Childhood Maltreatment Is Associated with Larger Left
Thalamic Gray Matter Volume in Adolescents with
Generalized Anxiety Disorder
Mei Liao1, Fan Yang1, Yan Zhang1, Zhong He2, Ming Song3, Tianzi Jiang3, Zexuan Li1, Shaojia Lu1,
Weiwei Wu1, Linyan Su1*, Lingjiang Li1*
1Department of Psychiatry, the Second Xiangya Hospital of Central South University, Changsha, China, 2Department of Radiology, the Second Xiangya Hospital of
Central South University, Changsha, China, 3National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China
Background: Generalized anxiety disorder (GAD) is a common anxiety disorder that usually begins in adolescence.
Childhood maltreatment is highly prevalent and increases the possibility for developing a variety of mental disorders
including anxiety disorders. An earlier age at onset of GAD is significantly related to maltreatment in childhood. Exploring
the underpinnings of the relationship between childhood maltreatment and adolescent onset GAD would be helpful in
identifying the potential risk markers of this condition.
Methods: Twenty-six adolescents with GAD and 25 healthy controls participated in this study. A childhood trauma
questionnaire (CTQ) was introduced to assess childhood maltreatment. All subjects underwent high-resolution structural
magnetic resonance scans. Voxel-based morphometry (VBM) was used to investigate gray matter alterations.
Results: Significantly larger gray matter volumes of the right putamen were observed in GAD patients compared to healthy
controls. In addition, a significant diagnosis-by-maltreatment interaction effect for the left thalamic gray matter volume was
revealed, as shown by larger volumes of the left thalamic gray matter in GAD patients with childhood maltreatment
compared with GAD patients without childhood maltreatment as well as with healthy controls with/without childhood
maltreatment. A significant positive association between childhood maltreatment and left thalamic gray matter volume was
only seen in GAD patients.
Conclusions: These findings revealed an increased volume in the subcortical regions in adolescent GAD, and the alterations
in the left thalamus might be involved in the association between childhood maltreatment and the occurrence of GAD.
Citation: Liao M, Yang F, Zhang Y, He Z, Song M, et al. (2013) Childhood Maltreatment Is Associated with Larger Left Thalamic Gray Matter Volume in Adolescents
with Generalized Anxiety Disorder. PLoS ONE 8(8): e71898. doi:10.1371/journal.pone.0071898
Editor: Bogdan Draganski, Centre Hospitalier Universitaire Vaudois Lausanne - CHUV, UNIL, Switzerland
Received January 24, 2013; Accepted July 4, 2013; Published August 12, 2013
Copyright: ? 2013 Liao 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: This study was supported by the National Natural Science Foundation of China (30830046 & 81171286 & 91232714 to Lingjiang Li, 81171291 to Linyan
Su, 81101004 to Yan Zhang), the National 973 Program of China (2009CB918303 to Lingjiang Li) and Program of Chinese Ministry of Education (20090162110011
to Lingjiang Li). 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 (LL); email@example.com (LS)
Generalized anxiety disorder (GAD) is a common anxiety
disorder that usually begins in adolescence, and it affects about
5.7% people in the general population . GAD often co-occurs
with major depressive disorder  and causes significant distress or
impairment in life . However, GAD is less studied compared to
other anxiety disorders , despite its high prevalence and clinical
The core feature of GAD is pathological anxiety, which is
believed to arise from abnormalities in cortical/subcortical
interactions based on fear conditioning framework [5,6,7].
Sensory fibers from multiple sensory modalities arrive at the
amygdala passing through the thalamus . The amygdala
integrates different information and induces autonomic and
behavioral fear response . The thalamus plays an important
role in filtering sensory information and emotional regulation
. The insular cortex seems to be associated with modulating
subjective feeling states and interoceptive awareness . The
prefrontal cortex is involved in emotional regulation by down-
regulating the activity of the amygdala and related limbic
structures . The medial prefrontal cortex and hippocampus
are involved in the process of learning and remembering threat
stimulus [5,6]. Deficits in any of these brain regions or
connections between these brain regions might result in
pathological anxiety [5,6,7,11].
