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Motor cortex changes in a patient with hemicerebellectomy
ELSEVIER
Electroencephalography
and clinical Neurophysiology
97 (1995) 259-263
Motor cortex changes in a patient with hemicerebellectomy V. Di Lazzaro
*,
’
D. Restuccia, R. Nardone, M.G. Leggio, A. Oliviero, P. Profice, P. Tonali, M. Molinari
Istituto di Neurologia
Uniuersith Cattolica, Large A. Gemelli 8, 00168 Rome, Italy Accepted for publication:
16 May 1995
Abstract
To evaluate reorganisation of motor pathways following a cerebellar lesion, we studied motor cortex excitatory responses and inhibitory effects after transcranial stimulation, together with segmental spinal cord excitability, in one patient who had undergone hemicerebellectomy. We compared the results obtained using different forms of stimulation capable of activating the cortico-spinal tract at different sites. Results were compared between sides. We previously reported that the threshold for responses is higher in the motor cortex contralateral to the impaired hemicerebellum and the right/left threshold asymmetry is clearly greater than normal when a circular coil centred over the vertex is used. In the present study, using electrical anodal stimulation, no side difference was observed. Significant interside differences were absent also when the durations of the silent periods or the mean amplitude of the flexor carpi radialis H reflex between the two sides were compared. The outcome is that the interside differences previously observed are mainly due to reduction in the intrinsic excitability properties of the motor cortex functionally related to the impaired hemicerebellum and not to modification of the inhibitory properties of the cortex or to spinal mechanisms.
Keywords:
Cerebellum;
Motor cortex; Magnetic
stimulation;
Electrical
stimulation
1. Introduction The strict functional
relationship
between
the cerebel-
lum and the motor cortex suggests
that cerebellar lesions may determine alterations in the activity of cortical descending motor pathways. In experimental animals it has been reported that either lesions or stimulation of the cerebellum can produce excitability changes of the motor cortex (for a review see Dow and Moruzzi, 1958). In a recent study we showed that motor cortex excitability after magnetic stimulation is reduced in patients with focal cerebellar lesions (Di Lazzaro et al., 1994a). Thus, threshold for magnetic stimulation is increased for the motor cortex contralateral to the lesioned hemicerebellum. This finding has been confirmed by others (Meyer et al., 1994). However, the evidence of an increased threshold provides
* This work was supported by Telethon -Italy (Grant No. 578). * Corresponding author. Tel.: 06 30154435; Fax: 06 35501909. 0924-980X/9.5/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSD10013-4694(95)00110-7
no information about where the excitability changes have taken place, i.e., in the motor cortex or the spinal cord, or both. The aim of the present study was to identify the site of excitability changes observed in patients with cerebellar lesions. One representative patient from those already described (Di Lazzaro et al., 1994b) was studied using different electrophysiological techniques. To ascertain whether the observed excitability changes were due to functional changes in the cortico-cortical connections or at the subcortical level, we compared the data obtained using different techniques of central motor pathway stimulation, magnetic and electrical, known to activate the cortico-spinal tract at different sites (Day et al., 1989; Amassian et al., 1990; Rothwell et al., 1991; Werhahn et al., 1994). The relevance of inhibitory circuit changes in determining the degree of motor cortex excitability after cerebellar lesion has been evaluated by measuring silent periods evoked by cortical stimulation. H reflex testing was performed to determine whether excitability changes at the spinal cord level might account for the observed increase in the motor threshold.
V. Di Lazzaro et al. / Electroencephalography
260
and clinical Neurophysiology 97 (1995) 259-263
2. Patient and methods
Normal limits for threshold were defined SD. of the values in controls.
as mean f 2.5
2.1. Patient The silent period The silent period was elicited using a figure-eight coil with the current flowing in a PA direction while the subject held a tonic voluntary contraction of approximately 20% of the maximum voluntary contraction of ADM. We used increasing intensities of the magnetic shock starting from a value equal to AMT up to an intensity equal to AMT plus 30% of the maximal stimulator output in steps of 10%. Five stimulations were performed for each intensity value. Duration of the silent period on one side at different intensities was compared with the contralateral side using paired Student’s t test. In comparing silent period durations, magnetic stimulation intensities were considered as absolute values relative to maximal magnetic stimulator output and as relative to AMT.
