age differences in the frontal lateralization of verbal and spatial

Age Differences in the Frontal Lateralizationof Verbal and Spatial Working MemoryRevealed by PET

Patricia A Reuter-Lorenz John Jonides and Edward E SmithUniversity of Michigan

Alan HartleyScripps College

Andrea Miller Christina Marshuetz and Robert A KoeppeUniversity of Michigan

Abstract

amp Age-related decline in working memory figures promi-nently in theories of cognitive aging However the effects ofaging on the neural substrate of working memory are largelyunknown Positron emission tomography (PET) was used toinvestigate verbal and spatial short-term storage (3 sec) inolder and younger adults Previous investigations withyounger subjects performing these same tasks have revealedasymmetries in the lateral organization of verbal and spatialworking memory Using volume of interest (VOI) analysesthat specifically compared activation at sites identified withworking memory to their homologous twin in the oppositehemisphere we show pronounced age differences in thisorganization particularly in the frontal lobes In younger

adults activation is predominantly left lateralized for verbalworking memory and right lateralized for spatial workingmemory whereas older adults show a global pattern ofanterior bilateral activation for both types of memoryAnalyses of frontal subregions indicate that several underlyingpatterns contribute to global bilaterality in older adults mostnotably bilateral activation in areas associated with rehearsaland paradoxical laterality in dorsolateral prefrontal sites(DLPFC greater left activation for spatial and greater rightactivation for verbal) We consider several mechanisms thatcould account for these age differences including thepossibility that bilateral activation reflects recruitment tocompensate for neural decline amp

Few domains of human cognition remain untouched bythe effects of aging Such global decline has promptedthe search for cognitive mechanisms capable of exert-ing widespread effects mechanisms such as workingmemory which is known to play a central role inhuman cognition (Baddeley 1986 Carpenter amp Just1989) Indeed behavioral research implicates age-re-lated declines in working memory as a source ofcognitive aging effects across a variety of domains(for example Salthouse 1991) Over the past 10 yearsconsiderable progress has been made toward specifyingthe neural mechanisms underlying working memory inthe human brain (Petrides Alivisatos Meyer amp Evans1993 Smith amp Jonides 1998 cf Goldman-Rakic 1992)However relatively little is known about the effects ofnormal aging on the circuitry of working memoryGiven the central importance of working memory tocognition and to age-related cognitive decline weinvestigated the effects of age on the neural substrate

of working memory using positron emission tomogra-phy (PET)

Working memory refers to the capacity to hold in-formation in mind for short periods of time (that is 30sec or less) and to use or manipulate that information inthinking and problem solving tasks Thus workingmemory is thought to include storage mechanisms thatmaintain its contents in an active state and executiveprocesses that perform various operations on the storedinformation (Baddeley 1986 Jonides 1995) There is alarge body of evidence indicating that the workingmemory system is composed of verbal and spatial sub-systems that are lateralized to the left and right hemi-spheres respectively (see Jonides et al 1996 for areview) This asymmetrical organization was first evidentthrough case reports of the selective loss of verbalworking memory following left-hemisphere damage(see Vallar amp Shallice 1990) and spatial working memorydeficits consequent to right-hemisphere damage The

copy 2000 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 121 pp 174ndash187

lateralized lesions affecting these cases caused dramaticimpairments in short-term memory reducing itrsquos capa-city from a normal level of five to seven items to adysfunctional level of one or two items

The asymmetrical organization of verbal and spatialworking memory has been largely corroborated byneuroimaging studies of healthy young right-handedadults particularly for tasks that emphasize short-terminformation storage (see DrsquoEsposito et al 1998 SmithJonides amp Koeppe 1996 for reviews compare Gold-berg Berman Randolph Gold amp Weinberger 1996Owen Evans amp Petrides 1996) Verbal storage taskshave been associated with a predominance of left-hemi-sphere activation in Brocarsquos area supplementary motorcortex premotor cortex superior and inferior parietalcortex (Awh et al 1996 Fiez et al 1996 Jonides et al1998 Schumacher et al 1996) Likewise during spatialstorage tasks activation predominates in right-hemi-sphere regions homologous to those active duringverbal storage along with right frontal activation inBrodmannrsquos area (BA 47) and in visual association cortex(that is BA 18 Jonides et al 1993) The lateralizedfrontal components of this circuitry are thought tomediate rehearsal or maintenance of phonological andspatial information represented more posteriorly in theleft and right hemispheres respectively (Awh amp Jonides1997 Awh et al 1996) When executive components areadded to the storage tasks by requiring contextualtagging or manipulation of the stored items for exam-ple activation of dorsolateral prefrontal sites (DLPFCBA 45 46 9) is evident Differential activation of left andright DLPFC has been reported for such verbal andspatial working memory tasks (eg Smith Jonides ampKoeppe 1996) although overall the magnitude ofasymmetry for these more complex working memorytasks may be less than in simple storage tasks

How might aging affect the neural circuitry of workingmemory A few possibilities present themselves Pre-frontal regions seem particularly vulnerable to the ef-fects of aging (Raz in press) and changes in frontal lobefunction are hypothesized to be the source of variouscognitive deficits found in older adults (see Moscovitchamp Winocur 1995 Raz in press for reviews) Frontaldysfunction has been linked to age-related impairmentsin long-term memory attention and inhibitory processes(Chao amp Knight 1997 Jonides et al in press West1996) We might expect then that the anterior compo-nents of the working memory system might show great-er age-related changes than posterior componentsSome recent evidence from a study examining theeffects of age on working memory for faces suggeststhis may the case (Grady et al 1998)

Another possibility is that aging leads to a decline inthe functional specificity of the working memory sys-tem Neuroimaging evidence for declining specificitycomes from a PET study of the lsquolsquowhatrsquorsquo vs lsquolsquowherersquorsquoprocessing streams in older and younger adults (Grady

et al 1992 1994) Subjects performed a face-matchingtask intended to activate the whatventral stream or alocation-matching task designed to activate the wheredorsal stream Younger participants showed the ex-pected dissociation between dorsal and ventral streamprocessing face-matching produced more ventralstream activation and location-matching evoked moredorsal stream activation In contrast older adultsshowed significant activation of dorsal and ventral sitesduring both tasks More recently studies of episodicmemory have demonstrated that older adults departfrom the pattern of lateralized prefrontal activity thathas been shown to differentiate encoding and retrievalprocesses in younger adults (that is Cabeza et al 1997Grady et al 1995 Madden et al 1999 Tulving KapurCraik Moscovitch amp Houle 1994) Some studies reportmore bilateral activation in older than younger adultsduring retrieval and others find greater left than rightactivation in anterior sites where younger subjects showthe opposite pattern

We might expect then that aging would also alter thelateral organization of the working memory systemHere we report PET evidence of age differences inthe asymmetrical organization of verbal and spatialworking memory particularly in the frontal lobes foryounger adults activation is predominantly left latera-lized for verbal working memory and right lateralizedfor spatial working memory whereas older adults showactivation in left and right frontal sites for both types ofmemory

We tested two groups of older (62ndash75 years) andyounger (18ndash30 years) female1 adults in two workingmemory tasks that emphasized short-term informationstorage and had the same basic structure (Figure 1) Inthe verbal-storage task subjects were presented withfour target letters they stored them in memory for 3 secand then they indicated whether or not a probe lettermatched any target In the spatial-storage task threetarget locations were marked on the screen subjectsstored them for 3 sec and then indicated whether or nota probe location matched any target location Eachmemory task was paired with a control task designedto include all of the cognitive components of thememory task (for example perceptual encoding re-sponse selection preparation and initiation) exceptthe working memory component (that is immediatematching) Thus subtracting the images of the controlcondition from the images of the memory conditionshould reveal primarily the brain areas that are activeduring verbal or spatial working memory respectively Itis important to bear in mind that because our PETanalyses rely on subtraction logic the results reflectactivation changes in the memory task relative to thecontrol tasks for each age group and not age differencesin the absolute levels of neural activity associated withworking memory processes Thus any age differenceswe report could be due to group differences in the

