Developmental amnesia and its relationship to degree of hippocampal atrophy.

Abstract

Two groups of adolescents, one born preterm and one with a diagnosis of developmental amnesia, were compared with age-matched normal controls on measures of hippocampal volume and memory function. Relative to control values, the preterm group values showed a mean bilateral reduction in hippocampal volume of 8-9% (ranging to 23%), whereas the developmental amnesic group values showed a reduction of 40% (ranging from 27% to 56%). Despite equivalent IQ and immediate memory scores in the two study groups, there were marked differences between them on a wide variety of verbal and visual delayed memory tasks. Consistent with their diagnosis, the developmental amnesic group was impaired relative to both other groups on nearly all delayed memory measures. The preterm group, by contrast, was significantly impaired relative to the controls on only a few memory measures, i.e., route following and prospective memory. We suggest that early hippocampal pathology leads to the disabling memory impairments associated with developmental amnesia when the volume of this structure is reduced below normal by approximately 20-30% on each side. Whether this is a sufficient condition for the disorder or whether abnormality in other brain regions is also necessary remains to be determined.

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ARTICLES
Hippocampal Volume and Everyday Memory in
Children of Very Low Birth Weight
ELIZABETH B. ISAACS, ALAN LUCAS, WUI K. CHONG, STEPHEN J. WOOD, CHERYL L.
JOHNSON, CLARE MARSHALL, FARANEH VARGHA-KHADEM, AND DAVID G. GADIAN
MRC Childhood Nutrition Research Centre [E.B.I., A.L.], Cognitive Neuroscience Unit [E.B.I., S.J.W.,
F.V.-K.], and Radiology and Physics Unit [D.G.G.], Institute of Child Health, London WC1N 1EH, and
Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH
[W.K.C., C.L.J., C.M.], United Kingdom
Children born preterm and of very low birth weight have an
increased incidence of learning difficulties, but little is known
about the specific nature of their cognitive deficits and the
underlying neuropathology. We hypothesized that their vulnera-
bility to hypoxic, metabolic, and nutritional insults would lead to
reduced hippocampal volumes and to deficits in memory because
of the role of the hippocampus in this domain of cognition.
Neuropsychological and magnetic resonance imaging methods
were used to investigate this hypothesis in adolescents born
preterm (?30 wk gestation, n ? 11) or full-term (n ? 8). The
preterm group had significantly smaller hippocampal volumes
bilaterally, despite equivalent head size, and showed specific
deficits in certain aspects of everyday memory, both on objective
testing and as indicated by parental questionnaires. The preterm
group also had a specific deficit in numeracy. The reduced
hippocampal volumes and deficits in everyday memory have
previously been unrecognized, but their prevalence in a group of
neurologically normal children is striking. (Pediatr Res 47: 713–
720, 2000)
Abbreviations
CAVLT-2, Children’s Auditory-Verbal Learning Test, 2nd
edition
Cho, choline-containing compounds
Cr, creatine ? phosphocreatine
IQ, intelligence quotient
MRI, magnetic resonance imaging
MRS, magnetic resonance spectroscopy
NAA, N-acetylaspartate
PIQ, performance IQ
ppm, parts per million
RBMT, Rivermead Behavioural Memory Test
VIQ, verbal IQ
VLBW, very low birth weight
WISC-III, Wechsler Intelligence Scale for Children, 3rd
edition
WOND, Wechsler Objective Numerical Dimensions
WORD, Wechsler Objective Reading Dimensions
3-D, three dimensional
There have been many reports of cognitive and learning
difficulties in children born preterm at VLBW (1). Most studies
have focused on assessment of intelligence and academic
attainments, with few investigating the more selective impair-
ments that may underlie these broader cognitive deficits (2–4).
Although there have been reports of cerebral abnormalities in
the preterm brain on the basis of autopsy and, more recently,
neuroimaging studies (5–8), there have been few attempts to
explore the association between such abnormalities and spe-
cific cognitive impairments.
The hippocampus is a structure known to be susceptible to
damage in preterm infants; Fuller et al. (9) reported that 67%
of their sample of preterm infant brains showed hippocampal
abnormalities at autopsy. The hippocampus, both in animals
and humans, is known to be selectively vulnerable to a wide
variety of neurologic insults, including hypoxic-ischemic in-
jury (10–12), hypoglycemia (13), undernutrition (14), and
hypothyroidism (15). Because preterm infants, particularly
those of VLBW, are liable to suffer from a variety of hypoxic,
metabolic, and nutritional insults, a high incidence of hip-
pocampal abnormality might be predicted in this population.
If some preterm babies were to suffer hippocampal patho-
logic injury, what implications might this have for the subse-
quent development of their cognitive function? Inasmuch as
the hippocampus plays a special role in cognitive memory,
both in animals and humans (16), abnormalities in this struc-
ture should be associated with memory impairments. Neuro-
imaging studies in a variety of adult populations, including the
normal elderly (17, 18), the elderly with Alzheimer’s disease
Received August 11, 1999; accepted January 5, 2000.
