The cortical generators of the contingent negative variation in humans: a study with subdural electrodes

Electroencephalography and clinical Neurophysiology 104 (1997) 257–268

The cortical generators of the contingent negative variation in humans: a study with subdural electrodes Toshiaki Hamano a , c ,*, Hans O. Lu¨ders a, Akio Ikeda d, Thomas F. Collura a, Youssef G. Comair b, Hiroshi Shibasaki d a

Department of Neurology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Department of Neurosurgery, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA c Department of Neurology, Kyoto University School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan d Department of Brain Pathophysiology, Kyoto University School of Medicine, Shogoin, Sakyo-ku, Kyoto 606, Japan b

Accepted for publication: 9 January 1997

Abstract Contingent negative variations (CNVs) and Bereitschaftspotentials (BPs) were recorded from subdural electrodes implanted in 14 patients with intractable epilepsy. For recording CNVs, a Go/NoGo S2 choice reaction-time paradigm was employed. Two seconds after presentation of a low tone burst (S1), either a medium (S2m) or a high tone burst (S2h) was delivered at random. Patients were instructed to make middle finger extensions after S2m but not after S2h. For recording BPs, patients repeated self-paced middle finger extensions. BPs were recorded from the primary motor area (MI), the primary sensory area (SI) and the supplementary sensorimotor area (SSMA). CNVs showed a patchy distribution in the prefrontal area and SSMA for the early component and in the prefrontal area, MI, SI, temporal area, occipital area and SSMA for the late component. These results suggest that the CNV recorded from the scalp is the summation of multiple cortical potentials which have different origins and different functions. The cortical distribution of the late CNVs was different from that of BPs. Late CNVs are not equivalent to BPs and are not related to motor preparation alone. After S2, 3 kinds of potentials, probably related to decision making, somatosensory feedback and motor execution under specific conditions, respectively, were observed.  1997 Elsevier Science Ireland Ltd. Keywords: Contingent negative variation (CNV); Bereitschaftspotential (BP); Go/NoGo S2 choice reaction-time paradigm; Subdural electrodes

1. Introduction The contingent negative variation (CNV) is a slow negative shift of EEG which is elicited between warning (S1) and imperative (S2) stimuli when motor response to S2 is required. Although numerous studies have been done since the first report by Walter et al. (1964), there is still controversy regarding the neuronal generators of the CNV and its relationship to Bereitschaftspotentials (BPs) which precede self-paced voluntary movements (Kornhuber and Deecke, 1965).

* Corresponding author. Tel.: +81 75 7513770; fax: +81 75 7619780.

0168-5597/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0921-884X(97)9610 7-5

In scalp recordings, the CNV is widely distributed over the head with its highest amplitude at the frontal and central electrodes. Studies with intracranial recordings using invasive electrodes in animals and humans have stressed the role of the frontal lobe as a possible generator of CNV. Rebert (1972) recorded CNVs in a simple cued reaction-time paradigm in monkeys. CNVs were obtained from the motor and premotor cortices. The premotor responses were larger than those in the motor cortex. Hablitz (1973) reported that CNVs were obtained from many regions in the frontal lobe including the prefrontal, premotor and motor cortices. As far as invasive recordings of CNVs in humans are concerned, very few data have been available so far. By comparing potentials recorded from scalp electrodes with those from intracerebral and subdural electrodes in humans, Wal-

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ter (1967) concluded that CNVs arose from many areas of the frontal cortex. However, as Rebert (1976) pointed out, in most of these studies including both human and animal experiments, recordings were made only from the midline regions. Systematic studies covering all cortical regions, including the mesial surface of the brain, have not been reported yet. Recent studies with magnetoencephalography (MEG) have provided useful pieces of information regarding the cortical generators of the CNV. Fenwick et al. (1993), by recording the contingent magnetic variation (CMV) with a Go/NoGo paradigm, showed that the CMV consisted of multiple generators not only in the frontal cortex but also in the temporal, parietal and occipital cortices. Elbert et al. (1994) also recorded CMVs with a Go/NoGo paradigm and concluded that the generators of the CMV were distributed in the motor, sensory and association cortices. Another issue in debate is the relationship between the CNV, especially the late CNV, and the BP, a slow negative potential preceding self-paced voluntary movements. CNVs are divided into two components, namely the early and late CNV (Loveless and Sanford, 1974; Gaillard, 1976; Rohrbaugh et al., 1976). The early CNV persists for 1–1.5 s after S1, and is maximum at the frontal scalp. The late CNV, which is maximum at the central scalp, starts to develop about 1 s before S2. Rohrbaugh and Gaillard (1983) showed that when there was no motor response CNV waveforms could be well approximated by the long duration slow negative waves elicited by non-paired stimuli. Their finding indicated that CNV consists of early CNV alone when motor responses are not required and suggested that the late CNV is equivalent to the BP. On the other hand, several investigators showed that late CNVs could be obtained without motor responses (Cohen and Walter, 1966; Donchin et al., 1972; Klorman and Ryan, 1980; Ruchkin et al., 1986). These studies suggested that the late CNV is related not only to motor preparation but also to anticipation of the imperative stimuli and that late CNV is not equivalent to the BP. In good agreement with these observations, Ikeda et al. (1994) reported that BPs were abolished in some pathological states in humans in spite of persistent CNVs. However, whether the late CNV is primarily related to motor preparation or not is still an open question (Tecce and Cattanach, 1993). In the present study, to identify the generators of the CNV in human cerebral cortex and to clarify the relationship between the late CNV and the BP, CNVs in a Go/ NoGo S2 choice reaction-time paradigm and BPs with self-paced voluntary movements were recorded from subdural electrodes implanted in 14 patients with intractable epilepsy. Although the polarity of the slow EEG shift recorded in the present CNV paradigm was not always negative, the term ‘contingent negative variation’ was still used in this article for the sake of convenience.

