- Email: [email protected]
Effect of hemisphere-selective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity
;
,
..
,
.
rz
ELSEVIER
Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
o
Effect of hemisphere-selective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity Dirk Sander *, Bernd-U. Meyer, Simone R6richt, Jiirgen KlingelhiSfer Department of Neurology, Technical University of Munich, Mi~hlstrafle28, 81675 Munich, Germany Accepted for publication: 29 August 1994
Abstract
The changes of cerebral hemodynamics following repetitive hemisphere-selective magnetic stimulation over the motor cortex were investigated in 8 healthy volunteers. Bilateral simultaneous monitoring of middle cerebral artery blood flow velocity was done using transcranial Doppler ultrasonography during magnetic stimulation with single, double and triple stimuli with interstimulus intervals of 100 msec. Magnetic cortex stimulation was followed by a significant increase of ipsilateral flow velocity ranging from 5.3% + 2.7% for single stimuli up to 8.5% + 4.1% for triple stimuli and by a smaller increase of contralateral flow velocity. The ipsilateral increases are comparable to those measured previously during voluntary finger movements and indicate a physiological cortex stimulation. In parallel, the average sum of the baseline to peak hand motor response amplitudes increased from 1.5 + 0.7 mV (single stimuli) to 4.5 + 3.2 mV (triple stimuli). The increase of flow velocity in the non-stimulated hemisphere occurred during the absence of motor responses and might reflect a transcallosal activation of inhibitory neuronal structures. The occurrence of maximum velocity responses within 2-3 heartbeats following the first cortex stimulus points to a fast adjustment of cerebral perfusion in response to transcranial brain stimulation. No significant change of flow velocity was observed following motor responses evoked by unilateral magnetic stimulation of the brachial plexus or following acoustic artifacts of the coil discharge. Keywords: Magnetic cortex stimulation; Repetitive stimulation; Safety aspects; Middle cerebral artery blood flow velocity; Transcranial Doppler ultrasonography
1. Introduction
Transcranial magnetic brain stimulation over the sensorimotor cortex predominantly excites cortical motoneurons transsynaptically and thereby produces excitatory and inhibitory effects when the induced currents flow in a postero-anterior direction over the motor strip (Werhan et al. 1994). Inhibitory effects of cortex stimulation such as interhemispheric inhibition (Ferbert et al. 1992) and postexcitatory inhibition can be observed as silent periods during tonic electromyographic activity (Uncini et al. 1993) or as a reduced excitation effect of a test stimulus following a preceding conditioning stimulus. Excitatory effects are attributed to activation of Betz cells in the primary motor cortex with subsequent descending volleys of excita-
* Corresponding author. Tel.: 089/4140-4602.
tion being conducted along monosynaptic corticomotoneuronal fibers (Day et al. 1989). These effects can be quantified by measuring the size of cortically elicited electromyographic responses. A different approach towards quantification of neuronal activity during magnetic stimulation could probably be the estimation of cerebral perfusion in the middle cerebral artery (MCA) territory by transcranial Doppler ultrasonography (TCD). TCD is a proven method for detecting changes of cerebral perfusion within seconds (Aaslid et al. 1989; Conrad and Klingelhiffer 1989). Because of the close coupling between neuronal activity, brain metabolism (which mainly reflects synaptic activity) and blood flow (Kuschinsky 1991; Wise et al. 1991) following functional brain activity, the question arose whether similar changes of cerebral perfusion occurred following magnetic brain stimulation. Another important question is the assessment of the safety of magnetic brain stimulation. Especially with repetitive magnetic brain stimulation there might be some risk of eliciting epileptic fits (Pascual-Leone et al. 1993).
0924-980X/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0013 - 4694( 9 4 ) 0 0 2 4 7 - 9
EEM 94504
44
D. Sander et al. / Electroencephalography and clinicaI Neurophysiology 97 (1995) 43-48
Therefore it was the second aim of this study to investigate whether the changes of blood flow velocity following artificial transcranial activation of the motor cortex exceed those during physiological motor activity (Matzander et al. 1992) and thus indicate abnormal short-term cortex activation during stimulation. Mainly because of methodological limitations only a few investigations have so far addressed these topics. Studies using single photon emission tomography during magnetic stimulation found a slight increase of cerebral blood flow after magnetic brain stimulation (Shafran et al. 1989; Dressier et al. 1990); studies using positron emission tomography could not measure cerebral blood flow changes within the first 50 sec following stimulation and therefore failed to detect short-term changes (Hamano et al. 1993). Experiments on cats could not exclude a direct activation of the corticospinal tract, so these results could not be transferred to the conditions in human subjects (Eyre et al. 1990). A previous TCD investigation was only performed unilaterally and without concomitant measurement of blood pressure (Rossini et al. 1990). To approach both questions we chose continuous bilateral TCD monitoring of MCA blood flow velocities in combination with continuous recording of blood pressure, heart rate and end-expiratory PCO 2 to exclude non-specific cerebrovascular effects.
newick, USA) using a tightly wound circular coil with an angulated extension, a outer diameter of 8 cm, and 14 windings (for technical details of the coil see Cohen et al. 1990). The current pulse is a single "cosine" wave with a duration of 200 /zsec. The switching elements transfer up to 225 J per pulse which is equivalent to 71% of the intensity of the conventionally used Cadwell MES-10 stimulator. For stimulation of the motor cortex the coil was held flat on the scalp with the angulated edge of the coil placed approximatly over C3 according to the International 10-20 System, so that strictly contralateral hand motor responses occurred. Cortex stimulation was performed with 80-100% of the maximal output of the stimulator. Electromyographic recordings were taken from both first dorsal interosseous muscles using surface electrodes. Signals were amplified with a Toennies Myograph II with bandpass filtering between 20 Hz and 3000 Hz. Data were collected with a CED 1401 A / D converter (sampling frequency 3000 Hz/channel) and were analyzed offline using CED data collection programs.
TCD and additional measurements The intracranial blood flow patterns of both MCAs were continuously and simultaneously recorded with a
L Cortex8 0 % 2. Probands and methods Continuous monitoring of MCA flow velocity, blood pressure, heart rate and end-expiratory CO 2 was performed during transcranial magnetic stimulation over the left motor cortex with a focal pointed stimulation coil. Stimulation was done with single, double and triple magnetic 10-Hz stimuli given at intervals of 30 sec during a period of 5 min. Higher numbers of stimuli and shorter interstimulus intervals were not used to avoid the risk of eliciting epileptic fits (Dhuna et al. 1991). Stimulation was performed with suprathreshold stimuli so that at rest visible muscle twitches and electromyographic responses occurred in contralateral hand muscles. To exclude flow velocity changes due to acoustic input secondary to the acoustic artifact during discharge of the coil, measurements were also done during stimulation in front of the left ear. To exclude flow velocity changes due to afferents following the muscle twitch, stimulation of the right brachial plexus was additionally performed using stimulus intensities that produced hand motor responses of the same size as those following stimulation of the motor cortex. Experiments were done after obtaining informed consent in 8 healthy volunteers (age: 24-36 years, 4 males) lying comfortably on a bed.
