Brain, Vol. 123, No. 8, 1710-1721,
August 2000
© 2000 Oxford University Press
Role of primary sensorimotor cortices in generating inhibitory motor response in humans
1 Departments of Brain Pathophysiology, 2 Neurosurgery and 3 Neurology, Kyoto University School of Medicine, Kyoto 606 and 4 Department of Neurosurgery, Mie University School of Medicine, Japan
Correspondence to:
Akio Ikeda, MD, Departments of Brain Pathophysiology and Neurology, Kyoto University School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan E-mail: akio{at}kuhp.kyoto-u.ac.jp
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Abstract |
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To clarify the mechanism by which inhibitory motor responses such as cortical negative myoclonus are generated in humans, three patients with medically intractable partial epilepsy (two with frontal lobe epilepsy and one with parietal lobe epilepsy) were studied by means of direct cortical stimulation with a single electric pulse through subdural electrodes. All underwent chronic long-term video/EEG monitoring, cortical mapping by 50 Hz electric cortical stimulation and recording of cortical somatosensory evoked potentials with chronically implanted subdural grid electrodes (3 mm in diameter and centre-to-centre distance of 1 cm) to map both epileptogenic and functional zones. After these clinical evaluations, cortical stimulation by single electric pulse (0.3 ms duration, 1 Hz) was carried out through pairs of subdural electrodes located at the primary sensorimotor area (MI-SI), pre-supplementary motor area (pre-SMA) and lateral negative motor area (lateral NMA), while surface EMG was recorded from the muscles of the contralateral hand. The results showed that (i) in all subjects, single pulse stimulation of MI-SI elicited a motor evoked potential (MEP) followed by a silent period (SP) in the contralateral distal hand muscles, the latter lasting 300 ms after the stimulus. The duration of SP was proportional to the size of the preceding MEP. In one subject, SP without any preceding MEP was elicited, and, in another subject, there was a short SP immediately before MEP in the contralateral thenar muscle. (ii) Following the stimulation of either pre-SMA or lateral NMA, no SP was observed. It is concluded that the inhibitory mechanism within the MI-SI, but probably not in the non-primary motor areas, either closely linked to or completely independent of excitation, most likely plays an important role in eliciting brief negative motor phenomena such as cortical negative myoclonus or SP.
inhibitory motor response; silent period; electric cortical stimulation; subdural electrodes; functional mapping
APB = abductor pollicis brevis; DEL = deltoid; ECR = extensor carpi radialis; FCR = flexor carpi radialis; MI = primary motor area; MI-SI = primary sensorimotor area; MEP = motor evoked potential; NMA = negative motor area; ODM = opponens digiti minimi; SEP = somatosensory evoked potentials; SI = primary somatosensory area; SMA = supplementary motor area; SP = silent period; TMS = transcranial magnetic stimulation
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Negative or inhibitory motor phenomena have attracted increasing attention in clinical neurology because they are related directly not only to the pathophysiology of many neurological disorders manifesting epileptic symptoms (cortical negative myoclonus and focal atonic seizures) or involuntary movements (dystonia), but also to higher motor control in humans. There are two kinds of cortical myoclonus; positive and negative, which are clearly distinguishable from each other using electrophysiological techniques (Tassinari et al., 1998
). The mechanism by which negative myoclonus of cortical origin is generated has not yet been clarified (Shahani and Young, 1976). EEG activity preceding the cortical negative myoclonus was reported to show a different scalp distribution from that preceding the positive myoclonus (Rubboli et al., 1995; Baumgartner et al., 1996). In relation to this, the silent period (SP) induced by transcranial magnetic stimulation (TMS) could provide us with a clue, because it is thought to activate intracortical inhibitory interneurons (Rothwell, 1994). However, TMS has a limitation in the precise identification of the stimulus location on the brain and, furthermore, it is uncertain how large the activated cortical area is. Direct cortical stimulation by means of subdural electrodes has a great advantage in that the exact stimulus point on the human brain is specified. Noachtar and colleagues reported a patient with epileptic negative myoclonus in whom subdural electrodes were implanted for epilepsy surgery (Noachtar et al., 1997). Left postcentral spikes were followed consistently by SPs in the right arm with a latency of 20–30 ms. However, it was uncertain in that particular case whether the spikes were also present in the primary motor area (MI) which might have contributed to the SPs and, furthermore, they could not elicit an SP by stimulating the postcentral cortex with either single or repetitive shocks.