Clinical and radiological data of this patient have already been described in a previous paper (Di Lazzaro et al., 1994b). Briefly, the patient, a 48-year-old male, had undergone left hemicerebellectomy because of a vascular malformation. When the electrophysiological study was performed 4 years after surgery, neurological examination revealed only slight dysmetria of the left upper limb and was otherwise normal. In particular, there were no upper motor neurone signs and the plantar responses were flexor bilaterally. Central motor conduction time was bilaterally normal for both upper and lower limbs. 2.2. Methods Motor cortex stimulation Transcranial stimuli were delivered by a Novametrix Magstim 200 magnetic stimulator or a Digitimer D180 high voltage electric stimulator. Magnetic stimulation was achieved by stimuli given through either a circular coil centred over the vertex or a figure-eight coil held in two different orientations over the left or right motor strips with the induced current flowing either in a postero-anterior (PA) or latero-medial (LM) direction. Transcranial electrical stimuli were given through two Ag/AgCl electrodes fixed to the scalp with collodion. The cathode was placed over the vertex, and the anode 7 cm laterally on a line joining the vertex with the external auditory meatus. Compound motor action potentials (CMAPs) were recorded from the abductor digiti minimi (ADM) muscle through surface electrodes and amplified with filter settings of 2 Hz and 5 kHz. We defined resting motor threshold (RMT) as the minimum stimulus intensity that evoked 100% of responses in 20 consecutive stimulations while recording from relaxed muscles. The difference for RMT between sides was evaluated in the controls and in the patient. We also evaluated the effect of voluntary activation by measuring the active motor threshold (AMT) using the circular coil. Control values were obtained in 15 normal subjects (mean age 47 years; SD. 16.8; range 25-71; 14 men>.
Table 1 Threshold
values (% maximal
stimulator
Spinal excitability H reflexes were recorded from flexor carpi radialis muscle (FCR) using the stimulation and recording parameters described by the IFCN committee (Kimura et al., 1994). Baseline-to-peak amplitude of the H reflex was measured in 20 consecutive recordings for each side and amplitude values were compared using paired Student’s t test. Moreover, we compared the H-max/M-max ratio for each side.
3. Results
3.1. Cortical excitability Table 1 summarises neurophysiological findings in controls and in the patient. In the patient, the RMT was higher in the motor cortex contralateral to the missing hemicerebellum than in the ipsilateral motor cortex, and the right/left asymmetry was clearly above normal limits when using the circular coil or figure-eight coil with the current flowing in a PA direction; however, there were no asymmetries when the motor cortex was stimulated with electrical anodal stimuli or the figure-eight coil with the current flowing in the LM direction (Fig. 1). Voluntary
output) Active motor treshold
Resting motor threshold Circular coil
Patient Upper normal limits a Increased
value
Figure-8 PA
Figure-8 LM
Electrical anodal
Circular coil
R
L
Difference between sides
R
L
Difference between sides
R
L
Difference behveen sides
R
L
Difference between sides
R
L
Difference between sides
72
49
23 a 8.6
72
59
13 a 8.9
73
72
1 12.2
79
79
0 18.8
49
31
18 a 8.1
V. Di Lauaro
et al. /Electroencephalography
and clinical Neurophysiology
muscle activation did not modify the threshold asymmetry. Indeed, AMT evaluated with the circular coil was higher in the motor cortex contralateral to the missing hemicerebelhim.
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6
3.2. The silent period The mean duration of silence for the patient is shown in Fig. 2, and representative records at different stimulus intensities are shown in Fig. 3. The duration of the silent period increased with increasing stimulus intensity. Between side comparisons showed different results according to the scale of magnetic stimuli intensities. When intensities were considered relative to AMT, silence comparisons showed significant side differences with longer duration after stimulation of the motor cortex contralateral to the missing hemicerebellum (Fig. 2A and 3). However, this difference was not present when intensities were considered relative to the maximal magnetic stimulator output (Fig. 2B and 3). 3.3. Spinal excitability In the patient, the mean amplitude of right FCR H reflex was 0.220 mV (S.D. 0.1 mV>; the mean amplitude of the left FCR H reflex was 0.282 mV (S.D. 0.13 mV; Fig. 4). Paired comparison of the amplitudes showed that there was no significant asymmetry (P > 0.5). H-max/M-
*
Fig. 2. Duration of silent periods after stimulation of the motor cortex ipsilateral (left motor cortex) and contralateral (right motor cortex) to the hemicerebellectomy. Magnetic stimulus intensities are expressed as relative to AMT (A), and as absolute values relative to the maximal magnetic stimulator output (B). Silent periods recorded after stimulation of the right motor cortex are longer than those recorded after stimulation of the left motor cortex when stimulus intensities are considered relative to AMT, there is no side difference when they are considered relative to the stimulator output. * P < 0.05; * * P < 0.001.
max ratio for the right side was 0.034 and for the left side 0.04. Thus the two sides presented comparable values.
