NeuroImage 105 (2015) 76–83

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NeuroImage
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Memory function and hippocampal volumes in preterm born

very-low-birth-weight (VLBW) young adults
Synne Aanes a,⁎, Knut Jørgen Bjuland a, Jon Skranes a,b, Gro C.C. Løhaugen a,b
a
Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway
b
Department of Pediatrics and Rehabilitation, Sørlandet Hospital, Arendal, Norway

a r t i c l e i n f o a b s t r a c t

Article history: The hippocampi are regarded as core structures for learning and memory functions, which is important for daily
Accepted 8 October 2014 functioning and educational achievements. Previous studies have linked reduction in hippocampal volume to
Available online 16 October 2014 working memory problems in very low birth weight (VLBW; ≤1500 g) children and reduced general cognitive
ability in VLBW adolescents. However, the relationship between memory function and hippocampal volume
Keywords:
has not been described in VLBW subjects reaching adulthood. The aim of the study was to investigate memory
Magnetic resonance imaging
Brain development
function and hippocampal volume in VLBW young adults, both in relation to perinatal risk factors and compared
Hippocampus to term born controls, and to look for structure–function relationships. Using Wechsler Memory Scale-III and
Memory function MRI, we included 42 non-disabled VLBW and 61 control individuals at age 19–20 years, and related our findings
Very low birth weight to perinatal risk factors in the VLBW-group. The VLBW young adults achieved lower scores on several subtests of
Preterm birth the Wechsler Memory Scale-III, resulting in lower results in the immediate memory indices (visual and auditory),
the working memory index, and in the visual delayed and general memory delayed indices, but not in the audi-
tory delayed and auditory recognition delayed indices. The VLBW group had smaller absolute and relative hippo-
campal volumes than the controls. In the VLBW group inferior memory function, especially for the working
memory index, was related to smaller hippocampal volume, and both correlated with lower birth weight and
more days in the neonatal intensive care unit (NICU). Our results may indicate a structural–functional relation-
ship in the VLBW group due to aberrant hippocampal development and functioning after preterm birth.
© 2014 Elsevier Inc. All rights reserved.

Introduction
Children born preterm with very-low-birth-weight (VLBW) are at in-
creased risk of perinatal brain injury and aberrant brain development that
could have negative long-term cognitive consequences (Nosarti et al.,
2012). In addition to general cognitive deficits (Løhaugen et al., 2010),
VLBW individuals have an increased risk of neuropsychological deficits
in attention/executive (Skranes et al., 2009; Bayless and Stevenson,
2007; Kulseng et al., 2006) and memory functions (Bohm et al., 2004;
Woodward et al., 2005; Isaacs et al., 2000; Rose et al., 2001, 2005; de
Haan et al., 2000) compared to term-born controls.
Memory is a complex process involving encoding, storage and
retrieval of information, often divided into short-term or working mem-
ory and long-term memory. Long-term memory is further divided into
implicit (priming and procedural) and explicit (semantic and episodic
memory) (Schacter and Tulving, 1994). Episodic memory is “the con-
scious recollection of specific personal events (episodes), as well as the
⁎ Corresponding author at: Department of Laboratory Medicine, Children's and
Women's Health, Norwegian University of Science and Technology, P.O. Box 8905, 7491
Trondheim, Norway.
E-mail address: synnea@stud.ntnu.no (S. Aanes).
context (time and place) in which they occurred” (Strauss et al., 2006).
Clinical measures of episodic memory involve free recall, cued recall
and recognition of words, pictures, and faces (Strauss et al., 2006).
Memory deficits have been reported in preterm infants as young as
12 months old (Woodward et al., 2005; Rose et al., 2005; de Haan et al.,
2000). de Haan et al. (2000) and Rose et al. (2005) demonstrated im-
paired recall in a deferred imitation task at 19 months and 12 months
of age, respectively. However, Rose et al. described an improvement in
memory function from 19 to 36 months of age in their preterm born
study population, but the infants did not catch up with the full-term
controls. In older preterm born children and adolescents, some studies
have reported impairments in memory function (Isaacs et al., 2000;
Taylor et al., 2000; Narberhaus et al., 2007) while others have not
found any specific memory deficits (Rushe et al., 2001) and studies
are lacking in adults born preterm.
Lesion studies have shown that the hippocampi are important brain
structures for normal development of episodic memory (Gadian et al.,
2000; Scoville and Milner, 1957; Bohbot et al., 2000). Individuals with
developmental amnesia, due to a selective, bilateral injury to the hippo-
campi early in childhood, display impairments in memory and general
cognitive abilities, which plausibly are related to hypoxic–ischemic
injury (Gadian et al., 2000; Vargha-Khadem et al., 1997; Isaacs et al.,

