We studied the discharge pattern of single motor units (SMUs) in the left and right biceps muscles from a patient with nonspastic weakness of the left arm. Detailed statistical analysis of the behavior of discharge patterns of 4 of 4 single motor units on the affected side showed abnormalities with characteristic features of an upper motor neuron lesion. Five out of 5 single motor units recorded from the right biceps were normal. An upper motor neuron lesion affecting the left arm, predicted by our results, was confirmed by magnetic resonance imaging (MRI), which showed a lesion in the right precentral gyrus. It appears that changes in single motor unit firing characteristics, caused by an upper motor neuron lesion, can be detected at a time when there is no evidence of increased “tone” and/or hyperreflexia (spasticity) in the affected extremity. Key words: motor unit upper motorneuron spasticity MUSCLE & NERVE 14:64-69 1991
ABNORMAL SINGLE MOTOR UNIT BEHAVIOR IN THE UPPER MOTOR NEURON SYNDROME BHAGWAN T. SHAHANI, MD, D Phil, MARGARET M. WIERZBICKA, PhD, and STEPHEN W. PARKER, MD
Statistical analysis of single motor unit interdischarge intervals during sustained voluntary contractions has been used to demonstrate quantitative changes in the motoneuron discharge characteristics produced by various lesions within the central and/or peripheral nervous system. ‘ L V ” “ ~ ’ ~ ) l~7~ ’ Most studies have been performed in patients with spastic paresis due to supraspinal lesions,1.23“3’’l7 only a few studies are available in spasticity with spinal involvement. 1,1”5 Characteristic changes in the relationship of adjacent interspike intervals have been particularly reported in patients with “spasticity” caused by cerebral lesions. However, it is not known whether these changes in the behavior of the pattern of S M U discharge are related to positive symptoms (hyperreflexia, increased tone, etc.) or negative symptoms (weakness, loss of dexterity, etc.) of an upper motor neuron lesion. All previously reported studies have been performed in patients who had hyperreflexia and increased
From the Clinical Neurophysiology Laboratory, Massachusetts General Hospital and Department of Neurology, Harvard Med~calSchool, Boston, Massachusetts. Address reprint requests to Dr. B. T.Shahani, Clinical Neurophysiology, Bigelow 12, Massachusetts General Hospital, Boston, MA 021 14. Accepted for publication January 23, 1990. CCC 0148-639X/91/01064-06 $04.00 0 1991 John Wiley & Sons, Inc.
64
Single Motor Unit Behavior
tone (spasticity). Our patient presented with flaccid weakness due to an upper motor neuron lesion. The present report, for the first time, demonstrates that characteristic changes seen in the behavior of SMUs in spasticity may be associated with negative rather than positive symptoms of an upper motor neuron lesion.
CASEREPORT
A 60-year-old left-handed woman had history of a right mastectomy for breast cancer (21 years ago) and lymphoma (8 years ago) which was treated with chemotherapy. Four months prior to evaluation there had been recent activity of lymphoma requiring radiation to the area of the right kidney. Three months prior to examination the patient noted the onset of a clumsy feeling in the left hand. This became progressively worse, causing difficulty in writing or buttoning with the left hand. In addition to clumsiness, the patient noted mild weakness and “cold” feeling in her left hand. On examination the patient was alert and cooperative with fluent speech. Tongue and palate moved well. Extraocular movements were full. There was no facial weakness. Shoulder shrug and sternocleidomastoid muscle functions were normal bilaterally. There as mild atrophy and weakness of the left hand. Grip on the left side was only
MUSCLE & NERVE
January 1991
slightly weaker than on the right side. Muscle strength was graded from 0 to 10 as follows:
0 1 2 3 4 5 6 7
N o movement Trace of contraction More than 1 but less than 3 Active movement with gravity eliminated More than 3 but less than 5 Active movement against gravity More than 5 but less than 7 Active movement against gravity and minimal resistance 8 Active movement against gravity and moderate resistance 9 More than 8 but less than 10 10 Active movement against “full” resistance There was 7/10 strength in flexors of the distal phalanges of all fingers and also 7/10 strength in extensors of the hand and fingers. There was 9/10 strength in the interossei muscles. There was no definite weakness of muscles acting on the wrist, elbow, or shoulder. Biceps and brachioradialis reflexes were 2+ bilaterally. T h e left triceps jerk was slightly less than the right. There was no reflex asymmetry or weakness in the lower extremities and the toes were downgoing. Appreciation of cold was slightly less over the left hand than the right side. There was questionable decrease in pinprick sensation in the left hand. ‘l’here was no abnormality of sensation of any other part of the left upper extremity. T h e EMG and nerve conduction studies were performed two weeks after the above noted examination. On the same day median somatosensory-evoked potentials were performed and were normal. These electrophysiological studies suggested an upper motor neuron lesion. A C T scan of the head was performed 12 days after the EMG and revealed no abnormality. Because of progressive weakness of the left hand the patient was admitted to the hospital approximately 38 days after the EMG. At that time there was only trace flexion and extension of fingers of the left hand. Wrist flexors were 2/10 and wrist extensors were 0/10. Left biceps flexion was 8/10 and extension at the elbow was 7/10. T h e left shoulder was 9/10. T h e right arm was normal. Biceps and triceps jerks were 2+ bilaterally. A lumbar puncture revealed 2 or 3 lymphocytes per cubic millimeter. ‘The protein was 38, glucose 55, VDRL nonreactive and gold sol curve 122222 1111. Neurophysiological studies with SMU recordings were performed from left and right biceps during steady voluntary contraction.
