Electroencephalography and clinical Neurophysiology, 81 (1991) 209-215 © 1991 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/91/$03.50 ADONIS 0924980X91000755
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E L M O C O 90073
Age-dependent decline in motor evoked potential (MEP) amplitude: with a c o m m e n t on changes in Parkinson's disease * Andrew Eisen, Stan Siejka, Michael Schulzer and Donald Calne Department of Medicine (Neurology), University of British Columbia, Vancouver (Canada) (Accepted for publication: 13 August 1990)
Summar3
Peak-to-peak measurement of the m a x i m u m amplitude motor evoked potential (MAXMEP) elicited by 20 consecutive transcranial magnetic stimuli recorded from the contracting thenar and hypothenar muscles measured 9.8___2.0 mV and 7.25 + 2.9 mV respectively ( P < 0.01). The ratio of M A X M E P / C M A P measured 92.6_+25.8% and 54.8+12.3% respectively ( P < 0.001). Repeat studies showed good individual reproducibility. Amplitudes declined linearly with age (r = - 0 . 8 3 6 for thenar M A X M E P P < 0.001). It is argued that M A X M E P related to age is more meaningful than the M E P / C M A P wave ratio and is proportional to the number of fast conducting cortical motor neurons excited. In 7 / 1 8 patients with Parkinson's disease (PD) M A X M E P was increased; in 2 other patients M A X M E P was decreased for their age.
Key words: Motor evoked potential; Transcranial magnetic stimulation; Parkinson's disease; Amplitude; Aging
The clinical utility of non-invasive transcranial magnetic stimulation has broadened within recent years (Barker et al. 1986; Murray 1988; Thompson et al. 1988; Eisen and Shytbel 1990). This technique originally described by Barker et al. (1985) has proved a safe and innoxuous means of stimulating the intact human motor cortex in awake humans and thereby assessing conduction in central motor pathways. From our own experience using it in a variety of diseases, it is apparent that latency may be normal or only modestly prolonged in the face of obvious motor deficit (Eisen and Shytbel 1990; Eisen et al. 1990). This observation is shared by other physiological methods designed to measure central or peripheral conduction and reflects the integrity of some fast conducting axons in disease. For example the MEP is often only modestly delayed in latency, despite motor weakness, in motor neuron disease (Hugon et al. 1987; Schriefer et al. 1989; Eisen et al. 1990), in compressive myelopathy (Masur et al. 1989), as well as some patients with multiple sclerosis (Hess et al. 1987b; Ingram et al. 1988; Eisen et al. 1989). In other conditions such as Parkinson's disease and Huntington's disease,
* Supported by grants from the Medical Research Council of Canada, The British Columbia Health Care Research Foundation and The Dystonia Medical Research Foundation.
Correspondence to: Dr. Andrew Eisen, The Neuromuscular Diseases Unit (EMG), Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC V5Z 1M9 (Canada).
which involve the motor systems, the latency of the MEP and central motor conduction are also normal (Dick et al. 1984; T h o m p s o n et al. 1986; Barker et al. 1988b; Eisen et al. 1989, 1990). In contrast, in recovered motor stroke, or motor neuron disease in which upper motor neuron signs predominate, it may not be possible to elicit any MEP despite good muscle bulk and strength (Inghilleri et al. 1988). Loss of cortical or spinal motor neurons and associated gliosis of motor tracts are more likely to affect the amplitude of the MEP before or even to the exclusion of any abnormality of latency. This situation parallels the amplitude reduction of muscle and nerve compound action potentials that typify axonal degeneration affecting the peripheral nervous system (Kimura 1984; D a u b e 1986). However, both intra- and inter-individual MEP amplitude can vary considerably (Wiesendanger 1988; Amassian et al. 1989). This has rendered use of amplitude measurement of the MEP in the clinical setting problematical. Here we report an approach to amplitude measurement which we believe is sufficiently reproducible and reliable to be employed clinically. We have measured changes that occur with age and have studied a group of patients with Parkinson's disease where the MEP latency and central motor conduction times have been reported to be normal (Dick et al. 1984; Barker et al. 1988b). The results we report relate primarily to the thenar muscle complex which we have routinely used for study
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A. EISEN ET AL.
of u p p e r l i m b M E P s in the p a s t (Eisen a n d Shytbel 1990). However, b e c a u s e cortical s t i m u l a t i o n very likely activates u l n a r as well as m e d i a n nerve c o m p o n e n t s of this muscle group, s o m e studies have also b e e n d o n e b y r e c o r d i n g from the h y p o t h e n a r muscle complex.
subjects studies were r e p e a t e d twice at intervals of 6 - 8 weeks. Surface disk e l e c t r o d e s filled with electrogel were used to r e c o r d b o t h C M A P s a n d M E P s . T h e G1 elect r o d e was p l a c e d over the muscle e n d p l a t e region a n d the G 2 e l e c t r o d e over the distal t e n d i n o u s insertion of the muscle.