http://dx.doi.org/10.1016/j.neuroimage.2014.10.023
1053-8119/© 2014 Elsevier Inc. All rights reserved.
 S. Aanes et al. / NeuroImage 105 (2015) 76–83
2003). The hippocampi are vulnerable to ischemic episodes, and this
form of injury is also seen in preterm born neonates (Volpe, 2012). Hip-
pocampal volume is shown to be smaller in VLBW infants (Peterson
et al., 2000), children (Isaacs et al., 2004; Abernethy et al., 2004), adoles-
cents (Nosarti et al., 2002) and adults (Allin et al., 2004) compared
to full-term controls, and some studies have also found a relationship
between hippocampal volume and memory function in preterm
children (Isaacs et al., 2000; Vargha-Khadem et al., 1997). However,
studies conducted so far have examined memory function and its rela-
tion to hippocampal volume in preterm children and adolescents while
knowledge is lacking about memory functions and their relationship to
hippocampal morphology in adults born preterm.
The first aim of our study was to compare memory functions in
a group of VLBW young adults with term-born controls, applying the
full Wechsler Memory Scale, 3rd edition (WMS-III). Secondly, we
wanted to compare volumes of right and left hippocampi in the two
study groups by cerebral MRI using an automated segmentation method.
The third aim was to explore any associations between hippocampal
volumes and the results in the memory tests, and finally to explore
whether perinatal risk factors influenced the test results and MRI find-
ings in the VLBW group. We hypothesized that the VLBW group would
have reduced memory functions and smaller hippocampi compared to
controls, and that perinatal risk factors would be associated with the re-
sults. We also hypothesized that there would be an association between
performance on memory tests and hippocampal volumes in both groups,
but most pronounced in the VLBW group based on expected increased
hippocampal pathology and lower test results in this group.
Material and methods
This study is part of a hospital based, long term follow-up study of a
3-year cohort of VLBW children and term born controls born in 1986–
88, investigating the clinical consequences of VLBW assessed by neuro-
psychological testing and brain development evaluated with structural
cerebral MRI. The data collection for the study was carried out between
October 2006 and December 2008 at age 19–20 years of the participants.
Participants
The original cohort has been described in detail previously
(Løhaugen et al., 2010).
VLBW group
Inclusion criteria were those born preterm with very low birth
weight (VLBW: birth weight ≤1500 g), who were admitted to the neo-
natal intensive care unit (NICU) at the St. Olav University Hospital in
Trondheim, Norway in 1986–1988. Of 121 neonates, 88 survived the
newborn period. One child with Down's syndrome, nine children who
were not reachable at follow-up, and two with severe cerebral palsy
who were unable to perform the neuropsychological tests were excluded
from long term follow-up, resulting in 76 VLBW children eligible for par-
ticipation, of whom 55 (72%) consented to the examinations at 19 years
of age. Fifty VLBW subjects consented to MRI examinations, but one did
not consent to the cognitive assessment. Three MRI examinations had
to be excluded due to overall poor image quality and two with mild CP
were excluded from further analysis, leaving 44 non-CP VLBW partici-
pants that had a combined MRI and cognitive assessment.
Controls
The control group was recruited from a 10% random sample of term
born (gestational age ≥ 37 completed weeks) children with birth
weight N 10th percentile to mothers who were enrolled for follow-up
before week 20 of pregnancy in the Trondheim region as part of a
multi-center study in 1986–88. In total, 122 children were included as
controls. At the follow-up at age 19–20, ten individuals could not be
traced and two were excluded due to congenital malformations, leaving
77
110 eligible for participation. Twenty-nine did not consent to partici-
pate due to lack of motivation or time, resulting in 81 (74%) controls
that participated in the cognitive testing. Sixty-six consented to the MRI
examination, and of these sixty-one also met for neuropsychological
testing.
Non-participants
There were no significant differences between participants and non-
participants regarding birth weight, gestational age at birth, maternal
age and education at time of childbirth (data not shown).
Cognitive and neuropsychological assessments
The Wechsler Memory Scale, version 3 (WMS-III) (Tulsky, 2003)
was used to assess auditory (verbal) and visual episodic memory, both
immediate, delayed and recognition, in addition to working memory.
The six primary subtests were used in this analysis: Logical Memory I
& II, Verbal Paired Associates I & II, Faces I & II, Family Pictures I & II,
Letter-Number Sequencing and Spatial Span (see supplemental material
