NeuroImage 11, 424–446 (2000)doi:10.1006/nimg.2000.0572, available online at http://www.idealibrary.com on
Working Memory for Letters, Shapes, and Locations: fMRI Evidenceagainst Stimulus-Based Regional Organization
in Human Prefrontal CortexLeigh E. Nystrom,* Todd S. Braver,† Fred W. Sabb,* Mauricio R. Delgado,‡
Douglas C. Noll,§ and Jonathan D. Cohen*,¶
*Department of Psychology, Princeton University, Princeton, New Jersey 08544; †Department of Psychology, Washington University,St. Louis, Missouri 63130; ‡Department of Neuroscience and ¶Department of Psychiatry, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260; and §Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109
Working memory (WM) is the limited-capacity stor-age system involved in maintenance and manipulationof information over short periods of time (Baddeley,1986). Attempts to localize brain regions responsiblefor WM processes, involved in all forms of higher-levelcognition, have consistently implicated regions withinfrontal cortex. Studies of human patients with frontal
cortical lesions have often found impairments of WMfunctions (for reviews, see Petrides, 1989; Stuss et al.,1994). Neurophysiological studies of primates havefound cells in prefrontal cortex that fire during thedelay periods in tasks requiring the short-term inter-nal maintenance of target information (for reviews, seeFuster, 1997; Goldman-Rakic, 1987; Miller, 2000). Inaddition, over the past half-decade, the explosion ofhuman functional neuroimaging experiments has rein-forced earlier human and primate neurobiological find-ings, supporting the conclusion that the human pre-frontal cortex (PFC) plays a critical role in the storageand manipulation of information in WM (e.g., Awh etal., 1996; Baker et al., 1996; Barch et al., 1997; Bravert al., 1997; Cohen et al., 1994, 1997; Courtney et al.,996, 1997, 1998; D’Esposito et al., 1995, 1998; Fiez etl., 1996; Goldberg et al., 1996; Haxby et al., 1995;onides et al., 1993, 1997; McCarthy et al., 1994, 1996;wen et al., 1996, 1998; Paulesu et al., 1993; Petrides
t al., 1993a,b; Salmon et al., 1996; Schumacher et al.,996; Smith et al., 1995, 1996; Swartz et al., 1995;weeney et al., 1996).The theme of a growing body of recent neuroimaging
xperiments has been the attempt to partition prefron-al cortex into smaller regions that may subserve dif-erent components of WM. Baddeley (1986) has pro-osed that WM is not served by a unitary system, butather by several distinct functional units: a centralxecutive that supplies attentional control plus sepa-ate subordinate systems that are used to hold partic-lar types of information in a form available for re-rieval and/or manipulation by the central executive.ccording to Baddeley, one of these subordinate “slave”ystems holds verbal (phonological/articulatory) infor-ation, while another deals with visuospatial informa-
ion. In light of the putative dominance of the leftemisphere for verbal processes and the right hemi-phere for nonverbal functions (Sperry, 1974), it has
425WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
been proposed that WM processes subdivide along thesame dimensions within frontal cortex, with verbalWM implemented in the left frontal cortex and visualWM in the right. Some neuroimaging studies havespecifically addressed this possibility, offering tenta-tive evidence for a relative, although not absolute, left–right specialization of verbal versus nonverbal WMfunctions (Smith and Jonides, 1997).
In addition to this verbal/nonverbal dimension, asecond contrasting dimension has arisen from studiesof primate neuroanatomy and neurophysiology. Thissecond dichotomy contrasts WM of spatial versus non-spatial (or object) information, motivated by the divi-sion of posterior cortical regions into a dorsal pathwayrepresenting spatial (“where”) and a ventral pathwayrepresenting visual form (“what”) information (Unger-leider and Haxby, 1984). Some anatomical evidencesuggests connectivity of differing degrees betweenfrontal areas and these two posterior cortical streams.For instance, ventrolateral frontal areas receive inputfrom inferotemporal cortex (Webster et al., 1994),whereas middorsolateral frontal regions receive inputfrom posterior parietal cortex (Cavada and Goldman-Rakic, 1989; but see also Petrides, 1994). Lesions orcooling of ventrolateral frontal cortex can impair non-human primates’ performance on object-recognitionWM tasks, while lesions to dorsolateral frontal cortexcan impair performance on object-location WM tasks(for reviews, see Petrides, 1994; Fuster, 1997). Fur-thermore, Goldman-Rakic and colleagues have re-ported individual cells within dorsolateral cortex thatappear to specialize in coding for the spatial location ofobjects during a delay period (Funahashi et al., 1989,1990) and a separate set of neurons within ventrolat-eral cortex coding for the visual object identities (Wil-son et al., 1993). These findings have led to the claimthat primate prefrontal cortex is divided between adorsal partition supporting spatial WM and a ventralpartition supporting object WM (Goldman-Rakic, 1988,1995). Motivated by this claim, neuroimaging studiesof human frontal cortex have attempted to find re-gional variation in frontal activation during spatialversus object WM tasks, sometimes using tasks mod-eled directly on the nonhuman primate WM paradigms(e.g., Baker et al., 1996; Courtney et al., 1996, 1998;McCarthy et al., 1996; Owen et al., 1998; Smith et al.,1995).
Collectively, the findings from neuroimaging inves-tigations of both verbal/nonverbal and spatial/objectdissociations have been inconclusive. Two recent com-prehensive literature reviews and meta-analyses haveconcluded that the existing body of neuroimaging stud-ies fails to support a dorsal/ventral dissociation be-tween spatial and nonspatial WM functions (Owen,1997; D’Esposito et al., 1998). In addition to some sup-portive evidence, they report an abundance of findingscontradicting the dissociation, including object-related
dorsal activation and spatial-related ventral activa-tion. With regard to a left/right dissociation, D’Espositoet al. (1998) found some suggestions of a relative spe-cialization for right-hemisphere processing of spatialinformation and left-hemisphere processing of nonspa-tial information, but only within ventral and notwithin dorsal PFC regions. This finding was not in-tended to specifically address the question of verbalversus nonverbal hemispheric specialization, however,as tasks were collapsed across both verbal and nonver-bal stimuli. Nevertheless, there does seem to be anindication of a relative preference for processing ofverbal materials in the left ventrolateral frontal re-gion. A third review (Fiez et al., 1996) found a dissoci-ation much like the one found by D’Esposito et al.(1998): a left lateralization of activation within ventralfrontal cortex for verbal WM processes. This left-hemi-sphere specialization is not surprising, given that theleft ventral region implicated in these two reviews istypically identified as Broca’s area, known for over acentury to be specialized for speech-related processes.Thus, meta-analyses provide some evidence for thespecialization of left ventral frontal cortex—perhapsmerely Broca’s area—for verbal processing, but littleadditional support for either of the two hypothesizeddissociative dimensions.
Meta-analyses, however, are limited in that theycompare results from different types of WM tasks, per-formed by different subjects in different labs. Accord-ingly, while they can map the central tendencies offocal activations in different stimulus conditions acrossstudies, they cannot directly compare the degree towhich these areas activate in the different stimulusconditions. To produce solid evidence for dissociations,within-subject experimental manipulations of thestimulus dimensions are necessary. To date, therehave been several within-subject experiments directlytesting for dissociations between object and spatialWM (Baker et al., 1996; Belger et al., 1998; Courtney etal., 1996, 1998; McCarthy et al., 1996; Owen et al.,1998; Petit et al., 1998; Smith et al., 1995), but fewerdirectly contrasting verbal and spatial WM (D’Espositoet al., 1998; Smith et al., 1996) or verbal and object WM(Paulesu et al., 1993; Salmon et al., 1996).
In addition to within-subject experimental manipu-lations, an ideal test for dissociations would involvedirect statistical comparisons between all conditions toavoid false-positive findings. Indirect comparisons,such as visual inspections of contrasting statisticalmaps or tabulations of Talairach coordinates, are lessthan sufficient. For example, suppose that the samesingle brain area participates equally in two WM tasksinvolving two different stimulus types, yet the areadiffers in its response to the two correspondingmatched control tasks. Without direct statistical com-parisons between all four conditions, a false inferenceof WM-related dissociation could be drawn, as the WM-
426 NYSTROM ET AL.
minus-control subtractions within each stimulus typemay not be distinguishable from a situation in whichthe area responded equally to the control tasks butdifferently between WM tasks. Problems with indirectcomparisons of subtraction images can be further com-pounded by the statistical thresholding used in mostneuroimaging analyses. Activation patterns are ig-nored below arbitrary significance thresholds; conse-quently, if the experiment has limited power and acti-vation is detectable only at levels of significance closeto threshold, noisy distributions of activation will ap-pear in statistical maps. Inferences of dissociation aresometimes drawn from the apparent absence of activa-tion in a brain region based on statistical thresholdsleft to the discretion of investigators, when in factactivation may be present, unexamined, just below thearbitrary threshold. Instead of using indirect compar-isons, direct statistical evidence for dissociations canbe accomplished using fully factorial ANOVA or GLMmodels, with one factor for stimulus type and a secondfactor for WM load. A main effect of stimulus type willidentify stimulus-specific brain regions, though notnecessarily WM related; the interaction between thetwo factors can identify regions specific to WM process-ing of one or the another stimulus type.
