Cortical current density reconstruction of interictal epileptiform activity in temporal lobe epilepsy

Cortical current density reconstruction of interictal epileptiform activity intemporal lobe epilepsy

H.-J. Huppertza,b,*, S. Hoegga,b, C. Sickb, C.H. LuÈckingb, J. Zentnerc,A. Schulze-Bonhagea, R. Kristeva-Feigeb

aEpilepsy Center, University of Freiburg, Breisacher Strasse 64, D-79106 Freiburg, GermanybDepartment of Neurology, University of Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany

cDepartment of Neurosurgery, University of Freiburg, Breisacher Strasse 64, D-79106 Freiburg, Germany

Accepted 4 May 2001

Abstract

Objective: To investigate the value of cortical current density (CCD) reconstruction in localizing intracranial generators of interictal

epileptiform activity in mesial and lateral temporal lobe epilepsy (TLE).

Methods: Non-linear minimum L1-norm CCD reconstruction (with current sources restricted to the individual cortical surface and a

realistic boundary element method (BEM) head model) was used to localize and to study the propagation of interictal epileptiform EEG

activity in 13 pre-surgical patients with TLE.

Results: In all but one patient with mesial temporal lesions, an initial activation maximum corresponding to the ascending part of averaged

sharp waves was found in the ipsilateral anterior basolateral temporal lobe, mostly extending up to the affected mesial structures whose

resection rendered the patients seizure-free. In all 3 patients with lateral temporal lesions, the activation was initially con®ned to temporal

neocortex immediately adjacent to the epileptogenic lesion. Towards the peak of sharp waves, two patients showed a propagation of interictal

activity to anterior and posterior and partly contralateral temporal regions. A conventional EEG analysis based on amplitude maxima or

phase reversal would have missed the initial onset zone.

Conclusions: The ®ndings demonstrate that CCD reconstruction can be a valuable additional non-invasive component in the multimodal

pre-surgical evaluation of epilepsy patients. q 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Epilepsy; Interictal epileptic activity; Electroencephalography; Magnetic resonance imaging; Source modeling; Current density reconstruction

1. Introduction

In the past years, source modeling based on scalp-

recorded EEG has been increasingly used to localize epilep-

togenic foci in the pre-surgical evaluation of epilepsy

patients. In the commonly applied equivalent current dipole

model, synchronously activated cortical areas are repre-

sented by one or more dipolar electric model sources

(Henderson et al., 1975; Cohen and Cuf®n, 1983; Scherg,

1990). From the distribution of scalp-recorded EEG poten-

tials and the shapes and conductivities of the different head

compartments (e.g. brain, skull, skin), an inverse solution is

calculated for the location, orientation, and strength of

possibly underlying intracranial sources. Recent advances

include the co-registration of EEG data with anatomical

information from magnetic resonance images (MRI) and

the use of realistic head models (Gevins et al., 1990; Roth

et al., 1993; Buchner et al., 1995; Kristeva-Feige et al.,

1997; Grimm et al., 1998; Koles, 1998; Ball et al., 1999).

Equivalent current dipole modeling based on EEG or

magnetoencephalography (MEG) has been successfully

used in localizing intracranial generators of interictal and

ictal epileptiform activity (Ebersole, 1994; Baumgartner et

al., 1995; Assaf and Ebersole, 1997; Boon et al., 1997;

Krings et al., 1998; Diekmann et al., 1998). The results

were in agreement with those of other imaging modalities

(MRI, positron emission tomography (PET), single photon

emission computed tomography (SPECT)) and intracranial

EEG recordings (Nakasato et al., 1994; Stefan et al., 1994;

Merlet et al., 1996; Roth et al., 1997; Shindo et al., 1998;

Merlet and Gotman, 1999; Krings et al., 1999; Boon et al.,

1999; Huppertz et al., 2001; Kobayashi et al., 2001).

However, equivalent current dipole algorithms are a

simpli®cation since they rely on the assumption that

Clinical Neurophysiology 112 (2001) 1761±1772

1388-2457/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved.

PII: S1388-2457(01)00588-0

www.elsevier.com/locate/clinph

CLINPH 2001511

* Corresponding author. Tel.: 149-761-270-5001; fax: 149-761-270-

5003.

E-mail address: [email protected] (H.-J. Huppertz).

synchronously activated cortical areas are well represented

by their centers of mass and their mean surface normals. In

addition, they require a priori knowledge of the number of

active sources (Fuchs et al., 1999). Therefore, a growing

emphasis has been on developing distributed source models

as in current density reconstructions, which represent more

realistically active brain regions, and which need no

assumptions about the number, shape, or size of activated

areas (Ebersole, 1999; Fuchs et al., 1999). Several methods

have been proposed (Wang et al., 1992; Ilmoniemi, 1993;

Pascual-Marqui et al., 1994; Hamalainen and Ilmoniemi,

1994; Phillips et al., 1997; Lantz et al., 1997; Uutela et

al., 1999; Fuchs et al., 1999; Grave de Peralta Menendez

et al., 2000). They all have in common a pre-determined

distribution of elementary current dipoles on given positions

in the head, either on a regular grid or constrained to the

cortical surface. While the positions of these dipoles are

®xed, their orientations and strengths must be determined.

The fact that the number of sensors or electrodes is usually

much smaller than the number of modeling dipoles leads to

a highly underdetermined problem, which can only be

solved by additional constraints (e.g. minimum norm).

The constraining model term has to be weighted against

the data term by a regularization parameter (Ebersole,

1999; Fuchs et al., 1999).

