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Intracortical facilitation and inhibition after paired magnetic stimulation in humans under anesthesia
ELSEVIER
Neuroscience
Letters 199
(1995)155-l 57
Intracortical facilitation and inhibition after paired magnetic stimulation in humans under anesthesia Hiroshi Nakarnura*, Hideki Kitagawa, Yoshiharu Kawaguchi, Haruo Tsuji, Haruo Takano, Shinichi Nakatoh Department
of Orthopedic Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugiiani, Toyama 930-01, Japan Received 19 May 199.5;revised version received 7 September 1995; accepted 14 September 1995
Abstract
The evoked spinal cord potential (ESCP) and the evoked compound muscle action potential (ECMAP) after paired transcranial magnetic stimulation were recorded simultaneously in eight subjects undergoing spine surgery. The ESCP was composed of a shortlatency initial wave (D-wave) followed by later waves (I-waves). The mean conduction velocity of each wave was approximately 60 m/s. The interstimulus interval (ISI) affected the amplitude of both ESCP and ECMAP; the amplitude was inhibited at short ISIS (2 ms and 5 ms), was facilitated at IS1 of 10 ms, and was inhibited again at longer ISIS (50 ms, 100 ms and 200 ms). The changes in later I-waves were prominent compared to the stable D-wave. These results suggest that transcranial magnetic stimulation alters the excitability of the motor crortex by affecting synaptic transmission to corticomotor (CM) neurons. The inhibition of the motor cortex at longer ISIS may contribute to a silent period following transcranial magnetic stimulation. Keywords: Transcranial magnetic stimulation; Motor cortex; Facilitation; Inhibition; Paired stimulation; Spinal cord potential; Human
The method of paire:d transcranial stimulation made it possible to examine changes in motor pathway excitability following conditioning transcranial stimulation [3,7, 11,141. However, it is still unclear whether cortical or spinal mechanisms participate in such changes. In order to investigate these excitability changes in the motor cortex, we recorded the ESCP and the ECMAP simultaneously after paired transcranial magnetic stimulation over the anesthetized human motor cortex. The study comprised eight patients (six males, two females, between the ages of 38 and 60 years) undergoing spine surgery. All patients gave written informed consent to take part in the study, which was approved by the Ethics Committee of the Toyama Medical and Pharmaceutical University. The patients were anesthetized (with nitrous oxide, 52 + 10%; ketamine, 1.6 + 0.3 mg/kg per h; and fentanyl, 0.8 + 0.8pg/kg per h) and paralyzed (with vecuronium bromide, 0.08 + 0.02 mg/kg per h). The neuromuscular blockage level was maintained at approximately 80%, i.e. about 20% single twitch using a microinfusion pump, and the patients were monitored with a * Corresponding
author. Tel.: +81 764 342281; fax: +81 764 345035.
Datex Relaxograph (Datex Instrumentarium OY, Helsinki, Finland). The anesthetic protocol has been described in detail in a previous report [lo]. In three patients, isoflurane or sevoflurane was administered at the end of the recording session in order to examine the effects of these volatile anesthetic agents. Magnetic stimulation was performed using two stimulators (MAGSTIM Model 200; The Magstim Company, Whitland, Dyfed, UK) connected to the same Double Cone Coil through a Bistim Module (The Magstim Company). The coil was fixed on the optimum scalp position to elicit ECMAP in the contralateral muscles (six upper limbs, two lower limbs). Paired stimuli were delivered at ISIS of 2, 5, 10, 25, 50, 100, 200, 400, and 800 ms. The intensities of the conditioning stimuli were fixed at the suprathreshold of the ESCP (1.2-1.6 times the threshold of the ESCP) and the subthreshold of the ECMAP (0.8-0.9 times the threshold of the ECMAP). Intensities of the test stimuli were fixed at the suprathreshold of the ECMAP (1. l-l .4 times the threshold of the ECMAP). The threshold of the ESCP was 40-60% of the maximum output of the stimulator, and the threshold of the ECMAP was 1.2-1.8 times higher than that of the ESCP. ESCPs were recorded using
0304-3940/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-394n~95~1~n31 -II
H. Nakamura et al. /Neuroscience
156
ESCP Nl
baseline
2 ms
10 ms
100 ms
800
ms
J-
50 VJ +
2ms
Fig. 1. ESCPs (left) and ECMAPs (right) of a Sl-year-old male who suffered a C5/6 disc hemiation following paired magnetic stimulation. ESCPs were recorded at the C3/4 level and ECMAPs were recorded from the extensor digitorum muscle. Upper traces are baseline potentials stimulated by 100% output of the stimulator. The numbers at the left of each trace are the ISIS. Conditioning stimuli were 80% and test stimuli were 100% of output. Test stimuli were given at the start of the sweep. ECMAP threshold was 90%.