Correspondence: Elizabeth Isaacs, M.D., MRC Childhood Nutrition Research Centre,
Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Supported by the Medical Research Council and the Wellcome Trust.
0031-3998/00/4706-0713
PEDIATRIC RESEARCH
Copyright © 2000 International Pediatric Research Foundation, Inc.
Vol. 47, No. 6, 2000
Printed in U.S.A.
ABSTRACT
713

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(19), and patients with amnesia (20), have all demonstrated
memory impairments in conjunction with decreases in hip-
pocampal volume. Such studies in the pediatric population are
few. Rose and Feldman (2) reported poorer performance by
11-y-old preterm children compared with a full-term group on
a variety of memory tasks; this was related to the presence and
severity of respiratory distress syndrome. They speculated that
insult to the vulnerable hippocampus had occurred, but they
had no supporting data. A recent report by Vargha-Khadem et
al. (21) provided strong support for the view that the hip-
pocampus is particularly important in subserving episodic
memory, the memory for events experienced by an individual.
They described a dissociation between episodic memory and
semantic memory (memory for facts) in three children with
severe bilateral hippocampal atrophy; all showed profound
difficulties in episodic memory but relatively preserved seman-
tic memory as shown by tests of intelligence, language, and
academic attainment. Memory deficits were demonstrated on
both laboratory-based tasks and, strikingly, measures of every-
day memory function.
Therefore, given the expected high incidence of hippocam-
pal abnormality in children born at VLBW, we hypothesized
that they would have deficits in memory, particularly in epi-
sodic compared with semantic memory. To test this hypothesis,
we investigated memory function and hippocampal abnormal-
ities using neuropsychological assessment and magnetic reso-
nance techniques in a group of adolescents who had been
VLBW babies.
METHODS
Subjects
Subjects were selected from a large cohort of children, born
preterm, who had taken part in a randomized feeding trial,
between 1982 and 1985, at one of five centers in the United
Kingdom (22). Eleven children from this cohort took part in
the present study (eight boys and three girls). All were born at
?30 wk gestation (median, 28 wks; range, 27–29 wks) and
weighed ?1500 g at birth (median, 998 g; range, 840-1490 g).
None of the infants had recorded intraventricular hemorrhages.
All babies had respiratory disease, with eight of the 11 requir-
ing intubation within the first 30 min after birth. The median
number of days ventilation for the group was 9 d (range, 7–40
d) and the median number of days in ?30% oxygen was 35 d
(range, 9–69 d). However, none had evidence of birth as-
phyxia: none had meconium staining in the liquor and none had
an Apgar score of ?4 at 5 min. Only one baby had a fetal heart
rate that dipped below 100, but in this case, the scalp pH was
?7.25 and 5-min Apgar score was 6. The children were all
described as neurologically normal when examined by a pedi-
atrician in a follow-up study at the age of 7.5–8 y. All attended
mainstream schools at the time of the present assessment, and
none had a statement of special educational needs, although
five had received some learning support in the past.
The control group consisted of eight age-matched children
(three boys and five girls) born full-term (median gestation,
39.5 wks; range, 38–41 wks), median birth weight was 3622 g
(range, 2717–4754 g), and all had had a normal neonatal
course.
At the time of assessment, both groups had a median age of
13 y, 6 mo. All 19 children were right-handed. All children and
parents gave informed written consent, and the study was
approved by the local hospital and regional ethics committees.
Neuropsychological protocol
An initial 2-h neuropsychological assessment was conducted
at the child’s home or school, with a second taking place on the
same day that the magnetic resonance studies were performed
at Great Ormond Street Hospital for Children.
Intelligence. To establish whether any deficits in memory
were independent of reduced intelligence, the WISC-III (23)
was administered in full, allowing index scores to be calculated
(Verbal Comprehension, Perceptual Organization, Freedom
from Distractibility, Processing Speed), in addition to VIQ and
PIQ.
Everyday memory. This was the main focus of interest and
was measured in two ways. 1) The RBMT (24) had proved
sensitive to the everyday memory deficits shown by the am-
nesic children reported by Vargha-Khadem et al. (21). This test
uses activities closer to real life than the usual laboratory-based
tasks, while providing an objective measure of everyday mem-
ory. A Standardized Profile Score is obtained by assigning a
value of 0, 1 or 2 to each of the 12 subtests. 2) A parental
questionnaire (25) was used to assess the frequency of different
types of everyday memory problems encountered by the child;
parents rated each of 28 items from A (has not occurred in the
past 3 mo) to I (occurs once a day). Scores of 1 to 9 were
assigned to ratings A to I, and these were summed for each
child.
