www.elsevier.com/locate/yebeh

Epilepsy & Behavior 8 (2006) 742–749

Reliability of language mapping with magnetic sourceimaging in epilepsy surgery candidates

Dongwook Lee a,b,c,*, Stephen M. Sawrie a, Panagiotis G. Simos d,Jeff Killen a, Robert C. Knowlton a

a Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USAb Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, USA

c Psychology Department, Mississippi State Hospital, Whitfield, MS, USAd Department of Psychology, University of Crete, Rethymnon, Greece

Received 21 October 2005; revised 23 February 2006; accepted 27 February 2006Available online 17 April 2006

Abstract

The external validity of a noninvasive language mapping protocol with magnetoencephalography (MEG) has been establishedthrough direct comparisons with invasive functional mapping techniques. This study examines the test–retest and interrater reliabilityof this protocol under realistic testing conditions in 21 epilepsy surgery candidates. Brain activation maps were obtained in the context ofan auditory word recognition task and represented by temporally contiguous dipolar activity sources. Both the duration and strength ofthe associated magnetic flux were used as measures of the magnitude of regional brain activity. Hemispheric asymmetry indices based onthese measures showed good interrater reliability and intraparticipant reproducibility. Similar findings were obtained with respect to thelocation of the geometric center of receptive language-specific cortex (Wernicke’s) area in the dominant hemisphere. The results furthersupport the adequacy of this MEG-based brain mapping protocol as a noninvasive tool for receptive language localization in epilepsysurgery candidates.� 2006 Elsevier Inc. All rights reserved.

Keywords: Magnetoencephalography; Language mapping; Reliability; Epilepsy surgery; Magnetic source imaging

1. Introduction

Localization of language-specific cortex in neurosurgerycandidates has been the focus of many clinical and researchstudies [1–4]. Considering the importance of language func-tion, it is not surprising that surgeons are interested inlocating cortical areas responsible for this crucial cognitiveability. Historically, the intracarotid amobarbital proce-dure (Wada test) has served this goal [5,6]. This procedureinvolves unilateral hemispheric anesthetization for a shortperiod. Typical uses of the test include the lateralizationof language abilities and memory function and presurgicalrisk assessment. Direct cortical stimulation is another com-mon method to identify the brain regions mediating lan-

1525-5050/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2006.02.012

* Corresponding author. Fax: +1 205 801 8169.E-mail address: dlee3@alumni.uchicago.edu (D. Lee).

guage functions. This procedure involves direct electricalstimulation of brain tissues either intraoperatively or extra-operatively via implanted subdural electrodes [7,8]. Despitethe ‘‘directness’’ and the usefulness of these procedures,they carry significant risk [9], and the scope of the behav-ioral assessment during these procedures is limited. Nonin-vasive localization of language function, using magneticsource imaging (MSI) and functional magnetic resonanceimaging (fMRI), has many advantages over invasive meth-ods. Noninvasive methods effectively eliminate the morbid-ity (associated with both intracranial mapping and theWada test), do not suffer from validity problems due topossible cross-flow of arterial blood (the Wada test), reduceoperation time, sample the whole brain, and allow test–re-test reliability studies.

There have been reports of good agreement betweenintracarotid amobarbital procedure and fMRI studies of

D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749 743

interhemispheric asymmetries associated with languagefunction [10–12]. Good agreement has also been reportedbetween the Wada test and magnetic source imaging(MSI), a newer functional imaging method based on mag-netoencephalography (MEG) [13–15].

MSI measures changes in magnetic flux produced byintracellular electrical currents in neuronal populationsthat show transient, stimulus-locked increases in neuronalsignaling. The reliability and validity of MSI data for thepurpose of lateralization and localization of cortical areasduring the performance of language tasks have been dem-onstrated in several studies (for a recent review, see [16]). Aprevious study using healthy volunteers demonstrated thatMEG estimates of the location of receptive language-spe-cific cortex (Wernicke’s area) display a very high degreeof intraparticipant–intrasession reproducibility [17].Results suggested that MEG may be a reliable tool fordetermination of hemispheric dominance for language insurgical patients. However, some concerns exist over thesubjectivity of analysis techniques involved in postprocess-ing of MSI data. For MEG language mapping to be usedclinically, it is important to establish its ability to producereliable results for individual patients by different raters. Itis equally important to establish that results are stableacross repeated measurements in realistic environments(e.g., clinical settings). The goal of the present study wasto evaluate the reproducibility of a MEG data acquisition,signal processing, and source modeling approach acrosssuccessive measurements and different raters in a cohortof epilepsy surgery candidates. In addition, measurementerror due to head localization error was left free to varyacross different recording sessions with the same patient.

