
==== Front
Soc Cogn Affect Neurosci
Soc Cogn Affect Neurosci
scan
Social Cognitive and Affective Neuroscience
1749-5016
1749-5024
Oxford University Press UK

39167467
10.1093/scan/nsae053
nsae053
Original Research & Neuroscience
AcademicSubjects/SCI01880
Altered dynamic functional connectivity of nucleus accumbens subregions in major depressive disorder: the interactive effect of childhood trauma and diagnosis
Zou Yurong Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China

Yu Tong Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510370, China

Zhu Liwen Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China

Xu Qing Department of Clinical Psychiatry, The Third Hospital of Longyan, Longyan, Fujian 364000, China

Li Yuhong Department of Publicity and Health Education, Shenzhen Longhua District Central Hospital, Shenzhen 518000, China

Chen Juran General Outpatient Clinic, The Zhongshan Torch Hi-tech Industrial Development Zone Community Health Service, Zhongshan 528437, China

Luo Qianyi Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510370, China

https://orcid.org/0000-0002-9115-7374
Peng Hongjun Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou 510370, China
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou 510370, China

*Corresponding authors. Department of Clinical Psychology, The Affiliated Brain Hospital, Guangzhou Medical University, No.36, Mingxin Road, Liwan District, Guangzhou 510370, China. E-mails: doctorluoqianyi@163.com; pengdoctor2@163.com.
‡ Yurong Zou and Tong Yu contributed to this work equally.

2024
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15 8 2024
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© The Author(s) 2024. Published by Oxford University Press.
2024
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Abstract

Major depressive disorder (MDD) with childhood trauma represents a heterogeneous clinical subtype of depression. Previous research has observed alterations in the reward circuitry centered around the nucleus accumbens (NAc) in MDD patients. However, limited investigations have focused on aberrant functional connectivity (FC) within NAc subregions among MDD with childhood trauma. Thus, this study adopts analyses of both static FC (sFC) and dynamic FC (dFC) to examine neurobiological changes in MDD with childhood trauma. The bilateral nucleus accumbens shell (NAc-shell) and nucleus accumbens core (NAc-core) were selected as the seeds. Four participant groups were included: MDD with childhood trauma (n = 48), MDD without childhood trauma (n = 30), healthy controls (HCs) with childhood trauma (n = 57), and HCs without childhood trauma (n = 46). Our findings revealed both abnormal sFC and dFC between NAc-shell and NAc-core and regions including the middle occipital gyrus (MOG), anterior cingulate cortex, and inferior frontal gyrus in MDD with childhood trauma. Furthermore, a significant correlation was identified between the dFC of the left NAc-shell and the right MOG in relation to childhood trauma. Additionally, abnormal dFC moderated the link between childhood abuse and depression severity. These outcomes shed light on the neurobiological underpinnings of MDD with childhood trauma.

major depressive disorder
childhood trauma
nucleus accumbens
functional connectivity
Guangzhou Medical University Research Capacity Enhancement Program 2024SRP203 Guangzhou Health Science and Technology Program 20241A011053 Guangdong Natural Science Foundation, China 2015A030313800 Guangzhou Medical University Research Capacity Enhancement Program 2024SRP203 Guangzhou Health Science and Technology Program 20241A011053 Guangdong Natural Science Foundation, China 2015A030313800
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pmcIntroduction

Major depressive disorder (MDD) is a mental disorder with a global prevalence of approximately 4.4% (Marwaha et al. 2023). It is strongly associated with cardiovascular disease (Zhang et al. 2020), diabetes mellitus (Otte et al. 2016), self-inflicted fatality (Otte et al. 2016), and other deleterious outcomes (Zhao et al. 2022), engendering a considerable societal encumbrance (Otte et al. 2016). Notably, a considerable fraction of patients with MDD, ranging from one-third to half, are nonresponsive to assorted pharmacological interventions with antidepressant properties (Marwaha et al. 2023). One of the key reasons for the poor efficacy of MDD treatment is the presence of multiple clinical phenotypes of depression. Among these, MDD with childhood trauma is recognized as one of the most prevalent clinical phenotypes (Misiak et al. 2017).

Childhood trauma is a severe and enduring chronic stressor, encompassing physical abuse (PA), emotional abuse (EA), sexual abuse (SA), physical neglect (PN), and emotional neglect (EN) (Danese and Baldwin 2017). Previous studies have confirmed the association between childhood trauma and MDD, identifying childhood trauma as a significant risk factor for MDD (Wiersma et al. 2009, McKay et al. 2021). Furthermore, individuals with childhood trauma exhibit more pronounced and enduring symptoms, earlier onset, higher rates of comorbidity, diminished responsiveness to pharmacological and psychological interventions, and higher rates of relapse compared to those without childhood trauma (Group 2022). Despite the well-established linkage between childhood trauma and MDD, the precise mechanisms through which childhood trauma increases the risk of MDD onset remain unknown.