4. Discussion
Fig. 1. Threshold for motor responses using different forms of activation of central motor pathways in a patient with hemicerebellar ablation. The ordinate shows the percentage of output of the magnetic stimulator. The threshold is higher for the motor cortex contralateral to the hemicerebellectomy when either a circular coil centred over the vertex or a figure-eight coil held on the parasagittal line with the induced current in the brain flowing in a postero-anterior (PA) direction is used; there is no side difference when either electrical anodal stimulation or a figure-eight coil held on the parasagittal line with the induced current in the brain flowing in a latero-medial (LM) direction is used. * = difference between sides above normal limits.
As previously described (Di Lazzaro et al., 1994a), our patient showed a higher threshold to magnetic stimulation using a circular coil centred over the vertex for the motor cortex contralateral to the missing hemicerebellum. On the other hand, when electrical anodal stimulation was used, threshold asymmetry was no longer present. Magnetic stimulation with a large circular coil centred over the vertex tends to activate pyramidal tract neurones transsynaptically producing descending volleys termed “I waves,” at least at low to moderate intensities, while electrical anodal stimulation activates the axons of pyramidal tract neurones directly, probably at the first and second nodes in the white matter, producing descending volleys termed “D waves” (Day et al., 1989; Amassian et al., 1990). The D
262
V. Di Lazzaro et al. /Electroencephalography
and clinical Neurophysiology
97 (1995) 259-263
Right motor cortex stimulation
84%
Left motor cortex stimulation
84%
54%
-I
1 mV
50 ms Fig. 3. Silent periods obtained at different stimulus intensities. Top traces represent silent periods recorded after stimulation of motor cortex functionally related to the impaired hemicerebellum, the right motor cortex, at a value corresponding to active motor threshold, 54% of the maximal magnetic stimulator output, and 30% above this value. Middle traces represent silent periods recorded after stimulation of the left motor cortex at a value corresponding to active motor threshold, 44% of the maximal magnetic stimulator output, and 30% above this value. Silent periods are shorter after stimulation of the left motor cortex, although CMAP amplitudes are similar to those obtained after stimulation of the right motor cortex. The use of the same stimulus intensities in the two motor cortices elicits silent periods of comparable duration. Compare lower and upper traces. The vertical dotted line indicates the end of the silent period after right motor cortex stimulation.
wave activity may not suffice to bring the spinal motor neurone to discharge, particularly when recording from relaxed muscles because the resting potential of spinal motor neurones is well below the threshold. Thus, to produce discharge, temporal summation with a second EPSP produced by subsequent I waves is needed. Right flexor carpi radialis
Left flexor carpi radialis
200 uv 5ms Fig. 4. H reflex recorded in relaxed flexor carpi radialis muscle of the patient. Each trace is the mean of 20 sweeps. The size of the response is similar on both sides.