Table 1Clinical information of participantsa

Patient ID Age Onset Seizure location

S1 40 9 Left anterior temporaS2 27 14 Left frontalS3 43 10 Left frontal/temporaS4 49 42 Left extratemporalS5 12 5 Left centralS6 13 6 Left temporal/frontaS7 35 11 Left temporalS8 38 Childhood Left temporalS9 24 21 Left posterior parietaS10 12 11 Left temporalS11 50 45 Left parietalS12 43 15 Left frontalS13 17 1 Left and right tempoS14 17 8 Left frontal and tempS15 47 41 Left temporalS16 10 5 Right frontotemporaS17 49 45 Right temporalS18 63 8 Left temporalS19 16 15 Left temporalS20 17 5 Left frontotemporalS21 30 14 Right temporal

a SPS, simple partial seizure; CPS, complex partial seizure; GTCS, generaliz

2. Materials and methods

2.1. Participants

Twenty-one epilepsy surgery candidates (10 females, 11 males)performed an auditory recognition task for words. Their averageage was 31.1 ± 16, and except for one patient, they were all right-handed. All patients underwent video/EEG monitoring, structuralMRI, and neuropsychological testing, in addition to the MSI proce-dure. English was the primary language for all patients (Table 1).Patients were asked to sign a consent form before participating inthe study, after the procedures involved had been explained. TheUniversity of Alabama at Birmingham Institutional Review Boardapproved the study.

2.2. Procedures

2.2.1. Stimuli and tasks

The participants were tested on a continuous recognition task for spo-ken words. The same set of 90 abstract English nouns with score of 3.0 orlower on the Paivio Concreteness Scale (1968) [18] was used over two ses-sions. The words were recorded by a native speaker of English with a flatintonation and stored on a Macintosh computer, and they were between300 and 750 ms in duration. During the learning phase, each participantwas presented with a list of 30 target words that they were asked to mem-orize. Target words were presented only once except when the participantscould recall fewer than three words immediately after the initial presenta-tion of the list. MEG recordings were obtained during a subsequent testphase that consisted of six blocks of 40 stimuli (30 targets that repeatedin every block in a different random order and a different set of 10 distrac-tors in each block). Stimuli were presented binaurally at a randomly vary-ing interstimulus interval of 3–4 seconds via long plastic tubes terminatingin ear inserts. A personal computer (eMac running on OS 9) was used topresent the spoken words through the delivery system. The entire record-ing session lasted approximately 35 minutes. Patients were instructed toremain perfectly motionless except when they raised their index finger toindicate that an item was a target word. The use of the right or left indexfinger was counterbalanced across trial blocks for each participant. Short

Hand Seizure type Etiology/pathology

l RH SPS, CPS EpilepsyRH GTCS Epilepsy

l RH SPS, CPS EpilepsyRH CPS, GTCS EpilepsyRH CPS Epilepsy

l RH CPS EpilepsyRH CPS EpilepsyRH CPS, GTCS Epilepsy, MVA

l RH CPS MVARH CPS EpilepsyRH SPS OligodendrogliomaRH CPS, GTCS Epilepsy

ral RH CPS Epilepsyoral LH CPS Epilepsy

RH CPS Epilepsyl RH CPS Epilepsy

RH CPS EpilepsyRH CPS, GTCS EpilepsyRH CPS EpilepsyRH CPS EpilepsyRH CPS Epilepsy

ed tonic–clonic seizure; MVA, motor vehicle accident.

744 D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749

breaks were given between blocks as needed. The entire procedure wasrepeated 15 minutes later in a second recording session using the samestimuli and task, but without repeating the target words for memorization.

2.2.2. MSI recording and analyses

MSI scans were obtained in a magnetically shielded room (Vacuum-schmelze GmbH, Hanau, Germany) with a whole-head neuromagnetom-eter (4D Neuroimaging, Inc., Magnes 2500 WH) that consists of 148axial magnetometer coils placed in a cryogenic container. The signals werefiltered online with a bandpass filter between 0.1 and 50 Hz and digitizedwith a sampling rate of 250 samples per second starting 150 ms before, andcontinuing for 1000 ms after, stimulus onset. The single-trial MEG epochsrecorded during the two sessions of the task were averaged separately,resulting in a single time-series waveform of magnetic flux for each record-ing session and each set of the 148 sensors. Data were processed by tworaters (R1 and R2) familiar with the general procedures for data reductionand analysis proposed by the Houston group [19]. Each rater, however,performed the analyses independently, adopting slightly different strate-gies, and were blind to the other rater’s results. An important differencein the analysis procedures was that Rater 1 performed rigorous epoch-by-epoch rejection of trials that contained eye movement, myogenic, ormechanical artifacts, whereas rater 2 included all epochs in the averageddata. Finally, the averaged epochs were digitally filtered with a bandpassfilter of 1 to 20 Hz to improve signal quality and adjusted relative to themean amplitude in the 150-ms prestimulus period.

