Relative Shift in Activity from Medial to Lateral FrontalCortex During Internally Versus Externally Guided

Word Generation

Bruce Crosson Joseph R Sadek Leeza Maron Didem GokcayCecile M Mohr Edward J Auerbach Alan J Freeman

Christiana M Leonard and Richard W Briggs

Abstract

amp Goldberg (1985) hypothesized that as language outputchanges from internally to externally guided productionactivity shifts from supplementary motor area (SMA) to lateralpremotor areas including Brocarsquos area To test this hypothesis15 right-handed native English speakers performed three wordgeneration tasks varying in the amount of internal guidanceand a repetition task during functional magnetic resonanceimaging (fMRI) Volumes of significant activity for each taskversus a resting state were derived using voxel-by-voxelrepeated-measures t tests (p lt 001) across subjects Changes

in the size of activity volumes for left medial frontal regions(SMA and pre-SMABA 32) versus left lateral frontal regions(Brocarsquos area inferior frontal sulcus) were assessed as internalguidance of word generation decreased and external guidanceincreased Comparing SMA to Brocarsquos area Goldbergrsquoshypothesis was not verified However pre-SMABA 32 activityvolumes decreased significantly and inferior frontal sulcusactivity volumes increased significantly as word generationtasks moved from internally to externally guided amp

How does the human brain initiate the expression ofthought in language A comprehensive understandingof the brainrsquos language systems necessitates an answerto this question An appreciation of language initiationmechanisms could facilitate treatment development forlanguage initiation deficits in aphasia For some timecognitive neuroscientists have known that the medialfrontal cortex plays a role in language initiation How-ever the nature of this involvement has yet to bedetermined

Medial frontal lesions cause akinetic mutism inwhich speech is initiated only with significant externalprompting (Barris amp Schuman 1953 Nielson amp Jacobs1951) Regarding the absence of spontaneous lan-guage Luriarsquos (1966) report of a medial frontal lesioncase indicated that thoughts were not present toexpress This phenomenon suggests that the medialfrontal cortex plays a role in initiating the cognitiveaspects of spontaneous language After evaluating em-pirical evidence on this subject Picard and Strick(1996) Passingham (1993) and Goldberg (1985) con-cluded that the degree of involvement of medialfrontal structures and which medial structures partici-pate depends upon the nature of the language that isinitiated

Goldberg (1985) suggested that involvement of med-ial frontal cortex depends upon whether language istriggered by internal or external contingencies He fo-cused on the divergent roles of the supplementarymotor area (SMA) and lateral premotor cortex Goldbergspeculated that Brocarsquos area was prominent in the lateralpremotor cortex of humans (p 578) especially whenconsidering language functions Traditionally Brocarsquosarea has been designated as the posterior portion ofthe inferior frontal gyrus ie pars opercularis (Brod-mannrsquos area [BA] 44) and pars triangularis (BA 45)Although recent literature indicates important functionaldivisions within medial BA 6 that might have influencedhis conclusions (see below) SMA was considered toconsist of the entire medial BA 6 at the time Goldbergwrote his review He surmised that SMA was primarilyinvolved in internally generated language and actionswhereas lateral premotor cortex was involved in lan-guage or actions that are externally referenced

Passinghamrsquos (1993) subsequent review on medialversus lateral premotor cortex arrived at a similar con-clusion In reference to selection of movement Passing-ham believed that lateral premotor cortex made greatercontributions when movements were driven by externalcues and medial premotor cortex played a greater rolewhen no external cues were available (ie when move-ment was driven from internal models) However Pas-singham (1993) also concluded that neither internallyUniversity of Florida

copy 2001 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 132 pp 272ndash283

cued nor externally cued movements were the exclusivedomains of SMA and lateral premotor cortex respec-tively Rather it was the balance of activity within thetwo cortices that was important

Yet the literature has not unambiguously supportedthis conclusion In comparing right-hand motor tasksDeiber et al (1991) found less activity in the left SMA forexternally than internally cued tasks However lessactivity in left prefrontal cortex (BAs 9 and 46) alsowas observed for externally than for internally guidedmovements In addition lateral premotor activity wasgreater for internally cued movement than for a fixed-movement control task whereas this region did notdemonstrate significant activity changes for externallycued movement versus the same control task Withrespect to language Frith Friston Liddle and Frack-owiak (1991) compared generation of words beginningwith the letter F (internally driven word production) torepetition of words (externally driven word production)Word generation produced more activation of both themedial frontal (centered in BA 32) and lateral frontal(centered in BA 46) cortex Similar but less extensivechanges occurred for an internally as opposed to anexternally guided finger movement task Unfortunatelyneither Deiber et al (1991) nor Frith et al (1991)explored whether changes for medial and lateral frontalcortex were similar in magnitude Although both areasshow decreases from internally to externally drivenactivity a difference in the relative proportions ofchange could indicate a shift in the balance of medialversus lateral frontal activity Further these studies werenot consistent in what elements of medial frontal (BA 32or medial BA 6) or lateral frontal (BAs 9 and 46 or lateralBA 6) cortex were involved in the activity changes

Subsequent to Goldbergrsquos review Matsuzaka Aizawaand Tanji (1992) and others (eg Luppino MatelliCamarda amp Rizzolatti 1993) indicated that medial BA6 can be divided into a posterior region mainly con-nected to lateral motor and premotor systems (SMAproper) and an anterior region primarily connected tolateral frontal cortex (pre-SMA) In monkeys areas with-in the cingulate sulcus (cingulate motor areas) also haveconnections similar to SMA and pre-SMA The mostrostral cingulate motor area has connections to lateralprefrontal cortex similar to pre-SMA while the moreposterior cingulate motor areas are connected to lateralpremotor and motor cortex similar to SMA (Picard ampStrick 1996 He Dum Strick 1995 Dum amp Strick 1991Hutchins Martino amp Strick 1988) Picard and Strick(1996) surmised that the human equivalent of monkeycingulate motor areas lie primarily in supracallosal BA32 Assuming the organization of this region to be similarto cingulate motor areas in monkeys the anterior por-tion of supracallosal area 32 should be connected tolateral prefrontal cortex and the posterior portion ofsupracallosal area 32 should be connected to lateralprefrontal and motor areas Activity from previous lan-guage initiation studies has occupied both BA 32 andmedial BA 6 (Crosson Rao et al 1999 Picard amp Strick1996 Warburton et al 1996) Picard and Strick attrib-uted functional significance to the anterior to posteriorconnectivity patterns Simple activities such as repetitionof words or phrases tend to engage SMA but complexactivities such as the generation of words or phrasesinvolve pre-SMA and the anterior portion of supracallo-sal BA 32

The purpose of the current study was to assess therelative contributions of medial and lateral frontal cortex

Table 1 Medial and Lateral Frontal Activity Volumes for Generation Tasks and Repetition

Free Generation Paced Generation

Regionof Interest L Anatomic Areas Local Max

Averaget test valuefor cluster L Anatomic Areas Local Max

Averaget Test Valuefor Cluster

Brocarsquos Area 3685 BA 44 Ins (ndash 37254) tav e ra g e=545 3080 BAs 45 and 47 Ins (ndash 40302) ta ve r ag e =510

Inferior Frontal Sulcus 1190 BAs 6 and 8 (ndash 46038) tav e ra g e=524 1945 BAs 6 8 9 and 46 (ndash 391133) ta ve r ag e =492

Lateral Premotor Areas 1192 BAs 4 and 6 (ndash 47ndash 748) ta ve r ag e =549

270 BAs 6 and 42 (ndash 34ndash 346) tav e ra g e=466

265 BA 6 (ndash 31446) ta ve r ag e =500

SMA 500 post md BA 6 (ndash 12466) tav e ra g e=516 none ndash ndash

pre-SMA 2203 ant md BAs 6and 32

(ndash 62042) tav e ra g e=555 1432 ant md BAs 6and 32

(ndash 42144) ta ve r ag e =515

BA = Brodmannrsquos area Ins = Insula SMA = supplementary motor area pre-SMA = pre-supplementary motor area ant = anterior postvolumes in essentially the same regions Volumes of activity change gt250 l t test p lt 001

Crosson et al 273

during word generation as task demands shifted frominternally to externally guided Three word generationparadigms were performed during functional magneticresonance imaging (fMRI) Free generation requiredsubjects to generate as many exemplars as possible froma given semantic category and was the most internally(ie least externally) guided Paced generation re-quired subjects to generate a word from the givensemantic category every time they heard the cue lsquolsquonextrsquorsquoThis external pacing cue made paced generation moreexternally guided than free generation Semantic ge-neration was the most externally guided word genera-tion task Subjects were given a semantic category and acue describing a category member Subjects generatedthe word from the category that matched the descriptivecue For example after the category lsquolsquobirdrsquorsquo subjectsheard descriptive cues like lsquolsquoredrsquorsquo or lsquolsquoflightlessrsquorsquo towhich they might answer lsquolsquocardinalrsquorsquo or lsquolsquoemursquorsquo respec-tively For purposes of comparison subjects also per-formed a task during which they simply repeated givenwords Since repetition was totally dependent uponexternal input it was more externally guided than theword generation tasks

We hypothesized that as word production becamemore externally guided in the steps between freegeneration and word repetition the ratio of medialto lateral frontal activity would become smaller Thishypothesis was tested for both SMA and pre-SMABA32 separately Both Brocarsquos area (Goldberg 1985) andother lateral frontal cortex (Deiber et al 1991 Frithet al1991) have been implicated in externally guidedcompared to internally guided actions Because var-ious word generation studies have implicated differentlateral frontal regions in word generation (pars orbi-

talis by Petersen Fox Posner Mintun amp Raichle 1988BAs 9 and 46 by Frith et al1991 inferior frontalsulcus by Warburton et al 1996) composite groupimages (statistical parametric maps) were used toallow for exploration of different lateral frontal areasPilot work in our laboratory (Crosson et al 1998)indicated that the size of significantly activated vo-lumes could be used to assess task differences inextent of activity Average intensities within signifi-cantly activated volumes were also used to assessintensity of activity

RESULTS

Each experimental task was compared to the restingcontrol state using voxel-wise t tests across the 15neurologically normal subjects The voxel-wise prob-ability threshold was set at p lt 001 Because of thelarge number of t tests conducted activity volumeswere required to exceed 229 l the volume thresholddetermined by a random waveform analysis Table 1shows significant activity volumes within the frontallobe for each of the three word generation tasks andrepetition

The size of significant activity volumes was comparedbetween tasks for selected brain regions Brocarsquos areaSMA and pre-SMABA 32 were selected for this compar-ison based on the analysis of Goldberg (1985) andsubsequent studies dividing medial BA 6 into SMA andpre-SMA (Luppino et al 1993 Matsuzaka et al 1992)One other lateral frontal region was selected for thisanalysis based upon its activation in all three wordgeneration tasks The core of the region was withinthe banks of the most posterior portion of the inferior

