putative tests of frontal lobe function: a pet-study of...

Putative Tests of Frontal Lobe Function:A PET-Study of Brain Activation During

Stroop's Test and Verbal Fluency*

Barbara Ravnkilde1, Poul Videbech1, Raben Rosenberg1, Albert Gjedde2, and Anders Gade3

1Institute for Basic Psychiatric Research, Department of Biological Psychiatry, Psychiatric Hospital,Aarhus University Hospitals, Denmark, 2The PET-Center, Aarhus Kommunehospital,

Aarhus University Hospitals, Denmark, and 3Department of Psychology,University of Copenhagen, Denmark

ABSTRACT

Stroop's test and the Verbal Fluency test are commonly argued to be measures of the integrity of the prefrontalcortex. This assumption has only to some degree been con®rmed by lesion studies. In the present study, PositronEmission Tomography (PET) with H2

15O was used to further validate Stroop's test and the Verbal Fluency asmeasures of frontal lobe function; both tests were implemented as activation paradigms during scanning ofnormal middleaged individuals. Stroop interference was found to activate the left anterior cingulate cortex, thesupplementary motor cortex, thalamus, and the cerebellum. Although the prominent anterior cingulateactivation is in the frontal lobe, it is not prefrontal. Verbal Fluency activated the left inferior frontal cortex andthe left dorsolateral prefrontal cortex, the supplementary motor cortex, the anterior cingulate cortex and thecerebellum. These results bring this latter test closer to being a speci®c test of prefrontal function.

Stroop's test (Stroop, 1935) and the Verbal Flu-

ency test (Borkowski, Benton, & Spreen, 1967)

are classic experimental paradigms used in both

clinical neuropsychological and research settings.

Both tests are commonly assumed to be

measures of the integrity of the prefrontal cor-

tex. Theoretically, the Stroop test has been linked

to effortful processing (Cohen, Dunbar, &

McClelland, 1990), attention, and response selec-

tion or inhibition. Fluency tasks have been linked

with response initiation, access to semantics,

strategy and attention (Frith, Friston, Liddle, &

Frackowiak, 1991; Ruff, Light, Parker, & Levin,

1997). These functions are arguably dependent on

prefrontal cortex integrity.

Several studies have attempted to validate

these assumptions in neurological patients with

and without prefrontal lesions. Generally, it has

been con®rmed that the two tests, especially

Verbal Fluency, have some degree of sensitivity to

prefrontal lesions, but results on speci®city have

been con¯icting (Reitan & Wolfson, 1994; Stuss,

Floden, Alexander, Levine, & Katz, 2001).

Use of the Stroop test as a sensitive and speci®c

test of frontal lobe function is mainly based on the

study by Perret (1974) on presurgical tumor pati-

ents. Patients with tumors in the left frontal lobe

were much slower in naming incongruent colors

than any of the right hemisphere groups and

patients with posterior left hemisphere lesions.

Vendrell et al. (1995), however, found an increased

error rate only in patients with right prefrontal

lesions, and naming time in the incongruent part of

the test did not differ signi®cantly in any of the

�This research was presented in part at the INS 23rd Mid-Year Meeting in Brussels, Belgium, July 2000.Address correspondence to: Barbara Ravnkilde, Institute for Basic Psychiatric Research, Department of BiologicalPsychiatry, Psychiatric Hospital, Aarhus University Hospitals, Skovagervej 2, 8240 Risskov, Denmark. E-mail:[email protected] for publication: December 13, 2001.

Journal of Clinical and Experimental Neuropsychology 1380-3395/02/2404-534$16.002002, Vol. 24, No. 4, pp. 534±547 # Swets & Zeitlinger

patient groups compared with controls. Vendrell

et al. also noted that 71% of the patients with pre-

frontal lesions performed entirely normally on the

Stroop test. Other studies have also failed to ®nd

differences between patients with prefrontal le-

sions and controls (Ahola, Vilkki, & Servo, 1996;

Stuss et al., 1998).

