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NeuroImage 21 (2004) 1368–1376

Age differences in orbitofrontal activation: an fMRI investigation

of delayed match and nonmatch to sample

Melissa Lamar,a,* David M. Yousem,b and Susan M. Resnicka

aLaboratory of Personality and Cognition, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USAbDepartment of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287, USA

Received 7 July 2003; revised 22 November 2003; accepted 25 November 2003

Several investigations have suggested that the orbitofrontal cortex

(OFC) may be particularly vulnerable to the effects of age-related

changes. We recently reported behavioral data indicating greater age

differences in orbitofrontal tasks when directly compared to tasks

tapping dorsolateral prefrontal functions. The present study was

designed to investigate the neural underpinnings of age differences in

OFC functioning. Event-related functional magnetic resonance imag-

ing (fMRI) was performed during delayed match and nonmatch to

sample tasks, previously shown to differentially activate medial and

lateral OFC in young adults. Sixteen healthy younger [age = 26.7(5.6)]

and 16 healthy older individuals [age = 69.1 + 5.6] with similar levels of

education and general cognitive functioning participated in the

experiment. Participants chose the stimulus from a pair of stimuli

matching a previously viewed target (match to sample) or chose the

nontarget item (nonmatch to sample) depending upon a trial-specific

instruction word. Consistent with previous studies, SPM99 analyses of

the younger age group revealed activation for medial OFC regions

during the match task compared to the nonmatch task and lateral OFC

activation during the nonmatch task compared to the match task. In

contrast, older adults showed prefrontal activation only during the

match relative to the nonmatch task and posterior temporal and limbic

involvement during the nonmatch relative to the match task. Between-

group analyses confirmed within-group results suggesting differential

age-related recruitment of prefrontal regions when performing match

and nonmatch tasks. Results suggest that OFC recruitment during

these cognitive tasks changes with age and should be evaluated within

the context of other prefrontal subregions to further define differential

age effects on frontal functions.

Published by Elsevier Inc.

Keywords: fMRI; Orbitofrontal cortex; Age-related differences

Prefrontal regions are among the most sensitive to the effects of

aging. Changes in prefrontal cortex usually precede age-related

changes in the majority of other cortical regions in individuals

without dementia (Raz, 2000). These changes, both behavioral and

physiological, include reduced working memory capacity, de-

1053-8119/$ - see front matter. Published by Elsevier Inc.

doi:10.1016/j.neuroimage.2003.11.018

* Corresponding author. Department of Psychiatry, Columbia Univer-

sity and NYSPI, Unit #74, 1051 Riverside Drive, New York, NY 10032.

Fax: +1-212-543-0522.

E-mail address: [email protected] (M. Lamar).

Available online on ScienceDirect (www.sciencedirect.com.)

creased synaptic density, and reduced concentration of neuro-

transmitters (see West, 1996 for review). A number of cross-

sectional magnetic resonance imaging (MRI) studies of age differ-

ences in gray matter volumes suggest decreased volume within the

orbitofrontal cortex (OFC) in the elderly (Convit et al., 2001; Raz

et al., 1997; Resnick et al., 2000). These findings have led to a

more detailed investigation of age effects on prefrontal behavior.

Recent behavioral studies of prefrontal aging are beginning to

corroborate OFC vulnerability with age. For example, we compared

older (60–80 years old) and younger (20–40 years old) adults

across cognitive measures of orbitofrontal-associated skills includ-

ing inhibition and advantageous decision making and dorsolateral-

associated skills including working memory and self-monitoring

within a multivariate framework. Younger adults outperformed their

older counterparts on OFC tasks only (Lamar and Resnick, in

press). Another study using similar age groups found age effects

on all dorsolateral tasks of working memory and self-monitoring as

well as one orbitofrontal task of emotional identification (MacPher-

son et al., 2002). Finally, in a study of younger (21–43 years old)

and older (72–94 years old) adults, Salat et al. (2002) found older

adults committed more errors across all orbitofrontal and dorsolat-

eral tasks administered. The latter two studies did not directly

compare orbitofrontal and dorsolateral task performance within

one analysis making statements regarding differential behavioral

vulnerability of prefrontal regions difficult. Thus, further investi-

gation is necessary to understand the implications of age-related

orbitofrontal structural change on functional abilities.

The goal of the present research was to investigate the neural

correlates of age-related differences within OFC by assessing

performance on tasks previously shown to elicit OFC involvement.