Single Motor Unit Behavior
An MRI scan revealed a right precentral gyrus lesion. A C‘1’ scan revealed a low absorption area in the right precentral gyrus. A stereotactic biopsy of the left precentral gyrus was consistent with progressive multifocal leukoencephalopathy. Subsequently, the patient developed weakness of the left leg. Repeat MRI scans revealed more extensive cerebral lesions. The patient was treated with a course of intravenous acyclovir. She is still alive 2.5 years later with slight improvement in gait and left leg function but no improvement in the left arm.
QUANTITATIVE ASSESSMENT OF THE SINGLE MOTOR UNITS FIRING PATTERN Methods. EMG and nerve conduction studies were performed using commercially available EMG equipment (TECA). Single motor units were recorded from left and right biceps brachii during approximately 1 min of sustained isometric contraction. T h e contraction force was measured with a force transducer and displayed for visual feedback on oscilloscope in front of the patient. SMUs were recorded with a single fiber EMG needle electrode (TECA), which was carefully positioned to obtain the best possible isolation of the SMU from the background activity of more distant motor units. EMG signals from the electrodes were preamplified, filtered with band pass 800 Hz to ti kHz and together with the force signal output of the bridge amplifier, were recorded simultaneously on FM tape recorder (Kacal). Data processing was performed off-line. Recording epochs were selected of approximately 20 seconds long during which SMUs fired steadily. Recording segments with obvious lapses in SMU firing or contaminated with discharges of other motor units were rejected. Intervals between successive discharges of the same SMU were measured using an LSI 11/23 computer, a Schmitt trigger, and a programmable clock. The amplitude of the trigger level was adjusted individually for each SMU being analyzed. In addition, the hard copies of the SMU discharges arid Schmitt trigger pulses were visually inspected to ensure that triggering occurred on the correct SMU [Fig. 2(C)]. T h e S M U firing pattern was described in terms of the following statistical parameters: (i) mean firing frequency, (ii) variability in Successive interdischarge intervals, arid (iii) Hoating serial correlation coefficient. T h e variability o f the interdischarge intervals (VAR) was calculated as suggested by P r o c h a ~ k a and ’ ~ Andreassen’
MUSCLE & NERVE
January 1991
65
component to the serial correlation and therefore might mask the presence of negative serial correlation between the adjacent intervals.” In addition to the evaluated numerical parameters, graphical representation of the results including a torque-instantaneous firing frequency plot and a joint interval histogram (JIH) were provided. Instantaneous frequency was calculated as the reciprocal of each interspike interval and was plotted as a function of elapsed time. In the JIHs, the duration of one interdischarge interval was represented on the abcissa vs. the duration of the next interval on the ordinate.
/n is the mean interval, n is a number of evaluated intervals, and Ziis i-th interval. The VAR was used here to measure a variability between neighbor intervals rather than overall variability of the intervals expressed by the standard deviation (SD). Floating serial correlation (F) was calculated with formulas derived by Andreassen3
RESULTS
‘x
Statistical analysis of the interdischarge intervals showed substantial qualitative and quantitative differences in the firing pattern of SMUs recorded from left and right biceps. Comparison of the statistical parameters in between sides for all SMUs studied is shown in Table 1. All 5 SMUs recorded from the right biceps had normal discharge patterns. A typical torqueinstantaneous plot for the SMUs recorded from the right side is shown in Figure 1(A). The patient was able to maintain a steady torque level with little variation in force output, as seen in normal subjects. A “spiky” appearance of the instantaneous firing frequency plot is characteristic of the normal discharge pattern showing considerable variability in length of neighboring interdischarge intervals. A JIH plotted from the same SMU recording [Fig. l(B)] shows an elliptical cluster of points whose longer axis has a negative slope. T h e negative serial correlation coefficient reflects the tendency for long and short intervals to alternate, a common feature of normal discharge patterns, particularly for SMUs firing faster than 10 Hz.