2. Materials and methods 2.1. Materials Fourteen patients (13–50 years old) with intractable epilepsy, who had invasive monitoring with chronically implanted subdural electrodes for presurgical evaluation, participated in this study. Informed consent was obtained from every subject following the procedures approved by the local Institutional Review Board. None of the patients showed impairment of motor function on neurological examination. Eight patients showed lesions in the MRI. The lesions were located in the right cingulate gyrus in one patient, in the left cingulate gyrus in two patients, in the left frontal lobe in one patient, in the right parieto-occipital area in two patients, in the right occipital lobe in one patient and in the left occipital lobe in one patient. Seven patients had subdural plates on the right hemisphere and 5 on the left hemisphere. The other two patients had subdural plates bilaterally. 2.2. Experimental paradigms BPs were recorded in 10 patients. They were instructed to perform a series of voluntary brisk extension of the middle finger at the metacarpophalangeal joint contralateral to the side of the subdural electrode placement. In patients with bilateral electrodes, the middle finger contralateral to the hemisphere which had more electrodes was used. The movements were repeated at a self-paced rate of approximately once every 5 s. One patient was instructed to do abduction of the thumb instead of extension of the middle finger. CNVs were recorded in 14 patients. A Go/NoGo S2 choice reaction-time paradigm was employed for CNV recordings (Ikeda et al., 1994). A pair of tone bursts was delivered to the patient through a headphone. The warning signal (S1) was a low (1000 Hz) tone burst of 20 ms duration. Two seconds after S1, either a high (2000 Hz) tone burst (S2h) or a medium (1500 Hz) tone burst (S2m) also of 20 ms duration was delivered at random but with equal probability of occurrence. The interval between S2 and the next S1 varied between 3 and 5 s. Patients were instructed to make the same movements as employed for the BP recording as soon as possible after S2m (Go trial), but not to move after S2h (NoGo trial). In 4 patients who had only CNV recordings, extension of the middle finger was used as the motor task. 2.3. Data acquisition The subdural electrodes consisted of stainless steel electrodes of 3 mm in diameter embedded in a 1.5 mm thick silastic sheet. Center to center distance between electrodes was 1 cm. In both BP and CNV recordings, the EEG activity was recorded with a band-pass filter of 0.016–100 Hz. A

T. Hamano et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 257–268

scalp electrode placed on the mastoid process ipsilateral to the movements was used as reference. EMG was recorded from a pair of surface electrodes placed over the finger extensor muscles or thenar eminence with a band-pass filter of 5–100 Hz. All signals were digitized with a sampling frequency of 200 Hz and stored in a computer with an automated long-term EEG monitoring system ‘Epilog’ (Collura et al., 1992) for off-line analysis. 2.4. Data analysis BPs were obtained by averaging the EEG activity using the EMG onset as a trigger pulse. CNVs for Go and NoGo trials were obtained separately by averaging the EEG using S2m and S2h, respectively, as a trigger signal. The Go trials were averaged also time-locked to the EMG onset. For averaging EEG, a special computer program which is a modification of the method described by Barrett et al. (1985) was used. An off-line analysis was performed on a trial-to-trial basis with the signal set shifted to line up each trial according to the onset of EMG or S2. Trials contaminated with artifacts were eliminated from the averaging. EEG was averaged from 3000 ms before to 2000 ms after the EMG onset or S2. Measurement of latency and amplitude of each potential was computer-assisted and based on calibration data collected at the beginning of the experiment. Baseline was determined by averaging the epoch between 2500 ms and 2000 ms before the EMG onset or S2 for BP or CNV recording, respectively. For Go trials averaged time-locked to the EMG onset, the epoch between 3000 ms and 2500 ms before the EMG onset was used as a baseline. Presence of BP or CNV was determined by 3 of the authors (T.H., H.O.L. and A.I.) by visual inspection. Only the electrodes which showed a slow negative or positive shift of EEG more than 10 mV before the EMG onset or S2 were taken into consideration. 2.5. Cortical stimulation In order to map cortical function, electric current was applied to each electrode at varying intensities to elicit movement or sensation. Details of the methodology used for cortical stimulation have been described elsewhere (Lu¨ders et al., 1987). In brief, the stimuli consisted of 5 s trains of alternating square-wave pulses, 0.3 ms in duration with a regular repetition rate of 50 Hz. At all electrodes, the initial stimulus intensity was 1 mA, with gradual 1 mA increments until the subject experienced symptoms or signs. The maximum intensity was 15 mA. In the lateral convexity, the cortical areas which produced contralateral muscle contractions or paresthesias were identified as the primary motor area (MI) or the primary sensory area (SI), respectively. In the mesial surface, the supplementary sensorimotor area (SSMA) was distinguished from the MI by the specific type of motor responses (Lim et al., 1994). Stimulation of the SSMA also produced eye move-

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ments, paresthesias and negative motor effects (Lim et al., 1994). 2.6. Localization of the subdural electrodes In this study the data recorded from electrodes placed ipsilateral to the movements (33 electrodes) were excluded because there were not a sufficient number of electrodes to perform a detailed analysis. In 8 patients who showed lesions in the MRI, data recorded from electrodes on or close to the lesions were excluded from the analysis. Thus, 761 electrodes contralateral to the requested movement were analyzed in 14 patients. For the purpose of data analysis the brain was divided into the following regions: prefrontal area (lateral, mesial and basal), MI, SI, parietal area (lateral and mesial), temporal area (lateral and basal), occipital area (lateral, mesial and basal) and SSMA. Electrodes placed in the MI, SI and SSMA were identified by the results of the electric stimulation. Electrodes in the other areas were identified by analysis of skull X-rays, MRIs and direct observation during surgery.