Verbal and nonverbal recall. A series of memory tests
commonly used in the laboratory to measure the acquisition
and retention of experimental material was given: 1) The
Wechsler Memory Scale—Form I (26) was administered in the
standard way, but with age corrections for children younger
than the age of 18 (27). Measures of immediate and delayed
recall were obtained for a) logical memory: two prose passages
were read for immediate and unalerted recall after a 90-min
delay; b) paired-associate learning: 10 pairs of words, six
semantically related (e.g. up-down) and four unrelated (e.g.
cabbage-pen), were read three times for immediate recall after
each presentation and delayed recall after a 90-min delay; and
c) visual reproduction: reproduction of geometric designs was
obtained immediately after presentation and after a 40-min
delay. 2) The CAVLT-2 (28) measures various aspects of
verbal memory and learning: immediate memory, level of
learning, interference effects, delayed recall, and recognition.
A list of 16 words was read to the child five times with free
recall after each presentation; to determine the effects of inter-
ference, a second 16-word list was read once for immediate
recall followed by recall of the original list. 3) The Design
Learning subtest of the Adult Memory and Information Pro-
cessing Battery (29) was administered as a visual analog of the
CAVLT-2. A pattern, formed by joining dots in a matrix, was
presented for five learning trials; measures analogous to those
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ISAACS ET AL.

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of the CAVLT-2 were obtained. 4) The Rey-Osterrieth Com-
plex Figure (30), a complicated geometric design, was copied
and then recalled after 40 min. 5) Three subtests of the
WISC-III (Information, Vocabulary, and Comprehension)
were used to assess semantic memory and word knowledge.
Attainment measures. Tests of attainment in the areas of
literacy and numeracy provided additional measures of seman-
tic memory as well as information about the child’s level of
function in the academic environment: 1) All three subtests
(Basic Reading, Spelling, and Reading Comprehension) of the
WORD test (31) were administered to assess literacy skills. 2)
Both subtests (Mathematics Reasoning and Numerical Opera-
tions) of the WOND test (32) were given.
The WORD and WOND manuals list the subtest scores that
a child with any given WISC-III IQ would be expected to
obtain, allowing the comparison of expected and observed
values and the statistical evaluation of differences between
them.
Magnetic resonance protocol
MRI and MRS studies were performed on a 1.5-tesla Sie-
mens system. Structural MRI investigations included 1) mag-
netization prepared rapid acquisition gradient echo (33) 3-D
volume acquisition with repetition time of 10 ms; echo time, 4
ms; inversion time, 200 ms; flip angle, 12°; matrix size, 256 ?
256; field of view, 250 mm; partition thickness, 1.25 mm; 128
sagittal partitions in the third dimension, and acquisition time,
8.3 min; and 2) coronal and axial turbo spin-echo T2-weighted
scans with repetition time of 4600 ms; echo time, 90 ms; and
acquisition time, 4.3 min for each orientation. The images were
reviewed by an experienced pediatric neuroradiologist, blind to
the group membership of the children, who recorded the
presence of focal, central, or generalized atrophy and abnor-
malities in the basal ganglia and the hippocampi.
In addition to visual inspection of the structural MRI scans,
two quantitative techniques, volumetry and T2relaxometry,
were used for the assessment of hippocampal abnormalities. To
measure volumes, the 3-D data sets were reformatted into
1-mm-thick contiguous slices in a tilted coronal plane that was
perpendicular to the long axis of the hippocampus. Cross-
sectional areas were measured along the entire length of the
hippocampi, using every third slice as described previously
(34). The volumes were calculated by summing the cross-
sectional areas and multiplying by the distance between the
measured slices (i.e. 3 mm). Intracranial volumes were mea-
sured from the unreformatted sagittal 3-D MRI data sets (34).
The hippocampal volumes were then corrected for intracranial
volume (34) and are presented here in this corrected form. The
volume measurements were made blind to group membership.
T2relaxometry provides a quantitative way of detecting
abnormalities that are more conventionally evaluated by visual
inspection of T2-weighted images. Hippocampal water T2val-
ues were obtained from T2maps constructed from a 16-echo
sequence, as previously described (34, 35). The cross-section
from which the hippocampal T2values were taken was ori-
ented in a tilted coronal plane along the anterior border of the
brain stem perpendicular to and at the level of the body of the
hippocampus. T2values were measured by placing a region of
interest in the largest possible circular area within the hip-
pocampus while avoiding boundaries at which partial volume
effects with cerebrospinal fluid may occur.
For the assessment of more diffuse or widespread temporal
lobe pathology,1H MRS data were obtained from 2- ? 2- ?
2-cm cubes centered on the medial portions of the right and left
temporal lobes, using a 90–180-180 spin-echo technique, as
described previously (36, 37). The positioning and volume of
the selected regions are such that the hippocampi make only a
minor contribution to the observed signal intensities, so the1H
MRS findings are essentially reporting on abnormalities that
extend beyond the hippocampus. Signal intensities at 2.0 ppm
(primarily NAA), 3.0 ppm (Cr), and 3.2 ppm (Cho) were
measured from the peak areas by integration. The data are
presented in the form of the signal intensity ratio NAA/(Cho ?