1
I>--
F=n-1
[(Zi - FMI,) (Zi+l - FMIi+1)/FSD2]
i= 1
where:
.1
F S D ~=
x zj
i+9
F M I ~= 19j
is a floating mean
= j - g
5
n-l
(Zl - FMIJ2 is a floating SD‘
i = 1
The floating mean interval (FMI) was evaluated with a “moving window” 19 intervals long. Such window length was reported to be efficient in following short-term trends in SMU firing and not producing a large negative bias on the serial correlation. l o The floating serial correlation was used to minimize the effect of long-term trends on the serial correlation coefficient. Otherwise, long periods of monotonic increasing or decreasing firing frequency would contribute a positive
~
~~
Table 1. Statistical parameters evaluated for SMUs recorded from left (affected) and right biceps Right side
SMU # 1 2 3 4
5 Mean:
Left side
(Hz)
F
VAR (ms)
MFR (Hz)
TOR (Nm)
F
VAR (ms)
-0.42 -0.23 -0.20 -0.22 -0.51 -0.32
14 13 15 10 13 13
15.3 16.7 10.2 16.6 15.4 14.8
8.5 7.2 0.3 3.7 4.2 4.8
0.81 0.73 0.58 0.49
9 10 7 9
11.8 9.7 12.7 11.2
1.2 0.2 2.9 7.6
0.65
8.75
11.4
2.96
MFR
F = floating serial correlation coefficient, VAR = measure of variability of the length of consecutive mterdischarge intervals, MFR rate, TOR = mean torque recorded at the elbow loint
66
Single Motor Unit Behavior
=
MUSCLE & NERVE
TOR (Nm)
mean finng
January 1991
t 1: "1 T a E I N SEQ#5
IIEC
FIGURE 1. Firing pattern of the SMU recorded from the right biceps. (A) Torque (top) and the instantaneous firing frequency (bottom); (B) Joint interval histogram (R = serial correlation coefficient, F = floating serial correlation coefficient; calculated in relation to the moving average of i9 intervaIs)3
Four SMUs recorded from the affected side showed abnormal discharge behavior. Large fluctuations in torque, accompanied by a slow frequency oscillations in instantaneous firing frequency were observed [Fig. 2(A)]. In comparison to the right side, SMUs recorded from the affected arm had lower discharge frequencies (Table 1) and showed reduced variability in length of' the consecutive interdischarge intervals ( P < 0.05, Wilcoxon test). Analysis of the serial interdepen-
I::
2.-
10
dence of adjacent time intervals revealed a strong positive serial correlation. Corresponding JIHs (Fig. 2B) showed points clustered in ellipses whose longer axes had positive slopes. Statistically, such positive serial correlation indicates that there are abnormal trends in SMU firing patterns with a series of short interdischarge intervals followed by a series of longer interdischarge intervals and vice versa. This trend can even be noticed in the SMU spike train [Fig. 2(C)].
-
C
Ill11 I I i 1 1 111111111 1 I I I 1 I 1111111 I I I I 1 i II I I *# # # #
*
# # #
*
#***###*#
*
Single Motor Unit Behavior
#
#
** *
-
####### # # I
**# *
# #
#
FIGURE 2. Firing pattern of the SMU recorded from the left (affected) biceps. (A) Torque (top) and the instantaneous firing frequency (bottom); (6) Joint interval histogram; (C) Raw data obtained during recording session. Upper trace SMU discharges, dots Schrnitt trigger firings, bottom recorded force. Time calibration is 1 sec. Note intermittent grouping of short and long interdischarge intervals
MUSCLE & NERVE
January 1991
67
For example, SMUs recorded from patients with basal ganglia disorders (Parkinson's and HuntingQuantitative evaluation of motor dysfunction proton's disease) showed discharge irregularities with duced by any lesion within the nervous system is significantly hi her variability of interdischarge inimportant in clinical studies and treatment of paterval lengths! Typical findings in patients with tients with a variety of motor disorders. Any volspastic paresis, '2.1.5- 17 attributed to supraspinal leuntary motor act requires proper activation of apsions include changes in the temporal order of adpropriate groups of muscles in order to generate jacent intervals leading to positive serial correlathe desired force necessary to accomplish the tion, decreased variability in length of consecutive planned movement. Since the lower motor neuron interdischarge intervals, and lower discharge freis the final common pathway for the motor sysquency. Patients with spastic paresis have difficulty tem, abnormalities of motor control must be remaintaining constant force. Kecordings of instanflected in altered S M U behavior. taneous firing frequency usually show similar fluc'There are 2 neurological mechanisms responsituations to that of the force output. Statistical evalble for force generation: (i) recruitment of new uation of firing patterns provides a quantitative SMUs and (ii) modulation o f the firing rates of measure of the impaired regulation of timing of SMUs already recruited. We will discuss only the motor unit discharges i n patients with disorders of second mechanism. T h e technique used in this the central and/or peripheral nervous system. study was introduced by Freund" and further deIn o u r patient, study of the affected biceps veloped by Andreassen and Kosenfalck.'