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Early maternal support has been shown to promote specific gene expression, neurogenesis, adaptive stress responses, and larger hippocampal volumes in developing animals. In humans, a relationship between psychosocial factors in early childhood and later amygdala volumes based on prospective data has been demonstrated, providing a key link between early experience and brain development. Although much retrospective data suggests a link between early psychosocial factors and hippocampal volumes in humans, to date there has been no prospective data to inform this potentially important public health issue. In a longitudinal study of depressed and healthy preschool children who underwent neuroimaging at school age, we investigated whether early maternal support predicted later hippocampal volumes. Maternal support observed in early childhood was strongly predictive of hippocampal volume measured at school age. The positive effect of maternal support on hippocampal volumes was greater in nondepressed children. These findings provide prospective evidence in humans of the positive effect of early supportive parenting on healthy hippocampal development, a brain region key to memory and stress modulation.
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Maternal support in early childhood predicts larger
hippocampal volumes at school age
Joan L. Luby
, Deanna M. Barch
, Andy Belden
, Michael S. Gaffrey
, Rebecca Tillman
, Casey Babb
Tomoyuki Nishino
, Hideo Suzuki
, and Kelly N. Botteron
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110;
Department of Psychology, Washington University in St. Louis,
St. Louis, MO 63130; and
Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110
Edited by Marcus E. Raichle, Washington University in St. Louis, St. Louis, MO, and approved January 4, 2012 (received for review November 1, 2011)
Early maternal support has been shown to promote specic gene
expression, neurogenesis, adaptive stress responses, and larger
hippocampal volumes in developing animals. In humans, a relation-
ship between psychosocial factors in early childhood and later
amygdala volumes based on prospective data has been demon-
strated, providing a key link between early experience and brain
development. Although much retrospective data suggests a link
between early psychosocial factors and hippocampal volumes in
humans, to date there has been no prospective data to inform this
potentially important public health issue. In a longitudinal study of
depressed and healthy preschool children who underwent neuro-
imaging at school age, we investigated whether early maternal
support predicted later hippocampal volumes. Maternal support
observed in early childhood was strongly predictive of hippocam-
pal volume measured at school age. The positive effect of maternal
support on hippocampal volumes was greater in nondepressed
children. These ndings provide prospective evidence in humans of
the positive effect of early supportive parenting on healthy hippo-
campal development, a brain region key to memory and stress
parental support
The suggestion that environmental enrichment early in life
results in enhanced brain development was rst proposed and
investigated by Hebb in the late 1940s and was empirically vali-
dated in rodents 20 y later (1). These ndings provided some of the
rst quantitative evidence supporting the tangible role of envi-
ronmental experience on structural brain development. More re-
cent research has extended these ndings by investigating the
biological mechanisms by which psychosocial factors inuence
neuronal development. Of critical importance to the study of risk
for psychopathology, animal models have elucidated the mecha-
nisms by which maternal nurturance, a uniquely powerful form
of early enrichment, promotes adaptive programming of the
hypothalamicpituitaryadrenal axis stress response and hippo-
campal development (2, 3). Improvements in the capacity for
stress modulation have been shown to be related to epigenetic
modications whereby methylation of multiple genes results in
changes in gene expression for glucocorticoid and mineralcorti-
coid receptors (4, 5). These changes are associated with increases
in dendritic branching and neurogenesis and related increases in
hippocampal volumes (69). Consistent with this phenomenon
and conversely, the stress of early maternal deprivation has been
shown to have negative effects on this cascade (10, 11). A similar
relationship between early nurturance and stress modulation has
also been reported in nonhuman primates (12, 13). This work has
shown that early nurturing in nonhuman animals facilitates the
offsprings enduring capacity for adaptive stress modulation, a
phenomenon with potentially powerful public health implications
if also operational in humans.
Building on these animal ndings, there has been a surge of
interest in the effects of early experience on brain development
in humans (14). Numerous studies have documented a relation-
ship between key early environmental factors and later cognitive
and socio-emotional outcomes. Studies of Romanian orphans,
using the naturalistic stress of institutional care, have shown that
enhanced early caregiving through placement in therapeutic
foster care had a robust and positive impact on cognitive, social,
and emotional outcomes (15, 16). Differential patterns of DNA
methylation in children raised in institutions compared with
those raised by their biological parents have recently been pro-
vided, suggesting that the epigenetic phenomenon known in
animals might also be operative in human development (17).
Prospective evidence of the impact of early nurturance on
structural brain development has been provided in a few studies
to date. Tottenham et al. (18) reported that institutionalized
orphans who experienced environmental enrichment in the form
of earlier adoption displayed smaller amygdala volumes (an an-
atomical variation associated with better emotion regulation),
but they did not nd a relationship with hippocampal volumes.
Lupien et al. (19) also reported larger amygdala but no change in
hippocampal volumes in a sample of children exposed since birth
to maternal depression, the latter a condition known to be as-
sociated with decreased parenting sensitivity and responsiveness
(20). In another small study group, larger right amygdala vol-
umes were found in institutionalized children compared with
noninstitutionalized control subjects (21). Additionally, a study
of a small group of premature infants demonstrated that early
environmental enhancement in the neonatal intensive care unit
was associated with positive changes in brain structure, evi-
denced by higher relative anisotropy in several specicwhite
matter tracts (22). Rao et al. (23) found a relationship between
increased early higher-quality parental care and smaller hippo-
campal volumes in a sample of children exposed to cocaine in
utero, ndings in the opposite direction of that expected from the
animal data. These studies, although suggestive, have not yet
provided ndings in humans analogous to the animal literature
and are limited by the use of populations also exposed to multiple
perinatal and postnatal stressors and traumas known to impact
brain development.