for description of subtests). The combined scores of the subtests pro-
duced eight index scores: Auditory Immediate (subtests Logical Memory
I and Verbal Paired Associates I), Visual Immediate (subtests Faces I and
Family Pictures I), Immediate Memory (sum of Auditory Immediate and
Visual Immediate indices), Auditory Delayed (subtests Logical Memory
II and Verbal Paired Associates II), Visual Delayed (subtests Faces II and
Family Pictures II), Auditory Recognition Delayed (recognition scores
from subtests Logical Memory II and Verbal Paired Associates II), General
Memory Delayed (sum of Auditory Delayed, Visual Delayed and Auditory
Recognition Delayed indices) and Working Memory (subtests Letter-
Number Sequencing and Spatial Span) (Table S1). The auditory tasks re-
quire the participant to learn and remember language based material,
and include remembering two different stories (Logic Memory I & II)
and verbal pairs (Verbal Paired Associates I & II). Visual tasks include
remembering faces (Faces I & II) and pictures of everyday situations
(Family Pictures I & II) both immediately and delayed. In addition, a
delayed recognition task from the stories in the Logic Memory and the
Verbal Paired Associates (Auditory Recognition Delayed index) was in-
cluded. The Wechsler Adult Intelligence Scale (WAIS-III) (Tulsky, 2003)
was used to assess general cognitive ability and the results have been
published previously (Løhaugen et al., 2010). US standardized norms
were used for the WMS-III since Norwegian norms do not exist.
Perinatal variables
Perinatal variables included known risk factors for possible poor
neurological outcome; birth weight, gestational age, Apgar score at 1
and 5 min, days on mechanical ventilator, and total days in the NICU.
Socioeconomic status
Socioeconomic status (SES) was calculated according to
Hollingshead's Two Factor index of Social Position, based on the educa-
tion and occupation of one parent, or the mean index from both parents
(Hollingshead, 1957).
MR imaging
Image acquisition
Cerebral MRI was performed on a 1.5 T Siemens Magnetom Sym-
phony with Quantum gradients (30 mT/m) and a quadrature head
coil. A structural T1-weighted magnetization prepared rapid acquisition
gradient echo (MPRAGE) sequence was acquired with the following
specifications: TR = 7.1 ms, TE = 3.45 ms, TI = 1000 ms, flip angle
7o, FOV 256 × 256, slab thickness 170 mm, slice thickness 1.33 mm, ac-
quisition matrix 256 × 192 × 128, reconstructed to 256 × 256 × 128,
78 S. Aanes et al. / NeuroImage 105 (2015) 76–83
giving a reconstructed voxel resolution of 1 × 1× 1.33 mm, and acquisi-
tion duration of 8.5 min.
Image analysis
Two MPRAGE sequences acquired during each MRI scan were
registered to correct for head motion and averaged into a single
image. Volumetric segmentation and cortical surface reconstruction
were performed with the freely available FreeSurfer image analysis
suite version 5.1 (https://surfer.nmr.mgh.harvard.edu/) (Dale et al.,
1999; Fischl et al., 1999a, 1999b). An automatic algorithm that included
motion correction of multiple T1 image (Reuter et al., 2010), and
removal of non-brain tissue (Segonne et al., 2004) was applied. The
automated method would then perform Talairach transformation and
segmentation of subcortical white matter and deep gray matter
volumes (including hippocampus) (Fischl et al., 2002, 2004). In order
to compare the volumes of cortical and subcortical structures, volumes
were aligned and registered to a common space using the surface based
method in FreeSurfer. These procedures register each subject to a
spherical atlas based on individual cortical folding patterns, and match
geometry across subjects with minimized metric distortions (Fischl
et al., 1999b). All processed images were controlled with the following
script: http://surfer.nmr.mgh.harvard.edu/fswiki/QATools and visually
inspected for errors in the segmentation process by two trained techni-
cians and a medical doctor. No manual segmentation was performed
and scans with obvious errors due to motion or dental braces were
discarded. Images with low signal-to-noise-ratio (SNR) and with signif-
icant hemispheric differences of the size of the two hippocampi were
checked very carefully for segmentation errors. We rejected the specific
volumes with segmentation errors from the data analysis resulting in
the exclusion of two right hippocampal volumes in the VLBW group
and volumes of one left and one right hippocampus in the control
group.
Statistical analysis
IBM SPSS Statistics version 21 was used to perform the analysis. Dif-
ferences in group means for variables that had a normal distribution
were compared with the Student t test. Outcome measures that were
not normally distributed were analyzed by the Mann–Whitney U test.
To perform group comparisons of mean values of neuropsychological
scaled scores we used a univariate general linear model with group as
