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Transcallosal inhibition in cortical and subcortical cerebral vascular lesions
JOURNALOF THE
NEUROLOGICAL SCIENCES
ELSEVIER
Journalof the NeurologicalSciences144(1996)160-170
Transcallosal inhibition in cortical and subcortical cerebral vascular lesions Babak Boroojerdi ‘, Klaus Diefenbach a, Andreas Ferbert ‘“ aDepartment ofNeurology, RWTHAachen, Germany bDepartment ofNeurology, Stadt Kliniken Kasse~ Mtinchebergstr, 41-43, Kasse134125, Germany
Received8 February1996;revised14June 1996;accepted19June 1996
Abstract The excitability of the motor cortex after transcranial magnetic stimulation was investigatedin IO patients with purely subcortica~ and in 22 patients with cortical-subcortical cerebrovasctrlar lesions. In the first investigation we applied magnetic double stimuli over both motor cortices with different inter-stimulus intervals. The first (conditioning) stimulus was applied to the affected hemisphere and the second stimulus (test stimulus) to the unaffected side. The responses of the first dorsal interosseal (FDI) muscle, contralateral to the test stimulus, were recorded after applying the test stimulus alone and at inter-stimulus intervals of 5 ms, 7 ms, 15 ms, 30 ms and 60 ms. In a second investigation the patients were asked to activate their non-paretic first dorsal interosseus muscle and the magnetic stimulus was applied over the affected hemisphere. The EMG responses were rectified and averaged. Patients with subcortical cerebral lesions below the centrum semiovale (i.e., having no effect on the transcallosal fibres) displayed a pronounced inhibition of one motor cortex after the stimulation of the contralateral side, comparable with normal subjects. Patients with cortical-subcortical cerebral lesions displayed only partly less inhibition of their motor cortex but the results in this group were not uniform. Since inhibition was preserved in patients with subcortical lesions, which had destroyed the corticospinal tract, we conclude that this inhibition is not mediated through an ipsilateral projection but via a transcallosal route. Keywords: Transcranialmagneticstimulation;Transcallosalinhibition;Motorcortex;Corpuscallosum
1. Introduction Transcallosal connections between the motor cortices of both hemispheres have been recognized for many years andOkuda, 1962; Amassian et al., (Curtis, 1940; .%mtrma 1989). There are several methods for the functional investigation of transcallosal connections: by recording evoked potentials over the contralateral hemisphere (’transcallosal response’, Curtis, 1940; Amassian et al., 1989), or by giving a first (conditioning) stimulus to one hemisphere and testing the excitability of the opposite hemisphere with a second (test) stimulus. In cats the stimulation of the motor cortex has inhibitory and excitatory effects on the contralateral side. Using microelectrode recording techniques, Asanuma and Okuda (1962) revealed an excitatory
“ Correspondingauthor. Tel: +49 (561) 980-3400.Fax: +49 (561) 980-6979. 0022-510X/96/$15.00 Publishedby Elsevier Science B.V. PII S 0022-5 10 X(96 )O0222-5
area to precisely homologous areas of the opposite hemisphere. This excitatory field was surrounded by a much larger inhibitory zone. Since the advent of focal transcranial magnetic stimulation with a figure eight-shaped coil makes the application of the stimulus selectively to one motor cortex possible, it has become feasable to investigate similar questions in man without discomfort to the subject or patient. The change in the excitability of one hemisphere induced by the stimulation of the opposite hemisphere can be assessed by comparing the conditioned with the unconditioned test response. With focal magnetic stimuli applied to each motor cortex at various interstimulus intervals, there is some indication of excitation with intervals of 4–5 ms (non-significant trend). With intervals starting at 6–7 ms and extending to 30–60 ms, a pronounced inhibition was found; it also depended on stimulus variables. The response to the test stimulus can be inhibited by up to 80% (Ferbert et al., 1992). There is another way to test inhibition which is medi-
B. Boroojerdi et al. /Jourrral ?frhe Neurological Sciences 144 (1996) 160–170
ated by a transcallosal mechanism. Instead of giving two shocks to either hemisphere, a single focal stimulus is applied to one motor cortex, while the other motor cortex maintains a steady contraction of the contralateral first dorsal interosseus muscle (FDI). The ongoing EMG activity is then suppressed in the FDI ipsilateral to the stimulus. Several arguments indicate that this inhibition is not being mediated by an ipsilateral descending inhibitory projection but rather by a transcallosal route. If the ipsilateral projection was really the underlying mechanism for this inhibition, one would expect that in subcortical lesions leading to dense hemiplegia of the opposite hand but leaving corpus callosum fibres intact, the motor cortex upstream the lesion would still be functioning by inducing transcallosal inhibition. Conversely, one would expect that in lesions comprising also the cortex, corpus callosum fibres would also be affected leading to loss or abnormal inhibition. It was the aim of this study to investigate transcallosal inhibition in cerebral lesions with different locations. Preliminary results of this study have been published elsewhere (Ferbert et al., 1994).
2. Patients and methods We investigated a total of 32 patients with either ischemic infarction (n = 29) or intracerebral hemorrhage (n = 3), with the patients’ consent obtained before the investigations. The stroke had occurred between 4 days and 4 years (median 1 month) prior to the electrophysioIogical investigation. In 26 patients there was a dense hemiparesis with complete paralysis of the hand contralateral to the lesion. The remaining patients had moderate or good recovery following a period of severe hemiparesis. The left hemisphere was affected in 19 patients and the right hemisphere in 13 patients. The clinical parameters of the patients are given in Table 1. All patients underwent computerised tomography and had a visible lesion which had induced the clinical syndrome. At the time of electrophysiological investigations, the investigators were unaware of the results of the CT scan. The lesions, as identified by computerised tomography, were subdivided into purely subcortical and cortical-subcortical domains. Ten patients had subcortical cerebrovascular lesions at the level of the basal ganglia, thalamus, internal capsule and the pens. In all these patients, the lesion was located below the centrum semiovale. The remaining 22 patients had cortical-subcortical cerebral lesions. 2.1. Irwwstigation I (double stimulus) This test was performed in 19 patients. Fig. 1 shows an schematic set-up. We used two magnetic stimulators (Magstim 200). One stimulator which provided the conditioning stimulus was connected to a figure of eight coil, outer
161
Table 1 List of the patients investigated Patient
Sex
Age
1. B.D. 2. W.S. 3. W.W. 4. H.J. 5. U.B. 6. M.K. 7. G.F. 8. EL. 9. E.S. 10. F.W. 11. L.S. 12. E.D. 13, E.B. 14. GE, 15. W.S. 16. M.P. 17. M.H. 18. F.J. 19. D.M. 20. H.P. 21. G.C. 22. R.P. 23. M.P. 24. J.J. 25. G.D. 26, J.W. 27. J.M. 28. KG. 29. R.V. 30. M.H. 31. M.L. 32. J.B.
M M M F F M M M F M M F F M F M M M F F F M M M F M M M F F F M
69 67 70 85 51 52 47 63 55 63 69 81 63 60 65 41 52 58 46 83 70 61 54 26 55 48 69 50 62 61 67 66
Age of stroke (months)
CT lesion
“- ‘ paresm tiana
0
I-Thalamus I-Thalamus I-Thalamus IH-Brainstem I-BG I-BG I-BG IH-BG IH-BG I-BG I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA 1-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA IH-Frontal I-MCA I-MCA I-MCA I-MCA I-MCA
paralysis R paralysis R paralysis R paralysis R paralysis R paralysis L paralysis R paralysis R paralysis R paralysis L paralysis L paralysis L paralysis R paralysis L paralysis R paralysis R paralysis R paralysis L paralysis L paralysis L paralysis L paralysis R paralysis L paralysis L paralysis L paralysis R mild paresis R mild paresis R mild paresis R mild paresis R mild paresis R mild paresis R
o
1 1
3 1 I
1 1 1 6
50 16 2 0 19 1 3 1
11 12 30 1 19 8
Patients 1–10 had purely subcortical lesions and complete paralysis of one hand. Patients 11–26 had cortical-subcortical cerebral lesions and complete paralysis of one hand. In patients 27–32 an initial severe paresis of one hand had made a nearly complete recovery. M = male; I = cerebral infarction; BG = basal ganglia; F = female; IH = intracerbral hemorrhage; MCA = middle cerebral artery.
diameter of each loop being 9 cm. The center of the double coil was placed over the hand area 6–7 cm lateral to Cz with the current flow in the medial part of the coil in the posterior-anterior direction. Thereby, the induced current in the brain flows into the anterior-posterior direction. The intensity of this stimulator was tested by placing the figure eight-shaped coil over the non-affected hemisphere. Such a testing of threshold was only possible over the non-affected hemisphere, since there was no response in the FDI contralateral to the affected hemisphere at any stimulus intensity. However, for the experiment this coil was placed over the affected hemisphere. An intensity of 3070 above the threshold (where one could get responses in about 50% of trials with relaxed muscles) was used throughout this investigation. The other stimulator was connected to a large circular
B, Boroojerdi et aL/Journal of the Neurological Sciences 144 (1996) 160--170
162
c.