An increasing body of retrospective data also suggests a re-
lationship between early nurturance, or the lack of nurturance
based on the experience of trauma, and later stress reactivity and
hippocampal volumes in a variety of human populations, in-
cluding those with depression (24, 25). Importantly, numerous
studies have reported that major depressive disorder (MDD) is
associated with smaller hippocampal volumes in adults (26, 27).
The ndings in children and adolescents are less consistent than
in adults, with some investigators reporting no hippocampal
volume differences (28, 29) and others reporting decreased
Author contributions: J.L.L., D.M.B., and K.N.B. designed research; C.B. and T.N.
performed research; R.T. analyzed data; and J.L.L., D.M.B., A.B., M.S.G., C.B., T.N., H.S.,
and K.N.B. wrote the paper.
The authors declare no conict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.
To whom correspondence should be addressed. E-mail:
February 21, 2012
vol. 109
no. 8
volume (3032). Importantly, numerous developmental studies
have demonstrated that poor-quality parenting (e.g., non-
supportive or harsh) is a risk factor for childhood MDD (33).
Further, a few studies suggest that smaller hippocampal volumes
in adolescents at risk for MDD are associated with increased
susceptibility to the effects of psychosocial stress and subsequent
risk for recurrence or development of MDD (23, 34). A similar
process has also been identied in a twin sample, in which
smaller hippocampal volumes increased the risk for development
of stress-related psychopathology (35). Taken together, these
ndings suggest intriguing, although potentially complex, rela-
tionships among experiences of early stress, low nurturance,
stress reactivity, and hippocampal volumes in humans, opening
the possibility that the well-characterized phenomena identied
in animals may also be operative in humans.
Given these converging lines of evidence, one hypothesis is that
impairments in early maternal nurturing contribute to enhanced
and maladaptive stress reactivity, reduced hippocampal volumes,
and increased risk for depression. As described above, there is
some prospective evidence in humans for the effects of maternal
nurturance on structural brain development of the amygdala in
high-risk samples, as well as evidence for nurturance-dependent
alterations in DNA methylation in similar samples. In addition,
retrospective data have established a link between early inter-
ruptions of maternal care, depression, and hippocampal volumes.
However, to date there has been no prospective data documenting
the positive relationship between early maternal nurturance and
structural development of the hippocampus in either typically
developing children or groups at risk for MDD, despite a well-
documented relationship in animals and a putative mechanism of
the developmental psychopathology hypothesis stated above. The
hippocampus is of particular interest given the compelling ndings
on the role of early nurturance and its structural development
from animal studies described above. If a relationship between
early nurturance and hippocampal development is present in
humans, it would ll a key gap in the literature and open the door
to prospective investigation of healthy brain development as well
as mechanisms for the development of depression in certain at-risk
groups as outlined. To address this question, we investigated the
relationship between maternal nurturance objectively measured
through structured observation during the preschool period of
development and later hippocampal volume measured at school
age. These data were derived from a sample of depressed pre-
schoolers and age-matched healthy and other psychiatriccom-
parison groups, followed prospectively into school age, at which
time neuroimaging was conducted. Examining the relationship
between early maternal nurturance and laterhippocampal volume
in both healthy and depressed children allowed us to secondarily
examine mediators and/or moderators in the relationships be-
tween hippocampal volume, maternal nurturance, and childhood
Subjects were 92 children participating in a longitudinal study of
preschool depression who met all inclusion/exclusion criteria for
magnetic resonance brain imaging at ages 713 y. These children
were nonleft-hand-dominant children with usable left and/or
right hippocampus T1-weighted MRI volume data, who also had
parentchild interaction data acquired at ages 35 y, allowing us
to examine the relationship between early maternal support and
later childhood hippocampal volume. Demographic character-
istics of the study sample divided by depression severity scores
are listed in Tables 1 and 2.
Sex, age, and parental income were examined in separate re-
peated-measures models to determine whether they were sig-
nicantly related to hippocampal volume. Sex was signicantly
associated with hippocampal volume (P= 0.036), whereas age
(P= 0.955) and parental income (P= 0.088) were not. Therefore,
sex was included as a covariate in subsequent analyses. A repeated-
measures mixed model with compound symmetric covariance
structure was used to model the effects of maternal support, pre-
school depression severity, and their interaction on hippocampal
volume (Table 3). Brain hemisphere (left or right) and sex were
included as covariates in the model. The overall model was sig-
nicant (χ
=57.84,P<0.001), with maternal support (F
18.58, P<0.001) and the interaction of maternal support and
preschool depression severity (F
=4.07,P= 0.047) signicantly
associated with hippocampal volume. The estimated increase in
hippocampal volume by unit of increased maternal support (a
frequency) was 13.4 mm
. A model including the three-way in-
teraction of brain hemisphere, maternal support, and preschool
depression severity was conducted to determine whether the in-
teraction was specic to one hemisphere (Table 3). The three-way
interaction was not signicant (F
= 0.04, P= 0.848). Finally,
medication use, internalizing and externalizing symptom severity,
traumatic life events, and maternal history of depression were
added to the model as covariates. After controlling for these var-
iables, maternal support (F
= 18.09, P<0.001) and the in-
teraction of maternal support and preschool depression severity
=5.09,P= 0.027) were still signicantly associated with
hippocampal volume.