The present study was aimed at localizing cortical

generators of interictal epileptiform activity in patients

with temporal lobe epilepsy (TLE) by means of cortical

current density (CCD) reconstruction as described recently

by Fuchs et al. (1999). So far, there have been only a few

reports about the application of this method for investigating

somatosensory evoked potentials or localizing the source of

epileptiform activity in up to 5 patients with TLE (Waberski

et al., 1998, 1999, 2000). In this study, we wanted to eval-

uate if the method helps (1) to estimate the extension of

active brain regions, (2) to investigate the timing and propa-

gation of interictal epileptiform activity, and (3) to discri-

minate between mesial and lateral TLE. The results of

source reconstruction were validated by comparison with

the sites of the structural lesions, the post-operative

outcome, and in two patients with the results of intracranial

EEG recordings. In addition, the reconstruction results were

compared to those of equivalent current dipole (ECD)

modeling (Henderson et al., 1975; Cohen and Cuf®n,

1983; Scherg, 1990).

2. Methods

2.1. Patients

Thirteen patients (7 males, 6 females, 13±64 years) with

medically refractory epilepsy were selected from our

video-EEG monitoring unit according to the following

criteria: (1) presence of interictal epileptiform activity

(spikes, sharp waves) in the EEG and (2) TLE according

to pre-surgical evaluation. All patients had a similar

evaluation that included high-resolution MRI, interictal

and ictal video-EEG, neuropsychological testing, in 8

cases interictal PET, in 7 cases interictal, in one case

ictal SPECT, and in 3 cases magnetic resonance spectro-

scopy (MRS) of the hippocampi. Additional intracranial

EEG recordings were necessary in two patients: patient 6

had non-lesional TLE and intrahippocampal depth elec-

trode recordings established a seizure onset zone in the

right anterior hippocampus. In patient 7, a temporomesial

seizure onset zone could only be veri®ed by left-sided

intrahippocampal depth electrodes and temporo-lateral

and -basal strip electrodes.

Post-operatively, 11 patients had excellent outcome,

consistent with class I of the Engel classi®cation (mean

follow-up, 250 days) (Engel et al., 1993). One patient

showed a running-down phenomenon of the post-operative

seizure frequency and has been seizure-free for 3 months

now. Another patient (patient 7) still suffers from seizures

whose semiology has changed, however, possibly due to an

intracerebral hemorrhage during operation. However, he

belonged to the two patients whose epileptogenic zone

had been veri®ed pre-operatively by intracranial EEG

recordings.

In all patients, neuropathological analysis of the resected

tissue was performed. The results of the pre-surgical evalua-

tion and the post-operative outcome are summarized in

Table 1.

2.2. EEG recordings

All measurements were performed during pre-surgical

video-EEG recording in our monitoring unit (Neuro®le

NT EEG system). The EEGs were recorded from 23±31

scalp electrodes, placed according to the 10-20 system,

with special coverage of the temporal lobes by a minimum

of 4 additional sub-equatorial electrodes at anterior

temporal (T1, T2) and mastoidal (MN1, MN2) positions

(reference electrode on the forehead; electrode resistances

below 10 kV, sampling rate 256 Hz, 16-bit resolution, band-

pass ®lter 1.59±97 Hz). Additional bilateral sphenoidal

electrodes (SP1, SP2) were used for identi®cation of epilep-

tiform activity, but not for source reconstruction. Eye move-

ments and blinks were monitored to exclude artifacts.

Together with the EMG of the masseter muscle, they helped

to de®ne sleep stages.

Spikes and sharp waves were identi®ed visually accord-

ing to IFSECN criteria (Chatrian et al., 1974) and marked

provisionally on the highest negative peak in the EEG (after

re-referentiating to a common average montage). Using a

separate EEG analyzing software (Vision Analyzer, Brain

Products), the marker positions were automatically adjusted

to the earliest negative peak around the manually set

markers. Artifact-free EEG epochs of 1000 ms before to

1000 ms after the marker positions were baseline-corrected

and averaged. Epileptic discharges that differed by their

H.-J. Huppertz et al. / Clinical Neurophysiology 112 (2001) 1761±17721762

waveform or scalp topography were averaged in separate

groups. Baseline-correction and calculation of the signal-to-

noise ratio (SNR) were based on the EEG data from 1000 to

200 ms before marker positions. Source reconstruction was

applied to time points from 20 ms before to 12 ms after the

peak of the averaged epileptiform discharges.

For subsequent EEG/MRI co-registration, the electrode

positions were digitized using an ultrasound localizing

device (ZEBRIS) and the head contour was obtained by

collecting approximately 1600±2000 points while moving

the digitizer across the head surface. The transformation of

electrode positions and MRI data into the same co-ordinate

system was based on matching the digitized head surface

with the head contour as segmented from MRI data by using

an automatic surface matching technique (Huppertz et al.,

1998). This procedure seems to be more reliable than

matching a small number of reference points because the

digitization error of single points largely averages out when

surfaces consisting of thousands of points are ®tted (Peliz-

zari et al., 1989; Kober et al., 1993).

2.3. Cortical current density reconstruction

Source reconstruction was performed using non-linear

CCD analysis. In contrast to linear CCD implementations

minimizing the L2-norm of the reconstructed currents (mini-

mum norm least squares, MNLS) (Ilmoniemi, 1991), the

method calculates a regularized solution with a minimal

sum of absolute current densities (minimum L1-norm).

