European Child & Adolescent Psychiatry

https://doi.org/10.1007/s00787-020-01697-z

ORIGINAL CONTRIBUTION

Neuroanatomical changes associated with conduct disorder in boys:

influence of childhood maltreatment
Yidian Gao1,2,3 · Yali Jiang1,2,3 · Qingsen Ming4 · Jibiao Zhang1,2,3 · Ren Ma1,2,3 · Qiong Wu1,2,3 · Daifeng Dong1,2,3 ·
Xiaoqiang Sun1,2,3 · Jiayue He1,2,3 · Wanyi Cao1,2,3 · Shuwen Yuan5 · Shuqiao Yao1,2,3

Received: 6 September 2019 / Accepted: 22 November 2020

© Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Childhood maltreatment (CM) poses a serious risk to the physical, emotional and psychological well-being of children, and
can advance the development of maladaptive behaviors, including conduct disorder (CD). CD involves repetitive, persistent
violations of others’ basic rights and societal norms. Little is known about whether and how CM influences the neural mecha-
nisms underlying CD, and CD-characteristic neuroanatomical changes have not yet been defined in a structural magnetic
resonance imaging (sMRI) study. Here, we used voxel-based morphometry (VBM) and surface-based morphometry (SBM)
to investigate the influence of the CD diagnosis and CM on the brain in 96 boys diagnosed with CD (62 with CM) and 86
typically developing (TD) boys (46 with CM). The participants were 12–17 years of age. Compared to the CM− CD group,
the CM+ CD group had structural gray matter (GM) alterations in the fronto-limbic regions, including the left amygdala,
right posterior cingulate cortex (PCC), right putamen, right dorsolateral prefrontal cortex (dlPFC) and right anterior cingu-
late cortex (ACC). We also found boys with CD exhibited increased GM volume in bilateral dorsomedial prefrontal cortex
(dmPFC), as well as decreased GM volume and decreased gyrification in the left superior temporal gyrus (STG) relative to
TD boys. Regional GM volume correlated with aggression and conduct problem severity in the CD group, suggesting that
the GM changes may contribute to increased aggression and conduct problems in boys with CD who have suffered CM. In
conclusion, these results demonstrate previously unreported CM-associated distinct brain structural changes among CD-
diagnosed boys.

Keywords Adolescents · Antisocial behavior · Conduct disorder · Childhood maltreatment · MRI · Gray matter

Introduction

Conduct disorder (CD) is a behavioral and emotional dis-

Supplementary Information The online version contains order characterized by a repetitive and persistent pattern
supplementary material available at https​://doi.org/10.1007/s0078​ of violating the basic rights of others and major societal
7-020-01697​-z.
norms or rules during childhood or adolescence [1]. Typi-
* Shuqiao Yao cally, individuals with CD may exhibit aggression towards
shuqiaoyao@csu.edu.cn; shuqiaoyao@163.com people or animals, property destruction, deceitfulness, theft
and serious violations of rules [1]. CD is a relatively com-
1
Medical Psychological Center of Second Xiangya Hospital, mon developmental psychiatric disorder in children, includ-
Central South University, Changsha, Hunan, China
ing adolescents, with a worldwide prevalence of 2–2.5% [2],
2
Medical Psychological Institute of Central South University, and perhaps one in ten individuals exhibiting signs of CD at
Changsha, Hunan, China
some point before adulthood [3].
3
National Clinical Research Center on Psychiatry Structural magnetic resonance imaging (sMRI) studies
and Psychology, Changsha, Hunan, China
have provided insights into brain structural changes under-
4
Department of Psychiatry, The First Affiliated Hospital lying CD, including alterations in gray matter (GM) vol-
of Soochow University, Suzhou, Jiangsu, China
ume, cortical surface area, cortical thickness and gyrifica-
5
Department of Radiology, Second Xiangya Hospital, Central tion. Such CD-associated alterations have been observed in
South University, Changsha, Hunan, China

