Epilepsy & Behavior 13 (2008) 350–356

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Epilepsy & Behavior

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Functional MRI and Wada studies in patients with interhemisphericdissociation of language functions

Dongwook Lee *, Sara J. Swanson, David S. Sabsevitz, Thomas A. Hammeke,F. Scott Winstanley, Edward T. Possing, Jeffrey R. BinderDepartment of Neurology and the Comprehensive Epilepsy Center, Medical College of Wisconsin, Milwaukee, WI, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 3 March 2008Revised 10 April 2008Accepted 11 April 2008Available online 27 May 2008

Keywords:Language dissociationLanguage mappingFunctional magnetic resonance imagingWada testIntracarotid amobarbital testEpilepsyInterhemispheric dissociationDiscordance

1525-5050/$ - see front matter � 2008 Elsevier Inc. Adoi:10.1016/j.yebeh.2008.04.010

* Corresponding author. Address: Department of NWisconsin, 9200 West Wisconsin Avenue, Milwaukee259 9012.

E-mail address: dolee@mcw.edu (D. Lee).

Rare patients with chronic epilepsy show interhemispheric dissociation of language functions on intra-carotid amobarbital (Wada) testing. We encountered four patients with interhemispheric dissociationin 490 consecutive Wada language tests. In all cases, performance on overt speech production taskswas supported by the hemisphere contralateral to the seizure focus, whereas performance on compre-hension tasks was served by the hemisphere with the seizure focus. These data suggest that speech pro-duction capacity is more likely to shift hemispheres than is language comprehension. Wada and fMRIlanguage lateralization scores were discordant in three of the four patients. However, the two methodsaligned more closely when Wada measures loading on comprehension were used to calculate lateraliza-tion scores. Thus, interhemispheric dissociation of language functions could explain some cases of discor-dance on Wada/fMRI language comparisons, particularly when the fMRI measure used is not sensitive tospeech production processes.

� 2008 Elsevier Inc. All rights reserved.

1. Introduction ation) to reflect ‘‘expressive” linguistic capacities, whereas

Measurement of language lateralization, using either the intra-carotid amobarbital (Wada) test or functional magnetic resonanceimaging (fMRI), is a routine part of the presurgical evaluation ofpatients with intractable epilepsy. Knowledge about languagedominance can be useful for predicting cognitive morbidity fromsurgery. Patients with epilepsy have a higher incidence of atypicallanguage representation than the healthy population [1–3]. Manyfactors are known to influence language lateralization. The roleof early brain injury in language reorganization is well documented[1–6]. Location of the seizure focus, seizure frequency, size of brainlesion, and handedness also influence language reorganization andshifting of language abilities [7–11].

Although atypical language representation is not uncommonamong patients with chronic epilepsy, a strong difference in later-alization between different language skills is rare. Kurthen at al.[12] reported four cases of dissociation of language functions dur-ing Wada testing among 144 patients. These authors consideredcounting backward; speech production on tasks of naming, repeti-tion, and reading; and dysphasic errors (paraphasias and persever-

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eurology, Medical College of, WI 53226, USA. Fax: +1 414

comprehension of spoken commands and questions was used toassess ‘‘receptive” language functions. Their findings demonstratedthat in rare cases, the expressive language system can be located inone hemisphere and receptive language ability in the other. In astudy examining bilateral language representation among patientswith epilepsy, Risse and co-authors [2] mentioned that they foundonly two patients among more than 500 Wada studies whose re-sults suggested interhemispheric dissociation of language skills.The Wada test used by these authors assessed automatic speech,naming, reading, and auditory comprehension. Dissociations intheir two patients reportedly reflected differential lateralizationon comprehension and overt speech production tasks. No furtherinformation is available about these patients because neither metcriteria for inclusion in the study.