bipolar catheter electrodes (with an interelectrode distance of 1.5 cm) in the cervical epidural space rostra1 to the pathological spinal segment. In four subjects, recordings were performed at two different sites along the spinal cord to calculate conduction velocity. ECMAPs were recorded with needle electrodes placed in the limb muscles using the tendon-belly method. The recorded signals were amplified and filtered (bandwidth 0.5-5 kHz), and 4-8 sweeps were averaged for each observation using a Dantee 1500 EMG system (Dantec Medical Inc., Copenhagen, Denmark). The latencies of ESCPs were measured to the negative peaks and the amplitudes were measured from peak-to-peak. The latencies of ECMAPs were measured at the onset, and the amplitudes were measured from peak-to-peak. The ESCP was composed of multiple volleys between four and seven waves (Fig. 1 left), and the mean conduction velocity of each wave was 66 * 15 m/s (Nl wave), 66 f 18 m/s (N2 wave), 57 + 9 m/s (N3 wave) and 65 f 16 m/s (N4 wave). The amplitude of the ESCP following the test stimulus was altered according to the ISI. It was attenuated at short ISIS (2 ms and 5 ms), enlarged at an IS1 of 10 ms, and again attenuated at longer ISIS (50 ms, 100 ms and 200 ms). These changes were prominent in later waves, in contrast with the stable Nl wave (Fig. 1 left, Fig. 2). In a similar manner, the amplitude of ECMAP after test stimulus was attenuated at short ISIS,
Letters 199 (I 995) 15.5-l 57
enlarged at an IS1 of 10 ms and again attenuated at longer ISIS (Fig. 1 right, Fig. 2). The Nl wave in the present study was analogous to the D-wave observed in animal experiments [9,13], as confirmed by its resistance to deep volatile anesthesia [l]. The later waves that followed the D-wave were suggested to be analogous to I-waves, which were activated transynaptically via cortical interneurons, because of their high anesthetic sensitivity and conduction velocity. The present study reveals that after delivery of the test stimulus, trans-synaptic I-waves changed remarkably according to the conditioning stimulus. We conclude that the conditioning stimulus affects the excitability of the motor cortex by corticocortical or corticopetal input, resulting in Iwave change after delivery of the test stimulus. Excitatory corticopetal input to CM neurons [5,12] may contribute to the facilitation of the motor cortex at an IS1 of 10 ms. The enlargement of ECMAP was caused not only by the summation at the spinal level, but also by facilitation at the cortical level. The discrepancy in IS1 values for the maximal ECMAP enlargement between that reported in this study (10 ms) and that reported in others (10-30 ms) [3,11,14] may be explained by the lesser size and number of I-waves under suppressive anesthesia. The present study reveals the biphasic inhibitory effects of condition-
2
5
10
25
50
100
200
400
800
IS1 (ms) Fig. 2. Amplitude ratio (average * SD) of the ESCPs (from Nl to N4, n = 8) and the ECMAPs (n =4). At each ISI, the amplitude of the conditioned response is expressed as a percentage of the amplitude of the baseline response. The inhibition and facilitation were prominent in later waves of ESCP.