Early studies on the Verbal Fluency test

indicated that the critical lesion for impaired

performance was in the left frontal lobe (Milner,

1964; Perret, 1974; Ramier & Hecaen, 1970) or

bilaterally in the frontal lobes (Benton, 1968;

Borkowski et al., 1967). Using a written version

Pendleton, Heaton, Lehman, and Hulihan (1982)

con®rmed this, but also indicated a sensitivity to

focal lesions with other localizations, especially

diffuse lesions. The Verbal Fluency test did not

differentiate between patients with frontal lobe

dementia and Alzheimer patients (Pasquier,

Lebert, Lavenu, & Petit, 1998), probably due to

the de®cits in semantic memory associated with

temporal lobe pathology in Alzheimer patients.

Verbal Fluency may also be sensitive to left focal

temporal lobe lesions (Jokeit, Heger, Ebner, &

Markowitsch, 1998; Martin, Loring, Meador, &

Lee, 1990). In spite of the lack of speci®city to

lesions of the prefrontal cortex, direct compar-

isons have usually indicated a maximal sensitivity

to prefrontal lesions.

Neuroimaging offers the opportunity to sup-

plement previous clinical validations of neuro-

psychological tests with the mapping of the

functional anatomy (regional cerebral blood

¯ow/rCBF or metabolism/rgluCMB) underlying

test performance. The purpose of the present

study was to validate the use of Stroop's test and

the Verbal Fluency test as measures of frontal lobe

function by implementing both tests as activation

paradigms during Positron Emission Tomography

(PET) scanning of normal individuals.

Speci®cation of this assessment is described in

the following together with ®ndings from pre-

vious activation studies.

Stroop's TestThe basic principle of the test is to create inter-

ference between word reading and color naming

(Mitrushina, Boone, & D'Elia, 1999; Shum,

McFarland, & Bain, 1990). We chose to include

the congruent condition in this version of Stroop's

test which is a color naming task of matching

colors and color words (e.g., the word red printed

in red) and the incongruent condition in which the

colors of mismatching words and colors have to

be named (e.g., the word red printed in green).

Reading is a highly automatized process. Color

naming is a less automatic process which is

vulnerable to interference from the more auto-

matic process. This interference is observed as an

increase in reaction time and errors from

congruent to incongruent tasks. The Stroop

paradigm is suitable as an activation paradigm

of effortful processing as it consists of identical

tasks, except for the critical component of effort

to counteract the interference in the incongruent

version. Previous studies of primarily young

healthy subjects have tried to localize the

particular areas involved in the processes of

selective attention. The most consistent ®ndings

have been increased rCBF in the anterior

cingulate gyrus and prefrontal cortex during the

performance of Stroop's test (Audenaert et al.,

2001; Bench et al., 1993; Carter, Mintun, Nichols,

& Cohen, 1997; George et al., 1997; Larrue,

Celsis, Bes, & Marc Vergnes, 1994; Pardo, Pardo,

Janer, & Raichle, 1990; Peterson et al., 1999;

Taylor, Kornblum, Lauber, Minoshima, &

Koeppe, 1997).

The Verbal Fluency TestIn this study we used the phonological Verbal

Fluency test (outlined by Lezak, 1995) asking the

subjects to produce as many words as possible

beginning with the letter `T' during the scan.

Contrary to Stroop's test this test does in itself

not hold different operations which can be

subtracted from one another to isolate one speci®c

component in functional imaging. Therefore,

comparisons have typically been made with either

a resting condition or fairly low-level control

tasks such as word repetition, word reading, or an

extrinsic word monitoring task, for example

deciding whether a word is meaningful or not

(Frith et al., 1991). In this study we compared the

Verbal Fluency task of generating `T-words' with

a simple reading task, the reading of neutrally

colored color words. This reading task should not

hold the intrinsic (self-generating) aspect since

PUTATIVE TESTS OF FRONTAL LOBE FUNCTION 535

the ability to read is highly automatized and does

not require the need to inhibit competing words.

Yet, the reading task shares most other cognitive

components with the Verbal Fluency task, namely

the identi®cation and pronunciation of words,

visual stimulation (the subject was also given

visual stimulus while generating words), and the

auditory attendance to the subject's own voice.

In previous neuroimaging studies word gen-

eration has mainly activated areas in the frontal

cortex (Audenaert et al., 2000), speci®cally in the

dorsolateral left prefrontal cortex (Frith et al.,

1991; Petersen, Fox, Posner, Mintun, & Raichle,

1988; Phelps, Hyder, Blamire, & Shulman, 1997;

Warkentin & Passant, 1997; Warkentin, Risberg,

Nilsson, Karlson, & Graae, 1991). Two of these

studies also found activation in the anterior

cingulate gyrus. In addition to the prefrontal

activation, SchloÈsser et al. (1998) reported a right

cerebellar activation. Parks et al. (1988) and

Philpot, Banerjee, Needham Bennett, Costa, and

Ell (1993) showed activations in the frontal cortex

in both hemispheres.

