Abstract
Background: Childhood trauma plays a crucial role in the dysfunctional reward circuitry in major depressive disorder (MDD). We sought to explore the effect of abnormalities in the globus pallidus (GP)–centric reward circuitry on the relationship between childhood trauma and MDD.
Methods: We conducted seed-based dynamic functional connectivity (dFC) analysis among people with or without MDD and with or without childhood trauma. We explored the relationship between abnormal reward circuitry, childhood trauma, and MDD.
Results: We included 48 people with MDD and childhood trauma, 30 people with MDD without childhood trauma, 57 controls with childhood trauma, and 46 controls without childhood trauma. We found that GP subregions exhibited abnormal dFC with several regions, including the inferior parietal lobe, thalamus, superior frontal gyrus (SFG), and precuneus. Abnormal dFC in these GP subregions showed a significant correlation with childhood trauma. Moderation analysis revealed that the dFC between the anterior GP and SFG, as well as between the anterior GP and the precentral gyrus, modulated the relationship between childhood abuse and MDD severity. We observed a negative correlation between childhood trauma and MDD severity among patients with lower dFC between the anterior GP and SFG, as well as higher dFC between the anterior GP and precentral gyrus. This suggests that reduced dFC between the anterior GP and SFG, along with increased dFC between the anterior GP and precentral gyrus, may attenuate the effect of childhood trauma on MDD severity.
Limitations: Cross-sectional designs cannot be used to infer causality.
Conclusion: Our findings underscore the pivotal role of reward circuitry abnormalities in MDD with childhood trauma. These abnormalities involve various brain regions, including the postcentral gyrus, precentral gyrus, inferior parietal lobe, precuneus, superior frontal gyrus, thalamus, and middle frontal gyrus.
Clinical trial registration: ChiCTR2300078193
Introduction
Childhood trauma refers to distressing experiences that occur during the formative years, typically from 0–16 years of age.1 Childhood trauma can be classified into 5 distinct categories, namely emotional neglect, physical neglect, emotional abuse, physical abuse, and sexual abuse.1–3 Childhood trauma is a well-known risk factor for major depressive disorder (MDD),4 with a notable linkage with high prevalence of depression,2 low remission rates,5 and protracted convalescence.2 Patients with MDD exhibit abnormalities in the brain’s reward circuitry, including diminished reward sensitivity,6 issues with reward and risk decision-making,7,8 emotional negativity bias,9 and reward-dependence behaviours.10 Previous studies have demonstrated that childhood trauma exerts discernible effects on cerebral developmental trajectories,11–13 particularly by perturbing the customary operation of the brain’s reward circuits.1,14 Consequently, elucidating abnormalities in the reward circuitry among patients with MDD and childhood trauma is crucial for understanding underlying neurobiological mechanisms.
The basal ganglia play a crucial role in regulating various neurologic functions in the brain, including motor control, memory, emotion, reward processing, habit formation, and motor learning.15,16 In the context of MDD with childhood trauma, the basal ganglia are believed to be implicated in the emotional and cognitive disturbances involving the different ways of emotion generation, as well as regulation from the bottom–up (in response to inherently emotional perceptual properties of the stimulus) or from the top–down (in response to cognitive evaluations),15 which may contribute to the development of depression and related symptoms (e.g., Functional connectivity of the globus pallidus in MDD with childhood trauma emotional dysregulation, cognitive impairment, social dysfunction).16 Studying the basal ganglia can lead to a deeper understanding of how this region is affected by childhood trauma and how it contributes to the pathogenesis of depression.
Recent research has emphasized the central role of the globus pallidus in the reward circuitry. For instance, Ottenheimer and colleagues17 observed a higher number of reward-sensitive neurons in the globus pallidus than in the nucleus accumbens when measuring electrophysiological activity in rats performing reward-related tasks. Moreover, a reward-related signal associated with preferences was found in the globus pallidus, which could flexibly report the relative value of reward outcomes under various conditions.17 Stevenson and colleagues18 discovered that the ability to discriminate potential rewards and punishments and respond to them depends on the activation of the ventral pallidum. Maintaining a balance between the inhibition and stimulation of neurons in the ventral pallidum contributes to the regulation of behavioural motivation.18 These findings effectively establish the globus pallidus is not merely a relay station for downstream signals from reward neurons but a central brain region in the reward circuitry.