." It almuscle reveals pathologic SM U discharge patterns lows quantitative analysis of any isolated S M U dissimilar to that reported in spastic muscles. O u r recharge during a steady muscle contraction. sults suggest an upper motor neuron lesion which Usually, low-threshold S M U s firing at frequencies is confirmed by MKI scanning. Figure 3 shows the 6 to 20 Hz, are the easiest S M U s to record in isowell-localized lesion of the right precentral gyrus. lation with routine E M G electrodes. At higher We conclude that abnormalities of S M U behavior force levels recording of S M U s requires the use of documented by computer analysis of firing pathigh impedance tungsten semi-micro electrodes. These electrodes were originally introduced foirecordings from human nerves in muscle spindle afferents," but more recently have been used in studying S M U behavior during maximal voluntary contraction,4 fatigue," o r tremor. 12 Normal S M U discharge patterns have been described in different muscles from the loweri,:'~i7 and ~ p p e r " ~ ~ ~ ~extremities. ' ~ " ) ~ ' ' It was found that S M U discharge times often show a negative serial correlation. Physiological mechanisms responsible for discharge by discharge alterations in firing times of SMUs resulting in negative serial correlation are not known. Several interpretations have been offered including motor neuron afterhyperpolarization," Kenshaw cell inhibition,' and peripheral feedback mechanisms.'*" It has been speculated that negative serial correlation serves to provide a compensatory mechanism for shortterm stabilization of force, thereby minimizing the fluctuation in force output.'"" 111 this study, SMU recordings from the right biceps showed typically norrnal firing patterns, consistent with previous studies of S M U hchavior in normal muscles. Significant quantitative differences in S M U disFIGURE 3. Magnetic resonance image (MRI) of the lesion locharge patterns during sustained isometric contraccated in the right precentral gyrus in areas mediating arm and tion have been reported in a f'ew studies in patients hand function. Subsequent needle biopsy indentified progressive with various movement d i s o r d e ~ s . ' ~ 2 ~ " ~ ~ ' ~ ' 0 ~multifocal ' " - i 7 leukoencephalopathy. DISCUSSION
68
Single Motor Unit Behavior
MUSCLE & NERVE
January 1991
terns may correlate best with the negative symptoms of the upper niotor neuron syndrome. With this technique, changes in the discharge pattern of SMUs can be detected at a time when there is no evidence of clinical “spasticity.” It is of interest to address another problem related to studies of S M U s behavior. In recordings from normal muscles it was found that the serial correlation coefficient becomes less negative and even positive when firing rate decreases.’33This dependence might suggest that the positive serial correlation reported in previous studies of spastic-
ity was simply due to the fact that S M U s discharged more slowly than normal (most often i t i the 5-7 Hz range). In the present study, the mean discharge frequencies of SMUs, recorded on the symptomatic side, ranged from 9.7- 12.7 Hz. This would usually lead to negative serial correlation in normal muscle, but in our study we observed large positive serial correlations. These data indicate that changes in timing of SMUs discharges is indeed the inherent property of the lesion and not a phenomenon related to slowing of S M U s firing rates.
REFERENCES 1. Andreassen S: 1ntcwal Pattern ofsznglr Molor Cinils. University Press, Aalborg, 1978, p p 1-220. 2. Andreassen S, Kosenfalck A: Impaired regulation of. the firing pattern of single niotor units. Musclr Neme 1978; 1:4 16-4 18. 3. Andreassen S, Kosenfalck A: Regulation of the firing pattern of single motor units. J Nrurol Neurosurg Psychiatry 1Y80;43:897-906. 4. Bellernare F, Woods JJ, Johansson K, Bigland-Ritchie B: Motor-unit discharge rates in maximal voluntary contractioris of. three human muscles. J Neurophysiol 1983;
5.
6.
7. 8.
9.
10.
50: 1380- 1392. 13iglandLRitchie 8, Johansson R, Lippold OCJ, Smith S, Woods JJ: Changes in niotoneurone firing rates during sustained maximal voluntary contractions. J Physzol 1983;340:335-346. Dengler K, Wolf W, Schubert M, Struppler A: Discharge pattern of single motor units in basal ganglia disorders. Neurology 1986;36:1061- 1066. Elbe RJ, Randall JE: Motor unit activity responsible for 8to 12-Hz component of‘ human physiological finger tremor. J Neuropliysiol 1976;39:370-383. Freund HJ, Buedingen HJ, Dietz V: Activity of single niotor units from human forearm muscles during voluntary isometric contractions. J NeurophyszoE 1975;38:933-946. Freund HJ, Dietz V, Wita CW, Kapp H: Discharge characteristics of single motor units in normal subjem and patients with supraspinal motor disturbances, in Desmedt J E (cd): Ncw Developments in Eleclromyograp/~yand Clinical NeurophysioloLgy,Basel, Karger, 1973, vol 3, pp 242-250. Freund HJ, llefter H, Homberg V: Motor unit activity in
Single Motor Unit Behavior
11. 12.
13. 14.
15. 16.
17.