Because of the less study on GAD, the model for the neural
circuitry of GAD is extrapolated from findings in other anxiety
disorders, with limited empirical data available. Although a few
structural neuroimaging studies have been performed in adoles-
cents with GAD, the results are inconsistent. De Bellis et al. 
observed an increased amygdala volume in GAD patients
compared to healthy subjects, whereas another study  found
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a reduced left amygdala volume in adolescents with different
anxiety disorders compared to healthy subjects, and a more
pronounced decreased amygdala volume in GAD patients as
opposed to those with other anxiety disorders. In addition, two
studies in adult GAD patients showed larger amygdala [14,15] and
dorsomedial prefrontal cortex  in GAD patients relative to
healthy subjects. Given the current limited and inconsistent
structural neuroimaging data from GAD patients, the first purpose
of the present study was to explore alterations of gray matter
volumes in adolescent GAD patients.
Childhood maltreatment is highly prevalent with estimations
of more than 30% of the adult population having experienced
at least one form of maltreatment during childhood , and it
increases the possibility for developing a variety of mental
disorders including anxiety disorders . Maltreatment in-
cludes physical, emotional and sexual abuse, as well as physical
and emotional neglect . Epidemiological studies have shown
that 40% individuals having experienced childhood maltreat-
ment, whether retrospectively or prospectively ascertained,
develop anxiety disorders . An earlier age at onset of
GAD is significantly related to maltreatment in childhood .
Hence, exploring the underpinnings of the relationship between
childhood maltreatment and adolescent onset GAD would be
helpful in identifying the potential risk markers for this disease.
Recently, more and more studies have focused on the
neurobiological consequences of childhood maltreatment. In
animal studies, early adverse experiences, such as maternal
separation or abuse, induce a series of long-term alterations on
cognitive and emotional regulation, hypothalamus-pituitary-
adrenal axis function, and brain morphology . Alterations
of brain structure, including decreased dendritic spine density,
delayed maturation of neurons, altered neuronal structure and
synapse formation, and reduced neurogenesis, have been found
in the hippocampus, amygdala and prefrontal cortex [21,22].
Significant morphological microglial activation has been ob-
served in the thalamus and hippocampus in the rodent after
stress . In human studies, neuroimaging techniques have
been widely used to investigate the changes of brain structure.
In healthy subjects  or participants regardless of diagnosis
[25,26,27], childhood maltreatment is frequently associated with
reduced gray matter volumes in the hippocampus [24,25,26]
and prefrontal cortex [24,26,27]. A meta-analysis  exhibited
that amygdala volume in subjects with maltreatment-related
posttraumatic stress disorder did not differ from that in healthy
controls. However, recently two studies [29,30] have reported
an increased amygdala volume, whereas one study  have
found a decreased amgdala volume in healthy adolescents who
had experienced childhood maltreatment. Besides, reduced gray
matter volumes in the insular  and thalamus , as well as
increased gray matter volumes in the superior temporal gyrus
 have been reported in healthy samples with childhood
abuse. Most brain regions mentioned above are involved in
anxiety circuitry, and these maltreatment-related gray matter
volume changes were investigated in healthy subjects or
participants regardless of diagnosis. Why some subjects having
experienced childhood maltreatment eventually develop into
GAD, but not the other? Is there any childhood maltreatment
related brain structure alteration associated with the occurrence
of GAD? The second purpose of the present study, therefore,
was to investigate the possible alterations of gray matter volume
involved in the association between childhood maltreatment and
Materials and Methods
Twenty-six patients with GAD (14/12, with/without childhood
maltreatment) and 25 healthy controls (HCs) (12/13, with/without
childhood maltreatment), were enrolled in the present study. All
subjects were recruited from local high schools in Hunan Province
via advertisements and school notices from Oct. 2011 to Jul. 2012.