Table 1 ( continued )

Semantic Generation Repetition

L Anatomic Areas Local Max

Averaget Test Valuefor Cluster L Anatomic Areas Local Max

Averaget Test Valuefor Cluster

2327 BAs 45 and 47 Ins (ndash 431915) ta v e ra g e=518 269 BA 45 (ndash 36265) tav e ra g e=495

2775 BAs 6 8 and 9 (ndash 382230) ta v e ra g e=533

920 BAs 4 and 6 (ndash 52ndash 444) tav e ra g e=512

574 BA 6 (ndash 39145) ta v e ra g e=503

363 BAs 6 and 44 (ndash 57520) tav e ra g e=466

none ndash ndash 574 post md BA 6 (ndash 62 57) tav e ra g e=519

615 ant md BAs 6 and 32 (ndash 41846) ta v e ra g e=529 321 ant md BAs 6 and 32 (ndash 7654) tav e ra g e=508

= posterior md = medial Local Max = location within the activity cluster of the maximum t value activity volumes in the same row indicates

274 Journal of Cognitive Neuroscience Volume 13 Number 2

frontal sulcus (BAs 6 and 8) For paced generation andsemantic generation it extended anteriorly along thesulcus into BAs 9 and 46 Comparisons between tasksrepresenting the progression from most internally tomost externally guided are presented below For eachregion two-tailed probabilities are Bonferroni correctedto a probability level of p lt 05 for all comparisons in theregion No comparison was conducted when no activitywas present within a region for a specific task

Figure 1 shows activity volumes in SMA pre-SMABA32 Brocarsquos area and the banks of the inferior frontalsulcus Activity in SMA was present only during the freegeneration and repetition tasks The volume of activatedvoxels was not significantly different between these tasks(z = 101 p gt 30) However significant activity waspresent in pre-SMABA 32 for all tasks The activityvolume became systematically smaller as tasks pro-gressed from internally to externally guided It waslargest for the free generation task and became signifi-

cantly smaller from free generation to paced generation(z = ndash 539 p lt 001) from paced generation tosemantic generation (z = ndash 666 p lt 001) and fromsemantic generation to repetition (z = ndash 339 p lt 001)Brocarsquos area showed a similar though somewhat lessdramatic pattern than pre-SMABA 32 with activityvolumes becoming smaller as tasks progressed frominternally to externally guided The activity volumedecreased significantly from free generation to pacedgeneration (z = ndash 292 p lt 005) from paced genera-tion to semantic generation (z = ndash 406 p lt 001) andfrom semantic generation to repetition (z = ndash 1220 p lt001) Activity volumes in the inferior frontal sulcus werepresent only for the word generation tasks and showedthe opposite pattern to pre-SMABA 32 increasing insize as word generation progressed from internal toexternal guidance The activity volume increased signifi-cantly from free generation to paced generation (z =609 p lt 001) and from paced generation to semantic

Figure 1 Activity volumes displayed on sagittal sections The anatomy was averaged for the 15 subjects for active areas red represents p lt 001yellow represents p lt 0001 The top row shows medial frontal activity 5 mm to the left of midline (Activity labeled as pre-SMA represents activity inboth pre-SMA and BA 32) The verticle green line represents the plane used to divide SMA and pre-SMA (4 mm anterior to the posterior margin ofthe anterior commissure) The middle and bottom rows emphasize differences in the inferior frontal sulcus (IFS) and Brocarsquos area (Brocarsquos) FreeGen = Free Generation Pace Gen = Paced Generation Sem Gen = Semantic Generation Rep = Repetition

Crosson et al 275

generation (z = 538 p lt 001) It is also of interest thatthe local maximum in the inferior frontal sulcus pro-gressed anteriorly as the word generation tasks movedfrom internal to external guidance For free generationthe local maximum was in BA 6 It progressed to theborder between BAs 6 and 8 in paced generation and tothe border between BAs 8 and 9 in semantic generation(see Table 1) Figure 2 illustrates changes in activityvolumes between tasks for pre-SMABA 32 Brocarsquos areaand the inferior frontal sulcus In summary in terms ofabsolute size of significant activity volumes SMA andBrocarsquos area did not meet Goldbergrsquos (1985) predictionof a shift from medial to lateral premotor activity as wordgeneration tasks shifted from internally to externallyguided However if Goldbergrsquos hypothesis is modifiedto focus on pre-SMABA 32 and lateral frontal cortex onthe banks of the inferior frontal sulcus then a medial tolateral shift did occur as word generation tasks shiftedfrom internally to externally guided Across the threeword generation tasks activity systematically decreasedin pre-SMABA 32 and significantly increased in thebanks of the inferior frontal sulcus as word generationshifts from internal to external guidance

The relationship between size for medial and lateralfrontal activity volumes also can be represented as amedial to lateral frontal ratio Figure 3 shows activityvolume ratios for pre-SMA to Brocarsquos area and for pre-SMABA 32 to inferior frontal sulcus Regarding therelationship between pre-SMABA 32 and Brocarsquos areathere was a consistent and modest decrease in themedial to lateral frontal ratio from the most internallyguided (free generation) to the most externally guided(semantic generation) word generation task In Brocarsquosarea the ratio is higher for repetition than for the wordgeneration tasks For the relationship between pre-

SMABA 32 and inferior frontal sulcus there was a largeand consistent decrease in the medial to lateral frontalratio from the most internally guided (free generation)to the most externally guided (semantic generation)word generation task There was no activity in theinferior frontal sulcus for repetition Thus ratios ofactivity volumes for pre-SMABA 32 compared both toBrocarsquos area and to the banks of the inferior frontalsulcus demonstrate relative medial to lateral frontalshifts as word generation tasks become more externallyguided The shift is much more modest for the Brocarsquosarea comparison than for the inferior frontal sulcuscomparison

Finally average functional intensities within significantactivity volumes were compared with t tests to ascertainif there were intensity differences within the volumesacross tasks (Table 2) Within brain areas probabilitylevels were Bonferroni corrected for the number ofcomparisons Functional intensities within SMA did notdiffer significantly between free generation and repeti-tion (t = ndash 015 df = 79 p gt 80) For pre-SMABA 32the only significant difference in functional intensitieswas that the functional intensity for free generation wasgreater than that for paced generation (t = 321 df =272 p lt 005) Thus while the activity volume of pacedgeneration was second in size only to that of freegeneration for pre-SMABA 32 paced generation wasthe only task to show a significantly smaller averagefunctional intensity than free generation For Brocarsquosarea free generation showed significantly greater aver-age functional intensities than paced generation (t =375 df = 508 p lt 001) and repetition (t = 371 df =296 p lt 001) For the inferior frontal sulcus both freegeneration (t = 298 df = 235 p lt 005) and semanticgeneration (t = ndash 476 df = 297 p lt 001) showed

Figure 3 Medial to lateral frontal ratios plotted for pre-SMABA 32 toinferior frontal sulcus (IFS) and for pre-SMABA 32 to Brocarsquos area Theshift from medial to lateral frontal dominance is particularly obvious forthe IFS ratio See Figure 1 for x-axis key

Figure 2 Pre-SMABA 32 and lateral frontal activity volumes plottedacross tasks As word generation moved from internally to externallyguided activity volumes for pre-SMABA 32 and Brocarsquos area generallydecreased but activity volumes for the inferior frontal sulcus (IFS)increased See Figure 1 for x-axis key

276 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

cued nor externally cued movements were the exclusivedomains of SMA and lateral premotor cortex respec-tively Rather it was the balance of activity within thetwo cortices that was important

Yet the literature has not unambiguously supportedthis conclusion In comparing right-hand motor tasksDeiber et al (1991) found less activity in the left SMA forexternally than internally cued tasks However lessactivity in left prefrontal cortex (BAs 9 and 46) alsowas observed for externally than for internally guidedmovements In addition lateral premotor activity wasgreater for internally cued movement than for a fixed-movement control task whereas this region did notdemonstrate significant activity changes for externallycued movement versus the same control task Withrespect to language Frith Friston Liddle and Frack-owiak (1991) compared generation of words beginningwith the letter F (internally driven word production) torepetition of words (externally driven word production)Word generation produced more activation of both themedial frontal (centered in BA 32) and lateral frontal(centered in BA 46) cortex Similar but less extensivechanges occurred for an internally as opposed to anexternally guided finger movement task Unfortunatelyneither Deiber et al (1991) nor Frith et al (1991)explored whether changes for medial and lateral frontalcortex were similar in magnitude Although both areasshow decreases from internally to externally drivenactivity a difference in the relative proportions ofchange could indicate a shift in the balance of medialversus lateral frontal activity Further these studies werenot consistent in what elements of medial frontal (BA 32or medial BA 6) or lateral frontal (BAs 9 and 46 or lateralBA 6) cortex were involved in the activity changes

Subsequent to Goldbergrsquos review Matsuzaka Aizawaand Tanji (1992) and others (eg Luppino MatelliCamarda amp Rizzolatti 1993) indicated that medial BA6 can be divided into a posterior region mainly con-nected to lateral motor and premotor systems (SMAproper) and an anterior region primarily connected tolateral frontal cortex (pre-SMA) In monkeys areas with-in the cingulate sulcus (cingulate motor areas) also haveconnections similar to SMA and pre-SMA The mostrostral cingulate motor area has connections to lateralprefrontal cortex similar to pre-SMA while the moreposterior cingulate motor areas are connected to lateralpremotor and motor cortex similar to SMA (Picard ampStrick 1996 He Dum Strick 1995 Dum amp Strick 1991Hutchins Martino amp Strick 1988) Picard and Strick(1996) surmised that the human equivalent of monkeycingulate motor areas lie primarily in supracallosal BA32 Assuming the organization of this region to be similarto cingulate motor areas in monkeys the anterior por-tion of supracallosal area 32 should be connected tolateral prefrontal cortex and the posterior portion ofsupracallosal area 32 should be connected to lateralprefrontal and motor areas Activity from previous lan-guage initiation studies has occupied both BA 32 andmedial BA 6 (Crosson Rao et al 1999 Picard amp Strick1996 Warburton et al 1996) Picard and Strick attrib-uted functional significance to the anterior to posteriorconnectivity patterns Simple activities such as repetitionof words or phrases tend to engage SMA but complexactivities such as the generation of words or phrasesinvolve pre-SMA and the anterior portion of supracallo-sal BA 32

The purpose of the current study was to assess therelative contributions of medial and lateral frontal cortex

Table 1 Medial and Lateral Frontal Activity Volumes for Generation Tasks and Repetition

Free Generation Paced Generation

Regionof Interest L Anatomic Areas Local Max

Averaget test valuefor cluster L Anatomic Areas Local Max

Averaget Test Valuefor Cluster

Brocarsquos Area 3685 BA 44 Ins (ndash 37254) tav e ra g e=545 3080 BAs 45 and 47 Ins (ndash 40302) ta ve r ag e =510

