- Email: [email protected]
Relationships between MUNE and muscle strength
Motor Unit Number Estimation (Supplements to Clinical Neurophysiology Vol. 55) Editor: M.B. Bromberg ß 2003 Elsevier Science B.V. All rights reserved.
258
Chapter 28
Relationships between MUNE and muscle strength A. Gordon Smitha,b,* and Victoria Lawsona a
Department of Neurology, University of Utah, Salt Lake City, UT 84132, USA Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
b
Introduction Muscle weakness is the primary cause of disability among patients with motor neuron disorders and motor predominant peripheral neuropathies. It is therefore appropriate that measures of muscle strength have traditionally provided the primary means of following disease progression and response to therapeutic agents. During the progressive middle phase of amyotrophic lateral sclerosis (ALS), the decline in muscle strength is linear. However, this ®nding is misleading in that it does not accurately re¯ect the primary pathology, motor unit loss. There is now great interest in preventing motor unit loss early in the disease course, ideally before the development of symptomatic weakness. Motor unit number estimation (MUNE) provides a means of assessing the primary pathology of motor neuron disorders. MUNE may also be useful in following clinically relevant processes secondary to a primary pathology. Charcot±Marie±Tooth disease type I (CMT1) is an autosomal dominant disorder involving duplication of the gene for peripheral myelin protein 22 and resultant demyelination. All patients with CMT1, regardless of the degree of weakness, have *Correspondence to: A. Gordon Smith, Department of Neurology, University of Utah, 50 North Medical Drive, Room 3R152, Salt Lake City, UT 84132, USA. Tel.: 801585-5884, Fax: 801-585-2054. e-mail: [email protected] doi: 10.1016/S1567-424X(03)00028-X
slowed nerve conduction velocity. Nerve conduction velocity does not correlate well with strength. It has been well demonstrated that strength in CMT1 patients shows higher correlations with measures of axon loss (Krajewski et al., 2000). MUNE is therefore a useful technique in the study of subjects with a primary demyelinating pathology that results in secondary axonal loss, leading to muscle weakness. This chapter will review the relationship between MUNE and strength and highlight the role of MUNE in assessing the primary process of motor neuron disease, or the secondary axonal loss of CMT1.
Motor neuron disease There is a growing body of data regarding the use of MUNE in subjects with ALS. In principle, MUNE holds great promise as a means of following motor unit loss, even prior to the development of clinically evident muscle weakness. Several groups have investigated the relationship between strength and MUNE in subjects with ALS. Bromberg et al., (1993). correlated biceps-brachialis MUNE using spike triggered averaging with elbow ¯exion strength among 31 subjects with ALS. There was not a signi®cant relationship between MUNE and strength (r=0.37). The poor correlation was thought to be secondary to the eects of collateral reinnervation. Armon et al. (1997) found a better
259
correlation between thenar, hypothenar, and toe extensor MUNE and grip or dorsi¯exor strength using the manual incremental stimulation technique (correlation coecients 0.55±067). Their subjects had lower MUNE values and were likely in a phase of the disease where reinnervation was failing. Longitudinal studies provide further support for the concept that MUNE declines prior the development of muscle weakness because of the eects of collateral sprouting and reinnervation. Felice performed MUNE using multiple point stimulation and measured strength serially in 21 ALS subjects. MUNE declined prior muscle strength and was a more sensitive measure of disease progression (Felice, 1997). Yuen and Olney performed serial MUNE (statistical technique), strength measurements and ®ber density in 10 subjects with ALS. As expected, MUNE declined at a greater rate than grip strength although there was a signi®cant correlation between the two (r=0.55, P<0.0015). While ®ber density was not correlated with strength (r=0.084), it increased during the study. Furthermore, subjects with a more robust increase in ®ber density had slower clinical progression (Yuen and Olney, 1997). While MUNE provides a good measure of the primary pathology of ALS, ®ber density measures collateral reinnervation, the compensatory response to motor unit loss. This response explains the relatively poor correlation between MUNE and strength. The relationship between MUNE and strength is dependent on the muscle group tested. Many investigators have used grip dynamometry to follow upper extremity muscle strength quantitatively. Multi-channel electromyography recordings during grip indicate both forearm and upper arm muscles contribute to grip strength (Bromberg and Larson, 1996). Most MUNE techniques utilize distal muscle groups (thenar or hypothenar). Future studies correlating strength and MUNE should measure strength and MUNE in the same group.