Cr), which provides a simple index of spectral abnormality,
with abnormally low values indicative of neuronal loss or
damage and/or astrocytosis (36, 37).
Statistics
Because of relatively small groups, with unequal numbers of
subjects, and the skewed distribution of some variables, all
comparisons between groups were made using nonparametric
statistics. Differences between the two groups were evaluated
using the Mann-Whitney U test (unrelated samples) or the Wil-
coxon Signed Ranks Test (related samples), and correlations were
calculated using Kendall’s or Spearman’s coefficients.
RESULTS
Intelligence
The WISC-III IQ and index score results are shown in Table
1. VIQ differed between the preterm and full-term groups (U ?
16.5; p ? 0.023), but the median scores of both groups fell
within the average range. The difference in PIQ approached
significance (U ? 22.0; p ? 0.068). Neither group showed a
significant VIQ ? PIQ discrepancy (preterm, Z ? ?0.311; p ?
0.755; full-term, Z ? ?0.423; p ? 0.673). The only index
score to show a significant group difference was Freedom from
Distractibility (U ? 10.5; p ? 0.006). Comparisons on the 13
subtest scaled scores showed that the groups differed on two
subtests only, those constituting the Freedom from Distracti-
Table 1. Mean IQ and factor index scores (WISC-III) for the
preterm and full-term groups
Test
Preterm group
median (range)
(n ? 11)
Full-term
group median
(range)
(n ? 8)
p values
IQ values
Verbal
Performance
Index scores
Verbal comprehension
Freedom from distractibility
Perceptual organization
Processing speed
90.0 (79–111) 108.5 (89–133)
92.0 (76–112) 101.5 (91–127)
0.023
NS
93.0 (78–111) 107.5 (85–126)
94.0 (66–106) 106.5 (84–140)
89.0 (74–113) 102.5 (83–132)
101.0 (70–125) 105.0 (87–122)
NS
0.006
NS
NS
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bility Index Score: Digit Span (U ? 9.0; p ? 0.004) and
Arithmetic (U ? 10.5; p ? 0.005). Digit Span consists of both
forward and backward recall; although the preterm group’s
median score for the backward recall of digits was lower than
the score of the full-term group, forward recall was similar in
the two groups.
Memory
Verbal and nonverbal recall. Table 2 presents the results for
the laboratory measures of verbal and nonverbal recall, illus-
trating that most of these did not distinguish between the two
groups. The few measures that did show a significant difference
between groups were all indices of immediate, rather than
delayed, recall. Furthermore, the difference was sometimes
caused by an above-average level of performance by the
full-term group and not a below-average score in the preterm
group.
Everyday memory. There was a highly significant difference
between the preterm and full-term children for scores on the
RBMT (Fig. 1 and Table 3). Most children of this age make
few errors on this test (maximal score, 24), and, in keeping
with this, seven of the eight full-term children had total scores
in the Normal range (22–24), six with a maximal score of 24
and one with a score of 22. One full-term child’s score of 21
placed him in the Poor Memory Range (17–21). In contrast to
this, seven children in the preterm group scored in the Poor
Memory range, with two others in the Normal (scores of 22
and 24) and two in the Moderately Impaired (10–16) ranges
(scores of 15 and 16). There was a highly significant difference
(U ? 7.5; p ? 0.002) between the scores of the preterm and
full-term groups (median scores, 19 and 24, respectively), with
little overlap between the two distributions. RBMT scores did
not correlate significantly with VIQ (? ? 0.391; p ? 0.098).
For more detailed examination of performance on the
RBMT, median scores on the subtests were compared using the
Mann-Whitney U test. As shown in Table 3, the three items
involving prospective memory (remembering to take a mes-
sage, remembering to ask a question to each of a verbal cue and
a buzzer) were grouped together, as were immediate and
delayed route following and immediate and delayed story
recall. There were significant differences in performance be-
tween the groups on the prospective memory items, on route
finding and on orientation, whereas the difference on the date
subtest approached significance. Performance on the remaining
subtests was similar in both groups. Examination of individual
performance by preterm children showed that ?50% made
errors in following a five-stage route (both immediately after
demonstration and in the delayed recall condition), in remem-
bering to carry out prospective tasks, and on questions relating
to orientation and date. In contrast, only two children born
full-term made errors on any of these items, one on orientation
and one on route following.