Inferior Frontal Sulcus 1190 BAs 6 and 8 (ndash 46038) tav e ra g e=524 1945 BAs 6 8 9 and 46 (ndash 391133) ta ve r ag e =492

Lateral Premotor Areas 1192 BAs 4 and 6 (ndash 47ndash 748) ta ve r ag e =549

270 BAs 6 and 42 (ndash 34ndash 346) tav e ra g e=466

265 BA 6 (ndash 31446) ta ve r ag e =500

SMA 500 post md BA 6 (ndash 12466) tav e ra g e=516 none ndash ndash

pre-SMA 2203 ant md BAs 6and 32

(ndash 62042) tav e ra g e=555 1432 ant md BAs 6and 32

(ndash 42144) ta ve r ag e =515

BA = Brodmannrsquos area Ins = Insula SMA = supplementary motor area pre-SMA = pre-supplementary motor area ant = anterior postvolumes in essentially the same regions Volumes of activity change gt250 l t test p lt 001

Crosson et al 273

during word generation as task demands shifted frominternally to externally guided Three word generationparadigms were performed during functional magneticresonance imaging (fMRI) Free generation requiredsubjects to generate as many exemplars as possible froma given semantic category and was the most internally(ie least externally) guided Paced generation re-quired subjects to generate a word from the givensemantic category every time they heard the cue lsquolsquonextrsquorsquoThis external pacing cue made paced generation moreexternally guided than free generation Semantic ge-neration was the most externally guided word genera-tion task Subjects were given a semantic category and acue describing a category member Subjects generatedthe word from the category that matched the descriptivecue For example after the category lsquolsquobirdrsquorsquo subjectsheard descriptive cues like lsquolsquoredrsquorsquo or lsquolsquoflightlessrsquorsquo towhich they might answer lsquolsquocardinalrsquorsquo or lsquolsquoemursquorsquo respec-tively For purposes of comparison subjects also per-formed a task during which they simply repeated givenwords Since repetition was totally dependent uponexternal input it was more externally guided than theword generation tasks

We hypothesized that as word production becamemore externally guided in the steps between freegeneration and word repetition the ratio of medialto lateral frontal activity would become smaller Thishypothesis was tested for both SMA and pre-SMABA32 separately Both Brocarsquos area (Goldberg 1985) andother lateral frontal cortex (Deiber et al 1991 Frithet al1991) have been implicated in externally guidedcompared to internally guided actions Because var-ious word generation studies have implicated differentlateral frontal regions in word generation (pars orbi-

talis by Petersen Fox Posner Mintun amp Raichle 1988BAs 9 and 46 by Frith et al1991 inferior frontalsulcus by Warburton et al 1996) composite groupimages (statistical parametric maps) were used toallow for exploration of different lateral frontal areasPilot work in our laboratory (Crosson et al 1998)indicated that the size of significantly activated vo-lumes could be used to assess task differences inextent of activity Average intensities within signifi-cantly activated volumes were also used to assessintensity of activity

RESULTS

Each experimental task was compared to the restingcontrol state using voxel-wise t tests across the 15neurologically normal subjects The voxel-wise prob-ability threshold was set at p lt 001 Because of thelarge number of t tests conducted activity volumeswere required to exceed 229 l the volume thresholddetermined by a random waveform analysis Table 1shows significant activity volumes within the frontallobe for each of the three word generation tasks andrepetition

The size of significant activity volumes was comparedbetween tasks for selected brain regions Brocarsquos areaSMA and pre-SMABA 32 were selected for this compar-ison based on the analysis of Goldberg (1985) andsubsequent studies dividing medial BA 6 into SMA andpre-SMA (Luppino et al 1993 Matsuzaka et al 1992)One other lateral frontal region was selected for thisanalysis based upon its activation in all three wordgeneration tasks The core of the region was withinthe banks of the most posterior portion of the inferior

Table 1 ( continued )

Semantic Generation Repetition

L Anatomic Areas Local Max

Averaget Test Valuefor Cluster L Anatomic Areas Local Max

Averaget Test Valuefor Cluster

2327 BAs 45 and 47 Ins (ndash 431915) ta v e ra g e=518 269 BA 45 (ndash 36265) tav e ra g e=495

2775 BAs 6 8 and 9 (ndash 382230) ta v e ra g e=533

920 BAs 4 and 6 (ndash 52ndash 444) tav e ra g e=512

574 BA 6 (ndash 39145) ta v e ra g e=503

363 BAs 6 and 44 (ndash 57520) tav e ra g e=466

none ndash ndash 574 post md BA 6 (ndash 62 57) tav e ra g e=519

615 ant md BAs 6 and 32 (ndash 41846) ta v e ra g e=529 321 ant md BAs 6 and 32 (ndash 7654) tav e ra g e=508

= posterior md = medial Local Max = location within the activity cluster of the maximum t value activity volumes in the same row indicates

274 Journal of Cognitive Neuroscience Volume 13 Number 2

frontal sulcus (BAs 6 and 8) For paced generation andsemantic generation it extended anteriorly along thesulcus into BAs 9 and 46 Comparisons between tasksrepresenting the progression from most internally tomost externally guided are presented below For eachregion two-tailed probabilities are Bonferroni correctedto a probability level of p lt 05 for all comparisons in theregion No comparison was conducted when no activitywas present within a region for a specific task

Figure 1 shows activity volumes in SMA pre-SMABA32 Brocarsquos area and the banks of the inferior frontalsulcus Activity in SMA was present only during the freegeneration and repetition tasks The volume of activatedvoxels was not significantly different between these tasks(z = 101 p gt 30) However significant activity waspresent in pre-SMABA 32 for all tasks The activityvolume became systematically smaller as tasks pro-gressed from internally to externally guided It waslargest for the free generation task and became signifi-

cantly smaller from free generation to paced generation(z = ndash 539 p lt 001) from paced generation tosemantic generation (z = ndash 666 p lt 001) and fromsemantic generation to repetition (z = ndash 339 p lt 001)Brocarsquos area showed a similar though somewhat lessdramatic pattern than pre-SMABA 32 with activityvolumes becoming smaller as tasks progressed frominternally to externally guided The activity volumedecreased significantly from free generation to pacedgeneration (z = ndash 292 p lt 005) from paced genera-tion to semantic generation (z = ndash 406 p lt 001) andfrom semantic generation to repetition (z = ndash 1220 p lt001) Activity volumes in the inferior frontal sulcus werepresent only for the word generation tasks and showedthe opposite pattern to pre-SMABA 32 increasing insize as word generation progressed from internal toexternal guidance The activity volume increased signifi-cantly from free generation to paced generation (z =609 p lt 001) and from paced generation to semantic

Figure 1 Activity volumes displayed on sagittal sections The anatomy was averaged for the 15 subjects for active areas red represents p lt 001yellow represents p lt 0001 The top row shows medial frontal activity 5 mm to the left of midline (Activity labeled as pre-SMA represents activity inboth pre-SMA and BA 32) The verticle green line represents the plane used to divide SMA and pre-SMA (4 mm anterior to the posterior margin ofthe anterior commissure) The middle and bottom rows emphasize differences in the inferior frontal sulcus (IFS) and Brocarsquos area (Brocarsquos) FreeGen = Free Generation Pace Gen = Paced Generation Sem Gen = Semantic Generation Rep = Repetition

Crosson et al 275

generation (z = 538 p lt 001) It is also of interest thatthe local maximum in the inferior frontal sulcus pro-gressed anteriorly as the word generation tasks movedfrom internal to external guidance For free generationthe local maximum was in BA 6 It progressed to theborder between BAs 6 and 8 in paced generation and tothe border between BAs 8 and 9 in semantic generation(see Table 1) Figure 2 illustrates changes in activityvolumes between tasks for pre-SMABA 32 Brocarsquos areaand the inferior frontal sulcus In summary in terms ofabsolute size of significant activity volumes SMA andBrocarsquos area did not meet Goldbergrsquos (1985) predictionof a shift from medial to lateral premotor activity as wordgeneration tasks shifted from internally to externallyguided However if Goldbergrsquos hypothesis is modifiedto focus on pre-SMABA 32 and lateral frontal cortex onthe banks of the inferior frontal sulcus then a medial tolateral shift did occur as word generation tasks shiftedfrom internally to externally guided Across the threeword generation tasks activity systematically decreasedin pre-SMABA 32 and significantly increased in thebanks of the inferior frontal sulcus as word generationshifts from internal to external guidance

The relationship between size for medial and lateralfrontal activity volumes also can be represented as amedial to lateral frontal ratio Figure 3 shows activityvolume ratios for pre-SMA to Brocarsquos area and for pre-SMABA 32 to inferior frontal sulcus Regarding therelationship between pre-SMABA 32 and Brocarsquos areathere was a consistent and modest decrease in themedial to lateral frontal ratio from the most internallyguided (free generation) to the most externally guided(semantic generation) word generation task In Brocarsquosarea the ratio is higher for repetition than for the wordgeneration tasks For the relationship between pre-

SMABA 32 and inferior frontal sulcus there was a largeand consistent decrease in the medial to lateral frontalratio from the most internally guided (free generation)to the most externally guided (semantic generation)word generation task There was no activity in theinferior frontal sulcus for repetition Thus ratios ofactivity volumes for pre-SMABA 32 compared both toBrocarsquos area and to the banks of the inferior frontalsulcus demonstrate relative medial to lateral frontalshifts as word generation tasks become more externallyguided The shift is much more modest for the Brocarsquosarea comparison than for the inferior frontal sulcuscomparison

Finally average functional intensities within significantactivity volumes were compared with t tests to ascertainif there were intensity differences within the volumesacross tasks (Table 2) Within brain areas probabilitylevels were Bonferroni corrected for the number ofcomparisons Functional intensities within SMA did notdiffer significantly between free generation and repeti-tion (t = ndash 015 df = 79 p gt 80) For pre-SMABA 32the only significant difference in functional intensitieswas that the functional intensity for free generation wasgreater than that for paced generation (t = 321 df =272 p lt 005) Thus while the activity volume of pacedgeneration was second in size only to that of freegeneration for pre-SMABA 32 paced generation wasthe only task to show a significantly smaller averagefunctional intensity than free generation For Brocarsquosarea free generation showed significantly greater aver-age functional intensities than paced generation (t =375 df = 508 p lt 001) and repetition (t = 371 df =296 p lt 001) For the inferior frontal sulcus both freegeneration (t = 298 df = 235 p lt 005) and semanticgeneration (t = ndash 476 df = 297 p lt 001) showed

Figure 3 Medial to lateral frontal ratios plotted for pre-SMABA 32 toinferior frontal sulcus (IFS) and for pre-SMABA 32 to Brocarsquos area Theshift from medial to lateral frontal dominance is particularly obvious forthe IFS ratio See Figure 1 for x-axis key