First, 1885 subjects finished the 41-item self-report questionnaire,
the Screen for Child Anxiety Related Emotional Disorders
(SCARED) [34,35]. The SCARED is a reliable and valid
screening tool for childhood anxiety disorders, with an optimal
total cutoff point score of 25 to separate children with anxiety
disorders from those without [34,35]. Then, 508 subjects with
positive SCARED scores and 165 in 1377 subjects with negative
SCARED scores were diagnosed with DSM-IV criteria and the
Schedule for Affective Disorders and Schizophrenia for School
Age Children-Present and Lifetime (K-SADS-PL) version  by
the same clinician. The K-SADS-PL is a semi-structured
instrument to ascertain present and lifetime history of psychiatric
disorders. In this study the age range of subjects was 16 to 18, so
we only interviewed the adolescent. Inclusion criteria for patients
in this study were current first-episode, medication-naive, gener-
alized anxiety disorder without co-morbidity disorders. HCs met
criteria for no mental disorders or physical diseases and were
selected to match GAD patients on age, gender, and childhood
maltreatment. Exclusion criteria for all subjects included current
major depression disorder, other anxiety disorders, Tourette’s
syndrome, conduct disorder, suicidal ideation, lifetime mania,
psychosis, or pervasive developmental disorders, mental retarda-
tion, any neurological abnormalities, history of seizures, head
trauma or unconsciousness, and use of psychoactive substances.
All subjects enrolled in this study were medication-naı ¨ve, right-
handed, and volunteered to participate in this study. Written
informed consent was obtained from each adolescent and one of
his or her legal guardians after the study had been fully explained.
This study was approved by the Ethics Committee of the Second
Xiangya Hospital of Central South University, China. Psycholog-
ical counselors who are responsible for the mental health of the
adolescent in these high schools were present in the study. We
were asked to give a global evaluation and necessary advices to all
SCARED but declined to MRI scans and participants who did
not meet the inclusion criteria of this study. All potential
participants who declined to participate were not disadvantaged
in any other way by not participating in the study.
The Childhood Trauma Questionnaire (CTQ) , a 28-item
retrospective self-report questionnaire with a total sum score
between a minimum of 25 and a maximum of 125, was
administered to assess childhood maltreatment in all subjects.
The five CTQ subscales respectively assess five kinds of childhood
maltreatment, including physical abuse, sexual abuse, emotional
abuse, physical neglect, and emotional neglect . Childhood
maltreatment (CM) was defined as a ‘‘moderate to severe’’ score
on any of five subscales. Moderate-severe cutoff scores for each
subscale are $ 13 for emotional abuse; $ 10 for physical abuse or
neglect; $ 15 for emotional neglect; $ 8 for sexual abuse .
The rest of the subjects were considered to be subjects without
childhood maltreatment (WCM) according to the CTQ. Addi-
tionally, all the patients were assessed with the Penn State Worry
Questionnaire (PSWQ)  and the Beck Depression Inventory
(BDI) . The two questionnaires were introduced to assess
Childhood Maltreatment and Thalamic Volume
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anxiety and depression levels in adolescent GAD patients. Table 1
contains the demographic and clinical measures between GAD
patients and HCs with nested with or without childhood
Structural Magnetic Resonance Imaging (MRI)
MRI examinations were conducted at the Second Xiangya
Hospital of Central South University, in China and performed
with a Philips 3.0 Tesla Scanner, equipped with a SENSE-8
channel head coil. For each participant, T1-weighted high-
resolution anatomical images were obtained using a 3-dimensional
(3D) rapid acquisition gradient echo sequence, repetition time
(TR)=7.5 milliseconds, echo time (TE)=3.7 milliseconds, flip
angle=8u, field of view=256 mm6256 mm, slice=180, voxel
size=1 mm61 mm61 mm.
Image analysis was conducted with SPM8 (http://www.fil.ion.
ucl.ac.uk/spm/) and the VBM8 toolbox (VBM8, version 435;
http://dbm.neuro.uni-jena.de/vbm8/). Individual structural im-
ages were preprocessed with the VBM8 toolbox following the
default parameter. T1-weighted images were corrected for bias-
field inhomogeneities, spatially normalized to the Montreal
Neurological Institute standard template space, and segmented
into gray matter, white matter and cerebrospinal fluid, within a
unified model  including high-dimensional DARTEL normal-
ization. Gray matter segments were modulated by the non-linear
components only, which allows comparing the absolute amount of
tissue corrected for individual brain sizes. The voxel resolution
after normalization was 1.5 mm61.5 mm61.5 mm. The check
data quality function was adopted to check homogeneity of gray
matter images. No inconsistencies were found among these gray
matter images. Finally, the segmented, modulated gray matter
images were smoothed by a Gaussian kernel of 8 mm FWHM.
