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Epilepsy & Behavior 9 (2006) 339–344

Structured cueing on a semantic fluency task differentiates patientswith temporal versus frontal lobe seizure onset

Daniel L. Drane a,b,*, Gregory P. Lee c, Helen Cech c, Justin S. Huthwaite d,George A. Ojemann b,e, Jeffrey G. Ojemann b,e, David W. Loring f, Kimford J. Meador f

a Department of Neurology, University of Washington School of Medicine, Seattle, WA, USAb University of Washington Regional Epilepsy Center, Harborview Medical Center, Seattle, WA, USA

c Department of Neurology, Medical College of Georgia, Augusta, GA, USAd Georgia School of Professional Psychology, Atlanta, GA, USA

e Department of Neurological Surgery, University of Washington, Seattle, WA, USAf Department of Neurology, University of Florida, Gainesville, FL, USA

Received 3 May 2006; revised 14 June 2006; accepted 16 June 2006Available online 25 July 2006

Abstract

Patients with frontal lobe dysfunction (e.g., Huntington’s disease) reportedly benefit more from cueing on measures of semantic flu-ency than do patients with damage to temporal lobe structures (e.g., Alzheimer’s disease). This differential benefit from cueing suggeststhat different neurocognitive functions are impaired in these two groups. Patients with frontal lobe dysfunction are presumed to havedifficulty with the executive aspects of this generative fluency task, whereas patients with temporal lobe impairment are limited by deficitsin semantic memory. We studied the performance of patients with complex partial seizures of frontal or temporal lobe onset, as deter-mined by video/EEG monitoring, on standard and cued measures of semantic fluency administered in a counterbalanced sequence acrossgroups. These groups did not differ significantly in terms of age, education, gender, age at seizure onset, total number of antiepilepticdrugs, or IQ, and all patients subsequently underwent surgery for intractable epilepsy. Patients with frontal lobe dysfunction (FL group)performed significantly worse than patients with temporal lobe impairment (TL group) on the standard semantic fluency paradigm (TLgroup: M = 18.4, SD = 4.7; FL group: M = 11.1, SD = 5.3), t (27) = �3.75, P < 0.001. Nevertheless, results of an ANCOVA demon-strated that the FL group showed significantly greater performance improvement than the TL group when provided with a cued semanticfluency format, even after controlling for baseline differences in ability on the standard semantic fluency task (TL group: M = 0.45,SD = 3.8; FL M = 9.4, SD = 5.1), F (1,29) = 12.37, P = 0.002. These findings support previous research suggesting that frontal and tem-poral structures contribute uniquely to semantic generative fluency and suggest that using a combination of standard and cued semanticfluency tasks may help confirm localization of seizure onset in partial epilepsy by localizing the associated cognitive dysfunction.� 2006 Elsevier Inc. All rights reserved.

Keywords: Semantic fluency; Frontal and temporal lobe epilepsy; Localization of seizures

1. Introduction

Recent studies suggest that benefits obtained fromsemantic cueing are greater for patient groups experiencing

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

doi:10.1016/j.yebeh.2006.06.010

* Corresponding author. Present address: Neuropsychology Laboratory,University of Washington Regional Epilepsy Center, Harborview MedicalCenter, Box 359745, 325 Ninth Avenue, Seattle, WA 98104, USA. Fax: +1206 731 6007.

E-mail address: ddrane@u.washington.edu (D.L. Drane).

frontal system dysfunction than they are for patients whosecerebral impairment is concentrated in more posteriorregions. For example, patients with Huntington’s or Par-kinson’s disease, subcortical conditions that are often asso-ciated with frontal system dysfunction, were shown tobenefit from a cued semantic fluency task more thanAlzheimer’s patients [1]. It has been posited that the mech-anism of impairment underlying limitations in semantic flu-ency differs on the basis of anterior versus posterior

Table 1Demographic and seizure-related variables and relevant neurocognitivescores of patients with epilepsy with either frontal lobe or temporal lobeseizure onset