Reuter-Lorenz et al 175

control conditions or the memory tasks Although wehave no way to know for certain we assume that age hasa greater effect on the neural substrate of working

memory than on the substrate of the immediate match-ing tasks and that this age effect is evident in ourdifferences images

RESULTS

Verbal Working Memory

Performance Data

Both groups showed nearly perfect accuracy on thecontrol task scoring 99 correct or higher howeveran analysis of variance indicated that the youngersubjects were faster than the elderly on both tasks(control task F(1 22)=617 p=02 memory taskF(1 22)=299 p=0001) and more accurate on thememory task (F(1 22)=614 p=02 see Table 1)

PET Data

The averaged subtraction images indicate approxi-mately 10 more activation in the younger adults thanthe older group (see Table 2) Due to the relativelysmall sample size however only a site in left thalamusand right cerebellum reached conventional levels ofsignificance using post hoc tests in the younger groupIn order to establish that the present results are none-theless representative of the verbal working memorycircuitry in the younger brain regions of interest(ROIs) derived from our previous results using thistask (see Awh et al 1996 Smith et al 1996 Experi-ment 1) were applied to the current data set from theyoung subjects Seven of the nine regions were sig-nificant at the plt05 level (regions in Brocarsquos area BA6 BA 407 on the left and anterior cingulate) Theremaining two were significant at the 10 level (leftinsular right cerebellum) Likewise when the ninemost active regions from the present study wereapplied to the data set reported by Smith et al

Figure 1 Cognitive tasks Sequence of events and timing parametersfor the verbal (a) and spatial (b) working memory and control tasksFor the spatial control task only one dot location varies across trialsthe top and bottom dots appear in the same locations for each trial

Table 1 Mean Accuracy (Proportion Correct) Response Times and Standard Errors for Younger and Older Participants in theVerbal and Spatial Working Memory Tasks with Each Corresponding Control Condition

Verbal Spatial

Accuracy Response Time Accuracy Response Time

Younger Control 099 524 099 5290003 28 0195 23

Memory 097 654 091 7060017 28 141 17

Older Control 099 6109 099 7410004 20 028 23

Memory 092 843 092 9150012 20 138 22

176 Journal of Cognitive Neuroscience Volume 12 Number 1

(1996) all but one was significant at the plt05 level(left BA 7) This reciprocity establishes that the resultsobtained with this working memory task are replicablein younger adults

Post hoc analyses of the activation images from theolder adults showed significant activation in area 6bilaterally left cerebellum and right dorsolateral pre-frontal area 469 (see Table 2) Thus post hoc analysessuggest laterality differences between the two agegroups In order specifically to test age differences inlaterality we devised an analysis that targeted the verbalworking memory circuitry as delineated by previouspublished reports Although these studies have all usedyounger adults as participants and therefore may notbe fully representative of the circuitry of older adults wenevertheless constructed ROIs from these previous stu-dies because they are the basis of our neuroanatomicalknowledge about working memory To minimize theinfluence of any idiosyncratic effects in any one studywe culled ROIs from a range of PET studies (Awh et al1996 Fiez et al 1996 Grasby et al 1993 Paulesu Frithamp Frackowiak 1993 Petrides et al 1993 Salmon et al1996 Schumacher et al 1996) Figure 2a illustrates thelocations of these ROIs in a sagittal projection thatcollapses across the x plane in Talairach space Weassessed the laterality of activations within each agegroup by comparing activation in each region of interestwith the activation in the homologous site in theopposite hemisphere

Laterality Comparisons in PET

A set of 85 ROIs was derived from published reports ofpeak pixels active during PET studies of verbal workingmemory tasks including our own (see Figure 2) Themajority of these regions were in the left hemisphereand include frontal sites in BA 45 46 10 and 9 44(Brocarsquos area) 6 (premotor and supplementary motorsites) parietal sites in areas 40 and 7 and temporal sitesin 42 and 22 Spherical volumes 15 cm in diameter(volumes of interest VOIs) were constructed aroundreported peak pixels replicated in the symmetricallocation in the opposite hemisphere and then appliedto each subjectrsquos memory-minus-control subtractionimages thereby permitting a comparison of the averageactivation changes across homologous regions To as-sess differences in asymmetry in the front and back ofthe cortex an anterior subset (n=34) was defined inTalairach space as those ROIs with a ygt0 and a posteriorsubset (n=33) with yltndash 10 and zgtndash 10

The results from paired t tests comparing averageactivation for each specified subset of VOIs against zeroare illustrated in Figure 3a and 3b The first thing tonotice about Figure 3 is that older and younger adultsshow approximately the same activation across theentire set of VOIs and in some cases older adultsshow greater activation than the younger group These

features of the data argue that this VOI analysis was notsystematically biased against finding activation in theolder group For the posterior VOIs both groupsshowed significant activation in the left hemisphere(paired t tests evaluated vs 0 older t(15)=596p=0001 younger t(7)=3971 plt003) and neithergroup showed any hint of reliable activation in theset of right-hemisphere VOIs (older t(15)=04 p=45younger t(7)=ndash 112 p=46 see Figure 2b) For bothgroups this leftright activation difference was reliable(older t(15)=3795 p=0009 younger t(7)=4793p=001) Moreover there was no difference betweenthe groups in the magnitude of this asymmetry (un-paired t test comparing average leftndashright differencesfor younger vs older groups (that is difference ofdifferences t(22)=014 p=495 all tests one-tailed)

A strikingly different pattern is evident for theanterior VOIs (see Figure 3a) Again the youngeradults show asymmetrical activation There is signifi-cant net activation in the left VOIs (t(7)=496p=0008) but not the right (t(7)=993 p=178)and this leftndashright activation difference approachessignificance (t(7)=176 p=061) In contrast for old-er adults the anterior VOIs in both hemispheres aresignificantly active (left t(15)=336 p=002 rightt(15)=460 p=0002) and there is no difference inthe degree of left-hemisphere and right-hemisphereactivation (t(15)=ndash 115 p=134) Indeed the magni-tude of asymmetry is significantly different betweenthe two age groups (unpaired t test comparingaverage leftndashright differences for younger vs oldergroups t(22)=215 p=021)

This anterior subset of VOIs was further divided intofour major subregions (medial SMA lateral SMA DLPFC(469) Brocarsquos area (44)) and age differences in late-rality were examined in these areas separately Severalanterior VOIs (n=7) that were part of the larger subsetwere not included in this analysis because they wereanatomically disparate and there were too few from anyone region (that is three or less) to constitute a separatesubregion At this finer grain the results are morecomplex and less robust however there are severalnoteworthy patterns As can be seen from Table 3 bothgroups showed bilateral activation in the VOIs withinmedial SMA which may have resulted in part from thesize of the VOIs and from the limited spatial resolutionof PET In lateral SMA both groups tended towardgreater left than right activation with the older adultsshowing stronger asymmetry than the younger groupBrocarsquos area was highly activated on the left and deac-tivated on the right in the younger group whereas olderadults showed significant activation bilaterally InDLPFC the younger group showed significant activationonly on the left whereas the older group showedsignificant activation on the right with only a weaktendency toward left activation in this region Thus incontrast with the left lateralized activity in the younger


Table 2 Regions of Significant Task-Related Activity for Both Age Groups in the Verbal and Spatial Tasks

Stereotactic Coordinate

Brodmannrsquos Area x y z Percent Change z Score

Verbal

Younger subjects (n=8)

Left thalamus 6 ndash 17 2 532 454

Right cerebellum ndash 33 ndash 53 ndash 25 502 429

Right 6 ndash 3 1 52 494 422

Left 6 8 8 47 481 410

Left 6 48 ndash 1 29 480 409

Left 32 1 12 38 478 408

Left 40 33 ndash 51 38 464 396

Left 4 30 ndash 8 45 461 393

Left 7 ndash 30 ndash 58 43 449 383

Older subjects (n=16)