A negative motor response is defined as the inability to continue voluntary phasic movements or sustained muscle contraction without disturbance of consciousness, elicited by high frequency cortical stimulation with subdural electrodes (Lüders et al., 1988). A negative motor area (NMA) in humans is identified at the lateral frontal area just rostral to the primary face motor area (primary negative motor area: primary NMA), and at the mesial frontal area just rostral to the SMA proper (supplementary NMA) (Lüders et al., 1995). Thus, it is plausible that the mechanism by which an epileptic negative myoclonus or SP is generated might be related to these NMAs (Tassinari et al., 1995; Baumgartner et al., 1996).
In the present study, as a part of presurgical evaluations of patients with intractable partial epilepsy, we stimulated the peri-rolandic cortex by single electric shocks, and obtained data suggesting the importance of the primary sensorimotor cortices (MI-SI) in generating the inhibitory motor phenomena, which might be related to the pathogenesis of cortical negative myoclonus. Patients 2 and 3 (Ikeda et al., 1999; Matsumoto et al., 1999) are discussed elsewhere for entirely different purposes.
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Patients and methods |
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Patients
We recorded motor evoked potentials (MEPs) and SPs after electric cortical stimulation in three patients with medically intractable partial seizures of neocortical origin (two women and one man, age 25–30 years). All three patients had subdural grid electrodes implanted chronically as a part of their final presurgical evaluations for their epilepsy surgery in Kyoto University Hospital (Table 1
). Informed consent was obtained from all the patients after the purpose and possible consequence of the studies were explained, in accordance with the Clinical Research Protocol No. 79 approved by the Ethical Committee of Kyoto University Graduate School of Medicine.
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The subdural electrodes (AD-TECH, Racine, Wis., USA) were made of platinum. Each electrode was 3 mm in diameter, and the centre-to-centre inter-electrode distance was 1 cm. This invasive technique helps to identify (i) the extent of the epileptogenic region by seizure recording and (ii) the function of the cortex around the epileptogenic region by high frequency electric cortical stimulation and by recording somatosensory evoked potentials (SEPs) (Hahn and Lüders, 1987
).
Patient 1 had three subdural electrode grids, 4 x 8 (A), 2 x 8 (B) and 2 x 6 electrodes (C), on the right frontoparietal area (Fig. 1A). Patient 2 had two 2 x 8 grids (Fig. 1B) and one 4 x 5 grid (not shown in Fig. 1B) on the right frontoparietal area. Patient 3 had one 4 x 5 grid (B) on the left frontoparietal cortex and one 2 x 8 grid (A) on the left mesial frontal region (Fig.1C). The functional and anatomical location of these electrodes was defined as described under `Cortical mapping' (see below). All the patients had an increased signal abnormality on T2-weighted MRI which was confirmed later by surgery; in the left premotor cortex (astrocytoma grade II) in patient 1 (the area corresponding to the lower part of plates B and C in Fig. 1A), in the right lateral parietal cortex (gliosis) in patient 2 (A6–A8, A14–A16, B6–B8 and B14–B16 in Fig. 1B) and in the high lateral convexity of the left frontal lobe (cortical dysplasia) in patient 3 (B17–B19 and its more superior areas in Fig. 1C).
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Cortical mapping
High frequency electric cortical stimulation and the recording of SEPs were done for each individual electrode for clinical purposes (Lüders et al., 1987
). Details of the methodology for stimulation and the subsequent cortical mapping are described elsewhere (Lüders et al., 1987; Ikeda et al., 1992).