Age EffectsIn the majority of the above neuroimaging studies

the subjects were young adults. However, there

are some indications that activation patterns may

change with age. For instance, the frontal activa-

tion seen in memory tasks may be more hetero-

geneous in elderly subjects than in younger

subjects (Madden et al., 1999). Nielson, Garavan,

Ross, Rao, and Stein (1999) reported a more

diffuse frontal activation in a `go±no go' task in

elderly subjects compared with young.

The subjects selected for the present study

were middleaged. Results from this age group

may also be more relevant for the neuropsycho-

logical applicability of these tests.

METHODS

SubjectsForty-six normal volunteers, mean age 41� 11:6years (range 21±65 years, 16 males/30 females),participated in the study as part of a larger studydealing with affective disorders (Ravnkilde et al.,2001; Videbech et al., 2001a, 2001b, 2001c). Thesubjects were recruited by newspaper advertisement

and had an average of 12:4� 2:4 years of education.Exclusion criteria were known organic brain disease,known drug or alcohol dependence, or ongoingabuse (according to ICD-10 and DSM-IIIR).According to the Old®eld scale of handedness(Old®eld, 1971) only 3 were left-handers. All sub-jects underwent an extensive examination programconsisting of both a physical examination and aneurological examination. Subjects were screenedby blood tests and urine samples for signi®cantmedical diseases or hidden abuse of psychoactivesubstances. Subjects were also excluded if the MRIscans showed any cerebral focal abnormality orgeneralized brain disease except so called whitematter lesions (Fazekas et al., 1993). Both theHamilton Depression Scale (Hamilton, 1967) and astructured psychiatric interview (SCID for DSM-III±R; Spitzer, Williams, Gibbon, & First, 1992) wereadministered. None of the subjects or their ®rstdegree relatives had any history of psychiatricdisorders. All subjects gave written informed con-sent. The project was approved by the Scienti®cEthical Committee for Aarhus County and by theDanish Data Protection Agency.

Imaging ProceduresAll subjects underwent measurement of cerebralblood ¯ow during a total of ®ve scans usingradioactive water (H2

15O) in a Siemens Ecat ExactHR47 Positron Emission Tomograph with a frame of40 s for each scan. All scans were performedbetween 9 and 12 a.m. to account for diurnal varia-tion in blood ¯ow.

The subjects were supine with their heads ®xed ina vacuum pillow to reduce head movement. Earplugswere used to dampen background noise, and roomlights were dimmed. Five studies, one at rest andfour activation tasks, were completed once for eachsubject. All instructions and injections were givenby the same two persons. Further details of imagingand statistical methods are described elsewhere(Videbech et al., 2001b).

T1-weighted magnetic resonance images of thesubjects' brains were coregistered to the coordinatesystem by Talairach and Tournoux (1988) using anautomatic algorithm with a linear 12 parameters ®t.Furthermore, each subject's MR image was coregis-tered to the PET images from the resting state usingthe MINC-TRACC algorithm, with a linear 6parameters ®t. The other PET images were thencoregistered to this same PET image. This procedureis described in detail by Videbech et al. (2001b) andwas done to correct for movement artifacts in thesubtractions and to allow for precise anatomical local-ization of the activations. The radioactivity in everyvoxel was normalized to the average activity of all

536 BARBARA RAVNKILDE ET AL.

intracranial voxels to minimize effects of intersubjectvariation of the global cerebral blood ¯ow.

Statistical AnalysisStatistical analysis of the images was performedusing the Montreal method (Worsley, Evans, Mar-rett, & Neelin, 1992) as implemented in the DOTsoftware program. A within-subject subtraction ofthe congruent version of Stroop's test from theincongruent version, and a subtraction of a simplereading task from the Verbal Fluency task (asdescribed below) were performed. This procedurewas followed by a computation of voxel-by-voxelmultiple regression statistic of the regional cerebralblood ¯ow (rCBF) differences controlling for ageand gender. A voxel-speci®c standard deviation wasused for the calculations. Correcting for multiplecomparisons a t value of 5.63 was set as thethreshold for statistical signi®cance ( p < :05 ±corresponding to a whole brain volume of 1400 mlwith df � 45; Videbech et al., 2001b).

