Right amygdala–right precuneus connectivity is

associated with childhood trauma in major depression

patients and healthy controls
Jie Fan,1,2,3 Feng Gao,1 Xiang Wang,1 Qian Liu,1 Jie Xia,1 Yan Han,1 Jinyao Yi,1 Changlian Tan,4 and Xiongzhao Zhu 1,2,3

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1
Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
2
Medical Psychological Institute of Central South University, Changsha, Hunan 410011, China
3
National Clinical Research Center for Mental Disorders, Changsha, Hunan 410011, China
4
Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
Correspondence should be addressed to Xiongzhao Zhu, Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan
410011, China. E-mail: xiongzhaozhu@csu.edu.cn.

Abstract
The present study investigated the effect of childhood trauma (CT) on amygdala and hippocampus functional connectivity (FC) and the
association with clinical presentations of major depressive disorder (MDD). Participants included 73 MDD patients (42 with moderate-
to-severe CT and 31 with no or low CT) and 64 healthy controls (HC; 30 with moderate-to-severe CT and 34 with no or low CT). Seed-based
whole-brain resting-state FC analyses were performed with seeds located in amygdala and hippocampus. Individuals with moderate-
to-severe CT, irrespective of MDD diagnosis, had decreased right amygdala–right precuneus connectivity compared to those with no
or low CT. Right amygdala–right precuneus connectivity was significantly correlated with physical and social trait anhedonia in MDD.
Mediation effects of this FC on relationship between CT (specifically neglect but not abuse) and trait anhedonia in MDD were significant.
MDD patients demonstrated increased right amygdala–left middle frontal gyrus FC, decreased right amygdala–right medial superior
frontal gyrus (mSFG) FC and decreased right hippocampus–bilateral mSFG FC relative to HC. Findings highlight the effect of CT on right
amygdala–right precuneus FC irrespective of MDD diagnosis. FC of right amygdala–right precuneus may be involved in the mechanism
linking CT and depression through its association with trait anhedonia.

Key words: childhood trauma; trait anhedonia; depression; amygdala; hippocampus

Introduction
Major depressive disorder (MDD) is one of the most common
psychiatric conditions, of which the core symptoms were low
mood and anhedonia. Previous studies have well established that
childhood trauma (CT) is one of the strongest risk factors in
the development of later-life MDD (Tunnard et al., 2014); how-
ever, the precise mechanism by which CT leads to MDD remains
unclear. CT putting individuals at risk for mental health prob-
lems is probably due to its effect on the developing brain, as
during childhood, the brain is immature, and the brain struc-
ture and function might be modified by the traumatic events to
a relatively great extent (Glaser, 2014). Hence, the exploration
of the effect of CT on brain associated with depression might
be a potential strategy to reveal the mechanisms linking CT
and MDD.
Both amygdala and hippocampus are important areas that
have been centrally implicated in MDD (Cullen et al., 2014; Mahar
et al., 2014). Amygdala has wide functional connectivity (FC) with
both cortical and subcortical brain regions (Ochsner et al., 2012).
The amygdala connectivity has been proposed to be involved in
critical functions related to depression including modulation of
sensory information, generation of emotion experience and emo-
tion regulation (Banks et al., 2007; Morawetz et al., 2020). It was not
only a central region in the limbic circuit responsible for negative
emotion processing (Morawetz et al., 2020) but also an impor-
tant area in the reward system involved in the positive emotion
processing (Murray, 2007). Hippocampus plays an important role
in the processing and regulation of threat and fear and repre-
sents a vital position in the stress-related pathology (Mahar et al.,
2014). Previous studies have revealed that CT might have effects
on structure and function of both amygdala and hippocampus
(Dannlowski et al., 2012; Herringa et al., 2013; Hanson et al., 2015;
Bounoua et al., 2020; Nogovitsyn et al., 2020). These findings indi-
cate that the connectivity of amygdala and hippocampus might
play a quite important role in the neural mechanisms via which
CT leads to depression.

© The Author(s) 2023. Published by Oxford University Press.