Since the descending volley, capable of evoking a CMAP, is not pure I wave actvity with electrical stimulation but mainly depends on D wave activity, the cellular mechanisms underlying spinal activation after electrical and magnetic cortical stimulation should be different. In particular, CMAPs evoked by magnetic stimulation should be more susceptible to changes in the level of motor cortex excitability than those evoked by electrical stimulation in which intracortical phenomena play a less important role. Furthermore, several studies have suggested a transsynaptic action of magnetic stimuli because magnetic induced CMAPs are highly sensitive to the level of cortical excitability. Conversely, electrically induced CMAPs are not very sensitive, if at all, to cortical excitability changes. These differences between magnetic and electrical induced CMAPs have been shown after somatosensory (Day et al., 1988) or cerebellar stimulation (Ugawa et al., 1991), and with cortico-cortical (Kujirai et al., 1993) or transcallosal inhibition (Ferber? et al., 1992). Taking into account the above data, the evidence in our patient of a circular coil magnetic threshold increase with normal anodal electrical threshold in the motor cortex contralateral to the missing hemicerebellum indicates that the cerebellar lesion induced central motor circuit excitability changes mainly through cortico-cortical mechanisms. Even using electrical anodal stimulation at rest,
V. Di Lauaro
et al. /Electroencephalography
when the descending volley evoking CMAPs is presumably not pure D wave activity, there was no threshold asymmetry in our patient. One possible explanation of this finding is that there is a differential sensitivity of the generators of early or late I waves to the withdrawal of cerebellar inputs. Similar differences have been reported during anaesthesia with volatile agents (Hicks et al., 1992). Thus, if I wave components present a different sensitivity to cerebellar withdrawal, excitabilty changes will be apparent only when multiple I waves are needed to evoke CMAPs (magnetic stimulation with a circular coil centred over the vertex). When a single I wave added to the preceding D wave activity suffices to bring spinal motoneurones to discharge (electrical anodal stimulation at rest) no threshold asymmetry will be detected. It has also been suggested that by using a different orientation of the figure-eight coil it is possible to activate central motor pathways at different sites (Werhahn et al., 1994). With the coil held on a parasagittal line with the induced current in the brain flowing in a latero-medial direction, cortico-spinal fibres would be activated directly, just as when using electrical anodal stimulation. With the current flowing in a postero-anterior direction cortico-spinal fibres would be activated transsynaptically just as when using magnetic stimulation with a circular coil centred over the vertex. Our results support this hypothesis. Thus, magnetic stimulation with a figure-eight coil with PA orientation provided results comparable to those obtained using the circular coil centred over the vertex, and an LM orientation provided results comparable to those obtained using electrical anodal stimulation. The evidence that stimuli of equal absolute intensity produced silent periods of comparable duration on both sides suggests that the threshold for the inhibitory effects of magnetic stimulation is substantially unchanged in the motor cortex functionally related to the missing hemicerebellum. Therefore, threshold asymmetry observed after a unilateral cerebellar lesion is more likely to be due to modification in the excitatory than in the inhibitory cortical circuits. In line with reports on experimental animals (Dow and Moruzzi, 1958), motor cortex excitability changes are probably related to the withdrawal of the tonic background support of the cerebellum to the motor cortex. The hypothesis that segmental spinal cord circuits might be involved in the observed increase of the magnetic threshold is clearly ruled out by the finding of normal H reflex testing. In conclusion, our findings, which will need confirmation in a larger sample of patients, document that motor cortex threshold modifications observed after lesions of the cerebella-cortical pathway may be related to modification in the intrinsic excitability properties of the motor cortex, specifically to a reduction in motor cortex excitability. Furthermore, comparison between different central motor pathway stimulation techniques allowed us to confirm
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differences in the site of excitation orientations.
using
different
coil
Acknowledgements We would like to thank Mr. F. Rinaldi for his technical assistance.
References Amassian, V.E., Quirk, G.J. and Stewart, M. (1990) A comparison of cortico-spinal activation by magnetic coil and electrical stimulation of monkey motor cortex. Electroenceph. clin. Neurophysiol., 77: 390401. Day, B.L., Dressler, D., Maertens de Noordhout, A., Marsden, C.D., Nakashima, K., Rothwell, J.C. and Thompson, P.D. (1988) Differential effect of cutaneous stimuli on responses to electrical or magnetic stimulation of the human brain. J. Physiol. (Lond.1, 399: 68P. Day, B.L., Dressler, D., Maertens de Noordhout, A., Marsden, C.D., Nakashima, K., Rothwell, J.C. and Thompson, P.D. (1989) Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J. Physiol. (Lend.), 412: 449-473. Di Lazzaro, V., Restuccia, D., Molinari, M., Leggio, M.G., Nardone, R., Fogli, D. and Tonali, P. (1994a) Excitability of the motor cortex to magnetic stimulation in patients with cerebellar lesions. J. Neurol. Neurosurg. Psychiat., 57: 108-110. Di Lazzaro, V., Molinari, M., Restuccia, D., Leggio, M.G., Nardone, R., Fogli, D. and Tonali, P. (1994bl Cerebro-cerebellar interactions