The difference between the median scores for the two groups
on the second measure of everyday memory, namely the
Table 2. Scores on long-term memory tests for the preterm and
full-term groups
Test
Preterm group,
median (range)
(n ? 11)
Full-term group,
median (range)
(n ? 8)
p
values
Wechsler memory scale
Immediate recall (%)
Stories
Paired associates
Designs
Delayed recall (% of
immediate)
Stories
Paired associates
Designs
CAVLT-2 (raw scores)
Immediate recall
Immediate span
Level of learning
Interference trial
Immediate recall
Delayed recall
% of immediate
Recognition
Coughlan (raw scores)
Immediate recall
Immediate span
Level of learning
Interference trial
Immediate recall
Delayed recall
Rey-Osterrieth figure (%)
Copy
Recall
30.4 (22.8–51.1)
88.1 (66.7–97.6)
71.4 (64.3–100)
43.3 (18.9–61.4)
88.1 (78.6–100)
91.1 (67.9–96.4)
0.039
NS
0.038
64.0 (29–93)
100.0 (90–111)
84.2 (42.1–130)
79.5 (48.5–92)
100.0 (90–100)
96.5 (73.7–104.4)
NS
NS
NS
11.0 (9–15)
36.0 (26–45)
5.0 (3–7)
11.0 (6–16)
13.5 (10–18)
39.5 (34–47)
6.5 (5–9)
12.0 (9–15)
NS
0.041
NS
NS
88.9 (72.7–112.5)
30.0 (28–32)
89.7 (75–127.3)
32.0 (30–32)
NS
NS
8.5 (4–15)
36.0 (19–43)
5.0 (1–8)
9.0 (4–9)
9.0 (4–9)
12.5 (7–18)
42.0 (32–45)
7.0 (3–9)
9.0 (8–9)
8.9 (0–4)
NS
0.050
NS
NS
NS
71.3 (51.3–82.5)
46.3 (16.3–60)
78.4 (72.5–85)
46.9 (36.3–75)
NS
NS
Figure 1. Distribution of RBMT scores for the preterm and full-term groups.
Individual scores are shown; the height of the bar represents the median value.
Table 3. Comparisons of scores on the RBMT subtests for the
preterm and full-term groups
RBMT subtest (maximum score)
Mann-Whitney
U value
p values
Remembering names of person in
photograph (2)
Prospective items (6) (response to
question; response to buzzer;
remembering message)
Picture recognition (2)
Copying a route (4) (immediate
and delayed)
Orientation (2)
Date (2)
Face recognition (2)
Story recall (4) (immediate and
delayed)
40.00.39
16.00.007
42.5
20.5
0.82
0.03
24.0
28.0
43.0
36.0
0.05
0.06
0.88
0.22
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parental questionnaire, was not significant when the total
scores were compared. It was clear, however, that certain
behaviors were reported to occur more frequently in the pre-
term children than in the full-term. Responses to each item on
the questionnaire were therefore compared by Mann-Whitney
U tests, and the results are presented in Table 4. Although
frequency ratings were higher for the preterm group on all 28
items, seven of the items (the items at the top of Table 4)
proved markedly more effective than the remaining 21 in
discriminating between the two groups. Median scores for this
abbreviated questionnaire (preterm, 19.6; full-term, 8.5) were
significantly different (U ? 17.5; p ? 0.03). Similarities were
apparent between the items on this abbreviated questionnaire
and the activities that posed difficulties on the RBMT; the
correlation between these two sets of scores approached sig-
nificance (Kendall ? ?0.30; p ? 0.097) and was in the
expected negative direction because low scores on the RBMT
and high scores on the questionnaire both denote poor every-
day memory.
Attainments. The results of tests of academic attainment are
shown in Table 5. There were no significant differences be-
tween the groups on any of the measures of the WORD: Basic
Reading (single-word accuracy), Spelling, or Reading Com-
prehension (with no memory requirement). In neither group
were the scores significantly lower than those predicted by
WISC-III IQ values for any of the three subtests, indicating
that development of literacy skills was commensurate with
overall intellectual level.
The same was not true, however, of numeracy skills. The
preterm group scored significantly lower than the full-term
group on both subtests of the WOND: Mathematics Reasoning
(orally presented problems to assess mathematical reasoning)
and Numerical Operations (written problems assessing calcu-
lation ability involving all the basic arithmetic operations). In
addition, and unlike the children born full-term, the scores
obtained by the preterm group on the Numerical Operations
subtest were significantly lower than IQ predictions, i.e. they
showed a selective deficit for this aspect of mathematics. A
significant discrepancy between expected and obtained scores
was shown by six of the 11 children born preterm; although
this discrepancy was not statistically significant for the other
five (mean, 13.4 points), it was nevertheless larger than in the
full-term group (mean, 3.3 points).
Magnetic Resonance
Visual inspection of scans. Of the 11 preterm children, only
one had an MRI brain scan that was considered to be entirely
normal on visual inspection. Four children demonstrated cen-
tral atrophy in the form of enlargement of the lateral and third
ventricles and normal sulcal spaces, and five showed reduced
bulk of white matter in the parietooccipital region with a
reduction in the size of the body of the corpus callosum. One
demonstrated focal atrophy with focal enlargement of a part of
a lateral ventricle. Three cases were noted to have small
hippocampi, and in all of these, the reductions were bilateral.