FL group(n = 9)

TL group(n = 20)

U P

Age (years) 34.4 (8.3)a 31.7 (9.0) 74.0 0.45Education 10.9 (2.9) 12.6 (2.7) 56.0 0.10WAIS-R Full Scale IQb 87.13 (6.2) 89.3 (15.8) 60.0 0.81WAIS-R Verbal IQ 84.1 (5.6) 89.1 (15.4) 58.0 0.71Digit Span (SS) 8.9 (2.6) 9.6 (3.8) 66.5 0.93Age at seizure onset 20.6 (13.9) 19.9 (13.7) 40.0 0.95Number of AEDs 2.0 (0.7) 1.9 (0.9) 77.0 0.51

v2 P

Gender (% females) 33.0% 30.0% 0.03 0.86Seizure laterality

(% left hemisphere onset)44.4% 50.0% 0.08 0.78

a Mean (SD).b WAIS-R, Wechsler Adult Intelligence Scale—Revised; n.s., nonsignif-

icant; SS, scaled score; AEDs, antiepileptic drugs. Patients with frontallobe onset and those with temporal lobe onset were shown not tosignificantly differ on any of the included variables when compared usingeither a Mann–Whitney U (continuous variables) or v2 analysis (categor-ical variables).

340 D.L. Drane et al. / Epilepsy & Behavior 9 (2006) 339–344

cerebral damage. Restricted semantic fluency amongpatients with frontal system impairment is thought to haveseveral potential causes, including a retrieval problemresulting from deficits in the executive aspects of searchingone’s own semantic memory stores or deficits involving ini-tiation of action or self-monitoring [1–4]. In contrast, sim-ilar semantic fluency limitations observed among patientswith more posterior lesions, particularly those involvingthe temporal lobes, are thought to be attributable to defi-cits in semantic memory [3,5].

Growing evidence points to the complementary roles ofstorage and retrieval respectively played by temporal andfrontal regions in the performance of semantic fluencytasks. Lesions in either of these areas have been shown toresult in decreased semantic fluency performance [6,7]. Inaddition, functional neuroimaging studies have demon-strated the importance of these regions in both healthy con-trol subjects and patient groups [8–10]. For example,numerous studies using functional magnetic resonanceimaging (fMRI) have demonstrated activation of the leftinferior frontal gyrus during the generation of semanticexemplars [11–13]. Frith and colleagues [8], using PETtechnology to study cerebral blood flow during a semanticfluency task, found primary activation of the left dorsolat-eral prefrontal cortex and a bilateral decrease in the tempo-ral cortices. These findings were interpreted as showing aninhibitory modulation of temporal regions by the prefron-tal cortex as the basis of word generation. Finally, there arealso a number of functional neuroimaging studies that sug-gest that semantic knowledge may be represented in dis-tributed neural sites in the temporal lobes [14,15]. Takentogether, these lesion and functional neuroimaging studieshave led to a semantic network model involved with wordgeneration that comprises distributed systems involvingboth the frontal and temporal lobes [16].

Given that patients with epilepsy with frontal or tempo-ral lobe seizure onset have been shown to be impaired onsemantic fluency tasks [6], these groups appear to be naturaltarget populations for examining this differentialphenomena. The performance of patients with frontal lobe(FL) seizure onset would be expected to improve when pro-vided with a cued semantic paradigm that gives them addi-tional organizational structure, whereas the performance ofpatients with temporal lobe (TL) epilepsy would not beexpected to show the same benefit. Should this dissociationhold up between these patient groups, standard versus cuedsemantic fluency performance could be of use in confirminglocalization of seizure onset. Likewise, with the difficultyinvolved in developing measures that reliably capture the‘‘control’’ features of executive processing [17], this differen-tial pattern of semantic fluency performance could also addto the available tools in this seemingly elusive domain ofneuropsychological assessment. In the study reported here,we examined the performance of patients with complex par-tial seizures of frontal or temporal lobe onset, as determinedby video/EEG monitoring, to determine the robustness ofprevious findings using a different patient population.