in man: neurophysiological studies in patients with focal cerebellar lesions. Electroenceph. clin. Neurophysiol., 93: 27-34. Dow, R.S. and Moruzzi, G. (1958) The Physiology and Pathology of the Cerebellum. University of Minnesota Press, Minneapolis, MN. Ferbert, A., Priori, A., Rothwell, J.C., Day, B.L., Colebatch, J.G. and Marsden, C.D. (1992) Interhemispheric inhibition of the human motor cortex. J. Physiol. (Land.), 453: 525-546. Hicks, R., Burke, D., Stephen, J., Woodforth, I. and Crawford, M. (1992) Cortico-spinal volleys evoked by electrical stimulation of human motor cortex after withdrawal of volatile anaesthetics. J. Physiol. (Lond.1, 456: 393-404. Kimura, J., Daube, J., Burke, D., Hallett, M., Cruccu, G., Ongerboer de Visser, B.M., Yanagisawa, N., Shimamura, M. and Rothwell, J.C. (1994) Human reflexes and late responses. Report of an IFCN committee. Electroenceph. clin. Neurophysiol., 90: 393-403. Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P. and Marsden C.D. (19931 Cortico-cortical inhibition in human motor cortex. J. Physiol. (Land.), 471: 501-520. Meyer, B.U., Roricht, S. and Machetanz, J. (1994) Reduction of corticospinal excitability by magnetic stimulation over the cerebellum in patients with large defects of one cerebellar hemisphere. Electroenceph. clin. Neurophysiol., 93: 372-379. Rothwell, J.C., Thompson, P.D., Day, B.L., Boyd, S. and Marsden, C.D. (19911 Stimulation of the human motor cortex through the scalp. Exp. Physiol, 76: 59-200. Werhahn, K.J., Fong, J.K.Y., Meyer, B.U., Priori, A., Rothwell, J.C., Day, B.L. and Thompson, P.D. (1994) The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseous muscle. Electroenceph. clin. Neurophysiol., 93: 138-146. Ugawa, Y., Day, B.L., Rothwell, J.C., Thompson, P.D., Merton, P.A. and Marsden, C.D. (1991) Modulation of motor cortex excitability by electrical stimulation over the cerebellum in man. J. Physiol. (Land.), 441: 57-72.
Electroencephalography
and clinical Neurophysiology
97 (1995) 259-263
Motor cortex changes in a patient with hemicerebellectomy V. Di Lazzaro
*,
’
D. Restuccia, R. Nardone, M.G. Leggio, A. Oliviero, P. Profice, P. Tonali, M. Molinari
Istituto di Neurologia
Uniuersith Cattolica, Large A. Gemelli 8, 00168 Rome, Italy Accepted for publication:
16 May 1995
Abstract
To evaluate reorganisation of motor pathways following a cerebellar lesion, we studied motor cortex excitatory responses and inhibitory effects after transcranial stimulation, together with segmental spinal cord excitability, in one patient who had undergone hemicerebellectomy. We compared the results obtained using different forms of stimulation capable of activating the cortico-spinal tract at different sites. Results were compared between sides. We previously reported that the threshold for responses is higher in the motor cortex contralateral to the impaired hemicerebellum and the right/left threshold asymmetry is clearly greater than normal when a circular coil centred over the vertex is used. In the present study, using electrical anodal stimulation, no side difference was observed. Significant interside differences were absent also when the durations of the silent periods or the mean amplitude of the flexor carpi radialis H reflex between the two sides were compared. The outcome is that the interside differences previously observed are mainly due to reduction in the intrinsic excitability properties of the motor cortex functionally related to the impaired hemicerebellum and not to modification of the inhibitory properties of the cortex or to spinal mechanisms.
Keywords:
Cerebellum;
Motor cortex; Magnetic
stimulation;
Electrical
stimulation
1. Introduction The strict functional
relationship
between
the cerebel-
lum and the motor cortex suggests
that cerebellar lesions may determine alterations in the activity of cortical descending motor pathways. In experimental animals it has been reported that either lesions or stimulation of the cerebellum can produce excitability changes of the motor cortex (for a review see Dow and Moruzzi, 1958). In a recent study we showed that motor cortex excitability after magnetic stimulation is reduced in patients with focal cerebellar lesions (Di Lazzaro et al., 1994a). Thus, threshold for magnetic stimulation is increased for the motor cortex contralateral to the lesioned hemicerebellum. This finding has been confirmed by others (Meyer et al., 1994). However, the evidence of an increased threshold provides
* This work was supported by Telethon -Italy (Grant No. 578). * Corresponding author. Tel.: 06 30154435; Fax: 06 35501909. 0924-980X/9.5/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSD10013-4694(95)00110-7
no information about where the excitability changes have taken place, i.e., in the motor cortex or the spinal cord, or both. The aim of the present study was to identify the site of excitability changes observed in patients with cerebellar lesions. One representative patient from those already described (Di Lazzaro et al., 1994b) was studied using different electrophysiological techniques. To ascertain whether the observed excitability changes were due to functional changes in the cortico-cortical connections or at the subcortical level, we compared the data obtained using different techniques of central motor pathway stimulation, magnetic and electrical, known to activate the cortico-spinal tract at different sites (Day et al., 1989; Amassian et al., 1990; Rothwell et al., 1991; Werhahn et al., 1994). The relevance of inhibitory circuit changes in determining the degree of motor cortex excitability after cerebellar lesion has been evaluated by measuring silent periods evoked by cortical stimulation. H reflex testing was performed to determine whether excitability changes at the spinal cord level might account for the observed increase in the motor threshold.