One child was noted to have signal abnormalities in the basal
ganglia; the abnormality was seen in the putamen bilaterally.
Of the eight children born at term, all were judged to have
brain scans that were entirely normal.
Quantitative measures. The quantitative MRI and MRS data
are presented in Table 6. Median intracranial volume did not
differ significantly between the two groups (U ? 36.5; p ?
0.536). Occipital-frontal circumference data obtained when the
children were seen at 7 y of age confirmed the normality of the
preterm group’s head size. When compared with reference
charts (38), one measurement fell at the second percentile,
Table 4. Comparisons of frequency of items on the parental
questionnaire for preterm and full-term groups
Questionnaire item
Mann-Whitney
U value
p values
Forgetting details of things done regularly
Getting details of things told mixed up
Getting lost, making wrong turns in a relatively
new place
Needing to check whether something has been
done
Doing some routine thing twice
Repeating things, asking same question twice
Forgetting to do planned things
Telling a story or joke twice
Letting self ramble on
Failing to recognize familiar places
Getting lost, making wrong turns in a familiar
place
Finding that famous faces look unfamiliar
Forgetting something told recently; needs
reminding
Forgetting to tell important messages
Forgetting where things are kept
Forgetting important details of events
happening the day before
Difficulty in picking up new skills
Failing to recognize close friends
Losing things around the house
Losing track of theme of a written story
Forgetting to take things, leaving behind
Finding words “on tip of tongue”
Forgetting just when something happened
Finding a TV story difficult to follow
Starting to read a book read before
Losing thread of conversation
Forgetting important personal details
Forgetting changes in daily routines
20.0
19.5
24.5
0.03
0.03
0.06
23.0 0.06
28.0
25.5
25.0
30.0
29.5
36.0
36.0
0.06
0.08
0.09
0.16
0.18
0.22
0.22
36.0
31.0
0.22
0.27
31.0
33.5
36.0
0.27
0.34
0.35
36.5
40.0
34.0
36.5
36.0
37.0
38.0
38.5
40.5
42.0
43.0
42.5
0.39
0.39
0.40
0.49
0.50
0.52
0.55
0.58
0.65
0.85
0.88
0.89
Table 5. Mean literacy (WORD) and numeracy (WOND)
attainment test scores for the preterm and full-term groups
Test
Standard scores
p values
Preterm
group,
median
(range)
(n ? 11)
Full-term
group, median
(range)
(n ? 8)
WORD
Basic reading
Spelling
Reading comprehension
WOND
Mathematics reasoning
Numerical operations
95.0 (87–142)
93.0 (79–124)
92.0 (80–111)
105.5 (91–117)
104.5 (97–123)
99.0 (89–121)
NS
NS
NS
93.0 (79–110)
81.0 (71–103)
107.5 (93–124)
111.5 (94–119)
0.023
0.0001
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EVERYDAY MEMORY IN PRETERM CHILDREN

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whereas all others were well within the average range, with
half falling at or above the 50th percentile.
Two quantitative magnetic resonance techniques, namely
volumetric measurements and T2relaxometry, were used for
the assessment of hippocampal abnormalities. Hippocampal T2
values did not reveal any abnormalities, with no significant
difference between the two groups (left, U ? 41.5; p ? 0.835;
right, U ? 33.0; p ? 0.358). However, there was a highly
significant difference between groups for both left and right
hippocampal volumes (left, U ? 6.0; p ? 0.002; right, U ?
6.0; p ? 0.002), and no hippocampus of a child born preterm
was larger than the full-term group median. Because there was
no significant difference between left and right hippocampal
volumes for either group, a mean hippocampal volume was
calculated for each subject. Figure 2 shows the distribution of
these measures.
1H MRS, based on the signals from NAA, Cr, and Cho, was
used for the assessment of more-diffuse temporal lobe abnor-
malities, extending beyond the hippocampus, that can be dif-
ficult to visualize on MRI (39). The difference between the
group values for the NAA/(Cho ? Cr) signal intensity ratios
was significant for the right temporal lobe (U ? 11.0; p ?
0.016), but not for the left (U ? 14.5; p ? 0.140). However, 17
of the 18 values obtained from the preterm group were above
a cut-off point of 0.72 previously used to denote the lower limit
of normality (36, 37). Thus, the major group difference as seen
on the quantitative magnetic resonance measures is the bilat-
eral reduction in hippocampal volume.