Magnetic stimulation and electromyographic recording Magnetic stimulation was performed with the high speed Cadwell magnetic stimulator (Cadwell Laboratories, Ken-
RIDI ¸
(~
R ID
LID!
t
I
1 mV
Stimulus
50 ms
Fig. 1. Motor responses in small hand muscles (first interosseus dorsalis) following magnetic stimulation over the contralateral (left) motor cortex with single (right hand; upper trace) and double (right hand; middle trace) stimuli and interstimulus intervals of 100 msec. The two lower traces show motor responses for the contralateral (right) and ipsilateral (left) hand following triple stimulation. Cortex stimulation was performedwith 80% of the maximal stimulator output. For each condition 10 responses were averaged.
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
computer-assisted pulsed 2-Mhz Doppler device (DWL H~imodop, Sipplingen, Germany). After optimization of the Doppler signal of both MCAs, the probes were fixed mechanically with a specially developed probe holder. The analog-to-digital-converted envelope curves of the Doppler frequency spectrum (sampling frequency of 50 Hz) were processed on a personal computer. The mean flow velocity (MFV) was calculated from cardiac cycle to cardiac cycle on the basis of the original recording using a computer-assisted integration procedure. The end-expiratory CO 2 was measured with a capnometer (Normocap, Datex, Finland) and blood pressure was continuously monitored by finger pulse pressure measurements according to the Penaz methodology (Finapress, Ohmeda, USA) (Wessling et al. 1982; Boehmer 1987). In each subject the MFV and blood pressure curves were averaged according to the first cortex stimulus. The last 10 sec prior to the cortex stimulus were defined as the baseline value. The 20-sec interval following the stimulus was then related to the averaged baseline values (Fig. 2). Thus, in each volunteer a series of 10 time sweeps with a duration of 30 sec was averaged for each of the five experimental conditions.
Statistical analysis All values are given as mean _ standard deviation. The statistical analysis was carried out using one-way analysis of variance. When the overall F value indicated significant differences, a subsequent post hoc analysis was performed using the Scheff6 test for multiple comparisons. Comparisons between the the ipsi- and contralateral values were performed using the Wilcoxon signed rank test. A calculated difference of P < 0.05 was considered to be statistically significant.
45
Flow uelocity and blood pressure changes following motor cortex stimulation Ipsilateral to the stimulated left motor cortex a significant ( P < 0.001; ANOVA) increase of averaged MFV occurred which was 5.3% + 2.7% following single stimuli and 8.5% + 4.1% following triple stimulation (Figs. 2 and 3). Post hoc testing revealed significant differences from baseline values for double ( P < 0.04) and triple ( P < 0.005) stimulation. The ipsilateral percentage increase of the MFV was correlated with the average sum of the baseline to peak amplitude of the cortically elicited hand motor responses. The increase of the amplitude of the cortically elicited excitatory responses was paralleled by an increase of the MFV (Fig. 4). A smaller increase of Triple s t i m u l a t i o n
-6 > •>
I.I
Contralateral
0
~
0,9
I
,
1
.
.
.
"@ 1,1
.
Blood pressure
1.0
0,9
o
s
lo
15
20
Time [s]
Plexus s t i m u l a t i o n 1.1
Ipsilateral
3. Results ~,
1.0
0>
0.9
•>
1.1 ~
®
Cortically elicited motor responses The size of cortically elicited electromyographic responses in small hand muscles was measured as baseline to peak amplitude. This was done assuming that the initial negative component of the usually biphasic potential at least roughly correlates with the number of activated alpha motoneurons and thus indirectly also with the number of cortically activated excitatory motor cells. When single stimuli were given the average response size was 1.5 _+ 0.7 mV (n = 8 subjects, 10 responses in each subject). When pairs of stimuli with intervals of 100 msec were given the average sum of the response amplitudes was 2.4 _+ 2.3 mV. When three stimuli were given the average sum of response amplitudes was 4.5 + 3.2 mV. In comparison with the first response the relative amplitudes of the second and third response were on average 67% and 92%, respectively. Examples of averages of the motor responses obtained in one subject under different stimulation conditions are shown in Fig. 1.
0
Contralateral
1.0
8 0.9 -@ 1.1
~-
Blood pressure
1.0 O.9
o
5
lO
1'5
--
2'o
2's
3'o
Time [s] Fig. 2. Changes of mean flow velocity of the left (ipsilateral to stimulation) and right (contralateral) middle cerebral artery and blood pressure following transcranial focal stimulation of the left motor cortex with triple stimuli (upper trace) as well as stimulation(lower trace) of the right brachial plexus. Examples of findings in a 26-year-old male volunteer. The vertical line represents stimulus onset. The data were normalized based on the first 10 sec before stimulation. The curves show the averaged data from 10 sweeps. Stimulation conditions as in Fig. 1.
46
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43--48
15
12-
9-
M
6-
0
.c_
Single
Double
Triple
Acoustic
Plexus
Stimulation Ipsilateml
[
' I Contralateral
~
Blood pressure
Fig. 3. Average percentage increase (according to baseline values) of mean flow velocity of the left (ipsilateral to stimulation) and right (contralateral) middle cerebral artery and of the blood pressure following single, double, and triple stimulation of the left motor cortex for all volunteers (n = 8 subjects, 10 sweeps in each subject). As controls the findings following acoustic and plexus stimulation are shown. Stimulation conditions as in Fig. 1.
averaged MFV occurred in the contralateral hemisphere (Figs. 2 and 3) with significant differences from baseline levels only for triple stimulation ( P < 0.01; Scheff6 post hoc test; Fig. 3). However, no motor activity originated
14-
12
E 10
~o 8
| E
6-
m
4-
~,_
O-
~
i
i
i
i
"'1
0
1
2
3
4
5
Sum of
response amplitudes [mV]
Fig. 4. Correlationof the sum of the averaged baseline to peak amplitudes of fight-sided hand motor responses and the increase of the mean blood flow velocity in the left middle cerebral artery (mean values + standard deviation) following transcranial magnetic stimulation over the left motor cortex with single, double and triple stimuli given with intervals of 100 msec.