fixed factor, adjusted for sex and SES. To compare the hippocampal
volumes in the two groups a univariate general linear model, with
group as fixed factor, and sex and age at MRI was used. Both absolute
hippocampal volumes and volumes adjusted for total intracranial
volume were calculated. We explored the associations between perinatal
variables and measures of memory outcome and absolute hippocampal
volumes, respectively by using partial correlations. Clinical outcomes
were adjusted for sex and SES, while sex and age were included as covar-
iates in the morphometric analysis. We also controlled for degree of im-
maturity, i.e. gestational age at birth when looking at the relationship
between outcome variables and days in NICU and days on mechanical
ventilator, respectively. Partial correlations were also used to evaluate
the relationship between memory function and hippocampal corrected
volumes within the two groups. Two tailed p-values ≤ .05 were consid-
ered to be statistically significant.
Ethics
The Regional Committee for Medical Research Ethics (Health Region
IV) approved the study protocol (Project number: 4.2005.2605). Written
informed consent was obtained from each participant when they came
for cognitive assessment.
Results
Clinical characteristics
Mean birth weight and gestational age for the VLBW adults were
1234 (SD 225) grams and 29.5 (SD 2.4) weeks, while the controls had
mean birth weight of 3697 (SD 497) grams and mean gestational age
of 39.7 (SD 1.3) weeks (Table 1). Sixteen of the 44 VLBW young adults
were born small for gestational age (SGA). The VLBW group had lower
head circumference at birth and lower Apgar scores than controls
(p b .001). At the time of assessment the VLBW adults had received
more special education, and fewer attended school or were employed.
The VLBW group had lower mean full IQ than controls (89 versus 100,
p b .001). No group differences were found regarding sex, maternal
age at childbirth, socio-economic status (SES), participant's dominant
hand, or age at MRI (Table 1).
Memory test results
The VLBW adults had significantly lower scores than controls on
most WMS-III indices (Table 2). There was no difference in memory
function between the VLBW young adults born small for gestational
age (SGA) compared to those born appropriate for gestational age
(AGA) (data not shown). Within immediate memory the VLBW group
scored lower in both the Visual Immediate and the Auditory Immediate
indices due to lower scores on the subtests Faces I, Family Pictures I,
Logic Memory I and Verbal Paired Associates I, however only the latter
subtest reached statistical significance. Of the delayed memory indices
the VLBW group obtained inferior scores in the Visual Delayed index,
scoring lower in both the Faces II and Family Pictures II subtests. There
was a trend toward lower Auditory Delayed index, though this did not
reach significance, while the Auditory Recognition Delayed index was
similar in the two groups (Table 2). The VLBW group also obtained
lower scores in the Working Memory index, reaching significance
in the visual subtest (Spatial Span), but not in auditory/verbal subtest
(Letter Number Sequencing). The memory profile depicting the subtest
scores for the two groups is presented in Fig. 1, showing that the VLBW
young adults had lower numeric scores than controls in all subtests,
reaching significance in four subtests.
Associations between perinatal variables and WMS-III indices
When exploring the associations between perinatal variables and
WMS-III indices in the VLBW group, there were significant negative
correlations between number of days on ventilator and the Auditory
Delayed and Working Memory indices, while days in NICU were nega-
tively correlated with all memory indices (Table 3). Positive associations
were found between birth weight and all WMS-III indices, except for the
Visual Delayed and the Working Memory indices, while gestational age
did not correlate to any of the WMS-III indices in the VLBW group.
Hippocampal volumes
The VLBW subjects had significantly lower total intracranial volume
and absolute hippocampal volumes than controls when adjusting for
sex and age at scan. The group differences in hippocampal volumes
remained significant when corrected for total intracranial volume
(Table 4). Scatterplots of all participant's left and right hippocampal
corrected volumes are included in Fig. 2. The AGA VLBW subgroup
had smaller left hippocampi compared to the SGA subgroup (data not
shown).
Associations between perinatal variables and hippocampal volumes
No significant correlation was found between the number of days
on ventilator and hippocampal volumes. The number of days in NICU
was negatively correlated with total [r = − .374, p = .021], left [r =
− .377, p = .017] and right [r = − .341, p = .036] hippocampal
 S. Aanes et al. / NeuroImage 105 (2015) 76–83 79

