Reduced Cingulate Gyrus Volume Associated with
Enhanced Cortisol Awakening Response in Young
Healthy Adults Reporting Childhood Trauma
Shaojia Lu1., Weijia Gao1., Zhaoguo Wei1,2, Weiwei Wu1, Mei Liao1, Yuqiang Ding1,3, Zhijun Zhang4,
1Mental Health Institute, The Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan,
China, 2Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, China, 3Key Laboratory of Arrhythmias, Ministry of Education, East Hospital,
Tongji University School of Medicine, Shanghai, China, 4The Department of Neuropsychiatry and Institute of Neuropsychiatric Research Affiliated ZhongDa Hospital of
Southeast University, Nanking, Jiangsu, China, 5Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, China
Background: Preclinical studies have demonstrated the relationship between stress-induced increased cortisol levels and
atrophy of specific brain regions, however, this association has been less revealed in clinical samples. The aim of the present
study was to investigate the changes and associations of the hypothalamic-pituitary-adrenal (HPA) axis activity and gray
matter volumes in young healthy adults with self-reported childhood trauma exposures.
Methods: Twenty four healthy adults with childhood trauma and 24 age- and gender-matched individuals without
childhood trauma were recruited. Each participant collected salivary samples in the morning at four time points:
immediately upon awakening, 30, 45, and 60 min after awakening for the assessment of cortisol awakening response (CAR).
The 3D T1-weighted magnetic resonance imaging data were obtained on a Philips 3.0 Tesla scanner. Voxel-based
morphometry analyses were conducted to compare the gray matter volume between two groups. Correlations of gray
matter volume changes with severity of childhood trauma and CAR data were further analyzed.
Results: Adults with self-reported childhood trauma showed an enhanced CAR and decreased gray matter volume in the
right middle cingulate gyrus. Moreover, a significant association was observed between salivary cortisol secretions after
awaking and the right middle cingulate gyrus volume reduction in subjects with childhood trauma.
Conclusions: The present research outcomes suggest that childhood trauma is associated with hyperactivity of the HPA axis
and decreased gray matter volume in the right middle cingulate gyrus, which may represent the vulnerability for
developing psychosis after childhood trauma experiences. In addition, this study demonstrates that gray matter loss in the
cingulate gyrus is related to increased cortisol levels.
Citation: Lu S, Gao W, Wei Z, Wu W, Liao M, et al. (2013) Reduced Cingulate Gyrus Volume Associated with Enhanced Cortisol Awakening Response in Young
Healthy Adults Reporting Childhood Trauma. PLoS ONE 8(7): e69350. doi:10.1371/journal.pone.0069350
Editor: Yong Fan, Institution of Automation, CAS, China
Received March 11, 2013; Accepted June 8, 2013; Published July 24, 2013
Copyright: ? 2013 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors sincerely thank the support of funds from the Major Project of Chinese National Programs for Fundamental Research and Development
(973 program, 2009CB918303 to LJL), the National Natural Science Foundation of China (30830046, 81171286 & 91232714 to LJL), the Innovation Project of Hunan
Graduate Education (CX2012B100 to SJL), and National Hi-Tech Research and Development Program of China (863 program, 2008AA02Z413 to ZJZ). The funders
had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
. These authors contributed equally to this work.
Early life stress, including childhood trauma, which is very
common in our society, has been established as a great risk factor
in the subsequent development of multiple psychiatric disorders
and unfavorable behavior patterns . Previous studies have
investigated the possible pathways from early life stress to
psychosis, however, to date, little is known about the mechanisms
underlying this association . Recently, biological mechanisms
such as dysfunction of the hypothalamic-pituitary-adrenal (HPA)
axis  and altered volumes of specific brain regions  after
exposures to early life stress have been reported which may help to
elucidate the close relationship between early life stress and onset
Although not always consistent, findings for hyperactivity of the
HPA axis as indicated by increased cortisol and adrenocortico-
tropin-releasing hormone (ACTH) responses to a psychological
stress task  and to the dexamethasone/corticotropin-releasing
factor (Dex/CRF) test , hypersecretion of salivary cortisol over
the daytime hours , and enhanced cortisol awakening response
(CAR)  among individuals with early life stress independent of
psychosis diagnosis have been observed in an emerging body of
investigations. With regard to anatomical magnetic resonance
imaging studies, increasing evidence has shown a strong link
PLOS ONE | www.plosone.org1July 2013 | Volume 8 | Issue 7 | e69350
between decreased hippocampus volume and early life stress
[4,8,9]. Moreover, childhood emotional maltreatment was report-
ed to be associated with profound reductions of medial prefrontal
cortex (mPFC) volume  and in another study early deprivation
was revealed to be correlated with reduced orbital-frontal cortical
volume in postinstitutionalized children . In line with these,
the extent of gray matter loss in the cingulate cortex was suggested
to be related to a history of early adverse events in a group of
depression patients as well, although the sample size of the
experimental group was relatively small .