For high frequency cortical stimulation, repetitive square wave electric currents of alternating polarity with a pulse width of 0.3 ms and a frequency of 50 Hz were delivered (SEN-7203 and ss-102J, Nihon-Kohden, Tokyo, Japan) to each subdural electrode. Train duration was set to 2–5 s. Initially, one subdural electrode which did not show any interictal or ictal epileptiform discharges and at which repetitive electric stimulation elicited no positive responses was selected as the stimulus reference, and it was used as the reference for stimulating all the other electrodes. Throughout stimulation, ECoGs (electrocorticographs) were monitored continuously to observe any induced afterdischarges or EEG seizure patterns. Stimulus current was increased gradually until (i) the maximum of 15 mA was reached or (ii) afterdischarges were elicited with intensity <15 mA. Positive motor and sensory areas were defined by positive responses occurring at the contralateral body part being consistent with the somatotopy. A negative motor response was defined as the cessation of voluntary tonic muscle contraction or of rapid alternating movements without loss of awareness during the stimulation (Lüders et al., 1987).
Cortical SEPs to electric stimulation of the median nerve at a rate of 1.1 Hz were recorded from subdural electrodes. In all three patients, the location of the central sulcus was determined by intraoperative visual inspection and based on the phase reversal of the initial cortical response of SEPs to medial nerve stimulation (P20 and N20). For patient 3, in whom the mesial frontal cortex was studied, the method for defining the precise location of pre-SMA and SMA proper was described elsewhere (Ikeda et al., 1999). Based on the atlas of Talairach and Tournoux (Talairach and Tournoux, 1988) and the histological analysis in human SMA (Zilles et al., 1996), the electrodes located on the mesial surface of the superior frontal gyrus just anterior to the VAC (vertical anterior commissural) line were judged to be on the pre-SMA. Since A7 and A8 in patient 3 were located anterior to the VAC line and yet were within the 20 mm distance anteriorly, these were judged to be on the pre-SMA.
The results of electric cortical stimulation showed that B1, A2 and A10 in patient 1 elicited positive motor responses in the left fingers, left elbow and left fingers, respectively. A11 elicited a sensory response in the left hand (Fig. 1A
). In patient 2, A4–A6, A11–A13 and B4 showed positive motor responses in the left hand. A7, B5, B7, B12 and B13 elicited a sensory response in the left hand. B11 elicited both positive motor and sensory responses in the left hand, and A14 elicited a sensory response in the left trunk. Stimulation of B9 elicited negative motor responses in both hands and tongue, and A3 in the left hand and foot. B2 elicited a positive motor response in the face, and B3 produced tonic eye deviation to the left (Fig. 1B). In patient 3, positive motor and sensory responses were produced by stimulating A2–A5, suggesting the SMA proper. A7 and A8 elicited no responses. Sensory responses were elicited in the right hand by stimulating B2, B6, B7, B11 and B16, and in the right foot by stimulating B17. B12 elicited a positive motor response in the right hand, and B13 elicited a negative motor response in the right hand. B18 elicited a positive motor response in the proximal part and a negative motor response in the distal part of the right upper limb simultaneously. B12 produced a positive motor response in the right hand, while B8 and B9 elicited speech arrest (Fig. 1C).
Single pulse electric cortical stimulation
After completing cortical mapping as described above, a single pulse electric stimulus was presented to each selected pair of adjacent subdural electrodes. Electric square wave currents with a pulse width of 0.3 ms were delivered (SEN-7203 and ss-102J, Nihon-Kohden) with alternating polarity once every second for 10 s in patients 1 and 2. In patient 3, a 1 Hz train of either positive or negative polarity was given for 10 s each, and both train settings were examined in all the selected electrode pairs, because EMG responses produced by a unidirectional stimulus gradually decreased.
In patient 1, four different pairs of adjacent electrodes were investigated: MI (A2–A3), MI-SI (A10–A18), posterior parietal area (A25–A26) and lateral premotor area (B4–B5) (Fig. 1A). In patient 2, four different pairs were investigated: three pairs at MI (A4–A12, A5–A13, A12–B4) and one pair at the lateral NMA (B1–B9) (Fig. 1B). In patient 3, six different pairs were investigated: one each at MI-SI (B7–B12), primary somatosensory area (SI) (B1–B2), lateral NMA (B13–B14), the area producing speech arrest (B8–B9), the lateral premotor area (B4–B5) and pre-SMA (A7–A8) (Fig. 1C).
