Preserved hippocampus activation in normal aging as revealed by fMRI.
ABSTRACT The hippocampus is deteriorated in various pathologies such as Alzheimer's disease (AD) and such deterioration has been linked to memory impairment. By contrast, the structural and functional effects of normal aging on the hippocampus is a matter of debate, with some findings suggesting deterioration and others providing evidence of preservation. This constitutes a crucial question since many investigations on AD are based on the assumption that the deterioration of the hippocampus is the breaking point between normal and pathological aging. A growing number of fMRI studies specifically aimed at investigating hippocampal engagement in various cognitive tasks, notably memory tasks, but the results have been inconclusive. Here, we optimized the episodic face-name paired-associates task in order to test the functioning of the hippocampus in normal aging. Critically, we found no difference in the activation of the hippocampus between the young and a group of older participants. Analysis of individual patterns of activation substantiated this impression. Collectively, these findings provide evidence of preserved hippocampal functioning in normal aging.
- SourceAvailable from: Richard Henson[show abstract] [hide abstract]
ABSTRACT: This review considers event-related functional magnetic resonance imaging (fMRI) studies of human recognition memory that have or have not reported activations within the medial temporal lobes (MTL). For comparisons both between items at study (encoding) and between items at test (recognition), MTL activations are characterized as left/right, anterior/posterior, and hippocampus/surrounding cortex, and as a function of the stimulus material and relevance of item/source information. Though no clear pattern emerges, there are trends suggesting differences between item and source information, and verbal and spatial information, and a role for encoding processes during recognition tests. Important future directions are considered.The Quarterly Journal of Experimental Psychology 01/2005; 58(3-4):340-60. · 4.67 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Brain aging research relies mostly on cross-sectional studies, which infer true changes from age differences. We present longitudinal measures of five-year change in the regional brain volumes in healthy adults. Average and individual differences in volume changes and the effects of age, sex and hypertension were assessed with latent difference score modeling. The caudate, the cerebellum, the hippocampus and the association cortices shrunk substantially. There was minimal change in the entorhinal and none in the primary visual cortex. Longitudinal measures of shrinkage exceeded cross-sectional estimates. All regions except the inferior parietal lobule showed individual differences in change. Shrinkage of the cerebellum decreased from young to middle adulthood, and increased from middle adulthood to old age. Shrinkage of the hippocampus, the entorhinal cortices, the inferior temporal cortex and the prefrontal white matter increased with age. Moreover, shrinkage in the hippocampus and the cerebellum accelerated with age. In the hippocampus, both linear and quadratic trends in incremental age-related shrinkage were limited to the hypertensive participants. Individual differences in shrinkage correlated across some regions, suggesting common causes. No sex differences in age trends except for the caudate were observed. We found no evidence of neuroprotective effects of larger brain size or educational attainment.Cerebral Cortex 12/2005; 15(11):1676-89. · 6.83 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: This longitudinal study used FDG-PET imaging to predict and monitor cognitive decline from normal aging. Seventy-seven 50-80-year-old normal (NL) elderly received longitudinal clinical examinations over 6-14 years (561 person-years, mean per person 7.2 years). All subjects had a baseline FDG-PET scan and 55 subjects received follow-up PET exams. Glucose metabolic rates (MRglc) in the hippocampus and cortical regions were examined as predictors and correlates of clinical decline. Eleven NL subjects developed dementia, including six with Alzheimer's disease (AD), and 19 declined to mild cognitive impairment (MCI), on average 8 years after the baseline exam. The baseline hippocampal MRglc predicted decline from NL to AD (81% accuracy), including two post-mortem confirmed cases, from NL to other dementias (77% accuracy), and from NL to MCI (71% accuracy). Greater rates of hippocampal and cortical MRglc reductions were found in the declining as compared to the non-declining NL. Hippocampal MRglc reductions using FDG-PET during normal aging predict cognitive decline years in advance of the clinical diagnosis. Future studies are needed to increase preclinical specificity in differentiating dementing disorders.Neurobiology of aging 06/2008; 29(5):676-92. · 5.94 Impact Factor
Preserved Hippocampus Activation in Normal Aging
as Revealed by fMRI
Jonas Persson,1* Gre ´goria Kalpouzos,2Lars-Go ¨ran Nilsson,1Mats Ryberg,3
and Lars Nyberg2,4
such as Alzheimer’s disease (AD) and such deterioration has been
linked to memory impairment. By contrast, the structural and func-
tional effects of normal aging on the hippocampus is a matter of
debate, with some findings suggesting deterioration and others provid-
ing evidence of preservation. This constitutes a crucial question since
many investigations on AD are based on the assumption that the dete-
rioration of the hippocampus is the breaking point between normal
and pathological aging. A growing number of fMRI studies specifically
aimed at investigating hippocampal engagement in various cognitive
tasks, notably memory tasks, but the results have been inconclusive.
Here, we optimized the episodic face-name paired-associates task in
order to test the functioning of the hippocampus in normal aging. Crit-
ically, we found no difference in the activation of the hippocampus
between the young and a group of older participants. Analysis of indi-
vidual patterns of activation substantiated this impression. Collectively,
these findings provide evidence of preserved hippocampal functioning
in normal aging. V V
The hippocampus is deteriorated in various pathologies
C 2010 Wiley-Liss, Inc.