We implemented a delayed match and nonmatch to sample task

paradigm during functional magnetic resonance imaging (fMRI)

given its previously documented ability to elicit OFC activation

(Elliott and Dolan, 1999). Using fMRI, Elliott et al. demonstrated

that young healthy adults aged 25–40 showed prominent activation

in medial orbitofrontal regions during a delayed match to sample

(DMTS) relative to nonmatch to sample task while the lateral

regions of OFC were involved in delayed nonmatch to sample task

(DNMTS) performance (Elliott and Dolan, 1999). Thus, we chose

to implement these tasks to study age-related changes in brain

functioning, given their differential sensitivity to OFC subregions.

It is important to note that the literature concerning delayed

match and nonmatch to sample tasks highlights several regions of

M. Lamar et al. / NeuroImage 21 (2004) 1368–1376 1369

involvement in successful performance. Nonhuman primate studies

of match and nonmatch paradigms consistently show the impor-

tance of both anterior prefrontal regions (Bachevalier and Mishkin,

1986; Kowalska et al., 1991) and more posterior temporal regions

(Cirillo et al., 1989; Meunier et al., 1997) for successful perfor-

mance. Thus, lesions in either the ventromedial, that is, OFC, gyrus

rectus, and anterior cingulate, or dorsolateral prefrontal cortex will

negatively impact DNMTS performance in monkeys (Bachevalier

and Mishkin, 1986; Kowalska et al., 1991). Likewise, transection

of the temporal stem connecting OFC to the anterior temporal

regions or lesions to anterior temporal regions negatively impacts

match and nonmatch performance in nonhuman primates (Cirillo et

al., 1989; Meunier et al., 1997). Human studies of patient groups

with neuropathological involvement to temporal regions corrobo-

rate the role of the temporal lobe in delayed match and nonmatch

performance (Holdstock et al., 1995; Oscar-Berman and Bonner,

1985). Thus, while we chose the delayed match and nonmatch

tasks to help differentiate specific regions of OFC in younger and

older adults, many regions beyond OFC are integral to the

successful performance on these tasks.

We hypothesized that aging alters the relationship between

regions of OFC and specific cognitive functions. We predicted

that younger participants would show brain activation within the

medial OFC during a delayed match to sample task and activation

within the lateral OFC during a delayed nonmatch to sample task.

In contrast, older adults would show less specificity within

orbitofrontal regions during match and nonmatch tasks. Further-

more, we predicted that between-group analyses would reveal

differing patterns of activation for younger and older adults with

younger adults showing greater activation of OFC for delay tasks

relative to older adults and older adults showing a more diffuse

pattern of prefrontal activation in comparison to younger adults.

Materials and methods

Participants

The present sample included 32 right-handed men and women

from two age ranges: 20–40 and 60–80 years. The younger group

consisted of eight men and eight women 27.9 (5.6) years of age

and 15.2 (2.5) years of education. The older group of eight men

and eight women averaged 69.1 (5.6) years of age with similar

years of education as their younger counterparts (Table 1). The

local institutional review board approved this study and all subjects

gave written informed consent.

The Mini-Mental State Exam (MMSE; Folstein et al., 1974)

provided a brief screen for cognitive impairment, and the Center for

Epidemiologic Studies of Depression (CESD; Radloff, 1977; Radl-

Table 1

Sample characteristics

Younger adults

(n = 16)

Older adults

(n = 16)

Age in years 27.9 (5.6) 69.1 (5.6)

Education in years 15.2 (2.5) 15.4 (3.5)

Sex (M/F) 8:8 8:8

MMSE Total 29.5 (0.6) 29.0 (1.2)

CESD 8.2 (4.6) 4.4 (4.8)

MMSE = Mini-Mental State Examination; CESD = Center for Epide-

miologic Studies of Depression.

off and Teri, 1986) quantified depressive symptomatology. Individ-

uals with scores exceeding 16 on the CESD (Garrison et al., 1991;

Radloff and Teri, 1986) or scores below age and education based cut-

offs on the MMSE (26 for older adults; (NIMH, 1984) were

excluded from the analysis. The remaining subjects were signifi-

cantly different on CESD scores (P = 0.02) only. It is important to

note that nondepressed younger adults typically endorse more items

on the CESD and other measures of depressive symptomatology,

consistent with greater tendencies to report depressive symptoms

(Garrison et al., 1991). However, none of the participants showed

CESD scores in a range that would be diagnostic of depression.

Additional exclusionary criteria for the current study included: a

diagnosis of dementia, depression or other psychiatric illness, a his-

tory of head injury, stroke or other central nervous system disorder,

diabetes, or cardiovascular disease including treated hypertension.

Thus, our sample represents exceptionally healthy individuals.