However, the globus pallidus is not a singular, homogeneous entity, but rather comprises functionally and structurally heterogeneous nuclei. Traditional investigations have anatomically divided the globus pallidus along the medial–lateral axis into inner and outer components.19–21 In a groundbreaking study, Tian and colleagues22 used a sample of more than 1000 healthy adults to establish a novel brain atlas applicable to subcortical nuclei. This innovative work diverged from conventional methods that relied on structural magnetic resonance imaging (MRI) to map brain anatomy.22 Instead, they employed functional MRI to elucidate the intricate organizational patterns of the human subcortex, ultimately creating the most detailed subcortical gradient map to date.22 Based on their atlas, the globus pallidus was divided into 4 subregions, namely the bilateral anterior globus pallidus and the bilateral posterior globus pallidus ( Figure 1).22 The anterior globus pallidus primarily serves motivational and cognitive functions, while the posterior globus pallidus is mainly involved in the regulation of motor functions, particularly precise grip motor parameters.23
Visualization of the globus pallidus subregions. L = left; R = right.
Numerous studies have discovered the temporal correlation of low-frequency fluctuations across the resting human brain, which is measured as functional connectivity by resting-state functional MRI (rs-fMRI).24,25 Building on the assumption of the enduring spatial and temporal stability of functional connectivity, Biswal and colleagues24 unveiled functional associations among disparate cortical domains through the assessment of blood oxygen level–dependent (BOLD) signals during the quiescent state of cerebral activity. Accordingly, static functional connectivity has emerged as a prevalent approach employed to investigate the temporal covariation of BOLD signals across diverse enclaves of the brain. With the development of analysis strategies exploring brain functional networks, researchers have put forward dynamic functional connectivity to describe the time-varying nature of functional connectivity by applying the sliding window approach.26 Although traditional static functional connectivity could represent the average functional connectivity in a short time and provide valuable information about functional communication within our brain,25 dynamic functional connectivity may find more sensitive and specific markers of brain disease.27 However, dynamic functional connectivity has the drawback of its sensitivity to noise, and the triggering mechanism behind the temporal variability of functional connectivity remains unclear.28 In this work, we decided to use both static and dynamic functional connectivity analysis.27
The methods of static and dynamic functional connectivity analysis have been extensively employed to investigate anomalous brain functionality among people experiencing depression. For example, Sato and colleagues29 found aberrant static functional connectivity between the left and right globus pallidus among people with subthreshold depression, alongside its associated dysfunctions such as dysphoria and diminished responsiveness to rewarding stimuli. Furthermore, Shunkai and colleagues30 delved into abnormal hippocampal subregions using seed-based dynamic functional connectivity and revealed that dysfunctional connectivity was linked to deficits in working memory in melancholic depression. Similarly, Luo and colleagues31 examined deviations in brain functionality among patients with MDD and childhood trauma; they observed abnormal static and dynamic functional connectivity between the amygdala subregions and cerebral regions associated with theory of mind. We sought to investigate abnormalities in static and dynamic functional connectivity within the reward circuitry, centred on the globus pallidus, among patients with MDD and childhood trauma.
Within the present study, we undertook analyses involving static and dynamic functional connectivity, employing each of the 4 subregions of the globus pallidus as the seed. The primary objective of this study was to unveil the abnormal characteristics pertaining to the functioning of the reward circuitry among patients with MDD and childhood trauma. Furthermore, we directed our efforts toward disentangling the distinct effects arising from the traumatic consequences of childhood trauma and the pathophysiological manifestations of depression on abnormal patterns of functional connectivity. Drawing on the foundation of previous functional connectivity investigations involving patients with MDD and childhood trauma,31–34 we formulated a hypothesis positing that this population would manifest anomalous functional connectivity within the globus pallidus–centred reward circuitry, distinguishing them from their counterparts who contend solely with MDD.29,35,36 This study offers a perspective on the potential neurobiological mechanisms of patients with MDD and childhood trauma by investigating the role of globus pallidus dysfunction in this context.
