Intracranial EEG Substrates of Scalp EEG Interictal Spikes

Epilepsia, 46(5):669 676, 2005 Blackwell Publishing, Inc. C 2005 International League Against Epilepsy Intracranial EEG Substrates of Scalp EEG Interictal Spikes James X. Tao, Amit Ray, Susan Hawes-Ebersole, and John S. Ebersole Department of Neurology, Adult Epilepsy Center, University of Chicago, Chicago, Illinois, U.S.A. Summary: Purpose: To determine the area of cortical generators of scalp EEG interictal spikes, such as those in the temporal lobe epilepsy. Methods: We recorded simultaneously 26 channels of scalp EEG with subtemporal supplementary electrodes and 46 to 98 channels of intracranial EEG in 16 surgery candidates with temporal lobe epilepsy. Cerebral discharges with and without scalp EEG correlates were identified, and the area of cortical sources was estimated from the number of electrode contacts demonstrating concurrent depolarization. Results: We reviewed 600 interictal spikes recorded with intracranial EEG. Only a very few of these cortical spikes were associated with scalp recognizable potentials; 90% of cortical spikes with a source area of >10 cm 2 produced scalp EEG spikes, whereas only 10% of cortical spikes having <10 cm 2 of source area produced scalp potentials. Intracranial spikes with <6cm 2 of area were never associated with scalp EEG spikes. Conclusions: Cerebral sources of scalp EEG spikes are larger than commonly thought. Synchronous or at least temporally overlapping activation of 10 20 cm 2 of gyral cortex is common. The attenuating property of the skull may actually serve a useful role in filtering out all but the most significant interictal discharges that can recruit substantial surrounding cortex. KeyWords: Intracranial EEG Scalp EEG Interictal spikes Cortical sources Subdural electrodes Spike generator Temporal lobe epilepsy. Interictal epileptiform discharges from scalp EEG play an important role in the lateralization and localization of epileptogenic foci in the presurgical evaluation (1 3). Scalp interictal spikes may even provide more reliable localization than ictal discharges because seizure propagation has often occurred by the time ictal rhythms are recorded by scalp electrodes. In addition, muscle and movement artifacts commonly obscure seizure rhythms (4,5). Other technologies currently used for epileptic focus localization, such as magnetoelectroencephalograpy (MEG) and functional magnetic resonance imaging (f MRI), also are largely dependent on the analysis of interictal spikes (6,7). Despite the importance and widespread use of interictal EEG spikes, their underlying cerebral substrate is mostly speculative. The area of cerebral sources of scalp EEG spikes has seldom been confirmed directly. Misconceptions are therefore prevalent regarding the extent of cerebral activation required to generate those that are recordable at the scalp. In 1965, Cooper et al. (8) proposed that 6cm 2 of synchronized cortical activity was probably necessary. This figure has gained widespread acceptance. Their model, however, used in vitro measurements of a Accepted December 26, 2004. Address correspondence and reprint requests to Dr. J. Tao at Department of Neurology, Adult Epilepsy Center, University of Chicago, 5841 South Maryland Ave. MC2030, Chicago, IL 60637, U.S.A. E-mail: jtao@neurology.bsd.uchicago.edu piece of fresh cadaver skull, a pulse generator connected to saline-soaked cotton balls placed on the inside of the skull, an artificial dura made from a polyethylene sheet, and EEG recording electrodes on the exterior surface of the skull bone. The 6 cm 2 estimate of the necessary size for cortical sources was based on the area of multiple pinholes punched into the polyethythene sheet when the artificial EEG signals were first recorded from the electrodes on the outside of the skull. Not only was this an artificial model, but measurements also were made in the absence of any background activity. Thus 6 cm 2 may not accurately reflect the necessary size of cortical sources for scalp EEG spikes in clinical recordings. Modern EEG recording technology provides the opportunity for simultaneous scalp and intracranial EEG recording in epilepsy surgery candidates. Such in vivo measurements are ideal for studying the cortical substrates of scalp EEG spikes. The goal of the present investigation was to determine the area of cortical sources that generate scalprecordable potentials that can be recognized by traditional visual inspection of the EEG. MATERIALS AND METHODS Simultaneous cortical and scalp EEG recordings were obtained from16 patients with temporal lobe epilepsy during intracranial EEG monitoring. Standard subdural electrode strips and grids were used. Each strip consisted of 669