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2 Social Cognitive and Affective Neuroscience, 2023, Vol. 00, No. 00
Resting-state functional magnetic resonance imaging (fMRI)
is a popular and reliable tool for probing neural FC based on
a certain brain region. Some studies have explored the effect
of CT on amygdala and hippocampus FC. For example, previ-
ous studies have found that a high level of CT was associated
with a decreased FC between hippocampus and subgenual ante-
rior cingulate cortex (sgACC) and between amygdala and ventral
medial prefrontal cortex, sgACC, insula, and posterior cingulate
and increased connectivity between amygdala and dorsal pre-
frontal cortex, hippocampus, parahippocampal gyrus, inferior
temporal gyrus, orbitofrontal cortex, cerebellum, and brainstem
(Herringa et al., 2013; Birn et al., 2014; Dean et al., 2014; Cancel
et al., 2017). These findings were revealed in samples with dif-
ferent mental illness diagnosis, such as samples with posttrau-
matic stress disorder (Birn et al., 2014), or schizophrenia (Cancel
et al., 2017), or methamphetamine dependence (Dean et al., 2014)
and in individuals who did not meet the mental illness criteria
yet (Herringa et al., 2013). CT’s effect on amygdala and hip-
pocampus FC in depression as well as its association with the
manifestations of depression remains unclear. In addition, there
is now considerable evidence that CT was not a unitary con-
struct. Neglect and abuse, which were categorized as different
CT dimensions, may influence the neural development in dis-
tinct ways (McLaughlin et al., 2014; McLaughlin and Sheridan,
2016). Whether the effects on amygdala and hippocampus FC dif-
fered between neglect and abuse CT dimensions calls for further
clarification.
To sum, the present study was designed to examine the
impact of CT on FC of amygdala and hippocampus and
to examine its association with the clinical presentations of
depression. Medication-free MDD patients and healthy controls
(HC) with different levels of CT were included in the study.
Resting-state FC was assessed to evaluate the amygdala- and
hippocampus-based FC. We first established the effects of CT
on amygdala and hippocampus FC, and then, the mediation
effect of these FCs on the relationship between CT and its
dimensions and the clinical presentations of depression was
explored.
Methods
Participants
A total of 73 MDD patients (42 with moderate-to-severe and
31 with no or low CT) and 64 HC (30 with moderate-to-severe
and 34 with no or low CT) participated in the present study.
MDD patients were recruited from the psychology clinic at the
Second Xiangya Hospital, Changsha, China. They were all expe-
riencing a first episode of depression and had never received
psychotropic medication. Exclusion criteria included a history
of major medical or neurological problems and any axis I psy-
chiatric disorder comorbidity. Two experienced psychiatrists con-
firmed the diagnosis of MDD and comorbidity for each patient
according to the Structural Clinical Interview for the DSM-IV
Axis I (SCID-I).
Subjects in HC group were students or staff recruited from col-
leges and communities in Changsha. They were also screened for
psychiatric disorders by two experienced psychiatrists using the
SCID-I. Exclusion criteria were history or family history of any
psychiatric illnesses, any psychotropic medication and any major
medical or neurological problems.
The Childhood Trauma Questionnaire (CTQ) (Bernstein et al.,
1994) was used to perform the with moderate-to-severe CT vs.
with no or low CT group classification (see details in the ‘Clini-
cal assessments’ section). All participants were adults (≥18 years
old) and right-handed. A subset of this data set has been previ-
ously published (Fan et al., 2020), in which we investigated the
effects of CT on anhedonia in depression via reward system. This
data set mainly enlarged the sample size of MDD with no or low
CT and HC with moderate-to-severe CT to increase the statistical
power. The main results of the previous study were replicated with
this data set, which we have detailed in the Supplement (Analysis
of striatum-based FC, Tables S1–S3, Figure S1). The study was
approved by the Ethics Committee of the Second Xiangya Hospi-
tal of Central South University, and all the participants provided
written informed consent.
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Clinical assessments
The CTQ (Bernstein et al., 1994) was used to assess the sub-
jects’ maltreatment experiences during childhood. It comprised
five factors that also formed into two CT dimensions: neglect
(emotional and physical neglect) vs. abuse (emotional, physical
and sexual abuse). The following criteria, which have been illus-
trated in the CTQ manual (Bernstein and Fink, 1998), and used in
many previous studies (Tyrka et al., 2009; Dannlowski et al., 2012;
Chaney et al., 2014), were used to classify participants into with
moderate-to-severe CT group or with no or low CT group, wherein
moderate-to-severe CT was indicated by scores on at least one
subscale above the following thresholds: emotional neglect ≥15,
physical neglect ≥10, emotional abuse ≥13, physical abuse ≥10,
and sexual abuse ≥8.
Participants also finished the Beck depression inventory (BDI)
(Beck, 1965), the State Trait Anxiety Inventory, the 61-item revised
Physical Anhedonia Scale (PAS) and the Revised Social Anhedonia
Scale (RSAS) (Chapman, et al., 1976) to evaluate the depression,
anxiety and physical and social trait anhedonia, respectively. The
Perceived Stress Scale (PSS) (Cohen et al., 1983) was administered
to evaluate the perceived stress during the last month. PSS was
measured for the purpose of controlling for the potential con-
founding effects caused by more recent stressors in the studies
of impacts of childhood stress, as many prior studies have done
(Dannlowski et al., 2012; Grosse et al., 2016). Verbal intelligence
was evaluated with verbal intelligence subscales in the Wechsler
Abbreviated Scale of Intelligence (Wechsler, 1981).
Imaging procedures
Image acquisition and preprocessing
Subjects were imaged with a 3 T Siemens Skyra magnetic res-
onance scanner at the Second Xiangya Hospital. Resting-state
data were acquired using an echoplanar imaging sequence with
2500 ms repetition time (TR), 25 ms echo time (TE), 39 axial
slices, 3.5 mm slice thickness, no gap, 3.8 × 3.8 × 3.5 mm voxel size,
200 volumes, 90∘ flip angle, 240 mm field of view and 64 × 64
data matrix. In addition, the three-dimensional T1-weighted,
magnetization-prepared rapid gradient echo sagittal images were
acquired with 1900 ms TR, 2.01 ms TE, 176 slices, 1.00 mm slice
thickness, 1.0 × 1.0 × 1.0 mm voxel size, 9∘ flip angle, 900 ms inver-
sion time, 256 mm field of view and 256 × 256 matrix.
Image preprocessing was performed on Data Processing Assis-
tant for Resting-State fMRI (DPARSF V2.3) (http://www.restfmri.
net/forum/dparsf). After removing the first 10 volumes, the fol-
lowing procedures were completed: slice time correction, realign-
ment of head motion, spatial normalization, spatial smooth-
ing (full width at half maximum = 8 mm), linear detrending,
 J. Fan et al. 3

