1. health and fitness
2. disease

Available online at www.sciencedirect.com
Psychiatry Research: Neuroimaging 156 (2007) 185 – 197
www.elsevier.com/locate/psychresns
Hippocampus and amygdala volumes in a random community-based
sample of 60–64 year olds and their relationship to cognition
Jerome J. Mallera,⁎, Kaarin J. Ansteya , Chantal Réglade-Meslina ,
Helen Christensena , Wei Wenb , Perminder Sachdevb
a
Centre for Mental Health Research, The Australian National University, Canberra, Australia
School of Psychiatry, University of New South Wales, and Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia
b
Received 5 May 2005; received in revised form 8 December 2005; accepted 21 June 2007
Abstract
Reduced volumes of the hippocampus (HC) and amygdala (AG) are potential biomarkers for Alzheimer's disease (AD) and
other neuropsychiatric disorders. Published studies on HC and AG volumes suffer from methodological limitations, and a valid and
reliable normative database does not exist. This study aimed to establish a database of HC and AG volumes from a large
community sample of participants 60–64 years old and relate them to cognition. A total of 452 randomly selected participants
(from 622 approached) were retained in the study (238 males, 214 females), and all received brain MRI scans, as well as cognitive
and physical assessments. HC and AG volumes were estimated from manual tracings on T1-weighted images, and intracranial
volume (ICV) was obtained from an automated program. In both sexes, right hippocampi were larger than left, while left
amygdalae were larger than right. The only correlation to remain significant after normalization was left HC volume and percent
retention of a word list in females. This study provides a HC and AG volumetrics database and describes its relationship with
cognitive performance in a representative sample using a standard methodology that will be a reference for future studies. It will
therefore have clinical applicability in early AD and other disorders.
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Hippocampus; Amygdale; MRI; Volumetrics; Sex; Memory
1. Introduction
1.1. Normative volumetrics
Medial temporal lobe (MTL) structures, in particular
the amygdala (AG) and hippocampus (HC), show
atrophy in the early stages of Alzheimer's disease
⁎Corresponding author. Centre for Mental Health Research,
Building 63, Eggleston Road, Australian National University, Acton
ACT 0200, Australia. Tel.: +61 2 6125 1030; fax: +61 2 6125 0733.
E-mail address: [email protected] (J.J. Maller).
(AD) and are potential markers for pre-clinical AD
(Bobinski et al., 1995; Golebiowski et al., 1999; Laakso,
2002). Volumetric abnormalities in these structures have
also been noted in other neuropsychiatric disorders such
as schizophrenia, depression, and post-traumatic stress
disorder (Garcia, 2002; Nelson et al., 1998). A number of
case-control studies have examined the volumes of these
structures (e.g. Convit et al., 2000; Mega et al., 2002;
Seab et al., 1988), and related them to clinical parameters, but these studies often have small control groups,
making for low generalizability to the broader community. Magnetic resonance imaging (MRI) parameters,
0925-4927/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pscychresns.2007.06.005
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J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
delineation of structures, and methods of normalization
for brain volume also vary among studies. All of these
factors may affect volumetric results (Brierly et al., 2002;
Jack, 1994; Laakso et al., 1997; Luft et al., 1996). Many
of these important past studies were performed as
pilot investigations and identified important clinical
effects that illustrated the ultimate need for a normative
database.
Brierly et al. (2002) conducted a systematic review
and meta-analysis of 51 studies on volumetric MRI
of the AG. An overall volumetric estimate was not
meaningful, and they concluded that the main methodological factor to influence AG measurement was
anatomical definition. Hippocampal volumetrics also
differ greatly between studies, mostly due to the studies' inclusion or exclusion of different portions of the
HC, i.e. the head, body and tail. A recent review by
Anstey and Maller (2003) expanded on these differences in the context of studies investigating mild
cognitive impairment. They and others have concluded
that normative data on volumes of medial temporal
lobe structures are required to enable comparability
between studies and for clinical applications of volumetric research. Toward that end, this article reports
normative data for a large representative sample of 60–
64 individuals by using comprehensive, consistent and
reliable anatomical methodology, and clear statistical
analytical techniques.
1.2. Normative volumetrics and cognition
Gradual decline in cognitive ability is characteristic
of longitudinal studies of the elderly (DeCarli, 2003),
with 25% of individuals over 65 years of age having
sufficient cognitive problems, short of dementia, to
affect the quality of their lives (Unverzagt et al. 2001).
In particular, memory is commonly the first neuropsychological skill to decline (Bartres-Faz et al., 2001;
Convit et al., 2003) and may be a key indicator of the
development of neurodevelopmental disorders such
as Alzheimer's disease, the most common form of
dementia. Investigators have suggested that clinically
recognized memory dysfunction may be a feature of
normal ageing (Goldman and Morris, 2001), but that
substantive loss in memory and other cognitive abilities
is not part of ‘normal’ ageing (Rubin et al., 1998; Wilson
et al., 1999).
Reduced HC volume has been found to be significantly associated with memory loss (e.g. Convit
et al., 2003; Hackert et al., 2002; Lye et al., 2004).
