The latency fluctuation of single motor unit potentials (MUPH) in the H-reflex is greater than the latency fluctuation of MUPs in the direct (MUPM) and recurrent (MUP,) responses. This has been attributed to the variability in the impulse generation at the site of nerve stimulation, and to the variation in the synaptic delay at the anterior horn cell. We studied the latency fluctuation of single motor unit H-reflex in patients with motor neuron disorders (MND) in comparison with normal subjects. The mean jitter of the H-reflex was 264.3 2 17.8 ps (mean ? SEM) in 30 MUP, recorded from 10 patients with ALS, 302.7 2 25.2 ps in 16 MUP, from 6 patients with chronic motor neuron diseases, as compared with 137.4 ? 7.3 ps in 34 MUPH recorded from 10 normal subjects. This difference, which persisted even after the correction for the latency variation of MUPM, cannot be explained on the basis of an enhanced reciprocal inhibition. Thus, the increased latency fluctuation of the single motor unit H-reflex in patients with MND may reflect changes in the motoneuron pool excitability that may be secondary to altered intrinsic electrophysiological properties of motoneurons, or to an abnormal temporal and spatial summation of synaptic inputs on motoneurons. Key words: monosynaptic reflex jitter amyotrophic lateral sclerosis motoneuron synaptic delay MUSCLE & NERVE 151656-6601992
SINGLE MOTOR UNIT H-REFLEX IN MOTOR NEURON DISORDERS BETTY SOLIVEN, MD, and RICARDO A. MASELLI, MD
Changes in the amplitude and recovery cycle of the surface recorded monosynaptic H-reflex has been used to study the excitability of the alpha motoneuron.9”2 In order to study the central synaptic function of individual motoneurons, attempts have been made to record the H-reflex of a single motoneuron. This was groven technically possible in man by Trontelj’:’,’ as early as 2 decades ago. T h e main advantage of such studies is that they can reveal information that may be masked by the summation of responses of diff-erent motoneurons when using a surface recording. I t has been shown that there is considerable variation in the latency of successive H-responses of a
From the Department of Neurology and the Brain Research Institute, University of Chicago, Chicago, Illinois Presented at the AAEM Annual Meeting, Washington DC, September 1989 Acknowledgments: The authors thank Drs E Salazar and R. Roos for referring the patients to our EMG laboratory This work was supported in part by a grant from Amyotrophic Lateral Sclerosis Association Address reprint requests to Betty Soliven, MD, Department of Neurology, Box 425, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637 Accepted for publication October 2, 1991 CCC 0148-639X/92/060656-05 $04 00 0 1992 John Wiley & Sons, Inc
656
H-Reflex in Motor Neuron Disease
single motoneuron when compared with the latency fluctuation of motor unit potentials in the direct (M) and recurrent (F) responses. The aim of this investigation was to determine whether this technique could be used to assess the changes of motoneuron pool excitability in patients with motor neuron diseases (MND). We report here our initial results of jitter measurements and the rate of occurrence of the single motor unit H-reflex in normal subjects and in patients with motor neuron diseases. In addition, we compared the response of the single motor unit H-reflex to conditioning stimuli applied to the peroneal nerve of normal subjects and of patients with MND. MATERIALS AND METHODS
Ten control subjects (7 males, 3 females), aged 24 to 72 years (mean 45.4 k 4.9 years); 10 patients (5 males, 5 females) with amyotrophic lateral sclerosis (ALS), aged 46 to 70 years (mean 58.7 2 3.5 years); and 6 patients (2 males, 4 females) with either postpolio muscular atrophy (PPMA) or spinal muscular atrophy (SMA), aged 29 to 70 years (mean 47.8 k 5.6 years), were studied. All control subjects were healthy, without any known history of neuromuscular diseases.
Subjects.