To parse the source of the interaction between maternal
support and preschool depression severity, we dichotomized sub-
jects into those with zero to three preschool depression symp-
toms (severity scores found in healthy samples, therefore a
subgroup with no clinical depression) and those with four to nine
preschool depression symptoms (high severity consistent with
clinical depression) and then examined the relationship of ma-
ternal support and hippocampal volume in these groups. Fig. 1 A
and Bshow the association of maternal support with left and
right hippocampal volume in these groups. Of note, there were
two subjects in the nondepressed group with maternal support
scores considerably greater than the others in this group. To test
whether these subjects were multivariate outliers, the Mahala-
nobis distance (MD) and its probability were calculated for all
nondepressed subjects (36). No subjects had P(MD) <0.001, so
no subjects were considered outliers, and all data were included
in the analyses (notably, even if these subjects are excluded, the
effect of maternal support on hippocampal volume remains
highly signicant). The relationship between maternal support
and hippocampal volume was signicant only in low-severity/
nondepressed children (F
= 9.22, P= 0.004) and not in de-
pressed/high-severity children (F
= 2.37, P= 0.134). We then
divided children into four groups (Fig. 2), illustrating that non-
depressed children with high maternal support had signicantly
larger hippocampal volumes than the following three groups:
nondepressed children with low maternal support (9.2% smaller
volume) and depressed children with high (6.0% smaller vol-
ume) or low maternal support (10.6% smaller volume).
These study ndings provide evidence in humans replicating the
positive relationship between early experiences of maternal nur-
turance and hippocampal volume well demonstrated in animal
models. Using data from a prospective, longitudinal study of de-
pressed preschoolers and comparison groups who underwent
neuroimaging at school age, we found that observationally mea-
sured maternal support during a mildly stressful interactive task in
early childhood was a powerful predictor of larger hippocampal
volume in both hemispheres at school age. The relationship be-
tween maternal support and hippocampal volume remained sig-
nicant even when other variables known to impact hippocampal
volume (e.g., stressful life events, sex, and depression severity)
were included in the model.
Further, maternal support and depression severity interacted
in predicting volume. Positive maternal support was a stronger
Luby et al. PNAS
February 21, 2012
vol. 109
no. 8
predictor of greater hippocampal volume in nondepressed
children. These ndings suggest that early maternal support
exerts a positive inuence on hippocampal development in
children without depression but not in depressed children, in
whom the negative effects of this risk condition seem to impede
the potential benets of maternal support. As such, our ndings
did not support the hypothesis that the inuence of maternal
support on hippocampal volume would be found among children
with depression. Instead, these results suggest that either
depression has an effect on hippocampal volumes that is not
mediated by maternal support or that an examination of ma-
ternal support before the onset of depression is needed to ade-
quately test this risk hypothesis. Our sample of depressed
children all had very-early-onset depression that was present
before our assessment of maternal support. Other limitations to
the design include the fact that maternal support was measured
only in early and not later in childhood and that earlier experi-
ences of nurturing before age 3 y, shown to be important to
Table 1. Characteristics of the sample, part 1
Preschool depression
severity score 49(n=41)
Preschool depression
severity score 03(n= 51)
Sex 0.46 0.499
Female 56.1 23 49.0 25
Male 43.9 18 51.0 26
Age (y) FE 0.560
6 2.4 1 (1 M, 0 F) 0.0 0 (0 M, 0 F)
7 4.9 2 (0 M, 2 F) 7.8 4 (1 M, 3 F)
8 9.8 4 (1 M, 3 F) 13.7 7 (5 M, 2 F)
9 34.1 14(4M,10F) 39.2 20(9M,11F)
10 24.4 10 (6 M, 4 F) 27.5 14 (10 M, 4 F)
11 19.5 8 (5 M, 3 F) 11.8 6 (1 M, 5 F)
12 4.9 2 (1 M, 1 F) 0.0 0 (0 M, 0 F)
Parental education 2.87 0.412
High school diploma 14.6 6 7.8 4
Some college 41.5 17 33.3 17
4-y college degree 17.1 7 29.4 15
Graduate education 26.8 11 29.4 15
Psychotropic medication use 1.74 0.187
Yes 29.3 12 17.6 9
No 70.7 29 82.4 42
Maternal history of depression 0.80 0.370
Yes 42.5 17 33.3 17
No 57.5 23 66.7 34
Maternal prenatal tobacco use 1.05 0.307
Yes 27.8 10 18.2 8
No 72.2 26 81.8 36
Maternal prenatal alcohol use 4.31 0.038
Yes 36.1 13 15.9 7
No 63.9 23 84.1 37
F, female; FE, Fishers exact test; M, male.
Table 2. Characteristics of the sample, part 2
depression severity
score 49(n=41)
depression severity
score 03(n=51)
tPMean SD Mean SD
Maternal support 12.17 9.13 12.12 8.91 0.03 0.978
Preschool depression severity 5.12 1.25 1.41 1.04 15.53 <0.001
Internalizing dimensional score 6.66 3.21 3.10 1.97 6.23 <0.001
Externalizing dimensional score 10.12 7.39 4.25 4.38 4.49 <0.001
No. of traumatic life events 2.78 1.76 1.57 1.37 3.67 <0.001
IQ score 104.1 14.1 108.2 15.9 1.30 0.197
Birth weight (kg) 3.24 0.55 3.34 0.63 0.86 0.392
Gestational age (wk) 38.82 2.09 39.06 2.38 0.50 0.620
Days in NICU 0.31 0.98 3.50 14.92 1.35 0.185
Hippocampus volume, right (mm
) 1,720 169 1,789 212 1.66 0.101
Hippocampus volume, left (mm
) 1,715 136 1,781 195 1.79 0.078
IQ, intelligence quotient; NICU, neonatal intensive care unit.
| Luby et al.
developmental outcomes, were not prospectively studied. Pro-
spective research in high-risk samples before the onset of de-
pression may be needed to specically assess whether hippocampal
volume mediates a relationship between poor early nurturance and
subsequent risk for depression.