For recording the surface EMG from the deltoid (DEL), extensor carpi radialis (ECR) and abductor pollicis brevis (APB) muscles of the contralateral upper limb and from the APB of the ipsilateral hand, a pair of shallow cup electrodes were attached on the skin over each of those muscles. In patient 1, surface EMG was also recorded from the flexor carpi radialis (FCR) and opponens digiti minimi (ODM) muscles of the contralateral upper limb.
Initially, the patients were asked to keep all the monitored muscles at rest, while a single electric stimulus was given as described above (`resting condition'). Current intensity was increased gradually until the maximum of 15 mA was reached or MEPs were elicited at any monitored muscle. Immediately after completing the resting condition, the `contraction condition' was investigated. Stimulus current was set to the level which elicited MEPs during the resting condition. If MEPs were not elicited with a stimulus intensity below the maximum of 15 mA during the resting condition, a current of 15 mA was delivered during the contraction condition. In the contraction condition, the patients were asked to maintain moderate contraction of all the investigated muscles throughout the 10-s period of stimulation. For any stimulus electrode pair, at least two identical stimulus sets were given to confirm the reproducible EMG responses.
For EMG recording, the analysis window was set to 0–300 ms from the electric stimulus in patients 1 and 2, and to 0–600 ms in patient 3. The bandpass filter was set to 20–1500 Hz (BIO-TOP, NEC Medical Inc., Tokyo, Japan). The signals were digitized with a sampling rate of 1700 Hz in patients 1 and 2, and 850 Hz in patient 3, and all signals were rectified. Ten responses for each stimulus set were averaged (Pathfinder II, Nicolet Biomedical Inc., Wis., USA). For both the resting and contraction conditions, onset latency and peak amplitude of MEPs were measured for each monitored muscle. In the contraction condition, onset latency and duration of SP were measured for each stimulus set and, when the SP was associated with MEP, the correlation between the SP duration and the MEP amplitude was analysed.
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Results |
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Single pulse cortical stimulation in the resting condition
In patient 1, MEPs were elicited in the contralateral ECR, APB and ODM at a current level of 6.9 mA (stimulating the primary motor area: A2–A3), and the onset latencies of MEPs in those muscles were 17.4, 20.4, and 20.4 ms, respectively. When stimulating MI-SI (A10–A18) at 8.9 mA, an MEP was elicited only in the ECR with an onset latency of 18.4 ms. No MEPs were elicited in the other muscles at those current levels when stimulating those two sites. When stimulating other different pairs (A25–A26, posterior parietal area; B4–B5, lateral premotor area), no MEPs were elicited in any muscle even at the maximum current of 15 mA.
In patient 2, MEPs were elicited in the contralateral ECR at the current level of 11.3 mA (stimulating MI: A5–A13), and its onset latency was 16.2 ms. No MEPs were elicited in the other muscles at this current level. When stimulating three other different sites (A4–A12 and A12–B4, MI; B1–B9, lateral NMA), no MEPs were elicited in any muscles.
In patient 3, no MEPs were elicited in any of the muscles investigated when stimulating six different sites even at the maximum current of 15 mA.
Single pulse cortical stimulation during muscle contraction (Table 2)
In patient 1, stimulation at A2–A3 with 2.4 mA did not elicit MEPs in the contralateral ECR or APB. Stimulation with 3.0 mA elicited the smallest MEP with onset latencies of 15.0 (ECR) and 18.6 ms (APB) with a barely recognizable SP. The larger the stimulus current given, the larger the MEP and the longer the SP elicited in both the APB and ECR (Fig. 2A). There was a linear correlation between the amplitude of MEPs and the duration of the induced SPs in both muscles (n = 11, r2 = 0.8923, P < 0.001) (Fig. 2B). Stimulation at A10–A18 elicited no MEP in the APB, but SPs were clearly induced with a current intensity of 
5.5 mA. The onset latency of the SP was constant at ~45 ms regardless of the stimulus intensity. The duration of the SP was proportional to the stimulus intensity (Fig. 3). MEPs were elicited in the ECR (onset latency of 16.2 ms), FCR (16.8 ms) and ODM (21.0 ms) when stimulating A10–A18, and SPs were observed only in association with MEPs. When stimulating B4–B5 and A25–A26, neither MEPs nor SPs were induced in any muscle investigated.