This non-linear CCD solution is more focal and of higher

spatial resolution than the corresponding MNLS solution

(Ball et al., 1999; Sick et al., 2000). In addition, it is more

robust with regard to outliers in the measured data. Both

effects result from the fact that large currents or data values

are not punished by their squared strength as in the MNLS

method, but contribute only with their (weighted) absolute

H.-J. Huppertz et al. / Clinical Neurophysiology 112 (2001) 1761±1772 1763

Table 1

Diagnoses, results of pre-surgical evaluation, and post-operative outcome of all patientsa

Patient Diagnosis (MRI/histology) PET SPECT MRS Operation Outcomeb

Mesial temporal lesions

1 Right hippocampal sclerosis Right temporal pole No pathology AHE I

2 Right hippocampal sclerosis Right temporal

neocortex

Left TL Both hippocampi (R . L) AHE I

3 Left hippocampal sclerosis AHE I

4 Left hippocampal sclerosis Left mesial TL AHE I

5 Left hippocampal sclerosis Left

hippocampus 1 left

superior temporal

gyrus

Left TL No pathology AHE IIc

6 No lesion in MRI,

histologically signs of right

hippocampal sclerosis

Right lateral TL and

OL 1 left PL and OL

Right mesial TL AHE I

7 Left hippocampal sclerosis Left TL and PL Left mesial TL AHE IVd

Mesial temporal lesions extending to temporal neocortex

8 Right hippocampal

sclerosis 1 focal cortical

dysplasia of the temporal pole

Right TL 1 PL ATLE I

9 Right hippocampal

sclerosis 1 focal cortical

dysplasia of the temporal pole

No pathology No pathology Both hippocampi (R . L) ATLE I

10 Glioneuronal hamartia in the

right mesial TL including basal

neocortex

LE (including AHE) I

Lateral temporal lesions

11 Glioneuronal hamartia in the

left inferior temporal gyrus

Left inferior

TL 1 right and left FL

Right FL 1 TL LE I

12 Ganglioglioma in the left

basolateral TL

LE I

13 Dysembryoplastic

neuroepithelial tumor in the

right lateral TL

LE I

a FL, frontal lobe; TL, temporal lobe; PL, parietal lobe; OL, occipital lobe. AHE, selective amygdalohippocampectomy; ATLE, anterior temporal 2/3-

lobectomy; LE, lesionectomy.b According to Engel classi®cation.c Running-down phenomenon, seizure-free for the last 3 months.d New post-operative seizure type after intra-operative hemorrhage, seizures of old semiology disappeared.

values to the function to be minimized (Wagner, 1998;

Fuchs et al., 1999).

To avoid over®tting, a reasonable CCD solution should

not explain more of the data than that above the noise level.

Thus, the regularization parameter l that weighted the

constraining model term against the data term was deter-

mined by iterative adjustment until a residual deviation of

the CCD solution of 1/SNR (with 5% tolerance) was

achieved (x 2-criterion) (Wagner, 1998; Fuchs et al., 1999).

Realistic 3-compartment boundary element method

(BEM) head models with about 4000 (range 3600±4300)

nodes per model were set up from the MRI data (MPRAGE

sequence with TR/TE/alpha� 9.7 ms, 4 ms, 128 on a 1.5 T

Magnetom Vision, Siemens) by segmentation and triangu-

lation of the 3 main compartments: brain with CSF (inside

of skull), skull and skin (Wagner et al., 1995; Huppertz et

al., 2001). The conductivities of the different tissues were

de®ned as 0.33 S/m for the skin, 0.0042 S/m for the skull,

and 0.33 S/m for the brain (Geddes and Baker, 1967). A

separate compartment representing the cerebrospinal ¯uid

was not de®ned because of potential mathematical errors

arising from closely spaced boundary surfaces in a BEM

model, in this case the surfaces of brain and cerebrospinal

¯uid (Fuchs et al., 1998).

To include physiologic knowledge and the individual

brain morphology, the CCD reconstructions were performed

on about 28 000 supporting points distributed over the corti-

cal surface as segmented from the individual MRI. The

elementary current dipoles on these supporting points

were restricted to be normal with respect to the cortical

surface. To account for the depth dependency of the CCD

reconstruction algorithm and to compensate for the lower

gains of deeper dipole moments, the current locations were

weighted by the inverse of the square root of the gains in the

lead-®eld matrix (with locationwise singular value decom-

position of the lead-®eld before gain determination).

Compared to the usage of full gains as suggested by Fuchs

et al. (1998), this depth normalization seems to provide

more accurate solutions and avoids to overemphasize deep

sources (Sick et al., 2000).

Image segmentation, volume conductor modeling, source

reconstruction, and visualization were performed using the

CURRY software (Neurosoft, Inc.). Minimum Lp-norm with

the norms of both the data and the model term set to 1 (thus

equaling minimum L1-norm) were selected as the recon-

struction mode. The regularization parameter l was

adjusted manually according to the criterion described

above. Only currents with at least 50% of the current

strength at the maximum current density were considered.

The reconstruction results, i.e. the elementary current

dipoles were encoded as arrows of different sizes, colors,

and orientations overlaying the segmented cortex.

2.4. Equivalent current dipole modeling

In addition to CCD analysis, the same EEG data sets were

subjected to single ECD modeling (Henderson et al., 1975;

Cuf®n, 1985; Scherg, 1990). The calculation was done with

the CURRY software (Neurosoft, Inc.) and based on the

same BEM head models as described above. The source

space was de®ned as the compartment `brain with CSF'

(inside of skull), reduced by 3 mm in a closing operation

to avoid potential mathematical errors in the vicinity of

boundary surfaces in a BEM model (Fuchs et al., 1998).

