The somatosensory evoked magnetic fields

Progress in Neurobiology 61 (2000) 495±523

www.elsevier.com/locate/pneurobio

The somatosensory evoked magnetic ®elds Ryusuke Kakigi a,*, Minoru Hoshiyama a, Motoko Shimojo a, Daisuke Naka a, Hiroshi Yamasaki a, Shoko Watanabe a, Jing Xiang a, Kazuaki Maeda a, Khanh Lam a, Kazuya Itomi a, Akinori Nakamura b a

Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan b Department of Biofunctional Research, National Institute for Longevity Sciences, Oobu, Aichi, Japan Received 29 September 1999

Abstract Averaged magnetoencephalography (MEG) following somatosensory stimulation, somatosensory evoked magnetic ®eld(s) (SEF), in humans are reviewed. The equivalent current dipole(s) (ECD) of the primary and the following middle-latency components of SEF following electrical stimulation within 80±100 ms are estimated in area 3b of the primary somatosensory cortex (SI), the posterior bank of the central sulcus, in the hemisphere contralateral to the stimulated site. Their sites are generally compatible with the homunculus which was reported by Pen®eld using direct cortical stimulation during surgery. SEF to passive ®nger movement is generated in area 3a or 2 of SI, unlike with electrical stimulation. Longlatency components with peaks of approximately 80±120 ms are recorded in the bilateral hemispheres and their ECD are estimated in the secondary somatosensory cortex (SII) in the bilateral hemispheres. We also summarized (1) the gating e€ects on SEF by interference tactile stimulation or movement applied to the stimulus site, (2) clinical applications of SEF in the ®elds of neurosurgery and neurology and (3) cortical plasticity (reorganization) of the SI. SEF speci®c to painful stimulation is also recorded following painful stimulation by CO2 laser beam. Pain-speci®c components are recorded over 150 ms after the stimulus and their ECD are estimated in the bilateral SII and the limbic system. We introduced a newly-developed multi (12)-channel gradiometer system with the smallest and highest quality superconducting quantum interference device (micro-SQUID) available to non-invasively detect the magnetic ®elds of a human peripheral nerve. Clear nerve action ®elds (NAFs) were consistently recorded from all subjects. # 2000 Elsevier Science Ltd. All rights reserved.

Contents 1.

Introduction and aims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496

2.

MEG system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497

Abbreviations: BESA, brain electric source analysis; C3, C4, Cz, position based on the 10±20 international EEG system. C3 and C4 are around the hand sensory area of the left and right hemisphere, respectively, and Cz was around the vertex; ECD, equivalent current dipole(s); EEG, electroencephalography; FE, femoral nerve; FMRI, functional MRI; GOF, goodness of ®t; MEG, magnetoencephalography; MRI, magnetic source imaging; MSR, magnetic shielded room; NAF, nerve action ®eld; NAP, nerve action potential; PE, peroneal nerve; PET, positron emission tomography; PPC, posterior parietal cortex; PT, posterior tibial nerve; RV, residual valiance; SEF, somatosensory evoked magnetic ®eld(s); SEP, somatosensory evoked potential; SU, sural nerve; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; SQUID, super conducting interference device; VAS, visual analogue scale. * Corresponding author. Tel.: +81-564-55-7765, 7769; fax: +81-564-52-7913. E-mail address: [email protected] (R. Kakigi). 0301-0082/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 3 0 1 - 0 0 8 2 ( 9 9 ) 0 0 0 6 3 - 5

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3.

SEF following stimulation applied to various parts of the body 3.1. Lower limb stimulation . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Truncal stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Upper limb stimulation . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Lip stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Scalp and shoulder stimulation . . . . . . . . . . . . . . . . . . . 3.6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.

Topography of SII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

5.

Analysis using the multidipole model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

6.

SEF following passive movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

7.

Sensori-motor interaction in SEF . . . . . . . . . . . . . . . . . . . . . . . 7.1. E€ects of movement interference (gating) . . . . . . . . . . . . 7.2. E€ects of tactile stimulation on SEF . . . . . . . . . . . . . . . . 7.3. E€ects of visual and auditory stimulation on SEF . . . . . . 7.4. Intracerebral interaction produced by bilateral stimulation

8.

SEF studies on plasticity in SI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510

9.

Clinical application of SEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

10.

Other important ®ndings of SEF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513

11.

12.

SEF following painful CO2 laser stimulation . 11.1. General ®ndings . . . . . . . . . . . . . . . . 11.2. Analysis using a multi-dipole model . . 11.3. E€ects of distraction on pain SEF . . . 11.4. General discussion of pain SEF . . . . .

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506 506 507 509 509

513 513 515 515 516

Micro-SQUID. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519

1. Introduction and aims The evaluation of averaged electroencephalography (EEG) following somatosensory stimulation, i.e. somatosensory evoked potential (SEP), is one of the most useful methods for investigating the human somatosensory system. A large number of studies have utilized computerized bit-mapped images of scalp topography of SEP in attempts to elucidate each identi®able component (see Kakigi and Shibasaki, 1991, 1992). However, scalp-recorded EEG could not provide enough resolution to estimate the location of the electrical source in the brain. This is because the in¯uence of volume currents on scalprecorded EEG severely a€ects source identi®cation. Furthermore, the large inter-individual variability of intervening tissues, including scalp, skull and cerebrospinal ¯uid, makes it dicult to estimate the dipole location.

Another noninvasive technique for investigating the bioelectrical functions of the brain, magnetoencephalography (MEG), has been developed over the past 25 years. MEG has several theoretical advantages over EEG in localizing cortical sources (brain dipoles), because the magnetic ®elds recorded on the scalp are less a€ected by volume currents and anatomical inhomogeneities. MEG has excellent spatial and temporal resolution, in the order of mm and ms (Hari, 1991; Hamalainen, 1992). The spatial resolution of MEG is almost the same as that of functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), but the temporal resolution is much better. Therefore, we can analyze MEG responses to somatosensory stimulation for not only detecting cortical sources but also measuring the time taken for signals (activities) to transfer in the brain in the order of milliseconds. However, there are four main disadvantages of MEG. The

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®rst is that it is dicult for MEG to detect brain dipoles radial to the skull, which are mainly generated in the gyrus. In other words, dipoles tangential to the skull generated in the wall of the sulcus, i.e. area 3b or 4 along the central sulcus, are easily detected by MEG. The second is that activities in the white matter are not detected by MEG, since generators of MEG are apical dendrites of the pyramidal cells in the cortex. The third disadvantage is that it is dicult for MEG to detect dipoles generated in the deep areas, since magnetic ®elds recorded from outside of the scalp rapidly decrease with increasing depth. The fourth one is that it is dicult for MEG to detect multiple generators (dipoles). Therefore, a special new algorithm is needed for calculating multiple sources. Researches must be careful of the advantages and disadvantages of MEG. In the 20 years since the averaged MEG values following somatosensory stimulation, i.e. somatosensory evoked magnetic ®eld (SEF), were ®rst reported (Brenner et al., 1978; Kaufman et al., 1981; Hari et al., 1983, 1985; Wood et al., 1985; Sutherling et al., 1988), many studies have been conducted and their number continues to increase. In this paper, therefore, we will introduce SEF ®ndings in humans, particularly those unique and interesting aspects, mainly by describing recent studies of SEF in our department. First, our MEG system is explained brie¯y and then the detailed results of SEF, mainly topography of the primary and secondary somatosensory cortex, SI and SII, respectively, are described. Three recent hot topics, SEF to passive movement, ®ndings of sensori-motor interaction on SEF and pain-related SEF are discussed. We describe two important matters, the clinical applications of SEF and cortical somatosensory plasticity identi®ed by recording SEF. Finally, preliminary ®ndings for the newly developed device, a very small and close-spaced superconducting quantum interference device (micro-SQUID), are introduced. 2. MEG system The magnetic ®elds recorded from the human brain are very small, approximately ten thousands to a million times smaller than the Earth's steady magnetic ®eld and environmental ®elds (caused by a train, for example). A superconducting quantum interference device (SQUID) is necessary to detect these weak brain ®elds. We use dual 37-channel axial-type ®rstorder biomagnetometers (Magnes, Biomagnetic Technologies (BTi), San Diego, CA) (Fig. 1). The waveforms from 74 channels are thus simultaneously recorded. The detection coils of the biomagnetometers are arranged in a uniformly distributed array in concentric circles over a spherically concave surface. All