13
Vol.:(0123456789)

several forebrain structures, including (but not limited to)
the orbitofrontal cortex (OFC), superior frontal gyrus, ante-
rior insula, precuneus, middle temporal gyrus and superior
temporal gyrus (STG), as well as subcortical regions (e.g.,
amygdala and putamen) [4–8]. Some CD-associated brain
structural alterations have been shown to correlate with CD
symptom severity [9, 10], indicating that the changes are
more pronounced in severe CD [4, 5, 7].
Although constructive results have been obtained, there
have been some marked inconsistencies among neuroim-
aging studies of CD, particularly with respect to findings
in frontotemporal and limbic regions [5, 11, 12]. Examina-
tion of these inconsistencies in the literature has led to the
supposition that CD may have differing etiologies, courses,
and comorbidity risks [12–15]. CD is comprised of several
heterogeneous phenotypes that differ with respect to the
age-of-onset (childhood-onset versus adolescent-onset CD),
callous-unemotional traits (i.e., lack of empathy, diminished
guilt, callous use of others, and shallow emotions), and
comorbidity with attention-deficit/hyperactivity disorder or
oppositional defiant disorder [16].
Apart from the above phenotypic variances, childhood
maltreatment (CM) may also be an important factor underly-
ing inconsistencies across CD studies. CM poses a serious
risk to the physical, emotional, and psychological well-being
of affected individuals, often being a precipitating factor for
maladaptive behavioral patterns, such as CD and substance
abuse disorders [17]. Conversely, a propensity toward dis-
ruptive and aggressive behaviors, as occurs in CD, may lead
youths into high-risk situations where CM is more likely to
occur [18, 19]. Prior studies have emphasized the influence
of CM on the developing brain, including potentially leading
to brain anatomy and functional alterations with life-long
consequences for mental health [20, 21]. Clarifying the role
that CM plays in the occurrence and development of CD will
help us to interpret inconsistent findings in the literature.
In a review of neuroimaging literature examining CM as
a risk factor for prevalent disorders (i.e., major depression,
substance abuse, anxiety disorders, and posttraumatic stress
disorder), Teicher and Samson found that alterations asso-
ciated with these disorders, such as hippocampal volume
reduction and amygdala hyperactivity, are more consistently
observed in participants who experienced CM [22]. In gen-
eral, individuals diagnosed with these disorders who have a
history of CM have shown an earlier age-of-onset, greater
symptom severity, more comorbidity, and poorer treatment
responses than their non-maltreated counterparts. Accord-
ingly, Teicher and Samson concluded that CM exposure may
be an important factor in determining differing phenotypic
expressions of the same diagnosis [22].
Phenotypes of CD with distinct ages-of-onset, severities,
comorbidity profiles, and treatment responses have also been
described [12–15]. Previous sMRI studies revealed that the
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European Child & Adolescent Psychiatry
regional brain structural alterations, such as alterations in
lateral and ventromedial fronto-limbic regions that mediate
behavioral and affect control, have been consistently associ-
ated with CM [21, 23]. Generally, however, investigations
of CM effects on neural abnormalities have not included
youths diagnosed with CD. Little is known about whether
the CM-related differences exist in youths with CD. The
current lack of sMRI data regarding brain anatomical dif-
ferences between CD groups with versus and without CM
has hindered elucidation of the neurobiological bases of the
heterogeneous phenotypes within CD and, thus, limited our
ability to personalize interventions. Disentangling whether
and how individuals with CD with versus without CM
should lead to a better understanding of the etiology of CD
and thus improve treatment practices.
In this context, the main aim of the current study was to
examine whether boys with CD would show particular brain
structural alterations associated with CM. Voxel-based mor-
phometry (VBM) and surface-based morphometry (SBM)
methods were used to identify cortical and subcortical struc-
tural changes, including GM, cortical thickness, gyrifica-
tion, and sulcus depth. First, we hypothesized that boys diag-
nosed with CD who had a history of CM (CM+ CD group)
would exhibit more severe conduct problems and a higher
level of aggression than those who had not suffered CM
(CM− CD group). Second, we hypothesized that relative to
our CM− CD group, our CM+ CD group would show altered
GM structures in brain regions implicated in threat detec-
tion and emotion processing, such as the anterior insula and
amygdala, which have been found to be altered in individuals
with CM [20, 21]. We also hypothesized that the strength
of core CD features, namely conduct problems and aggres-
sion, would correlate with CM-associated brain structural
changes [10, 22].
Methods
Participants
Since sex differences have been reported in previous neu-
roimaging CD research [7, 24], only boys were enrolled in
this study. A total of 98 adolescent CD boys (age range,
12–17 years) were recruited from outpatient clinics affili-
ated with the Second Xiangya Hospital of Central South
University in Changsha, Hunan, China. A typically devel-
oping (TD) control group was included. A total of 90 TD
boys were recruited through flyers in local middle schools.
All participants and their parents were made aware of the
purpose of the study and gave written informed consent for
participation.
All participants underwent an independent struc-
tured clinical interview by two well-trained psychiatrists.
European Child & Adolescent Psychiatry
Diagnoses of CD were made based on the Chinese ver-
sion of the Structured Clinical Interview for the DSM-IV-
TR Axis I Disorders-Patient Edition (SCID-I/P) [25]; the
Chinese SCID-I/P was adapted for use in both CD patients
and healthy individuals [26, 27]. Psychiatrists rated each
CD symptom item of the SCID-I/P as (0) absent, (1) sub-
clinical, or (2) clinically present. Medication status was also
determined in the interview. Diagnostic interviews with
participants and caregivers were carried out separately;
if the results of the two differed, the psychiatrists made a
final diagnostic decision. All CD patients recruited met the
DSM-IV-TR criteria for CD. None had a history of psy-
chotropic medication treatment prior to or during the study
(treatment-naïve). TD volunteers were interviewed by the
same psychiatrists and subjected to the SCID-I/P. Informa-
tion provided by TD subjects was verified by their parents
on an as-needed basis. None of the TD participants met the
criteria for CD. Exclusion criteria for both groups included:
current or prior history of any (other) psychiatric, behavior
or emotional disorder (including, among others, posttrau-
matic stress disorder and obsessive-compulsive disorder);
a pervasive developmental or chronic neurological disorder
(e.g., autism), Tourette’s syndrome; persistent headaches,
head trauma; alcohol or substance abuse in the past year;
a contraindication for sMRI; or a full-scale IQ score < 80
on the Wechsler Intelligence Scale for Children-Chinese
revision (C-WISC) [28]. All the subjects were right-handed
according to the Edinburgh Handedness Inventory [29].
Behavioral measures
The short form of the Childhood Trauma Questionnaire
(CTQ-SF) was used to determine which boys met the cri-
teria for CM [30]. The CTQ-SF is a 28-item self-report
instrument that examines five types of CM during both
pre-adolescent and teenaged childhood periods: physical
abuse, emotional abuse, sexual abuse, physical neglect, and
emotional neglect. The items are rated on a 5-point scale
from 1 (never true) to 5 (very often true). Cutoff scores dis-
tinguishing four levels (none, low, moderate, or severe) of
each CM type were applied. Individuals were considered to
have a history of CM if one or more subscales met the cutoff
criteria (moderate or severe). Thus, the participants were
assigned to a CM+ group if they met the moderate or severe
cutoff thresholds for at least one type of CM. Participants
were assigned to a CM− group if their responses indicated
the none or low level for all five types of CM [30, 31].
The Chinese version of the Subjective Socioeconomic
Status Scale (SSS) was used to quantify each participant’s
socio-economic status [32]. The Chinese version of the
Center for Epidemiologic Studies Depression Scale (CES-D)
[33] and the Multidimensional Anxiety Scale for Children
(MASC) [34, 35] were used to rate depression and anxiety
severity, respectively. The Strengths and Difficulties Ques-
tionnaire (SDQ) which exhibited high levels of reliability
and validity in Chinese adolescents was used to measure
conduct problems [36, 37], and the Aggression Question-
naire was used to measure the aggressive behavior intensity
[38].
Neuroimaging
Acquisition of sMRI data
A Siemens Skyra 3.0-Tesla scanner (Siemens Medical
Inc., Erlangen, Germany) with a standard head coil was
used to collect images at the Medical Imaging Depart-
ment in Second Xiangya Hospital. Data were acquired
with a T1-weighted MPRAGE (magnetization-prepared
rapid gradient-echo) sequence with the following param-
eters: voxel size = 1 × 1 × 1 ­mm3, repetition time = 8.5 ms,
echo time = 3.743 ms, f lip angle = 8°, acquisition
matrix = 256 × 256 pixels, field of view = 256 × 256, number
of slices = 180, and slice thickness = 1 mm.
Quality control
Images were inspected for scanner artifacts and gross neu-
roanatomical abnormalities (e.g., tumors or cysts) by a
radiologist. After image pre-processing, the Computational
Anatomy Toolbox (CAT12, http://www.neuro​.uni-jena.de/
cat/) provided ratings of image data quality, which were
used to identify problems with individual images. These
ratings assess basic image properties, noise and geometric
distortions (e.g., due to motion) and combine them into a
weighted image quality rating (IQR), representing good
image quality. All the scans rated B and above in IQR, rep-
resenting good image quality. Finally, an automated quality
check using covariance analysis on the sample homogeneity
of segmented gray matter images was performed in CAT12
toolbox [39]. Two CD participants and four TD participants
were excluded due to excessive movements during scanning,
leaving 86 TD participants and 96 participants with CD in
the final sample (Table 1).
Image processing
Images were cropped and reoriented following the anterior-
posterior commissure line with the MRIcro tool (http://
www.cabia​tl.com/mricr​o/mricr​o/mricr​o.html). To optimize
the registration, the Template-O-Matic toolbox was used to
create standardized apriori tissue probability maps (TPMs)
based on the participants’ age range [40]. Then, we con-
ducted GM volume measurements with voxel-based mor-
phometry (VBM) and conducted cortical measurements
with surface-based morphometry (SBM) using CAT12 and
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Table 1  Demographic and clinical characteristics of study participants