The intracranial generators (i.e., activity sources) of the observedevent-related magnetic field records (ERFs) at successive 4-ms intervalswere modeled as moving equivalent current dipoles (ECDs) using a finiteversion of the nonlinear Levenberg–Marquardt algorithm [20]. The spatialcoordinates of each source were computed with reference to the best-fittingsphere, with the radius and the center of the sphere determined by the localcurvature of the subject’s head at the region containing the magnetic fluxextrema. For a given point in time, the source modeling algorithm wasapplied to the magnetic flux measurements obtained from a group of35–40 magnetometers, always including both extrema. Computation ofthe activity sources was restricted to those latency periods during whicha single pair of magnetic flux extrema dominated the left and/or righthalves of the head surface.

Currently, the single-moving-ECD-source model is part of the stan-dard analysis protocol in essentially all clinical applications of MSI. More-over, in a variety of both clinical and research applications, a singleactivity source is sufficient to account for 90–95% of the variance in theERF recorded at a given point following stimulus onset. The localizationaccuracy of the single-ECD model for activity sources reflecting language-specific neurophysiological operations has been found to be excellent whencompared with the results of invasive electrical stimulation mapping stud-ies [21,22]. The algorithm used in this study searched for the activitysource that was most likely to have produced the observed dipolar mag-netic field distribution at a given point. Source solutions were consideredsatisfactory if they were associated with a correlation coefficient of at least0.90 between the observed and best predicted magnetic field distributionsand a confidence volume less than 10 cm3.

The location of activity sources was computed with reference to aCartesian coordinate system defined by the set of three anatomical land-marks (fiduciary points): the right external meatus, the left external mea-tus, and the nasion. Structural MRI scans were obtained on a 1.5-Tscanner (GE, Milwaukee, WI; T1-weighted gradient echo volumetric 3Dacquisition, 1.5-mm thickness). Coregistration of the MEG coordinatesystem onto the MRI scan was performed by visually aligning each fidu-cial point onto the corresponding anatomical landmarks.

The total duration of dipolar magnetic activity in regions commonlybelieved to be part of the brain mechanism that supports receptive lan-guage functions served as an index of the degree of regional neurophysio-logical engagement. Duration was indexed by the total number ofmagnetic activity sources localized in each region during the late portionof the ERF (i.e., between 200 and 800 ms after stimulus onset). In previousstudies with healthy volunteers and patients, this measure produced themost conclusive results as an index of the degree of task-specific regional

cortical engagement [13–15,17,22–24]. As expected from the results of pre-vious studies [7,8,10–15] using the same task and identical recording andanalysis procedures, the vast majority of activity sources were found intemporal and inferior parietal cortices. An interhemispheric asymmetry

index was created for all patients as follows: asymmetry index(AI) = (number of sources in the left hemisphere � number of sources inthe right hemisphere)/total number of sources in both hemispheres. Basedon previous validation studies [19], an AI <�0.1 is considered indicative ofright hemisphere dominance for language functions and an AI >+0.1 isindicative of left hemisphere dominance. Intermediate values suggestbihemispheric representation of language functions.

In a second set of analyses, we focused on the subset of activitysources localized in the posterior portion of the superior temporalgyrus, often extending ventrally into the superior temporal sulcus andcaudally into the supramarginal gyrus. Portions of this region, oftenslightly different ones across patients, correspond to Wernicke’s area.A previous MEG/electrocortical stimulation study [21] indicated thatthis region can be consistently identified by late activity sources thatoccur reliably in both the spatial (as defined by a distance 61 cm)and temporal (as defined by latency overlap 6150 ms) domains acrosssuccessive replications of the task (for a detailed description of themethod for deriving activity source clusters associated with Wernicke’sarea activation, see [19]). Four indices were derived for dipolar sourceslocated in this region: distance, signal strength, correlation, and confi-dence volume.