497

Fig. 1. The MEG system (Magnes, Biomagnetic Technologies (BTi)) in our laboratory. We use two sets of 37-channel magnetometers.

of the sensor coils are thus equally sensitive to the brain's weak magnetic signals. Each device is 144 mm in diameter with a radius of 122 mm. The outer coils are 72.58 apart and each coil is connected to a SQUID. The spacing between centers of coils is 22 mm. The coils are 20 mm in diameter and have a 50 mm baseline. The magnetically shielded room used (MSR, Vacuumschmelze) has a three-layer design consisting of an aluminum shell with one layer of soft magnetic material (Mumetal) with high permeability on each side of the aluminum. By signi®cantly reducing the ambient and radio frequency noise, the MSR provides the necessary magnetically quiet environment for MEG (Pantev et al., 1991). Our MEG system consists of: (1) an MSR; (2) the SQUID sensor unit; (3) a data acquisition processor; and (4) a master analysis processor. With our MEG system, dual probes are centered at the C3 and C4 positions. The International 10/20 EEG

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Fig. 2. The left and right hemispheres are recorded simultaneously using the two sets of magnetometers. When a vertical area is recorded, e.g. the foot area of the SI is analyzed, one magnetometer is used.

system, was used in all instances to cover the left and right hemisphere (Fig. 2). When the lower limb area of the SI was examined, one probe was centered at the Cz position around the vertex (the International 10/20 EEG system) (Fig. 2). The responses were usually recorded with a 0.1±100 or 200 Hz bandpass ®lter and digitized at a sampling rate of 2048 or 4096 Hz. The analysis window was 300 ms after the stimulus and direct current (dc) was o€set using a prestimulus period (100 ms) as the baseline. Two or three hundred trials were averaged in one session. A spherical model (Sarvas, 1987) was ®tted to the digitized shape of the head of each subject and the location (x, y and z location), orientation and amplitude of the best-®tted equivalent current dipole(s) (ECD) were estimated at each time point. The origin of the head-based coordinate system was the midpoint between the preauricular points. The x-axis indicated the coronal plane with a positive value toward the left preauricular point and the z-axis lay on the transverse plane perpendicular to the x±y line with a positive value toward the upper side. The correlation between the recorded measurements and the values expected from the ECD estimate was calculated as a measure of how closely the measured values corresponded to the theoretical ®eld generated by the model and the observed ®eld. Magnetic resonance imaging (MRI) was obtained

using a Magnex 150XT 1.5T system (Shimadzu, Kyoto, Japan). The T1-weighted coronal, axial and sagittal images with a contiguous 1.5 mm slice thickness were used for overlays with ECD sources detected by MEG. The same anatomical landmarks used to create the MEG head-based on the three-dimensional (3D) coordinate system (the nasion and bilateral preauricular points) were visualized in the MRI images by axing to these points high-contrast cod liver oil capsules (3 mm diameter), the short relaxation time of which provides a high-intensity signal in T1-weighted images. The common MEG and MRI anatomical landmarks allowed easy transformation of the headbased 3D coordinate system (nasion and entrance of the auditory meatus of the left and right ear) used for the MEG source analysis to the MRI. The MEG source locations were converted into pixels and slice values using the MRI transformation matrix and inserted onto the corresponding MRIs.

3. SEF following stimulation applied to various parts of the body Since the landmark studies of Foerster (1936) and Pen®eld and Boldray (1937) on the motor and sensory representations in the human cerebral cortex based on direct electrical stimulation of the cortical surface, it

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has been well known that the primary sensorimotor cortex is organized in an orderly somatotopic way which has been termed the `homunculus' representation of the cutaneous body surface. We are now studying SEF following stimulation applied to various parts of the body in normal subjects to examine the homunculus by this non-invasive method. As described in Section 1, MEG detects only a speci®c orientation of brain current tangential to the skull. Therefore, dipoles generated in area 3b or 4 (which is located on the posterior and anterior bank of the central sulcus, respectively) are easily detected, but dipoles in area 1 or 3a (which is located on the crown and the bottom of the central sulcus, respectively) are not. There are many important reports on the receptive sites following stimulation of the lower limb (Hari et al., 1984; Kaukolanta et al., 1986; Huttunen et al., 1987; Rogers et al., 1994; Hari et al., 1996), the urogenital organs (Nakagawa et al., 1998), the upper limb (Huttunen et al., 1987; Tiihonen et al., 1989; Rossini et al., 1989, 1994; Baumgartner et al., 1991; Suk et al., 1991; Akhtari et al., 1994; Buchner et al., 1994; Gallen et al., 1994; Schnitzler et al., 1995a,b; Kawamura et al., 1996; Mauguiere et al., 1997a,b; Shimizu et al., 1997; Tecchio et al., 1998; Jousmaki and Hari, 1999), face (Karhu et al., 1991; Mogilner et al., 1994) and multiple sites (Narich et al., 1991; Yang et al., 1993; Gallen et al., 1994). However, we here have concentrated mainly on results in our department. 3.1. Lower limb stimulation In our ®rst study, we investigated the topography of SEF following stimulation of the right and left posterior tibial nerves at the ankle in ®ve normal subjects (10 nerves) (Kakigi et al., 1995a). The main de¯ections, N37m±P45m±N60m±P75m, and their counterparts, P37m±N45m±P60m±N75m (Fig. 3), were identi®ed in the hemisphere contralateral to the stimulated nerve. The term `37m', for example, means the magnetic de¯ection whose peak latency is about 37 ms. According to the conventional nomenclature for the SEP and SEF, `N' and `P' mean `negative' and `positive' in SEP, respectively, and `outgoing' and `ingoing' in SEF, respectively. The ECD of all main de¯ections were located in the foot area of the SI, probably in area 3b, which mainly responds to the signals ascending through cutaneous ®bers. The restricted minor de¯ections, P40m±N40m and N45m±P45m, were considered to be generated in area 1 in the SI. Although ECD generated in area 1 are thought to be mainly oriented radially, the magnetometer probably detected their slight tangential components as P40m±N40m and N50m±P50m in this study. Since the generator sources of P37m±P37m, P40m±N40m and N45m±p45m were temporally changed and interfered with each other, the

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Fig. 3. SEF following right posterior tibial nerve stimulation recorded at the Cz position in one subject. Representative waveforms recorded at four channels are shown to indicate the nomenclature of each de¯ection. The N40m±P40m and N50m±P50m are clearly independent from the P37m±N37m, N45m±P45m, P60m±N60m and N75m±P75m. Adopted from Kakigi et al. (1995a).

direction of the ECD appeared to be rotated with the passage of time (Fig. 4). Small middle-latency de¯ections, N100m±P100m, were clearly identi®ed in two subjects. The ECD of these de¯ections were found in the second somatosensory cortex (SII) in both hemispheres. In the second study, we recorded the SEF following the stimulation of various nerves of the lower limb, posterior tibial (PT) and sural (SU) nerves at the ankle, the peroneal nerve (PE) at the knee and the femoral nerve (FE) overlying the inguinal ligament in seven normal subjects (14 limbs) and con®rmed the usefulness of SEF in clarifying the di€erentiation of the receptive ®elds (Fig. 5) (Shimojo et al., 1996a). The results were summarized as follows: (1) the ECDs of magnetic ®elds following stimulation of the PT and SU were located very close to each other, along the interhemispheric ®ssure in all 14 limbs. They were directed horizontally to the hemisphere ipsilateral to the stimulated nerve. (2) The ECD following stimulation of the FE was clearly di€erent from that seen in the other nerves, in terms of the location and/or direction, in all 14 limbs. The ECDs of the 14 limbs were classi®ed into two types according to the distance of ECD from PT and FE; Type 1 (>1 cm, nine limbs) and Type 2 (<1 cm, ®ve limbs) (Fig. 6). The ECD following FE stimulation was located on the crown of the postcentral gyrus or at the edge of the interhemispheric ®ssure in Type 1 and was close to the ECDs following PT and SU stimulation along the interhemispheric ®s-

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sure in type 2. (3) The ECD following PE stimulation was located along the interhemispheric ®ssure in all 14 limbs, as for PT and SU. Its location was slightly but signi®cantly higher than that of PT and SU stimulation in Type 1 and was close to the ECDs following PT and SU stimulation in Type 2. The present ®ndings indicated that approximately 65% (9 of 14) of the limbs showed particular receptive ®elds compatible with the homunculus. The large inter- and the intraindividual (left-right) di€erences found in this study indicated signi®cant anatomical variations in the area of the lower limb in the sensory cortex in humans.

noise ratio and diculty in ®xing the stimulation electrode. M17 was absent or small in amplitude. The latency of M25 was from short to long in the order Th6, Th8 and Th10 (P < 0.05). ECD of all components for each site stimulation were located in the truncal area of the SI (Fig. 7). The locations of the ECD tend to be arranged from lateral to medial in the sequence Th6, Th8 and Th10 (Fig. 7). Therefore, we consider that the representation area of the trunk is small, and the receptive area for the stimulation of Th6, Th8 and Th10 dermatomes are very close to or overlap each other.