MUSCLE & NERVE
June 1992
Electrodiagnostic Studies. H-reflexes were elicited in the lower limbs of all subjects in a supine position. The skin temperature of the subjects was kept above 32°C. Monopolar electrodes at the gastrocnemius were used for recording with the filter setting of 500 Hz to 10 kHz. Square pulses of 0.5-ms duration, 70 to 100 V, were delivered through surface electrodes to the tibia1 nerve at the popliteal fossa at a frequency of 0.5 Hz. Two stimulus intensities were used: (1) a stimulus intensity sufficient to elicit a single motor unit H-reflex (MUP,) that fulfills the criteria described below; and (2) a stimulus intensity needed to elicit a single motor unit M response (MUP,), which is greater than that needed to elicit MUP,,. T h e motoneuron recruited in the reflex response may not have been the same one elicited in the direct response and, therefore, it was not always possible to measure the latency variation of the same motoneuron in both direct and reflex responses. For conditioning, stimuli of an intensity above the motor threshold were delivered to the peroneal nerve at the ankle. T h e interval between the conditioning stimuli and the test stimuli were varied from 20 to 60 ms. The criteria for the identification of a single MUP,, as depicted in Figure 1, include: (a) reproducibility of waveforms (shape and duration); (b) simple pattern; (c) resemblance to the voluntary motor unit potential; (d) all-or-none response, and (e) disappearance when the voltage is further increased. Once a single motor unit in the 28- to 35-ms latency range fulfilling the above criteria was isolated, a series of 50 stimuli were given at a
M
H
FIGURE 1. An example of a motor unit fulfilling the criteria for identification as a single motor unit H-reflex (MUP,). M: direct responses; H: reflex responses; V: a voluntary motor unit. See text for details.
H-Reflex in Motor Neuron Disease
frequency of 0.5 Hz. T o determine the rate of occurrence, the number of times an H-reflex was elicited was counted and normalized to the nuniber of stimuli. T o examine the latency fluctuation of MUPI,, successive responses of the same motoneuron in groups of 10 were superimposed and automatically calculated with the built-in software of the TECA Mystro MS20 (TECA Corp., Pleasantville, NY). The results are expressed as the mean of the consecutive differences of the latencies (MCD), as is done for the SFEMG calculation of jitter. l 1 Data are given as mean 2 standard errors of the mean (SEM).
RESULTS
On the average, 2 to 4 single motor unit H-reflex potentials (MUP,) were recorded from each subject. For 1 control subject, the test was performed 3 times on separate occasions to examine the variability of the results. A total of 34 MUP, were recorded from the control subjects (CTRL), 30 MUPI, from patiepts with ALS and 16 MUP,, from patients with SMA or PPMA (chronic MND). T h e clinical characteristics of the patients are shown in Table 1. The mean latency of the MUP,, obtained in the gastrocnemius was 33.4 t 0.6 ms for control subjects, 35.0 t 1.1 ms for ALS patients, and 34.2 t 0.5 ms for patients with chronic MND. T h e rate of occurrence of MUP,, was 74 t 6% ( n = 12) for controls, 68 2 7% ( n = 8) for ALS patients, 54 + 6% ( n = 7) for chronic M N D patients ( P < 0.05, control subjects vs. chronic MND). The mean MCD of the MUP, was 137.4 f 7.3 ps ( n = 34) for control subjects, 264.3 2 17.8 ps (n = 30) for ALS and 302.7 25.2 ps ( n = 16) for chronic MND (Fig. 2) ( P < 0.0005 for ALS vs. CTRL, chronic M N D vs. CTRI, using Student’s t test). The mean jitter t SEM of MUP,, recorded from each patient is shown in Table 1. For 1 control subject who underwent the test on 3 separate occasions (4 MUP,, per test), the mean jitter values were: 130 ps, 132.7 ps, 157 ps, with a SD of 15 ps). To examine the possibility that the lower rate of occurrence of MUPI, in patients with chronic MND could contribute to the increase in jitter, we also recorded 6 MUPH with lower rates of occurrence (30% to 40%) from 2 control subjects by lowering the stimulus intensity at random to simulate blocking. MCD of these 6 MUP,, was 116.7 2 9.2 ps, which was not significantly different from the MCD of MUP, with a higher rate of occurrence.