Methods
F o r t y - o n e c o n t r o l volunteers w i t h o u t neurological o r o t h e r k n o w n disease were recruited. T h e i r ages r a n g e d f r o m 23 to 82 years ( m e a n 51.7 years). T h e r e were 34 w o m e n . Eighteen p a t i e n t s with P a r k i n s o n ' s disease were also studied. T h e i r ages varied f r o m 44 to 77 years ( m e a n 63.9 years) a n d 12 were men. T h e m a j o r i t y were on m e d i c a t i o n at the time of study. L e n g t h a n d severity of disease were variable. W e d i d n o t a t t e m p t to correlate these variables with e l e c t r o p h y s i o l o g i c a l results. E l e c t r o m y o g r a p h i c responses were r e c o r d e d f r o m the t h e n a r muscle c o m p l e x in 33 subjects a n d f r o m the h y p o t h e n a r muscles in 17 subjects. R e c o r d i n g s were m a d e from b o t h muscles in 12 subjects. T h e subject was seated c o m f o r t a b l y in a t e m p e r a t u r e m a i n t a i n e d env i r o n m e n t ( 2 0 - 2 2 ° C ) . A c o m p o u n d muscle a c t i o n p o t e n t i a l ( C M A P ) was elicited b y a s u p r a m a x i m a l electrical stimulus delivered to the m e d i a n o r u l n a r nerve at the wrist. Its a m p l i t u d e was m e a s u r e d p e a k - t o - p e a k . M o t o r evoked p o t e n t i a l s ( M E P s ) were elicited b y transcortical m a g n e t i c s t i m u l a t i o n using a D a n t e c circular coil, with an o u t e r d i a m e t e r of 14 c m a n d a 2 c m central hole. T h e center of the coil was p l a c e d over the vertex. This p o s i t i o n was a d j u s t e d as necessary to o b t a i n the m a x i m u m a m p l i t u d e M E P . In each subject the stimulator o u t p u t was a d j u s t e d to 20% a b o v e threshold. M E P s were elicited with the target muscle c o n t r a c t i n g at between 15 a n d 20% of m a x i m u m force. This was m o n i t o r e d d u r i n g the r e c o r d i n g session b y a force transducer. T w e n t y consecutive M E P s were o b t a i n e d at intervals which v a r i e d f r o m a b o u t 1.5 to 4 sec. P e a k - t o p e a k a m p l i t u d e of the largest a n d in s o m e instances the m e a n of the 20 responses were measured. In 3 n o r m a l
Results
T a b l e s I a n d II s u m m a r i z e the n o r m a l findings. T h e r e were significant differences b e t w e e n y o u n g versus o l d e r subjects with respect to C M A P ( c o m p o u n d muscle action potential), M A X M E P (the m a x i m u m a m p l i t u d e M E P of 20 consecutive responses) a n d A V M E P (the m e a n of 20 responses; m e a s u r e d o n l y for the t h e n a r muscle). W i t h i n the 10 o r 20 trials M A X M E P o c c u r r e d r a n d o m l y b u t with an average f r e q u e n c y 2.1 + 1.1 times out of 10 consecutive stimuli ( T a b l e I). T h e r e l a t i o n s h i p between thenar CMAP amplitude, MAXMEP and A V M E P with respect to age is d e p i c t e d in Fig. 1. S i m p l e linear regression s h o w e d that w h e n these variables were i n d i v i d u a l l y c o r r e l a t e d with age, all correlations were significant ( T a b l e III). Partial c o r r e l a t i o n coefficients ( T a b l e IV) suggest that at a n y given age C M A P a n d M A X M E P (or A V M E P ) are, however, uncorrelated. L i n e a r regressions r e l a t i n g M A X M E P a n d A V M E P to age, b a s e d u p o n the 33 n o r m a l subjects, in w h o m responses were r e c o r d e d f r o m the t h e n a r muscle, indic a t e d a significant r e d u c t i o n in M E P a m p l i t u d e with age (see Fig. 2 a n d T a b l e I). T h e regressions c o n t a i n e d no statistically significant n o n - l i n e a r c o m p o n e n t s . Thenar MAXMEP/CMAP and AVMEP/CMAP ratios for all ages, m e a s u r e d 92.6 + 25.8% ( M A X M E P ) a n d 73.7 + 23.1% ( A V M E P ) . T h e f r e q u e n c y d i s t r i b u tions of these ratios are shown in Fig. 3. H y p o t h e n a r MAXMEP/CMAP r a t i o for all ages m e a s u r e d 54.8 + 12.3% which was s i g n i f i c a n t l y less t h a n for the t h e n a r muscle ( P < 0.01).