It has been well known that glucocorticoids have neurotoxic
effects in the central nervous system in some circumstances .
In addition, it is quite interesting that the altered brain regions
reported in subjects with early life stress contain high concentra-
tions of glucocorticoid receptors and act as well- documented roles
in regulating HPA activity . Hence, stress-related dysfunction
of the HPA axis and atrophy of the regulator regions may
precipitate a vicious circle which will result in greater exposure to
glucocorticoids and more severe damage to these brain regions.
This relationship has been revealed in preclinical studies , but
it is less explored in clinical samples. Therefore, the aim of the
present study was to investigate the changes and associations of the
HPA activity and gray matter volumes in young healthy adults
with self-reported childhood trauma exposures. To assess the HPA
axis activity, the CAR, a reliable biological marker of reflecting the
dynamic activity of the HPA axis , was administered to
evaluate morning cortisol release to awaken. Based on previous
findings, we hypothesized that childhood trauma could induce
hyperactivity of the HPA axis and decreased gray matter volume
in brain regions such as hippocampus, PFC, or cingulate gyrus;
and there could be associations between increased cortisol
concentrations and atrophy of those brain regions.
The study group comprised 48 subjects (male/female, 18/30),
ages 18–33 years, including 24 subjects with childhood trauma
experiences (CT group) and 24 age- and gender- matched subjects
without childhood trauma exposures (non-CT group). For
assignment to the CT group, individuals must have had
experienced chronic moderate-severe trauma exposures (abuse
or/and neglect) before the age of 16. All participants were
recruited from a survey that we had carried out to investigate the
occurrence of childhood trauma in local communities and
universities. Subjects responded with no direct reference to
childhood trauma as a key variable in the study. All subjects were
thoroughly interviewed by two professional psychologists and were
free from any current or lifetime history of psychiatric disorders
according to Diagnostic and Statistical Manual of Mental
Disorders, IV Edition (DSM- IV) criteria, as screened with the
Structured Clinical Interview for DSM-IV interview (SCID). The
general exclusions were as follows: (1) left handedness, (2) standard
scores .50 on Zung’s self-rating depression scale (SDS)  or
.40 on Zung’s self-rating anxiety scale (SAS) , (3) significant
medical illness, (4) presence of major sensorimotor handicaps, (5)
history of seizures, head trauma, or unconsciousness, (6) intake of
any psychotropic medication or hormone, (7) alcohol or substance
abuse, (8) women with pregnancy or in lactation or menstrual
period, and (9) contraindications to MRI scan, including metallic
implants, retractors or braces, and claustrophobia.
This study was approved by the ethic committee of the Second
Xiangya Hospital of Central South University. A complete
description of the study was provided to every subject, after that
written informed consent was obtained from each participant.