V. Di Lazzaro et al. / Electroencephalography
260
and clinical Neurophysiology 97 (1995) 259-263
2. Patient and methods
Normal limits for threshold were defined SD. of the values in controls.
as mean f 2.5
2.1. Patient The silent period The silent period was elicited using a figure-eight coil with the current flowing in a PA direction while the subject held a tonic voluntary contraction of approximately 20% of the maximum voluntary contraction of ADM. We used increasing intensities of the magnetic shock starting from a value equal to AMT up to an intensity equal to AMT plus 30% of the maximal stimulator output in steps of 10%. Five stimulations were performed for each intensity value. Duration of the silent period on one side at different intensities was compared with the contralateral side using paired Student’s t test. In comparing silent period durations, magnetic stimulation intensities were considered as absolute values relative to maximal magnetic stimulator output and as relative to AMT.
Clinical and radiological data of this patient have already been described in a previous paper (Di Lazzaro et al., 1994b). Briefly, the patient, a 48-year-old male, had undergone left hemicerebellectomy because of a vascular malformation. When the electrophysiological study was performed 4 years after surgery, neurological examination revealed only slight dysmetria of the left upper limb and was otherwise normal. In particular, there were no upper motor neurone signs and the plantar responses were flexor bilaterally. Central motor conduction time was bilaterally normal for both upper and lower limbs. 2.2. Methods Motor cortex stimulation Transcranial stimuli were delivered by a Novametrix Magstim 200 magnetic stimulator or a Digitimer D180 high voltage electric stimulator. Magnetic stimulation was achieved by stimuli given through either a circular coil centred over the vertex or a figure-eight coil held in two different orientations over the left or right motor strips with the induced current flowing either in a postero-anterior (PA) or latero-medial (LM) direction. Transcranial electrical stimuli were given through two Ag/AgCl electrodes fixed to the scalp with collodion. The cathode was placed over the vertex, and the anode 7 cm laterally on a line joining the vertex with the external auditory meatus. Compound motor action potentials (CMAPs) were recorded from the abductor digiti minimi (ADM) muscle through surface electrodes and amplified with filter settings of 2 Hz and 5 kHz. We defined resting motor threshold (RMT) as the minimum stimulus intensity that evoked 100% of responses in 20 consecutive stimulations while recording from relaxed muscles. The difference for RMT between sides was evaluated in the controls and in the patient. We also evaluated the effect of voluntary activation by measuring the active motor threshold (AMT) using the circular coil. Control values were obtained in 15 normal subjects (mean age 47 years; SD. 16.8; range 25-71; 14 men>.
Table 1 Threshold
values (% maximal
stimulator
Spinal excitability H reflexes were recorded from flexor carpi radialis muscle (FCR) using the stimulation and recording parameters described by the IFCN committee (Kimura et al., 1994). Baseline-to-peak amplitude of the H reflex was measured in 20 consecutive recordings for each side and amplitude values were compared using paired Student’s t test. Moreover, we compared the H-max/M-max ratio for each side.