The goodness of ®t (GoF) was determined as the percentage

of EEG data explained by the solution of the ECD location.

Only ECD results with a GoF . 95% were accepted and

visualized in the MRI data sets.

3. Results

In all patients, interictal epileptiform discharges ipsilat-

eral to the side of their epileptogenic lesion could be

recorded. In 4 patients (1, 9, 6, 4), an additional, relatively

small sub-group (,20%) of sharp waves with their scalp

maximum in temporal electrodes contralateral to the lesion

was observed, mostly in sleep stages 1±2. Since it is known

that during non-REM sleep, spike, and sharp waves tend to

spread from the primary focus to ipsi- and contralateral

brain regions (Sammaritano et al., 1991; Gigli and Valente,

2000), these data were not subjected to CCD analysis.

Contralateral sharp waves were taken into account only in

patient 11 who showed an almost even distribution of right-

and left-sided temporal sharp waves.

The ®nal averaged data included 29±212 (mean, 114)

single epileptiform discharges per patient and sharp wave

group. The SNR ranged from 3.4 to 29.7 (mean, 15.4) in the

ascending part of the averaged sharp wave (at 220 ms) and

from 7.6 to 67.4 (mean, 26.4) at the peak. This allowed

source reconstructions with residual deviations of 3.7±

29.1% (mean, 12.5%) at 220 ms and of 1.5±13.1%

(mean, 5.6%) at the sharp waves' peak.

The results of CCD reconstruction are shown in Table 2.

The patients were divided into 3 groups according to the site

of their epileptogenic lesion.

3.1. Patients with mesial temporal lesions

For both the ascending part and the peak of the averaged

sharp waves, the CCD reconstruction showed in all 7

patients an activation of the basolateral temporal lobe ipsi-

lateral to the epileptogenic lesion. In most cases, the activa-

tion was con®ned to anterior temporal regions and extended

on the basal surface of the temporal lobe up to mesial struc-

tures (Fig. 1). Only in patients 1 and 7, sub-groups of sharp

waves with amplitude maxima at T4 and MN1, respectively,

were localized in the middle and posterior basolateral

temporal lobe.

In some patients, additional activations were found in the

ipsilateral insula (e.g. patient 1), in the basal to polar frontal

lobe (e.g. patients 2, 4, and 7), and in the contralateral

temporal lobe (e.g. patients 4 and 7). However, these were


only weak activations, the activation maxima were still in

the basolateral temporal lobe. Only in patient 2, the analysis

of sharp waves at 220 ms yielded an activation in the basal

to polar frontal lobe that exceeded the temporal activation.

At the peak of the averaged sharp waves, the CCD recon-

struction showed again a maximum in the anterior basolat-

eral temporal lobe.

Over the time course of 220 to 112 ms around the peak

of averaged sharp waves, the source reconstructions

displayed only slight propagation of interictal epileptiform


Table 2

Results of CCD reconstructiona

Patient Localization of earliest sharp wave

peak 1 number of sharp waves

(SNR at peak)

CCD localization (and residual deviation) at:

220 ms 212 ms 0 ms (peak) 112 ms


1 T2 97 SWs (34.1) Basolateral anterior TL 1 slight

activation of insula and basal FL

! ! !

(4.0%) (3.6%) (2.8%) (3.4%)

T4 86 SWs (26.0) Basolateral middle TL 1 slight

activation of insula

! ! !

(5.2%) (4.3%) (3.8%) (3.4%)

2 Fp2 95 SWs (17.5) Basal to polar FL 1 basolateral

anterior TL

! Basolateral anterior TL 1 slight

activation of basal to polar FL

!

(14.1%) (8.6%) (6.0%) (5.5%)

3 SP1 184 SWs (12.2) Basolateral anterior TL (11.4%) ! ! !(9.3%) (8.5%) (8.7%)

4 F7 29 SWs (8.3) Minimal activation of basolateral

anterior TL and Fl 1 contralateral

TL

Basolateral anterior TL ! !

(25.7%) (16.0%) (12.5%) (12.5%)

5 SP1 184 SWs (22.9) Basolateral anterior TL ! ! !(10.9%) (6.5%) (4.6%) (4.0%)

6 F8 36 SWs (7.6) Basolateral anterior TL ! Basolateral anterior TL 1 slight

activation of posterolateral TL

!

(29.1%) (17.5%) (13.1%) (15.7%)

7 F7 106 SWs (37.2) Basal and lateral anterior

TL 1 adjacent basal FL (3.7%)

! ! !

(2.7%) (2.6%) (3.3%)

MN1 53 SWs (34.2) Basolateral posterior TL Basolateral posterior

TL 1 slight activation of FL

Basolateral posterior

TL 1 slight activation of FL

and contralateral TL

Basal and lateral anterior

TL 1 basal FL 1 contralat.

TL

(5.5%) (4.1%) (3.1%) (2.9%)


8 T4 126 SWs (35.1) Basolateral anterior TL ! ! !(4.6%) (3.4%) (2.7%) (3.2%)

9 F8 212 SWs (67.4) Basolateral middle to anterior TL ! ! !(3.9%) (2.1%) (1.5%) (1.6%)

10 SP2 139 SWs (9.6) Basolateral anterior

TL 1 FL 1 contralateral

temporal pole

! ! !