Assessment of childhood trauma
The existence or absence of childhood trauma was determined
by the childhood trauma questionnaire (CTQ) in all subjects. The
CTQ is a 28-item retrospective self-report questionnaire designed
to assess five types of negative childhood experiences by five sub-
scales: emotional abuse, emotional neglect, sexual abuse, physical
abuse, and physical neglect, respectively. Subjects who score
higher than the threshold of a sub-scale are treated as existence of
corresponding childhood trauma experience. The cutoffs of each
sub-scale for moderate-severe exposure are: 1) emotional abuse
$13, 2) emotional neglect $15, 3) sexual abuse $8, 4) physical
abuse $10, and 5) physical neglect $10. This reliable question-
naire has great internal consistency and criterion-related validity in
clinical and community samples; the good internal consistency
coefficients for the five subscales are demonstrated in many studies
Salivary samples were collected on the magnetic resonance
imaging scan day (weekdays) using SalivetteH collection devices
(Sarstedt, Nu ¨mbrecht, Germany) at altogether four time-points
throughout the morning: immediately upon awakening, 30, 45,
and 60 min following awakening. Samples were centrifuged at
3000 rpm (rounds per minute) for 10 min and recovered saliva
samples were stored at 270uC until analysis. Participants are
instructed not to brush their teeth and eat before completing
sampling, or engage in heavy exercise during the collecting hour.
Additionally, they were asked to refrain from smoking and from
drinks except water . Moreover, all subjects had to report the
time they went to bed as well as the time they woke up .
The DRGH Salivary Cortisol ELISA Kit, SLV –2390 (Marburg,
Germany) was used to measure salivary cortisol concentrations.
The range of the assay is between 0.537–80 ng/ml. The intra- and
inter-assay variability coefficients are 1.5–4.5% and 5.8–7.5%,
respectively. As measures of the CAR, the area under the curve
relative to ground (AUCg) and the area under the curve with
respect to increase (AUCi) were calculated using the formulas
described by Pruessner et al., (2003). The AUCg is a measure of
the total cortisol secretion throughout the first hour following
awakening, whereas the AUCi values reflect the dynamic of the
CAR, which is more related to the sensitivity of the HPA system
and focuses on the cortisol changes over time after awakening
Imaging data were acquired using a Philips 3.0-T scanner
(Philips, Best, The Netherlands) in the Magnetic Resonance
Center belonging to the Second Xiangya Hospital of Central
South University. Subjects were asked to lie on the scanner and
keep eyes closed. A standard birdcage head coil was used, and the
restraining foam pads were placed on two sides of the head to
minimize head motion while cotton plug was used with the
purpose of diminishing the noise. For each subject, a high-
resolution T1-weighted sequence using a three-dimensional
magnetization prepared rapid acquisition gradient echo sequence
was used. Images of the whole brain were acquired in an axial
orientation with the following parameters: slice thickness =1 mm,
Cingulate Gyrus Volume, CAR, and Childhood Trauma
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gap =0 mm, repetition time =7.6 ms, echo time =3.7 ms,
inversion time =795 ms, field of view =256*256 mm2, flip angle
=8u, matrix size =256*256, resolution =1.0*1.0*1.0, slices
=180, scan time =295899.
Voxel-based Morphometry (VBM) analysis
All T1-weighted high-resolution anatomical data were prepro-
cessed by using the previous method [26,27]. The analyses were
performed using the Statistical Parametric Mapping 8 (SPM8)
software (Wellcome Department of Imaging Neuroscience, Uni-
versity College London, UK; http://www.fil.ion.ucl.ac.uk/spm) in
a Matlab environment. The VBM8 Toolbox (http://dbm.neuro.
uni-jena.de/vbm.html) was used for preprocessing the structural
images in SPM8 with default parameters. The data was bias-
corrected, tissue classified, and normalized to Montreal Neuro-
logical Institute space using linear (12-parameter affine) and non-
linear transformations within a unified model . Then data
analyses were performed on gray matter segment which was
multiplied by the non-linear components derived from the
normalization matrix in order to preserve actual gray matter
value locally (modulated gray matter volume). Finally, the
modulated gray matter volume was smoothed with a Gaussian
kernel of 8 mm full width at half maximum.
Data analyses were carried out using Statistical Package for the
Social Sciences version 16.0 (SPSS Inc., Chicago, IL, USA).
Independent two-sample t tests and Chi-square tests (x2) were
respectively used to tests for the continuous variables and
categorical variables between the two groups. Salivary cortisol
samples after awakening were analyzed using repeated measures
ANOVA with time as the within-subjects factor and group as the
between-subjects factor. The potential confounders, such as age,
gender, time of awakening, hours of sleep, body mass index (BMI),
and smoking, were included as covariates in the measures
ANOVA to investigate possible effects on cortisol concentrations.