KEY WORDS:aging; episodic memory; functional MRI; Hippocampus
The importance of hippocampal (HC) structures for various forms of
memory is well documented (e.g., Scoville and Milner, 1957; Milner
et al., 1998). In particular, episodic memory, that is memory for past
experiences that are rich in contextual detail rely heavily on HC struc-
tures. Functional neuroimaging, such as functional magnetic resonance
imaging (fMRI), is a powerful tool for investigating HC involvement in
cognitive tasks. Although a growing number of fMRI studies specifically
investigated HC involvement in various cognitive tasks, many of them
failed to find activation in the HC (Henson, 2005). This is challenging
in several ways, but can be especially problematic
when investigating alterations in HC activation in
different populations, such as elderly individuals. The
development of tasks that reliably engage hippo-
campal regions is therefore crucial for various clinical
Whereas several different tasks have been proposed to
be useful for examining hippocampus activation in
fMRI and positron emission tomography studies, we
were particularly interested in a task that robustly shows
HC activation during both encoding and retrieval and
also provides a measure of memory performance. The
face-name paired-associates (FN-PA) task can be used
to investigate theories of episodic memory function in
general and HC function in particular (Sperling et al.,
2001; Zeineh et al., 2003). Moreover, this task
addresses a common complaint in elderly individuals,
which is the difficulty of remembering names of newly
met persons. Thus, the FN-PA task has face validity as
an experimental control.
Recent accounts of episodic memory function in
humans have emphasized the role of the HC in form-
According to this view, the HC participates in the for-
mation of representations linking multiple items. An
essential feature of relational binding is that associa-
tions are formed between multiple elements, and that
the discrete elements as well as the relationships
among them are accessible (Cohen and Eichenbaum,
1993). The HC receives perceptual information from
sensory regions, and serves to establish relationships
among distinct percepts. Thus, including an encoding
condition that requires binding of elements in mem-
ory should increase the likelihood for detecting reli-
able HC activation. In the current study, we used
both a within-modality (visual presentation of both
the face and name) and a between-modality (visual
presentation of the face and auditory presentation of
the name) version to assess whether binding between
visual and auditory items would elicit stronger HC
activation (c.f. Henson, 2005).
One instantiation of binding is when experiences
are formed by associating a particular item with infor-
mation about the context in which the item was
studied (i.e., source information). The retrieval of
source information may involve a distinct psychological
Jonas Persson and Gre ´goria Kalpouzos contributed equally to this work.
Grant sponsor: The Swedish Research Council; Grant number: 2006–1,661.
*Correspondence to: Jonas Persson, Department of Psychology, Stock-
holm University, Frescati Hagv, 14, 106 91 Stockholm, Sweden.
Accepted for publication 22 February 2010
Published online 17 May 2010
1Department of Psychology, Stockholm University, 106 91 Stockholm,
Umea ˚ University, 90187, Umea ˚, Sweden;3Department of Public Health
and Clinical Medicine, Umea ˚ University, 90187, Umea ˚, Sweden;
4Department of Radiation Sciences (Diagnostic Radiology), Umea ˚ Uni-
versity, 90187, Umea ˚, Sweden
Additional Supporting Information may be found in the online version of
2Department of Integrative Medical Biology (Physiology),
HIPPOCAMPUS 21:753–766 (2011)
C2010 WILEY-LISS, INC.
process (recollection) compared with retrieving context-free
item information based on feelings of familiarity (Mandler,
1980; Yonelinas, 2002). It has been suggested that only the for-
mer process may engage the hippocampus (Eldridge et al.,
2000; see also Nyberg et al., 1996b). Hence, the absence of
hippocampal activation in previous investigations of episodic
memory retrieval may in part be explained by the frequent use
of familiarity-based recognition tasks. By including a forced-
choice cued recall condition with three alternatives, we hoped
to increase the recollection component, and therefore increase
the chances of detecting HC activation at retrieval.
A prerequisite for evaluating HC activity in various clinical
populations such as Alzheimer’s disease (AD) would be to estab-
lish the integrity of HC activation in nonpathological aging. This
issue is still debated, since some studies show deterioration of the
HC, while others claim its preservation (see Buckner, 2004; Hed-
den and Gabrieli, 2004 for reviews). This issue is crucial because
AD strongly affects the HC. While physiopathological and struc-
tural MRI studies showed atrophy of the HC related to neuronal
death in AD as well as in preclinical stages of the disease (Mild
Cognitive Impairment, MCI, for review, see Che ´telat and Baron,
2003), functional neuroimaging revealed different patterns of
HC dysfunction at different stages of the disease (see below).
Thus, early functional alterations of HC activity could constitute
a marker of ongoing neurodegenerative processes. However, a
key question is to know if this structure shows functional altera-
tion in nondiseased elderly people. The region-of-interest (ROI)
method has revealed HC atrophy with advancing age (Raz et al.,
2004; Raz et al., 2005; Du et al., 2006) whereas whole-brain
investigations suggested that medial temporal lobe regions would
be less affected by aging than certain other structures such as
frontal cortex (Good et al., 2001; Grieve et al., 2005; Kalpouzos
et al., 2009). Further underscoring the complexity of the issue,
two additional points must be considered. The first one relates to
different aging effects on substructures of the medial temporal
lobe. Some authors found more deterioration in the surrounding
areas of the HC (entorhinal cortex, posterior parahippocampal
gyrus) rather than in the HC per se (see for example Dickerson
et al., 2009), while others found the reverse pattern (Raz et al.,
2004; Raz et al., 2005), or a similar atrophy rate of the entorhinal
cortex and the HC (Du et al., 2006). The second point is that
HC volume reduction, similar to patterns of cognitive decline
(Ro ¨nnlund et al., 2005), could be nonlinear in the course of nor-
mal aging. That is, a more pronounced HC volume decline may
occur after the seventh or eighth decade of life, while parahippo-
campal volume decline could be linear (Allen et al., 2005).