(12.9%) (12.2%) (10.7%) (11.9%)


11 SP1 103 SWs (23.5) Middle inferior TL ± immediately

adjacent to the lesion

Middle inferior TL ± adjacent

to the lesion

Anterolateral and posterior TL Middle inferior TL ± adjacent

to the lesion

(10.1%) (8.3%) (5.6%) (4.1%)

SP2 137 SWs (28.7) Contralateral anterolateral TL Contralateral anterior

basolateral TL

Contralateral anterior

basolateral TL 1 slight

activation of basal FL

!

(27.7%) (8.1%) (3.5%) (3.9%)

12 F7 57 SWs (17.5) Middle inferior TL ± immediately

under the lesion

! Basolateral anterior and middle

inferior TL 1 contralateral TL

Basolateral anterior to

posterior TL 1 contralateral

TL

(28.0%) (11.8%) (6.0%) (6.9%)

13 SP2 182 SWs (40.4) Lateral and slightly basal

activation of TL ± immediately

anterior to the lesion

! ! !

(3.9%) (3.4%) (2.6%) (2.7%)

a FL, frontal lobe; TL, temporal lobe; PL, parietal lobe; OL, occipital lobe; SWs, sharp waves; ! , unchanged CCD localization compared to the preceding

time point.

activity in this patient group. In patient 7, for example, the

analysis of a sub-group of sharp waves with amplitude

maxima at MN1 showed a shift of the activation from

posterior to anterior basolateral temporal regions and an

extension to the ipsilateral frontal and contralateral temporal

lobe. In patient 6, the activation extended from anterior to

posterior basolateral temporal regions. As mentioned, the

activation maximum in patient 2 shifted from the ipsilateral

frontal to the anterior basolateral temporal lobe. In the other

cases, the CCD reconstruction results for the ascending part

and the peak of sharp waves differed only in terms of current

strengths, which increased towards the peak.

3.2. Patients with mesial temporal lesions extending to

temporal neocortex

For all patients in this group, the CCD reconstructions

over the investigated time course of 220 to 112 ms yielded

activation maxima in the anterior or middle to anterior baso-

lateral temporal lobe ipsilateral to the epileptogenic lesion.

In patient 10, the activation was not con®ned to this region,

but included to a lesser degree the ipsilateral frontal lobe

and the contralateral temporal pole. Towards the sharp wave

peak, the activation focussed on the anterior basolateral

temporal lobe with mesial extension up to the border of

the glioneuronal hamartia.

3.3. Patients with lateral temporal lesions

In all 3 patients, the CCD reconstruction for both the

ascending part and the peak of averaged sharp waves

showed an activation close to the epileptogenic lesion. For

patient 13, the activation remained exclusively con®ned to

the close vicinity of the lesion over the investigated time

course. In contrast, patients 11 and 12 showed a propagation

and extension of interictal epileptiform activity from an

inferior mid-temporal location (immediately adjacent to

their lesion) to anterior and posterior temporal regions,

and in patient 12 also to the contralateral temporal lobe

(Figs. 2 and 3). As mentioned above, about half of the

sharp waves in patient 11 had their initial amplitude maxi-

mum in the contralateral sphenoidal electrode. Their source

reconstruction showed an activation of the contralateral

antero- and basolateral temporal lobes.

3.4. Comparison between the results of CCD reconstruction

and ECD modeling

In contrast to the extended results of CCD reconstruction,

the point-like dipole locations of single ECD modeling

could be determined with gyral or even subgyral accuracy.

They are shown in Table 3 together with the corresponding

GoF values.

In most cases, the ECD results coincided well with the

activation maxima of the CCD solutions. In patients with

mesial temporal lesions, e.g. dipole locations in the anterior

part of the inferior temporal or the parahippocampal gyrus

(e.g. patients 2, 3, 5, and 7) corresponded to initial CCD

activation maxima in the anterior basolateral temporal lobe.

When the CCD solutions showed activations of the posterior

temporal lobe (e.g. sharp waves at T4 in patient 1 or at MN1

in patient 7), the ECD results were accordingly shifted to

middle or posterior parts of the basolateral temporal lobe.

In patient 1 where the CCD reconstruction indicated addi-

tional involvement of insula and basal frontal lobe for sharp

waves at T2, the dipole was located in the middle of the

different activation areas, i.e. in the anterior to middle part

of the superior temporal gyrus. A similar situation was

found in patient 10 where CCD reconstruction showed

extended activation in the basolateral anterior temporal,

basal frontal, and contralateral temporal lobe while the

dipole location was found in the posterior part of ipsilateral

orbital gyri. It should be noticed that the ECD results in

patient 1 were accompanied by high GoF values ranging

from 97 to almost 99%. Generally, this indicates that apply-

ing a single dipole model was adequate and only a limited

cortex area was activated.


Fig. 1. CCD reconstruction results for the peak of averaged sharp waves in 4

patients with hippocampal sclerosis. The elementary current dipoles are

encoded as arrows of different sizes, colors, and orientations overlaying

the segmented cortex, which is shown in side, frontal, and bottom view. The

affected hippocampi were segmented separately and are shown in brown

color. For each patient, the residual deviation and the current maximum (i.e.

the maximum dipole moment per area) of the CCD solution are displayed.

The current distributions were clipped at 50% of the maximum current

density.

Within the group of patients with lateral temporal lesions,

ECD and CCD reconstruction results totally coincided for

patient 13 and for the sharp waves at SP2 in patient 11.