Although the Wada test has been the gold standard for manyyears for assessing language dominance, fMRI has recentlyemerged as a viable noninvasive alternative to the Wada. Manystudies have examined the degree of concordance between thesemethods. Although several initial studies with small patient sam-ples reported 100% concordance [13–20], more recent, larger seriesshow discordance rates in the range of 5–25% [21–24]. The degreeof discordance varies depending on region of interest (e.g., frontalvs temporal) over which the lateralization measure is computed,methods used to determine laterality (e.g., placement of cutoffscores), seizure location (e.g., temporal vs extratemporal),

D. Lee et al. / Epilepsy & Behavior 13 (2008) 350–356 351

language (e.g., semantic judgment vs fluency), and control/contrasttasks (perceptual controls vs rest) employed during fMRI, and theWada language tasks used.

Discrepancies between Wada and fMRI could arise from severalfactors, as each test has potential methodological limitations. Thevalidity of the Wada test can be compromised by obtundation,insufficient anesthetization, interhemispheric arterial crossflow,and the relatively brief period available for testing. FunctionalMRI results can be affected by head motion, insufficient statisticalpower due to inadequate number of trials or image volumes [25],and poor task compliance. Functional MRI procedures also mustbe carefully designed to activate a wide range of language pro-cesses yet avoid activation of nonlanguage systems (e.g., attention,low-level audition, or vision) engaged by the language task(s).Functional MRI and Wada are fundamentally different in that oneis an activation method and the other is a transient ‘‘lesion” para-digm. Discrepancies could thus arise when the fMRI lateralizationscore reflects activation that is not essential for performance.

Discordance might also arise when the fMRI protocol does notexamine the same set of language processes assessed during Wadatesting. During the Wada procedure, each hemisphere is tested onmultiple language tasks (i.e., comprehension, naming, repetition,and reading), whereas fMRI protocols often use a single task or taskcontrast. Functional MRI protocols may thus be more sensitive tosome language processes than others. Given this difference be-tween the two techniques, discordance could arise in some casesas a result of differential lateralization of certain language capaci-ties (e.g., speech production) relative to others (e.g., language com-prehension). In such cases, the Wada lateralization score would bemore likely to show bilateral language representation, whereasfMRI might suggest a more lateralized language system becauseof inability to detect particular language components.

We describe four patients who showed clear interhemisphericdissociation of language functions on Wada testing. For these pa-tients, one type of language task (either production or comprehen-sion) was supported exclusively by one hemisphere, whereas theother type was supported by the opposite hemisphere. All four pa-tients underwent fMRI language mapping to determine if patientswith this pattern of bilateral language would show discordance be-tween Wada and fMRI and to examine several hypotheses aboutthe underlying reason for this discordance. This study providesthe first fMRI data on patients with clear signs of interhemisphericdissociations in language functions.

2. Methods

2.1. Patient selection and Wada testing

The patients were selected from 490 consecutive adults who underwent com-prehensive evaluation for surgical treatment of medically intractable epilepsy. Ofthis sample, 269 patients underwent both Wada and fMRI tests, including all 4 ofthe patients described in this article. In addition to fMRI, the presurgical evaluationfor epilepsy included long-term video/EEG monitoring, neuropsychological testing,structural brain MRI, and a standardized Wada test. The Wada procedure was sim-ilar to that described by Loring et al. [5] and was described in detail elsewhere[14,16]. Baseline testing of memory and language was conducted 2 hours beforethe Wada test. Internal carotid artery angiograms were obtained and inspectedfor any vascular abnormalities prior to Wada testing. With the patient in a supineposition with arms outstretched, 75 to 100 mg of sodium amobarbital was injectedby hand over a 4- to 5- second interval into the internal carotid artery while the pa-tient counted aloud by ones. The side of suspected seizure focus was injected first.Simultaneous EEG recording was conducted during the procedure to monitor theonset and cessation of slowing in the injected hemisphere. If contralateral flaccidhemiplegia was not present, an additional 25-mg bolus of amobarbital was injected.Counting, comprehension, naming, repetition, and reading were scored based onthe number of correct responses. Counting scores were based on a rating of count-ing disruption at the initiation of the Wada test. Comprehension was assessed usinga modified token task and the ability to follow two simple midline commands(‘‘touch your nose” and ‘‘stick out your tongue”). Naming was assessed by havingthe patient name objects and portions of objects pictured in line drawings. Repeti-