Experimental TasksFour out of the ®ve scans were accompanied byactivation tasks. The order of the tasks was ®xed. Toisolate and visualize the active neural systemsparticularly involved in processing the Stroopinterference task and the Verbal Fluency test, singlewords and visual stimuli were presented individuallyon a video monitor placed 50 cm in front of thesubject's face outside the scanner.

The activation tasks were presented as follows:

� A resting state in which the subject had to focus ona small white cross as a ®xation point on themonitor screen.

� Reading color words printed in white.� Naming the color of matching color words (e.g.,

the word red displayed in red color), the congruentversion of Stroop's test.

� Naming the color of incongruent color words(e.g., the word red displayed in green color), theincongruent Stroop's test.

� Naming as many words as possible beginning withthe letter `T' while focusing eyes on a ¯ashing bigwhite cross on the screen, the Verbal Fluency test.

The color word stimulus consisted of a randomlyordered presentation of the four colors, red, green,yellow, and blue. No colors or color words wererepeated consecutively. The words were approxi-mately 150 mm�50 mm presented in capital lettersagainst a black background. A small white tread-cross was placed 5 mm above the word stimuli as a®xation mark. The stimuli were displayed for 1 swith an interstimulus interval of 1 s. In all tasks thesubjects were given instructions to react as quicklyas possible to each presented stimulus, and in theincongruent condition of the Stroop task they wereasked explicitly not to read the color words. Practiceof a few stimuli from each condition was given once,prior to the actual ®ve scans. In some subjectsreaction times were measured for the four activationtasks during each scan using a microphone placed onthe subject's chest and connected to a computer.

RESULTS

Reaction Time and Word GenerationThe mean reaction time recorded for the congruent

Stroop was 398:4� 88:8 ms and 690:7� 125:2 ms

Table 1. Local Maxima (Incongruent Stroop Minus Congruent Stroop).

Localization Brodmannarea no.

No. ofmax

X Y Z min t--max t p

Left supplementarymotor cortex

6 2 ÿ4.0 15.0 46.5 5.90±7.25 .023

Right thalamus 1 2.7 ÿ21.2 4.5 6.71 .002Left insula 1 ÿ30.8 18.4 ÿ3.0 6.57 .003Left anterior

cingulate gyrus32 1 ÿ1.3 18.4 34.5 6.22 .009

Right cerebellum 1 0.0 ÿ53.8 ÿ30.0 6.09 .013Left cerebellum 1 ÿ8.0 ÿ64.2 ÿ33.0 6.01 .018Right frontal lobe

white matter (WM)1 10.7 6.4 54.0 6.00 .017

Left frontal lobe(WM)

1 ÿ34.8 8.1 22.5 6.22 .009

Note. Localization of signi®cant activations. Brodmann area number. Number of local maxima in speci®c area.Talairach coordinates (x; y; z) for highest activation. Range of t-values. P-value. When local maxima are multiple,p-value equals least signi®cant activation.


for the incongruent Stroop (N � 39). The differ-

ence in reaction time between the two tasks was

statistically signi®cant (t-test, p < :001). In the

congruent situation the subjects produced an

average of 0.68 errors, whereas the error rate

was an average of 1.6 in the incongruent situation.

During the Verbal Fluency test the subjects

produced an average of 16� 6 (range 5.5±29.2)

words/min (N � 41).

The PET activations in Tables 1 and 2 are

reported as local maxima. Stroop activations are

shown in Figure 1, Verbal Fluency activations in

Figure 2.

Stroop

When subtracting the congruent Stroop task from

the incongruent task (Table 1), the left anterior

cingulate gyrus (p < :01) as well as the left

Table 2. Local Maxima (Verbal Fluency Minus Reading Task).

Localization Brodmannarea no.