2.2.2.1. Distance. The position of each ECD with respect to the origin ofthe MEG Cartesian coordinate system was given in x (anterior–posterior),y (mesial–lateral), and z (inferior–superior) coordinates. To obtain a morestable estimate of the geometric center (i.e., centroid) of each ECD cluster,spatial coordinates were averaged across all activity sources constitutingeach cluster, separately for each session and rater. Next, the linear dis-placement (d) of the cluster centroid across raters was computed usingthe formula

d ¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiðx1 � x2Þ2 þ ðy1 � y2Þ

2 þ ðz1 � z2Þ2q

;

where x, y, and z are the mean Cartesian coordinates for eachcluster of activity sources in centimeters, and the subscripts indi-cate separate data sets compiled by each rater.

2.2.2.2. Signal strength. The strength of neurophysiological activity corre-sponding to each ECD was measured by the net global field power (RMS)of the measured magnetic flux in each activity source (in femtotesla, fT).Net RMS values across all consecutive activity sources forming each clus-ter served as estimates of the strength of electromagnetic activity for theduration of the cluster.

2.2.2.3. Correlation and confidence volume. Two indices of the quality ofdipole fitting were assessed: correlation and confidence volume. Thecorrelation coefficient of the dipole fit reflects the statistical similaritybetween the recorded magnetic flux at a given point during the ERFand the magnetic flux values estimated using forward calculations basedon the final (accepted) activity source. To account for an inherentuncertainty in the dipole’s location and orientation, confidence regionswere used. The confidence region contains the most probable set of dipolarcoordinates associated with a 95% confidence value.

3. Results

Asymmetry indices were calculated based on the num-ber of consecutive ECDs localized in temporal and infe-rior parietal regions in each hemisphere. Pearsoncorrelation coefficients for AIs between raters for eachsession and between sessions for each rater are listed inTable 2 (Table 3 lists individual AIs).

Table 4AIs for each patient based on data obtained during the two consecutiverecording sessions

Patient ID Rater 1 Rater 2

Session 1 Session 2 Session 1 Session 2

S1 �0.38 �0.22 �0.32 �0.15S2 0.61 .68 0.56 0.50S3 0.52 0.47 0.32 .44S4 1.00 1.00 1.00 1.00S5 �0.13 �0.04 �0.09 �0.41S6 0.48 0.19 0.85 0.21S7 0.67 0.55 0.70 0.44S8 0.51 0.66 .54 0.79S9 0.52 0.64 0.74 .39S10 �0.17 0.16 �0.13 �0.04S11 �0.50 �0.52 0.51 �0.36S12 0.42 0.25 0.61 0.14S13 0.58 0.15 0.58 0.30S14 �0.01 �0.12 0.02 0.06S15 0.73 0.40 0.73 0.62S16 0.18 0.22 0.09 0.08S17 �0.12 �0.10 �0.72 �0.42S18 0.63 �0.47 0.81 �0.44S19 0.47 0.94 0.64 0.26S20 0.31 0.30 0.08 0.22S21 0.38 0.66 0.76 0.90

Table 3AIs for each patient by two independent raters collapsed across recordingsessionsa

Patient ID Rater 1 Rater 2

S1 �0.28 �0.23S2 0.63 0.53S3 0.49 0.38S4 1.00 1.00S5 �0.09 �0.25S6 0.38 0.59S7 0.59 0.55S8 0.58 0.66S9 0.58 0.54S10 0.00 �0.08S11 �0.52 �0.03S12 0.36 0.42S13 0.34 0.44S14 �0.05 0.04S15 0.60 0.67S16 0.20 0.08S17 �0.11 �0.61S18 �0.27 �0.23S19 0.64 0.47S20 0.31 0.13S21 0.50 0.82

a Criteria for determination of language dominance: �0.1 to0.1 = bilateral, 0.1 to 1.0 = left, and �1.0 to �0.1 = right.

Table 2Intersession and interrater reliability estimates of hemispheric asymmetriesin the duration of neurophysiological activity in temporal and inferiorparietal cortices

Session 1 Session 2 R1 R2

R1–R2 R1–R2 Session 1–session 2 Session 1–session 20.75 0.86 0.69 0.60

D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749 745

When AIs were averaged across sessions, as is customaryfor clinical determinations of hemispheric dominance, theoverall interrater reliability was 0.88 (P < 0.0001). The pro-portions of patients who appeared to be left and right hemi-sphere dominant for language based on rater’s 1 results were67 and 19%, respectively (14% of patients had AIs indicativeof bihemispheric representation of language functions). Cor-responding figures were 62, 19, and 19% for rater 2. Among21 patients, there were three disagreements between raters(cases 5, 11, and 16), which were judged to have bilateral lan-guage representation by one rater and either left or righthemisphere dominance by the other (Table 4). In all threecases, the two raters were in agreement with respect to thedirection of hemispheric asymmetry.