*
MUSCLE & NERVE
June 1992
657
Table 1. Summary of the clinical characteristics of the patients. ~~
~
Patients
Age (yrs)
Sex
Duration (yrs)
A Patients with the diagnosis of ALS 69 2 1 M 39 15 F 2 46 2 3 F 62 12 4 F 55 1 5 M
6 7 8 9 10
58 65 65
F M
F
70
M M
62
25 1 15 1 2
MCD,
(JLS)*
MCD,
*
357 93 222 2 41 222 t 23 395 i 61 203 2 1 6 2 237 2 33 5 221 t 21 o t 278 ? 16 2451-
(JLS)*
DX
75 NDS NDS 112 66 7 NDt. ND* NDS 28 6 33
6 Patients with chronic motor neuron disorder (mainly lower motor neuron involvement) 1 2 3 4
5 6
F
44 29 53
F
F
50
F M
41 70
M
15 15 5 5 4 3
369 2 30 223t 334 t 79 313 k 66 255 ? 31 250t
87 NDS 57,37 38 59 5 50
SMA HEX§ PPMA PPMA PPMA PPMA
'MCD, and MCD, represent the jitter of single motor unit H reflex and of single motor unit M measured in mean consecutive d/fferences ?The value represents the mean of the jitter of 2 MUP, #Not done §A pabent wifh hexaminidase deficiency that presented with chronic MND
Figure 2 illustrates examples of superimposed MUP,, showing an increase in MCD from a patient with postpolio syndrome and a patient with ALS, as compared with that recorded from a control subject. The histogram distributions of these MUP, are shown in Figure 3. The direct responses ( M ) had a considerably smaller jitter than the reflex responses of the same motoneuron. T h e latency fluctuation of M responses was also increased in patients with MND, as compared with that recorded from controls. However, the difference in the MUP,, jitter between controls arid patients with MND persisted even af-ler correcting for the latency fluctuation of M responses. Mean MCD for M responses was 39.8 4.3 IJ.S (n = 9) for control subjects and 63.0 2 15.2 p s ( n = 5) for ALS ( P < 0.05) arid 54.7 & 7.5 p s (n = 6) for chronic MND ( P < 0.05). T o determine whether the increased latency variation of MUP,, in patients with ALS resulted from an altered reciprocal inhibition, we studied the effect of applying conditioning stimuli to the peroneal nerve (ankle) on the latency variation of' 4 MUP,, from patients with ALS and 4 MUP,, from control subjects. When the peroneal nerve stimulus preceded the tibia1 nerve stimulus by 20 to 40 ins, the mean jitter values of MUP, in-
*
658
H-Reflex in Motor Neuron Disease
creased by 45 k 13% in control subjects and by 53 k 20% in patients with ALS, suggesting that there was no difference in the reciprocal inhibition between the control group and the ALS group. DISCUSSION
Although the responses of motoneurons to monosynaptic inputs from the primary endings of muscle spindles have been investigated in various species using intracellular r e c ~ r d i n g , ~ . the ~.~ characteristics of central synaptic function can only be studied indirectly in humans. Methods employed to study monosynaptic reflexes of humans include: (1) motoneuron excitability and its inhibition or facilitation based on amplitude changes of surface-recorded H - r e f l e ~ ~(2) ~ ' esti~; mation of the number of EPSPs required to discharge a motoneuron using the phenomena of subliminal fringes and spatial summation lo; (3) estimation of the rise times of the composite EPSPS from the changes in probability of discharge of voluntarily activated single motor units after stimulation'; and (4) variability in the latency of single motor unit H-reflex using single fiber E M G . ~ 15.14 , ~ . Trontelj l 4 suggested that a considerable part of the reflex jitter must be due to the
MUSCLE & NERVE
June 1992
A . CONTROL
A. CONTROL
is
I
I% Imsec
B. POLIO
B. ALS 10 1
C. ALS
1 msec C. CHRONIC MND
FIGURE 2. Examples of superimposed MUP, showing an increase in MCD in a patient with postpolio syndrome (313 ks) and in a patient with ALS (326 ks),as compared with a control subject (176 ps).
variation in the synaptic delay that resulted either from variation in synaptic inputs to the motoneuron under study or from random fluctuations in its firing threshold. However, the latency fluctuation of the single motor unit H-reflex includes the neuromuscular jitter as well as the variability of impulse initiation at the site of stimulation; contribution of both factors could be estimated from the latency variation of direct responses, assuming that afferent and motor fibers have similar thresholds of excitation at the site of stimulation. We used Trontelj’s method to study the responses of motoneurons to afferent synaptic inputs in patients with MNDs, as compared with control subjects. Our study demonstrates that there is significantly greater latency variation of the single motor unit H-reflex in patients with M N D s when compared with that recorded from control subjects ( P < 0.0005). Although the mean jitter of the direct response was also greater for these patients, it could not account for the increasedjitter of MUP, in MNDs. T h e difference in the jitter of MUP,, persisted even after correcting for the latency variation of M responses, suggesting an increased variability in the synaptic delay at the anterior horn cell. Although the jitter of
H-Reflex in Motor Neuron Disease
5~
FIGURE 3. Histogram distribution of the MUP, in control subjects, ALS patients, and chronic MND patients.