3.2. Truncal stimulation

3.3. Upper limb stimulation

For sensory perception, the trunk is innervated by spinal nerves which enter the dorsal root. Each spinal nerve is distributed to a well de®ned area of skin called the dermatome. It is strange that the trunk of the dermatome occupies a large part of the body, but its space in the homunculus is very small. We analyzed the location of ECD of SEF following electrical stimulation of the skin at Th4, Th6, Th8, Th10 and Th12 dermatomes in 14 normal subjects (Itomi et al., 2000a). Three de¯ections, M17, M25 and M40, were obtained within 60 ms after the stimulation of Th6, Th8 and Th10 dermatomes. We named each component only by their latency. No consistent de¯ection could be identi®ed following Th4 and Th12 dermatomal stimulation, probably due to a poor signal to

A SEF following upper limb stimulation is usually recorded following stimulation of the median nerve at the wrist (Kakigi, 1994) or ®ngers (Xiang et al., 1997a). N20m±P30m±N40m±P60m±N90m and their counterparts, P20m±N30m±P40m±N60m±P90m, were identi®ed in the hemisphere contralateral to the stimulation (Kakigi, 1994). Restricted de¯ections, P25m and N25m, were recorded like the P40m±N40m and N45m±P45m of the lower limb stimulated SEF, and were thought to be generated in area 1 (Kakigi, 1994). However, the `dipole rotation' found in the lower limb SEF was not identi®ed in the upper limb SEF, probably due to an anatomical di€erence. We, using stimulation of the middle ®nger, reported 1M, 2M, 3M and 4M components which corresponded to N20m±P20m, P30m±N30m, P60m±N60m and

Fig. 4. Isocontour maps (20fT/step) of six representative periods between 36.1 and 45.1 ms following right posterior tibial nerve stimulation in one subject. The probe was centered on the vertex (Cz). The outward ¯ux is marked by thin lines, the inward ¯ux by dotted lines and zero points by thick lines. The ECD are estimated under the crossing point of the zero line and the line connected the maximum points of the outward and inward ¯uxes. The depth of the ECD depends on the distance between the maximum points of the outward and inward ¯ux. The direction of the ECD appeared to be rotated with the passage of time. Adopted from Kakigi et al. (1995a).

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N90m±P90m, respectively (Xiang et al., 1997a). We named each component by the order of appearance rather than their latency. This nomenclature has also recently become popular in the study of SEF. E indicates electrical stimulation. The ECDs of 1M, 2M and 3M were located in the hand area of the SI, probably in area 3b, but the 4M was located in the SII (Fig. 8). In the hemisphere ipsilateral to the simulation, a 4M(I) (I indicates ipsilateral) component whose peak latency was approximately 80±100 ms was recorded, and its ECD was estimated to be in SII, like the 4M recorded from the contralateral hemisphere.

501

upper and lower lips was investigated in 6 normal subjects, to identify the bilateral receptive ®elds in the SI (Hoshiyama et al., 1996). A pair of silver ball electrodes attached to the tips of a T-shaped aluminum wire (newly designed equipment) was used for stimulation. When the lateral side of the upper lip was stimulated, P20m and its counter part, N20m, were identi®ed in the hemisphere contralateral to the stimulated side. The ECD of N20m±P20m were located in the lip areas of the SI (Figs. 9 and 10). Middle-latency de¯ections

3.4. Lip stimulation The topography of SEF following stimulation of the

Fig. 5. Chart showing SEF following stimulation of the posterior tibial and sural nerve at the ankle, the peroneal nerve at the knee and the femoral nerve overlying the inguinal ligamentum of the right lower limb in one subject. Waveforms recorded at 37 channels are superimposed. Four components indicated by arrows are identi®ed in each waveform. Adopted from Shimojo et al. (1996a).

Fig. 6. MRIs showing the location and direction of ECDs of the 1M following stimulation of four nerves of the right lower limb in two subjects. In subject 1, the ECD following the femoral nerve stimulation is located on the crown of the postcentral gyrus directed to the inferior and posterior sides. In contrast, the ECDs following stimulation of the other nerves are located along the interhemispheric ®ssure directed to the right hemisphere. The ECDs of the other nerves are located very close together, but that following peroneal nerve stimulation is slightly higher than that following the stimulation of the other two nerves. This type of receptive ®eld is classi®ed as Type 1. In subject 2, the ECD following the stimulation of each nerve are located close together, along the interhemispheric ®ssure. Those following stimulation of the posterior tibial and sural nerve were directed to the right hemisphere horizontally, but those following stimulation of the peroneal and femoral nerves were directed anteriorly and posteriorly, respectively. This type of receptive ®eld is classi®ed as Type 2. L, left; R, right. Adopted from Shimojo et al. (1996a).

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(N40m±P40m, N60m±P60m and N80m±P80m) were identi®ed in the bilateral hemispheres (Figs. 9 and 10). Long-latency de¯ections (P110m±N110m) were recognized in both hemispheres and their ECD were located inferior to the SI, in an area considered to be the SII (Figs. 9 and 10). When the lower lip was stimulated, the ECD of short and middle latency de¯ections were located at a site in the SI inferior to or near those elicited by the upper lip stimulation. The ECD of P110m±N110m were located in an area of the SII similar to that observed upon stimulation of the upper lip.

3.5. Scalp and shoulder stimulation To study the SEF following scalp stimulation, we used a special sensory output tapping device (9037953, BTi) rather than conventional electrical stimulation, because the stimulation site and recording site were very close to each other (Hoshiyama et al., 1995). The tapping device, consisting of a small balloon (diameter 1 cm) attached to the scalp, was used for stimulation. The air pressure to in¯ate the small balloon was 15psi, which induced the mechanical stimu-

Fig. 7. The ECD of the M25 component to the right Th6, Th8 and Th10 stimulation are overlapped on the two-dimensional MRI in subject 1 (a) and subject 2 (b). The ECD to stimulation of all three sites were located very close to each other in the trunk area of the SI in the left hemisphere. Adopted from Itomi et al. (2000a).

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lation of 30 g/cm2 at the stimulated sites, i.e. the forehead. The ECD of the initial magnetic ®eld, 1M, was identi®ed in the SI in the hemisphere contralateral to the stimulation. The ECD position of 1M in the SI generated after the scalp stimulation was inferior and close to the hand area of the SI, which was consistent with the layout of the homunculus (Fig. 11). The ECD of the subsequent magnetic ®eld, 2M, was identi®ed in the bilateral SII (Fig. 11). The shoulder, posterior neck and lower part of the head occupied a strange area of the homunclus between the trunk and arm, which separately localized from the face area of the homunclus. We recorded SEF following stimulation of the lower part of the posterior head around the mastoid and shoulder (Itomi et al., 2000b). In most subjects, the ECD to the mastoid and shoulder stimulation were located in the area slightly lateral and inferior to the ECD location for the trunk stimulation. However, in some subjects, the ECD to the mastoid stimulation was located near the face stimulation. This may be due to an anatomical variation in each subject.

