Reliability of dipole models of epileptic spikes

Clinical Neurophysiology 110 (1999) 1013±1028

Reliability of dipole models of epileptic spikes I. Merlet, J. Gotman* Montreal Neurological Institute, and Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada Accepted 8 November 1998

Abstract Objective: In order to validate dipole-modeling results, we compared dipole localizations with the distribution of intracerebral potentials occurring simultaneously with scalp EEG paroxysms. Methods: Firstly, scalp EEGs were recorded from 11 patients. Dipole sources were estimated on averaged spikes and projected on 3DMRIs. Secondly, stereoelectroencephalography (SEEG) was recorded from implanted electrodes with direct identi®cation onto MRI. Simultaneously with SEEG, control scalp electrodes were pasted where spikes peaked during the ®rst session. SEEG was averaged, triggered by the main peak of scalp spikes. Results: SEEG activity during scalp spikes always involved several contacts. In 13 of 14 spikes, maximal ®elds occurred in neocortical regions. In 4 of 5 cases where intracerebral activity was simple, spikes could be modeled by one source. In all cases where intracerebral activity was complex, spikes had to be modeled by several sources. The main dipole source was 11 ^ 4:2 mm from the SEEG contact showing the maximal intracerebral potential. Early and late dipole localization and SEEG ®elds were concordant in two thirds of cases. Conclusion: Results indicate that in our group of patients scalp spikes re¯ect activity in large neocortical areas and never activity limited to mesial structures. Dipole locations and time activation were con®rmed most often and were more reliable for sources representing the main negative component than for early or late sources. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Interictal spikes; Dipole Modeling; scalp EEG; Intracerebral recordings

1. Introduction Intracranial EEG recordings remain to date the preferred method to localize the epileptogenic zone in patients having a complex epileptic problem and who are candidates for surgical treatment. The limited availability and the high cost of this technique greatly limit its routine use however, and represents a rate-limiting factor to surgery. Moreover, accurate estimation of the 3D distribution of the epileptic zone by intracranial EEG is hampered by the limited number of electrodes that can be implanted and by the restricted `®eld of view' of each electrode (Gloor, 1985). Non-invasive methods of localizing the generators of epileptic activity have been developed during the last decade and have been applied to scalp interictal and ictal epileptic signals. The most common such method is dipole modeling and the main results obtained with this method can be summarized as follows, temporal lobe spikes can be modeled by dipole sources most often distributed over distinct temporal lobe areas suggesting interactions between * Corresponding author. Tel.: 1 514-398-1953; fax: 1 514-398-8106. E-mail address: [email protected] (J. Gotman)

mesio-basal and neocortical areas (Ebersole, 1994; Ebersole, 1997; Baumgartner et al., 1995; Merlet et al., 1996; Merlet et al., 1997; Boon et al., 1997). Modeling the spikes in patients having seizures originating in mesio-temporal regions gives consistently dipole sources with a main orientation suggesting predominant activation of mesio-basal regions. Spikes in patients with neocortical temporal seizures can be modeled by sources with a main orientation suggesting the involvement of lateral neocortical structures (Ebersole, 1997). Modeling of interictal and ictal signals gave consistent results in temporal lobe epilepsy (Lantz et al., 1994; Lantz et al., 1996; Boon and D'HaveÂ, 1995; Boon et al., 1997; Pacia and Ebersole, 1997). Modeling results have also provided consistent information regarding the postsurgical evolution of operated patients, and regarding some sub-types of temporal and rolandic epilepsies (Wong, 1989; Wong, 1993; Ebersole and Wade, 1990; Ebersole and Wade, 1991; Weinberg et al., 1990; Ebersole, 1991, Ebersole, 1994; Ebersole, 1997). Dipole modeling of interictal spikes results are in agreement with other data such as interictal hypometabolism on PET data or modeling of magnetic spikes recorded by MEG (Lantz et al., 1994; Merlet et al., 1996; Merlet et al., 1997; Diekmann et al., 1998).

1388-2457/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(98)00062-5

CLINPH 98113

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Table 1 Patient description a EEG abnormalities Patient

Sex

Age

Ictal symptoms

1

M

38

Aura/myoclonus of the mouth

2

M

26

3

M

20

4

F

28

5

F

40

6

F

28

7 8

M M

33 36

9

F

13

10

F

49

11

M

26

a

Spikes

Localization of scalp maximum

MRI

1

F9 1 F10

Sensation in the left eye/loss of contact Fear/lip smacking/gestual automatisms Fear/staring/gestual automatisms Aura/loss of contact/oro-facial automatisms/vocalization Staring/lip smacking/hand automatisms Absences Moaning/vocalization/R lower and upper extremitites involvement

1

F10

1

F9

L Temporal and L hemispheric atrophy Atrophy around the lateral ventricular region Normal

1

T10

Normal

1

T9 1 T10

R hippocampal atrophy

1

F9 1 T10

Normal

1 1

T9 Fp1

Normal Periventricular white matter lesions 1 hippocampal atrophy

Vocalization/contraction of the superior members 1 L arm elevation 1-Drop attacks 2-R arm dystonia 1 extension, ¯exion of the L arm Ascending warm feeling/loss of contact/laughing

1

F4

1

T6

R cortical dysplasia between the superior and middle frontal gyrus Previous R temporal resection (ant 2/3 of the R temporal lobe)

1

F10

Previous R front resection (frontal pole and anterior part of the orbital gyrus)

M, male; F, female; R, right; L, left.