CM–TD (N = 40) CM + TD CM–CD CM + CD Diagnosis effect Maltreatment Interaction
(N = 46) (N = 34) (N = 62) effect
Mean (SD) Mean (SD) Mean (SD) Mean (SD) F (P)a F (P) F (P)

Age, years 15.2 (0.84) 15.2 (1.04) 15.0 (1.28) 14.8 (1.13) 1.96 (0.16) 0.02 (0.88) 0.24 (0.63)
IQ 110.72 (9.10) 107.75 (7.55) 104.48 (11.91) 100.01 (11.58) 4.11 (0.045) 1.40 (0.24) 0.02 (0.89)
SSS 6.38 (1.00) 6.14 (0.95) 7.28 (1.09) 6.34 (1.75) 2.56 (0.11) 1.49 (0.22) 0.27 (0.60)
CES-D scores 13.48 (5.10) 18.69 (7.14) 18.00 (9.24) 29.80 (10.76) 15.01 (< 0.001) 11.19 (0.001) 0.19 (0.66)
MASC scores 32.53 (16.53) 34.71 (18.88) 37.17 (16.14) 47.92 (17.57) 8.72 (0.004) 0.12 (0.74) 0.08 (0.77)
CTQ scores
Emotional 6.70 (1.76) 7.50 (2.82) 7.21 (2.13) 11.53 (3.74) 14.18 (< 0.001) 7.03 (0.009) 1.56 (0.22)
abuse
Physical abuse 5.25 (0.81) 6.07 (1.96) 5.62 (0.99) 10.00 (4.03) 10.62 (0.001) 15.21 (< 0.001) 5.40 (0.021)
Sex abuse 5.23 (0.48) 5.30 (0.66) 5.41 (0.74) 8.02 (3.48) 8.69 (0.004) 6.44 (0.012) 5.46 (0.021)
Emotional 9.00 (2.78) 12.33 (3.63) 9.79 (4.66) 14.71 (4.81) 1.60 (0.21) 32.63 (< 0.001) 1.38 (0.24)
neglect
Physical 7.25 (1.37) 11.11 (1.73) 8.27 (1.61) 11.53 (2.82) 0.12 (0.73) 123.19 (< 0.001) 0.44 (0.51)
neglect
Total scores 33.43 (4.57) 42.30 (6.67) 36.30 (6.25) 55.79 (10.36) 15.07 (< 0.001) 67.82 (< 0.001) 6.38 (0.012)
SDQ scores
Emotion symp- 1.93 (1.67) 2.67 (2.01) 2.44 (1.96) 4.28 (2.44) 3.59 (0.06) 10.87 (0.001) 1.82 (0.18)
tom
Conduct prob- 2.35 (1.29) 2.40 (1.47) 3.53 (1.93) 4.79 (1.74) 32.38 (< 0.001) 2.03 (0.16) 1.58 (0.21)
lem
Hyperactivity 3.03 (1.86) 3.80 (1.74) 4.26 (2.11) 6.18 (2.03) 16.19 (< 0.001) 14.70 (< 0.001) 2.69 (0.10)
Peer problem 2.50 (1.48) 3.04 (1.38) 2.59 (1.33) 3.21 (1.83) 0.22 (0.64) 8.01 (0.005) 0.73 (0.39)
Prosocial 7.85 (1.96) 6.80 (1.44) 6.44 (2.60) 5.51 (2.43) 7.38 (0.007) 9.39 (0.003) 0.10 (0.75)
­behaviorb
AQ scores
Anger 9.20 (4.19) 9.96 (4.33) 13.12 (4.24) 15.92 (5.74) 34.37 (< 0.001) 0.70 (0.40) 0.01 (0.98)
Hostility 9.75 (2.99) 11.00 (4.83) 11.12 (2.45) 16.21 (4.15) 17.72 (< 0.001) 6.77 (0.010) 0.84 (0.36)
Attack 14.05 (6.08) 14.94 (6.41) 16.21 (3.44) 20.76 (5.44) 12.50 (0.001) 3.87 (0.05) 1.18 (0.28)
Verbal attack 6.90 (2.59) 6.60 (2.50) 7.01 (1.07) 7.91 (1.44) 3.30 (0.07) 0.13 (0.72) 1.41 (0.24)
Total scores 39.90 (13.69) 42.51 (13.81) 47.45 (7.18) 60.78 (10.62) 31.71 (< 0.001) 4.67 (0.032) 0.97 (0.33)
GM volume 582.25 (70.00) 599.28 (96.37) 590.63 (80.67) 573.81 (73.99) 1.66 (0.20) 0.30 (0.59) 0.19 (0.66)
(ml)
WM volume 483.51 (38.04) 491.26 (50.37) 479.52 (48.41) 474.82 (48.55) 0.34 (0.56) 0.13 (0.72) 0.43 (0.51)
(ml)
CSF volume 511.62 (81.77) 520.39 (94.46) 519.04 (109.79) 530.41 (78.66) 2.10 (0.15) 0.02 (0.88) 0.52 (0.47)
(ml)
TIV (ml) 1580.41 (94.27) 1610.93 1589.19 1579.07 (118.42) < .001 (0.99) 0.17 (0.68) 1.27 (0.26)
(126.28) (118.59)