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rare and frequent, or target and non-target stimuli) (Hari et al., 1990, 1993; Forss et al., 1995; Mima et al., 1998a) make the SII components increase in amplitude. This ®nding suggested that SII activities are more a€ected by volitional or attention e€ects than the SI activities. We analyzed the topography of SII to somatosensory stimulation applied to various parts of the body of normal subjects using SEF (Maeda et al., 1999). SII components were found about 80±100 ms after stimulation as the middle-latency components. SII in the bilateral hemisphere was activated on stimulation of the unilateral side of the body, that is, SII in humans has a `bilateral function'. Although there were large interindividual di€erences, the receptive ®elds ranked (Fig. 13); (1) anterior±posterior direction: lower lip±upper lip±thumb±middle ®nger±foot, (2) medial±lateral direction: foot±middle ®nger±thumb±upper lip±lower lip and (3) lower±upper direction: lower lip±upper±lip±

3.6. Summary We made a complete homunculus in ®ve normal subjects (Nakamura et al., 1998). We recorded SEF following stimulation of 19 sites (tongue, lower lip, upper lip, thumb, index ®nger, middle ®nger, ring ®nger, little ®nger, radial palm, ulnar palm, forearm, elbow, upper arm, chest, thigh, ankle, big toe, second toe and ®ve toe) and put their ECD on the MRI of each subject (Fig. 12). These representation areas were generally arranged in the above order from inferior to superior, lateral to medial and anterior to posterior. The changes in the coordinates were compatible with the anatomy of the central sulcus and the homunculus. The ECD location of the upper lip could be distinguished from that on the lower lip, the former located more superior than the latter in all subjects. Each ®nger representation area of the thumb, index ®nger, middle ®nger, ring ®nger and little ®nger was distinguishable. They were represented sequentially from thumb to little ®nger, ascending the postcentral sulcus. 4. Topography of SII One of the major advantages of SEF is that it easily records activities in the SII, where it is dicult for SEP to detect activities due to the location and direction of dipole sources (Hari et al., 1983, 1990, 1993; Elbert et al., 1995a; Forss et al., 1995; 1998; Mima et al., 1997, 1998a). A random or long interstimulus interval stimulation rate (Wikstrom et al., 1996; Nagamine et al., 1998) and the oddball paradigm (using

Fig. 8. The ECD of the main components of SEF, recorded at the C4 position (right hemisphere) following electrical stimulation of the left middle ®nger, overlapped on axial, coronal and sagittal MRI views in one subject. The right side of the MRI indicates the right hemisphere. ECD of the 1M, 2M and 3M are located around the ®nger area of the SI, but the 4M is located on the superior bank of the Sylvian ®ssure, probably in SII. Adopted from Xiang et al. (1997a).

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thumb±middle ®nger±foot. In general, these ®ndings are similar to those obtained in studies of animals (Whitzel et al., 1969) and humans (Hari et al., 1993). However, the di€erentiation was not as clear as that seen in the homunculus in the SI. The SII is located at a site more anterior, medial and upper than the auditory cortex. 5. Analysis using the multidipole model Forss et al. (1994a,b; 1995) reported a middlelatency component whose peak latency was about 80± 100 ms generated by the activation of the posterior parietal cortex (PPC) in response to upper limb stimulation. We also investigated PPC activities to determine its fundamental role as a somatosensory associated area using MEG (Hoshiyama et al., 1997). We studied SEF following the stimulation of the median nerve, posterior tibial nerve and lip, using the brain electric source analysis (BESA) system (Scherg, 1995). In the ®ve-dipole model, the ECDs of the middle-latency SEF after stimulation of the median and posterior tibial nerve were identi®ed in the contralateral SI and in the bilateral SII and PPC, while all activities of the middle-latency SEF after lip stimu-

lation appeared to be restricted to the contralateral SI and bilateral SII (Fig. 14). At around 80 ms in latency, the ECD location in the PPC after median nerve stimulation was, on the average, 2.4 cm posterior, 2.9 cm median and 2.6 cm superior to the hand area of the SI. The ECD in the PPC after posterior tibial nerve stimulation was also located posterior to the foot area of the SI, but it was close to the SI, the distance between them being approximately 1.3 cm. The ECD in the PPC was almost equally demonstrated in each hemisphere. These ®ndings suggested that the somatosensory associated cortex in the PPC has a somatotopic organization in parallel with the homunculus in the SI, but the hand area was much wider than the foot area. It was not clear whether the lip area in the PPC was absent or was too close to be separated from the SI. More detailed studies using other software programs may be necessary to determine the activities of the PPC in humans. 6. SEF following passive movement SEP or SEF following conventional electrical stimulation or mechanical tap or air-pu€ applied to the skin probably ascend through cutaneous ®bers and reach

Fig. 9. Thirty-seven superimposed waveforms in a subject are shown to illustrate the nomenclature for each identi®able component following upper and lower lip stimulation. The short-latency and middle- and long-latency SEF recorded from the contralateral and ipsilateral hemisphere to the stimulated side are shown in the upper and middle trace, respectively. The lower traces were recorded following stimulation of the midline of the lip. N100m±P100m are attenuated in amplitude as compared with those recorded in the contralateral hemisphere. Adopted from Hoshiyama et al. (1996).

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area 3b (Kakigi and Shibasaki, 1984; Hashimoto, 1988). By contrast, after passive movements of the ®ngers, signals mainly ascend through proprioceptive and muscle a€erents and reach area 2 and/or 3a in the SI. There are only a small number of reports concerning SEPs in response to passive movement, mainly due to technical diculties. To our knowledge, ours were the ®rst reports on SEF in response to passive movement (Xiang et al., 1997a,b). We made a new device for measuring MEG in response to passive movement. To avoid magnetic noise, all parts were made of plastic, wood or optic ®bers. The ®nger was moved approximately 208 and its angular velocity was approximately 525±5308/s. Four main components were identi®ed at the hemisphere contralateral to the moved ®nger in all 10 subjects: 1M(P), 2M(P). 3M(P) and 4M(P). `P' meant `passive movement'. The 1M(P) was clearly identi®ed only in three subjects and was smaller than other components (Fig. 15). The ECD of 1M(P) were located around the ®nger area of the SI and oriented either posteriorly or anteriorly. Since area 2 is situated on the post-central gyrus and area 3a is situated at the bottom of the central sulcus, the orientation of the ECD generated in area 2 or 3a is mainly radial. However, since every generator dipole is separated into radial and tangential

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vectors, we suspect that the tangential vector of the dipole generated in area 2 or 3a could be detected in the three subjects, but was too small to be detected in the seven other subjects. The 2M(P) and 3M(P) were usually combined as one large de¯ection with two peaks (Fig. 15). Because the ECDs of 2M(P) and 3M(P) were located around the ®nger area of the sensorimotor cortex and both were oriented posteriorly (Fig. 16), they were thought to be generated in area 4 and/or 3b and their activities have temporal overlapping. Their activities are probably spread from area 3a or 2. The 4M(P) has large inter-individual di€erence in terms of amplitude and latency. The ECD of 4M(P) was also located around the ®nger area of the SI and was oriented anteriorly. The 4M(PI), the main component recorded from the hemisphere ipsilateral to the moved ®nger, was located in the upper bank of the Sylvian ®ssure, probably in the SII. Five components, 1M(E), 2M(E), 3M(E), 4M(E) and 4M(EI), were identi®ed following electrical stimulation of the same ®nger (Fig. 15). `E' meant `electrical stimulation'. However, the SEF following passive movement were clearly di€erent from the SEF following electrical stimulation, in terms of waveforms and source locations, probably due to di€erences in the ascending ®bers and receptive ®elds.

Fig. 10. The isocontour map and the dipole display on the MRI of the de¯ections following right upper lip stimulation in one subject. The magnetometer was centered on the lip area of the SI of the left (A) and the right hemisphere (B). The contour step is 100 fT. The left and upper sides show the anterior and vertical areas, respectively. The ECD of the short- and middle-latency de¯ections are located around the SI. The position and direction of the ECD of P100m±N100m are clearly di€erent from those of the short- and middle-latency de¯ections. Their ECD are located in the superior bank of the Sylvian ®ssure, in the SII. Adopted from Hoshiyama et al. (1996).