Regarding HC activation in episodic memory tasks in normal
aging, in some studies functional alterations were found in the
parahippocampal cortex rather than in the HC, and particularly
in older individuals showing memory impairment (Daselaar
et al., 2003; Gutchess et al., 2005). However, several studies also
showed HC hypoactivation in older individuals (see Hedden and
Gabrieli, 2004 for a review). For example, in comparison to
young adults, Daselaar et al. (2006) found HC activity reduction
during recollection but increased rhinal activity during familiar-
ity-based recognition in older participants. According to the
authors, familiarity-based recognition supported by fronto-rhinal
activity would compensate for recollection impairment due to
HC-posterior cortical dysfunction. However, in studies where the
FN-PA task has been used, it seems that healthy young and
elderly individuals showed equivalent HC activation (Sperling
et al., 2003; Rand-Giovannetti et al., 2006; Miller et al., 2008).
By contrast, while decreased HC activation was found in AD
patients for the same task (Sperling et al., 2003; Celone et al.,
2006), hyperactivation of this structure was generally found in
MCI patients, maybe reflecting compensatory attempts (Celone
et al., 2006; but see Petrella et al., 2006). Interestingly, Dickerson
et al. (2005) found hyperactivation in MCI patients and no
difference in HC volume when compared with normal controls,
suggesting that HC dysfunction can be detected before volumet-
It is noteworthy that in the majority of studies, only the
encoding phase of the FN-PA task was scanned, with the re-
trieval phase taking place outside the scanner. Even though
these studies showed reliable HC activation bilaterally during
encoding in both young and older subjects (Sperling et al.,
2003; Dickerson et al., 2005; Celone et al., 2006; Miller et al.,
2008), since both encoding and retrieval could be impaired in
normal and pathological aging, we chose to scan both the
encoding and retrieval phases of the task. Kirwan and Stark
(2004) scanned HC activity during both encoding and retrieval
of the FN-PA task, and the authors detected right HC activa-
tion during the two phases in young subjects. Activity in both
left and right HC were detected in encoding and retrieval by
Zeineh et al. (2003). Finally, Pariente et al. (2005) found, in a
similar task, right HC activation in both encoding and retrieval
in healthy older subjects but not in AD patients, suggesting
reliable HC activity during retrieval in healthy individuals.
In view of the many unclear and inconsistent findings as
reviewed above, the main aim of the present study was to assess
the FN-PA task in healthy young and older adults in order (1)
to test its validity in eliciting robust HC activation, and (2) to
directly examine age-related changes in HC activity. Within
each group, we used voxel-based whole brain analyses to iden-
tify HC activation, and we further investigated HC activity
change at the subject level using functional ROIs. Comparisons
between young and older adults were assessed using both voxel-
based and ROI analyses. A secondary aim of the study was to
study patterns of frontal activity during episodic encoding and
retrieval in young individuals, and to examine age-related fron-
tal activity changes since many studies have reported frontal
functional changes with advancing age (see Cabeza et al., 2002;
Persson and Nyberg, 2006).
Sixteen healthy young and 20 older subjects participated in
the study (Young group: eight females and eight males; mean
age, 25; age range, 21–39. Older group, 20 females; mean age,
PERSSON ET AL.
61.3; age range, 52–69). All participants except one older indi-
vidual were right-handed, native Swedish speakers, had normal
or corrected-to-normal vision, and had no known neurological
problems that might cause dementia. None of the subjects was
a smoker. The older subjects were examined by a physician and
serum was drawn for health analyses. They were healthy with
no evidence of heart disease, kidney problems, hyper- or hypo-
thyreosis, ostheoporosis or diabetes. Three were treated with
monotherapy for mild hypertension, and two took low doses of
inhalation steroids occasionally. Otherwise no prescription
drugs were used. Informed consent was obtained from all par-
ticipants in accordance with the guidelines of the Swedish
Council for Research in the Humanities and Social Sciences.
fMRI Activation Task
For the encoding condition, each of the face-name stimuli
(Fig. 1) consisted of a face shown on a black background with
a fictional first name printed to the right-hand side of the face,
forming a face-name pair. In addition to visual presentation of
names, auditory presentation of names was assessed in the
young group only. The faces in the current protocol were digi-
tal color photographs taken of individuals unknown to the sub-
jects. There were equal numbers of male and female faces. Pop-
ular first names were obtained and assigned to each face by the
investigators. For the auditory presentation, names were
recorded in a female (for female faces) or male (for male faces)
voice, and each of the names was synchronized for onset time
(i.e., each auditory name was presented along with each visual
face, 1,000 ms after visual presentation onset). Subjects were
instructed to remember the name associated with each face.
For the retrieval task, each face was presented along with
three letters of which one corresponded to the first letter in the
name-face pair. The task was to indicate the letter that corre-
sponded to the name that was presented together with the face.
The top letter corresponded to the index finger, the middle let-
ter to the middle finger, and the bottom letter to the ring fin-
ger. If subjects could not remember a particular face-name pair,
they were instructed to respond by guessing.