motor disorders, in Shahani B‘r (ed): Elcctro,tLyograp/Ly in CNS Disordrn: Crnfrol E M G , Boston, Butterworth, 1983, pp 29-43. Hagbarth K-E, Young RK: Participation of the stretch rcflex in human physiological tremor. Hrazi~ 1979; 102:509526. Logigian EL, Wierzbicka MM, Bruyninckx F, Wiegtier AW, Shahani B T , Young RR: Motor unit synchronization in physiologic, enhanced physiologic and voluntary trenioiin man. Ann NeuIol 1988;23:242-250. Person RS, Kudina LP: Discharge frequency and discharge pattern of human units during voluntary contraction o f muscle. Electroenceph Clin Neurophysiol 1972;32:47 1-488. Prochazka VJ, Conrad €3, Sinderniann F: Computerizecl single-unit interval analysis and its clinical application, in ip/~y Desinedt J E (ed): New Developmrnts in 6 l c , ( t l - o m y c ~ ~ ~ and Clznical Neurophy.\iolqy, Basel, Karger, 1973, vol 2, pp 462468. Rosenfalck A, Andreassen S: Impaired regulation of force and firing pattern of single motor units i n patients with spasticity. J N e u d Neurosurg P.sychzat?y 1980;43:907-9113. Young RR, Shahani BT: A clinical neurophysiologic~al analysis of single motor unit discharge patterns i n spasticity, in Feldman R G , Young KK, and Koella (etls): Spccsticity: Dz.\oi-dered Motor Control, Chicago, Year Book, 1980, p p 219-231. Young RR, Wierzbicka MM: Kehaviour of single tilotor units in normal subjects and in patients with spastic paresis, in Delwaide PJ, Young RR (eds): Clznicrrl Nrzr,.o~~~/i~.sio/o~~ zn Spasticily: Coiatrzbution to A.\se.ssmonl and P a t h o p l ~ y . s i ~ ~ l o ~ ~ , Atnstei-dam, Elsevier, 1958, p p 27-37.
MUSCLE &. NERVE
January 1991
69
ABNORMAL SINGLE MOTOR UNIT BEHAVIOR IN THE UPPER MOTOR NEURON SYNDROME BHAGWAN T. SHAHANI, MD, D Phil, MARGARET M. WIERZBICKA, PhD, and STEPHEN W. PARKER, MD
Statistical analysis of single motor unit interdischarge intervals during sustained voluntary contractions has been used to demonstrate quantitative changes in the motoneuron discharge characteristics produced by various lesions within the central and/or peripheral nervous system. ‘ L V ” “ ~ ’ ~ ) l~7~ ’ Most studies have been performed in patients with spastic paresis due to supraspinal lesions,1.23“3’’l7 only a few studies are available in spasticity with spinal involvement. 1,1”5 Characteristic changes in the relationship of adjacent interspike intervals have been particularly reported in patients with “spasticity” caused by cerebral lesions. However, it is not known whether these changes in the behavior of the pattern of S M U discharge are related to positive symptoms (hyperreflexia, increased tone, etc.) or negative symptoms (weakness, loss of dexterity, etc.) of an upper motor neuron lesion. All previously reported studies have been performed in patients who had hyperreflexia and increased
From the Clinical Neurophysiology Laboratory, Massachusetts General Hospital and Department of Neurology, Harvard Med~calSchool, Boston, Massachusetts. Address reprint requests to Dr. B. T.Shahani, Clinical Neurophysiology, Bigelow 12, Massachusetts General Hospital, Boston, MA 021 14. Accepted for publication January 23, 1990. CCC 0148-639X/91/01064-06 $04.00 0 1991 John Wiley & Sons, Inc.
64
Single Motor Unit Behavior
tone (spasticity). Our patient presented with flaccid weakness due to an upper motor neuron lesion. The present report, for the first time, demonstrates that characteristic changes seen in the behavior of SMUs in spasticity may be associated with negative rather than positive symptoms of an upper motor neuron lesion.
CASEREPORT
A 60-year-old left-handed woman had history of a right mastectomy for breast cancer (21 years ago) and lymphoma (8 years ago) which was treated with chemotherapy. Four months prior to evaluation there had been recent activity of lymphoma requiring radiation to the area of the right kidney. Three months prior to examination the patient noted the onset of a clumsy feeling in the left hand. This became progressively worse, causing difficulty in writing or buttoning with the left hand. In addition to clumsiness, the patient noted mild weakness and “cold” feeling in her left hand. On examination the patient was alert and cooperative with fluent speech. Tongue and palate moved well. Extraocular movements were full. There was no facial weakness. Shoulder shrug and sternocleidomastoid muscle functions were normal bilaterally. There as mild atrophy and weakness of the left hand. Grip on the left side was only
MUSCLE & NERVE
January 1991
slightly weaker than on the right side. Muscle strength was graded from 0 to 10 as follows:
0 1 2 3 4 5 6 7
N o movement Trace of contraction More than 1 but less than 3 Active movement with gravity eliminated More than 3 but less than 5 Active movement against gravity More than 5 but less than 7 Active movement against gravity and minimal resistance 8 Active movement against gravity and moderate resistance 9 More than 8 but less than 10 10 Active movement against “full” resistance There was 7/10 strength in flexors of the distal phalanges of all fingers and also 7/10 strength in extensors of the hand and fingers. There was 9/10 strength in the interossei muscles. There was no definite weakness of muscles acting on the wrist, elbow, or shoulder. Biceps and brachioradialis reflexes were 2+ bilaterally. T h e left triceps jerk was slightly less than the right. There was no reflex asymmetry or weakness in the lower extremities and the toes were downgoing. Appreciation of cold was slightly less over the left hand than the right side. There was questionable decrease in pinprick sensation in the left hand. ‘l’here was no abnormality of sensation of any other part of the left upper extremity. T h e EMG and nerve conduction studies were performed two weeks after the above noted examination. On the same day median somatosensory-evoked potentials were performed and were normal. These electrophysiological studies suggested an upper motor neuron lesion. A C T scan of the head was performed 12 days after the EMG and revealed no abnormality. Because of progressive weakness of the left hand the patient was admitted to the hospital approximately 38 days after the EMG. At that time there was only trace flexion and extension of fingers of the left hand. Wrist flexors were 2/10 and wrist extensors were 0/10. Left biceps flexion was 8/10 and extension at the elbow was 7/10. T h e left shoulder was 9/10. T h e right arm was normal. Biceps and triceps jerks were 2+ bilaterally. A lumbar puncture revealed 2 or 3 lymphocytes per cubic millimeter. ‘The protein was 38, glucose 55, VDRL nonreactive and gold sol curve 122222 1111. Neurophysiological studies with SMU recordings were performed from left and right biceps during steady voluntary contraction.