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7. Sensori-motor interaction in SEF 7.1. E€ects of movement interference (gating) SEP (see Kakigi, 1986; Jones et al., 1989) and SEF (Rossini et al., 1989; Schnitzler et al., 1995a,b) following electrical stimulation are markedly modi®ed by voluntary (active) movements of the body near the stimulated nerve; this particular phenomenon is known as `gating', but the mechanisms and sites responsible for gating have not been elucidated. We, therefore, examined the `gating' e€ects of active and passive movements of the toes and by `movement imagery' (mental moving of the toe without actual movements) on SEF following stimulation of the posterior tibial nerve in normal subjects (Kakigi et al., 1997). The SEF was triggered not by continuous movements but by time-locked electrical stimulation to the posterior tibial nerve, to determine the e€ects of continuous and concurrent movements on time-locked electricallystimulated SEF. Active and passive movements signi®cantly attenuated the short- and long-latency cortical components (P < 0.001) with no latency change and the e€ects of the active movements were larger than those of the passive movements (Fig. 17). Therefore,

both centrifugal and centripetal mechanisms should be considered. The gating e€ects on all components may occur in the SI in the hemisphere contralateral to the stimulated nerve, because all of the ECD of the components in the `control' and each `interference' waveform were located there. The probable mechanism is based on the e€ects of the continuous excitations of neurons in area 3a and/or 4 by active movements on neurons in area 3b concerned with the processing of input from the cutaneous mechanoreceptor. Active movements of the toes contralateral to the stimulated nerve caused no signi®cant gating e€ect. Similar results were obtained by SEF study following the median nerve stimulation (Kakigi et al., 1995b). The short-latency components were not consistently changed by `movement imagery', but the middle- and long-latency components were enhanced (Fig. 17). Their ECD were located in the SI contralateral to the stimulated nerve and in the SII in bilateral hemispheres (Fig. 18). The reason why the movement imagery enhanced the components generated in the SI remains to be elucidated, but neurons in the motor cortex might be activated by continuous movement imagery and a€ect the somatosensory evoked brain responses. Enhancement of the SEF components gener-

Fig. 11. The isocontour maps showing the location and direction of the dipole (arrow) after the right forehead stimulation recorded from the contralateral and ipsilateral (C and I) hemisphere. The ECD are overlaid on MRI. The ECD of 1M is located around the SI in the hemisphere contralateral to the stimulation. The position and direction of the ECD of 2M are clearly di€erent from those of 1M. Their ECD are located in the superior bank of the Sylvian ®ssure, SII, in bilateral hemispheres. Adopted from Hoshiyama et al. (1995).

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ated in the SII was observed when subjects paid close attention to the infrequent (target) stimulation when the so-called `oddball' paradigm was used (Hari et al., 1990). In contrast, activities in the SII following median nerve stimulation were markedly reduced or disappeared during sleep (Kitamura et al., 1996). Therefore, we speculated that brain responses to somatosensory stimulation, particularly components generated in the SII, were a€ected by volitional changes. 7.2. E€ects of tactile stimulation on SEF Both SEP (see Kakigi and Jones, 1985, 1986; Kakigi, 1986) and SEF (Schnitzler et al., 1995a,b) following electrical stimulation are also a€ected by the tactile stimulation of various parts of the body. Interaction caused by the stimulation of di€erent nerves (Huttunen et al., 1992) or di€erent ®ngers (Biermann et al., 1998) was also reported. The change to the waveforms induced by tactile interference was clearly di€erent from that due to movement interference as

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described above, probably due to di€erences in the ascending ®bers of the peripheral nerve and receptive sites in the sensory cortex. We examined the changes of SEF following electrical stimulation of the right median nerve (Kakigi et al., 1996a). Continuous light tactile stimulation was delivered to the right (ipsilateral) and left (contralateral) palm by the experimenter concurrently and continuously with the right median nerve stimulus, using a soft wad of tissue paper. Six components, 1M±6M, were identi®ed (Fig. 19) (Notice that the 4M and 5M in Fig. 19 correspond to 3M (E) and 4M (E) in Fig. 15). The ECDs of all of the components under the interference conditions, some of which showed a de®nite waveform change compared with the control condition, were located in the SI in the left (contralateral) hemisphere and their positions were very close to those of the control waveform. When stimulation was applied to the ipsilateral hand, all components except for the 3M were attenuated in all subjects (P < 0.0001) (Fig. 19). The SEF is thought to have been generated

Fig. 12. Detailed somatosensory receptive map represented by MEG. The three-dimensional brain image was reconstructed using MRI of this subject. Each receptive area, which was estimated to be located in the posterior bank of the central sulcus, was projected onto the cortical surface. The size of each ellipse re¯ects the presumed size of the activated cortical area. Note that the receptive area for the toes is on the medial side of the left hemisphere. Adopted from Nakamura et al. (1998).

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in area 3b which responds mainly to tactile stimulation. The attenuation of the components generated in the SI during the generation of interference by tactile interference of the ipsilateral hand was therefore considered to be a result of partial `saturation' of a cortical area concerned with the processing of input from the tactile mechanoreceptor, such that it was

Fig. 13. ECD location in SII following somatosensory stimulation applied to various parts of the body and auditory stimulation overlapped on MRI in a representative subject. All ECD are projected to a slice in which ECD to the thumb stimulation was found, since it is easily understood by this procedure, and since it is impossible to show all slices in which each ECD is located. The relationship of each ECD was easily found by these ®gures. There was a large interindividual topographic di€erence in the SII, but no clear topographic order in the SII, unlike the homunculus in the SI. However, there was a tendency of the topographic order as follows; anterior±posterior direction: lower lip±upper lip±thumb±middle ®nger±tibial nerve, medial±lateral direction: tibial nerve±middle ®nger±thumb± upper lip±lower lip, lower±upper direction: lower lip±upper±lip± thumb±middle ®nger±tibial nerve. The auditory cortex is located at a site more posterior, lateral and lower than the SII. Adopted from Maeda et al. (1999).

Fig. 14. The temporal activation pattern and localization of each source in one subject. Left, temporal activation pattern of each source obtained by spatio-temporal source analysis. The horizontal bar indicates the time axis (extending from 0 to 200 ms). The dashed and solid lines in the lower part of each column show average global ®eld power (GFP) and residual variance (RV, variance (%)), respectively, in the logarithmic scale over the ®t interval. Right, the head diagrams indicate the locations of the dipole sources of the subject. The line and its length from each point indicate the direction and the magnitude of the dipole current, respectively. C-SI: the SI in the hemisphere contralateral to the stimulation; I-SII and C-SII: the SII in the hemispheres ipsilateral and contralateral to the stimulation; IPPC and C-PPC: posterior parietal cortex (PPC) in the hemispheres ipsilateral and contralateral to the stimulation. Adopted by Hoshiyama et al. (1997).

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unable to respond to the coherent volley evoked by the median nerve impulses. When tactile interference was applied to the contralateral hand, only the 2M component, whose peak latency was about 20±30 ms, was signi®cantly enhanced (P < 0.05); the other components showed no signi®cant change (Fig. 19). Iwamura et al. (1994) reported the presence of neurons which receive somatosensory signals from bilateral hands in the postcentral somatosensory cortex (areas 2 and 5) in the monkey. Allison et al. (1989) studied the ipsilateral SEP recorded from the cortical surface in humans, and considered that their generators were in areas 4, 2 and 7. Hoshiyama et al. (1997) also reported the activity of the bilateral PPC in SEF using a multidipole model (Fig. 14). These ®ndings indicate that the enhancement of the 2M may be due to the e€ects of the activities of such ipsilateral responses on current dipoles generated in area 3b, probably through the corpus callosum. Similar results were obtained when tactile interference was applied to SEF following stimulation of the posterior tibial nerve (Naka et al., 1998).

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7.3. E€ects of visual and auditory stimulation on SEF Some areas of the brain such as Brodmann's areas 5 and 7 in the parietal lobe or superior part of the temporal lobe have been considered polysensory (Hyvarinen and Poranen, 1974). We, therefore, suspect that the integrative processing of various kinds of sensations such as somatosensory, visual and auditory stimulation also takes place in these areas in the human brain. However, to our knowledge, no study has reported the e€ects of visual or auditory stimulation on SEF. We, therefore, investigated the e€ects of continuous visual (cartoon and random dots motion) and auditory (piano playing) stimulation on SEF following electrical stimulation of the median nerve (Lam et al., 1999). In the hemisphere contralateral to the stimulated nerve, the middle-latency components (35±60 ms in latency) were signi®cantly enhanced by visual, but not by auditory stimulation (Fig. 20). The dipoles of all components within 60±70 ms of the stimulation were estimated to be very close to each other, around the hand area of the SI. In the ipsilateral hemisphere, the middle-latency components (70±100 ms in latency), the dipoles of which were estimated to be in the SII, were markedly decreased in amplitude by both the visual and auditory stimulation (Fig. 21). These changes of waveforms by visual and auditory stimulation are thought to be due to the e€ects of the activation of polymodal neurons, which receive not only somatosensory but also visual and/or auditory inputs, in area 5 and/or 7 as well as in the median superior temporal region and superior temporal sulcus, although a change of attention might also be one of the factors causing such ®ndings. 7.4. Intracerebral interaction produced by bilateral stimulation

Fig. 15. The SEF following passive movement and electrical stimulation of the left middle ®nger recorded at the C4 (contralateral hemisphere to stimulation) and C3 (ipsilateral hemisphere to stimulation) position simultaneously in a representative subject showing the nomenclature of each recognizable component. Waveforms recorded at the 37 channels are superimposed. 1M(P), the ®rst response following passive ®nger movement, is small in amplitude or absent. However, 2M(P) and 3M(P) are clearly larger than 2M(E) and 3M(E). 2M(P) and 3M(P) appear to be one component with two peaks. `P' and `E' mean passive movement and electrical stimulation, respectively. Adopted from Xiang et al. (1997a).