All subjects completed 20-s blocks of (i) FN-PA encoding (ii)
FN-PA retrieval, and (iii) the control task, that alternated during
the scanning session. Each encoding and retrieval stimulus was
presented for 4 s with a fixed interstimulus interval of 1 s.
In the control condition, a fixation cross was presented in the
center of the visual field for 1,500–2,500 ms. The fixation cross
was randomly replaced with a circle which appeared for 500 ms.
The task was to indicate, as quickly as possible, when the fixation
cross changed to a circle. The circle was followed by a second pre-
sentation of a fixation cross that was presented for 2,000–3,000
ms, resulting in a total presentation time of 5 s.
Subjects completed four trials during each block and, with a
24 block (young group) or 20 block (old group) experiment, the
scanning session resulted in a total of 32 face-name pairs for the
young subjects, and 24 face-name pairs for the older subjects.
The total fMRI scan time was below 10 min for each participant.
Immediately prior to entering the scanner, the subjects were fami-
liarized with the task by completing a 1-min practice version of
the task. E-Prime (Psychology Software Tools, Inc., Pittsburgh,
USA; www.pstnet.com/eprime) was used for generating and pre-
senting the stimuli, as well as for recording responses.
The study was carried out on a Philips 3.0 Tesla high-speed
echoplanar imaging device using a quadrature headcoil. For func-
tional scanning, the following parameters were used: repetition
time: 1512 ms (31 slices acquired), echo time: 30 ms, flip angle:
708, field of view: 22 3 22 cm, 64 3 64 matrix and 4.65 mm
slice thickness. To avoid signals arising from progressive satura-
tion, ten dummy scans were performed prior to image acquisi-
tion. Structural high-resolution T1 images were also acquired: a
3D turbo field-echo sequence was used with the following pa-
rameters: repetition time: 10.5 ms, echo time: 5 ms, flip angle:
88, and field of view: 24 3 24 cm. Totally, 170 sagittal slices
with a slice thickness of 1 mm were acquired in 336 3 332 mat-
rices and reconstructed to 800 3 800 matrices. All images were
sent to a PC and converted to Analyze format.
Functional images were preprocessed and analyzed using
SPM5 (Wellcome Department of Imaging Science, Functional
Imaging Laboratory-http://www.fil.ion.ucl.ac.uk/fil.html) imple-
mented in Matlab 7.6 (Mathworks Inc, MA). After correcting
for differences in slice timing within each image volume, all
images were realigned to the first image volume acquired, then
normalized to standard anatomic space defined by the MNI
atlas (SPM5), and finally spatially smoothed using a 8.0-mm
full-width at half-maximum Gaussian filter kernel.
Each of the experimental conditions was modeled as a fixed
response (box-car) waveform convolved with the canonical he-
modynamic response function. Covariates of no interest
included the six realignment parameters to account for motion
artifacts. Single-subject statistical contrasts were set up using
the general linear model, and group data were analyzed in a
random-effects model separately for the young and older
groups. Statistical parametric maps were generated using t sta-
tistics to identify regions activated according to the model.
Using the explicit masking option of SPM5, images were
masked so as to include only gray-matter voxels of interest.
The mask was created using the coregistered, segmented, and
normalized structural T1 images of the subjects. Given the
potential relationship between brain atrophy and functional
activation, we also performed structural analysis on the
T1-weighted high-resolution data using voxel-based morphom-
etry (VBM). Controlling for global gray matter loss, these anal-
yses show that the hippocampus is one of the brain areas that
undergoes the least age-related structural deterioration (for
methods and similar results, see Good et al., 2001; Grieve
et al., 2005; Kalpouzos et al., 2009), supporting our main
hypothesis of a relative preservation of the hippocampus in old
age. We cannot, however, rule out the possibility that other
parts of the MTL, like the entorhinal cortex are subject to
HIPPOCAMPAL FUNCTIONING IN NORMAL AGING
structural deterioration (indeed, this region was not part of the
least deteriorated regions in our VBM analysis).
Marsbar toolbox (http://marsbar.sourceforge.net/) was used
to create the hippocampal ROIs and extract each ROIs mean
BOLD parameter estimate value for each encoding and re-
trieval condition subject by subject. Reported activations passed
a maximum threshold of 0.05 using FDR correction for
within-group results, and an uncorrected threshold of 0.001 for
group comparisons (cluster size larger than 10 voxels).
Behavioral results are shown in Table 1. Response time (RT)
was based on correct responses only, and we distinguished
between incorrect responses and nonresponses. In the young
group, there were no significant behavioral differences between
visual and auditory presentation of names (accuracy: t(30) 5
20.09, P 5 0.93; RT: t(30) 5 21.47, P 5 0.15). For the
VISUAL/VISUAL condition, there were no significant differen-
ces between the young and the older groups (accuracy: t(34) 5
20.40, P 5 0.69; RT: t(34) 5 0.39, P 5 0.70). An ANOVA
was performed on the noncorrect responses (group was the
between-subject factor and type of noncorrect responses was
the within-subject factor). There were no significant effect of
the group (F < 1), significant effect of the type of noncorrect
responses with more incorrect responses than nonresponses
(F(1,34) 5 11.42, P < 0.002), and no significant interaction
effect between the two factors (F < 1). It should be noted,
however, that the lower number of trials for older adults might
have affected the behavioral performance (in particular the ac-
curacy) by reducing the interference from ‘‘nontarget’’ trials, as
well as decreasing the time interval between encoding and re-
trieval. Therefore, some caution should be taken when directly
comparing behavioral performance between the age-groups.