2. Methodology

2.1. Subjects

This study included 29 patients with intractable epilepsyof either unilateral frontal or temporal lobe origin. Allpatients included in this study were right-handed and lefthemisphere dominant for language. Handedness was deter-mined with the Benton Handedness Inventory [18], andlanguage dominance was evaluated using the intracarotidamobarbital (Wada) procedure [19]. Patients were excludedif they had evidence of a structural lesion other than mesialtemporal sclerosis. Site and laterality of seizure onset weredetermined through the use of multiple scalp/sphenoidalictal recordings with simultaneous audio/video recordingof behavioral phenomena. Results from MRI, neuropsy-chological examination including Wada testing, and, whereavailable, ictal and interictal SPECT scanning were alsoconsidered in determining the focus of seizure onset. Inaddition, all of the patients diagnosed with frontal lobeseizure onset underwent invasive monitoring, as did anyof the patients with temporal lobe onset for whom lateral-ization/localization issues were not clear-cut from the othersources of information. Frontal lobe seizure onset wasobserved in 9 patients with epilepsy (4 left frontal/5 rightfrontal), and temporal lobe onset was observed in theremaining 20 patients with epilepsy (10 left temporal/10right temporal). These groups did not differ significantlyin terms of age, education, gender, age at seizure onset,laterality of seizure onset, number of antiepileptic drugstaken, or IQ, and all patients ultimately underwent surgeryfor intractable epilepsy. Demographic data, seizure-relatedvariables, and relevant neurocognitive scores are providedin Table 1.

Table 2Performance of epilepsy patients with either frontal lobe or temporal lobeseizure onset on standard and cued semantic fluency measures

FL group(n = 9)

TL group(n = 20)

t P

Total exemplars(standard format)

11.1 (5.3)a 18.4 (4.7) �3.75 0.001

Total exemplars(cued format)

20.2 (6.9) 18.9 (5.1) 0.60 0.55

Change score 9.4 (5.1) 0.45 (3.8) 5.30 <0.001

a Mean (SD).

D.L. Drane et al. / Epilepsy & Behavior 9 (2006) 339–344 341

2.2. Procedures

All subjects were administered a standard version and acued version of a semantic fluency task developed by Ran-dolph et al. [1]. The standard semantic task consisted ofnaming as many exemplars of a category as possible duringa 60-second time interval. Categories included ‘‘animals’’and ‘‘supermarket items.’’ The cued semantic task also last-ed a total of 60 seconds. However, it was broken into four15-second-blocks that were each preceded by a cuedretrieval aid. Semantic cues consisted of specific descriptivecriteria from the two general categories used during thestandard administration. The animal category cues were(1) animals that people keep in their home as pets, (2) ani-mals that are found on a farm, (3) animals that live in thejungle, and (4) animals that live in the water. The super-market category cues included (1) fruits and vegetables,(2) meat and seafood, (3) things people drink, and (4)household cleaning products. Category types (‘‘animal’’vs ‘‘supermarket items’’) and administration procedure(standard vs cued) were counterbalanced across patientsto control for differences in category difficulty and possiblepractice effects. Each patient received a different semanticcategory type for the standard and cued administrations.

The FL and TL groups were compared using appropri-ate parametric tests (e.g., t statistic, analysis of covariance)using Version 12.0 of SPSS for Windows [20]. As perfor-mance on the semantic fluency paradigm used in the cur-rent study appears to be normally distributed, we did notfeel compelled to use nonparametric statistics. Althougherror variance differed between the FL and TL groupsfor some of the semantic fluency scores analyzed, SPSSprovides an alternative t value that corrects for thisunequal variance [20]. As we did not include a controlgroup in the current study, we compared each individual’suncued semantic fluency performance with available nor-mative data to evaluate the degree of actual impairmentin these two groups [21]. We considered a patient to beimpaired if he or she performed greater than one standarddeviation below the mean as compared with individualsmatched for age and education.