3. Results 3.1. Auditory evoked potential (AEP) (Fig. 1) AEPs elicited by both S1 and S2 of the CNV paradigm had the same waveform and distribution for both stimuli. AEPs with a clear negative peak at about 100 ms after S1 or S2 were obtained from 40 electrodes located close to the Sylvian fissure in 3 patients who had a large subdural plate on the lateral convexity (Fig. 1A). Among them 17 electrodes were in the face motor area as shown by electric stimulation. This negative peak seemed to correspond to the N100 of the long latency AEP recorded with scalp electrodes. In a small number of electrodes in two patients, the subdurally recorded N100 was followed by a slow potential of relatively low amplitude, lasting about 1 s (Fig. 1A). Besides the N100, potentials occurring between 100 and 450 ms after S1 or S2 were recorded from 89 electrodes (11 patients) placed in various areas including the lateral prefrontal area, MI, SI, lateral parietal area, lateral and basal temporal areas, lateral, mesial and basal occipital areas and SSMA (Fig. 1B). Regarding these later components of the AEP, there was substantial interindividual and inter-electrode variability in waveform and latency. 3.2. Bereitschaftspotential (BP) (Fig. 2) The BP was defined as a slow negative or positive potential preceding the EMG onset in the voluntary movement paradigm. BPs started 0.5–2 s before the EMG onset. Occasionally the slope of the BP became steeper 100–900 ms before the EMG onset (negative slope, NS′) (Shibasaki et

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electrodes in the hand motor area, hand sensory area or SSMA. 3.3. Contingent negative variation (CNV) (Fig. 3)

Fig. 1. Schematic representation of the subdural electrodes placement and AEPs in patient 1 (a 50 year old male) (A) and patient 2 (a 15 year old female) (B). Only selected electrodes are shown. The types of response to electric stimulation of each electrode are shown by the symbols in the figure. MRI revealed cystic lesions in the white matter of the right occipital lobe in patient 2. (A) Negative peaks of 100 ms latency followed by a slow potential lasting for about 1 s recorded from an electrode (H5) in the lateral temporal area. AEPs with N100 peak were obtained from the electrodes surrounded by the solid line in the schema. (B) Negative peaks of 230 ms latency overlapping on CNV recorded from an electrode (E3) in the lateral occipital area. AEPs with peaks of the same latency were obtained from the electrodes surrounded by the solid line in the schema.

al., 1980). The BP peaked 90–500 ms after the EMG onset (motor potential peak). This negative or positive shift of the BP returned to baseline 0.5–2 s after the EMG onset, but occasionally it was followed by another potential (Fig. 2A). The number of electrodes which showed BP in each area is indicated in Table 1. Among the 10 patients (502 electrodes) who had the voluntary movement paradigm, 8 (55 electrodes) showed BPs. The BPs were recorded predominantly from the MI, SI (Fig. 2A) and SSMA (Fig. 2B). In 6 patients who had 21 electrodes in the hand motor area, 4 showed clear BPs in 15 electrodes. Only one out of 21 electrodes which were placed in the MI outside the hand motor area showed BPs. Among 15 electrodes placed in the hand sensory area (4 patients), 5 electrodes (4 patients) showed BPs. Among 5 patients in whom electrodes were placed in the SSMA, BPs were recorded in all patients (15 out of 32 electrodes). Isolated electrodes in the prefrontal area (11 electrodes in 4 patients out of 147 electrodes in 9 patients) and in the parietal area (6 electrodes in 2 patients out of 126 electrodes in 7 patients) showed BPs. However, all these electrodes were located in close proximity to the MI, SI or SSMA. None of the electrodes placed in the temporal area (70 electrodes in 5 patients) or the occipital area (65 electrodes in 3 patients) showed BPs. In the two patients who showed no BPs, there were no