TD, typically developing; CD, conduct disorder; CM−, childhood maltreatment absence; CM+, childhood maltreatment presence; IQ, intelligence
quotient; SSS, the Subjective Socioeconomic Status Scale; CES-D, the Center for Epidemiologic Studies Depression Scale; MASC, the Multi-
dimensional Anxiety Scale for Children; CTQ, the Childhood Trauma Questionnaire; SDQ, the Strengths and Difficulties Questionnaire; AQ, the
Aggression Questionnaire; GM, gray matter; WM, white matter; CSF, cerebrospinal fluid; TIV, total intracranial volume
a
Bold font indicates statistical significance at P < 0.05
b
Higher prosocial behavior subscale scores refer to more prosocial behaviors

Statistical Parametric Mapping software (SPM12; Wellcome
Department of Cognitive Neurology, London, UK; http://
www.fil.ion.ucl.ac.uk/spm) based on Matlab 2017a (Math-
works, Natick, MA). High-resolution T1-weighted scans
were segmented with reference to the TPMs into GM and
white matter images in CAT12 [39]. The Diffeomorphic
Anatomical Registration Through Exponentiated Lie Alge-
bra (DARTEL) toolbox was used to import the segmented
GM and white matter images into a native space, create a
template from the subjects’ merged images, and to warp,