regressing out of nuisance covariates (six head motion param-
eters, white matter signal, cerebrospinal fluid signal and global
signal) and temporal band-pass filtering (0.01–0.08 Hz). We also
calculated the frame-wise displacement (FD) and scrubbed any
frame with FD >0.5 mm (Power et al., 2012).
Seed definition and FC analysis
After preprocessing, the seed-based whole-brain FC was calcu-
lated. Seeds were located in the bilateral amygdala and bilat-
eral hippocampus. These seeds were defined as spheres with
a 4 mm radius centered on the following coordinates (Montreal
Neurological Institute): left amygdala (−23, −6, −20), right amyg-
dala (21, −6, −20), left hippocampus (−31, −25, −11) and right
controlled as covariates when investigating the effect of diagno-
sis. The recent stress level as indicated by PSS scores was addi-
tionally controlled when investigating the effects involving CT.
Significance threshold for imaging analysis was set at cluster-
level family-wise error (FWE)–corrected P < 0.05, starting from
an uncorrected voxel-level P-value of 0.001. After establishing
CT’s effects on clinical variables and FC, correlation analyses and
mediation analysis were carried out to examine the relationships
among CT as well as dimensions of neglect and abuse, abnormal
FCs and depression, anhedonia and anxiety levels in MDD and HC
separately.
Results
Demographic and clinical variables

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hippocampus (29, −25, −11) (Lancaster et al., 2000; Birn et al., 2014).
Statistical analysis
Two sample t-tests, one-way analysis of variances and χ2 tests
were adopted to evaluate the demographic and clinical differ-
ences among the four groups: MDD with moderate-to-severe CT,
MDD patients with no or low CT, HC with moderate-to-severe CT
and HC with no or low CT.
The 2 (diagnosis: MDD, HC) × 2 (CT: moderate-to-severe, no or
low) analysis of covariances were performed on FC images gener-
ated by each amygdala and hippocampus seed using SPM12. Age,
gender, verbal intelligence and head parameter (mean FD) were
The four groups did not differ in gender distribution and verbal
intelligence. However, the age of MDD with moderate-to-severe
CT group was greater than that of both HC groups. The two patient
groups and the two HC groups did not differ in age to each other.
Both patient groups scored higher on PAS, State Anxiety Inven-
tory (SAI), Trait Anxiety Inventory (TAI), and PSS compared to
HC groups, while there were no differences between two patient
groups and two HC groups. MDD with moderate-to-severe CT
scored higher on BDI than MDD with no or low CT. For both patient
groups and HC groups, individuals with moderate-to-severe CT
scored higher on RSAS compared to individuals with no or low

