Epilepsia, 48(2):305314, 2007 Blackwell Publishing, Inc.

C 2007 International League Against Epilepsy

Cortical Activation Mapping of Epileptiform Activity Derived from Interictal ECoG Spikes
Yuan Lai, Wim van Drongelen, Kurt Hecox, David Frim, Michael Kohrman, and Bin He
Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota; and Department of Pediatrics and Surgery, University of Chicago, Chicago, Illinois, U.S.A.

Summary: Purpose: To develop and evaluate a new cortical activation mapping (CAM) method to obtain the neuronal activation sequences from the cortical potential distributions. Methods: Interictal electrocorticogram (ECoG) recordings were analyzed for eight pediatric epilepsy patients to find the cortical activation maps, which were compared with the patients seizure-onset zones identified from ictal ECoG recordings. Various relations between the local activation time and cortical potential were assumed. The most effective relation was determined by accessing their capability to predict the seizure-onset zone. Computer simulations using a moving dipole source model were also conducted to test the present approach in imaging the propagated cortical activity. Results: In both clinical data analysis and computer simulations, the maximal amplitude proved to be the most effective criterion with which to determine the local cortical activation

time. The present method successfully predicted the seizureonset zone in seven of eight patients by the CAM analysis of ECoG-recorded interictal spikes (IISs). For patients with multiple seizure foci, each focus can be revealed by analyzing IISs with different spatial patterns. Conclusions: The time difference between spike peaks of the interictal events in the leading channel and other channels can be effectively defined as the local cortical activation time. The cortical activation mapping method based on this time latency can be used to predict the seizure-onset zones, suggesting that the present CAM method is useful to assist the presurgical evaluation for the epilepsy patients. Key Words: Cortical activation mappingInterictal spike ElectroencephalographyECoGNeuronal propagation Activation timeSeizure-onset zoneCortical potential distributionEpilepsySource localization.

The interictal spike (IIS) is often used to locate epileptiform activity and thus is clinically important. It is usually assumed that regions displaying the largest amplitude of spikes are within the epileptogenic zone, and consequently, such regions should be resected if possible to render the patients seizure free (Tsai et al., 1993a, 1993b; Kanazawa et al., 1996). However, the IISs may propagate from their initial sites by uncertain neural pathways (Alarcon et al., 1994, 1997; Ebersole, 2000; Ulbert et al., 2004). Therefore one cannot conclude that the potential amplitude distribution at the spike peak best represents the character of the spike source unless the distribution does not change with temporal evolution of the interictal discharge. The distinction between primary and propagated spikes was introduced as early as 1950s (Penfield and Jasper, 1954). Recent studies suggest rapid propagation of IISs
Accepted September 13, 2006. Address correspondence and reprint requests to Dr. B. He at University of Minnesota, Department of Biomedical Engineering, 7-105 Hasselmo Hall, 312 Church Street SE, Minneapolis, MN 55455, U.S.A. E-mail: binhe@umn.edu doi: 10.1111/j.1528-1167.2006.00936.x

during the discharges (Sutherling and Barth, 1989; Alarcon et al., 1994, 1997; Emerson et al., 1995; Merlet et al., 1996; Merlet and Gotman, 1999; Leal et al., 2002; Lantz et al., 2003; Asano et al., 2003). Thus it is important to discern where the IIS starts and how it propagates to locate its generators accurately. It has been shown that the identification of brain regions initiating the epileptiform activities can be potentially used to reduce the necessary resection area (Alarcon et al., 1997). Both human and animal experiments have been designed to study the initiation and propagation of the epileptiform activity (Alarcon et al., 1994; Tsau et al., 1999; Ulbert et al., 2004). Alarcon et al. (1994) used both depth and surface electrodes to record the interictal discharges, where the results regarding latency and spatial distribution suggest that relatively large areas of neocortex and archicortex can be simultaneously or consecutively activated through fast association fibers or propagation along the cortex during interictal activities. Tsau et al. (1999) found that spontaneous epileptiform activity could be initiated in various cortical layers on neocortical slices harvested from rats. The activations were found to start from a small area (less than 0.04 mm3 ) and spread smoothly 305

306
TABLE 1. Summary of patients in the present study
Patient 1 2 3 4 5 6 7 8 Age (yr) 8 6 7 16 12 12 10 11 Gender F M M M M F F M Res. 2 2 2 1 2 2 2 1 Operation RT, RP LF, LP LF, LP LF, LT RF, RP LF, LO LP LO