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modulate, normalize, and smooth the individual results with
an 8-mm full-width at half-maximum (FWHM) isotropic
Gaussian kernel [41]. The Masking Toolbox (http://www0.
cs.ucl.ac.uk/staff​/g.ridgw​ay/maski​ng/) was used to create
an explicit mask. The Masking Toolbox uses an automatic
mask-creation strategy to find an optimal threshold to bina-
rize an average image [42]. The total intracranial volume
(TIV) for each participant was calculated and used as a
covariate of no interest for further statistical analyses. The
SBM measures, namely cortical thickness, gyrification, and
sulcus depth, were performed in CAT12 with default param-
eters during segmentation. The automated method in CAT12
allowed us to achieve central surface reconstructions and
cortical thickness measurements in one step; subsequently,
topological defects of cortical surface mesh were repaired
with a spherical harmonic method [41]. A 15-mm FWHM
isotropic Gaussian kernel was used for thickness data and a
20-mm FWHM isotropic Gaussian kernel for folding data
(gyrification and sulcus depth).
Statistical analysis
Behavioral and clinical data
Two-way analyses of variance were used to detect the main
effects of diagnosis (CD vs. TD), CM (CM+ vs. CM−), and
CD diagnosis-by-CM interactions. Age and IQ score were
included as covariates of no interest for analyses of CES-D,
MASC, SDQ, and AQ results. Statistical analyses were car-
ried out in SPSS 21.0 software (SPSS, Chicago, IL).
Imaging data
Following pre-processing, smoothed images were analyzed
in a 2 × 2 factorial design, with CD diagnosis as one factor
and the presence of CM as the second factor. For VBM only,
the amygdala and anterior insula were defined as regions of
interest (ROIs) by Automatic Anatomical Labeling (AAL)
[43] in the Wake Forest University (WFU) Pickatlas Toolbox
[44] because they have been both consistently associated
with CM [20, 21] and CD [4, 5, 8] in prior neuroimaging
studies. For each ROI, a small-volume correction (SVC) was
applied to control family-wise error (FWE) rate at P < 0.025
(Bonferroni correction) [45, 46]. For both VBM and SBM
analyses, whole-brain analyses were performed to further
investigate potential changes in GM and cortical measures.
A significance threshold of P < 0.05 was used with cluster-
level FWE rate correction for multiple comparisons [45, 46].
Before the cluster-wise correction, the voxel-wise threshold
applied to the statistical maps was P < 0.001 uncorrected.
Covariates of no interest included age as well as IQ, TIV,
CES-D, MASC and SDQ-hyperactivity scores in the VBM
analysis, and included age as well as IQ, CES-D, MASC and
SDQ-hyperactivity scores in the SBM analysis. In regions
showing any main effect or interaction, brain morphometric
data were extracted for post hoc analysis (Bonferroni cor-
rection). The correlation analyses between morphometric
measures showing the main effect of CM or diagnosis-by-
CM interaction with clinical data (i.e., AQ total scores and
SDQ conduct problem subscores) were conducted with TD
and CD groups in SPSS 21.0 software.
Results
Behavioral and clinical variables
The demographic and clinical characteristics of the study
sample are summarized in Table 1. The TD and CD groups
(including CM+ and CM− individuals) were similar with
respect to age and SSS. CDs scored higher than TDs on the
CES-D, MASC, SDQ (conduct problem and hyperactivity
subscales), and AQ (anger, hostility, attack subscales and
total scale scores). Relative to TD boys, CD boys reported
lower IQ and a lower level of prosocial behavior (Table 1).
Apart from the main effect of diagnosis, CM− boys
scored lower for CES-D, SDQ (emotion symptom, hyper-
activity, and peer problem subscales), AQ (hostility subscale
and total scores) and scored higher for SDQ prosocial behav-
ior subscales than CM+ boys. No interaction was detected
for demographic and clinical variables. After controlling
for age and IQ, no significant differences were detected in
global GM/white matter/cerebrospinal fluid volumes or TIV
between CM+ and CM− boys (Table 1).
VBM
ROI analysis revealed a significant CD diagnosis-by-CM
interaction in the left amygdala (peak voxel = [− 26, − 6,
− 12], KE = 85, Z = 3.77, PSVC = 0.002; Fig. 1a), indicating
that the CM+ CD group showed increased GMV in the left
amygdala compared with the CM− CD group (P = 0.036),
whereas no significant difference was detected between
CM+ and CM− TD groups (Fig. 1b). No other main effect
or interaction was found in the ROI analysis.
As shown in Table 2, whole-brain analysis detected main
effects of diagnosis, with CD boys exhibiting decreased GM
volume in the left STG (Fig. 2a) and increased GM vol-
ume in bilateral dorsal medial prefrontal cortex (dmPFC;
Fig. 2b) relative to TD boys. Apart from the main effect of
diagnosis, the whole-brain analysis also revealed significant
positive CD diagnosis-by-CM interactions in the right pos-
terior cingulate cortex (PCC, extending to the precuneus,
lingual gyrus and cerebellum; Fig. 2c) and in the right puta-
men (extending to the right caudate; Fig. 2d), indicating that
CM+ TD boys showed reduced GM volumes in these regions
13

Fig. 1  Region of interest analysis revealing a significant conduct dis-
order (CD) diagnosis-by-childhood maltreatment (CM) interaction
in the left amygdala. a Significant CD diagnosis-by-CM interaction
in the left amygdala (peak voxel = [− 26, − 6, − 12]). b Gray mat-
ter (GM) volume comparison in the left amygdala between typically
developing (TD) and CD boys with (+) or without (−) CM. CM+ CD
boys showed increased left amygdala GM volume relative to CM−
than the CM− TD boys, whereas the CM+ CD boys showed
increased regional GM volumes than the CM− CD boys.
The whole-brain analysis also found significant negative
diagnosis-by-CM interactions in the right dorsal lateral pre-
frontal cortex (dlPFC, extending to the supplementary motor
area; Fig. 2e) and right inferior frontal gyrus (IFG; Fig. 2f).
Further analysis revealed that the CM+ CD boys exhibited
reduced GM volume in the right dlPFC than the CM− CD
boys, whereas no such difference was detected among TD
boys. Moreover, CM+ TD boys showed increased GM vol-
ume in the right IFG than the CM− TD boys, whereas no
such difference was detected among CD boys. No main
effect of CM was detected in the whole-brain analysis.
SBM
Whole-brain SBM analysis revealed a main effect of diag-
nosis on gyrification, suggesting decreased left STG gyri-
fication (extending to the temporal pole) in boys diagnosed
with CD than in TD boys (peak voxel = [− 37, 6, − 27],
KE = 266, Z = 4.48, PFWE = 0.001; Fig. 3a). There was a sig-
nificant CD diagnosis-by-CM interaction for sulcal depth in
the right anterior cingulate cortex (ACC; extending to the
right dmPFC; peak voxel = [13, 15, 38], KE = 180, Z = 3.76,
PFWE = 0.019; Fig. 3b), with the CM+ TD group showing
a deeper ACC sulcus than the CM− TD group, whereas
the CM+ CD group had a shallower ACC sulcus than the
CM− CD group. No main effects of diagnosis or CM or
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European Child & Adolescent Psychiatry
CD boys, whereas no volumetric difference was found in the same
region between CM− and CM+ TD boys. The image is thresholded
at PFWE < 0.05, small-volume correction. The color bar represents T
statistics. The error bar illustrates standard errors. CD, conduct dis-
order; CM, childhood maltreatment; GM, gray matter; TD, typically
developing; FWE, family-wise error
interactions between these variables were detected for corti-
cal thickness.
Correlations between clinical and morphometric
data
Correlation analyses were conducted within TD and CD
groups separately to investigate the relationships between
clinical variables (i.e., AQ total scores and SDQ conduct
problem subscores) and morphometric measures showing
main effect of CM and diagnosis-by-CM interactions after
controlling for age and IQ (see Figure S1 in the Supple-
mentary Materials for scatter plots). The correlation analysis
within the CD group revealed the left-amygdala GM volume
(peak voxel = [− 26, − 6, − 12]) correlated positively with
AQ total scores (r = 0.53, P = 0.002) and SDQ conduct prob-
lem subscores (r = 0.49, P = 0.005). The results remained
significant after controlling for age, IQ and CM (i.e., CTQ
total scores; P < 0.05). In addition, right-PCC GM volume
(peak voxel = [14, − 62, 2]) correlated positively with AQ
total scores (r = 0.36, P = 0.049) and SDQ conduct problem
subscores (r = 0.37, P = 0.038). These results were no longer
significant after controlling for age, IQ and CM.
Within the TD group, the SDQ conduct problem sub-
scores negatively correlated with the left-amygdala
(r = − 0.22, P = 0.043) and right-PCC GM volume
(r = − 0.27, P = 0.013). The SDQ conduct problem sub-
scores also positively correlated with the right dlPFC (peak
European Child & Adolescent Psychiatry