from this hemisphere during stimulation. In contrast, neither acoustic stimuli (acoustic artifact of the coil during discharge) nor plexus stimulation led to a significant increase of averaged MFV (Fig. 3). Following repetitive stimulation blood pressure increased slightly but without significant differences from baseline values (Figs. 2 and 3). Acoustic stimuli or stimulation of the brachial plexus did not dearly influence the blood pressure (Figs. 2 and 3). No significant differences for heart rate or PCO 2 were noticed during any of the experimental conditions. Following the magnetic cortex stimulus, 20% of the maximum flow velocity response was reached ipsilaterally after 1.4 + 0.4 sec and contralaterally after 1.8 + 0.6 sec (side difference, P < 0.001). The maximum flow velocity response was observed 3.2 ± 0.7 sec (ipsilateral) and 3.6 __+ 0.5 sec (contralateral, P < 0.05) following stimulus onset. The velocity values returned to the baseline within 7.5 + 1.0 see (ipsilateral hemisphere) and 7.6 + 1.1 sec (contralateral; not significant).
4. Discussion
The general finding of the study was that magnetic stimuli applied transcranially over the motor cortex of one hemisphere increased the flow velocity in the ipsilateral M C A and to a lesser degree in the contralateral MCA. The
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
ipsilateral MFV increase reached a maximum of 8.5% and thus did not exceed values measured during physiological cortex activation such as the performance of unilateral finger movements (Matzander et al. 1992). The ipsilateral flow velocity increase paralleled both the number of repetitive applied magnetic stimuli and the sum of the amplitudes of the excitatory hand motor responses. However, this finding does not exclude the possibility that the activation of inhibitory cortical elements contributed to the MFV increase since excitatory and inhibitory cortical mechanisms are usually activated simultaneously (Uncini et al. 1993). No evidence was found that beside cortex activation by magnetic stimulation afferent inputs resulting from muscle jerks or from acoustic artifacts during coil discharge had an influence on the flow velocity changes. Assuming a close coupling between neuronal activity, brain metabolism and cerebral blood flow (Paulson and Newman 1987; Kuschinsky 1991; Wise et al. 1991; Iadecola 1993), these findings indicate that the ipsilateral increase of the MCA flow velocity reflected the overall activation of excitatory and inhibitory neural cortical elements due to magnetic brain stimulation. It could be argued that TCD records flow velocity rather than cerebral blood flow. However, the relationship between blood flow velocity and blood flow within the large basal intracranial arteries is linear as long as alterations of the cerebral vascular bed are restricted to the small cortical resistance vessels. Recent reports indicate that the cross-sectional areas of the large intracranial arteries do not change during stepwise alterations of arterial blood pressure (Aaslid et al. 1989). Furthermore, autoregulatory changes in arterial diameter occur mainly in the small cortical resistance vessels, distal to the basal cerebral arteries (Kontos et al. 1978). Changes in MCA diameter do not invalidate the use of velocity measurements for the study of cerebral autoregulatory dynamics (Aaslid et al. 1991). Thus relative changes in flow velocity may directly reflect relative changes in cerebral blood flow (Lindegaard et al. 1987) and may be a reliable parameter for measuring the dynamics of cerebral perfusion changes during motor cortex stimulation. Moreover, a recent study comparing TCD and cerebral blood flow measurements showed that MCA flow velocity changes reflected changes in cerebral perfusion during muscle exercise (Jorgensen et al. 1992). The nearly constant blood pressure, heart rate and end-expiratory CO 2 concentration suggested that cardiovascular regulatory mechanisms do not influence the observed increases of MCA flow velocities. To the best of our knowledge this study for the first time combined simultaneous bilateral TCD monitoring of MCA flow velocities with repetitive magnetic brain stimulation. This experimental approach allows the study of MCA velocity changes within the non-stimulated hemisphere. In comparison with the stimulated side, the increase of cerebral perfusion was clearly smaller but nevertheless significant in the contralateral non-activated hemi-
47
sphere. Again, the flow velocity increase was similar to that observed during voluntary motor activity with the hand ipsilateral to the recorded hemisphere (Matzander et al. 1992). However, on the basis of our experiments it cannot be decided whether the mechanisms being activated during voluntary motor acts and during cortex stimulation are the same. While the flow velocity increase accompanying voluntary motor acts might, among other areas, in particular be due to an activation of ipsilateral supplementary motor areas (Zeffiro et al. 1990), hemisphere-selective magnetic stimulation over the primary motor cortex did not simultaneously activate the supplementary motor area. Since no electromyographic activity occurred ipsilateral to the stimulated hemisphere, it might be speculated that the flow velocity increase paralleled a transcallosal activation of neuronal structures in the opposite hemisphere with a net inhibitory effect on the motor cortical output. This can be assumed on the basis of recent findings that magnetic stimulation of the motor cortex on one side reduced the excitability of the opposite motor cortex and suppressed tonic electromyographic activity originating from this hemisphere. Both effects have been attributed to an interhemispheric transsynaptic inhibition conducted along callosal fibers (Ferbert et al. 1992; Meyer et al. 1994). In comparison with the hemisphere ipsilateral to stimulation, the contralateral maximum increase of flow velocity occurred 0.4 sec later. At first, this time difference seems too long to reflect the early inhibitory transcallosal effect with latencies of about only 10 msec. However, due to the averaging technique used, the minimum time resolution to detect significant MFV changes was in the range of 0.2-0.4 sec. Based on the present findings it is therefore not possible to ascertain whether the observed contralateral MFV increase was due to the early transcallosal inhibition or, for example, reflects a late rise of cortical excitability as it can be observed during tonic EMG activity about 0.1-0.2 sec following the onset of transcallosal inhibition. Compared with other techniques currently used in the measurement of regional cerebral hemodynamics, TCD provides a real-time resolution and makes it possible to detect fast and short-lasting changes of cerebral perfusion. Following magnetic stimulation the maximal velocity increases were reached after only 3.2 sec (ipilateral MCA) and 3.6 sec (contralateral MCA). This fast velocity response is similar to that following visual (Conrad and KlingelhiAfer 1989) and cognitive (Markus and Boland 1992) activation and indicates a rapid regulatory response with a fast adjustment of cerebral perfusion to altered metabolic requirements (Paulson and Newman 1987; Iadecola 1993). With regard to the safety of the diagnostic application of transcranial magnetic brain stimulation it was found that cerebral blood flow velocity changes following a short series of magnetic brain stimuli were within the range observed during physiological motor acts and thus did not point to any dangerous excessive motor cortex excitation.