Y. LAI ET AL. Patient 1 underwent a right anterior temporal lobectomy including resection of the parahippocampal gyrus, and a separate right parietal topectomy. Seizure frequency was reduced from 10 seizures per week to 2.75 per week, after surgery. Patient 2 underwent a left frontal lobectomy and a left parietal topectomy and was seizure free at 2 year follow-up. Patient 3 underwent left frontal and left parietal topectomies, experiencing 85% seizure reduction after surgery. Patient 4 underwent left frontal lobectomy and left temporal lobe disconnection and hippocampectomy. The patient was seizure free at the 2 year postoperative check. Patient 5 underwent a right subtotal frontal lobectomy, and a right parietal topectomy, and initially experiencing a 90% reduction in seizures. Seizures recurred prompting a second surgery, for a right functional hemispherectomy and leading to seizure free at 6 month follow-up. Patient 6 underwent left frontal and left occipital topectomies and had seizure reduction from seven to eight per week to two per week. Patient 7 underwent a left partial occipital lobectomy, and seizures were reduced from multiple daily seizures to five seizures per week. Patient 8 underwent a left occipital lobectomy and was seizure free at 1 year follow-up. For each patient, long-term ECoG recordings were carefully inspected for the occurrence of interictal spikes. Only those patients whose interictal ECoG spikes showed time delays >10 ms at various recording sites were recruited in the present study, so that the latency difference could be determined without ambiguity under the 400-Hz ECoG sampling rate. Data acquisition During the surgical monitoring for the epilepsy patients, ECoGs were recorded by using multiple rectangular electrode grids (8 8, 8 6, 8 4, etc.) and strips (8 1, 6 1, 4 1) with interelectrode distances of 810 mm placed directly on the cortical surface. The ECoG recordings were referenced to the contralateral mastoid, sampled at 400 Hz, and band-pass filtered from 1 to 100 Hz (BMSI 6000; Nicolet Biomedical Inc., Madison, WI, U.S.A.). For each patient, multiple interictal spikes were visually identified according to the IFSECN criteria (Chatrian et al., 1974). A time window of 200 ms centered at the peak of the global field power (GFP) was used to select the spike epochs for further analysis. In cases in which >50-ms latency differences were observed, only multichannel patterns, repeatedly recorded, were analyzed to exclude the possibility that the large latency differences did not represent recordings from independent asynchronous interictal foci (Alarcon et al., 1994). Cortical activation mapping We hypothesized that the latency differences among different ECoG recording sites were caused by neuronal propagation, that is, not due to volume conduction. Unlike cortical current density imaging (Dale and Sereno, 1993;

Outcome SSR SF SSR SF SF SSR SSR SF

L, left; R, right; T, temporal; P, parietal; F, frontal; O, occipital; SSR, substantial seizure reduction; SF, seizure free; Res., resection.

from the initiation site to adjacent cortical areas, suggesting that the initiation site is very confined to one of the cortical layers. Ulbert et al. (2004) concluded from their laminar analysis of human interictal spikes that the cortical layer where the initial depolarization occurs may differ according to whether the IIS is locally generated or propagated from a distant location. All of these studies show the clinical importance of studying the initiation and propagation of the IIS and its significance in assisting presurgical assessment. In the present study, we propose a new activationmapping method to image the neuronal propagations from subdural ECoG recorded during interictal spikes. The performance of the proposed method was evaluated by comparing the results with the patients seizure-onset zone identified from ECoG ictal recordings and surgical outcomes. It should be mentioned that our special interest in pediatric patients makes the subdural ECoG recording appropriate to be used because children usually have superficial neocortical epileptogenic foci close to the subdural recording surface, generating much less deviation than those foci located in deep structures such as the hippocampus or amygdala. MATERIALS AND METHODS Patients Eight pediatric patients (three girls, five boys; 6 to 16 years old; Table 1) with medically intractable partial seizures were studied by using a protocol approved by the Institutional Review Boards of the University of Minnesota and the University of Chicago. Preoperative MRI/CT scans and interictal and ictal long-term videoEEG monitoring were conducted in the Pediatric Epilepsy Center at the University of Chicago Childrens Hospital. Among these patients, postoperative diagnosis showed that seven of them had two epileptogenic foci, and one of them had single focus. All patients had extratemporal seizure foci (including frontal, parietal, and occipital lobes) no matter how many brain areas were involved in the seizure generation.
Epilepsia, Vol. 48, No. 2, 2007

