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Psychology and Aging2001, Vol. 16, No. 3, 371-384

Copyright 2001 by the American Psychological Association, Inc.0882-7974/01/S5.00 DOI: 10.1037//0882-7974.16.3.371

Age Differences in Prefrontal Cortical Activity in Working Memory

Bart Rypma, Vivek Prabhakaran, John E. Desmond, and John D. E. Gabriel!Stanford University

Working memory (WM) declines with advancing age. Brain imaging studies indicate that ventralprefrontal cortex (PFC) is active when information is retained in WM and that dorsal PFC is furtheractivated for retention of large amounts of information. The authors examined the effect of aging onactivation in specific PFC regions during WM performance. Six younger and 6 older adults performeda task in which, on each trial, they (a) encoded a 1- or 6-letter memory set, (b) maintained these lettersover 5-s, and (c) determined whether or not a probe letter was part of the memory set. Comparisons ofactivation between the 1- and 6-letter conditions indicated age-equivalent ventral PFC activation.Younger adults showed greater dorsal PFC activation than older adults. Older adults showed greaterrostral PFC activation than younger adults. Aging may affect dorsal PFC brain regions that are importantfor WM executive components.

Working memory (WM) can be defined as the cognitive appa-ratus that allows individuals to temporarily maintain and manipu-late information in mind. Evidence from behavioral research indi-cates declines in WM with advancing age (e.g., Salthouse &Babcock, 1991). WM can be divided into separate components,including slave system buffers for the short-term retention of smallamounts of information and a supervisory attentional system orcentral executive that controls allocation of attention and coordi-nates information held in the slave system buffers (Baddeley,1986; Norman & Shallice, 1980).

Behavioral studies with monkeys have indicated a critical rolefor prefrontal cortex (PFC) in mediating WM performance. Ana-tomical tracing and metabolic imaging studies with monkeys in-dicate that PFC mediates WM performance (e.g., Funahashi,Bruce, & Goldman-Rakic, 1989; Fuster & Alexander, 1971;Goldman-Rakic & Friedman, 1991; Kubota & Niki, 1971). Single-cell recording of monkey brains has shown persistent activity indorsolateral PFC cells during the delay period of a detayed-match-to-sample task (Goldman-Rakic & Friedman, 1991). Moreover,monkeys with principal sulcus lesions show location-specific def-icits in delayed response performance. Behavioral studies witholder monkeys show performance deficits compared with theiryounger counterparts on similar delayed response WM tasks (e.g.,Bachevalier et al., 1991; Bartus, Dean, & Fleming, 1979; Presty etal., 1987).

Bart Rypma and John E. Desmond, Department of Psychology, StanfordUniversity; Vivek Prabhakaran, Program in Neuroscience, Stanford Uni-versity; John D. E. Gabrieli, Department of Psychology and Program inNeuroscience, Stanford University.

This work was supported by Grants AG055701, AG12995, andAG11121 from the National Institute on Aging. We thank Gary H. Gloverfor assistance in scanning and Margaret Zhao for assistance in data anal-ysis.

Correspondence concerning this article should be addressed to BartRypma, who is now at Department of Psychology, University of California,Berkeley, 3210 Tolman Hall, Berkeley, California 94720-1650. Electronicmail may be sent to [email protected].

Similar to older monkeys, older humans perform less well thanyounger humans on a variety of delayed response tasks, suggestingthat similar cortical mechanisms may underlie the age-relatedperformance changes in monkeys and humans. Disproportionateage-related prefrontal decline has been documented in anatomicaland physiological studies of human and nonhuman primate brains.Structural magnetic resonance imaging (MRI) studies have foundgreater age differences in PFC than in other regions (e.g., Raz etal., 1997). Histological studies have found age-related differencesin numbers of neurons (e.g., Brizzee, Ordy, & Bartus, 1980),susceptibility to amyloid plaques (e.g., Heilbroner & Kemper,1990), loss of synapses (Huttenlocher, 1979), dendritic arboriza-tions (Haug & Eggers, 1991), and white matter (e.g., Peters et al.,1996) in the PFC of older brains. Selective age-related declines indopamine, a critical neurotransmitter for WM functions, have alsobeen observed in PFC (Goldman-Rakic & Brown, 1981; Beal etal., 1991). These age-related physiological changes may be relatedto the age differences observed in WM performance (Gabrieli,1996).

Advancing age may have selective effects on different compo-nents of WM. The phonological loop, or verbal slave system,appears to be minimally affected by aging. For example, digit-spanperformance, in which participants recall a digit string immedi-ately following presentation, often appears unaffected by healthyaging (Botwinick & Storandt, 1974; Bromley, 1958; Craik, 1968;Drachman & Leavitt, 1972; Friedman, 1974; Gilbert, 1941; Gilbert& Levee, 1971; Kriauciunas, 1968; Taub, 1973).

In contrast to digit-span tasks, age-related effects are often seenwhen a delay is imposed between presentation and recollection.For instance, age-related WM performance declines are more oftenobserved when delay intervals are increased in short-term memorytasks (e.g., Craik, 1977; Nielsen-Bohlman & Knight, 1995; Poon& Fozard, 1980; Smith, 1975). The amount of information thatmust be held in mind (i.e., memory load) also exacerbates age-related differences in WM performance. A number of studiesexamining the effects of varying memory loads on delayed re-sponse task performance have shown greater age differences withhigher than with lower memory loads (Anders, Fozard, & Lil-

371

372 RYPMA, PRABHAKARAN, DESMOND, AND GABRIELI

lyquist, 1972; Anders & Fozard, 1973; Eriksen, Hamlin, & Daye,1973; Marsh, 1975). Anders et al. (1972), for instance, examinedage-differential performance when participants had to remembervarious numbers of digits across an unfilled delay interval. Theyobserved increasing age differences in performance with increas-ing memory load, indicating faster memory retrieval rates inyounger than in older participants. However, other studies usingsimilar designs have not observed age differences in memoryretrieval rate (e.g., Boaz & Denney, 1993; Kirsner, 1972).