Experimental paradigm

We chose to emulate the design format originally used by

Elliott and Dolan (1999) to maximize the likelihood of replicating

their findings with the current research paradigm. The task per-

formed in the scanner consisted of three conditions, a delayed

match to sample task, a delayed nonmatch to sample task, and a

perceptual control task. Stimuli consisted of complex color figures

varying in both color and form with aspects of stimuli, for

example, color, or exact stimuli repeatedly used across trials. A

fixation cross, lasting a minimum of 3 s, allowed for a jittered

interval at the beginning of each trial block. Another fixation cross

of 8-s duration provided a break between individual trials

contained within each trial block. After three consecutive trials

under a particular condition, the fixation cross was replaced by an

instruction word to indicate the next condition type was about to

begin. The order of each condition was randomized for the initial

participant and this order was used for all subsequent participants

for ease of data analysis. The total number of correct responses was

tallied for each condition (maximum per condition = 18).

Delayed match and nonmatch to sample task conditions

During both the match and nonmatch conditions, participants

were first presented with a single color figure on the screen for 1 s.

Instructions stressed committing the figure to memory because

after a 5-s delay, two color figures were presented side by side for a

maximum of 3 s or until the subject responded. The delayed match

to sample (DMTS) task required that participants choose the

stimulus from the pair that matched the previously viewed target.

In contrast, the delayed nonmatch to sample task (DNMTS)

required that participants choose the novel stimulus from the pair

of stimuli after viewing the target. Both tasks involve memory and

associating stimuli with a correct response; in addition, the

DNMTS also requires inhibiting the impulse for a familiar

response (Elliott and Dolan, 1999).

Perceptual control task condition

During the control condition, participants were presented with a

random sequence of single and paired complex color figures that did

not match each other. They were told they did not have to remember

the items but only needed to respond with a button press should two

color figures appear on the screen after the 5-s delay period.

Fig. 2. Significant activations using small volume correction for younger

adults: (a) medial OFC activation for DMTS–DNMTS, x V = �9.6, y V =19.96, z V = �8.04, and (b) lateral OFC activation for DNMTS–DMTS,

x V = 23.84, y V = 31.6, z V = �12.72.

Table 2

Behavioral performance data

Younger adults

(n = 16);

mean (SD)

Older adults

(n = 16);

mean (SD)

P value

DMTS task

Items correct 16.06 (1.6) 11.31 (3.7) <0.001

DNMTS task

Items correct 15.06 (1.8) 10.70 (3.7) <0.001

Perceptual–motor

control task

Items correct 16.25 (2.4) 14.13 (3.5) 0.06

DMTS = Delayed Match-to-Sample; DNMTS = Delayed Nonmatch-to-

Sample.

M. Lamar et al. / NeuroImage 21 (2004) 1368–13761370

MRI image acquisition and processing

MRI scans were acquired on a Phillips 1.5 T Gyroscan NT

Intera along the horizontal plane. A brief sagittal scout image was

acquired for localization. Subsequent images were acquired paral-

lel to the plane containing the anterior and posterior commissures

to encompass the entire frontal lobe with emphasis on capturing

orbitofrontal regions; thus, portions of the cerebellum and the most

dorsal aspects of the parietal lobes were not imaged. Once aligned,

a two-dimensional structural image was acquired for anatomical

overlay (matrix = 256 � 256, voxel dimensions = 0.938 � 0.938 �3.75 mm). Functional imaging followed during which time the

experimental paradigm was performed for approximately 18 min.

The fMRI run began with 14 preliminary scans to achieve

equilibrium that were not included in the analysis. Twenty-five

interleaved slices of 3.75-mm thickness with no interslice gap were

acquired with the following imaging parameters: TR = 2.0, TE =

40, flip angle = 90j, FOV = 240 mm, matrix = 64 � 64, voxel

dimensions = 3.75 � 3.75 � 3.75 mm.

Images were processed and analyzed using statistical parametric

mapping (SPM99; Friston, 2002) implemented in MATLAB 5

(Mathworks, Sherborn, MA) on a SGI workstation. Slice time

Fig. 1. Group mean EPI images superimposed on group mean anatomical images for younger (left panel) and older (right panel) adults separately, presented at

the level of z V = �18.