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In patient 2, when stimulating A5–A13 with a current of 11.3 mA, MEPs were elicited in the DEL, ECR and APB, and the onset latencies in the DEL and ECR were 10.8 and 15.6 ms, respectively. EMG discharge in APB was diminished transiently 24.6 ms after the stimulation, and a clear MEP occurred at 32.4 ms (Fig. 4A
). The SPs were also induced after the MEP. The relationship between the amplitude of MEPs and the duration of SPs was compared between the ECR and APB (Fig. 4B). SPs were induced equally in the two muscles, whereas the preceding MEP amplitude was distinctly smaller in the APB than in the ECR. This was in contrast to the finding in patient 1 (Fig. 2B).
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In patient 3, the onset latencies of the MEPs induced by stimulating six different pairs of electrodes are listed in Table 2
. Stimulation at three different pairs (B7–B12, B8–B9 and B13–B14) elicited both MEPs and the associated SPs. Stimulation of the hand area of the left SI (B1–B2) elicited MEPs in the right APB, but SPs were not elicited consistently and several SPs of ~50 ms duration, if present, were observed regardless of the size of the MEPs. Stimulation of the pre-SMA (A7–A8) and the lateral premotor area (B4–B5) did not elicit either MEPs or SPs. In all the responses showing both MEPs and SPs in patient 3, the amplitude of MEPs and the duration of the associated SP showed a positive correlation (n = 64, r2 = 0.6817, P < 0.001) (Fig. 5A). This tendency was prominent in the responses when stimulating B13–B14 (n = 37, r2 = 0.846, P < 0.001) (Fig. 5B) and B7–B12 (n = 10, r2 = 0.7227, P < 0.01) (not shown), but not when stimulating B1–B2 (Fig. 5C).
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Ipsilateral MEPs were observed only in APB in patient 3 whose onset latency was 1.2 ms longer than that observed in the contralateral APB (Table 2
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Responses to the stimulation of non-primary motor areas
Among four non-primary motor areas including: two NMAs determined by high frequency cortical stimulation, one in patient 2 (B1–B9) and the other in patient 3 (B13–B14); the lateral premotor area in patient 1 (B4–B5); and the pre-SMA in patient 3 (A7–A8), only one electrode pair at NMA in patient 3 (B13–B14) showed both MEPs and an associated SP when stimulated. The responses were almost identical to those seen after MI stimulation in the same patient. Another three sites did not show any responses.
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Discussion |
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In relation to the pathophysiology of negative or inhibitory motor phenomena seen in neurological disorders such as epileptic negative myoclonus and focal atonic seizures, the present study showed important evidence, by means of direct cortical stimulation with a single electric shock delivered to subdural electrodes in humans, that transient, inhibitory motor response is at least related to a dysfunction of MI-SI. Three important findings were disclosed: (i) MEPs followed by SPs were elicited commonly by stimulation of MI-SI, and the SP duration was positively correlated with the MEP amplitude. (ii) Pure SPs were induced by stimulating a part of the MI-SI, 1 cm posterior to the area which generated the combined MEP–SP in the same muscle. (iii) Single pulse stimulation in the non-primary motor area, including the so-called NMA, did not generate an SP.
Based on TMS studies, it has been suggested that the SP is a separate phenomenon from an MEP (Hallett, 1995), because (i) SP has the lower threshold and can occur independently of MEP and (ii) SP and MEP behave differently as the stimulus intensity increases (Inghilleri et al., 1993); the amplitude of MEPs and the stimulus strength are correlated initially, but at a level close to the maximum stimulus strength, the amplitude of MEPs becomes saturated, whereas the duration of SPs lengthens as the stimulus intensity increases further (Inghilleri et al., 1993; Taylor et al., 1997), and (iii) the scalp location where the stimulation produces SPs and MEPs is different (Wassermann et al., 1993).