MUP,, may increase with increasing age,’ the finding of increased MUP,, jitter in both the ALS group (older than controls) and chronic MND group (same age group as controls) suggests that the increase in jitter may be related to the anterior horn cell involvement. The rate of occurrence of MUP,, in patients with chronic MNDs is less frequent than that of control subjects or ALS patients. A lower rate of occurrence of MUP,., could result in an irregular activation rate that could contribute to the variation in the propagation velocity of nerve and action potential. However, as we have shown here, the lower rate of occurrence of MUP, alone cannot account for the increase in jitter of MUP,, recorded from patients with chronic MND. Possible explanations for the increased variation in synaptic delay at the anterior horn cell in
MUSCLE i 3 NERVE
June 1992
659
jitter is increased in patients with motor neuron patients with MNDs include: (1) altered segmental disorders, suggesting either a decreased effectiveor suprasegmental synaptic inputs resulting in ness of temporal and spatial summation of Ia inprolonged EPSP rise time, and reduced composite puts o n motorneurons or compromised intrinsic EPSP amplitude; and (2) changes in the intrinsic electrophysiological properties of motoneurones electrophysiological properties of motoneurons, in these patients. resulting in changes in excitability. Alteration in the distribution, density and voltage-dependent properties of ion channels could result in changes in the membrane potential of motoneurons. ConREFERENCES versely, changes in membrane potential could afI . Hoorman G , Lee RG, Kecker WJ, Tanaka K: Incrcased refect the activation and inactivation of ion channels ciprocal I-A inhibition following spinal cord irijury in humans. Soc Neuruccz (Abslrj 1990; 16:584. as well as synaptic transmission. For example, a 2. Burke D, Gandevia SC, Mckeon B: Mono-synaptic and olidepolarized membrane potential could also result gosynaptic c-onrributions to human ankle jerk and H-rein reduced EPSP amplitudes or altered EPSP Hex. ,I Neurophyszol 1984;52:435-448. 3. Crone C, Hulthorn H, Jespersen B, Nielsen J: Reciprocal slopes. Unfortunately, most of these parameters la inhibition between ankle flexors and extensors in man. ,I cannot be tested directly in humans. However, inPhysiol 1 9 8 7 ; W : 163- 185. creased MUP,, jitter due to altered synaptic inputs 4. Eccles J C , Eccles RM, Lundberg A : Synaptic actions on niotoneurones in relation to the two components of group could be examined using a variety of inhibitory I muscle afferent volley. J Physzol 1957;136:527-546. and facilitatory stimuli. The existence of recipro5. Eccles RM, Willis RD: The effect of repetitive stiniulation cal inhibition mediated by IA fibers from the antagupon monosynaptic transmission in kittens. ,I I ’ h y , d 1965; 176:311-321. onist muscle, tibialis anterior, is ~ell-established.~~ 6. Jabre J F , Stdlberg EV: Single fibre EMG study of the Our finding that the magnitude of inhibition proflexor carpi radialis H-reflex. Mxsrle Nerve 1989;12:.523duced by conditioning stimuli to the peroneal 527. 7. Jabre JF, Rainville J : T h e evaluation of central monosynnerve preceding the test stimuli to the tibia1 nerve aptic transmission using single motor unit studies. Muscle did not differ significantly between ALS patients Nrr.iir 19‘30;13:874a. and controls suggests that the increased latency 8. Kudo N, Yamada ‘1.: Development of monosynaptic stretch reflex in the rat: a n in vitr-o study.] Physiol 1(385;369:127variation of MUP,, in ALS patients was not due to 144. an increase in reciprocal inhibition. Increased re9. Magladcry .JW, ’l’easdall KD, Park AM, 1,anguth HW: ciprocal inhibition has been reported following I.:lectrophysiological studies of reHcx activity in patients with lesions of the nervous system. 1. Bull John Hopkins spinal cord injury where descending motor pathHosp 1952;Y 1 :219-244. ways to the spinal cord were damaged.’ A possible 10. McCoinas A.1, Mirsky M , Velho F, Struppler A: Soleus modisturbance in temporal or spatial summation of toneurone excitability in man: an indirect approach for obtaining quantitative data. J iVrurol Neurosurg I’cychiat~y the inhibitory and facilitatory inputs of motoneu1979;42:109- 101JO. rons, resulting in increased MUP, jitter in M N D I 1. Stalherg E, ‘I’rontelj ,JV: Single Fibre Elerlromyoquphy. Surcannot be excluded. However, the finding of inrey, U K Mirvalle Press, 1979, pp 155- 159. 12. Teasdall RL), Park AM, Languth HW, Magladrry JW: creased reflex jitter in patients with or without upElcctro;r,hysiological studies of. reflex activity in patients per motor neuron signs, in progressive (ALS) as with lesions of the nervous system. 11. Bull John I i o f k n s well as chronic M N D (polio), indicates an interplay Hosp 1952;91:245-256. 13. ‘l‘rontelj J V : 11-reflex of single niotoneurons in inan. Naof multiple factors contributing to increased variature 1968;220:1043- 1044. tion in synaptic delay in motor neuron disorders. 14. Trontelj J V : A study of’ {he H-rcllex by single fibre EMG.J We conclude that single motor unit H-reflex Neurol Neurosurg P.\ychiatry 1973;36:951-9