The present series of experiments provided con-trolled comparisons between WM for three differenttypes of stimuli. All three experiments used consistentmethodologies and analyses in a widely used WM par-adigm. Experiment 1 tested WM for letters and ab-stract shapes, holding spatial locations constant, andthereby provided a test of verbal versus nonverbal WM.Experiment 2 involved WM for spatial locations andletters to test spatial versus (verbal) nonspatial WM.Experiment 3 contrasted WM for shapes versus loca-tions, diminishing the verbal component through artic-ulatory suppression, to directly test spatial versus
FIG. 1. Trial schematic of n-back task conditions (e.g., Braver etconditions, while the target changes by condition.
(nonverbal, nonspatial) object WM. Although a directthree-way comparison between WM for letters, shapes,and locations would have been desirable within sub-jects, it was not feasible due to the conflicting demandsof having to collect sufficient numbers of trials of eachtype while having to restrict the duration of the timeeach subject spent in the scanner. Furthermore, asnoted later under General Discussion, the possibility ofdiscovering dissociations may be diminished in anyparadigm that interleaves task demands to maintaindifferent types of information. This danger would havebeen magnified if all three types of task had beencombined within an hour-long session.
All three experiments used the “n-back” task, inwhich subjects view a continuous sequence of stimuli,deciding for each stimulus whether it matches thestimulus shown N stimuli earlier in the sequence (Awhet al., 1996; Braver et al., 1997; Cohen et al., 1994,1997; Gevins and Cutillo, 1993; Smith et al., 1996). Forexample, in a 3-back condition of the letter n-back task,subjects should respond positively whenever the letterthey see is the same as the one viewed three lettersearlier (see Fig. 1). In a 0-back condition, subjectsrespond positively to any appearance of a prespecifiedletter. At all levels of WM load, both the series ofstimuli and the responses can be identical; only thetask instructions distinguish between conditions. Anadditional attraction of the n-back paradigm is that itcan be used equally well with different types of stimuli,including letters, shapes, and spatial locations. Forexample, stimuli can be letters (verbal) or shapes (non-verbal) that appear at varying locations, and subjectscan be asked to respond to repeats of either stimulusidentity (nonspatial) or location (spatial). Thus, byvarying WM load and crossing this with stimulus type,it was possible to identify areas of brain activity re-lated to WM function and to evaluate their specificity
, 1997). Note that the sequence of stimuli may be identical between
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427WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
to information type in a series of within-subject exper-iments.
EXPERIMENT 1: LETTERS VERSUS SHAPES
The first experiment contrasted WM for letters ver-sus abstract visual shapes. This comparison addressesthe hypothesis that human PFC has regional special-izations for verbal versus nonverbal information. Al-though a direct comparison between letter and shapememory requires the use of somewhat different stimuliacross the two types, this contrast avoids conflationwith the hypothesized contrast between spatial andnonspatial WM, because both letters and shapes can bepresented centrally, holding spatial location constant.
The letters condition was an extension of prior func-tional magnetic resonance imaging (fMRI) experi-ments using the n-back letter task (Braver et al., 1997,in which a subset of this experiment’s data was origi-nally reported). In our earlier studies, we observedbilateral activation of both dorsolateral (BA 46/9) andventrolateral (BA 44) PFC, as well as bilateral activa-tion of premotor (BA 6) and parietal (BA 7/40) cortex,all regions commonly coactivated in WM tasks. Inter-estingly, although activation was bilateral, there was atendency for right prefrontal regions to have a largerspatial extent of activation than regions in the lefthemisphere, which is inconsistent with the hypothesisthat left frontal cortex is relatively specialized for ver-bal WM. Parenthetically, it is worth noting that acti-vation of both dorso- and ventrolateral regions in thisnonspatial task also argued against a ventral special-ization for nonspatial information.
The shapes condition in Experiment 1 was developedas a direct analogue to the letters condition, with the
FIG. 2. Task conditions specific to th
only difference being the presentation of abstract, un-familiar shapes in place of letters (see Fig. 2). Theshape stimuli were drawn from the standard set ofAttneave and Arnoult (1956), normed for verbalizabil-ity. Stimuli with the lowest verbalizability scores werechosen, following use of such stimuli in a previous PETstudy of WM (Smith et al., 1995, Experiment 2). Thesetimuli provide the opportunity to contrast Baddeley’swo proposed slave WM stores (Baddeley, 1986): theerbal articulatory loop, presumably used to rememberetters, and the nonverbal visuospatial sketchpad, usedo remember visual shapes.
Two prior experiments have directly compared ver-al with nonverbal nonspatial WM processes, usingerbal tasks with consonants and visual tasks withorean letters for which subjects had no verbal repre-
entation (Paulesu et al., 1993; Salmon et al., 1996). Inoth experiments, relatively greater activation wasound with the verbal tasks in left premotor and leftosterior inferior frontal (Broca’s) areas, as well as leftuperior temporal, bilateral insula, left inferior pari-tal, and bilateral sensorimotor activation. Paulesund colleagues also obtained activation bilaterally inhe supplementary motor areas (SMA) and cerebellum,long with right-lateralized homologues of each of theireft-hemisphere activations (albeit with lower statisti-al significance). In Salmon et al. (1996), activation inhe visual WM task was found primarily in the leftarieto-occipital sulcus plus bilateral activation in sev-ral occipital areas, with some tentative reports of leftnferior temporal and left middle and medial frontalctivation; Paulesu et al. (1993) did not report visualask activation. Thus, existing studies have reportedo evidence of a right-hemisphere dominance for non-erbal WM processes, while supporting a relative, but
-back variant used in Experiment 1.
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not absolute, left-hemisphere dominance for verbalWM processes.
Materials and Methods
Subjects
Informed consent was obtained from eight neurolog-ically normal right-handed subjects (two female, sixmale). Their ages ranged from 18 to 25 years (M 521.8). All subjects were given practice with the taskand were scanned only after reaching a criterion levelof performance (75% accuracy or greater) in each con-dition.
Cognitive Task
Subjects performed a variant of the n-back task us-ing letters and abstract shapes as memoranda (see Fig.2). Four levels of memory load (0-, 1-, 2-, and 3-back)were presented in a factorial design fully crossed withthe two levels of stimulus type (letters and shapes),yielding a total of eight task conditions. Trials wereblocked by condition, with 19 trials per block and 56blocks presented in a pseudorandom order which en-sured that each of the eight conditions was presentedonce within every set of 8 blocks.
A block of a single condition lasted 63 s, consisting ofa 3-s presentation of task instructions (e.g., “Target 52-back letter repeats”), followed by a 3-s pause andthen 19 3-s test trials. Each test trial began with a 0.5-spresentation of a stimulus (letter or shape), followed bya 2.5-s blank-screen interstimulus interval. The use ofa 3-s trial duration replicated the trial durations in ourearlier letter n-back experiments (Braver et al., 1997,Experiment 1). At the end of each set of trials, subjectssaw the word PAUSE for approximately 20 s before thenext block of trials began, providing a rest period whilefMRI data were written to disk. Seven sets of eightblocks were run within a period of approximately 70min.