Table 3

Within-group analyses: younger adult activations

Region BA X V Y V Z V Peak

Z

DMTS correct–DNMTS correct

Superior frontal gyrus L BA 8 �16 1 49 3.24

R BA 8 13 4 51 4.17

Middle frontal gyrus L �34 16 29 3.21

Medial orbitofrontal L BA 25 �9 20 �8 3.95

�13 16 �12 3.61

Frontal white matter

extending into the

anterior cingulate

L BA 32 �11 39 10 3.79

R BA 32 15 39 10 3.56

Lingual gyrus L BA 19 �16 �69 �5 4.01

R 25 �89 �6 3.22

Fusiform gyrus L BA 18 �36 �48 �10 4.06

Middle temporal gyrus R 45 �28 �14 3.84

Amygdala R 27 �3 �16 3.53

Precuneus L BA 31 �18 �73 35 3.43

R BA 18/19 20 �77 29 4.05

Supramarginal gyrus L �43 �48 36 3.17

Inferior parietal lobule L BA 40 �36 �42 55 3.34

Middle occipital gyrus R BA 19 15 �92 14 3.34

Inferior occipital gyrus L BA 18 �20 �89 �3 3.99

Cerebellum L �15 �81 �24 4.04

R 22 �40 �22 4.29

DNMTS correct–DMTS correct

Superior frontal gyrus L BA 10 �22 55 13 4.20

R BA 10 20 51 1 3.91

Middle frontal gyrus L BA 8 �29 18 44 3.65

R 25 53 16 3.63

Lateral orbitofrontal gyrus R BA 11 24 31 �13 3.54


correction was performed to adjust for signal differences over time in

the interleaved acquisition paradigm. Each volume was coregistered

and realigned, then normalized to the standard template provided in

SPM99 that is based on the Montreal Neurological Institute (MNI)

Reference Brain. The volumes were smoothed using a 7.5-mm full-

width half-maximum isotropic Gaussian kernel.

fMRI image analysis

We determined events of interest for each participant as those

occurring during the response phase of each trial when participants

must choose either the match or nonmatch response. First level

analyses were conducted for each individual participant accounting

for correct and incorrect responses to match, nonmatch, and control

tasks as separate conditions within the same model. Individual

analyses were performed using a simple box car function convolving

for hemodynamic response function (hrf) alone. Low- and high-pass

filters were employed and proportional scaling was used to adjust for

global changes. Second-level group analyses were conducted within

each age group to investigate possible support for previous results of

medial OFC involvement in DMTS relative to DNMTS task

performance and lateral OFC involvement in DNMTS relative to

DMTS task performance (Elliott and Dolan, 1999). These second-

level within-group analyses were conducted for the entire brain

volume as well as limited to frontal regions using a frontal lobe mask

to reduce the number of statistical comparisons and increase power

to detect OFC activations given our a priori hypotheses regarding

this region. The frontal mask we employed was constructed using

the MNI brain atlas delineated by Kabani et al. (1998). We isolated

regions of the frontal lobe, including superior, medial, middle, and

inferior frontal gyri, medial and lateral OFC, and frontal white matter

but excluded premotor and cingulate regions. We also performed

small volume correction analyses centered on the voxel coordinates

defined by the results of Elliott and Dolan (1999). This small volume

correction analysis was performed for the entire brain volume aswell

as the frontal volume.Within-group analyses for whole brain images

were performed for DMTS relative to the perceptual control condi-

tion and DNMTS relative to the perceptual control condition to

facilitate interpretation of second-level between-group analyses

comparing younger and older adults on these contrasts.

To account for the difference between the MNI/SPM99 repre-

sentation and the original Talairach coordinate space, we adjusted

coordinates in MNI space using the formula X V = 0.88X � 0.8; Y V =0.97Y � 3.32; Z V = 0.05Y + 0.88Z � 0.44 (www.mrc-cbu.cam.

ac.uk), where X, Y, and Z represent MNI space and X V, Y V, and Z Vare adjusted coordinates in Talairach space. Anatomic localization

was determined through overlays on the standard T1-weighted

MRI provided by the MNI and verified against anatomic atlases

(Mai et al., 1997; Talairach and Tournoux, 1988). All neuro-

imaging results are for correct responses only with significance

set at an uncorrected P level of 0.001 unless otherwise specified to

remain consistent with previous work using this experimental

paradigm (Elliott and Dolan, 1999).
Caudate L �11 �9 15 3.24
Middle temporal gyrus L BA 21 �55 �56 0 4.00

R BA 39 54 �57 11 3.47

Middle occipital gyrus L BA 19 �50 �69 7 3.47

Uncorrected P level of 0.001; X V, Y V, Z V correspond to recalculated

Talairach coordinates based on the formula X V = 0.88X � 0.8; Y V =

0.97Y � 3.32; Z V = 0.05Y + 0.88Z � 0.44, where X, Y, and Z represent

MNI space and X V, Y V, and Z V are adjusted coordinates in Talairach

space; BA = Brodman’s areas.