The reliability of four MEG-derived parameters ofactivity in the vicinity of Wernicke’s area within as wellas between raters was also examined: distance, signalstrength, confidence volume, and correlation.

3.1. Distance

The average distance between the centers of the sourceclusters obtained by each rater in the vicinity of Wernicke’s

area (dominant hemisphere) was 0.36 ± 0.32 cm (in casesof bilateral language dominance, the average of the twohemispheres was used). For R1, the average distancebetween the centroids of the source clusters in Wernicke’sarea across sessions was 0.75 ± 0.49 cm, and for the mag-netic source maps obtained by R2, 0.72 ± 0.43 cm (Fig. 1).

3.2. Signal strength

The net RMS value for the cluster of activity sourcescomputed in Wernicke’s area by R1 was 121 ± 38, andin the analysis performed by R2, it was 128 ± 43 fT.Table 5 lists average net RMS values across sessions andraters. Corresponding correlation indices are also listed inTable 6. The overall interrater reliability (data collapsedacross sessions) was 0.91 (P < 0.0001).

3.3. Confidence volume

The mean 95% confidence volume for Wernicke’s areasource clusters (dominant hemisphere) was 0.40 ± 0.38and 0.47 ± 0.78 cm3 for R1 and R2, respectively. Meanconfidence volumes for each session were 0.43 and0.37 cm3 for R1 and 0.46 and 0.47 cm3 for R2.

3.4. Correlation

The mean correlation coefficient indices reflecting thequality of dipole fit across sessions were 0.96 ± 0.012 forR1 and 0.96 ± 0.013 for R2, indicating that the computeddipolar solutions accounted for more than 90% of the var-iance in the recorded magnetic flux at each time point.

Fig. 1. Clusters of magnetic activity sources in the posterior portion of the superior temporal gyrus in a representative participant, demonstratinginterrater differences in source localization. White circles and gray squares represent activity sources obtained by R1 and R2, respectively.

Table 5Inter- and intrarater reliability for the dominant hemisphere: summary statistics

Interrater reliability (R1 vs R2) Intrarater reliability (sessions 1 & 2)

R1 R2

Distance (cm) 0.36 0.75 0.72Signal strength (fT) 121 vs 128 121 & 121 132 & 125Confidence volume (cm3) 0.40 vs 0.47 0.43 & 0.37 0.46 & 0.47Correlation (r) 0.96 vs 0.96 0.96 & 0.96 0.96 & 0.96

Table 6Intersession and interrater reliability estimates for net RMS in the vicinityof Wernicke’s area

Session 1 Session 2 R1 R2

R1–R2 R1–R2 Session 1–session 2 Session 1–session 20.81 0.92 0.72 0.67

746 D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749

4. Discussion

MEG data collected from 21 epilepsy surgery candidateswere used to examine the reliability of a closely superviseddata analysis protocol designed to provide estimates ofhemispheric dominance and estimates of the location ofWernicke’s area in the dominant hemisphere. Two separate

sessions of an auditory word recognition task were admin-istered to each patient, and each data set was analyzedindependently by two neurophysiologists. Interrater reli-ability coefficients ranged from 0.88 for hemispheric asym-metry indices in the duration of language-related activity to0.91 for the strength of magnetic activity originating inWernicke’s area. Test–retest reliability indices ranged from0.60 to 0.69 for different experts with respect to the formermeasure and were slightly higher (0.67–0.72) for the lattermeasure.

Previous studies have investigated the reproducibility ofMEG-derived indices of language dominance and of thelocation of Wernicke’s area within the same recordingsession as determined by the same neurophysiologistand under optimized testing conditions [13,17,20]. It is

D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749 747

important to note that the two neurophysiologists in thepresent study used slightly different approaches to deriveregional activation maps. For instance, rater 1 performedrigorous epoch rejection prior to averaging, whereas rater2 included all recorded epochs in the averaging. Such differ-ences may, in part, explain the observed discrepanciesbetween experts. Establishing acceptable rates of interrateragreement is essential, especially in view of the existingcontroversies over the subjectivity of analysis methods infunctional neuroimaging studies. The present results addfurther support to the robustness of the language mappingprotocol using a spoken word recognition task to evokebrain activity in receptive language-related areas and a seriesof temporally contiguous ECDs to model underlying neuro-physiological activity. Evidence that this protocol can besuccessfully applied to presurgical determination of hemi-spheric dominance has been obtained independently in atleast two patient series in Houston and Madrid [15,19].

