MEG localization of rolandic spikes with respect to SI and SII cortices in benign rolandic epilepsy

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1 NeuroImage 20 (2003) MEG localization of rolandic spikes with respect to SI and SII cortices in benign rolandic epilepsy Y.Y. Lin, a,b,c, * Y.H. Shih, b,c K.P. Chang, c,d W.T. Lee, e H.Y. Yu, b,c J.C. Hsieh, a,c T.C. Yeh, a,c Z.A. Wu, b,c and L.T. Ho a,c a Integrated Brain Research Unit, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan b Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan c School of Medicine, National Yang-Ming University, Taipei, Taiwan d Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan e Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan Received 3 February 2003; revised 13 August 2003; accepted 14 August 2003 Abstract The purpose of this study was to study the relationship between interictal spike sources and somatosensory cortices in benign rolandic epilepsy of childhood (BREC) using a whole-scalp neuromagnetometer. We recorded spontaneous magnetoencephalography (MEG) and EEG signals and cortical somatosensory-evoked magnetic fields (SEFs) to electric stimulation of the median nerve in 9 children with BREC. Interictal rolandic discharges (RDs) and SEFs were analyzed by equivalent current dipole (ECD) modeling. Based on the orientation and locations of corresponding ECDs, we compared generators of RDs with primary (SI) and second somatosensory cortices (SII). Our results showed that RDs and SII responses had similar ECD orientation on the magnetic field maps. The ECDs of RDs were localized and mm anterior to SI and SII, respectively. The spatial distance on average from the location of RDs to SII ( mm) cortex was significantly shorter than to SI cortex ( mm) (P 0.01, Wilcoxon signed-rank test). In conclusion, the cortical generators for RDs in patients with BREC are localized in the precentral motor cortex, closer to hand SII than to SI cortex Elsevier Inc. All rights reserved. Keywords: Magnetoencephalography; Benign rolandic epilepsy of childhood; Source localization; SI; SII Introduction Benign rolandic epilepsy of childhood (BREC) is a common primary partial epilepsy syndrome. The clinical characteristics are onset between 2 and 13 years, a normal neurodevelopmental profile, and nocturnal or diurnal brief seizures with stereotyped motor and sensory behaviors. The prognosis is excellent, with a complete recovery of clinical symptoms by the age of 15 years (Lombroso, 1967; Blom et al., 1972; Lerman and Kivity, 1975; Luders et al., 1987; * Corresponding author. Neurology, Neurological Institute, Taipei Veterans General Hospital, No.201, Sec.2, Shih-Pai Rd., Taipei 112, Taiwan. Fax: address: yylin@vghtpe.gov.tw (Y.Y. Lin). Beydoun et al., 1992; Holmes, 1993; Legarda and Jayakar, 1995). The interictal electroencephalography (EEG) shows normal background activity and scalp-negative spikes, maximal in amplitude in the centrotemporal region (Lischka and Graf, 1992; Loiseau and Duche, 1992; Van der Meij et al., 1992; Holmes, 1993; Baumgartner et al., 1996; Minami et al., 1996). Interictal EEG spikes of patients with BREC have been analyzed with an emphasis on voltage gradients (Lombroso, 1967), scalp topography (Gregory and Wong, 1984; Van der Meij et al., 1992), and dipole localizations (Weinberg et al., 1990; Wong, 1991; Baumgartner et al., 1996). These studies have suggested that the spikes are generated in the rolandic region. In more recent magnetoencephalographic (MEG) (Minami et al., 1996; Kubota et al., 1996, 2000; Kamada et /$ see front matter 2003 Elsevier Inc. All rights reserved. doi: /j.neuroimage