However, for the sharp waves at SP1 and F7 in patients

11 and 12, respectively, the ECD results were located

more anteriorly in the inferior temporal lobe as compared

to the CCD solution. Especially for the ascending part of

sharp waves, the dipoles were located signi®cantly anterior

to the epileptogenic lesion and failed to show the propaga-

tion of interictal activity from the vicinity of the lesions to

other temporal areas.

Finally, it is noteworthy that for quite a number of

patients, reliable ECD results are missing in Table 3 because

of unacceptably low GoF values, especially for the ascend-

ing part of the averaged sharp waves (i.e. at 220 ms) and in

case of generally low SNR (e.g. patients 4, 6, and 10).

4. Discussion

The present study investigated the value of CCD recon-

struction in localizing generators of interictal epileptiform

activity in patients with TLE. No prior assumptions about

the number and location of sources were made, except that

all sources were constrained to a surface representing the

individual cortical gray matter. The results were validated

by comparison with the sites of the structural lesions, whose

epileptogenic nature was con®rmed by an excellent post-

operative outcome in 12 patients, and the results of intra-

cranial EEG recordings in the remaining patient.

In all but one patients with mesial temporal lesions, an

initial activation maximum corresponding to the ascending

part of averaged sharp waves was found in the anterior

basolateral temporal lobe ipsilateral to the side of the epilep-

togenic lesion. On the basal surface of the temporal lobe,

this activation mostly extended up to mesial structures, i.e.

the hippocampus and amygdala. Only in patient 2, the loca-

lization results indicated that initially frontal areas were

predominantly involved in the generation of interictal

epileptiform activity before the activation maximum shifted

and focussed in the anterior basolateral temporal lobe for the

peak of the averaged sharp waves. One could speculate that

via fasciculus uncinatus, the affected hippocampus ®rst

in¯uenced fronto-basal areas before adjacent temporal

neocortical tissue was involved.


Fig. 2. CCD reconstruction results of a patient with a glioneuronal hamartia

in the left inferior temporal lobe (patient 11, lesion shown in brown color).

Sharp waves with amplitude maxima at SP1 were averaged and investi-

gated from 20 ms before to 12 ms after the peak to study the propagation of

interictal epileptiform activity. For each time point, the residual deviation

and the current maximum of the CCD solution are displayed.

Fig. 3. Propagation of interictal epileptiform activity in a patient with a

ganglioglioma in the left basolateral temporal lobe and sharp waves with

amplitude maxima at F7 (patient 12). Over the time course of the averaged

sharp waves, the interictal epileptiform activity propagates from an inferior

mid-temporal location immediately adjacent to the lesion to anterior and

posterior temporal regions and also to the contralateral temporal lobe.

No patient showed an activation con®ned to the mesial

temporal lobe. In all cases, the CCD localizations primarily

comprised basolateral temporal regions and only extended

up to mesial structures. This is in line with the results of a

previous study where equivalent current dipole localizations

did not appear in the epileptogenic hippocampi, but in adja-

cent temporal neocortex, i.e. the inferior temporal or medial

occipitotemporal gyrus (Huppertz et al., 2001). The reason

could be that in cases of mesial temporal lesions, epilepti-

form activity generated in the temporobasal or temporolat-


Table 3

Results of ECD localizationa

Patient Localization of earliest sharp

wave peak 1 number of sharp

waves (SNR at peak)

ECD localization (and GoF) at:

220 ms 212 ms 0 ms (peak) 112 ms


1 T2 97 SWs (34.1) Anterior to middle part of

superior temporal gyrus

! ! !

(98.01%) (97.3%) (97.0%) (98.9%)

T4 86 SWs (26.0) Middle part of inferior

temporal gyrus

Middle part of superior

temporal gyrus

Transverse temporal gyri ±

insula

!

(98.2%) (98.2%) (98.0%) (97.5%)

2 Fp2 95 SWs (17.5) Anterior part of inferior

temporal gyrus

Temporal pole ! Anterior part of superior

temporal gyrus

(97.0%) (97.4%) (97.9%) (97.9%)

3 SP1 184 SWs (12.2) Inferior temporal gyrus,

near temporal pole

! ! !

(97.9%) (98.1%) (97.9%) (98.2%)

4 F7 29 SWs (8.3) ± Temporal pole Temporal pole ±

(94.1%) (95.0%) (95.8%) (94.5%)

5 SP1 184 SWs (22.9) Anterior part of inferior

temporal gyrus

! Medial occipitotemporal

gyrus, close to the pes of

hippocampus

!

(97.8%) (98.4%) (98.5%) (98.5%)

6 F8 36 SWs (7.6) ± ± ± ±

(86.0%) (90.7%) (92.7%) (91.8%)

7 F7 106 SWs (37.2) Anterior part of

parahippocampal gyrus

! Temporal pole !

(97.7%) (98.0%) (98.2%) (98.3%)

MN1 53 SWs (34.2) Posterior part of


! ! Anterior part of


(96.1%) (96.5%) (97.1%) (97.6%)


8 T4 126 SWs (35.1) Anterior part of medial

occipito-temporal gyrus

! ! !

(98.1%) (98.7%) (98.7%) (98.5%)

9 F8 212 SWs (67.4) Temporal pole ! ! Anterior part of


(98.9%) (99.2%) (99.3%) (99.0%)

10 SP2 139 SWs (9.6) ± Posterior part of orbital gyri ± Posterior part of orbital gyri

(91.8%) (95.3%) (94.8%) (95.2%)


11 SP1 103 SWs (23.5) Anterior part of inferior

temporal gyrus

Middle part of superior

temporal gyrus

Transverse temporal gyri ±

insula

!