Table 1. Demographic and clinical characteristics of MDD with moderate-to-severe CT, MDD with no or low CT, HC with moderate-to-
severe CT and HC with no or low CT groups

Statistics
MDD with moderate- MDD with no or HC with moderate-to- HC with no or low
Characteristics to-severe CT (N = 42) low CT (N = 31) severe CT (N = 30) CT (N = 34) F/t/𝜒2 P

Age (years) 23.83 (5.91) 22.97 (5.85) 20.47 (2.71) 20.82 (2.73) 4.32 0.006
Gender (female, %) 23 (54.76) 23 (74.19) 16 (53.33) 17 (50.0) 4.66 0.198
Verbal intelligence 47.52 (7.48) 45.48 (8.22) 49.13 (7.55) 47.68 (7.55) 1.23 0.300
Duration (weeks) 23.31 (5.88) 22.13 (5.93) – – 0.83 0.407
Age onset 22.24 (5.83) 21.20 (5.92) – – 0.74 0.462
CTQ total 54.79 (11.08) 35.94 (4.57) 47.27 (10.15) 32.76 (4.42) 54.75 <0.001
Physical neglect 11.79 (3.05) 7.48 (1.46) 11.43 (3.28) 6.76 (1.40) 37.95 <0.001
Physical abuse 8.07 (3.22) 5.32 (0.83) 6.73 (2.84) 5.42 (0.97) 11.57 <0.001
Emotional neglect 18.12 (3.96) 9.94 (3.03) 14.00 (4.48) 8.91 (2.70) 50.08 <0.001
Emotional abuse 10.93 (4.48) 7.45 (2.28) 8.73 (3.20) 6.58 (1.58) 13.14 <0.001
Sexual abuse 5.88 (1.66) 5.74 (1.23) 6.37 (1.96) 5.18 (0.39) 3.63 0.015
Neglect 29.90 (5.42) 17.42 (3.58) 25.43 (5.89) 15.56 (3.59) 73.36 <0.001
Abuse 24.88 (7.72) 18.52 (2.66) 21.83 (6.37) 17.21 (1.98) 14.92 <0.001
BDI 30.79 (9.63) 25.26 (9.46) 7.70 (4.88) 5.29 (4.50) 97.02 <0.001
RSAS 22.43 (7.19) 18.35 (7.00) 13.33 (4. 17) 8.91 (4.42) 35.78 <0.001
PAS 31.62 (11.44) 26.13 (12.27) 18.30 (6.35) 13.91 (7.12) 24.02 <0.001
SAI 60.05 (12.59) 54.94 (9.92) 39.67 (8.13) 35.68 (8.75) 47.29 <0.001
TAI 63.26 (8.85) 58.68 (7.15) 43.87 (7.09) 39.53 (9.43) 67.80 <0.001
PSS 27.50 (6.52) 25.29 (6.63) 16.00 (5.36) 13.26 (4.94) 48.39 <0.001
FD 0.07 (0.03) 0.07 (0.04) 0.08 (0.02) 0.08 (0.03) 0.43 0.735
Frames censored (%) 0.04 (0.07) 0.01 (0.01) 0.02 (0.04) 0.02 (0.04) 2.68 0.050

Means with s.d. in parentheses.