Methods
Participants
In our previous research, we explored alterations in the functionality of amygdala subregions among patients with MDD and childhood trauma using the same database as used here.31 However, this study diverges from the previous one in that the primary focus of the earlier research was to observe abnormalities in the limbic system, particularly in the amygdala, associated with negative emotion regulation. In contrast, the present study sought to examine anomalies in the reward circuitry, specifically centred around the globus pallidus, linked to abnormalities in regulating positive emotions. Discovering putamen-related functional abnormalities associated with reward among patients with MDD and childhood trauma is critical for understanding their lack of motivation, heightened reward anticipation, and difficulty experiencing reward satisfaction.34,37,38
We rigorously analyzed our sample size estimation by using PASS software to ensure scientific accuracy. First, considering how the interaction effect between degree of depression and trauma experience factors can significantly influence 2-way analysis of variance (ANOVA), we conducted factorial ANOVA with preset parameters (α = 0.05, 1-β = 0.8, k = 4), and an expected main effect size of 0.25, along with the interaction effect size of 0.3. We calculated the initial target sample size for each group to be 23 and the total sample size to be 92. Furthermore, we determined the dropout-inflated enrolment sample size to be 29 for each group (116 total).
We recruited patients with MDD from the Affiliated Brain Hospital of Guangzhou Medical University, along with healthy controls recruited from the nearby community. We matched controls for age, sex, and education, and ensured they exhibited no psychiatric disorders by psychiatric screening. The diagnostic process for MDD adhered to the DSM-5 criteria and was administered by 2 psychiatrists. To gauge the severity of both depression and anxiety, we employed the Hamilton Depression Rating Scale (HAMD)39,40 and the Hamilton Anxiety Rating Scale (HAMA),41 respectively. To quantify the severity of childhood trauma, we employed the Childhood Trauma Questionnaire (CTQ).3,42,43 The CTQ is regarded as an authoritative and foundational tool for quantifying the enduring effects of early-life adversity before the age of 16 years on an individual.44,45 It encompasses 5 distinct dimensions, namely emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect.42,43 The CTQ subscales are evaluated based on predefined threshold scores (emotional abuse score ≥ 13, physical abuse score ≥ 10, sexual abuse score ≥ 8, emotional neglect score ≥ 15, and physical neglect score ≥ 10).3,42,43 We employed the CTQ subscale scores to ascertain the occurrence of childhood trauma and used the CTQ total score to quantify the severity of childhood trauma. We also used neglect (sum of emotional and physical neglect) and abuse (sum of emotional, physical, and sexual abuse) scores.
Organized according to their respective histories of early-life adversity, we categorized participants into those with MDD and childhood trauma, those with MDD without childhood trauma, controls with childhood trauma, and controls without childhood trauma. We excluded patients with profound mental disorders, such as posttraumatic stress disorder, bipolar disorder, and anxiety disorders; patients who had previously undergone electroconvulsive therapy or who had taken psychotropic medications; and patients with contraindications pertinent to rs-fMRI, including those with conditions such as claustrophobia.
MRI data acquisition
We acquired MRI data with a 3.0 T Philips scanner at the radiology department of The Affiliated Brain Hospital of Guangzhou Medical University in China. We instructed study participants to maintain a state of stillness and calmness while closing their eyes during the 8-minute scanning procedure. The functional scans of the resting state were recorded using a gradient-echo echoplanar imaging sequence, which consisted of 33 slices with a total of 240 time points. The repetition time was set at 2000 ms, with an echo time of 30 ms, a flip angle of 90°, a field of view of 220 × 220 mm2, and a slice thickness and interslice gap of 4 mm and 0.6 mm, respectively. The acquisition matrix was set at 64 × 64.