Figure 2 Pre-SMABA 32 and lateral frontal activity volumes plottedacross tasks As word generation moved from internally to externallyguided activity volumes for pre-SMABA 32 and Brocarsquos area generallydecreased but activity volumes for the inferior frontal sulcus (IFS)increased See Figure 1 for x-axis key

276 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

during word generation as task demands shifted frominternally to externally guided Three word generationparadigms were performed during functional magneticresonance imaging (fMRI) Free generation requiredsubjects to generate as many exemplars as possible froma given semantic category and was the most internally(ie least externally) guided Paced generation re-quired subjects to generate a word from the givensemantic category every time they heard the cue lsquolsquonextrsquorsquoThis external pacing cue made paced generation moreexternally guided than free generation Semantic ge-neration was the most externally guided word genera-tion task Subjects were given a semantic category and acue describing a category member Subjects generatedthe word from the category that matched the descriptivecue For example after the category lsquolsquobirdrsquorsquo subjectsheard descriptive cues like lsquolsquoredrsquorsquo or lsquolsquoflightlessrsquorsquo towhich they might answer lsquolsquocardinalrsquorsquo or lsquolsquoemursquorsquo respec-tively For purposes of comparison subjects also per-formed a task during which they simply repeated givenwords Since repetition was totally dependent uponexternal input it was more externally guided than theword generation tasks

We hypothesized that as word production becamemore externally guided in the steps between freegeneration and word repetition the ratio of medialto lateral frontal activity would become smaller Thishypothesis was tested for both SMA and pre-SMABA32 separately Both Brocarsquos area (Goldberg 1985) andother lateral frontal cortex (Deiber et al 1991 Frithet al1991) have been implicated in externally guidedcompared to internally guided actions Because var-ious word generation studies have implicated differentlateral frontal regions in word generation (pars orbi-

talis by Petersen Fox Posner Mintun amp Raichle 1988BAs 9 and 46 by Frith et al1991 inferior frontalsulcus by Warburton et al 1996) composite groupimages (statistical parametric maps) were used toallow for exploration of different lateral frontal areasPilot work in our laboratory (Crosson et al 1998)indicated that the size of significantly activated vo-lumes could be used to assess task differences inextent of activity Average intensities within signifi-cantly activated volumes were also used to assessintensity of activity

RESULTS

Each experimental task was compared to the restingcontrol state using voxel-wise t tests across the 15neurologically normal subjects The voxel-wise prob-ability threshold was set at p lt 001 Because of thelarge number of t tests conducted activity volumeswere required to exceed 229 l the volume thresholddetermined by a random waveform analysis Table 1shows significant activity volumes within the frontallobe for each of the three word generation tasks andrepetition

The size of significant activity volumes was comparedbetween tasks for selected brain regions Brocarsquos areaSMA and pre-SMABA 32 were selected for this compar-ison based on the analysis of Goldberg (1985) andsubsequent studies dividing medial BA 6 into SMA andpre-SMA (Luppino et al 1993 Matsuzaka et al 1992)One other lateral frontal region was selected for thisanalysis based upon its activation in all three wordgeneration tasks The core of the region was withinthe banks of the most posterior portion of the inferior

Table 1 ( continued )

Semantic Generation Repetition

L Anatomic Areas Local Max

Averaget Test Valuefor Cluster L Anatomic Areas Local Max

Averaget Test Valuefor Cluster

2327 BAs 45 and 47 Ins (ndash 431915) ta v e ra g e=518 269 BA 45 (ndash 36265) tav e ra g e=495

2775 BAs 6 8 and 9 (ndash 382230) ta v e ra g e=533

920 BAs 4 and 6 (ndash 52ndash 444) tav e ra g e=512

574 BA 6 (ndash 39145) ta v e ra g e=503

363 BAs 6 and 44 (ndash 57520) tav e ra g e=466

none ndash ndash 574 post md BA 6 (ndash 62 57) tav e ra g e=519

615 ant md BAs 6 and 32 (ndash 41846) ta v e ra g e=529 321 ant md BAs 6 and 32 (ndash 7654) tav e ra g e=508

= posterior md = medial Local Max = location within the activity cluster of the maximum t value activity volumes in the same row indicates

274 Journal of Cognitive Neuroscience Volume 13 Number 2

frontal sulcus (BAs 6 and 8) For paced generation andsemantic generation it extended anteriorly along thesulcus into BAs 9 and 46 Comparisons between tasksrepresenting the progression from most internally tomost externally guided are presented below For eachregion two-tailed probabilities are Bonferroni correctedto a probability level of p lt 05 for all comparisons in theregion No comparison was conducted when no activitywas present within a region for a specific task

Figure 1 shows activity volumes in SMA pre-SMABA32 Brocarsquos area and the banks of the inferior frontalsulcus Activity in SMA was present only during the freegeneration and repetition tasks The volume of activatedvoxels was not significantly different between these tasks(z = 101 p gt 30) However significant activity waspresent in pre-SMABA 32 for all tasks The activityvolume became systematically smaller as tasks pro-gressed from internally to externally guided It waslargest for the free generation task and became signifi-

cantly smaller from free generation to paced generation(z = ndash 539 p lt 001) from paced generation tosemantic generation (z = ndash 666 p lt 001) and fromsemantic generation to repetition (z = ndash 339 p lt 001)Brocarsquos area showed a similar though somewhat lessdramatic pattern than pre-SMABA 32 with activityvolumes becoming smaller as tasks progressed frominternally to externally guided The activity volumedecreased significantly from free generation to pacedgeneration (z = ndash 292 p lt 005) from paced genera-tion to semantic generation (z = ndash 406 p lt 001) andfrom semantic generation to repetition (z = ndash 1220 p lt001) Activity volumes in the inferior frontal sulcus werepresent only for the word generation tasks and showedthe opposite pattern to pre-SMABA 32 increasing insize as word generation progressed from internal toexternal guidance The activity volume increased signifi-cantly from free generation to paced generation (z =609 p lt 001) and from paced generation to semantic

Figure 1 Activity volumes displayed on sagittal sections The anatomy was averaged for the 15 subjects for active areas red represents p lt 001yellow represents p lt 0001 The top row shows medial frontal activity 5 mm to the left of midline (Activity labeled as pre-SMA represents activity inboth pre-SMA and BA 32) The verticle green line represents the plane used to divide SMA and pre-SMA (4 mm anterior to the posterior margin ofthe anterior commissure) The middle and bottom rows emphasize differences in the inferior frontal sulcus (IFS) and Brocarsquos area (Brocarsquos) FreeGen = Free Generation Pace Gen = Paced Generation Sem Gen = Semantic Generation Rep = Repetition

Crosson et al 275

generation (z = 538 p lt 001) It is also of interest thatthe local maximum in the inferior frontal sulcus pro-gressed anteriorly as the word generation tasks movedfrom internal to external guidance For free generationthe local maximum was in BA 6 It progressed to theborder between BAs 6 and 8 in paced generation and tothe border between BAs 8 and 9 in semantic generation(see Table 1) Figure 2 illustrates changes in activityvolumes between tasks for pre-SMABA 32 Brocarsquos areaand the inferior frontal sulcus In summary in terms ofabsolute size of significant activity volumes SMA andBrocarsquos area did not meet Goldbergrsquos (1985) predictionof a shift from medial to lateral premotor activity as wordgeneration tasks shifted from internally to externallyguided However if Goldbergrsquos hypothesis is modifiedto focus on pre-SMABA 32 and lateral frontal cortex onthe banks of the inferior frontal sulcus then a medial tolateral shift did occur as word generation tasks shiftedfrom internally to externally guided Across the threeword generation tasks activity systematically decreasedin pre-SMABA 32 and significantly increased in thebanks of the inferior frontal sulcus as word generationshifts from internal to external guidance

The relationship between size for medial and lateralfrontal activity volumes also can be represented as amedial to lateral frontal ratio Figure 3 shows activityvolume ratios for pre-SMA to Brocarsquos area and for pre-SMABA 32 to inferior frontal sulcus Regarding therelationship between pre-SMABA 32 and Brocarsquos areathere was a consistent and modest decrease in themedial to lateral frontal ratio from the most internallyguided (free generation) to the most externally guided(semantic generation) word generation task In Brocarsquosarea the ratio is higher for repetition than for the wordgeneration tasks For the relationship between pre-

SMABA 32 and inferior frontal sulcus there was a largeand consistent decrease in the medial to lateral frontalratio from the most internally guided (free generation)to the most externally guided (semantic generation)word generation task There was no activity in theinferior frontal sulcus for repetition Thus ratios ofactivity volumes for pre-SMABA 32 compared both toBrocarsquos area and to the banks of the inferior frontalsulcus demonstrate relative medial to lateral frontalshifts as word generation tasks become more externallyguided The shift is much more modest for the Brocarsquosarea comparison than for the inferior frontal sulcuscomparison

Finally average functional intensities within significantactivity volumes were compared with t tests to ascertainif there were intensity differences within the volumesacross tasks (Table 2) Within brain areas probabilitylevels were Bonferroni corrected for the number ofcomparisons Functional intensities within SMA did notdiffer significantly between free generation and repeti-tion (t = ndash 015 df = 79 p gt 80) For pre-SMABA 32the only significant difference in functional intensitieswas that the functional intensity for free generation wasgreater than that for paced generation (t = 321 df =272 p lt 005) Thus while the activity volume of pacedgeneration was second in size only to that of freegeneration for pre-SMABA 32 paced generation wasthe only task to show a significantly smaller averagefunctional intensity than free generation For Brocarsquosarea free generation showed significantly greater aver-age functional intensities than paced generation (t =375 df = 508 p lt 001) and repetition (t = 371 df =296 p lt 001) For the inferior frontal sulcus both freegeneration (t = 298 df = 235 p lt 005) and semanticgeneration (t = ndash 476 df = 297 p lt 001) showed

Figure 3 Medial to lateral frontal ratios plotted for pre-SMABA 32 toinferior frontal sulcus (IFS) and for pre-SMABA 32 to Brocarsquos area Theshift from medial to lateral frontal dominance is particularly obvious forthe IFS ratio See Figure 1 for x-axis key

Figure 2 Pre-SMABA 32 and lateral frontal activity volumes plottedacross tasks As word generation moved from internally to externallyguided activity volumes for pre-SMABA 32 and Brocarsquos area generallydecreased but activity volumes for the inferior frontal sulcus (IFS)increased See Figure 1 for x-axis key

276 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

frontal sulcus (BAs 6 and 8) For paced generation andsemantic generation it extended anteriorly along thesulcus into BAs 9 and 46 Comparisons between tasksrepresenting the progression from most internally tomost externally guided are presented below For eachregion two-tailed probabilities are Bonferroni correctedto a probability level of p lt 05 for all comparisons in theregion No comparison was conducted when no activitywas present within a region for a specific task