670 J. X. TAO ET AL. FIG. 1. A three-dimensional reconstruction (CURRY 4.5) of a patient s skull after subdural electrode placement. Note minimal skull defects over the left temporal region. A: anterior; P: posterior. four to eight platinum disk electrodes spaced 10 mm between centers. The disks were embedded in a 0.7-mmthick Silastic strip and had an exposed surface diameter of 2.3 mm. Grid electrodes (4 8) contained 32 platinum contacts in a rectangular array with the same 10-mm center-to-center distance. In our standard implantation, a 4 8 grid was positioned to encompass the anterior and midtemporal regions. Two strips were placed to record from the anterior and inferior temporal tip. Using sterile procedures, standard EEG electrodes [International 10 20 plus supplementary subtemporal electrodes: F9, T9, M1 (mastoid), F10, T10, M2] were applied with collodion to the scalp of the implanted patients. Occasionally one or two of the electrodes were displaced 1 to 2 cm from standard positions because of surgical scars and soft tissue swelling. These electrodes were usually near the C - shaped scalp incision in frontocentral and superior temporal regions. Typically these displaced electrodes did not record the principal negative field of temporal lobe spikes. A volumetric computer tomography (CT) scan of the head with 1.0-mm axial slices was obtained after implantation and before monitoring to reconstruct in three dimensions the patient s skull, skull defects (Fig. 1), and subdural electrode locations (CURRY, Compumedics/Neuroscan El Paso, TX, U.S.A.). Patients with significant skull defects, which resulted in noticeable breach rhythms on scalp EEG by visual inspection, were excluded from this study. The positions of subdural electrodes also were coregistrated with a presurgical volumetric magnetic resonance image (MRI) by using mutually identifiable surface fiducials to provide 3-D visualization of electrode locations relative to cortical anatomy (Fig. 2). Continuous recordings of simultaneous scalp EEG (26 channels) and intracranial EEG (46 to 98 channels) were obtained with a 128-channel monitoring system (Stellate). The system input range was 2.0 mv, and data were digitized with a 12-bit analog-to-digital converter (an amplitude resolution of 0.448 µv). EEG data were digitized at 200 Hz and bandpass filtered (0.3 to 70 Hz). All data were recorded in a common referential montage relative to scalp electrode CPZ. Additional digital filters were used with scalp data as necessary to minimize artifact and improve the signal-to-noise ratio. Cortical interictal spikes that had a source extent completely within or nearly within the coverage of intracranial electrodes were selected for analysis. Accordingly, most of the selected cortical spikes originated from the lateral and inferolateral aspect of the anterior to midtemporal lobe, which was covered by the subdural electrode grid. Although cortical spikes in patients with temporal lobe epilepsy were commonly observed in the temporal tip region (11,12), they were not usually selected for the study because their source area was often not resolved sufficiently with the implanted subdural strip electrodes. We defined scalp EEG interictal spikes as recognizable when they possessed an amplitude 50% higher than the EEG background and a discrete voltage field and produced clear disruption of the EEG background. FIG. 2. 3-D visualization of subdural electrodes in the same patient as in Fig. 1 obtained from coregistration of postimplant CT and presurgical MRI. Note the extensive electrode coverage of the left anterior and infero-lateral temporal cortex. Standard subdural electrodes employed in this study including one 4 8 left mid temporal grid (LMT1-32), one 1 8 left anterior temporal strip (LAT1-8), and one 1 4 left inferior temporal strip (LIT1-4). The important electrodes that are necessary for identification of all subdural electrodes are indicated in the schematic figure.