The factors that mediate age-differential or age-equivalent WMperformance are not yet clearly understood, but the observation ofgreater age differences as delay or load increases suggests thatdifferent components of WM may be differentially susceptible tothe deleterious effects of advancing age. It may be that WMmechanisms that allow maintenance of lower memory loads arerelatively unaffected by aging. Other memory mechanisms thatallow maintenance of higher memory loads may be more availableto younger adults than to older adults. The observation that aginghas a greater effect on WM under conditions of increased mne-monic demand suggests that executive components may be differ-entially affected by advancing age.

The disproportionate effect of increasing memory load on olderpeoples' WM performance may reflect a distinction between slavesystem components for the short-term maintenance of informationand an executive component for manipulation of information in theservice of optimizing short-term memory performance (cf. Craik &Jennings, 1992). The notion that rehearsal mechanisms mediatelow memory-load performance whereas additional memory mech-anisms must be recruited for high memory-load performance hasbeen supported in a number of studies of short-term memorycapacity (e.g., Baddeley & Hitch, 1974; Glanzer & Razel, 1974;Waugh & Norman, 1965). Waugh and Norman (1965), for in-stance, administered a cued-recall procedure in which participantswere given lists of 16 digits and asked to rehearse only thecurrently presented digit. The last digit served as a probe and wasa repetition of an earlier digit in the list. Participants were requiredto report the digit immediately prior to the earlier occurrence of theprobe digit in the list. The probability of correctly recalling a listitem diminished precipitously for those that occurred more thanthree list items prior to the final digit probe. They concluded thatthe number of items actually held in short-term storage is severelylimited and that additional memory systems were necessary for thesuccessful retention of long lists. On the basis of their data, Waughand Norman developed an estimation procedure for determiningthe amount of information actually maintained in short-term stor-age (see also Murdock, 1967; Tulving & Colotla, 1970). Applica-tion of that procedure has consistently yielded estimates of be-tween two and three items of information, although the size of theitems (e.g., letters, words, or sentences) may vary considerably(Glanzer & Razel, 1974).

Results from behavioral studies support the notion of executiveinvolvement in WM maintenance tasks with above-capacity mem-ory loads. Baddeley and Hitch (1974), for instance, required par-ticipants to comprehend prose passages while holding zero, three,or six letters in WM. When they compared comprehension in thezero- and three-letter memory-load conditions, performance didnot change (73% and 70% accuracy, respectively). This resultsuggests that when participants must carry out a complex taskwhile retaining a subcapacity memory load, resources can be

devoted entirely to the more demanding task. Significant decre-ments in prose comprehension were observed, however, whenparticipants were required to hold six items in WM (60% accura-cy). This result suggests that memory loads that approach thecapacity of short-term storage may require involvement of exec-utive functions.

Neuroimaging studies suggest that PFC may be functionallysubdivided in such a way as to support such a two-component WMsystem. Rypma, Prabhakaran, Desmond, Glover, and Gabrieli(1999) observed prefrontal cortical activation in a WM task inwhich participants were required to maintain one, three, or sixletters for 5 s. When participants were required to maintain threeletters in WM, relative to one letter, activation in frontal regionswas limited to left ventral PFC corresponding to Brodmann's Area(BA) 44. When participants were required to maintain six letters,relative to one letter, additional activation of bilateral dorsolateralPFC, corresponding to BAs 9 and 46, was observed, suggestingthat this brain region may mediate the involvement of additionalmemory mechanisms necessary for successful maintenance oflarger memory loads. Thus, it may be that subcapacity (i.e., two tothree items) maintenance of verbal information (which is notgenerally affected by aging) is supported by left ventrolateralregions of PFC (cf. Awh et al., 1996; Paulesu, Frith, & Frackow-iak, 1993). Left and right dorsolateral PFC regions may be en-gaged selectively in WM to support supracapacity informationmaintenance, where age-related performance differences are oftenobserved. These results are consistent with other neuroimagingstudies indicating different roles for dorsolateral and ventrolateralPFC in WM tasks (e.g., D'Esposito et al., 1995; Petrides, 1996).

The locations of the prefrontal activations (i.e., ventrolateralPFC under low memory-demand conditions and dorsolateral PFCunder high memory-demand conditions) in Rypma et al.'s (1999)study are consistent with behavioral studies indicating only slavesystem involvement under low memory-demand conditions butadditional executive involvement under high memory-demandconditions (e.g., Baddeley & Hitch, 1974). Further, the dorsolat-eral PFC activations observed by Rypma et al. are similar to thosefound in WM studies using more complex tasks (Cohen et al.,1994, 1997; Corbetta, Miezin, Dobmeyer, Shulman, & Petersen,1991; D'Esposito et al., 1995; Petrides, Alivisatos, Evans, &Meyer, 1993; Petrides, Alivisatos, Meyer, & Evans, 1993; Prab-hakaran, Smith, Desmond, Glover, & Gabrieli, 1997; Prabhakaran,Narayanan, Zhao, & Gabrieli, 2000; Prabhakaran, Rypma, & Gab-rieli, 2001). It may be that suprathreshold maintenance of infor-mation requires cognitive operations similar to those required inthese more complex tasks. These operations include monitoringthe contents of WM (such as would be required in self-orderedtasks; Petrides, Alivisatos, Evans, & Meyer, 1993; Petrides, Alivi-satos, Meyer, & Evans, 1993), updating of the contents of WM(such as would be required in n-back tasks; Cohen et al., 1994,1997), coordination of slave system processes (such as would berequired in dual tasks; e.g., D'Esposito et al., 1995), allocation ofattention among multiple stimulus domains (such as would berequired in divided attention tasks; e.g., Corbetta et al., 1991),organization and planning of behavior (such as would be requiredin high-level reasoning tasks, e.g., Baker et al., 1996; Gabrieli,1996; Prabhakaran et al., 1997; Prabhakaran et al., 2001), andstrategy shifting (Deiber et al., 1991; Jenkins, Brooks, Nixon,Frackowiak, & Passingham, 1994). These cognitive operations are

AGE DIFFERENCES IN PREFRONTAL CORTEX 373

among those that WM executive processes have been posited toperform.