Figure 1 shows activity volumes in SMA pre-SMABA32 Brocarsquos area and the banks of the inferior frontalsulcus Activity in SMA was present only during the freegeneration and repetition tasks The volume of activatedvoxels was not significantly different between these tasks(z = 101 p gt 30) However significant activity waspresent in pre-SMABA 32 for all tasks The activityvolume became systematically smaller as tasks pro-gressed from internally to externally guided It waslargest for the free generation task and became signifi-

cantly smaller from free generation to paced generation(z = ndash 539 p lt 001) from paced generation tosemantic generation (z = ndash 666 p lt 001) and fromsemantic generation to repetition (z = ndash 339 p lt 001)Brocarsquos area showed a similar though somewhat lessdramatic pattern than pre-SMABA 32 with activityvolumes becoming smaller as tasks progressed frominternally to externally guided The activity volumedecreased significantly from free generation to pacedgeneration (z = ndash 292 p lt 005) from paced genera-tion to semantic generation (z = ndash 406 p lt 001) andfrom semantic generation to repetition (z = ndash 1220 p lt001) Activity volumes in the inferior frontal sulcus werepresent only for the word generation tasks and showedthe opposite pattern to pre-SMABA 32 increasing insize as word generation progressed from internal toexternal guidance The activity volume increased signifi-cantly from free generation to paced generation (z =609 p lt 001) and from paced generation to semantic

Figure 1 Activity volumes displayed on sagittal sections The anatomy was averaged for the 15 subjects for active areas red represents p lt 001yellow represents p lt 0001 The top row shows medial frontal activity 5 mm to the left of midline (Activity labeled as pre-SMA represents activity inboth pre-SMA and BA 32) The verticle green line represents the plane used to divide SMA and pre-SMA (4 mm anterior to the posterior margin ofthe anterior commissure) The middle and bottom rows emphasize differences in the inferior frontal sulcus (IFS) and Brocarsquos area (Brocarsquos) FreeGen = Free Generation Pace Gen = Paced Generation Sem Gen = Semantic Generation Rep = Repetition

Crosson et al 275

generation (z = 538 p lt 001) It is also of interest thatthe local maximum in the inferior frontal sulcus pro-gressed anteriorly as the word generation tasks movedfrom internal to external guidance For free generationthe local maximum was in BA 6 It progressed to theborder between BAs 6 and 8 in paced generation and tothe border between BAs 8 and 9 in semantic generation(see Table 1) Figure 2 illustrates changes in activityvolumes between tasks for pre-SMABA 32 Brocarsquos areaand the inferior frontal sulcus In summary in terms ofabsolute size of significant activity volumes SMA andBrocarsquos area did not meet Goldbergrsquos (1985) predictionof a shift from medial to lateral premotor activity as wordgeneration tasks shifted from internally to externallyguided However if Goldbergrsquos hypothesis is modifiedto focus on pre-SMABA 32 and lateral frontal cortex onthe banks of the inferior frontal sulcus then a medial tolateral shift did occur as word generation tasks shiftedfrom internally to externally guided Across the threeword generation tasks activity systematically decreasedin pre-SMABA 32 and significantly increased in thebanks of the inferior frontal sulcus as word generationshifts from internal to external guidance

The relationship between size for medial and lateralfrontal activity volumes also can be represented as amedial to lateral frontal ratio Figure 3 shows activityvolume ratios for pre-SMA to Brocarsquos area and for pre-SMABA 32 to inferior frontal sulcus Regarding therelationship between pre-SMABA 32 and Brocarsquos areathere was a consistent and modest decrease in themedial to lateral frontal ratio from the most internallyguided (free generation) to the most externally guided(semantic generation) word generation task In Brocarsquosarea the ratio is higher for repetition than for the wordgeneration tasks For the relationship between pre-

SMABA 32 and inferior frontal sulcus there was a largeand consistent decrease in the medial to lateral frontalratio from the most internally guided (free generation)to the most externally guided (semantic generation)word generation task There was no activity in theinferior frontal sulcus for repetition Thus ratios ofactivity volumes for pre-SMABA 32 compared both toBrocarsquos area and to the banks of the inferior frontalsulcus demonstrate relative medial to lateral frontalshifts as word generation tasks become more externallyguided The shift is much more modest for the Brocarsquosarea comparison than for the inferior frontal sulcuscomparison

Finally average functional intensities within significantactivity volumes were compared with t tests to ascertainif there were intensity differences within the volumesacross tasks (Table 2) Within brain areas probabilitylevels were Bonferroni corrected for the number ofcomparisons Functional intensities within SMA did notdiffer significantly between free generation and repeti-tion (t = ndash 015 df = 79 p gt 80) For pre-SMABA 32the only significant difference in functional intensitieswas that the functional intensity for free generation wasgreater than that for paced generation (t = 321 df =272 p lt 005) Thus while the activity volume of pacedgeneration was second in size only to that of freegeneration for pre-SMABA 32 paced generation wasthe only task to show a significantly smaller averagefunctional intensity than free generation For Brocarsquosarea free generation showed significantly greater aver-age functional intensities than paced generation (t =375 df = 508 p lt 001) and repetition (t = 371 df =296 p lt 001) For the inferior frontal sulcus both freegeneration (t = 298 df = 235 p lt 005) and semanticgeneration (t = ndash 476 df = 297 p lt 001) showed

Figure 3 Medial to lateral frontal ratios plotted for pre-SMABA 32 toinferior frontal sulcus (IFS) and for pre-SMABA 32 to Brocarsquos area Theshift from medial to lateral frontal dominance is particularly obvious forthe IFS ratio See Figure 1 for x-axis key

Figure 2 Pre-SMABA 32 and lateral frontal activity volumes plottedacross tasks As word generation moved from internally to externallyguided activity volumes for pre-SMABA 32 and Brocarsquos area generallydecreased but activity volumes for the inferior frontal sulcus (IFS)increased See Figure 1 for x-axis key

276 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

generation (z = 538 p lt 001) It is also of interest thatthe local maximum in the inferior frontal sulcus pro-gressed anteriorly as the word generation tasks movedfrom internal to external guidance For free generationthe local maximum was in BA 6 It progressed to theborder between BAs 6 and 8 in paced generation and tothe border between BAs 8 and 9 in semantic generation(see Table 1) Figure 2 illustrates changes in activityvolumes between tasks for pre-SMABA 32 Brocarsquos areaand the inferior frontal sulcus In summary in terms ofabsolute size of significant activity volumes SMA andBrocarsquos area did not meet Goldbergrsquos (1985) predictionof a shift from medial to lateral premotor activity as wordgeneration tasks shifted from internally to externallyguided However if Goldbergrsquos hypothesis is modifiedto focus on pre-SMABA 32 and lateral frontal cortex onthe banks of the inferior frontal sulcus then a medial tolateral shift did occur as word generation tasks shiftedfrom internally to externally guided Across the threeword generation tasks activity systematically decreasedin pre-SMABA 32 and significantly increased in thebanks of the inferior frontal sulcus as word generationshifts from internal to external guidance

The relationship between size for medial and lateralfrontal activity volumes also can be represented as amedial to lateral frontal ratio Figure 3 shows activityvolume ratios for pre-SMA to Brocarsquos area and for pre-SMABA 32 to inferior frontal sulcus Regarding therelationship between pre-SMABA 32 and Brocarsquos areathere was a consistent and modest decrease in themedial to lateral frontal ratio from the most internallyguided (free generation) to the most externally guided(semantic generation) word generation task In Brocarsquosarea the ratio is higher for repetition than for the wordgeneration tasks For the relationship between pre-

SMABA 32 and inferior frontal sulcus there was a largeand consistent decrease in the medial to lateral frontalratio from the most internally guided (free generation)to the most externally guided (semantic generation)word generation task There was no activity in theinferior frontal sulcus for repetition Thus ratios ofactivity volumes for pre-SMABA 32 compared both toBrocarsquos area and to the banks of the inferior frontalsulcus demonstrate relative medial to lateral frontalshifts as word generation tasks become more externallyguided The shift is much more modest for the Brocarsquosarea comparison than for the inferior frontal sulcuscomparison

Finally average functional intensities within significantactivity volumes were compared with t tests to ascertainif there were intensity differences within the volumesacross tasks (Table 2) Within brain areas probabilitylevels were Bonferroni corrected for the number ofcomparisons Functional intensities within SMA did notdiffer significantly between free generation and repeti-tion (t = ndash 015 df = 79 p gt 80) For pre-SMABA 32the only significant difference in functional intensitieswas that the functional intensity for free generation wasgreater than that for paced generation (t = 321 df =272 p lt 005) Thus while the activity volume of pacedgeneration was second in size only to that of freegeneration for pre-SMABA 32 paced generation wasthe only task to show a significantly smaller averagefunctional intensity than free generation For Brocarsquosarea free generation showed significantly greater aver-age functional intensities than paced generation (t =375 df = 508 p lt 001) and repetition (t = 371 df =296 p lt 001) For the inferior frontal sulcus both freegeneration (t = 298 df = 235 p lt 005) and semanticgeneration (t = ndash 476 df = 297 p lt 001) showed

Figure 3 Medial to lateral frontal ratios plotted for pre-SMABA 32 toinferior frontal sulcus (IFS) and for pre-SMABA 32 to Brocarsquos area Theshift from medial to lateral frontal dominance is particularly obvious forthe IFS ratio See Figure 1 for x-axis key

Figure 2 Pre-SMABA 32 and lateral frontal activity volumes plottedacross tasks As word generation moved from internally to externallyguided activity volumes for pre-SMABA 32 and Brocarsquos area generallydecreased but activity volumes for the inferior frontal sulcus (IFS)increased See Figure 1 for x-axis key

276 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

significantly greater functional intensities than pacedgeneration It is worth noting that differences in func-tional intensities frequently did not follow the samepattern as progressions in volume size For word gen-eration tasks volume size followed orderly progressionsin accordance with degree of internal versus externalguidance for pre-SMABA 32 Brocarsquos area and the banksof the inferior frontal sulcus such progressions were notseen for functional intensities In particular the in-creased volume in the inferior frontal sulcus betweenfree and paced generation was actually accompanied bya decrease in average functional intensity for the respec-tive volumes

DISCUSSION

Our findings can be best summarized as follows For pre-SMABA 32 and the posterior inferior frontal gyrus (parsorbitalis and Brocarsquos area plus anterior insula) there wasa general decrease in activity volumes from free genera-tion to paced generation from paced generation tosemantic generation and from semantic generation torepetition For cortex on the banks of the posteriorinferior frontal sulcus there was an area of activityconfined to the most posterior portion of this region(BAs 6 and 8) during free generation This area ex-panded from free generation to paced generation (BAs6 8 9 and 46) and expanded again within these areasfrom paced generation to semantic generation Therewas no significant activity in this region during repeti-tion For SMA a volume of equal size was present duringfree generation and repetition no significant SMA activ-ity was present during paced generation or semanticgeneration Thus when considering absolute volumes ofactivity Goldbergrsquos (1985) hypothesis regarding SMAand Brocarsquos area was not strictly confirmed There wasno consistent decrease in SMA activity volumes acrossgeneration tasks and activity volumes in Brocarsquos areadecreased instead of increased as word generationprogressed from internally to externally guided How-ever if Goldbergrsquos hypothesis is modified to focus onpre-SMABA 32 instead of SMA and cortex on the banks

of the posterior inferior frontal sulcus instead of Brocarsquosarea the hypothesis was confirmed Pre-SMABA 32activity showed consistent decreases in activity volumesand the inferior frontal sulcus cortex showed consistentincreases as word generation progressed from internallyto externally guided