48
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
Acknowledgment Supported by the Bundesministerium fiir Forschung und Technologic, 01KL9001M and by the Frrderverein der Neurologischen Klinik.
References Aaslid, R., Lindegaard, K.F., Sorteberg, W. and Nornes, H. Cerebral autoregulation dynamics in humans. Stroke, 1989, 20: 45-52. Aaslid, R,, Newell, D.W., Stooss, R., Sorteberg, W. and Lindegaard, K.F. Assessment of cerebral autoregnlation dynamics from simultaneous arterial and venous transcranial Doppler recordings in humans. Stroke, 1991, 22: 1148-1154. Boehmer, R.D. Continuous, real-time, noninvasive monitor of blood pressure: Penaz methodology applied to the finger. J. Clin. Monit., 1987, 3: 282-287. Cohen, L.G., Roth, B.J., Nilsson, J., Dang, N., Panizza, M., Bandinelli, S., Friauf, W. and Hallett, M. Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroenceph. clin. Neurophysiol., 1990, 75: 350-357. Conrad, B. and Klingelhi~fer, J. Dynamics of regional cerebral blood flow for various stimuli. Exp Brain Res., 1989, 77: 437-441. Day, B.L., Dressier, D., Maertens de Noordhout, A., Marsden, C.D., Nakashima, K., Rothwell, J.C. and Thompson, P.D. Electric and magnetic stimulation of the human motor cortex: surface EMG and single motor unit responses. J. Physiol. (London), 1989, 412: 449-473. Dhuna, A., Gates, J. and Pascual-Leone, A. Transcranial magnetic stimulation in patients with epilepsy. Neurology, 1991, 41: 1067-1971. Dressier, D., Voth, E., Feldmann, M. and Benecke, R. Safety aspects of transcranial brain stimulation in man tested by single photon emission tomography. Neurosci. Lett., 1990, 119: 153-155. Eyre, J.A., Flecknell, P.A., Kenyon, B.R., Koh, T.H.H.G. and Miller, S. Acute effects of electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate in the cat: an evaluation of safety. J. Neurol. Neurosurg. Psychiatry, 1990, 53: 507-513. Ferbert, A., Priori, A., Rothwell, J.C., Day, B.L., Colebatch, J.G. and Marsden, C.D. Interhemispheric inhibition of the human motor cortex. J. Physiol. (London), 1992, 453: 525-546. Hamano, T., Kaji, R., Fukuyama, H., Sadato, N. and Kimura, J. Lack of prolonged cerebral blood flow change after transcranial magnetic stimulation. Electroenceph. clin. Neurophysiol., 1993, 89: 207-210. Iadecola, C. Regulation of the cerebral microcirculation during neuronal activity: is nitric oxide the missing link? Trends Neurosci., 1993, 16: 206-214. Jorgensen, L.G., Perko, M., Hanel, B., Schroeder, T.V. and Secher, N.H. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J. Appl. Physiol., 1992, 72: 11231132. Kontos, H.A., Wei, E.P., Navari, R.M., Levasseur, J.E., Rosenblum, W.I.
and Patterson, J.L. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am. J. Physiol., 1978, 234: H371-H383. Kuschinsky, W. Coupling of function, metabolism, and blood flow in the brain. Neurosurg. Rev., 1991, 14: 163-168. Lindegaard, K.F., Lunder, T., Wiberg, J., Sjoberg, D., Aaslid, R. and Nomes, H. Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements. Stroke, 1987, 18: 1025-1030. Markus, H.S., Boland, M. "Cognitive activity" monitored by noninvasive measurement of cerebral blood flow velocity and its application to the investigation of cerebral dominance. Cortex, 1992, 28: 575-581. Matzander, G., Klingelhrfer, J., Wittich, I., Sander, D. and Conrad, B. Effect of different hemisphere-specific brain activities on hemodynamics in the middle cerebral artery territory. J. Neurol., 1992, 237 (Suppl. 3): $28. Meyer, B.-U., Rrricht, S. and Einsiedel, H. Interhemispheric inhibition and excitability of corticospinal tracts in patients with agenesis of the corpus callosum: a study with focal transcranial magnetic stimulation of the motor cortex. J. Neurol., 1994, 241: 274. Pascual-Leone, A., Houser, C.M., Reese, K., Shotland, L.I., Grafmann, J., Sato, S., Vails-Sole, J., Brasil-Neto, J.P., Wasserman, E.M., Cohen, L.G. and Hallet, M. Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroenceph. clin. Neurophysiol., 1993, 89: 120-130. Paulson, O.B. and Newman, E.A. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science, 1987, 237: 896-898. Rossini, P.M., Silvestrini, M., Zarola, F., Caramia, M.D., Mariorenzi, R., Traversa, R., Martino, G., Baggio, C. and Bolcino, G. Effects of non-invasive magnetic brain stimulation on transcranial Doppler and computerized EEG. Electroenceph. clin. Neurophysiol., 1990, 75: S130. Shafran, B., Maccabee, P.J., Amassian, V.E., Cracco, R.Q., Strashun, A., Vaquer, R. and Singman, R. Spectamine imaging of cerebral blood flow during voluntary movement and focal stimulation of motor cortex with magnetic coil. Soc. Neurosci. Abstr., 1989, 15: 789. Uncini, A., Treviso, M., Di Muzio, A., Simone, P. and Pullman, S. Physiological basis of voluntary activity inhibition induced by transcranial cortical stimulation. Elcctroenceph. clin. Neurophysiol., 1993, 89: 211-220. Werhan, K.J., Fong, J.K.Y., Meyer, B.-U., Priori, A., Rothwell, J.C., Day, B.L. and Thompson, P.D. The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseus muscle. Electroenceph. clin. Neurophysiol., 1994, 93: 138-146. Wesseling, K.H., de Witt, B., Settels, J.J. and Klawer, W.H. On the indirect registration of finger blood pressure after Penaz. Funkt. Biol. Med., 1982, 1: 245-250. Wise, R., Chollet, F., Hadar, U., Friston, K., Hoffuer, E. and Frackowiak, R. Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain, 1991, 114: 1803-1817. Zeffiro, T., Leiderman, D., Bierner, S., Dubinsky, R. and Hallett, M. Regional cerebral blood flow changes in cortical motor areas during unilateral wrist movement. Mov. Disord., 1990, 5: 19P.
,
..