In the present study, we sought to test the possibility thatage-related differences in processes related to dorsolateral frontalbrain regions contribute to the age differences observed in perfor-mance on WM maintenance tasks. We compared cortical activityobserved by Rypma et al. (1999) while younger participants main-tained one or six letters with the cortical activity of older partici-pants under the same conditions. In this comparison, younger andolder participants were required to maintain the same amounts ofinformation in the task. The question of interest was whether asupracapacity WM load would result in age-differential activationin prefrontal brain regions typically associated with tasks thatrequire manipulation of supracapacity amounts of information heldin WM, specifically, dorsolateral PFC.

Method

Participants

Six older (3 men and 3 women, M age = 68.6 years, range = 62-73years) and 6 younger people (2 men and 4 women, M age = 25.3 years,range = 22-29 years) participated in the experiment. Younger participantswere recruited from the Stanford University Psychology Department. Olderparticipants were recruited from respondents to a newspaper ad. All olderparticipants were healthy community-dwelling individuals living in the SanFrancisco Bay Area. Younger and older participants scored equivalently onthe National Adult Reading Test (Nelson & Willison, 1991;M younger = 39, M older = 40, t < 1; Table 1) and the Mini-Mental StatusExam (MMSE; Folstein, Folstein, & McHugh, 1975; M younger = 30,M older = 29, t < 1). The high scores of the older adults on the MMSEdemonstrated their intact cognitive status. Listening Span (Daneman &Carpenter, 1983) performance tended to be higher for younger than forolder participants (M younger = 4.5, M older = 3.3, f[10] = 1.78, p< .10).Younger participants completed more Digit-Symbol Substitutions from theWechsler Adult Intelligence Scale (WAIS; Wechsler, 1981) than did olderparticipants (M younger = 69, M older = 47, r[10] = 3.76, p < .003).Digit-span (also from the WAIS) performance tended to be higher foryounger than for older participants (M younger = 7.8, M older = 7.2, /[10]= 1.86, p < .09).

Cognitive Task

The cognitive task was modeled after the item-recognition task devel-oped by Steinberg (1966). Each trial of the item-recognition task wascomposed of three phases (see Figure 1). Phase 1 (1,500 ms) was atarget-presentation phase in which six uppercase consonant letters ap-

Table 1Mean Standardized Test Scores and Standard Errors(in Parentheses)

Age group

Abilities test Older adults Younger adults

National Adult Reading TestMini-Mental Status ExamListening SpanDigit-Symbol Substitution TestForward Digit Span

40(1.4)29 (0.8)3.3 (0.5)47 (4.6)7.2 (0.2)

39 (2.2)30 (0.0)

4.5 (0.4)69(3.1)a

7.8 (0.2)

R K

G ((

1

: v

:) P

5s

r

C

(R K V)+

(G C P)

i

5s

r

P —

* Indicates statistically significant difference between age groups.

Trial Sequence for 6- v. 1-Letter Condition

Phase 1:Target Presentation

(Encoding)

Phase 2:Waiting Period(Maintenance)

Phase 3:

Probe(Retrieval)

Figure 1. Trial sequence and examples of stimuli in the one-letter andsix-letter memory-load conditions.

peared on the computer screen. Participants encoded either one or six ofthese letters. Letters to be remembered were enclosed in parentheses (sixletters always appeared on the screen in order to equate the perceptualdemands of the two conditions). Phase 2 (5,000 ms) was an unfilledmaintenance interval in which the participants viewed a blank screen.Phase 3 (2,000 ms) was a retrieval phase in which a single lowercase"probe" letter appeared among a series of dashes. On one half of the trials,the probe letter matched one of the letters shown in the target-presentationphase ("same" trials); on the other half of the trials, the probe letter did notmatch one of the letters in the target-presentation phase ("different" trials).On one half of the one-letter different trials were "catch trials" in which theprobe letter was one of the five to-be-ignored letters that appeared in thepresentation phase. On the other half of the one-letter different trials theprobe letter was not one of the five to-be-ignored letters that appeared inthe presentation phase. These catch trials were included so that we coulddetermine whether or not participants noticed the periodic changes betweenone- and six-letter trials. Participants were to respond with a right-thumbbutton press if the probe letter matched one of the to-be-rememberedletters. Each trial was followed by a 500-ms intertrial interval. The taskalternated between blocks of one-letter trials and six-letter trials, and therewere 4 trials per block. There were 24 trials in each memory-load condi-tion. Each block was 36 s long. The entire task involved six alternatingcycles and took 432 s.

MRI Scanning Procedure

Imaging was performed with a 1.5T whole-body MRI scanner (GeneralElectric Medical Systems Signa, Rev. 5.6, Waukesha, WI). For functionalMRI (fMRI), a prototype whole-head coil was used for signal amplifica-tion. Head movement was minimized with a bite bar formed with eachparticipant's dental impression. A T2* sensitive gradient-echo spiral pulsesequence (Meyer, Hu, Nishimura & Macovski, 1992), which is relativelyinsensitive to cardiac pulsatility motion artifacts (Noll, Cohen, Meyer, &Schneider, 1995), was used for fMRI with parameters of TR = 720 ms,TE = 40 ms, and flip angle = 65°. Four interleaves were obtained for eachimage, with a total acquisition time (sampling interval) of 2.88 s per imageand an inplane resolution of 2.35 mm X 2.35 mm. Tl-weighted, flow-compensated, spin-warp anatomy images (TR = 500 ms, minimum TE)


were acquired for all sections that received functional scanning. Voxelsfound to be significantly activated during the functional scan were overlaidon these structural images. Eight 6-mm thick slices were acquired in thehorizontal plane of the Talairach and Tournoux (1988) atlas startingfrom 7.5 mm below the anterior commissure (AC)-posterior commissure(PC) plane, with a 1 -mm interslice interval. Stimuli were generated from acomputer and back-projected onto a screen located above the participant'sneck by using a magnet-compatible projector. Visual images were viewedfrom a mirror mounted above the participant's head. The sequence of thepresentations of the stimuli was synchronized with the imaging sequence ofthe scanner.