Statistical analysis for the demographic and clinical measures
was performed by means of a general linear model with a 2
(diagnosis: GAD vs HCs)62 (childhood maltreatment: CM vs
WCM) comparison, chi-square test or t test, as needed, in SPSS16.
Image statistics were conducted with second-level models in
SPM8. The smoothed gray matter images were entered into a
voxel-by-voxel general linear model with a 2 (diagnosis: GAD vs
HCs)62 (childhood maltreatment: CM vs WCM) comparison,
controlling for age and gender, to assess the diagnosis main effect
(GAD . or , HCs), the maltreatment main effect (CM . or ,
WCM), and the diagnosis-by-maltreatment interaction effects.
According to the aim of this study, the diagnosis main effect and
the diagnosis-by-maltreatment interaction effects were of partic-
ular interest. We defined the amygdala, thalamus, insula,
hippocampus and prefrontal cortex (especially the medial
prefrontal cortex) as our regions of interest (ROIs), given their
important roles in anxiety circuitry. The ROIs were defined
according to Tzourio-Mazoyer et al.  and the ROIs masks
were created by means of the WFU PickAtlas . Then a
supplementary whole brain analyses was conducted to examine
non-hypothesized regions. For ROIs and whole brain analysis, a
family wise error (FWE) rate correction for multiple comparisons
was used with a threshold of p , .05. For the brain region of
significant diagnosis-by-maltreatment interaction effect, the mean
contrast values were extracted from each subject and further
analyzed with SPSS16. We conducted a general linear model
analysis and simple effect analysis to show the diagnosis-by-
maltreatment interaction effect.
To supplement the interaction effect, we further conducted a
whole brain regression analysis in SPM8 to investigate the
relationship between childhood maltreatment and regional gray
matter volume by regressing CTQ scores on the gray matter
volume images in the separated groups, as well as in the combined
group. A family wise error (FWE) rate correction for multiple
comparisons was also used with a threshold of p , .05.
Demographic and Clinical Measures
The results are listed in Table 1. There were no significant
differences between the groups in age, gender, CTQ scores, and
subscales of the CTQ. No significant differences were found in
Table 1. Demographic, Questionnaire data of adolescent GAD patients and healthy controls.
GAD (26)HCs (25)
Age (year)17.060.20 16.6760.2216.5860.22 16.8560.21F1,47=0.308 0.582
CTQ 46.7961.3532.0861.46 45.0061.46 32.7061.40F1,47=0.173 0.680
Emotional Abuse9.1462.32 5.6760.997.5862.84 6.9261.55F1,47=0.069 0.794
Emotional Neglect13.6462.79 7.8362.0412.4263.32 8.3161.65F1,47=0.2810.599
Physical Abuse 6.2962.435.2560.876.0061.21 5.5460.97F1,47=0.0000.997
Physical Neglect11.0061.887.2561.36 10.4262.287.9261.89F1,47=0.0090.927
Sexual Abuse 6.7161.825.0860.29 5.7561.495.1560.38F1,47=1.7100.197
BDI9.5464.61 8.6764.48–– t=0.479 0.637
PSWQ 52.569.0857.8368.64–– t=21.526 0.140
Means and standard deviations (6) are given.
GAD, generalized anxiety disorder; HCs, healthy controls; CTQ, childhood trauma questionnaire; BDI, the Beck Depression Inventory; PSWQ, the Penn State Worry
Questionnaire; CM, childhood maltreatment; WCM, without childhood maltreatment.
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BDI and PSWQ scores between adolescent GAD patients with or
without childhood maltreatment.