The CNV was defined as a slow negative or positive potential recorded between S1 and S2 in the CNV paradigm which was not a part of the AEP. When a CNV existed at an electrode which also showed a BP, the CNV significantly modified the waveform of the BP. Eleven (96 electrodes) out of 14 patients (761 electrodes) showed CNVs. Two types of CNVs were identified. In Type 1 CNV (Fig. 3A,B), the negative or positive shift started immediately after S1. The onset of Type 1 CNV was sometimes obscured by the overlapping AEPs. In Type 2 CNV (Fig. 3C,D), the slow negative or positive shift started 1–0.5 s before S2. The absolute amplitude of the CNV measured at the time of S2 varied between 10 and 100 mV. CNVs peaked about 200–900 ms after S2 and then gradually returned to the baseline 0.5–2 s after S2 (CNV resolution). When CNVs with Go trials were averaged time-locked to the EMG onset, the peak was shifted to 0–300 ms before the EMG onset. In some electrodes the CNV with Go trials and NoGo trials showed a different waveform after S2 (62 electrodes in 9 patients) (Fig. 3A,B,D). There were substantial interindividual differences in the distribution of the CNVs. Tables 2 and 3 indicate the number of electrodes which showed Type 1 and Type 2 CNV, respectively. In 7 patients CNVs were obtained from more than two areas of the brain. CNVs were recorded from a small number of electrodes or a single electrode in each area. Type 1 CNVs, which correspond to the early and late CNVs recorded from scalp electrodes, were obtained only from the prefrontal area and the SSMA. Four out of 10 patients (23 out of 160 electrodes) who had electrodes in the prefrontal area showed Type 1 CNVs. Among the 23 electrodes which showed Type 1 CNVs in the prefrontal area, 5 were in the mesial prefrontal area and 18 were in the lateral prefrontal area. Out of 5 patients with electrodes in the SSMA (32 electrodes), 3 (6 electrodes) showed Type 1 CNVs. Type 2 CNVs, which correspond to the late CNVs recorded from scalp electrodes, were obtained from the prefrontal area, MI, SI, temporal area and occipital area. In 10 patients with electrodes placed in the prefrontal area (160 electrodes), Type 2 CNVs were obtained in 4 patients (6 electrodes). Five out of 6 electrodes which showed Type 2 CNVs in the prefrontal area were located in the lateral prefrontal area. Out of 8 patients (121 electrodes) who had electrodes in the temporal area, 3 (6 electrodes) showed Type 2 CNVs. Out of 6 electrodes which showed Type 2 CNVs in the temporal area, 5 were placed in the anterior basal temporal area. Out of 6 patients (243 electrodes) who had electrodes in the occipital area, 3 patients (52 electrodes) showed Type 2 CNVs. Among 52 electrodes which showed Type 2 CNVs in the occipital area, 29 were in the lateral occipital area, 10 were in the mesial occipital area

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Fig. 2. Schematic representation of the subdural electrodes placement and BPs in patient 3 (a 15 year old male) (A) and patient 4 (a 14 year old male) (B). Only selected electrodes are shown. Vertical lines indicate EMG onset. Patient 3 had a MRI lesion in the mesial parietal lobe. The shadowed area in patient 4 shows the extent of the MRI lesion. (A) Electrodes A5, A6, B6 and B7 in MI and A7 in SI showed clear negative BPs starting 600–1200 ms before the EMG onset. The BPs peaked 90 ms after the EMG onset, then returned to the baseline 550 ms after the EMG onset in A6 or were followed by another potential 270–410 ms after the EMG onset in A5, A7, B6 and B7. (B) Electrodes A3 and B2 in the SSMA showed positive BPs starting 1900 ms before the EMG onset. In A3, the BP was followed by a negative NS′ 860 ms before the EMG onset. In B2, the BP was followed by a positive NS′ 590 ms before the EMG onset. No recording was made from A4 because of malfunction of the electrode.

and 13 were in the basal occipital area. Out of 9 patients who had electrodes in the MI or SI, only one patient showed CNVs in these area (two electrodes in the MI and one in the SI). There was no clear difference in distribution between CNVs which showed the same waveform after S2 in the Go and NoGo trials and those which showed different waveform after S2 in the two trials. 3.4. BP and CNV in motor areas (Fig. 4) In MI, only two electrodes in one patient showed CNVs. These two electrodes showed BPs in the voluntary movement paradigm. In the other patients who had electrodes in the MI, the electrodes which produced BPs in the voluntary movement paradigm showed potentials only after S2 in the CNV Go trials but no potential before S2 when the averaging was made time-locked to S2. When the averaging was

made time-locked to the EMG onset, a small potential preceding the EMG onset could be obtained although its onset latency was later than that of BP (Fig. 4A). Among 32 electrodes placed in the SSMA (5 patients), BPs were recorded from 15 electrodes. Out of these 15 electrodes which elicited BPs, only 3 showed CNVs (Fig. 4B). CNVs were also obtained from 3 electrodes which did not show BPs in the voluntary movement paradigm. The distribution of the CNVs and BPs in the hemisphere contralateral to the movements is shown in Fig. 5. 3.5. Potentials recorded after S2 (without preceding CNV) (Fig. 6) Three different kinds of potentials without a preceding CNV were recorded after S2 in the CNV paradigm. The first is a potential which was elicited both in the CNV Go and CNV NoGo trials, but not in the voluntary move-

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Fig. 3. Schematic representation of the subdural electrodes placement and CNVs in patient 3 (A), patient 5 (a 30 year old male) (B), patient 2 (C), and patient 6 (a 39 year old male) (D). Only selected electrodes are shown. MRI revealed cortical dysplasia in the right mesial occipital area in patient 6. Two types of CNVs were recorded subdurally from various cortical areas. (A) Type 1 CNVs recorded from an electrode (A2) in the lateral prefrontal area. A slow negative shift of EEG started 2000 ms before S2 in the CNV NoGo and Go trials. When the averaging was made time-locked to the EMG onset in the Go trials (CNV GoEMG trials), the slow negative shift started 2500 ms before the EMG onset. Type 1 CNVs were obtained from the electrodes surrounded by the solid line in the schema. (B) Type 1 CNVs recorded from an electrode (F2) in the lateral prefrontal area. A slow negative shift of EEG started 2000 ms before S2 in the CNV NoGo and Go trials. In the CNV GoEMG trials, the slow negative shift started more than 2500 ms before the EMG onset. Type 1 CNVs were also obtained from electrode A1. (C) Type 2 CNVs recorded from an electrode (D4) in the lateral occipital area. A slow negative shift of EEG started 900 ms before S2 in the CNV NoGo and Go trials. In the CNV GoEMG trials, the slow negative shift started 1450 ms before the EMG onset. Type 2 CNVs were obtained from the electrodes surrounded by the solid line in the schema. (D) Type 2 CNVs recorded from an electrode (B10) in the anterior part of the basal temporal area. A slow positive shift of EEG started 610 ms before S2 in the CNV NoGo and Go trials. AEPs with a positive peak of 200 ms latency were also recorded. In the CNV GoEMG trials, the slow positive shift started 910 ms before the EMG onset. Type 2 CNVs were also obtained from electrode B11.