T//
tioned test response (e.g. inhibition to 20% means inhibition by 80%). 2.2. IrwsestigationII (single stimuhs)
Fig. 1. Schematic presentation of investigation I. The affected hemisphere is stimulated by a figure of eight-shaped coil (conditioning stimulus), the contralateral side by a circular coil (test stimulus). Two different sites of lesions (cortical and subcortical) are shown.
coil (outer diameter 14 cm) and placed laterally over the non-affected hemisphere. This coil provided the test shock. The muscle response to this stimulus will subsequently be called the ‘test response’. By placing the coil in such a lateral position stimuli often induced a facial twitch ipsilateral to the coil. In previous experiments we have never found ipsilateral FDI responses to stimuli from a coil in this position. The intensity of the test shock was adjusted to produce a fairly stable, but small response in the contralateral unaffected FDI (0.5– 1.5 mV). Recordings were made from the FDI of either hand (Nicolet Pathfinder I). Since there was significant trouble with stimulus artefacts in investigation II, we used small subcutaneously placed platinum needle electrodes. Preliminary experiments using electrical stimulation of the ulnar nerve had shown amplitude differences of not more than 109’owhen comparing subcutaneous needle electrodes with surface electrodes. The use of needle electrodes significantly reduced the stimulus artefact to an often barely visible level. To minimize variability of responses due to varying degree of pre-innervation, muscles were relaxed throughout the experiment. Six different stimulus parameters were ‘pseudo-randomly’ applied: test shock on its own (condition 1); test shock preceded by the conditioning shock by 5 ms (condition 2); 7 ms (condition 3); 15 ms (condition 4); 30 ms (condition 5) and 60 ms (condition 6). Pseudo-randomization had to be pre-programmed and remained then the same for all patients. Ten to twenty responses were averaged to overcome inherant amplitude variability. The averaged amplitudes of conditioned test responses were expressed as percentage of the uncondi-
Thirty-two patients were tested. Only the stimulator connected to the figure eight coil was used for this investigation. The coil was placed over the motor hand area of the affected hemisphere using the same parameters as in investigation L Repeated stimulation at a frequency of 0.2 Hz was used. The patient was asked to produce a strong contraction of the non-affected FDI and had a feedback of the strenght of his contraction by a loudspeaker. To prevent fatigue the patient was asked to contract from about 2 seconds before the stimulus and maintain the contraction for up to one second after the stimulus. The EMG was rectified and 20–40 sweeps with a sweep time of 200–350 ms (including 50–70 ms pre-stimulus time) were averaged using a Pathfinder I or a Viking (Nicolet) device. Stimulation in the absence of voluntary contraction was performed in a separate trial to define the baseline. The amplitude from the baseline to the pre-stimulus EMG activity, as well as to the EMG activity during maximal inhibition, was measured. Maximal inhibition was expressed as percentage of the baseline EMG. If the pre-stimulus EMG was noisy, a mean between the largest and the smallest value was calculated.
3. Results 3.1. Experiment I The results of a normal subject to transcranial magnetic stimulation, characterised in ‘Investigation I’ are shown in Fig. 2. The response to the test stimulus, shown on the lower left panel is inhibited when preceded by a conditioning stimulus. Maximal inhibition occurred with an interstimulus interval of 7 and 15 ms. In patients, a relatively large variability of the different unconditioned test responses was detected. This was partially due to the fact that some patients had difficulties in maintaining their muscle relaxation throughout the course of a trial (i.e. 10 min or so). However, the different conditions including the control condition (test shock on its own) were applied pseudo-randomly; therefore a systematic error can be excluded. In 10 patients the lesion was purely subcortical (Table 1). The lesion did not extend into the centrum semiovale. In 16 patients the lesion was located in the cortex and the underlying subcortical white matter. Six of the ten patients with purely subcortical lesions were assessed in experiment I. The results of 5 of these patients could be analyzed. The results of the sixth patient had to be excluded because the unconditioned test response disappeared during the course of the trial, possibly due to head movements
of the Neurological Sciences 144 (1996) 160–170
B. Boroojerdi et al. /Journal
Table 2 Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals (ISI) Patient
Unconditioned 5 ms response
7 ms 15 ms 30 ms 60 ms
100% 100%
40% 20% 43% 67% 44% 43% 7~o
In all five patients, there was a clear of the patient. inhibition from 7 ms post-stimulus onwards. The results of this investigation are shown in Table 2 and Fig. 3. An example
6
70% 45% 96% 111% 82% 81% 10%
10070 100%
100% 1007. o%
61% 33% 6470 63% 41% 52~o 6%
26Y0 33% 52% 38Y0 18% 33% 5%
in a single patient
is shown
in Fig. 4.
1n patients with cortical-subcortical infarctions there was also an inhibition, but this was less pronounced com-
3 Excluded 7 8 9 10 Mean amplitude S.E.M.
163
pared to the group with purely subcordcal lesions inter-stimulus intervals of 7, 15, and 30 ms. The results
1027C 87% 83% 47% 24% 69% 13%
this investigation are shown in Table 3 and Fig. 5. An example of this inhibition which was observed oily at 1S1 of 30 and 60 ms is shown in Fig. 6. However, the difference between the two patient groups did not reach significance, probably due to the small
All patients had purely subcortical cerebral lesions. S.E.M. = standard error of the mean.
CONDITSTIM
at of
number
of patients
in the
course of the inhibition in Fig. 7.
subcordcal
in the two patient
group. groups
The
time
is shown
-1
I
12m9
1s1
E ~‘- t~”’ t
60 ms
I
30 nrs
* ,-
15 ms 7
ms
5 m9
TEST STIM ALONE
‘=
Fig. 2. Example of investigation I in a normal subject. The conditioning stimulus Wasapplied over the left motor cortex 5 ms, 7 ms, 15 ms, 30 ms and 60 ms before the stimulation of the right motor cortex (test stimulus). The response of the right FDI (opposite to the conditioning stimulus) is recorded on the right panel, the response of the left FDI on the left panel. The conditioning stimulus is indicated by the arrow. The test stimuli are indicated by stimulus artefacts at various intervals. The unconditioned response to the test stimulus is shown in the left lowest line. There is an inhibition of the left FDI response with inter-stimulus intervals of 5 ms, 7 ms, 15 ms and 30 ms. Vertical calibration bar: left panel: 2 mV, right panel: 0,5 mV.
%
140 120 -
100 80 60 40 -
20 o’ 0
,
10
,
40
30
20
—
Patient 6
+
P.tl.nt
4
Patlont8
*
Patlont10
7
+
,
t
1
50
60
70
p.tl.”t a
ISI (ins)
Fig. 3. Relative amplitude [%] of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals. All patients had subcortical cerebral lesions.
B. Boroojerdi et al. /Journal ofthe Neurological Sciences 144 (1996) 160-170
164
CONDIT STIM -..
1—..-.
1s1
I
60 ms
12ms
,.. ,- .———
-”—-— ----------
Table 3 Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals (ISI)
o.5nrv
1 30 ms %.--—
Patient
Unconditioned 5 ms response
13 14 15 16 18 19 20 21
10070 100% 100YO ioo70 100% 100%
—----—’l’—————’”——————— 15 ms
--r-———f——~” 7 ms -H 6 ms -kT,,,--
22 23 Excluded
TEST STIM ALONE
100% 100% 100%
7 ms
15 ms 30 ms 60 ms
83% 82% 92% 80% 94% 98% 85% 80970 38’-% 21% 181% 1497, 1037C 43%
69% 83% 95% 937c 26% 11070 88%
50% 36’% 647G 202% 25% 72% 22%
68% 27% 50% i2770 38% 76% 15%
20% 337. 116% 50%
10% 52%
5% 107.
19% 35%
24 25
100% 100%
138% 727. 55% 31% 79% 101% 1157. 50%
26
10070
1727. 80%
62%
4770
41% 78%
Mean amplitude 100% S.E.M. 0%
10070 74% I3% 10%
727o 9%
51’% 14%
51% 9%
34%
All patients had cortical-subcortical cerebral lesions, 3.2.