(97.2%) (96.1%) (95.9%) (95.4%)

SP2 137 SWs (28.7) ± Contralateral inferior

temporal gyrus, near

temporal pole

Anterior part of contralateral

superior temporal gyrus

!

(81.2%) (97.0%) (97.4%) (97.1%)

12 F7 57 SWs (17.5) ± Anterior part of inferior

temporal gyrus

Anterior part of inferior

temporal to lateral occipito-

temporal gyrus

!

(67.0%) (97.7%) (98.3%) (98.3%)

13 SP2 182 SWs (40.4) Temporal pole ±

immediately anterior to the

lesion

! ! !

(99.0%) (98.9%) (98.8%) (98.5%)

a SWs, sharp waves. ±, dipole localization not accepted because of low GoF (GoF , 95%).; ! , unchanged dipole localization compared to the preceding

time point.

eral cortex can mask activity generated in deeper structures,

or that epileptiform activity is not `visible' for surface elec-

trodes until it has propagated to adjacent neocortex. The

lack of identi®able scalp potentials when activation is

con®ned to the hippocampus has been explained by the

relatively small activated tissue volume and the curved

geometry causing external ®eld cancellation (Lopes da

Silva and Van Rotterdam, 1993; Pacia and Ebersole,

1997). According to Alarcon et al. (1994), physiologically

unrealistic voltage gradients would be necessary for deep

sources to evoke detectable scalp potentials. This view is

supported by ®ndings of Merlet and Gotman (1999) who

compared dipole locations based on scalp EEG paroxysms

with intracerebral potentials recorded simultaneously. They

never observed scalp EEG spikes corresponding to focal

activity limited to mesial temporal structures. The lateral

temporal neocortex was always involved. Recently, the

same authors compared source localizations of ictal epilep-

tic activity with intracerebral EEG and also concluded that

mesial temporal seizure discharges did not contribute to

scalp EEG activity (Merlet and Gotman, 2001). Therefore,

the ability to detect and localize pure mesial epileptic activ-

ity perhaps does not depend on the choice of the source

reconstruction technique, whether it is CCD reconstruction,

low-resolution electromagnetic tomography (LORETA)

(Pascual-Marqui et al., 1994; Lantz et al., 1997) or synthetic

aperture magnetometry (SAM) (Robinson and Vrba, 1999),

but is generally limited due to anatomical and physiological

reasons.

In all 3 patients with lateral temporal lesions, the present

study showed an initial activation of a small temporal region

immediately adjacent to the lesion whose later resection

rendered the patient seizure-free. In one patient, the activa-

tion remained con®ned to the close vicinity of the lesion

while the others displayed a propagation of interictal activ-

ity to anterior and posterior and partly contralateral

temporal regions. An analysis restricted to the peak of

their sharp waves would have failed to localize the onset

of interictal activity close to their lesions (Figs. 2 and 3).

Although this study was not planned as a systematic

comparison of electric source reconstruction to other

imaging techniques like PET, SPECT, or MRS, it should

be mentioned that on a lobar level, the CCD reconstruction

of interictal epileptiform activity in our patients was more in

accordance with the location of the epileptogenic lesions

than the results of the aforementioned methods. Three of

8 SPECT and one of 3 MRS investigations showed no

pathology or gave falsely lateralizing results, and 4 of 8

PET ®ndings were of little localizing value, i.e. displayed

interictal hypometabolism in more than one lobe (Table 1).

The ®ndings of this study demonstrate that the novel

approach of CCD reconstruction is able to localize correctly

cortical areas involved in the generation of interictal epilep-

tiform activity. In contrast to source reconstructions based

on dipolar source models, which characterize only the

center of mass of activated brain regions, the CCD recon-

struction gives an impression how far the activation extends

and helps to delineate the irritative zone. Especially in case

of extended irritative areas involving more than one lobe, a

single dipole solution can give a misleading impression of

focality and the dipole can be shifted to unexpected loca-

tions, e.g. the superior temporal gyrus for the sharp waves at

T2 in patient 1 or the orbital gyri in patient 10 who both had

mesial temporal lesions. Fitting a second or third dipole

might have helped to visualize additionally active brain

areas, but relatively high GoF values of 97±99% at least

in patient 1 did not give ground for such an approach.

However, to what extent the results of CCD reconstruc-

tion exactly overlap with the irritative zone cannot be

derived from this study, but has to be determined by simula-

tions or studies in patients with implanted grid electrodes.

As shown by the results of patients 11 and 12, the method

of CCD reconstruction is also able to investigate the propa-

gation of interictal activity. A conventional EEG analysis

based on amplitude maxima or phase reversal would have

attributed their sharp waves at F7 and SP1, respectively, to

the anterior temporal lobe and would have missed the mid-

temporal onset zone adjacent to the lesion. These cases

underline the importance of analyzing the whole time

course and not only the peak of sharp waves, which may

be dominated by propagated activity (Scherg et al., 1999).

Interestingly, the results of dipole modeling for the ascend-

ing part of averaged sharp waves in these two patients were

also located in the anterior inferior temporal lobe, i.e. near

the electrode contact with the highest amplitude and did not

visualize the onset zone near the mid-temporal lesion. This

indicates that in some cases, CCD reconstruction can be

superior to single dipole modeling, possibly due to the inclu-

sion of source orientation as an additional constraint.