Within- and between-group whole-brain analyses
Young group. Note that although all retrieval conditions were
similar, we separate between the condition in which the face/
name appeared visually during encoding (retrieval visual), and
the condition in which the face was presented visually and the
name was presented auditory during encoding (retrieval
Across the visual and auditory conditions (Fig. 2, Supporting
Information Table 1), we found activation of the HC during
both encoding and retrieval in the left and right hemispheres,
when compared with baseline. While activity was located on
the whole structure during encoding, only the posterior part of
the HC was engaged at retrieval. A direct comparison between
encoding and retrieval revealed more HC activity at encoding,
particularly in the anterior part of the structure.
During both encoding and retrieval vs. the control baseline,
activation was found in the HC bilaterally (Table 2). When
directly contrasting encoding and retrieval, encoding showed
more HC activation than retrieval for both visual and auditory
conditions. These activations were further investigated by com-
paring auditory–visual encoding with visual–visual encoding
(Fig. 3). This contrast revealed a specific area of activation in the
left anterior HC, suggesting that at least some encoding related
activity may be associated with cross-modal binding during audi-
In addition to reliable responses in the hippocampus, activa-
tion was found in regions of the lateral prefrontal cortex (PFC)
RT Hits (ms)
Noncorrect responses (%)
Incorrect responses (%)
RT Hits (ms)
Noncorrect responses (%)
Incorrect responses (%)
control conditions respectively. [Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]
Representative samples of stimulus material for the encoding, retrieval and
PERSSON ET AL.
and the anterior cingulate cortex, as well as in other regions of
the brain. Across conditions (Fig. 2, Supporting Information
Table 1), direct comparisons between encoding and retrieval
showed more left than right frontal activation during encoding
(mainly dorsal frontal cortex, BA 9), while retrieval elicited spe-
cific right frontal areas, (frontopolar cortex BA 10, inferior fron-
tal cortex BA 47) and the anterior cingulate cortex (BA 32).
Older group. As for the young group, in comparison with the
baseline condition, bilateral hippocampal activation was found
in the older group during both encoding and retrieval, (Table 2,
Fig. 4A, for the sake of comparison, the results from the visual
condition in the young group are also given in Fig. 4B). In
both comparisons (and more particularly during retrieval, simi-
lar to the young group), activation seemed to be restricted to
more posterior parts of the HC, even though activity during
encoding was more extended towards the head of the structure
in the left hemisphere. In contrast to the young participants,
encoding did not elicit more HC activation than retrieval.
However, a cluster in the left HC appears for the contrast
encoding vs. retrieval at P 5 0.0038 uncorrected for multiple
comparisons, corresponding to a T-value of 2.98, peak coordi-
nates [226; 218; 220]. Activation was also found in other
areas of the brain (Supporting Information Table 2), overlap-
ping with the ones found in the young group, and especially in
the PFC with more left than right dorsal frontal cortex (BA 9)
during encoding, and specific right frontal areas during retrieval
(inferior frontal cortex BA 47, anterior cingulate BA 10/32).
Group comparisons. For both comparisons between encoding
and retrieval vs. baseline, the older subjects showed less activity
in occipital areas than the younger ones (Figs. 5A,C, Support-
ing Information Table 3). Moreover, in the comparison
between encoding and baseline, the elderly also showed less
activation of the entorhinal cortex. The older subjects activated
more than the younger individuals the cerebellum in both the
encoding and retrieval vs. baseline comparisons (Figs. 5B,D,
Supporting Information Table 3), and, specifically, they showed
more activity in the left frontal cortex for the retrieval vs. base-
line contrast in comparison with the young subjects (BA 8/9/
46). We found no age differences in HC activity.
ual and auditory conditions in the young group (threshold P < 0.05
FDR corrected for multiple comparisons, except for the encoding >
Voxel-based analyses showing activation across vis-
retrieval contrast where the results are displayed at P < 0.01 FDR
correction). [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
HIPPOCAMPAL FUNCTIONING IN NORMAL AGING
Since previous studies highlighted different neurocognitive
processes in aging according to subjects’ performance, particu-
larly in prefrontal areas at retrieval (Cabeza et al., 2002; Rajah
and D’Esposito, 2005), we further examined the relationships
between activity at encoding and retrieval and performance in
the elderly group by assessing regression analyses in SPM. In
particular we focused on left dorsal frontal areas and the medial
temporal lobe, in keeping with the results of the comparisons
between the young and older groups (Fig. 6). Positive correla-
tions between performance and activity during encoding
showed a cluster located in the right parahippocampal cortex
(coordinates [30; 224; 220], r 5 0.58, P 5 0.008). Positive
correlations between performance and activity during retrieval
also showed a cluster in the right entorhinal/perirhinal cortex
([28; 10; 226], r 5 0.68, P 5 0.0009). Negative correlations
between performance and activity during retrieval showed two
left dorsal frontal clusters, close to the ones we found in the
group comparison. The one was located in the left BA 9
([234; 28; 50], r 5 20.62, P 5 0.003) and the other one,
more medial, in the left BA 8 ([26; 20; 58], r 5 20.71, P 5
0.0004). We did not find the HC activity to be correlated with
performance. We further investigated relationships between
medial temporal and frontal activity. Within retrieval, correla-
tions between entorhinal/perirhinal and left BA 8 and BA 9
regions were negative but did not reached statistical significance
(entorhinal/perirhinal - BA 8: r 5 20.34, P 5 0.14; entorhi-
nal/perirhinal - BA 9: r 5 20.19, P 5 0.43), the correlation
between the two frontal areas was significant (r 5 0.66, P 5
0.001). We also found no significant negative correlations
between parahippocampal activity at encoding and frontal
activity at retrieval (parahippocampal - BA 8: r 5 20.30, P 5
0.20; parahippocampal - BA 9: r 5 20.26, P 5 0.27) but a
significant positive correlation between parahippocampal activ-
ity at encoding and entorhinal/perirhinal activity at retrieval
(r 5 0.61, P 5 0.004).