3. Results

We first calculated a cued–uncued difference score(change score) for each patient, as we felt that this repre-sented a good way to capture the relative benefit that eachgroup received from the provision of cueing on oursemantic fluency paradigm. The FL group improved byan average of 9.4 exemplars generated (SD = 5.1), whereasthe TL group improved by an average of only 0.45 item(SD = 3.8), t (27) = 5.30, P < 0.001. Although this changescore clearly differed between the FL and TL groups, thiscomparison is not the best way to statistically demonstrategroup differences, as change scores tend to be vulnerable tothe impact of regression to the mean. In addition, thissimple comparison also fails to consider baseline

differences in uncued performance. In fact, a comparisonof the two group’s uncued semantic fluency performancedemonstrated that the FL group was more impaired thanthe TL group on the uncued (baseline) task,t (27) = �3.75, P = 0.001. Therefore, one would have toconsider the possibility that the TL group experienced lessimprovement with cueing simply because they were lessimpaired on the standard task. Group means for perfor-mance on the standard and cued semantic fluency tasksand the change score are provided in Table 2.

We next employed a 2 (seizure focus: TL vs FL) · 2 (sei-zure laterality: dominant hemisphere vs nondominanthemisphere) mixed design analysis of covariance(ANCOVA) to examine the main effects of seizure focusand seizure laterality and their interaction on cued seman-tic fluency performance while controlling for any potentialbaseline differences in performance. We used the cued scoreas the dependent variable in this analysis while using eachgroup’s performance on the standard semantic fluency taskas a covariate. This method again demonstrates that themain effect for seizure focus remains significant even whencontrolling for baseline differences on the uncued task,F (1, 29) = 12.37, P = 0.002, g2 = 0.34. Although therewas also a trend for laterality, F (1,29) = 2.99, P = 0.09,g2 = 0.11, the effect size was small and an examination ofactual fail rates by laterality suggested that any differencewas clinically irrelevant (see below for a listing of the per-centages of impairment by seizure laterality and focus).The interaction of seizure laterality and seizure focus wasnot significant.

We next compared each patient’s uncued semantic fluen-cy performance with available normative data to evaluatethe relative level of impairment experienced by each ofthe two groups. Seven of nine (77.8%) patients with FLonset and 7 of 20 (35.0%) patients with TL onset wereimpaired in their respective uncued semantic fluency per-formance. This rate of baseline impairment proved signifi-cantly worse for the FL group using a v2 analysis,v2 (1,14) = 4.55, P = 0.03. We also compared failure ratesacross groups after dividing them by both seizure focus(FL/TL) and seizure laterality (left hemisphere/right hemi-sphere). The FL group continued to exhibit worse perfor-mance on the uncued semantic fluency task than did theTL group regardless of seizure laterality (percentage

342 D.L. Drane et al. / Epilepsy & Behavior 9 (2006) 339–344

impaired: right FL = 80%; left FL = 75%; right TL = 30%;left TL = 40%). Once again, consideration of laterality ofseizure onset did not appear to add anything beyond ourinitial examination of seizure focus. However, it does high-light the fact that a significant proportion of patients withTL and FL onset demonstrate impaired semantic fluencyperformance regardless of seizure laterality.

As another check of our statistical analysis aboveregarding the significant difference between groups on thechange score, we examined the change score of only thosepatients who were impaired on the uncued task. Using a t-test comparison, even when considering only the patientswho were impaired on this task at baseline, the patientswith FL onset exhibited significantly greater improvementon this measure than did the patients with TL onset (FLM = 9.0, SD = 4.6; TL M = 1.4, SD = 4.4), t (12) = 3.1,P = 0.008. Moreover, all seven patients with FL onsetwho performed in the impaired range showed an improve-ment of at least five exemplars when provided with cueing(range = 5–18). In contrast, only one of the patients withTL onset who performed in the impaired range improvedby as much as five exemplars (range = �5 to 10), with fourof the seven declining with cueing or staying the same.