During the first 150–200 ms after stimulus onset, activitysources were localized in the vicinity of the primary audito-ry cortex without consistent hemispheric differences. Thisearly activity was considered to be associated with primarysensory processing of the word stimuli. Late activity sourc-es were localized predominantly in the posterior part of thesuperior and middle temporal gyri and the supramarginalgyrus. Involvement of superior temporal cortex during per-formance of both expressive and receptive language taskshas been consistently demonstrated in PET [25–27] andfMRI [28,29] studies. Activation of the middle temporalgyrus has also been reported in numerous neuroimagingstudies [16,30,31]. In addition to the lateral temporalregion, activation of medial temporal aspects of the tempo-ral lobe (MTL), in the vicinity of the hippocampus andparahippocampal gyrus, was also observed in severalpatients. This finding can be explained by the recognitionmemory requirement imposed by the task. Involvementof the MTL in tasks that require encoding and retrievalof episodes has been suggested by lesion, invasive electro-physiological, and neuroimaging studies [32–37].

The close interrater and intersession agreement regard-ing the anatomical location of the center of the magneticsource clusters in temporal/temporoparietal cortex is ofparticular importance as a prerequisite for localizationaccuracy of our functional brain mapping protocol. Dif-ferences in this estimate between raters, as well as betweensessions (for both raters), were in all cases smaller than1 cm, which, incidentally, corresponds to the spatial reso-lution limit of the ‘‘gold standard’’ in functional brainmapping, invasive electrocortical stimulation. Consideringthe complexity of receptive language function and thewidespread functional anatomical map, this outcome issurprisingly reliable. Statistical estimates of localizationaccuracy were also within this range, as indicated by con-fidence volume estimates for activity sources in Wer-nicke’s area lower than 0.5 cm3. In contemplating theuse of language mapping information on presurgicalpatients with epilepsy, the volume of the tissue is of inter-

est to the neurosurgeon. When dipolar activity sources,each represented by a single point in space, are overlaidon a structural magnetic resonance image, the apparentlocation of the source could be misleading if associatedconfidence volumes are large.

The mean displacement of the center of the activitysource clusters in the vicinity of Wernicke’s area found inthe present study is almost identical to the figure reportedin a previous investigation using the same task and analysisprocedures with healthy volunteers (0.75 cm in the presentstudy and 0.8 cm in Simos et al. [38]). The agreementbetween studies is especially important considering the factthat between-session displacement of the source clusters inthe present study incorporated head localization error.Although a single set of head position estimates wereobtained for both recording sessions in the Simos et al.’sstudy [38], head position estimates were independentlyobtained for each recording session in the present study.The contribution of head position localization error toactivity source localization estimates can be as high as4 mm [39]. It is also important to note that reliability esti-mates were obtained in the present study under realistictesting conditions, namely, in the course of regular clinicalevaluations in a consecutive series of 21 epilepsy patients.Given that the fidelity of recorded data can be significantlyaffected under these conditions by a variety of factors,including patient movement during head digitization, mag-netic noise during MEG data acquisition introduced byhead motion, scalp electrodes for simultaneous EEGrecording, and frequent interictal activity, the reliabilityestimates obtained in the present study are particularlynoteworthy.

A complementary and more direct index of the magni-tude of regional neurophysiological activity, namely, globalfield power (RMS) for the cluster of activity sources in tem-poroparietal cortex, also showed excellent stability bothbetween sessions and between raters. Thus, mean interses-sion differences obtained in the present study were 3.05 fTfor rater 1 and 6.1 fT for rater2, corresponding to less than5% of net RMS, a value that compares favorably with theestimate of less than 2% obtained in a previous study withhealthy volunteers under optimized testing conditions.

A final issue that deserves discussion concerns individualvariability on AI scores. The reported incidence of lefthemisphere dominance among all patients undergoingintracarotid amobarbital procedure ranges across studiesfrom 63 to 96% for right-handers and from 48 to 75% forleft-handed and ambidextrous patients [40,41]. In the cur-rent study, as many as seven patients were judged to haveatypical hemispheric dominance. Clinical studies suggestthat the incidence of atypical representation of languagefunctions is even higher among patients with early lefthemisphere lesions [40]. With the exception of one patient,all of the patients in the present study who showed evidenceof atypical hemispheric dominance had a seizure focus inthe left hemisphere, and five of six of the remaining patientshad seizure onset in childhood. Interestingly, the patient

748 D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749

with presumed bilateral representation of language func-tions and right hemisphere seizure focus had seizure onsetin adulthood.