Table 1
Clinical characteristics of the two study groups.

VLBW Controls p-Value

n Mean (SD/%) Range n Mean (SD/%) Range

Birth weight (g) 44 1234 (225) 550–1500 61 3697 (497) 2670–5140 b0.001
Gestational age (weeks) 44 29.5 (2.4) 24–35 61 39.7 (1.3) 37–43 b0.001
Head circumference at birth (cm) 37 27.4 (2.0) 23.5–30.7 57 35.4 (1.2) 32.4–37.5 b0.001
Sex male (number, %) 44 18 (40.9) – 61 26 (42.6) – .861
Maternal age at child birth (years) 44 29.1 (4.6) 21.6–40.4 61 30.3 (4.1) 22.8–39.3 0.160
Socioeconomic status (SES) 44 3.4 (1.3) 1–5 61 3.7 (0.9) 1–5 0.131
Dominant right hand (number, %) 44 39 (88.6) – 61 58 (95.1) – .219

Clinical data
APGAR 1 min 43 7 1–9 56 9 7–9 b0.001
APGAR 5 min 43 9 1–10 57 10 1–10 b0.001
Days in NICU 43 66.6 (31.9) 23–193 – – – –
Days on mechanical ventilator 42 3.12 (7.5) 0–44 – – – –
Small for gestational age (number) 44 16 – 61 0 – –
Age at MRI (years) 44 20.2 (0.8) 18.9–22.1 61 20.3 (0.5) 19.0–21.4 0.266
Received special education in school (number, %) 44 9 (20.5) – 61 2 (3.3) – 0.005
In school or employed at time of study (number, %) 44 37 (86.0) – 61 57 (93.4) – 0.050
WAIS-III Full IQ 44 89 (13.0) 50–110 61 100 (11.0) 80–114 b0.001

Subject characteristics; Student's t-test was used for parametric data, Mann–Whitney U-test for non-parametric data, Pearson Chi-Square for categorical data. Abbreviations: VLBW = very low
birth weight group. Controls = control group, WAIS: Wechsler Adult Intelligence Scale 3rd edition.

volume — the longer stay in NICU, the smaller hippocampal volumes.
Positive correlations were found between birth weight and all hippo-
campal volumes [total: r = .380, p = .016, left: r = .362, p = .019,
right: r = .326, p = .040], while gestational age was not significantly
correlated to any of the volumes.
and perinatal morbidity in the VLBW group. Our results indicate that
VLBW young adults are at a disadvantage compared to controls in learn-
ing and memory tasks apart from delayed memory and recognition of
verbal material.