No. ofmax

X Y Z min t ÿmax t p

Left cingulate gyrus

Right cingulate gyrus

322432

211

ÿ5.41.39.4

25.337.335.6

34.56.0

18.0

10:53ÿ 16:438.39

10.50

.000

.000

.000

Left supplementarymotor cortex

644

71

ÿ5.4ÿ40.2

16.78.1

58.528.5

7:51ÿ 13:9710.89

.000

.000

Left inf. frontal gyrusRight inf. frontal gyrus

4747

31

ÿ46.957.6

18.430.4

1.5ÿ1.5

8:78ÿ 10:797.45

.000

.000

Left dorsolateral pre-frontal cortex

459

11

ÿ45.6ÿ28.1

23.640.8

16.528.5

10.625.97

.000

.019

Left fronto-orbitalgyrus

1125

11

ÿ28.1ÿ13.4

44.28.1

ÿ16.5ÿ16.5

7.117.08

.001

Left thalamusRight thalamus

43

ÿ5.42.7

ÿ22.9ÿ17.7

6.012.0

6:31ÿ 8:366:31ÿ 7:99

.007

.007

Left cerebellumRight cerebellum

914

ÿ5.442.9

ÿ59.0ÿ77.9

ÿ12.0ÿ34.5

5:85ÿ 12:426:83ÿ 10:55

.028

.003

Left inferior/superiortemporal gyrus

2138

11

ÿ54.9ÿ40.2

ÿ41.818.4

ÿ13.5ÿ37.5

7.206.63

.001

Left superioroccipital gyrus

19 1 ÿ12.1 ÿ84.8 39.0 7.62 .000

Right cuneus 1 17.4 ÿ67.6 15.0 7.17 .001

Left superiorparietal lobe

7 1 ÿ10.7 ÿ76.2 52.5 5.99 .018

Right insulaLeft insula

13

37.5ÿ32.2

18.421.8

ÿ3.01.5

9.619:28ÿ 10:85

.000

.000

Left anteriorinternal capsule

1 ÿ13.4 ÿ4.0 ÿ3.0 7.39 .000

Right globus pallidus 1 14.7 ÿ0.5 ÿ7.5 6.74 .002

Brainstem 1 2.7 ÿ2.2 ÿ10.5 7.71 .000

Left frontal lobe (WM)Right frontal lobe (WM)

72

ÿ33.524.1

47.651.1

10.5ÿ6.0

8:36ÿ 13:125:87ÿ 5:92

.000

.025

Left temporal (WM) 1 ÿ25.5 ÿ24.6 ÿ3.0 6.55 .003

Note. Localization of signi®cant activations. Brodmann area number. Number of local maxima in speci®c area.Talairach coordinates (x; y; z) for highest activation. Range of t-values. P-value. When local maxima are multiple,p-value equals least signi®cant activation.


supplementary motor cortex (p < :05) showed

signi®cant activations. The cerebellum reached

signi®cant levels bilaterally ( p < :05). The right

thalamus, the left insula ( p < :01), and white

matter in the right frontal lobe ( p < :05) were

also activated. The left prefrontal cortex was not

signi®cantly activated. The highest activation

within the prefrontal cortex was t � 4:27, p > :2.

In the subtraction of the Stroop test a single

signi®cant deactivation (local minima) was found

in the right temporal gyrus ( p < :05).

Verbal Fluency

In the Verbal Fluency test the reading of neutral

color words was subtracted from the Verbal Flu-

ency task of naming words beginning with the

Fig. 1. The coregistered PET and MR images demonstrating the subtracted Stroop activations in the left anteriorcingulate gyrus, left supplementary motor cortex and cerebellum.


letter `T.' This subtraction gave signi®cant activa-

tions in several brain regions (Table 2). The

primary activations were seen in the left supple-

mentary motor cortex, the dorsolateral prefrontal

cortex, the left and right inferior frontal cortex,

and in the left and mid anterior cingulate gyrus

( p < :001). The left fronto-orbital cortex was also

activated ( p < :001). The thalamus was activated

bilaterally ( p < :01) as was the insula (p < .001).

Many signi®cant activation sites were detected in

the cerebellum mainly in the right side ( p < :01).

A few maxima were located in the left temporal

cortex (p < :001), the left occipital cortex (p <:001), and the left parietal cortex (p < :05).

Local minima were detected in both occipital

lobes ( p < :001) and in the right temporal cortex

( p < :01) when making this subtraction.

Correcting for gender and age did not alter the

results signi®cantly for either Stroop's test or the

Verbal Fluency test.