The nucleus accumbens (NAc) is a central component of the reward circuit, traditionally recognized as a key structure in regulating cognition, motivation, and emotional processes (Floresco 2015). Emerging evidence indicates that childhood trauma can lead to structural and functional alterations in the NAc, thereby influencing the regulation of reward anticipation circuits (Teicher et al. 2016, Fan et al. 2021, Madden et al. 2023). However, the NAc is not a homogeneous nucleolus but consists of nucleus accumbens core (NAc-core) and nucleus accumbens shell (NAc-shell), with different subregions exerting different effects on behavior and emotion regulation (Chen et al. 2023). The NAc-core plays a key role in motivating individuals toward approach-related stimuli (Ito et al. 2004) and is closely associated with goal-directed behaviors (Floresco 2015, Zinsmaier et al. 2022). Meanwhile, the NAc-shell is involved in processing the excitatory effects of anticipated reward stimuli on goal-directed behaviors (Corbit et al. 2001). We selected the NAc subregion as the seed region for whole-brain functional connectivity (FC) analysis to explore reward circuit abnormalities in MDD with childhood trauma.

FC refers to the temporal correlation of neurophysiological indicators between different brain regions (Friston et al. 1993). Based on the assumption of spatial and temporal stability of FC, functional connections between different cortical areas were discovered by measuring blood-oxygen-level-dependent (BOLD) signals during resting-state brain activity (Biswal et al. 1995). Since then, static functional connectivity (sFC) has become a common method to investigate the temporal correlation of BOLD signals between different brain regions. Traditional sFC represents the average FC values over a short period, providing valuable insights into internal functional communication in the brain (van den Heuvel and Hulshoff Pol 2010). However, brain activity changes over time and in response to different task demands (Hutchison et al. 2013), while sFC fails to fully capture these complex and dynamic changes. With the development of strategies for analyzing brain functional networks, researchers discovered that dynamic functional connectivity (dFC) could be more sensitive for capturing and identifying neuroimaging-based biomarkers for brain disorders (Calhoun et al. 2014), including MDD (Zhu et al. 2020), and idiopathic generalized epilepsy (Liu et al. 2017). A combined analysis involving sFC and dFC was used in this study to comprehensively understand the neurobiological alterations in MDD.

Previous studies have examined the functionality of the NAc subregion in patients with depression. For example, Kroemer et al. discovered that aberrant FC within the NAc is related to appetite fluctuations in depression patients, indicating that abnormal NAc connectivity may influence the relationship between emotions and eating (Kroemer et al. 2022). Moreover, Hu et al. demonstrated that alterations in NAc subregion functionality mediate the link between MDD and anhedonia, indicating that abnormalities in the reward circuit centered on the NAc are tightly linked to a lack of pleasure in the core symptoms of depression (Hu et al. 2023). Similarly, Fan et al. discovered that childhood trauma may impact trait anhedonia by influencing the reward system and its associated functional connections (Fan et al. 2021). However, current research on functional abnormalities of the NAc subregion in MDD patients with childhood trauma is limited. It remains unclear whether there are abnormalities in the reward circuitry of MDD patients with childhood trauma and whether such abnormalities are influenced by experiences of maltreatment.

Based on previous studies (Wang et al. 2021, Luo et al. 2022, Xue et al. 2022, Shunkai et al. 2023, Nie et al. 2024), we hypothesized that (i) MDD patients with childhood trauma exhibit abnormal sFC and dFC patterns in the NAc subregions compared to those without childhood trauma and (ii) abnormal sFC and dFC are associated with childhood trauma. We used a combined sFC and dFC analysis to test our hypothesis and examine functional abnormalities in the NAc-centered reward circuits in MDD patients. Our findings could improve the understanding of the potential neurobiological basis underlying the increased risk of MDD due to childhood trauma and may serve as diagnostic biomarkers for neuroimaging.

Materials and methods

Participants

A total of 181 participants were included in the baseline data from a registered clinical trial (ChiCTR2300078193). This study was approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University. All participants provided written informed consent. In our previous studies, we used this database to investigate changes in the amygdala and thalamic subregion function in MDD patients with childhood trauma. However, this study differs from the previous one: the earlier studies aimed to observe abnormalities in the limbic system (amygdala) (Luo et al. 2022) and the emotional regulation hub (thalamus) (Yu et al. 2024), which were associated with negative emotional regulation in MDD patients with childhood trauma. In contrast, this study focused on examining abnormalities in the reward circuit, particularly centered around the NAc, which is associated with abnormalities in regulating positive emotions. Identifying reward-related NAc functional abnormalities in MDD patients with childhood trauma is crucial for understanding issues such as lack of motivation, heightened anticipation of rewards, and difficulty in experiencing reward satisfaction (Guyer et al. 2006, Fan et al. 2021, Nagy et al. 2021).