3. Results
3.1. Cortical excitability Table 1 summarises neurophysiological findings in controls and in the patient. In the patient, the RMT was higher in the motor cortex contralateral to the missing hemicerebellum than in the ipsilateral motor cortex, and the right/left asymmetry was clearly above normal limits when using the circular coil or figure-eight coil with the current flowing in a PA direction; however, there were no asymmetries when the motor cortex was stimulated with electrical anodal stimuli or the figure-eight coil with the current flowing in the LM direction (Fig. 1). Voluntary
output) Active motor treshold
Resting motor threshold Circular coil
Patient Upper normal limits a Increased
value
Figure-8 PA
Figure-8 LM
Electrical anodal
Circular coil
R
L
Difference between sides
R
L
Difference between sides
R
L
Difference behveen sides
R
L
Difference between sides
R
L
Difference between sides
72
49
23 a 8.6
72
59
13 a 8.9
73
72
1 12.2
79
79
0 18.8
49
31
18 a 8.1
V. Di Lauaro
et al. /Electroencephalography
and clinical Neurophysiology
muscle activation did not modify the threshold asymmetry. Indeed, AMT evaluated with the circular coil was higher in the motor cortex contralateral to the missing hemicerebelhim.
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6
3.2. The silent period The mean duration of silence for the patient is shown in Fig. 2, and representative records at different stimulus intensities are shown in Fig. 3. The duration of the silent period increased with increasing stimulus intensity. Between side comparisons showed different results according to the scale of magnetic stimuli intensities. When intensities were considered relative to AMT, silence comparisons showed significant side differences with longer duration after stimulation of the motor cortex contralateral to the missing hemicerebellum (Fig. 2A and 3). However, this difference was not present when intensities were considered relative to the maximal magnetic stimulator output (Fig. 2B and 3). 3.3. Spinal excitability In the patient, the mean amplitude of right FCR H reflex was 0.220 mV (S.D. 0.1 mV>; the mean amplitude of the left FCR H reflex was 0.282 mV (S.D. 0.13 mV; Fig. 4). Paired comparison of the amplitudes showed that there was no significant asymmetry (P > 0.5). H-max/M-
*
Fig. 2. Duration of silent periods after stimulation of the motor cortex ipsilateral (left motor cortex) and contralateral (right motor cortex) to the hemicerebellectomy. Magnetic stimulus intensities are expressed as relative to AMT (A), and as absolute values relative to the maximal magnetic stimulator output (B). Silent periods recorded after stimulation of the right motor cortex are longer than those recorded after stimulation of the left motor cortex when stimulus intensities are considered relative to AMT, there is no side difference when they are considered relative to the stimulator output. * P < 0.05; * * P < 0.001.
max ratio for the right side was 0.034 and for the left side 0.04. Thus the two sides presented comparable values.
4. Discussion
Fig. 1. Threshold for motor responses using different forms of activation of central motor pathways in a patient with hemicerebellar ablation. The ordinate shows the percentage of output of the magnetic stimulator. The threshold is higher for the motor cortex contralateral to the hemicerebellectomy when either a circular coil centred over the vertex or a figure-eight coil held on the parasagittal line with the induced current in the brain flowing in a postero-anterior (PA) direction is used; there is no side difference when either electrical anodal stimulation or a figure-eight coil held on the parasagittal line with the induced current in the brain flowing in a latero-medial (LM) direction is used. * = difference between sides above normal limits.
As previously described (Di Lazzaro et al., 1994a), our patient showed a higher threshold to magnetic stimulation using a circular coil centred over the vertex for the motor cortex contralateral to the missing hemicerebellum. On the other hand, when electrical anodal stimulation was used, threshold asymmetry was no longer present. Magnetic stimulation with a large circular coil centred over the vertex tends to activate pyramidal tract neurones transsynaptically producing descending volleys termed “I waves,” at least at low to moderate intensities, while electrical anodal stimulation activates the axons of pyramidal tract neurones directly, probably at the first and second nodes in the white matter, producing descending volleys termed “D waves” (Day et al., 1989; Amassian et al., 1990). The D
262
V. Di Lazzaro et al. /Electroencephalography
and clinical Neurophysiology
97 (1995) 259-263
Right motor cortex stimulation
84%
Left motor cortex stimulation
84%
54%
-I
1 mV
50 ms Fig. 3. Silent periods obtained at different stimulus intensities. Top traces represent silent periods recorded after stimulation of motor cortex functionally related to the impaired hemicerebellum, the right motor cortex, at a value corresponding to active motor threshold, 54% of the maximal magnetic stimulator output, and 30% above this value. Middle traces represent silent periods recorded after stimulation of the left motor cortex at a value corresponding to active motor threshold, 44% of the maximal magnetic stimulator output, and 30% above this value. Silent periods are shorter after stimulation of the left motor cortex, although CMAP amplitudes are similar to those obtained after stimulation of the right motor cortex. The use of the same stimulus intensities in the two motor cortices elicits silent periods of comparable duration. Compare lower and upper traces. The vertical dotted line indicates the end of the silent period after right motor cortex stimulation.
wave activity may not suffice to bring the spinal motor neurone to discharge, particularly when recording from relaxed muscles because the resting potential of spinal motor neurones is well below the threshold. Thus, to produce discharge, temporal summation with a second EPSP produced by subsequent I waves is needed. Right flexor carpi radialis
Left flexor carpi radialis
200 uv 5ms Fig. 4. H reflex recorded in relaxed flexor carpi radialis muscle of the patient. Each trace is the mean of 20 sweeps. The size of the response is similar on both sides.