Thus, these studies suggest that dipole modeling might be a useful non-invasive tool to help predict which patients can have temporal resections without intracranial recordings, or to help determine electrode placement in patients in whom intracranial electrodes are required. These methods, however, have important weaknesses. Dipole models are not always well adapted to epileptic signals, since they represent the generator as a point source whereas it is most likely to be an extended area. For this reason, a dipole situated in a given region is usually considered to re¯ect more the center of mass of a large active area than a discrete activation. The accuracy of dipole location has been estimated to be around 10 mm (Cohen et al., 1990; Cuf®n et al., 1991; Mosher et al., 1993). This depends however, on the generator localization since, theoretically, deep sources can be localized with less accuracy than super®cial ones (Mosher et al., 1993; Yvert et al., 1997), at least for models using the sphere as an approximation of the head. As a consequence, mesio-temporal sources are dif®cult to assess with precision when modeling scalp EEG data. Moreover, in contrast to several of the studies quoted above, some authors have observed that most of the epileptic spikes arising from deep mesial structures, and particularly from the hippocampus, as recorded by intracranial electrodes, remain undetectable on scalp EEG recordings (Rassmussen, 1982; Alarcon et al., 1994; Munari et al., 1994). These observations ques-

tion the reliability of mesial temporal sources identi®ed by dipole modeling of scalp recorded spikes. In a recent study however, we modeled the scalp EEG signal concomitant with deep mesio-temporal spike, and we could demonstrate the reliability of sources located in the deep mesio-basal aspect of the temporal lobe (Merlet et al., 1998a). Whereas most of the studies mentioned above compared dipole models of spikes to other data (MRI lesions, seizure onset) we wanted to obtain a better understanding of how well the spike models represent the intracerebral electrical ®elds, with the expectation that this will improve the intrinsic diagnostic value of scalp EEG in epilepsy. In the present study, our aim was therefore to validate dipole modeling by investigating the relationships between surface scalp spikes and intracranial spikes by simultaneous EEG/SEEG recordings. In particular 3 main questions were addressed: (1) Is the dipole that models a scalp spike located in the region of the maximal electric ®eld; (2) When a spike can be recorded at the surface, what are the spatial characteristics of the underlying activated area? In particular, can a spike restricted to the mesio-temporal area generate a spike on scalp EEG? Can a focal neocortical spike generate a spike on scalp EEG? Or is it necessary to have a large active region, independently of mesio-lateral considerations?; (3) When dipole modeling suggests a propagation between distinct areas, do the intracerebral recordings show a spike

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Fig. 1. Spatio-temporal approach of dipole modeling. Each source is calculated over the time intervals indicated below the EEG spike. The ®rst source (early) is ®tted alone over the early peak, the second source (main) is ®tted over the early and main peaks (interval 2) by keeping the ®rst dipole active. A third source (late) is calculated over the early, main and late peaks, by keeping the ®rst and second source active. In the example illustrated here (spike 11) this late source was interacting with the main dipole and we considered thus that its activity was negligible.

activity in each of these suspected areas, and are there any intracerebral indices of propagation? 2. Methods 2.1. Patients Recordings were obtained in 11 patients (6 males) aged 13±49, referred for a presurgical evaluation to the Montreal Neurological Institute because of partial seizures resistant to drug therapy. As described in Table 1, all these patients showed focal spikes on their standard EEG recording, involving either one or both temporal regions independently (Patients 1±8), frontal regions (Patients 9, 10), or the temporo-parieto-occipital region (Patient 11). 2.2. Scalp EEG data 2.2.1. Recordings For each of the 11 patients, we collected long-term Video-EEG data (3±7 days) prior to invasive recordings, by means of 28 scalp channels referenced to FCz (Harmonie, Stellate Systems). The signal was ampli®ed ( £ 2400), band-pass ®ltered between 0.3 and 60 Hz, and digitized at 200 Hz. Additional channels were added to the conventional 10±20 system at the zygomatic (Zy1, Zy2) and supraorbital (SO1, SO2) positions bilaterally, and for a special coverage of the low temporal regions at F9±10, T9±10 and P9±10

positions. These scalp recording will be referred in the following as `Session one' scalp recordings. 2.2.2. Spike detection and averaging Prior to visual analysis of the traces, automatic spike detection was run on-line during the recordings. These detected periods were then read into a system allowing averaging (Focus 2.0). Spikes were automatically compared in terms of both topography and morphology, and classi®ed. After checking for possible false detections or classi®cations, spikes belonging to a same group were averaged (14±80 spikes) into periods of 1 s centered on the main negative peak. Some patients had two spike foci (labeled as L if left and as R if right) and a total of 14 averages were further analyzed over the 11 patients. 2.2.3. Dipole modeling of EEG spikes Dipole modeling was carried out on averaged spikes, by means of the brain electric source analysis software (BESAw, Scherg, 1990). We ®rst used a `single moving dipole' approach where one solution is calculated for each sampling point. This provides, for the time interval under consideration, a pattern of dipolar sources with given location, orientation, and amplitude. Such a dipolar solution, which is often characterized by `epicenters' of activity with low residual variance, allowed us to de®ne `clusters' of dipoles and to estimate both the number of sources being active and the time interval of their maximal activity. In practice, these intervals corresponded to the main de¯ec-

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Table 2 Electrode placement during the session two recordings a SEEG Patients 1 2 3 4 5 6 7 8 9 10 11