Right 632 ndash 1 8 45 463 576

Left 64 48 ndash 1 22 463 576

Left cerebellum 15 ndash 64 ndash 16 449 558

Right 469 ndash 39 35 29 417 519

Left 6 30 3 47 346 430


Left 17 8 ndash 87 9 327 406

Left 740 35 ndash 58 43 327 406

Left 40 44 21 20 325 403

Spatial


Left 719 24 ndash 64 40 298 534

Left 40 37 ndash 49 38 286 514

Right 40 ndash 42 ndash 40 38 279 501

Left 6 24 ndash 8 47 272 489




Left 46 28 ndash 8 50 289 593


Left 7 19 ndash 67 45 267 547



Left 40 46 ndash 49 40 239 491

(continued)


group the global picture of bilateral anterior activationin the older adults is the result of several underlying butweaker patterns activation of left lateral SMA bilateralactivation of Brocarsquos area and activation of right DLPFCThe patterns of activation in these frontal subregionsreveal that the global anterior bilaterality in older adultsis a composite picture of a verbal working memorycircuitry whose components are distributed across bothhemispheres We note that the bilateral activation ofBrocarsquos area and right DLPFC activation that are uniqueto the older group has been replicated in a different dataset from our lab (Jonides et al in press) and will be thefocus of a separate report We consider the functionalsignificance of these patterns after presenting the resultsfrom the spatial working memory task

PET-Performance Relations

In order to evaluate whether the patterns of lateralityobserved in our two age groups are related to taskperformance we conducted a series of correlationalanalyses For the PET data we derived difference scoresby subtracting the net activation levels in the right VOIsfrom the net activation in the left VOIs reported aboveWe computed three difference scores for each subject forthe anterior and posterior subsets and for the entire setof VOIs In addition to using the difference scorescorrelations were also performed using the net activa-tions for the left and right anterior posterior and full-hemisphere VOIs The percent correct score and averagereaction time for the working memory task performedduring PET were transformed into z scores based onseparate distributions for each group In addition foreach subject we calculated a combined z score by sub-tracting the z score for reaction time from the z score foraccuracy (subtraction was used because better perfor-mance is indicated by higher accuracy but by lowerresponse time and so subtraction adjusts for this reci-procal relationship Salthouse 1992) These correlations

were computed for the younger and older subjectsseparately and for the two groups combined

Only two correlations reached significance and thesewere for the older group The combined z score waspositively correlated with the magnitude of activation forall the left ROIs combined and for the left posteriorsubset alone (plt05 uncorrected for multiple correla-tions) This significant correlation indicates that greaterleft-hemisphere activation particularly in posterior re-gions is associated with better performance in the oldergroup The correlation between the combined z and leftanterior subset was not significant for the older groupnor were any of the correlations for the younger orcombined groups Finally the three performance mea-sures were also correlated with the left and right activa-tion levels for each of the four anterior subregions andthe leftndashright difference score for each region Only twocorrelations reached significance at a level of plt01 Forthe older group activation of left Brocarsquos area wasnegatively correlated with response time and for theyounger group the activation of left lateral SMA wasnegatively correlated with response time

In a further attempt to relate activation patterns toperformance we undertook an additional analysis Amedian split was used to group the older adults basedon their response speed because this measure spanneda wider range of performance than did accuracy Thelaterality of DLPFC activation differed significantly (t testcomparing leftndashright difference scores for the two sub-groups t(14)=250 plt013) The fast group showedDLPFC activation bilaterally whereas for the slow grouponly right DLPFC was activated coupled with nonsigni-ficant deactivation of left DLPFC Both groups showedbilateral activation of Brocarsquos area

Spatial Working Memory

The first experiment provides clear evidence that thepattern of laterality associated with the anterior compo-

Table 2 (continued)



Spatial

Left 7 30 ndash 58 47 228 467



Right 6 ndash 46 8 32 212 436

The thresholds for significant z scores with correction for multiple comparisons are as follows Verbal younger=423 older=435 spatialyounger=423 older=435 Note that for the verbal task the presence of fewer significant sites for the younger subjects is due to the smaller n notsmaller magnitude changes In addition note that the magnitudes of the activations for the spatial task are lower than for the verbal task This is inpart but not entirely due to the increased scatter fraction in 3-D (spatial study) compared to 2-D (verbal study) scans which causes up to a 20reduction in the apparent activation magnitude However reduced statistical noise in the 3-D study more than compensates and thus the z score(signal-to-noise ratio) for a given magnitude change is higher for the spatial study


nents of the verbal workingmemory systemdiffers inolderand younger adults Given that verbal and spatial workingmemory are characterized by opposite patterns of asym-metry in the younger brain we might expect that thecircuitry of spatial working memory like verbal workingmemory would show age differences in laterality Indeedthe following experiment confirmed this prediction

Two new groups of younger and older adults partici-pated in the spatial memory and control tasks illustratedin Figure 1b while PET images were obtained The olderadults who participated in this experiment met anaccuracy criterion (see Methods section below) Thiswas done to maximize the similarity in performance ofyounger and older participants and to insure that anyage-related accuracy differences on this task did notsignificantly exceed those that were present in theverbal task

Performance Data

There were no group differences in control or memoryaccuracy although the responses of senior subjects weresignificantly slower (control F(1 18)=1822 p=0005memory F(1 18)=211 p=0002 see Table 1)

PET Data

The averaged subtraction images revealed approxi-mately equivalent levels of activation in the two agegroups (see Table 2) Post hoc analyses revealedpeaks of significant activation in parietal areas 7 and40 in both hemispheres and in premotor cortexbilaterally in younger and older subjects It is apparentfrom Table 2 that the activations from the spatial taskare lower in magnitude than in the verbal task forboth groups Nevertheless the significance levels ofthe spatial memory activations are high because thereare more scans per condition and the scanning wasdone in 3-D thereby improving the signal-to-noiseratio (see Methods section) In addition the presentresults replicate previous results from this lab (Jonideset al 1993) and vice versa the four ROIs from thisprior work were also active in our present sample ofyounger subjects (all prsquoslt05 right BA 40 6 47 19)Likewise the six most active sites from our presentyoung sample were significantly activated in the origi-nal subject group


Age differences in laterality were evaluated as in theverbal study using a new set of 98 regions from pub-lished reports of spatial working memory tasks (Court-ney Ungerleider Keil amp Haxby 1996 Goldberg et al1996 Owen et al 1996 Smith et al 1996 1995 seeFigure 2) The majority of these regions were in the righthemisphere The anterior subset (n=32 ygt0) includesfrontal sites in BA 9 46 47 premotor and supplemen-tary motor cortex The posterior sites (n=59 yltndash 10and zgtndash 10) include parietal (BA 40 7) striate andextrastriate loci (BA 18 19) and precuneus (BA 31) Forthe posterior set both groups showed significant netactivation in the left and right hemispheres (older leftt(9)=246 plt018 right t(9)=427 p=001 younger

Figure 2 These figures indicate the location of the verbal (top) andspatial (bottom) regions of interest obtained from prior studies thatused PET to study verbal and spatial working memory Because theseglass brain images collapse across the x-axis (leftright) they reveal onlythe y (anteriorposterior) and z (dorsalventral) of location eachvolume To compare the laterality of the working memory circuitry inolder and younger adults volumes were formed around each of theseregions and a twin volume was created in the homologous site in theopposite hemisphere (see text for details) Laterality was assessed bycomparing the activity in each volume with the activity in itshomologous twin


left t(9)=281 p=010 right t(9)=232 p=022 seeFigure 3d) For both groups the magnitude of posteriorleft-hemisphere and right-hemisphere activation wasapproximately equiva lent (older left vs rightt(9)=851 p=208 younger left vs right t(9)=111p=292) An unpaired t test comparing the averagerightndashleft differences for younger vs older groups wasnot significant t(18)=356 p=363 Finding posteriorbilaterality in both subject groups for this spatial task isconsistent with other cognitive neuroscience evidencefor left-hemisphere and right-hemisphere contributionsto visuospatial processes (Ivry amp Robertson 1998)