660
H-Reflex in Motor Neuron Disease
MUSCLE & NERVE
June 1992
SINGLE MOTOR UNIT H-REFLEX IN MOTOR NEURON DISORDERS BETTY SOLIVEN, MD, and RICARDO A. MASELLI, MD
Changes in the amplitude and recovery cycle of the surface recorded monosynaptic H-reflex has been used to study the excitability of the alpha motoneuron.9”2 In order to study the central synaptic function of individual motoneurons, attempts have been made to record the H-reflex of a single motoneuron. This was groven technically possible in man by Trontelj’:’,’ as early as 2 decades ago. T h e main advantage of such studies is that they can reveal information that may be masked by the summation of responses of diff-erent motoneurons when using a surface recording. I t has been shown that there is considerable variation in the latency of successive H-responses of a
From the Department of Neurology and the Brain Research Institute, University of Chicago, Chicago, Illinois Presented at the AAEM Annual Meeting, Washington DC, September 1989 Acknowledgments: The authors thank Drs E Salazar and R. Roos for referring the patients to our EMG laboratory This work was supported in part by a grant from Amyotrophic Lateral Sclerosis Association Address reprint requests to Betty Soliven, MD, Department of Neurology, Box 425, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637 Accepted for publication October 2, 1991 CCC 0148-639X/92/060656-05 $04 00 0 1992 John Wiley & Sons, Inc
656
H-Reflex in Motor Neuron Disease
single motoneuron when compared with the latency fluctuation of motor unit potentials in the direct (M) and recurrent (F) responses. The aim of this investigation was to determine whether this technique could be used to assess the changes of motoneuron pool excitability in patients with motor neuron diseases (MND). We report here our initial results of jitter measurements and the rate of occurrence of the single motor unit H-reflex in normal subjects and in patients with motor neuron diseases. In addition, we compared the response of the single motor unit H-reflex to conditioning stimuli applied to the peroneal nerve of normal subjects and of patients with MND. MATERIALS AND METHODS
Ten control subjects (7 males, 3 females), aged 24 to 72 years (mean 45.4 k 4.9 years); 10 patients (5 males, 5 females) with amyotrophic lateral sclerosis (ALS), aged 46 to 70 years (mean 58.7 2 3.5 years); and 6 patients (2 males, 4 females) with either postpolio muscular atrophy (PPMA) or spinal muscular atrophy (SMA), aged 29 to 70 years (mean 47.8 k 5.6 years), were studied. All control subjects were healthy, without any known history of neuromuscular diseases.
Subjects.
MUSCLE & NERVE
June 1992
Electrodiagnostic Studies. H-reflexes were elicited in the lower limbs of all subjects in a supine position. The skin temperature of the subjects was kept above 32°C. Monopolar electrodes at the gastrocnemius were used for recording with the filter setting of 500 Hz to 10 kHz. Square pulses of 0.5-ms duration, 70 to 100 V, were delivered through surface electrodes to the tibia1 nerve at the popliteal fossa at a frequency of 0.5 Hz. Two stimulus intensities were used: (1) a stimulus intensity sufficient to elicit a single motor unit H-reflex (MUP,) that fulfills the criteria described below; and (2) a stimulus intensity needed to elicit a single motor unit M response (MUP,), which is greater than that needed to elicit MUP,,. T h e motoneuron recruited in the reflex response may not have been the same one elicited in the direct response and, therefore, it was not always possible to measure the latency variation of the same motoneuron in both direct and reflex responses. For conditioning, stimuli of an intensity above the motor threshold were delivered to the peroneal nerve at the ankle. T h e interval between the conditioning stimuli and the test stimuli were varied from 20 to 60 ms. The criteria for the identification of a single MUP,, as depicted in Figure 1, include: (a) reproducibility of waveforms (shape and duration); (b) simple pattern; (c) resemblance to the voluntary motor unit potential; (d) all-or-none response, and (e) disappearance when the voltage is further increased. Once a single motor unit in the 28- to 35-ms latency range fulfilling the above criteria was isolated, a series of 50 stimuli were given at a
M
H
FIGURE 1. An example of a motor unit fulfilling the criteria for identification as a single motor unit H-reflex (MUP,). M: direct responses; H: reflex responses; V: a voluntary motor unit. See text for details.