Charcot±Marie±Tooth disease In contrast to motor neuron disorders, the primary process in CMT1 is considered to be
peripheral nerve demyelination. This process, in and of itself, does not result in muscle weakness. In large CMT-1A pedigrees there can be marked variability of phenotypic expression of weakness, but all individuals have markedly slow conduction velocities (Kaku et al., 1993; Birouk et al., 1997). This observation supports the notion that muscle weakness is caused by axonal loss and denervation, not slow conduction velocity, and that the abnormalities of PMP-22 not only aect myelin structure and function but also aect the underlying axon. There is little speci®c information on the distribution and degree of denervation because most reports on CMT phenotype focus on the electrodiagnostic measurement of conduction velocity (Birouk et al., 1997). More recently, Krajewski et al. performed MUNE of the thenar muscle group using the statistical method. MUNE was dicult to obtain in patients with severe weakness due to high nerve stimulation thresholds. Despite this technical diculty, MUNE correlated with thumb abduction strength (r=0.51, P<0.01) but not with median nerve conduction velocity (r=0.08) (Krajewski et al., 2000). Because of the high stimulation threshold in patients with demyelinating CMT, our group has focused on the use of non-stimulation based techniques to perform MUNE in this patient population. In order to measure strength and MUNE in the same muscle group we have developed a manipulandum that measures strength of ®fth ®nger abduction. The ®fth digit is isolated and hand and forearm secured in order to minimize contribution from more proximal muscles. We have performed hypothenar and biceps bachii MUNE using spike triggered averaging in eight subjects with genetically con®rmed CMT1A. Results were correlated with motor conduction velocity, hypothenar strength measured with the manipulandum, and grip dynamometry (Jamar). As anticipated, there was a poor correlation between hypothenar MUNE and ulnar motor conduction velocity (correlation coecient 0.2). There was a much stronger correlation between hypothenar strength and MUNE (correlation coecient 0.65). The correlation between hypothenar MUNE and grip strength was less robust
260
Fig. 1. Grip strength was poorly correlated with ADQH MUNE (r=0.44) (A), while there was a stronger correlation with ADQH strength (r=0.65) (B).
(correlation coecient 0.45) (Fig. 1). There was a poor correlation between CMAP amplitude and strength, probably because of the eects of collateral reinnervation. The spike triggered averaging technique was well tolerated by all subjects. Our experience suggests stimulation based techniques are both technically challenging and more uncomfortable for CMT1 subjects. During the collection of surface motor unit action potentials for calculation of MUNE, the waveform characteristics of the averaged intramuscular motor unit action potential were collected. Mean motor unit amplitude in the abductor digiti mini was signi®cantly higher in subjects with CMT1A when compared to 10 control subjects of similar age and gender (1340 vs. 863 mV). This ®nding is consistent with the presence of ongoing collateral sprouting and reinnervation that compensates for axonal loss.
These results indicate that weakness in CMT1A is due to secondary axonal loss, not primary demyelination. As with motor neuron disease, however, the correlation between MUNE and strength is lessened by the eects of collateral sprouting and reinnervation. MUNE is therefore an appropriate means to follow progression of axonal loss and holds promise as an endpoint measure for treatment trials in hereditary peripheral neuropathy.
Conclusions While muscle weakness is the primary cause of disability in motor neuron disease and CMT, muscle strength has many determinants that are independent of the disease process. Disuse, premorbid conditioning, nutrition and many other issues in¯uence strength. MUNE is clearly related to
261
strength in patients with progressive denervating conditions. However, MUNE actually provides a more representative measure of the pathophysiologic cause of weakness than strength measurements can provide. MUNE therefore provides a unique and valuable progression measure for use in therapeutic trials in denervating illness. Other progression measures are necessary to follow compensatory reinnervation however. Motor unit action potential amplitude and ®ber density are appropriate measures of reinnervation. Compound muscle action potential amplitude and strength measures provide a composite measure of the severity motor unit or axon loss and the success of collateral sprouting and reinnervation.