On each trial, subjects observed stimuli presented inthe center of a visual display, projected into the MRscanner from a Macintosh computer running PsyScopesoftware (Cohen et al., 1993). Letters were presented in
24-point Helvetica font, in randomly chosen upper- orowercase. The letter stimuli were chosen from a set of8 letters (all consonants except L, W, and Y) selectedo minimize the lexicality and pronounceability oftrings of sequential letters. Shape stimuli were chosenrom a set of 40 Attneave shapes: 6-sided random ab-tract polygons (Attneave and Arnoult, 1956). Subjectsesponded to each stimulus presentation by pressingne of two buttons on a response box held in their rightand, with a fiber-optic connection to the Macintoshomputer. To respond to a stimulus as a target, sub-ects pressed the button under their index finger; to
espond to a stimulus as a nontarget, they pressed theutton under their middle finger.In the 0-back condition, a single stimulus was spec-
fied as the target in the instructions at the beginningf a block (e.g., “Target 5 X” or “Target 5 this shape:.”). In the 1-back condition, the target was any stim-lus identical to the immediately preceding stimulus.n the 2-back and 3-back conditions, the target was anytimulus identical to the stimulus presented two orhree trials prior, respectively (see Figs. 1 and 2). Sub-ects were told not to distinguish between upper- andowercase presentations of the same letter. This mixingf cases was intended to encourage subjects to encodend rehearse letter stimuli as verbal phonemes, in-tead of as visual letter forms. Stimuli were targets on3% of trials; of the remaining 66% nontargets, 6% ofhe stimuli were chosen from each of the other three-back conditions, while 48% used stimuli that had notppeared in any of the previous three trials. Thus, therequency and distribution of repeated items was theame across all levels of load.
RI Scanning Procedures
Images were acquired using a conventional 1.5-T GEigna whole-body scanner and standard RF head coilt the MR Research Center at the University of Pitts-urgh Medical Center. Twenty-seven contiguous slices3.75-mm3 isotropic voxels) were obtained parallel to
the AC-PC line. Double-oblique slice locations wereprescribed following a procedure designed to maximizereliability of localization across subjects (Noll et al.,1997). Structural images were acquired in the samelocations as the functional images, using a standardT1-weighted pulse sequence. Functional images wereacquired using a 4-interleave spiral pulse sequence(TR 5 750 ms, TE 5 35 ms, FOV 24 cm, flip 40°; Nollet al., 1995). This T2*-weighted pulse sequence allowed9 slices to be acquired every 3 s, completing a set of 27slices every 9 s. The same set of 9 slices was scannedfor three consecutive trials at a time, following which adifferent set of 9 slices was scanned. Slice set order wascounterbalanced across blocks to control for asynchro-nous acquisitions across regions. Scanning occurredduring only 12 of the 19 trials in each block. No scanswere acquired during the first 4 trials to allow theloading of subjects’ working memories and the settlingof the fMRI signal to a steady state. The other 3 un-scanned trials occurred while switching between sets of9 slices. Thus, 4 complete 27-slice volumes were ac-quired in each block of 19 trials; with 56 blocks run, atotal of 224 functional volumes were collected.
Behavioral Data Analysis
Behavioral data were analyzed to confirm subjectcompliance with task performance and the effective-ness of the manipulation of WM load and to evaluate
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429WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
relative performance across stimulus type. Subjects’performance was evaluated with 4 (load) 32 (stimulustype) ANOVAs, using both response time (RT) andaccuracy measures.
Imaging Data Analysis
Functional images from each subject were correctedfor head movement using 6-parameter rigid-bodytransformations determined by an automated algo-rithm (Woods et al., 1992). Structural images fromach of the eight subjects were coregistered to a com-on reference brain using a 12-parameter affine trans-
ormation (Woods et al., 1993). The transform of thetructural images was applied to the functional imagesrom each subject, then the transformed functionalmages were smoothed using a three-dimensionalaussian filter (8-mm FWHM) to accommodate be-
ween-subject anatomic differences. The functional im-ges were also globally mean-normalized to equateverall image intensities over time and between sub-ects.
A repeated-measures two-way mixed-model ANOVAas performed independently on each voxel in the en-
ire set of coregistered data, treating subjects as aandom factor and WM load and stimulus type as with-n-subjects factors. Voxels were identified that exhib-ted either a significant main effect of stimulus typeF(1,7) 5 12.25, P , 0.01) or a load-by-stimulus type
interaction (F(3,21) 5 4.87, P , 0.01). These twoANOVA terms identify only those voxels that signifi-cantly differ in their response to the two stimulustypes. The main effect of load was not formally exam-ined, because it does not distinguish between stimulustypes and therefore cannot identify dissociations. Fur-thermore, areas of dissociation, responsive to one andnot the other stimulus type, would not necessarily ap-
FIG. 3. Behavioral data from Experiment 1. Bar graphs denote ewith the scale on the left. Error bars represent standard errors.
pear in a map of main effect of load, given the dilutionof the mean load effect from the “nonpreferred” stimuli.
Regions comprising eight or more contiguous su-prathreshold voxels were then identified, as a precau-tion against type 1 errors (Forman et al., 1995), ensur-ing an effective image-wide false-positive rate of 0.01.Only those regions that exhibited increased activationwith higher memory loads in at least one of the stim-ulus conditions were included for further analysis. Theregions meeting these criteria were overlaid onto thestructural MR scan corresponding to the referencebrain and then transformed to the standard Talairachstereotaxic space (Talairach and Tournoux, 1988) us-ing AFNI software (Cox, 1996).
Results
Behavioral Data
As shown in Fig. 3, response latencies increasedsignificantly with increased load (F(3,21) 5 23.13; P ,0.0001), as did error rates (F(3,21) 5 25.17; P ,0.0001). Response times did not significantly differ be-tween stimulus types (F(1,7) 5 1.87; P . 0.1), andthere was no interaction between load and stimulus-type effects on RT (F(3,21) 5 2.10; P . 0.1). However,ubjects made more errors overall with shapes thanith letters (F(1,7) 5 10.72; P , 0.05). This main effect
was moderated by a significant interaction (F(3,21) 54.90; P , 0.01); at the two lower loads, accuracy did notdiffer between stimulus types, whereas at higher loads,accuracy was worse with shapes than with letters.
Imaging Data
The ANOVA on the fMRI data yielded several re-gions meeting the criteria of voxel-wise significance(P , 0.01), extent (eight or more contiguous voxels),
r rate with the scale on the right. Line graphs denote reaction time,
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430 NYSTROM ET AL.
and load-related signal increases. Six regions exhibiteda significant main effect of stimulus type (see Fig. 4aand Table 1). In four of the six regions, the mean MRsignal was higher in the Shapes conditions: right su-perior parietal lobe (BA 7), left inferior parietal lobe(BA 40), right middle frontal gyrus (BA 46), and aregion covering part of the anterior cingulate (BA 32)and a portion of the medial frontal gyrus (BA 8). Thetwo regions with higher mean signal during the Lettersconditions included a region straddling the inferiorportion of the left precentral gyrus (BA 6) and the leftsuperior temporal gyrus (BA 22) and one covering an-other portion of the anterior cingulate (BA 32), supe-rior and posterior to the previously noted anterior cin-gulate region, and a portion of the medial frontal gyrus(BA 6).
In addition to areas exhibiting a main effect of stim-ulus type, there were two areas associated with a sig-nificant interaction between load and stimulus type(P , 0.01; see Fig. 4b and Table 1). One of these waswithin the anterior cingulate (BA 32), corresponding toa subset of the voxels in the more rostral of the tworegions observed in the stimulus type main effect. Inthis region, higher memory loads increased the MRsignal to a greater extent in the Shapes conditions thanit did in the Letters conditions. The second region wasobserved in the left precentral gyrus (BA 6), just supe-rior to BA 44. In this region, the MR signal increasedmore in the Letters than in the Shapes conditions athigher levels of load.
Discussion
Experiment 1 provided only limited evidence for aleft/right asymmetry in verbal/nonverbal WM pro-cesses. The asymmetry manifested as regions exhibit-ing a greater sensitivity to letters than to shapes in leftpremotor and temporal regions. In addition, the asym-metry also appeared in a medial region in the anteriorcingulate (AC) and SMA (or more precisely, “pre-SMA”;cf. Petit et al., 1998; Picard and Strick, 1996). No letter-specific areas were found lateralized to the right hemi-sphere. Conversely, the right dorsolateral prefrontalcortex (DLPFC) contained one region, showing rela-tively greater activation with shapes WM. Additionalregions responding more to shapes were observed inthe AC and in two posterior cortical regions, the rightsuperior parietal lobe and the left supramarginal gy-rus. In the left frontal areas, no regions respondedmore in the Shape conditions. Thus, on the surface,
FIG. 4. Regions of activity in Experiment 1 associated with (a)significant interactions between load (0-back through 3-back) and srelative to signal in the 0-back Letters condition. Four representativspace (Talairach and Tournoux, 1988). Slices are shown at heights zsubsequent figures. Images are displayed according to the radiologsubsequent figures.
these results extend those of Paulesu et al. (1993) andalmon et al. (1996), in appearing to support a fullouble dissociation between left and right frontal re-ions for verbal versus nonverbal processes. However,uch a conclusion must be tempered by important qual-fications.