2 2052 Y.Y. Lin et al. / NeuroImage 20 (2003) Table 1 Clinical information of the 9 patients with benign rolandic epilepsy of childhood Patient (sex) Age (years) Onset age (years) Seizure pattern EEG NE MRI of brain Medication Follow-up 1 (F) 12 5 Nocturnal generalized seizures 2 (F) 9 6 Nocturnal clonic convulsion of right limbs 3 (F) 9 8 Focal twitching of right face and mouth angle 4 (F) 8 7 Focal twitching of right mouth angle followed by clonic seizures of right limbs 5 (M) 8 6 Nocturnal generalized tonic-clonic seizures 6 (M) 9 5 Nocturnal salivation, clonic convulsion of right limbs 7 (F) 8 7 Tonic convulsion of right limbs 8 (F) 9 8 Anarthria, generalized convulsion 9 (F) 8 7 Nocturnal salivation, clonic convulsion of right limbs Right and left centrotemporal spikes Right and left centrotemporal spikes Right and left centrotemporal spikes Right and left centrotemporal spikes Right and left centrotemporal spikes Normal Normal None Three seizures, no seizures from age of 11 Normal Normal Carbamazepine 100 mg bid Six seizures, no seizures from age of 8 Normal Normal None Four seizures Normal Normal Valproate mg bid Ten seizures, no more seizures for 6 months Normal Normal None Three seizures, no seizures from age of 8 Left centrotemporal spikes Normal Normal Valproate 250 mg bid Nine seizures, no seizures from age of 9 Left centrotemporal spikes Normal Normal None Ten seizures Right centrotemporal spikes Normal Normal None Two seizures Right centrotemporal spikes Normal Normal None Two seizures NE, neurological examination; MRI, magnetic resonance imaging; F, female; M, male. al., 1998) and EEG (Manganotti et al., 1998a, 1998b; Ferri et al., 2000) studies, the generators of the rolandic discharges (RDs) have been identified in the rolandic region near to the somatosensory cortex; consequently a generation mechanism similar to that for the middle-latency somatosensory-evoked responses has been proposed (Minami et al., 1996). However, the neuronal generation mechanisms between RDs and somatosensory cortices remain still unclear. By detecting magnetic fields from cortical currents, MEG is well suited for investigation of various brain activations within cortical sulci, and has been applied for detailed analysis of primary (SI) and second somatosensory cortical (SII) responses (Hari et al., 1983, 1984, 1990, 1993; Hämäläinen et al., 1993; Huttunen et al., 1996; Mauguière et al., 1997a, 1997b; Forss and Jousmäki 1998; Hari, 1998; Mima et al., 1998; Kakigi et al., 2000; Lin et al., 2000; Lin and Forss, 2002). Using a whole-scalp MEG system, we recorded RDs and cortical somatosensory responses to electric stimulation of median nerves in 9 patients with BREC. We analyzed the corical generators of spontaneous spikes and evoked SI and SII responses with equivalent current dipole (ECD) modeling. To our knowledge, few previous studies (Kubota et al., 2000) have specifically compared the cortical generators for RDs, SI, and SII responses. The aims of this study were (1) to compare the orientations of ECDs among rolandic spikes, SI, and SII responses, (2) to clarify the anatomical relationship between cortical sources for rolandic spikes, SI, and SII responses. Materials and methods Patients We studied 9 children (2 boys, 7 girls; ages 8 12 years) who were diagnosed as having benign rolandic epilepsy according to infrequent motor seizures, normal neurodevelopment, and evidence of centrotemporal spikes on scalp EEG recordings. All patients and their parents gave informed consent to the experimental procedures. Table 1 shows the clinical information of these patients. All patients were normal at the neurological examination and none of them had any brain lesions on magnetic resonance (MR) images. Patients 7 and 9 were left handed and the others were right handed. Patients 1, 2, 5, 6, and 9 had nocturnal seizures, whereas daytime seizures were noted in the other patients. Only Patients 2, 4, and 6 were being treated with antiepileptic drugs at the time of the recording in the present study.