CORTICAL ACTIVATION MAPPING DURING INTERICTAL SPIKES Babiloni et al., 2005) or cortical potential imaging (He et al., 1999, 2001, 2002; Zhang et al, 2003), which represent electrical current density or potential field distributions over the cortical surface at each instant, cortical activation mapping (CAM) attempts to obtain the sequence of propagation of neuronal activation over the surface of the cortex from the spatiotemporal cortical potential distributions. In the present study, the cortical activation refers to the neuronal activity due to the propagation as observed over the cortical surface. It does not refer to cortical electrical or pharmacologic stimulation. In the present study, we assumed that a relation exists between the local neuronal activation time and the cortical surface potentials. By analyzing the subdurally recorded interictal spikes, we aimed to find a relation in terms of the degree of consistency with respect to the seizure onset and propagation. The activation time is defined as the time instant when the local tissue is excited. Four criteria have been considered by using the peak amplitude, peak first derivative, peak second derivative, and peak laplacian as indicators of cortical neuronal activation. In other words, the cortical activation time is determined from the time instant, when the absolute value of (a) the amplitude of ECoG, (b) the first temporal derivative of ECoG, (c) the second temporal derivative of ECoG, and (d) the surface laplacian of ECoG reaches their maximum. For these four relations, we tested their abilities for predicting the initiation and propagation of the epileptiform activities by analyzing the subdurally recorded interictal spikes found in eight pediatric epilepsy patients. We assumed that the cortical sites that show the shortest latency may represent the initiation zone and those cortical sites with later activations are to be found on the propagation pathways of the epileptiform activities. All ECoG channels were classified into activated or inactivated channels according to their peak activities. A channel is determined to be activated if its maximal amplitude exceeds 150% of the background activity. For the activated channels, the four aforementioned criteria were used to determine the local activation times as an estimation of the cortical neuronal activation sequence during the propagation of interictal spikes. The estimated cortical activation sequences were then compared with the ictal subdural recordings. The subdural ictal ECoG recordings were visually inspected to determine the onset zone and the pathway by which the activities spread to neighboring cortical areas. The relation that led to the most consistent estimation of propagation pattern was considered the optimal relation, suggesting that it can indicate the initiation and propagation of epileptiform activities. Computer simulations Besides the clinical data analysis, computer simulations were conducted to demonstrate the abilities of different criteria in estimating the cortical activation sequence. The physiologic mechanism for the generation of human

307

interictal spikes is still poorly understood and therefore complicated to model. Previous studies showed that single moving dipoles can be used to model the generators of interictal epileptiform discharges (Krings et al., 1998; Lemieux et al., 2001). Here we assumed a simplified source model to generate the IISs, in which a single moving dipole of constant strength traveled along a line inside the brain. The three-concentric-sphere head model was used as the volume conductor model to calculate analytically the dipole-generated cortical potential distributions, from which the local activation times were estimated by using the four given relations. These estimated activation sequences have been compared with the traces of the moving dipoles to evaluate if and how CAM analysis can reflect the source activities. Different source configurations have been tested in the computer simulations with various dipole eccentricities and orientations. In a certain group of simulations, the dipole was assumed to move along the diagonal on the cortical electrode grid with a constant speed. The reference local activation time was then determined by the time when the dipole was closest to the specified cortical sites. Because the local activation times at these cortical sites were also calculated by using the four different criteria, the correlation coefficients were computed between the reference and calculated activation times. The relation that gives the most consistent results is considered to represent the optimal relation between the potential distribution and local cortical activation time. RESULTS The CAM analysis was performed to analyze ECoG recordings during interictal spikes for eight pediatric patients with intractable seizures who either were seizure free or had substantial seizure reduction after surgical resection. For each patient, only the interictal ECoG spikes with 10-ms latency difference (four time points at 400Hz sampling rate) between the occurrences of peaks at various recording sites were analyzed. Cortical activation mapping in patients The CAM analysis was performed in all eight patients by using the four criteria. Typical results from two patients (patients 3 and 5) are shown in Figs. 1 and 2. According to the results from all of the patients with the exception of patient 6, the peak amplitude criterion returned the most consistent estimate of ictal-onset zone (IOZ). The peak first derivative criterion also revealed the initiation zones that surround the IOZ, although it is not as accurate as the peak amplitude criterion. In most patients, the peak second derivative and peak laplacian criteria did not provide reliable estimates of the IOZ. Fig. 1a shows one example of an ECoG-recorded interictal spike for patient 5. The time latencies can be observed from the occurrence of the spike peak in different channels. Clinical diagnosis found this patient to have had a right frontal seizure focus. Figs. 1be are the
Epilepsia, Vol. 48, No. 2, 2007

308

Y. LAI ET AL.

FIG. 1. Cortical activation mapping (CAM) analysis for patient 5. a: ECoG waveforms during an interictal spike recorded by 6 x 8 subdural electrodes. b: Cortical activation time (CAT) determined by the time of occurrence of peak amplitude of the ECoG recordings from different channels. c: CAT obtained by the peak rst derivative criteria. d: CAT obtained by peak second derivative criteria. e: CAT obtained by peak laplacian criteria. f: ECoG recording channels and ictal-onset zone (IOZ). Black circles, Subdural electrodes. Pink circles, Cortical area where seizures started.