Table 1 Number of electrodes which showed BP Pt. no. Prefrontal area

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Tot.

Lat.

Mes.

5/5

1/4

Bas.

0/8

Primary motor area

Primary sensory area

Parietal area

Temporal area

Occipital area

Hand area

Oth.

Hand area

Oth.

Lat.

Mes.

Lat.

Bas.

Lat.

Mes.

Bas.

4/4

0/9

2/8

1/1

0/32

0/6

0/9 /5

/37

/8 0/12

/14

4/5

1/4

0/5

SSMA

6/12

0/12

0/8

2/7

/13 0/15 0/16 0/13 0/9 2/36 0/1

1/6 0/8

0/1 0/4 0/12

7/103 4/28

0/16

/11

0/1

5/5 0/6 0/12 0/16

0/11 1/2

0/12

0/7

0/1 0/1

0/6 1/1 0/1 6/9

2/2

/6

15/21

1/1 0/2 1/3

1/21

1/2

5/15

0/1 1/1

2/5

5/88

/22

0/22

0/12

0/10 3/5 2/4

0/11 0/8 0/9

1/38

/13 0/12

0/5 0/4 0/12

0/5

0/4

/40 /23 0/27

/12 /12 0/28

2/4

0/37

/11 0/33

/21 /11 0/10

15/32

The number of electrodes which showed BP/number of electrodes placed in each area in each patient is shown. The voluntary movement paradigm was not performed in patients 2, 5, 13 and 14. These patients are no included in Total. Pt., patient; La., lateral; Mes., mesial; Bas., basal; Oth., others; Tot., total.

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T. Hamano et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 257–268 Table 2 Number of electrodes which showed Type 1 CNV Pt. no. Prefrontal area

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Tot.

Lat.

Mes.

0/5

0/4

Bas.

7/8

Primary motor area

Primary sensory area

Parietal area

Temporal area

Occipital area

Hand area

Oth.

Hand area

Oth.

Lat.

Mes.

Lat.

Bas.

Lat.

Mes.

Bas.

0/4

0/9

0/8

0/1

0/32

0/6

0/9 0/5

0/37

0/8 0/12

0/14

0/5

0/4

0/5

SSMA

1/12

0/12

1/8

3/7

2/13 0/15 9/16 0/13 0/9 0/36 0/1

0/6 4/8

0/1 0/4 0/12

18/116 5/28

0/16

0/11

0/1

0/5 0/6 0/12 0/16

0/11 0/2

0/12

0/7

0/1 0/1

0/6 0/1 0/1 0/9

0/2

0/6

0/21

0/1 0/2 0/3

0/27

0/2

0/15

0/1 0/1

0/5

0/99

0/22

0/22

0/12

0/10 0/5 2/4

0/11 0/8 0/9

0/38

0/13 0/12

0/5 0/4 0/12

0/5

0/4

0/40 0/23 0/127

0/12 0/12 0/60

0/4

0/59

0/11 0/62

0/21 0/11 0/56

6/32

The number of electrodes which showed Type 1 CNV/number of electrodes placed in each area in each patient is shown. Pt., patient; La., lateral; Mes., mesial; Bas., basal; Oth., others; Tot., total.

ment paradigm (Fig. 6A). This potential (Type A potential) was infrequently seen but widely distributed in the mesial and basal prefrontal (5 electrodes in two patients), lateral and mesial parietal (6 electrodes in 3 patients), lateral and basal temporal (3 electrodes in one patient) and mesial occipital (3 electrodes in one patient) areas. Type A potentials usually started 150–500 ms after S2 and peaked 500–1000 ms after S2. Its duration was 500–1800 ms with its absolute peak amplitude ranging 10–200 mV. When averaged timelocked to the EMG onset in the CNV Go trials, Type A potential started before the EMG onset. The second potential was elicited both in the CNV Go trials and the voluntary movement paradigm but not in the CNV NoGo trials (Fig. 6B). This potential (Type B potential) was seen in the MI (4 electrodes in two patients), SI (6 electrodes in two patients) and lateral parietal area (17 electrodes in 6 patients). The same potential was also obtained from the mesial and basal occipital areas (9 electrodes in two patients). Its onset and peak latency was 300–700 ms and 700–1600 ms after S2, respectively, and its duration was 500–1500 ms. The absolute peak amplitude was 30– 50 mV. When averaged time-locked to the EMG onset in the CNV Go trials, the waveform was almost identical to that elicited with the voluntary movement paradigm. The third potential was elicited only in the CNV Go trials, and was never seen in the CNV NoGo trials. In the voluntary movement paradigm, it was either absent or very small, if any (Fig. 6C). This potential (Type C potential) was obtained from the lateral prefrontal (8 electrodes in 3 patients), lateral and mesial parietal (4 electrodes in one patient) and lateral and basal occipital areas (8 electrodes in one patient). The onset and peak latency was 150–500 ms and 500–1000 ms after S2, respectively, with its absolute peak amplitude of 20–50 mV. The duration was 500–1700

ms. When averaged time-locked to the EMG onset, the onset latency was 0–300 ms before the EMG onset. The schematic representation of each potential is shown in Fig. 7. 4. Discussion 4.1. Auditory evoked potential (AEP) Although the neural origins of long latency components