Fig. 2. The coregistered PET and MR images demonstrating the subtracted Verbal Fluency activations in the leftanterior cingulate gyrus, left supplementary motor cortex, left dorsolateral prefrontal cortex, and leftinferior-, and orbito-frontal cortex. Activations are also seen in the temporal cortex.


DISCUSSION

Stroop's TestIn this study the subtraction of two tasks only

diverging in one aspect has resulted in signi®cantly

increased anterior cingulate activity. The divergent

aspect is hypothesized to be the attentional

demands of the selection process between compet-

ing cognitive processes, reading and color naming.

Several previous studies using this single-trial

Stroop procedure for cognitive activation have also

found increased rCBF of the anterior cingulate

gyrus although only one study (George et al., 1997)

reported activation limited to the left side of this

structure as in our study. However, a left hemi-

sphere predominance is in accordance with most

studies using lateralized stimuli (MacLeod, 1991)

and at least one lesion study (Perret, 1974).

The area our study has illuminated as a core

structure in selective attention is well in accor-

dance with the tripartite attentional system describ-

ed by Posner (Posner & Dehaene, 1994; Posner &

Raichle, 1995). According to this network theory

of the attentional system, the anterior cingulate

gyrus is active whenever a con¯ict is present

between simultaneous processes (Posner &

DiGirolamo, 1998). The con¯ict is evident from

the difference in reaction time between the incon-

gruent and the congruent Stroop task. Some

component has been added in the incongruent

condition making the time to respond longer than

in the corresponding congruent task.

This con¯ict requires some sort of control

mechanism or a selective attentional function of

response selection. Presumably, the anterior

cingulate inhibits the automatic response to the

word name in order to facilitate or selectively

attend to the execution of the less automatic

process ± that of ink-color naming in Stroop's test.

Recent studies con®rm that the anterior cingulate

gyrus is indeed involved in detecting and

monitoring the occurrence of con¯icts in informa-

tion processing, although it may not exert the

attentional control mechanism in selecting partic-

ular stimuli for action (Botvinick, Nystrom,

Fissell, Carter, & Cohen, 1999; MacDonald,

Cohen, Stenger, & Carter, 2000).

The inconsistent ®ndings as to whether selec-

tive attention tasks involve the right or the left half

of the cingulate structure may not be as important

a discussion as the question of which different

processes are actually entailed within this rela-

tively large brain structure. The hemispheric

differences of these speci®c processes may well

be decided by particular features of the task

stimuli such as patterns, symbols, or colors.

Although the anterior cingulate gyrus forms a

component of a higher level system for response

selection or con¯ict monitoring it may be implic-

ated in other functions as well. Activation of this

structure has also been reported in studies of

divided attention (Corbetta, Miezin, Dobmeyer,

Shulman, & Petersen, 1991), pain (Coghill et al.,

1994), motor action (Paus, Petrides, Evans, &

Meyer, 1993), and expectation (Murtha, Chert-

kow, Beauregard, Dixon, & Evans, 1996). It has

also been assigned a role in emotion (Devinsky,

Morrell, & Vogt, 1995).

These apparently con¯icting results may relate

to different parts of the anterior cingulate gyrus.

Devinsky et al. (1995) have proposed a subdivi-

sion of the anterior cingulate cortex into areas

related to either emotional or cognitive functions.

The cognitive divisions include Brodmann's areas

32 and 24 (caudal) whereas the emotional divi-

sions involve areas 25, 33, and 24 (rostral). Bush

et al. (1998) provided a map of anterior cingulate

activation points from many different paradigms.

Activations from cognitive/motor tasks (including

attention) were clearly clustered in the caudal

division of the anterior cingulate gyrus, providing

solid support for the proposed subdivision. We

note that the activation in our study is close to the

center of this `cognitive cluster.'

According to this subdivision the activation seen

in Stroop's test, which was localized to Brodmann's

area 32 in our study, cannot be ascribed to mere

motivation to respond or, for instance, to antici-

patory anxiety caused by procedural factors. An-

other ®nding supporting the role of the anterior

cingulate gyrus in attention was reported by

Raichle et al. (1994). In this study the anterior

cingulate activation in a verb generation task was

eliminated after practice (i.e., automatization) and

reinstated with novel stimuli.

Contrary to some other studies we did not ®nd

activations in either prefrontal cortices when

making the subtraction of the two tasks. Clinically


Stroop's test has been used as an estimate of pre-

frontal damage, but our result is at variance with

this. Our ®ndings, thus, suggest that the prefrontal

activation may not be as essential a component of

selective attention as the cingulate activation.