H-Reflex in Motor Neuron Disease
frequency of 0.5 Hz. T o determine the rate of occurrence, the number of times an H-reflex was elicited was counted and normalized to the nuniber of stimuli. T o examine the latency fluctuation of MUPI,, successive responses of the same motoneuron in groups of 10 were superimposed and automatically calculated with the built-in software of the TECA Mystro MS20 (TECA Corp., Pleasantville, NY). The results are expressed as the mean of the consecutive differences of the latencies (MCD), as is done for the SFEMG calculation of jitter. l 1 Data are given as mean 2 standard errors of the mean (SEM).
RESULTS
On the average, 2 to 4 single motor unit H-reflex potentials (MUP,) were recorded from each subject. For 1 control subject, the test was performed 3 times on separate occasions to examine the variability of the results. A total of 34 MUP, were recorded from the control subjects (CTRL), 30 MUPI, from patiepts with ALS and 16 MUP,, from patients with SMA or PPMA (chronic MND). T h e clinical characteristics of the patients are shown in Table 1. The mean latency of the MUP,, obtained in the gastrocnemius was 33.4 t 0.6 ms for control subjects, 35.0 t 1.1 ms for ALS patients, and 34.2 t 0.5 ms for patients with chronic MND. T h e rate of occurrence of MUP,, was 74 t 6% ( n = 12) for controls, 68 2 7% ( n = 8) for ALS patients, 54 + 6% ( n = 7) for chronic M N D patients ( P < 0.05, control subjects vs. chronic MND). The mean MCD of the MUP, was 137.4 f 7.3 ps ( n = 34) for control subjects, 264.3 2 17.8 ps (n = 30) for ALS and 302.7 25.2 ps ( n = 16) for chronic MND (Fig. 2) ( P < 0.0005 for ALS vs. CTRL, chronic M N D vs. CTRI, using Student’s t test). The mean jitter t SEM of MUP,, recorded from each patient is shown in Table 1. For 1 control subject who underwent the test on 3 separate occasions (4 MUP,, per test), the mean jitter values were: 130 ps, 132.7 ps, 157 ps, with a SD of 15 ps). To examine the possibility that the lower rate of occurrence of MUPI, in patients with chronic MND could contribute to the increase in jitter, we also recorded 6 MUPH with lower rates of occurrence (30% to 40%) from 2 control subjects by lowering the stimulus intensity at random to simulate blocking. MCD of these 6 MUP,, was 116.7 2 9.2 ps, which was not significantly different from the MCD of MUP, with a higher rate of occurrence.
*
MUSCLE & NERVE
June 1992
657
Table 1. Summary of the clinical characteristics of the patients. ~~
~
Patients
Age (yrs)
Sex
Duration (yrs)
A Patients with the diagnosis of ALS 69 2 1 M 39 15 F 2 46 2 3 F 62 12 4 F 55 1 5 M
6 7 8 9 10
58 65 65
F M
F
70
M M
62
25 1 15 1 2
MCD,
(JLS)*
MCD,
*
357 93 222 2 41 222 t 23 395 i 61 203 2 1 6 2 237 2 33 5 221 t 21 o t 278 ? 16 2451-
(JLS)*
DX
75 NDS NDS 112 66 7 NDt. ND* NDS 28 6 33
6 Patients with chronic motor neuron disorder (mainly lower motor neuron involvement) 1 2 3 4
5 6
F
44 29 53
F
F
50
F M
41 70
M
15 15 5 5 4 3
369 2 30 223t 334 t 79 313 k 66 255 ? 31 250t
87 NDS 57,37 38 59 5 50
SMA HEX§ PPMA PPMA PPMA PPMA
'MCD, and MCD, represent the jitter of single motor unit H reflex and of single motor unit M measured in mean consecutive d/fferences ?The value represents the mean of the jitter of 2 MUP, #Not done §A pabent wifh hexaminidase deficiency that presented with chronic MND