Fig. 4. BPs and CNVs recorded from the MI in patient 3 (A) and the SSMA in patient 4 (B). (A) Although BP starting 600 ms before the EMG onset was clearly recorded from electrode B6 placed in the MI (see Fig. 2A) in the voluntary movement paradigm (VM), no EEG shift was obtained preceding S2 in the CNV NoGo trials or CNV Go trials. When the averaging was made time-locked to the EMG onset in the Go trials (CNV GoEMG trials), a small potential preceding the EMG onset was obtained. (B) In both the CNV NoGo and Go trials, positive Type 1 CNVs were recorded from electrode A3 placed in the SSMA (see Fig. 2B). The voluntary movement paradigm produced a positive BP starting 1900 ms before the EMG onset followed by a negative NS′ 860 ms before the EMG onset.

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Fig. 5. Distribution of BPs and CNVs in the hemisphere contralateral to the movements. The ratio of electrodes which showed BPs (A), early CNVs (B) and late CNVs (C), respectively, to the total number of electrodes placed in each area, is shown. PF, prefrontal area; MI, primary motor area; SI, primary sensory area; P, parietal area; T, temporal area; O, occipital area; SSMA, supplementary sensorimotor area.

of AEP are still unknown, there are some studies indicating that intact temporal lobes are necessary for the generation of long latency AEPs. Long latency AEPs could not be recorded in patients with bilateral destruction of the temporal lobe (Woods et al., 1987). Vaughan and Ritter (1970) reported that components N100, P200 and N200 of the AEP recorded over the scalp have a phase reversal over the temporal lobe. Studies with MEG have shown that the superior temporal gyrus is a generator source of M100, the magnetic counterpart of N100 (Pantev et al., 1990; Rogers et al.,

1990). In the present study negative peaks of 100 ms latency after S1 or S2, corresponding to N100 of the long latency AEP recorded with scalp electrodes, were obtained in 3 patients. The distribution of these peaks was mainly in the area around the Sylvian fissure. Some electrodes which showed N100 were placed in the face motor area. These findings indicate that subdurally recorded N100 is generated not only in the superior temporal gyrus but also in other areas including the MI. In two patients, the N100 component of AEPs was followed by a slow potential which lasted for about 1 s. Rohrbaugh et al. (1978) reported that even non-paired auditory stimuli could induce long lasting slow negative waves. This potential may be related to the processing of the auditory stimuli and certainly may contribute to the early CNV recorded with scalp electrodes. Besides N100, potentials with later peak latency were recorded from various areas in 11 patients. Because of substantial interindividual and inter-electrode variability of the waveform and latency, it was not feasible to determine the relationship between these potentials and the components of the AEPs recorded with scalp electrodes. Neshige and Lu¨ders (1992) recorded event-related potential (ERP) in 3 patients with subdural electrodes. P300 and N300 was obtained from the midtemporal area and the inferior frontal area, respectively. Donchin and Smith (1970) pointed out that P300 component could be recorded in a CNV paradigm. Some of the later peaks recorded with subdural electrodes in the present study may be related to endogenous potentials such as P300 or N300. 4.2. Generator sources of CNV CNVs were obtained in the majority of patients and usually from a small number of electrodes or an even iso-

Table 3 Number of electrodes which showed Type 2 CNV Pt. no. Prefrontal area

1 2 3 4 5 6 7 8 9 10 11 12 13 14 Tot.

Lat.

Mes.

0/5

0/4

Bas.

0/8

Primary motor area

Primary sensory area

Parietal area

Temporal area

Occipital area

Hand area

Oth.

Hand area

Oth.

Lat.

Mes.

Lat.

Bas.

Lat.

Mes.

Bas.

2/4

0/9

1/8

0/1

0/32

0/6

0/9 0/5

8/37

0/8 0/12

1/14

0/5

0/4

0/5

SSMA

0/12

12

0/8

0/7

2/13 0/15 0/16 2/13 0/9 1/36 0/1

0/6 0/8

0/1 1/4 0/12

5/116 0/28

1/16

0/11

0/1

0/5 0/6 0/12 0/16

0/11 0/2

0/12

0/7

0/1 0/1

0/6 0/1 0/1 0/9

0/2

0/6

2/21

0/1 0/2 0/3

0/27

0/2

1/15

0/1 0/1

0/5

0/99

1/22

7/22

0/12

0/10 0/5 0/4

0/11 0/8 0/9

0/38

0/13 2/12

0/5 0/4 0/12

0/5

0/4

14/40 0/23 29/127

10/12 0/12 10/60

0/4

1/59

3/11 5/62

12/21 0/11 13/56

0/32

The number of electrodes which showed Type 2 CNV/number of electrodes placed in each area in each patient is shown. Pt., patient; La., lateral; Mes., mesial; Bas., basal; Oth., others; Tot., total.