For instance, an examination of the pattern of activ-ty within the right DLPFC shape-sensitive region re-eals that it was also sensitive to letter WM. It exhib-ted a more linear response to increasing WM load withetter than with shape stimuli, and the 3-back level ofoad there was no difference in MR signal responseetween stimulus types. The same right DLPFC regionas appeared in earlier letter n-back studies (Braver etl., 1997; Cohen et al., 1997). Furthermore, this sameeneral region was found to be sensitive to spatial WMnd not object WM in an earlier PET study (Smith etl., 1995, Experiment 2). Thus, it would be problematico consider this right DLPFC region dedicated to WMrocessing of object shape alone.Moreover, the left-lateralized regions, more sensitive
o manipulations of letter WM, were not in the DLPFCt all, but rather in more posterior premotor and su-erior temporal (auditory association) areas. Surpris-ngly, there was no Broca’s area (left area 44/45) regionound to be differentially sensitive to letter WM, evenhough this area is considered central to verbal WMehearsal; the aforementioned letter-specific regionsere located just posterior and inferior to Broca’s area.
n the premotor region, exhibiting a true statisticalnteraction between memory load and stimulus type,he interaction was not the result of activation occur-ing only with letters at higher loads, which wouldndicate a clean dissociation, but rather a more com-lex relationship wherein both activations increased toncreasing load with stimulus types.
Furthermore, the left supramarginal gyrus, a pari-tal region commonly believed to be part of the verbalM articulatory loop along with Broca’s area (Paulesu
t al., 1993), showed greater activation for shapes.his, along with the failure to differentially activateroca’s area, raises a suspicion that subjects may havesed verbal strategies for naming and subvocally re-earsing shapes, despite our efforts to use objects de-igned to be difficult to name. Indeed, posttest inter-iews with subjects revealed that most attempted toerbally label at least some subset of the shape stimuli.one reported success in attempting to label all of the
hapes, however, so it appears that they relied on a
nificant main effects of stimulus type (Letters vs Shapes) and (b)ulus type. Graphs plot percentage signal change in each conditionxial slices are shown from a reference brain registered to Talairach8, 124, 140, and 156 mm. The same four slices are depicted in all
convention (left hemisphere is shown on the right) in this and all
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431WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
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432 NYSTROM ET AL.
combination of verbal and visual maintenance strate-gies. This concern limits the conclusions that can bedrawn from this experiment about regional specializa-tions for nonverbal WM. Experiment 3, below, ad-dresses this issue of verbal strategy confounds throughthe use of vocal suppression of verbal WM processes inan experiment involving the same shape stimuli.
An additional caveat about the current experimentaldata arises from the fact that despite our efforts toequate the difficulty of the n-back task between the twostimulus types, the behavioral data indicated that theShapes conditions were somewhat more difficult athigher levels of WM load. This inequality might ac-count for the anterior cingulate region demonstratingshape WM sensitivity, as the AC is commonly found tobe sensitive to increases of task difficulty and degra-dation of performance (Barch et al., 1997; Dehaene etal., 1994; Gehring et al., 1993; Paus et al., 1993). Ofcourse, this fails to explain the other AC region show-ing letter WM sensitivity. Note, however, that thisletter-related medial region was localized not only tothe AC, but also contained adjoining portions of thepre-SMA, from the same Brodmann’s area as the let-
TAB
Location of Regions of Activation Obtained in Each Experwith Mean and Peak Significance Leve
Shapes . Locations L inf frontalInteractions R ant cingulate
R mid frontalR premotorL mid frontal 1 L inf frontal
ter-related region in the premotor cortex. Both areas,pre-SMA and premotor, are believed to be used inverbal planning (Fiez et al., 1996; Paulesu et al., 1993).Considerations of task difficulty may also cloud inter-pretation of the response of the parietal regions, acti-vated in both Letters and Shapes conditions, but to agreater degree in Shapes conditions perhaps due sim-ply to the increased difficulty.
Finally, while the WM task was identical in bothShapes and Letters conditions, the visual stimulithemselves differed. This raises the possibility thatthe different patterns of activation may have beendue, at least in part, to different activation fromletters due to differences in low-level visual complex-ity. Some investigations of spatial WM have avoidedthe problem by presenting a particular type of stim-ulus (letter, face, or shape) in different locations,contrasting spatial and nonspatial WM with identi-cal stimulus arrays (e.g., Courtney et al., 1996;
mith et al., 1995). Experiments 2 and 3, below,employed this same strategy in combination withmanipulations designed to avoid possible verbal en-coding of nonverbal stimuli.
1
ent by Brodmann’s Area (BA) and Talairach Coordinates,dicated as a Standardized Z Statistic
433WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
EXPERIMENT 2: LETTERS VERSUSSPATIAL LOCATIONS
This experiment contrasted WM processes with let-ters versus spatial locations. It was designed, in part,to minimize the likelihood that subjects would bedriven to maintain nonverbal stimuli using a verbalcoding strategy. Posttest questioning of pilot subjectsrevealed that in a spatial variant of the n-back task,subjects reported using a geometric nonverbal strategyto remember and sequentially order spatial locations,perhaps akin to covert eye-movement planning or vi-sual imagery. This nonverbal strategy is just the typeof process that Baddeley (1986) proposed should occurin the visuospatial “scratchpad” slave system. Further-more, by presenting letters in varying locations withsequential n-back trials, the same set of stimuli couldbe used in all conditions, differentiating between letterWM and location WM simply through task instruc-tions. This would ensure that subjects receive identicalvisual displays in both conditions and eliminate a po-tential confound between WM and differential low-level visual experience. Finally, this task provided an-other opportunity to equate performance betweenstimulus types, to minimize the chance that one typewould activate some regions more strongly due to in-creased effort.
Note that a contrast between letters and spatial lo-cations tests both of the two hypothesized dissocia-tions: the verbal/nonverbal dichotomy tested in Exper-iment 1 and also the spatial/nonspatial contrastadvocated by Goldman-Rakic (1995). According to thelatter contrast, one would expect to find more dorsalactivation with spatial WM task and more ventral ac-tivation with the letter (nonspatial) task. Evidence in-consistent with this hypothesis has already been re-ported in Experiment 1, in which both types ofstimulus (centrally presented letters and shapes) pre-sumably recruited only nonspatial WM. Whereas thedorsal/ventral hypothesis predicts that both types ofnonspatial stimuli should activate only ventral frontalregions, we in fact observed activation in right dorsalPFC for shapes WM.
Two prior experiments have also compared letterand location WM activation, yet they arrived at twodifferent conclusions. The first, a PET experiment bySmith et al. (1996, Experiment 2), compared letter withlocation WM using 3-back and 0-back tasks. Theyfound activation in the letter conditions in Broca’sarea, and bilaterally in the DLPFC, and parietal cor-tex, although activation in the right hemisphere wasless significant than in the left. In the location condi-tions, activation was also found bilaterally in parietalareas, DLPFC, and SMA, although the magnitude ofactivation was greater on the right. Their analysis waslimited by the fact that they compared only the resultsof the 3-back minus 0-back subtractions with each
stimulus type, without directly comparing the twotypes. Smith et al. (1996) concluded that, despite thebilateral appearance of regions, these results sup-ported the hypothesis of a left/right asymmetry be-tween verbal and nonverbal WM processes. It is worthnoting that these results did not support a dorsal/ventral dissociation, however. In contrast, in an fMRIexperiment by D’Esposito et al. (1998), no differencesat all were found between activation in letter and lo-cation WM conditions. This second experiment there-fore found no evidence for either a left/right or a dorsal/ventral dissociation. On the other hand, one might becautious in drawing negative conclusions from this sec-ond experiment because it involved different stimulusarrays in the letter and location conditions and be-cause, like the Smith et al. (1996) experiments, itlacked a direct statistical comparison between activa-tion in the two types of stimulus conditions.
Materials and Methods
Subjects
Informed consent was obtained from seven neurolog-ically normal right-handed subjects (three female, fourmale). Their ages ranged from 18 to 27 years (M 520.6). All subjects were given practice with the taskand were scanned only after reaching a criterion levelof performance, at least 75% accuracy in all conditions.
Cognitive Task
Subjects performed a variant of the n-back task us-ing both spatial locations and letters as memoranda(see Fig. 5). Two levels of memory load (0- and 3-back)were presented in a factorial design fully crossed withthe two levels of stimulus type (Locations and Letters),yielding four task conditions. The 1-back and 2-backconditions from Experiment 1 were eliminated in orderto increase statistical power in the two extreme levelsof WM load by doubling the relative number of trials inthese two conditions. Trials were blocked by condition,with 19 trials per block and 32 blocks presented inpseudorandom order, which ensured that each of thefour conditions was presented once within every set of4 blocks.