References Armon, C., Brandstater, M. and Peterson, G. Motor unit number estimates and quantitative muscle strength measurements of distal muscles in patients with amyotrophic lateral sclerosis. Muscle and Nerve, 1997, 20: 449±501.
Birouk, N., Gouider, R., Le Guren, E., Gugenheim, M., Tardieu, S. and Maisonobe, T. Charcot±Marie±Tooth disease type 1A with 17p11.2 duplication: clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain, 1997, 120: 813±823. Bromberg, M., Forshew, D., Nau, K., Bromberg, J., Simmons, Z. and Fries, T. Motor unit number estimation isometric strength and electromyographic measures in amyotrophic lateral sclerosis. Muscle and Nerve, 1993, 16: 1213±1219. Bromberg, M. and Larson, W. Relationships between motor unit number estimates and isometric strength in distal muscles in ALS/MND. J. Neurolog. Sci., 1996, 139 (Suppl.): 38±42. Felice, K. A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle and Nerve, 1997, 20: 179±185. Kaku, D., Parry, G., Malamut, R., Lupski, J. and Garcia, C. Nerve conduction studies in Charcot-Marie Tooth polyneuropathy associated with a segmental duplication of chromosome 17. Neurology, 1993, 43: 1806±1808. Krajewski, K., Lewis, R., Fuerst, D., Turansky, C., Hinderer, S., Garbern, J., Kamholz, J. and Shy, M. Neurological dysfunction and axonal degeneration in Charcot-MarieTooth disease type 1A. Brain, 2000, 123: 1516±1527. Yuen, E. and Olney, R. Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis. Neurology, 1997, 49: 573±578.
262
Discussion after Section VII Mark Bromberg, Salt Lake City, Utah Let me ask a question of Ming about the motor unit that later in its lifetime could not keep up with the discharge rate, do you think that was due to central or peripheral failure?
Ming Chan, Edmonton, Alberta I can only speculate. It is possible that it could be due to a reduction of central descending motor drive to the motor unit. On the other hand, it is also possible that the membrane physiological characteristics in the anterior horn cell could have changed, leading to reduced excitability of the alpha motor neuron itself. In support of the latter, the persistence of the alpha motor neuron response declined markedly over the 2-year period.
Richard Olney, San Francisco, California We have tracked two or three ®nal surviving motor units in people with the statistical technique. We were still able to electrically stimulate the nerve to activate them every three months for 6±9 months, but often the patients could not recruit the motor units voluntarily. This supports a central failure.
Timothy Doherty, London, Ontario I have a question for FrancËois. In your experience with the AMPS technique, as you follow patients with depleting motor unit pools, did you ®nd it progressively more dicult to isolate individual motor unit potentials, suggesting that there may be problems with either distal branching or decrement in individual potentials?
FrancËois Wang, LieÂge, Belgium No, it was not more dicult when the motor unit numbers were very low.
Richard Olney, San Francisco, California I have a question for Robin or Mike. I think that Robin's data showed non-linearity in that units got bigger when more units were activate, and I think that Mike's data from yesterday showed just the opposite eect. I wonder if you or anyone who understands non-linearity well enough can comment on what is going on or how do we explain this dierence?
Michael Slawnych, Calgary, Alberta I can comment on the work I presented yesterday. I presented a simple model system made up as a series of parallel motor units, in which the contribution of a motor unit decreases as the number of active motor units increases. There is not a wealth of data to support this model, and I presented the only data I was able to ®nd by two dierent groups. One set of data was by Parry and colleagues (J. Neurol. Sci. 1977, 33: 283±296),
and they looked at motor units under conditions when very few motor units were active and under conditions when many motor units were active. They showed how the contribution of a motor unit decreases by approximately 20±25%. The other group showed a decrease as well, but much smaller, on the order of about 6%.
Robin Conwit, Baltimore, Maryland We were looking at the average size of motor unit potentials and not the relative contribution of each one. The larger-size units may have aected the average to a greater extent, and that may explain the discrepancy.
Jack Petajan, Salt Lake City, Utah How did you identify which active units to study at various levels of contraction?