Similarly, the entorhinal cortex has also been found to
be reduced in size in those with pre-clinical dementia
(Strange et al., 1999), consistent with the distribution of
plaques and tangles in the earliest stages of AD (Braak
and Braak, 1997; Krasuski et al., 1998). However, the
“bigger is better” hypothesis of the relationship between
HC volume and memory performance has not been
supported in many populations investigated. Differences
in the type and amount of material to be recalled, the
length of the delay, the modality in which the information was presented, or a combination of these factors
may have contributed to the mixed findings of reported
brain–behavior associations (e.g. Chantome et al., 1999;
Sullivan et al., 1995; van Petten et al., 2004). Furthermore, there have been differences in sample sizes, sex
composition, and ranges of age and education; MRI
acquisitions varied as well. Recently, a meta-analysis of
33 studies of HC volumes and memory performance
(van Petten, 2004) and of 15 studies of HC volumes and
memory performance by the current authors (unpublished) found that the finding of a positive relationship
between HC volume and verbal memory (immediate or
delayed recall) was inconsistent, and that the relationship was more likely to be found in older age groups; the
relationship in young groups was more often null or
negative. This suggests that the relationship between
HC volume and memory performance may vary with
age, such that there is a weak or significant negative
effect in youth, null in middle-age, and positive in older
aged individuals. However, it may be that no significant
relationship early on becomes significant because of
decline in some individuals, i.e. the base volume is
unrelated to memory, but decline in volume is related to
decline in memory.
Structural and functional studies suggest a major role
for the AG in the emotional modulation of memory
(Abe, 2001; Cahill et al., 1996; Phelps and Anderson,
1997), while the HC has been shown to be more related
to the formation, storage and recall of any type of
memory (Brewer and Moghekar, 2002; Preston and
Gabrieli, 2002). Clearly what is needed is a study to not
only estimate HC and AG volumes in a reliable and
detailed fashion, but to also measure memory performances in a large sample of normal individuals. This
article responds to this need. We hypothesize that (1)
population estimates of HC and AG volumetry are
influenced by sex and intracranial volume (ICV, used
as a proxy for premorbid brain size), (2) HC volumes
have a significantly negative correlation with memory
performance, specifically the left hippocampus with
verbal delayed recall (and by measuring only verbal
episodic memory, a dissociation will be shown, i.e.
episodic memory for words will be related to HC
volume but not AG volume), and (3) ICV will confound
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
the relationships of HC and AG volumetry with
cognition.
2. Method
2.1. Subjects
Participants were sampled randomly from the electoral rolls for Canberra, ACT, and the neighboring city
of Queanbeyan, NSW, Australia (enrolment to vote is
compulsory for Australian citizens), as part of the PATH
Through Life Project, which is a longitudinal study of
social, psychological and biological risk factors for highprevalence mental health problems. The project involves
cohorts initially aged 20–24, 40–44, or 60–64 years who
are to be followed up every 4 years for 20 years. Further
details on the full PATH Through Life Project have been
published previously (Anstey et al., 2004; Sachdev et al.,
2004). The response rate for the 60–64 age group was
58.3%. When characteristics of this sample were
compared with census data on the population, the sample
was found to be better educated, but to be similar in
marital status and employment status.
During the community survey, respondents were
asked whether they would be willing to undergo an MRI
scan, and 2076 out of 2551 (81.5%) said they would.
Subsequently, a randomly selected sub-sample of 622 of
the willing 2076 people were invited to undergo a scan
and 478 participated (76.8%). Those who said during
the initial interview that they were unwilling to have
a scan were significantly (P b 0.05) more likely to be
female, to be of non-English speaking background, to
be less educated, with poorer physical health and to have
lower cognitive test scores. Those who refused to undergo a scan when actually invited were significantly
more likely to be of non-English speaking background,
to be less educated, with poorer physical health and to
have lower cognitive scores. There was no significant
difference in depression or anxiety (as measured by the
Goldstein scales; Goldberg et al., 1988) at either stage.
2.2. Procedure
2.2.1. Survey procedure and cognitive testing
Each participant was interviewed individually by a
member from a team of professional survey interviewers
experienced in epidemiological and social surveys. The
screening was conducted by trained interviewers i.e.
information from the general PATH interview was used,
with medical conditions being self-reported. Individuals
in the 60–64 year old cohort were given the Mini-Mental
State Examination (MMSE; Folstein et al., 1975), as
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well as other cognitive tasks to perform including the
immediate and delayed recalls of the first trial from
the California Verbal Learning Test (CVLT; Delis et al.,
1987), which were used to assess short- and long-term
episodic memory. Verbal working memory was assessed
by the Digit Span Backward (DSB) subtest from the
Wechsler Memory Scale (Wechsler, 1945), psychomotor
speed by the Symbol–Digit Modalities Test (SDMT;
Smith, 1982), and reading vocabulary as a proxy for
premorbid intelligence by the Spot-the-Word Test
Version A (STW; Baddeley et al., 1992). Reaction time
(RT) was tested using a small box held with both hands,
with left and right buttons at the top to be depressed by
the index fingers. There were four blocks of 20 trials
measuring simple RT, followed by two blocks of 20 trials
measuring choice RT. For simple RT everyone used their
right hand regardless of dominance. Simple RT was
measured over 80 trials, and choice RT was measured
over 40 trials. More details on the RT protocol are
available in Anstey et al. (2004).