Although we controlled for administration order effectsat the group level by counterbalancing the sequence of taskadministration (i.e., cued vs uncued) across groups, weused t-statistic analyses to determine if there were anyorder effects at the level of the individual on any of thesemantic scores. Sequence of task administration did notsignificantly impact any of the semantic scores (uncued,cued, or change scores). We also used correlational analy-ses to determine if any demographic factors significantlyimpacted performance scores as well. There were no signif-icant correlations between the semantic scores and age,education, gender, or duration of epilepsy.

4. Discussion

These findings indicate that frontal and temporal lobestructures contribute uniquely to semantic generative fluen-cy [1,3] and indicate that intact frontal system functioningis required for optimal task performance on such measures.As reported in prior studies [1,4], it appears that frontalsystem dysfunction contributes to poor word retrieval, aspatients with FL epilepsy demonstrated significantimprovement in the generation of category exemplars whenprovided with structured cueing. This suggests that suchpatients have not experienced a primary degradation ofsemantic memory. Instead, this pattern of performanceseems more consistent with a model of retrieval dysfunc-tion based on poor search strategies of more broadly dis-tributed semantic memory networks.

In our sample, impaired performance on a baselineuncued semantic fluency task was more prevalent amongpatients with FL seizure onset (77.8%), although suchdeficits were observed in a significant number of patientswith TL seizure onset as well (35%). Impaired performance

was observed for both groups at a similar rate regardless ofthe laterality of seizure onset. These findings are consistentwith prior behavioral studies [1,3,22,23], which have dem-onstrated that standard semantic fluency tasks can beimpacted by dysfunction in a wide range of brain regions.Such findings have led researchers to propose that semanticfluency is a complex cognitive task requiring the interactionof distributed neural networks, encompassing aspects oflanguage functioning, executive control processes, atten-tion, and semantic memory.

Some prior studies exploring the relationship of verbalfluency performance to specific regions of brain dysfunc-tion have found greater impairment on semantic fluencytasks in patients with TL injury as compared with thosewith FL injuries [24,25], although patients with FL epilepsyconsistently show deficits on these tasks as well. Given suchresults in prior studies, one might have expected worse per-formance on our semantic fluency task by our TL group.That is, the FL group exhibited a higher rate of impairmenton the baseline uncued semantic fluency task as comparedwith the TL group. Of note, however, the prior studiesdemonstrating decreased semantic fluency deficits inpatients with TL epilepsy involved patients with structurallesions (e.g., tumors, aneurysms), many of whom hadalready undergone surgery, or patients with diffuse neuro-logic disease (e.g., Alzheimer’s disease). As our patientswith epilepsy lacked structural lesions and had not under-gone surgery at the time of testing, it seems possible thatdifferences in the rate of impairment between groups onthis task may be related to the nature of the underlyingpathology. In other words, perhaps it takes a greaterthreshold of neurologic disease or a more widespreadregion of impairment to disrupt the semantic memory com-ponent of this task.

We also considered the possibility that differences indemographic factors might have accounted for baseline dif-ferences between groups. The FL group tended to haveslightly fewer years of education than did the TL group,although this difference did not achieve statistical signifi-cance. Nevertheless, we did not find any significant correla-tions between semantic fluency performance and anydemographic factors, including age, education, gender,and duration of epilepsy.

As some of the newer antiepileptic drugs (AEDs) appearto negatively impact verbal fluency in general (e.g., topira-mate, zonisamide) [26,27], differences in AED usage acrosspatient groups represents a potential confound for all ver-bal fluency studies conducted with patients with epilepsy.In the current study, there were no significant differencesacross groups in the number of total AEDs administered.In addition, only two patients were taking either topira-mate or zonisamide, and neither demonstrated impairedperformance on the semantic fluency task. Although wecannot completely rule out the impact of AEDs on seman-tic fluency performance, it does not appear to represent asignificant factor in the differential performance betweenFL and TL groups in the current study.