Table 2  Whole-brain results revealing main effects and interactions in gray matter volumes controlling for age, IQ, TIV, anxiety, depression and
hyperactivity
Hemisphere MNI coordinates Z value PFWE KE
L/R
x y z

(a) Main positive effect of diagnosis (CD < TD)

STG, ext. middle temporal gyrus and fusiform gyrus L − 50 − 20 0 4.34 0.008 1385
− 50 − 14 − 23 4.17
− 51 − 12 −6 3.73
(b) Main negative effect of diagnosis (CD > TD)
dmPFC L/R −2 59 29 4.45 0.025 1040
−2 50 42 4.20
2 32 45 4.11
(c) Positive diagnosis-by-CM interaction (CM+ TD < CM− TD, CM+ CD > CM− CD)
PCC, ext. precuneus, lingual gyrus and cerebellum R 14 − 62 2 4.49 < 0.001 2840
− 11 − 56 20 3.98
−9 − 69 15 3.73
(d) Positive diagnosis-by-CM interaction (CM+ TD < CM− TD, CM+ CD > CM− CD)
Putamen, ext. caudate R 24 15 14 3.92 0.040 906
21 −5 26 3.54
(e) Negative diagnosis-by-CM interaction (CM+ CD < CM− CD, no difference between CM+/CM− TD)
dlPFC, ext. supplementary motor area R 14 14 68 4.28 0.008 1384
17 30 59 4.26
17 −2 63 3.66
(f) Negative diagnosis-by-CM interaction (CM+ TD > CM− TD, no difference between CM+/CM− CD)
IFG R 39 45 −6 4.27 0.008 1370
30 48 5 3.97
41 39 21 3.87

CD, conduct disorder; TD, typically developing; CM, childhood maltreatment; CM+, childhood maltreatment presence; CM−, childhood mal-
treatment absence; IQ, intelligence quotient; TIV, total intracranial volume; STG, superior temporal gyrus; dmPFC, dorsal medial prefrontal cor-
tex; PCC, posterior cingulate cortex; dlPFC, dorsal lateral prefrontal cortex; IFG, inferior frontal gyrus; EXT., extending to; FWE, family-wise
error

voxel = [14, 14], r = 0.24, P = 0.027) and right-IFG GM vol-
ume (peak voxel = [39, 45, − 6], r = 0.31, P = 0.004). After
controlling for age, IQ and CM, the positive correlation
between right-IFG GM volume and SDQ conduct problem
subscores remained significant (r = 0.24, P = 0.028). No sig-
nificant correlations were detected for regions showing main
effects or interactions in the SBM analysis. However, the
significance of these results did not survive at Bonferroni
correction (P > 0.05/20).
Discussion
The current study sought to expand upon previous research
using sMRI to examine neuroanatomical changes, for the
first time to the best of our knowledge, among boys diag-
nosed with CD, comparing those with CM versus those
without a history of CM. We observed a higher level
of aggression and a lower level of prosocial behaviors
in CM+ youths relative to CM− youths. In line with our
hypotheses, we found combined effects of CD diagnosis and
CM on GM structural characteristics. Compared with the
CM− CD group, the CM+ CD group displayed altered GM
in brain regions involved in threat detection, emotional regu-
lation, reward anticipation, and emotional empathy [46–49],
including the limbic system (i.e., amygdala), prefrontal (i.e.,
right dlPFC and right ACC) and parietal cortex (i.e., right
PCC/precuneus) as well as the striatum (i.e., right putamen
and caudate) after regressing out for potential confound-
ers. Moreover, we also detected decreased GM volume and
decreased gyrification in the left STG as well as increased
GM volume in bilateral dmPFC in CD boys relative to TD
boys, suggesting that CD may be generally associated with
delayed brain development in these regions. Regional GM
volumes correlated with AQ total scores and SDQ conduct
problems subscores within CD boys, suggesting that GM
changes may be more pronounced in boys with severe CD.
Taken together, these results support our hypothesis that
there were certain brain structural differences between the
CM– CD and CM+ CD groups of boys, indicating that these