L A, H A, H, C A, H, C A, H, C, FO, FC, FS A, H A, H, C, FS, FO, FC A, H, FS A,H, FO, FS, FC

ECoG R

L

A, H A, H A, H, C A, H, C A, H, C A, H, FS, FO A, H, FO, FC, FS FC, FO, FS, FL

L1±5

Scalp EEG (Session two) R

L

R

E1±E16

F9, T9, P9 Zy1, F9 F9, T9, P9 F9, TP, P9 Zy1, SO1, F9 Zy1, F9, T9 F9, T9, P9 F9, T9 Fp1, F9, Tp, P9 Fp1, SO1, F9 F9, T9, P9

F10, T10, P10 Zy2, F10 F10, T10, P10 F10, T10, P10 Zy2, SO2, F10 Zy2, F10, T10 F10, T10 F10, T10 Fp2, F10,T10, P10 Fp2, SO2, F10 F10, T10, P10

E1±E4 R1±5 E1±14

a

A, amygdala; H, anterior hippocampus; C, middle hippocampus; FO, Orbito-frontal; FC, frontal cingulate gyrus; FS, SMA; FL, frontal in a dysplastic lesion (Patient 13). The location of epidural electrodes is indicated in Fig. 2B. R, right; L, left.

tions during the spike complex, i.e. the early positive, the main negative and the late positive phases. For the following steps, in order to take into account the spatio-temporal evolution of the paroxysms, static dipoles with ®xed location and orientation but time varying activity were used. As illustrated in Fig. 1, a ®rst source was ®tted over the early phase. This source being kept active but ®xed, a second dipole was then ®tted over an interval including both the early and main peaks. Finally, the ®rst two sources being kept active, a third source was calculated over the interval covering the whole spike complex. When sources 1, 2 or 2, 3 showed interactions, only the dipole modeling the main negative peak was maintained. When several dipoles were necessary to explain the averaged spike, the latencies between dipole components were determined from the time difference between the maximal source waveform amplitude of the different components. The dipole location (Cartesian x, y, z coordinates), orientation (u, fangles) and amplitude (dipolar moment m) were estimated within a 4 shell spherical model of the head. Goodness of ®t was estimated in terms of residual variance (RV), i.e. the percentage of the spike variance that could not be explained by the model. This value was generally computed over the whole spike interval (120±240 ms). However, in Patient 10 the ®tting interval was reduced to 55 ms corresponding to the spike itself, since we could not ®nd any solution over the slow wave. 2.3. Intracranial data 2.3.1. Recordings Depth electrodes (nine contacts of 0.5 mm separated by 5 mm) were implanted with the help of a MRI guided system (Viewing Wand System, ISG Technologies, Mississauga, Ontario, Canada) according to the method of Olivier et al. (1996), this system allowed to guide implantation by visualizing, on the patient's MRI, the trajectory through the distal target such as amygdala or hippocampus, and to obtain for

each depth electrode, after implantation, the target and entry points on the MRI. The deepest contact of the SEEG electrode is labeled one and the most super®cial is labeled 9. As described on Table 2, 2±10 SEEG electrodes could be implanted in the temporal lobe unilaterally (Patient 2), or bilaterally (Patients 1, 4±6), in both temporal and frontal regions unilaterally (Patients 3, 7, 8), or bilaterally (Patient 9), and in the frontal lobe (Patient 10). Four of these patients had additionally 4±16 epidural electrodes. Patient 11 had only epidural electrodes placed over the central, posterior temporal and parietal regions. Intracerebral data were referenced to an epidural electrode, placed in the parietal region contralaterally to the suspected focus or, in case of bilateral implantation, on the side of the less active focus. Simultaneously to intracranial recording, 4±8 scalp electrodes were pasted bilaterally on the scalp below the bandage, at positions where maximal spikes had been detected on the EEG recordings of Session one. These traces will be referred thereafter as `Session two' scalp recordings. 2.3.2. Spike detection and averaging In order to obtain the reproducible intracranial activity associated to a spike on scalp EEGs, we averaged the intracranial signal by using as trigger the main negative peak of the surface EEG spikes. As far as possible, we compared carefully the morphology and topography of spikes obtained in Session two with those obtained in Session one. When they were very similar, the assumption was made that in Session 1 and in Session 2 spikes were originating from the same intracerebral generators. In addition to our group of 11 patients, non comparable signals appeared for two other patients. For the ®rst one, spikes were on the left during session 1 and on the right during session two. This discordance may be attributed to the long time delay between the two recording sessions. In the second case, spikes were considered as non-comparable as the patient had a cerebral vascular accident between the two recording sessions. Results concerning these two patients were therefore not included.

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Fig. 2. Cortical area involved during the scalp EEG spike. (A) Temporal cases, (B) extratemporal cases. Stars indicate the contact where the maximal intracerebral activity was recorded. The diagrams show a schematic location of the intracerebral and epidural electrodes. The gray boxes represent the intracranial contacts involved during the spike activity. For example, in spike 1, contacts 1±8 of the RA electrode, 3±8 of the RH electrode, as well as the 4 epidural electrodes on the temporal lobe were active during the scalp EEG spike.

Averaged intracranial signals associated with scalp EEG spikes were then analyzed by determining the 4 following characteristics: (1) the contacts involved in the paroxysm, e.g. in spike two, contacts 1±8 of the RA electrode and 1±4 of the RH electrode were considered as active (Fig. 2); (2)

the contact where the maximal amplitude signal occurred simultaneously with the main negative peak at the surface; (3) the contacts where intracerebral peaks were detected before and after this maximum; (4) the time difference between the early or late peaks and the maximal activity.