Memory profile
Associations between WMS-III indices and hippocampal volumes
Our study presents a comprehensive assessment of memory
Positive correlations were found between total, right and left hippo-
functions in VLBW young adults, and the reduced scores indicate that
campal absolute volumes and all WMS-III indices in the VLBW group
being born VLBW influences memory functions into young adulthood.
(data not shown). When correcting for total intracranial volume corre-
The inferior results were not confined to specific memory indices, but
lations remained significant for five out of eight memory indices, six out
affected both immediate, delayed and working memory. The memory
of eight indices and only the Working Memory index for total, left and
profile reflected mildly to moderately reduced scores on all subtests,
right hippocampal volumes, respectively (Table 5).
and the VLBW young adults achieved significantly lower scores than
controls in about half of the subtests.
Discussion Immediate memory reflects what one is able to reproduce immedi-
ately after information has been presented to you. The VLBW group
In this study the VLBW young adults had lower performance in retained less information than the controls both verbally and visually,
seven out of eight Wechsler Memory Scale (WMS-III) indices, indicating indicating a learning disadvantage. The consequences may be that the
inferior memory functions compared to term born controls. The VLBW VLBW group needs more repetitions during learning to be able to repro-
young adults also had smaller absolute and corrected hippocampal duce the information. This may result in learning problems, and con-
volumes compared to controls. Inferior memory function was related tribute to inferior educational achievement, as already described by
to smaller volume of hippocampi, and both correlated with birth weight others (Løhaugen et al., 2010; Hack, 2006).
The Visual Delayed and the General Memory Delayed indices were
lower in the VLBW group than for controls, while the Auditory Delayed
Table 2
Memory results (WMS-III indices) in the two study groups. index revealed a tendency toward lower scores in the VLBW young
adults (p = .081). A few other studies have reported impaired visual
WMS-III indices VLBW group Controls (n = 61) p-Value
delayed memory in VLBW children (Thompson et al., 2013; Rickards
(n = 44)
et al., 1993), but none of these studies have used the Wechsler Memory
Mean 95% CI Mean 95% CI
Scale-III to assess this part of delayed memory and there is no agree-
(SE) (SE)
ment as to what extent the memory for verbal material is affected in
Visual Immediate 86 (1.8) 82–89 92 (1.5) 89–95 0.010 VLBW groups. While some studies have shown reduced verbal memory
Auditory Immediate 92 (2.3) 88–97 99 (2.0) 95–103 0.027
Immediate Memory 87 (2.0) 83–91 95 (1.7) 91–98 0.006
in preterm born children (Taylor et al., 2000) and adolescents (Gimenez
Visual Delayeda 82 (1.7) 79–86 88 (1.4) 86–91 0.007 et al., 2004), others have not reported such difficulties (Narberhaus
Auditory Delayed 95 (1.9) 91–99 99 (1.6) 96–102 0.081 et al., 2007; Rushe et al., 2001) and studies are lacking in adult popula-
Auditory Recognition Delayed 98 (2.1) 94–102 100 (1.8) 96–104 0.527 tions. The lower score in the Visual Delayed index than in the Auditory
General Memory (Delayed)a 87 (1.8) 85–92 94 (1.5) 91–97 0.026
Delayed index among the VLBW young adults in our study may be related
Working Memory 90 (1.8) 86–94 96 (1.5) 93–99 0.009
to increased vulnerability of the white matter in the visual system to hyp-
Univariate general linear model with group as fixed factor and socioeconomic status and oxic–ischemic injuries in preterm born subjects (Thompson et al., 2013).
sex as covariates.
Abbreviations: VLBW: very low birth weight; Controls: term born controls; SE: standard
We have reported that reduced visual perceptual and visual–motor inte-
error; WMS-III: Wechsler Memory Scale 3rd edition. gration in the same VLBW study population at age 15 correlated to re-
a
n = 43 in the VLBW group. duced white matter integrity in long association tracts evaluated with
80 S. Aanes et al. / NeuroImage 105 (2015) 76–83

Fig. 1. Memory profile with scaled scores of the six different WMS-III subtests (Faces I & II, Family Pictures I & II, Logic Memory I & II, Verbal Paired Associates I & II, Spatial Span and Letter-
Number Sequencing) in the two study groups. General linear model with group as fixed factor and sex and socioeconomic status as covariates.

diffusion tensor imaging (Skranes et al., 2007). We speculate that reduced
white matter connectivity in tracts transferring visual information, also
may influence visual memory function.
Our finding of memory deficits in the VLBW group contradicts Rushe
et al. (2001), who reported no significant difference in memory perfor-
mance in preterm born adolescents compared to controls. Apart from
age (14–15 years of age), the study population was similar to our cohort
of VLBW young adults with respect to birth weight and gestational age.
However, the tests to assess memory function used by Rushe et al. were
different from ours, as they used only one subtest from the Wechsler
Memory Scale, Paired Associate Learning, together with subtests from
the Rivermead Behavioural Memory Test (RBMT) and the Rey–
Osterrieth Complex Figure Test (ROCFT), to assess delayed verbal mem-
ory and visual memory, respectively. On the ROCFT, Rushe et al. found
no difference between the groups, while we found significantly lower
scores in visual memory. We speculate that this may be related to the
ROCFT offering a prolonged exposure to the stimuli to be remembered
as the participant is asked to copy a geometrical figure without a time
limit, while the visual subtests from the WMS-III only allow for a short
exposure, rendering more load on visual working memory that we
also found to be inferior in the VLBW group.
Table 3
Associations between perinatal variables and memory function in VLBW young adults at
age 20 years.
WMS-III indices (n = 44) Days on Days in NICU
ventilator (n = 43)
(n = 42)
r p-Value r p-Value
The only memory result that was similar in the two groups in our
study was the Auditory Recognition Delayed index, indicating that rec-
ognition function seems relatively unaffected in the VLBW group. Rec-
ognition and recall memory may consist of different processes, where
only some being dependent on the hippocampi. Recognition memory
is theorized to consist of two processes: familiarity and recollection,
i.e. if stimuli seem familiar or if you remember it. Recall on the other
hand, is postulated to be purely based on recollection of the stimuli
(Strauss et al., 2006). Rose et al. (2001) found that this model may
also fit for subjects born preterm, and reported that prematurity,
which increases the risk of hippocampal injury, affected recollection
but not familiarity. The distinct impairment in recollection memory
may reflect a deficit more related to retrieval of already stored informa-
tion (Strauss et al., 2006). Our findings with lower score in the Auditory
Delayed index, but not in the Auditory Recognition Delayed index in the
VLBW group partly support this model.
Inferior working memory function has previously been described in
several VLBW groups (Skranes et al., 2009; Kulseng et al., 2006;
Grunewaldt et al., 2013), and has also been related to the increased
rate of Attention Deficit Hyperactivity Disorder (ADHD) and Attention
Deficit Disorder (ADD) symptoms reported in preterm born subjects
(Indredavik et al., 2004). We found that the VLBW group achieved
lower scores on both the visual (Spatial Span) and the verbal (Letter-
Number Sequencing) working memory subtests, although only the
Spatial Span subtest reached statistical significance. This is in line with
other studies reporting that visual spatial working memory is especially
vulnerable in preterm born infants (Woodward et al., 2005), children
Birth weight (Isaacs et al., 2000) and adolescents (Curtis et al., 2006), while verbal
(n = 44) memory has been reported as adequate (Bohm et al., 2004; Sansavini
et al., 2007).
r p-Value