3 Y.Y. Lin et al. / NeuroImage 20 (2003) Fig. 1. Simultaneous MEG and EEG recordings from Patient 1 with bilaterally synchronous (BSRD) and unilateral rolandic discharges (RD_R, RD_L), maximal over the temporoparietal (T-P) head regions. The arrows indicate the peak timing of individual spikes. The right inserts show the schematic placement of EEG electrodes and MEG sensors viewed from the top (upper) or the right (lower). The demonstrated MEG signals in this figure were taken from the gradiometers of the blackened sensor elements. The signals were low-pass filtered at 40 Hz. ECG, electrocardiogram; R, right; L, left. MEG recordings MEG recordings were conducted in a magnetically shielded room with a whole-scalp 306-channel neuromagnetometer (Vectorview, 4-D Neuroimaging, San Diego, CA) that comprises 102 identical triple-sensor elements (see the right lower insert of Fig. 1). Each sensor element consists of two orthogonal planar gradiometers and one magnetometer coupled to three SQUIDs (superconducting quantum interference devices) and thus provides three independent measures of the magnetic fields. During the recordings, the patient was sitting comfortably with the head supported against the helmet of the magnetometer. The exact location of the head with respect to the sensors was found by measuring magnetic signals produced by currents led to four head indicator coils, placed at known sites on the scalp. The locations of the coils with respect to anatomical landmarks on the head were determined with a three-dimensional (3-D) digitizer to allow alignment of the MEG and MR image coordinate systems (Hämäläinen et al., 1993). MR images of the patient s brain were acquired with a 3-T Bruker Medspec300 scanner (Germany). For spontaneous brain activities, we placed scalp EEG electrodes according to the International system, and recorded simultaneously EEG and MEG for 3- to 4-min epochs. In total, 10 recording epochs were obtained for each patient. Head position was measured immediately prior to each recording session. For somatosensory evoked fields (SEFs), the left and right median nerves were stimulated in subsequent runs with 0.2-ms constant electric pulses, delivered at the wrist with an interstimulus interval (ISI) of 3 s (Patients 1, 2, 4, 5, 8, and 9) or 1 s (Patients 3, 6, and 7). Stimulus intensities were strong enough to produce a thumb twist varying from 4.5 to 7.5 ma. The recording passbands and signal digitization rates were and 600 Hz, respectively, and 150 evoked responses were averaged on-line. Responses coincident with prominent vertical electro-oculogram signals ( 150 V) were automatically rejected from averaging. The analysis epoch of 600 ms included a prestimulus baseline of 200 ms. In addition, we also collected raw data during electric stimulation for off-line evaluation of evoked spikes. SEF recordings under each condition were repeated at least once to ensure reliability of the evoked responses. Identification of spikes Interictal spikes were visually checked on both EEG and MEG channels. Identified spikes were collected and classified into 3 groups: unilateral rolandic discharges (RD) in the left hemisphere (RD_L), RD in the right hemisphere (RD_R), and bilaterally synchronous rolandic discharges

4 2054 Y.Y. Lin et al. / NeuroImage 20 (2003) Fig. 2. Topographic distribution of unilateral rolandic discharges from left (RD_L) and right hemispheres (RD_R) of Patient 2. The sensor array of 204 planar gradiometers is flattened to a plane and viewed from above with the subject s nose pointing upwards. Signals of RD_L and RD_R are clearly seen on the central region of the left and the right hemisphere, respectively. The left third of the corresponding bottom insert shows the enlargement of encircled spike complex (solid line) superimposed by predicted signal (dashed line) according to single equivalent current dipole (ECD) at the main spike peak (vertical line). The middle third of each insert shows the magnetic field pattern, orientation, and location of the corresponding ECD (arrow) superimposed on the sensor array viewed from the left (RD_L) or the right (RD_R). The shadowed area indicates magnetic flux out of the head. The right third of each insert shows the source waveform and goodness-of-fit (g) value of the ECD as a function of time. (BSRD) (Lin et al., 2003). BSRDs were defined as those bilaterally simultaneous spikes with side-to-side time lag of main peaks less than 50 ms. Source modeling We applied the ECD modeling to analyze interictal spikes and SEF responses recorded by the 204 planar gradiometers. Epochs of ms in duration, with clear spikes or SEF signals, were visually selected for further analysis. During these time windows (from the beginning of the main deflection to its return to the baseline level) the magnetic field patterns were first visually surveyed in 2-ms