This study included 78 right-handed, drug-naive, first-episode MDD patients from the Affiliated Brain Hospital of Guangzhou Medical University. MDD was diagnosed by two clinically experienced psychiatrists following the DSM-5 diagnostic criteria. Moreover, 103 right-handed healthy controls (HCs) matched for age, gender, and education level, who underwent screening tests for potential psychiatric problems before recruitment, were included. Depression severity was assessed using the Hamilton Depression Rating Scale (HAMD) (Helmreich et al. 2012). Childhood traumatic experiences were measured using the childhood trauma questionnaire (CTQ) (Bernstein et al. 1994, 1997, 2003), which consisted of five aspects: PA, EA, SA, PN, and EN. The CTQ is a reliable instrument for assessing the psychological effects of childhood trauma among individuals who have experienced maltreatment before the age of 16 years (Bernstein et al. 1994, 1997, 2003). The cut-off scores for each CTQ subscale are as follows: PA score ≥10, EA score ≥13, SA score ≥8, PN score ≥10, and EN score ≥15. In this study, a score exceeding these thresholds on any of the CTQ subscales was considered indicative of childhood trauma (Fink et al. 1995, Bernstein et al. 1997).

The participants were categorized into the following groups according to the aforementioned criteria: MDD with childhood trauma (n = 48), MDD without childhood trauma (n = 30), HCs with childhood trauma (n = 57), and HCs without childhood trauma (n = 46). Participants fulfilling one of the following criteria were excluded: (i) patients diagnosed with any major psychiatric disorder other than depression (like bipolar disorder, anxiety, or posttraumatic stress disorder); (ii) patients who had previously received psychotropic medication or undergone electroconvulsive therapy; and (iii) patients with contraindications for resting-state functional magnetic resonance imaging (rs-fMRI). Further details about these participants were provided in our previous studies (Luo et al. 2022, Yu et al. 2024).

MRI data acquisition

Neuroimaging data were acquired using a 3.0 Tesla Philips magnetic resonance scanner at the Affiliated Brain Hospital of Guangzhou Medical University. The participants were meticulously instructed to maintain a state of immobility, with their eyes closed throughout the scanning procedure, ensuring relaxation and wakefulness. BOLD signals were captured accurately during an 8-minute scanning session, yielding 240 time points. Functional scans were conducted using a gradient-echo echoplanar imaging sequence, with the following parameters: 33 slices, 4 mm of slice thickness, an inter-slice gap of 0.6 mm, repetition time of 2000 ms, echo time of 30 ms, flip angle of 90 degrees, field of view measuring 220 × 220 mm2, and an acquisition matrix of 64 × 64.

MRI data preprocessing

The rs-fMRI data were preprocessed using the Data Processing Assistant for Resting-State fMRI (DPABI V5.2). To attain a steady state of longitudinal magnetization, the initial 10 volumes were excluded, leaving 230 volumes. Subsequently, slice time and head motion corrections were performed. For head motion correction, six rigid body motion parameters were used, and the mean framewise displacement (FD) (Jenkinson et al. 2002) was calculated by averaging the FD values across all time points for each participant; individuals with a mean FD of >2 mm were excluded. The images were then normalized to the standard Montreal Neurological Institute (MNI) space echo-planar imaging template and resampled to a voxel size of 3 × 3 × 3 mm3. Then, the images were smoothed using a Gaussian kernel with a full width at half-maximum of 4 mm. Finally, a bandpass filter within the frequency range of 0.0–0.08 Hz was applied to the processed images. Moreover, regression analysis was performed with white matter and cerebrospinal fluid signals as nuisance covariates to reduce the impact of physiological noise.