13

Fig. 2  Significant main effects of conduct disorder (CD) diagnosis
and diagnosis-by-childhood maltreatment (CM) interactions for gray
matter (GM) volumes detected by VBM whole-brain analysis. a Boys
with CD exhibited decreased GM volume in the left superior fron-
tal gyrus (STG, extending to middle temporal gyrus and fusiform
gyrus) than typically developing (TD) boys. b Boys with CD exhib-
ited increased GM volume in bilateral dorsal medial prefrontal cortex
(dmPFC) than TD boys. c A positive diagnosis-by-CM interaction in
the right posterior cingulate cortex (PCC, extending to precuneus, lin-
gual gyrus and cerebellum). CM+ TD boys showed significant lower
GM volume in the right PCC than CM− TD boys, whereas CM+ CD
boys showed significant higher right PCC GM volume than CM− CD
boys. d A positive diagnosis-by-CM interaction in the right puta-
men (extending to caudate), indicating that CM+ TD boys showed
significant lower right putamen GM volume than CM− TD boys,
whereas CM+ CD boys showed significant higher right putamen GM
two groups, while sharing the same CD diagnosis, may be
presenting different patterns of brain structural alterations
influenced by exposure to CM.
It is noteworthy that we detected a significant CD diagno-
sis-by-CM interaction for GM volume of the left amygdala,
which has been identified as a major mediator of threatening
cue detection [50, 51] and of emotion processing and regu-
lation [52, 53]. Both a non-human primate study [54] and
clinical observations [55, 56] have connected maltreatment
from parents with increased amygdala volume. Moreover,
13
European Child & Adolescent Psychiatry
volume than CM− CD boys. e A negative diagnosis-by-CM interac-
tion in the right dorsal lateral prefrontal cortex (dlPFC, extending to
the supplementary motor area). CM+ CD boys showed significant
lower GM volume in the right dlPFC than CM− CD boys, whereas
no difference found between CM+ and CM− TD boys. f A negative
diagnosis-by-CM interaction in the right inferior frontal gyrus (IFG).
CM + TD boys showed increased GM volume in the right IFG than
the CM− TD boys, whereas no such difference was detected among
CD boys. The image is thresholded at P < 0.001, uncorrected for dis-
play purpose. The color bar represents T statistics. VBM, voxel-based
morphometry; GM, gray matter; CD, conduct disorder; TD, typically
developing; CM, childhood maltreatment; CM+, childhood maltreat-
ment presence; CM−, childhood maltreatment absence; STG, supe-
rior temporal gyrus; dmPFC, dorsal medial prefrontal cortex; PCC,
posterior cingulate cortex; dlPFC, dorsal lateral prefrontal cortex;
IFG, inferior frontal gyrus; FWE, family-wise error
functional MRI studies have found that individuals with
maltreatment histories had an elevated amygdalar response
when processing emotional faces, particularly those seen as
threatening [21]. This finding has been consistently observed
in maltreated individuals across childhood [57, 58] and
adulthood [59–61]. However, both hyperactivity [62, 63] and
hypoactivity [50, 64] of the amygdala in empathy processing
tasks have been reported in functional MRI studies involving
participants diagnosed with CD. In the present study, we
found volumetric difference in the left amygdala between
European Child & Adolescent Psychiatry
Fig. 3  Significant main effect of conduct disorder (CD) diagnosis on
gyrification and diagnosis-by-childhood maltreatment (CM) interac-
tion for sulcus depth detected by SBM whole-brain analysis. a Com-
pared to typically developing (TD) boys, boys diagnosed with CD
exhibited decreased gyrification of the left superior temporal gyrus
(STG, extending to the temporal pole). b CM+ TD boys had a deeper
anterior cingulate cortex (ACC) sulcus than CM− TD boys, whereas
our CM− and CM+ CD groups, but no main effect of CD
diagnosis nor a difference between the CM− and CM+ TD
groups was observed, suggesting that a left amygdala volu-
metric increase might be specific to CD boys with a his-
tory of CM. The increased left amygdala volume found in
our CM+ CD group may indicate an enhanced capacity to
detect affective information in the social environment [65]
resulting from the influence of CM. Thus, boys with CD
and CM might be more sensitive to environmental cues, and
thus more hypervigilant to anger signals, than boys with CD
without CM [64]. The present study also observed correla-
tions between left amygdala volume with aggression and
conduct problems in boys with CD, which may help explain
the particularly severe aggression and conduct problems dis-
played by CD boys with CM.
The whole-brain analysis of VBM revealed significant
positive CD diagnosis-by-CM interactions in the right
putamen (extending to caudate) and right PCC (extending
to right precuneus, lingual gyrus and cerebellum). The
putamen and caudate (i.e., dorsal striatum) are typically
involved in cognitive and motor aspects of incentive-based
CM+ CD boys had a shallower ACC sulcus than CM− CD boys.
Images are thresholded at PFWE < 0.05. The color bar represents T sta-
tistics. SBM, surface-based morphometry; TD, typically developing;
CD, conduct disorder; CM, childhood maltreatment; CM+, childhood
maltreatment presence; CM−, childhood maltreatment absence; STG,
superior temporal gyrus; ACC, anterior cingulate cortex
behaviors (e.g., linking actions with outcomes and action
selection) [66], and contributes to reward processing and
decision making [67]. Prior fMRI studies reported func-
tional abnormalities in the putamen related to abnormal
neural responses to negative emotional stimuli and rewards
of individuals with CM [68, 69]. The PCC/precuneus has
also been suggested to play a key role in the classical ‘core
brain network’ for theory-of-mind [70, 71]. Our findings
are largely consistent with previous sMRI studies of CM
effects reporting abnormal GM volumes in the dorsal
striatum [72, 73] and the PCC/precuneus [73, 74], which
may underlie the deficits in reward processing, decision
making and mentalizing in individuals with CM. Notably,
our result indicated that CM+ TD boys showed significant
higher GM volume in the right putamen and right PCC
than the CM− TD boys, whereas the CM+ and CM− CD
boys showed opposite patterns. These findings might sug-
gest that the effect of exposure to threatening experiences
on the dorsal striatum and PCC volume might be interfered
or modulated by other potential factors (e.g., genetic effect
and callous-unemotional traits).
13