The pattern is markedly different for the anterior VOIs(see Figure 3c) Younger adults show significant activa-tion only in the right hemisphere (left t(9)=532p=304 right t(9)=221 plt027) whereas older adultsshow significant activation in both hemispheres (leftt(9)=231 p=022 right t(9)=214 p=030) As in theverbal data set the younger group shows significantlylateralized activity and the older group does not (young-er right vs left t(9)=ndash 182 p=050 older right vs leftt(9)=415 p=343) This age difference in activationasymmetry approaches significance (unpaired t testcomparing rightndashleft difference scores for younger vsolder groups t(18)=ndash 154 p=070)

Within the anterior subset of VOIs three mainsubregions were identified and examined separatelyfor differences in laterality lateral SMA DLPFC (BA469) ventrolateral prefrontal cortex (VPFC BA 47)Nine VOIs from the anterior subset were not includedin this analysis because they did not form an anato-mically cohesive subregion with more than three VOIsFor the younger group activation in each of the threesubregions was right lateralized with p values differingfrom zero at the plt05 level for right SMA and rightVPFC along with a nonsignificant tendency towardgreater right than left DLPFC activation (see Table3) Tested against zero the older group showedactivation in left and right SMA left DLPFC and rightVPFC (all prsquoslt05) Note that in the post hoc analysisreported in Table 2 both groups show peaks ofactivation in left and right lateral premotor cortexThe VOI analysis probed regions of SMA that wereanterior to left-sided peaks that emerged in the posthoc analyses ( ygt1 and y=ndash 8 respectively) Takentogether the post hoc and VOI analyses reveal thatthe older group had significant SMApremotor activitybilaterally whereas in the younger group left activa-tion was restricted to the posterior premotor regionThus as with the verbal data the components of the

Figure 3 Working memory induced activation changes Graphs depict percent change in activation for the memory minus control subtractions forthe verbal and spatial tasks Asterisks denote significance levels when comparing activation changes to zero using one-tailed tests plt10 plt03plt001 The graphs demonstrate the lack of age differences in the posterior VOIs for the verbal (b) and spatial (d)tasks In contrast the anteriorVOIs demonstrate lateralized activations for younger adults but bilateral activations for older adults (verbal (a) and spatial (b))


anterior working memory circuitry tend to be distrib-uted across the left-hemisphere and right-hemispherein older adults whereas for the younger group thiscircuitry is more lateralized


For the spatial working memory performance and PETwe performed the same sets of correlations describedabove for the verbal task None of these correlationsreached significance A median split of fast and slowperformers also yielded no significant differences mostlikely due to the small number of subjects in each groupand the lack of variability in response speed

GENERAL DISCUSSION

The results from this investigation show pronouncedage differences in activation of the anterior componentsof the neural circuitry associated with verbal and spatialworking memory Younger adults show opposite pat-terns of lateralized frontal activity depending on the typeof material being retained in working memory withgreater left-hemisphere activation for verbal materialsand greater right-hemisphere activation for spatial ma-terials By contrast older adults engage left and rightfrontal regions for both types of memory Analyses ofseparate subregions of frontal cortex generally corrobo-rate the opposite patterns of laterality for verbal andspatial memory in younger adults These subregionanalyses also reveal that the overall picture of bilateral

anterior activation in older adults results from severalunderlying patterns In contrast to the younger groupolder adults showed bilateral activity in BA 44 (Brocarsquosarea) and lateral SMA in the verbal and spatial tasksrespectively In addition they showed a paradoxicalpattern of lateralization in DLPFC with greater rightthan left activation in this region in the verbal taskand greater left than right activation in the spatial task Itshould be noted however that some of the patterns ofactivation within the anterior subregions are less robustthan the global picture of anterior bilaterality in theolder adults Nonetheless we offer some speculationsabout the functions of these component patterns thatare amenable to further research

In the present verbal memory results as well asseveral others from this laboratory younger adultsshow activation in Brocarsquos area coupled with nonsigni-ficant deactivation in the homologous site in theopposite hemisphere (for example Jonides et al inpress) In contrast older adults in the present studyshowed significant activation in Brocarsquos area and in itsright-hemisphere homologue In addition to its puta-tive role in speech production and other linguisticprocesses Brocarsquos area is considered to be part ofthe verbal working memory rehearsal circuit that main-tains phonological information in an active state over ashort retention interval (for example Awh et al 1996)It has been hypothesized that inhibitory interactionsbetween Brocarsquos area and its right-hemisphere homo-logue normally limit right-sided contributions to lan-

Table 3 Mean Percent Activation Change in the Anterior Subregions of the Verbal and Spatial VOIs

Younger Adults Older AdultsYoung vs Old

Verbal Left Right LndashR Left Right LndashR LndashR

Brocarsquos change 261 ndash 106 361 266 088 177p value 00015 0203 00028 00003 002 019 0077

SMA lat change 075 ndash 0002 075 139 028 112p value 021 049 020 0008 031 006 0378

SMA med change 340 316 028 310 330 ndash 020p value 001 0019 019 00002 00002 0306 0212

DLPFC change 203 077 126 060 253 ndash 193p value 0006 0267 020 017 00004 0009 0019

Spatial Left Right RndashL Left Right RndashL RndashL

SMA lat change 061 117 056 129 085 ndash 062p value 014 0014 0198 0047 0046 0322 019

VPFC change ndash 017 060 077 025 077 052p value 033 003 009 028 0015 022 034

DLPFC change ndash 015 062 077 071 012 ndash 059p value 038 019 008 0047 037 0066 002

T-tests comparing each region to zero were liberal in that they were not corrected for multiple comparisons and they are one-tailed The p valuesfor these tests are reported beneath the mean percentage of activation change for each region except in the last column which reports the p valuesfor unpaired tests comparing the left-right differences scores from the younger and older groups


guage processing and that the latent linguistic abilitiesof the right hemisphere can facilitate recovery fromaphasia (Kinsbourne 1971) Indeed several neuroima-ging studies of patients with language recovery orcompensation after focal left-hemisphere damage (thatincluded Brocarsquos area in some cases) report activationin the right frontal operculum (BA 4445) which in-dicates a capacity for this region to participate inlanguage processes (Buckner Corbetta Schatz Raichleamp Petersen 1996 Weiller et al 1995) Other reports ofrecovery from deficits indicate that bilateral activationof homologous regions could be a general mechanismof compensatory processing (for example Engelienet al 1995) In view of these results it seems feasiblethat the bilateral activation of Brocarsquos area in the olderadult group reflects compensatory recruitment thatmaintains the functioning of the rehearsal circuit inthe aging brain

In spatial working memory lateral regions of SMAhave been attributed a prominent role in rehearsalprocesses that maintain location information in anactivated state (Awh amp Jonides 1997 Courtney PetitMaisog Ungerleider amp Haxby 1998) VOIs within thisfrontal subregion were uniquely activated in both hemi-spheres in the older group in our spatial workingmemory task whereas in the younger group this sub-region was activated primarily on the right The evi-dence for greater bilaterality in this area for older thanyounger subjects is certainly less robust than the resultsfor Brocarsquos area in the verbal task Thus while wecautiously suggest that compensatory recruitment alsocharacterizes the pattern of activation associated withvisuospatial rehearsal this interpretation must be re-garded as speculative