Definition of regions of interest

Due to its comprehensive and multi-level organizational structure, multimodal validation, and personalized characterization, the brain atlas introduced by Tian et al. has emerged as a significant tool for comprehensive connectomics research and cortical–subcortical connectivity studies (Tian et al. 2020). In seed-based sFC and dFC analyses, four subregions of the NAc from this brain atlas were selected as regions of interest (ROIs), including the bilateral NAc-shell and bilateral NAc-core. The voxels of each NAc subregion are shown in Supplementary Table S7.

sFC analysis

sFC analysis was conducted using the DPABI software. Time series data were extracted from the four subregions of the NAc (designated as ROI), and voxel-wise correlations were determined between these regions and other brain areas, generating sFC maps. These sFC maps were subjected to z-score transformation to enhance the normality of data distribution.

dFC analysis

The Hamming sliding-window method was selected to determine the dFC of the NAc subregion using the Temporal Dynamic Analysis toolkits integrated into DPABI software (version 5.2) (Yan et al. 2016). A window length of 50 TRs and a step width of 1 TR were used to conduct dFC analysis. A total of 181 sliding windows of dFC were acquired during the scanning process. Previous studies have demonstrated that a window length of 50 TRs optimizes the balance between the reliability of FC calculations and the capture of rapid dynamic changes, whereas shorter windows (e.g. 30 TRs) might increase the risk of introducing spurious fluctuations, and longer windows (e.g. 70 TRs) might obscure the characteristics of temporal variability dynamics (Liao et al. 2019, Shunkai et al. 2023). However, alternative window lengths (30 and 70 TRs) were calculated to investigate potential effects on dFC results (Liao et al. 2014).

A correlation map was generated for each sliding window by calculating the temporal correlation coefficient between the time series of the NAc subregion and all other voxels, yielding 181 correlation maps for each participant. Subsequently, the standard deviation was calculated from these 181 correlation maps, producing dFC maps representing the temporal variance of FC within each NAc subregion and reflecting FC fluctuations. The dFC maps were then subjected to Fisher’s r-to-z transformation to enhance the normality of the correlation distribution. All dFC maps were further smoothed using a 4 mm full-width at a half-maximum Gaussian kernel. Similarly, dFC pattern calculations were performed with sliding window lengths of 30 and 70 TRs to evaluate the reliability of our findings further (Liao et al. 2014). Further details are provided in the Supplementary material.

Statistical analysis

Demographic and clinical differences among the four groups were assessed using one-way analysis of variance (ANOVA), two-sample t-tests, and χ2 tests using Statistical Package for Social Sciences software (version 25.0; SPSS Inc., Chicago, IL, USA). To analyze group differences in dFC and sFC between MDD patients with and without childhood trauma and HCs with and without childhood trauma, two-way ANOVA was used to explore the interactions, followed by t-tests to investigate the trauma effect (comparing groups with and without trauma experiences) and the depression effect (comparing depression and HC groups), and Benjamini–Hochberg (B–H) correction. These methods allowed us to investigate whether the abnormal FC patterns in MDD patients with childhood trauma were due to the psychological impact of childhood trauma, the etiological effect of MDD, or the interactive effect between MDD and childhood trauma. Additionally, demographic characteristics were included as nuisance covariates in the preceding analyses.

Next, to investigate the relationship between FC values and childhood trauma severity (measured by the total CTQ and subscale scores), the FC values of clusters with significant inter-group differences in the two-way ANOVA were extracted, and a partial correlation analysis was performed using B–H correction. Furthermore, moderation analyses were conducted to determine whether abnormal FC patterns moderated the association between depression severity and childhood trauma. To comprehensively investigate the role of different child trauma subtypes, the child trauma indicators (independent variables) were CTQ, EA, PA, SA, EN, and PN scores. The severity of depression (dependent variable) was evaluated using the HAMD scores. The analysis was conducted using the PROCESS 4.1 toolbox (https://processmacro.org/index.html).

The steps of moderation analysis were as follows: In Step 1, age, gender, and education were entered. In Step 2, age, gender, education, childhood trauma, and abnormal dFC variability were entered as predictors to evaluate their relationship with depression severity. In Step 3, an interaction term (childhood trauma × abnormal dFC) was introduced to evaluate moderation effects. Before conducting the moderation regression analysis, mean centering was applied to the independent and moderating variables to address potential collinearity concerns (Holmbeck 1997). After determining the significance of the interaction term, a simple effects plot was generated by graphing childhood trauma (X) against depression severity (Y) to visually depict the moderation impact of abnormal dFC (M). A conventional 5% significance level (two-tailed test) was used.

Results

Demographics and clinical information

No significant inter-group differences were observed in age, gender, or mean FD between the MDD patients with and without childhood trauma, as well as the HCs with and without childhood trauma (P > .05). There were no significant differences in the HAMD scores between MDD patients with and without childhood trauma (P > 0.05). However, significant group differences were observed in the total CTQ scores, as well as in the EA, PA, EN, and PN subscale scores across the four groups (P < .05) (Table 1).

Table 1. Demographic and clinical characteristics of participants.