Data Analysis

Image analysis was performed off-line by transferring the raw data to aSun SparcStation (Sun Microsystems, Mountain View, CA). We used agridding algorithm to resample the raw data into a Cartesian matrix priorto processing with 2-dimensional Fast Fourier Transform. Once individualimages were reconstructed, the time series of each pixel was obtained andcorrelation methods that take advantage of periodically oscillating para-digms were used to analyze functional activation (Friston, Jezzard, &Turner, 1994). As described by Friston et al. (1994), the hypothesizedneural activity was modeled with a square wave reference function thatvaried in time at the same frequency at which the task varied between highand low memory-load conditions. That is, the frequency of the square wavewas computed from the number of task cycles divided by the total time ofthe experiment.

Because the fMRI signal reflects hemodynamic activity that follows thehypothesized neural activity, the hypothesis reference function was con-volved with an estimate of the hemodynamic response function derivedfrom previous data collected at our site. For the experiments, one task cycleconsisted of a control block and an experimental block each of equalduration. In each scan, there were six task cycles presented over a 432-stime period (frequency = 0.0139 Hz).

To perform analyses in PFC regions, we drew regions of interest aroundinferior (ventrolateral) PFC, middle (dorsolateral) PFC, and superior (ros-trolateral) PFC gyri on the basis of the anatomical definition of these gyriin a standard anatomical atlas (Duvernoy, 1991). To construct functionalactivation maps, the data were analyzed by using a cross-correlationmethod. Voxels that satisfied the criterion of z a 1.96 (representing asignificance of p £ .025, one-tailed) were selected. Raw functional imageswere motion corrected and then spatially filtered by using a Gaussian filterof 8 mm full-width at half-maximum. This map was then processed with amedian filter with a spatial extent of two voxels to emphasize spatiallycoherent patterns of activation. The filter was used on the assumption thatvoxels with spuriously high z values (i.e., false positives due to Type Ierrors) are less likely to occur in clusters than voxels with genuinely highz values, and thus clusters of voxels with high z values are more likely toreflect an active region. The resulting map was overlaid on the Tl-weighted structural image.

To obtain composite maps of activation over all participants, averagefunctional activation maps were created by transforming each section fromeach participant to a corresponding standardized horizontal section(Talairach & Tournoux, 1988) at the same distance above and below theAC-PC plane (Desmond et al., 1995). This transformation was doneindividually for all horizontal sections. Following transformation, compos-ite maps were computed by using a two-stage approach as described byHolmes and Friston (1998). For this approach, the first stage uses all of theimages obtained from the scan session for each participant to compute asingle contrast image at each slice. The second stage then assesses whichvoxels of the mean contrast image were significantly different from zero,using a degrees of freedom value that reflects the number of participantsrather than the number of scans. Thus, in the first stage, the correlationbetween the reference waveform and the fMRI time series for a given

participant was summarized into one z image map at each slice, represent-ing the high-versus low-load contrast for that participant. In the secondstage, the null hypothesis that the mean z value at each voxel is zero wastested, and voxels that reached a statistical threshold corresponding to p <.005 or lower were displayed on each map.

Results

Behavioral Results

To examine age differences between older and younger partic-

ipants, we conducted a 2 (younger vs. older group) X 2 (memory-

load conditions) analysis of variance on reaction time (Figure 2)

and accuracy data (Table 2). All participants responded more

slowly with increasing WM load, F(l, 10) = 68.9, MSB = 8,023.3,

p < .0001. Older participants showed a trend toward responding

more slowly than younger participants, F(l, 10) = 3.1,

MSE = 29,215.8, p < .09 (R2 = .25). The Memory Load X Age

Group interaction was not significant (F < \;R2= .03), indicating

that increases in reaction time with increases in WM load were

equivalent between younger and older participants.

Participants were less accurate with increasing WM loads, F(l,

10) = 13.2, MSE = 0.02, p < .005. Older participants tended

toward lower accuracy than younger participants, F(l, 10) = 3.1,

MSE = 0.03, p < .10 (R2 = .23). The Memory Load X Age Group

interaction was not significant (F < 1; R2 = .04), indicating that

decreases in accuracy with increases in WM load were equivalent

between younger and older participants. Nonparametric tests of the

relative differences between the one-letter and six-letter conditions

in younger and older participants were also not significant. There

were also no age-related differences in performance on catch trials.

fMRI Results

The 6-load versus 1-load scan (referred to as the 6-1 scan from

now on) yielded a number of activations greater for the 6-load than

the 1-load task (see the top portion of Table 3 and Figure 3, top

panel). For younger participants, major foci of activity occurred

bilaterally in inferior frontal gyms (BAs 44, 45, and 47) and

precentral gyrus (BA 6), more in spatial extent on the left than on

1100

1000

5 900

i= 800

700

600

500

-Older•Younger

1 Letter 6 LettersMemory Load

Figure 2. Reaction time results for older participants (diamonds) andyounger participants (squares) in the one-letter and six-letter memory-loadconditions.


Table 2Mean Accuracy Rate and Standard Errors (in Parentheses)

Memory load

Group

Older adultsCatch trials

Younger adultsCatch trials

1 letter

0.89 (0.05)0.94 (0.09)0.97 (0.02)1.00(0.00)

6 letters

0.67 (0.09)

0.82 (0.06)

the right. Middle frontal gyms activity was also observed bilater-ally (BAs 8, 9, and 46) but was greater (i.e., z values were greater),and extended more superiorly, on the right than on the left.Activation also occurred in bilateral superior frontal regions (BA10) and was greater in dorsal-ventral extent on the right than onthe left. Other regions of major activity in this scan were anteriorcingulate (BA 32), medial frontal gyrus (BA 24), right caudate,and thalamus bilaterally. Minor foci of activity occurred bilaterallyin middle temporal lobes (BA 21), left superior occipital gyrus(BA 19), and bilaterally in inferior parietal lobules (BA 40).

For older participants (see the middle portion of Table 3 andFigure 3, middle panel) major foci of activity occurred in inferiorfrontal gyrus (BAs 44, 45, and 47), lateralized to the left hemi-sphere, and precentral gyrus (BA 6), more in spatial extent on theleft than on the right. Major foci of activation also occurred insuperior and medial frontal regions (BA 10), more on the left thanon the right. Minor foci of activity occurred in middle frontal gyrusbilaterally (BAs 9 and 46). Other regions of activity in this scanincluded anterior cingulate (BA 32) and inferior parietal lobule(BA 40). Minor foci of activity occurred in middle and superiortemporal lobe (BA 39), middle occipital gyrus, and cuneus (BA19).

