Magnetoencephalographic yield of interictal spikes in temporal lobe epilepsy Comparison with scalp EEG recordings

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1 NeuroImage 19 (2003) Magnetoencephalographic yield of interictal spikes in temporal lobe epilepsy Comparison with scalp EEG recordings Y.Y. Lin, a,b,c,d, * Y.H. Shih, c,e J.C. Hsieh, a,c,d H.Y. Yu, b,c C.H. Yiu, b,e T.T. Wong, c,e T.C. Yeh, a,c S.Y. Kwan, b,c L.T. Ho, a,b D.J. Yen, b,c Z.A. Wu, b,c and M.S. Chang c a Integrated Brain Research Unit, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan b Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan c School of Medicine, National Yang-Ming University, Taipei 112, Taiwan d School of Life Science, National Yang-Ming University, Taipei 112, Taiwan e Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan Received 6 August 2002; revised 28 January 2003; accepted 18 March 2003 Abstract To compare magnetoencephalography (MEG) with scalp electroencephalography (EEG) in the detection of interictal spikes in temporal lobe epilepsy (TLE), we simultaneously recorded MEG and scalp EEG with a whole-scalp neuromagnetometer in 46 TLE patients. We visually searched interictal spikes on MEG and EEG channels and classified them into three types according to their presentation on MEG alone (M-spikes), EEG alone (E-spikes), or concomitantly on both modalities (M/E-spikes). The M-spikes and M/E-spikes were localized with MEG equivalent current dipole modeling. We analyzed the relative contribution of MEG and EEG in the overall yield of spike detection and also compared M-spikes with M/E-spikes in terms of dipole locations and strengths. During the 30- to 40-min MEG recordings, interictal spikes were obtained in 36 (78.3%) of the 46 patients. Among the 36 patients, most spikes were M/E-spikes (68.3%), some were M-spikes (22.1%), and some were E-spikes (9.7%). In comparison with EEG, MEG gave better spike yield in patients with lateral TLE. Sources of M/E- and M-spikes were situated in the same anatomical regions, whereas the average dipole strength was larger for M/E- than M-spikes. In conclusion, some interictal spikes appeared selectively on either MEG or EEG channels in TLE patients although more spikes were simultaneously identified on both modalities. Thus, simultaneous MEG and EEG recordings help to enhance spike detection. Identification of M-spikes would offer important localization of irritative foci, especially in patients with lateral TLE Elsevier Science (USA). All rights reserved. Keywords: Magnetoencephalography; Scalp EEG; Spike detection; Interictal spikes; Temporal lobe epilepsy Introduction In epileptic patients, interictal spikes are closely related to the epileptic focus (Barth et al., 1984; Baumgartner et al., 1995; Merlet et al., 1996). Some studies have described a correlation between a successful outcome after surgery for temporal lobe epilepsy (TLE) and a high lateralization value * 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). of interictal spikes before surgery (Lieb et al., 1981; Chee et al., 1993; King et al., 1995; Holmes et al., 1997). Videoscalp electroencephalography (EEG) monitoring has been applied routinely for localization of epileptic spikes in patients with medically intractable epilepsy. However, in some patients scalp EEG provides inadequate localization, and thus intracranial EEG recordings with depth or subdural electrodes must be performed. These invasive procedures, however, carry significant risks (Arroyo et al., 1993; Spencer et al., 1993). Magnetoencephalography (MEG) is a totally noninvasive tool for localization of epileptic activity (Barth et al., /03/$ see front matter 2003 Elsevier Science (USA). All rights reserved. doi: /s (03)