	MDD with childhood trauma (n = 48)	MDD without childhood trauma (n = 30)	HC with childhood trauma (n = 57)	HC without childhood trauma (n = 46)	F/t/χ2	P	
Age	28.1 ± 6.524	29.07 ± 7.913	26.82 ± 7.033	27.28 ± 6.065	0.824	.482	
Gender (males/females)	25/23	11/19	27/30	17/29	2.436	.119	
Educational level	12.92 ± 3.319	13.73 ± 3.35	14.14 ± 2.799	14.54 ± 2.335	2.671	.049	
HAMD score	29.46 ± 8.543	29.73 ± 5.458	–	–	0.081	.970	
Mean FD (mm)	0.462 ± 0.214	0.559 ± 0.183	0.532 ± 0.119	0.521 ± 0.124	0.069	.893	
CTQ score	55.33 ± 12.575	29.7 ± 4.535	43.6 ± 8.252	31.26 ± 4.234	85.943	<.001*	
EA	11.02 ± 4.987	5.73 ± 1.461	7.81 ± 3.17	6.13 ± 1.47	23.49	<.001*	
PA	8.06 ± 4.503	5.57 ± 1.165	6.6 ± 2.137	5.41 ± 0.777	9.170	<.001*	
SA	6.02 ± 2.686	5.2 ± 0.407	5.67 ± 1.286	5.3 ± 0.662	2.271	.082	
EN	18.04 ± 3.984	7.43 ± 2.921	13.51 ± 4.822	8.22 ± 2.43	72.382	<.001*	
PN	12.19 ± 3.486	5.77 ± 1.04	10.02 ± 2.781	6.2 ± 1.24	65.192	<.001*	
* P < .001.

NAc subregions-based sFC analysis

A significant difference in sFC was observed only between the right NAc-core and the left anterior cingulate cortex (ACC) (Table 2). MDD patients with childhood trauma exhibited reduced sFC between the right NAc-core and the left ACC compared to HCs with and without childhood trauma. Similarly, a decrease in sFC was observed in MDD patients without childhood trauma compared to HCs without childhood trauma (Fig. 1).

Table 2. Two-way ANOVA of NAc seed-based dFC and sFC.

	Seed	Effect	Brain region	Cluster size	X	Y	Z	F/t	
Static	Right NAc-core	Traumatic effect	Left ACC	144	−3	15	27	−5.3173	
Dynamic	Left NAc-shell	Interaction effect	Right MOG	12	30	−93	6	21.8774	
Right NAc-shell	Etiological effect	Right IFGtri	79	48	24	27	5.4351	
Interaction effect	Right IFGop	13	60	12	15	18.8841	
Right NAc-core	Interaction effect	Left ACC	18	−12	48	−3	20.4588	
The coordinates are in the MNI coordinate system.

Figure 1. Significant sFC differences among MDD with childhood trauma, MDD without childhood trauma, HC with childhood trauma, and HC without childhood trauma. (a) Decreased sFC between the right NAc-core seed and the left ACC. (b) Multiple comparisons of sFC between the right NAc-core seed and the left ACC.

Between-group dFC patterns of NAc subregions

A two-way ANOVA revealed that dFC abnormalities were influenced by the interaction effect of childhood trauma and depression in the following regions: left NAc-shell and right middle occipital gyrus (MOG); right NAc-shell and right opercular part of the inferior frontal gyrus (IFGop); and right NAc-core and left ACC. Moreover, an abnormal dFC influenced by the etiological effects of depression was observed between the right NAc-shell and the right triangular part of the inferior frontal gyrus (IFGtri) (Table 2; Fig. 2). However, no significant difference was observed in the dFC analysis when the left NAc-core was selected as ROI.

Figure 2. Significant dFC differences among MDD with childhood trauma, MDD without childhood trauma, HC with childhood trauma, and HC without childhood trauma. (a) Increased dFC between the left NAc-shell and the right MOG. (b, c) Increased dFC between the right NAc-shell and the right IFGtri, right IFG. (d) Increased dFC between the right NAc-core and the left ACC. (e) Multiple comparisons of dFC.

In the left NAc-shell seed-based dFC analysis, MDD with childhood trauma showed a higher dFC between the left NAc-shell and the right MOG compared to MDD patients without childhood trauma. In the right NAc-shell seed-based dFC analysis, a decreased dFC was observed between the right NAc-shell and right IFGop in MDD patients with childhood trauma compared to those without childhood trauma. Contrarily, HCs with childhood trauma exhibited increased dFC in the right NAc-shell and right IFGop compared to HCs without childhood trauma. In the right NAc-core seed-based dFC analysis, increased dFC was observed in the right NAc-core and left ACC, while a decrease in dFC was observed between the right NAc-core and left ACC in MDD patients with childhood trauma compared to those without childhood trauma. Post hoc tests confirmed that the significantly aberrant dFC was primarily caused by the interaction effect (Fig. 2, Table 2).