H. Nakamura et al. /Neuroscience Letters 199 (1995) 155-i-157
ing stimulation. The early inhibition of the ESCP at ISIS of 2-5 ms supports Kujirai’s hypothesis [ 1l] that the motor cortex is inhibited up to 6 ms following transcranial magnetic stimulation. The late inhibition of the ESCP at ISIS of 50-200 ms corresponds to reports that cortical inhibitory mechanisms produce the latter part of the silent period that follows cortical stimulation [2,4,6]. We assume that GABA* receptors can play an important role in early inhibition of the motor cortex, because the ISIS of early inhibition coincide with the latency and the duration of GABA* receptor-mediated IPSPs [8]. In addition, the refractory period of CM neurons and interneurons may contribute to early inhibition. GABAa receptors in the motor cortex can particilpate in the late inhibition, because the ISIS of late inhibition coincide with the latency and the duration of GABAB receptor-mediated IPSPs [8], although we cannot exchlde a participation of subcortical inhibitory loops to the motor cortex from the thalamus, cerebellum, and the basal ganglia in the late inhibition. In conclusion, the transcranial magnetic stimulation alters the excitability of the motor cortex by inhibiting or facilitating synaptic transmission to CM neurons. We would like to t;hank Ms. Cleat Szczepaniak for editorial assistance. 111 Amassian, V.E., Stewart, M., Quirk, G.J. and Rosenthal, J.L., Physiological basis of motor effects of a transient stimulus to cerebral cortex, Neurosurgery, 20 (1987) 74-93. VI Cantello, R., Gianelli, h4., Civardi, C. and Mutani, R., Magnetic brain stimulation: the silent period after the motor evoked potential, Neurology, 42 (199:2) 1951-1959. [31 Claus, D., Weis, M., Jahnke, U., Plewe, A. and BrunhBlzl, C., Corticospinal conduction studied with magnetic double stimulation in the intact human, J. Neurol. Sci., 111 (1992) 180-188.
157
[41 Fuhr, P., Agostino, R. and HaIlett, M., Spinal motor neuron excitability during the silent period after cortical stimulation, Electroencephalogr. Clin. Neurophysiol., 81 (1991) 257-262. PI Ghosh, S. and Potter, R., Corticocortical synaptic influences on morphologically identified pyramidal neurones in the motor cortex of tbe monkey, J. Physiol. (London), 400 (1988) 617-629. WI Inghilleri, M., Berardelli, A., Cruccu, G. and Manfredi, M., Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction, J. Physiol. (London) 466 (1993) 521534. [71 lnghilleri, M., Berardelli, A., Cruccu, G., Priori, A. and Manfmdi, M., Motor potentials evoked by paired cortical stimuli, Electroencephalogr. Clin. Neurophysiol., 77 (1990) 382-389. PI Kang, Y., Kaneko, T., Ohishi, H., Endo, K. and A&i. T., Spatiotemporally differential inhibition of pyramidal cells in the cat motor cortex, J. Neurophysiol., 71 (1994) 280-293. [91 Kemell, D. and Wu, C.P., Responses of the pyramidal tract to stimulation of the baboon’s motor cortex, J. Physiol. (London), 191 (1967) 653-672. HO1 Kitagawa, H., Nakamura, H., Kawaguchi, Y., Tsuji, H., Satone, T., Takano, H. and Nakatoh, S., Magnetic evoked compound muscle action potential neuromonitoring in spine surgery, Spine, 20 (1995) in press. illI Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P. and Marsden, CD., Corticocortical inhibition in human motor cortex, J. Physiol. (London), 471 (1993) 501-519. WI Kosar, E., Waters, R.S., Tsukahara, N. and Asanuma, H., Anatomical and physiological properties of the projection from the sensory cortex to the motor cortex in normal cats: the difference between corticocorticaI and thalamocortical projections, Brain Res., 345 (1985) 68-78. 1131 Patton, H.D. and Amassian, V.E., Single- and multiple-unit analysis of cortical stage of pyramidal tract activation, J. Neurophysiol., 17 (1954) 345-363. 1141 Valls-Sol& J., Pascual-Leone, A., Wassermann, E.M. and Hallett, M., Human motor evoked responses to paired tramcranial magnetic stimuli, Electroencephalogr. Clin. Neurophysiol., 85 (1992) 355-364.