Results

Behavioral performance

The total number of correct responses ranged from 0 to 18 for

all conditions. The number of correct responses for younger

adults ranged from 11 to 18 across experimental conditions and

9–18 for the perceptual control task. Older adults showed a

wider range of scores than their younger counterparts, ranging

from 4 to 18 for experimental tasks and 7–18 for the perceptual

control task. Means and standard deviations indicated that scores

were above chance for both age groups [Young: Match =

16.06(1.6), Nonmatch = 15.06(1.8); Old: Match = 11.31(3.7),

Nonmatch = 10.7(3.7)]. Individual t test results are presented in

Table 2, with significant group differences observed for experi-

mental conditions (P < 0.001). A more detailed analysis of

behavioral results in a larger sample is presented elsewhere

(Lamar and Resnick, in press).

Signal acquisition for orbitofrontal regions

To investigate the presence of adequate signal in younger and

older adults’ orbitofrontal regions, we superimposed group mean

EPI images onto group mean anatomical images for younger and

older adults separately (Fig. 1) using MRIcro software version 1.36

http:\\www.mrc-cbu.cam.ac.uk

Table 4

Within-group analyses: older adult activations


Z

DMTS correct–DNMTS correct

Superior frontal gyrus L �22 �11 48 3.30

DNMTS correct–DMTS correct

Middle temporal gyrus L BA 39 �41 �67 19 5.56*

Superior frontal gyrus R BA 10 10 51 �1 3.24

Middle frontal gyrus R BA 9 40 29 29 3.45

Medial frontal gyrus R BA 8 4 43 39 3.18

Frontal white matter

extending into

anterior cingulate

R BA 32 15 37 10 3.37

Post central gyrus L BA 4 �15 �34 59 3.17

Mid-dorsolateral thalamus R 14 �28 1 3.72

Insula R 43 1 3 4.22

Caudate L �13 22 8 3.22

Inferior temporal gyrus L BA 37 �55 �48 �13 3.26

Parahippocampal gyrus L �24 �19 �19 3.31

Cuneus L BA 18 �16 �92 12 3.53


Cerebellum L �36 �52 �24 3.52

*Corrected P level of 0.05, all other coordinates: uncorrected P level of

0.001; X V, Y V, Z V correspond to recalculated Talairach coordinates based on

the formula X V = 0.88X � 0.8; Y V = 0.97Y � 3.32; Z V = 0.05Y + 0.88Z �0.44, where X, Y, and Z represent MNI space and X V, Y V, and Z V are adjustedcoordinates in Talairach space; BA = Brodman’s areas.

Table 5

Between-group analyses


Z

DMTS correct–perceptual control correct: young > old

Superior frontal gyrus L �15 22 46 3.59

Middle frontal gyrus R 29 33 29 3.30

Cingulate L BA 32 �18 39 12 3.18

R BA 24 1 �1 40 3.15

Cuneus L BA 18 �15 �89 13 4.25

R BA 18 17 �90 18 3.61

Precuneus L BA 7 �11 �63 31 3.16

Fusiform gyrus L BA 36 �48 �40 �20 3.13

Corpus callosum R Genu 6 22 1 3.11

Thalamus R 11 �28 0 3.41


Cerebellum L �46 �46 �25 3.29

R 38 �57 �33 3.17

Old > young

Superior temporal gyrus R BA 22 57 �24 5 4.39

Inferior temporal gyrus R BA 20 47 �17 �20 4.38

Lingual gyrus R BA 18 13 �52 4 3.27

Insula L �38 �21 16 3.12

DNMTS correct –perceptual control correct: young > old

Superior frontal gyrus L �24 16 48 3.32

Middle frontal gyrus L BA 46 �36 37 19 3.37

R 25 12 48 3.13

Lateral orbitofrontal gyrus R BA 47 38 16 �8 3.23

Cingulate L BA 32 �4 10 37 3.43

Insula R 34 12 0 3.43

Old > young

Ventrolateral thalamus R 13 �13 1 3.75

Cuneus L �13 �67 8 3.67

R BA 17 3 �79 8 3.66

Posterior cingulate L BA 23 �6 �59 9 3.32

Transverse temporal gyrus L BA 41 �55 �21 11 3.31

Fusiform gyrus R 45 �36 �13 3.10

Inferior temporal gyrus R BA 45 48 17 �20 3.79

Cerebellum L �32 �46 �20 3.14

Uncorrected P level of 0.001; X V, Y V, Z V correspond to recalculated

Talairach coordinates based on the formula X V = 0.88X � 0.8; Y V = 0.97Y �3.32; Z V = 0.05Y + 0.88Z � 0.44, where X, Y, and Z represent MNI space

and X V, Y V, and Z V are adjusted coordinates in Talairach space; BA =

Brodman’s areas.


for Windows (www.mricro.com). Visual inspection of these images

suggests that our results focus on posterior rather than anterior

OFC given the low signal in the anterior region. Younger and older

adults showed a similar signal, with only a 2% difference between

the number of pixels present across the entire EPI volume for

younger versus older adults. Pixel comparisons of anatomical

images revealed a 1% difference between younger and older adults.