Correlation analyses

Partial correlation analysis with B–H correction was conducted using the dataset of all participants to investigate the relationship between aberrant FC and childhood trauma, with age, gender, and educational level as covariates. A significant negative correlation was observed between the sFC of the right NAc-core and left ACC and the total CTQ (pr = −0.207, Padj = .01), PA (pr = −0.217, Padj = .01), and EN scores (pr = −0.181, Padj = .02). The dFC between the left NAc-shell and the right MOG was positively correlated with the total CTQ (pr = 0.233, Padj = .01), SA (pr = 0.175, Padj = .02), EN (pr = 0.227, Padj = .01), and PN scores (pr = 0.207, Padj = .01) (Table 3, Fig. 3).

Figure 3. The correlation analyses between FC pattern and childhood trauma in MDD patients. Padj, P-value after correction by the BH method.

Table 3. Correlation analyses of childhood trauma and the sFC/dFC.

	Brain region	CTQ total score	EA	PA	SA	EN	PN	
Static	sFC of the right NAc-core and left ACC	−0.207*	−0.112	−0.217*	−0.078	−0.181*	−0.146	
Dynamic	dFC of the left NAc-shell and right MOG	0.233**	0.143	0.073	0.175*	0.227**	0.207**	
dFC of the right NAc-shell and right IFGtri	0.087	0.064	0.04	−0.028	0.109	0.06	
dFC of the right NAc-shell and right IFGop	−0.043	−0.044	−0.068	−0.103	−0.021	0.023	
dFC of the right NAc-core and left ACC	0.090	0.103	0.004	−0.023	0.092	0.084	
* Padj < .05.

** Padj < .01.

Moderation analysis

A moderation analysis using multiple linear regression was conducted to investigate the moderating influence of FC (moderating variable) on the relationship between childhood trauma (independent variable) and depression severity (dependent variable). There was no moderation effect in the sFC between childhood maltreatment and depression severity. As for dFC, in Step 1 (P = .574) and Step 2 (P = .842), the predictors were not significant (Table 4). However, in Step 3, the predictor (interactions of dFC between the right NAc-core and left ACC and childhood abuse) reached significance (R2 = 0.051, P = .009), indicating that the interaction between childhood abuse and aberrant dFC of the right NAc-core and left ACC could predict the severity of MDD (B = −0.614; P = .009). Details of the moderation model are listed in Table 4, while the results of the simple slope test, conducted using the Johnson–Neyman approach, are displayed in Fig. 4.

Figure 4. Aberrant dFC of the right NAc-core and left ACC is moderating the relationship between childhood abuse and depression severity.

Table 4. dFC variability of the right NAc-core and left ACC as a moderator in the relationship between childhood abuse and depression severity.

Predictor variable	R2	F	B	t	
Step 1	
Age	0.011	0.666	−0.111	−1.338	
Gender	−0.105	−0.093	
Education	−0.063	−0.328	
Step 2	
Age	0.013	0.465	−0.109	−1.300	
Gender	−0.096	−0.084	
Education	−0.057	−0.292	
Childhood abuse	−0.011	−0.126	
dFC between the right NAc-core and left ACC	−0.947	−0.562	
Step 3	
Age	0.051**	1.556	−0.064	−0.760	
Gender	0.076	0.067	
Education	−0.025	−0.131	
Childhood abuse	0.035	0.388	
dFC between the right NAc-core and left ACC	−0.586	−0.352	
Childhood abuse × dFC of the right NAc-core and left ACC	−0.614	−2.633**	
The model examines the moderating role of the dFC between the right NAc-core and left ACC in the relationship between childhood trauma and depression severity.

** P < .01.

Validation

The calculations of dFC patterns were repeated using sliding window lengths of 30 and 70 TRs to validate the reliability of the results of this study. In the analysis with a sliding window length of 30 TRs, MDD patients with childhood trauma exhibited increased dFC between the left NAc-shell and right MOG and reduced dFC between the right NAc-shell and right IFGtri and right IFGop compared to MDD patients without childhood trauma. Additionally, with a window length of 70 TRs, increased dFC was observed between the right NAc-shell and right IFGtri, and right NAc-core and left ACC in MDD patients with childhood trauma than those without childhood trauma. Most results in the validation analysis were consistent with those from the 50 TRs sliding window length. Further details are provided in the Supplementary material.