,
.
rz
ELSEVIER
Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
o
Effect of hemisphere-selective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity Dirk Sander *, Bernd-U. Meyer, Simone R6richt, Jiirgen KlingelhiSfer Department of Neurology, Technical University of Munich, Mi~hlstrafle28, 81675 Munich, Germany Accepted for publication: 29 August 1994
Abstract
The changes of cerebral hemodynamics following repetitive hemisphere-selective magnetic stimulation over the motor cortex were investigated in 8 healthy volunteers. Bilateral simultaneous monitoring of middle cerebral artery blood flow velocity was done using transcranial Doppler ultrasonography during magnetic stimulation with single, double and triple stimuli with interstimulus intervals of 100 msec. Magnetic cortex stimulation was followed by a significant increase of ipsilateral flow velocity ranging from 5.3% + 2.7% for single stimuli up to 8.5% + 4.1% for triple stimuli and by a smaller increase of contralateral flow velocity. The ipsilateral increases are comparable to those measured previously during voluntary finger movements and indicate a physiological cortex stimulation. In parallel, the average sum of the baseline to peak hand motor response amplitudes increased from 1.5 + 0.7 mV (single stimuli) to 4.5 + 3.2 mV (triple stimuli). The increase of flow velocity in the non-stimulated hemisphere occurred during the absence of motor responses and might reflect a transcallosal activation of inhibitory neuronal structures. The occurrence of maximum velocity responses within 2-3 heartbeats following the first cortex stimulus points to a fast adjustment of cerebral perfusion in response to transcranial brain stimulation. No significant change of flow velocity was observed following motor responses evoked by unilateral magnetic stimulation of the brachial plexus or following acoustic artifacts of the coil discharge. Keywords: Magnetic cortex stimulation; Repetitive stimulation; Safety aspects; Middle cerebral artery blood flow velocity; Transcranial Doppler ultrasonography
1. Introduction
Transcranial magnetic brain stimulation over the sensorimotor cortex predominantly excites cortical motoneurons transsynaptically and thereby produces excitatory and inhibitory effects when the induced currents flow in a postero-anterior direction over the motor strip (Werhan et al. 1994). Inhibitory effects of cortex stimulation such as interhemispheric inhibition (Ferbert et al. 1992) and postexcitatory inhibition can be observed as silent periods during tonic electromyographic activity (Uncini et al. 1993) or as a reduced excitation effect of a test stimulus following a preceding conditioning stimulus. Excitatory effects are attributed to activation of Betz cells in the primary motor cortex with subsequent descending volleys of excita-
* Corresponding author. Tel.: 089/4140-4602.
tion being conducted along monosynaptic corticomotoneuronal fibers (Day et al. 1989). These effects can be quantified by measuring the size of cortically elicited electromyographic responses. A different approach towards quantification of neuronal activity during magnetic stimulation could probably be the estimation of cerebral perfusion in the middle cerebral artery (MCA) territory by transcranial Doppler ultrasonography (TCD). TCD is a proven method for detecting changes of cerebral perfusion within seconds (Aaslid et al. 1989; Conrad and Klingelhiffer 1989). Because of the close coupling between neuronal activity, brain metabolism (which mainly reflects synaptic activity) and blood flow (Kuschinsky 1991; Wise et al. 1991) following functional brain activity, the question arose whether similar changes of cerebral perfusion occurred following magnetic brain stimulation. Another important question is the assessment of the safety of magnetic brain stimulation. Especially with repetitive magnetic brain stimulation there might be some risk of eliciting epileptic fits (Pascual-Leone et al. 1993).
0924-980X/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0013 - 4694( 9 4 ) 0 0 2 4 7 - 9
EEM 94504
44
D. Sander et al. / Electroencephalography and clinicaI Neurophysiology 97 (1995) 43-48
Therefore it was the second aim of this study to investigate whether the changes of blood flow velocity following artificial transcranial activation of the motor cortex exceed those during physiological motor activity (Matzander et al. 1992) and thus indicate abnormal short-term cortex activation during stimulation. Mainly because of methodological limitations only a few investigations have so far addressed these topics. Studies using single photon emission tomography during magnetic stimulation found a slight increase of cerebral blood flow after magnetic brain stimulation (Shafran et al. 1989; Dressier et al. 1990); studies using positron emission tomography could not measure cerebral blood flow changes within the first 50 sec following stimulation and therefore failed to detect short-term changes (Hamano et al. 1993). Experiments on cats could not exclude a direct activation of the corticospinal tract, so these results could not be transferred to the conditions in human subjects (Eyre et al. 1990). A previous TCD investigation was only performed unilaterally and without concomitant measurement of blood pressure (Rossini et al. 1990). To approach both questions we chose continuous bilateral TCD monitoring of MCA blood flow velocities in combination with continuous recording of blood pressure, heart rate and end-expiratory PCO 2 to exclude non-specific cerebrovascular effects.
newick, USA) using a tightly wound circular coil with an angulated extension, a outer diameter of 8 cm, and 14 windings (for technical details of the coil see Cohen et al. 1990). The current pulse is a single "cosine" wave with a duration of 200 /zsec. The switching elements transfer up to 225 J per pulse which is equivalent to 71% of the intensity of the conventionally used Cadwell MES-10 stimulator. For stimulation of the motor cortex the coil was held flat on the scalp with the angulated edge of the coil placed approximatly over C3 according to the International 10-20 System, so that strictly contralateral hand motor responses occurred. Cortex stimulation was performed with 80-100% of the maximal output of the stimulator. Electromyographic recordings were taken from both first dorsal interosseous muscles using surface electrodes. Signals were amplified with a Toennies Myograph II with bandpass filtering between 20 Hz and 3000 Hz. Data were collected with a CED 1401 A / D converter (sampling frequency 3000 Hz/channel) and were analyzed offline using CED data collection programs.
TCD and additional measurements The intracranial blood flow patterns of both MCAs were continuously and simultaneously recorded with a
L Cortex8 0 % 2. Probands and methods Continuous monitoring of MCA flow velocity, blood pressure, heart rate and end-expiratory CO 2 was performed during transcranial magnetic stimulation over the left motor cortex with a focal pointed stimulation coil. Stimulation was done with single, double and triple magnetic 10-Hz stimuli given at intervals of 30 sec during a period of 5 min. Higher numbers of stimuli and shorter interstimulus intervals were not used to avoid the risk of eliciting epileptic fits (Dhuna et al. 1991). Stimulation was performed with suprathreshold stimuli so that at rest visible muscle twitches and electromyographic responses occurred in contralateral hand muscles. To exclude flow velocity changes due to acoustic input secondary to the acoustic artifact during discharge of the coil, measurements were also done during stimulation in front of the left ear. To exclude flow velocity changes due to afferents following the muscle twitch, stimulation of the right brachial plexus was additionally performed using stimulus intensities that produced hand motor responses of the same size as those following stimulation of the motor cortex. Experiments were done after obtaining informed consent in 8 healthy volunteers (age: 24-36 years, 4 males) lying comfortably on a bed.