2 1116 Y.Y. Lin et al. / NeuroImage 19 (2003) , 1984; Modena et al., 1982; Sato and Smith, 1985; Ricci et al., 1987; Rose et al., 1987a, 1987b; Sutherling et al., 1987, 1988; Sutherling and Barth, 1989; Stefan et al., 1990, 1992, 1994, 2000; Tiihonen et al., 1990; Eisenberg et al., 1991; Ogashiwa et al., 1991; Yotsumoto et al., 1991; Paetau et al., 1992, 1994, 1999; Hari et al., 1993; Nakasato et al., 1994; Smith et al., 1995; Ebersole, 1997b; Knowlton et al., 1997; Merlet et al., 1997; Mikuni et al., 1997; Ko et al., 1998; Minassian et al., 1999; Wheless et al., 1999; Baumgartner et al., 2000; Iwasaki et al., 2002; Oishi et al., 2002; Lin et al., 2003a,b). MEG is less affected by conductivity properties than EEG; thus MEG may localize the spike sources more accurately (Cuffin and Cohen, 1979; Nakasato et al., 1994; Wheless et al., 1999). Several studies have compared MEG with EEG in epileptic source localization (Sutherling and Barth, 1989; Stefan et al., 1992; Nakasato et al., 1994; Ko et al., 1998; Minassian et al., 1999; Wheless et al., 1999; Oishi et al., 2002); however, little is known about the comparison of spike presentations between these two modalities in patients with TLE. Merlet and colleagues (1997) observed asynchronous peaks for MEG and EEG spikes. Some studies have shown the selective presentation of some interictal spikes on MEG without concomitants on EEG (Ogashiwa et al., 1991; Ko et al., 1998), but there remains no detailed comparison of spike detection between MEG and scalp EEG in various types of TLE. Using a whole-scalp neuromagnetometer, we conducted simultaneous MEG and scalp EEG recordings in TLE patients and identified three types of spikes according to their preferential presentation on MEG channels (M-spikes), or EEG channels (E-spikes), or simultaneously on both modalities (M/E-spikes). The goals of this study are to investigate the following three questions: (1) What is the percentage of M-spikes in the overall yield of interictal spikes in various types of TLE? (2) Would MEG help to detect interictal spikes in mesioanterior TLE compared with lateral TLE? (3) Are M-spikes different from M/E-spikes in terms of dipole locations and strengths? Materials and methods Patients One hundred twenty-five patients with medically intractable TLE underwent presurgical evaluation in the Epilepsy Monitoring Unit (EMU) of Taipei Veterans General Hospital between December 2000 and December Of the 125 patients, 46 (25 women, 21 men; age years) were randomly selected during the presurgical examination to undergo simultaneous MEG and scalp EEG recordings for this study. Each patient gave informed consent prior to this study. Presurgical workup included intensive video-scalp EEG monitoring, magnetic resonance (MR) imaging, positron emission tomography (PET), interictal and postictal single-photon emission computed tomography (SPECT), neuropsychological assessment, and tests of language and memory with intracarotid amobarbital injection (Lin et al., 1997). Seizures were documented according to the International League Against Epilepsy classification (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). Twenty-two patients had mesial TLE (MTLE) based on the convergence of presurgical evaluation data, including typical clinical seizure semiology, anterior temporal spikes on interictal EEG, and evidence of mesial temporal lobe sclerosis (MTS) on MR imaging. Fourteen patients had nonsclerotic anterior TLE defined by clinical seizure semiology of mesial temporal lobe onset, presence of maximal epileptic discharges on anterior temporal electrodes (F7, F8, Ch1, or Ch2) on interictal or ictal EEG, and evidence of either non-mts abnormalities or normal patterns on MR images of anterior temporal structures. Ten patients were diagnosed as having lateral TLE according to seizure semiology and EEG evidence of 90% of maximal epileptic activities located over the mid- or posterior temporal electrodes (T3 T5, T4 T6). MEG/EEG recordings MEG recordings were conducted in a magnetically shielded room with a whole-scalp 306-channel neuromagnetometer (Vectorview, 4-D Neuroimaging, San Diego, CA) comprising 102 identical triple sensor elements (Lin et al., 2003a,b). Each sensor element consists of two orthogonal planar gradiometers and one magnetometer coupled to 3 SQUIDs (superconducting quantum interference devices) and thus provides three independent measures of the magnetic fields. During the recordings, the patient sat comfortably with the