The experience of a nurturing caregiver early in life has proven
to be one of the most essential prerequisites for healthy de-
velopment and adaptive functioning in mammals (37). The cur-
rent data provide evidence that the well-established signicant
impact of positive parenting on enhancing and maintaining
hippocampal neuroplasticity, likely through epigenetic mecha-
nisms enhancing neurogenesis, as suggested by the work of
Naumova et al. (17), may also to be operative in humans. Fur-
ther, it was notable that this effect remained robust even after
controlling for other factors known to impact hippocampal vol-
ume, such as stressful life events and maternal history of de-
pression. Importantly, although 96.7% of caregivers in this study
sample were mothers, we expect that this effect pertains to the
primary caregiver (the provider of nurturance) whether it be
mother, father, grandparent, or other.
Whether maternal support early in childhood is more or less
powerful than at later periods of development is of interest and
remains unclear from these data. However, sensitive periods for
the importance of maternal support have been suggested by early
adoption studies (15). However, given the central role of the
caregiver in the life of the young child, this developmental period
would seem to be an optimal time for enhancing the early ma-
ternalchild relationship. On the basis of these data, one cannot
rule out that the relationship between maternal support and
hippocampal volume in offspring is based on genetic factors, that
supportive caregivers could have larger hippocampal volumes
and then have biological children with larger volumes. However,
there is no evidence in the literature of a relationship between
hippocampal volume and supportive care giving in adults. The
Fig. 1. (A) Left side hippocampal volume by preschool depression severity and maternal support. (B) Right side hippocampal volume by preschool depression
severity and maternal support.
Table 3. Repeated-measures mixed models of hippocampal volume
Model Estimate Fdf P
Model 1
Left brain hemisphere 3.20 0.06 1, 75 0.811
Female sex 78.87 5.76 1, 87 0.019
Preschool depression severity 7.68 0.39 1, 87 0.533
Maternal support 13.38 18.58 1, 87 <0.001
Preschool depression severity ×maternal support 1.59 4.07 1, 87 0.047
Model 2
Left brain hemisphere 5.40 0.09 1, 74 0.761
Female sex 78.82 5.75 1, 87 0.019
Preschool depression severity 7.63 0.39 1, 87 0.536
Maternal support 13.37 18.55 1, 87 <0.001
Preschool depression severity ×maternal support 1.61 4.02 1, 87 0.048
Preschool depression severity ×maternal support ×left brain hemisphere 0.06 0.04 1, 74 0.848
Model 3
Left brain hemisphere 0.74 0.00 1, 74 0.954
Female sex 75.57 4.62 1, 80 0.035
Psychiatric medication use 49.08 1.26 1, 80 0.265
Internalizing dimensional score 11.24 1.87 1, 80 0.175
Externalizing dimensional score 4.01 1.42 1, 80 0.237
Number of traumatic life events 11.17 0.86 1, 80 0.357
Maternal history of depression 28.95 0.59 1, 80 0.446
Preschool depression severity 11.30 0.44 1, 80 0.511
Maternal support 14.25 18.09 1, 80 <0.001
Preschool depression severity ×maternal support 1.92 5.09 1, 80 0.027
Luby et al. PNAS
February 21, 2012
vol. 109
no. 8
available data also suggest that heritability of hippocampal vol-
umes is moderate and lower than many other brain regions (38).
Furthermore, numerous studies have demonstrated that the
hippocampus is sensitive to environmental and psychosocial
inuences in both animals and humans, making a purely genetic
mechanism less likely (9, 39). Despite these assurances, longi-
tudinal scan data, including scans at the preschool period, would
be necessary to clarify the role of genetic factors, a conclusion
underscored by previous research showing that smaller hippo-
campal volumes increased the risk for development of stress-
related psychopathology, suggesting that complex interactive
processes could be at play (35).
These data extend the current literature, establishing the cru-
cial role of the caregiver in early childhood for healthy social and
emotional development by demonstrating that the early experi-
ence of supportive caregiving also positively impacts structural
development of the hippocampus, at least in children without
early-onset depression. Notably, the relationships between ma-
ternal support and hippocampal volumes remained highly sig-
nicant when comorbid internalizing and externalizing symptoms
were controlled in the analysis. The importance of this effect is
underscored by the fact that the hippocampus is a brain region
central to memory, emotion regulation, and stress modulation, all
areas key to healthy social adaptation. We believe these ndings
have potentially profound public health implications and suggest
that greater public health emphasis on early parenting could
be a very fruitful social investment. The nding that early par-
enting support, a modiable psychosocial factor, is directly re-
lated to healthy development of a key brain region known to
impact cognitive functioning and emotion regulation opens an
exciting opportunity to impact the development of children in
a powerful and positive fashion. This nding, when replicated,
would strongly suggest enhancement of public policies and pro-
grams that provide support and parenting education to caregivers
early in development.
Materials and Methods
Participants. The study sample was originally recruited between the ages of 3
and 6 y from daycare centers and preschools in the St. Louis metropolitan area
using a screening checklist to oversample children with symptoms of de-
pression (40). Healthy preschoolers and those with other psychiatric dis-
orders were included as comparison groups for the original study sample
ascertainment. Preschoolers with neurological or chronic medical problems
or those with signicant developmental delays were excluded. Informed
consent (or assent) was obtained from all study subjects, who were fully
informed about the nature and consequences of the study procedures be-
fore participation. Children and their caregivers were assessed at four to six
annual waves before the time of scanning.