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Fig. 3. Simple versus Complex intracerebral ®elds. (A) Simple spikes. The maximal ®eld, recorded at RH6 for spike 3R, gradually decreases on the adjacent intracerebral contacts. No asynchronous activity is recorded elsewhere. (B) Complex spikes. In spike 8, an early activity is present at RA5, followed by a maximal activity at RA2, and by a late ®eld at RO1. Contacts 1 are the deepest, and contacts 9 are the most super®cial. A, amygdala; H, anterior hippocampus; C, middle hippocampus; O, orbito-frontal; E, early intracerebral ®eld(s); M, maximal intracerebral ®eld; L, late intracerebral ®eld; L, left; R, right.

2.4. MRI/electrophysiological correlation Dipole source coordinates were superimposed on each patient's MRI, as recently described (Merlet et al., 1999). On this 3D MRI and for each patient, the target and entry points of intracerebral electrodes, as well as the position of the epidural electrodes, were automatically provided (see above). For the intracerebral electrodes, we reconstructed a posterior position of each contact by determining the equation of the segment joining the target and entry points and then the 3D coordinates of the contacts.

This allowed us to obtain on the same MRI volume the dipoles and the intracerebral contact locations, we measured then the distance and the lateral (x), anteroposterior (y), and vertical (z) displacements between, (1) the contact where maximal activity was detected and the source showing the main activity and (2) the contacts where early or late activities were recorded and the early or late sources. We selected to use the maximum of the amplitude, instead of the phase reversal, as the marker of the closest

F9 T9

F10 Fp1

F4/Fp2 T6/T10

6L 7

8 9

10 11

Ant. cing.g. Post. MT g.

Ant. MT FOrb g.

ST/MT g. MT g.

Ant. MT g.

5.9 9.1

17.6 5.0

13.6 12.5

10.3

Mean ^ SD 11:0 ^ 4:2

FC3 E13

RA2 LO5

LA4 LA6

RA4

± Supramarg. g

7.2 (RA5) ±

2 20

-

2 20 2 50 2 10 2 50, 2 24 -

E10

RA5

± LA1 LH1 RA1, RH1 ±

11.8

±-

4.7 17 13.3 8.07

Mean ^ SD 11:0 ^ 4:7

2 15

2 15

± 2 43 2 25 2 52 2 24

SEEG Dist. Delay/mS Location Delay/max

±

5.5 (RH2)

6.3 (LH4)

Closest

Hipp. Hipp. ± FOrb. g. MF g. ± ± SMA

Insula

5

25 65 ± 20 10

50

LH1 LH1 LFO1 RO1 LC7 LC5 LS3 FS6

±

8.9 3.7 ± 9.1 9.2 ± ± 8.5 Mean ^ SD 7:9 ^ 2:4

33 20 24 23 13 54 54 10

92.2 97.1

96.8 96.1

97.5 95.6

97.9

93.9 96.7 95.8 93.2 96.58 97.8 98.6

Dipole SEEG Distance Gof.(%) Location Delay/mS Location Delay/max

Late sources

g, gyrus; ant, anterior; post, posterior; mes, mesial, MT, middle temporal; ST, superior temporal; FOrb, Fronto-orbital; Cing, cingulate; temp-ins jct, temporo-insular junction. Hipp, hippocampus; supramarg, supramarginal; MF, middle frontal; SMA, supplementary motor area; gof, goodness of ®t.

a

F10

±

Dipole Location

Early source(s)

T pole 7.6 (LA6) 1-Uncus 2-Temp-ins jct ± 1-Int. T pole 2-Hipp. 8.8 (LA 6) ± 9.1 (LH4)

7.5 (RH4) 12.3 (La3)

6R

11.0 4.1 14.7 14.9 12.7 7.8 15.4

9.8 (RA3)

RA4 RA5 LA4 RH6 LA4 RA3 LA4

F10 T10 T9 T10 F9 F10 F9

1 2 3L 3R 4L 4R 5

Mes. T pole MT g. Insula ST/MT g. St g. Mes. T pole St g.

Closest

Spikes Elect. max Dipole location SEEG max Distance

Main source (mS)

Table 3 Dipole modeling result a

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temporo-parietal spike 11, an early activity peaked in the supramarginal gyrus, 20 ms before the main posterior temporal activity. For frontal spikes 9, 10 no early peaks were identi®ed but late activities were present in the middle frontal and dorso-mesial frontal gyri (spike 9), and in the SMA (spike 10).

Fig. 4. Classi®cation of dipole results.

position to the generator, as phase reversal were not always present and could occur between non adjacent contacts. 3. Results 3.1. Intracranial activity during surface EEG spikes In all 14 spikes, averaging triggered by surface EEG spikes lead to high-amplitude timed-locked activities on intracerebral or intracranial traces. During the surface spike, the intracerebral signal was never focal. For temporal cases, 8±21 SEEG contacts were involved during a surface spike (Fig. 2A), and for extratemporal cases 15±20 contacts participated in the spike activity (Fig. 2B). In 13 out of 14 spikes, the maximal intracerebral activity was neocortical. The intracerebral ®eld never involved only the deepest mesial contacts of the intracerebral electrodes. In one instance, although the activity spread to several lateral contacts, the maximal activity occurred in the amygdala (spike eight). For 5 of 11 spikes of temporal origin, the intracranial signal was characterized by a maximum culminating at the time of the surface EEG spikes and by a synchronous activity gradually decreasing on the adjacent contacts. This type of activity will be called here `simple' (Fig. 3A). In the remaining 6 temporal spikes, asynchronous activities were detected in addition to the maximal synchronous peak. They either lead or followed the maximal activity. This type of activity will be called here `complex' (see example on Fig. 3A). In 3 spikes, early peaks culminated 10±50 ms before the maximum. In spike 4R this activity was located in the amygdala, and in spikes 5, 6R, two distinct early peaks were identi®ed before the maximum: the earliest one was in the amygdala and was followed by an activity in the anterior aspect of the hippocampus. For spikes 6L, 7 no early activity was detected on deep contacts, but late peaks following the maximum by 10 and 20 ms respectively appeared in the uncal region. In spikes 7, 8 an additional activity was present in the orbito-frontal region (Fig. 3B). The 3 extratemporal spikes were always associated on intracerebral electrodes with a complex activity. For the