Differences in activation between younger and older partici-pants were compared directly by using random effects r-test com-parisons between age groups (see the bottom portion of Table 3and Figure 3, bottom panel). Results of these tests indicatedactivation that was greater for younger than older participants inleft precentral gyrus (BA 6), middle frontal gyrus (BAs 9 and 46),right cingulate gyrus (BA 30), and left precuneus (BA 7), as wellas left caudate, putamen bilaterally, and left insula. Activation thatwas greater for older participants than younger participants oc-curred in left superior and medial frontal gyri (B A 10). No differ-ences between younger and older participants were observed in leftinferior frontal regions (i.e., BAs 44, 45, and 47).

To examine patterns of functional activation differences indistinct PFC regions, two further analyses were performed. First,the significant activations (the number of suprathreshold voxels inthe composite maps) observed in the analyses of younger and olderparticipants were summed according to hemisphere (left and right)and PFC region (ventral, dorsal, and rostral; see Figure 4).Younger participants showed greater activation (measured by thenumber of suprathreshold voxels) than older participants princi-pally in dorsolateral PFC regions corresponding to BAs 9 and 46.Younger and older participants showed equivalent activation inleft ventrolateral PFC corresponding to BAs 44, 45, and 47. Olderparticipants showed greater activation than younger participants inleft rostral PFC regions corresponding to BA 10.

The above analysis of suprathreshold voxels relies on use of aparticular statistical threshold (z > 1.96 in this case). In a secondanalysis we examined age-differential dorsolateral activation andage-equivalent ventrolateral activation by age-group comparisonsof PFC activation without assumptions inherent in the use of a zthreshold. To examine age differences in PFC regional activationindependent of a z threshold, we drew regions of interest aroundinferior (ventrolateral) PFC and middle (dorsolateral) PFC regionson the basis of their definition in a standard anatomical atlas(Duvemoy, 1991). We then computed for each participant a rela-tive ratio of regional activity, defined as the regional, or ROI-wise,z-value increase (relative to baseline) to the corresponding z-valueincrease across the entire set of slices that contained the ROI.Examination of age differences in relative ratios in each regionallowed us to compare, between younger and older participants,the extent of activation increase in a region, relative to increasesthat would be expected to occur in any random brain region,independent of any z threshold. Age differences in relative ratios ofactivity were assessed separately in each hemispheric region, be-tween younger and older participants, with Mann-Whitney tests.Means of relative ratios for younger and older participants inmiddle and inferior frontal gyri are shown in Table 4. The largestdifference between younger and older participants was in rightmiddle frontal gyrus, and this difference was significant (p = .05).No other comparisons approached significance (all ps > .10).

Discussion

This study compared activation in younger and older adultsperforming a WM maintenance task that included encoding, main-taining, and retrieving high or low loads of verbal information. Ininferior frontal gyri (ventrolateral PFC) there was greater left- thanright-hemisphere activity and no apparent age-related differences.In the middle frontal gyri (dorsolateral PFC) younger participantsshowed greater right- than left-hemisphere activity, and there wasgreater activity in younger participants than older participants.Older participants did, however, show greater activity relative toyounger participants in left superior frontal gyri (rostrolateralPFC).

Interpreting Age-Related Differences in JMR1 Results

Drawing inferences from random-effects tests regarding agedifferences in the neural substrates of cognitive processes fromfMRI data rely on the assumption of an age-equivalent relationshipbetween neural activity and the blood-oxygen-level-dependent he-modynamic response function (HRF) and adequate statisticalpower. The HRF-age-equivalence assumption has been tested in anumber of studies (D'Esposito, Zarahn, Aguirre, & Rypma, 1999;Ross et al., 1997; Taoka et al., 1998) with results indicatingage-related increases in noise components of the HRF but not insignal components (D'Esposito et al., 1999). D'Esposito et al.pointed out that, with findings of uniform age-related reductions inneuroimaging signal (as measured by t or z statistics, e.g.), attri-bution of the results to changes in hemodynamic coupling cannotbe ruled out. If, however, age-related reductions in some regions,but age-related increases in others, are observed, it is unlikely thatage-related changes in hemodynamic coupling could account for


Table 3Regions of Significant Activation in Younger and Older Participants

Lobe Region of activationHemisphere/Brodmann's

Talairach

X y zZ

score Voxels"

Younger participants

Frontal

CingulateParietal

Temporal

Occipital

Subcortex

Superior/middle

Middle

Middle/inferior

Inferior frontal

Inferior/premotorInferior/insulaPremotor

Medial frontalAnteriorInferior parietalSupramarginal/angularSuperior parietalSuperiorMiddle

Middle/inferior

Lingual

CuneusPrecuneus

Caudate/putamen/GPCaudate

Globus pallidusPutamenCaudate/putamen/globus

pallidus/claustrumThalamus

L10L46/10RIOR9R6,8L46RIOR44,45,46,10R45/46R45,46,10L45L46L44R44L44/6L45L6

B8B24/32L40L39L7L22/42L21L21/37R21L37/21R37/21L18/19R19R18R31L7RRLLL

RB

-27-37

282941

-4825333235

-49-39-52

41-52-38-59-51

01

-49-30-25-66-53-57

43-49

56-18

125

200

1614

-18-13-20

24-6

53293531

143531223282635552

224

-52420

-34-53-63-34-30-53-50-56-45-73-59-9

-69-73

10c

62

11

22-22

120123245818

2024

11220323212124545324532458181

-4-4

11

2420458

2020-412

112

4.073.723.723.723.723.044.073.723.533.723.943.313.723.723.723.723.533.723.183.723.163.553.333.723.973.723.143.603.603.483.402.942.743.383.433.673.263.233.01