MRI data preprocessing
The rs-fMRI data underwent preprocessing using Data Processing & Analysis for Brain Imaging (DPABI) software (version 5.2).46 We discarded the initial 10 volumes to eliminate steady-state longitudinal magnetization, leaving 230 volumes, which were subsequently corrected for slice time and head motion. Based on the report of Jenkinson and colleagues,47 head motion correction was executed by using the Friston 24-parameter model. We gathered the mean framewise displacement, computed from each time point for every participant; we included only those with a mean framewise displacement value of less than 0.2 mm in our analysis.47 Subsequently, the images were normalized to the standard Montreal Neurological Institute’s echo-planar imaging template and resampled to 3 × 3 × 3 mm3. After spatial normalization, we applied a 4 mm full-width at half maximum (FWHM) Gaussian kernel to smooth the images. To mitigate the effect of physiologic artifacts, white matter and cerebrospinal fluid signals were regarded as nuisance covariates and ruled out. The preprocessed images were ultimately subjected to a temporal band-pass filter between 0.01 and 0.08 Hz for further analysis. We chose not to use global signal regression in this study, given our interest in exploring differences in brain function between different groups, including people with MDD who had experienced childhood trauma, those with MDD who had not experienced childhood trauma, and healthy people with and without traumatic childhood experiences. Global signal regression could potentially distort the results of between-group analysis.48 In addition, whole-brain signals are important in the context of psychiatric disorders, and not considering them could result in a loss of valuable representation.48 Current and widely cited studies have also avoided regressing global signals during preprocessing analyses.49,50
Definition of regions of interest
Tian and colleagues22 used functional MRI to map the intricate subcortical organization of the human brain. This atlas, which can be integrated with existing cortical maps, is designed to characterize the connections between the cortex and subcortical regions. Based on this atlas, we identified 4 subregions within the globus pallidus, namely the bilateral anterior and posterior globus pallidus, which were used as regions of interest in seed-based static and dynamic functional connectivity analyses.22
Static functional connectivity analysis
We conducted static functional connectivity analysis of the bilateral anterior globus pallidus and posterior globus pallidus using DPABI software.46 We extracted the time series from the regions of interest and subsequently performed voxel-wise correlation analyses, examining the connectivity patterns between subregions of the globus pallidus and other brain regions. The resultant maps of static functional connectivity were subsequently enhanced through the application of a z transformation, thereby augmenting the normality of the data distribution.
Dynamic functional connectivity analysis
For the dynamic functional connectivity analysis, we adopted the Hamming sliding window approach, employing the temporal dynamic analysis toolkit in DPABI software.46 We chose a window length of 50 time points (TRs) and a step width of 1 TR for conducting the dynamic functional connectivity analysis. Previous research has shown that a window length of 50 TR strikes an optimal balance between the accuracy of functional connectivity calculations and the ability to capture swift dynamic alterations.31,34,51 This choice minimizes the risk of introducing erroneous fluctuations, associated with shorter windows, and the risk of obscuring the temporal dynamics’ characteristics, associated with longer windows. Furthermore, we employed additional window lengths (30 TR and 70 TR) to explore potential implications on dynamic functional connectivity outcomes.
For each sliding window, we acquired correlation maps by computing temporal correlation coefficients between the time series of globus pallidus subregions and those of all other brain voxels. Consequently, each individual had a total of 181 correlation maps derived from sliding windows. Each correlation map underwent Fisher z transformation to enhance the normal distribution of the data. We generated the dynamic functional connectivity maps by calculating the standard deviation of the 181 z-value maps obtained from the sliding windows. For improved comparability and interpretability among different individuals, these dynamic functional connectivity maps were z-standardized. Lastly, we applied a Gaussian kernel with a FWHM of 4 mm to all maps. We also executed analogous calculations of dynamic functional connectivity patterns using the sliding window lengths of 30 TR and 70 TR, aimed at corroborating the robustness of our findings (Appendix 1, available at www.jpn.ca/lookup/doi/10.1503/jpn.240019/tab-related-content).
Statistical analysis
To explore between-group differences in demographic characteristics (e.g., age, sex, education), clinical features (HAMD and HAMA scores), and severity of childhood trauma (total and subscale scores of CTQ), we applied Student t tests, χ2 tests, and 1-way ANOVA using SPSS version 27.0.
We employed 2-way ANOVA with Benjamini–Hochberg post hoc tests to examine the variations in dynamic and static functional connectivity between the 4 groups (corrected p < 0.05). During the 2-way ANOVA, demographics were regarded as nuisance covariates. With the use of 2-way ANOVA, we could identify which factor — etiological, traumatic, or interaction — was responsible for any abnormal dynamic and static functional connectivity of the globus pallidus subregions among patients with MDD and those with childhood trauma.
To investigate the relationships between abnormal dynamic functional connectivity and childhood trauma, we used partial correlation analyses with the Benjamini–Hochberg correction to calculate adjusted (adj) p values. The demographic factors were accounted for as nuisance covariates.