A block of a single condition lasted 1.4 min, consist-ing of a 4-s presentation of task instructions (e.g., “Tar-get 5 3-back LOCATION repeats”, “Target 5 1-backLETTER repeats”), followed, after a 4-s pause, by 194-s test trials. The duration of each trial was extendedby 1 s relative to those in Experiment 1 to accommo-date a newer fMRI pulse sequence that allowed for thesimultaneous collection of images in an increased num-ber of slice planes. Each test trial consisted of thepresentation of a letter in a noncentral location, 500 msin duration, followed by 3.5 s of blank screen. Followingevery block of 19 trials, subjects saw the word PAUSE
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434 NYSTROM ET AL.
for approximately 30 s before the next block of trialsbegan. Thirty-two blocks of trials were run within aperiod of approximately 1 h.
Letters were chosen from the same set of 18 conso-nants used in Experiment 1. The locations of letterpresentation were chosen from a set of 18 positionsevenly spaced around the circumference of an approx-imately 3-in. diameter circle centered in the display.Eighteen positions were used to discourage a verbalcoding for locations by decreasing the configural famil-iarity and ease of naming each of the locations, asmight occur with a more familiar configuration like 8locations (akin to a compass) or 12 locations (like theface of a clock). Subjects responded to each letter pre-sentation in the same manner as in Experiment 1.
The 0-back conditions were modified to help equateperformance between stimulus types. In pilot testing,it was found that if subjects were given only a singlespatial location as their fixed 0-back Locations target,they could simply move their gaze to that spot andmonitor for the appearance of letters, ignoring all otherstimuli and qualitatively altering the nature of thetask. Therefore, in the 0-back Locations condition, sub-jects were shown three different spots on the screen,marked with dots, and told that a letter appearing inany of the three locations should be considered a tar-get. To equate performance between stimulus types,the 0-back Letters condition was then modified topresent three different letters as the fixed target setrather than just one.
As before, 33% of trials contained targets; of theremaining 66% nontargets, 6% of the stimuli were cho-sen from each of the three other n-back conditions(including 1- and 2-back distractors), while 48% usednew stimuli that had not appeared in any of the pre-vious three trials.
FIG. 5. Task conditions specific to th
MRI Scanning Procedures
Images were acquired using the same 1.5-T scan-ner used in Experiment 1. Twenty-six contiguousslices (3.75-mm3 isotropic voxels) were obtained par-allel to the AC-PC line. Structural images were ac-quired in the same locations as the functional im-ages, using a standard T1-weighted pulse sequence.Functional images were acquired using a 2-inter-leave spiral pulse sequence (TR 5 2000 ms, TE 5 35
s, FOV 24 cm, flip 80°). This T2*-weighted pulseequence allowed 26 slices to be acquired every 4 s.ifteen functional volumes were collected withinach 19-trial block, with scans synchronized to trialnsets. No scans were collected during the first 4rials of each block, to allow the loading of subjects’orking memories and the settling of the fMRI sig-al to steady state. With 32 blocks, a total of 480unctional volumes were collected.
maging Data Analysis
Functional images were prepared for analysis as inxperiment 1. A repeated-measures ANOVA was used
o identify voxels exhibiting signal increases withigher memory load along with either: (1) a significantain effect of stimulus type or (2) a load-by-stimulus
ype interaction (for each, F(1,6) 5 13.75, P , 0.01).Again, the additional constraint that regions containeight or more contiguous voxels ensured an effectiveimage-wide a of P , 0.01 (Forman et al., 1995).
Results
ehavioral Data
Subjects’ performance was evaluated using 2load) 3 2 (stimulus type) ANOVAs, using both RT and
-back variant used in Experiment 2.
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435WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
accuracy measures (see Fig. 6). As in Experiment 1,RTs increased significantly with increased load(F(1,6) 5 39.52; P , 0.001), as did error rates (F(1,6) 511.97; P , 0.05). Response times did not differ signif-icantly between stimulus types (F(1,6) 5 3.50; P . 0.1).However, error rates were higher with locations thanwith letters (F(1,6) 5 7.38; P , 0.05). There was nosignificant interaction between load and stimulus typeeffects for RT (F(1,6) 5 2.91; P . 0.1) or accuracy(F(1,6) 5 0.46; P . 0.1).
Imaging Data
Five regions were observed that exhibited a maineffect of stimulus type in the ANOVA on the MR signal,along with increased activation during higher WM load(see Fig. 7a and Table 1). In all five regions, the meanMR signal was higher in the Location conditions thanin the Letter conditions. The regions were located bi-laterally in both the right and the left middle frontalgyri (BA 6/8), in a large region spanning the rightinferior parietal lobe (BA 40), the right superior pari-etal lobe (BA 7), and the bilateral precuneus (BA 7) andin the right inferior frontal gyrus (BA 44) and in theleft fusiform gyrus (BA 19).
In addition, three regions were obtained from theinteraction between stimulus type and load (see Fig. 7band Table 1). In all three, the slope of the increase insignal between 0-back and 3-back loads was higher forletters than for locations. In one of the regions, withinthe right inferior parietal lobe (BA 40), the mean signalwas higher in the Location conditions at both levels ofWM load. In the other two regions, the Letter condi-tions yielded higher signals with 3-back loads: in theanterior cingulate (BA 32) and to a lesser extent in theright inferior frontal gyrus (BA 45/47).
FIG. 6. Behavioral data from Experiment 2. Bar graphs denote ewith the scale on the left. Error bars represent standard errors.
Discussion
This experiment failed to confirm either of the twohypothesized stimulus-type WM dissociations. First,with regard to the verbal versus nonverbal WM dichot-omy, this experiment obtained no clearly verbal-specificregions in the left hemisphere. This fails to support thehypothesis that verbal WM processes are left lateralizedand nonverbal WM processes right lateralized. The onlyexclusively left-lateralized frontal region was an area inleft premotor cortex anterior to the frontal eye fields, andit was more active in the spatial Location conditions. Theregion found in the left anterior cingulate activated morewith letters than with locations at the higher level of WMload; however, at the lower load, the opposite was true.All of the other regions, including a left precuneus region,showed greater activation in the nonverbal, spatial Loca-tion conditions, although these were also the more diffi-cult conditions.
Second, with regard to the spatial/nonspatial WMdichotomy, there were no ventral regions responding toa greater extent in nonspatial (Letter) conditions. Thetwo ventral regions, identified in different parts of theright inferior frontal gyrus, were both more active inthe spatial condition.
It might be noted that several of the regions showinga greater sensitivity to spatial locations, in bilateralsuperior frontal sulcus between Brodmann’s areas 6and 8 and in right-lateralized parietal regions, gener-ally coincide with existing models of the spatial atten-tion and eye-movement systems (e.g., Posner and Pe-tersen, 1990). These particular regions also replicatethe findings of other prior experiments attempting tolocalize spatial WM processes (e.g., Courtney et al.,1996, 1998; Petit et al., 1998; Sweeney et al., 1996; butsee also Owen et al., 1998).
r rate with the scale on the right. Line graphs denote reaction time,
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436 NYSTROM ET AL.
437WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
It was surprising that differential letter versus loca-tion activation was not obtained in a traditionally ob-served verbal WM region like Broca’s area. As in Ex-periment 1, this raises the concern that subjects mighthave used verbal coding strategies in the nonverbaltasks. In contrast to the reports from subjects in Ex-periment 1, subjects in this experiment did not reportusing a verbal strategy for the location task. However,it remains possible that subjects used verbal codes forlocations in a nonconsciously accessible manner.
Concerns also persist regarding the differential dif-ficulty of the tasks. Despite pilot testing to equatedifficulty between stimulus types, the behavioral datarevealed that subjects performed the letter WM taskmore accurately than the location task. The higheroverall levels of MR signal obtained in the location taskmay reflect greater effort expended for locations andtherefore greater sensitivity to areas related to spatialWM. Interestingly, however, activity in the anteriorcingulate region seems to have paralleled measures ofbehavioral performance irrespective of stimulus type.While the mean activation of this region failed to differbetween stimulus types, the slope of the load-relatedincrease in MR signal was greater for letters than forlocations, paralleling the slope of the RT curve and theincrease in error rates, which was greater with letters.This relationship between stimulus type and amount ofload-related increases in activation held true for sev-eral other areas as well and was apparently an under-lying cause of all three regions showing statistical in-teraction. None of the interactions exhibited a patternindicative of a strong dissociation, which would predictthat a region would be responsive to WM load onlywhen tested with one or the other stimulus type.