The discrimination of mesial and lateral TLE by CCD

reconstruction is limited by the aforementioned fact that

epileptiform activity arising from mesial structures does

not seem to become visible for surface electrodes until

propagation to adjacent neocortical tissue. However, this

handicap is valid for all source reconstruction methods. In

addition, the results of this study, although derived from a

limited number of patients so far, indicate that the involve-

ment of basal temporal regions during the ascending part of

sharp waves can be a hint to a mesial origin of the epilepti-

form activity. In patient 7, for example, the CCD recon-

struction could have helped to avoid invasive recording if

one had interpreted the early involvement of basal temporal

regions in both sharp wave groups (F7 and MN1) as a reli-

able marker of a mesially located epileptogenic zone.

Several methodological problems associated with CCD

reconstruction should be mentioned. First of all, a suf®cient

SNR is mandatory for reliable reconstruction results.

Although the non-linear L1-norm has been reported to

perform better than linear methods such as MNLS or

LORETA (Pascual-Marqui et al., 1994; Lantz et al., 1997)

with respect to localization accuracy and spatial resolution,

the L1-norm algorithm suffers most from low SNRs by


showing scattered and spurious results for deep source loca-

tions (Fuchs et al., 1999). But what is a reasonable SNR

below which reconstruction results are no longer trust-

worthy? In the present study, SNR values ranged from 3.4

to 67 (average, 15.4 for 220 ms and 26.4 for the peak of

sharp waves). For SNR values below 8 (mostly at 220 ms in

the ascending part of sharp waves), both very focussed (e.g.

patients 6 and 12 with SNR� 3.4 and 3.5, respectively) and

somewhat distributed, but nevertheless reasonable recon-

struction results (e.g. patients 4 and 10 with SNR� 3.9

and 7.4, respectively) were found. Thus, there is probably

no de®nite cut-off value but an SNR range of 8±3 where

localization results become more and more questionable and

should be validated by other imaging methods. However,

the present study is not adequate to answer this question in

detail. Again, simulation studies with different SNR values

and sources in different depths are necessary to solve this

problem (Sick et al., in preparation).

The problem of choosing a correct regularization para-

meter is closely related to the SNR of the data. In contrast to

source reconstruction based on one or two equivalent

current dipoles, small residual deviations between measured

and calculated EEG potentials are no longer a good criterion

for the quality of the CCD reconstruction results. They can

always be achieved by selecting small values for the regu-

larization parameter, i.e. down-weighting the model term. In

case of over®tting the data by using a wrong regularization

parameter, the algorithm starts to ®t the noise or correlated

background features of the data, which leads to spurious

results or ghost sources. Therefore, it is important to esti-

mate the noise in the data and adjust the regularization

parameter accordingly (Fuchs et al., 1999).

The computational effort is high since adjusting the regu-

larization parameter has to be done iteratively. With almost

30 000 cortical supporting points in our patients, each itera-

tion required about 4±5 min on a PC with Pentium III

600 MHz CPU. Usually, 4±8 iterations were necessary

until the residual deviation of the CCD solution matched

the inverse of the SNR of the data. Since the automatic

algorithm did not reliably converge, the new value for the

regularization parameter had to be chosen manually for each

iteration. However, these problems will hopefully be over-

come by the development of better performing CPUs and

reliable automatic algorithms for the adjustment of the regu-

larization parameter.

In the present study, the elementary current dipoles on the

cortical supporting points were restricted to be normal with

respect to the cortical surface. Since including the surface

normals punishes cortical supporting points with wrong

normal orientation, the results sometimes appeared some-

what fragmented for lower SNR values (e.g. current dipoles

of signi®cant strength were found only on top of the gyri,

but not in adjacent sulci or vice versa), while for the same

data, the CCD reconstruction with rotating current dipoles

showed coherent activation areas. Nevertheless, the more

constrained source model with surface normals was chosen

because with rotating current dipoles, the activation was

usually con®ned to the cortical area immediately below

the surface electrode showing the highest amplitude for

the investigated time point. Only the inclusion of surface

normals forced the algorithm to adequately emphasize more

distant, but correctly orientated areas. This may also explain

the difference to the recent results of Waberski et al. (2000)

who found no advantage of current density reconstruction

compared to single moving dipole or spatio-temporal dipole

modeling. They used the same reconstruction technique

with a non-linear L1-norm formulation except that the calcu-

lation was done with a smaller number of cortical support-

ing points (15 000±18 000) and, above all, without a

constraint for source orientation.

In conclusion, the results of this study indicate that the

method of CCD reconstruction is able to reliably identify

brain regions involved in the generation of interictal epilep-

tiform activity. In particular, it may help to localize the

cortical area generating the earliest part of the epileptiform

discharge, to study the propagation, and to assess the exten-

sion of the irritative zone. It can indicate the epileptogenic

nature of a structural lesion or guide the placement of intra-

cranial electrodes when necessary. On the other hand, it may

increase con®dence in the localization of the epileptogenic

zone and thereby obviate the need for invasive recordings.

Compared to equivalent current dipole modeling, CCD

reconstruction has the advantage that no prior assumptions

about the number of active sources are required. The method

seems to be a valuable additional non-invasive component

in the multimodal pre-surgical evaluation of epilepsy

patients.

Acknowledgements

The study was partly supported by grants from the

Deutsche Forschungsgemeinschaft (KR 1392/7-1) and the

Research Fund of the Albert-Ludwigs-University Freiburg.

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Cortical current density reconstruction of interictal epileptiform activity in temporal lobe epilepsy