Magnetic stimulation and electromyographic recording Magnetic stimulation was performed with the high speed Cadwell magnetic stimulator (Cadwell Laboratories, Ken-
RIDI ¸
(~
R ID
LID!
t
I
1 mV
Stimulus
50 ms
Fig. 1. Motor responses in small hand muscles (first interosseus dorsalis) following magnetic stimulation over the contralateral (left) motor cortex with single (right hand; upper trace) and double (right hand; middle trace) stimuli and interstimulus intervals of 100 msec. The two lower traces show motor responses for the contralateral (right) and ipsilateral (left) hand following triple stimulation. Cortex stimulation was performedwith 80% of the maximal stimulator output. For each condition 10 responses were averaged.
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
computer-assisted pulsed 2-Mhz Doppler device (DWL H~imodop, Sipplingen, Germany). After optimization of the Doppler signal of both MCAs, the probes were fixed mechanically with a specially developed probe holder. The analog-to-digital-converted envelope curves of the Doppler frequency spectrum (sampling frequency of 50 Hz) were processed on a personal computer. The mean flow velocity (MFV) was calculated from cardiac cycle to cardiac cycle on the basis of the original recording using a computer-assisted integration procedure. The end-expiratory CO 2 was measured with a capnometer (Normocap, Datex, Finland) and blood pressure was continuously monitored by finger pulse pressure measurements according to the Penaz methodology (Finapress, Ohmeda, USA) (Wessling et al. 1982; Boehmer 1987). In each subject the MFV and blood pressure curves were averaged according to the first cortex stimulus. The last 10 sec prior to the cortex stimulus were defined as the baseline value. The 20-sec interval following the stimulus was then related to the averaged baseline values (Fig. 2). Thus, in each volunteer a series of 10 time sweeps with a duration of 30 sec was averaged for each of the five experimental conditions.
Statistical analysis All values are given as mean _ standard deviation. The statistical analysis was carried out using one-way analysis of variance. When the overall F value indicated significant differences, a subsequent post hoc analysis was performed using the Scheff6 test for multiple comparisons. Comparisons between the the ipsi- and contralateral values were performed using the Wilcoxon signed rank test. A calculated difference of P < 0.05 was considered to be statistically significant.
45
Flow uelocity and blood pressure changes following motor cortex stimulation Ipsilateral to the stimulated left motor cortex a significant ( P < 0.001; ANOVA) increase of averaged MFV occurred which was 5.3% + 2.7% following single stimuli and 8.5% + 4.1% following triple stimulation (Figs. 2 and 3). Post hoc testing revealed significant differences from baseline values for double ( P < 0.04) and triple ( P < 0.005) stimulation. The ipsilateral percentage increase of the MFV was correlated with the average sum of the baseline to peak amplitude of the cortically elicited hand motor responses. The increase of the amplitude of the cortically elicited excitatory responses was paralleled by an increase of the MFV (Fig. 4). A smaller increase of Triple s t i m u l a t i o n
-6 > •>
I.I
Contralateral
0
~
0,9
I
,
1
.
.
.
"@ 1,1
.
Blood pressure
1.0
0,9
o
s
lo
15
20
Time [s]
Plexus s t i m u l a t i o n 1.1
Ipsilateral
3. Results ~,
1.0
0>
0.9
•>
1.1 ~
®
Cortically elicited motor responses The size of cortically elicited electromyographic responses in small hand muscles was measured as baseline to peak amplitude. This was done assuming that the initial negative component of the usually biphasic potential at least roughly correlates with the number of activated alpha motoneurons and thus indirectly also with the number of cortically activated excitatory motor cells. When single stimuli were given the average response size was 1.5 _+ 0.7 mV (n = 8 subjects, 10 responses in each subject). When pairs of stimuli with intervals of 100 msec were given the average sum of the response amplitudes was 2.4 _+ 2.3 mV. When three stimuli were given the average sum of response amplitudes was 4.5 + 3.2 mV. In comparison with the first response the relative amplitudes of the second and third response were on average 67% and 92%, respectively. Examples of averages of the motor responses obtained in one subject under different stimulation conditions are shown in Fig. 1.
0
Contralateral
1.0
8 0.9 -@ 1.1
~-
Blood pressure
1.0 O.9
o
5
lO
1'5
--
2'o
2's
3'o
Time [s] Fig. 2. Changes of mean flow velocity of the left (ipsilateral to stimulation) and right (contralateral) middle cerebral artery and blood pressure following transcranial focal stimulation of the left motor cortex with triple stimuli (upper trace) as well as stimulation(lower trace) of the right brachial plexus. Examples of findings in a 26-year-old male volunteer. The vertical line represents stimulus onset. The data were normalized based on the first 10 sec before stimulation. The curves show the averaged data from 10 sweeps. Stimulation conditions as in Fig. 1.
46
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43--48
15
12-
9-
M
6-
0
.c_
Single
Double
Triple
Acoustic
Plexus
Stimulation Ipsilateml
[
' I Contralateral
~
Blood pressure
Fig. 3. Average percentage increase (according to baseline values) of mean flow velocity of the left (ipsilateral to stimulation) and right (contralateral) middle cerebral artery and of the blood pressure following single, double, and triple stimulation of the left motor cortex for all volunteers (n = 8 subjects, 10 sweeps in each subject). As controls the findings following acoustic and plexus stimulation are shown. Stimulation conditions as in Fig. 1.
averaged MFV occurred in the contralateral hemisphere (Figs. 2 and 3) with significant differences from baseline levels only for triple stimulation ( P < 0.01; Scheff6 post hoc test; Fig. 3). However, no motor activity originated
14-
12
E 10
~o 8
| E
6-
m
4-
~,_
O-
~
i
i
i
i
"'1
0
1
2
3
4
5
Sum of
response amplitudes [mV]
Fig. 4. Correlationof the sum of the averaged baseline to peak amplitudes of fight-sided hand motor responses and the increase of the mean blood flow velocity in the left middle cerebral artery (mean values + standard deviation) following transcranial magnetic stimulation over the left motor cortex with single, double and triple stimuli given with intervals of 100 msec.