Significant post hoc tests (P < 0.05, Bonferroni corrected): age: MDD with moderate-to-severe CT > HC with moderate-to-severe CT = HC with no or low CT; CTQ
total: MDD with moderate-to-severe CT > HC with moderate-to-severe CT > MDD with no or low CT = HC with no or low CT; physical neglect: MDD with
moderate-to-severe CT = HC with moderate-to-severe CT > MDD with no or low CT = HC with no or low CT; physical abuse: MDD with moderate-to-severe
CT > MDD with no or low CT = HC with no or low CT; emotional neglect: MDD with moderate-to-severe CT > HC with moderate-to-severe CT > MDD with no or low
CT = HC with no or low CT; emotional abuse: MDD with moderate-to-severe CT > HC with moderate-to-severe CT = MDD with no or low CT = HC with no or low
CT; sexual abuse: HC with moderate-to-severe CT > HC with no or low CT; neglect: MDD with moderate-to-severe CT > HC with moderate-to-severe CT > MDD with
no or low CT = HC with no or low CT; abuse: MDD with moderate-to-severe CT > MDD with no or low CT = HC with no or low CT; abuse: MDD with
moderate-to-severe CT = HC with moderate-to-severe CT > HC with no or low CT; BDI: MDD with moderate-to-severe CT > MDD with no or low CT > HC with
moderate-to-severe CT = HC with no or low CT; RSAS: MDD with moderate-to-severe CT > MDD with no or low CT > HC with moderate-to-severe CT > HC with no
or low CT; PAS, SAI, TAI, PSS: MDD with moderate-to-severe CT = MDD with no or low CT > HC with moderate-to-severe CT = HC with no or low CT.
MDD, major depressive disorder; CT, childhood trauma; HC, healthy controls; CTQ, Childhood Trauma Questionnaire; BDI, Beck Depression Inventory; RSAS, the
Revised Social Anhedonia Scale; PAS, Physical Anhedonia Scale; SAI, State Anxiety Inventory; TAI, Trait Anxiety Inventory; PSS, Perceived Stress Scale; FD,
frame-wise displacement.
4 Social Cognitive and Affective Neuroscience, 2023, Vol. 00, No. 00

CT. Two patient groups had similar age onset and illness duration.
There were no significant differences in head motion parame-
ters as indicated by mean FD and percentage of censored frames
among the four groups (Table 1).
Effects of CT on FC with seeds in amygdala and
hippocampus
Significant main effects of CT were detected on right amygdala–
generated FCs. Participants with moderate-to-severe CT showed
decreased right amygdala–right precuneus FC than those with no
or low CT (P < 0.05 FWEcorr-cluster) (Table 2, Figure 1A). Significant
main effects of diagnosis were revealed on right amygdala– and
right hippocampus–generated FCs. MDD patients had increased
right amygdala–left middle frontal gyrus (MFG) FC, decreased
right amygdala–right medial superior frontal gyrus (mSFG) FC
and decreased right hippocampus–bilateral mSFG FC than HC
(P < 0.05 FWEcorr-cluster) (Table 2, Figure 1B–D). No significant
diagnosis × CT interactions for all four seeds were found.
Correlation and mediation analyses
Results showed that right amygdala–right precuneus FC was
significantly correlated with trait social anhedonia (r = −0.42,
P < 0.001) and trait physical anhedonia (r = −0.36, P = 0.002)
(Figure 1E), while it was not correlated with depression (r = −0.10,

Table 2. Diagnosis and CT effects on functional connectivity with seed located in the amygdala and hippocampus

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P-value
Seeds Brain regions Voxel Peak coordinates (x/y/z; MNI) Peak t values (FWEcorr-cluster)

Effect of CT: with moderate-to-severe CT < with no or low CT

Right amygdala Right precuneus 42 15 −57 42 4.92 0.012
Effect of diagnosis: MDD > HC
Right amygdala Left middle frontal gyrus 38 −30 51 12 5.45 0.020
(BA 10, 46)
Effect of diagnosis: MDD < HC
Right amygdala Right medial superior frontal 87 6 54 39 4.56 <0.001
gyrus (BA 9, 10)
Right hippocampus Bilateral medial superior frontal 61 −9 60 30 4.31 <0.001
gyrus (BA 9, 10)
BDI controlled additionally
Effect of CT: with moderate-to-severe CT < with no or low CT
Right amygdala Right precuneus 39 15 −57 42 5.06 0.017

BA, Broadmann area; x, y, z, coordinates of peak locations in the Montreal Neurological Institute space (MNI). P < 0.05, cluster-level FWE corrected with voxel-level
starting from P < 0.001 uncorrected.