head supported against the helmet-shaped bottom of the magnetometer. In this study, data analysis was based on signals of the 204 planar gradiometers. For scalp EEG recordings, 21 gold-disk electrodes were placed according to the International System with the addition of bilateral cheek electrodes (Sadler and Goodwin, 1989; Krauss et al., 1992). Fig. 1 shows the spatial arrays for MEG sensors and scalp EEG electrodes used in this study. The exact location of the head with respect to the MEG 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). All patients were informed of their MEG measurement appointment at least 1 day in advance and told to keep themselves relatively deprived of sleep before the measurement. During simultaneous MEG and EEG recordings, pa-

3 Y.Y. Lin et al. / NeuroImage 19 (2003) during sleep. For patients with bilateral interictal discharges, we analyzed only those spikes on the main epileptogenic side, which was determined by convergent results of presurgical studies. For each spike identified in either MEG or EEG, we reevaluated it on both MEG and EEG simultaneously to confirm its modality-related distribution. We defined three types of interictal spikes according to their presentation on MEG alone without EEG concomitants (M-spikes), on EEG alone without MEG concomitants (E-spikes), or simultaneously on MEG and EEG channels (M/E-spikes). The M-spikes and M/E-spikes were localized with MEG equivalent current dipole (ECD) modeling. ECD modeling Fig. 1. The spatial coverage of magnetoencephalographic (MEG) and scalp electroencephalographic (EEG) recordings. Left: The arrays of neuromagnetic sensors viewed from the top (upper) or the right (lower). The insert shows one enlarged sensor element consisting of two orthogonal planar gradiometers and one magnetometer. Right: Placement of scalp EEG electrodes according to the International System, viewed from the top (upper) or the right (lower). tients were allowed to fall asleep with their eyes closed. Spontaneous signals were recorded for 3 4 min in each session. In total, recording sessions were obtained. Head position was measured immediately prior to each session. The raw data were bandpass-filtered between 0.03 and 130 Hz, sampled at a digitization rate of 400 Hz, and stored in magnetic optical disks for off-line analysis. Spike identification Interictal spikes were collected during off-line visual search on MEG and EEG channels. For EEG spike recognition, Cz reference montages, and transverse and longitudinal bipolar montages were applied to identify unequivocal epileptic spikes. For MEG spike recognition, we divided the 204 gradiometer channels into eight regions with channels in each and looked for spike activities region by region. Sharp MEG signals clearly distinguishable from ongoing background activities, seen on at least three to five nearby channels of the individual region, were selected and then regarded as MEG spikes if clear magnetic dipole patterns were identified with reasonable localization in the temporal structures. We rejected sharp signals suspected of clear contribution from heart beats, eye movements, physiological rhythmic discharges, or vertex sharp activities To identify the source of an individual spike, we selected an epoch of ms duration consisting of a clear interictal spike. During the time window starting from the beginning of the main spike deflection to its return to the baseline, we visually surveyed the magnetic field patterns in 2-ms steps. Clear dipole patterns were identified around the peak of the main spike deflection and were characterized by a magnetic extremum surrounded by clear in-flux and outflux isofield contours. The single ECDs around the spike peak were then calculated by a least-squares search using a subset of channels around the maximum peak. These calculations resulted in the 3-D locations, orientations, and strengths of the ECDs in a spherical conductor model, which were based on this patient s MR images. Goodnessof-fit (g) of individual dipole model was also calculated to estimate what percentage of the measured signal variance was accounted