Within-group analyses: young adults

Delayed match to sample relative to delayed nonmatch to sample

Consistent with previous studies comparing DMTS with

DNMTS (Elliott and Dolan, 1999), within-group analyses both

with and without the frontal mask revealed activation of the medial

orbitofrontal cortex (BA25). Using small volume correction with a

10-mm sphere, medial OFC activation was significant at a corrected

P value <0.01 (Fig. 2a). Other regions of frontal activation included

bilateral superior (BA8) and left middle frontal gyri.

Additional areas of activation associated with DMTS relative to

DNMTS revealed through whole brain analysis included the

frontal white matter extending into the anterior cingulate (BA32)

bilaterally, right middle temporal gyrus, left fusiform, right amyg-

dala, bilateral lingual (BA 19) and precuneus (BA31 and BA18/

19), left supramarginal gyrus, and inferior parietal lobule (BA40)

as well as regions of occipital cortex and cerebellum (Table 3).

Delayed nonmatch to sample relative to delayed match to sample

Consistent with previous studies (Elliott and Dolan, 1999),

within-group analyses of DNMTS relative to DMTS using the

frontal mask showed activation of the lateral orbitofrontal cortex

(BA11). Small volume correction showed significant activation

within the lateral orbitofrontal cortex at a corrected P value <

0.004 (Fig. 2b). Other regions of activation revealed through

analysis both with and without the frontal mask included the

bilateral superior (BA 10) and middle (BA8) frontal regions. The

masked analysis also revealed activation in the right inferior

frontal gyrus. Additional areas activated outside of the frontal

cortex included left caudate, bilateral middle temporal regions

(BA21 and BA39), and the left middle occipital gyrus (BA19)

(Table 3).

Delayed match to sample relative to perceptual control

Within group analyses of the brain revealed activation of the

right middle and bilateral medial (BA6) prefrontal regions in

younger adults. Additionally, the right cingulate (BA24) and

precentral (BA4) gyrus were activated as were the left post-

central (BA3) regions. Younger adults showed activation of the

http:\\www.mricro.com


left supramarginal gyrus and right fusiform (BA18). Cuneus

(BA18) and precuneus showed bilateral activation during match

relative to perceptual control conditions as did cerebellar

regions.

Delayed nonmatch to sample relative to perceptual control

Similar to the comparison of match to control conditions,

younger adults showed middle frontal (BA9) and medial (BA32)

prefrontal activation during the nonmatch relative to the perceptual

control condition. Additionally, younger adults showed activation

of the right superior prefrontal cortex (BA6) and right lateral OFC

(BA47). Bilateral cingulate (BA24) as well as left dorsomedial

thalamic regions showed activation in younger adults during the

nonmatch relative to perceptual control condition as did the left

postcentral gyrus, left middle temporal gyrus, and left middle

occipital region (BA19). The right lingual (BA18) and supra-

marginal gyri showed task activation and the inferior parietal

Fig. 3. Comparisons of between-group analyses of (a) DMTS–Perceptual Contro

DNMTS–Perceptual Control for young > old (bottom left panel) and old > youn

lobule was also activated on the right. Bilateral activations were

seen for the precuneus, cuneus (BA18), and cerebellum.

Within-group analyses: older adults

Delayed match to sample relative to delayed nonmatch to sample

Analyses with and without the frontal masking technique failed

to show activation of the medial OFC regions in older adults. This

was also true for analysis using small volume correction. The left

superior frontal gyrus was the only identified brain region activated

at the uncorrected P level of 0.001 (Table 4).

Delayed nonmatch to sample relative to delayed match to sample

Analyses with and without frontal masking failed to reveal

lateral OFC activation during DNMTS task performance relative to

DMTS task performance in older adults. This was also true for

analysis using small volume correction. Regions of activation

l for young > old (top left panel) and old > young (top right panel) and (b)

g (bottom right panel) using an uncorrected P level of 0.001.


common to both masked and unmasked analyses included superior

(BA10), middle (BA9), and medial (BA8) frontal regions in the

right hemisphere. Masked analysis also revealed bilateral frontal

white matter activation possibly extending into the anterior cingu-

late regions; however, whole brain analysis confirmed right ante-

rior cingulate (BA32) activation only.