Considering the possibility of abnormal dynamic functional connectivity serving as a moderator factor in the relationship between childhood trauma and depression severity, we conducted a moderator analysis using the PROCESS 3.3 toolbox for SPSS software (https://processmacro.org/index.html). In the moderation analyses, childhood trauma was considered as the independent variable, aberrant dynamic functional connectivity as the moderating variable, and depression severity as the dependent variable. To eliminate problematic multicollinearity effects, the moderator and their interaction terms were both centred on the mean.52 Such transformations do not affect the significance level of the interaction terms or the simple slopes of any plotted regression lines. In addition, we included demographic variables such as age, sex, and education in the first step of the analysis. In the second step, we added childhood trauma (measured by the CTQ total score, neglect total score, and abuse total score) and aberrant variability in dynamic functional connectivity. Finally, in the third step, we added the interaction between childhood trauma and aberrant variability in dynamic functional connectivity. If the interaction had a significant effect, this would represent how aberrant variability in dynamic functional connectivity moderated the relationship between childhood trauma and HAMD score. We used 3 levels of the moderating variable, grouped as high (above mean + 0.5 standard deviation [SD]), moderate (mean – 0.5 SD to mean + 0.5 SD), and low (below mean – 0.5 SD) dynamic functional connectivity; we selected these thresholds to have similar numbers of participants in each subgroup. We considered a conventional 5% (2-tailed) threshold to be statistically significant.
Ethics approval
This study was approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University. All participants provided written informed consent.
Results
Demographics and clinical features
We enrolled 181 participants, including patients with MDD and childhood trauma (n = 48), patients with MDD without childhood trauma (n = 30), controls with childhood trauma (n = 57), and controls without childhood trauma (n = 46). Demographics are presented in Table 1. Physical neglect (37.4%) represented the highest proportion of all forms of childhood trauma, while sexual abuse (6.6%) represented the lowest proportion among participants with childhood trauma (n = 105). We found no significant differences in age, sex, education, or framewise displacement across groups (p > 0.05). Similarly, HAMD and HAMA scores did not differ between patients with and without childhood trauma (p > 0.05). We found significant differences across the 4 groups in CTQ total scores, neglect total scores, abuse total scores, and each of the subscales of emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect (p < 0.05).
Demographics and clinical features among patients with major depressive disorder (MDD) and healthy controls with or without childhood trauma
Static functional connectivity
We did not observe significant differences in the static functional connectivity of the globus pallidus subregions.
Dynamic functional connectivity
Using 2-way ANOVA, we detected significant group differences of abnormal dynamic functional connectivity in subregions of the globus pallidus. We identified the different effects attributed to the abnormal dynamic functional connectivity in pallidum subregions (i.e., the etiological effect of depression, the traumatic effect of childhood trauma, or interaction effect of depression plus childhood trauma). We then applied multiple comparisons with Benjamini–Hochberg correction (Table 2 and Figure 2).
Significant differences in dynamic functional connectivity (dFC) among patients with major depressive disorder (MDD) and childhood trauma, patients with MDD without childhood trauma, healthy controls (HC) with childhood trauma, and HC without childhood trauma, including between (A) the right posterior globus pallidus and left postcentral gyrus, (B) the right posterior globus pallidus and left inferior parietal gyrus, (C) the right posterior globus pallidus and right precentral gyrus, (D) the right anterior globus pallidus and right precuneus, (E) the right anterior globus pallidus and right superior frontal gyrus, (F) the left posterior globus pallidus and left superior frontal gyrus, (G) the left posterior globus pallidus and left thalamus, (H) the left anterior globus pallidus and right middle frontal gyrus, (I) the left anterior globus pallidus and right postcentral gyrus, and (J) the left anterior globus pallidus and right precentral gyrus. (K) Results of multiple comparisons of dFC. See Related Content tab for accessible version.
Two-way analysis of variance of seed-based dynamic functional connectivity in the globus pallidus
Anterior globus pallidus
As shown in Table 2, significant group differences in dynamic functional connectivity were exhibited between the right anterior globus pallidus and right precuneus (traumatic effect), the right anterior globus pallidus and right superior frontal gyrus (interaction effect), the left anterior globus pallidus and right middle frontal gyrus (interaction effect), the left anterior globus pallidus and right postcentral gyrus (interaction effect), and the left anterior globus pallidus and right precentral gyrus (interaction effect).