The relationship between pre-SMABA 32 and the twolateral frontal areas (Brocarsquos area inferior frontal sulcus)also can be assessed as ratios of medial to lateral frontalactivity volumes Specifically for pre-SMABA 32 and theinferior frontal sulcus there was a clear decrease in theratio as word generation shifted from internally toexternally guided indicating a shift from medial tolateral frontal activity within these regions In spite ofthe fact that pre-SMABA 32 and Brocarsquos area bothshowed decreased activity volumes as word generationprogressed from internally to externally guided therelative rate of decrease in volumes was somewhatgreater for pre-SMABA 32 than for Brocarsquos area In thissense there also was a shift from medial to lateral frontalprominence in the relationship of these areas as wordgeneration became more externally guided

The response of medial and lateral frontal cortexduring repetition deserves further consideration Be-cause during repetition a subjectrsquos response is totallydetermined by external input it can be considered moreexternally driven than any of the word generation tasksIndeed regarding activity volumes in pre-SMABA 32 theconsistent decrease from internally to externally guidedword generation tasks continued as the activity volumedecreased from semantic generation to repetition Inabsolute terms this trend was also true for Brocarsquos areathough the drop off was much steeper in Brocarsquos areathan in pre-SMABA 32

However it was in the activity volumes for cortex ofthe inferior frontal sulcus where the difference betweenrepetition and the word generation tasks became ob-vious Activity volumes in this region increased as wordgeneration tasks shifted from internal to external gui-dance but during repetition the most externally guidedword production task there was no activity in thisregion This facet of the data necessitates further con-

Table 2 Studentrsquos t Values Comparing Average Functional Intensities Between Tasks for Each Brain Area

Tasks Compared

BrainRegion

FreeversusPaced

Freeversus

Semantic

Freeversus

Repetition

Pacedversus

Semantic

Pacedversus

Repetition

Semanticversus

Repetition

SMA ndash ndash ndash 015 ndash ndash ndash

Pre-SMA 321a 146 269 ndash 079 044 098

Brocarsquos Area 375a 271 371a ndash 092 122 179

Inferior Frontal Sulcus 298a ndash 081 ndash ndash 476a ndash ndash

aExceeds Bonferroni corrected probability for p lt 05 within each area

Crosson et al 277

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

sideration of the reasons for the medial to lateral frontalshift Obviously it is not just the dimension of internalversus external guidance which controls the amount ofcortex activated along the inferior frontal sulcus Thenature of the task also has an impact on which frontalareas are recruited How then does repetition differfrom the word generation tasks such that it does notengage cortex on the banks of the inferior frontal sulcusThe probable answer is that all the word generationtasks in this study require semantic processing (iemembership in the given semantic category) Ellis andYoung (1988) indicated that semantic processing can bebypassed during repetition instead relying on proces-sing of the word forms (ie lexical features of thewords) Thus with respect to cortex of the inferiorfrontal sulcus it appears to be the internal versusexternal guidance of semantically based selection thatdrives changes in activity volumes between tasks Put ina more general way the type of task determines thespecific frontal region that becomes active and withinthe type of task the degree of internal versus externalguidance will determine the spatial extent of activitywithin the specific region

Support for this interpretation can be found in theliterature on aphasia In transcortical motor aphasia(TCMA) patients have difficulty initiating language out-put (Alexander 1997) Of specific relevance to thecurrent discussion is the finding that patients with TCMAhave highly impaired generation of word lists from asemantic cue while repetition is intact or nearly so(Freedman Alexander amp Naeser 1984) FurtherMcCarthy and Warrington (1984) showed that repetitioncould be impeded in patients with TCMA if the repeti-tion task was semantically loaded suggesting that TCMAis in part a semantic deficit The most common lesionsite for TCMA is in the left frontal cortex superior topars triagularis and pars opercularis (ie superior toBrocarsquos area) (Freedman et al 1984) in other words inthe neighborhood of the inferior frontal sulcus Thesedata provide converging evidence that the cortex of theinferior frontal sulcus above Brocarsquos area is involved inword generation from semantic cues but not involved inrepetition

Differences in intensity of activity within the identifiedregions (SMA pre-SMABA 32 Brocarsquos area cortex onthe banks of the inferior frontal sulcus) generally did notfollow the same pattern of increase or decrease as didthe activity volumes and therefore give further clues asto the nature of the activity in these regions In parti-cular the volume of activity along the inferior frontalsulcus that expanded systematically as word generationmoved from internal to external guidance did not de-monstrate the same progression for intensity of activityAs the volume of significant activity enlarged from freegeneration to paced generation the intensity of theactivity within the activated region decreased Thenfrom paced generation to semantic generation the

intensity within the activated volume increased againWe offer the following hypothesis regarding these differ-ing patterns between volume and intensity Sensoryassociation cortex projects to the frontal lobe Specifi-cally association cortex early in the stream for auditoryprocessing projects to BA 8 on the convexity Furtherdownstream more processed information projects moreanteriorly to BAs 9 and 46 The most processed auditoryinformation projects to the orbitofrontal region BA 13(Pandya amp Yeterian 1985) When demands for proces-sing external information are minimal (free generation)activity on the banks of the inferior frontal sulcus isconfined to the posterior portion BAs 6 and 8 Whenthe external cue in paced generation must be processedto time responses frontal cortex connected to higherlevel auditory processing regions was recruited How-ever the demands for integrating the external cue withthe semantic nature of the response were not high forpaced generation all the subject needed to know wasthat the cue had occurred not the specific semanticproperties of the cue Since the demands for integratinginformation extracted from the cue with the semanticproperties were not high for paced generation theintensity of activity need not have been high In semanticgeneration the subject had to explicitly integrate thesemantic nature of the cue with the semantic propertiesof the response matching the feature described by thecue with the response This increased demand forintegrating the semantic properties of the cue with thesemantic response resulted in an intensity increase forcortex in the activated region of the inferior frontalsulcus The reversal of intensity differences betweenpaced generation and semantic generation was uniqueto cortex on the banks of the inferior frontal sulcus (seeTable 2)

Two limitations in the current study should be men-tioned briefly (a) When comparing the generation tasksmore words were produced during the 174-sec half-cycle for free generation than were produced during the174-sec half-cycle for paced generation and semanticgeneration However the difference in the number ofwords generated cannot account for all the findingsFirst a drop in the volume of activation for pre-SMABA32 and Brocarsquos area occurred from paced to semanticgeneration in spite of the nearly identical number ofwords generated for these tasks Second larger activityvolumes around the inferior frontal sulcus were found inpaced and semantic generation than in free generationin spite of the fact that fewer words were produced inpaced and semantic generation than in free generationThird the number of words produced was greater forrepetition than for any other task yet the largest de-creases in activity volumes for pre-SMABA 32 and forBrocarsquos area occurred from free generation to repetition(b) For the paced generation task it is possible thatsubjects sometimes were able to think of the nextresponse before the pacing cue was given and had to

278 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

inhibit its production until the pacing cue was givenAgain this possibility cannot account for the pattern ofresults in Table 1 First if an inhibition component tothe paced generation task were a prominent featurethen the area responsible for inhibition should haveemerged as most active for paced generation No suchfrontal area was found Second this type of inhibitionwould not have been a prominent feature of the otherword generation tasks thus it cannot account for thesystematic changes between the three word generationtasks

Nonetheless these task differences are worth metho-dological consideration One recent study conductedword generation with an event-related paradigm inwhich a single response was given for each cue (BirnBandettini Cox amp Shaker 1999) If free generationand semantic generation were compared using anevent-related paradigm it would solve both of theabove mentioned problems Since only a single res-ponse is given for each cue the number of responseswould be equated As the response would be given assoon as it was conceived there would be no inhibitioncomponent

To summarize both pre-SMABA 32 and Brocarsquosarea showed significant decreases in activity volumesas word generation progressed from internally toexternally guided and a further decrease in activityvolume from externally guided word generation (se-mantic generation) to repetition which is completelyguided by the external cue Cortex around the inferiorfrontal sulcus showed the opposite pattern for wordgeneration an increase in activity volume as wordgeneration moved from internally to externally guidedHowever there was no activity around the inferiorfrontal sulcus for repetition indicating that repetitionwas qualitatively different than the word generationtasks and that even within the domain of languagedifferent regions of lateral frontal cortex may need tobe explored for different kinds of tasks Strictly speak-ing Goldbergrsquos (1985) hypothesis regarding a shiftfrom SMA to Brocarsquos area prominence as languagetasks shift from internal to external guidance was notconfirmed However if the task is limited to genera-tion of category exemplars and if pre-SMABA 32 andcortex around the inferior frontal sulcus are examinedinstead of SMA and Brocarsquos area respectively then amedial to lateral frontal shift was demonstrated in thecurrent study as word generation shifted from intern-ally to externally guided

METHODS

Subjects

Fifteen students faculty or staff at the University ofFlorida andor residents of Gainesville Florida (eightmale seven female) participated Ages ranged from 19 to31 years (mean = 230 SD = 35) education ranged

from 13 to 20 years (mean = 165 SD = 20) All subjectsspoke English as a native language and according to theEdinburgh Handedness Inventory (Oldfield 1971) wereright handed (mean laterality quotient = 796 SD =167) All subjects gave written informed consent inaccordance with a protocol approved by the HealthCenter Institutional Review Board at the University ofFlorida

Word Production Tasks

All subjects performed the three word production tasksand the word repetition task silently during scanningsessions (a) In free generation subjects received asemantic category and generated as many exemplars aspossible after hearing the cue lsquolsquobeginrsquorsquo and until theyheard the cue lsquolsquoendrsquorsquo at the end of the 174-sec taskperiod For example subjects might hear the categorylsquolsquobirdsrsquorsquo then they would generate the names of as manybirds as they could during the task period Because therewas no external guidance regarding when to produce anexemplar or what exemplar to produce free generationwas the most internally guided and the least externallyguided word generation task (b) In paced generationsubjects received a semantic category followed by theword lsquolsquonextrsquorsquo repeated six times at evenly spaced intervalsduring the 174-sec task period Each time subjects heardlsquolsquonextrsquorsquo they generated one new category member Forexample subjects might hear the category lsquolsquobirdsrsquorsquo thenevery time they heard the word lsquolsquonextrsquorsquo they wouldgenerate the name of a different bird Because theexternal cue determined when subjects produced aword paced generation was more externally guided thanfree generation (c) In semantic generation subjectsreceived a semantic category followed by six descriptorsevenly spaced during the 174-sec task interval For eachdescriptor subjects generated one category member thatmatched the descriptor For example subjects mighthear the category lsquolsquobirdsrsquorsquo followed by the descriptorslsquolsquored flightless bald rsquorsquo For these descriptors thesubjects might generate the category members lsquolsquocardinal emu eagle rsquorsquo respectively Exemplars weregenerated one at a time immediately after each descrip-tor Because the descriptors acted not only as a cue toproduce a word but also determined what word wasproduced semantic generation was the most externallyguided word generation task (d) In repetition subjectsrepeated 10 words one at a time during each 174-sectask period In repetition the word produced was totallydetermined by external input