FIG. 2.

CAM analysis for patient 3. For details, see the caption of Fig. 1.

Epilepsia, Vol. 48, No. 2, 2007

CORTICAL ACTIVATION MAPPING DURING INTERICTAL SPIKES

309

FIG. 3. An example in which CAM analysis does not correspond to IOZ determined from ictal ECoG recordings. a: Waveforms of interictal ECoG recordings from patient 6. b: CAT map obtained from CAM analysis. c: Illustration of IOZ in patient 6 determined from ictal ECoG recordings. Black circles, Subdural grid electrodes. Pink circles, IOZ determined from ictal ECoG recordings.

activation time mappings determined by criteria (a) through (d), respectively. From Figs. 1b and c, time latencies of 50 ms among various channels were revealed, suggesting that the interictal activity initiated from the lower left corner of the electrode plate and propagated to the opposite corner. As comparison, it is hard to tell where the interictal event started from Figs. 1d and e. Figure 1f displays the configuration of subdural electrodes, and those electrodes marked as pink are the seizure onset identified by examining the ictal ECoG recordings in the same patient. The results of CAM analysis for patient 3 are displayed in Fig. 2. This patient had a left parietal seizure focus as shown in Fig. 2f, where the seizures were identified to initiate from the pink channels numbered 16, 24, and 32. In comparing Figs. 2b to e with Fig. 2f, the activation mapping determined by criterion (a) is most consistent with

the IOZ identified from the ictal ECoG recording. Figures 2d and e show disordered activation patterns, where the initiation of the interictal activity can hardly be recognized from these patterns. For patient 6, the cortical area initiating the interictal spikes revealed by CAM analysis was localized in the area adjacent to the IOZ, as determined from ictal ECoG recordings. Figure 3a shows one typical interictal ECoG waveform in patient 6. Obvious time delays can be observed among the different recording channels from the waveform. Figure 3b displays the results by CAM analysis for this interictal spike. However, the revealed initiation cortical area of the IIS does not overlap with the IOZ, which is represented by the pink electrodes on the enlarged display of the intracranial electrode grid shown in Fig. 3c, but rather is in an area with 2 cm distance from the IOZ. The CAM analysis of other IISs in this patient
Epilepsia, Vol. 48, No. 2, 2007

310

Y. LAI ET AL.

FIG. 4. Illustration of CAM analysis for patients with multiple epileptogenic foci. a: Waveforms of IISs with pattern 1 in patient 7. b: CAM analysis of the IIS shown in (a). c: Waveforms of IISs with pattern 2. d: CAM analysis of IISs shown in (c). e: Two epileptogenic zones have been indicated with blue circles. Focus 1 included channels 3, 4, 11, 12, and 13. Focus 2 included channels 33 and 34.

rendered similar results as that in Fig. 3b. Among the eight total patients in the present study, this is the only patient whose CAM analysis cannot successfully predict the IOZ. In the present study, patients 17 had two epileptogenic foci located in either the same or different lobes. Inspection of their interictal spikes showed that different spatiotemporal patterns existed among the IISs in the same patient. Clustering of the IISs according to their spatiotemporal patterns is thus needed before the CAM analysis for each type of IIS. Patient 7 had two seizure foci located in the left parietal lobe, as shown in Fig. 4e. Focus 1 was more anterior and superior than focus 2. Two different patterns of interictal ECoG spikes have been identified for this patient. Pattern 1 always involved more anterior and superior parietal activity, as shown in Fig. 4a. The results from the CAM analysis for this type of IISs in Fig. 4b revealed the location of seizure generator 1. Figure 4c shows the typical waveform of pattern 2, which mainly contains the more posterior and inferior parietal activity. The CAM analysis for the IISs with pattern 2 successfully indicated the location of seizure focus 2, as shown in Fig. 4d. These results suggest that IISs with different patterns should be classified according to their spatial distributions for the patients with multiple seizure foci (six of eight patients in the present study) and then analyzed separately to locate the individual epileptogenic zone.

Cortical activation mapping by computer simulations Figures 5 and 6 show the results of the CAM analysis from the computer simulations by using the protocol described in the Methods section. A single moving dipole oriented either radially or tangentially with different eccentricities (0.60 to 0.85) was used to generate the cortical potential distributions, from which the cortical activation sequences were estimated by using criteria (a)(b). Although only the results from eccentricity of 0.80 are included in Figs. 5 and 6, similar results were obtained from simulations with other eccentricities. Table 2 summarizes the results from these computer simulations by providing the correlation coefficient (CC) between cortical activation mapping and dipole moving patterns. It can also be seen that the maximum amplitude criterion gives the most consistent estimation of the source movement. Fig. 5a shows the volume conductor, the locations of the cortical electrodes, and the trace of the moving dipole. A radial dipole was assumed to move from the lower left corner to the upper right corner under the grid electrodes. Fig. 5b displays the simulated cortical potential distributions generated by the moving dipole. Figs. 5cf are the activation mapping results on the 8 8 grid pad by using four different criteria: maximal amplitude (C1), maximal first derivative (C2), maximal second derivative (C3), and maximal surface laplacian (C4), respectively. Considering that the dipole was moving from corner to corner at