To summarize, the current study demonstrates excellentinterrater and good test–retest reliability for four MEG-de-rived indices of regional language-specific activity support-ing the potential utility of MEG as a noninvasive languagemapping tool that may replace or reduce the need forextended invasive language mapping in neurosurgery. Itis particularly noteworthy that good concordance wasobtained across centers, even with slightly different analysiscriteria adopted by different neurophysiologists. This,however, also highlights the need for standardization ofanalysis and interpretation procedures to facilitate imple-mentation of the technique by more imaging centersworldwide. An unsupervised analysis protocol, whichincorporates artifact rejection, contour map selection,dipole fitting, and computation of a laterality index for lan-guage-related activity, is in the final stages of testing, andpreliminary data indicate good concordance with manualuser-guided procedures, such as those described in the cur-rent study.

Acknowledgment

This research was supported in part by a grant from theEpilepsy Foundation of America to D. Lee.

References

[1] Hickok G, Poeppel D. Dorsal and ventral streams: a framework forunderstanding aspects of the functional anatomy of language.Cognition 2004;92:67–99.

[2] Kho KH, Leijten FS, Rutten GJ, et al. Discrepant findings for Wadatest and functional magnetic resonance imaging with regard tolanguage function: use of electrocortical stimulation mapping toconfirm results [case report]. J Neurosurg 2005;102:169–73.

[3] Pataraia E, Billingsley-Marshall RL, Castillo EM, et al. Organiza-tion of receptive language-specific cortex before and after lefttemporal lobectomy. Neurology 2005;64:481–7.

[4] Sabsevitz DS, Swanson SJ, Hammeke TA, et al. Use of preoperativefunctional neuroimaging to predict language deficits from epilepsysurgery. Neurology 2003;60:1788–92.

[5] Loring DW, Meador KJ, Lee GP, et al. Cerebral language lateral-ization: evidence from intracarotid amobarbital testing. Neuropsych-ologia 1990;28:831–8.

[6] Wada J, Rasmussen T. Intracarotid injection of sodium amytal forthe lateralization of cerebral speech dominance: experimental andclinical observations. J Neurosurg 1960;17:266–82.

[7] Luders H, Lesser RP, Hahn J, et al. Basal temporal language areademonstrated by electrical stimulation. Neurology 1986;36:505–10.

[8] Ojemann GA. Functional mapping of cortical language areas inadults: intraoperative approaches. Adv Neurol 1993;63:155–63.

[9] Dion JE, Gates PC, Fox AJ, et al. Clinical events followingneuroangiography: a prospective study. Stroke 1987;18:997–1004.

[10] Aldenkamp AP, Boon PA, Deblaere K, et al. Usefulness oflanguage and memory testing during intracarotid amobarbitaltesting: observations from an fMRI study. Acta Neurol Scand2003;108:147–52.

[11] Gaillard WD, Balsamo L, Xu B, et al. fMRI language task panelimproves determination of language dominance. Neurology2004;63:1403–8.

[12] Spreer J, Arnold S, Quiske A, et al. Determination of hemispheredominance for language: comparison of frontal and temporal fMRIactivation with intracarotid amytal testing. Neuroradiology 2002;44:467–74.

[13] Breier JI, Simos PG, Zouridakis G, et al. Language dominancedetermined by magnetic source imaging: a comparison with the Wadaprocedure. Neurology 1999;53:938–45.

[14] Breier JI, Simos PG, Wheless JW, et al. Language dominance inchildren as determined by magnetic source imaging and theintracarotid amobarbital procedure: a comparison. J Child Neurol2001;16:124–30.

[15] Maestu F, Ortiz T, Fernandez A, et al. Spanish language mappingusing MEG: a validation study. NeuroImage 2002;17:1579–86.

[16] Billingsley-Marshall RL, Simos PG, Papanicolaou AC. Reliabilityand validity of functional neuroimaging techniques for identifyinglanguage-critical areas in children and adults. Dev Neuropsychol2004;26:541–63.

[17] Breier JI, Simos PG, Zouridakis G, Papanicolaou AC. Lateralizationof activity associated with language function using magnetoenceph-alography: a reliability study. J Clin Neurophysiol 2000;17:503–10.

[18] Paivio A, Yuille JC, Madigan SA. Concreteness, imagery, andmeaningfulness valuses for 925 nouns. J Exp Psychol Monogr1968;76:1–25.