for by the dipole. Around the peak of individual main spike deflection, we enrolled the single ECD with the highest g value for further analysis. In this study, we accepted only ECDs with g 80%. In agreement with previous MEG studies (Paetau et al., 1992; Knowlton et al., 1997; Baumgartner et al., 2000; Iwasaki et al., 2002; Lin et al., 2003b), single ECD well explained most measured spike signals; thus, we used a single ECD as the neural source of individual spike activity. Data analysis and statistics We calculated the number of M/E-, M-, and E-spikes in each patient obtained during the min recordings. Spike detection index (SDI) of MEG was defined as the ratio between the sum of M/E- and M-spikes and the sum of M/E-, M-, and E-spikes. SDI of the EEG was defined as the ratio between the sum of M/E- and E-spikes and the sum of M/E-, M-, and E-spikes. Within individual TLE categories (MTLE, nonsclerotic anterior TLE, and lateral TLE), spike detection yields of MEG and scalp EEG were quantitatively compared by using SDI. Moreover, we calculated and compared the average locations and strengths of M/E- and

4 1118 Y.Y. Lin et al. / NeuroImage 19 (2003) M-spike sources in patients with at least 15 corresponding spikes. Analysis of variance (ANOVA) with repeated measurement was used to evaluate the difference between MEG and EEG in spike detection for various epilepsy types. We adjusted the significant level by a two-sided Bonferroni multiple-comparison procedure in all pairwise comparisons. P value below 0.05 was considered significant. Results Thirty-six (78.3%) of the 46 patients had interictal spikes during our min MEG recordings. Among the 36 patients, three spike patterns were identified according to their preferential presentation either on MEG (M-spikes) or on EEG (E-spikes) or simultaneously on both modalities (M/E-spikes). Table 1 shows the general information and Table 1 General information and spike types of the 36 patients with unequivocal spikes during simultaneous MEG/EEG recordings a Patient no. Sex Age (yr) Side of seizure focus MRI Surgery (pathology) Surgical follow-up Outcome b Spike types SDI M/E- M- E- MEG EEG MTLE 1 M 40 R MTS, R ATL, (Gliosis) 22 mo I F 26 L MTS, L ATL, (Gliosis) 19 mo I F 28 R MTS, R ATL, (Gliosis) 22 mo I M 32 L MTS, L ATL, (Gliosis) 25 mo III F 26 R MTS, R ATL, (Gliosis) 19 mo I M 33 R MTS, R ATL, (Gliosis) 20 mo I M 35 R MTS, R ATL, (Gliosis) 11 mo I F 24 L MTS, L ATL, (Gliosis) 12 mo I M 27 L MTS, L ND M 26 L MTS, L ND M 31 L MTS, L ND M 44 L MTS, L ND M 33 R MTS, R ND F 30 L MTS, L ATL, (Gliosis) 11 mo I M 25 R MTS, R ATL, (Gliosis) 7 mo I F 25 R MTS, R ATL, (Gliosis) 3 mo I M 27 R MTS, R ATL, (Gliosis) 1 mo I Non sclerotic anterior TLE 18 F 40 R Tumor, R, MT ATL, (Ganglioglioma) 22 mo II F 22 R Tumor, R, MT LN, (Astrocytoma) 19 mo II F 15 L CH, L, AT ND M 27 L Tumor, L, AT ND F 30 R Normal ATL, (Gliosis) 24 mo I M 38 R Normal ND M 40 R CA ND M 37 L CH, L, AT LN MR, (CH) 8 mo I F 34 L CH, L, AT LN MR, (CH) 4 mo I F 42 L CH, L, AT ND F 22 L Normal ATL, (Gliosis) 1 mo I Lateral TLE 29 F 32 R Normal ND M 31 L VD ND M 42 L Encephalom, L, FT ND F 35 R Tumor, R, PT LN, (Astrocytoma) 22 mo IV F 11 R Encephalom, R, PT ND F 12 R Encephalom, R, PT CR, (Astrocytoma) 6 mo I M 23 L Normal ND F 25 R Normal ND a MEG, magnetoencephalography; EEG, electroencephalography; MRI, magnetic resonance imaging; M/E-, spikes found on both MEG and EEG; M-, spikes found on MEG alone; E-, spikes found on EEG alone; SDI, spike detection index; SDI of MEG, the ratio between the sum of M/E- and M-spikes and the sum of M/E-, M-, and E-spikes; SDI of EEG, the ratio between the sum of M/E- and E-spikes and the sum of M/E-, M-, and E-spikes; TLE, temporal lobe epilepsy; R, right; L, left; MTS, mesial temporal lobe sclerosis; CH, cavernous hemangioma; CA, cerebellar atrophy; VD, ventricular dilatation; Encephalom, encephalomalacia; AT, anterior temporal; PT, posterior temporal; ATL, anterior temporal lobectomy; LN, lesionectomy; ND, not done; MR, marginal resection; CR, cortical resection; mo, months. b Seizure outcome classified by the criteria of Engel (1987).