The other subregion that contributes to the globalpattern of age differences in anterior laterality isDLPFC In both tasks older adults show a lateralitypattern that is opposite to that shown by the young-er group In general activation of DLPFC is charac-teristic of working memory tasks that requireinformation storage plus processing and manipulationof the stored contents (for example DrsquoEsposito et al1998 Smith amp Jonides 1999) In studies of humanworking memory DLPFC has thus been identifiedwith executive processes rather than rehearsal SuchDLPFC activation tends to be significant in bothhemispheres (for example Jonides et al 1997)however when asymmetries are observed they occurin the expected direction with left-hemisphere pre-dominance for verbal materials and right-hemispherepredominance for spatial materials (see DrsquoEsposito etal 1998 Smith et al 1996) One recent exceptionmay shed light on the present results Rypma Prab-hakaran Desmond Glover amp Gabrieli (1999) foundbilateral DLPFC activation in younger adults greateron the right than left in a verbal-storage task butonly for a memory load of six items Smaller memory

loads activated predominantly left-hemisphere sitesand did not activate DLPFC in either hemisphereRypma et al suggest DLPFC activation reflects therecruitment of executive processes to augment simplerehearsal processes that may be inadequate for re-taining larger memory loads According to this argu-ment the right DLPFC activation in older adultsreflects their need to invoke executive processes atlighter memory loads compared to younger adultsLikewise left DLPFC activation in the spatial taskcould augment rehearsal processes that are otherwiseinadequate to meet the memory demands Unfortu-nately this interpretation of the present results forolder adults does not clarify why the laterality of theDLPFC activation is opposite to the pattern typicallyfound for verbal and spatial tasks

Age differences in DLPFC activation and its lateralityhave been reported in several other studies with differ-ent stimulus materials and different task demands Gra-dy et al (1998) for example found left DLPFC activationthat was unique to older adults in a working memorytask using faces Cabeza et al (1997 in press) found agedifferences in prefrontal activation in BA 10 during anepisodic retrieval task (see also Madden et al 1999)There have been numerous speculations about thefunction of these age differences including age-relatedincreases in attentional processing or semanticassocia-tive processing (see Grady et al 1998 for a review) It isunclear how any of these suggestions would account forthe paradoxical patterns of DLPFC activation that weobserved for verbal and spatial working memory Never-theless it seems plausible that the present effects reflectage differences in the recruitment of executive processesmediated by DLPFC The question of whether age altersexecutive processing brought to bear on encodingmaintenance or retrieval from short-term memory canultimately be addressed with the temporal resolution offunctional MRI in future studies Whatever its role thereis some suggestion from the present data set thatparadoxical laterality is less efficient In the verbal taskslower adults showed greater right than left DLPFCactivation whereas the faster group showed bilateralDLPFC activation

The age-related differences that we have observednaturally raise the question of whether older and young-er adults are using different strategies or whether thesame cognitive strategies in the older brain are beingmediated by different brain regions Although self-re-ports are weak indications of the underlying cognitiveoperations the debriefing phase of our experimentsdoes offer some information about strategy use In theverbal working memory experiment both age groupsuniversally reported using verbal rehearsal strategiesand not spatial ones Likewise in the spatial studyspatial strategies and not verbal ones were equallyprominent for both groups Finally the use of a spatialstrategy would be expected to lead to more errors to


near than to far foils in the spatial-memory task (Smith ampJonides 1998) An analysis of errors made on this taskrevealed that both older and younger subjects showedthis effect of distance and it was if anything slightlystronger in the older group These pieces of evidenceargue against the possibility that older adults are usingverbal strategies in spatial tasks and vice versa Insteadthey favor the idea that any reorganization or compen-satory recruitment that may be occurring in the olderbrain serves to bolster the use of the same cognitivestrategies used in the younger adults

In closing we must consider the possibility that theage differences we observed are artifacts of the agingprocess rather than indications of changes in neuralfunction In particular neuroimaging studies of agingmust be concerned with hemodynamic differences be-tween older and younger brains (eg DrsquoEsposito Zar-ahn Aguirre amp Rypma 1999) Our normalizationprocedures correct for age-related reductions in globalblood-flow by transforming the radioactive counts ob-tained from each individual to a standard scale More-over the key results entail age-related increases inactivation which are not readily explained by age reduc-tions in global blood flow Of greater concern are thepotentially confounding effects of localized cortical atro-phy Regions of prefrontal cortex are among those mostaffected by atrophic effects of aging (eg Raz in press)Because the present age differences in activation arelocated primarily in frontal areas they could conceivablyresult from region-specific atrophy in older adults ratherthan from functional alterations of the working memorycircuitry While regional atrophy is likely to affect anarearsquos function it could also cause localized reductionsin the PET signal due to reduced hemodynamic activityand partial volume effects within the atrophic regions(eg Labbe Froment Ashburner amp Cinotti 1996) Im-portantly our results indicate that older adults showincreased activation in specific frontal areas comparedto younger adults Such increases are more likely theresult of age-related alterations in neural activity thanregional atrophy

CONCLUSIONS

The main result from the present set of experiments isthat the anterior components of the working memorycircuitry are bilaterally organized in older adultswhereas younger adults show opposite patterns oflaterality for verbal and spatial working memory Therewere no age differences in posterior working memorysites Our results therefore suggest that the effects ofnormal aging on the neural substrate of working mem-ory are selective in that the frontal components of theworking memory circuitry show greater vulnerability toaging than the posterior components The decreasedanterior lateralization in older adults may be compen-satory insofar as it reflects the recruitment of addi-

tional brain regions to augment task performance (cfReuter-Lorenz Stanczak amp Miller in press) The para-doxical laterality associated with activation of DLPFC inolder adults underscores the fact that aging can havehighly localized effects involving executive processingregions Understanding the functional consequences ofthese age differences is an important agenda item forfuture research

METHODS


Subjects

Eight younger (21ndash30 years mean age 233) and 16 older(65ndash75 years mean age 699) female adults participatedin this study and were paid for their time Older adultswere recruited through the University of MichiganInstitute of Gerontology and through newspaper adver-tisements Younger adults were recruited through Uni-versity of Michigan subject pools and throughnewspaper advertisements All participants were right-handed free of positive neurological histories and hadnormal or corrected-to-normal vision The two agegroups had similar education levels (younger 15 yearsolder 16 years)

Task and Procedure

In the verbal memory task four upper case letterscomprised the memory set on each trial The letterswere randomly chosen from the set of consonants Theletters were printed in Helvetica (24-point bold) Theywere positioned at the four corners of an imaginarysquare centered on the fixation point (see Figure 1a)The probe letter appeared in the center of the screenreplacing the fixation point and was always lowercaseIn half of the trials the probe matched one of the lettersin the memory set and in the other half it did not Inthe control task the memory set consisted of only oneletter presented in each of the four corners of theimaginary square

Each memory trial began with the onset of the fixationpoint in an otherwise blank field for 500 msec Then thememory set appeared for 500 msec followed by a 3000-msec retention interval The response period began withthe appearance of the probe letter and lasted for 1500msec Subjects indicated whether the probe matchedthe identity of one of the target letters by pressing oneof two keys on the mouse As can be seen from Figure 1each trial in the control condition lasted the sameamount of time but some of the event durations weredifferent The initial fixation period (or intertrial inter-val) was 3200 msec followed by a 500-msec exposure ofthe one-item target set After a brief 300-msec intervalthe probe letter appeared for 1500 msec during whichtime the subject responded


Subjects participated in one behavioral session tofamiliarize themselves with the verbal memory andcontrol tasks This session consisted of approximately20 trials of practice in the memory condition followedby 96 experimental trials After a brief practice run in thecontrol condition 48 trials of experimental data wereobtained The PET session typically occurred within 7days following this behavioral session In the PET ses-sion subjects participated in two scans for each of thetwo tasks in a counterbalanced order Two blocks of 24trials were completed for each task There were approxi-mately 11 trials per scan


Subjects

Two new groups of younger (n=10 18ndash25 years meanage=212) and older (n=10 62ndash73 years mean age674) female adults participated in the PET phase of thisstudy The two age groups had similar levels of educa-tion (younger 15 years older 16 years) Nine additionalolder adults participated in only the practice phase butwere excluded from the PET phase because their spatialmemory accuracy performance was greater than onestandard deviation below that of the younger partici-pants We were concerned that by including such poorperforming individuals in our older sample we would beless able to attribute group differences to the effects ofage Moreover we wanted the age-related differences inperforming the spatial task to be similar to and certainlyno greater than the age-related differences associatedwith verbal performance Participants were recruited asdescribed above