Measures. At each annual wave, parents were interviewed about their child
using the Preschool Age Psychiatric Assessment (PAPA), an age-appropriate
diagnostic interview addressing the childs psychiatric symptoms and stressful
life events with established reliability (41). The PAPA was used to derive
depression severity scores by summing all symptoms of depression, a variable
previously shown to be a sensitive measure of the severity of illness (42).
Further details on training and administration of the PAPA in the study
sample can be found in Luby et al. (40).
At the second annual wave, when subjects were between the ages of
4 and 7 y, parent and child were also observed interacting in a mildly
stressful challenging task in the laboratory, the waiting task,during
which maternal support was measured. The waiting task is a parentchild
interaction paradigm designed to elicit mild stress for both members of
thedyad(43).Thetaskrequiresthechild to wait for 8 min before opening
a brightly wrapped gift, which is sitting within arms reach. Concurrently
the childs primary caregiver completes questionnaires. The supportive
and/or nonsupportive care giving strategies that the parent uses to help
regulate the childs impulse and desire to open the gift immediately are
coded by staff trained to reliability. Each display of specictypesofsup-
portive strategies by the caregiver is counted as 1 unit. Several research
groups have previously reported acceptable psychometric properties for
the task, and it is a well-validated approach to measuring parenting
strategy during which maternal support and responsiveness was evalu-
ated (43, 44).
Maternal history of depression was measured using the Family Interview
for Genetic Studies (45), a widely used and well-validated measure of family
history of psychiatric disorders. Detailed methods of training and adminis-
tration are described by Luby et al. (40).
Structural Imaging Methods. Parents of either healthy or depressed study
subjects who were participants in a longitudinal study of preschool-onset
depression were screened by phone to determine whether any exclusion
criteria for MRI scanning were present. Exclusion criteria included (i) con-
traindications for MRI scanning; (ii ) head injury with loss of consciousness >5
min; (iii) stroke, seizure disorder, or other chronic neurological or medical
illness with known neurological impact; (iv) diagnosis of a pervasive de-
velopmental disorder; and (v) treatment for lead poisoning.
All MR scans were performed on a Siemens 3.0-T Tim Trio dedicated
research scanner. Subjects were scanned without sedation in a semi-
standardized position. Two 3D T1-weighted magnetization prepared rapid
gradient echo research-tailored MR scans (1-mm isotropic voxels) were ac-
quired sagittally (repetition time 2,400 ms, echo time 3.16 ms, inversion
time 1,200 ms, ip angle 8°, slab 160 mm, 160 partitions, 256 ×256 matrix,
eld of view 256, total scanning time 12:36). Images were coregistered and
averaged to increase signal to noise ratio (46), then 16-bit image data were
linearly interpolated to 0.5-mm
voxels and converted to 8-bit using AN-
ALYZE (47).
Hippocampal volumes were derived from a well-established template-
based automated segmentation using high-dimensional transformation
methods (4850). Briey, hippocampal segmentations and volumes were
derived from an atlas- or template-based automated segmentation using
a high-dimensional transformation after placement of standardized land-
marks by an experienced rater (C.B.) (51) and preliminary transformations
using these landmarks. Hippocampus boundary denitions were standard-
ized as detailed in previous reports (48, 52). As specied by these denitions,
a template segmentation was created by hand (C.B.) and based on one
subject with typical anatomy and reviewed by neuroanatomical gold stan-
dard experts (K.N.B. and Mohktar Gado). This gold standard hippocampal
segmentation was converted to a 3D tessellated surface. Using the land-
marks, the target (subject) images were oriented to the template image by
initially applying a rigid landmark transformation algorithm, followed by
a more precise target to template nonlinear, large deformation landmark
matching algorithm (LDL). Voxel intensities in each target image were scaled
to more closely match those of the template image. A high-dimensional
transformation, large deformation diffeomorphic metric mapping (51), was
then used to generate a transformed template surface. After inverting the
LDL algorithm described above, the transformed template surface repre-
sented the target (subject) hippocampus. The reliability of this process is
equivalent or superior to manual outlining by experts (52). All segmentation
results were blindly reviewed for accuracy (C.B.), and inadequately dened
hippocampi were not included in analyses. Hippocampal volumes included
all hippocampal gray matter and white matter contained within the
segmented structure.
ACKNOWLEDGMENTS. The authors thank Michael J. Miller and Tilak
Ratnanather of the Center for Imaging Science, The Johns Hopkins University,
for their technical assistance and insights with the implementation of the
large deformation diffeomorphic metric mapping to quantify the hippo-
Fig. 2. Hippocampus volume by preschool depression severity and maternal
| Luby et al.
campus volumes. Funding for this study was provided by National Institute of
Mental Health Grants MH64769 (to J.L.L.) and MH090786 (to J.L.L., D.M.B.,
and K.N.B.). The data reported in this paper are archived at the Washington
University School of Medicine.
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Luby et al. PNAS
February 21, 2012
vol. 109
no. 8
... Lower sensitivity and less secure attachment in infancy have predicted larger amygdala and hippocampal volumes at later ages (e.g., Bernier et al., 2019;Cortes Hidalgo et al., 2019;Khoury et al., 2019;Lee et al., 2019;Lyons-Ruth et al., 2016;Rao et al., 2010). In contrast, lower maternal nurturance or sensitivity assessed nearer to school age has shown inconsistent effects on hippocampal volume in childhood (Kok et al., 2015;Luby et al., 2012). ...