4, A 69-year-old male with a right-sided infarction of the basal ganglia and internal capsule. There is an inhibition of the test response beginning at 1S1of 5 ms and increasing from 7 ms onwards. Upper panel: Average of 10 single responses. Lower panel: Superimposition of the single responses. Fig,
’10
Experiment II
Fig. 8 shows a representative EMG trace of a normal subject who underwent experiment II. Patients contracted their FDI in the pre-stimulus period resulting in a mean level of the rectified averaged EMG of 231–584 wV, median 308 IAV(subcortical infarctions) and 66–615 p.V, median 237 PV (cortical-subcortical infarctions). The results of experiment II could be analyzed in eight of the ten patients with pure subcortical cerebral lesions and complete paralysis of the corresponding hand. The remaining two patients were unable to produce a strong
200
150
100
50
0 o
10
20
30
40
50
60
70
ISI
(ins)
Fig. 5, Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscleat different inter-stimulus intervals. All patients had cortical-subcortical lesions.
165
B. Boroojerdi et al. /Journal of the Neurological Sciences 144 (1996) 160–170
CONDIT STIM
“+
Table 4 Onset latency, duration and the relative amount of the inhibition of the averaged rectified ongoing EMG in patients with purely subcortical cerebral lesions after the stimulation of the affected hemisphere (Investigation 11)
ISI I
I
Patient
Latency (ins)
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( wV)
1
36
30 85
0 0
427 584
38 35 40
60 22 40
0 48 0
369 288 222
38 32 35
40 26 52
11 0 0
308 23 I 200
15ms 7 ms I 6 ms
35 2 3 Excluded
II
4 5 6 7 Excluded 8 9 10
TEST STIM ALONE
i
I 2nrv 12ms
Fig. 6. Double stimulation experiment in a 55-year-old female patient with a cortical infarction. Clear inhibition of the test response is only present at 1S1of 30 and 60 ms.
The mean EMG activity was measured during the prestimulation period.
T % 100 90 -
80 70 60 -
40 30 20
10[
o~ o
10
20 ‘
30
SUBCORTICAL
40
50
60
70
ISI (ins)
+CORTICAL
Fig. 7, Time course of the interhemispheric inhibition (mean values and standard errors) for Patients with subcortical and cOmbined cOrtical-subcortical lesions.
STIM I
20ms Fig. 8. Rectified, averaged EMG of the FDI after focal magnetic stimulation of the ipsilateral motor cortex in a normal subject. There is a nearly complete inhibition of the ongoing EMG activity beginning at 35 ms after the stimulus. The bar at the bottom indicates the zero level of the EMG.
166
B. Boroojerciiet al, /Journal qf’the Neurological Sciences 144 (1996) 160–170
STIM
I t
i f /,
‘1 ‘I(IJII i IIJ ‘~’ I 1 [ l.. ‘
1/
‘i
,l,!l; 11. 1
1(
//lj
II
‘1,4, / ++~.Jl.
Ei&INE
125uV 20ms
Fig. 9. A 52-year-old male with a dense right hemiplegia and a purely subcortical ischaemic lesion on CT, There is a strong inhibition of the rectified, averaged EMG of the left FDI after left motor cortex stimulation. The lesion does not extend into the centrum semiovale and spares the corpus callosum fibres.
t?. Boroojerdi et al. /Jourmd
of the Neurological Sciences 144 (1996) 160–170
contraction before each stimulus. Either the contraction came too late or it came too early and ended before the stimulus. Therefore the results from these two patients had to be excluded. In all patients, the EMG activity was suppressed to values between O and 4890 of the pre-stimuIUSbaseline. Fig. 9 shows a typical example. The onset latency of the inhibition ranged from 32 to 38 ms post stimulus. The results are summarized in Table 4. In 14 of the 16 patients with cortical-subcortical infarctions results of experiment II could be analyzed. In 4 patients, inhibition was lacking and in the remaining pa-
BASELINE
167
tients, inhibition ranged from 20to 8070(see Table 5). The onset latency of the inhibition ranged from 35 to 110 ms post stimulus. An example is given in Fig. 10. In addition to the patients with dense hemiplegia, we investigated 6 patients who initially displayed a severe paresis of the FDI, due to cortical cerebral infarctions, following by a nearly complete recovery. In this group we performed only investigation II. Both hemispheres were stimulated in patients 27, 28 and 29 and the responses of the ipsilateral FDI were recorded. In the remaining patients we only stimulated over the affected hemisphere. Table 6
—
IZoouv
20ms
Fig. 10. An 81-year-old female with a left hemiplegia. CT shows a cortical-subcortical cerebral infarction. There is no inhibition of the ongoing rectified, averaged EMG of the right FDI after the right motor cortex stimulation.
168
B. Boroojerdi et al. /Journal of the Neurological Sciences 144 (1996) 160–170
Table 5 Onset latency, duration and the relative size of the ongoing EMG Inhibition in patients with cortical-subcortical lesions (Investigation II) Patient
Latency (ins)
11 53 12 No inhibition 13 No inhibition 14 57 15 110 16 No inhibition 17 35 18 37 19 Excluded 20 No inhibition 21 38.5 22 Excluded 23 40 44 24 25 57 26 38
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( wV)
57
45
222
24 26
55 78
155 400
74 83
45 33
177 222
4.1. Results obtained with double magnetic stimulation 28
0
38 41 34 24
45
100
20 47 24
667 566 550
615
Table 6 Onset latency, duration and the relative size of the ongoing EMG inhibition in patients with an initial dense paresis of one hand followed by a good recovery (Investigation II) Patient
Latency (ins)
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( LLV)
27 L. FDI I-LFDI 28 L. FDI R. FD1 29 L. FDI R. FDI
43 43
43 55 49 49 35
o 0 0
769 693 692 385 538 384 538 769 246
30 31 32
30 30 35 46 34 31 38
the fibres of the corpus callosum are derived from a separate population of neurones and are not collaterals of the corticospinal tract fibres (Catsman-Berrevoetes et al., 198f)). If one considers transcallosal connections between both motor cortices to be functionally relevant, then one should expect a differential effect of lesions to both corticospinal and transcallosal fibres on the one side and of those lesions purely affecting corticospinal fibres on the other side. Such functional tests have been developed using magnetic brain stimulation and we have applied these tests to patients with cerebral vascular lesions of various location.
0
46 48 46
47 31 0 0 0 0
In patients 27, 28 and 29 we stimulated both hemispheres. All patients had lesions in their left motor cortex.
shows the results of this investigation. With one exception, there was a complete inhibition of the EMG in all patients with an onset latency of 30–43 ms.
4. Discussion The function of callosal connections between the motor cortex of each side has been extensively investigated in animal experiments (Curtis, 1940; Asanuma and Okamoto, 1959; Asanuma and Okuda, 1962; Berhtcchi, 1990). It is therefore surprising, that little is known about the importance of interhemispheric connections in human motor behaviour with the exception of observations after callosotomy (Sperry, 1974). Anatomically, it has been shown that
In the first experiment two magnetic stimulators were used to investigate the effect of a conditioning stimulus over the motor cortex of one hemisphere on the size of EMG responses of the first dorsal interosseal (FDI) muscle evoked by a magnetic test stimulus given over the opposite hemisphere. Similar experiments in normal subjects have shown that a single conditioning shock to one hemisphere could produce an inhibition of the test response evoked by the magnetic stimulation of the contralateral side, when the conditioning-test interval was between 6 and 30–60 ms (Ferbert et al., 1992). In the first group of our patients we investigated patients with pure subcortical cerebral lesions at the level of the basal ganglia, thakuntts, internal capsule or pens. The callosal pathways between the hemispheres were preserved and the corticospinal tract was affected below the centrum semiovale. Thus, subcortical lesions were not only subcortical in the strict sense of the word, but also excluded the centrum semiovale that contains transcallosal fibres. On this level a vascular lesion could destroy the corticospinal pathways without affecting the callosal fibres, which are already separated from the latter. In this group of patients, results comparable to the data in normal subjects were obtained. The transcranial conditioning magnetic stimulation over one hemisphere could inhibit the EMG responses evoked by the stimulation of the other hemisphere at inter-stimulus intervals of 7, 15, 30 and 60 ms. 4.2. Inhibition of the ipsilateral tonic EMG actiuity In the second experiment the effect of magnetic conditioning stimuli of the affected motor cortex on the ongoing voluntary EMG activity of the ipsilateral (non-paretic) FDI was investigated. It has been shown that in normal subjects the EMG response of the FDI could be inhibited by the transcranial magnetic stimulation of the ipsilateral motor cortex with an onset latency of 30–35 ms (i.e. 10–15 ms after the minimum corticomuscular conduction time to the muscle), lasting for about 30 ms (Ferbert et al., 1992). It was suggested by those authors that inhibition, produced by this method has a similar mechanism as inhibition