Neuroscience
Letters 199
(1995)155-l 57
Intracortical facilitation and inhibition after paired magnetic stimulation in humans under anesthesia Hiroshi Nakarnura*, Hideki Kitagawa, Yoshiharu Kawaguchi, Haruo Tsuji, Haruo Takano, Shinichi Nakatoh Department
of Orthopedic Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugiiani, Toyama 930-01, Japan Received 19 May 199.5;revised version received 7 September 1995; accepted 14 September 1995
Abstract
The evoked spinal cord potential (ESCP) and the evoked compound muscle action potential (ECMAP) after paired transcranial magnetic stimulation were recorded simultaneously in eight subjects undergoing spine surgery. The ESCP was composed of a shortlatency initial wave (D-wave) followed by later waves (I-waves). The mean conduction velocity of each wave was approximately 60 m/s. The interstimulus interval (ISI) affected the amplitude of both ESCP and ECMAP; the amplitude was inhibited at short ISIS (2 ms and 5 ms), was facilitated at IS1 of 10 ms, and was inhibited again at longer ISIS (50 ms, 100 ms and 200 ms). The changes in later I-waves were prominent compared to the stable D-wave. These results suggest that transcranial magnetic stimulation alters the excitability of the motor crortex by affecting synaptic transmission to corticomotor (CM) neurons. The inhibition of the motor cortex at longer ISIS may contribute to a silent period following transcranial magnetic stimulation. Keywords: Transcranial magnetic stimulation; Motor cortex; Facilitation; Inhibition; Paired stimulation; Spinal cord potential; Human
The method of paire:d transcranial stimulation made it possible to examine changes in motor pathway excitability following conditioning transcranial stimulation [3,7, 11,141. However, it is still unclear whether cortical or spinal mechanisms participate in such changes. In order to investigate these excitability changes in the motor cortex, we recorded the ESCP and the ECMAP simultaneously after paired transcranial magnetic stimulation over the anesthetized human motor cortex. The study comprised eight patients (six males, two females, between the ages of 38 and 60 years) undergoing spine surgery. All patients gave written informed consent to take part in the study, which was approved by the Ethics Committee of the Toyama Medical and Pharmaceutical University. The patients were anesthetized (with nitrous oxide, 52 + 10%; ketamine, 1.6 + 0.3 mg/kg per h; and fentanyl, 0.8 + 0.8pg/kg per h) and paralyzed (with vecuronium bromide, 0.08 + 0.02 mg/kg per h). The neuromuscular blockage level was maintained at approximately 80%, i.e. about 20% single twitch using a microinfusion pump, and the patients were monitored with a * Corresponding
author. Tel.: +81 764 342281; fax: +81 764 345035.
Datex Relaxograph (Datex Instrumentarium OY, Helsinki, Finland). The anesthetic protocol has been described in detail in a previous report [lo]. In three patients, isoflurane or sevoflurane was administered at the end of the recording session in order to examine the effects of these volatile anesthetic agents. Magnetic stimulation was performed using two stimulators (MAGSTIM Model 200; The Magstim Company, Whitland, Dyfed, UK) connected to the same Double Cone Coil through a Bistim Module (The Magstim Company). The coil was fixed on the optimum scalp position to elicit ECMAP in the contralateral muscles (six upper limbs, two lower limbs). Paired stimuli were delivered at ISIS of 2, 5, 10, 25, 50, 100, 200, 400, and 800 ms. The intensities of the conditioning stimuli were fixed at the suprathreshold of the ESCP (1.2-1.6 times the threshold of the ESCP) and the subthreshold of the ECMAP (0.8-0.9 times the threshold of the ECMAP). Intensities of the test stimuli were fixed at the suprathreshold of the ECMAP (1. l-l .4 times the threshold of the ECMAP). The threshold of the ESCP was 40-60% of the maximum output of the stimulator, and the threshold of the ECMAP was 1.2-1.8 times higher than that of the ESCP. ESCPs were recorded using
0304-3940/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-394n~95~1~n31 -II
H. Nakamura et al. /Neuroscience
156
ESCP Nl
baseline
2 ms
10 ms
100 ms
800
ms
J-
50 VJ +
2ms
Fig. 1. ESCPs (left) and ECMAPs (right) of a Sl-year-old male who suffered a C5/6 disc hemiation following paired magnetic stimulation. ESCPs were recorded at the C3/4 level and ECMAPs were recorded from the extensor digitorum muscle. Upper traces are baseline potentials stimulated by 100% output of the stimulator. The numbers at the left of each trace are the ISIS. Conditioning stimuli were 80% and test stimuli were 100% of output. Test stimuli were given at the start of the sweep. ECMAP threshold was 90%.