To investigate the intracerebral interactions in response to somatosensory stimulation, we recorded SEF following the simultaneous stimulation of bilateral median nerves (Shimojo et al., 1996b) as well as posterior tibial nerves (Shimojo et al. 1997). SEF were recorded following simultaneous bilateral median nerve stimulation (`bilateral' waveform). The SEF following right median nerve stimulation and that following left median nerve stimulation were summated (`summated' waveform). A `di€erence' waveform was induced by subtraction of the bilateral waveform from the summated waveform. Short-latency de¯ections showed no consistent di€erences between the summated and bilateral waveforms, but the middle-latency de¯ection, N60m±P60m, in the bilateral waveform was signi®cantly (P < 0.01) smaller than that in the summated waveform. The long-latency de¯ection, the N90m±P90m, in the bilateral waveform

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was markedly (P < 0.001) reduced in amplitude compared with the summated waveform (Fig. 22). The di€erences were clearly identi®ed in the di€erence waveform, in which the main de¯ection, U90m±D90m, was found in all subjects. The ECDs of the short- and middle-latency de¯ections were located in the SI, but the ECDs of the N90m±P90m and U90m±D90m were located in the bilateral SII (Fig. 23). Similar results of SEF change were obtained by simultaneous stimulation of the bilateral posterior tibial nerves (Shimojo et al., 1997) When the midline of the lip was stimulated, N110m±P110m, which was generated in the bilateral SII, was also markedly attenuated or disappeared (see Fig. 9) (Hoshiyama et al., 1996). This ®nding was compatible with that obtained by simultaneous bilateral stimulation of median as well as posterior tibial nerve stimulation. Neurons in the SII di€er from those in the SI in that their receptive ®elds are larger, encompassing ipsi-

Fig. 16. The ECD of the main components of SEF recorded at the C4 position (right hemisphere) following passive movement of the left middle ®nger overlapped on axial, coronal and sagittal MRI views in one subject. The right side of the MRI indicates the right hemisphere. All of the main components are located around the ®nger area of the sensorimotor cortex. Adopted from Xiang et al. (1997a).

lateral as well as contralateral areas of the body surface for 63% of the units studied in unanesthetized cats (Robinson, 1973) and 90% of the units in unanesthetized monkeys (Whitzel et al., 1969). Jones and Powell (1970), reviewing previous studies, suggested that the SII is an area for the interhemispheric convergence of sensory input of all somatic modalities at a relatively low level of cortical function. It, therefore, seems appropriate that some particular interactions take place in the SII following bilateral side stimulation.

8. SEF studies on plasticity in SI Plasticity of the SI is one of the most interesting topics in the study of SEF. A change of homunculus is reported to be due to limb dea€erentation after amputation (Elbert et al., 1994, 1997; Yang et al., 1994;

Fig. 17. The SEF recorded at the Cz position around the vertex following stimulation of the left posterior tibial nerve in the control and each interference session in one subject. The waveforms of all 37 channels are superimposed. The short-latency components are attenuated in the ipsilateral active and ipsilateral passive sessions. There is no signi®cant change by contralateral active interference. In the movement imagery session, the short-latency components showed no signi®cant change. However, the middle-latency component indicated by # was enhanced and the long-latency component indicated by ## was found. Adopted from Kakigi et al. (1997).

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Flor et al., 1995; Knecht et al., 1995, 1996, 1998; Weiss et al., 1998). Yang et al. (1994) and Elbert et al. (1994) ®rst reported the marked intrusion of facial representations into the digit and hand area after upper limb amputation. Phantom-limb pain is a frequent consequence of limb amputation. Flor et al. (1995) reported a very strong direct relationship between the amount of reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation and suggested that phantom-limb pain is related to, and may be a consequence of, plastic changes in the SI. Knecht et al. (1996) reported that phantom sensations could be evoked from sites on the face and the trunk ipsilateral but also contralateral to the amputation and that the amount of reorganization strongly correlates with the number of sites, be it ipsi- or contralateral, from where painful stimuli evoked referred sensation. These ®ndings suggested the involvement of bilateral pathways and demonstrated that the perceptual changes go beyond what can be explained by shifts in neighboring cortical representational zones. Mogilner et al. (1993) reported somatosensory cortical plasticity in patients who were studied before and after surgery for webbed ®ngers (syndactyly). The presurgical maps displayed shrunken and nonsomatotopic hand representations. Within weeks of the surgery,

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cortical reorganization occurring over distances of 3±9 mm was evident, correlating with the new functional status of the separated digits. Such a reorganization of SI was also reported in patients with stroke and neoplasm (Rossini et al., 1998a,b). Elbert et al. (1995b) reported an interesting study. They examined SEF following stimulation of the thumb and little ®nger of the left hand in string players and compared their results with controls. They found that the cortical representation of the digits of the left hand of string players was larger than that in controls, and that the amount of cortical reorganization in the representation of the ®ngering digits was correlated with the age at which the person had begun to play. These results suggest that the representation of di€erent parts of the body in the SI of humans depends on use and changes to conform the current needs and experiences of the individual. Sterr et al. (1998a,b) studied SEF in blind multi®nger Braille readers. They found that the cortical somatosensory representation of the ®ngers was frequently topographically disordered in these subjects; in addition, they frequently misperceived which of these ®ngers was being touched by a light tactile stimulus. Therefore, use-dependent cortical reorganization can be associated with functionally relevant changes in the perceptual and behavioral capacities of the individual.

Fig. 18. Localization of ECD of the middle-latency component enhanced by the movement imagery recorded from the C3 position (left hemisphere) following the right tibial nerve stimulation. The ECD are located on the superior bank of the Sylvian ®ssure, around the SII of the left hemisphere. When the magnetometer is placed at the C4 position (right hemisphere), the ECD are identi®ed in the SII of the right hemisphere. Adopted from Kakigi et al. (1997).

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9. Clinical application of SEF The clinical application of MEG including SEF is an important subject. However, the number of papers on it is still small. SEF is used for neurosurgery (Gallen et al., 1993; Kamada et al., 1993; Sobel et al., 1993; Nakasato et al., 1996, 1999). SEF before surgery is used to localize the central sulcus, since space occupying lesions such as tumors frequently shift the central sulcus. As compared with direct recording of SEP from cortex using subdural electrodes, non-invasive SEF recording is much safer. In the ®eld of neurology, SEF is useful to detect functional abnormalities in patients with cerebrovascular diseases (Maclin et al., 1994; Wikstrom et al., 1996). Wikstrom et al. (1996) reported SEF ®ndings in 15 patients in the acute stage of stroke involving sen-

Fig. 19. SEF following the right median nerve stimulation recorded at the C3 position (left hemisphere) in one subject. Waveforms recorded at all 37 channels are superimposed. Control: SEF with no interference; ipsilateral and contralateral: SEF with tactile interference applied to the hand ipsilateral and contralateral to the stimulated nerve, respectively. After interference was applied to the ipsilateral hand, 3M (indicated by ) was clearly increased, but the other components including the 2M (indicated by ) were attenuated. After interference was applied to the contralateral hand, 2M (indicated by ) was clearly enhanced, but other components were not changed. Adopted from Kakigi et al. (1996a).

sorimotor cortical and/or subcortical structures in the territory of the middle cerebral artery. Patients with pure motor stroke showed no SEF, but patients with pure sensory stroke showed markedly attenuated or absent SEF. Abnormal SEF ®ndings were more clearly correlated with an impairment of two-point discrimination than of joint-position or vibration senses. A large amplitude of SEP (giant SEP) is recorded in patients with cortical re¯ex myoclonus. We reported that giant SEP are generated in area 3b of SI (Kakigi and Shibasaki, 1987). Recent SEF studies con®rmed this hypothesis (Uesaka et al., 1993, 1996; Karhu et al., 1994; Mima et al., 1998b). In addition, Mima et al. (1998b) found other components which are located in the anterior bank of the central sulcus and suggested

Fig. 20. SEF recorded at the C4 position (contralateral) following stimulation of the left median nerve in the control and each multimodal stimulus condition in one subject. The waveforms of all 37 channels are superimposed. The middle-latency components indicated by  and  were enhanced in the cartoon and dots sessions. Adopted from Lam et al. (1999).