Fig. 1. Effect of CT and diagnosis on amygdala and hippocampus FC and the association with trait anhedonia. Image analysis revealed that
participants with moderate-to-severe CT, irrespective of MDD diagnosis, had decreased FC between right amygdala seed and right precuneus
compared to those with no or low CT (A). MDD patients generally had increased FC between right amygdala seed and left MFG (B) and decreased FC
between right amygdala seed and right mSFG (C) and between right hippocampus and bilateral mSFG relative to HC (D). The right amygdala–right
precuneus connectivity was significantly correlated with physical and social trait anhedonia in MDD (E). Significance threshold for image analyses was
set at P < 0.05, FWE cluster-level corrected, starting from voxel-level P < 0.001 uncorrected.
 J. Fan et al. 5

P = 0.399) and anxiety (SAI: r = −0.22, P = 0.060; TAI: r = −0.13,
P = 0.268) in MDD patients (Table S4). The mediation analy-
sis revealed that the mediation effect of right amygdala–right
precuneus FC on the relationship between CT and physical
trait anhedonia [𝛽 = 0.08, bootstrapped 95% confidence inter-
val (CI) = 0.0132–0.1780, P = 0.022] and between CT and social
trait anhedonia (𝛽 = 0.09, bootstrapped 95% CI = 0.0110–0.1120,
P = 0.017) in MDD was both significant. After controlling for
FC mediation effects, the direct effect of CT on physical trait
anhedonia (𝛽 = 0.03, bootstrapped 95% CI = −0.1827 to 0.2430,
P = 0.825) and on social trait anhedonia (𝛽 = 0.04, bootstrapped
95% CI = −0.0436 to 0.2065, P = 0.225) was not significant (Table 3).
Correlation and mediation analyses further conducted to distin-
guish the different effects of neglect and abuse dimensions of CT
levels in MDD. The main findings were as follows: (i) individu-
als with moderate-to-severe CT, irrespective of MDD diagnosis,
had decreased right amygdala–right precuneus FC than those
with no or low level of CT; (ii) decreased right amygdala–right
precuneus FC was significantly correlated with social and phys-
ical trait anhedonia in MDD, and the mediation effects of this
FC on relationship between CT, especially the neglect dimension
while not the abuse, and trait anhedonia were significant; and (iii)
MDD patients generally had increased right amygdala–left MFG
FC, decreased right amygdala–right mSFG FC and decreased right
hippocampus–bilateral mSFG FC compared to HC. These findings
highlight the effect of CT on right amygdala–right precuneus FC,
suggesting that this FC and the associated trait anhedonia might
be manifested as important mechanisms involved in depression

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on right amygdala–right precuneus FC and on anhedonia. Results
showed that correlations between neglect and anhedonia and FC
were stronger than those of abuse (Table S5), and the mediation
effects of right amygdala–right precuneus FC on the relationship
between neglect (but not abuse) and trait anhedonia were signifi-
cant (Table 3, Figure 2). No other significant correlations between
the altered FCs and depression and anxiety levels were detected
in both MDD and HC (Ps > 0.05, Table S4).
Discussion
The present study examined the effects of CT on FC of amyg-
dala and the association with anhedonia, anxiety and depression
following CT.
In the present study, we firstly identified the effect of CT on
FC between right amygdala and right precuneus. Individuals with
high levels of CT showed lower levels of FC. This finding was
consistent with previous ones that revealed CT’s effect on pre-
cuneus during mentalizing task (Quide et al., 2017) and detected
a correlation between CT and decreased amygdala–precuneus FC
during an emotional valence task (Cancel et al., 2017). Alterations
in amygdala and precuneus connectivity were also proposed in
the mechanism of depression by other studies (Luking et al., 2011;
Cullen et al., 2014). These findings may support our results, sug-
gesting the critical role of CT targeting amygdala–precuneus FC,
accounting for later-life depression.

Table 3. Mediation effects of right amygdala–right precuneus FC on the relationship between CT as well as its dimensions (neglect vs.
abuse) and anhedonia in MDD patients

95% CI 95% CI
Effect 𝛽 Boot LLCI Boot ULCI P Effect 𝛽 Boot LLCI Boot ULCI P

CTQ total→ FC → social anhedonia CTQ total → FC → physical anhedonia

Indirect effect 0.09 0.0110 0.1120 0.017 Indirect effect 0.08 0.0132 0.1780 0.022
Direct effect 0.04 −0.0436 0.2065 0.225 Direct effect 0.03 −0.1827 0.2430 0.825
Total effect 0.13 0.0018 0.2639 0.047 Total effect 0.11 −0.1122 0.3261 0.334
Neglect → FC →social anhedonia Neglect → FC → physical anhedonia
Indirect effect 0.10 0.0231 0.2024 0.021 Indirect effect 0.09 0.0273 0.3080 0.017
Direct effect 0.19 −0.0309 0.3842 0.126 Direct effect 0.11 −0.1904 0.5182 0.430
Total effect 0.29 0.0572 0.4848 0.019 Total effect 0.20 −0.0557 0.6610 0.153
Abuse → FC → social anhedonia Abuse → FC → physical anhedonia
Indirect effect 0.05 −0.0216 0.1767 0.191 Indirect effect 0.05 −0.0296 0.2848 0.191
Direct effect 0.06 −0.1708 0.2964 0.616 Direct effect −0.06 −0.4903 0.2962 0.627
Total effect 0.11 −0.1312 0.3735 0.354 Total effect −0.01 −0.4276 0.4041 0.962