Approval for the study was obtained from the human
research ethics committees of the Australian National
University and the University of New South Wales, and
all participants provided written informed consent.
Assessments were conducted between April 2001 and
July 2002, and the time between assessments and MRI
scanning was no more than 12 months for any participant.
2.2.2. Image acquisition
Imaging was conducted on a 1.5 Tesla Gyroscan MRI
scanner (ACS-NT, Philips Medical Systems, Best,
Netherlands) for T1-weighted 3-D structural and T2weighted FLAIR (fluid attenuated inversion recovery)
sequence MRI. A 2D scout mid-sagittal cut for anterior–
posterior commissure plane alignment was first acquired. Then 3-D structural MRI was acquired in coronal
orientation using a T1-weighted fast field echo sequence
(TR/TE/NEX = 28.05/2.64/2; flip angle = 30; matrix
size = 256 × 256; FOV = 260 × 260 mm; slice thickness = 2.0 mm, inter-slice distance = 1.0 mm), yielding
over-contiguous coronal slices 1.0 mm thick with an inplane spatial resolution of 1.016 × 1.016 mm/pixel. The
FLAIR sequence was acquired in coronal orientation
(TR/TE/TI/NEX = 11000/140/2600/2; matrix size =
256 × 256; FOV = 230 × 230 mm; slice thickness =
4.0 mm with no gap between slices) with in-plane spatial resolution of 0.898 × 0.898 mm/pixel. The total time
of each subject's scanning session was approximately
20 min. As 26 of the scans were untraceable due to
excessive artifact (15 males and 11 females), the total
number of participants with traceable MR images totaled
452 (238 males, 214 females).
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2.2.3. Volumetric measurement
The volumes of brain anatomical regions were determined by two researchers (JM, CM), each manually outlining the periphery of the regions of interest (ROI) on a
subset of the coronal T1-weighted slices (approximately
50:50) using Analyze 5.0 (Brain Imaging Resource, Mayo
Clinic, Rochester, MN). The boundaries of the ROIs were
outlined with a cordless infrared light-driven cursor, and
the number of voxels within the regions was calculated
to produce a total volume for the ROI. The outlining of
the structures always proceeded from anterior to posterior,
and the AG was traced first. The HC included the dentate
gyrus, the hippocampus proper, and the subicular complex (Duvernoy, 1999). We often used axial orientation to
validate neuroanatomical boundaries.
Amygdala boundaries were based on studies by
Watson et al. (1997) with a modification as suggested by
Brierly et al. (2002). That is, we checked for the most
anterior margin (nucleus) of the AG (Fig. 1A) by continuing to move anteriorly and verifying that this ovoid
structure disappeared from view. Watson's method of
determining the anterior margin of the AG is the section
where the lateral sulcus closes to form the endorhinal
sulcus (Watson's method); however, this method may be
less reliable in atrophy-prone elderly. Hippocampal
boundaries were also based on those outlined by Watson
et al. (1997), but we were careful to exclude hippocampal sulcal cavities (HSC) at the lateral aspect of
the hippocampal fissure as HC volume and not to mistake the uncal recess of the temporal horn for an HSC.
An HSC was defined as round or curvilinear in shape
on coronal orientation and crescent shaped on axial,
and followed the isotense signal characteristics of CSF
(Fig. 1D). The most posterior and final slice of the HC
Fig. 1. Examples from MRI slices illustrating boundaries of the amygdala and hippocampus from anterior to posterior. (A) Anterior tip of the
amygdala. (B) Anterior separation of the amygdala from the hippocampus. Note the protrusion of the IHLV and the clear strip of white matter (alveus)
as the boundary between the two structures. (C) IHLV becomes clearer and HC becomes larger. (D) Hippocampal boundaries posterior to last slice of
amygdala showing the choroidal fissure. Note the exclusion of HSC volume from the HC volume area outlined. (E) Most posterior slice taken for the
right HC. (F) One slice posterior to (E) showing clear separation of the crus of the fornix from the wall of the lateral ventricle on the right (arrow
head).
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
was defined as the slice before the most anterior section
where the crus of the fornix was seen to clearly separate
from the wall of the lateral ventricle (Fig. 1E and F).
Boundaries were CSF-GM and GM-WM contrasts. Fig.
2 is an illustration of a right-side hippocampus and
amygdala rendered from the full set of manual tracings
from the above MRI example.
Data were normalized by dividing each HC or AG
volume by the individual's total intracranial volume
(ICV). This was estimated from their T1-weighted images. The ICV procedure was achieved through an automated process using SPM99 (Wellcome, UK). In order to
determine correspondence between the automated method
used in this article and results from manual tracings, five
T1-weighted scans were randomly selected and the ICV
determined by manually outlining the cranial cavity of
each slice (approximately 252 slices per scan); the error
between these volumes and those produced by the automated procedure was below 5% (see Wen and Sachdev,
2004, for a full description of the process).