steps to create the initial estimate of the number of active sources within that time period and to estimate the stability of the magnetic ECD field pattern. The ECDs, best describing the measured data, were found by a least-squares search using subsets of channels around the maximum signals. These calculations resulted in the 3-D location, orientation, and strength of the ECD in a spherical conductor. The goodness-of-fit (g) value of the dipole model was calculated to evaluate how well the measured signals were explained by the ECD. In this study, only ECDs with g 85% at selected periods of time in a subset of channels were applied for the subsequent analysis. After obtaining the individual dipoles, all channels and the whole signal duration were taken into account in computing a time-varying multidipole model. We evaluated the validity of the multidipole model by comparing the measured signals with the responses predicted by the model. If signals of some brain region were left inadequately explained by the model, the data were reevaluated for more accurate estimation of the generators. This approach, explained previously in detail (Hämäläinen et al., 1993), has been successfully applied in previous MEG studies (Hari et al., 1984, 1993; Hämäläinen et al., 1993; Forss et al., 1994,

5 Y.Y. Lin et al. / NeuroImage 20 (2003) , 1999; Huttunen et al., 1996; Lin et al., 2000, 2003; Lin and Forss, 2002). Data analysis and statistics In this paper, we applied the sources of unilateral RDs in subsequent comparison with SEF generators in the same hemisphere. After artifact rejection, at least 10 consecutive RDs with good signal-to-noise ratio were identified in individual hemispheres of each patient. We calculated the average location coordinates for RDs, SI, and SII sources. We defined RD SI as the spatial distance between RD and SI generators in the same hemisphere; RD SII was the distance between RD and SII generators in the same hemisphere. Statistical difference between RD SI and RD SII was tested by the Wilcoxon signed-rank test. We also assessed the difference between RD and SI or SII sources in terms of individual x-, y-, or z-coordinate axes by the Wilcoxon signed-rank test. P 0.05 was taken as the significance threshold. Results Waveforms and source localization of RDs Fig. 1 shows the typical rolandic spikes on simultaneous EEG and MEG recordings of Patient 1. RDs occurred either on one side only (RD_R or RD_L) or synchronously in both hemispheres (BSRD). On EEG, the largest phase-reversal negativity was identified on centroparietal electrodes. These spikes were simultaneously observed on corresponding temporoparietal MEG channels. In principle, in MEG one does not refer to individual signals using positive/negative polarities. To clearly describe various deflections of an individual RD complex in MEG, however, we referred to positive/negative waves according to corresponding polarities in simultaneous EEG recordings. Fig. 2 shows the topographic distributions of RD_R (right half) and RD_L signals (left half) on MEG from Patient 2. Clear RD_R and RD_L signals are present in the right and left temporoparietal regions, respectively. The encircled RDs were enlarged to show the characteristic four deflections: preceding small positive waves (portion a), prominent negative sharp waves (portion b), the following positive waves (portion c), and negative slow waves (portion d). The enlarged signals in corresponding inserts also show the close resemblance of the measured signals (solid lines) to the predicted signals (dashed lines) based on a single-dipole model at the peaks (vertical lines) of the prominent negative sharp waves. The ECDs of typical RDs were vertical in orientation as shown in the middle of the inserts. Source localization of SEFs Fig. 3 shows the topographic distribution (left panel) and ECD characteristics (right panels) of SEFs to left median nerve stimulation in Patient 2. The somatosensory responses were distributed in the right parietal and bilateral temporoparietal regions. Clear magnetic dipole patterns were identified at corresponding response deflections peaking at 24, 203, and 201 ms, respectively. The high g value of the dipole fitting and the close resemblance between measured (solid lines) and predicted signals (dashed lines) indicated the 3 ECDs could successfully model the cortical generators of the somatosensory responses. The right third of the right upper panel shows the waveforms of the 3 ECDs as a function of time for the 3 ECDs in the right SI and bilateral SII cortices. The right lower panel shows the ECDs locations of somatosensory responses superimposed on MR images in comparison with locations of RDs from the same patient. The source of the early SEF responses at 24 ms was in the postcentral wall of the central fissure, presumably in area 3b of the SI cortex (Hari et