Structural Alterations in Gray Matter Volumes
We found no diagnosis or maltreatment main effects in all
ROIs, controlling for age and gender. However, a significant
diagnosis-by-maltreatment interaction effect was observed in the
left thalamus (F1,45=14.96; p=0.031, FWE corrected; x=28,
y=210, z=1, cluster size=83 voxels), as shown in Figure 1. No
other ROIs showed significant interaction effect.
The whole brain analysis revealed a significant diagnosis main
effect in the right putamen (F1,45=29.51; p=0.044, FWE
corrected; x=27, y=11, z=10, cluster size=263 voxels), with
larger gray matter volume of the right putamen in adolescent
GAD patients compared to healthy controls (GAD . HCs;
Figure 2). No maltreatment main effect was found in the whole
brain analysis controlling for age and gender. Whole brain analysis
found no other brain regions except the left thalamus exhibited
significant interaction effect.
Since a significant diagnosis-by-maltreatment interaction effect
was observed in the left thalamus, the mean contrast values of this
brain region were extracted. The general linear model analysis in
SPSS, controlling for age and gender, also showed a significant
diagnosis-by-maltreatment interaction effect in the left thalamus,
that was adolescent GAD patients with childhood maltreatment
had significantly larger gray matter volumes than adolescent GAD
patients without childhood maltreatment and both HCs in the left
(Figure 1). We compared subjects with childhood maltreatment
and those without childhood maltreatment on each diagnosis level.
The results exhibited that the maltreatment-related alteration in
the left thalamus was only observed in adolescents with GAD
(t=23.514, p=.002), but not in HCs (p . .05).
The regression analysis only yielded a strong positive association
between CTQ scores and left thalamic gray matter volume in
adolescent GAD patients (x=25, y=224, z=15; t=6.16,
df=24; p FWE-corrected=0.036, cluster size=237), as shown in
Figure 3. No brain regions were found to be significantly
associated with CTQ scores in HCs or combined group.
We employed high-resolution structural magnetic resonance
imaging and voxel-based morphometry approaches to study
alterations in gray matter volume, as well as the association
between childhood maltreatment and alterations in gray matter
volume in adolescent GAD patients in the current study. The
results of the present study showed larger gray matter volume in
the right putamen in adolescent GAD patients and a diagnosis-by-
maltreatment interaction effect in the left thalamus. Further
analysis exhibited the significant maltreatment-related alteration in
the left thalamus was only found in adolescents with GAD, but not
The finding that exhibited no alterations in prior-set ROIs but
larger gray matter volumes in an unexpected brain region, the
putamen, in GAD subjects seems interesting. To the best of our
knowledge, this is the first investigation in GAD reporting
putaminal gray matter alterations. The putamen, which belongs
to the basal ganglia, has widely spread functional connections with
cortical and subcortical areas in the brain . The putamen has
been suggested to be related to a number of anxiety disorders and
anxiety symptoms, such as GAD , social anxiety disorder ,
posttraumatic stress disorder , panic disorder , obsessive-
compulsive disorder , lactated-induced anxiety  and
anxiety symptoms in Parkinson disease . Besides, GAD
patients often accompany with somatic symptoms which are
associated with sympathetic dysregulation . Previous research-
Figure 1. The diagnosis-by-maltreatment interaction effect in the left thalamus. Left: Statistical parametric map depicting interaction effect
in the left thalamus (p , 0.05, FWE corrected). Color scales represent F-values. Right: The interaction graph showing left thalamic gray matter volume
differences between the groups, in which adolescent GAD patients with childhood maltreatment have more gray matter volumes in the left thalamus
than those without childhood maltreatment and both HCs. GAD, generalized anxiety disorder, HCs, healthy controls, CM, childhood maltreatment,
WCM, without childhood maltreatment.
Childhood Maltreatment and Thalamic Volume
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es suggested several adrenergic receptors and dopamine receptors
exerting an important influence on sympathetic regulation exist in
the putamen [52,53] . Therefore, alterations in the putamen might
be associated with somatic anxiety symptoms of GAD.