TABLE I Thenar motor evoked potential amplitudes in normal subjects. Young and older groups are defined as < 40 years and > 45 years respectively. MAXMEP and AVMEP refer to maximum and mean amplitudes of 20 sequentially evoked responses. Frequency of MAXMEP refers to the frequency with which the largest MEP was recorded out of 10 sequential responses. All values are expressed as the mean+ 1 S.D. Student's t test was employed to calculate the probabilities. Variable
Young group (N =13) (mean age 33.1 yrs)
Older group (N = 20) (mean age 63.3 yrs)
P value
CMAP(mV) MAXMEP(mV) AVMEP(mV) MAXMEP/CMAP (%) AVMEP/CMAP (%) Frequency ofMAXMEP
13.4 _+ 1.6(11.6- 17) 12.1 _+ 1.4(10 - 14.5) 9.0 _+ 1.1 (7.8- 11.5) 90.3 ___14.7 (71 -122) 67.2 ___11.9 (53 - 97) 1.8 ___ 1.0 (1 - 4)
8.0 + 1.4 (5.8- 11.8) 7.5 + 2.5 (3 - 11.8) 6.2 + 2.4 (2 - 10.6) 93.7 _+ 23.8 (34 -139) 77.5 + 27.9 (25 -134) 2.2 _+ 1.2 ( 1- 5)
209
E L M O C O 90073
Age-dependent decline in motor evoked potential (MEP) amplitude: with a c o m m e n t on changes in Parkinson's disease * Andrew Eisen, Stan Siejka, Michael Schulzer and Donald Calne Department of Medicine (Neurology), University of British Columbia, Vancouver (Canada) (Accepted for publication: 13 August 1990)
Summar3
Peak-to-peak measurement of the m a x i m u m amplitude motor evoked potential (MAXMEP) elicited by 20 consecutive transcranial magnetic stimuli recorded from the contracting thenar and hypothenar muscles measured 9.8___2.0 mV and 7.25 + 2.9 mV respectively ( P < 0.01). The ratio of M A X M E P / C M A P measured 92.6_+25.8% and 54.8+12.3% respectively ( P < 0.001). Repeat studies showed good individual reproducibility. Amplitudes declined linearly with age (r = - 0 . 8 3 6 for thenar M A X M E P P < 0.001). It is argued that M A X M E P related to age is more meaningful than the M E P / C M A P wave ratio and is proportional to the number of fast conducting cortical motor neurons excited. In 7 / 1 8 patients with Parkinson's disease (PD) M A X M E P was increased; in 2 other patients M A X M E P was decreased for their age.
Key words: Motor evoked potential; Transcranial magnetic stimulation; Parkinson's disease; Amplitude; Aging
The clinical utility of non-invasive transcranial magnetic stimulation has broadened within recent years (Barker et al. 1986; Murray 1988; Thompson et al. 1988; Eisen and Shytbel 1990). This technique originally described by Barker et al. (1985) has proved a safe and innoxuous means of stimulating the intact human motor cortex in awake humans and thereby assessing conduction in central motor pathways. From our own experience using it in a variety of diseases, it is apparent that latency may be normal or only modestly prolonged in the face of obvious motor deficit (Eisen and Shytbel 1990; Eisen et al. 1990). This observation is shared by other physiological methods designed to measure central or peripheral conduction and reflects the integrity of some fast conducting axons in disease. For example the MEP is often only modestly delayed in latency, despite motor weakness, in motor neuron disease (Hugon et al. 1987; Schriefer et al. 1989; Eisen et al. 1990), in compressive myelopathy (Masur et al. 1989), as well as some patients with multiple sclerosis (Hess et al. 1987b; Ingram et al. 1988; Eisen et al. 1989). In other conditions such as Parkinson's disease and Huntington's disease,
* Supported by grants from the Medical Research Council of Canada, The British Columbia Health Care Research Foundation and The Dystonia Medical Research Foundation.