... In addition, a meta-analysis of research on humans who experienced childhood abuse revealed mixed findings, with reduced hippocampal volume seen among adults exposed to childhood abuse, but no differences in hippocampal volume seen among children exposed to abuse (Reim et al., 2015). Notably, however, our findings are consistent with human studies of younger children, which have shown associations between higher cortisol levels and increased hippocampal volumes (Wiedenmayer et al., 2006) and between exposure to insensitive parenting in infancy and increased hippocampal volumes across ages (Bernier et al., 2019;Lee et al., 2019;Khoury et al., 2019;Rao et al., 2010;Rifkin-Graboi et al., 2015; but see Kok et al., 2015;Luby et al., 2012). In addition, greater maternal postnatal anxiety (known to be correlated with elevated maternal and infant cortisol) is associated with greater infant right hemisphere hippocampal growth (Qiu et al., 2013). ...
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Despite a large animal literature documenting the role of low maternal nurturance and elevated glucocorticoid production on offspring limbic development, these pathways have not yet been assessed during human infancy. Informed by animal models, the present study examined whether 1) maternal disrupted interaction is related to infant cortisol levels, 2) infant cortisol levels are associated with infant limbic volumes, and 3) infant cortisol levels mediate associations between maternal disrupted interaction and infant limbic volumes. Participants included 57 mother-infant dyads. Infant saliva was measured at one time point before and two time points after the Still-Face Paradigm (SFP) at age 4 months. Five aspects of maternal disrupted interaction were coded during the SFP reunion episode. Between 4 and 25 months (M age = 11.74 months, SD = 6.12), under natural sleep, infants completed an MRI. Amygdala and hippocampal volumes were calculated via automated segmentation. Results indicated that 1) maternal disrupted interaction, and specifically disoriented interaction, with the infant was associated with higher infant salivary cortisol (AUCg) levels during the SFP, 2) higher infant AUCg was related to enlarged bilateral amygdala and hippocampal volumes, and 3) infant AUCg mediated the relation between maternal disrupted interaction and infant amygdala and hippocampal volumes. Findings are consistent with controlled animal studies and provide evidence of a link between increased cortisol levels and enlarged limbic volumes in human infants. Results further suggest that established interventions to decrease maternal disrupted interaction could impact both infant cortisol levels and infant limbic volumes.
... Lower maternal sensitivity (Kok et al., 2015) and less secure infant attachment (LeBlanc et al., 2017) predicted lower GMV, but not WMV, in middle childhood. In contrast, lower sensitivity and less secure attachment predicted increased amygdala and hippocampal volumes at later ages (Bernier et al., 2019;Cortes Hidalgo et al., 2019;Khoury et al., 2019;Lee et al., 2019;Lyons-Ruth et al., 2016;Moutsiana et al., 2015;Rao et al., 2010; but see Kok et al., 2015;Luby et al., 2012). Increased childhood limbic volumes related to insensitive parenting in infancy contrast with the decreased limbic volumes related to childhood abuse . ...
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Distinct neural effects of threat versus deprivation emerge by childhood, but little data are available in infancy. Withdrawn versus negative parenting may represent dimensionalized indices of early deprivation versus early threat, but no studies have assessed neural correlates of withdrawn versus negative parenting in infancy. The objective of this study was to separately assess the links of maternal withdrawal and maternal negative/inappropriate interaction with infant gray matter volume (GMV), white matter volume (WMV), amygdala, and hippocampal volume. Participants included 57 mother-infant dyads. Withdrawn and negative/inappropriate aspects of maternal behavior were coded from the Still-Face Paradigm at four months infant age. Between 4 and 24 months (M age = 12.28 months, SD = 5.99), during natural sleep, infants completed an MRI using a 3.0 T Siemens scanner. GMV, WMV, amygdala, and hippocampal volumes were extracted via automated segmentation. Diffusion weighted imaging volumetric data were also generated for major white matter tracts. Maternal withdrawal was associated with lower infant GMV. Negative/inappropriate interaction was associated with lower overall WMV. Age did not moderate these effects. Maternal withdrawal was further associated with reduced right hippocampal volume at older ages. Exploratory analyses of white matter tracts found that negative/inappropriate maternal behavior was specifically associated with reduced volume in the ventral language network. Results suggest that quality of day-to-day parenting is related to infant brain volumes during the first two years of life, with distinct aspects of interaction associated with distinct neural effects.
... Second, mother's absence may hinder children's development more severely than father's absence [25,36,42]. One possible explanation is that maternal care and parent-child interaction play a vital role in a child's brain development [93,94]. ...
Children's well-being of immigrants is facing several challenges related to physical, mental, and educational risks, which may obstacle human capital accumulation and further development. In rural China, due to the restriction of Hukou registration system, nearly 9 million left-behind children (LBC) are in lack of parental care and supervision in 2020 when their parents internally migrate out for work. Through the systematic scoping review, this study provides a comprehensive literature summary and concludes the overall negative effects of parental migration on LBC's physical, mental (especially for left-behind girls), and educational outcomes (especially for left-behind boys). Noticeably, both parents' and mother's migration may exacerbate LBC's disadvantages. Furthermore, remittance from migrants and more family-level and social support may help mitigate the negative influence. Finally, we put forward theoretical and realistic implications which may shed light on potential research directions. Further studies, especially quantitative studies, are needed to conduct a longitudinal survey, combine the ongoing Hukou reform in China, and simultaneously focus on left-behind children and migrant children.
... Lower maternal sensitivity (Kok et al., 2015) and less secure infant attachment (LeBlanc et al., 2017) predicted lower GMV, but not WMV, in middle childhood. In contrast, lower sensitivity and less secure attachment predicted increased amygdala and hippocampal volumes at later ages (Bernier et al., 2019;Cortes Hidalgo et al., 2019;Khoury et al., 2019;Lee et al., 2019;Lyons-Ruth et al., 2016;Moutsiana et al., 2015;Rao et al., 2010; but see Kok et al., 2015;Luby et al., 2012). Increased childhood limbic volumes related to insensitive parenting in infancy contrast with the decreased limbic volumes related to childhood abuse . ...