The amygdala plays an important role in processing emotional
valence and generating rapid fear response [5,6,8]. Several studies
on GAD have reported alterations of gray matter volumes in the
amygdala. Two studies in adult GAD patients exhibited larger
amygdala [14,15], whereas the other two studies in adolescent
GAD patients yield inconsistent results in the amygdala [12,13].
Three of these studies investigated GAD patients with co-morbid
diagnosis [12,13,14], while GAD patients in this study had no co-
morbidity disorders. This might partly explain the different
findings on the amygada. Although one previous study also
examined GAD patients without co-morbid diagnosis, all the
subjects were female. Gender differences on amygdala gray matter
volume have been reported in many researches [54,55,56]. In
addition, as we described earlier, childhood maltreatment has
been suggested to be associated with alterations of the amygdala
volume [29,30,31]. All factors mentioned above might complicate
the results on alteration of the amygdala.
This is the first study to investigate the possible association
between childhood maltreatment and gray matter volumes in
GAD patients. Epidemiological evidences have shown that
childhood maltreatment would increase the risk of GAD [17,18].
Our finding suggested a diagnosis-by-maltreatment interaction
effect in the left thalamus and revealed a strong positive association
between childhood maltreatment and left thalamic gray matter
volume only in GAD patients. It partially suggested that the left
thalamus might be the childhood maltreatment related brain
structure that would increase the risk of GAD. The diagnosis-by-
maltreatment interaction effect in the left thalamus might be the
reason why some subjects with childhood maltreatment develop
into GAD but not the others. The thalamus, a major relay center
of the brain with strong reciprocal connections with cortical and
subcortical structures, such as the prefrontal cortex and amygdala,
Figure 2. Increased right putaminal gray matter volume in adolescent GAD patients compared to healthy controls (p , , 0.05, FWE
corrected). Color scales represent t-values.
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is a critical component of the cortical-(amygdalo)-thalamic circuits
which plays a crucial role, not only in filtering sensory information,
but also in higher cognitive functions and emotional regulation
[6,7,9,57]. Changes in the thalamus, which is implicated in
sensory information filtering and alertness [9,57,58], might induce
pathological anxiety. Chronic stress increases the state of alertness
, which is associated with the thalamus . Consistent with
our result, a Positron Emission Tomography study  revealed
significantly greater regional cerebral glucose metabolism in
thalamus in adult monkeys who experienced early life stress
compared to controls, and another study  showed that young
adults who experienced corporal punishment in childhood
exhibited increased cerebral blood volume in the thalamus.
Greater activation or increased volumes in the thalamus might
suggest a general problem with sensory information processing,
perhaps indicating hyper-vigilance, which is thought to be
involved in the pathophysiology of GAD. Structural and
functional alterations in the thalamus might reflect a maltreat-
ment-related increase in sensitivity to conditional sensory infor-
mation in the environment.
However, one previous study  compared 31 physically
abused children and 41 non-abused children regardless of mental
disorders, and found reduced bilateral thalamic gray matter
volumes. In our study, the more reported forms of maltreatment
Figure 3. Statistical parametric map depicting the positive association between childhood maltreatment (Childhood Trauma
Questionnaire [CTQ] scores) and left thalamic gray matter volume (mean contrast values) in GAD patients (p , , 0.05, FWE
corrected). Color scales represent t-values.
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were physical and emotional neglect. It is possible that different
forms of childhood maltreatment might be associated with
different alteration patterns of the thalamic gray matter volume.
In addition, the study conducted by Hanson et al.  investigated
the possible linking between physical abuse and neurophysiological
alterations in a general population regardless of mental disorders,
whereas we focused on a possible association between childhood
maltreatment and brain deficits in GAD patients. The heteroge-
neity of the sample might also account for the inconsistent results.