Additional areas of activation in other brain regions revealed for

older adults included the left postcentral gyrus (BA4), right insula

and mid-dorsolateral thalamus, left caudate, inferior temporal

(BA37) and parahippocampal gyri, cuneus (BA18), middle occip-

ital (BA19), and cerebellar regions (Table 4). Of note, middle

temporal activation (BA39) was significant at the corrected P level

of 0.05.


Within group analyses of the brain revealed activation of the

superior temporal regions bilaterally (left BA42; right BA22) as

well as bilateral lingual gyrus activation (BA18). Additional areas

of activation in older adults were seen for right inferior parietal

lobule (BA40), left cuneus (BA17), and left cerebellar regions.

Within-group analysis for match relative to perceptual control did

not reveal any areas of activation within the prefrontal cortex for

older adults.


In contrast to the match relative to the perceptual control

condition, the nonmatch comparison to the control revealed

prefrontal activation within the right middle frontal gyrus

(BA9). Additionally, the right inferior parietal lobule, right

precuneus, and right lingual regions (BA17) evidenced activation

in older adults as did the bilateral cuneus (BA18 and 19) and

cerebellar regions.

Between-group comparisons


Younger compared to older adults showed greater activation,

that is, higher peak z values at the voxel level, in superior and

middle prefrontal regions, bilateral anterior cingulate (BA32 and

24), cuneus (BA18) and cerebellar regions, left precuneus (BA7),

and fusiform (BA36) gyri as well as the right genu of the corpus

callosum, thalamus, and middle occipital (BA19) regions. In

contrast, older adults, when compared to their younger counter-

parts, showed greater activation of the right superior (BA22) and

inferior (BA20) temporal regions as well as right lingual gyrus

(BA18) and left insula (Table 5). Fig. 3a contrasts younger adults’

anterior involvement to older adults’ more posterior involvement

during task performance.


Younger compared to older adults showed greater activation,

that is, higher peak z values at the voxel level, in the right lateral

OFC (BA47) as well as right superior and bilateral middle (BA46)

frontal regions in addition to the left cingulate (BA32) and right

insula. In contrast, older adults displayed greater activations

relative to their younger counterparts in more posterior regions

of brain (Fig. 3b). Specifically, this analysis revealed involvement

of the ventrolateral thalamus on the right, bilateral cuneus (BA17),

left posterior cingulate (BA23), and transverse temporal gyri

(BA41), right fusiform, and inferior temporal regions (BA45) as

well as left cerebellum (Table 5).

Discussion

The purpose of the present research was to determine the

physiological significance of age-related structural and behavioral

changes within specific orbitofrontal regions. Consistent with our

hypothesis, younger adults displayed activation of medial OFC

during the match condition and lateral OFC activation during the

nonmatch condition. Thus, we replicated previous results differen-

tiating OFC regions using the delay task paradigm (Elliott and

Dolan, 1999). In contrast, older adults did not show significant

activation within the medial or lateral OFC.

Considering other regions that have been implicated in studies

using this experimental paradigm, younger but not older adults also

showed significant activation of the amygdala and middle temporal

gyrus during DMTS performance relative to DNMTS performance,

regions previously implicated in performance through fMRI

(Elliott and Dolan, 1999) and human lesion (Owen et al., 1995)

studies. In contrast, older but not younger adults showed para-

hippocampal and dorsomedial thalamic activations during DNMTS

relative to DMTS performance, two regions implicated in a

previous fMRI study of younger adults (Elliott and Dolan, 1999)

and a lesion study using the delayed match and nonmatch para-

digms (Owen et al., 1995). Older adults also showed increased

activation of the insula and thalamus as well as regions extending

into the anterior cingulate, all of which share rich connections to

lateral OFC (Hof et al., 1995; Morecraft et al., 1992). Thus,

younger adults activated specific orbitofrontal regions previously

associated with match and nonmatch task performance, while older

adults activated more posterior brain regions associated with these

tasks, including regions with direct neural connections to OFC.

Within the context of previously documented areas of involve-

ment associated with DMTS and DNMTS, it becomes apparent

that the present findings comparing DMTS and DNMTS perfor-

mance reveal age differences in anterior–posterior patterns of

activation. Further support for this anterior–posterior age differ-

ence is seen in between-group analyses. As seen in Fig. 3, analyses

for both match and nonmatch conditions revealed that younger

adults activated the prefrontal regions to a greater extent than older

adults who activated more posterior regions. In fact, within-group

analyses for DMTS relative to perceptual control revealed that

older adults did not activate the prefrontal regions at all. Thus,

during DMTS, older adults showed greater recruitment of temporal

cortices while younger adults utilized frontal regions involved in

attentional processing and conflict resolution. Similarly, on

DNMTS, older adults relied more heavily on posterior brain

regions including temporal and occipital regions while younger

adults continued to recruit frontal regions including lateral OFC.