Reliability of the regional volumetric measures was
assessed by an intra- and inter-class correlation formula
that presumes random selection of raters, ICC (Shrout
and Fleiss, 1979). The two tracers yielded ICCs in a pilot
study (n = 5) that were well within acceptable limits
189
(N0.90). ICC between raters was determined (n = 10)
after every 50 brain measurements. Each tracer further
measured 10 brains in order to examine inter-rater
consistency. ICCs were recalculated once 450 scans had
been traced for the ROIs.
2.3. Statistical analysis
The data were analyzed by using SPSS-PC version
11.5 software (Chicago, Ill.). The data were screened for
variability and potential outliers. Analysis of variance
(ANOVA) and paired t-tests were used to compare the
means between volumes of both sides of the brains, and
for the effect of sex and ICV.
3. Results
3.1. Demographic variables
Men and women had a mean age of 62.62 (1.42) years
and 62.60 (1.45) years, respectively. Female participants
had significantly fewer years of education than did males
(males: 14.52 (2.46), females 13.61 (2.69); F (1, 451) =
13.93, P b 0.01), but they did not differ on MMSE scores
(males: mean = 29.25 (1.17), females: mean = 29.39
Fig. 2. Four different views of the 3D rendered right-side hippocampus and amygdala. (A) Sagittal: approximately aligned with long axis of HC; (B)
Coronal: approximately aligned with AC–PC; (C) Coronal: as in (B) but rotated left approximately 45° to more clearly expose detail of medial body
of the hippocampus; (D) Coronal: tilted anterior–posterior. Green = hippocampus; Red = amygdala. (For interpretation of the references to colour in
this figure legend, the reader is referred to the web version of this article.)
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J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
(1.08); F (1,451) = 1.01, P N 0.05). Eleven participants
scored below 27 on the MMSE (males = 7, females = 4), of
whom one male and two females scored below 24 on the
MMSE (commonly regarded as the threshold for clinical
dementia). As this study's sample is intended to represent
a random population, these participants were retained.
Likewise, the 329 participants with medical conditions
(54 with heart trouble, 40 with diabetes, 19 who had had a
stroke, 184 with hypertension, 32 with asthma) and the 22
who were found on MRI to have a neuroanatomical
abnormality (4 adenomas, 3 meningiomas, and 1 of each
of the following: tumour, haemangioma, lipoma, normal
pressure hydrocephalus, infarct-like lesion, cyst, aneurysm, sequelae of temporal stroke) were also retained.
3.2. Volumetrics
ICCs between the two raters for the right HC and left
HC were 0.970 and 0.937, respectively, and 0.943 and
0.974 for the right and left AG, respectively (overall
average for the four structures was 0.956). ICCs between
raters ranged from 0.948 to 0.989 and 0.981 to 0.993 for
the right and left HC, and from 0.975 to 0.989 and 0.995
to 0.996 for the right and left AG, respectively (averaged
0.982 and 0.996).
3.2.1. ICV
The mean ICV of males (1.59 l, S.D. = 0.15) was
larger than those of females (1.40 l, S.D. = 0.13; F (1,
451) = 225.44, P b 0.01).
3.2.2. Hippocampus
Hippocampal volumes were normally distributed.
3.2.2.1. Non-normalized hippocampal volumes. The
average non-normalized right and left hippocampal
volumes were larger in males than in females (F (1,
451) = 50.59, P b 0.01 and F (1, 451) = 48.75, P b 0.01,
respectively). For both sexes, the average right volume
was significantly larger than for the left HC (males; t
(237) = 3.01, P b 0.01; females; t (213) = 2.63, P b 0.01).
3.2.2.2. Normalized hippocampal volumes. Dividing
the raw right and left HC volumes by ICV produced
significantly larger right and left hippocampal volumes
for females than for males (right; F (1, 451) = 6.27,
P b 0.05, left; F (1, 451) = 7.10, P b 0.01). Males and
females both had significantly larger right HC than left
HC volumes (males; t (237) = 3.56, P b 0.01; females; t
(213) = 2.75, P b 0.01).
3.2.3. Amygdala
Amygdalar volumes were normally distributed.
3.2.3.1. Non-normalized amygdalar volumes. The
average right and left non-normalized AG volumes
were significantly larger in males than in females (right
F (1, 451) = 30.62, P b 0.01; left F (1, 451) = 54.66,
P b 0.01). While the average left AG volume was larger
than the average volume of the right AG for both sexes,
this was only significant for males (males t (237) = 3.56,
P b 0.01).
3.2.3.2. Normalized amygdalar volumes. Right and
left AG volumes did not differ between males and
females when they were normalized by ICV. Mean left
AG volumes normalized by ICV were larger than those
Table 1
Raw (mm3) and normalized hippocampal and amygdalar volumetrics for males 60–64 years of age
N
Mean
Standard error of mean
S.D.