EXPERIMENT 3: SPATIAL LOCATIONSVERSUS SHAPES
This experiment examined the remaining contrastbetween locations and shapes. Because it does not in-volve letter stimuli, it provided the opportunity to ex-clude the possibility of verbal coding strategies, con-scious or otherwise. We did this by using articulatorysuppression methods standard in cognitive psycholog-ical research. During the interstimulus interval be-tween presentations of stimuli (shapes appearing invarying locations), subjects were asked to read aloudwords as presented in the center of the screen at a rateof one every 800 ms. This secondary word-reading taskengaged the full print-to-speech verbal articulatorysystem and presumably interfered with any other useof verbal working memory (Baddeley, 1986). Any addi-
FIG. 7. Regions of activity in Experiment 2 associated with (a)significant interactions between load (0-back and 3-back) and stimuluto signal in the 0-back Letters condition.
tional activation arising from verbal processes engagedduring the word-reading task should not appear in theanalyses, because they would be equated across stim-ulus conditions.
Several earlier experiments have examined the con-trast between object and spatial WM (Baker et al.,1996; Belger et al., 1998; Courtney et al., 1996, 1998;McCarthy et al., 1996; Owen et al., 1998; Petit et al.,1998; Smith et al., 1995). Of these, the experiments ofCourtney and her colleagues (1996, 1998; Petit et al.,1998; cf. Haxby, this issue) used the best-matchedstimuli: displays of faces appearing in varying loca-tions. Across experiments, they found support for adorsal/ventral dissociation between spatial and objectWM processes. In the PET experiment of Courtney etal. (1996), the areas activating to a greater extent withlocation WM tasks included bilateral frontal regions atthe superior frontal sulci, along with bilateral parietaland occipital regions. Areas activating to a greaterextent with face WM tasks included right orbital, infe-rior, and middle frontal regions, along with bilateraloccipital and temporal regions. In a subsequent fMRIexperiment (Courtney et al., 1998), they found similarresults, although the inferior and middle frontal acti-vation, greater in the face conditions, was left lateral-ized instead of right lateralized.
These results differ from those of other experimentsdirectly contrasting object and spatial WM processes.Smith et al. (1995, Experiment 2) found right inferiorfrontal activation, along with right occipital and pari-etal activation in a location condition and left inferiortemporal and parietal activation in a shape condition(with no frontal activation). McCarthy et al. (1996)found bilateral middle frontal and left inferior frontalactivation in a shape condition, but right-lateralizedactivation in middle frontal region with a location con-dition. Baker et al. (1996) obtained similar results, inwhich shape and location WM tasks both activatedmiddle frontal regions, more strongly on the left forshapes and on the right for locations, plus a rightinferior frontal region in the location task; parietalregions were activated by both tasks. Belger et al.(1998) observed activation in a right middle frontalregion with a location task and bilateral middle frontalactivation and left inferior frontal activation in a shapetask; again, parietal activation was obtained with bothstimulus types. Finally, Owen et al. (1998) found nodifferences between activation in a spatial versus anonspatial visual WM task in frontal cortical regions,but greater parietal activation in the spatial conditionand greater temporal activation in the nonspatial con-dition. Across all of these studies, there are many in-
ificant main effects of stimulus type (Letters vs Locations) and (b)ype. Graphs plot percentage signal change in each condition relative
signs t
438 NYSTROM ET AL.
consistent findings and no clear trend exhibited for adorsal/ventral difference in spatial versus nonspatialWM processing. A different trend emerges across stud-ies, though, yielding tentative support for a relativeleft/right hemispheric difference between shape andlocation WM, respectively. This trend parallels the hy-pothesized dissociation between verbal and nonverbalWM, and may in fact result from subjects processingshape identity information using verbal recording.
Materials and Methods
Subjects
Informed consent was obtained from 10 neurologi-cally normal right-handed subjects (5 female, 5 male).Their ages ranged from 18 to 22 years (M 5 20.2). Allsubjects were given practice with the task and werescanned only after reaching a criterion level of perfor-mance (75% accuracy or greater) in all conditions.
Cognitive Task
Subjects performed a variant of the n-back task,using both spatial locations and abstract shapes asmemoranda (see Fig. 8). Because the secondary, word-reading task also made the primary WM task moredifficult, due to the increased difficulty of any dual-taskparadigm, the 2-back rather than the 3-back load con-dition was used as the high WM load condition. Twolevels of memory load (0- and 2-back) were presented ina factorial design fully crossed with the two levels ofstimulus type (Locations and Shapes), yielding fourtask conditions. Trials were blocked by condition, with22 trials per block and 32 blocks presented in pseudo-random order, which ensured that each of the four
FIG. 8. Task conditions specific to th
conditions was presented once within every set of 4blocks.
In the 0-back conditions of this experiment, subjectsdetected a single prespecified location or shape, as inExperiment 1. We had used three 0-back positions inExperiment 2 to prevent subjects from fixing their gazeon the 0-back target position. In the current dual-taskdesign words were presented in the center of the dis-play, to which subjects were required to reorient theirgaze between presentations of shape/location stimuli.Thus, subjects could not avail themselves of the strat-egy of fixing their gaze to avoid WM load.
A block of a single condition lasted 1.3 min, consist-ing of a 3.2-s instruction (e.g., “Target 5 2-backSHAPE repeats”), followed, after a 3.2-s pause, by 223.2-s test trials. At the beginning of each trial, a shapewas presented in a noncentral location for 500 ms.Additionally, words were presented centrally for 500ms at three times during each trial: 800, 1600, and2400 ms after the beginning of the trial. Followingevery block of 22 trials, subjects saw the word PAUSEfor approximately 0.5 min before the next block oftrials began, allowing them a rest period while datawere loaded off the scanner. Thirty-two blocks of trialswere run within a period of approximately 1 h.
Shape stimuli were chosen from the same set of 406-sided random polygons used in Experiment 1. Thelocations of shape presentation were chosen from thesame set of 18 positions used in Experiment 2. Subjectsresponded to shape and location stimuli as in Experi-ments 1 and 2.
Stimuli for the secondary task were chosen from aset of 430 one-syllable words. Subjects responded toeach word presentation simply by immediately readingthe word aloud. Although we were unable to continu-
-back variant used in Experiment 3.
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439WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
ously monitor the speech of subjects above the noiseproduced by the scanner, subjects were periodicallymonitored to ensure that they were responding vocallyto each word presentation.
As in Experiments 1 and 2, 33% of the trials con-tained targets; of the remaining 66% nontargets, 6%of the stimuli were chosen from each of the threeother n-back conditions (including 1- and 3-back),
hile 48% used new stimuli unrelated to the previ-us three trials.
RI Scanning Procedures and Imaging DataAnalysis
Images were acquired using the same 1.5-T scannersed in Experiments 1 and 2. Twenty contiguous slices
3.75-mm3 isotropic voxels) were obtained parallel tothe AC-PC line. Structural images were acquired in thesame locations as the functional images, using a stan-dard T1-weighted pulse sequence. Functional imageswere acquired using a 2-interleave spiral pulse se-quence (TR 5 1600 ms, TE 5 35 ms, FOV 24 cm, flip60°). This T2*-weighted pulse sequence allowed 20slices to be acquired every 3.2 s. Twenty-two functionalvolumes were collected within each 22-trial block;scans were synchronized to trial onsets. With 32blocks, a total of 704 functional volumes were collected.Functional images were prepared for analysis in thesame manner as in Experiments 1 and 2; significancethresholds were again set to P , 0.01 (F(1,9) 5 10.56).
Results
Behavioral Data
Subjects’ performance was evaluated using 2(load) 3 2 (stimulus type) ANOVAs, using both RT andaccuracy measures (see Fig. 9). As in Experiments 1
FIG. 9. Behavioral data from Experiment 3. Bar graphs denote eith the scale on the left. Error bars represent standard errors.
and 2, RTs increased significantly with increased load(F(1,9) 5 19.35; P , 0.005), as did error rates (F(1,9) 582.76; P , 0.0001). While RTs to shape stimuli weresignificantly slower (F(1,9) 5 11.17; P , 0.01), subjects’error rates did not differ between shapes and locations(F(1,9) 5 0.52; P . 0.1). As with Experiments 1 and 2,there was no interaction between load and stimulus-type effects on RT (F(1,9) 5 0.57; P . 0.1). However, asin Experiment 1, the interaction was significant withrespect to accuracy (F(1,9) 5 6.49; P , 0.05). Subjects’accuracy was reduced more by increasing WM loadswhen the memoranda were shapes than when theywere spatial locations.