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the importance of the motor cortex for generation of cortical re¯ex myoclonus. Karhu et al. (1992) reported SEF in 10 patients with multiple sclerosis. Seven patients showed abnormally large-amplitude SEF at 60±80 ms; ®ve of them had multiple lesions around lateral ventricles. In two patients with plaques at the level of third and fourth ventricles and medulla, the 30 ms responses were enlarged. The results suggest that early and middlelatency SEF components re¯ect parallel processing of somatosensory input. 10. Other important ®ndings of SEF Recently, studies combining MEG with other modalities for imaging, such as fMRI, have been conducted. In the ®eld of SEF, three studies, to our knowledge, have compared the source localization of the somatosensory cortex (Grimm et al., 1998; Stippich et al., 1998) or epileptic focus (Seeck et al., 1998). Another recent topic of SEF study is high-frequency oscillations (>300 Hz) whose latency was almost the same as the primary component of SEF (Curio et al.,

Fig. 21. SEF recorded at the C3 position (ipsilateral) following stimulation of the left median nerve in the control and each multimodal stimulus condition in subject 12. The waveforms of all 37 channels are superimposed. The MI component was markedly attenuated in the cartoon and music sessions (especially in the cartoon session), but was not changed in the dots session. Adopted from Lam et al. (1999).

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1994; Hashimoto et al., 1996; Sakuma and Hashimoto, 1999; Sakuma et al., 1999b). They were generated in SI and much reduced in amplitude during sleep (Hashimoto et al., 1996). Hashimoto et al. (1996) proposed the hypothesis that the somatic evoked high-frequency oscillations represent activity of GABAergic inhibitory interneurons controlling output pyramidal cells in the cortex. 11. SEF following painful CO2 laser stimulation 11.1. General ®ndings The cerebral representation of pain perception in humans is poorly understood compared with that of other sensations such as touch or vibration. This is mainly because of a lack of appropriate instrumentation for stimulation and recording (Kakigi and Shibasaki, 1984). To our knowledge, only a few systematic studies of SEF following painful stimulation have been conducted. Hari et al. (1983) used painful electrical stimulation of tooth pulp. Huttunen et al. (1986) used CO2 gas stimulation of the nasal mucosa. Howland et al. (1995) applied high-intensity painful electrical stimulation. They reported that the current sources

Fig. 22. The `bilateral', `summated' and `di€erence' waveforms recorded at the C3 position in one subject. Each waveform was obtained by the superimposition of all 37 channels. Waveforms recorded at all 37 channels are superimposed. The N90m±P90m in the bilateral waveform is smaller than those in the summated waveform, and U90m±D90m is found in the di€erence waveform. Adopted from Shimojo et al. (1996b).

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Fig. 23. Localization of representative ECDs of the N90m±P90m in the bilateral and summated waveforms, and that of the U90m±D90m in the di€erence waveforms recorded at the C3 position overlapped on MRI in one subject. The ECDs were located in the SII. Adopted from Shimojo et al. (1996b).

were located at or near the SII or the frontal operculum. We have also used high-intensity electrical stimulation to the upper and lower limbs and found ECDs in not only the SII but also the cingulate cortex (Kitamura et al., 1995, 1997; Hoshiyama and Kakigi, 2000; Yamasaki et al., 2000). We recently developed new device which induced painful impact stimuli (ArendtNielsen et al., 1999). An airgun was placed outside the shielded room and small plastic bullets were ®red at the arm and trunk of di€erent intensities. The evoked SEF responses had a major component with the characteristically polarity-reversal de¯ections and the ECD were estimated in the SII of the bilateral hemispheres. A low power and long wavelength CO2 laser beam induces sensations of pain or heat when applied to the skin. From studies in normal subjects and in patients with various types of sensory impairment, it has been established that CO2 laser stimuli cause the excitation of nociceptive receptors in the skin and that their signals ascend through small myelinated ®bers (Ad) of the peripheral nerves and are probably mediated through the spinothalamic tract with an approximate conduction velocity of 10±15 m/s. We have, therefore, studied SEF following painful CO2 laser stimulation to elucidate the mechanisms of pain processing in the human brain (Kakigi et al., 1995c, 1996b; Watanabe et al., 1998; Yamasaki et al., 1999). Bromm et al. (1996) also reported SEF following painful CO2 laser stimulation.

Fig. 24. Superimposed waveforms recorded from all 37 channels from the hemisphere contralateral to the painful CO2 laser stimulation in two subjects. The ®rst component (1M) appeared to be a simple polarity-reversal de¯ection in subject 1, but it appeared to be a hybrid of some components in subject 2. Adopted from Watanabe et al. (1998).

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A consistent and clear magnetic ®eld (termed 1M) was identi®ed in the bilateral cerebral hemisphere following stimulation of each arm in all 11 subjects examined (Fig. 24). Its onset and peak latencies varied among the subjects, being about 120±180 and 180±220 ms, respectively. When a conventional single ECD analysis was used, the ECDs were estimated to be located around the SII or insula in bilateral hemispheres (Kakigi et al., 1995c, 1996b; Watanabe et al., 1998; Yamasaki et al., 1999) (Fig. 25). The peak latency of the SII response recorded from the hemisphere contralateral to the stimulation was signi®cantly (P < 0.01) shorter (approximately 20±25 ms) than that recorded from the ipsilateral hemisphere (Yamasaki et al., 1999). 11.2. Analysis using a multi-dipole model Since various sites are thought to be responsible for pain perception, we adopted a multi-dipole model, brain electric source analysis (BESA) (Scherg, 1995), for elucidating mechanisms of pain perception in humans (Watanabe et al., 1998). The residual variance (%RV) indicated the percentage of data which cannot be explained by the model. The goodness of ®t (GOF) was expressed in % as (100ÿ%RV). The results showed that the four-dipole model was the most appropriate (Fig. 26). Source 1 and 2 was located in

515

the SII in the hemisphere contralateral and ipsilateral to the stimulation, respectively, and source 3 and 4 in the anterior medial temporal area, around the amygdalar nuclei or hyppocampal formation, in the hemisphere contralateral and ipsilateral to the stimulation, respectively. The GOF of this model was over 90%. When we placed source 5 around the arm area of the SI in the hemisphere contralateral to the stimulated arm, its activity was very small or absent and the change of GOF was small (Fig. 26). When we placed source 6 in the cingulate cortex, its waveform was a bit strange and the change of GOF was also small (Fig. 26). The contributions of sources 5 and 6 were thus very small or absent. In addition, although we tested to calculate the other dipole (source 7) in all subjects, source 7 accounted only for drift and not for any signi®cant activity. 11.3. E€ects of distraction on pain SEF Pain perception was changed by attention or distraction e€ects. Therefore, we aimed to compare the e€ects of distraction on pain SEF and SEP (Yamasaki et al., 1999). Painful CO2 laser stimuli were applied to the right forearm of ten healthy subjects. A table with 25 random two-digit numbers was shown to the subjects, who were asked to add ®ve numbers of each line in their mind (calculation task) or to memorize the num-

Fig. 25. The location of ECD of the 1M overlapped on the axial, coronal and sagittal images of the MRI. The ECD was estimated to be located in the upper bank of the Sylvian ®ssure, around the SII, in bilateral hemispheres. Adopted from Yamasaki et al. (1999).