T. Hamano et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 257–268

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Fig. 6. Three kinds of potentials recorded after S2 (arrows). (A) Type A potentials recorded from an electrode (C1) in the mesial prefrontal area in patient 4. The onset latency of the Type A potential in the CNV Go and NoGo trials was 190 ms after S2. When the averaging was made time-locked to the EMG onset in the Go trials (CNV GoEMG trials), the onset latency was 180 ms before the EMG onset. (B) Type B potentials recorded from an electrode (B8) in the SI in patient 3. The onset latency of the Type B potential in the CNV Go trials or the voluntary movement paradigm (VM) was 680 ms after S2 or 180 ms after EMG onset, respectively. In the CNV GoEMG trials, the onset latency was 320 ms after the EMG onset. Type B potentials were obtained from the electrodes surrounded by the solid line in the schema. (C) Type C potentials recorded from an electrode (C1) in the lateral occipital area in patient 6. The onset latency of the Type C potential in the CNV Go trials was 180 ms after S2. In the CNV GoEMG trials, the onset latency was 230 ms before the EMG onset. Type C potentials were obtained from the electrodes surrounded by the solid line in the schema.

lated electrode in two or more areas. This multiregional and patchy distribution of CNVs corresponds to the findings of Walter (1967), although this author placed electrodes only over the frontal cortex in his study. Type 1 CNVs, which correspond to the early and late CNVs recorded from scalp electrodes, were obtained from the prefrontal area and SSMA. Type 2 CNVs, which correspond to the late CNVs recorded from scalp electrodes, were obtained from the prefrontal, temporal and occipital areas. Type 2 CNVs were also recorded from a small number of electrodes in the MI and SI in one patient. These findings are essentially in agreement with the results of previous studies investigating the scalp distribution of early and late CNVs. Early CNVs are maximum anterior to the vertex while the late CNVs are maximum more posteriorly (Gaillard, 1976; Rohrbaugh et al., 1976). The role of the frontal cortex as a generator of the CNV has been stressed by early studies. In animal studies using invasive electrodes, CNVs were recorded from the frontal cortex including the prefrontal area, premotor area and MI (Borda, 1970; Donchin et al., 1971; Rebert, 1972; Hablitz, 1973; McSherry and Borda, 1973). Walter (1967) also recorded CNVs from the frontal cortex with subdural electrodes in humans. Recently other cortical areas have also been considered as possible generators of the CNV. Gemba et al. (1990) recorded field potentials in a CNV paradigm in the monkeys. Sustained surface-negative, depth-positive

potentials were recorded from the bilateral prefrontal areas, premotor areas and SSMA. Gradually increasing surface-negative, depth-positive potentials were also recorded from the MI and SI contralateral to the moving hand. Fenwick et al. (1993) recorded contingent magnetic variations (CMVs) in a Go/NoGo paradigm. In their experiment each S1 provided information about whether the corresponding trial was Go or NoGo. The early CMVs were recorded from the parietal association areas and the primary sensorimotor area in the NoGo trials and from the occipital cortex and posterior temporal area in the Go trials. The late CMVs were recorded from the primary sensorimotor area and the anterior temporal pole in the NoGo trials, and the posterior parietal region in the Go trials. Elbert et al. (1994) also recorded CMV using a Go/NoGo paradigm and found that a significant temporal activity contributes to both the early and the late CMV. Moreover, a single equivalent dipole was not a satisfying model either for the early or for the late CMV component. They concluded that CMV had multiple generator sources distributed in the motor, sensory and association cortices. Although the precise distribution of the cortical generators reported in those studies is different from that revealed by the present study, the existence of multiple CNV generators in the areas other than the frontal cortex was confirmed. After S2, CNVs returned gradually to the baseline. In some electrodes the CNV Go trials and NoGo trials elicited

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T. Hamano et al. / Electroencephalography and clinical Neurophysiology 104 (1997) 257–268

Fig. 7. Schematic representation of the Type A, B and C potentials. The Type A potential was elicited in the CNV Go and NoGo trials but not in the voluntary movement paradigm (VM). The Type B potential was obtained in the CNV Go trials and the voluntary movement paradigm but not in the CNV NoGo trials. The Type C potential was elicited only in the CNV Go trials.

different waveforms after S2. This was probably caused by different brain activities associated with motor execution in the CNV Go trials and motor inhibition in the CNV NoGo trials. Another possible cause accounting for the difference of waveform might be the somatosensory input produced by the movements in the CNV Go trials. At least a part of the movement-related potentials after the EMG onset is produced by somatosensory feedback (Tarkka and Hallet, 1991). Therefore, it is expected that the CNV Go trials would also produce similar potentials after S2. 4.3. Late CNV and BP Loveless and Sanford (1974) found that CNVs consisted of two distinct components, the early and the late CNV, when recorded with long interstimulus intervals between S1 and S2. The early CNV is considered to be an eventrelated potential related to S1 and varies as a function of modality (Gaillard, 1976; Ritter, 1980) or intensity of S1 (Loveless and Sanford, 1975). The nature of the late CNV has been controversial. According to Rohrbaugh and Gail-