tion was assessed by asking the patient to repeat three phrases of varying difficulty.Patients were asked to read two sentences aloud for assessment of reading. Thesetasks were then repeated during the period of hemianesthesia until the patient per-formed at baseline level. Only trials presented prior to return of motor function inthe contralateral upper extremity were scored. A rating of paraphasic errors wasalso included in the scoring, based on the total number of semantic or phonemicparaphasic errors that occurred during the language assessment. Approximately30 minutes after the first injection, the identical procedure was repeated on thecontralateral hemisphere. A Wada laterality index (Wada LI) was calculated for eachpatient as the difference between the percentage of correct responses during anes-thetization of the right hemisphere (WL, test left condition) and the percentage ofcorrect responses during anesthetization of the left hemisphere (WR, test right con-dition). This approach yields LIs ranging between +100 (strong left hemispheredominance) and �100 (strong right hemisphere dominance). Wada LI calculationswere performed by a neuropsychologist blind to the fMRI results.

In addition to an overall Wada LI, separate lateralization indexes were calcu-lated using tasks that load heavily on either speech production (LIsp) or compre-hension (LIc). The speech production LI was computed using performance oncounting, naming, and repetition. Reading was not included because motor returnoften occurred before reading was assessed. The LIc was computed based on perfor-mance of midline commands and the modified token test. Although all of thesetasks make demands on a variety of language-specific processes (e.g., lexical,semantic, and phonological) as well as on various general-purpose processes (e.g.,sensory, attention, working memory, response selection), this grouping provides arelatively clear separation between tasks that make strong demands on overtspeech production without strong demands on comprehension, and vice versa.Additionally, the grouping was chosen because this is the only type of interhemi-spheric dissociation that was observed in our sample. Patients with clear signs ofinterhemispheric dissociation between these factors were then selected based onthe LIsp and LIc measures. Four of the 490 patients studied showed a clear dissoci-ation, with intact comprehension and impaired speech production during one injec-tion and the opposite pattern during the other injection.

2.2. Functional MRI image acquisition

MRI studies were conducted on a 1.5-T GE Signa scanner (GE Medical, Milwau-kee, WI, USA) using a three-axis local gradient coil and insertable transmit/receiveradiofrequency coil (Medical Advances, Milwaukee, WI, USA). Functional MRI useda gradient echo, echo-planar sequence (TE 40 ms, TR 3000–4000 ms, field of view24 cm, matrix 64 � 64, and slice thickness 7–8 mm). Functional slices were ac-quired in the sagittal plane, with 14 to 21 contiguous slices covering the wholebrain. High-resolution, T1-weighted anatomical reference images were obtainedas a set of 124 contiguous sagittal slices using a three-dimensional spoiled-gradi-ent-echo sequence.

2.3. Functional MRI activation tasks

Stimuli used for the fMRI protocol were tones and auditory words presentedbinaurally using a computer playback system. The protocol used a block designwith alternation between a semantic decision task and a tone decision task, detailsof which were described previously [14,26]. Briefly, patients heard trains of three toseven tones in the tone decision (control) task. Each tone had a frequency of either500 or 750 Hz. Patients were instructed to press a button for any train containingtwo high-pitch (750-Hz) tones. In the semantic decision task, patients heard spokenEnglish nouns designating animals (e.g., ‘‘chicken”) and responded according tospecified semantic criteria. Target words were animals that are both ‘‘found inthe United States” and ‘‘used by humans.” The two tasks were matched for stimulusintensity, average stimulus duration, average trial duration, and frequency of posi-tive targets. The semantic decision–tone decision contrast is thought to highlightactivation in speech perception, phonological word-form, semantic memory, andlexical–semantic retrieval systems, as well as language-specific working memorycomponents. This fMRI protocol produces strongly left-lateralized frontal, temporal,and parietal lobe activation in most right-handed [3] and non-right-handed [27]people. The degree of lateralization is highly correlated with Wada language later-alization [14] and predicts language outcome in patients undergoing left temporallobe resection [28].