Visual Immediate −.062 .706 −.435 .005 .407 .008

Auditory Immediate −.269 .098 −.459 .003 .518 b.001
Hippocampal volumes
Immediate Memory −.163 .321 −.460 .003 .524 b.001
Visual Delayed −.042 .802 −.441 .005 .287 .069 The hippocampal volumes were significantly smaller in the VLBW
Auditory Delayed −.320 .047 −.619 b.001 .547 b.001 young adults compared to controls. This was also true after controlling
Auditory Recognition −.177 .280 −.575 b.001 .359 .019
for total intracranial volume. This is in agreement with Isaacs et al.
Delayed
General Memory (Delayed) −.176 .290 −.600 b.001 .425 .006 (2000) who reported smaller volumes of the hippocampi in preterm
Working Memory −.369 .021 −.592 b.001 .258 .098 born children at age 13.5 years (Isaacs et al., 2000). Fearon et al.
Partial correlations, adjusted for sex, gestational age and socioeconomic status. Abbrevia-
(2004) investigated hippocampal volumes in a group of 23-year-old
tions: VLBW = very low birth weight; WMS-III: Wechsler Memory Scale 3rd edition. preterm born adults and compared the volume to term-born adult sib-
Correlations with p-values ≤ .05 are in bold font. lings. They reported smaller hippocampal volumes in the VLBW adults,
 S. Aanes et al. / NeuroImage 105 (2015) 76–83 81

Table 4
Absolute and corrected hippocampal volumes (cm3) for the two study groups.

VLBW Controls p-Value

n Mean (SE) 95% CI n Mean (SE) 95% CI

Total intracranial volume 44 1506.14 (19.62) 1467.19–1545.01 61 1587.93 (16.54) 1555.10–1620.75 0.002
Total absolute hippocampal volume 42 7.33 (0.11) 7.10–7.55 59 7.94 (0.10) 7.75–8.14 b0.001
Left absolute hippocampal volume 44 3.66 (0.06) 3.54–3.77 60 3.94 (0.05) 3.84–4.04 b0.001
Right absolute hippocampal volume 42 3.67 (0.06) 3.55–3.79 60 4.00 (0.05) 3.90–4.11 b0.001

Volumes corrected for ICV:

Total hippocampal volume 42 7.49 (0.10) 7.30–7.68 59 7.83 (0.08) 7.67–7.99 0.010
Left hippocampal volume 44 3.75 (0.05) 3.65–3.84 60 3.88 (0.04) 3.80–3.97 0.037
Right hippocampal volume 42 3.75 (0.05) 3.64–3.85 60 3.95 (0.04) 3.86–4.04 0.005

Univariate general linear model with group as fixed factor and sex and age at MRI as covariates for the absolute volumes. The volumes were then corrected for total intracranial volume, sex
and age at MRI in another GLM-analysis. Abbreviations: VLBW = very low birth weight group. Controls; control group. ICV = intracranial volume.