Background: Maternal stress (MS) is a well-documented risk factor for impaired emotional development in offspring. Rodent models implicate the dentate gyrus (DG) of the hippocampus in the effects of MS on offspring depressive-like behaviors, but mechanisms in humans remain unclear. Here, we test across two independent cohorts whether MS is associated with depressive symptoms and with DG micro- and macro-structural alterations in offspring. Methods: We analyzed DG DTI mean diffusivity (DG-MD) and volume in a 3-Generation Family Risk for Depression study (TGS; n=69, mean age 35.0) and the Adolescent Brain Cognitive Development Study (ABCD; n=5196, mean age 9.9) using generalized estimating equation models and mediation analysis. MS was assessed by the Parenting Stress Index (in TGS) and a measure compiled from the Adult Response Survey (ABCD). PHQ-9 and rumination scales (TGS) and Child Behavior Checklist (ABCD) measured offspring depressive symptoms at follow-up. Schedule for Affective Disorders and Schizophrenia-Lifetime interview measured depression diagnoses. Results: Across cohorts, MS was associated with future symptoms and higher DG-MD (indicating disrupted microstructure) in offspring. Higher DG-MD was associated with higher symptom scores measured 5 years (TGS) and 1-year (ABCD) after MRI. In ABCD, DG-MD is increased in high-MS offspring who have depressive symptoms at follow-up, but not in offspring who remain resilient or whose mother had low MS. Conclusions: Converging results across two independent samples extend previous rodent studies and suggest a role for the DG in exposure to MS and offspring depression.
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In children, psychotic-like experiences (PLEs) are related to risk of psychosis, schizophrenia, and other mental disorders. Maladaptive cognitive functioning is a well-known risk factor and early marker for psychosis, schizophrenia, and other mental disorders. Since cognitive functioning is linked to various genetic and environmental factors during development, we hypothesize that it mediates the effects of those factors on childhood PLEs. Using large longitudinal data, we tested the relationships of genetic and environmental factors (such as familial and neighborhood environment) with cognitive intelligence and their relationships with current and future PLEs in children. To estimate associations against potential confounding bias, we leveraged large-scale multimodal data of 6,602 children (aged 9-10 years old; 47.15% females; 5,211 European-ancestry) from the Adolescent Brain and Cognitive Development Study. Linear mixed model and a novel structural equation modeling (SEM) method that allows estimation of both components and factors were used to estimate the joint effects of cognitive phenotypes polygenic scores (PGSs), familial and neighborhood socioeconomic status (SES), and supportive environment on NIH Toolbox cognitive intelligence and PLEs. We adjusted for ethnicity (genetically defined), schizophrenia PGS, and additionally unobserved confounders (using computational confound modeling). We identified that lower cognitive intelligence and higher PLEs correlated significantly with several genetic and environmental variables: i.e., lower PGSs for cognitive phenotypes, lower familial SES, lower neighborhood SES, lower supportive parenting behavior, and lower positive school environment. In SEM, lower cognitive intelligence significantly mediated the genetic and environmental influences on higher PLEs (Indirect effects of PGS: β range=-0.0355~ -0.0274; Family SES: β range=-0.0429~ -0.0331; Neighborhood SES: β range=0.0126~ 0.0164; Positive Environment: β range=-0.0039~ -0.003). Supportive parenting and a positive school environment had the largest total impact on PLEs (β range=-0.152~ -0.1316) than any other genetic or environmental factors. Our results reveal the role of genetic and environmental factors on children’s PLEs via its negative impact on cognitive intelligence. Our findings have policy implications in that improving the school and family environment and promoting local economic development might be a way to enhance cognitive and mental health in children.
Background: Development of children born very preterm (VPT) is evaluated using the Bayley Scales of Infant Development. Early Bayley scores may not predict later outcomes. We studied whether VPT Bayley trajectories in the early years predicted school readiness better than single assessments. Methods: We prospectively evaluated 53 VPT at 4-5 years using standardized measures of school readiness, including the domains of cognition, early mathematical and literacy abilities, and motor skills. Predictors were Bayley-III scores obtained 1-5 times/child between 6 and 35 months. Linear mixed models (LMM) with random effects extracted estimated random effect for slope (change in Bayley score/1 year) and fixed+random effect sum for the intercept (initial Bayley score) for each participant, to then evaluate 4-5-year outcomes prediction. Results: Variability of individual trajectories prevailed across developmental domains. For the initial LMM, adding Bayley change to models with only initial score improved model fits for several Bayley-III domains. Models containing estimates for initial Bayley scores and Bayley change explained significantly more variability in school readiness scores (21-63%) than either variable alone. Conclusion: Neurodevelopmental follow-up of VPT is more relevant to school readiness when children are assessed multiple times in the first 3 years. Neonatal intervention research could use early trajectories rather than single timepoints as outcomes. Impact: This study is the first to examine individual Bayley scores and trajectories to predict school readiness of formerly preterm children at 4-5 years. Modeling demonstrated extreme variability of individual trajectories compared to the group's average trajectories. Models containing initial Bayley scores and Bayley change over time explained more variability in preschool readiness than either variable alone. Using the Bayley to predict future school readiness is enhanced by administration across multiple follow-up visits and inclusion of change across the first 3 years. Follow-up care models and clinical trial design for neonatal interventions may benefit from a trajectory-based approach to outcomes evaluation.