Significant indirect effects are highlighted in bold. confidence interval (CI); lower limit of confidence interval (LLCI); upper limit of confidence interval (ULCI).

Fig. 2. Mediation effects of right amygdala and right precuneus connectivity on relationship between neglect and physical and social trait
anhedonia. (A) Mediation effect of the right amygdala and right precuneus FC on the relationship between neglect and physical trait anhedonia was
significant (𝛽 = 0.09, bootstrapped 95% CI = 0.0273–0.3080). (B) Mediation effect of the right amygdala and right precuneus FC on the relationship
between neglect and social trait anhedonia was significant (𝛽 = 0.10, bootstrapped 95% CI = 0.0231–0.2024). After controlling for indirect effects, the
direct effect of CT on trait anhedonia was not significant. Mediation analyses were generated by using the bootstrap method from 5000 bootstrapped
samples. *P < 0.05; **P < 0.01; ***P < 0.001.
6 Social Cognitive and Affective Neuroscience, 2023, Vol. 00, No. 00
Precuneus was a heterogeneous brain region, of which the dif-
ferent subregions may have different connectivity patterns and be
involved in distinct cognitive functions such as visuospatial pro-
cessing (Nicole et al., 2005), mental imagery (Cavanna and Trimble,
2006), retrieval of episodic information (Dorfel ̈ et al., 2009), reflec-
tive self-related processing (Lou et al., 2004) and awareness and
conscious information processing (Vogt and Laureys, 2005). The
precuneus identified in the present study was located in the
dorsal-posterior subregion. It was proposed that this subregion
was more likely to be involved in the visuospatial information
processing and motor imagery (Zhang and Li, 2012). FC between
amygdala and this precuneus subregion has been revealed in
previous task fMRI studies and suggested to be involved in emo-
tion regulation through directing attention toward or away from
emotional stimulus (Ferri et al., 2016). Attention control was an
important emotion regulation strategy, which can influence indi-
viduals’ emotion experience (Morawetz et al., 2017). In the present
study, we revealed that this FC was correlated with trait anhe-
donia in MDD and found that the mediatory effect of this FC on
the relationship between CT and trait anhedonia was significant.
Precuneus-related FC and morphometry of precuneus associated
with positive emotion have also been reported by previous stud-
ies (Luo et al., 2017; Liu et al., 2021). Our findings further help link
the amygdala–precuneus connectivity alterations accompanied
with CT to the behavioral targets in MDD, raising the possibil-
ity that the alterations in amygdala–precuneus FC in individuals
who experienced CT were associated with their decreased ability
to experience pleasure probably through the failures in emo-
tion regulation via attention deployment, which may be involved
in the mechanism of depression following CT. Anhedonia was
defined as the decreased enjoyment and interest during daily life.
It was found to be related to deficits not only in brain reward
system underlying hedonic experience (Wang et al., 2014; Bolton
et al., 2018) but also in brain regions subserving the emotional
processing and social cognition processes (Germine et al., 2011;
Wang et al., 2014; Gunther et al., 2017). Our previous study has
demonstrated that CT has effects on state anhedonia in MDD
and has effects on physical anhedonia in HC via core reward
circuit (Fan et al., 2020), which may complement the present find-
ings, highlighting the effect of CT on anhedonia, and suggesting
the mediation of not only dysfunction in reward system but also
deficits in brain regions underlying emotional cognition aspects
involved in links between CT and anhedonia.
Moreover, our results revealed that, when the distinct CT types
were taken into consideration, the neglect showed a stronger
magnitude of association with amygdala–precuneus FC and anhe-
donia as compared with abuse, and amygdala–precuneus FC
mediated the relationship between neglect but not abuse and
anhedonia. These findings further suggest that these effects were
more likely to be driven by neglect. Neglect and abuse were
proposed to influence distinct neural circuits (McLaughlin and
Sheridan, 2016). Several previous studies have demonstrated that
individuals exposed to neglect were at greater risks for anhedo-
nia via deficits in reward-learning processing (Mehta et al., 2010;
Goff et al., 2013; McLaughlin and Sheridan, 2016; Wismer Fries
and Pollak, 2017; Sheridan et al., 2018). Our findings were in line
with the previous ones but also indicate that the broader range of
involved neural mechanism should be considered when exploring