Robin Conwit, Baltimore, Maryland At ®rst we had hoped to track the same units and follow them at dierent levels of contraction, but we found it exceedingly dicult, even when we tried using wire electrodes that were left in place. We just looked at representative samples and chose 15±20 surface motor unit potentials at each force level that had the correct size, shape, and seemed to have a ®ring rate histogram that was physiologic.
Jack Petajan, Salt Lake City, Utah I have a question for Ming Chan related to the type of exercise when you were ``training'' the motor units. In a small muscle might the training actually be damaging?
Ming Chan, Edmonton, Alberta I think it is a mis-advertisement to use the word ``training'' because high-frequency repetitive stimulation is a highly arti®cial way of activating those motor units. Those units probably do not ®re in that kind of vigorous pattern. We actually counted the number of impulses, 24,000 a day. All of them recovered to their baseline value within 5 weeks after the training program ended, so the changes I showed during training were reversible. We characterized the tetanic tension of these motor units and picked a stimulation frequency that produced a 50% maximum tetanic tension, and that worked out to be between 30 and 40 Hz.
Jasper Daube, Rochester, Minnesota Two questions. The ®rst based on the question to FrancËois regarding decrement with unstable motor units. In the multiple point stimulation technique applied to ALS patients who have unstable motor units, there may be diculty in identifying single motor unit potentials because they may decrement immediately. Do you ®nd that a diculty?
263
Timothy Doherty, London, Ontario
Jasper Daube, Rochester, Minnesota
I have found it dicult at times. However, with the multiple point stimulation technique, it can be recognized easily and lessened by reducing the stimulation frequency.
The other question is whether there are dierences between the spike triggered averaging and the decomposition techniques. Would you expect the same results from the two techniques?
Clifton Gooch, New York, New York
Timothy Doherty, London, Ontario
A few comments. I think that decrement occurs in a subpopulation of motor units in ALS, and it may or may not correlate with decrement observed in the CMAP. In my experience, I tend to reject those motor units for analysis or for tracking because it can sometimes be dicult to be certain that they are a single motor unit or whether they represent alternation or recruitment of a second smaller unit.
No direct comparisons have been made between single motor unit spike triggered averaging and multiple unit spike triggered averaging by decomposition. In the decomposition technique, higher threshold motor units and larger amplitude motor units are collected, and this may have an eect.
258
Chapter 28
Relationships between MUNE and muscle strength A. Gordon Smitha,b,* and Victoria Lawsona a
Department of Neurology, University of Utah, Salt Lake City, UT 84132, USA Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
b
Introduction Muscle weakness is the primary cause of disability among patients with motor neuron disorders and motor predominant peripheral neuropathies. It is therefore appropriate that measures of muscle strength have traditionally provided the primary means of following disease progression and response to therapeutic agents. During the progressive middle phase of amyotrophic lateral sclerosis (ALS), the decline in muscle strength is linear. However, this ®nding is misleading in that it does not accurately re¯ect the primary pathology, motor unit loss. There is now great interest in preventing motor unit loss early in the disease course, ideally before the development of symptomatic weakness. Motor unit number estimation (MUNE) provides a means of assessing the primary pathology of motor neuron disorders. MUNE may also be useful in following clinically relevant processes secondary to a primary pathology. Charcot±Marie±Tooth disease type I (CMT1) is an autosomal dominant disorder involving duplication of the gene for peripheral myelin protein 22 and resultant demyelination. All patients with CMT1, regardless of the degree of weakness, have *Correspondence to: A. Gordon Smith, Department of Neurology, University of Utah, 50 North Medical Drive, Room 3R152, Salt Lake City, UT 84132, USA. Tel.: 801585-5884, Fax: 801-585-2054. e-mail: [email protected] doi: 10.1016/S1567-424X(03)00028-X
slowed nerve conduction velocity. Nerve conduction velocity does not correlate well with strength. It has been well demonstrated that strength in CMT1 patients shows higher correlations with measures of axon loss (Krajewski et al., 2000). MUNE is therefore a useful technique in the study of subjects with a primary demyelinating pathology that results in secondary axonal loss, leading to muscle weakness. This chapter will review the relationship between MUNE and strength and highlight the role of MUNE in assessing the primary process of motor neuron disease, or the secondary axonal loss of CMT1.