Single Motor Unit Behavior
An MRI scan revealed a right precentral gyrus lesion. A C‘1’ scan revealed a low absorption area in the right precentral gyrus. A stereotactic biopsy of the left precentral gyrus was consistent with progressive multifocal leukoencephalopathy. Subsequently, the patient developed weakness of the left leg. Repeat MRI scans revealed more extensive cerebral lesions. The patient was treated with a course of intravenous acyclovir. She is still alive 2.5 years later with slight improvement in gait and left leg function but no improvement in the left arm.
QUANTITATIVE ASSESSMENT OF THE SINGLE MOTOR UNITS FIRING PATTERN Methods. EMG and nerve conduction studies were performed using commercially available EMG equipment (TECA). Single motor units were recorded from left and right biceps brachii during approximately 1 min of sustained isometric contraction. T h e contraction force was measured with a force transducer and displayed for visual feedback on oscilloscope in front of the patient. SMUs were recorded with a single fiber EMG needle electrode (TECA), which was carefully positioned to obtain the best possible isolation of the SMU from the background activity of more distant motor units. EMG signals from the electrodes were preamplified, filtered with band pass 800 Hz to ti kHz and together with the force signal output of the bridge amplifier, were recorded simultaneously on FM tape recorder (Kacal). Data processing was performed off-line. Recording epochs were selected of approximately 20 seconds long during which SMUs fired steadily. Recording segments with obvious lapses in SMU firing or contaminated with discharges of other motor units were rejected. Intervals between successive discharges of the same SMU were measured using an LSI 11/23 computer, a Schmitt trigger, and a programmable clock. The amplitude of the trigger level was adjusted individually for each SMU being analyzed. In addition, the hard copies of the SMU discharges arid Schmitt trigger pulses were visually inspected to ensure that triggering occurred on the correct SMU [Fig. 2(C)]. T h e S M U firing pattern was described in terms of the following statistical parameters: (i) mean firing frequency, (ii) variability in Successive interdischarge intervals, arid (iii) Hoating serial correlation coefficient. T h e variability o f the interdischarge intervals (VAR) was calculated as suggested by P r o c h a ~ k a and ’ ~ Andreassen’
MUSCLE & NERVE
January 1991
65
component to the serial correlation and therefore might mask the presence of negative serial correlation between the adjacent intervals.” In addition to the evaluated numerical parameters, graphical representation of the results including a torque-instantaneous firing frequency plot and a joint interval histogram (JIH) were provided. Instantaneous frequency was calculated as the reciprocal of each interspike interval and was plotted as a function of elapsed time. In the JIHs, the duration of one interdischarge interval was represented on the abcissa vs. the duration of the next interval on the ordinate.
/n is the mean interval, n is a number of evaluated intervals, and Ziis i-th interval. The VAR was used here to measure a variability between neighbor intervals rather than overall variability of the intervals expressed by the standard deviation (SD). Floating serial correlation (F) was calculated with formulas derived by Andreassen3
RESULTS
‘x
Statistical analysis of the interdischarge intervals showed substantial qualitative and quantitative differences in the firing pattern of SMUs recorded from left and right biceps. Comparison of the statistical parameters in between sides for all SMUs studied is shown in Table 1. All 5 SMUs recorded from the right biceps had normal discharge patterns. A typical torqueinstantaneous plot for the SMUs recorded from the right side is shown in Figure 1(A). The patient was able to maintain a steady torque level with little variation in force output, as seen in normal subjects. A “spiky” appearance of the instantaneous firing frequency plot is characteristic of the normal discharge pattern showing considerable variability in length of neighboring interdischarge intervals. A JIH plotted from the same SMU recording [Fig. l(B)] shows an elliptical cluster of points whose longer axis has a negative slope. T h e negative serial correlation coefficient reflects the tendency for long and short intervals to alternate, a common feature of normal discharge patterns, particularly for SMUs firing faster than 10 Hz.