3.2. Dipole modeling Relationships between dipole locations and intracerebral ®eld distributions are described for all patients on Table 3 and summarized on Fig. 4. Scalp EEG spikes were adequately modeled by 1±3 sources (model accounting for 92.2±98.6% of the whole spike variance, i.e. 3:9 ^ 1:8% mean Residual Variance). When several sources were needed to explain the data, the dipole with the maximal activity mainly explained the negative peak of the paroxysm. The time activation curves of the different dipoles strongly overlapped, but their respective onset of activation differed, the activity of the early source always leading the main source activity, which itself preceded the onset of the late source activation. From the 5 spikes showing a `simple' activity on intracranial data, 4 were modeled by a single source explaining adequately the whole spike, e.g. spike 1 in Fig. 4. In the remaining case however (spike 2 in Fig. 5), a late dipole was necessary to explain the EEG data, whereas no late ®eld was visible on intracranial recordings. We will come back later on the fact that this dipole was far from any electrode. For the 9 EEG spikes associated with a `complex' deep activity, surface signals were always modeled by several sources, e.g. spike 6R in Fig. 6. 3.2.1. Relationships between main sources and maximal intracerebral ®elds Results could be classi®ed into 3 different groups: (A) The dipole was close to an intracranial contact, in this case, the sources could be (1) spatially and temporally consistent, (2) spatially inconsistent or (3) temporally inconsistent with the intracranial ®eld distribution; (B) No dipole was associated with an intracranial ®eld; (C) the dipole was far from any SEEG contact (Fig. 4). On average, dipoles exhibiting the maximal activity were 11 ^ 4:2 mm from the SEEG contact where the maximal activity was identi®ed. From the 14 main sources calculated, 9 were spatially consistent with the intracranial ®eld distribution (group A1 of Fig. 4), in these cases, dipoles were always situated in an explored region, and were closest to the contact which demonstrated the maximal intracranial ®eld, or just one contact away. Moreover, time activation of the dipole was in agreement with intracranial data. Fig. 7 illustrates such a consistency for the main source of a frontal spike (spike 10). In 4 of 14 cases, main sources were closest to an intracranial contact located more than one contact away from the one showing the maximal ®eld (group A2 of Fig. 4). This inconsistency could correspond to a dipole either deeper (spike 3R), or more lateral (spikes 5, 6L, 8),

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Fig. 5. Simple intracerebral ®elds versus 1-dipole models. Spike 1 illustrates a simple ®eld and a single source model, where the dipole is very close to the maximum of the ®eld. In case of spike 2 (bottom), the main source is also located near the maximum of the ®eld, but a late source was found in the right insula, far from any intracerebral. M, maximal intracerebral activity; Dm, main source; Square, main dipole; Triangle, late dipole.

than the contact recording the maximal ®eld. For example, in spike 5, the main source was closest to LA6 whereas the maximal synchronous ®eld was recorded at LA4 (Fig. 8A). Finally, the remaining spike (Spike 3L, Fig. 8C), was modeled by a source located in the insula, just above the contact where the maximal intracerebral ®eld was recorded, but in a non-explored region (group C of Fig. 4). 3.2.2. Localization of early and late sources On average, early or late dipoles were 11:2 ^ 6:9 mm from the SEEG contact where the early or late peaks were identi®ed. From the 16 early or late activities, 8 sources were spatially and temporally consistent with the intracra-

nial ®elds (group A1 of Fig. 4). For example, spike 6R could be modeled by 2 distinct early dipoles, matching the two intracerebral early peaks (Fig. 6) In spike 6L the late hippocampal dipole was consistent with a intracranial ®eld on the most mesial contact of the hippocampal electrode (Fig. 8B). Spatial inconsistency of more than one contact (group A2) was only found for one early activity (spike 5, Fig. 8A). Finally, two spikes (spikes 7, 8) were inconsistent in time with the intracranial data (group A3), the delay between early and main source activities (or main and late) differed for more than 10 ms from the delay between the corresponding early and main intracerebral peaks (or main and late), e.g. spike 7 in Fig. 9.

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Fig. 6. Example of spatial and temporal concordance. Model of spike 6R suggests 3 sources. The ®rst early dipole (De1) is concordant with the ®rst early intracerebral ®eld in the amygdala, the second early dipole (De2) is concordant with the second early intracerebral peak in the hippocampus, and the main dipole (Dm) is concordant with the maximal intracerebral ®eld in the middle temporal gyrus. Note that source De2 is closer to contact RH2 than RH1.A, amygdala; H, anterior hippocampus; E, early intracerebral ®eld, M, maximal intracerebral ®eld; De, early source; Dm, main source; Square, main dipole, Circle, early dipoles; R, right.