Discussion

In this study, a combined analysis of sFC and dFC was used to investigate the aberrant FC patterns in the NAc subregions in MDD patients with and without childhood trauma, as well as in HCs with and without childhood trauma. The sFC analysis revealed that MDD patients with childhood trauma exhibited reduced sFC between the right NAc-core and left ACC compared to HCs with and without childhood trauma. The following results were obtained through dFC analysis: (i) MDD patients with childhood trauma exhibited increased dFC between the left NAc-shell and right MOG, as well as the right NAc-core and left ACC, compared to MDD patients without childhood trauma. (ii) Decreased dFC was observed between the right NAc-shell and right IFGop in MDD patients with childhood trauma compared to those without childhood trauma. (iii) HCs with childhood trauma exhibited increased dFC between the right NAc-shell and right IFGop compared to those without childhood trauma. (iv) The abnormal dFC pattern between the left NAc-shell and right MOG showed positive correlations with the total CTQ and subscale scores. (v) The aberrant dFC pattern between the right NAc-core and left ACC showed a moderation effect on the relationship between childhood abuse and depression severity. Our results elucidate the complex relationship between childhood trauma, NAc dysfunction, and depression. The abnormal FC patterns within the NAc subregions in MDD patients with childhood trauma are described in the following sections.

Anomalous sFC of the right NAc-core in MDD with childhood trauma

The sFC analysis revealed an abnormal sFC between the right NAc-core and the left ACC. Moreover, the aberrant sFC was negatively correlated with the severity of childhood trauma. Regarding traumatic subtypes, correlation analyses revealed that abnormal sFC was primarily associated with PA and EN. The NAc is a central hub of the reward circuit. Conversely, the ACC is a crucial brain region of the mesolimbic system and is involved in reward-related processing (Rolls 2019). Previous studies have identified regions of the reward circuit in the brains of maltreated individuals with diminished BOLD responses to anticipated or earned rewards (Wang et al. 2014, Hanson et al. 2015). Additionally, numerous studies have reported abnormalities in the ACC of individuals who have experienced maltreatment, specifically regarding cortical thickness (Kelly et al. 2013, 2016) and volume (Kitayama et al. 2006, Tomoda et al. 2009). The NAc and ACC are key components of the reward circuit involved in reward detection and response; our findings demonstrated a significant association between them. Moreover, abnormalities in this circuit have been associated with childhood maltreatment, emphasizing the crucial roles played by the reward and response circuits in this context. The observed abnormal sFC illustrates the pathophysiological changes resulting from childhood trauma in a subtle manner.

Abnormal dFC of the left NAc-shell in MDD with childhood trauma

An increased dFC between the left NAc-shell and the right MOG was observed in MDD patients with childhood trauma compared to those without childhood trauma. The MOG plays a crucial role in processing visual information and perceiving facial emotional stimuli (Tu et al. 2013). Studies have indicated that structural and functional abnormalities in the MOG may contribute to depression. For instance, Maller et al. (2014) proposed that the curvature of the occipital lobe may be a characteristic feature of MDD. Furthermore, a meta-analysis revealed that MDD patients with suicidal tendencies exhibit aberrant FC in the bilateral occipital lobes (Chen et al. 2022). This could be related to the cognitive bias of depressed patients toward negative emotional information, as their increased focus on negative emotions may exacerbate or perpetuate their depressive symptoms (Disner et al. 2011). In certain cases, NAc activation may be significantly influenced by negative reinforcers (Floresco 2015). The increased FC between the left NAc-shell and the right MOG may indicate a strengthening of connectivity between visual information and reward processing. This excessive connectivity enhancement could lead to heightened reward anticipation, resulting in increased reward-seeking behavior, especially with excessive attention to negative emotional information. Based on these findings, we hypothesized that visual stimuli related to negative information may lead to the overactivation of the NAc, which could be a susceptibility factor contributing to the cognitive and emotional symptoms observed in MDD. To validate these findings, further neuropsychological and task-based fMRI assessments are required.

Anomalous dFC of the right NAc-shell in MDD with childhood trauma

A decreased dFC was observed between the right NAc-shell and the right IFGop, highlighting the significant contribution of NAc-shell dysfunction in MDD patients with childhood trauma. The NAc-shell mediates the excitatory effect of anticipatory reward stimuli on goal-directed behavior. A study revealed that the ventromedial prefrontal cortex exhibits a strong output to the NAc (Heather Hsu et al. 2020). The IFG is a central region of the prefrontal cortex involved in response inhibition, consisting of three subregions, the pars opercularis (IFGop), pars triangularis (IFGtri), and pars orbitalis (IFGorb), among which the IFGop is considered to be the main subregion of inhibition (Aron et al. 2014). Inhibition is a key executive control process capable of curbing inappropriate behavior (Verbruggen and Logan 2008). Numerous studies have demonstrated that MDD patients exhibit impaired inhibitory control in cognition, potentially leading to their inability to restrain attention toward negative stimuli and enhance processing of negative stimuli, eventually inducing negative emotions and preventing recovery, similar to the mechanism of depressive rumination (Aker et al. 2016, Yao et al. 2022). Based on these findings, we hypothesize that the decreased dFC between the right NAc-shell and right IFGop may reduce the individual response efficiency. Consequently, the inhibitory control ability is decreased, making it difficult to effectively inhibit attention to negative stimuli, aggravating the persistence of depressive symptoms.