B. Boroojerdi et al. /Journal of the Neurological Sciences 144 (1996) 160–170
produced by the above mentioned double stimulus technique. When we applied this technique to patients with pure subcortical cerebrovascular lesions below the centrum semiovale, we observed a preserved inhibition of the EMG activity with an onset latency of 32–38 ms which lasted for 22–85 ms. What are the explanations for the inhibition of the FDI by an ipsilateral transcranial magnetic stimulation? Since the excitability of alpha motoneurones, assessed by eliciting H-reflexes during the inhibition period shows no change, this ipsilateral inhibition acts at a level above the alpha motoneurones (Wassermann et al., 1991; Ferbert et al., 1992). Another argument, which favours a cortical level of inhibition is that a conditioning magnetic stimulus can not significantly suppress test responses evoked by low intensity anodal test stimuli. These stimuli most likely activate corticospinal fibres directly within the white matter (D-waves), whilst transcranial magnetic stimuli activate cortical interneurones (Hess et al., 1987; Day et al., 1989; Amassian et al., 1990; Burke et al., 1990; Edgley et al., 1990; Edgley et al., 1992; Kujirai et al., 1993). One could suggest an ipsilateral descending inhibition from the motor cortex to the FDI of the same side. This ipsilateral inhibitory projection should, as the corticospinal tract, be similarly affected by the subcortical cerebral lesions, unless this hypothetical projection travelled far from the corticospinal tract and remained unaffected by the lesion. However, if we consider a similar course for the two tracts, then one would not only expect paralysis of the opposite hand, but also loss of inhibition in the ipsilateral hand. Since this was not the case, a direct ipsilateral descending projection seems to be unlikely. The tract mediating the inhibition must run far from the lesion, most likely connected to the opposite hemisphere via the corpus callosum. Preliminary results suggest that there is apparently no inhibition of motor responses of one motor cortex after transcranial magnetic stimulation of the contralateral side in patients with an agenesis of the corpus callosum (Rothwell et al., 1991). This supports the suggestion of a transcallosal route of the described inhibition. Recently published investigations in patients with abnormalities of corpus callosum have shown that a transcranial magnetic stimulation over one motor cortex can suppress the tonic voluntary EMG activity in the ipsilateral FDI in patients with a preserved anterior part of the truncus corporis callosi. In patients with abnormalities in this part of the corpus callosum, the inhibition was delayed or even absent (Meyer et al., 1995). These results are supported by anatomical studies in rhesus monkey, which have shown that the transcallosal fibres from the primary motor cortex cross the midline at the second quarter of the truncus corporis callosi (Pandya and Seltzer, 1986). Although in monkeys the areas, which represent the distal parts of the limbs have only few transcallosal connections (Curtis, 1940; Killackey et al., 1983; Gould et al., 1986), our results suggest a prominent inhibitory link between these
169
areas in man. There are two possible explanations for this phenomenon: A relatively sparse callosal connection can result in a prominent inhibitory input or this inhibition can occur via an indirect transcallosal pathway. Interhemispheric connections below the level of the corpus callosum could be at least partly responsible for our results. These hypothetical pathways may have possibly been affected by the subcortical lesions mentioned above, and may well be responsible for the late part of the inhibition, i.e. with interstimuls intervals of 30 ms or more. 4.3. Interhemispheric inhibition in patients with an initially secere paresis of the FDI, followed by a nearly complete recovery In this group our results were again comparable with the data in normal subjects. We observed, with a single exception, a complete inhibition of the FDI after transcranial magnetic stimulation of the ipsilateral motorcortex. Since these patients all had a nearly complete recovery of their paresis, we assume that the transcallosal fibres were still intact and could transmit the inhibition. 4.4. Results in patients with cortical-subcorticul cerebrocuscular lesions A second group of patients with cortical-subcortical cerebrovascular lesions was investigated. In investigation I (double stimulation) an inhibition of the EMG response evoked by the test stimulation of the non-affected motor cortex, preceded by the conditioning stimulation of the contralateral (affected) side at inter-stimulus intervals of 7, 15 and 30 ms was observed. This inhibition was less pronounced than that observed in the first group of patients. In the second investigation (single stimulation) an inhibition was detected in some patients of this group with an onset latency of 35–1 10 ms post stimulus, lasting for 24–83 ms. In some patients the inhibition was lacking. In contrast to the clear results in patients with purely subcortical cerebral lesions, the data from patients with cortical-subcortical cerebral infarctions were less conclusive. One would expect a lack of transcallosal inhibition in these patients. Although these patients showed less inhibition of the test response at inter-stimulus intervals up to 30 ms, the later part of the inhibition was even more pronounced in some cases. A possible explanation for this unexpected result could be that all these patients had cortical-subcortical lesions of their motor cortex leading to a complete paralysis of the contralateral hand, irrespective of the exact site at which the corticospinal tract was affected. Thus, one could suppose that, at least in some patients, the subcortical extension of the cerebral infarction towards the internal capsule and not the cortical lesion itself was responsible for the hemiplegia. Such a lesion could leave the callosal pathways intact, leading to a preserved transcallosal inhibition of the contralateral motor
170
B, Boroojerdi et cd,/Journal crf”theNeurological Sciences 144 (1996) 160–170
cortex. Investigation of patients with purely cortical lesions (e.g. affecting only area 4) would verify this suggestion. 4.5. Possible mechanism underlying the corticocortical inhibition There are several reports of the inhibitory phenomena after a single cortical stimulation. Krnjevic et al. showed that a stimulus to the cortex of cats, rabbits or monkeys can reduce the excitability of the motor cortex for up to 300 ms. It has been suggested that this inhibitory effect is due to the activation of intracortical GABAergic interneurones, including basket cells (Krnjevic et al., 1966a; Krnjevic et al., 1966b; Krnjevic et al., 1966c; Krnjevic, 1983). If this is the case with the transcranial magnetic stimulation in man, this method will be a powerful and non-invasive tool for investigating GABAergic inhibitory systems of the human motor cortex. In conclusion, we have shown that the motor cortex, upstream to a hemispheric or brainstem lesion to the corticospinal tract, can have residual function even if its output through the corticospinal tract is completely destroyed. There is good evidence that this residual function acts on the opposite motor cortex through transcallosal fibres and can be assessed by transcranial magnetic stimulation. The extent to which interhemispheric connections are affected might be of importance for the recovery of hemiplegia.
Acknowledgements The authors are grateful to Dr. G. Brook (Technical university, Aachen) for reviewing the English version of the manuscript.
References Amassian, V.E., Cracco, R.Q. and Maccabee, P.J. (1989) Focal stimulation of human cerebral cortex with the magnetic coil: a comparison with electrical stimulation. Electroenceph. Clin. Nersrophysiol., 74: 401-416. Amassian, V.E., Quirk, K.J. and Stewart, M. (1990) A comparison of corticospinal activation by magnetic coil and electrical stimulation of monkey motor cortex. Electroenceph. Clin. Neurophysiol., 77: 390– 407. Asanuma, H. and Okamoto, K. (1959) Unitary study on evoked activity of callosal neurones and its effect on pyramidal tract cell activity on cats. Jpn. J. Physiol., 9: 473–483. Asanuma, H, and Okuda, O. (1962) Effects of transcallosal volleys on pyramidal tract cell activity of cat. J, Neurophysiol., 25: 198-208. Berlucchi, G, (1990) Commisurotomy studies in animals. In: BOller F, Grafman J, editors. Handbook of Neuropsychology. Vol 4, Elsevier, Amsterdam, 9–47. Burke, D., Hicks, R.G. and Stephen, J.P.H. (1990) Corticospinal volleys evoked by anodal and cathodal stimulation of human motor cortex. J. Physiol., 425: 283-299.