Functional Region-of-Interest Analyses
of the Hippocampus
To allow between-group comparisons, only the visual/visual
condition was considered in the ROI analysis. Analysis of HC
activity for each condition and for each subject revealed a posi-
tive baseline-to-encoding signal change for all subjects in the
left hippocampus. One subject failed to activate the right hip-
pocampus at encoding, but all subjects activated at least the left
or the right hippocampus. Regarding the baseline-to-retrieval
signal change, all but one subjects activated either left of right
HC. Note that this subject activated the left and right hippo-
campi during encoding (Table 3, Fig. 7A).
The results showed that all older subjects activated the hip-
pocampus at encoding, and only two failed to show HC base-
line-to-retrieval signal change increase. These subjects, however,
activated the hippocampus during encoding (Table 3, Fig. 7B).
We compared the signal change obtained for each subject, each
condition and each (right and left) HC ROI to highlight any age-
related magnitude differences. As for the whole-brain compari-
sons, where no HC difference was found between the young and
the older groups, none of the four comparisons showed significant
age differences (Encoding, left hippocampus: t(34) 5 0.31, P 5
0.76; Encoding, right hippocampus: t(34) 5 0.87, P 5 0.39; Re-
trieval, left hippocampus: t(34) 5 21.28, P 5 0.21; Retrieval,
right hippocampus: t(34) 5 21.04, P 5 0.30).
This study convincingly showed that the FN-PA task reliably
elicits HC activation in healthy young individuals. Importantly,
this task also elicits robust HC activation in healthy older indi-
viduals, and no difference in HC activation was found between
the two age groups, suggesting that the HC is functionally well
preserved in normal aging.
vs. Retrieval Visual
vs. Retrieval Auditory
aPeaks located in the perirhinal/parahippocampal cortex.
bPeak located in the lateral part of the HC.
PERSSON ET AL.
Hippocampal Functions in Episodic Memory
The finding of bilateral HC activation during both encoding
and retrieval suggests that the hippocampus is critically involved
in relational binding during encoding and subsequent retrieval of
associative information, mostly based on recollection rather than
familiarity processes (Cabeza, 2006). In line with previous studies
which used a similar task (Sperling et al., 2001; Zeineh et al.,
2003), we found HC activation during encoding in comparison
with a control task. The integration of information across
domains is immensely important for forming relational represen-
tations, and binding together distinct elements of experience. In
addition, we also found HC activation during retrieval, support-
ing models suggesting that integrated information allows for a
partial cue to activate an entire hippocampal representation
(O’Reilly and Rudy, 2001). The bilateral HC activity is probably
related to the fact that the FN-PA task requires verbal and
In order to specifically address the question of differential HC
recruitment across memory conditions, we directly compared
activation during encoding and retrieval. The finding of greater
bilateral activation in the HC during encoding compared to re-
trieval suggests stronger engagement of HC-related processing
during encoding. This observation is in line with previous results
showing HC activation when encoding was compared to re-
trieval, and no activation when retrieval was contrasted with
encoding (see Schacter and Wagner, 1999). In comparison with
the control condition, encoding activated both the anterior and
posterior parts of the HC, whereas retrieval activated the poste-
rior part only. This finding is partly in line with earlier proposals
by Lepage et al. (1998) that the anterior HC is more engaged
during encoding and the posterior HC is more involved in
retrieval processes. Direct comparisons between encoding and
retrieval confirmed a preferential (but not exclusive) activation of
the anterior HC during encoding. This preferential anterior HC
between the auditory encoding and the visual encoding conditions.
Results are displayed at P < 0.05 FDR correction. More activity was
found in the auditory encoding condition in six regions: left HC
[x;y;z] < 5 > [224 ; 214; 218], t value 5 5.29, cluster size k 5 68
voxels; left and right middle and superior temporal cortex (BA 20/
Voxel-based comparison in the young group
21/22), [250; 228; 22], t 5 11.56, k 5 3,730 and [56; 220; 22],
t 5 12.27, k 5 4,366 respectively; right middle temporal cortex
(BA 37), [62; 260;12], t 5 3.52, k 5 11; right pallidum and
putamen [30; 220; 8], t 5 4.29, k 5 60; right thalamus [8; 26; 2],
t 5 3.9, k 5 10. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
HIPPOCAMPAL FUNCTIONING IN NORMAL AGING
activation during encoding fits with the hypothesis suggested by
several authors that this part of the structure would be specifically
involved in (successful) binding processes (Chua et al., 2007),
such as a name with a face.
One noteworthy observation was the activation in the left
anterior HC elicited when a visually presented face was paired
with an auditory presented name compared with when both
the name and face was presented visually. One possibility is
that increased HC activation is a result of cross-modal integra-
tion during encoding, compared with unimodal binding of in-
formation. At least one previous study supports this view show-
ing a similar crossmodal effect in the perirhinal cortex (Taylor
et al., 2006).