2.4. Functional MRI data analysis

All analyses were performed at the individual subject level. Image volumeswere registered to minimize effects of head motion. Identification of event-relatedMRI signal changes was performed using multiple regression implemented in AFNI[29]. Task regressors were derived by convolving a boxcar function representing thetask block alternation with a canonical hemodynamic response function. Otherregressors modeled head motion and linear and second-order trends. Correlationmaps were thresholded at voxelwise P < 0.001 and a minimum cluster size of200 ll to give a whole-brain corrected P < 0.05 as determined by Monte-Carlo sim-ulation (AlphaSim in AFNI). The same thresholding was applied to each patient.Activation volumes were determined in each patient by counting the voxels in each

FMRI vs. Wada LIs

-100

-50

0

50

100

-100 -50 0 50 100

Wada

FM

RI

LI

LIc

LIsp

S1

S3

S4

S2

Fig. 1. Concordance and discordance between Wada and fMRI LI indices. LI, TotalWada Laterality Index; LIc, Wada Laterality Index—comprehension; Lisp, Wada L-aterality Index— speech production.

352 D. Lee et al. / Epilepsy & Behavior 13 (2008) 350–356

hemisphere that passed the threshold. Region-of-interest (ROI) volumes were de-fined based on the average left hemisphere activation map from 80 normal, right-handed subjects [27,30]. Mirror-image right hemisphere ROIs were created byreflecting these volumes symmetrically across the midline. The following ROIs werecreated: frontal (lateral and medial frontal areas), temporoparietal (lateral andmedial temporal areas and parietal areas, mainly angular gyrus), and whole hemi-sphere (combining all individual ROIs). Functional MRI LIs were calculated for eachpatient for each of these three ROIs, using the formula ([VL – VR] / [VL + VR]) � 100,where VL and VR are activation volumes for the homologous left and right ROIs. Thisapproach yields fMRI LIs ranging between +100 (strong left hemisphere dominance)and �100 (strong right hemisphere dominance). Following previous precedent[3,27], LI values >20 were considered left hemisphere language dominant, LIsbetween �20 and +20 were considered bilateral/symmetric, and LIs <�20 were con-sidered right hemisphere dominant. Functional MRI LIs were calculated using auto-mated scripts by an investigator blinded to the Wada results. Reliability of the fMRIprotocol has been previously explored [26,31,32]. Test–retest comparisons (withinand across sessions) showed good reproducibility of both activation patterns andlaterality indexes.

3. Results

Demographic and relevant epilepsy-related information for thefour patients is summarized in Table 1. The differences betweenWada LIs and fMRI LIs (absolute values) were relatively large forthree patients (discordant cases: S1 = 93, S2 = 43, and S3 = 113),whereas the difference for the remaining patient was relativelysmall (concordant case: S4 = 14). Both S1 and S2 had Wada LIsshowing relatively symmetric language representation (S1: �16,S2: +10) and had fMRI LIs showing clear left dominance (S1: +77,S2: +53). S3 showed a different pattern of discordance, with weakleft dominance on Wada (+49) and strong right dominance on fMRI(�64) (see Fig. 1).