Catsman-Berrevoetes, C.E., Lemon, R.N., Vanburgh, C.A., Bentivoglio, M. and Kuypers, H.G.J.M. (1980) Absence of callosal collaterals derived from rat corticospinal neurones. A study using fluorescent retrograde tracing and electrophysiological techniques. Exp, Brain Res,, 39: 433–440. Curtis, H.J. (1940) Intercortical connections of corpus callosum as indicated by evoked potentials. J, Neurophysiol,, 3: 407–413, Day, B,L., Dressier, 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,, 412: 449–473. Edgley, S.A., Eyre, J.A,, Lemon, R.N. and Miller, S. (1990) Excitation of the corticospinal tract by electromagnetic and electrical stimulation of the scalp in the macaque momkey. J, Physiol., 425: 301–325, Edgley, S,A,, Eyre, J.A., Lemon, R.N. and Miller, S. (1992) Direct and indirect activation of corticospinal neurones by electrical and magnetic stimulation in the anesthetized macaque monkey. J. Physiol., 446: 224P. Ferbert, A,, Priori, A., Rothwell, J.C,, Day, B.L., Colebatcb, J,G. and Marsden, C,D. (1992) Interhemispheric inhibition of the human motor cortex. J. Physiol., 453: 525–546, Ferbert, A., Boroojerdi, B., Diefenbach, K. and Buchner, H. (1994) Transcallosal inhibition of the motor cortex in patients with hemiplegia of vascular origin. J, Neurol. Neurosurg, Psychiat,, 57: 514. Gould, H.J., Cusick, C.G,, Pens, T.P, and Kaas, J.H. (1986) The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eyefields in owl monkeys. J. Comp. Neurol., 247: 297-325, Hess, C,W,, Mills, K.R. and Murray, N.M.F. (1987) Responses in small hand muscles from magnetic stimulation of the human brain. J. Physiol., 388: 397–419. Killackey, H,P,, Gould, H,J,, Cusick, C.G., Pens, T.P. and Kaas, J.H, (1983) The relation of corpus callosum connections to architectonic fields and body surface maps in sensorimotor cortex of new and old world monkeys. J. Comp. Neurol., 219: 384–419. Krnjevic, K,, Randic, M. and Straughan, D,W, (1966a) An inhibitory process in the cerebral cortex. J. Physiol., 184: 16-48. Krnjevic, K., Randic, M. and Straughan, D.W. (1966b) Nature of a cortical inhibitory process. J. Physiol., 184: 49–77. Krnjevic, K,, Randic, M. and Straughan, D,W. (1966c) Pharmacology of cortical inhibition. J. Physiol., 184: 78– 105. Krnjevic, K. (1983) GABA-mediated inhibitory mechanisms in relation to epileptic discharges. In: Basic Mechanisms of Neuronal Hyperexcitability. New York: Alan R. Liss., 249–280. Kujirai, T., Caramia, M.D., Rotbwell, J,C., Day, B.L,, Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P. and Marsden, CD. (1993) Corticocortical inhibition in human motor cortex. J. Physiol., 471: 501-519. Meyer, B.U., Roricht, S., Griifin von Einsiedel, H., Kruggel, F. and Weindl, A. (1995) Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients with abnormalities of the corpus callosum. Brain, 118: 429–440. Pandya, D.N. and Seltzer, B. (1986) The topography of commissural fibres. In: Lopre’F, Ptito M, Jasper HH, editors. Two Hemispheres — One Brain: Functions of the Corpus Callosum. New York: Alan R. Liss, 47–73. Rothwell, J.C., Colebatch, J., Britton, T.C., Priori, A., Thompson, PD., Day, B.L. and Mrsden, C.D. (1991) Physiological studies in patients with mirror movements and agenesis of the corpus callosum. J. Physiol., 438: 34P. Sperry, R.W. (1974) Lateral specialisation in the surgically separated hemispheres. In: Schmitt FO, Worden FG, editors. The Neuroscience Third Study Program, MIT Press, Cambridge, MA, USA, 5–19. Wassermann, EM., Fuhr, P., Cohen, L.G. and Hallett, M. (1991) Effects of transcranial magnetic stimulation on ipsilateral muscles. Neurology, 41: 1795–9.
NEUROLOGICAL SCIENCES
ELSEVIER
Journalof the NeurologicalSciences144(1996)160-170
Transcallosal inhibition in cortical and subcortical cerebral vascular lesions Babak Boroojerdi ‘, Klaus Diefenbach a, Andreas Ferbert ‘“ aDepartment ofNeurology, RWTHAachen, Germany bDepartment ofNeurology, Stadt Kliniken Kasse~ Mtinchebergstr, 41-43, Kasse134125, Germany
Received8 February1996;revised14June 1996;accepted19June 1996
Abstract The excitability of the motor cortex after transcranial magnetic stimulation was investigatedin IO patients with purely subcortica~ and in 22 patients with cortical-subcortical cerebrovasctrlar lesions. In the first investigation we applied magnetic double stimuli over both motor cortices with different inter-stimulus intervals. The first (conditioning) stimulus was applied to the affected hemisphere and the second stimulus (test stimulus) to the unaffected side. The responses of the first dorsal interosseal (FDI) muscle, contralateral to the test stimulus, were recorded after applying the test stimulus alone and at inter-stimulus intervals of 5 ms, 7 ms, 15 ms, 30 ms and 60 ms. In a second investigation the patients were asked to activate their non-paretic first dorsal interosseus muscle and the magnetic stimulus was applied over the affected hemisphere. The EMG responses were rectified and averaged. Patients with subcortical cerebral lesions below the centrum semiovale (i.e., having no effect on the transcallosal fibres) displayed a pronounced inhibition of one motor cortex after the stimulation of the contralateral side, comparable with normal subjects. Patients with cortical-subcortical cerebral lesions displayed only partly less inhibition of their motor cortex but the results in this group were not uniform. Since inhibition was preserved in patients with subcortical lesions, which had destroyed the corticospinal tract, we conclude that this inhibition is not mediated through an ipsilateral projection but via a transcallosal route. Keywords: Transcranialmagneticstimulation;Transcallosalinhibition;Motorcortex;Corpuscallosum
1. Introduction Transcallosal connections between the motor cortices of both hemispheres have been recognized for many years andOkuda, 1962; Amassian et al., (Curtis, 1940; .%mtrma 1989). There are several methods for the functional investigation of transcallosal connections: by recording evoked potentials over the contralateral hemisphere (’transcallosal response’, Curtis, 1940; Amassian et al., 1989), or by giving a first (conditioning) stimulus to one hemisphere and testing the excitability of the opposite hemisphere with a second (test) stimulus. In cats the stimulation of the motor cortex has inhibitory and excitatory effects on the contralateral side. Using microelectrode recording techniques, Asanuma and Okuda (1962) revealed an excitatory
“ Correspondingauthor. Tel: +49 (561) 980-3400.Fax: +49 (561) 980-6979. 0022-510X/96/$15.00 Publishedby Elsevier Science B.V. PII S 0022-5 10 X(96 )O0222-5
area to precisely homologous areas of the opposite hemisphere. This excitatory field was surrounded by a much larger inhibitory zone. Since the advent of focal transcranial magnetic stimulation with a figure eight-shaped coil makes the application of the stimulus selectively to one motor cortex possible, it has become feasable to investigate similar questions in man without discomfort to the subject or patient. The change in the excitability of one hemisphere induced by the stimulation of the opposite hemisphere can be assessed by comparing the conditioned with the unconditioned test response. With focal magnetic stimuli applied to each motor cortex at various interstimulus intervals, there is some indication of excitation with intervals of 4–5 ms (non-significant trend). With intervals starting at 6–7 ms and extending to 30–60 ms, a pronounced inhibition was found; it also depended on stimulus variables. The response to the test stimulus can be inhibited by up to 80% (Ferbert et al., 1992). There is another way to test inhibition which is medi-
B. Boroojerdi et al. /Jourrral ?frhe Neurological Sciences 144 (1996) 160–170
ated by a transcallosal mechanism. Instead of giving two shocks to either hemisphere, a single focal stimulus is applied to one motor cortex, while the other motor cortex maintains a steady contraction of the contralateral first dorsal interosseus muscle (FDI). The ongoing EMG activity is then suppressed in the FDI ipsilateral to the stimulus. Several arguments indicate that this inhibition is not being mediated by an ipsilateral descending inhibitory projection but rather by a transcallosal route. If the ipsilateral projection was really the underlying mechanism for this inhibition, one would expect that in subcortical lesions leading to dense hemiplegia of the opposite hand but leaving corpus callosum fibres intact, the motor cortex upstream the lesion would still be functioning by inducing transcallosal inhibition. Conversely, one would expect that in lesions comprising also the cortex, corpus callosum fibres would also be affected leading to loss or abnormal inhibition. It was the aim of this study to investigate transcallosal inhibition in cerebral lesions with different locations. Preliminary results of this study have been published elsewhere (Ferbert et al., 1994).
2. Patients and methods We investigated a total of 32 patients with either ischemic infarction (n = 29) or intracerebral hemorrhage (n = 3), with the patients’ consent obtained before the investigations. The stroke had occurred between 4 days and 4 years (median 1 month) prior to the electrophysioIogical investigation. In 26 patients there was a dense hemiparesis with complete paralysis of the hand contralateral to the lesion. The remaining patients had moderate or good recovery following a period of severe hemiparesis. The left hemisphere was affected in 19 patients and the right hemisphere in 13 patients. The clinical parameters of the patients are given in Table 1. All patients underwent computerised tomography and had a visible lesion which had induced the clinical syndrome. At the time of electrophysiological investigations, the investigators were unaware of the results of the CT scan. The lesions, as identified by computerised tomography, were subdivided into purely subcortical and cortical-subcortical domains. Ten patients had subcortical cerebrovascular lesions at the level of the basal ganglia, thalamus, internal capsule and the pens. In all these patients, the lesion was located below the centrum semiovale. The remaining 22 patients had cortical-subcortical cerebral lesions. 2.1. Irwwstigation I (double stimulus) This test was performed in 19 patients. Fig. 1 shows an schematic set-up. We used two magnetic stimulators (Magstim 200). One stimulator which provided the conditioning stimulus was connected to a figure of eight coil, outer
161
Table 1 List of the patients investigated Patient
Sex
Age
1. B.D. 2. W.S. 3. W.W. 4. H.J. 5. U.B. 6. M.K. 7. G.F. 8. EL. 9. E.S. 10. F.W. 11. L.S. 12. E.D. 13, E.B. 14. GE, 15. W.S. 16. M.P. 17. M.H. 18. F.J. 19. D.M. 20. H.P. 21. G.C. 22. R.P. 23. M.P. 24. J.J. 25. G.D. 26, J.W. 27. J.M. 28. KG. 29. R.V. 30. M.H. 31. M.L. 32. J.B.