Values are given as mean 6 standard deviation. The level of two-
tailed statistical significance was set at p,0.05 for all tests.
For gray matter volume, two-sample t-test on a voxel-by-voxel
basis was performed to determine the difference between the two
groups. The statistical threshold was set at p,0.05, corrected for
multiple comparisons with false discovery rate (FDR) correction.
To evaluate any correlations between CTQ scores or CAR data
and gray matter structural changes in individuals with childhood
trauma, whole brain multiple regression analyses integrated in
SPM basic models were performed at p,0.05 (FDR corrected).
Moreover, Spearman rank correlation analysis was used to
evaluate the relationship between CTQ scores and CAR data.
As indicated in Table 1, the two groups of subjects did not
differ with respect to age (t=20.075, p=0.940), gender
(x2=0.000, p=1.000), educational level (t=21.407, p=0.166),
BMI (t=1.839, p=0.072), SAS score (t=1.430, p=0.160), SDS
score (t=1.014, p=0.316), and smoking status (Fish’s exact test
=2.063, p=0.609). As we would expect, the two experimental
groups differed on levels of CTQ and its sub-scales except sexual
abuse (t=3.234,11.38, p,0.01). The most common aspect of
childhood trauma experience in the present sample was emotional
neglect (17, 70.8%); a proportion of 62.5% (15) of traumatic
subjects experienced at least two forms of childhood trauma
Cortisol awakening response
There was no significant difference between two groups for time
of awakening (CT group 6:46619 min vs non-CT group
6:40622 min, p , 0.05) or hours of sleep (CT group
7.0460.69 h vs non-CT group 6.7860.47 h, p , 0.05). A
repeated-measures ANOVA of the morning salivary cortisol
concentrations revealed a significant main effect of group
p=0.000), and a group * time effect (F=3.667, p=0.014). There
were no main or interactive effects of age, gender, BMI, smoking,
time of awakening or hours of sleep on cortisol levels when
introduced as covariates in the ANOVA. Independent two-sample
t tests of the individual time points showed that salivary cortisol
concentrations were significantly higher in traumatic subjects at 30
and 45 min following awakening (see figure 1A). Meanwhile, a
statistically significant increase was observed for AUCg of salivary
cortisol secretion in subjects who had self-reported childhood
trauma experiences (see figure 1B). With respect to AUCi, the
CT group also showed a higher level than the non-CT group with
a statistically significant difference (see figure 1C).
Table 1. Demographic and clinical characteristics of all
CT group, n=24 non-CT group, n=24
Mean SD RangeMean SD Range
Age (Years)21.5 3.98 18–3321.5 3.6918–33
Gender (Male/Female)9/15 9/15
Educational level (Years)14.0 1.30 12–1714.7 1.9212–18
BMI (kg/m2)21.62.0517.7–25.020.6 1.62 18.3–23.3
SDS score 36.2 6.0625–4634.5 5.3027–48
SAS score 34.04.51 26–40 32.04.78 25–40
Smoking, n (%)
0 21(87.5) 22(91.7)
# 10 1(4.17)2(8.3)
Emotional abuse** 9.212.36 6–156.21 1.225–9
Physical abuse**7.83 2.935–14 5.711.33 5–9
Sexual abuse 5.460.83 5–75.38 0.58 5–6
Emotional neglect** 15.23.287–20 7.382.65 5–13
Physical neglect** 10.22.72 5–175.63 0.935–8
Total**47.9 6.0839–58 30.24.6325–40
CT exposures, n (%)
Single Exposure 9(37.5)
BMI, body mass index; CT, childhood trauma; CTQ, childhood trauma
questionnaire; SAS, self-rating anxiety scale; SD, standard deviation; SDS, self-
rating depression scale.
Cingulate Gyrus Volume, CAR, and Childhood Trauma
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Voxel-based analysis of morphometry
As compared with subjects without childhood trauma, individ-
uals with adverse experiences in childhood showed significant
volume reduction in the right middle cingulate gyrus (see
Figure 2). However, no region with significantly increased
volume in traumatic subjects was observed.