Task and Procedure

In the memory condition three black dots (078 dia-meter) were presented The dot positions were locatedon four imaginary circles around the fixation point withradii subtending 38 48 58 and 68 of visual anglerespectively For mismatch trials the location of theprobe could be either near (248) or far (328) fromone of the target locations In the control conditionthree black dots also appeared however two dotsremained stationary for an entire block of trials Thestationary locations were either above and below fixa-tion or to the left and right of fixation The single dotthat varied in location could be in any of the positions asdescribed above for the memory trials except thoseoccupied by the stationary dots The miss trials could benear or far as described above For both memory andcontrol blocks half blocks contained matching probesand the other half contained mismatching probesequally divided between near and far misses

The trial events were analogous to those in the verbaltask (see Figure 1b) For the memory condition a 500-msec fixation period was followed by a 500-msec ex-

posure of the spatial memory set After a 3000-msecretention interval the probe circle appeared for 1500msec during which time the subject pressed a mousekey to indicate whether or not the probe locationmatched any of the target locations In the control taskthe fixation periodintertrial interval was 3300 msec thetarget display appeared for 500 msec followed by a 200-msec delay and the appearance of the probe for 1500msec Data from eight scans of each of the two spatialtasks was obtained There were approximately 11 trialsper scan

Image Acquisition

A Siemens ECAT EXACT-47 PET scanner (Siemens Med-ical Systems Knoxville TN) was used in 2-D acquisitionmode for the verbal experiment Subjects were posi-tioned in the scanner and head position was recordedand verified before each scan A bolus of 50 mCi of [15O]water was delivered intravenously over a 10-sec intervalThe spatial-experiment scans were acquired in 3-Dmode A 10-mCi bolus of [15O] water was delivered overa 10-sec interval Data were acquired for 60 sec For 2-Dstudies data acquisition was initiated when the true-coincidence event rate exceeded the random-coinci-dence event rate For 3-D scans acquisition was initiatedwhen true coincidences reached one-half of randomsAttenuation correction was calculated from measuredtransmission scans and no correction for scatteredevents was performed Data were reconstructed usingfiltered back projection yielding images sets with 47contiguous slices spaced 3375 mm apart with a resolu-tion of sup110 mm full-width at half-maximum (FWHM)Scans were separated by 10- (2-D) or 8-min intervals (3-D) to allow for radioactive decay to near backgroundlevels

Image Analysis

A detailed description of the image analysis protocol isgiven elsewhere (Jonides et al 1997) In brief it con-sisted of the following steps (a) intrasubject registrationcorrected for motion between scans for each subject(Minoshima Koeppe Fessler amp Kuhl 1993a) (b) eachsubjectrsquos image sets were then normalized and reor-iented (Minoshima Berger Lee amp Mintun 1992 1993)and then nonlinearly warped (Minoshima Koeppe Freyamp Kuhl 1994) into a stereotactic coordinate system(Talairach amp Tournoux 1988) (c) statistical maps wereproduced using in-house software (Minoshima et al1993a) based on the method of Friston Frith Liddle ampFrackowiak (1991) except that across-subject standarddeviations of the voxels averaged across the brain wereused to create a pooled estimate of variance as de-scribed by Worsley Evans Marrett amp Neelin (1992) A4-pixel FWHM Gaussian filter was applied to each sub-jectrsquos scans prior to statistical analysis Significance


thresholds were calculated as derived by Friston et al(1991)

Acknowledgments

This research was supported in part by a grant from the Officeof Naval Research and in part by grants from the NationalInstitute on Aging (NIA AG8808 AG13027) all to the Universityof Michigan The research assistance of Anna Cianciolo ElisaRosier Michael Kia Edward Awh Leon Gmeindl and DavidBadre is gratefully acknowledged The authors thank TimothySalthouse for his comments on earlier versions of this paper

Reprint requests should be sent to Patricia A Reuter-LorenzDepartment of Psychology University of Michigan 525 EUniversity Ave Ann Arbor MI 48109-1109 or via e-mailparlumichedu

Note

1 Some male participants were also run in the verbalworking memory experiment As a group the older malesperformed more poorly on the task than the older femaleswhose performance more closely matched the younger groupTherefore in the verbal study we opted to focus on the femaledata set to minimize confounding the effects of age andperformance Accordingly in the spatial study only femalesparticipated We note however that in the verbal study oldermales like older females activated anterior sites in bothhemispheres

REFERENCES

Awh E amp Jonides J (1997) Spatial-selective attention andspatial-working memory In R Parasuraman (Ed) The at-tentive brain (pp 353 ndash380) Cambridge MA MIT Press

Awh E Jonides J Smith E E Schumacher E H Koeppe RA amp Katz S (1996) Dissociation of storage and rehearsal inverbal-working memory Evidence from positron emissiontomography Psychological Science 7 25ndash31

Baddeley A (1986) Working memory Oxford EnglandClarendon Press

Buckner R L Corbetta M Schatz J Raichle M E ampPetersen SE (1996) Preserved speech abilities and com-pensation following prefrontal damage Proceedings of theNational Academy of Science 93 1249ndash1253

Cabeza R Grady C L Nyberg L McIntosh A R Tulving EKapur S Jennings J M Houle S amp Craik F I M (1997)Age-related differences in neural activity during memoryencoding and retrieval A positron emission tomographystudy Journal of Neuroscience 17 391ndash 400

Carpenter P A amp Just M A (1989) The role of workingmemory in language comprehension In D Klahr amp KKotovsky (Eds) Complex information processing Theimpact of Herbert A Simon (pp 31ndash 68) Hillsdale NJErlbaum

Chao L L amp Knight R T (1997) Prefrontal deficit in atten-tion and inhibitory control with aging Cerebral Cortex 763ndash69

Courtney S Ungerleider L G Keil amp Haxby J V (1996)Object and spatial visual-working memory activate separateneural systems in human cortex Cerebral Cortex 6 39ndash 49

Courtney S Petit L Maisog J Ungerleider L G amp Haxby J(1998) An area specialized for spatial working memory inthe human frontal cortex Science 279 1347ndash1349

DrsquoEsposito M Aguirre GK Zarahn E Ballard D Shin RK amp Lease J (1998) Functional MRI studies of spatial andnonspatial working memory Cognitive Brain Research 71ndash13

DrsquoEsposito M Zarahn E Aguirre G amp Rypma B (1999) Theeffect of normal aging on the coupling of neural activity tothe bold hemodynamic response Neuroimage 10 6ndash14

Engelien A Silsberg D Stern E Huber W Doring WFrith C amp Frackowiak RSJ (1995) The functional anato-my of recovery from auditory agnosia Brain 118 1395 ndash1409

Fiez J A Raife E A Balota D A Schwarz J P Raichle ME amp Petersen S E (1996) A positron emission tomographystudy of the short-term maintenance of verbal informationJournal of Neuroscience 16 808ndash822

Friston K J Frith C D Liddle P F amp Frackowiak R S J(1991) Comparing functional (PET) images The assessmentof significant change Journal of Cerebral Blood Flow Me-tabolism 11 690 ndash699

Goldberg T E Berman K F Randolph C Gold J M ampWeinberger D R (1996) Isolating the mnemonic compo-nent in spatial delayed response A controlled PET 15O-la-beled water regional-cerebral blood flow study in normalhumans Neuroimage 3 69ndash78

Goldman-Rakic P S (1992) Working memory and the mindScientific American 267 110 ndash117

Grady C L Haxby J V Horwitz B Schapiro M BRapoport S I Ungerleider L G Mishkin M Carson RE amp Herscovitch P (1992) Dissociation of object andspatial vision in human extrastriate cortex Age-relatedchanges in activation of regional cerebral blood flowmeasured with [1 5O] water and positron emission tomo-graphy Journal of Cognitive Neuroscience 4 23ndash34

Grady C L Maisog J M Horwitz B Ungerleider L GMentis M J Salerno J A Pietrini P Wagner E amp HaxbyJ V (1994) Age-related changes in cortical bloodflow acti-vation during visual processing of faces and location Jour-nal of Neuroscience 14 1450 ndash1462