1
I>--
F=n-1
[(Zi - FMI,) (Zi+l - FMIi+1)/FSD2]
i= 1
where:
.1
F S D ~=
x zj
i+9
F M I ~= 19j
is a floating mean
= j - g
5
n-l
(Zl - FMIJ2 is a floating SD‘
i = 1
The floating mean interval (FMI) was evaluated with a “moving window” 19 intervals long. Such window length was reported to be efficient in following short-term trends in SMU firing and not producing a large negative bias on the serial correlation. l o The floating serial correlation was used to minimize the effect of long-term trends on the serial correlation coefficient. Otherwise, long periods of monotonic increasing or decreasing firing frequency would contribute a positive
~
~~
Table 1. Statistical parameters evaluated for SMUs recorded from left (affected) and right biceps Right side
SMU # 1 2 3 4
5 Mean:
Left side
(Hz)
F
VAR (ms)
MFR (Hz)
TOR (Nm)
F
VAR (ms)
-0.42 -0.23 -0.20 -0.22 -0.51 -0.32
14 13 15 10 13 13
15.3 16.7 10.2 16.6 15.4 14.8
8.5 7.2 0.3 3.7 4.2 4.8
0.81 0.73 0.58 0.49
9 10 7 9
11.8 9.7 12.7 11.2
1.2 0.2 2.9 7.6
0.65
8.75
11.4
2.96
MFR
F = floating serial correlation coefficient, VAR = measure of variability of the length of consecutive mterdischarge intervals, MFR rate, TOR = mean torque recorded at the elbow loint
66
Single Motor Unit Behavior
=
MUSCLE & NERVE
TOR (Nm)
mean finng
January 1991
t 1: "1 T a E I N SEQ#5
IIEC
FIGURE 1. Firing pattern of the SMU recorded from the right biceps. (A) Torque (top) and the instantaneous firing frequency (bottom); (B) Joint interval histogram (R = serial correlation coefficient, F = floating serial correlation coefficient; calculated in relation to the moving average of i9 intervaIs)3
Four SMUs recorded from the affected side showed abnormal discharge behavior. Large fluctuations in torque, accompanied by a slow frequency oscillations in instantaneous firing frequency were observed [Fig. 2(A)]. In comparison to the right side, SMUs recorded from the affected arm had lower discharge frequencies (Table 1) and showed reduced variability in length of' the consecutive interdischarge intervals ( P < 0.05, Wilcoxon test). Analysis of the serial interdepen-
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dence of adjacent time intervals revealed a strong positive serial correlation. Corresponding JIHs (Fig. 2B) showed points clustered in ellipses whose longer axes had positive slopes. Statistically, such positive serial correlation indicates that there are abnormal trends in SMU firing patterns with a series of short interdischarge intervals followed by a series of longer interdischarge intervals and vice versa. This trend can even be noticed in the SMU spike train [Fig. 2(C)].
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FIGURE 2. Firing pattern of the SMU recorded from the left (affected) biceps. (A) Torque (top) and the instantaneous firing frequency (bottom); (6) Joint interval histogram; (C) Raw data obtained during recording session. Upper trace SMU discharges, dots Schrnitt trigger firings, bottom recorded force. Time calibration is 1 sec. Note intermittent grouping of short and long interdischarge intervals
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For example, SMUs recorded from patients with basal ganglia disorders (Parkinson's and HuntingQuantitative evaluation of motor dysfunction proton's disease) showed discharge irregularities with duced by any lesion within the nervous system is significantly hi her variability of interdischarge inimportant in clinical studies and treatment of paterval lengths! Typical findings in patients with tients with a variety of motor disorders. Any volspastic paresis, '2.1.5- 17 attributed to supraspinal leuntary motor act requires proper activation of apsions include changes in the temporal order of adpropriate groups of muscles in order to generate jacent intervals leading to positive serial correlathe desired force necessary to accomplish the tion, decreased variability in length of consecutive planned movement. Since the lower motor neuron interdischarge intervals, and lower discharge freis the final common pathway for the motor sysquency. Patients with spastic paresis have difficulty tem, abnormalities of motor control must be remaintaining constant force. Kecordings of instanflected in altered S M U behavior. taneous firing frequency usually show similar fluc'There are 2 neurological mechanisms responsituations to that of the force output. Statistical evalble for force generation: (i) recruitment of new uation of firing patterns provides a quantitative SMUs and (ii) modulation o f the firing rates of measure of the impaired regulation of timing of SMUs already recruited. We will discuss only the motor unit discharges i n patients with disorders of second mechanism. T h e technique used in this the central and/or peripheral nervous system. study was introduced by Freund" and further deIn o u r patient, study of the affected biceps veloped by Andreassen and Kosenfalck.'