Brain regions including the hippocampus [24,25,26] and
prefrontal cortex [24,26,27] have been frequently reported to be
associated with childhood maltreatment. Preclinical studies have
confirmed that early adverse experiences induce alterations of the
hypothalamus-pituitary-adrenal axis functions and further result in
stress-related changes on the hippocampus  and prefrontal
cortex .We did not find any significant association between
childhood maltreatment and the hippocampus and prefrontal
cortex at a harsh statistical threshold in this study. However, we
found a negative association between childhood maltreatment and
left prefrontal gray matter volume in GAD patients and combined
group, at a more lenient threshold of p , .001, uncorrected. The
maltreatment-related alteration in the prefrontal cortex is consis-
tent with previous findings [24,26,27]. As concluded in a review,
prolonged stress exposure causes architectural changes in
prefrontal dendrites . The prefrontal cortex is critically
implicated in emotion regulation processes by down-regulating
the limbic structures [5,6,11]. Volume reduction in the prefrontal
cortex could be associated with insufficiencies in emotion
regulation and therefore increase the vulnerability for pathological
anxiety . The hippocampus did not show any association with
childhood maltreatment in any group even at a lenient threshold
of p , .001, uncorrected. A possible explanation for this
phenomenon is delayed effects of early stress on hippocampal
development . Reduced hippocampal volume has been
consistently reported in adults with histories of childhood
maltreatment, but this change has been rarely found in children
with childhood maltreatment . Animal studies also suggested
that effects of early life stress on hippocampal morphology do not
become apparent until adulthood .
The findings in the present study showed lateralization, such as
larger right putaminal gray matter volume, and a positive
association between childhood maltreatment and left thalamic
gray matter volume in GAD patients. The reason for such
lateralization might be the cases that findings on one side exceed
the statistical threshold, while results on the other side did not. In
this study, a positive association between childhood maltreatment
and right thalamic gray matter volume was found at a more
lenient threshold of p , .005, uncorrected. This association was
not apparent at a more rigorous statistical threshold. However,
even at a more lenient threshold of p , .005, uncorrected, no
difference was found in left putaminal gray matter volume
between GAD patients and HCs. The lateralization to the right
is consistent with valence lateralization hypothesis, which suggests
the right hemisphere is dominant for negative emotions . The
lateralization phenomena revealed in this study needs to be further
clarified in the future study.
Some limitations of the current study must be acknowledged.
First, the sample in this study was relatively small and we only
studied first-episode, medication-naive, adolescent GAD patients
aged 16 to 18, which might limit the generalizability of our
findings. Second, the childhood trauma questionnaire introduced
to assess childhood maltreatment is a retrospective self-report
questionnaire, which could result in a recall bias. Although one
epidemiological study  found no differences between prospec-
tive and retrospective reports in predicting associations between
childhood maltreatment and adult psychopathology, patients with
GAD could have a more negative recall bias and a better memory
of childhood maltreatment. Third, this is a cross-sectional study,
which cannot explain the direct relationships between childhood
maltreatment and the occurrence of GAD. Forth, image pre-
processing steps such as registration and smoothing in voxel-based
morphometry might lead to different results .
In conclusion, we reported an increased gray matter volume of
the right putamen in subjects with GAD relative to HCs, and a
strong positive association between childhood maltreatment and
left thalamic gray matter volume only in GAD patients. The
increased gray matter volume of the right putamen suggests that
pathological change of the putamen may be one of the neural
substrates underlying the occurrence of GAD. The thalamus
might be involved in the association between childhood maltreat-
ment and the occurrence of GAD. In future studies, the impact of
childhood maltreatment should be noted. Since childhood
maltreatment is closely associated with GAD and increases the
risk of this disorder by modulating brain structures, it seems that
neuroimaging studies have been confounded by those multiple
effects caused by childhood maltreatment. It should also be noted
that there are sensitive periods during which specific brain regions
are vulnerable to early adversity , and childhood maltreat-
ment-related brain structural alterations might occur at a specific
age. Anyway, a longitudinal investigation with a large sample is
required to validate the results in our study.
We would like to thank Professor Baoci Shan for his advice on data
analyzing and Professor Yuqiang Ding for his help on language editing.
Conceived and designed the experiments: LL LS. Performed the
experiments: ML FY YZ ZH SL WW. Analyzed the data: ML ZL.
Contributed reagents/materials/analysis tools: MS TJ. Wrote the paper:
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