Instead the supplementary motor cortex was

activated. The lateral and mesial premotor cort-

ices (BA 6) have been associated with the neural

systems underlying visuospatial attention (Nobre

et al., 1997) and with the temporal orienting of

attention, for example in the ability to focus resour-

ces in order to optimize behavior at a particular

moment in time (Coull, Frith, Buchel, & Nobre,

2000). The visuospatial and temporal aspects are

part of the performance on Stroop's test when the

test is presented on a computer monitor at a paced

speed. The activation of this particular brain

area has also been noticed in previous studies

(Pardo et al., 1990; Peterson et al., 1999; Taylor,

Kornblum, Lauber, Minoshima, & Koeppe, 1997).

The signi®cant cerebellar activation may also

be of some interest. It is now recognized that the

cerebellum not only participates in motor activ-

ities, but is in fact active during many different

and also purely mental activities (Desmond &

Fiez, 1998; Jenkins & Frackowiak, 1993; Jernigan

et al., 1998; Thach, 1996). Hence, the activity seen

in this study should not necessarily be ascribed to

the motor aspect of producing speech, which was

also assumed to be identical in the two Stroop

tasks. Recent PET-studies have shown a cerebel-

lar activation in connection with language tasks

that merely involve inner speech production, with-

out the actual vocalization of words (Gabrieli,

Poldrack, & Desmond, 1998; Schlosser et al.,

1998). So it seems that the cerebellum is some-

how a partaker when we are composing words

without being a true center of speech or language.

The fact that subjects are unavoidably aware of

two words at a time in Stroop's test, the color

name and the printed word, may be one explana-

tion why the cerebellum seems so active during

the task.

The Verbal Fluency TestThe fact that the subtraction task for the Verbal

Fluency test is not as suitable in terms of sharing

common features as the congruent Stroop test

when compared to the incongruent Stroop, may

partly explain why this subtraction results in sever-

al signi®cantly activated brain areas. On the other

hand, it may be an illustration of how a relatively

simple cognitive task actually may involve several

different cognitive components served by a cortical

network (Friston, Frith, Liddle, & Frackowiak,

1993). Details have varied between studies, prob-

ably mainly due to the use of different subtraction

tasks. However, our results are generally consistent

with other studies of Verbal Fluency activation

particularly in showing a left prefrontal and inferior

frontal lobe activation.

The role of the left dorsolateral prefrontal

cortex in the performance of Verbal Fluency can

be seen both as a semantic role and as an initiating

and modulating role. Based on a number of PET-

studies, the hypothesis has been suggested that

the left prefrontal cortex is involved in retrieval

of information from semantic memory (Petersen

et al., 1988), although recent fMRI studies have

added to the complexity of the exact relationship

between retrieval and this brain area (Mitchell,

Johnson, Raye, & D'Esposito, 2000).

This memory function is concerned with

people's general knowledge of the world and

also in the encoding process into episodic mem-

ory which is the conscious recollection of person-

ally experienced events (Nyberg, Cabeza, &

Tulving, 1996). The Verbal Fluency test does entail

both these functions concurrently. In order to

generate different words the subject has to retri-

eve these from semantic memory, but at the same

time the subject has to store the event of gene-

rating the speci®c words (the occurrence) into

episodic memory in order to avoid repetitions.

The activations seen in the left inferior frontal

gyrus tend to be related to semantic search or

access (Baker, Frith, & Dolan, 1997; Buckner &

Koutstaal, 1998). Gabrieli et al. (1998) hypothe-

sized that activation in the inferior prefrontal area

occurs during semantic, relative to non-semantic,

tasks for the generation of words. Furthermore it

was hypothesized that it re¯ects a domain-speci®c

semantic working memory capacity invoked

particularly when a response must be selected

among many alternatives, as is the case when

generating words with a ®xed letter.