Imaging Data
Three regions were obtained exhibiting a main effectof stimulus type in the ANOVA on the fMRI signalalong with increased activation with higher WM load(see Fig. 10a and Table 1). The mean fMRI signal washigher in the Location conditions in the right middlefrontal gyrus (BA 6/8) and in a large region includingthe right inferior parietal lobe (BA 40) as well as bilat-eral (predominantly right) superior parietal lobes andbilateral precuneus (BA 7). In contrast, the signal washigher in the Shapes conditions in the left inferiorfrontal gyrus (BA 44/45).
Four regions were obtained from the interaction be-tween stimulus type and load (see Fig. 10b and Table1). These areas were located in the right anterior cin-gulate (BA 32), the right precentral gyrus (BA 6), theright middle frontal gyrus (BA 9/8), and the left inferiorand middle frontal gyri (BA 9/8/44), an area just supe-rior to the left inferior frontal region obtained in themain effect of stimulus type. In all four regions, theslope of the signal increase between 0-back and 2-backloads was higher with Shapes than with Locations;
r rate with the scale on the right. Line graphs denote reaction time
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440 NYSTROM ET AL.
441WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
while the mean signal was higher with Locations at0-back loads, it was equal or higher with Shapes at2-back loads.
Discussion
At first glance, the distribution of regions in Exper-iment 3 detected by the main effect of stimulus typeseems to lend support to the hypothesis that WM forspatial information is localized to dorsal frontal cortex,while WM for nonspatial information is subserved byventral frontal cortex. There were only two frontalregions observed in this main effect: (1) a more shape-sensitive region in the left inferior gyrus and (2) a morelocation-sensitive region in the right superior frontalsulcus. This second region is located in approximatelythe same place as a similarly location-sensitive regionfound in Experiment 2. Additional location-sensitiveregions in parietal cortex, mostly in the right hemi-sphere, also replicated nearly identical location-sensi-tive parietal regions in Experiment 2. The location-sensitive areas, frontal and parietal, also replicate theareas previously identified by Courtney and colleagues(1996, 1998) in tests of spatial WM. Furthermore, thelaterality of these regions is consistent with the tenta-tive finding of a left/right asymmetry between nonspa-tial and spatial WM found in other earlier studies.
Nevertheless, the pattern of activation in regionsexhibiting an interaction between load and stimulus-type must temper any strong conclusion about dorsal/ventral dissociations. These regions were in primarilydorsal frontal areas, yet they exhibit complex patternsof response to the various conditions that do not indi-cate a sensitivity particular to spatial WM manipula-tions. The pattern of interaction in these regions is notindicative of a dissociation, with only location stimulicausing increased activation with increasing WM load.Quite the contrary, in all four regions, the slope of theload-related increase in activation was greater forshapes than for locations. In fact, in two of them, rightAC and left DLPFC/premotor cortex, the activation inShape 2-back conditions exceeds that of Location2-back conditions. In a third region in the rightDLPFC, the activation in Location conditions is higheroverall, yet remains unchanged with increasing WMload, whereas the activation in the Shape conditionsincreases with load. The responses of these regionsmay be complex, but it is clear nonetheless that onecannot safely label them as specialized for spatial WM.Note that Postle et al. (this issue) used designs andmaterials very similar to those of the present study and
FIG. 11. Regions of activity associated with increased WM loadfor each stimulus type in each experiment. Color scale indicates thesignificance of a one-tailed matched-sample t statistic contrastingMR signal increases with high WM load conditions (2-back and/or3-back) relative to low WM load conditions (1-back and/or 0-back).The maps illustrate this contrast from: (a) Experiment 1, Letters; (b)Experiment 1, Shapes; (c) Experiment 2, Letters; (d) Experiment 2,Locations; (e) Experiment 3, Shapes; and (f) Experiment 3, Loca-tions.
FIG. 10. Regions of activity in Experiment 3 associated with (a) significant main effects of stimulus type (Location vs Shape) and (b)significant interactions between load (0-back and 2-back) and stimulus type. Graphs plot percentage signal change in each condition relativeto signal in the 0-back Shapes condition.
442 NYSTROM ET AL.
obtained no evidence for frontal dissociations betweenWM for shapes versus locations.
It might be possible to characterize the activation ofthese regions as a result of differential task perfor-mance. As discussed under Experiments 1 and 2, acti-vation of the anterior cingulate is often found to closelyfollow task difficulty, as measured by behavioral per-formance. In this experiment as well, the activation ofthe AC region mirrored error rates. Error rates werehigher with locations at the 0-back load, increased forboth stimulus types with increased load, but becamehigher with shapes at the 2-back load. The activation ofthe AC region exhibited an identical pattern of in-creases with all four conditions. A similar case mightbe made to explain the other three regions exhibitinginteractions. However, there were no preexisting hy-potheses to lead us to expect that the activation ofthese other regions should track errors, as there waswith the AC.
The use of verbal strategies with nonverbal stimuli,a potential confound in Experiments 1 and 2, shouldhave been minimized or eliminated by the addition ofthe articulatory-suppression secondary task. It is sur-prising, therefore, that this experiment was the onlyone to identify a region within Broca’s area. This regionexhibited significantly greater activation for shapesthan for locations. Because subjects in the two earlierexperiments reported using verbal coding strategies inShape, but not Location, conditions, this result may beinterpreted as evidence that the vocal suppression taskwas not completely successful in eliminating verbalrehearsal strategies. Alternatively, the activation inBroca’s area may indicate that the shapes task and theword-reading task mutually interfered to a greaterextent, relative to the locations task, making Broca’sarea “work harder” during that dual-task combination.
GENERAL DISCUSSION
The three experiments reported here present a com-plex series of results that do not lend themselves to anysimple interpretation. At the very least, however, theychallenge hypotheses about the functional organiza-tion of WM in the PFC according to simple distinctionssuch as verbal versus nonverbal or object versus spa-tial WM. The regions of activation did not dividecleanly along either the left/right or the dorsal/ventraldimensions that have been hypothesized for stimulus-based dissociations. While there may be some concernsremaining about particular shortcomings of each ex-periment, taken as a whole, this set of studies broadlysupports the notion of a frontal cortex in which theregions engaged by manipulations of WM load are re-sponsive to every type of stimulus information. Onepossible exception may be the regions of relative selec-tivity for spatial information in the (posterior) superiorfrontal sulcus obtained in both Experiments 2 and 3, as
well as in experiments by Courtney and colleagues(1996, 1998). Even those reliably identified regions,however, responded with increased activation tohigher WM loads in both the letters and the shapesconditions, thereby failing to meet the strictest crite-rion for a dissociation.
Because of the lack of clean dissociations obtained inthese studies, a reexamination of the data was war-ranted, to more specifically explore the null hypothesisthat the human PFC is not reliably differentiated withregard to WM for letters, shapes, and locations. In allthree experiments, the cortical regions considered thusfar have been identified using statistics designed tolocate dissociations between conditions: main effects ofstimulus type and interactions between WM load andstimulus type.
Both for illustrative purposes and as a check that ourtasks did indeed invoke WM-related areas of PFC, weperformed a series of post hoc contrasts on each exper-iment’s imaging data, separately identifying areas foreach stimulus type that showed significant load-re-lated increases in MR signal. As shown in Fig. 11, theresults of these contrasts indicate that roughly thesame cortical areas responded to increases in WM loadacross all stimulus types in all three experiments. Ac-tivation was observed bilaterally in premotor, supple-mentary motor, anterior cingulate, superior and infe-rior parietal, and superior, middle, and inferior frontalareas—all regions that are commonly implicated inWM tasks. Not a single area can be found that acti-vated with one stimulus type without activating theother two as well. There are no dissociations apparentin these maps between left and right hemispheric ac-tivation with verbal versus nonverbal stimuli nor isthere any apparent distinction between dorsal andventral activation for spatial versus nonspatial stim-uli. This demonstrates that the tasks were indeed suc-cessful in eliciting load-responsive activity and thatsimilar areas were activated by tasks that involvedWM for different materials, suggesting that there is asingle common WM system operating across all threestimulus types.
Nevertheless, before accepting the null hypothesisthat rejects the existence of stimulus-based dissocia-tions of WM regions, it would be wise to first considerseveral alternate explanations for a failure to obtainsuch dissociations. For one, it is possible that stimulus-based dissociations do exist, but on a scale too small tobe detected using current fMRI techniques. The spatialresolution of fMRI images in these experiments, lessthan 1 cm3 per voxel, was certainly sufficient to detectdissociations on the gross scales—left/right hemi-spheric or superior/inferior—proposed by the verbal/nonverbal and spatial/nonspatial hypothesis. More-over, prior studies providing evidence of thesedissociations, especially those that used PET technol-
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443WORKING MEMORY FOR LETTERS, SHAPES, AND LOCATIONS
ogy, have had poorer spatial resolution (e.g., Courtneyet al., 1996; Smith et al., 1995, 1996).