Grady C L McIntosh A R Horwitz B Maisog J MaUngerleider L G Mentis M J Pietrini P Schapiro M Bamp Haxby J V (1995) Age-related reductions in humanrecognition memory due to impaired encoding Science269 218 ndash221

Grady C L McIntosh A R Bookstein F Horwitz B Ra-poport S I amp Haxby J V (1998) Age-related changes inregional cerebral blood flow during working memory forfaces Neuroimage 8 409 ndash425

Grasby P M Frith C D Friston K J Bench C FrackowiakR S J amp Dolan R J (1993) Functional mapping of brainareas implicated in auditory-verbal memory function Brain116 1ndash20

Ivry R B amp Robertson L C (1998) The two sides to per-ception Cambridge MA MIT Press

Jonides J (1995) Working memory and thinking In DOsherson amp E E Smith (Eds) An invitation to cognitivescience Cambridge MA MIT Press

Jonides J Smith E E Koeppe R A Awh E Minoshima Samp Mintun M A (1993) Spatial working memory in humansas revealed by PET Nature 363 623 ndash625

Jonides J Reuter-Lorenz P A Smith E E Awh E Barnes LL Drain H M Glass J Lauber E amp Schumacher E(1996) Verbal and spatial working memory In D Medin(Ed) Psychology of Learning and Motivation 34 43ndash88

Jonides J Schumacher E H Koeppe R A Smith E ELauber E amp Awh E (1997) Verbal working memory loadaffects regional brain activation as measured by PET Journalof Cognitive Neuroscience 9 462ndash 475

Jonides J Schumacher E H Smith E E Koeppe R A AwhE Reuter-Lorenz P A Marshuetz C amp Willis C R (1998)The role of parietal cortex in verbal-working memory TheJournal of Neuroscience 18 5026 ndash5034

Jonides J Marshuetz C Smith E E Reuter-Lorenz P A


Koeppe R amp Hartley A (in press) Changes in inhibitoryprocessing with age revealed by brain activation Journal ofCognitive Neuroscience

Kinsbourne M (1971) The minor cerebral hemisphere as asource of aphasic speech Archives of Neurology 25 302ndash306

Labbe C Froment J C Kennedy A Ashburner J amp CinottiL (1996) Positron emission tomography metabolic datacorrected for cortical atrophy using magnetic resonanceimaging Alzheimerrsquos Disease and Associated Disorders 10141ndash170

Madden D J et al (1999) Adult age differences in functionalneuroanatomy of verbal recognition memory Human BrainMapping 7 115 ndash135

Minoshima S Berger K L Lee K S Mintun M A (1992) Anautomated method for rotation correction and centering ofthree-dimensional functional brain images Journal of Nu-clear Medicine 33 1579 ndash1585

Minoshima S Koeppe R A Fessler J A amp Kuhl D E(1993) In K Uemura N A Lassen T Jones amp I Kanno(Eds) Quantification of brain functionmdashTracer kineticsand image analysis in brain PET (pp 409 ndash418) TokyoInternational Congress Series 1030 Excepta Medica

Minoshima et al (1993) Automated detection of the in-tercommissural line for stereotactic localization of func-tional brain images Journal of Nuclear Medicine 34322ndash329

Minoshima S Koeppe R A Frey K A amp Kuhl D E (1994)Anatomical standardization Linear scaling and nonlinearwarping of functional brain images Journal of NuclearMedicine 35 1528 ndash1537

Moscovitch M amp Winocur G (1995) Frontal lobes memoryand aging Structure and functions of the frontal lobes An-nals of the New York Academy of Sciences 769 115ndash150

Owen A Evans A C amp Petrides M (1996) Evidence for atwo-stage model of spatial working memory processingwithin the lateral frontal cortex A positron emission tomo-graphy study Cerebral Cortex 6 31ndash38

Paulesu E Frith C D amp Frackowiak R S J (1993) Theneural correlates of the verbal component of workingmemory Nature 362 342ndash344

Petrides M Alivisatos B Meyer E amp Evans A C (1993)Functional activation of the human frontal cortex during theperformance of verbal working memory tasks Proceedingsof the National Academy of Science 90 878 ndash882

Raz N (in press) Aging of the brain and its impact oncognitive performance Integration of structural and func-tional findings In F I M Craik amp T A Salthouse (Eds)Handbook of aging and cognitionmdashII Mahwah NJErlbaum

Reuter-Lorenz P A Stanczak L amp Miller A (in press)Neural recruitment and cognitive aging Two hemispheresare better than one especially as you age PsychologicalScience

Rypma B Prabhakaran V Desmond J E Glover G H ampGabrieli J D (1999) Load-dependent roles of frontal brainregions in the maintenance of working memory Neuro-Image 9 216 ndash226

Salmon E Van der Linden M Collett F Delfiore G MaquetP Degueldre C Luxen A amp Franck G (1996) Regionalbrain activation during working-memory tasks Brain 1191617ndash1625

Salthouse T (1991) Theoretical perspectives in cognitiveaging Hillsdale NJ Erlbaum

Salthouse T (1992) Mechanisms of age-cognition relationsin adulthood Hillsdale NJ Erlbaum

Schumacher E H Lauber E Awh E Jonides J Smith E Eamp Koeppe R A (1996) PET evidence for an amodal verbalworking-memory system Neuroimage 3 79ndash88

Smith E E amp Jonides J (1998) Neuroimaging analyses ofhuman working memory Proceedings of the NationalAcademy of Science 95 12061ndash12068

Smith E E Jonides J amp Koeppe R A (1996) Dissociatingverbal- and spatial-working memory using PET CerebralCortex 6 11ndash20

Smith E E Jonides J Koeppe R A Awh E Schumacher EH amp Minoshima S (1995) Spatial-versus-object workingmemory PET investigations Journal of Cognitive Neu-roscience 7 337ndash356

Talairach J amp Tournoux P (1988) Co-planar stereotaxicatlas of the human brain Stuttgart NY Thieme

Tulving E Kapur S Craik F I M Moscovitch M amp HouleS (1994) Hemispheric encodingretrieval asymmetry inepisodic memory Positron emission tomography findingsProceedings of the National Academy of Sciences USA 912012ndash2015

Vallar G amp Shallice T (1990) Neuropsychological impair-ments of short term memory Cambridge Cambridge Uni-versity Press

Weiller C Insensee C Rijntjes M Huber W Muller S BierD et al (1995) Recovery from Wernickersquos aphasia A posi-tron emission tomography study Annals of Neurology 37723 ndash732

West R L (1996) An application of prefrontal cortex theory tocognitive aging Psychological Bulletin 120 272ndash292

Worsley K J Evans A C Marrett S amp Neelin P (1992) Athree-dimensional statistical analysis for rCBF activationstudies in human brain Journal of Cerebral Blood FlowMetabolism 12 900 ndash918


lateralized lesions affecting these cases caused dramaticimpairments in short-term memory reducing itrsquos capa-city from a normal level of five to seven items to adysfunctional level of one or two items

The asymmetrical organization of verbal and spatialworking memory has been largely corroborated byneuroimaging studies of healthy young right-handedadults particularly for tasks that emphasize short-terminformation storage (see DrsquoEsposito et al 1998 SmithJonides amp Koeppe 1996 for reviews compare Gold-berg Berman Randolph Gold amp Weinberger 1996Owen Evans amp Petrides 1996) Verbal storage taskshave been associated with a predominance of left-hemi-sphere activation in Brocarsquos area supplementary motorcortex premotor cortex superior and inferior parietalcortex (Awh et al 1996 Fiez et al 1996 Jonides et al1998 Schumacher et al 1996) Likewise during spatialstorage tasks activation predominates in right-hemi-sphere regions homologous to those active duringverbal storage along with right frontal activation inBrodmannrsquos area (BA 47) and in visual association cortex(that is BA 18 Jonides et al 1993) The lateralizedfrontal components of this circuitry are thought tomediate rehearsal or maintenance of phonological andspatial information represented more posteriorly in theleft and right hemispheres respectively (Awh amp Jonides1997 Awh et al 1996) When executive components areadded to the storage tasks by requiring contextualtagging or manipulation of the stored items for exam-ple activation of dorsolateral prefrontal sites (DLPFCBA 45 46 9) is evident Differential activation of left andright DLPFC has been reported for such verbal andspatial working memory tasks (eg Smith Jonides ampKoeppe 1996) although overall the magnitude ofasymmetry for these more complex working memorytasks may be less than in simple storage tasks