5 Y.Y. Lin et al. / NeuroImage 19 (2003) Fig. 2. Three types of interictal spikes on simultaneous magnetoencephalographic (MEG) and scalp electroencephalographic (EEG) recordings in temporal lobe epilepsy (TLE) patients classified according to their preferential presentation on MEG channels alone (M-spikes), or on EEG channels alone (E-spikes), or simultaneously on both modalities (M/E-spikes). Eight MEG channels from bilateral temporal regions are displayed. On EEG channels, phase reversals of spike activities (arrows) are located at Ch2 and F8 electrodes in Patients 6 and 19, and at T4 electrodes in Patient 29. Both MEG and EEG signals are low-pass filtered at 50 Hz. ECG, electrocardiogram. numerical distribution of spike types for each of the 36 patients. After presurgical evaluation and MEG studies, 15 patients underwent tailored anterior temporal lobectomy (ATL). Four patients received lesionectomy with marginal resection for irritative foci. Patient 34 continued to suffer from seizures although she had undergone a resective surgery on the right temporal lobe 2 years prior to the present study. Pathological exam revealed astrocytoma cells in resected tissue. After this study, she underwent a second cortical resection around the previously operated site for removing epileptic irritative foci. Seizure outcome after epilepsy surgery was assessed in January 2003, according to Engel s classification (Engel, 1987). Further studies and subsequent surgery interventions have been planned for some of the other patients. Fig. 2 shows the characteristic patterns of M/E-, M-, and E-spikes from Patients 6, 19, and 29, who have been suffering from MTLE, nonsclerotic anterior TLE, and lateral TLE, respectively. Table 2 shows the amount of the three spike types in various categories of TLE. As a whole, most spikes were M/E-spikes (68.3%) and the rest were M-spikes (22.1%) and E-spikes (9.7%). Spike localization by MEG source modeling Fig. 3 shows the spatial distribution and source localization of MEG spikes in Patient 34. Interictal spikes were found over the magnetometers and planar gradiometers of the right posterior temporal region, but the signal-to-noise ratio was clearly better on the planar gradiometers than magnetometers. Based on signals of the planar gradiometers, the ECD around the maximum spike peak was obtained with a clear magnetic dipole pattern. We considered this ECD optimal for solution of spike localization because of the close resemblance of the measured signal (solid lines) to the waveforms (dashed line) predicted by the ECD signals, with goodness-of-fit at 80%. Coregistered on the patient s MR images and 3-D brain rendering, the ECD was found in the superior posterior border of a previously operated area in the right temporal lobe. After the study, she underwent marginal cortical resec-

6 1120 Y.Y. Lin et al. / NeuroImage 19 (2003) Table 2 Number of M/E-, M-, and E-spikes in patients with temporal lobe epilepsy (TLE) a Category Total spikes Spike types M/E- M- E- MTLE (n 17) (80.0%) 79 (13.2%) 41 (6.8%) NS-ATLE (n 11) (70.2%) 35 (12.0%) 52 (17.8%) LTLE (n 8) (47.1%) 162 (45.1%) 28 (7.8%) (68.3%) 276 (22.1%) 121 (9.7%) a M/E-spikes, spikes found on both MEG and EEG; M-spikes, spikes found on MEG without concomitants on EEG; E-spikes, spikes found on EEG without concomitants on MEG; MTLE, mesial TLE; NS-ATLE, nonsclerotic anterior TLE; LTLE, lateral TLE; MEG, magnetoencephalography; EEG, electroencephalography. tion. Pathological analysis of resected specimens showed an astrocytoma, possibly due to a recurrent tumor growth. In this study we present MEG data from planar gradiometers, because of a relatively poor signal-to-noise ratio of magnetometer signals in most of our patients. This is probably related to the high sensitivity of magnetometers to both cerebral and extracerebral magnetic fields (Hämäläinen et al., 1993). Compared with gradiometers, magnetometers would detect deeper neuronal excitations (Hämäläinen et al., 1993); thus, detailed comparisons between gradiometers and magnetometers will be conducted in a further study. Spike detection by MEG versus EEG in MTLE In the 17 MTLE patients, most spikes were M/E-spikes (80%), some were M-spikes (13.2%), and a few were E-spikes (6.8%) (see Table 2). The upper third of Fig. 4 shows the distribution of interictal M/E- (left panel) and M-spikes (right panel) of Patient 6 as presented in Fig. 2. The magnetic signals were largest in the right anterior temporal channels. The sources of M/E- and M-spikes were close to each other as shown on the patient s own MR images (middle panel). According to the SDI (Table 1), there was no significant difference between MEG and scalp EEG for spike detection in patients with MTLE (P 0.87). Twelve