Epilepsia, Vol. 48, No. 2, 2007

CORTICAL ACTIVATION MAPPING DURING INTERICTAL SPIKES

311

FIG. 5. Computer simulation of CAM analysis by using a single moving radial dipole. a: The sphere represents the outermost surface of the three-sphere head volume conductor. Black circles, Cortical electrodes. Pink circles, The trace of dipole moving from lower left corner to upper right corner. The eccentricity of the trace is 0.80. b: Cortical potential waveforms generated by the single moving radial dipole. cf: Cortical activation mapping from potential distributions using different criteria of maximal amplitude (C1), maximal rst derivative (C2), maximal second derivative (C3), and maximal laplacian (C4), respectively.

a constant speed, C1 gave the most reasonable estimation of the activation sequence, whereas C2, C3, and C4 generated less accurate or smeared results. Fig. 6a shows the cortical potential waveforms generated by a tangential dipole moving along the same route as shown in Fig. 5a. Figs. 6be display the activation maps with C1, C2, C3, and C4, respectively. Although the initiation location is roughly similar in these results, higher spatial resolution

can be observed in Fig. 6b than in the other results shown in Fig. 6ce. Further examination also reveals that C1 gives a more consistent estimation of the dipole source activities than the other criteria. DISCUSSION The present study represents, to our knowledge, the first effort to image the cortical neuronal activation

FIG. 6. Computer simulation of CAM analysis using single tangential dipole moving from lower left corner to upper right corner with an eccentricity of 0.80. ae: See the caption of Fig. 5.
Epilepsia, Vol. 48, No. 2, 2007

312

Y. LAI ET AL.

TABLE 2. Correlation coefficient between dipole moving pattern and cortical activation mappings determined by different criteria
Orientation Radial Eccentricity 0.60 0.70 0.80 0.85 0.60 0.70 0.80 0.85 Max amplitude 0.9750 0.9750 0.9747 0.9333 0.9441 0.9377 0.9248 0.9103 Correlation coefficient Max 1st derivative Max 2nd derivative 0.9327 0.9387 0.9246 0.8855 0.9451 0.9474 0.9477 0.8047 0.5754 0.6837 0.8309 0.8858 0.9125 0.9111 0.9040 0.7091 Max laplacian 0.4573 0.7095 0.9159 0.8448 0.8354 0.8586 0.8771 0.8114

Tangential

sequence quantitatively during the epileptiform interictal discharges from multichannel intracranial ECoG recordings. Although the approach itself is theoretically and mathematically simple, the present study suggests that it can be effectively used to identify the initiation and propagation of epileptiform activity. By comparing the results obtained from the CAM analysis with ECoG-recorded seizure activities in eight pediatric patients, it was demonstrated that the CAM analysis has successfully predicted the IOZ in the majority of cases (seven of eight patients). These promising results indicate that this method can potentially be applied to assist in the presurgical evaluation and surgical planning for patients with intractable epilepsy. Latency differences of paroxysmal interictal discharges at different recording sites are usually <50 ms and hence are not easily recognized by visual inspection of the ECoG recordings. The present method can quantitatively determine the cortical activation sequence based on the latencies among the spike peaks from ECoG recordings. It is postulated that cortical regions where the earliest changes of spikes occur indicate the pacemakers of epileptiform activities inside the epileptogenic zone, and these regions should be resected if possible to render a favorable surgical outcome. According to the results from both clinical data analysis and computer simulation, we conclude that the peak amplitude is the best criterion to estimate the cortical neuronal activation sequence from the ECoG recordings. The strong correlation between the initiation of interictal spikes and the IOZ as epileptogenic pacemaker revealed in the present study coincides with findings in a number of previous clinical studies (Alarcon et al., 1994, 1997; Holmes et al., 2000; Hufnagel et al., 2000; Shamato et al., 2002; Asano et al., 2004). Alarcon et al. (1997) studied the interictal events in patients with temporal epilepsy, and their results showed that the resection of cortical regions with leading spikes resulted in significantly better surgical outcomes. Holmes et al. (2000), in their study of extratemporal epilepsy, showed that strictly unifocal interictal epileptiform patterns on the scalp EEG were highly predictive of the IOZ (100% specificity) as well as successful postsurgical outcome (seizure free in 77% of patients).
Epilepsia, Vol. 48, No. 2, 2007