al., 1984, 1990; Wood et al., 1985; Allison et al., 1989; Baumgartner, 1993). The sources of longer latency components over bilateral temporoparietal regions were in the upper banks of the sylvian fissures in the parietal opercula, in line with previous MEG studies (Hari et al., 1984, 1990, 1993; Forss et al., 1994, 1996; Huttunen et al., 1996; Mauguière et al., 1997a; Kakigi et al., 2000; Lin et al., 2000; Lin and Forss, 2002). We regarded these sources as SII generators because these responses were bilateral in distribution and the locations were in line with previous reports on human SII cortices (Penfield and Jasper, 1954; Woolsey et al., 1979). For SEFs in 7 out of our patients, 3-ECD models yielded an adequate explanation for the somatosensory responses in contralateral SI and bilateral SII areas. In the other 2 patients, 4 ECDs were identified as sources of SEFs in SI, bilateral SII, and contralateral posterior parietal cortex (PPC). Typically, the earliest signal (N20m) of SI response peaked at ms and was followed by deflections of opposite polarity at ms (P35m) and ms (P50m). In this paper, we used the ECD at P35m as the generator of SI responses because it explained most SI responses including P50m deflection. SII responses in our patients peaked at ms ( ms). In this study we excluded those SEFs with concomitant evoked spikes by off-line evaluation of raw EEG and MEG signals obtained during SEFs recordings. Magnetic field patterns and ECD locations of RDs in comparison with SI and SII As shown in the helmet-shaped sensor arrays of Fig. 2 and Fig. 3, the magnetic field patterns and ECD orientations were similar between RDs and SII responses. Fig. 4 shows the source localization of RDs and SEFs from all patients superimposed on MR images. The gener-

6 2056 Y.Y. Lin et al. / NeuroImage 20 (2003) ators of SI and SII responses were located in the postcentral parietal cortex and the upper bank of the sylvian fissure, respectively. The spikes were localized in the precentral region anterior to both SI and SII cortices in Patients 1 8. RDs in Patient 9 were situated in the pericentral region between SI and SII areas. The right lower panel of this figure schematically showed the mean locations of RDs across subjects with respect to SI and SII cortices. Table 2 shows the mean coordinates (mean SEM) of RDs, SI, and SII sources from all patients. On average RD SI was mm, significantly longer than ( mm) RD SII (P 0.01, Wilcoxon signed-rank test). RDs were mm lower, and mm lateral to SI cortex. In addition, RDs were localized and mm anterior to SI and SII, respectively. Discussion ECD characteristics of RDs Most interictal EEG spikes in our patients with BREC were simultaneously seen on corresponding MEG channels (see Fig. 1), implying that the corresponding cortical intracellular currents for RDs appear as tangential dipoles. Previous EEG (Gregory and Wong, 1984; Wong, 1989; Yoshinaga et al., 1992) and recent MEG studies (Minami et al., 1996) also reported tangential dipoles for RDs In our study, RDs were characteristic of a prominent negative sharp wave preceded by a small positive wave and followed by a positive deflection and then a negative slow wave (see Fig. 2), in line with earlier reports (Lombroso, 1967; Gregory and Wong, 1984; Luders et al., 1987; Weinberg et al., 1990; Wong, 1991; Van der Meij et al., 1992; Baumgartner et al., 1996; Minami et al., 1996). The ECD of the most prominent negative component well explained most deflections of the spike complex, and therefore, we used single ECD at the negative sharp component as the source deflections of unilateral RDs. One recent study has also reported that ECDs of the main negative sharp waves are located in a relatively limited area, and other components of the spike complexes are localized in the vicinity of the main negative sharp waves (Minami et al., 1996). Source modeling of SI and SII responses in BREC patients MEG recordings allow noninvasive detection of several simultaneously active cortical areas. Previous neuromagnetic recordings have demonstrated activity in the SI and SII cortices (Hari et al., 1984, 1993; Sutherling et al., 1988; Forss et al., 1994, 1996, 1999; Huttunen et al., 1996; Hoshiyama et al., 1997; Mauguière et al., 1997a; Kakigi et al., 2000; Lin et al., 2000; Lin and Forss, 2002), as well as in the PPC (Forss et al., 1994, 1996, 1999; Hoshiyama et al., 1997). In all patients of this study, the activation of contralateral SI and bilateral SII cortices were consistently identified in response to unilateral median nerve stimulation with ISI at 1 s or 3 s,in line with earlier studies (Hari et al., 1984, 1993; Sutherling et al., 1988; Forss et al., 1994; 1996, 1999; Huttunen et al., 1996; Mauguière et al., 1997a; Kakigi et al., 2000; Lin et al., 2000; Lin and Forss, 2002). Two of our patients had additional activation in