patients underwent ATL and 11 of them have remained free from seizure after surgery (Engel class I; mean follow-up, 14 months). Patient 4 has suffered from repeated seizures after surgery although the seizure frequency has reduced (Engel class III; follow-up, 2 years). Spike detection by MEG versus EEG in nonsclerotic anterior TLE For the 11 patients with nonsclerotic anterior TLE, most spikes were M/E-spikes (70.2%), some were M-spike (12%), and some were E-spikes (17.8%) (Table 2). The middle third of Fig. 4 shows the distribution of interictal M/E- (left panel) and M-spikes (right panel) from Patient 19 as displayed in Fig. 2. The magnetic signals were largest in the right temporal channels. The sources of M/E- and M- spikes were close to each other, as shown on the patient s own MR images (middle panel). According to the SDI (Table 1), there was no significant difference between MEG and scalp EEG for spike detection in patients with nonsclerotic anterior TLE (P 0.86). Patient 18 has suffered from rare seizures after ATL (Engel class II; follow-up, 22 months). Patient 19 has suffered from rare seizures after resective surgery although the seizure frequency has reduced (Engel class II; follow-up, 19 months). Patients 22 and 28 have remained free from seizure after ATL (Engel class I; mean follow-up, 13 months). Patients 25 and 26 have been seizure free after a lesionectomy for cavernous hemangioma in the right anterior temporal area (Engel class I; mean follow-up, 6 months). Spike detection by MEG versus EEG in lateral TLE As shown in Table 1, M-spikes outnumbered M/E-spikes in 7 of the 8 patients with lateral TLE. M/E-spikes (47.1%) together with M-spikes (45.1%) represented the majority of spikes in our 8 patients with lateral TLE (Table 2). The lower third of Fig. 4 shows the distribution of interictal M/E- (left panel) and M-spikes (right panel) from Patient 29 as presented in Fig. 2. The magnetic signals were largest in the right midposterior temporal channels. The sources of M/E- and M-spikes were close to each other as shown on the patient s own MR images (middle panel). According to the SDI (Table 1), we found a significant difference between MEG and scalp EEG for spike detection in patients with lateral TLE (P ). Patient 32 has suffered from repeated seizures after resective surgery for the tumor lesion in the right posterior temporal lobe (Engel class IV; follow-up, 22 months). Patient 34 has been seizure free following a cortical resection around the margins of the previously operated area (see Fig. 3) in the right posterior temporal lobe (Engel class I; follow-up, 6 months). Comparisons of M/E- and M-spikes Table 3 shows the average source locations and strengths of 15 M/E- and M-spikes from 7 of our patients, who had at least 15 M/E- and 15 M-spikes in the present MEG/EEG

7 Y.Y. Lin et al. / NeuroImage 19 (2003) Fig. 3. Left: Spatial distribution of magnetoencephalographic (MEG) spikes from Patient 34. In each signal triplet, the left traces illustrate signals recorded by two orthogonal gradiometers (G1 and G2), and the right trace by one magnetometer (M) of a single sensor unit. Right upper: Enlarged spike signals from the encircled signal triplet. The measured signals (solid lines) were superimposed by the waveforms (dotted lines) predicted by the equivalent current dipole (ECD) at the peak (vertical line) of the spikes from planar gradiometers. Right middle: The magnetic field pattern and orientation of the ECD at the spike peak based on signals from gradiometers. Right lower: The source waveform of the ECD as a function of time. Bottom: Locations of the ECD superimposed on the magnetic resonance images (coronal and axial slices) and on the three-dimensional rendering of her brain viewed from the right. Arrows indicate the previously operated area with tissue loss. L, left; R, right. recordings. There was no significant difference in source locations between M/E- and M-spikes, whereas the strengths of M/E-spike sources are larger than those of M-spike sources (P ). Discussion Identification and localization of epileptic discharges play important roles in the determination of the epilepto-

8 1122 Y.Y. Lin et al. / NeuroImage 19 (2003) Fig. 4. Spatial distributions of M/E- (left panels) and M-spikes (right panels) from whole-scalp magnetoencephalographic (MEG) recordings in Patients 6, 19, and 29. The signals from MEG channels are projected on a plane; the head is viewed from the top and the nose points up. Each response pair illustrates signals recorded by the two orthogonal gradiometers of a signal sensor unit. Source locations of M/E- (squares) and M-spikes (circles) are superimposed on patient s own magnetic resonance imaging slices (middle panels). L, left; R, right.