Another possibility is that subjects encoded, main-tained, or manipulated stimuli using similar strategiesand mechanisms across the various stimulus types.For example, we have already discussed concerns thatsubjects may have used verbal strategies for rehears-ing putatively nonverbal stimuli, by naming the ab-stract shapes or the locations of stimuli. Similarly, it ispossible that subjects processed the abstract shapesusing a spatially based strategy (e.g., as configuralinformation). For example, it is possible to encode theidentity of a particular shape using a spatial coordi-nate system to record, relate, or traverse the variousvertices of the abstract polygons, thereby rendering theshapes task more spatial in nature. It is reasonable tothink that this type of configural strategy may be morecompelling for processing unfamiliar and nonnatural-istic shapes like those used in the present experiments.Presumably, if one presented familiar shapes or facesinstead of the abstract polygons, this strategy would beof less use to subjects (although a verbal strategymight then gain appeal.)
A third possibility is that the subjects employed sim-ilar WM processes with each stimulus type, not byprocessing one type of stimulus with a strategy nor-mally associated with another type, but rather by pro-cessing all stimuli using mixtures of all strategies,either simultaneously or alternatively across trials. Infact, the design of the current experiments, requiringthe switching between multiple tasks at fairly short(1-min) intervals, may have promoted an intermin-gling of multiple WM strategies. The fact that thestimulus presentations were identical between all con-ditions within Experiments 2 and 3 may have alsocontributed to a blending of spatial and nonspatialstrategies. This intermingling would not necessarily bea controlled or conscious strategy and therefore neednot have been reported in post test questioning.
A related possibility is that the relatively high cog-nitive demands placed on subjects by the n-back taskmay encourage recruitment of as many resources andcomplementary processing strategies as possible—again, with or without subjects’ conscious knowledge.Evidence consistent with this hypothesis arises fromrecent fMRI studies of episodic memory encoding andretrieval, in which the tasks might be presumed toplace less continuous demand on WM systems. In theseepisodic memory tasks, reliable within-subject evi-dence has been produced for a dissociation by stimulusdomain in inferior frontal regions, with a left lateral-ization for words versus a right lateralization for un-familiar faces (Kelley et al., 1998) or texture patternsWagner et al., 1998). At this time, however, it is un-lear whether these positive findings of frontal disso-iations differ from the negative findings of the presentxperiments because of the degree of WM involvement
or rather because of the involvement of episodic mem-ory systems.
Finally, just as multiple attributes of a stimulus(such as location and identity) are automatically en-coded and processed in multiple parallel streamswithin posterior cortical regions (Ungerleider andHaxby, 1984), perhaps multiple attributes are also au-tomatically processed in parallel streams within ante-rior WM systems. Subjects could still attend to oneparticular stimulus attribute (e.g., letter identity) inorder to make task-related decisions about stimuli,without this focus eliminating the simultaneous, oblig-atory or automatic maintenance of other attributes(e.g., letter location). If these parallel WM maintenanceprocesses were modulated by executive processes tofocus on task-relevant information, a stimulus-baseddissociation might be obtainable only in a diminishedform, if at all. It is possible that all WM-related areasactivate on a more global scale with all types of stimulidue to this obligate encoding of multiple dimensions ordue to highly distributed neural representations ofstimulus information. In the latter case, cognitivelyrelevant changes in brain activity may involve onlysubtle changes in the intensity of activity in differentareas, below the level of our ability to detect (due tonoise in the amplitude of the fMRI signal response).
With all of these caveats left under consideration, letus turn to alternate hypotheses that reject stimulus-based dissociations within frontal WM areas. Petridesand colleagues have proposed that the PFC is orga-nized according to the type of WM process applied to astimulus, irrespective of the stimulus type or modality(Petrides, 1994, 1995, 1996; Owen et al., 1996, 1998;Owen, 1997; Stern et al., this issue). In this theory, theprefrontal cortex is divided along a dorsal/ventral axis,but not according to the spatial/nonspatial distinctionfound in posterior cortical regions. Instead, it is pro-posed that ventrolateral prefrontal regions are used tomaintain information received from more posterior as-sociation areas, while dorsolateral prefrontal regionsare recruited only when executive processes are re-quired to manipulate or monitor information withinWM. Two recent reviews of WM neuroimaging experi-ments (Owen, 1997; D’Esposito et al., 1998) generallysupported the Petrides hypothesis, finding that exper-imental tasks that required maintenance alone tendedto activate ventral PFC, while tasks that involved morecomplex manipulations of information in WM tended toadditionally activate dorsal PFC. Note that while themechanisms underlying “maintenance” and “manipu-lation” proposed within this conceptual framework re-main somewhat underspecified at present, we expectthat a 0- or 1-back task would be classified as a main-tenance task, while a 2- or 3-back task would be seen asinvolving manipulation in addition to maintenance.The results of all of the present experiments wouldtherefore be generally consistent with this theory (see
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Fig. 11), as both dorsal and ventral PFC regions wereactivated in the 2- or 3-back tasks. However, we (andothers) have also obtained dorsal PFC activation in amaintenance-only Sternberg WM task (Nystrom et al.,1998; Rypma et al., 1999), an apparent contradiction tohe Petrides hypothesis.
It may simply be the case that WM representationsf stimulus information in PFC are organized alongess obvious dimensions than verbal code, shape, orocation. Information in frontal cortex may be far morebstract, combinatorial, or distributed than informa-ion in other regions of the brain. This would be con-istent with the fact that PFC is the cortical regionost phylogenetically enlarged in primates, especiallyumans (Fuster, 1997). It is also the region mostlosely identified with abstract and associative thoughtrocesses. Representations in PFC may therefore beefined by a complex, abstract, multimodal space thatoes not correspond in any obvious manner with theimpler dimensions coded in posterior cortical regionsCohen et al., 1996). Thus, posterior cortically codedimensions such as location or shape may not be theppropriate ones to use for probing frontal representa-ions.
Recent single-cell recording studies in nonhumanrimates lend support to this idea. Miller and col-eagues (Rainer et al., 1998a,b; Rao et al., 1997) have
produced striking evidence that lateral PFC neurons ofmonkeys may be tuned to represent either the locationor the shape of objects (or both), depending on currentexperimental context. Rao et al. (1997) found some
eurons specialized for object or spatial WM, butoughly half represented both types of information.hus, even though they observed a relative bias inome neurons, at a larger scale, analogous to the scalet which neuroimaging resolves areas, there was abso-ute overlap in WM functions. Even if the relative biasound in subsets of neurons were spatially organized at
finer scale, Miller’s data point to a much more dis-ributed form of representation in PFC than has tradi-ionally been considered.
Miller and colleagues have suggested that an equi-otentiality of information coding in PFC neurons wasvidenced specifically because the monkeys wererained in tasks requiring the simultaneous mainte-ance of multiple forms of information (spatial andbject) instead of only one. Earlier studies reportingegregation of neurons along dorsal/ventral spatial/onspatial dimensions (e.g., Wilson et al., 1993) hadrained and tested monkeys on these dimensions inde-endently. This pattern of physiological findings is con-istent with a previous computational modeling study,n which training blocked by stimulus modality wasound to produce representations of actively main-ained information that were modality-specific,hereas interleaved training produced multimodal,
onjunctive representations (Braver and Cohen, 1995).
herefore, we would suggest that the representationsn PFC are more plastic and more highly attuned tourrent task demands than the representations in pos-erior cortex (Cohen et al., 1996; Miller, 1999).
In summary, the findings from our studies present aomplex pattern of results. Regarding the central ques-ion of this special issue, they do not provide convincingupport for representational organization within hu-an PFC according to simple stimulus dimensions.hese findings, taken together with those reported inhe other articles in this issue, suggest that organiza-ion within the PFC may adhere to a scheme that isore complex than previous research has assumed.his poses a fascinating challenge for future re-earch—both to identify the relevant dimensions alonghich PFC may be organized and to understand how
his may arise during development and interact withngoing experience.
ACKNOWLEDGMENTS
This work was supported by a grant from the National Institute ofMental Health. The authors thank Micah Alpern, ChristyMarshuetz, and Nicole Garcia for their technical assistance, as wellas Deanna Barch and two anonymous reviewers for their thoughtfulcomments and helpful suggestions on an earlier version of the manu-script.
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