Percentiles
1
10
20
30
40
50
60
70
80
90
99
(R) HC
(L) HC
(R) AG
(L) AG
(R) HC divided
by ICV
(L) HC divided
by ICV
(R) AG divided
by ICV
(L) AG divided
by ICV
238
3029.07
29.28
451.59
2044.44
2425.89
2624.76
2786.09
2937.93
3056.86
3149.39
3276.68
3398.81
3578.60
4136.86
238
2975.27
27.12
418.45
1983.96
2398.03
2628.06
2767.22
2913.59
2989.82
3091.42
3196.63
3334.85
3482.16
3967.53
238
1268.96
17.48
269.73
675.77
972.61
1062.86
1122.99
1180.25
1236.78
1297.84
1356.54
1469.69
1631.22
2062.61
238
1318.27
16.81
259.38
770.16
1021.19
1096.90
1168.69
1230.15
1284.74
1337.24
1432.97
1518.78
1652.78
2141.09
238
1908.28
16.83
259.66
1353.61
1567.90
1683.14
1767.95
1832.27
1888.01
1958.51
2041.16
2135.32
2242.71
2594.79
238
1876.54
16.57
255.69
1375.53
1557.87
1660.27
1730.65
1801.07
1852.41
1928.33
1992.09
2091.86
2222.22
2564.46
238
799.56
10.56
162.65
469.39
611.84
669.34
709.08
744.85
780.68
811.74
868.02
930.35
1026.70
1334.02
238
831.52
10.47
161.54
470.24
656.62
707.62
741.90
770.28
812.42
851.43
883.83
934.90
1047.20
1349.65
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
on the right for males (t (237) = 3.62, P b 0.01). Normative HC and AG volumetrics are presented in Tables 1
and 2.
3.3. Behavior, comorbidities, MMSE performance, and
volumetrics
Post hoc analyses revealed no effect of any depression or anxiety variable upon volumetrics. Excluding
the 22 individuals with abnormalities on brain MRI
or with medical conditions made no difference to the
results. In addition, there were no significant differences
between those with any of these comorbidities and those
without.
While there was insufficient statistical power to
compare the volumetrics of those who scored below 27
on the MMSE against those who scored 27 or over (i.e.
to include those within 2 S.D. of the mean), their
exclusion made no difference to the significance levels
of the volumetric analyses. Furthermore, there were no
significant correlations between MMSE performance
and volumetrics, nor between years of education and
any of the raw volumetrics for either sex (all P N 0.05).
3.4. Laterality
From the tests of symmetry in Table 3, the differences between the right and left HC volumes were not
significant between the sexes. There was a significantly
larger difference between the right and left amygdalae in
males for raw volumes only (F (1, 450) = 4.22, P b 0.05).
The proportion of right-to-left HC or AG did not reach
significance between the sexes.
191
Table 3
Hippocampal and amygdalar laterality by sex
Structure
Male (n = 238)
Female (n = 214) P (M/F)
Hippocampus
53.80 (275.54) 38.41 (213.66) 0.511
(right–left): raw┼
Hippocampus
31.74 (174.18) 28.97 (154.05) 0.859
(right–left): /ICV
Hippocampus
40.41 (220.15) 36.63 (195.29) 0.848
(right–left) /TBV
Hippocampus
1.02 (0.9)
1.02 (0.08)
0.695
(right: left)
Amygdala
− 49.31 (213.47) − 11.13 (177.74) 0.041
(right–left): raw┼
Amygdala
− 31.96 (136.25) − 8.33 (128.52) 0.059
(right–left): /ICV
Amygdala
− 40.48 (172.32) − 10.68 (162.86) 0.060
(right–left) /TBV
Amygdala (right: left)
0.97 (0.16)
1.00 (0.16)
0.061
P (M/F) is the significance of the difference between the volumes of
males and females; ┼ cm3. The value rendered in bold is considered
significant at b 0.05.
3.5. Volumetrics and cognition: males versus females
Table 4 displays the average performances for the
subjects separately for males and females. There were
significant differences between males and females in their
performances on the CVLT-Immediate Recall (F (1, 450) =
26.02, P b 0.01), CVLT-Delayed Recall (F (1, 450)=
23.53, P b 0.01), and DS-B (F (1, 450) = 7.35, P b 0.01),
whereby the females performed significantly higher on the
CVLT scores but lower on DS-B. No differences were
found for CVLT-DIR, STW, SDMT, or MMSE. The mean
simple RT (80 trials) performance was lower (faster) for
males (F (1, 437)= 11.60, P b 0.01), and there was a trend
Table 2
Raw (mm3) and normalized hippocampal and amygdalar volumetrics for females 60–64 years of age
N
Mean
Standard error
of mean
S.D.