9 Y.Y. Lin et al. / NeuroImage 19 (2003) Table 3 Mean ( SEM) coordinates and strengths of consecutive 15 M/E- and M-spike sources in 7 patients with temporal lobe epilepsy a Patient no. M/E-spikes M-spikes x (mm) y (mm) z (mm) Strength (nam) x (mm) y (mm) z (mm) Strength (nam) b a M/E-spikes, spikes found on both MEG and EEG; M-spikes, spikes found on MEG without concomitants on EEG; MEG, magnetoencephalography; EEG, electroencephalography. The positive x-, y-, and z-axes go toward the right preauricular point, the nasion, and the vertex, respectively. b Significantly different from the strength of M/E-spikes (P ). genic focus and the subsequent ablative surgery (Rossi, 1973). EEG and MEG can detect the spike discharges extracranially by picking up the electric and magnetic fields generated during epileptic neuronal excitation, respectively. This study was conducted to see the spike detection yield of MEG and scalp EEG in TLE and to evaluate whether MEG offered additional value of interictal spike detection. We found that some spikes were exclusively present on MEG or on EEG only, although most spikes can be simultaneously observed on both modalities. Thus, simultaneous MEG and EEG recordings with a careful search of spike activity from each modality are important to enhance the detection and localization of spike activity, especially in patients with lateral TLE. Spike detection yield by simultaneous MEG and scalp EEG recordings In this study the diagnostic yield of simultaneous MEG and scalp EEG recordings over min was 78.3% in patients with TLE, higher than previous reports varying between 53% (Baumgartner et al., 2000) and 73% (Knowlton et al., 1997). Similar to the study by Knowlton and his colleagues (1997), the relatively high yield in our study is partly because we studied patients during presurgical evaluation at our EMU with partial reduction of antiepileptic medications. In contrast to a previous study using a 12-cmdiameter sensor array (Knowlton et al., 1997), we used a whole-scalp neuromagnetometer to record cerebral activity from the entire brain and accordingly yielded better spike detection. Another reason may be that 33 (91.7%) of the 36 patients with detected spikes fell asleep during recording. Waking recordings were found in 7 (70%) of the 10 patients with no detected spikes. Distributions of spike types Of the 36 patients, the majority (68.3%) of spikes appeared simultaneously over both MEG and EEG channels, in line with previous reports on TLE patients (Knowlton et al., 1997; Ko et al., 1998; Baumgartner et al., 2000). Previous studies have reported more EEG than MEG spikes in 2 TLE patients (Ko et al., 1998), but their observation might be biased because EEG was used to trigger data acquisition (Ko et al., 1998). Baumgartner and his colleagues (2000) also reported more EEG spikes without simultaneous MEG spikes than MEG spikes without EEG spikes, but they did not show specifically the relative percentage of M- and E-spikes in various types of TLE. In our study, there were more E-spikes (17.8%) than M-spikes (12%) in patients with nonsclerotic anterior TLE. In patients with mesial and lateral TLE, however, we found more M-spikes (13.2% and 45.1%, respectively) than E-spikes (6.8% and 7.8%, respectively). As a whole, M-spikes represented about 20% of all spikes identified in the 36 patients, clearly higher than the percentage (2.3%) in one previous study using a 37-channel neuromagnetometer (Ogashiwa et al., 1991). The higher yield of M-spikes in our study may be partly related to the advent of the whole-scalp MEG system, which allows simultaneous recordings of neuronal activities from the entire brain (Stefan et al., 1990; Ahonen et al., 1993; Vrba et al., 1999). In line with previous studies (Smith et al., 1995; Iwasaki et al., 2002), we also found some extratemporal M-spikes in some of our TLE patients. In the present study, we excluded those M-spikes in extratemporal regions that might be irritative discharges extending from the primary temporal foci (Smith et al., 1995; Iwasaki et al., 2002). Spike detection yield by MEG versus scalp EEG in mesioanterior TLE Previous simultaneous MEG and intracranial EEG recordings have shown that MEG cannot detect epileptic discharges confined to mesial temporal structures and that an extended cortical area involving also the lateral/basal temporal lobe is essential to produce detectable epileptic spikes recorded extracranially by MEG (Baumgartner et al., 2000; Oishi et al., 2002). In our study on patients with mesial and nonsclerotic anterior TLE, there was no signif-