In subjects with childhood trauma, the whole brain linear
regression analysis conducted with SPM8 yielded a strong negative
association of the right middle cingulate gyrus volume with CAR
AUCg (see Table 2), however, there were no brain areas
revealing significant correlations with CTQ scores at the defined
threshold. Finally, a positive association was observed between
CTQ total score and CAR AUCg (rs=0.674, p=0.000) in
individuals with childhood trauma experiences.
The present study investigated the HPA activity as measured by
CAR and brain structural (gray matter volume) changes in young
healthy adults with and without childhood trauma experiences.
The current results revealed a significantly enhanced CAR and
decreased gray matter volume in the right middle cingulate gyrus
(BA 24) and furthermore, a significant association between
morning salivary cortisol levels after awaking and the right middle
cingulate gyrus volume in subjects with childhood trauma. These
outcomes together with the previous preclinical findings suggested
that stress-related brain structural volume reductions might be the
consequences of prolonged exposure to increased levels of
glucocorticoids resulting from chronic early life stress .
The enhanced CAR in subjects reporting childhood trauma
experiences was a main finding of the present study which
indicated that childhood trauma seemed to be a good predictor of
hyperactivity of the HPA axis even in the absence of current
psychosis diagnosis. This indication was supported by prior studies
evaluating the effect of childhood parent loss on adult HPA axis
function  and investigating the relationship between childhood
abuse and HPA axis function using a DEX/CRH test in female
borderline personality disorder patients , both demonstrating
the association between early life stress and hyperactivity of the
HPA axis. Our neuroendocrine findings were also generally in
accordance with a previous report in young healthy adults with
low parental care experiences exhibiting an increased CAR and
increased afternoon/evening cortisol outputs . However,
hyperactivity of the HPA axis in subjects with early life stress
was not always replicated, both diminished cortisol responses in
healthy adults reporting significant childhood maltreatment 
and decreased CAR in healthy college students after early loss
experiences  were observed in relevant studies. Several
potential explanations have been posited to account for this
inconsistency, such as sex differences, differences in the timing and
severity of childhood trauma, genetic factors, and different
Figure 1. Changes in cortisol awakening response (CAR) across the experimental groups. (A) Independent two sample t tests revealed
that significant differences of salivary cortisol levels were found between two groups at 30 (t=2.389, p=0.021) and 45 min (t=2.565, p=0.014) after
awakening. Significant increases of cortisol levels were observed in subjects with childhood trauma experiences at those two time points. (B) The CAR
area-under-the-curve to ground (AUCg) was significantly differed between two groups (t=2.335, p=0.024). Consistent with cortisol levels at 30 and
45 min, subjects who had self-reported childhood trauma showed higher levels of CAR AUCg. (C) With respect to the CAR area-under-the-curve
increase (AUCi), significant difference was found as well (t=2.532, p=0.016). *Comparison with non-CT group, p ,0.05. CT, childhood trauma.
Figure 2. Region of different gray matter volume between individuals with and without childhood trauma. Decreased gray matter
volume was detected in the right middle cingulate gyrus (Brodman area 24, x=6, y=26, z=39, cluster size =303, z score =4.25, puncorrected,0.001,
pFDR corrected =0.047,) in subjects with childhood trauma. The right middle cingulate gyrus is shown in blue.