D.L. Drane et al. / Epilepsy & Behavior 9 (2006) 339–344 343

The current results are consistent with the view that idi-opathic seizure activity can contribute to cerebral dysfunc-tion that can be measured with standard neurocognitivetests, and that such information can often be helpful forconfirming the localization of seizure onset. While suchan approach has been of use with TL epilepsy (e.g., mate-rial-specific memory deficits are associated with the lateral-ity of onset of TL epilepsy) [28,29], frontal systemimpairment has been less reliably measured. These datasuggest that using a combination of standard and cuedsemantic fluency tasks may therefore improve localizationof cognitive dysfunction associated with seizure onset inpartial epilepsy. In contrast, given that lesions in a largenumber of brain regions can lead to impaired semantic flu-ency performance, the total number of exemplars generatedon a standard semantic fluency task appears to be of ques-tionable diagnostic utility when examined in isolation.

Future research should explore the possible relationshipbetween performance on our semantic fluency paradigmand other language tests that include cued and uncuedsemantic retrieval (e.g., multiple choice on confrontationalnaming tests), as well as other measures of verbal fluency(e.g., letter fluency). This could help to determine the spec-ificity versus generality of the retrieval deficit in the FLgroup and whether other tests could be used in combina-tion with this paradigm to enhance differential diagnosisof patients. For example, as prior research has establishedthat patients with FL epilepsy exhibit approximately equiv-alent dysfunction on semantic and letter fluency tasks,whereas patients with TL epilepsy perform worse onsemantic tasks [24,25], this pattern might be used in con-junction with the cued/uncued results to better differentiatepatient groups.

It also appears possible that baseline semantic fluencydeficits in the FL group could have more than one poten-tial cause. Although we have focused on the organizationalaspects of retrieval and suggested that the cued structureoffsets deficits in this regard, it is possible that poor self-monitoring could be contributing to task failure as well.The cued condition lessens the retrieval demands of thetask, but it also enhances self-monitoring by adding struc-ture to the situation and limiting the amount of time thatthe patient must continuously monitor his or her behavior(four 15-second intervals vs one 60-second interval). Thiscould potentially be examined in future studies by trackingintrusive or perseverative errors made by the FL group inboth the cued and uncued conditions. In the uncued condi-tion, retrieval deficits would be expected to lead to impov-erished production of exemplars while self-monitoringdeficits would result in higher error rates.

The use of standard and cued semantic fluency tasks forclinical purposes remains premature at this point. Furtherresearch is required with healthy subjects to ensure thatthese semantic categories are equivalent in difficulty andto establish normative data for clinical comparison. On apositive note, the original article using this cued anduncued semantic fluency paradigm demonstrated similar

results for both categories of objects in a small, healthycontrol sample [1]. In addition, there appeared to be noorder effects in the current study for cued versus uncuedadministration. Ideally, for clinical purposes, it wouldprobably be best to develop uncued and cued paradigmsthat are based on the same category of object (e.g., uncuedand cued versions of the animal fluency task administeredto each patient). It would also be helpful to develop suchparadigms for multiple categories of objects, as the seman-tic memory literature suggests that different categoriesthemselves may be mediated by different neural regions[30,31]. These issues were avoided in the current study byusing a counterbalanced administration. However,although this is an effective way to control for differentialcategory difficulty in group studies, this method would bedifficult to apply at the level of an individual patient. Nev-ertheless, the current study suggests that the developmentof appropriate cued and uncued semantic fluency para-digms would prove helpful for the localization of seizureonset, and would offer another potential means of assessingfrontal system functioning in general.

Acknowledgments

Parts of this article were originally presented at the 31stAnnual Meeting of the International NeuropsychologicalSociety, 2003, Honolulu, Hawaii. Preparation of this articlewas supported in part by the National Institute of Neuro-logical Disorders and Stroke (NINDS), National Institutesof Health (NIH) (Grant K23 NSO49100-01). This studywas approved by the institutional review board (Applica-tion 05-5738-G 01) of the University of Washington Med-ical School.

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