3.823.72

3982,0011,7302,1622,390

861,7954,0641,7335,006

239335549

2,1625,6481,348

3891,102

2924,413

560753444388891603101309290604139452129471

1,0001,028

46987

251

6162,923

Older participants

Frontal Superior/medialSuperior/medial/cingulate

SuperiorSuperior/middleMiddle

Middle/inferiorInferior frontal

Inferior frontal/premotorPremotor

L10L10.32

BIOR8L10R46RIOR 10,46R9.46L9R9R6L46L47L44L6,44,45L6R6

-24-28

-827

-2447422638

-434248

-47-48-48-55-49

48

4642

6131414641494318250

16204

-34

-4

2012

145

18

12202432326

241

24123232

3.043.04

3.282.422.893.232.332.473.043.042.522.082.233.283.043.042.332.94

2,7112,526

43459

31420949548345746636972

1,235182569

7,210281

2,055


Table 3 (continued)

Lobe Region of activationHemisphere/Brodmann's

Talairach

X y zZ

score Voxels"

Older participants (continued)

Cingulate

Parietal

Temporal

Occipital

Subcortex

Frontal

Cingulate

Parietal

TemporalOccipitalSubcortex

FrontalCingulateSubcortex

Anterior

Inferior parietal

SupramarginalSuperior

Middle

LingualCuneusPrecuneusOccipitalCaudate

Putamen

InsulaThalamus

Parahippocampal

SuperiorSuperior/cingulateMiddle/inferior

Inferior

Inferior/premotorAnterior

PosteriorInferiorInferior/superiorInferiorMiddleCaudate

Insula

SuperiorPosteriorInsula

L24R24/32L24L32R32R39R40L40R39L22R42L22L21R21L21L39L19R19L7R18RRLRLLRL19

Young-old

RIORIO/23LI 0/44RIO/44R45/46R9/46R45L45L44/45R44/45L44L44/6L24R32R23L40L40/7R37L19L

RR

Old-young

L10L23L

QO

2-11-7

53744

-3340

-5547

-43-52

59-40-50-30

8-20

203

1923

18-30-611

-29

2022

-3531383615

-32-36

39-58-48-3129

-52-27

57-48-9

-191831

-25-20-44

293810125

-56-55-50-58

8-27-41-14-15-52-58-55-93-60-93

14-8

-292

18-17-13-40

43364147173122171029„ -1

-24

20-38-33-64-44-77

248

13

52-63

3

-42032454524454532

18

20-4-4

812

12432

18

24-4-4121212-4

-416

11

1632

88

202045324532124545-4-4-416

18

1616

1

3.282.503.043.043.042.232.282.773.042.572.472.133.283.212.722.332.622.452.522.792.642.452.942.472.383.042.403.28

2.082.243.173.292.472.432.802.362.292.612.953.192.242.432.142.092.232.452.292.442.872.293.06

1.971.981.97

5891,198

767953948507258526655

7399

14264721754317810514410297

374112465

62163911211792

5324935190115194

66731124114542052948

205725877

15830

171363

89321

73043

150

Note. Rostrolateral prefrontal cortex (PFC) = Brodmann's Area (BA) 10; dorsolateral PFC = BAs <ventrolateral PFC = BAs 44, 45, and 47. L = left; R = right; B = bilateral.a Suprathreshold.

and 46;


Figure 3. Functional magnetic resonance imaging (fMRI) results of the young (top panel), old (middle panel),and unmatched /-test comparison of young and old (bottom panel) superimposed on pictures of axial cuts at 12mm (left column) and 32 mm (right column) above the anterior commissure-posterior commissure plane(Talairach & Tournoux, 1988). In the bottom panel, the yellow-to-red scale indicates significant age-differentialactivity favoring younger participants; white-to-blue scale indicates significant age-differential activity favoringolder participants.

these results. Such a pattern of results was observed in the presentstudy.

Conclusions about similarities and differences between twogroups depend on sufficient power to detect statistical effects. Therelatively small number of participants could raise concerns about

power in the present study. There was sufficient power, however,to detect effects favoring the younger group in some regions (e.g.,dorsolateral PFC) and the older group in other regions (e.g.,rostrolateral PFC). This result indicates that there was sufficientpower to detect age-related effects in the present study (e.g., Grady


1400 i

o- LeftVentral

LeftRostral

RightVentral

RightDorsal

RightRostral

Figure 4. Numbers of suprathreshold voxels in left- and right-hemisphere prefrontal regions in younger andolder participants.

et al., 1994). Further, the nearly identical levels of activation in leftventrolateral PFC (Figure 4) suggest that the lack of that age effectwas not due to insufficient power.

Another factor that complicates interpretation of age-differentialpatterns of activity is that, across studies, age-related differences inactivation have not been consistently linked to age-related in-creases or decreases in cognitive performance. Regions of in-creased activity in older adults, relative to younger adults, havebeen observed in a number of studies (e.g., Cabeza et al., 1997;Grady et al., 1992; Madden et al., 1999; Reuter-Lorenz et al., inpress). These age-related increases in activity have been accom-panied by age-equivalent performance in some cases (Cabeza etal., 1997) and age-differential performance in others (Reuter-Lorenz et al., 2000). Jonides et al. (2000) have observed still athird pattern of activation-performance relationships, age-relatedreductions in positron-emission tomography (PET) activation as-sociated with reduced cognitive performance in older personsrelative to younger persons.

Reuter-Lorenz et al. (2000) have reported age-related changes inthe hemispheric asymmetry of PFC activation during WM perfor-

Table 4Ratios of Regional Activity in Dorsolateral andVentrolateral PFC

Frontal region

Ventrolateral Dorsolateral

Group

Older adultsYounger adults

Left

1.451.72

Right

1.601.32

Left

1.171.11

Right

1.301.72a

Note. PFC = prefrontal cortex.a Indicates statistically significant regional age difference.

mance. Younger adults demonstrated asymmetric PFC activationas a function of the material being maintained in WM. Thus, PFCactivation was strongly left lateralized during a verbal WM taskand right lateralized for a spatial WM task. Older adults, however,showed bilateral PFC activation during both verbal and spatialWM tasks because of age-related increases in activity in thenonspecialized hemisphere. In the present study, we found a con-trasting influence of age on PFC laterality. Younger adults showeda right-hemisphere (dorsolateral PFC) activation increase in re-sponse to increasing verbal WM load, whereas older adults showeda left-hemisphere (rostrolateral PFC) activation increase in re-sponse to increasing verbal WM load.