Asano et al. (2004) also found that the first detectable peak has a high topographic correlation with the epileptic generator. All of these studies suggest that interictal events are highly predictive of seizure generators and thus are of great interest and importance in accurately locating the epileptogenic zones. Eight pediatric epilepsy patients were selected in the present study because obvious time latencies (four time points or 10 ms) were found among various channels in their interictal ECoG recordings, suggesting significant propagation during the interictal discharges. This propagation may happen in a larger population of patients, but it may not be detected under certain sampling rates (400 Hz in the present study). Propagation of the epileptiform activities can be fast and widespread, especially in neocortical epilepsy (Lee et al., 2000). In this case, the sequential activation of the neuronal population could be misinterpreted as simultaneous occurrences. Increase of the temporal resolution in EEG recordings is considered important to study further the cortical activation mapping in more patients. Irregular potential spatial distribution and significant difference in spike waveforms at different recording sites have been observed in other patients and in previous studies by other researchers (Alarcon et al., 1994), which cannot be interpreted by the passive spread of volumeconducted electric fields from a distant localized source. Instead, it suggests fast and widespread propagation along neural pathways during interictal discharge. Assuming that the spikes recorded at different locations represent synchronous activation of the underlying neuronal population, the peak of the spikes can be interpreted to reflect the onset of neuronal activation regardless of the spatial distributions of potential recordings. By encoding the time latencies into spatial maps, the CAM analysis can generate the topography of neuronal activation sequences, which indicate the primary and secondary sources of epileptiform activities. An agreement among researchers as to the mechanisms of generation of human IIS has not been reached. Previous studies show that human IISs are homologous to the paroxysmal depolarization shifts (PDSs) in animal models of epilepsy and giant excitatory postsynaptic potentials

CORTICAL ACTIVATION MAPPING DURING INTERICTAL SPIKES (EPSPs) (Ayala et al., 1973; Steriade 1998a, 1998b; Castro-Alamncos 2000). Conversely, different neurophysiologic synchronizing mechanisms have also been reported in the literature (Taylor et al., 1984; Korn et al., 1987; Amzica and Steriade, 2000; Kohling et al., 2001; Traub et al., 2001). Due to the uncertainty of the mechanisms of generation of both interictal and ictal discharges, the physiologic relation between IIS and seizure is not well understood. It remains an open question whether and how the occurrence of IISs can reflect the epileptogenic zone. In this study, the CAM analysis successfully predicted the seizure-onset zone in seven of eight patients but failed in patient 6, as shown in Fig. 3. The reason for this failure is unknown and requires additional exploration in additional patients. It might be explained by the discrepancies in the origin of IISs and seizure, but also could be generated by the vertical propagation of IISs in the human brain. The present method uses the two-dimensional cortical potential distribution to perform the CAM analysis. This works well with the pediatric patients with superficial neocortical epileptogenic foci, but it may generate inaccurate estimation of initiation of IISs in cases in which the IIS originates from deep cortical structures. Ulbert et al. (2004) concluded from their experiments that the human IISs start from cortical layer IV with powerful depolarization in the regions of the main route of ictal propagation, which spread transversely to both supra- and infragranular laminae. Because of this vertical propagation, the earliest activation detected by the subdural electrodes may actually represent neuronal activity that has propagated away from the initiation site. This misrepresentation is difficult to avoid when using the two-dimensional potential distribution but might be corrected by three-dimensional mapping if depth-potential recording or estimation is available. Further investigation is needed to fully address this issue. To further evaluate the performance of different criteria in imaging the activation sequence, computer simulations were conducted by using simplified models to estimate the cortical activation times from the potential distributions (Table 2). The results shown in Figs. 5 and 6, together with Table 2, reveal that the maximal-amplitude criterion gives the most consistent estimation of the source-activation pattern, which is also consistent with the results from clinical data analysis. Note that the single moving dipole is just a simplified implementation of generation of interictal epileptiform activity, whose starting location is suggestive of the initiation of IISs and apparently should be resected to generate favorable surgical outcome. To fully evaluate the performance by different criteria, simulations should be performed by using more-realistic source models both physiologically and pathologically. Note that the quantitative volumes of the performed resections are unclear from the present study because of the lack of postoperative MRIs. Such postoperative MRIs would provide a quantitative means of correlating the

313

origin of interictal epileptiform activity with the present findings from the CAM analysis. Such quantitative analysis would be desirable in future investigations more precisely to localize the epileptogenic zones, as indicated from the successful surgical treatments. For some patients, it appears that the IOZs were located at the edge of the grids (Figs. 1, 2, and 4). In this case, the possibility that the recorded epileptiform activities originate from remote locations and propagate to cortex underlying the grid electrodes should be excluded. Clinically this can be accomplished by validating ECoG activity against simultaneous scalp EEG recording, which would indicate activity significantly beyond the putative focus. The present study has shown the ability of the CAM analysis to generate the topography of the activation sequence of neuronal populations. The patterns of initiation and propagation of the IISs obtained from the CAM analysis have proved to be effective in predicting the IOZ in the pediatric epilepsy patients, suggesting that the present CAM method may be potentially used as an alternative to define the epileptogenic zone.
Acknowledgment: We thank Christopher Wilke for useful discussions and proofreading the manuscript. This work was supported in part by NIH RO1 EB00178, NSF BES-0411898, and partly supported by the Biomedical Engineering Institute of the University of Minnesota.