Figure 2 illustrates examples of superimposed MUP,, showing an increase in MCD from a patient with postpolio syndrome and a patient with ALS, as compared with that recorded from a control subject. The histogram distributions of these MUP, are shown in Figure 3. The direct responses ( M ) had a considerably smaller jitter than the reflex responses of the same motoneuron. T h e latency fluctuation of M responses was also increased in patients with MND, as compared with that recorded from controls. However, the difference in the MUP,, jitter between controls arid patients with MND persisted even af-ler correcting for the latency fluctuation of M responses. Mean MCD for M responses was 39.8 4.3 IJ.S (n = 9) for control subjects and 63.0 2 15.2 p s ( n = 5) for ALS ( P < 0.05) arid 54.7 & 7.5 p s (n = 6) for chronic MND ( P < 0.05). T o determine whether the increased latency variation of MUP,, in patients with ALS resulted from an altered reciprocal inhibition, we studied the effect of applying conditioning stimuli to the peroneal nerve (ankle) on the latency variation of' 4 MUP,, from patients with ALS and 4 MUP,, from control subjects. When the peroneal nerve stimulus preceded the tibia1 nerve stimulus by 20 to 40 ins, the mean jitter values of MUP, in-
*
658
H-Reflex in Motor Neuron Disease
creased by 45 k 13% in control subjects and by 53 k 20% in patients with ALS, suggesting that there was no difference in the reciprocal inhibition between the control group and the ALS group. DISCUSSION
Although the responses of motoneurons to monosynaptic inputs from the primary endings of muscle spindles have been investigated in various species using intracellular r e c ~ r d i n g , ~ . the ~.~ characteristics of central synaptic function can only be studied indirectly in humans. Methods employed to study monosynaptic reflexes of humans include: (1) motoneuron excitability and its inhibition or facilitation based on amplitude changes of surface-recorded H - r e f l e ~ ~(2) ~ ' esti~; mation of the number of EPSPs required to discharge a motoneuron using the phenomena of subliminal fringes and spatial summation lo; (3) estimation of the rise times of the composite EPSPS from the changes in probability of discharge of voluntarily activated single motor units after stimulation'; and (4) variability in the latency of single motor unit H-reflex using single fiber E M G . ~ 15.14 , ~ . Trontelj l 4 suggested that a considerable part of the reflex jitter must be due to the
MUSCLE & NERVE
June 1992
A . CONTROL
A. CONTROL
is
I
I% Imsec
B. POLIO
B. ALS 10 1
C. ALS
1 msec C. CHRONIC MND
FIGURE 2. Examples of superimposed MUP, showing an increase in MCD in a patient with postpolio syndrome (313 ks) and in a patient with ALS (326 ks),as compared with a control subject (176 ps).
variation in the synaptic delay that resulted either from variation in synaptic inputs to the motoneuron under study or from random fluctuations in its firing threshold. However, the latency fluctuation of the single motor unit H-reflex includes the neuromuscular jitter as well as the variability of impulse initiation at the site of stimulation; contribution of both factors could be estimated from the latency variation of direct responses, assuming that afferent and motor fibers have similar thresholds of excitation at the site of stimulation. We used Trontelj’s method to study the responses of motoneurons to afferent synaptic inputs in patients with MNDs, as compared with control subjects. Our study demonstrates that there is significantly greater latency variation of the single motor unit H-reflex in patients with M N D s when compared with that recorded from control subjects ( P < 0.0005). Although the mean jitter of the direct response was also greater for these patients, it could not account for the increasedjitter of MUP, in MNDs. T h e difference in the jitter of MUP,, persisted even after correcting for the latency variation of M responses, suggesting an increased variability in the synaptic delay at the anterior horn cell. Although the jitter of
H-Reflex in Motor Neuron Disease
5~
FIGURE 3. Histogram distribution of the MUP, in control subjects, ALS patients, and chronic MND patients.