M M M F F M M M F M M F F M F M M M F F F M M M F M M M F F F M
69 67 70 85 51 52 47 63 55 63 69 81 63 60 65 41 52 58 46 83 70 61 54 26 55 48 69 50 62 61 67 66
Age of stroke (months)
CT lesion
“- ‘ paresm tiana
0
I-Thalamus I-Thalamus I-Thalamus IH-Brainstem I-BG I-BG I-BG IH-BG IH-BG I-BG I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA 1-MCA I-MCA I-MCA I-MCA I-MCA I-MCA I-MCA IH-Frontal I-MCA I-MCA I-MCA I-MCA I-MCA
paralysis R paralysis R paralysis R paralysis R paralysis R paralysis L paralysis R paralysis R paralysis R paralysis L paralysis L paralysis L paralysis R paralysis L paralysis R paralysis R paralysis R paralysis L paralysis L paralysis L paralysis L paralysis R paralysis L paralysis L paralysis L paralysis R mild paresis R mild paresis R mild paresis R mild paresis R mild paresis R mild paresis R
o
1 1
3 1 I
1 1 1 6
50 16 2 0 19 1 3 1
11 12 30 1 19 8
Patients 1–10 had purely subcortical lesions and complete paralysis of one hand. Patients 11–26 had cortical-subcortical cerebral lesions and complete paralysis of one hand. In patients 27–32 an initial severe paresis of one hand had made a nearly complete recovery. M = male; I = cerebral infarction; BG = basal ganglia; F = female; IH = intracerbral hemorrhage; MCA = middle cerebral artery.
diameter of each loop being 9 cm. The center of the double coil was placed over the hand area 6–7 cm lateral to Cz with the current flow in the medial part of the coil in the posterior-anterior direction. Thereby, the induced current in the brain flows into the anterior-posterior direction. The intensity of this stimulator was tested by placing the figure eight-shaped coil over the non-affected hemisphere. Such a testing of threshold was only possible over the non-affected hemisphere, since there was no response in the FDI contralateral to the affected hemisphere at any stimulus intensity. However, for the experiment this coil was placed over the affected hemisphere. An intensity of 3070 above the threshold (where one could get responses in about 50% of trials with relaxed muscles) was used throughout this investigation. The other stimulator was connected to a large circular
B, Boroojerdi et aL/Journal of the Neurological Sciences 144 (1996) 160--170
162
c.
T//
tioned test response (e.g. inhibition to 20% means inhibition by 80%). 2.2. IrwsestigationII (single stimuhs)
Fig. 1. Schematic presentation of investigation I. The affected hemisphere is stimulated by a figure of eight-shaped coil (conditioning stimulus), the contralateral side by a circular coil (test stimulus). Two different sites of lesions (cortical and subcortical) are shown.
coil (outer diameter 14 cm) and placed laterally over the non-affected hemisphere. This coil provided the test shock. The muscle response to this stimulus will subsequently be called the ‘test response’. By placing the coil in such a lateral position stimuli often induced a facial twitch ipsilateral to the coil. In previous experiments we have never found ipsilateral FDI responses to stimuli from a coil in this position. The intensity of the test shock was adjusted to produce a fairly stable, but small response in the contralateral unaffected FDI (0.5– 1.5 mV). Recordings were made from the FDI of either hand (Nicolet Pathfinder I). Since there was significant trouble with stimulus artefacts in investigation II, we used small subcutaneously placed platinum needle electrodes. Preliminary experiments using electrical stimulation of the ulnar nerve had shown amplitude differences of not more than 109’owhen comparing subcutaneous needle electrodes with surface electrodes. The use of needle electrodes significantly reduced the stimulus artefact to an often barely visible level. To minimize variability of responses due to varying degree of pre-innervation, muscles were relaxed throughout the experiment. Six different stimulus parameters were ‘pseudo-randomly’ applied: test shock on its own (condition 1); test shock preceded by the conditioning shock by 5 ms (condition 2); 7 ms (condition 3); 15 ms (condition 4); 30 ms (condition 5) and 60 ms (condition 6). Pseudo-randomization had to be pre-programmed and remained then the same for all patients. Ten to twenty responses were averaged to overcome inherant amplitude variability. The averaged amplitudes of conditioned test responses were expressed as percentage of the uncondi-
Thirty-two patients were tested. Only the stimulator connected to the figure eight coil was used for this investigation. The coil was placed over the motor hand area of the affected hemisphere using the same parameters as in investigation L Repeated stimulation at a frequency of 0.2 Hz was used. The patient was asked to produce a strong contraction of the non-affected FDI and had a feedback of the strenght of his contraction by a loudspeaker. To prevent fatigue the patient was asked to contract from about 2 seconds before the stimulus and maintain the contraction for up to one second after the stimulus. The EMG was rectified and 20–40 sweeps with a sweep time of 200–350 ms (including 50–70 ms pre-stimulus time) were averaged using a Pathfinder I or a Viking (Nicolet) device. Stimulation in the absence of voluntary contraction was performed in a separate trial to define the baseline. The amplitude from the baseline to the pre-stimulus EMG activity, as well as to the EMG activity during maximal inhibition, was measured. Maximal inhibition was expressed as percentage of the baseline EMG. If the pre-stimulus EMG was noisy, a mean between the largest and the smallest value was calculated.
3. Results 3.1. Experiment I The results of a normal subject to transcranial magnetic stimulation, characterised in ‘Investigation I’ are shown in Fig. 2. The response to the test stimulus, shown on the lower left panel is inhibited when preceded by a conditioning stimulus. Maximal inhibition occurred with an interstimulus interval of 7 and 15 ms. In patients, a relatively large variability of the different unconditioned test responses was detected. This was partially due to the fact that some patients had difficulties in maintaining their muscle relaxation throughout the course of a trial (i.e. 10 min or so). However, the different conditions including the control condition (test shock on its own) were applied pseudo-randomly; therefore a systematic error can be excluded. In 10 patients the lesion was purely subcortical (Table 1). The lesion did not extend into the centrum semiovale. In 16 patients the lesion was located in the cortex and the underlying subcortical white matter. Six of the ten patients with purely subcortical lesions were assessed in experiment I. The results of 5 of these patients could be analyzed. The results of the sixth patient had to be excluded because the unconditioned test response disappeared during the course of the trial, possibly due to head movements
of the Neurological Sciences 144 (1996) 160–170
B. Boroojerdi et al. /Journal
Table 2 Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals (ISI) Patient
Unconditioned 5 ms response
7 ms 15 ms 30 ms 60 ms
100% 100%
40% 20% 43% 67% 44% 43% 7~o
In all five patients, there was a clear of the patient. inhibition from 7 ms post-stimulus onwards. The results of this investigation are shown in Table 2 and Fig. 3. An example
6
70% 45% 96% 111% 82% 81% 10%
10070 100%
100% 1007. o%
61% 33% 6470 63% 41% 52~o 6%
26Y0 33% 52% 38Y0 18% 33% 5%
in a single patient
is shown
in Fig. 4.
1n patients with cortical-subcortical infarctions there was also an inhibition, but this was less pronounced com-
3 Excluded 7 8 9 10 Mean amplitude S.E.M.
163
pared to the group with purely subcordcal lesions inter-stimulus intervals of 7, 15, and 30 ms. The results
1027C 87% 83% 47% 24% 69% 13%
this investigation are shown in Table 3 and Fig. 5. An example of this inhibition which was observed oily at 1S1 of 30 and 60 ms is shown in Fig. 6. However, the difference between the two patient groups did not reach significance, probably due to the small
All patients had purely subcortical cerebral lesions. S.E.M. = standard error of the mean.