Anomalous dFC of the right NAc-core in MDD with childhood trauma

The results of increased dFC between the right NAc-core and left ACC are consistent with those of Xiao and Zhang (Xiao and Zhang 2018), which suggest that ACC is activated by external noxious and contextual stimuli in response to pain, particularly affective pain (e.g. depressed mood). The ACC is commonly associated with emotional regulation (Phillips et al. 2003, Etkin et al. 2010), pain processing (Smith et al. 2021), and impulse control (Liu et al. 2012). A study revealed that childhood trauma significantly affects the cortical thickness and curvature of the ACC, providing morphological evidence for ACC abnormalities in MDD patients with childhood trauma (Luo et al. 2023). Similarly, Misquitta et al. (2021) discovered that chronic stress can lead to reduced volume and increased behavioral emotionality in the ACC, highlighting structural and morphological alterations in the ACC associated with stress-related (e.g. childhood trauma) disorders (including anxiety disorders and depression). The increased dFC between the right NAc-core and the left ACC may indicate an intensified interaction between these regions, which is associated with dysregulation in emotional regulation and reward processing. This dysregulation could make MDD patients more susceptible to the effects of negative emotions and reward deficits, exacerbating their depressive symptoms.

Correlations and moderation between abnormal variability values of dFC and childhood trauma

The aberrant dFC between the left NAc-shell and the right MOG was positively correlated with SA and childhood neglect. In line with our findings, Blair et al. (2019) discovered a correlation between childhood SA and enhanced processing of salient visual stimuli in brain regions related to emotional valuation. Additionally, the degree of neglect was associated with increased reactivity to prominent visual cues, indicating a general trend where trauma severity increased responsiveness to notable visual stimuli (Blair et al. 2019). Moreover, we observed that aberrant dFC variability plays a moderating role in the relationship between childhood abuse and MDD severity, further emphasizing its long-term impact on mental health.

Limitations

The present study has several limitations. First, cross-sectional studies cannot observe longitudinal changes or establish causal relationships. Second, the use of CTQ for retrospective assessment might have been influenced by participants’ current emotional state and the subjectivity of the assessor on the results. Third, the sample size in this study was relatively small, necessitating further research with larger sample sizes to validate the robustness of the impaired FC patterns in MDD patients with childhood trauma. Moreover, it is important to replicate our findings using high-resolution fMRI in future studies. Using an atlas generated from 7T MRI data to analyze 3T imaging data may introduce inaccuracies that affect the validity of the comparison. Finally, our study did not acquire task-based fMRI data; therefore, certain behaviors associated with the aforementioned brain regions should be interpreted cautiously.

Conclusion

In this study, aberrant FC patterns within the NAc subregions in MDD patients with childhood trauma were investigated using combined dFC and sFC analyses. Compared to MDD patients without childhood trauma, abnormal connectivity patterns were identified in different NAc subregions of MDD patients with childhood trauma, including the left NAc-shell, right NAc-shell, and right NAc-core. These results indicate an intrinsic link between aberrant FC patterns and childhood trauma, which not only contributes to a deeper understanding of the neurobiological underpinnings of MDD patients with a history of childhood trauma but also provides potential diagnostic markers and therapeutic targets for MDD patients with childhood trauma.

Supplementary Material

nsae053_Supp

Acknowledgements

None declared.

Author contributions

H.P. and Q.L. designed the study. Q.L., H.P., T.Y., Y.Z., Y.L., and J.C. performed data identification, screening, and inclusion. Q.L. and Y.Z. analyzed data, interpreted findings, and drafted the manuscript. Both authors reviewed and evaluated the manuscript. Both authors contributed significantly to the intellectual contents of the manuscript.

Supplementary data

Supplementary data is available at SCAN online.

Conflict of interest

None declared.

Funding

This work was supported by the Guangdong Natural Science Foundation, China (2015A030313800 to H.P.), the Guangzhou Medical University Research Capacity Enhancement Program, China (2024SRP203 to Q.L.), the Guangzhou Health Science and Technology General Guidance Project (20241A011053 to Q.L.), and the Guangzhou Research-oriented Hospital Foundation. The funding source had no role in the study design, analysis, or interpretation of data or in the preparation of the report or decision to publish.

Data availability

Data will be made available on request.
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