How might aging affect the neural circuitry of workingmemory A few possibilities present themselves Pre-frontal regions seem particularly vulnerable to the ef-fects of aging (Raz in press) and changes in frontal lobefunction are hypothesized to be the source of variouscognitive deficits found in older adults (see Moscovitchamp Winocur 1995 Raz in press for reviews) Frontaldysfunction has been linked to age-related impairmentsin long-term memory attention and inhibitory processes(Chao amp Knight 1997 Jonides et al in press West1996) We might expect then that the anterior compo-nents of the working memory system might show great-er age-related changes than posterior componentsSome recent evidence from a study examining theeffects of age on working memory for faces suggeststhis may the case (Grady et al 1998)

Another possibility is that aging leads to a decline inthe functional specificity of the working memory sys-tem Neuroimaging evidence for declining specificitycomes from a PET study of the lsquolsquowhatrsquorsquo vs lsquolsquowherersquorsquoprocessing streams in older and younger adults (Grady

et al 1992 1994) Subjects performed a face-matchingtask intended to activate the whatventral stream or alocation-matching task designed to activate the wheredorsal stream Younger participants showed the ex-pected dissociation between dorsal and ventral streamprocessing face-matching produced more ventralstream activation and location-matching evoked moredorsal stream activation In contrast older adultsshowed significant activation of dorsal and ventral sitesduring both tasks More recently studies of episodicmemory have demonstrated that older adults departfrom the pattern of lateralized prefrontal activity thathas been shown to differentiate encoding and retrievalprocesses in younger adults (that is Cabeza et al 1997Grady et al 1995 Madden et al 1999 Tulving KapurCraik Moscovitch amp Houle 1994) Some studies reportmore bilateral activation in older than younger adultsduring retrieval and others find greater left than rightactivation in anterior sites where younger subjects showthe opposite pattern

We might expect then that aging would also alter thelateral organization of the working memory systemHere we report PET evidence of age differences inthe asymmetrical organization of verbal and spatialworking memory particularly in the frontal lobes foryounger adults activation is predominantly left latera-lized for verbal working memory and right lateralizedfor spatial working memory whereas older adults showactivation in left and right frontal sites for both types ofmemory

We tested two groups of older (62ndash75 years) andyounger (18ndash30 years) female1 adults in two workingmemory tasks that emphasized short-term informationstorage and had the same basic structure (Figure 1) Inthe verbal-storage task subjects were presented withfour target letters they stored them in memory for 3 secand then they indicated whether or not a probe lettermatched any target In the spatial-storage task threetarget locations were marked on the screen subjectsstored them for 3 sec and then indicated whether or nota probe location matched any target location Eachmemory task was paired with a control task designedto include all of the cognitive components of thememory task (for example perceptual encoding re-sponse selection preparation and initiation) exceptthe working memory component (that is immediatematching) Thus subtracting the images of the controlcondition from the images of the memory conditionshould reveal primarily the brain areas that are activeduring verbal or spatial working memory respectively Itis important to bear in mind that because our PETanalyses rely on subtraction logic the results reflectactivation changes in the memory task relative to thecontrol tasks for each age group and not age differencesin the absolute levels of neural activity associated withworking memory processes Thus any age differenceswe report could be due to group differences in the




RESULTS


Performance Data


PET Data




Verbal Spatial


Younger Control 099 524 099 5290003 28 0195 23

Memory 097 654 091 7060017 28 141 17

Older Control 099 6109 099 7410004 20 028 23

Memory 092 843 092 9150012 20 138 22














Verbal




Right 6 ndash 3 1 52 494 422

Left 6 8 8 47 481 410

Left 6 48 ndash 1 29 480 409

Left 32 1 12 38 478 408

Left 40 33 ndash 51 38 464 396

Left 4 30 ndash 8 45 461 393



Right 632 ndash 1 8 45 463 576

Left 64 48 ndash 1 22 463 576


Right 469 ndash 39 35 29 417 519

Left 6 30 3 47 346 430


Left 17 8 ndash 87 9 327 406

Left 740 35 ndash 58 43 327 406

Left 40 44 21 20 325 403

Spatial


Left 719 24 ndash 64 40 298 534

Left 40 37 ndash 49 38 286 514


Left 6 24 ndash 8 47 272 489




Left 46 28 ndash 8 50 289 593


Left 7 19 ndash 67 45 267 547



Left 40 46 ndash 49 40 239 491

(continued)










Table 2 (continued)



Spatial

Left 7 30 ndash 58 47 228 467



Right 6 ndash 46 8 32 212 436





Performance Data


PET Data














GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES





























































RESULTS


Performance Data


PET Data




Verbal Spatial


Younger Control 099 524 099 5290003 28 0195 23

Memory 097 654 091 7060017 28 141 17

Older Control 099 6109 099 7410004 20 028 23

Memory 092 843 092 9150012 20 138 22














Verbal




Right 6 ndash 3 1 52 494 422

Left 6 8 8 47 481 410

Left 6 48 ndash 1 29 480 409

Left 32 1 12 38 478 408

Left 40 33 ndash 51 38 464 396

Left 4 30 ndash 8 45 461 393



Right 632 ndash 1 8 45 463 576

Left 64 48 ndash 1 22 463 576


Right 469 ndash 39 35 29 417 519

Left 6 30 3 47 346 430


Left 17 8 ndash 87 9 327 406

Left 740 35 ndash 58 43 327 406

Left 40 44 21 20 325 403

Spatial


Left 719 24 ndash 64 40 298 534

Left 40 37 ndash 49 38 286 514


Left 6 24 ndash 8 47 272 489




Left 46 28 ndash 8 50 289 593


Left 7 19 ndash 67 45 267 547



Left 40 46 ndash 49 40 239 491

(continued)










Table 2 (continued)



Spatial

Left 7 30 ndash 58 47 228 467



Right 6 ndash 46 8 32 212 436





Performance Data


PET Data














GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES







































































Verbal




Right 6 ndash 3 1 52 494 422

Left 6 8 8 47 481 410

Left 6 48 ndash 1 29 480 409

Left 32 1 12 38 478 408

Left 40 33 ndash 51 38 464 396

Left 4 30 ndash 8 45 461 393



Right 632 ndash 1 8 45 463 576

Left 64 48 ndash 1 22 463 576


Right 469 ndash 39 35 29 417 519

Left 6 30 3 47 346 430


Left 17 8 ndash 87 9 327 406

Left 740 35 ndash 58 43 327 406

Left 40 44 21 20 325 403

Spatial


Left 719 24 ndash 64 40 298 534

Left 40 37 ndash 49 38 286 514


Left 6 24 ndash 8 47 272 489




Left 46 28 ndash 8 50 289 593


Left 7 19 ndash 67 45 267 547



Left 40 46 ndash 49 40 239 491

(continued)










Table 2 (continued)



Spatial

Left 7 30 ndash 58 47 228 467



Right 6 ndash 46 8 32 212 436





Performance Data


PET Data














GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES



































































Table 2 (continued)



Spatial

Left 7 30 ndash 58 47 228 467



Right 6 ndash 46 8 32 212 436





Performance Data


PET Data














GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES





























































Performance Data


PET Data














GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES



































































GENERAL DISCUSSION


























CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES




































































CONCLUSIONS



METHODS


Subjects


Task and Procedure






Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES





























































Subjects


Task and Procedure




Image Acquisition


Image Analysis




Acknowledgments



Note


REFERENCES




























































Acknowledgments



Note


REFERENCES



























































age differences in the frontal lateralization of verbal and spatial

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