Motor neuron disease There is a growing body of data regarding the use of MUNE in subjects with ALS. In principle, MUNE holds great promise as a means of following motor unit loss, even prior to the development of clinically evident muscle weakness. Several groups have investigated the relationship between strength and MUNE in subjects with ALS. Bromberg et al., (1993). correlated biceps-brachialis MUNE using spike triggered averaging with elbow ¯exion strength among 31 subjects with ALS. There was not a signi®cant relationship between MUNE and strength (r=0.37). The poor correlation was thought to be secondary to the eects of collateral reinnervation. Armon et al. (1997) found a better
259
correlation between thenar, hypothenar, and toe extensor MUNE and grip or dorsi¯exor strength using the manual incremental stimulation technique (correlation coecients 0.55±067). Their subjects had lower MUNE values and were likely in a phase of the disease where reinnervation was failing. Longitudinal studies provide further support for the concept that MUNE declines prior the development of muscle weakness because of the eects of collateral sprouting and reinnervation. Felice performed MUNE using multiple point stimulation and measured strength serially in 21 ALS subjects. MUNE declined prior muscle strength and was a more sensitive measure of disease progression (Felice, 1997). Yuen and Olney performed serial MUNE (statistical technique), strength measurements and ®ber density in 10 subjects with ALS. As expected, MUNE declined at a greater rate than grip strength although there was a signi®cant correlation between the two (r=0.55, P<0.0015). While ®ber density was not correlated with strength (r=0.084), it increased during the study. Furthermore, subjects with a more robust increase in ®ber density had slower clinical progression (Yuen and Olney, 1997). While MUNE provides a good measure of the primary pathology of ALS, ®ber density measures collateral reinnervation, the compensatory response to motor unit loss. This response explains the relatively poor correlation between MUNE and strength. The relationship between MUNE and strength is dependent on the muscle group tested. Many investigators have used grip dynamometry to follow upper extremity muscle strength quantitatively. Multi-channel electromyography recordings during grip indicate both forearm and upper arm muscles contribute to grip strength (Bromberg and Larson, 1996). Most MUNE techniques utilize distal muscle groups (thenar or hypothenar). Future studies correlating strength and MUNE should measure strength and MUNE in the same group.
Charcot±Marie±Tooth disease In contrast to motor neuron disorders, the primary process in CMT1 is considered to be
peripheral nerve demyelination. This process, in and of itself, does not result in muscle weakness. In large CMT-1A pedigrees there can be marked variability of phenotypic expression of weakness, but all individuals have markedly slow conduction velocities (Kaku et al., 1993; Birouk et al., 1997). This observation supports the notion that muscle weakness is caused by axonal loss and denervation, not slow conduction velocity, and that the abnormalities of PMP-22 not only aect myelin structure and function but also aect the underlying axon. There is little speci®c information on the distribution and degree of denervation because most reports on CMT phenotype focus on the electrodiagnostic measurement of conduction velocity (Birouk et al., 1997). More recently, Krajewski et al. performed MUNE of the thenar muscle group using the statistical method. MUNE was dicult to obtain in patients with severe weakness due to high nerve stimulation thresholds. Despite this technical diculty, MUNE correlated with thumb abduction strength (r=0.51, P<0.01) but not with median nerve conduction velocity (r=0.08) (Krajewski et al., 2000). Because of the high stimulation threshold in patients with demyelinating CMT, our group has focused on the use of non-stimulation based techniques to perform MUNE in this patient population. In order to measure strength and MUNE in the same muscle group we have developed a manipulandum that measures strength of ®fth ®nger abduction. The ®fth digit is isolated and hand and forearm secured in order to minimize contribution from more proximal muscles. We have performed hypothenar and biceps bachii MUNE using spike triggered averaging in eight subjects with genetically con®rmed CMT1A. Results were correlated with motor conduction velocity, hypothenar strength measured with the manipulandum, and grip dynamometry (Jamar). As anticipated, there was a poor correlation between hypothenar MUNE and ulnar motor conduction velocity (correlation coecient 0.2). There was a much stronger correlation between hypothenar strength and MUNE (correlation coecient 0.65). The correlation between hypothenar MUNE and grip strength was less robust
260
Fig. 1. Grip strength was poorly correlated with ADQH MUNE (r=0.44) (A), while there was a stronger correlation with ADQH strength (r=0.65) (B).