Fig. 7. Example of concordance in case of a frontal spike. This spike could be modeled by two sources (no early), located in the frontal cingulate gyrus (main source) and in the mesial frontal cortex (late source). These dipoles were consistent with the intracerebral ®elds recorded respectively in the cigulate gyrus (maximal ®eld M) and in the SMA (late ®eld L). R, right; FS, SMA; FC, frontal cingulate gyrys; Dm, main source; Dl, late source; Square, main dipole; Triangle, late dipole.

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Fig. 8. Examples of discrepancy for main sources and of spatial discrepancy for early sources. (A) and (B) Spatial discrepancy: The maximal intracerebral ®eld is recorded at LA4 for spike 5 and spike 6L and the main dipoles are more lateral and closer to LA6. Moreover in the case of spike 5 a spatial discrepancy existed for one early source: Whereas the ®rst early source (De1) was very close to the ®rst peak at LA1, the second early source (De2) was close to LH4, although the actual early ®eld (E2) was recorded more mesially at LH1.(C) Non-validated case, for spike 3, the main source is located in the insula, far from any intracerebral contact. A, amygdala; H, anterior hippocampus; Dm, main source; E, early intracerebral ®eld; M, maximal intracerebral ®eld; L, late intracerebral ®eld; Square, main dipole; Circle, early dipoles; Triangle, late dipole; L, left; R, right.

Fig. 9. (A±C) Example of temporal discrepancy. For spike 7, the delay between the main and late source activities (on the left of the ®gure) was 65 ms, whereas the delay between the corresponding main (M) and late (L1) intracerebral peaks was 20 ms. The spatial agreement however, was excellent. A, amygdala; H, anterior hippocampus; FO, orbito-frontal;, M, maximal intracerebral ®eld; L, late intracerebral ®elds.

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Fig. 10. Example of non validated source. The early source (De) calculated for spike 4R is located in the temporal pole, anterior to the most anterior electrode (RA). We concluded in this case that the location of this source could not be con®rmed by intracerebral recordings.A, right amygdala; H, right anterior hippocampus; De, early dipole; Dm, main dipole; E, early intracerebral ®eld; M, maximal intracerebral ®eld; square, main dipole; circle, early dipole.

When early peaks were evident on intracerebral data, early dipoles were always needed for EEG spike modeling. In contrast, the relationship was not reciprocal for late events: late dipoles were always associated with late intracerebral activities, but late intracerebral activities could be recorded when late dipoles were not present (group B), indeed, in spikes 7, 9, 3 additional late activities were not associated with a corresponding late dipole (Table 3). Finally one early (spike 4R, Fig. 10) and one late (spike 2 Fig. 5) dipole were located in a non-explored region (the temporal pole for spike 4R and the insula for spike 2), far from any intracerebral electrode (group C). 4. Discussion Dipole modeling results have usually been compared to results of electroclinical studies or postsurgical outcome (Ebersole and Wade, 1990; Ebersole, 1994; Lantz et al., 1994), to MRI lesions (Stefan et al., 1992; Stefan et al., 1994), to a metabolic dysfunction as assessed by PET or SPECT (Stefan et al., 1992; Lantz et al., 1994; Merlet et al., 1996), or to ictal seizure onset on intracerebral recordings (Lantz et al., 1994; Boon et al., 1997; Ebersole, 1997). These comparisons provide an indirect validation of dipole modeling results: indeed, although related to a same epileptic process, the cerebral regions involved in ictal onsets (de®ning the so called `epileptogenic zone'), lesions, hypometabolism or low blood ¯ow, or the surgical resections, do not exactly match the interictal spiking zone, even if intersections certainly exist between all these zones. Consequently, comparing the localization of dipole sources of

interictal spikes with such data often lead to an impasse, since lack of congruent data does not provide proof that dipole modeling results are erroneous, and congruence only indicates that the model may be correct. Thus, inclusion of source localization techniques in the presurgical assessment of epileptic patients requires not only correlation studies between dipole models and other clinical tools such as PET, SPECT, MEG, MRI, or electroclinical data, but also a direct con®rmation of interictal spike modeling. This direct validation can be achieved by comparison between intracerebral and surface EEG data, optimally using simultaneous recordings. Such relationships between surface and intracranial or intracerebral ®elds have been previously investigated. In the study of Alarcon et al., (1994), no dipole modeling was performed and relationships between scalp and intracerebral data were only assessed in one subject. In other reports, an inverse approach was used for validation: spikes were detected on intracranial recordings, and the concomitant scalp EEG signal was then averaged and modeled (Lantz et al., 1996; Merlet et al., 1998). In these studies, therefore, the distributions of intracranial ®elds during a real scalp EEG spike were not explored. In another recent report, Rubboli et al., (1997) compared dipole locations with the cerebral regions exhibiting the most frequent spiking during the whole period of implantation. In this study however, the authors were not analyzing concomitant surface and intracerebral ®elds. Finally, it is noteworthy that in some of these studies, results of dipole modeling were presented within the spherical head model without projection onto brain anatomy (Lantz et al., 1996; Rubboli et al., 1997),