REFERENCES
Alarcon G, Guy CN, Binnie CD, Walker SR, Elwes RDC, Polkey CE. (1994) Intracerebral propagation of interictal activity in partial epilepsy: implications for source localisation. Journal of Neurology, Neurosurgery and Psychiatry 57:43549. Alarcon G, Garcia Seoane JJ, Binnie CD, Martin Mignel MC, Julen J, Polkey CE, Elwes RD, Ortiz Blasco JM. (1997) Origin and propagation of interictal discharges in the acute electrocorticogram: implications for pathophysiology and surgical treatment of temporal lobe epilepsy. Brain 120:22592282. Amzica F, Steriade M. (2000) Neuronal and glial membrane potentials during sleep and paroxysmal oscillations in the neocortex. Journal of Neuroscience 20:66486665. Asano E, Muzik O, Shah A, Juhasz C, Chugani DC, Sood S, Janisse J, Ergun EL, Ahn-Ewing J, Shen C, Gotman J, Chugani HT. (2003) Quantitative interictal subdural EEG analyses in children with neocortical epilepsy. Epilepsia 44:425434. Asano E, Muzik O, Shah A, Juhasz C, Chugani DC, Kagawa K, Benedek K, Sood S, Gotman J, Chugani HT. (2004) Quantitative visualization of ictal subdural EEG changes in children with neocortical focal seizures. Clinical Neurophysiology 115:27182727. Ayala GF, Dichter M, Gumnit RJ, Matsumoto H, Spencer WA. (1973) Genesis of epileptic interictal spikes: new knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxysms. Brain Research 52:117. Babiloni F, Babiloni C, Carducci F, Cincotti F, Astolfi L, Basilisco A, Rossini PM, Ding L, Ni Y, Cheng J, Christine K, Sweeney J, He B. (2005) Assessing time-varying cortical functional connectivity with the multimodal integration of high resolution EEG and fMRI data by directed transfer function. NeuroImage 24:118131. Castro-Alamancos MA. (2000) Origin of synchronized oscillations induced by neocortical disinhibition in vivo. Journal of Neuroscience 20:91959206. Chatrian GE, Bergamini L, Dondey M, Klass DW, Lennox-Buchtal M, Petersen I. (1974) A glossary of term most commonly used by clinical

Epilepsia, Vol. 48, No. 2, 2007

314

Y. LAI ET AL.
Lemieux L, Krakow K, Fish DR. (2001) Comparison of spike-triggered functional MRI BOLD activation and EEG dipole model localization. Neuroimage 14:10971104. Merlet I, Garcia-Larrea L, Gregoire MC, Lavenne F, Maugui` re e F. (1996) Source propagation of interictal spikes in temporal lobe epilepsy: correlations between spike dipole modelling and [18F]fluorodeoxyglucose PET data. Brain 119:377392. Merlet I, Gotman J. (1999) Reliability of dipole models of epileptic spikes. Clinical Neurophysiology 110:10131028. Penfield W, Jasper H. (1954) Epilepsy and the functional anatomy of the human brain. J & A. Churchill, London. Shamoto H, Nakajima T, Nakasato N, Iwasaki M, Shirane R, Itoh M, Yoshimoto T. (2002) Mesial temporal lobe epilepsy with lateral temporal lobe abnormalities in magnetoencephalography and glucose metabolism. Journal of Clinical Neuroscience 9:192 194. Steriade M and Contreras D. (1998) Spike-wave complexes and fast components of cortically generated seizures, I: role of neocortex and thalamus. Journal of Neurophysiology 80:14391455. Steriade M, Amzica F, Neckelmann D, Timofeev I. (1998) Spike-wave complexes and fast components of cortically generated seizures, II: extra- and intracellular patterns. Journal of Neurophysiology 80:14561479. Sutherling WW, Barth DS. (1989) Neocortical propagation in temporal lobe spike foci on magnetoencephalography and electroencephalography. Annals of Neurology 25:373381. Taylor C, Dudek F. (1984) Excitation of hippocampal pyramidal cells by an electrical field effect. Journal of Neurophysiology 52:126 142. Traub RD, Whittington MA, Buhl EH, LeBeau FE, Bibbig A, Boyd S, Cross H, Baldeweg T. (2001) A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia 42:153170. Tsau Y, Guan L, Wu JY. (1999) Epileptiform activity can be initiated in various neocortical layers: an optical imaging study. Journal of Neurophysiology 82:19651973. Tsai ML, Chatrian GE, Pauri F, Temkin NR, Holubkov AL, Shaw CM, Ojemann GA. (1993) Electrocorticography in patients with medically intractable temporal lobe seizures, I: quantification of epileptiform discharges prior to resective surgery. Electroencephalography and Clinical Neurophysiology 87:1024. Tsai ML, Chatrian GE, Holubkov AL, Temkin NR, Shaw CM, Ojemann GA. (1993) Electrocorticography in patients with medically intractable temporal lobe seizures, II: quantification of epileptiform discharges following successive stages of resective surgery. Electroencephalography and Clinical Neurophysiology 87:2537. Ulbert I, Heit G, Madsen J, Karmos G, Halgren E. (2004) Laminar analysis of human neocortical interictal spike generation and propagation: current source density and multiunit analysis in vivo. Epilepsia 45(suppl 4):4856. Zhang X, van Drongelen W, Hecox K, Towle VL, Frim DM, McGee A, He B. (2003) High resolution EEG: cortical potential imaging of interictal spikes. Clinical Neurophysiology 114:19631973.