from this hemisphere during stimulation. In contrast, neither acoustic stimuli (acoustic artifact of the coil during discharge) nor plexus stimulation led to a significant increase of averaged MFV (Fig. 3). Following repetitive stimulation blood pressure increased slightly but without significant differences from baseline values (Figs. 2 and 3). Acoustic stimuli or stimulation of the brachial plexus did not dearly influence the blood pressure (Figs. 2 and 3). No significant differences for heart rate or PCO 2 were noticed during any of the experimental conditions. Following the magnetic cortex stimulus, 20% of the maximum flow velocity response was reached ipsilaterally after 1.4 + 0.4 sec and contralaterally after 1.8 + 0.6 sec (side difference, P < 0.001). The maximum flow velocity response was observed 3.2 ± 0.7 sec (ipsilateral) and 3.6 __+ 0.5 sec (contralateral, P < 0.05) following stimulus onset. The velocity values returned to the baseline within 7.5 + 1.0 see (ipsilateral hemisphere) and 7.6 + 1.1 sec (contralateral; not significant).
4. Discussion
The general finding of the study was that magnetic stimuli applied transcranially over the motor cortex of one hemisphere increased the flow velocity in the ipsilateral M C A and to a lesser degree in the contralateral MCA. The
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
ipsilateral MFV increase reached a maximum of 8.5% and thus did not exceed values measured during physiological cortex activation such as the performance of unilateral finger movements (Matzander et al. 1992). The ipsilateral flow velocity increase paralleled both the number of repetitive applied magnetic stimuli and the sum of the amplitudes of the excitatory hand motor responses. However, this finding does not exclude the possibility that the activation of inhibitory cortical elements contributed to the MFV increase since excitatory and inhibitory cortical mechanisms are usually activated simultaneously (Uncini et al. 1993). No evidence was found that beside cortex activation by magnetic stimulation afferent inputs resulting from muscle jerks or from acoustic artifacts during coil discharge had an influence on the flow velocity changes. Assuming a close coupling between neuronal activity, brain metabolism and cerebral blood flow (Paulson and Newman 1987; Kuschinsky 1991; Wise et al. 1991; Iadecola 1993), these findings indicate that the ipsilateral increase of the MCA flow velocity reflected the overall activation of excitatory and inhibitory neural cortical elements due to magnetic brain stimulation. It could be argued that TCD records flow velocity rather than cerebral blood flow. However, the relationship between blood flow velocity and blood flow within the large basal intracranial arteries is linear as long as alterations of the cerebral vascular bed are restricted to the small cortical resistance vessels. Recent reports indicate that the cross-sectional areas of the large intracranial arteries do not change during stepwise alterations of arterial blood pressure (Aaslid et al. 1989). Furthermore, autoregulatory changes in arterial diameter occur mainly in the small cortical resistance vessels, distal to the basal cerebral arteries (Kontos et al. 1978). Changes in MCA diameter do not invalidate the use of velocity measurements for the study of cerebral autoregulatory dynamics (Aaslid et al. 1991). Thus relative changes in flow velocity may directly reflect relative changes in cerebral blood flow (Lindegaard et al. 1987) and may be a reliable parameter for measuring the dynamics of cerebral perfusion changes during motor cortex stimulation. Moreover, a recent study comparing TCD and cerebral blood flow measurements showed that MCA flow velocity changes reflected changes in cerebral perfusion during muscle exercise (Jorgensen et al. 1992). The nearly constant blood pressure, heart rate and end-expiratory CO 2 concentration suggested that cardiovascular regulatory mechanisms do not influence the observed increases of MCA flow velocities. To the best of our knowledge this study for the first time combined simultaneous bilateral TCD monitoring of MCA flow velocities with repetitive magnetic brain stimulation. This experimental approach allows the study of MCA velocity changes within the non-stimulated hemisphere. In comparison with the stimulated side, the increase of cerebral perfusion was clearly smaller but nevertheless significant in the contralateral non-activated hemi-
47
sphere. Again, the flow velocity increase was similar to that observed during voluntary motor activity with the hand ipsilateral to the recorded hemisphere (Matzander et al. 1992). However, on the basis of our experiments it cannot be decided whether the mechanisms being activated during voluntary motor acts and during cortex stimulation are the same. While the flow velocity increase accompanying voluntary motor acts might, among other areas, in particular be due to an activation of ipsilateral supplementary motor areas (Zeffiro et al. 1990), hemisphere-selective magnetic stimulation over the primary motor cortex did not simultaneously activate the supplementary motor area. Since no electromyographic activity occurred ipsilateral to the stimulated hemisphere, it might be speculated that the flow velocity increase paralleled a transcallosal activation of neuronal structures in the opposite hemisphere with a net inhibitory effect on the motor cortical output. This can be assumed on the basis of recent findings that magnetic stimulation of the motor cortex on one side reduced the excitability of the opposite motor cortex and suppressed tonic electromyographic activity originating from this hemisphere. Both effects have been attributed to an interhemispheric transsynaptic inhibition conducted along callosal fibers (Ferbert et al. 1992; Meyer et al. 1994). In comparison with the hemisphere ipsilateral to stimulation, the contralateral maximum increase of flow velocity occurred 0.4 sec later. At first, this time difference seems too long to reflect the early inhibitory transcallosal effect with latencies of about only 10 msec. However, due to the averaging technique used, the minimum time resolution to detect significant MFV changes was in the range of 0.2-0.4 sec. Based on the present findings it is therefore not possible to ascertain whether the observed contralateral MFV increase was due to the early transcallosal inhibition or, for example, reflects a late rise of cortical excitability as it can be observed during tonic EMG activity about 0.1-0.2 sec following the onset of transcallosal inhibition. Compared with other techniques currently used in the measurement of regional cerebral hemodynamics, TCD provides a real-time resolution and makes it possible to detect fast and short-lasting changes of cerebral perfusion. Following magnetic stimulation the maximal velocity increases were reached after only 3.2 sec (ipilateral MCA) and 3.6 sec (contralateral MCA). This fast velocity response is similar to that following visual (Conrad and KlingelhiAfer 1989) and cognitive (Markus and Boland 1992) activation and indicates a rapid regulatory response with a fast adjustment of cerebral perfusion to altered metabolic requirements (Paulson and Newman 1987; Iadecola 1993). With regard to the safety of the diagnostic application of transcranial magnetic brain stimulation it was found that cerebral blood flow velocity changes following a short series of magnetic brain stimuli were within the range observed during physiological motor acts and thus did not point to any dangerous excessive motor cortex excitation.