One of the primary roles of OFC is the acquisition of appro-

priate behaviors and the inhibition of inappropriate ones based on

reward contingencies (Elliott et al., 2000; Zald and Kim, 1996). In

keeping with previous research (Elliott and Dolan, 1999), our

results support a further subdivision of these roles within OFC.

Determining the match or familiar target item during DMTS

requires monitoring and continually updating the representation

of associations between initial stimuli and subsequent targets for

adequate error detection. In addition, choosing a familiar item

elicits feelings of reward (Elliott et al., 2000). Medial aspects of

OFC are associated with all of these cognitive (Eslinger, 1999;

Zald and Kim, 1996) and emotional (Rolls, 2000) processes. In

contrast, DNMTS requires an individual to choose the unfamiliar

response, which requires active inhibition of a prepotent and


instinctively preferred, that is, familiar, response (Elliott et al.,

2000). Lateral regions of OFC are more involved with suppressing

or inhibiting the tendency to choose the more familiar response

when such a choice is inappropriate for successful task completion

(Zald and Kim, 1996). Our results indicate that the functional

significance of medial and lateral OFC regions in decision-making

is most apparent in younger adults.

Increasing the delay interval during match and nonmatch tasks

recruits more posterior regions, particularly temporal lobes and

hippocampus, in younger subjects (Elliott and Dolan, 1999). We

used only a single 5-s delay in the current study. At this interval,

older adults failed to show OFC involvement and displayed greater

posterior involvement for both match and nonmatch conditions

than younger adults. Perhaps a delay of 5 s required older adults to

rely more heavily on posterior memory systems as opposed to

anterior prefrontal systems. Future aging studies reducing the delay

interval might elicit the medial or match and lateral or nonmatch

activation pattern, but the current study suggests that at a similar

delay interval, age differences in orbitofrontal activation do exist.

The current results suggest that in addition to previously docu-

mented structural changes in OFC with age (Convit et al., 2001; Raz

et al., 1997; Resnick et al., 2003), age-related functional changes

also exist within this region. However, this conclusion is not without

several caveats. While quantitative comparisons of whole brain EPI

images would suggest only a small percentage change in the number

of pixels acquired in older and younger adults with similar results for

anatomical comparisons, the impact of age-related atrophic changes

on functional MR signal is unknown. Furthermore, the hemody-

namic response function (hrf) has been reported to change with

aging (Huettel et al., 2001). Although we screened older participants

to ensure optimal regional cerebral blood flow, for example, exclud-

ing individuals with heart disease or those currently taking anti-

hypertensive medications, the natural effects of age on hrf could not

be controlled. Lastly, although results are based solely on correct

responses, group differences suggest that task difficulty may have

influenced results and may also help to explain the younger–

anterior, older–posterior pattern of activation.

Interestingly, our results do not conform to previously docu-

mented evidence suggesting that aging reduces lateralization for

other prefrontal regions outside OFC (Cabeza, 2002). Younger

adults in the current study displayed greater bilateral prefrontal

activations in comparison to older adults who displayed a more

lateralized profile, typically right greater than left. Perhaps when

faced with a novel task requiring a high degree of visual processing,

older adults relied more heavily on nonverbal strategies for accurate

performance, increasing right hemisphere activation, whereas youn-

ger adults may have augmented traditional nonverbal strategies with

other verbally mediated strategies, increasing bilateral activation.

Younger adults did, however, show greater lateralization of medial

and lateral OFC activation when compared to previous results

(Elliott and Dolan, 1999). Interestingly, the left-sided medial OFC

activation for DMTS relative to DNMTS and the right-sided lateral

OFC activation for DNMTS relative to DMTS correspond to the

hemisphere demonstrating the highest peak z values reported in the

Elliott and Dolan study (Elliott and Dolan, 1999).

To our knowledge, this is the first directed study of the physio-

logical implications of age-related changes in OFC structure and

function. Our findings would suggest that recruitment of orbito-

frontal regions to solve cognitive problems changes with age. A

review of fMRI studies across several cognitive domains revealed

that younger adults activate specific brain circuitry associated with a

particular process whereas older adults show a more diffuse pattern

of brain activation (Madden et al., 1999; Raz, 2000). Taken together,

this would suggest that older adults utilize a broader neural circuitry

than their younger counterparts during match and nonmatch tasks

perhaps in response to age-related structural declines in orbitofrontal

regions. While future studies should attempt to determine task

components that drive this change, for example, delay intervals or

strategy use, results would suggest that greater emphasis should be

placed on the physiological implications of age-related structural

changes within the prefrontal cortex, particularly OFC.

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