For paced generation and semantic generationsubjects were told to say the word lsquolsquopassrsquorsquo to them-selves if they could not think of an exemplar Eachlanguage production task alternated with 174-secperiods of rest during which subjects were discour-aged from thinking any words to themselves Threelists of six categories each were composed for the

Crosson et al 279

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

three generation tasks Categories for the lists weredrawn from various living and nonliving items Non-living categories included both natural and human-made items Examples of categories are lsquolsquobirdsrsquorsquolsquolsquoweather eventsrsquorsquo and lsquolsquotoolsrsquorsquo The three lists ofcategories were counterbalanced with the three wordgeneration tasks The rate of cuing for paced genera-tion and semantic generation was selected to optimizeboth speed and accuracy of word generation based onpilot data The speed of generation had to bematched to the slower responses to cues otherwiseaccuracy deteriorated In paced generation and seman-tic generation playing the cue lsquolsquonextrsquorsquo and the seman-tic descriptors respectively also occupied time duringthe 174-sec task period On the average playing thecues during paced generation occupied 17 sec moretime than playing the lsquolsquobeginrsquorsquo and lsquolsquoendrsquorsquo cues in freegeneration and playing the descriptors during seman-tic generation occupied 28 sec more time than play-ing cues in the free generation Because thepresentation of cues in paced and semantic generationhad to be matched to slower responses to cues andbecause the playing of these cues took more potentialword generation time than in free generation the rateof word generation could not be matched betweenpaced generation and semantic generation on the onehand and free generation on the other However therate of cue presentation for the paced and semanticgeneration tasks was precisely matched to each otherand based upon pilot data the rate of repetition waschosen to approximate the rate of word generation forthe free generation task

In order to determine average rates of word pro-duction for each task in our sample 10 of the 15subjects returned to the laboratory within a few daysof scanning sessions and performed each word pro-duction task aloud with the same stimuli as used inthe scanning experiments Responses were recordedand scored by a listener The average number ofwords generated in a 174-sec task period did notdiffer significantly between paced generation (59)and semantic generation (58) The average numberof words repeated in a 174-sec repetition period(100) was significantly greater than the number ofwords produced during either paced generation orsemantic generation The average number of wordsproduced during free generation (87) was intermedi-ate between repetition and paced or semantic gen-eration differing significantly from each of the othertasks

Stimulus Presentation

Each experimental run consisted of 64 cycles of rest-taskalternation beginning and ending with a rest period Allword production was accomplished silently to avoidimage artifacts created when subjects speak during

scanning and to avoid activation elicited when subjectshear their own voice Chao Haxby amp Martin (1999)Herholz et al (1996) Martin Wiggs Ungerleider andHaxby (1996) and Warburton et al (1996) have pre-viously used silent language production successfully infunctional imaging studies requiring word productionIn particular Warburton et al have shown that resultscan be reliably reproduced across studies we have hadsimilar findings in our laboratory (Crosson Radonovichet al 1999 Crosson Sadek et al 1999) The order ofpresentation of the four language production tasks wasrandomized In addition the three lists were counter-balanced across generation tasks

Word lists were presented using an IBM 380ED note-book computer and software written in our laboratoryfor stimulus presentation Output from the computerwas amplified using a Kenwood KR-A4070 amplifier andbiased toward the high end of the frequency spectrumusing a Realistic 31-2005 Ten Band Stereo FrequencyEqualizer to compensate for the loss of amplitude inhigher frequencies through the air conduction appara-tus Words were played through a JBL 2446J 16-laquo speak-er which was attached to an air conduction transducerconstructed at our facility Tubing in the air conductiontransducer was insulated to minimize contamination ofstimuli by scanner noise Foam insert ear phones werepositioned in the external auditory meatus as the finallink in the air conduction transducer These foam insertsattenuate scanner noise by approximately 20 dB soundpressure level (Binder et al 1995)

Before beginning experiments individual thresholdsfor word recognition were determined Words wereplayed above threshold while the scanner was operatingand sound levels were reduced until target words couldno longer be distinguished in a list of words Thenstimuli were delivered at 30ndash35 dB above thresholdBefore beginning the experiment this level of presenta-tion was verified to produce clearly understandablewords without discomfort during scanning

Image Acquisition

Functional structural and angiographic images wereacquired on a GE 15T Signa scanner using a dome-shaped quadrature radio frequency head coil Afterestablishing the auditory threshold and adjusting soundlevels for clear but comfortable presentation a series ofT1-weighted axial scout scans were acquired in order todetermine location of sagittal functional images Headalignment in the coil was adjusted if necessary suchthat the interhemispheric fissure was within 18 of ver-tical The most medial sagittal slice for functional imageswas placed such that the most medial edge of the slicecorresponded with the medial boundary of the lefthemisphere Nine slices (64ndash69 mm thick) were usedto cover the entire left hemisphere Before functionalimages were acquired during task presentation a time-

280 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

of-flight MR angiogram (TE = 66 msec TR = 40 msecFA = 608 FOV = 18 cm matrix = 256 pound 192) wasacquired using exactly the same nine slices used forfunctional images This way functional images could beoverlaid onto MR angiogram slices to ascertain theexistence of large vessel effects For functional scans aseries of 64 images was acquired for each of the ninesagittal slices using a gradient echo spiral scan technique(King Foo amp Crawford 1995 Noll Cohen Meyer ampSchneider 1995 Macovski 1985) with TE = 40 msec TR= 870 msec FA = 458 FOV = 18 cm matrix size =128 pound 128 four spirals) Subsequent to functional ima-ging runs structural images were acquired for 124 pound 13-mm-thick sagittal slices using a 3-D spoiled GRASSvolume acquisition (TE = 7 msec TR = 27 msec NEX= 1 FOV = 24 cm matrix size = 256 pound 192)

Image Analysis

Functional images were analyzed and overlaid ontoanatomic images with the Analysis of Functional Neuroi-maging (AFNI) program (Cox 1996a) To reduce effectsof motion images were spatially registered in-plane to abase image using an iterative procedure minimizing thevariance in voxel intensity ratios of the two imagesImages were visually inspected for gross artifact andviewed in a cine loop to detect residual motion If anytime series of a subject was judged to contain a sig-nificant number of images with gross artifacts or residualmotion the subjectrsquos data were eliminated from ana-lyses Significant artifacts and motion were detected inimages from one of 16 subjects leaving the 15 subjectsdescribed above Mean signal intensities for individualimages in the slice-time matrix were normalized to thegroup mean and voxels for which the standard devia-tion of the signal in the time series exceeded 5 of themean signal for the voxel were set to zero to attenuatelarge vessel effects and residual motion artifacts Lineardrift in the time series was removed using GramndashSchmidt orthogonalization A composite functional im-age was generated using magnitude of least squares fit(MLSF) between the acquired time series from eachvoxel and an ideal sinusoidal reference waveformtime-locked to the alternating cycles of word generationand rest (Bandettini Jesmanowicz Wong amp Hyde1993) MLSF is an additive function that contains infor-mation about the temporal correlation of the acquiredtime series with the selected reference wave form aswell as the amplitude of intensity changes in the ac-quired time series1 Because each spiral of the variousslices was collected at a slightly different time andbecause hemodynamic responses might vary slightlybetween brain regions nine phase-shifted sinusoidalreference waveforms were used to compensate for thetemporal difference The phase shifts were evenly dis-tributed across the time required to collect two imagesfor each of the nine slices (696 sec) The waveform

generating the highest correlation was used for eachvoxel

To standardize images across subjects whole-brainanatomic images and functional images were linearlyinterpolated to 1-mm3 voxels coregistered and con-verted to stereotactic coordinate space (Talaraich ampTournoux 1988) To accomplish the conversion to atlasspace the brain was divided into 12 compartments bythe midsagittal plane an axial plane through the anteriorcommissurendashposterior commissure line and coronalplanes through the posterior commissure and the pos-terior margin of the anterior commissure Each of thecompartments was scaled separately to match the di-mensions of the atlas (Cox 1996b) Functional imagevolumes were smoothed (3-mm FWHM Gaussian filter)to compensate for intersubject variability in structuraland functional anatomy Studentrsquos t tests were con-ducted on a voxel-by-voxel basis comparing alternationsbetween each of the four word production tasks and restto a null hypothesis of no change in activity from rest toword production Similar to recommendations by For-man et al (1995) we used both a statistical probabilitythreshold applied on a voxel by voxel basis and a cluster-size threshold of contiguous voxels to identify regions ofsignificant activity For each t test procedure minimumvolumes of significant activity ( p lt 001) were requiredto exceed the largest volume (ie 229 l) generatedfrom conducting analyses with nine random referencewaveforms on the four tasks Bullmore et al (1996) haveused randomization procedures to determine probabil-ity distributions for fMRI images though our method isless computationally intensive The probability level p lt001 was chosen because it is a common value used infunctional imaging studies and has produced stable andreproducible findings in our laboratory In order toenhance the distinction between activity clusters thinbands of activity connecting larger more coherent clus-ters were eliminated using the erode and dilate algo-rithms of AFNI Using the erode algorithm thefunctional intensity within each voxel was set to zero ifless than 95 of the voxels within a 18-mm radiuscontained significant activity The dilate algorithm re-stored voxels removed by erosion if there remained anonzero voxel within a 18-mm radius

Three regions of interest for analyses were specified apriori based on the analysis of Goldberg (1985) andsubsequent work on the medial frontal cortex Goldberghad designated SMA as the important region of medialfrontal cortex for consideration in language productionhowever since his analysis medial BA 6 has beendivided into SMA and pre-SMA (Luppino et al 1993Matsuzaka et al 1992) Pre-SMA along with adjacent BA32 seems somewhat more involved in word generation(Crosson Rao et al 1999 Picard amp Strick 1996) thanSMA Therefore supracallosal medial frontal cortex wasdivided into SMA and pre-SMABA 32 by a coronal plane4 mm anterior to the posterior margin of the anterior

Crosson et al 281

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

commissure This division was based on the most ante-rior peak for word repetition in Picard and Strickrsquos(1996) meta-analysis as well as determination of thepoint at which word generation and repetition havedivided into distinct clusters in previous studies inour laboratory (Crosson et al 1998 Crosson Radono-vich et al 1999) In addition to these two medialfrontal areas Brocarsquos area was selected as a lateralfrontal region for comparison to medial frontal activitybased on Goldbergrsquos analysis