In the present three patients, a total of 14 electrode pairs were investigated, seven of which produced EMG responses during muscle contraction. Three different patterns of relationship between MEPs and SPs were observed; type (i) the combined occurrence of MEPs and SPs; type (ii) SPs not preceded by MEPs; and type (iii) MEPs without consistent SPs. Among the seven pairs of electrodes, a type (i) response was seen in five pairs (71.4%), and types (ii) and (iii) in one pair each (14.3%). These three types of responses were also suggested by TMS, as described above. The present study showed that single pulse electric cortical stimulation of the peri-rolandic cortex can elicit SPs with or without preceding MEPs. In view of the fact that electric cortical stimulation using subdural electrodes clearly activates only the cortical surface just beneath the electrodes (Nathan et al., 1993), the occurrence of these three different patterns strongly suggests that cortical areas responsible for excitation and inhibition are located in close proximity (just 1 cm apart).
In the type (i) response, the amplitude of MEPs and the duration of SPs were correlated linearly, as shown in Figs 2 and 5A and B, although we did not take the level of muscle contraction precisely into account. This is in good agreement with the previous observation of epileptic negative myoclonus (Oguni et al., 1992) in which the amplitude of scalp-recorded spikes is positively correlated with the intensity of epileptic negative myoclonus. It suggests that this type of SP could be elicited by recurrent inhibitory activity produced primarily by excitatory pyramidal neurons. A group of the present authors observed cortical reflex negative myoclonus in the wrist extensor and flexor muscles which were elicited by electric stimulation of the median nerve during sustained muscle contraction in patients with progressive myoclonus epilepsy (Shibasaki et al., 1994). The occurrence of the stimulus-induced SP was significantly correlated with that of the giant SEPs, and when the SEP amplitude could be measured in each single-sweep record, there was a positive correlation between the duration of the induced SP and the amplitude of the N33 component of SEPs. Giant SEPs seen in patients with progressive myoclonus epilepsy can also arise from MI as shown by recent EMG analysis (Mima et al., 1993), which is in good agreement with the present finding, i.e. a type (i) pattern produced by stimulation of MI.
In contrast to type (i), a purely inhibitory activity was also observed as a type (ii) response. Previously, SPs without preceding MEPs, and epileptic negative myoclonus without preceding myoclonus, were only documented infrequently in humans. When Wassermann and colleagues (Wassermann et al., 1993) studied SPs and MEPs by TMS, they defined MEP as an excitatory response exceeding by at least 50 µV the background EMG level at a display gain of 50 µV per 1 cm division, and thus their analysis might have contained SPs with a small amplitude of preceding facilitation. Their finding that the cortical area producing SPs with little or no MEPs was 3–9 cm lateral to the area producing both MEPs and SPs is obviously different from ours. The difference might be due to the different methods of stimulation as well as the different criteria adopted for measuring MEPs and SPs. Rubolli and colleagues reported small spikes at the contralateral frontal area in specific association with epileptic negative myoclonus (Rubolli et al., 1995). However, `negative myoclonus' in their report appears to contain a small positive myoclonus preceding the SP. On the other hand, Davey and colleagues, using TMS, showed SPs without any prior excitatory response (Davey et al., 1994), and the optimal location (with the resolution of 2 cm) and orientation of the coil to induce SPs and MEPs were essentially the same. Our results further clarified that the cortical area which produced pure SPs is very close to but not completely identical to the area which produced MEPs upon stimulation, although both were located within the MI. It was also pointed out, using TMS, that the cortical area producing SPs was larger, encompassing and surrounding the area producing MEPs (Wilson et al., 1993). Our result could not argue this finding because the number of subdural electrode pairs investigated and the number of those producing responses by stimulation were both still small.