Among the discordant patients, S1 and S2 had seizures originat-ing in the left hemisphere, and language comprehension wasclearly represented in the left hemisphere on Wada testing;whereas S3 had right hemisphere seizures, and language compre-hension was strongly represented in the right hemisphere (Table2). When only comprehension components of the Wada test wereconsidered, language dominance on Wada testing more closelyaligned with the lateralization based on whole-hemisphere fMRIin all three discordant patients (Fig. 1). For S4, the comprehensioncomponent of the Wada test was less concordant with fMRI thanthe full Wada test.

To further examine the possible relationship between regionalfMRI activation patterns in anterior and posterior language areasand interhemispheric dissociation in language functions on Wadatesting, two ROI-based fMRI LIs (frontal and temporoparietal) werealso calculated. It was hypothesized that fMRI activation in thetemporoparietal region might be closely associated with the hemi-sphere serving language comprehension on Wada testing and thatfMRI activation in the frontal lobe might be associated with thehemisphere serving speech production. As seen in Table 2, the fMRILIs based on activation of the whole hemisphere and frontal andtemporoparietal regions were all similar to each other. For all ofthe discordant patients, the fMRI LIs agreed with Wada languagelateralization based on language comprehension rather than lan-guage production, regardless of the region on which the fMRI LIwas based. (See Fig. 2)

Table 1Demographic and epilepsy-related informationa

Patient Etiology Onset of epilepsy Epilepsy duration

S1 Idiopathic 9 37S2 Idiopathic Birth 31S3 Encephalitis 25 27S4 Idiopathic 14 20

a TLE, temporal lobe epilepsy; HA, hippocampal atrophy; PO Enc, parietal-occipitalInventory (right-handed: laterality quotient >50) [59].

4. Discussion

Epilepsy surgery candidates provide a unique opportunity toexamine the effects of a chronic focal abnormality on the cere-bral organization of language. It is well documented that pa-tients with early left hemisphere lesions, particularly non-right-handed patients, have a higher incidence of atypical (right orbilateral) representation of language functions. Atypical languagerepresentation is estimated to occur in 5 to 53% of right-handedepilepsy patients [1–3,7,33], whereas the incidence of atypicallanguage representation in the healthy right-handed populationis approximately 4–6% [3,11,34,35]. Prior reports of Wada lan-guage testing in large patient cohorts have noted rare cases withqualitatively different language abilities in the left and righthemispheres. Following the traditional distinction between‘‘expressive” and ‘‘receptive” language abilities, most of these pa-tients have been described as having interhemispheric dissocia-tion between speech production and comprehension abilities[2,12]. The most common pattern involves arrest of speech out-put on a variety of tasks (e.g., counting, naming, reading aloud,and repetition), with relatively preserved ability to follow com-mands after injection of one hemisphere, and the opposite pat-tern on injection of the other hemisphere. We observed thispattern in only 4 of 490 patients, consistent with two prior re-ports showing a combined incidence of 6 in more than 644 cases[2,12]. Although relatively rare, these patients provide an oppor-tunity to understand factors that influence language reorganiza-tion in chronic brain disease.

Seizure focus Dominant hand MRI Full Scale IQ

L TLE R L HA 116Left R L HA 80R TLE L R PO Enc 109L TLE R Normal 87

encephalomalacia. Handedness was determined using the Edinburgh Handedness

Table 2Wada and fMRI lateralization indicesa

Wada LI fMRI LI Wada LI – fMRI LI (absolute value)

Patient LI LIc Lisp Whole Frontal Temporo-parietal

S1 �16 80 �66 77 84 67 93S2 10 80 �35 53 56 43 43S3 49 �100 88 �64 �79 �24 113S4 �33 80 �70 �19 �21 �40 14

a LI, Total Laterality Index; LIc, Laterality Index—comprehension; LIsp, Laterality Index—speech production.

Fig. 2. FMRI activation map for each patient. Symmetric, sequential sagittal slices are shown. Activation maps were thresholded at uncorrected P < 0.001 and a minimumcluster size of 200 ll to give a whole-brain corrected P < 0.05. The images are presented as sequential sagittal slices from lateral to medial at regular 10-mm intervals. For eachpatient, the upper row shows left hemisphere sections, and the bottom row shows mirror-symmetric right hemisphere sections.