The variance between the results of the present study and thoseof Reuter-Lorenz et al. (2000) may be due to a number of factors.The older adults in the Reuter-Lorenz et al. study had significantlyslower response times than the younger adults, whereas the re-sponse times of the older adults in the present study were moresimilar to those of the younger adults. Also, the prior studystressed WM with both memory-load and retention-interval de-mands, whereas the present study stressed WM only with memoryload.

Studies with younger adults that have specifically examined therelationship between activity and performance have shown de-creased activation in dorsolateral PFC when their performance wasfast and accurate relative to when it was slower and less accurate.Older adults, in contrast, showed increased activation in dorsolat-eral PFC when their performance was fast and accurate relative towhen it was slower and less accurate (Rypma & D'Esposito, 1999,2000). These results suggest that fast, accurate performance onWM tasks (such as would be observed in subcapacity WM con-ditions) may be associated with an optimal activation level. Devi-ations above or below this optimal level may be associated withslower and less accurate performance (such as would be observedin supracapacity WM conditions; cf. Kimberg & Farah, 1993;


Kimberg, D'Esposito, & Farah, 1997; Servan-Schreiber, Printz, &Cohen, 1990). Such performance-activation relationships werealso observed in the present study. First, when participants wereslowed as a result of supracapacity WM conditions, youngerparticipants showed greater activation than older participants inregions critical to WM performance (i.e., dorsolateral PFC), pos-sibly reflecting cognitive processes that are more available toyounger than to older adults. Second, age-related increases inactivation were associated with age-equivalent performance, pos-sibly reflecting the operation of compensatory strategies in theolder participant group.

Age-related increases in activation have been interpreted asreflecting functional compensation by a number of researchers(e.g., Cabeza et al., 1997; Grady et al., 1994, 1995; Reuter-Lorenzet al., in press). In one PET study, Cabeza et al. (1997) suggestedthat age-related activation increases observed in insular regionsduring episodic encoding and PFC during episodic retrieval mayreflect functional compensation.

Ventrolateral Prefrontal Cortex

The requirement to maintain a supracapacity WM load resultedin age-equivalent activation in ventrolateral PFC regions. Indeed,analyses of suprathreshold activation revealed nearly identicalactivation for younger and older groups in left ventrolateral PFCcorresponding to BAs 44, 45, and 47. Posterior left ventral PFCregions have been implicated as an important constituent of thephonological loop or verbal slave system. For example, Broca'sArea and adjacent speech-related regions may mediate mainte-nance of stored information through a process of verbal rehearsal(Awh et al., 1996; Paulesu et al., 1993; Rypma et al., 1999; Vallar& Baddeley, 1984). In one study, for instance, brief retention ofphonological information resulted in activation associated withsubvocal rehearsal in left inferior frontal cortex (Paulesu et al.,1993).

The present result suggests that WM slave system processes,related to verbal rehearsal and supported by ventrolateral PFC,may be spared the deleterious effects of advancing age. Not allcognitive processes identified with inferior PFC appear to be sospared, however. Other neuroimaging studies have observed age-related reduction in inferior regions of prefrontal cortex (Buckner,Sanders, Kelley, Snyder, & Morris, 1999; Stebbins et al., 1997)during encoding of semantic information. Further research is re-quired to understand the circumstances under which age-differential or age-equivalent activation of the ventrolateral PFCregions is observed.

Dorsolateral Prefrontal Cortex

The requirement to maintain a supracapacity WM load resultedin far greater activation in younger than older participants indorsolateral PFC. This pattern of age differences in activationsuggests that cognitive operations required for optimal perfor-mance in supracapacity WM conditions may be more available toyounger than to older adults. It may be that supracapacity WMperformance requires manipulation of to-be-remembered informa-tion for-efficient storage and retrieval (Rypma et al., 1999; Rypma& D'Esposito, 1999, 2000).

Results from studies that explicitly require manipulation ofstored information support the idea that age differences in highmemory-load maintenance may be the result of an age-differentialability to effectively manipulate information in the service ofoptimizing memory performance. Results of several studies indi-cate large age differences in performance when participants mustreorder stored information prior to retrieval (Botwinick &Storandt, 1974; Bromley, 1958; Craik, Morris, & Gick, 1990)compared with when participants are required to recall list items inthe order that they were presented (Botwinick & Storandt, 1974;Bromley, 1958; Craik, 1968; Drachman & Leavitt, 1972; Fried-man, 1974; Gilbert, 1941; Gilbert & Levee, 1971; Kriauciunas,1968; Taub, 1973; Wiegersma & Meertse, 1990). Craik (1986), forinstance, observed age-equivalent performance in a standard digit-span task but age-differential performance on an alpha-span task inwhich participants were given lists of words and were required torecall them in alphabetical order. These results suggest that ma-nipulation processes that may be required for the successful main-tenance of supracapacity WM loads (i.e., more than two to threeitems) are impaired by aging. Several lines of brain imagingresearch indicate involvement of dorsolateral PFC in such manip-ulation processes in WM tasks (Braver et al., 1997; Cohen et al.,1997; D'Esposito et al., 1995) and other cognitive tasks believed torequire WM manipulation processes such as mental rotation tasks(e.g., Rypma et al., 1996; Zacks, Rypma, Gabrieli, Tversky, &Glover, 1999), divided attention tasks (e.g., Corbetta et al., 1991),and high-level reasoning tasks (e.g., Prabhakaran et al., 1997;Prabhakaran et al., 2001). Thus, age-related deficits in WM andother cognitive tasks may be tied to the disproportionate effect ofaging on dorsolateral PFC. Differentially greater involvement ofdorsolateral PFC by younger adults may reflect greater reliance onexecutive processes (e.g., mnemonic strategies), possibly at thetime of encoding (Rypma & D'Esposito, 1999), in order to sustainperformance in a high memory-load task (Rypma et al., 1999).