Percentiles
1
10
20
30
40
50
60
70
80
90
99
(R) HC
(L) HC
(R) AG
(L) AG
(R) HC divided
by ICV
(L) HC divided
by ICV
(R) AG divided
by ICV
(L) AG divided
by ICV
214
2744.92
26.74
214
2706.51
27.16
214
1140.92
14.74
214
1152.06
14.57
214
1972.52
19.54
214
1943.55
19.06
214
818.73
10.18
214
827.06
10.24
397.32
1961.72
2235.79
2352.86
2552.46
2640.65
2730.91
2838.70
2944.95
3076.98
3269.08
3877.84
397.32
1913.90
2222.89
2319.85
2458.59
2562.26
2711.31
2812.91
2956.13
3054.28
3215.72
4054.22
215.70
672.65
870.59
957.24
1026.11
1090.30
1144.46
1191.39
1237.81
1323.42
1395.63
1811.53
213.21
644.79
909.79
979.00
1023.25
1088.24
1125.37
1181.00
1244.51
1328.58
1463.19
1673.72
285.81
1325.16
1637.21
1716.26
1791.81
1875.40
1964.14
2040.10
2132.99
2221.79
2322.02
2762.12
278.88
1326.85
1579.55
1714.50
1785.38
1854.99
1922.93
2009.09
2092.74
2153.69
2310.22
2701.47
148.96
477.52
633.87
697.31
744.09
776.71
811.17
852.35
891.85
946.10
1012.29
1207.61
149.83
501.0242
652.44
710.69
739.63
777.87
812.10
848.58
896.42
943.82
1034.27
1191.06
192
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
for the males to also have performed faster on the choice
RT (40 trials) task (F (1, 435)= 3.40, P = 0.066).
Table 5
Correlations of neuropsychological performances with right and left
hippocampal volumes
3.5.1. Hippocampus and cognition
Variable
Subjects
Male
3.5.1.1. Males. Mean raw right HC volume did not
correlate significantly with any of the CVLT scores or
any other cognitive variable except STW (r = 0.139,
P b 0.05) and SDMT (r = 0.138, P b 0.05; Table 5). Left
raw HC correlated significantly with SDMT (r = 0.130,
P b 0.05). However, when controlling for years of
education, or when division was by ICV or TBV, there
were no significant differences.
Left and right normalized HC volumes did not
correlate with the cognitive variables, with or without
education as a covariate. There were no significant correlations between asymmetry volumetrics and cognitive
performances for either sex.
3.5.1.2. Females. For females, the mean raw left HC
volumes correlated significantly with the ratio of
Delayed recall to Immediate recall (DIR) to beyond
the 0.05 level (r = 0.146, P = 0.032). This association
was still significant after normalizing by ICV and TBV
(ICV normalized: r = 0.145, P = 0.034; TBV normalized
r = 0.161, P = 0.018), and controlling for years of education (raw: r = 0.138, P = 0.044; /ICV: r = 0.142, P =
0.039; /TBV: r = 0.158, P = 0.021). Right HC volumes
did not correlate significantly with any of the cognitive
variables, except there was a trend for the SDMT to
correlate with raw left HC volume (r = 0.131, P = 0.056)
but not after normalization.
The significant correlations between left HC volume
and DIR are beyond chance and hence not Type I errors.
That is, DIR was one of nine (11.11%) variables tested
Table 4
Average performances on tests of cognition
Variable
CVLT-immediate recall
CVLT-delayed recall
Delayed/immediate recall
MMSE
Spot-the-Word
SDMT
Digit span — backwards
RT — simple (80 trials)
RT — choice (40 trials)
Males
Females
P
Mean
S.D.
Mean
S.D.
6.98
6.11
0.88
29.22
52.68
50.94
5.22
0.24
0.31
1.93
2.11
.21
1.26
6.15
8.12
2.18
0.04
0.04
7.96
7.13
.89
29.39
51.97
51.10
4.68
0.26
0.32
2.15
2.35
.17
1.08
5.68
8.90
2.04
0.06
0.05
⁎⁎
⁎⁎
⁎⁎
⁎⁎
P is the significance of the difference between the performances of
males and females; ⁎⁎ = P b 0.01. For RT (simple 80 trials), male
n = 228 and female n = 212; for RT (choice 40 trials) male n = 227 and
female n = 211.
r
Right hippocampal volume
Spot-the-Word-# correct
(raw volume)
Normalized ICV
Normalized TBV
SDMT (raw volume)
Normalized ICV
Normalized TBV
Female
P
r
P
0.139 0.032 0.112 0.103
0.044
0.046
0.138
0.053
0.031
0.500
0.483
0.033
0.413
0.630
0.078
0.097
0.080
0.046
0.052
0.259
0.157
0.243
0.500
0.450
Left hippocampal volume
Delayed recall/1st trial (raw volume) −0.011 0.871 0.146 0.032
Normalized ICV
0.053 0.414 0.145 0.034
Normalized TBV
0.055 0.396 0.161 0.018
SDMT (raw volume)
0.130 0.045 0.131 0.056
Normalized ICV
0.039 0.550 0.097 0.159
Normalized TBV
0.017 0.789 0.104 0.130
r = correlation, P = significance. Values rendered in bold represent statistics that were considered significant at b0.05.
for correlations with volumetrics, which is greater than
chance (i.e. 5%).
3.5.2. Amygdala and cognition
There were no significant correlations between mean
AG volumes (raw, ICV or TBV normalized) and any of
the cognitive variables, for either sex. Controlling for
years of education made no difference to the results.