bipolar catheter electrodes (with an interelectrode distance of 1.5 cm) in the cervical epidural space rostra1 to the pathological spinal segment. In four subjects, recordings were performed at two different sites along the spinal cord to calculate conduction velocity. ECMAPs were recorded with needle electrodes placed in the limb muscles using the tendon-belly method. The recorded signals were amplified and filtered (bandwidth 0.5-5 kHz), and 4-8 sweeps were averaged for each observation using a Dantee 1500 EMG system (Dantec Medical Inc., Copenhagen, Denmark). The latencies of ESCPs were measured to the negative peaks and the amplitudes were measured from peak-to-peak. The latencies of ECMAPs were measured at the onset, and the amplitudes were measured from peak-to-peak. The ESCP was composed of multiple volleys between four and seven waves (Fig. 1 left), and the mean conduction velocity of each wave was 66 * 15 m/s (Nl wave), 66 f 18 m/s (N2 wave), 57 + 9 m/s (N3 wave) and 65 f 16 m/s (N4 wave). The amplitude of the ESCP following the test stimulus was altered according to the ISI. It was attenuated at short ISIS (2 ms and 5 ms), enlarged at an IS1 of 10 ms, and again attenuated at longer ISIS (50 ms, 100 ms and 200 ms). These changes were prominent in later waves, in contrast with the stable Nl wave (Fig. 1 left, Fig. 2). In a similar manner, the amplitude of ECMAP after test stimulus was attenuated at short ISIS,
Letters 199 (I 995) 15.5-l 57
enlarged at an IS1 of 10 ms and again attenuated at longer ISIS (Fig. 1 right, Fig. 2). The Nl wave in the present study was analogous to the D-wave observed in animal experiments [9,13], as confirmed by its resistance to deep volatile anesthesia [l]. The later waves that followed the D-wave were suggested to be analogous to I-waves, which were activated transynaptically via cortical interneurons, because of their high anesthetic sensitivity and conduction velocity. The present study reveals that after delivery of the test stimulus, trans-synaptic I-waves changed remarkably according to the conditioning stimulus. We conclude that the conditioning stimulus affects the excitability of the motor cortex by corticocortical or corticopetal input, resulting in Iwave change after delivery of the test stimulus. Excitatory corticopetal input to CM neurons [5,12] may contribute to the facilitation of the motor cortex at an IS1 of 10 ms. The enlargement of ECMAP was caused not only by the summation at the spinal level, but also by facilitation at the cortical level. The discrepancy in IS1 values for the maximal ECMAP enlargement between that reported in this study (10 ms) and that reported in others (10-30 ms) [3,11,14] may be explained by the lesser size and number of I-waves under suppressive anesthesia. The present study reveals the biphasic inhibitory effects of condition-
2
5
10
25
50
100
200
400
800
IS1 (ms) Fig. 2. Amplitude ratio (average * SD) of the ESCPs (from Nl to N4, n = 8) and the ECMAPs (n =4). At each ISI, the amplitude of the conditioned response is expressed as a percentage of the amplitude of the baseline response. The inhibition and facilitation were prominent in later waves of ESCP.