contralateral PPC. The peak latencies and amplitudes of SI responses in our BREC patients were compatible with those reported previously in adult subjects (Hari et al., 1984, 1993; Sutherling et al., 1988; Forss et al., 1994, 1996, 1999; Huttunen et al., 1996; Mauguière et al., 1997a; Kakigi et al., 2000; Lin et al., 2000; Lin and Forss, 2002). The peak latencies ( 174 ms) of SII responses in our BREC patients were clearly longer than those in adults ( 90 ms) (Hari et al., 1984, 1993; Sutherling et al., 1988; Forss et al., 1994, 1996, 1999; Huttunen et al., 1996; Mauguière et al., 1997a; Kakigi et al., 2000; Lin et al., 2000). At the present stage, however, we could not determine whether the relatively long peak latency of SII responses would be a characteristic abnormality or an age-related finding for children with BREC. Ferri and colleagues have observed than age-related decrease of giant somatosensory-evoked potentials (SEPs) amplitude in some BREC patients (Ferri et al., 2000). Further MEG studies in comparison with age-matched healthy children will help to evaluate the possible roles of the long-latency SII responses in patients with BREC. Anatomical relationship among RDs, SI, and SII Although previous studies of high-amplitude SEPs (Manganotti et al., 1998a, 1998b) and SEFs (Kubota et al., 2000) have suggested that RDs and giant somatosensory responses share common generators over the sensorimotor areas, the anatomical relationship among RDs, SI, and SII remains unclear. Using spike topography and functional MR images (fmri), Manganotti and colleagues have observed evoked rolandic spikes in association with focal activation of sensorimotor cortices in one BREC patient during finger-tapping stimulation (Manganotti et al., 1998c). However, fmri was unable to determine the activation sequence in the sensorimotor areas because of its limited temporal resolution. With excellent temporal resolution and reasonable spatial resolution, MEG is good for investigating the activation in cortical fissures including SI and SII responses (Hari et al., 1984, 1993; Hari and Forss, 1999; Lin et al., 2000; Lin and Forss, 2002). To determine the functional localization of RDs with respect to SI and SII, we studied SEFs in BREC patients who had no evoked spikes. Most RDs were located in the precentral cortex significantly closer to SII than SI area. The contribution of motor cortex in the generation of evoked spikes in BREC patients has been observed in one recent study using transcranial magnetic stimulation (Manganotti and Zanette, 2000).

7 Y.Y. Lin et al. / NeuroImage 20 (2003) Fig. 3. Topographic distribution of somatosensory evoked magnetic fields (SEFs) from Patient 2 in response to electric stimulation of the left median nerve at the wrist. The sensor array of 204 planar gradiometers is flattened to a plane and viewed from above with the subject s nose pointing upwards. Encircled responses are enlarged in the right upper panel of this figure. (Right upper) The enlarged signals (A, B, C) and their corresponding magnetic field patterns and waveforms of the 3 ECDs found at 24 ms, 203 ms, and 201 ms, respectively. The magnetic field patterns, orientations, and locations of corresponding ECDs (arrows) are shown on the sensor arrays viewed from the lateral side. The shadowed area indicates magnetic flux out of the head. Source waveforms and goodness-of-fit(g) values of the 3 ECDs are shown as a function of time corresponding to the generators of SI, SII_R, and SII_L responses. (Right lower) Some sources of SI, SII, and rolandic discharges (RDs) from Patient 2 superimposed on MR images. R, right; L, left; A, anterior; P, posterior. On the basis of giant somatosensory-evoked responses, previous studies have reported a close relationship between RDs and somatosensory-evoked responses (De Marco and Negrin, 1973; De Marco and Tassinari, 1981; Plasmati et al., 1992; Minami et al., 1996; Manganotti et al., 1998a; Kubota et al., 2000). In the present study, we found RDs located mm lateral to hand SI cortex. According to the sensory homunculus distribution, the lip SI is lateral to the hand SI (Penfield and Rasmussen, 1950). Thus, our results are in line with one earlier observation (Minami et al., 1996) that the RD locations were close to the lower lip SI cortex. Clinical and functional aspects of the cortical sources for RDs with respect to sensorimotor areas Clinically, the initial focal symptoms of BREC patients are usually characterized by unilateral perioral or lingual somatosensory symptoms (Lombroso, 1967; Blom et al., 1972; Lerman and Kivity, 1975). In the present study, 5 (70%) out of our 7 patients with initial focal seizures have perioral symptoms. We found that RD locations were closer to SII than SI. Based on our findings and one previous study using lower lip stimulation (Minami et al., 1996), we proposed that