4. Discussion
This study reports data on the volumes of the hippocampus and amygdala and on cognitive performances in
a large representative community-based sample of 60–
64 year old men and women. Quantitative volumetric
measures introduce a level of precision in the estimation
of volume that is simply not available by visually inspecting a set of MR images (Jack, 1994). Hence, these
norms have practical use for clinicians. For example,
subtle yet significant hippocampal atrophy over time
may be more detectable by volumetric analysis of the
MRI scans but not from visual inspection of them. Our
hippocampal volumes are in line with those reported
from other large studies of similarly aged individuals
(den Heijer et al., 2002; Hackert et al., 2002; MacLullich
et al., 2002; Raz et al., 1997), although slightly smaller,
which may be due to the use of thinner slices to trace
on than in these other studies and different planes of
acquisition (e.g. perpendicular to the AC–PC axis,
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
perpendicular to the long axis of the hippocampus, or no
correction at all). Furthermore, we were careful to
exclude hippocampal sulcal cavities and other fluidfilled spaces from hippocampal volume calculations.
Our amygdalar volumes were also within reported
ranges (Brierly et al., 2002; Convit et al., 1999; Gur
et al., 2002). Studies reporting larger volumes generally
have unfavorable attributes such as poor inter- and/or
intra-rater reliabilities, small samples, or have not
described their volumetric protocols (Filipek et al.,
1994; Goldstein et al., 2001; Lange et al., 1997); some
used younger subjects. Men had larger raw HC volumes,
while the average male HC was smaller than the average
female HC when considered as a proportion to ICV. The
right hippocampi were larger in both sexes, while the
opposite was the case for the amygdalae. These results
are consistent with the literature (e.g. Giedd et al., 1996;
Gur et al., 2002; Bilir et al., 1998; Duchesne et al.,
2002). Furthermore, raw HC and AG volumes are most
commonly reported to be larger in males than in females
(Gur et al., 2002; Lange et al., 1997; Pruessner et al.,
2000; Raz et al., 1997). While the average male ICV
may be larger than that of females (Jenkins et al., 2000;
Reynolds et al., 1999), the difference between the sexes
in their raw HC and AG volumes as a fraction of their
ICV may not be proportional; this may lead to no significant difference in normalized volumes between sexes
(Gur et al., 2002; Pruessner et al., 2000). Consistent
with the literature (e.g. Pedraza et al., 2004), an examination of the asymmetry showed that the ratio of rightto-left HC or AG did not reach significance between
the sexes.
4.1. Volumetrics and cognition
A supposition presented by van Petten et al. (2004)
was “that, in cognitively superior elderly samples (such
as that employed by that particular study), variation in
memory ability across individuals may be largely
determined by pre-existing differences rather than
differential degrees of age-related decline”, p. 17). The
results of the meta-analysis by van Petten (2004) yielded
no support for the ‘bigger is better’ hypothesis, but
rather found some support for both the developmental
and ageing hypotheses, in that the HC volume-memory
correlation tended to shift from negative to neutral to
positive as the age of the sample increased. While the
current study does not have a large enough age range to
comprehensively test this, the finding in the current
study lends support to a neutral to positive HC volumememory relationship when considering the differences
in this relationship between the sexes in this sample.
193
There was a significant correlation between HC
volume and the ratio between verbal delayed recall and
immediate recall (DIR) for females, and not with RT,
and AG volume did not relate to any cognitive variable
assessed. While performance on the SDMT significantly
correlated with right and left raw HC volume for males,
and STW performances significantly correlated with
right raw HC volumes (for males), these relationships
became non-significant when the influence of ICV (or
TBV) was considered through simple division, hence
showing that ICV is a confound upon the relationships
of HC and AG volumes with cognition. However, DIR
remained significantly correlated with left HC volume
(for females) after applying various normalization
methods, hence not supporting the relationship in this
case.
Similarly, Lye et al. (2004) recently reported that the
left HC volume was an important determinant of
retention on the CVLT in community-dwelling individuals aged 81 to 92 years. Although they did not report
on the relationship between volumetrics and immediate
recall, their results were consistent with our finding of
the relationship between retention (DIR) and left HC
volume.
4.2. The effect of normalization
A re-analysis of the data controlling for years of
education instead of ICV or TBV also rendered all of the
significant correlations between HC volume and cognition amongst the males non-significant, although it did
not alter the significant relationship between left HC
volume and DIR. This significant correlation between
raw left HC volume and DIR in females was virtually
unaltered by ICV normalization and higher when normalized by TBV. That reflects the fact that DIR did not
correlate significantly with ICV (r = 0.030, P = 0.665), or
with TBV (r = 0.003, P = 0.965). If significant correlations are reduced to non-significant when normalized,
then the results logically relate to the normalization
factor. That is, the two original factors are only related
through their strong associations with a third variable
(Atchley et al., 1976). In the current situation, ICV is a
primary normalization factor. One complicating factor is
that ICV was associated with education in our sample
(see Maller et al., submitted for publication).
4.3. Memory and the hippocampus
On average, females in our sample recalled 14%
(7.96/6.98) more information than men on the first trial,
and 17% (7.13/6.11) more on the delayed trial. Women
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J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
have previously been reported to outperform men on a
range of memory measures (e.g. Aartsen et al., 2004;
Larrabee and Crook, 1993), including the CVLT (e.g.