One aim of this study was to use a task that would elicit ro-
bust HC activation in young adults for further comparisons
with older subjects. In addition to the whole-brain analyses, we
extracted the HC activity subject by subject. It appeared that
none of the subjects showed decreased HC activity during vis-
ual–visual encoding in comparison to the baseline. Concerning
retrieval, only one subject showed decreased HC activity. Thus,
overall, all subjects activated the HC during the task. This
finding provided strong support to further use this task in older
subjects in order to evaluate age-related HC changes.
Activation of the Hippocampus in Normal Aging
Within the group of older participants, whole-brain analyses
showed activation of the HC during both encoding and retrieval
in comparison with the baseline condition. In contrast with the
young group, however, there was no evidence of more HC activa-
tion during encoding than during retrieval in the older group,
although both visual inspection of the SPMs and using a lower
statistical threshold indicated more extensive HC activation dur-
ing encoding. Thus, the nonsignificant difference could be due
to weak statistical power. Another possibility would be a selective
reduction of HC activation with advancing age during encoding.
However, the comparisons between the young and the older
groups did not support this possibility since no age effect was
found neither in the whole-brain analyses nor in the functional
ROI analyses. In order to test the robustness of HC activation in
the older group, we examined the HC activity change subject by
visual condition in the old subjects (A). For the sake of comparison,
the results from the visual condition in the young subjects are also
Voxel-based analyses showing activation in the
shown (B). Results are displayed at P < 0.05 FDR corrected for mul-
tiple comparisons. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
PERSSON ET AL.
subject. We obtained quite similar results as in the younger
group. Finally, the functional ROI analyses showed that all the
younger and older subjects activated the left or right HC during
either the encoding or the retrieval conditions, and the majority
activated the HC during both phases.
The findings of this study are in agreement with previous
studies showing similar HC activation in young and older
subjects in episodic memory tasks (Sperling et al., 2003;
Rand-Giovannetti et al., 2006). More specifically, in aging, it
seems that the HC is robustly activated during the encoding
of associated elements (Sperling, 2007). However, there are
discrepancies regarding age effects on the HC and recollection
processes. Indeed, some studies showed that elderly subjects
might compensate for recollection deficits by retrieving infor-
mation based on familiarity processes (Clarys et al., 2002). In
addition, some studies found reduced HC activity in older
individuals, associated with decreased recollection-based re-
trieval, but enhanced parahippocampal activity, associated
with increased familiarity-based retrieval (Cabeza et al., 2004;
Daselaar et al., 2006; but see Beason-Held et al. (2008a,
2008b) for an opposite trend). Although our task is supposed
to require more recollection-based retrieval processes, and
therefore HC activity, as found in the young subjects, our
findings of no HC difference with advancing age are in dis-
agreement with previous findings (but see Pariente et al., 2005
for HC activity in elderly subjects using the FN-PA para-
digm). Also in disagreement with previous findings, we found
a trend towards more activity of the entorhinal cortex during
encoding in the young than older individuals. One might
argue, however, that the lack of a hippocampal age-effect may
be related to the relatively young age-span for the older adults
(resulting in relatively high memory performance). All we can
say at this point is that for the individuals included in the
current study, robust activation was unrelated to neither age
nor memory performance. This is also in line with a number
of event-related studies that controlled for age-related perform-
ance differences, which have found no differential hippocam-
pal reduction in older adults (e.g., Miller et al., 2008).
baseline between young and older individuals. Results are displayed at P < 0.001 uncorrected
for multiple comparisons. [Color figure can be viewed in the online issue, which is available at
Voxel-based comparisons of the contrasts encoding > baseline and retrieval >
HIPPOCAMPAL FUNCTIONING IN NORMAL AGING
Frontal Areas Engaged During the FN-PA Task
Although the focus of the current study was on the hippo-
campus, it should be noted that several additional brain regions
were activated. Interestingly, a direct contrast of encoding and
retrieval conditions in the young group revealed that specific
prefrontal regions were recruited across conditions, which is
consistent with previous results (Nyberg et al., 1996a; Habib
et al., 2003). Indeed, in keeping with the hemispheric encod-
ing/retrieval asymmetry model (HERA; Habib et al., 2003)
and the episodic memory retrieval mode model (REMO; Lep-
age et al., 2000), specific left frontal areas were more active
during encoding than during retrieval (dorsal areas BA 9),
whereas several right frontal REMO sites were more engaged
during retrieval, including the frontal pole (BA 10), the oper-
cular area (BA 47), and the anterior cingulate gyrus (BA 32).
Several previous studies suggested that normal aging is char-
acterized by additional frontal activity in comparison with
young subjects, this additional activity being generally compen-
satory (Cabeza et al., 2002), or by under-recruitment of these
regions, when cognitive impairment is more pronounced (see
Persson and Nyberg, 2006 for a discussion). In the current
study, the comparisons between the young and elderly subjects,
who did not differ in terms of performance, showed more left
dorsal and dorsolateral frontal activation during retrieval in the
older participants. In order to test whether this overactivation
was compensatory or not, we correlated, within the older
group, brain activity at retrieval with performance. Left dorsal
and dorsolateral frontal activity was negatively correlated with
performance, suggesting that older individuals who performed
worse attempted to compensate for cognitive decline by recruit-
ing additional left dorsal frontal areas. This finding is in agree-
ment with Rajah and D’Esposito (2005) whose meta-analysis
revealed that left dorsal frontal additional activation in aging
was related to successful compensation. Also, Miller et al.