48
D. Sander et al. / Electroencephalography and clinical Neurophysiology 97 (1995) 43-48
Acknowledgment Supported by the Bundesministerium fiir Forschung und Technologic, 01KL9001M and by the Frrderverein der Neurologischen Klinik.
References Aaslid, R., Lindegaard, K.F., Sorteberg, W. and Nornes, H. Cerebral autoregulation dynamics in humans. Stroke, 1989, 20: 45-52. Aaslid, R,, Newell, D.W., Stooss, R., Sorteberg, W. and Lindegaard, K.F. Assessment of cerebral autoregnlation dynamics from simultaneous arterial and venous transcranial Doppler recordings in humans. Stroke, 1991, 22: 1148-1154. Boehmer, R.D. Continuous, real-time, noninvasive monitor of blood pressure: Penaz methodology applied to the finger. J. Clin. Monit., 1987, 3: 282-287. Cohen, L.G., Roth, B.J., Nilsson, J., Dang, N., Panizza, M., Bandinelli, S., Friauf, W. and Hallett, M. Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroenceph. clin. Neurophysiol., 1990, 75: 350-357. Conrad, B. and Klingelhi~fer, J. Dynamics of regional cerebral blood flow for various stimuli. Exp Brain Res., 1989, 77: 437-441. Day, B.L., Dressier, D., Maertens de Noordhout, A., Marsden, C.D., Nakashima, K., Rothwell, J.C. and Thompson, P.D. Electric and magnetic stimulation of the human motor cortex: surface EMG and single motor unit responses. J. Physiol. (London), 1989, 412: 449-473. Dhuna, A., Gates, J. and Pascual-Leone, A. Transcranial magnetic stimulation in patients with epilepsy. Neurology, 1991, 41: 1067-1971. Dressier, D., Voth, E., Feldmann, M. and Benecke, R. Safety aspects of transcranial brain stimulation in man tested by single photon emission tomography. Neurosci. Lett., 1990, 119: 153-155. Eyre, J.A., Flecknell, P.A., Kenyon, B.R., Koh, T.H.H.G. and Miller, S. Acute effects of electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate in the cat: an evaluation of safety. J. Neurol. Neurosurg. Psychiatry, 1990, 53: 507-513. Ferbert, A., Priori, A., Rothwell, J.C., Day, B.L., Colebatch, J.G. and Marsden, C.D. Interhemispheric inhibition of the human motor cortex. J. Physiol. (London), 1992, 453: 525-546. Hamano, T., Kaji, R., Fukuyama, H., Sadato, N. and Kimura, J. Lack of prolonged cerebral blood flow change after transcranial magnetic stimulation. Electroenceph. clin. Neurophysiol., 1993, 89: 207-210. Iadecola, C. Regulation of the cerebral microcirculation during neuronal activity: is nitric oxide the missing link? Trends Neurosci., 1993, 16: 206-214. Jorgensen, L.G., Perko, M., Hanel, B., Schroeder, T.V. and Secher, N.H. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J. Appl. Physiol., 1992, 72: 11231132. Kontos, H.A., Wei, E.P., Navari, R.M., Levasseur, J.E., Rosenblum, W.I.
and Patterson, J.L. Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am. J. Physiol., 1978, 234: H371-H383. Kuschinsky, W. Coupling of function, metabolism, and blood flow in the brain. Neurosurg. Rev., 1991, 14: 163-168. Lindegaard, K.F., Lunder, T., Wiberg, J., Sjoberg, D., Aaslid, R. and Nomes, H. Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements. Stroke, 1987, 18: 1025-1030. Markus, H.S., Boland, M. "Cognitive activity" monitored by noninvasive measurement of cerebral blood flow velocity and its application to the investigation of cerebral dominance. Cortex, 1992, 28: 575-581. Matzander, G., Klingelhrfer, J., Wittich, I., Sander, D. and Conrad, B. Effect of different hemisphere-specific brain activities on hemodynamics in the middle cerebral artery territory. J. Neurol., 1992, 237 (Suppl. 3): $28. Meyer, B.-U., Rrricht, S. and Einsiedel, H. Interhemispheric inhibition and excitability of corticospinal tracts in patients with agenesis of the corpus callosum: a study with focal transcranial magnetic stimulation of the motor cortex. J. Neurol., 1994, 241: 274. Pascual-Leone, A., Houser, C.M., Reese, K., Shotland, L.I., Grafmann, J., Sato, S., Vails-Sole, J., Brasil-Neto, J.P., Wasserman, E.M., Cohen, L.G. and Hallet, M. Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroenceph. clin. Neurophysiol., 1993, 89: 120-130. Paulson, O.B. and Newman, E.A. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science, 1987, 237: 896-898. Rossini, P.M., Silvestrini, M., Zarola, F., Caramia, M.D., Mariorenzi, R., Traversa, R., Martino, G., Baggio, C. and Bolcino, G. Effects of non-invasive magnetic brain stimulation on transcranial Doppler and computerized EEG. Electroenceph. clin. Neurophysiol., 1990, 75: S130. Shafran, B., Maccabee, P.J., Amassian, V.E., Cracco, R.Q., Strashun, A., Vaquer, R. and Singman, R. Spectamine imaging of cerebral blood flow during voluntary movement and focal stimulation of motor cortex with magnetic coil. Soc. Neurosci. Abstr., 1989, 15: 789. Uncini, A., Treviso, M., Di Muzio, A., Simone, P. and Pullman, S. Physiological basis of voluntary activity inhibition induced by transcranial cortical stimulation. Elcctroenceph. clin. Neurophysiol., 1993, 89: 211-220. Werhan, K.J., Fong, J.K.Y., Meyer, B.-U., Priori, A., Rothwell, J.C., Day, B.L. and Thompson, P.D. The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseus muscle. Electroenceph. clin. Neurophysiol., 1994, 93: 138-146. Wesseling, K.H., de Witt, B., Settels, J.J. and Klawer, W.H. On the indirect registration of finger blood pressure after Penaz. Funkt. Biol. Med., 1982, 1: 245-250. Wise, R., Chollet, F., Hadar, U., Friston, K., Hoffuer, E. and Frackowiak, R. Distribution of cortical neural networks involved in word comprehension and word retrieval. Brain, 1991, 114: 1803-1817. Zeffiro, T., Leiderman, D., Bierner, S., Dubinsky, R. and Hallett, M. Regional cerebral blood flow changes in cortical motor areas during unilateral wrist movement. Mov. Disord., 1990, 5: 19P.