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bers (memorization task) during the recording. Subjects declared a visual analogue scale (VAS) for rating subjective pain during each condition. In the SEF recording, the 1M was clearly identi®ed in the bilateral hemispheres in each distraction task in all subjects. Because the sequential activities were not clearly identi®ed in all subjects, we did not analyze them in this study. In the SEP recording, the middle-latency components whose peak latencies were approximately 240 and 340 ms, N240 and P340, were identi®ed in all subjects. N and P meant negative and positive component, respectively. The distraction tasks did not a€ect the 1M component, but signi®cantly attenuated EEG N240±P340 components (Fig. 27). The change of VAS score showed a positive correlation with a change of amplitude of N240±P340 complex, but not with 1M. Accounting for the di€erences of latency and distraction e€ects between 1M and N240, the 1M and N240± P340 complex probably re¯ect di€erent brain activities. We suspect that the 1M generated in SII-insula re¯ects the initial cortical activation in response to painful stimulation. The N240±P340 is considered to represent

the activities of multiple areas including the SII-insula and the limbic system and it seems reasonable that the activities in those areas are a€ected by attentional changes. 11.4. General discussion of pain SEF In our studies of SEF following painful CO2 laser stimulation (Kakigi et al., 1995c, 1996b; Watanabe et al., 1998; Yamasaki et al., 1999), the activities in the SI were not clearly identi®ed. We consider three main possibilities as to why the magnetic activities in the SI were very small or absent following CO2 laser stimulation. The ®rst is that the number of neurons activated by nociceptive stimulation is probably very small. The second is that a relatively large di€erence of latency in each trial (jittering) makes the component very small when a number of responses are averaged. The third possibility is that mainly neurons in area 1 are activated, as reported in monkeys by Kenshallo and Willis (1991). In such a case, since dipoles are usually radially oriented, activities in area 1 are not

Fig. 26. Temporal activation pattern and localization of each of the 6 sources of pain SEF following right arm stimulation calculated by BESA in one subject. Left, temporal activation pattern of each source obtained by spatio-temporal source analysis. The horizontal bar indicates the time axis (extending from 0 to 400 ms). Right, the head diagrams indicate the locations of the dipole sources of the subject. The line from each point indicate the direction of the dipole current. The four-source model, in which sources 1 and 2 are located in the SII in the hemispheres contralateral and ipsilateral to the stimulated arm and sources 3 and 4 are located in the anterior medial temporal area (probably in the amygdalar nuclei or hippocampal formation) in the hemispheres contralateral and ipsilateral to the stimulated arm, was considered to be the most informative model, since the GOF was over 90%. When we added source 5 in the SI contralateral to the stimulation, its activity was found to be small or absent. When we added source 6 in the cingulate cortex, its activity was unusual and did not increase the GOF. This is probably due to its deep location, where it is dicult for MEG to detect its activity. Adopted from Watanabe et al. (1998).

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clearly detected by MEG. One of or a mixture of these three reasons are possible, but we do not consider the third possibility to be very likely, because the activities which are considered to be generated in the SI were absent or recorded as only a small notch, even by EEG (SEP) recording. The cingulate cortex is probably activated by CO2 laser stimulation, but its waveform as analyzed by BESA in the present study was unusual and did not increase the GOF. This ®nding was probably due to

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the deep location of the cingulate cortex, where it was very dicult for the MEG to detect activities accurately. Compared with the cingulate cortex, the roles of the amygdalar nuclei and hippocampal formation in pain perception are not clearly elucidated. The inputs responsible for these activities were considered to ascend through the spino (trigemino)-ponto-amygdaloid pathway (Bernard and Besson, 1990). It is, therefore, possible that nociceptive inputs arrive at the contralateral SII, then the ipsilateral SII, the cingulate cortex, and reach the amygdalar nuclei or the hippocampal formation through this pathway. 12. Micro-SQUID

Fig. 27. Waveforms of pain SEF (MEG) and pain SEP (EEG). MEG waveforms recorded from 37 channels in the hemisphere contralateral and ipsilateral to the stimulated arm are superimposed. EEG recorded at the Cz (vertex) is shown. The amplitude of the 1M component of the MEG in the bilateral hemispheres did not show a signi®cant change in the calculation or memorization task. The N240±P340 component of EEG showed a signi®cant reduction in amplitude, particularly in the calculation task. Adopted from Yamasaki et al. (1999).

The nerve action ®elds (NAF) produced by longitudinal intracellular current in the peripheral nerve axons in vitro were ®rst reported by Wikswo and Freeman (1980), using a single channel magnetometer. In human, Erne et al. (1988) recorded NAF from the median nerve with a single channel magnetometer, and several studies of compound NAF using single-channel (Trahms et al., 1989) and multi-channel magnetometer systems followed (Hari et al., 1989; Hashimoto et al., 1991, 1994). Those results were reasonably consistent with the ®ndings of the nerve action potentials (NAP) (Buchthal and Rosenfalck, 1966). However, the details of the NAF were not disclosed and the spatial and temporal resolution were limited. The major reasons for this were the relatively large diameter of the coils and the large distance between the detecting coils and the nerve. We developed a new multi (twelve)-channel gradiometer system with the smallest and highest quality superconducting quantum interference device (microSQUID) available to non-invasively detect the magnetic ®elds of a human peripheral nerve (Hoshiyama et al., 1999). The coil-to-skin distance is 3.8 mm and the inner diameter of the detection coil is 3.0 mm. The twelve equally sensitive coils connected to the SQUID are placed in a uniform distribution (three rows  four lines) in an area of 2.16 cm2 (1.20  1.80 cm) (Fig. 28). With regard to the amplitude of NAF, we obtained large responses (5±8 pT), compared to those at 600 fT in previous studies (Hari et al., 1989; Hashimoto et al., 1991, 1994). Thus, in the present study, the advantages of the closed space gradiometer were represented in the spatial and temporal resolution as theoretically predicted (Wikswo et al., 1985; Roth et al., 1989; Wikswo, 1990). Similar NAFs were consistently recorded from all subjects. The detected waveform showed a clear biphasic con®guration (Fig. 29). Fig. 30 shows a series of two-dimensional isomagnetic ®eld topographical maps obtained following the index ®nger stimulation. During

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Fig. 28. Right, the cryogenic system including the liquid helium dewar and 12-channel SQUID probe. The magnetometer was a 12-channel specially made dBz/dz-type gradiometer (NIPS 12-channel closed spaced gradiometer, CONDUCTUS, San Diego, CA). Each coil was connected to the SQUID in liquid helium. Left lower, the placement of the detection coils relative to the right hand. The device was attached to the median nerve on the ventral surface of the left forearm at the wrist, and the index ®nger was electrically stimulated using a pair of ring electrodes (E). Left upper, expanded ®gure of the con®guration of 12 pairs of the detection and referential coils. Each pair of coils was uniformly arranged in a square area (1.60  1.80 cm). Each coil was 3.0 mm in diameter. The numbers of the detecting coils indicate the sensor channel shown in Fig. 29. Adopted from Hoshiyama et al. (1999).

the initial NAF de¯ection the isomagnetic ®eld maps showed the in¯ux and out¯ux of the magnetic ®eld which indicated the electrical current from the distal to the proximal part of the recording ®eld corresponding to the direction of the depolarizing intracellular cur-

rent ¯ow. During the second de¯ection, the pattern of the ¯ux was reversed which indicated the current from the proximal to the distal portion corresponding to the repolarizing current ¯ow. The leading magnetic bipolar ®elds corresponded to the depolarizing front, which

Fig. 29. The waveforms obtained from 12 channels of the magnetometer. Biphasic nerve action ®elds (NAF) are clearly shown. Adopted from Hoshiyama et al. (1999).

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Fig. 30. Left, the isomagnetic ®eld map obtained at each latency after the ®nger stimulation. Yellow to red indicate out¯ux of the magnetic ®eld and blue, in¯ux. The magnetic ®eld during the initial de¯ection of the waveform showed the nerve current from the distal to proximal part of the wrist. After showing the quadrupole pattern at the mid-point of the de¯ections (2.45 ms), the current with opposite direction moved from the distal to the proximal part. Right, the whole image of the NAF reconstructed from the isomagnetic ®eld maps at each latency. The total length of the polarized area was approximately 17 cm. A clear quadrupole pattern was obtained. This magnetic ®eld complex moved from the distal to the proximal part of the wrist at a velocity of 58.3 m/s. Adopted from Hoshiyama et al. (1999).

appeared at the timing of the fastest rising onset of the waveform (channel 4). The depolarizing phase ended and the following repolarizing front appeared at the mid-point between the de¯ections of biphasic waveforms. The average duration of the polarized phase was 2.9920.07 ms. The duration of the repolarization phase (1.3320.07 ms) was shorter than that of the depolarization phase (1.66 2 0.13 ms). To obtain the whole image of the NAF, we reconstructed the isomagnetic ®eld topographical maps according to the latency of the maps (Fig. 30). The NAF image represented a clear quadrupole (two dipoles) pattern. The nerve conduction velocity calculated from the onset of the waveform and the distance between the coils was 58.7 2 2.1 m/s. The NAF was distributed over an approximately 17 cm length along the nerve. The spatial extent of the depolarization and repolarization was approximately 7.5 and 9.5 cm, respectively. Acknowledgements We are very grateful to our colleagues, Dr. Y.

Kaneoke, Dr. S. Koyama, Dr. Y. Kitamura, Mr. O. Nagata, Mr. Y. Takeshima and Ms. A. Fukuda for technical support.

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