the effect of neglect on anhedonia.
In the present study, we revealed a similar right amygdala–
right precuneus FC alteration in HC with moderate-to-severe CT.
Main effects of CT while not CT and diagnosis interactions were
not novel findings. This result pattern was consistent with many
previous studies (van Harmelen et al., 2010; Chaney et al., 2014;
Opel et al., 2014; Lu et al., 2019; Meinert et al., 2019), indicating
that the neural alterations following CT may be a vulnerabil-
ity to future psychiatric conditions, and some brain alterations
previously attributed to MDD diagnosis might rather be character-
ized as a function of childhood maltreatment. We failed to detect
the significant correlation between this FC and trait anhedonia
in HC. The result of HC generally having lower trait anhedonia
as compared with MDD might help explain this phenomenon.
Further longitudinal studies are needed to examine the specific
relationship between brain and behavioral alterations in HC with
moderate-to-severe CT.
Besides the effects of CT, our analysis also revealed that MDD
patients generally had increased right amygdala–left MFG (dor-
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solateral prefrontal cortex) FC, decreased right amygdala–right
mSFG [dorsomedial prefrontal cortex (dmPFC)] FC and deceased
right hippocampus–bilateral dmPFC relative to HC. The role of
amygdala–frontal and hippocampus–frontal connectivity in emo-
tion processing and their critical role in MDD have been well
established in previous studies (Banks et al., 2007; Herringa et al.,
2013; Dorfel et al., 2014; Liu et al., 2017), which were in line with
our findings.
Several limitations should be noted when interpreting the
results of this study. First, the CTQ is retrospective. Second,
this is a cross-sectional study, and the FC, trait anhedonia and
depression were assessed at the same time point. Although the
mediation model (CT–FC–trait anhedonia) was significant, fur-
ther longitudinal investigations should be designed to confirm
the model. Third, the MDD and HC were not well matched on
age. To further clarify the possible effects of age on our finding,
we removed six older patients in MDD groups to create a sub-
set of subjects who were matched on age and reanalyzed the
imaging data. The results were similar to the original ones (see
details in Supplementary materials, Analysis of the effect of age,
Tables S6 and S7, and Figure S2). Also, our supplementary analy-
sis revealed that the altered FCs were not significantly correlated
with age in both MDD and HC (Table S8). These results indicate
that our main results were not likely driven by age differences.
Fourth, the present study design can be categorized as univari-
ate brain-wide association studies (BWAS). Our sample size might
not be big enough to capture the robust BWAS effects (Marek et al.,
2022). Also, only the univariate single seed definition scheme was
used for the resting-state FC analysis. These limitations may influ-
ence the robustness and generalizability of the present results
(Bryce et al., 2021). Further studies with longitudinal design and
large sample size combining with some multivariate methods are
called for to confirm the present findings.
Conclusion
In conclusion, this study showed that individuals of high levels
of CT had decreased right amygdala–right precuneus FC. This FC
was associated with trait anhedonia in MDD, and the relationship
among CT, right amygdala–right precuneus FC and trait anhedo-
nia was more likely to be driven by CT dimension of neglect. These
results may strengthen our insight into mechanisms linking CT to
MDD. In addition, it may thereby highlight the potential targets
for early detection and therapeutic intervention in individuals
with CT.
Supplementary data
Supplementary data are available at SCAN online.

Data availability
The data that support the findings of this study are availiable from
the corresponding author upon reasonable request.
Funding
This work was supported by grants from the National Natural Sci-
ence Foundation of China (to X.Z., grant number 82171532; to
J.F., grant number 82201673), the Natural Science Foundation of
Hunan Province of China (to J.F., grant number 2021JJ40828) and
the Scientific Research Launch Project for new employees of the
Second Xiangya Hospital of Central South University (to J.F.).
Conflict of interest
The authors declared that they had no conflict of interest with
respect to their authorship or the publication of this article.
Acknowledgements
We are grateful for the generosity of time and effort by all the
participants and all researchers who make this project possible.
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