Although both intracranial volume and head circumference
measurements obtained at age 7 y indicated that head size was
not reduced in the children born preterm, total brain volume
could have been reduced in some of these children as a result
of the atrophy noted on visual inspection of the scans. If
hippocampal volume reduction was secondary to this, then the
children who showed atrophy on visual inspection of the MRI
scans might be expected to have smaller hippocampi. When
hippocampal volumes of the preterm children with atrophy
were compared with those of preterm children without atrophy,
the difference was not significant for the left hippocampi (U ?
8.0; p ? 0.257) but was so for the right (U ? 0.0; p ? 0.008);
the group with atrophy, however, had larger left and right
hippocampi rather than smaller, indicating that the reduction in
hippocampal volume in the preterm group as a whole is not an
epiphenomenon of reduced head/brain size.
The atrophy and no-atrophy groups were compared on all
other neuropsychological and quantitative magnetic resonance
variables to determine whether the presence of atrophy was
associated with any specific deficits. The atrophy group had
significantly lower scores only on the Picture Completion
subtest of the WISC-III (U ? 2.0; p ? 0.021). In addition,
these children had significantly lower median T2values for
both left and right hippocampi (left, U ? 0.0; p ? 0.007; right,
U ? 3.0; p ? 0.035). However, the latter finding is unlikely to
have any functional significance as all four medians were
within the average range and pathology tends to be associated
with higher, rather than lower, T2values.
To determine the specificity of hippocampal volume as a
predictor of everyday memory performance, the following
imaging variables were entered in a stepwise multiple regres-
sion with RBMT scores as the dependent variable: mean
hippocampal volume, left and right MRS values, and left and
right T2values. Mean hippocampal volume was the only
variable that met the criteria for inclusion in the analysis (r2?
0.45), thus confirming the relationship between hippocampal
volume and RBMT scores.
DISCUSSION
The neuropsychological studies reported here reveal that the
children who had been VLBW babies showed deficits in
everyday memory. A clear differentiation between groups was
demonstrated in their scores on the RBMT, which is an objec-
tive measure of episodic memory in everyday situations. Such
Table 6. Mean MRI and MRS data for the preterm and full-term groups
Variable
Preterm group,
median (range)
Full-term group,
median (range)
p values
Volumetric measurements
Intracranial volume (cm3)
Left hippocampus (mm3)
Right hippocampus (mm3)
T2relaxation times (ms)
Left hippocampus
Right hippocampus
NAA/(Cho ? Cr)
Left temporal lobe
Right temporal lobe
(n ? 11)(n ? 8)
1436 (1284–1603)
3390 (3147–3812)
3379 (2949–3888)
(n ? 11)
104.0 (97–107)
104.0 (99–107)
(n ? 9)*
0.90 (0.65–1.07)
0.87 (0.74–0.99)
1466 (1324–1650)
4080 (3559–4291)
4012 (3637–4297)
(n ? 8)
104.0 (99–107)
103.5 (101–108)
(n ? 6)*
1.00 (0.88–1.10)
0.98 (0.87–1.04)
NS
0.002
0.002
NS
NS
NS
0.016
* Numbers reduced because of technical difficulties during scanning.
Figure 2. Distribution of mean hippocampal volumes for the preterm and
full-term groups. Individual scores are shown; the height of the bar represents
the median value.
718
ISAACS ET AL.

Page 7

deficits in everyday memory have not previously been recog-
nized in this population.
Several considerations make it unlikely that this deficit in
everyday memory is related to impaired cognition, even though
VIQ was significantly lower in the preterm compared with the
full-term group. The first is their unimpaired performance on a
wide variety of other memory measures. Second is the fact that
children of this cognitive level (i.e. toward the lower limit of
the average range) would not be expected to show deficits on
the RBMT (24). Moreover, the correlation between VIQ and
RBMT scores was not significant, indicating that the memory
impairment is independent of cognitive level.
The memory deficits of the preterm group in this study had
characteristics that were both similar to and different from
those of the amnesic children reported by Vargha-Khadem et
al. (21). Deficits in everyday memory, with relative preserva-
tion of most aspects of semantic memory, are consistent with
the results of the amnesic children who showed the same
pattern after early hippocampal pathology. Vargha-Khadem et
al. (21) concluded that the hippocampi, which showed severe
atrophy bilaterally in all cases, might have a special role in
subserving episodic memory, with subhippocampal cortices
mediating the acquisition of semantic memories. The preterm
children in the present study also showed reduced hippocampal
volumes compared with age matched full-term controls, in
conjunction with impairments in everyday memory, although
both the volume reductions and memory impairments were far
less severe than the deficits observed in the amnesic children.
The preterm group differed from the amnesic children in that
they failed, by and large, to show marked deficits on labora-
tory-based tasks of verbal and nonverbal recall. This may be
related to the smaller reductions in hippocampal volumes in the
former children. Furthermore, Vargha-Khadem et al. (21) re-
ported abnormally high hippocampal T2values in the amnesic
children, suggesting the presence of pathology in the remaining
hippocampal tissue. In contrast, T2values in the preterm group
were normal. It may be, therefore, that the children lie along a
continuum of hippocampal abnormality, with the amnesic chil-
dren showing more-severe memory impairments attributable to
the presence of tissue that is abnormal as well as reduced in
volume, and this may explain why they show additional defi-
cits that the preterm group does not. It is also possible that
some additional memory deficits will be demonstrable when
the study group is expanded to include more children.