D. Lee et al. / Epilepsy & Behavior 13 (2008) 350–356 353

354 D. Lee et al. / Epilepsy & Behavior 13 (2008) 350–356

Our patients had several notable features that may offer preli-minary clues to the presumed reorganization in language functionsthat occurred. First, all had had seizures for more than 20 yearsprior to Wada testing (average duration of 28 years). Although epi-lepsy of long duration is common among patients in surgical pro-grams (the average duration in our entire sample isapproximately 20 years), the fact that interhemispheric dissocia-tion of speech production and comprehension networks was notobserved in patients with shorter-duration epilepsy suggests thatit may be more likely in patients with longstanding epilepsy. Sec-ond, three of the four patients had seizures begin relatively late indevelopment (ages 9, 14, and 25), suggesting that interhemisphericseparation of production and comprehension processes may bemore likely to occur after language lateralization has been estab-lished in earlier years. Third, the three patients whose languagecomprehension was represented in the left hemisphere (S1, S2,and S4) were all right-handed and had seizure foci in the left hemi-sphere. Evidently, the presence of seizures in the temporal lobe re-sulted in a rightward shift of speech production processes, whilelanguage comprehension processes remained in the left hemi-sphere. In contrast, S3 showed right dominance for language com-prehension, was left-handed (with a left-handed father), and had aright hemisphere seizure focus. We speculate that S3 was origi-nally right dominant for language and, analogous to the other threepatients, experienced a shift of speech production processes to thehemisphere opposite the seizure focus. Thus, interhemispheric dis-sociation of language functions in all four patients was likely due toa shift of speech production capacities to the hemisphere contra-lateral to the seizure focus. In contrast, language comprehensionprocesses appear not to have shifted to the hemisphere oppositethe seizure focus, despite many years of recurring seizures.

We can only speculate on possible reasons why speech pro-duction capabilities in our patients showed greater capacity forinterhemispheric reorganization than comprehension processes.One possibility is that the articulatory skills indexed by speechproduction tasks emphasize motor, sensory, and motor planningprocesses that have a relatively symmetric representation in thenormal brain [36–41]. Thus, the nondominant hemisphere maypossess an innate ability to support speech production afterchronic damage to the dominant hemisphere [42–45]. Anotherlikely factor is the relatively more distributed anatomical repre-sentation of brain regions involved in comprehension, which in-clude large regions of the dominant temporal, parietal, andfrontal cortex [46], compared with the more focal representationfor speech articulation mechanisms in sensorimotor, premotor,and inferior prefrontal cortex [38,47,48]. As a result of this dif-ference, language comprehension processes may be better ableto reorganize intrahemispherically, whereas damage to the dom-inant hemisphere articulatory system is, at least in some pa-tients, more easily compensated by a shift of control to theopposite hemisphere. Janszky et al. [49] showed that higherinterictal spike frequency is associated with a shift (left to right)of word production ability in patients with temporal lobe epi-lepsy. Votes et al. [45] described a patient who showed in-creased fMRI activation in the right inferior frontal gyrus onverbal fluency tasks following a left hemispherectomy. Althoughall our cases suggest shifting of speech production, one of Kur-then and co-workers’ [12] cases indicates shifting of languagecomprehension, but not speech production. This patient had aleft temporoparietal seizure focus without evidence of frontaldamage and left parieto-occipital hypoperfusion on interictalSPECT. Wada testing suggested better comprehension ability inthe right and expressive speech in the left hemisphere. This pa-tient underwent left anterior two-thirds temporal lobectomy andshowed intact language abilities 3 months after surgery on neu-ropsychological assessment. Although Kurthen et al. [12]

acknowledge that determination of language dissociation in thispatient was complicated by persistent perseveration duringWada testing, this case raises the possibility of the shifting oflanguage comprehension by focal epileptic activities in temporo-parietal areas.