Because pre-SMABA 32 is connected to lateral frontalcortex and because various regions of lateral frontalactivity outside of Brocarsquos area have been found duringword generation (eg Warburton et al 1996 Frith etal 1991 Petersen et al 1988) it was necessary toexplore other lateral frontal cortex outside of Brocarsquosarea However previous literature did not allow for aspecific region to be defined For this reason we main-tained an exploratory approach to the analyses Signifi-cant volumes of activity in the left frontal lobe wereidentified as noted above and any volume present for allthree word generation tasks was included in furtheranalyses

These further analyses included comparisons of vo-lume and intensity of activity within areas and acrosstasks The primary analysis was comparison of volumeie the spatial extent of activity between tasks Thesecomparisons were accomplished as follows A rectangu-lar solid was defined for each area of significant activityby the maximum anteriorndashposterior medialndashlateral andinferiorndashsuperior extent of the area When a smallerrectangular solid for one task could be subsumed by alarger rectangular solid for another task with only minoradjustments in boundaries of the larger rectangularsolid the two volumes were considered to occupy thesame region and were listed in the same row of Table 1One region on the banks of the inferior frontal sulcusappeared in all three word generation tasks and wasanalyzed along with SMA pre-SMABA 32 and Brocarsquosarea For each of these four regions a rectangular solidwas defined that subsumed significant volumes of activ-ity for all tasks where significant activity was presentBecause voxels in Talairach space were constructedfrom larger voxels in the original functional imagesthe 1-mm3 voxels in Talairach space could not beconsidered independent A correction for independencewas applied by dividing the number of 1-mm3 voxels inTalairach space by the size of voxels from the originalspiral functional images 1325 mm3 for both the rec-tangular solid and the volumes of significant activityThen using these units of corrected volume the pro-portion of the rectangular solid occupied by significantactivity between tasks was compared using a binomialtest (Siegel 1956) The comparison of functional inten-sities between tasks within regions was accomplishedwith t tests that compared the mean functional intensity(t value) from one task to that of others within a region

(Table 2) When deriving the standard errors of themean for these comparisons the correction for inde-pendence was applied by dividing the number of 1-mm3

voxels in Talairach space by 1325 mm3Finally there was a possibility that differences in word

production rates between free generation and repeti-tion on the one hand versus paced generation andsemantic generation on the other hand influencedvolumes of activities in the various regions of interestTo equate for these effects and to facilitate comparisonsregarding the relative contributions of medial and lateralfrontal cortex for each task ratios of medial (pre-SMABA32) to lateral (Brocarsquos area inferior frontal sulcus)frontal activity were calculated If Goldberg (1985) wascorrect about a shift from medial to lateral frontalactivity as external guidance increases then the medialto lateral frontal activity ratios should decrease as wemove from the most internally driven word generationtask (free generation) to the most externally drivenword generation task (semantic generation) This pro-cedure provided a check on the other data analysismethods described above

Note

1 In statistical terms it can be shown that MLSF =rx ( t) pound r ( t)( x ( t) r ( t)) where x(t) is a vector representing theacquired data in a single voxel r(t) is a vector representingthe selected reference waveform for that voxel rx ( t) pound r ( t) isthe product-moment correlation between x(t) and r(t) x ( t)

is the standard deviation of x(t) and r ( t) is the standarddeviation of r(t) x (t) is a measure of the amplitude of x(t)and 1 r ( t) can be thought of as a constant applied to eachvoxel

REFERENCES

Alexander M P (1997) Aphasia Clinical and anatomic aspectsIn T J Feinberg amp M J Farah (Eds) Behavioral neurologyand neuropsychology (pp 133ndash149) New York McGraw-Hill

Bandettini P A Jesmanowicz A Wong E C amp Hyde J S(1993) Processing strategies for time-course data sets infunctional MRI of the human brain Magnetic Resonance inMedicine 30 161ndash173

Barris R W amp Schuman H R (1953) Bilateral anterior cin-gulate gyrus lesions Syndrome of the anterior cingulate gyriNeurology 3 44ndash52

Binder J R Rao S M Hammeke T A Frost J A Bandet-tini P A Jesmanowicz A amp Hyde J S (1995) Lateralizedhuman brain language systems demonstrated by task sub-traction functional magnetic resonance imaging Archives ofNeurology 52 593ndash601

Birn R M Bandettini P A Cox R W amp Shaker R (1999)Event-related fMRI of tasks involving brief motion HumanBrain Mapping 7 106ndash114

Bullmore E Brammer M Williams S C R Rabe-HeskethJanot N David A Mellers J Howard R amp Sham P(1996) Statistical methods of estimation and inference forfunctional MR image analysis Magnetic Resonance in Med-icine 35 261ndash277

Chao L L Haxby J V amp Martin A (1999) Attribute-based neural substrates in temporal cortex for perceiving

282 Journal of Cognitive Neuroscience Volume 13 Number 2

and knowing about objects Nature Neuroscience 2913ndash919

Cox R W (1996a) AFNI Software for analysis and visualiza-tion of functional magnetic resonance neuroimages Com-puters in Biomedical Research 29 162ndash173

Cox R W (1996b) MCW AFNImdashuser manual MedicalCollege of Wisconsin Analysis of Functional Neuro-Images Version 200 Milwaukee Medical College ofWisconsin

Crosson B Briggs R W Sadek J R Freeman A J GokcayD Gordon M B amp Leonard C M (1998) Medial frontalcortex in internally and externally guided language produc-tion Journal of the International NeuropsychologicalSociety 4 10

Crosson B Radonovich K Sadek J R Gokcay D Bauer RM Fischler I S Cato M A Maron L Auerbach E JBrowd S R amp Briggs R W (1999) Accessing knowledge ofemotional connotation in the left hemisphere during wordgeneration NeuroReport 2449ndash2455

Crosson B Rao S M Woodley S J Rosen A C HammekeT A Bobholz J A Mayer A Cunningham J M Fuller SA Binder J R Cox R W amp Stein E A (1999) Mapping ofsemantic phonological and orthographic verbal workingmemory in normal adults with FMRI Neuropsychology 13171ndash187

Crosson B Sadek J R Bobholz J A Gokcay D Mohr CM Leonard C M Maron L Auerbach E J Browd S RFreeman A J amp Briggs R W (1999) Activity in the para-cingulate and cingulate sulci during word generation AnfMRI study of functional anatomy Cerebral Cortex 9307ndash316

Deiber M-P Passingham R E Colebatch J G Friston KJ Nixon P D amp Frackowiak R S J (1991) Corticalareas and the selection of movement A study with posi-tron emission tomography Experimental Brain Research84 393ndash402

Dum R P amp Strick P L (1991) The origin of corticospinalprojections from the premotor areas in the frontal lobeJournal of Neuroscience 11 667ndash689

Forman S D Cohen J D Fitzgerald M Eddy W F MintunM A amp Noll D C (1995) Improved assessment of signifi-cant activation in functional magnetic resonance imaging(fMRI) Use of a cluster-size threshold Magnetic Resonancein Medicine 33 636ndash647

Freedman M Alexander M P amp Naeser M A (1984) Ana-tomic basis of transcortical motor aphasia Neurology 34409ndash417

Frith C D Friston K Liddle P F amp Frackowiak R S J(1991) Willed action and the prefrontal cortex in man Astudy with PET Proceedings of the Royal Society of LondonSeries B Biological Sciences 244 241ndash246

Goldberg G (1985) Supplementary motor area structure andfunction Review and hypotheses Behavioral and BrainSciences 8 567ndash616

He S-Q Dum R P amp Strick P L (1995) Topographic or-ganization of corticospinal projections from the frontal lobeJournal of Neuroscience 15 3284ndash3306

Herholz K Thiel A Wienhard K Pietrzyk U von Stock-

hausen H-M Karbe H Kessler J Bruckbauer T HalberM amp Heiss W-D (1996) Individual functional anatomy ofverb generation NeuroImage 3 185ndash194

Hutchins K D Martino A M amp Strick P L (1988) Corti-cospinal projections from the medial wall of the hemisphereExperimental Brain Research 71 667ndash672

King K F Foo T K F amp Crawford C R (1995) Optimizedgradient waveforms for spiral scanning Magnetic Resonancein Medicine 34 156ndash160

Luppino G Matelli M Camarda R M amp Rizzolatti G(1993) Corticocortical connections of area F3 (SMA-proper)and area F6 (pre-SMA) in the macaque monkey Journal ofComparative Neurology 338 114ndash140

Luria A R (1966) Human brain and psychological processesNew York Harper amp Row

Macovski A (1985) Volumetric NMR imaging with time-vary-ing gradients Magnetic Resonance in Medicine 2 29ndash40

Martin A Wiggs C L Ungerleider L G amp Haxby J V(1996) Neural correlates of category-specific knowledgeNature 379 649ndash652

Matsuzaka Y Aizawa H amp Tanji J (1992) A motor arearostral to the supplementary motor area (presupplementarymotor area) in the monkey Neuronal activity during alearned motor task Journal of Neurophysiology 68653ndash662

McCarthy R A amp Warrington E K (1984) A two-route modelof speech production Evidence from aphasia Brain 107463ndash486

Nielsen J M amp Jacobs L L (1951) Bilateral lesions of theanterior cingulate gyri Report of case Bulletin of the LosAngeles Neurological Society 16 231ndash234

Noll D C Cohen J D Meyer C H amp Schneider W J (1995)Spiral k-space MR imaging of cortical activation MagneticResonance Imaging 5 49ndash56

Oldfield R C (1971) The assessment and analysis of han-dedness The Edinburgh Inventory Neuropsychologia 997ndash113

Pandya D N amp Yeterian E H (1985) Architecture and con-nections of cortical association areas In A Peters amp E GJones (Eds) Cerebral cortex vol 4 Association andauditory cortices (pp 3ndash61) New York Plenum

Passingham R E (1993) The frontal lobes and voluntaryaction New York Oxford University Press

Petersen S E Fox P T Posner M I Mintun M amp Raichle ME (1988) Positron emission tomographic studies of the cor-tical anatomy of single-word processing Nature 331585ndash589

Picard N amp Strick P L (1996) Motor areas of the medial wallA review of their location and functional activation CerebralCortex 6 342ndash353

Siegel S (1956) Nonparametric statistics New YorkMcGraw-Hill

Talaraich J amp Tournoux P (1988) Co-planar stereotaxic at-las of the human brain 3-Dimensional proportional sys-tem An approach to cerebral imaging New York Thieme

Warburton E Wise R J S Price C J Weiller C Hadar URamsay S amp Frackowiak R J S (1996) Noun and verbretrieval by normal subjects Studies with PET Brain 119159ndash179

Crosson et al 283