Kramer et al., 1988; Lye et al., 2004). However, we did
not find such a difference in the mean retention in the
current sample as was reported in the sample of Lye
et al. (2004). If retention is dependent upon the level of
attention previously directed to encoding the information (which is indicated by the immediate recall
performance), then it may be that a threshold of attention has to be reached before the left HC mediates the
retention. That is, the relationship between left HC
volume and retention in our sample may be related to
attention and therefore possibly effort.
It is important at this point to acknowledge that a
non-significant correlation with HC volume does not
necessarily imply that the HC is not involved as volume
differs from function. Memory variability may result
from a number of factors including stimulus differences,
varying levels of attention and effort put forth across
stimuli, and other uncontrolled factors (Reber et al.,
2002a,b). The proper functioning of the HC depends
on its interactions with subcortical regions concerned
with emotion, motivation, arousal and attention (Shastri,
2002). For example, Thoenissen et al. (2002) reported
activity in the prefrontal and temporal regions to be
signs of awareness of regulation of actions. In other
words, under particular conditions (when effort is high),
the left HC mediates retention in our sample of females.
There is evidence in the literature to support this assumption. For example, Montaldi et al. (2002) found
that MTL activation increased in participants as a
proportion of response words successfully recalled and
that bilateral frontal lobe activation increased in
proportion to retrieval effort that was greater when
learning had been good. Hence, more effort leads to
increased MTL activation during memory recall.
Similarly, Reber et al. (2002a,b) showed that left MTL
activation was crucial for the encoding that actually
led to successful memory on that subsequent test, while
prefrontal activation was strongly associated with
intentional verbal encoding.
It may be that those in our sample with poor memories
had average size hippocampi relative to others in the
sample when we scanned them, but they may have had
much larger relative maximal volumes at some previous
point in time than others in the sample, and are now in the
process of (relatively) accelerated atrophy. Alternatively,
it may be that those in our sample with better memories
had average HC volumes when we scanned them, but
they were also close to their maximal HC volumes at
some prior point in time (i.e. less HC atrophy). If this
scenario is valid, the relationship between HC and
memory is different for the normal and pathological
ageing brains, which supports previous findings of
medial temporal lobe volumetric correlations with
memory performance in those with AD but not in
normal controls (Basso et al., 2006). Hence, it may be
that specific changes in HC volume may only become an
important influence upon verbal memory in the presence
of pathology (Squire, 2004). It is also possible that some
of our participants were in the pre-clinical stages of
dementia by virtue of their age.
The finding in the current study of no significant
relationships between AG volumes and cognitive
performances therefore supports those of past studies
(den Heijer et al., 2002; Mackay et al., 1998; YurgelunTodd et al., 2003). Furthermore, no relationships were
found between HC volumes and RT performances.
4.4. Limitations
While participants in this study did not undergo
medical or neurological assessments, self-reported medical and neurological conditions had no effect upon
reported volumes. Although this study reports on results
from healthy subjects, we did not exclude those with silent
brain lesions (Xu et al., 2000) such as subcortical silent
brain infarction, WMH on T2-weighted imaging, and
periventricular hyperintensity (Kobayashi et al., 1997).
However, this is not necessarily a limitation as we sought
a representative sample rather than a ‘super-normal’
sample.
We only administered Trial 1 and Immediate Recall
of the CVLT and not the full version. The full version
would have allowed us to more comprehensively
evaluate verbal memory performance in this sample
from perspectives such as learning styles of semantic
versus rote memory, for example.
4.5. Summary
The present study has many positive attributes, such
as employing a large sample randomly selected from
the community, representing both sexes equally, and
capturing a tight cohort in order to enhance the representativeness of these subvolumes for this age group.
Furthermore, very high reliability of the regional volumetric measures was achieved through regular assessment and the application of high-resolution MRI
utilizing acquisition protocols regarded to be imperative
for valid and reproducible results. Analyses showed that
medical and neurological conditions had no effect upon
reported volumes.
J.J. Maller et al. / Psychiatry Research: Neuroimaging 156 (2007) 185–197
The pattern in the interpretation of the current study's
results supports the assumption that there are at least two
types of ageing: ‘normal’ and ‘pathological’, and that
while larger hippocampal volume may not equate to any
cognitive advantage, this relationship may differ by sex.
Thus, it is imperative that the structures, functions,
connectivity and vulnerabilities of the MTL be elucidated.
If structural volumetrics of MTL regions are to be
understood on a larger scale in community samples, then
the normative database presented here, which is the first
wave of a longitudinal study, will be a valuable resource.
Acknowledgements
The authors are grateful to the staff of the Centre for
Mental Health Research ANU, in particular Patricia
Jacomb, Karen Maxwell, June Cullen, Tony Jorm, and
Rajeev Kumar, the National Capital Diagnostic Imaging
group, particularly Jeremy Price, and the Neuroimaging
Group, NPI, Prince of Wales Hospital, in particular
Michael Valenzuela. Grant support was provided by
NHMRC.
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