The memory deficits in the preterm group presented very
real difficulties in everyday life; responses to the parental
questionnaire identified these, demonstrating that the deficit in
RBMT scores is of more than just academic interest. Parents
and teachers also described such difficulties during interviews,
almost always ascribing these to lack of attention or even
naughtiness on the part of the child, with little recognition that
a specific memory deficit might be involved. Indeed, problems
in attention have been described in preterm children (40, 41),
and it is possible that these may coexist and contribute to their
impaired performance, particularly on tests of immediate re-
call. In this respect, it should be noted that the WISC-III
Freedom from Distractibility index score was significantly
lower for the preterm group compared with the full-term group.
The Freedom from Distractibility index, however, consists of
the Arithmetic and Digit Span subtests, and because the
WOND scores indicate poor mathematical ability in the pre-
terms, low index scores may be reflecting this, particularly
inasmuch as the digit span scores were age-appropriate. The
lower Freedom from Distractibility index score, therefore, may
not be indicative of attentional difficulties per se. It also seems
unlikely that problems with attention would produce such a
consistent pattern of failed items as seen on the RBMT.
Nevertheless, the role of attentional difficulties needs to be
addressed, and will be investigated through a larger study that
we are now undertaking with the same population.
The striking deficit in mathematics, particularly numerical
operations, is in marked contrast to adequate performance on
all aspects of literacy. Poor mathematical ability has been
reported in follow-up studies of preterm babies in the past (42,
43), so this was not an unexpected finding. Recent research has
indicated that areas of both the frontal and parietal lobes (44,
45) may be implicated in mathematics. Our results, however,
raise the possibility that a deficit in the spatial ability attributed
to the hippocampus (46) may underlie the difficulties with
mathematics, because of the spatial component involved in
numerical operations.
The hypothesis underlying this study was that deficits in
some aspects of episodic memory would be demonstrable in
conjunction with reductions in hippocampal volume. The re-
sults indicate that this is, in fact, the case. Hippocampal
volumes were demonstrably smaller in the preterm children,
appearing to be selectively so rather than as a by-product of a
general reduction in brain volume. Regression analyses indi-
cated that hippocampal volume was the best predictor of
performance on the RBMT. A recent study by Moradi et al.
(47) has reported the results of a group of children and
adolescents suffering from posttraumatic stress disorder on the
RBMT. Interestingly, like our preterm group, these children
showed difficulty on the prospective memory items and with
orientation; moreover, reductions in hippocampal volume in
sufferers of posttraumatic stress disorder have been reported by
Bremner et al. (48). However, we cannot preclude the possi-
bility that the impaired memory performance of the preterm
group may also be a reflection of additional abnormalities that
may be present elsewhere in the brain [for example, in the
prefrontal cortex, which is known to play a significant role in
episodic memory (49, 50)]. Indeed, we acknowledge the exis-
tence of other neural abnormalities when we report the results
of visual inspection of the magnetic resonance scans. We plan
to undertake voxel-based morphometry studies (51, 52) on our
expanded study group to help identify other areas of the brain
that may be structurally abnormal. Nevertheless, both the
prevalence and magnitude of structural hippocampal abnormal-
ities in our group of neurologically normal children born
preterm are striking.
Being born early and very small entails a major risk for
developing cognitive difficulties in childhood. Our findings
suggest that reduced hippocampal volumes and associated
everyday memory deficits may be an important factor in this
risk, playing a hitherto unacknowledged role in development.
The children in this study had all been small, sick infants who
719
EVERYDAY MEMORY IN PRETERM CHILDREN

Page 8

may have been vulnerable to a variety of insults in addition to
the respiratory distress syndrome for which they had required
ventilation. Determining the causality of the reduced hip-
pocampal volumes awaits the outcome of an investigation with
a larger sample of children so that the effects of other variables
can be examined. Early nutrition may be of particular impor-
tance inasmuch as the children in this study were part of the
cohort reported by Lucas et al. (53) to show substantial differ-
ences in IQ at age 7–8 y depending on nutritional intervention
shortly after birth. Sex may also be an important variable. It
proved to be of significance in the study by Lucas et al. (53),
and there are reports of interesting sex differences in brain
pathology in conditions such as schizophrenia (54) and epi-
lepsy (55). Whichever factor is causal, our observations sug-
gest an important mechanism underlying cognitive compro-
mise in this population of children.
Acknowledgments. The authors thank the children who took
part in this study, and their families and schools, for their keen
interest in participating.
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