(correlation coecient 0.45) (Fig. 1). There was a poor correlation between CMAP amplitude and strength, probably because of the eects of collateral reinnervation. The spike triggered averaging technique was well tolerated by all subjects. Our experience suggests stimulation based techniques are both technically challenging and more uncomfortable for CMT1 subjects. During the collection of surface motor unit action potentials for calculation of MUNE, the waveform characteristics of the averaged intramuscular motor unit action potential were collected. Mean motor unit amplitude in the abductor digiti mini was signi®cantly higher in subjects with CMT1A when compared to 10 control subjects of similar age and gender (1340 vs. 863 mV). This ®nding is consistent with the presence of ongoing collateral sprouting and reinnervation that compensates for axonal loss.
These results indicate that weakness in CMT1A is due to secondary axonal loss, not primary demyelination. As with motor neuron disease, however, the correlation between MUNE and strength is lessened by the eects of collateral sprouting and reinnervation. MUNE is therefore an appropriate means to follow progression of axonal loss and holds promise as an endpoint measure for treatment trials in hereditary peripheral neuropathy.
Conclusions While muscle weakness is the primary cause of disability in motor neuron disease and CMT, muscle strength has many determinants that are independent of the disease process. Disuse, premorbid conditioning, nutrition and many other issues in¯uence strength. MUNE is clearly related to
261
strength in patients with progressive denervating conditions. However, MUNE actually provides a more representative measure of the pathophysiologic cause of weakness than strength measurements can provide. MUNE therefore provides a unique and valuable progression measure for use in therapeutic trials in denervating illness. Other progression measures are necessary to follow compensatory reinnervation however. Motor unit action potential amplitude and ®ber density are appropriate measures of reinnervation. Compound muscle action potential amplitude and strength measures provide a composite measure of the severity motor unit or axon loss and the success of collateral sprouting and reinnervation.
References Armon, C., Brandstater, M. and Peterson, G. Motor unit number estimates and quantitative muscle strength measurements of distal muscles in patients with amyotrophic lateral sclerosis. Muscle and Nerve, 1997, 20: 449±501.
Birouk, N., Gouider, R., Le Guren, E., Gugenheim, M., Tardieu, S. and Maisonobe, T. Charcot±Marie±Tooth disease type 1A with 17p11.2 duplication: clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain, 1997, 120: 813±823. Bromberg, M., Forshew, D., Nau, K., Bromberg, J., Simmons, Z. and Fries, T. Motor unit number estimation isometric strength and electromyographic measures in amyotrophic lateral sclerosis. Muscle and Nerve, 1993, 16: 1213±1219. Bromberg, M. and Larson, W. Relationships between motor unit number estimates and isometric strength in distal muscles in ALS/MND. J. Neurolog. Sci., 1996, 139 (Suppl.): 38±42. Felice, K. A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle and Nerve, 1997, 20: 179±185. Kaku, D., Parry, G., Malamut, R., Lupski, J. and Garcia, C. Nerve conduction studies in Charcot-Marie Tooth polyneuropathy associated with a segmental duplication of chromosome 17. Neurology, 1993, 43: 1806±1808. Krajewski, K., Lewis, R., Fuerst, D., Turansky, C., Hinderer, S., Garbern, J., Kamholz, J. and Shy, M. Neurological dysfunction and axonal degeneration in Charcot-MarieTooth disease type 1A. Brain, 2000, 123: 1516±1527. Yuen, E. and Olney, R. Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis. Neurology, 1997, 49: 573±578.
262
Discussion after Section VII Mark Bromberg, Salt Lake City, Utah Let me ask a question of Ming about the motor unit that later in its lifetime could not keep up with the discharge rate, do you think that was due to central or peripheral failure?
Ming Chan, Edmonton, Alberta I can only speculate. It is possible that it could be due to a reduction of central descending motor drive to the motor unit. On the other hand, it is also possible that the membrane physiological characteristics in the anterior horn cell could have changed, leading to reduced excitability of the alpha motor neuron itself. In support of the latter, the persistence of the alpha motor neuron response declined markedly over the 2-year period.