Correspondence to: Dr. Andrew Eisen, The Neuromuscular Diseases Unit (EMG), Vancouver General Hospital, 855 West 12th Avenue, Vancouver, BC V5Z 1M9 (Canada).
which involve the motor systems, the latency of the MEP and central motor conduction are also normal (Dick et al. 1984; T h o m p s o n et al. 1986; Barker et al. 1988b; Eisen et al. 1989, 1990). In contrast, in recovered motor stroke, or motor neuron disease in which upper motor neuron signs predominate, it may not be possible to elicit any MEP despite good muscle bulk and strength (Inghilleri et al. 1988). Loss of cortical or spinal motor neurons and associated gliosis of motor tracts are more likely to affect the amplitude of the MEP before or even to the exclusion of any abnormality of latency. This situation parallels the amplitude reduction of muscle and nerve compound action potentials that typify axonal degeneration affecting the peripheral nervous system (Kimura 1984; D a u b e 1986). However, both intra- and inter-individual MEP amplitude can vary considerably (Wiesendanger 1988; Amassian et al. 1989). This has rendered use of amplitude measurement of the MEP in the clinical setting problematical. Here we report an approach to amplitude measurement which we believe is sufficiently reproducible and reliable to be employed clinically. We have measured changes that occur with age and have studied a group of patients with Parkinson's disease where the MEP latency and central motor conduction times have been reported to be normal (Dick et al. 1984; Barker et al. 1988b). The results we report relate primarily to the thenar muscle complex which we have routinely used for study
210
A. EISEN ET AL.
of u p p e r l i m b M E P s in the p a s t (Eisen a n d Shytbel 1990). However, b e c a u s e cortical s t i m u l a t i o n very likely activates u l n a r as well as m e d i a n nerve c o m p o n e n t s of this muscle group, s o m e studies have also b e e n d o n e b y r e c o r d i n g from the h y p o t h e n a r muscle complex.
subjects studies were r e p e a t e d twice at intervals of 6 - 8 weeks. Surface disk e l e c t r o d e s filled with electrogel were used to r e c o r d b o t h C M A P s a n d M E P s . T h e G1 elect r o d e was p l a c e d over the muscle e n d p l a t e region a n d the G 2 e l e c t r o d e over the distal t e n d i n o u s insertion of the muscle.
Methods
F o r t y - o n e c o n t r o l volunteers w i t h o u t neurological o r o t h e r k n o w n disease were recruited. T h e i r ages r a n g e d f r o m 23 to 82 years ( m e a n 51.7 years). T h e r e were 34 w o m e n . Eighteen p a t i e n t s with P a r k i n s o n ' s disease were also studied. T h e i r ages varied f r o m 44 to 77 years ( m e a n 63.9 years) a n d 12 were men. T h e m a j o r i t y were on m e d i c a t i o n at the time of study. L e n g t h a n d severity of disease were variable. W e d i d n o t a t t e m p t to correlate these variables with e l e c t r o p h y s i o l o g i c a l results. E l e c t r o m y o g r a p h i c responses were r e c o r d e d f r o m the t h e n a r muscle c o m p l e x in 33 subjects a n d f r o m the h y p o t h e n a r muscles in 17 subjects. R e c o r d i n g s were m a d e from b o t h muscles in 12 subjects. T h e subject was seated c o m f o r t a b l y in a t e m p e r a t u r e m a i n t a i n e d env i r o n m e n t ( 2 0 - 2 2 ° C ) . A c o m p o u n d muscle a c t i o n p o t e n t i a l ( C M A P ) was elicited b y a s u p r a m a x i m a l electrical stimulus delivered to the m e d i a n o r u l n a r nerve at the wrist. Its a m p l i t u d e was m e a s u r e d p e a k - t o - p e a k . M o t o r evoked p o t e n t i a l s ( M E P s ) were elicited b y transcortical m a g n e t i c s t i m u l a t i o n using a D a n t e c circular coil, with an o u t e r d i a m e t e r of 14 c m a n d a 2 c m central hole. T h e center of the coil was p l a c e d over the vertex. This p o s i t i o n was a d j u s t e d as necessary to o b t a i n the m a x i m u m a m p l i t u d e M E P . In each subject the stimulator o u t p u t was a d j u s t e d to 20% a b o v e threshold. M E P s were elicited with the target muscle c o n t r a c t i n g at between 15 a n d 20% of m a x i m u m force. This was m o n i t o r e d d u r i n g the r e c o r d i n g session b y a force transducer. T w e n t y consecutive M E P s were o b t a i n e d at intervals which v a r i e d f r o m a b o u t 1.5 to 4 sec. P e a k - t o p e a k a m p l i t u d e of the largest a n d in s o m e instances the m e a n of the 20 responses were measured. In 3 n o r m a l
Results
T a b l e s I a n d II s u m m a r i z e the n o r m a l findings. T h e r e were significant differences b e t w e e n y o u n g versus o l d e r subjects with respect to C M A P ( c o m p o u n d muscle action potential), M A X M E P (the m a x i m u m a m p l i t u d e M E P of 20 consecutive responses) a n d A V M E P (the m e a n of 20 responses; m e a s u r e d o n l y for the t h e n a r muscle). W i t h i n the 10 o r 20 trials M A X M E P o c c u r r e d r a n d o m l y b u t with an average f r e q u e n c y 2.1 + 1.1 times out of 10 consecutive stimuli ( T a b l e I). T h e r e l a t i o n s h i p between thenar CMAP amplitude, MAXMEP and A V M E P with respect to age is d e p i c t e d in Fig. 1. S i m p l e linear regression s h o w e d that w h e n these variables were i n d i v i d u a l l y c o r r e l a t e d with age, all correlations were significant ( T a b l e III). Partial c o r r e l a t i o n coefficients ( T a b l e IV) suggest that at a n y given age C M A P a n d M A X M E P (or A V M E P ) are, however, uncorrelated. L i n e a r regressions r e l a t i n g M A X M E P a n d A V M E P to age, b a s e d u p o n the 33 n o r m a l subjects, in w h o m responses were r e c o r d e d f r o m the t h e n a r muscle, indic a t e d a significant r e d u c t i o n in M E P a m p l i t u d e with age (see Fig. 2 a n d T a b l e I). T h e regressions c o n t a i n e d no statistically significant n o n - l i n e a r c o m p o n e n t s . Thenar MAXMEP/CMAP and AVMEP/CMAP ratios for all ages, m e a s u r e d 92.6 + 25.8% ( M A X M E P ) a n d 73.7 + 23.1% ( A V M E P ) . T h e f r e q u e n c y d i s t r i b u tions of these ratios are shown in Fig. 3. H y p o t h e n a r MAXMEP/CMAP r a t i o for all ages m e a s u r e d 54.8 + 12.3% which was s i g n i f i c a n t l y less t h a n for the t h e n a r muscle ( P < 0.01).
TABLE I Thenar motor evoked potential amplitudes in normal subjects. Young and older groups are defined as < 40 years and > 45 years respectively. MAXMEP and AVMEP refer to maximum and mean amplitudes of 20 sequentially evoked responses. Frequency of MAXMEP refers to the frequency with which the largest MEP was recorded out of 10 sequential responses. All values are expressed as the mean+ 1 S.D. Student's t test was employed to calculate the probabilities. Variable
Young group (N =13) (mean age 33.1 yrs)
Older group (N = 20) (mean age 63.3 yrs)
P value
CMAP(mV) MAXMEP(mV) AVMEP(mV) MAXMEP/CMAP (%) AVMEP/CMAP (%) Frequency ofMAXMEP
13.4 _+ 1.6(11.6- 17) 12.1 _+ 1.4(10 - 14.5) 9.0 _+ 1.1 (7.8- 11.5) 90.3 ___14.7 (71 -122) 67.2 ___11.9 (53 - 97) 1.8 ___ 1.0 (1 - 4)
8.0 + 1.4 (5.8- 11.8) 7.5 + 2.5 (3 - 11.8) 6.2 + 2.4 (2 - 10.6) 93.7 _+ 23.8 (34 -139) 77.5 + 27.9 (25 -134) 2.2 _+ 1.2 ( 1- 5)