A significant negative CD diagnosis-by-CM interaction
was also detected for the right dlPFC volume. The CM+ CD
group had lower GM volumes in the right dlPFC than the
CM− CD group, whereas no such difference was detected
among TD boys. The dlPFC is a core region of the dorsal
attention networks and is most typically associated with
higher cognitive processing, such as working memory,
planning and cognitive selection of sensory information and
response [23, 75, 76]. Several studies have found reduced
GM volume in the dlPFC in individuals with exposure to
CM [77–79]. Although not project directly to emotion gen-
erators, the dlPFC may be recruited during emotion regu-
lation [80] and influence emotional reactivity by altering
higher order perceptual attention systems [81]. As prior
literature demonstrated, the prefrontal cortex is thought to
be one of the last brain regions to mature and may be espe-
cially vulnerable to disruptions in development [82]. Deficits
in dlPFC may cause difficulties in considering alternatives,
even when it is known that current behaviors are not work-
ing [83, 84]. We did not find a difference between CM− and
CM+ TD boys in these regions, which suggests that these
CM-associated structural abnormalities occur in the context
of CD development only. The mechanisms underlying the
emergence of the alterations in children with CD need to be
clarified by future neuroimaging studies.
The SBM analysis revealed a CD diagnosis-by-CM inter-
action for sulcus depth in the right ACC (extending to the
right dmPFC). The CM+ CD group had shallower ACC sulci
than the CM− CD group, whereas the opposite pattern was
seen in TD boys. It could be that ACC sulcus variability
affects ACC morphometry and function [85]. The ACC lies
at the interface between the limbic system and the neocortex
and is the cortical region most frequently identified as abnor-
mal in both maltreated individuals [72, 86] and CD youths
[11]. Our data suggest that CM may influence the right ACC
sulcus in opposite ways in boys with CD versus in TD boys.
We observed main effects of CD diagnosis on GM vol-
ume in bilateral dmPFC (increased with CD) and on GM vol-
ume and gyrification in left STG (both decreased with CD).
The dmPFC and STG are involved in reward and punish-
ment processing [87], empathy [88, 89], and social interac-
tions [90]. Structural alterations in these regions have been
reported previously in subjects with CD [5, 10, 24, 91]. Con-
sistent with previous research, we found structural deficits
in bilateral dmPFC and left STG in association with CD in
general (Fig. 2). Besides, our findings suggest that CM− and
CM+ groups of boys with CD have overlapping as well as
distinct neural substrates, which might be due to different
etiologies. Consequently, these two patient subpopulations
might have differentially altered pathways and treatment
responses. On the basis of the present findings, we recommend
that researchers consider CM as an important factor, because
ignoring CM in a neuroimaging study may mask alterations
13
European Child & Adolescent Psychiatry
that are specific to only CM− or only CM+ CD groups or are
oppositely expressed between CM− and CM+ CD groups.
The strengths of the current study include its relatively
large, age- and socioeconomic status- matched sample,
the combined use of VBM and SBM methods to examine
multi-dimensional morphometric measures of brain struc-
ture, and the controlling for confounders such as age, depres-
sion, anxiety, IQ and TIV. However, the current study also
had several potential limitations that should be considered
when interpreting the results. First, because data describ-
ing this population are rare (especially for CM− adolescents
with CD), we were unable to match the IQ, depression,
and anxiety levels between the groups. Notwithstanding,
because IQ, depression, and anxiety assessment variables
were included as covariates of no interest in our main anal-
yses, the observed CD diagnosis-by-CM interactions can-
not be explained by differences in these variables. Still, we
acknowledge that additional replicative research in which
samples are matched for these variables is needed. Second,
although combining VBM and SBM provides advantages
in terms of a comprehensive examination of morphometric
changes, it might increase the risk for type I errors even with
our use of a stringent method to correct for multiple com-
parisons (whole-brain PFWE < 0.05) to mitigate against this
issue. Third, as an exploratory analysis, the multiple correla-
tion results were not corrected to provide more detailed and
complex information, which means these results should be
interpreted with caution. Moreover, the present study did not
assess the callous-unemotional traits and investigate how the
callous-unemotional traits interact with CM. Including the
callous-unemotional traits as covariates of interest in further
studies may provide a better understanding of the present
findings. Another limitation is that some translational stud-
ies have reported that CM effects on brain structure might
be period sensitive, persisting into early adulthood [21, 92].
Hence, a cross-sectional design is not sufficient to address
this question. Future longitudinal studies are needed to
investigate how CM interacts with the neural mechanisms
underlying CD. Finally, only boys were recruited due to rel-
evant reported sex differences. Consequently, the present
results may not generalize to girls. It is worth noting that
the distribution of severe cases was different across groups
(Table S3), which may affect the results. Future studies
could collect severity-matched participants to explore the
effect of CM severity on gray matter abnormalities in CD
youths.
Conclusion
The results from the study suggest that there are specific
brain structural differences between CM− and CM+ boys
with CD—including morphometric alterations in the left
European Child & Adolescent Psychiatry
amygdala, right PCC, right putamen, right dlPFC and right
ACC—that may contribute to the hyper-aggression and con-
duct problems exhibited by CM+ boys diagnosed with CD.
In addition, our findings point to structural deficits in the left
STG and bilateral dmPFC that appear to be associated with
CD in general. Taken together, our findings indicate that
CM− and CM+ CD groups of boys may represent different
expressions of psychopathology influenced by exposure to
CM with the CD population.
Acknowledgements This study was supported by grants from the
National Nature Science Foundation of China (Grant no. 81471384).
Yidian Gao is funded by the Fundamental Research Funds for the Cen-
tral Universities of Central South University (no. 2016zzts140). The
funding agencies have no role in the study design, data collection and
analysis, decision to publish, or preparation of the manuscript. We
would like to thank our participants and their families for taking part
in the study. We are also grateful to the clinicians and teachers for their
assistance with recruitment.
Compliance with ethical standards
Conflict of interest The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
Ethical approval The study was approved by the Ethics Committee
of the Second Xiangya Hospital of Central South University (No.
CSMC-2009S167) and has been performed in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki and
its later amendments.
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