CONDITSTIM
at of
number
of patients
in the
course of the inhibition in Fig. 7.
subcordcal
in the two patient
group. groups
The
time
is shown
-1
I
12m9
1s1
E ~‘- t~”’ t
60 ms
I
30 nrs
* ,-
15 ms 7
ms
5 m9
TEST STIM ALONE
‘=
Fig. 2. Example of investigation I in a normal subject. The conditioning stimulus Wasapplied over the left motor cortex 5 ms, 7 ms, 15 ms, 30 ms and 60 ms before the stimulation of the right motor cortex (test stimulus). The response of the right FDI (opposite to the conditioning stimulus) is recorded on the right panel, the response of the left FDI on the left panel. The conditioning stimulus is indicated by the arrow. The test stimuli are indicated by stimulus artefacts at various intervals. The unconditioned response to the test stimulus is shown in the left lowest line. There is an inhibition of the left FDI response with inter-stimulus intervals of 5 ms, 7 ms, 15 ms and 30 ms. Vertical calibration bar: left panel: 2 mV, right panel: 0,5 mV.
%
140 120 -
100 80 60 40 -
20 o’ 0
,
10
,
40
30
20
—
Patient 6
+
P.tl.nt
4
Patlont8
*
Patlont10
7
+
,
t
1
50
60
70
p.tl.”t a
ISI (ins)
Fig. 3. Relative amplitude [%] of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals. All patients had subcortical cerebral lesions.
B. Boroojerdi et al. /Journal ofthe Neurological Sciences 144 (1996) 160-170
164
CONDIT STIM -..
1—..-.
1s1
I
60 ms
12ms
,.. ,- .———
-”—-— ----------
Table 3 Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscle at different inter-stimulus intervals (ISI)
o.5nrv
1 30 ms %.--—
Patient
Unconditioned 5 ms response
13 14 15 16 18 19 20 21
10070 100% 100YO ioo70 100% 100%
—----—’l’—————’”——————— 15 ms
--r-———f——~” 7 ms -H 6 ms -kT,,,--
22 23 Excluded
TEST STIM ALONE
100% 100% 100%
7 ms
15 ms 30 ms 60 ms
83% 82% 92% 80% 94% 98% 85% 80970 38’-% 21% 181% 1497, 1037C 43%
69% 83% 95% 937c 26% 11070 88%
50% 36’% 647G 202% 25% 72% 22%
68% 27% 50% i2770 38% 76% 15%
20% 337. 116% 50%
10% 52%
5% 107.
19% 35%
24 25
100% 100%
138% 727. 55% 31% 79% 101% 1157. 50%
26
10070
1727. 80%
62%
4770
41% 78%
Mean amplitude 100% S.E.M. 0%
10070 74% I3% 10%
727o 9%
51’% 14%
51% 9%
34%
All patients had cortical-subcortical cerebral lesions, 3.2.
4, A 69-year-old male with a right-sided infarction of the basal ganglia and internal capsule. There is an inhibition of the test response beginning at 1S1of 5 ms and increasing from 7 ms onwards. Upper panel: Average of 10 single responses. Lower panel: Superimposition of the single responses. Fig,
’10
Experiment II
Fig. 8 shows a representative EMG trace of a normal subject who underwent experiment II. Patients contracted their FDI in the pre-stimulus period resulting in a mean level of the rectified averaged EMG of 231–584 wV, median 308 IAV(subcortical infarctions) and 66–615 p.V, median 237 PV (cortical-subcortical infarctions). The results of experiment II could be analyzed in eight of the ten patients with pure subcortical cerebral lesions and complete paralysis of the corresponding hand. The remaining two patients were unable to produce a strong
200
150
100
50
0 o
10
20
30
40
50
60
70
ISI
(ins)
Fig. 5, Relative amplitude (%) of the conditioned response of the non-paretic FDI compared to the unconditioned response of the same muscleat different inter-stimulus intervals. All patients had cortical-subcortical lesions.
165
B. Boroojerdi et al. /Journal of the Neurological Sciences 144 (1996) 160–170
CONDIT STIM
“+
Table 4 Onset latency, duration and the relative amount of the inhibition of the averaged rectified ongoing EMG in patients with purely subcortical cerebral lesions after the stimulation of the affected hemisphere (Investigation 11)
ISI I
I
Patient
Latency (ins)
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( wV)
1
36
30 85
0 0
427 584
38 35 40
60 22 40
0 48 0
369 288 222
38 32 35
40 26 52
11 0 0
308 23 I 200
15ms 7 ms I 6 ms
35 2 3 Excluded
II
4 5 6 7 Excluded 8 9 10
TEST STIM ALONE
i
I 2nrv 12ms
Fig. 6. Double stimulation experiment in a 55-year-old female patient with a cortical infarction. Clear inhibition of the test response is only present at 1S1of 30 and 60 ms.
The mean EMG activity was measured during the prestimulation period.
T % 100 90 -
80 70 60 -
40 30 20
10[
o~ o
10
20 ‘
30
SUBCORTICAL
40
50
60
70
ISI (ins)
+CORTICAL
Fig. 7, Time course of the interhemispheric inhibition (mean values and standard errors) for Patients with subcortical and cOmbined cOrtical-subcortical lesions.
STIM I
20ms Fig. 8. Rectified, averaged EMG of the FDI after focal magnetic stimulation of the ipsilateral motor cortex in a normal subject. There is a nearly complete inhibition of the ongoing EMG activity beginning at 35 ms after the stimulus. The bar at the bottom indicates the zero level of the EMG.
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B. Boroojerciiet al, /Journal qf’the Neurological Sciences 144 (1996) 160–170
STIM
I t
i f /,
‘1 ‘I(IJII i IIJ ‘~’ I 1 [ l.. ‘
1/
‘i
,l,!l; 11. 1
1(
//lj
II
‘1,4, / ++~.Jl.
Ei&INE
125uV 20ms
Fig. 9. A 52-year-old male with a dense right hemiplegia and a purely subcortical ischaemic lesion on CT, There is a strong inhibition of the rectified, averaged EMG of the left FDI after left motor cortex stimulation. The lesion does not extend into the centrum semiovale and spares the corpus callosum fibres.
t?. Boroojerdi et al. /Jourmd
of the Neurological Sciences 144 (1996) 160–170
contraction before each stimulus. Either the contraction came too late or it came too early and ended before the stimulus. Therefore the results from these two patients had to be excluded. In all patients, the EMG activity was suppressed to values between O and 4890 of the pre-stimuIUSbaseline. Fig. 9 shows a typical example. The onset latency of the inhibition ranged from 32 to 38 ms post stimulus. The results are summarized in Table 4. In 14 of the 16 patients with cortical-subcortical infarctions results of experiment II could be analyzed. In 4 patients, inhibition was lacking and in the remaining pa-
BASELINE
167
tients, inhibition ranged from 20to 8070(see Table 5). The onset latency of the inhibition ranged from 35 to 110 ms post stimulus. An example is given in Fig. 10. In addition to the patients with dense hemiplegia, we investigated 6 patients who initially displayed a severe paresis of the FDI, due to cortical cerebral infarctions, following by a nearly complete recovery. In this group we performed only investigation II. Both hemispheres were stimulated in patients 27, 28 and 29 and the responses of the ipsilateral FDI were recorded. In the remaining patients we only stimulated over the affected hemisphere. Table 6
—
IZoouv
20ms
Fig. 10. An 81-year-old female with a left hemiplegia. CT shows a cortical-subcortical cerebral infarction. There is no inhibition of the ongoing rectified, averaged EMG of the right FDI after the right motor cortex stimulation.
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B. Boroojerdi et al. /Journal of the Neurological Sciences 144 (1996) 160–170
Table 5 Onset latency, duration and the relative size of the ongoing EMG Inhibition in patients with cortical-subcortical lesions (Investigation II) Patient
Latency (ins)
11 53 12 No inhibition 13 No inhibition 14 57 15 110 16 No inhibition 17 35 18 37 19 Excluded 20 No inhibition 21 38.5 22 Excluded 23 40 44 24 25 57 26 38
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( wV)
57
45
222
24 26
55 78
155 400
74 83
45 33
177 222
4.1. Results obtained with double magnetic stimulation 28
0
38 41 34 24
45
100
20 47 24
667 566 550
615
Table 6 Onset latency, duration and the relative size of the ongoing EMG inhibition in patients with an initial dense paresis of one hand followed by a good recovery (Investigation II) Patient
Latency (ins)
Duration (ins)
Inhibition to % of prestimulus activity
Mean prestimulus EMG ( LLV)
27 L. FDI I-LFDI 28 L. FDI R. FD1 29 L. FDI R. FDI
43 43
43 55 49 49 35
o 0 0
769 693 692 385 538 384 538 769 246
30 31 32
30 30 35 46 34 31 38
the fibres of the corpus callosum are derived from a separate population of neurones and are not collaterals of the corticospinal tract fibres (Catsman-Berrevoetes et al., 198f)). If one considers transcallosal connections between both motor cortices to be functionally relevant, then one should expect a differential effect of lesions to both corticospinal and transcallosal fibres on the one side and of those lesions purely affecting corticospinal fibres on the other side. Such functional tests have been developed using magnetic brain stimulation and we have applied these tests to patients with cerebral vascular lesions of various location.