According to Frith et al. (1991) the activation

of the left dorsolateral prefrontal cortex in word


generation, however, re¯ects intrinsic, or self-

initiated, generation, whether the material is

semantic or not. If so, this area could be activated

by nonsemantic or nonverbal tasks as well. This

has been supported by PET-scans of tasks in

which the generated response was strictly motoric

(Pardo, Fox, & Raichle, 1991). The left dorso-

lateral prefrontal cortex has popularly been

named the `center of initiative' as the activity

here seems to precede the actual execution of the

activity (Pedersen et al., 1998). So the left

prefrontal cortex may be related to the initiating

component of the Verbal Fluency test whereas the

activation of the temporal cortex may represent

the semantic component. Listening to words

activates the temporal cortex (Wise, Hadar,

Howard, & Patterson, 1991) which is also the

case when hearing one's own voice. The identi-

®cation of words and the spreading activity of

word associations when producing words are

therefore plausible accounts of activity within the

temporal area. Frith, Friston, Liddle, and Frack-

owiak (1991) also found a deactivation in the left

superior temporal gyrus and suggested that the

relationship between the dorsolateral prefrontal

cortex and the temporal cortex is reciprocal in

nature with the prefrontal cortex being an

inhibitor of the activation in the temporal lobe.

We did not observe this deactivation in the left

hemisphere, but found an activation in corrobora-

tion with several previous studies (Boivin et al.,

1992; Parks et al., 1988; Philpot et al., 1993).

We also found activation of the anterior

cingulate gyrus, similar to that in Stroop's test,

and we therefore suggest that the cingulate gyrus

is responsible for the selection of the words in

question, that is, which associations in the temp-

oral cortex should be attended to and which

should be suppressed and ignored. The volitional

preference of one set of stimuli over another

seemed exactly to be the role of this area in

Stroop's test. In this view, the prefrontal cortex is

involved in initiations of the Verbal Fluency

performance task and possibly in the retrieval of

the words that are freely associated in the

temporal cortex, whereas the process of being

selectively attentive to a speci®cally requested

group of words is being performed by the anterior

cingulate gyrus.

The activations registered in the right cerebel-

lum have also been reported in previous studies

(e.g., Schlosser et al., 1998; or review by

Desmond & Fiez, 1998). Cerebellar activation

may be explained in general terms as above in the

discussion of Stroop's test, but is not really

understood. There is some indication that mild

de®cits in language production may occur

following cerebellar lesions (Leiner, Leiner, &

Dow, 1993), and patients with Broca's aphasia

show a crossed cerebellar diaschisis (Abe, Ukita,

Yorifuji, & Yanagihara, 1997).

Concluding DiscussionWith quali®cations, Stroop's test and the

Verbal Fluency test can be considered tests of

frontal lobe functions. One of the quali®cations,

applying to both tests, is related to the hetero-

geneous nature of the frontal lobes. Obviously

tests of circumscribed cognitive functions cannot

be expected to activate all areas of this large part

of the brain, and likewise, circumscribed lesions

outside the areas subserving these functions

cannot be expected to compromise them.

Stroop's test as used in this study, that is,

Stroop interference, is speci®cally related to the

caudal division of the anterior cingulate cortex.

While this is in the frontal lobe, it is not in the

prefrontal cortex. The Stroop test is commonly

regarded as a test of prefrontal function, but this

study as well as several previous imaging studies

questions this assumption which seems to have

been based on a single in¯uential lesion study

(i.e., Perret, 1974). On the positive side, the

anterior cingulate activation is obviously very

robust, and the test seems to be very suitable as a

measure of the attentional demands in effortful

processing regarded as a core function of the

caudal part of the anterior cingulate gyrus

(Devinsky et al., 1995).

The Verbal Fluency test has been shown to

activate large parts of the left dorsolateral

prefrontal cortex in many imaging studies. This

together with equally solid evidence from lesion

studies bring this test closer to what is commonly

understood by a `frontal lobe test,' that is, a test of

prefrontal function. It is less speci®c than Stroop's

test, however, as it also activates a temporal lobe

area in imaging studies and is affected by lesions


in the left temporal lobe. Other areas of activation

in our study (e.g., cerebellum, supplementary

motor area, cingulate gyrus) may be less robust in

imaging studies, and the sensitivity of the test to

lesions in these areas is, we believe, not known.

The speci®c purpose of the present study was

to establish the validity and applicability of the

two tests for studies of frontal lobe activation in

imaging of attention and related functions in

depression. The anterior cingulate gyrus and

dorsolateral prefrontal cortex are both believed

to be involved in major depression and their

successful and robust activation in middle-aged

normal subjects indicates that the two tests may

be useful in clinical studies.

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