Interhemispheric dissociation of language capabilities could ex-plain some cases of discordance between Wada and fMRI languagelateralization. If a Wada lateralization index calculated over all lan-guage subtests is used, the Wada and fMRI results were markedlydiscordant in two of our four patients and moderately discordantin another. Concordance was also poor using a Wada index basedon speech production tasks, but was much better overall whenusing only the comprehension components of the Wada. These re-sults are consistent with a previous report indicating that this fMRIprotocol gives different lateralization results than a Wada testbased only on side of speech arrest [50]. These patterns can be ex-plained by the fact that the fMRI task contrast used here empha-sizes speech perception and lexical–semantic retrieval processesand is not designed to activate speech articulation systems.

According to the traditional neuroanatomical view of language,which localizes speech production to Broca’s area in the frontallobe and speech comprehension to Wernicke’s area in the temporallobe, different patterns of lateralization in the frontal and temporallobes would be predicted in patients with interhemispheric disso-ciation of these functions. Specifically, fMRI activation in the tem-poral lobe and other posterior heteromodal regions is predicted tobe associated with the hemisphere serving language comprehen-sion in the Wada test. Similarly, frontal lobe activation is expectedto correlate with the hemisphere of speech production based onWada testing. In contrast to these predictions, we observed no dif-ferences in lateralization of activation in frontal and temporopari-etal ROIs, both of which were similar to the whole-hemispherelateralization pattern. The fMRI task contrast used in the presentstudy activates not only temporal and parietal regions but alsofrontal regions supporting language comprehension [31]. This re-sult is consistent with a large body of neuroimaging evidence indi-cating involvement of the prefrontal cortex in a variety of languageprocesses, including lexical–semantic retrieval and selection[46,51–55]. Because the frontal lobe supports a variety of linguisticprocesses, it is overly simplistic to equate the frontal lobe withspeech production. In our patients, the motor control processesnecessary for speech production appear to have shifted to thehemisphere contralateral to the seizure focus, whereas other fron-tal lobe language processes did not shift away from the seizurefocus.

Given its rare occurrence, dissociation of language functionscould not explain all cases of discordant Wada and fMRI tests,but it provides a potential explanation for some of these cases.Multiple language tasks assessing comprehension as well asspeech articulation might, in combination, yield more concordantresults between the Wada test and fMRI mapping. Several groupsof researchers have advocated such a ‘‘language panel” approachand reported that agreement between the Wada test and fMRI in-creased when multiple language tasks were incorporated into thefMRI studies [22,56–58]. On the other hand, this improvement inconcordance may have occurred simply because the combinationof several fMRI data sets enhances statistical power and reliabilityin areas where overlapping activation occurs across tasks [25].Other studies have shown that some tasks are better than othersfor the purpose of determining language lateralization. For exam-ple, listening to sentences, single-word reading, and object namingtasks, when compared with resting or passive baseline states, pro-duced lateralization results that were not well correlated withWada lateralization [17,18,22,58]. Thus, simply combining a num-ber of tasks may be ineffective if these tasks and their controls arenot suitably designed to target language processes of interest. In

D. Lee et al. / Epilepsy & Behavior 13 (2008) 350–356 355

addition to the multiple-task approach, multiple neuroimagingmodalities, including activation and deactivation methods suchas magnetoencephalography and transcranial magnetic stimula-tion, might be necessary to optimize the localization of componentlanguage functions.

Acknowledgments

Our thanks to Linda Allen, George Morris, Romila Mushtaq, Con-rad Nievera, and Manoj Raghavan for assistance with patientrecruitment. This work was supported by National Institute ofNeurological Diseases and Stroke Grant R01 NS35929, NationalInstitutes of Health General Clinical Research Center Grant M01RR00058, and the Charles A. Dana Foundation.

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