RDs are located in the precentral area near to both the SII cortex and the lower lip area of the SI cortex. The close locations for both RDs and SII responses agreed with earlier reports of RDs localization in lower rolandic-sylvian region (Gregory and Wong, 1984). The lack of electrical or clinical evidence for cortical deficits (Lombroso, 1967) would support a cortical generator near the sylvian fissure rather than the rolandic fissure. Previous EEG studies have shown normal early SEF responses (N20-P27) in BREC patients, suggesting that SI cortex may not be directly involved in the generation of RDs (Tassinari et al., 1988; Manganotti et al., 1998a, 1998b). Recent studies have suggested the contribution of pericentral areas to the formation of epileptogenicity in BREC (Gregory and Wong, 1984; Kubota et al., 1996; Minami et al., 1996; Kamada et al., 1998). Our results suggest that RDs

8 2058 Y.Y. Lin et al. / NeuroImage 20 (2003) Fig. 4. (Left and right upper) Source localization of rolandic spikes (red dots), SI (black dots), and SII responses (white squares) superimposed on patients own MR images. R, right; L, left; A, anterior; P, posterior. (Right lower) Mean locations (mean standard deviations) of rolandic spikes, SI, and SII responses shown in the schematic coordinate system of a spherical head model. The coordinate system in the x y plane is viewed from the top. The y z plane is viewed from the right or the left. The positive x-, y-, and z-axes go toward the right preauricular point, the nasion, and the vertex, respectively. originate mainly from the precentral motor cortex (8 out of the 9 patients), although postcentral cortex is also likely responsible for the epileptogenicity in BREC (1 out of the 9 patients). However, the mechanism of pre- and postcentral epileptogenicity in BREC is still unclear. According to the ascending sequential maturation theory in mammalian neocortical organization (Kawaguchi et al., 1983), the developmental processes of the thalamocortical projections vary between frontal and parietal cortices and there is a sequential synaptogenesis proceeding from the deep layer to the superficial layer. The maturation disturbance in the thalamocortical development process may underlie the hyperexcitability of related sensorimotor cortices (Kawaguchi et al., 1983; Kubota et al., 1996). BREC appears to be a maturational or developmental abnormality that can affect multiple brain areas without progressive neurophysiological or pathological deteriorations in the vast majority of patients (Beydoun et al., 1992). One recent study has reported the age-related amplitude reduction of giant middle-latency SEPs in BREC patients (Ferri et al., 2000), implying the maturational changes of cortical excitability. Our present data suggest the presence of cortical hyperexcitability around the lateral and inferior motor cortex closer to the SII than SI areas. Further studies

9 Y.Y. Lin et al. / NeuroImage 20 (2003) Table 2 Mean source coordinates (mean SEM) of SEFs and rolandic spikes Patient No. Source (peak latency) x (mm) y (mm) z (mm) 1 SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_L ( ms) SII_L ( ms) RD_L SI_L ( ms) SII_L ( ms) RD_L SI_R ( ms) SII_R ( ms) RD_R SI_R ( ms) SII_R ( ms) RD_R SEFs, somatosensory-evoked magnetic fields; SI, primary somatosensory cortex; SII, second somatosensory cortex; RD, unilateral rolandic discharge; R, right; L, left. The positive x-, y-, and z-axes go toward the right preauricular point, the nasion, and the vertex, respectively. on the neuronal excitability of the motor and SII cortices may facilitate better elucidation of the cortical generators for RDs in patients with BREC. Acknowledgments We thank Mr. Chih-Che Chou and Mr. Chou-Ming Cheng for technical assistance in the acquisition of MR images. We thank Ms. Wen-Yung Sheng for her invaluable assistance in our statistical analysis. This study was supported by research grants from Taipei Veterans General Hospital (VGH-93) and National Science Council (NSC B ), Taipei, Taiwan. References Allison, T., McCarthy, G., Wood, C.C., Darcey, T.M., Spencer, D.D., Williamson, P.D., Human cortical potentials evoked by stimulation of the median nerve. II. Cytoarchitectonic areas generating shortlatency activity. J. Neurophysiol. 62, Baumgartner, C., Clinical Electrophysiology of the Somatosensory Cortex. Springer, Wien. Baumgartner, C., Graf, M., Doppelbauer, A., Serles, W., Lindinger, G., Olbrich, A., Bacher, J., Pataraia, E., Almer, G., Lischka, A., The functional organization of the interictal spike complex in benign rolandic epilepsy. Epilepsia 37, Beydoun, A., Garofalo, E.A., Drury, I., Generalized spike-waves, multiple loci, and clinical course in children with EEG features of benign epilepsy of childhood with centrotemporal spikes. Epilepsia 33,

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