Since the descending volley, capable of evoking a CMAP, is not pure I wave actvity with electrical stimulation but mainly depends on D wave activity, the cellular mechanisms underlying spinal activation after electrical and magnetic cortical stimulation should be different. In particular, CMAPs evoked by magnetic stimulation should be more susceptible to changes in the level of motor cortex excitability than those evoked by electrical stimulation in which intracortical phenomena play a less important role. Furthermore, several studies have suggested a transsynaptic action of magnetic stimuli because magnetic induced CMAPs are highly sensitive to the level of cortical excitability. Conversely, electrically induced CMAPs are not very sensitive, if at all, to cortical excitability changes. These differences between magnetic and electrical induced CMAPs have been shown after somatosensory (Day et al., 1988) or cerebellar stimulation (Ugawa et al., 1991), and with cortico-cortical (Kujirai et al., 1993) or transcallosal inhibition (Ferber? et al., 1992). Taking into account the above data, the evidence in our patient of a circular coil magnetic threshold increase with normal anodal electrical threshold in the motor cortex contralateral to the missing hemicerebellum indicates that the cerebellar lesion induced central motor circuit excitability changes mainly through cortico-cortical mechanisms. Even using electrical anodal stimulation at rest,
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when the descending volley evoking CMAPs is presumably not pure D wave activity, there was no threshold asymmetry in our patient. One possible explanation of this finding is that there is a differential sensitivity of the generators of early or late I waves to the withdrawal of cerebellar inputs. Similar differences have been reported during anaesthesia with volatile agents (Hicks et al., 1992). Thus, if I wave components present a different sensitivity to cerebellar withdrawal, excitabilty changes will be apparent only when multiple I waves are needed to evoke CMAPs (magnetic stimulation with a circular coil centred over the vertex). When a single I wave added to the preceding D wave activity suffices to bring spinal motoneurones to discharge (electrical anodal stimulation at rest) no threshold asymmetry will be detected. It has also been suggested that by using a different orientation of the figure-eight coil it is possible to activate central motor pathways at different sites (Werhahn et al., 1994). With the coil held on a parasagittal line with the induced current in the brain flowing in a latero-medial direction, cortico-spinal fibres would be activated directly, just as when using electrical anodal stimulation. With the current flowing in a postero-anterior direction cortico-spinal fibres would be activated transsynaptically just as when using magnetic stimulation with a circular coil centred over the vertex. Our results support this hypothesis. Thus, magnetic stimulation with a figure-eight coil with PA orientation provided results comparable to those obtained using the circular coil centred over the vertex, and an LM orientation provided results comparable to those obtained using electrical anodal stimulation. The evidence that stimuli of equal absolute intensity produced silent periods of comparable duration on both sides suggests that the threshold for the inhibitory effects of magnetic stimulation is substantially unchanged in the motor cortex functionally related to the missing hemicerebellum. Therefore, threshold asymmetry observed after a unilateral cerebellar lesion is more likely to be due to modification in the excitatory than in the inhibitory cortical circuits. In line with reports on experimental animals (Dow and Moruzzi, 1958), motor cortex excitability changes are probably related to the withdrawal of the tonic background support of the cerebellum to the motor cortex. The hypothesis that segmental spinal cord circuits might be involved in the observed increase of the magnetic threshold is clearly ruled out by the finding of normal H reflex testing. In conclusion, our findings, which will need confirmation in a larger sample of patients, document that motor cortex threshold modifications observed after lesions of the cerebella-cortical pathway may be related to modification in the intrinsic excitability properties of the motor cortex, specifically to a reduction in motor cortex excitability. Furthermore, comparison between different central motor pathway stimulation techniques allowed us to confirm
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differences in the site of excitation orientations.
using
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coil
Acknowledgements We would like to thank Mr. F. Rinaldi for his technical assistance.
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