H. Nakamura et al. /Neuroscience Letters 199 (1995) 155-i-157
ing stimulation. The early inhibition of the ESCP at ISIS of 2-5 ms supports Kujirai’s hypothesis [ 1l] that the motor cortex is inhibited up to 6 ms following transcranial magnetic stimulation. The late inhibition of the ESCP at ISIS of 50-200 ms corresponds to reports that cortical inhibitory mechanisms produce the latter part of the silent period that follows cortical stimulation [2,4,6]. We assume that GABA* receptors can play an important role in early inhibition of the motor cortex, because the ISIS of early inhibition coincide with the latency and the duration of GABA* receptor-mediated IPSPs [8]. In addition, the refractory period of CM neurons and interneurons may contribute to early inhibition. GABAa receptors in the motor cortex can particilpate in the late inhibition, because the ISIS of late inhibition coincide with the latency and the duration of GABAB receptor-mediated IPSPs [8], although we cannot exchlde a participation of subcortical inhibitory loops to the motor cortex from the thalamus, cerebellum, and the basal ganglia in the late inhibition. In conclusion, the transcranial magnetic stimulation alters the excitability of the motor cortex by inhibiting or facilitating synaptic transmission to CM neurons. We would like to t;hank Ms. Cleat Szczepaniak for editorial assistance. 111 Amassian, V.E., Stewart, M., Quirk, G.J. and Rosenthal, J.L., Physiological basis of motor effects of a transient stimulus to cerebral cortex, Neurosurgery, 20 (1987) 74-93. VI Cantello, R., Gianelli, h4., Civardi, C. and Mutani, R., Magnetic brain stimulation: the silent period after the motor evoked potential, Neurology, 42 (199:2) 1951-1959. [31 Claus, D., Weis, M., Jahnke, U., Plewe, A. and BrunhBlzl, C., Corticospinal conduction studied with magnetic double stimulation in the intact human, J. Neurol. Sci., 111 (1992) 180-188.
157
[41 Fuhr, P., Agostino, R. and HaIlett, M., Spinal motor neuron excitability during the silent period after cortical stimulation, Electroencephalogr. Clin. Neurophysiol., 81 (1991) 257-262. PI Ghosh, S. and Potter, R., Corticocortical synaptic influences on morphologically identified pyramidal neurones in the motor cortex of tbe monkey, J. Physiol. (London), 400 (1988) 617-629. WI Inghilleri, M., Berardelli, A., Cruccu, G. and Manfredi, M., Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction, J. Physiol. (London) 466 (1993) 521534. [71 lnghilleri, M., Berardelli, A., Cruccu, G., Priori, A. and Manfmdi, M., Motor potentials evoked by paired cortical stimuli, Electroencephalogr. Clin. Neurophysiol., 77 (1990) 382-389. PI Kang, Y., Kaneko, T., Ohishi, H., Endo, K. and A&i. T., Spatiotemporally differential inhibition of pyramidal cells in the cat motor cortex, J. Neurophysiol., 71 (1994) 280-293. [91 Kemell, D. and Wu, C.P., Responses of the pyramidal tract to stimulation of the baboon’s motor cortex, J. Physiol. (London), 191 (1967) 653-672. HO1 Kitagawa, H., Nakamura, H., Kawaguchi, Y., Tsuji, H., Satone, T., Takano, H. and Nakatoh, S., Magnetic evoked compound muscle action potential neuromonitoring in spine surgery, Spine, 20 (1995) in press. illI Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P. and Marsden, CD., Corticocortical inhibition in human motor cortex, J. Physiol. (London), 471 (1993) 501-519. WI Kosar, E., Waters, R.S., Tsukahara, N. and Asanuma, H., Anatomical and physiological properties of the projection from the sensory cortex to the motor cortex in normal cats: the difference between corticocorticaI and thalamocortical projections, Brain Res., 345 (1985) 68-78. 1131 Patton, H.D. and Amassian, V.E., Single- and multiple-unit analysis of cortical stage of pyramidal tract activation, J. Neurophysiol., 17 (1954) 345-363. 1141 Valls-Sol& J., Pascual-Leone, A., Wassermann, E.M. and Hallett, M., Human motor evoked responses to paired tramcranial magnetic stimuli, Electroencephalogr. Clin. Neurophysiol., 85 (1992) 355-364.