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The brain is the central organ of the body's response to and perception of stress. Both the juvenile and the adult brain show a significant capacity for lasting physiological, structural and behavioral plasticity as a consequence of stress exposure. The hypothesis that epigenetic mechanisms might lie behind the lasting effects of stress upon the brain has proven a fruitful one. In this review, we examine the growing literature showing that stress has a direct impact on epigenetic marks at all life history stages thus far examined and how, in turn, epigenetic mechanisms play a role in altering stress responsiveness, anxiety and brain plasticity across the lifespan and beyond to succeeding generations. In addition, we will examine our own recent findings that stress interacts with the epigenome to regulate the expression of transposable elements in a regionally specific fashion, a finding with significant implications for a portion of the genome which is tenfold larger than that occupied by the genes themselves.
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Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r's > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to stress in the offspring.
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This paper examine the Euler-Lagrange equations for the solution of the large deformation diffeomorphic metric mapping problem studied in Dupuis et al. (1998) and Trouvé (1995) in which two images I 0, I 1 are given and connected via the diffeomorphic change of coordinates I 0○ϕ−1=I 1 where ϕ=Φ1 is the end point at t= 1 of curve Φ t , t∈[0, 1] satisfying .Φ t =v t (Φ t ), t∈ [0,1] with Φ0=id. The variational problem takes the form $$\mathop {\arg {\text{m}}in}\limits_{\upsilon :\dot \phi _t = \upsilon _t \left( {\dot \phi } \right)} \left( {\int_0^1 {\left\| {\upsilon _t } \right\|} ^2 {\text{d}}t + \left\| {I_0 \circ \phi _1^{ - 1} - I_1 } \right\|_{L^2 }^2 } \right)
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Previous studies with nonhuman species have shown that animals exposed to early adversity show differential DNA methylation relative to comparison animals. The current study examined differential methylation among 14 children raised since birth in institutional care and 14 comparison children raised by their biological parents. Blood samples were taken from children in middle childhood. Analysis of whole-genome methylation patterns was performed using the Infinium HumanMethylation27 BeadChip assay (Illumina), which contains 27,578 CpG sites, covering approximately 14,000 gene promoters. Group differences were registered, which were characterized primarily by greater methylation in the institutionalized group relative to the comparison group, with most of these differences in genes involved in the control of immune response and cellular signaling systems, including a number of crucial players important for neural communication and brain development and functioning. The findings suggest that patterns of differential methylation seen in nonhuman species with altered maternal care are also characteristic of children who experience early maternal separation.
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Maternal separation and poor maternal care in animals have been shown to have important effects on the developing hippocampus and amygdala. In humans, children exposed to abuse/maltreatment or orphanage rearing do not present changes in hippocampal volumes. However, children reared in orphanages present enlarged amygdala volumes, suggesting that the amygdala may be particularly sensitive to severely disturbed (i.e., discontinous, neglectful) care in infancy. Maternal depressive symptomatology has been associated with reductions in overall sensitivity to the infant, and with an increased rate of withdrawn, disengaged behaviors. To determine if poor maternal care associated with maternal depressive symptomatology has a similar pattern of association to the volumes of the hippocampus and amygdala in children, as is the case for severely disturbed infant care (orphanage rearing), we measured hippocampal and amygdala volumes as well as stress hormone (glucocorticoid) levels in children exposed (n = 17) or not (n = 21) to maternal depressive symptomatology since birth. Results revealed no group difference in hippocampal volumes, but larger left and right amygdala volumes and increased levels of glucocorticoids in the children of mothers presenting depressive symptomatology since birth. Moreover, a significant positive correlation was observed between mothers' mean depressive scores and amygdala volumes in their children. The results of this study suggest that amygdala volume in human children may represent an early marker of biological sensitivity to quality of maternal care.
Context: Childhood depression is a serious and relapsing psychiatric disorder. However, to date studies have focused mostly on children aged 6 years and older. Validation for depression in preschool children has been provided by 2 independent study samples. While several studies have demonstrated stability and poor outcomes of internalizing symptoms in preschoolers, there has not yet been longitudinal data available to inform the course of preschool depression and whether it shows homotypic continuity into early childhood. Objective: To examine the 24-month course of preschool depression and whether it showed homotypic vs heterotypic continuity or was a developmentally transient phenomenon. Design: Blindly rated, prospective, 24-month, longitudinal follow-up study. Setting: Community sites. Patients: Three hundred six preschoolers aged 3 to 6 years recruited from community sites and oversampled for symptoms of depression. Main Outcome Measure: Recurrence/stability of depression and predictors of course. Results: Preschoolers with depression at baseline had the highest likelihood of subsequent depression 12 and/or 24 months later compared with preschoolers with no baseline disorder and with those who had other psychiatric disorders. Preschoolers with depression at baseline were more likely to have later depression rather than other psychiatric disorders. Findings from a logistic regression analysis indicated that when controlling for demographic variables, risk factors, and comorbid disorders, depression during the preschool period and family history of affective disorders were the most robust and significant predictors of later depression. Conclusions: Preschool depression, similar to childhood depression, is not a developmentally transient syndrome but rather shows chronicity and/or recurrence. Homotypic continuity of preschool MDD during a 24-month period was found. These results underscore the clinical and public health importance of identification of depression as early as preschool. Further follow-up of preschoolers with depression is warranted to inform the longitudinal course throughout childhood.
Because the results of a regression analysis can be sensitive to outliers (either on y or in the space of the predictors), it is important to be able to detect such points. The author discusses and interrelates the following 4 diagnostics that are useful in identifying outliers: studentized residuals, the hat elements, Cook's distance, and Mahalanobis distance. Guidelines are given for interpretation of the diagnostics. Outliers will not necessarily be influential in affecting the regression coefficients. (27 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)