." It almuscle reveals pathologic SM U discharge patterns lows quantitative analysis of any isolated S M U dissimilar to that reported in spastic muscles. O u r recharge during a steady muscle contraction. sults suggest an upper motor neuron lesion which Usually, low-threshold S M U s firing at frequencies is confirmed by MKI scanning. Figure 3 shows the 6 to 20 Hz, are the easiest S M U s to record in isowell-localized lesion of the right precentral gyrus. lation with routine E M G electrodes. At higher We conclude that abnormalities of S M U behavior force levels recording of S M U s requires the use of documented by computer analysis of firing pathigh impedance tungsten semi-micro electrodes. These electrodes were originally introduced foirecordings from human nerves in muscle spindle afferents," but more recently have been used in studying S M U behavior during maximal voluntary contraction,4 fatigue," o r tremor. 12 Normal S M U discharge patterns have been described in different muscles from the loweri,:'~i7 and ~ p p e r " ~ ~ ~ ~extremities. ' ~ " ) ~ ' ' It was found that S M U discharge times often show a negative serial correlation. Physiological mechanisms responsible for discharge by discharge alterations in firing times of SMUs resulting in negative serial correlation are not known. Several interpretations have been offered including motor neuron afterhyperpolarization," Kenshaw cell inhibition,' and peripheral feedback mechanisms.'*" It has been speculated that negative serial correlation serves to provide a compensatory mechanism for shortterm stabilization of force, thereby minimizing the fluctuation in force output.'"" 111 this study, SMU recordings from the right biceps showed typically norrnal firing patterns, consistent with previous studies of S M U hchavior in normal muscles. Significant quantitative differences in S M U disFIGURE 3. Magnetic resonance image (MRI) of the lesion locharge patterns during sustained isometric contraccated in the right precentral gyrus in areas mediating arm and tion have been reported in a f'ew studies in patients hand function. Subsequent needle biopsy indentified progressive with various movement d i s o r d e ~ s . ' ~ 2 ~ " ~ ~ ' ~ ' 0 ~multifocal ' " - i 7 leukoencephalopathy. DISCUSSION
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terns may correlate best with the negative symptoms of the upper niotor neuron syndrome. With this technique, changes in the discharge pattern of SMUs can be detected at a time when there is no evidence of clinical “spasticity.” It is of interest to address another problem related to studies of S M U s behavior. In recordings from normal muscles it was found that the serial correlation coefficient becomes less negative and even positive when firing rate decreases.’33This dependence might suggest that the positive serial correlation reported in previous studies of spastic-
ity was simply due to the fact that S M U s discharged more slowly than normal (most often i t i the 5-7 Hz range). In the present study, the mean discharge frequencies of SMUs, recorded on the symptomatic side, ranged from 9.7- 12.7 Hz. This would usually lead to negative serial correlation in normal muscle, but in our study we observed large positive serial correlations. These data indicate that changes in timing of SMUs discharges is indeed the inherent property of the lesion and not a phenomenon related to slowing of S M U s firing rates.
REFERENCES 1. Andreassen S: 1ntcwal Pattern ofsznglr Molor Cinils. University Press, Aalborg, 1978, p p 1-220. 2. Andreassen S, Kosenfalck A: Impaired regulation of. the firing pattern of single niotor units. Musclr Neme 1978; 1:4 16-4 18. 3. Andreassen S, Kosenfalck A: Regulation of the firing pattern of single motor units. J Nrurol Neurosurg Psychiatry 1Y80;43:897-906. 4. Bellernare F, Woods JJ, Johansson K, Bigland-Ritchie B: Motor-unit discharge rates in maximal voluntary contractioris of. three human muscles. J Neurophysiol 1983;
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motor disorders, in Shahani B‘r (ed): Elcctro,tLyograp/Ly in CNS Disordrn: Crnfrol E M G , Boston, Butterworth, 1983, pp 29-43. Hagbarth K-E, Young RK: Participation of the stretch rcflex in human physiological tremor. Hrazi~ 1979; 102:509526. Logigian EL, Wierzbicka MM, Bruyninckx F, Wiegtier AW, Shahani B T , Young RR: Motor unit synchronization in physiologic, enhanced physiologic and voluntary trenioiin man. Ann NeuIol 1988;23:242-250. Person RS, Kudina LP: Discharge frequency and discharge pattern of human units during voluntary contraction o f muscle. Electroenceph Clin Neurophysiol 1972;32:47 1-488. Prochazka VJ, Conrad €3, Sinderniann F: Computerizecl single-unit interval analysis and its clinical application, in ip/~y Desinedt J E (ed): New Developmrnts in 6 l c , ( t l - o m y c ~ ~ ~ and Clznical Neurophy.\iolqy, Basel, Karger, 1973, vol 2, pp 462468. Rosenfalck A, Andreassen S: Impaired regulation of force and firing pattern of single motor units i n patients with spasticity. J N e u d Neurosurg P.sychzat?y 1980;43:907-9113. Young RR, Shahani BT: A clinical neurophysiologic~al analysis of single motor unit discharge patterns i n spasticity, in Feldman R G , Young KK, and Koella (etls): Spccsticity: Dz.\oi-dered Motor Control, Chicago, Year Book, 1980, p p 219-231. Young RR, Wierzbicka MM: Kehaviour of single tilotor units in normal subjects and in patients with spastic paresis, in Delwaide PJ, Young RR (eds): Clznicrrl Nrzr,.o~~~/i~.sio/o~~ zn Spasticily: Coiatrzbution to A.\se.ssmonl and P a t h o p l ~ y . s i ~ ~ l o ~ ~ , Atnstei-dam, Elsevier, 1958, p p 27-37.
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