lard (1983) the CNV consisted of the early CNV alone when no motor response was required. Their finding suggested that the late CNV is equivalent to the BP. However, other studies indicated that the late CNV could be elicited, without motor response, by attention to S2 (Klorman and Ryan, 1980), recognition of S2 (Cohen and Walter, 1966), calculation at the presentation of S2 (Donchin et al., 1972) or prediction of the modality of S1 and S2 (Donchin et al., 1972; Ruchkin et al., 1986). These authors concluded that the late CNV was the expression of summation of potentials generated by anticipation of S2 and those for motor preparation. Ikeda et al. (1994) reported a case with midbrain infarction disturbing selectively cerebellar efferent pathway who showed clear CNVs, but no BPs. Sasaki et al. (1990) compared the warning-imperative, visually initiated movement with the simple visually initiated reaction-time movement in monkeys. Cerebellar hemispherectomy did not prolong the reaction-time of the warningimperative, visually initiated movement, but marked delay in reaction-time was observed in the simple reaction-time movement. CNVs recorded from the prefrontal area, premotor area and somatosensory area were not affected by the cerebellar hemispherectomy, but CNVs recorded from the MI were reduced in amplitude. Both studies support the concept that the late CNV is not identical to the BP and that the late CNV includes potentials which are not associated with motor preparation. In the present study, BPs were recorded almost exclusively from the MI, SI and SSMA. These results are in good agreement with the results by Neshige et al. (1988) and Ikeda et al. (1992) in humans and by Hashimoto et al. (1981) in animals. In contrast with this, late CNVs were recorded mainly from the prefrontal area, temporal area, occipital area and SSMA. Late CNVs were obtained only from two electrodes in the MI which showed BPs in the voluntary movement paradigm. No clear CNVs were recorded from other electrodes in the MI. Even when averaged time-locked to the EMG onset in the CNV Go trials, potentials similar to the BPs were not seen before the EMG onset. These findings indicate that the late CNV elicited by the Go/NoGo S2 choice reaction-time paradigm used in the present study has different origins than the BPs preceding self-paced voluntary movements. In spite of a number of animal studies which showed that the MI is one of the cortical generators of CNVs (Borda, 1970; Donchin et al., 1971; Rebert, 1972; Hablitz, 1973; McSherry and Borda, 1973), in the present study no clear CNVs were obtained from the MI except for two electrodes in one patient. One possible explanation for this discrepancy is that in our study the subjects had to discriminate between S2m and S2h and to make a decision whether to move or not. Therefore, the reaction-time was much longer and its variation was larger than those of a standard S1-S2-reaction-time paradigm which does not require any choices. The slow potentials related to motor preparation generated from the MI might be canceled out when averaged using S2 as a

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trigger signal. However, the fact that no potentials or only small potentials could be seen before the EMG onset in the CNV Go trials when averaged time-locked to the EMG onset makes this possibility unlikely. Another possibility is that potentials for motor preparation might be suppressed or might not fully develop when the subjects concentrate on discrimination and/or decision making processes. Numerous studies in humans and animals indicate that the SSMA, in addition to the MI, is also related to motor preparation (Roland et al., 1980; Ikeda et al., 1992; Tanji, 1994). Among 15 electrodes which elicited BPs in the voluntary movement paradigm in the SSMA, only 3 showed CNVs. CNVs were also recorded from electrodes which did not show BPs. These findings also indicate that the late CNV is not equivalent to BP and that it is not merely reflecting brain activity related to motor preparation. 4.4. Potentials recorded after S2 Three kinds of potentials were recorded after S2 without preceding CNV only from a small number of electrodes. Type A potentials, recorded in both the CNV Go and NoGo trials but not in the voluntary movement paradigm, were obtained from the mesial and basal prefrontal, lateral and mesial parietal, lateral and basal temporal and mesial occipital areas. The CNV paradigm used in the present study required the subject to discriminate S2h and S2m to decide whether to move or not. This Type A potential is probably related to the decision-making process because no Type A potential was recorded in the voluntary movement paradigm which did not require a decision-making process. This potential corresponds to the ‘decision related potential’ described by Ikeda et al. (1996). Type B potentials, recorded in the CNV Go trials and the voluntary movement paradigm, but not in the CNV NoGo trials, seem to be related to the movement itself because they were induced only after movements were made. The waveform of the potential in the CNV Go trials averaged time-locked to the EMG onset was almost identical to that of the potential elicited by the voluntary movement paradigm which was also averaged time-locked to the EMG onset. The distribution of the Type B potentials was mainly in the MI, SI and lateral parietal area, suggesting that the Type B potential is derived from somatosensory feedback and/or activation of neurons in the MI necessary to execute the movement. Type B potentials were also obtained from the mesial and basal occipital areas in two patients. The significance of the Type B potentials observed in the occipital area is unclear. The Type C potentials, recorded only in the CNV Go trials, were obtained from the lateral prefrontal, lateral and mesial parietal and lateral and basal occipital areas. Sasaki and Gemba (1986) found a potential which was obtained only in NoGo trials with an onset latency of 110–150 ms. This potential was recorded from the prefrontal cortex of the monkey performing Go/NoGo choice reaction-time tasks.

267

They named this potential ‘NoGo potential’. Type C potential is quite different from the NoGo potential in waveform, time course and distribution. Although the function of the Type C potentials is unclear, it could be related to ‘motor execution’ under specific conditions in which discrimination of S2 is required. One or more of these 3 kinds of potentials occurring after S2 might be elicited in the electrodes which showed CNVs and could account for the difference of waveform after S2 between the CNV Go and NoGo trials. In the present study, however, only the electrodes without CNVs were analyzed, because distinction of these post-S2 potentials from CNV resolution was not feasible. In the present study the location and extent of the subdural electrode placements differed from patient to patient, and only subdural electrodes placed in the hemisphere contralateral to the finger movements were analyzed. In spite of these limitations, it is clearly documented that CNVs have a variety of multiple cortical generator sources not only in the frontal lobe but also in the temporal and occipital lobes. This study also shows that the late CNV is different from the BP. The potentials elicited by the CNV Go/NoGo S2 choice reaction-time paradigm employed in our study consist of several components which are related to different functions including stimulus processing, anticipation, motor preparation, decision making and somatosensory feedback.

Acknowledgements This study was partly supported by the Grants-in-Aid for Scientific Research 06404031, for International Scientific Research 07044258 and for Priority Scientific Research from the Japan Ministry of Education, Science and Culture for H.S.

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