0
46 48 46
47 31 0 0 0 0
In patients 27, 28 and 29 we stimulated both hemispheres. All patients had lesions in their left motor cortex.
shows the results of this investigation. With one exception, there was a complete inhibition of the EMG in all patients with an onset latency of 30–43 ms.
4. Discussion The function of callosal connections between the motor cortex of each side has been extensively investigated in animal experiments (Curtis, 1940; Asanuma and Okamoto, 1959; Asanuma and Okuda, 1962; Berhtcchi, 1990). It is therefore surprising, that little is known about the importance of interhemispheric connections in human motor behaviour with the exception of observations after callosotomy (Sperry, 1974). Anatomically, it has been shown that
In the first experiment two magnetic stimulators were used to investigate the effect of a conditioning stimulus over the motor cortex of one hemisphere on the size of EMG responses of the first dorsal interosseal (FDI) muscle evoked by a magnetic test stimulus given over the opposite hemisphere. Similar experiments in normal subjects have shown that a single conditioning shock to one hemisphere could produce an inhibition of the test response evoked by the magnetic stimulation of the contralateral side, when the conditioning-test interval was between 6 and 30–60 ms (Ferbert et al., 1992). In the first group of our patients we investigated patients with pure subcortical cerebral lesions at the level of the basal ganglia, thakuntts, internal capsule or pens. The callosal pathways between the hemispheres were preserved and the corticospinal tract was affected below the centrum semiovale. Thus, subcortical lesions were not only subcortical in the strict sense of the word, but also excluded the centrum semiovale that contains transcallosal fibres. On this level a vascular lesion could destroy the corticospinal pathways without affecting the callosal fibres, which are already separated from the latter. In this group of patients, results comparable to the data in normal subjects were obtained. The transcranial conditioning magnetic stimulation over one hemisphere could inhibit the EMG responses evoked by the stimulation of the other hemisphere at inter-stimulus intervals of 7, 15, 30 and 60 ms. 4.2. Inhibition of the ipsilateral tonic EMG actiuity In the second experiment the effect of magnetic conditioning stimuli of the affected motor cortex on the ongoing voluntary EMG activity of the ipsilateral (non-paretic) FDI was investigated. It has been shown that in normal subjects the EMG response of the FDI could be inhibited by the transcranial magnetic stimulation of the ipsilateral motor cortex with an onset latency of 30–35 ms (i.e. 10–15 ms after the minimum corticomuscular conduction time to the muscle), lasting for about 30 ms (Ferbert et al., 1992). It was suggested by those authors that inhibition, produced by this method has a similar mechanism as inhibition
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produced by the above mentioned double stimulus technique. When we applied this technique to patients with pure subcortical cerebrovascular lesions below the centrum semiovale, we observed a preserved inhibition of the EMG activity with an onset latency of 32–38 ms which lasted for 22–85 ms. What are the explanations for the inhibition of the FDI by an ipsilateral transcranial magnetic stimulation? Since the excitability of alpha motoneurones, assessed by eliciting H-reflexes during the inhibition period shows no change, this ipsilateral inhibition acts at a level above the alpha motoneurones (Wassermann et al., 1991; Ferbert et al., 1992). Another argument, which favours a cortical level of inhibition is that a conditioning magnetic stimulus can not significantly suppress test responses evoked by low intensity anodal test stimuli. These stimuli most likely activate corticospinal fibres directly within the white matter (D-waves), whilst transcranial magnetic stimuli activate cortical interneurones (Hess et al., 1987; Day et al., 1989; Amassian et al., 1990; Burke et al., 1990; Edgley et al., 1990; Edgley et al., 1992; Kujirai et al., 1993). One could suggest an ipsilateral descending inhibition from the motor cortex to the FDI of the same side. This ipsilateral inhibitory projection should, as the corticospinal tract, be similarly affected by the subcortical cerebral lesions, unless this hypothetical projection travelled far from the corticospinal tract and remained unaffected by the lesion. However, if we consider a similar course for the two tracts, then one would not only expect paralysis of the opposite hand, but also loss of inhibition in the ipsilateral hand. Since this was not the case, a direct ipsilateral descending projection seems to be unlikely. The tract mediating the inhibition must run far from the lesion, most likely connected to the opposite hemisphere via the corpus callosum. Preliminary results suggest that there is apparently no inhibition of motor responses of one motor cortex after transcranial magnetic stimulation of the contralateral side in patients with an agenesis of the corpus callosum (Rothwell et al., 1991). This supports the suggestion of a transcallosal route of the described inhibition. Recently published investigations in patients with abnormalities of corpus callosum have shown that a transcranial magnetic stimulation over one motor cortex can suppress the tonic voluntary EMG activity in the ipsilateral FDI in patients with a preserved anterior part of the truncus corporis callosi. In patients with abnormalities in this part of the corpus callosum, the inhibition was delayed or even absent (Meyer et al., 1995). These results are supported by anatomical studies in rhesus monkey, which have shown that the transcallosal fibres from the primary motor cortex cross the midline at the second quarter of the truncus corporis callosi (Pandya and Seltzer, 1986). Although in monkeys the areas, which represent the distal parts of the limbs have only few transcallosal connections (Curtis, 1940; Killackey et al., 1983; Gould et al., 1986), our results suggest a prominent inhibitory link between these
169
areas in man. There are two possible explanations for this phenomenon: A relatively sparse callosal connection can result in a prominent inhibitory input or this inhibition can occur via an indirect transcallosal pathway. Interhemispheric connections below the level of the corpus callosum could be at least partly responsible for our results. These hypothetical pathways may have possibly been affected by the subcortical lesions mentioned above, and may well be responsible for the late part of the inhibition, i.e. with interstimuls intervals of 30 ms or more. 4.3. Interhemispheric inhibition in patients with an initially secere paresis of the FDI, followed by a nearly complete recovery In this group our results were again comparable with the data in normal subjects. We observed, with a single exception, a complete inhibition of the FDI after transcranial magnetic stimulation of the ipsilateral motorcortex. Since these patients all had a nearly complete recovery of their paresis, we assume that the transcallosal fibres were still intact and could transmit the inhibition. 4.4. Results in patients with cortical-subcorticul cerebrocuscular lesions A second group of patients with cortical-subcortical cerebrovascular lesions was investigated. In investigation I (double stimulation) an inhibition of the EMG response evoked by the test stimulation of the non-affected motor cortex, preceded by the conditioning stimulation of the contralateral (affected) side at inter-stimulus intervals of 7, 15 and 30 ms was observed. This inhibition was less pronounced than that observed in the first group of patients. In the second investigation (single stimulation) an inhibition was detected in some patients of this group with an onset latency of 35–1 10 ms post stimulus, lasting for 24–83 ms. In some patients the inhibition was lacking. In contrast to the clear results in patients with purely subcortical cerebral lesions, the data from patients with cortical-subcortical cerebral infarctions were less conclusive. One would expect a lack of transcallosal inhibition in these patients. Although these patients showed less inhibition of the test response at inter-stimulus intervals up to 30 ms, the later part of the inhibition was even more pronounced in some cases. A possible explanation for this unexpected result could be that all these patients had cortical-subcortical lesions of their motor cortex leading to a complete paralysis of the contralateral hand, irrespective of the exact site at which the corticospinal tract was affected. Thus, one could suppose that, at least in some patients, the subcortical extension of the cerebral infarction towards the internal capsule and not the cortical lesion itself was responsible for the hemiplegia. Such a lesion could leave the callosal pathways intact, leading to a preserved transcallosal inhibition of the contralateral motor
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cortex. Investigation of patients with purely cortical lesions (e.g. affecting only area 4) would verify this suggestion. 4.5. Possible mechanism underlying the corticocortical inhibition There are several reports of the inhibitory phenomena after a single cortical stimulation. Krnjevic et al. showed that a stimulus to the cortex of cats, rabbits or monkeys can reduce the excitability of the motor cortex for up to 300 ms. It has been suggested that this inhibitory effect is due to the activation of intracortical GABAergic interneurones, including basket cells (Krnjevic et al., 1966a; Krnjevic et al., 1966b; Krnjevic et al., 1966c; Krnjevic, 1983). If this is the case with the transcranial magnetic stimulation in man, this method will be a powerful and non-invasive tool for investigating GABAergic inhibitory systems of the human motor cortex. In conclusion, we have shown that the motor cortex, upstream to a hemispheric or brainstem lesion to the corticospinal tract, can have residual function even if its output through the corticospinal tract is completely destroyed. There is good evidence that this residual function acts on the opposite motor cortex through transcallosal fibres and can be assessed by transcranial magnetic stimulation. The extent to which interhemispheric connections are affected might be of importance for the recovery of hemiplegia.
Acknowledgements The authors are grateful to Dr. G. Brook (Technical university, Aachen) for reviewing the English version of the manuscript.
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