(2008) found more frontal activity in old low-performing than
high-performing subjects but in the right hemisphere and dur-
ing encoding rather than retrieval; the authors interpreted their
findings in terms of compensation. Together with this effect in
the frontal lobe, we highlighted significant relationships
between performance and medial temporal lobe activity in both
encoding and retrieval. These correlations did not concern the
HC per se but the entorhinal/perirhinal cortex for retrieval, and
posterior parahippocampal cortex for encoding. In both cases,
the correlations were positive, suggesting that activity in the
right parahippocampal cortex during encoding would predict
performance at retrieval (see Kirwan and Stark, 2004 for simi-
lar results using the same task, and Bernard et al. (2001) for
between frontal (A) and medial temporal lobe activity (B) and performance during encoding
or retrieval (see the results section).
Scatter plots showing, within the old group (n 5 20), significant correlations
PERSSON ET AL.
verbal material), and that more activation of the entorhinal/
perirhinal cortex during retrieval would contribute to successful
retrieval (Du ¨zel et al., 2003; Kirwan and Stark, 2004). This
finding can be linked to the role of the parahippocampal cortex
in processing perceptual information, and more particularly the
entorhinal cortex, whose afferents come from sensory associa-
tion areas, which constitutes the gateway of information input
towards the HC (Squire et al., 2004). Since sensory processing
reduction characterizes aging (note both the reduced activity of
the right EC during encoding and the typical age-related
decrease of occipital activity in both encoding and retrieval, see
Davis et al., 2008), we further investigated the relationships
between the medial temporal and frontal areas. Although there
was a trend suggesting that reduced parahippocampal activity
could be accompanied with enhanced frontal activity, the
results did not reach statistical significance, and further studies
are needed to study the relationships in aging between medial
temporal and frontal lobe activity, knowing the importance of
connectivity between these two lobes in episodic memory
(Simons and Spiers, 2003).
Qualitative Individual Functional ROI Results During Visual Encoding and Retrieval
Left Right LeftRight
[228; 226; 210] [22; 226; 26] Left or Right [222; 228; 26] [24; 230; 24] Left or Right
Old[228; 232; 26] [28; 230; 28] Left or Right [222; 226; 210] [24; 228; 26] Left or Right
HIPPOCAMPAL FUNCTIONING IN NORMAL AGING
Overall, our findings concerning the entorhinal cortex
should be considered carefully since this region is primarily
affected by Alzheimer’s disease (Delacourte et al., 1999). Also,
these analyses were conducted in template space with a func-
tionally defined ROI, and in addition to the inherent difficul-
ties of fMRI resolution in small structures (such as the ento-
rhinal cortices), there may be age-related changes in whole
brain and MTL anatomy, even in the absence of early Alzhei-
mer’s pathology. Even though we cannot completely discard
the possibility of very early pathological stage in our sample
of old subjects, clinical examination and memory performance
do not support this hypothesis. Another hypothesis could be
that the under-activation of the entorhinal cortex is a specific
characteristic of aging that would underpin sensory processing
impairment, as suggested above, but is unrelated to pathologi-
One limitation of this study could be the age range of the
old group. The oldest individual enrolled in this study was 69
years old. The lack of age effects in HC activity could be due
to the fact that age impact on this structure has generally been
found in subjects older than 60 or even 70. However, the age
range of the older individuals chosen in the current study
would match the inclusion of individuals in longitudinal stud-
ies where the aim is generally to highlight markers of neurode-
generative processes several years before the first cognitive
symptoms appear. Indeed, some longitudinal studies showed
for example HC atrophy and hypometabolism in normal indi-
viduals who converted to MCI and/or AD several years later
(de Leon et al., 2001; Mosconi et al., 2008; Apostolova et al.,
A second limitation of this study could be that only women
constituted the group of older individuals. A majority of previ-
ous studies did not find any interaction between aging and gen-
der in HC volume (Allen et al., 2005; Greenberg et al., 2008)
neither when considering pathology (Bai et al., 2009). None-
theless, little is known regarding an interaction between aging
on which are superimposed loci where activation in the young (A)
and old groups (B) was significantly greater during VISUAL/VIS-
UAL encoding (top—left) and retrieval (bottom—left) trials than
control trials (FDR corrected threshold at P < 0.05). Middle panel
shows magnitude estimates (% signal change) for each of the
Coronal sections of an anatomical template brain
conditions respectively. To assess the robustness of the data across
participants, we plotted the magnitude estimates (% signal change)
for each individual subject (right hand panel). Note that the ma-
jority of subjects show a similar pattern of activation (i.e., encod-
ing and retrieval > control). [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
PERSSON ET AL.
and gender in activation. Thus, the present findings need to be
extended to males as well.
Here we demonstrated that the face-name paired-associates
task can be used to elicit HC activation bilaterally during both
encoding and retrieval. Importantly, this study further showed
preserved HC activation in healthy old individuals. Since no
age effects were found in HC involvement, the FN-PA task has
potential for the study of HC processing in pathological condi-
tions such as Alzheimer’s disease and even more in earlier stages
of the disease. Thus, this task, which do not last more than 10
min, could be used for clinical purposes as a diagnostic tool, as
well as the evaluation of treatments in clinical trials.
The authors are grateful to Carl-Johan Olsson for help in
data collection of the elderly participants.
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