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thus making the source locations more dif®cult to interpret in terms of cerebral anatomy. In the present study, our aim was to obtain a direct con®rmation of dipole model predictions with intracerebral recordings. Simultaneous recordings allowed us to analyze the intracranial signal associated with surface EEG spikes, and to verify dipole modeling results of interictal spikes in terms of anatomical location and time activation of the sources for each subject. 4.1. Distribution of intracerebral ®elds during surface EEG spikes 4.1.1. Extent of intracerebral ®elds during a scalp EEG spike When a spike was present at the surface of the scalp, we never observed very focal activity, occurring only at one intracerebral contact. At least 8 intracerebral contacts were involved in the surface EEG interictal paroxysm. If we consider for a simple calculation that 4 contacts (length of 16 mm) were active on 2 adjacent electrodes (separated by about 2 cm) a ®rst approximation of the surface of cortex involved during spike 3 for example, is around 3 cm 2. It seems dangerous however, to estimate the volume of active tissue, as the intracerebral electrodes were always implanted in the same plane (middle temporal gyrus) within the temporal lobe. These data are con®rmed in the case of spike 11, where 2 epidural electrodes, covering an area of about 4 cm 2, participated in the interictal spike. These estimates are obviously very rough, but they are certainly underestimates of the extent of brain region involved in spikes. They are consistent with the results of Cooper et al., (1965) and more recently of Ebersole (1997), which suggested a minimal cortical activation area of 6, 8 cm 2, to detect a signi®cant spike signal on scalp EEG. 4.1.2. Mesio-lateral distribution within the temporal lobe Since we did not record scalp spikes associated with a focal intracerebral ®eld, a fortiori we never recorded interictal spikes associated with a focal mesio-temporal spike limited to the amygdala or hippocampus. From our group of patients, 3 different situations could be observed, taking into account that spikes were always distributed over a large area: The maximal intracerebral ®eld (also reproducing the morphology of the surface EEG spike) simultaneously with the surface spike could be (1) neocortical only, (2) neocortical but associated with asynchronous activity in the amygdala or hippocampus, and (3) mesial but associated with an asynchronous activity in the neocortex (one case). This last situation therefore suggests that more than the depth of the source, a large extent of activated cortex appears necessary to record an interictal spike on the scalp. This large extent may be limited to neocortex or include neocortex and archicortex.

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4.1.3. Simple versus complex intracerebral ®elds Basically, our `simple spikes' i.e. synchronous intracerebral ®elds gradually decreasing on adjacent contacts, were always neocortical only. However, `complex spikes' always involved asynchronously the mesial and the neocortical temporal regions. However, in contrast to Alarcon et al., (1994), ®elds occurring in the mesial and neocortical structures were not simultaneous, but showed a reproducible delay ranging from 10 to 54 ms and a different morphology, with peaks preceding or following the main synchronous activity being sharper and faster. Therefore, simultaneous activation of archicortical and neocortical regions in the temporal lobe are not necessarily required, as previously suggested (Marks et al., 1992) to observe well de®ned surface spikes. Although 10 ms may be too short a delay to postulate propagation processes, our results are in favor of strong and time-locked interactions between mesial and lateral aspects of the temporal lobe. Moreover, in some of our `complex spikes' strong interactions were also suggested between temporal and orbito-frontal regions (cases 7, 8), which is in agreement with previous anatomical studies showing extensive projections between the amygdala, the temporal pole, the lateral neocortex and the orbital aspect of the frontal lobe (Amaral and Price, 1984). Within our group of `complex spikes', the successive activation of several structures within the temporal lobe, within the temporal and frontal lobes, within the temporal and parietal lobe or even within the frontal lobe, always showed time delays below 60 ms. However, despite this short latency, our results seem to favour propagation processes since (1) the morphology of peaks differed for the early, the main, and the late intracerebral ®elds and (2) these delays were reproducible (except in one instance, see below). However, the typical pattern observed in our group of `simple intracerebral ®elds', occurring simultaneously with surface EEG paroxysms, and gradually decreasing in amplitude to the surface, most certainly re¯ects only volume conduction from a spatially stable generator. 4.2. Dipole modeling predictions 4.2.1. Simple versus complex spikes predicted by dipole modeling Interestingly, our dipole modeling results predicted well the type of intracerebral ®elds occurring during interictal surface events: all spikes modeled with only 1 dipole had `simple' intracerebral ®elds, and all but one spikes, in which two or more sources were required, had `complex ` intracerebral ®elds. In one instance, the spike could be explained by two sources whereas `simple' activity was recorded intracerebrally. However, in that case, no real con®rmation was obtained from intracerebral recordings, since no electrode was implanted in the vicinity of the second dipole. Therefore our results strongly suggest that surface spikes associated with `simple ®elds' are due to the activity of a single

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generator, which may be detected synchronously (^10 ms) on the scalp. However, surface spikes associated with `complex' intracerebral ®elds may result from propagation processes between different anatomical regions, either within the temporal lobe or extratemporally. 4.2.2. Concordance between dipole modeling and intracerebral results Concordance or discordance between intracerebral and surface data can only be stated when dipoles where found in the vicinity of an intracerebral electrode, dipole sources located within a non-explored area were not considered as discordant, nor as concordant with SEEG data. Moreover, because of the low spatial sampling of depth electrodes, the contact recording the maximal ®eld was not necessarily in the spike generator. The only conclusion that could be derived is, which of the intracerebral contacts was closest to the actual generator? In particular we have no information regarding the distance between this generator and the recording site. According to this, distances that we calculated between the dipoles and the intracerebral contacts recording the corresponding activity cannot be considered as error measures. Concordance between dipole modeling results and intracerebral recordings implies both a spatial agreement between the source location and the contact recording the corresponding intracerebral ®eld, but also in case of complex spikes, a temporal agreement between delays observed for the dipole waveforms and delays seen in the intracerebral signals. This type of matching was obtained for 64% of main activities, 57% of early activities, and 44 % of late activities. Concordance was therefore greater for main sources, calculated over the main negative peak of the surface EEG spikes. Such a difference may be attributed to the poor signal-to-noise ratio during the early and late phases of the spike, when early and late dipoles were calculated. 4.2.3. Spatial incongruence This type of discordance was found when the SEEG contact closest to a dipole was not the site where the maximal intracerebral ®eld was recorded. In this case, we concluded that dipole modeling mislocated the source. This situation occurred for 29% of main sources and 14% of early sources. Dipoles in each case were located very close to a another intracerebral recording site, which could be either more lateral or more mesial than the actual contact recording the maximal ®eld. As such errors were not encountered in extratemporal regions, a ®rst conclusion was that the bad location of dipole sources could be related to the poor ®tting of the dipole sphere in the temporal lobe. However, since these mislocations were not systematically in the same direction (e.g. dipoles always located more lateral or more mesial) such a conclusion does not hold. A second interpretation concerning mislocations could be derived from the source orientation: indeed if the spike