A scattered location of excitatory and inhibitory responses within MI as in the present study was demonstrated previously in monkeys (Schmidt and McIntosh, 1990). Inhibitory responses were elicited by repetitive stimulation (13–17 pulses consisting of 300–400 Hz of 0.2 ms/phase), and brief, transient inhibition of ~40–100 ms duration was induced. They mapped both excitatory and inhibitory responses elicited by intracortical microstimulation, and the response pattern was found to change by moving the stimulating electrode as little as 200 µm. They concluded that the inhibitory effects were most likely to be produced by excitatory corticospinal pathways that synapse on inhibitory interneurons in the spinal cord, because inhibitory responses occurred not only on voluntary muscle contraction but also on vibration-induced muscle contraction in which contraction was produced via a segmental spinal cord reflex. It has been demonstrated in humans that the initial part of the SP (~50 ms duration) involves spinal mechanisms rendering the alpha motor neuron pool inexcitable because the H-reflex is modulated during this period (Fuhr et al., 1991). The inhibitory responses in the present study were longer in duration than those reported by Schmidt and McIntosh (Schmidt and McIntosh, 1990). Therefore, not only a spinal inhibitory mechanism but also an intracortical inhibitory mechanism seems to be responsible for producing the inhibitory response observed in the present study. In patient 2, one pair of electrodes elicited MEPs in the APB whose onset latency was 32.4 ms. Since simultaneously recorded MEPs at the DEL and ECR had onset latencies of 10.8 and 15.6 ms, respectively, and since the patient had no weakness in the APB, it is likely that the delayed MEPs in the APB simply represent pyramidal neurons of slow conduction velocity, as shown in an animal study (Takahashi, 1965). However, EMG discharges were decreased transiently from 24.6 ms after the stimulus to the MEP onset, and furthermore, as shown in Fig. 4B, the MEP amplitude of the APB was consistently smaller than that of the ECR, whereas the SP duration was similar in the two muscles. These findings could suggest that the inhibitory activity on MEPs was induced rather selectively in the APB when stimulating MI. Since MEPs were recorded by surface electrodes but not by needle electrodes, a composite of the excitatory and inhibitory activities arising from many motor units of the APB could have been recorded in the present study. This might explain why MEPs in the APB were smaller and delayed.
A type (iii) response was observed in one electrode pair at SI (Fig. 5C), which corresponded to only 14.3% of the responses induced. Therefore, when studied by TMS, which essentially stimulates a larger area of the cortex simultaneously, this response type can be obscured by other predominant type (i) responses. It is worthwhile mentioning here that, as shown in Fig. 5C, SPs were not induced consistently in proportion to MEP amplitude, but it seems that SPs, if induced, had a nearly fixed duration of ~50 ms. It may suggest that at this particular stimulus point, only a spinal, but not a cortical, inhibitory mechanism is activated. A similar tendency could also be seen in Fig. 5A; for the MEPs of amplitude ranging from 20 to 150 µV, the duration of the accompanying SPs was consistently ~50 ms.
There is a concern as to how electric cortical stimulation by subdural electrodes activates human cortex compared with TMS. When a magnetic coil stimulator is placed on the scalp, it is speculated that the rapid change in magnetic field readily penetrates the intervening soft tissues and skull and induces an electric current in the brain parallel to the scalp surface, and no current flow perpendicular to the surface. It could depolarize the horizontal interneurons or afferent fibres which might then excite pyramidal tract cells trans-synaptically (Rothwell, 1991). On the other hand, in electric current stimulation, the anodal stimulus commonly used can activate the majority of pyramidal neurons directly, because an anode on the surface of the cortex produces electric current which can flow into the vertically oriented dendrites of pyramidal neurons and then excite or depolarize the initial segment region or the first node of the axon. Cathodal electrical stimulation, conversely, can excite neurons in the outer cortical layer, which finally indirectly excites pyramidal cells, as interpreted in TMS (Hern et al., 1962; Amassian et al., 1990). This interpretation for electric brain stimulation is applicable not only for scalp stimulation but also for subdural direct cortical stimulation. Since we employed subdural electrodes with a diameter of 3 mm, it is most likely that the very much smaller cortical area just beneath the electrode was activated compared with transcranial stimulation, although it involves a larger cortical area compared with intracortical microstimulation as done in animals. Since we employed alternating, 1 Hz electric stimulation between the two adjacent subdural electrodes, it is possible that the responses were produced by both cathodal and anodal stimulations, the former of which theoretically activates interneurons in the superficial part of the cortex. Unidirectional, cathodal subdural stimulation might elicit responses that are equivalent to TMS. However, it was unsuccessful in patient 3 because EMG responses gradually became smaller and, once the polarity direction was changed, the responses recovered to the initial level. This is probably because polarization of the platinum electrodes lessened the actual stimulus current effects. `Vertical inhibition', an overall suppression of neuronal activity including in pyramidal tract neurons in the deep cortical layer for 200–400 ms after brief epileptic activity in the upper cortical layer, could be taken as negative motor response (Elger and Speckmann, 1983). Electric cortical stimulation, like a single epileptiform discharge occurring in the upper cortical layer, may elicit `vertical inhibition' which would be observed as a type (ii) response in the present study. However, the type (ii) responses occurred only in 14% of cases in the present study, whereas `vertical inhibition' was observed in all identified pyramidal neurons in the deep layer (Elger and Speckmann, 1983).