MUP,, may increase with increasing age,’ the finding of increased MUP,, jitter in both the ALS group (older than controls) and chronic MND group (same age group as controls) suggests that the increase in jitter may be related to the anterior horn cell involvement. The rate of occurrence of MUP,, in patients with chronic MNDs is less frequent than that of control subjects or ALS patients. A lower rate of occurrence of MUP,., could result in an irregular activation rate that could contribute to the variation in the propagation velocity of nerve and action potential. However, as we have shown here, the lower rate of occurrence of MUP, alone cannot account for the increase in jitter of MUP,, recorded from patients with chronic MND. Possible explanations for the increased variation in synaptic delay at the anterior horn cell in
MUSCLE i 3 NERVE
June 1992
659
jitter is increased in patients with motor neuron patients with MNDs include: (1) altered segmental disorders, suggesting either a decreased effectiveor suprasegmental synaptic inputs resulting in ness of temporal and spatial summation of Ia inprolonged EPSP rise time, and reduced composite puts o n motorneurons or compromised intrinsic EPSP amplitude; and (2) changes in the intrinsic electrophysiological properties of motoneurones electrophysiological properties of motoneurons, in these patients. resulting in changes in excitability. Alteration in the distribution, density and voltage-dependent properties of ion channels could result in changes in the membrane potential of motoneurons. ConREFERENCES versely, changes in membrane potential could afI . Hoorman G , Lee RG, Kecker WJ, Tanaka K: Incrcased refect the activation and inactivation of ion channels ciprocal I-A inhibition following spinal cord irijury in humans. Soc Neuruccz (Abslrj 1990; 16:584. as well as synaptic transmission. For example, a 2. Burke D, Gandevia SC, Mckeon B: Mono-synaptic and olidepolarized membrane potential could also result gosynaptic c-onrributions to human ankle jerk and H-rein reduced EPSP amplitudes or altered EPSP Hex. ,I Neurophyszol 1984;52:435-448. 3. Crone C, Hulthorn H, Jespersen B, Nielsen J: Reciprocal slopes. Unfortunately, most of these parameters la inhibition between ankle flexors and extensors in man. ,I cannot be tested directly in humans. However, inPhysiol 1 9 8 7 ; W : 163- 185. creased MUP,, jitter due to altered synaptic inputs 4. Eccles J C , Eccles RM, Lundberg A : Synaptic actions on niotoneurones in relation to the two components of group could be examined using a variety of inhibitory I muscle afferent volley. J Physzol 1957;136:527-546. and facilitatory stimuli. The existence of recipro5. Eccles RM, Willis RD: The effect of repetitive stiniulation cal inhibition mediated by IA fibers from the antagupon monosynaptic transmission in kittens. ,I I ’ h y , d 1965; 176:311-321. onist muscle, tibialis anterior, is ~ell-established.~~ 6. Jabre J F , Stdlberg EV: Single fibre EMG study of the Our finding that the magnitude of inhibition proflexor carpi radialis H-reflex. Mxsrle Nerve 1989;12:.523duced by conditioning stimuli to the peroneal 527. 7. Jabre JF, Rainville J : T h e evaluation of central monosynnerve preceding the test stimuli to the tibia1 nerve aptic transmission using single motor unit studies. Muscle did not differ significantly between ALS patients Nrr.iir 19‘30;13:874a. and controls suggests that the increased latency 8. Kudo N, Yamada ‘1.: Development of monosynaptic stretch reflex in the rat: a n in vitr-o study.] Physiol 1(385;369:127variation of MUP,, in ALS patients was not due to 144. an increase in reciprocal inhibition. Increased re9. Magladcry .JW, ’l’easdall KD, Park AM, 1,anguth HW: ciprocal inhibition has been reported following I.:lectrophysiological studies of reHcx activity in patients with lesions of the nervous system. 1. Bull John Hopkins spinal cord injury where descending motor pathHosp 1952;Y 1 :219-244. ways to the spinal cord were damaged.’ A possible 10. McCoinas A.1, Mirsky M , Velho F, Struppler A: Soleus modisturbance in temporal or spatial summation of toneurone excitability in man: an indirect approach for obtaining quantitative data. J iVrurol Neurosurg I’cychiat~y the inhibitory and facilitatory inputs of motoneu1979;42:109- 101JO. rons, resulting in increased MUP, jitter in M N D I 1. Stalherg E, ‘I’rontelj ,JV: Single Fibre Elerlromyoquphy. Surcannot be excluded. However, the finding of inrey, U K Mirvalle Press, 1979, pp 155- 159. 12. Teasdall RL), Park AM, Languth HW, Magladrry JW: creased reflex jitter in patients with or without upElcctro;r,hysiological studies of. reflex activity in patients per motor neuron signs, in progressive (ALS) as with lesions of the nervous system. 11. Bull John I i o f k n s well as chronic M N D (polio), indicates an interplay Hosp 1952;91:245-256. 13. ‘l‘rontelj J V : 11-reflex of single niotoneurons in inan. Naof multiple factors contributing to increased variature 1968;220:1043- 1044. tion in synaptic delay in motor neuron disorders. 14. Trontelj J V : A study of’ {he H-rcllex by single fibre EMG.J We conclude that single motor unit H-reflex Neurol Neurosurg P.\ychiatry 1973;36:951-9
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