although this difference did not reach significance, which may be due to
the rather small sample size in their study (n = 33 preterms and 18 con-
trol siblings). When looking at perinatal risk factors' influence on hippo-
campal volumes in adulthood we found relationships between
hippocampal volume and birth weight and number of days spent in
NICU, but not with gestational age. The lower the birth weight and the
longer the stay in the NICU, the smaller the hippocampal volume, even
after correcting for degree of prematurity. These correlations may indi-
cate that both intrauterine growth restriction and perinatal morbidity in-
terfere with normal maturation and growth of the hippocampi in preterm
born subjects. Thompson et al. (2008) have reported that the hippocampi
are particularly vulnerable to white matter injury (Thompson et al.,
2008). We have previously reported reduced fractional anisotropy (FA)
values in association tracts in the external capsule and inferior and middle
superior fascicles in the same cohort of VLBW young adults at age 14–
15 years (Skranes et al., 2007), in addition to entorhinal cortical thinning
(Skranes et al., 2012). The entorhinal cortex has important cortical projec-
tions to and from the hippocampi, and impaired microstructure in the
white matter networks of these areas may influence connectivity and
processing of information leading to cortical thinning and hippocampal
volume reduction due to the loss of afferent input to the hippocampi
through the hippocampal–entorhinal–neocortical network.
Relationship between volumes of the hippocampi and memory profile
The majority of significant associations between hippocampal
volumes and memory functions were found in the VLBW young adults,
although we did find some correlations in the control group. The VLBW
adults with the largest hippocampi had the highest scores in all indices
of the WMS-III. This is in agreement with a study by Thompson et al.
(2013) who investigated volume and shape variations of the hippocam-
pi measured at term-equivalent age (TEA) and memory function at age 7
in very preterm born children (Fearon et al., 2004). They also reported a
positive association between hippocampal volume and memory. In our
study the strongest correlation was found between hippocampal vol-
umes and the Working Memory index. This is in line with
Beauchamp et al. (2008), who reported similar correlations between
volume of hippocampi at TEA and working memory in 2-year-old
VLBW-children.
Our study shows that similar relationships between hippocampal
volumes at term equivalent age and later memory function in very
preterm born children, also apply to hippocampal volumes measured
in early adult life in the same patient group. We will argue that this
may indicate permanent trophic changes to and reduced hippocampal
growth resulting in reduced memory functions.

Fig. 2. Scatterplots of left and right hippocampal volumes for all the participants (VLBW in blue, controls in red). The volumes are corrected for total intracranial volume, sex and age at MRI
by a univariate general linear model.
82 S. Aanes et al. / NeuroImage 105 (2015) 76–83

Table 5
Associations between hippocampal volumes (total, left and right) corrected for total intracranial volume and memory functions assessed by the eight WMS-III indices in VLBW young
adults at 20 years of age.

WMS-III Indices (n = 44) VLBW group

Total hippocampal volume Left hippocampal volume Right hippocampal volume

(n = 42) (n = 44) (n = 42)

r p-Value r p-Value r p-Value

Visual Immediate .399 .013 .411 .009 .308 .060

Auditory Immediate .228 .168 .308 .053 .173 .299
Immediate Memory .376 .020 .433 .005 .298 .070
Visual Delayeda .323 .051 .338 .035 .241 .151
Auditory Delayed .231 .164 .317 .046 .147 .379
Auditory Recognition Delayed .277 .093 .276 .084 .268 .104
General Memory (Delayed)a .327 .049 .367 .021 .256 .127
Working Memory .336 .039 .250 .120 .374 .021

Partial correlations, adjusted for sex, socioeconomic status and age at MRI.
Abbreviations: VLBW = very low birth weight; WMS-III: Wechsler Memory Scale 3rd edition.
Correlations with p-values ≤ .05 are in bold font.
a
n = 43.

When correcting for intracranial volume we demonstrate more signif-
icant correlations for the left hippocampus, which correlated with all
memory indices except for the Auditory Recognition Delayed and the
Working Memory indices, than for the right, which only correlated with
the Working Memory index. This could be due to a functional lateraliza-
tion of the hippocampi where the left hippocampus seems more involved
with episodic memory and the right with spatial memory (Spatial Span
subtest). This is in accordance with previous studies, which have demon-
strated similar lateralization of the hippocampi in London taxi drivers
(Fewtrell et al., 2008) and patients with Alzheimer's disease (Han et al.,
2006), and also in a review paper (Reuter et al., 2012).
memory skills and smaller hippocampal volumes may indicate a struc-
ture–function relationship based on aberrant hippocampal develop-
ment and functioning due to preterm birth with perinatal morbidity.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.neuroimage.2014.10.023.
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Strength and limitations
The strength of the present study is the comprehensive assessment
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and non-significant results must be interpreted with caution. Neverthe-
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termediate accuracy in hippocampal segmentation (Morey et al., 2010).
However, all hippocampal segmentations were quality controlled by
inspection, and instead of manual correction of imperfect automated
segmentations and thereby introducing bias, such hippocampal volumes
were rejected from further analyses.
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