generator was prependicular to the implantation line of electrodes a phase reversal should occur. In that case the electrode contact located closest to the generator would not show a maximum of voltage but a low value. However we could not ®nd any interaction between the dipole orientation and the mislocation. We did not observe a systematic error when the dipole was perpendicular to the intracerebral electrode. In the rare cases where a phase reversal existed, the source was not always moved toward the minimum of voltage. Moreover, in most cases, there was no phase reversal thus suggesting a complex orientation of the generator. Our conclusion was therefore that mislocations could not be attributed to the source orientation. In one case (spike 8) the main source was neocortical, very close to the contact recording an early activity, whereas the maximal intracerebral ®eld was more mesial. By looking back at the non averaged data, we could show that although the surface spikes were very similar, their associated intracerebral ®elds differed: indeed, the delay between the two intracerebral peaks was not reproducible, the early neocortical peak occurring either before or simultaneously with the maximal ®eld in the amygdala. The mislocation of 3 other sources (early and main dipoles of spike 5, and main dipole of spike 6L) was associated with the presence of another dipole in the neighboring temporal mesial structures. In this case, dif®culties in the source separation may be invoked, the existence of a hippocampal dipole provoking a lateral displacement of other sources in order to avoid interactions between dipoles. Finally, for the remaining source (spike 3R) the separation between sources could not be invoked since the paroxysm was modeled by a single source. Nevertheless, over all cases, the distance between the mislocated dipole and the contact recording the maximal intracerebral activity always remained below 20 mm (range 13.6±17 mm) which may be within the con®dence limits of the method. 4.2.4. Temporal incongruence For two dipoles (one early and one late source) the delay between the source waveforms were not congruent with the observed delays between intracerebral peaks. In the ®rst instance (spike 8) the early source was activated at the time of the main activity: as explained above, this incongruence may be attributed to non reproducible intracerebral signals within the spike average. In the second instance, the late hippocampal source was activated 45 ms after the late intracranial peak (spike 7, see also Fig.8). We could not ®nd an explanation for this difference. 4.2.5. Incongruence by missing the source Over all spikes and for each kind of source (early, main or late) our results show that when early or late generators were suggested by dipole modeling, a corresponding early or late signal could be identi®ed on intracerebral contacts. This means that dipole modeling was not providing a false information regarding the complexity of spike generators. In contrast however, the reciprocal association was not true

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since one third of late activities detected on intracerebral recordings were not associated with a late source. This situation did not occur for early or main sources. This may be due to the spatio-temporal approach we used for modeling, constraining the late sources to be ®tted at the end, while early and main dipoles were kept active. This lead to solutions for which late sources could be removed because either (1) they were interacting with the other ones, and we then concluded that late generators could not be separated from early and main ones, or (2) they were pushed further away, in aberrant areas such as skull, eyes, or ears, with an almost ¯at activation curve, and we concluded that late sources had a negligible contribution to the spike. 5. Conclusion Our data con®rm that surface EEG spikes are associated with intracerebral ®elds distributed over a broad cortical area. We never observed scalp EEG spikes corresponding to focal activity limited to mesio-temporal structures. These structures could be recruited in combination with the neocortex however, but in all instances, the involvement of the lateral temporal neocortex was required. This suggests that modeling a spike by a single source located in the mesial aspect of the temporal lobe may be unreliable. From our results, dipole modeling of EEG spikes provided reliable information concerning the location and the activation timing of the underlying generators. Interestingly, assumptions concerning the complexity of spikes could be veri®ed by source localizing techniques: we never obtained false positive results in the sense that the several sources by dipole modeling were always veri®ed by the intracerebral recordings. It is noteworthy however, that the number of actual generators involved in some interictal spikes may be higher than the number of dipoles calculated. Over all spikes, the mean distance between dipoles and contacts recording the corresponding activity was on average 11 mm. Even in cases of discrepancy, this distance never exceeded 20 mm. This means that con®dence limits of 2 cm may be taken into account when modeling spikes, keeping in mind that these limits may be much less in the majority of cases. Acknowledgements We sincerely thank Drs. F. Dubeau, D. Gross, N. Bernasconi and A. Bernasconi for helpful advice concerning the patient pathology, Mrs. L. Allard and N. Drouin for technical support during EEG recordings, and M. Cyr, P. SaintJean, for assistance in MRI data analysis. This work was supported by grant MA-10189 from the Medical Research Council of Canada. Dr. I. Merlet was supported by a postdoctoral fellowship from the French MinisteÁre des Affaires EtrangeÁres.

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