EEG SUBSTRATES OF INTERICTAL SPIKES 671 FIG. 3. A: Intracranial EEG recording demonstrates a heterogeneous population of interictal spikes. B: Simultaneous scalp EEG recording. Note that only two of the intracranial spikes (labeled 1 and 2) generate recognizable scalp interictal potentials. LOF: left orbital frontal; LAT: left anterior frontal; LIT: left inferior temporal; LMT: left mid temporal. Intracranial spikes associated with scalp spikes were always easily discernable from ongoing activity, had a high signal-to-noise ratio, and involved multiple electrode contacts. The gyral area of scalp spike sources was estimated from the number of subdural grid electrode contacts demonstrating concurrent depolarization. RESULTS As previously observed in patients implanted for epilepsy surgery, most cortical interictal discharges recorded from subdural or depth electrodes were not evident in the scalp EEG (9,10). Cortical interictal spikes recorded from these patients with temporal lobe epilepsy were heterogeneous in source location, area, synchrony, and amplitude. Cortical source area appeared to be the most significant variable in determining whether spikes were recordable from the scalp. Only a small fraction of cortical spikes had sufficient extent (Fig. 3). Cortical spikes with 6 cm 2 of source area did not produce recognizable scalp potentials (Fig. 4). Cortical spikes associated with 6 10 cm 2 of synchronous cerebral depolarization rarely generated scalp-recordable EEG interictal spikes (Fig. 5), whereas spike sources having an area of 10 cm 2 commonly resulted in recognizable scalp potentials (Fig. 6). Furthermore, prominent scalp spikes were often associated with the activation of 30 cm 2 of cortex (Fig. 7), which is >70% of temporal lobe gyral cortex. Among the nearly 600 intracranial interictal spikes reviewed, 90% of those having a cortical source area of 10 cm 2 generated recognizable scalp spikes, whereas only 10% of intracranial spikes with <10 cm 2 of cortical area did so. DISCUSSION Cortical generators of EEG spikes produce threedimensional potential fields within the brain. From the surface of the scalp, these can be recorded as two-dimensional fields of time-varying voltage (13). Historically, determining the cerebral sources of scalp EEG potentials has been challenging (14,15). Inherent ambiguities exist in EEG source-modeling techniques attempting this inverse solution. These include not only the effects of an irregularly shaped skull that distorts and attenuates the EEG signal, but also our lack of appreciation for the extent of cerebral sources of scalp EEG. An early animal study by Delucchi et al. (16) showed that the scalp acts as a spatial averager of electrical activity and transmits only those components that are common to and synchronous over relatively large areas of the cortex. Cooper et al. (8) proposed that 6 cm 2 of cortical

672 J. X. TAO ET AL. FIG. 4. Simultaneous intracranial (A) and scalp (B) EEG recording of a left temporal spike (indicated by arrow). No scalp potential is evident from this cortical source. Neither is there an organized scalp voltage field associated with the intracranial spike (C). D illustrates the subdural electrodes recording a negative depolarization (black) during the spike. Note that the spike source area is approximately 6 cm 2. LOF: left orbital frontal; LAT: left anterior frontal; LIT: left inferior temporal; LMT: left mid temporal. activity was probably necessary to produce scalprecordable potentials. However, as explained previously, the in vitro design of their study was hardly comparable to the generation of human EEG. Additionally, measurements estimating source area were obtained in the absence of EEG background activity. Because visual recognition of a potential requires that it stand out from the EEG background, a 6-cm 2 source would not be likely to produce a recognizable scalp spike, even if their estimate for necessary source area was accurate. Our results demonstrate that cortical sources of scalp EEG spikes are larger than commonly thought. At least 10 cm 2 of synchronous or temporally overlapping cortical activity is usually necessary to produce scalp-recordable EEG spikes. Much larger cortical source areas, 20 30 cm 2, are common substrates for prominent scalp spikes. These observations add to our understanding of the cortical origin of scalp EEG. They have significant implications for both basic and clinical science in defining epileptogenic foci based on scalp EEG spikes. Several noninvasive techniques are attempting to characterize and depict graphically the extent of cortical involvement in epileptiform spikes. Among these are EEGtriggered f MRI (17,18) and a variety of extended-source