Richard Olney, San Francisco, California We have tracked two or three ®nal surviving motor units in people with the statistical technique. We were still able to electrically stimulate the nerve to activate them every three months for 6±9 months, but often the patients could not recruit the motor units voluntarily. This supports a central failure.
Timothy Doherty, London, Ontario I have a question for FrancËois. In your experience with the AMPS technique, as you follow patients with depleting motor unit pools, did you ®nd it progressively more dicult to isolate individual motor unit potentials, suggesting that there may be problems with either distal branching or decrement in individual potentials?
FrancËois Wang, LieÂge, Belgium No, it was not more dicult when the motor unit numbers were very low.
Richard Olney, San Francisco, California I have a question for Robin or Mike. I think that Robin's data showed non-linearity in that units got bigger when more units were activate, and I think that Mike's data from yesterday showed just the opposite eect. I wonder if you or anyone who understands non-linearity well enough can comment on what is going on or how do we explain this dierence?
Michael Slawnych, Calgary, Alberta I can comment on the work I presented yesterday. I presented a simple model system made up as a series of parallel motor units, in which the contribution of a motor unit decreases as the number of active motor units increases. There is not a wealth of data to support this model, and I presented the only data I was able to ®nd by two dierent groups. One set of data was by Parry and colleagues (J. Neurol. Sci. 1977, 33: 283±296),
and they looked at motor units under conditions when very few motor units were active and under conditions when many motor units were active. They showed how the contribution of a motor unit decreases by approximately 20±25%. The other group showed a decrease as well, but much smaller, on the order of about 6%.
Robin Conwit, Baltimore, Maryland We were looking at the average size of motor unit potentials and not the relative contribution of each one. The larger-size units may have aected the average to a greater extent, and that may explain the discrepancy.
Jack Petajan, Salt Lake City, Utah How did you identify which active units to study at various levels of contraction?
Robin Conwit, Baltimore, Maryland At ®rst we had hoped to track the same units and follow them at dierent levels of contraction, but we found it exceedingly dicult, even when we tried using wire electrodes that were left in place. We just looked at representative samples and chose 15±20 surface motor unit potentials at each force level that had the correct size, shape, and seemed to have a ®ring rate histogram that was physiologic.
Jack Petajan, Salt Lake City, Utah I have a question for Ming Chan related to the type of exercise when you were ``training'' the motor units. In a small muscle might the training actually be damaging?
Ming Chan, Edmonton, Alberta I think it is a mis-advertisement to use the word ``training'' because high-frequency repetitive stimulation is a highly arti®cial way of activating those motor units. Those units probably do not ®re in that kind of vigorous pattern. We actually counted the number of impulses, 24,000 a day. All of them recovered to their baseline value within 5 weeks after the training program ended, so the changes I showed during training were reversible. We characterized the tetanic tension of these motor units and picked a stimulation frequency that produced a 50% maximum tetanic tension, and that worked out to be between 30 and 40 Hz.
Jasper Daube, Rochester, Minnesota Two questions. The ®rst based on the question to FrancËois regarding decrement with unstable motor units. In the multiple point stimulation technique applied to ALS patients who have unstable motor units, there may be diculty in identifying single motor unit potentials because they may decrement immediately. Do you ®nd that a diculty?
263
Timothy Doherty, London, Ontario
Jasper Daube, Rochester, Minnesota
I have found it dicult at times. However, with the multiple point stimulation technique, it can be recognized easily and lessened by reducing the stimulation frequency.
The other question is whether there are dierences between the spike triggered averaging and the decomposition techniques. Would you expect the same results from the two techniques?
Clifton Gooch, New York, New York
Timothy Doherty, London, Ontario
A few comments. I think that decrement occurs in a subpopulation of motor units in ALS, and it may or may not correlate with decrement observed in the CMAP. In my experience, I tend to reject those motor units for analysis or for tracking because it can sometimes be dicult to be certain that they are a single motor unit or whether they represent alternation or recruitment of a second smaller unit.
No direct comparisons have been made between single motor unit spike triggered averaging and multiple unit spike triggered averaging by decomposition. In the decomposition technique, higher threshold motor units and larger amplitude motor units are collected, and this may have an eect.