Cingulate Gyrus Volume, CAR, and Childhood Trauma
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concomitant and subsequent psychosocial conditions in later life
In the present study, the right middle cingulate gyrus gray
matter volume reduction was detected in subjects with childhood
trauma. The cingulate gyrus, a part of the limbic system, plays a
critical role in two main neuroanatomic circuits that are believed
to be involved in mood regulation . The extensive connections
of the cingulate gyrus with the frontal lobe, the temporal lobe and
the striatal structures enable it to be an important area for the
integration of emotions . Our data was, at least in part,
comparable with findings of reduced gray matter volumes in the
cingulate gyrus in both healthy adolescents  and adults 
with high CTQ scores. Interestingly, smaller gray matter volume
in the cingulate gyrus was also present in patients with current or
remitted depression [37,38] and post traumatic stress disorder 
in previous anatomical MRI studies which had focused on this
region. In this regard, reduced cingulate gyrus volume before
illness onset which contributed a limbic scar induced by long-term
childhood trauma experiences in young healthy adults might
represent the psychobiological vulnerability for developing psy-
It has been demonstrated that hypercortisolism induced by
adrenalectomy with high-dose dexamethasone supplementation is
associated with a significant reduction in the volume of the
cingulate gyrus in rats . In this context, the observed
relationship between reduced cingulate gyrus and increased
salivary cortisol secretion after awaking in our study extended
that preclinical finding. As reported previously, the cingulate gyrus
contains high densities of glucocorticoid receptors in most layers
 which may make it one of the most vulnerable parts to the
neurotoxicity of increased glucocorticoids. In addition, the
cingulate gyrus also plays a crucial role in the regulation of the
HPA axis , and thus glucocorticoids induced damage to this
area may diminish its ability to exert negative feedback control
resulting in more glucocorticoid secretions. This cycle may help to
explain the origin of the present association in subjects with
childhood trauma, however, our study was cross-sectional
designed which precluded causal inferences. Further research will
be required to clearly clarify this causal relationship.
Unexpected from our initial expectations, this study did not
found any group differences of gray matter volume in hippocam-
pus and PFC that have predominantly been linked to childhood
trauma experiences. This may result from heterogeneity of
research samples or types of childhood trauma experiences.
Previous studies that have detected decreased gray matter volumes
in hippocampus and PFC associated with childhood trauma
experiences have measured this relationship in patients with
depression  or in a mixed study sample , including healthy
adults, patients with depression and/or anxiety disorder. There-
fore, volume reductions in hippocampus and PFC may probably
sever as results of co-appearance of childhood trauma and
psychosis but not childhood trauma alone. In addition, in our
sample, the subjects are young (average age=21.5) which may
restrain the time-dependent glucocorticoids induced atrophy of
key brain regions. Finally, most studies reporting neuroanatomical
correlates of childhood trauma with decreased hippocampus and
PFC volumes in adults have focused mainly on the impact of
sexual and/or physical abuse [42,43,44], but the most frequent
aspects of childhood trauma experiences in our samples are
physical and emotional neglect, which may also contribute to the
differences mentioned above.
Several limitations must be taken into account when interpret-
ing our findings. First, although it is suitable for CAR and VBM
analyses, the sample size in each group is relatively small which
restricts us to compare the different types of childhood trauma on
HPA axis activity and brain structural changes. Second, childhood
trauma experiences are evaluated by a retrospective self-reported
questionnaire; hence, the results could be influenced by informa-
tion biases. Finally, we cannot control for the subjects’ compliance
with the given sampling time schedule since a prior study has
indicated that the participants’ compliance with instructions is
generally low , which may influence the CAR outcomes.
However, our CAR results are characterized by a sharp increase
in cortisol levels following awaken, peaking at 30 min later which
well stands in line with other findings .
In conclusion, the present research outcomes suggest that
childhood trauma is associated with hyperactivity of the HPA axis
and decreased gray matter volume in the right middle cingulate
gyrus, which may represent the vulnerability for developing
psychosis after childhood trauma experiences. In addition, this
study demonstrates that gray matter loss in the cingulate gyrus is
related to increased cortisol levels.
The authors would like to thank all participants who took part in this study,
and the experts at the Magnetic Resonance Center of the Second Xiangya
Hospital for providing scan time and technical assistant.
Conceived and designed the experiments: SJL LJL ZJZ. Performed the
experiments: SJL ZGW WWW. Analyzed the data: WJG ML. Contributed
reagents/materials/analysis tools: WJG YQD. Wrote the paper: SJL LJL.
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AUCg, area-under-the-curve to ground; BA, Brodman area; CAR, cortisol awakening response; FDR, false discovery rate.
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PLOS ONE | www.plosone.org6 July 2013 | Volume 8 | Issue 7 | e69350