EEG SUBSTRATES OF INTERICTAL SPIKES 673 FIG. 5. Simultaneous intracranial (A) and scalp (B) EEG recording of a left temporal spike (indicated by arrow). Note the barely recognizable associated scalp potential. This potential does have an appropriate scalp voltage field (C). The approximate area of the cortical spike source is 10 cm 2 (D). Active electrodes: black. LOF: left orbital frontal; LAT: left anterior frontal; LIT: left inferior temporal; LMT: left mid temporal. models of EEG (19 22). Most of these methods apply statistical thresholds to their results to limit the extent of the spike source model, yet at present none uses a priori knowledge concerning the likely area of these sources. Our data show that most scalp-recordable, temporal lobe spikes originate from sources between 10 and 30 cm 2 in gyral area. We have no reason to suspect that sources of scalp EEG spikes from other areas of convexity cortex would be substantially different. Thus publications depicting significantly smaller or larger cortical sources for scalp EEG spikes are likely to be in error. Source models using the findings of this investigation to constrain solutions to a 10- to 30-cm 2 size should prove to be more realistic. Identifying the source area required for spikes originating from different temporal lobe regions was beyond the scope of this investigation. Given our customary placement of the subdural grid electrode, we chose to study spikes arising from the antero- and inferolateral temporal cortex. These sources resulted in a spike voltage field that was principally radial in orientation, which provides the highest level of detectability for EEG. Thus we believe that our results define the lower limit of source area for scalp spikes. It is likely that other temporal and extratemporal sources producing principally tangential voltage fields would require an even larger area to result in recognizable scalp EEG potentials. Thus given the attenuating property of the skull, most cortical spikes with extent of <10 cm 2 do not produce a recognizable scalp EEG potential. However, this may actually serve a useful role in filtering out all but the most significant spike sources that can recruit substantial surrounding cortex. Spikes recorded with intracranial EEG are numerous, variable, and commonly arise from multiple sources, including those distant from the epileptogenic focus. Accordingly, interictal activity is often considered to have little clinical importance. However, the select subpopulation of scalp-recordable spikes may have more localizing value in epilepsy evaluations than their numerous intracranial brethren (23).

674 J. X. TAO ET AL. FIG. 6. Simultaneous intracranial (A) and scalp (B) EEG recording of a left temporal spike (indicated by arrow). Note the distinct associated scalp potential and temporal scalp voltage field (C). The approximate area of the cortical spike source is 13 cm 2 (D). Active electrodes: black. LOF: left orbital frontal; LAT: left anterior frontal; LIT: left inferior temporal; LMT: left mid temporal. Although simultaneous scalp and intracranial recordings provide the most reliable data for assessing the relations between cortical sources and scalp EEG fields, this technique involves two potential technical confounds. A breach effect associated with the skull defect created for subdural electrode placement could have led to more prominent EEG potentials and an underestimation of the necessary cortical source area in normal conditions. In our study, the skull defect was minimal (see Fig. 1), and the bone flap was replaced after electrode implantation. This defect, a linear fissure <3 mm in width, was usually located above the midtemporal region and thus above the most active anterior and inferior temporal scalp electrodes. Localized EEG amplitude enhancement also was not observed visually or with voltage-field topography in those patients selected for study. Conversely, the Silastic membrane of the subdural grid could have had an attenuating effect on the voltage field, leading to an overestimation of the cortical source area needed to generate scalp-recordable spikes. This too is unlikely to have been a significant factor because appreciable amplitude asymmetry in EEG from the two temporal areas was not observed, and any additional attenuating effects of the Silastic membrane were likely to be small when compared with that of the skull. Furthermore, similar findings of necessary source area were obtained in a preliminary study that used only strip electrodes rather than a grid (13). Although difficult to determine precisely, if anything, these two

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