Libet and colleagues directly stimulated SI in patients with parkinsonism in the awake state and studied the effects of stimulus parameters under various settings of electric pulse, including a single setting (once every 30 s), 1 Hz as in the present study, and high frequency repetitive stimulation (Libet et al., 1964). They placed 1 mm pore electrodes, filled with 0.9% NaCl, side by side at a distance of 2 mm. When they studied the effects of pulse frequency on the threshold to induce sensory symptoms, a single pulse needed a current intensity as large as or slightly larger than that for 1Hz stimulation, and no facilitatory effects were observed in the 1Hz stimulus condition. Thus, it is most likely that the averaged responses across 10 consecutive trials of 1Hz stimulation obtained in the present study reflect the net responses based on single pulse stimulation. They also showed that unipolar, single pulse, cathodal stimulation had a slightly lower threshold than anodal stimulation to elicit sensory symptoms when SI was stimulated, and essentially no other differences were observed between the two stimulus conditions. However, the comparison of SPs between anodal and cathodal stimulation using single electric pulses has not been investigated so far.
All three patients in the present study were taking antiepileptic drugs (carbamazepine and/or phenytoin) when the electric cortical stimulation was carried out. Antiepileptic drugs, working as sodium and calcium channel blockers without neurotransmitter properties like these two drugs, elevated the motor threshold but did not change the intracortical excitability, SP or MEP amplitude by means of TMS (Ziemann et al., 1996; Chen et al., 1997). The effects of antiepileptic drugs should always be considered when interpreting results such as those in the present study.
It is still controversial as to whether or not non-primary motor areas generate SPs (Wassermann et al., 1993; Rubolli et al., 1995; Baumgartner et al., 1996; Noachtar et al., 1997). In the present study, we stimulated pre-SMA, NMA and lateral premotor area. One pair at NMA showed MEPs and associated SPs whose responses were almost identical to those seen by stimulation of MI. None of the other pairs elicited either MEPs or SPs by single pulse electric stimulation. A similar finding was also reported previously (Akamatsu et al., 1995; Noachtar et al., 1997). This negative finding, i.e. the absence of pure SPs, may be explained by the possibility that the maximum current intensity of 15 mA employed in the present study was not strong enough to induce an SP, because a negative motor response with high frequency stimulation usually can be elicited by higher current intensity than that which elicited positive motor responses at MI. However, this is unlikely because, according to the findings of TMS, the threshold to induce SPs is usually lower than that which induces MEPs (Wassermann et al., 1993; Davey et al., 1994). Therefore, an SP or epileptic negative myoclonus is caused specifically by a single electric pulse or isolated single epileptiform discharges, respectively, whereas a negative motor response is related specifically to high frequency repetitive electric stimulation of the cortex where temporal facilitation occurs, resulting in dysfunction of the NMA, the so-called `apraxia', rather than the silence of muscle activities (Lüders et al., 1995).
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This study was supported by Grants-in-Aid for Scientific Research (A) 09308031, (A) 08558083, on Priority Areas 08279106 and (C) 10670583 from the Japan Ministry of Education, Science, Sports and Culture, and Research for the Future Program from the Japan Society for the Promotion of Science JSPS-RFTF97L00201.
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Received August 26, 1999. Revised February 17, 2000. Accepted February 28, 2000.
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