomical estimation of the number of motor units in the monkey extensor digitorum brevis muscle. J Neurol Neurosurg Psychiatry 1977; 40:756.
- Lee RG, Ashby P, White DG, Aguayo AJ. Analysis of motor conduction velocity in the human median nerve by computer simulation of compound muscle action potentials. Electroencephalogr Clin Neurophysiol 1975; 39:225.
- Santo Neto H, de Carvalho VC, Marques MJ. Estimation of the number and size of human flexor digiti minimi muscle motor units using histological methods. Muscle Nerve 1998; 21:112.
- Neto HS, Filho JM, Passini R Jr, Marques MJ. Number and size of motor units in thenar muscles. Clin Anat 2004; 17:308.
- Galea V, de Bruin H, Cavasin R, McComas AJ. The numbers and relative sizes of motor units estimated by computer. Muscle Nerve 1991; 14:1123.
- Gooch CL. Repetitive axonal stimulation of the same single motor unit: a longitudinal tracking study. Muscle Nerve 1998; 21:1537.
- Bromberg MB, Larson WL. Relationships between motor-unit number estimates and isometric strength in distal muscles in ALS/MND. J Neurol Sci 1996; 139 Suppl:38.
- Gooch CL, Pullman SL, Shungu DC, et al. Motor unit number estimation (MUNE) in diseases of the motor neuron: utility and comparative analysis in a multimodal biomarker study. Suppl Clin Neurophysiol 2009; 60:153.
- Einsiedel LJ, Luff AR. Effect of partial denervation on motor units in the ageing rat medial gastrocnemius. J Neurol Sci 1992; 112:178.
- Jacob JM, Robbins N. Age differences in morphology of reinnervation of partially denervated mouse muscle. J Neurosci 1990; 10:1530.
- Bromberg MB. MUNIX and MUNE in ALS. Clin Neurophysiol 2013; 124:433.
- Hansen S, Ballantyne JP. A quantitative electrophysiological study of motor neurone disease. J Neurol Neurosurg Psychiatry 1978; 41:773.
- Dantes M, McComas A. The extent and time course of motoneuron involvement in amyotrophic lateral sclerosis. Muscle Nerve 1991; 14:416.
- Armon C, Brandstater ME. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve 1999; 22:1571.
- Carleton SA, Brown WF. Changes in motor unit populations in motor neurone disease. J Neurol Neurosurg Psychiatry 1979; 42:42.
- Mitsumoto H, Ulug AM, Pullman SL, et al. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology 2007; 68:1402.
- Smith B, Clarke J, Litchy W, et al. Longitudinal electrodiagnostic studies in ALS patients treated with recombinant human ciliary neurotrophic factor. Neurology 1995; 45:A448.
- Yuen EC, Olney RK. Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis. Neurology 1997; 49:573.
- Gooch CL, Shefner JM. ALS surrogate markers. MUNE. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5 Suppl 1:104.
- Shefner JM, Cudkowicz ME, Zhang H, et al. The use of statistical MUNE in a multicenter clinical trial. Muscle Nerve 2004; 30:463.
- Olney R, Yuen E, Engstrom J. The rate of change in motor unit number estimates predicts survival in patients with amyotrophic lateral sclerosis. Neurology 1999; 52 (Suppl 2):A3.
- van Dijk JP, Schelhaas HJ, Van Schaik IN, et al. Monitoring disease progression using high-density motor unit number estimation in amyotrophic lateral sclerosis. Muscle Nerve 2010; 42:239.
- Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362:59.
- Shefner JM, Reaume AG, Flood DG, et al. Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy. Neurology 1999; 53:1239.
- Azzouz M, Leclerc N, Gurney M, et al. Progressive motor neuron impairment in an animal model of familial amyotrophic lateral sclerosis. Muscle Nerve 1997; 20:45.
- Shefner JM, Cudkowicz M, Brown RH Jr. Motor unit number estimation predicts disease onset and survival in a transgenic mouse model of amyotrophic lateral sclerosis. Muscle Nerve 2006; 34:603.
- Reaume AG, Elliott JL, Hoffman EK, et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 1996; 13:43.
- Sorenson EJ, Daube JR, Windebank AJ. Motor unit number estimates correlate with strength in polio survivors. Muscle Nerve 2006; 34:608.
- Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve 2002; 25:445.
- Lehky TJ, Chen CJ, di Prospero NA, et al. Standard and modified statistical MUNE evaluations in spinal-bulbar muscular atrophy. Muscle Nerve 2009; 40:809.
- Suzuki K, Katsuno M, Banno H, et al. The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy. J Neurol Neurosurg Psychiatry 2010; 81:567.
- Swoboda KJ, Scott CB, Reyna SP, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009; 4:e5268.
- van Dijk JP, Verhamme C, van Schaik IN, et al. Age-related changes in motor unit number estimates in adult patients with Charcot-Marie-Tooth type 1A. Eur J Neurol 2010; 17:1098.
- Hansen S, Ballantyne JP. A quantitative electrophysiological study of uraemic neuropathy. Diabetic and renal neuropathies compared. J Neurol Neurosurg Psychiatry 1978; 41:128.
- Ballantyne JP, Hansen S. A quantitative assessment of reinnervation in the polyneuropathies. Muscle Nerve 1982; 5:S127.
- Martinez-Figueroa A, Hansen S, Ballantyne JP. A quantitative electrophysiological study of acute idiopathic polyneuritis. J Neurol Neurosurg Psychiatry 1977; 40:156.
- BASIC PRINCIPLES OF MOTOR NERVE FUNCTION
- PHYSIOLOGIC MEASURES OF MOTOR NERVE FUNCTION
- MUNE METHODS
- Incremental stimulation
- Multiple point stimulation
- Multipoint incremental method
- Statistical methods
- Motor unit number index (MUNIX)
- Comparison of major MUNE methods
- MUNE IN AGING AND DISEASE
- Normal aging
- Amyotrophic lateral sclerosis
- - MUNE in animal models of ALS
- MUNE in other neuromuscular diseases