electroencephalographers. Electroencephalography and Clinical Neurophysiology 37:538548. Dale AM, Sereno M. (1993) Improved localization of cortical activity by combining EEG and MEG with MRI cortical surface reconstruction: a linear approach. Journal of Cognitive Neuroscience 5:162176. Ebersole JS. (2000) Noninvasive localization of epileptogenic foci by EEG source modeling. Epilepsia 41:2433. Emerson RG, Turner CA, Pedley TA, Walczak TS, Forgione M. (1995) Propagation of patterns of temporal spikes. Electroencephalography and Clinical Neurophysiology 94:338348. He B, Wang Y, Wu D. (1999) Estimating cortical potentials from scalp EEGs in a realistically shaped inhomogeneous head model by means of the boundary element method. IEEE Transactions on Biomedical Engineering 46:12641268. He B, Lian J, Spencer KM, Dien J, Donchin E. (2001) A cortical potential imaging analysis of the P300 and novelty P3 components. Human Brain Mapping 12:120130. He B, Zhang X, Lian J, Sasaki H, Wu D, Towle VL. (2002) Boundary element method-based cortical potential imaging of somatosensory evoked potentials using subjects magnetic resonance images. NeuroImage 16:564576. Holmes MD, Kutsy RL, Ojemann GA, Wilensky AJ, Ojemann LM. (2000) Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal origin and postsurgical outcome. Clinical Neurophysiology 111:18021808. Hufnagel A, Dumpelmann M, Zentner J, Schijns O, Elger CE. (2000) Clinical relevance of quantified intracranial interictal spike activity in presurgical evaluation of epilepsy. Epilepsia 41:467 478. Kanazawa O, Blume WT, Girvin JP. (1996) Significance of spikes at temporal lobe electrocorticography. Epilepsia 37:5055. Kohling R, Gladwell SJ, Bracci E, Vreugdenhil M, Jefferys JG. (2001) Prolonged epileptiform bursting induced by 0-Mg(2+) in rat hippocampal slices depends on gap junctional coupling. Neuroscience 105:579587. Korn SJ, Giacchino JL, Chamberlin NL, Dingledine R. (1987) Epileptiform burst activity induced by potassium in the hippocampus and its regulation by GABA-mediated inhibition. Journal of Neurophysiology 57:325340. Krings T, Chiappa KH, Cuffin BN, Buchbinder BR, Cosgrove GR. (1998) Accuracy of electroencephalographic dipole localization of epileptiform activities associated with focal brain lesions. Annals of Neurology 44:7686. Lantz G, Spinelli L, Seeck M, de Peralta Menendez RG, Sottas CC, Michel CM. (2003) Propagation of interictal epileptiform activity can lead to erroneous source localizations: a 128-channel EEG mapping study. Journal of Clinical Neurophysiology 20:311 319. Leal AJ, Passao V, Calado E, Vieira JP, Silva Cunha JP. (2002) Interictal spike EEG source analysis in hypothalamic hamartoma epilepsy. Clinical Neurophysiology 113:19611969. Lee SA, Spencer DD, Spencer SS. (2000) Intracranial EEG seizure-onset patterns in neocortical epilepsy. Epilepsia 41:297307.

Epilepsia, Vol. 48, No. 2, 2007