[19] Papanicolaou AC, Simos PG, Castillo EM, et al. Magnetoencephalog-raphy: a noninvasive alternative to the Wada procedure. J Neurosurg2004;100:867–76.

[20] Sarvas J. Basic mathematical and electromagnetic concepts of thebiomagnetic inverse problem. Phys Med Biol 1987;32:11–22.

[21] Simos PG, Breier JI, Maggio WW, et al. Atypical temporal lobelanguage representation: MEG and intraoperative stimulation map-ping correlation. Neuroreport 1999;10:139–42.

[22] Simos PG, Breier JI, Wheless JW, et al. Brain mechanisms forreading: the role of the superior temporal gyrus in word andpseudoword naming. Neuroreport 2000;11:2443–7.

[23] Szymanski MD, Perry DW, Gage NM, et al. Magnetic sourceimaging of late evoked field responses to vowels: toward anassessment of hemispheric dominance for language. J Neurosurg2001;94:445–53.

[24] Simos PG, Breier JI, Zouridakis G, Papanicolaou AC. Assessment offunctional cerebral laterality for language using magnetoencephalog-raphy. J Clin Neurophysiol 1998;15:364–72.

[25] Demonet JF, Chollet F, Ramsay S, et al. The anatomy of phono-logical and semantic processing in normal subjects. Brain1992;115(Pt. 6):1753–68.

[26] Meyer PT, Sturz L, Schreckenberger M, et al. Preoperative mappingof cortical language areas in adult brain tumour patients using PETand individual non-normalised SPM analyses. Eur J Nucl Med MolImaging 2003;30:951–60.

[27] Price CJ, Wise RJ, Watson JD, et al. Brain activity during reading:the effects of exposure duration and task. Brain 1994;117:1255–69.

[28] Binder JR, Frost JA, Hammeke TA, et al. Human brain languageareas identified by functional magnetic resonance imaging. J Neurosci1997;17:353–62.

[29] Seghier ML, Lazeyras F, Pegna AJ, et al. Variability of fMRIactivation during a phonological and semantic language task inhealthy subjects. Hum Brain Mapp 2004;23:140–55.

[30] Binder JR, Frost JA, Hammeke TA, et al. Function of the leftplanum temporale in auditory and linguistic processing. Brain1996;119:1239–47.

[31] Dronkers NF, Wilkins DP, Van Valin Jr RD, et al. Lesion analysisof the brain areas involved in language comprehension. Cognition2004;92:145–77.

[32] McCarthy G, Nobre AC, Bentin S, Spencer DD. Language-relatedfield potentials in the anterior-medial temporal lobe: I. Intracranialdistribution and neural generators. J Neurosci 1995;15:1080–9.

[33] Okada YC, Kaufman L, Williamson SJ. The hippocampal formationas a source of the slow endogenous potentials. ElectroencephalogrClin Neurophysiol 1983;55:417–26.

D. Lee et al. / Epilepsy & Behavior 8 (2006) 742–749 749

[34] Smith ME, Stapleton JM, Halgren E. Human medial temporal lobepotentials evoked in memory and language tasks. ElectroencephalogrClin Neurophysiol 1986;63:145–59.

[35] Squire LR. Mechanisms of memory. Science 1986;232:1612–19.

[36] Stern CE, Corkin S, Gonzalez RG, et al. The hippocampal forma-tion participates in novel picture encoding: evidence from functionalmagnetic resonance imaging. Proc Natl Acad Sci USA1996;93:8660–5.

[37] Tesche CD, Karhu J, Tissari SO. Non-invasive detection of neuronalpopulation activity in human hippocampus. Brain Res Cogn BrainRes 1996;4:39–47.

[38] Simos PG, Sarkari S, Castillo EM, et al. Reproducibility of measuresof neurophysiological activity in Wernicke’s area: a magnetic sourceimaging study. Clin Neurophysiol 2005;116:2381–91.

[39] Knowlton RC, Laxer KD, Aminoff MJ, Roberts TP, Wong ST,Rowley HA. Magnetoencephalography in partial epilepsy: clinicalyield and localization accuracy. Ann Neurol 1997;42:622–31.

[40] Rasmussen T, Milner B. The role of early left-brain injury indetermining lateralization of cerebral speech functions. Ann NYAcad Sci 1977;299:355–69.

[41] Risse GL, Gates JR, Fangman MC. A reconsideration of bilaterallanguage representation based on the intracarotid amobarbitalprocedure. Brain Cogn 1997;33:118–32.