Age-related differences in PFC activation could have resultedfrom age-group differences in the six-letter condition, the one-letter condition, or both. Because the one-letter condition served asthe baseline in our experiment, it is not possible to determine withcertainty whether there were age-related differences in the one-letter condition per se. Age-related attenuation of activity in thedorsolateral PFC could have resulted from increased activity in theone-letter condition in older adults as opposed to decreased activ-ity in the six-letter condition in older adults. The possibility thatthere are age-related differences at low loads is suggested byresults from previous studies that have indicated greater dorsolat-eral PFC activity in older than in younger adults at low memoryloads in the presence of age-equivalent performance accuracy(four letters; Reuter-Lorenz et al., 2000). In contrast, however,other WM studies have shown age-equivalent performance witheven lower memory loads that more closely approximate theone-letter condition of the present study (two letters; Rypma &D'Esposito, 2000).

One reason to suspect an age-differential increase in activationin the one-letter condition is suggested by research indicating thatolder adults have greater difficulty in selective attention tasks thatrequire participants to inhibit the encoding of irrelevant letters orwords that are presented adjacent to to-be-attended letters (e.g.,Hasher, Stoltzfus, Zacks, & Rypma, 1991). In the one-letter con-dition of the present study, the target letter was embedded in an


array of six letters in order to equate the perceptual characteristicsof the one- and six-letter encoding phases. This feature of the taskmay have introduced attentional selection demands into the one-letter memory-load condition (i.e., it may have required partici-pants to inhibit encoding of the five irrelevant letters) that weredifferentially greater for older than for younger adults. Such age-related task-demand differences could potentially lead to an atten-uation of fMRI activation differences between the one- and six-letter conditions in the older group. Although we could not assessage-related differences in the one-letter condition of the presentstudy (given that it was our baseline condition), analyses of per-formance on the catch trials did not suggest such an inhibitiondeficit in the older adults. That is, we did not observe age-relateddifferences in accuracy between younger and older adults onone-letter trials where the correct response was different and theprobe letter came from the set of to-be-ignored letters seen in thetarget presentation phase (i.e., the catch trials). This result suggeststhat the selection demands in the one-letter condition were notgreater for older than for younger adults. It is still possible thateffective resolution of the interference created by the distractingletters led to age-differential increases in activation in the one-letter condition. However, studies that have specifically examinedage differences in interference resolution have implicated ventro-lateral prefrontal cortex (e.g., Jonides et al., 2000), a region thatshowed age-equivalent activation in the present study. Further, theresult reported by Jonides et al. (2000) was one of less activationin older adults compared with younger adults. Such a result wouldhave enhanced the one versus six difference in the older adults.Thus, it is reasonable to assume age-equivalent activation in theone-letter condition, although more research is certainly requiredto understand the conditions under which age-equivalent and age-differential activation is observed during WM maintenance tasks.

Rostrolateral Prefrontal Cortex

In the present study, an age-related increase in left superior, orrostrolateral, PFC regions (BA 10) occurred in the presence ofage-equivalent performance. This activation may reflect any ofseveral psychological processes. One possibility is that this age-related activation increase may reflect the processing of internalemotion associated with the high memory-demand condition. Ros-trolateral PFC activation has been observed in younger adults (e.g.,Lane et al., 1997) and older adults (e.g., Paradise et al., 1997)while viewing emotional stimuli. Alternatively, the age-relatedactivation increase may reflect compensatory WM processes. Ac-tivation in rostrolateral PFC regions (BA 10) has also been ob-served during episodic memory task performance (Andreasen etal., 1995; Cabeza, 2001; Cabeza et al., 1997; Nolde, Johnson, &D'Esposito, 1998; Schacter, Savage, Alpert, Rauch, & Albert,1996). These results, together with those of Rypma and D'Esposito(2000), suggest that older adults use alternative compensatorystrategies to successfully perform supracapacity WM tasks. Forinstance, older adults may place relatively greater emphasis on theuse of encoding operations. Increased activation in left prefrontalregions when memory tasks require additional encoding has beenobserved in previous brain imaging studies (e.g., Andreasen et al.,1995). Results from studies of episodic memory suggest that thegreater left prefrontal activation observed in older adults reflectstheir greater reliance on the use of more deliberative memory

processes (Nolde et al., 1998). Thus, differentially greater involve-ment of left medial PFC by older participants may reflect greaterreliance on compensatory strategies possibly related to a moredeliberative analysis of memory (Nolde et al., 1998; Schacter etal., 1996) or age-related changes in encoding strategies (Andreasenet al., 1995). Further studies are needed to constrain the interpre-tation of the age-associated increase in left BA 10 activation.

Caudate Nucleus

We also observed age-related reductions in activation in thehead of caudate. Clinical, anatomical, and electrophysiologicalstudies delineate a frontostriatothalamic loop in WM (e.g., Houk &Wise, 1993). One possible role of caudate nucleus in WM could beto mediate the sustained activity known to occur in dorsolateralPFC during the delay periods of trials in WM tasks (Cohen et al.,1997; Goldman-Rakic & Friedman, 1991). Houk and Wise (1993)have suggested that output from the striatum, whose cells codestimulus features relevant for WM, to the pallidum causes phasicinhibition of that structure and its inhibitory connection to thethalamus. As a result, resonating activity between the thalamus anddorsolateral prefrontal cortex could be expected to occur, givenknown bidirectional connections between these structures. Age-related reduction in such a mechanism could mediate age differ-ences in the availability of resources for WM maintenance andmanipulation (Gabrieli, 1996). The age-related changes in sus-tained activity in caudate and PFC regions observed in our studyand other studies are consistent with this hypothesis.

Conclusion

Results from the present study suggest a number of conclusionsregarding age-related differences in PFC regions during mainte-nance of information in WM. Left ventrolateral PFC showedage-equivalent activation in the present study. The age-equivalentactivation observed in ventrolateral PFC may support the sparingof the phonological loop in advancing age. Older participants hadreduced activation in right dorsolateral PFC and caudate. Thefunctional compromise of these brain regions may account forexecutive WM and other cognitive deficits that are characteristicof normal aging. The age-related activation increase in rostrolat-eral PFC may reflect a compensatory mechanism that contributedto the nearly age-equivalent performance we observed in thepresent study.

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Received December 30, 1999Revision received June 16, 2000

Accepted October 18, 2000

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