10 1124 Y.Y. Lin et al. / NeuroImage 19 (2003) icant difference in spike detection yield between MEG and scalp EEG based on the SDI values. Our results suggest that MEG and scalp EEG offer similar opportunity to detect spike activity produced by relatively extended activation from deep mesial temporal areas. Nevertheless, some spikes were exclusively identified on one modality but absent on the other (see Fig. 2 and Tables 1 and 2). Therefore, simultaneous MEG and scalp EEG recordings offer complementary information for the detection of spike discharges (Sutherling et al., 1988; Ogashiwa et al., 1991). Spike detection yield by MEG versus scalp EEG in lateral TLE Previous studies, based on simultaneous MEG and EEG spikes, have reported that MEG localization of spike dipoles was more successful in patients with lateral neocortical epilepsy than those with mesial TLE (Smith et al., 1995; Knowlton et al., 1997). The better localization may be explained by the increased sensitivity of both MEG and EEG to superficial sources (Smith et al., 1995; Knowlton et al., 1997) or by the more frequent spikes discharges in their patients with neocortical TLE (Knowlton et al., 1997). In the present study, we found significantly larger SDI values with MEG than EEG in patients with lateral neocortical TLE. Possible explanations may be the selected sensitivity of MEG to fissural sources and the transparency of skull and scalp tissues to MEG signals (Cuffin and Cohen, 1979; Nakasato et al., 1994; Wheless et al., 1999). As shown in Fig. 1, in comparison with scalp EEG, the whole-scalp MEG provides a more complete coverage around the head with 102 sensor elements. Each sensor element contains two orthogonal planar gradiometers and one magnetometer providing three independent measures of the magnetic fields, and thus offers better detection of brain activities from the entire brain. Moreover, the intersensor distance in MEG is 3.4 cm, whereas the interelectrode distance in scalp EEG is cm. Closer interelectrode placement may pick up the finer gradients of electric potentials and thus improve spatial resolution. In the present study, however, we do not compare the System EEG with higher density EEG in spike detection. Comparisons of M/E- and M-spikes EEG can reflect cerebral currents in all directions, but MEG selectively records the signals of tangential sources (Wood et al., 1985). In line with previous studies (Ko et al., 1998; Wheless et al., 1999; Baumgartner et al., 2000), we identified three types of interictal spikes in TLE patients according to their preferential presentation on MEG alone, on EEG alone, or simultaneously on both modalities. E- spikes indicate the epileptic activation radial to the scalp, which may not be detected by MEG (Wood et al., 1985; Ebersole, 1997a,b). The strengths of M/E-spikes were clearly larger than those of M-spikes (Table 3). Thus, M- spikes may represent the restrictive and selective tangential epileptic activation, whereas M/E-spikes may be regarded as the more widespread neuronal activation. Moreover, we found that, on average, M/E- and M-spikes were located on the same anatomical regions (see Fig. 4 and Table 3). Thus, M-spikes can be applied to determine the epileptic foci. Conclusions In patients with TLE, interictal spikes can be selectively present on MEG or EEG channels, although more would be simultaneously observed on both modalities. Thus, combination of both MEG and EEG offers a more complete identification of spike activities. Identification of M-spikes is helpful for localization of epileptic foci, especially in patients with lateral TLE. Acknowledgments We thank Miss Shu-Wen Chen, Mr. Chou-Ming Cheng, and Mr. Chih-Che Chou for technical assistance in the acquisition of MR images. 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