As shown in Figure 2, we observed higher dynamic functional connectivity between the right anterior globus pallidus and right precuneus among control participants with childhood trauma compared with those without childhood trauma. We detected lower dynamic functional connectivity between the right anterior globus pallidus and right superior frontal gyrus among patients with MDD and childhood trauma relative to controls with childhood trauma, but higher dynamic functional connectivity between these areas among controls with childhood trauma relative to controls without childhood trauma. We observed higher dynamic functional connectivity between the left anterior globus pallidus and right middle frontal gyrus among patients with MDD and childhood trauma than among patients with MDD without childhood trauma, but lower dynamic functional connectivity between these areas among patients with MDD without childhood trauma than among controls without childhood trauma. We observed higher dynamic functional connectivity between the left anterior globus pallidus and right postcentral gyrus among patients with MDD without childhood trauma relative to controls without childhood trauma, and among controls with childhood trauma relative to controls without childhood trauma. We observed lower dynamic functional connectivity between the left anterior globus pallidus and right precentral gyrus among patients with MDD and childhood trauma relative to those without childhood trauma, and higher dynamic functional connectivity between these areas among patients with MDD without childhood trauma than among controls without childhood trauma.
Posterior globus pallidus
As shown in Table 2, we found significant group differences in dynamic functional connectivity between the right posterior globus pallidus and left postcentral gyrus (interaction effect); the right posterior globus pallidus and left inferior parietal but supramarginal and angular gyri (interaction effect); the right posterior globus pallidus and right precentral gyrus (interaction effect); the left posterior globus pallidus and left superior frontal gyrus, medial orbital (interaction effect); and the left posterior globus pallidus and left thalamus (interaction effect).
As shown in Figure 2, we observed lower dynamic functional connectivity between the right posterior globus pallidus and left postcentral gyrus among patients with MDD and childhood trauma than among those with MDD without childhood trauma. We detected higher dynamic functional connectivity between these areas among patients MDD without childhood trauma relative to controls without childhood trauma, and among controls with childhood trauma compared with those without childhood trauma. We found higher dynamic functional connectivity between the right posterior globus pallidus and left inferior parietal lobe among patients with MDD without childhood trauma than among controls without childhood trauma. We observed lower dynamic functional connectivity between the right posterior globus pallidus and right precentral gyrus among patients with MDD and childhood trauma compared with patients with MDD without childhood trauma, and higher dynamic functional connectivity between these areas among patients with MDD without childhood trauma than among controls without childhood trauma. We found higher dynamic functional connectivity between the left posterior globus pallidus and left superior frontal gyrus (medial orbital) among patients with MDD and childhood trauma than among patients without childhood trauma. We observed lower dynamic functional connectivity between the left posterior globus pallidus and left thalamus among patients with MDD and childhood trauma relative to patients without childhood trauma, and higher dynamic functional connectivity between these areas among patients with MDD without childhood trauma compared with controls without childhood trauma, and among controls with childhood trauma than among those without childhood trauma.
Correlation analysis
As shown in Table 3 and Figure 3, partial correlation analysis with Benjamini–Hochberg correction showed that dynamic functional connectivity between the right anterior globus pallidus and right precuneus was positively correlated with emotional abuse (r = 0.155, padj = 0.04), emotional neglect (r = 0.185, padj = 0.03), physical neglect (r = 0.234, padj = 0.01), and CTQ total scores (r = 0.213, padj = 0.01). In addition, dynamic functional connectivity between the right anterior globus pallidus and right superior frontal gyrus was negatively correlated with emotional neglect scores (r = −0.176, padj = 0.02).
Correlation analyses of childhood trauma and the variability in dynamic functional connectivity (dFC), depicting the positive correlations between the dFC of the right anterior globus pallidus and right precuneus with the (A) Childhood Trauma Questionnaire (CTQ) total score, (B) emotional abuse score, (C) physical neglect score, and (D) emotional neglect (score), as well as (E) the negative correlation between the dFC of the right anterior globus pallidus and the right superior frontal gyrus with the emotional neglect score. adj = adjusted.
Correlation analyses of Childhood Trauma Questionnaire (CTQ) scores and the variability in dynamic functional connectivity among patients with major depressive disorder
Moderation analysis
We conducted moderation analyses to explore whether abnormal dynamic functional connectivity influenced the relationship between childhood trauma and depression severity. In the multiple linear regression model, abnormal dynamic functional connectivity was considered as the moderator variable, childhood trauma (including CTQ scores, neglect total scores, abuse total scores, and emotional abuse, physical abuse, sexual abuse, physical neglect, and emotional neglect scores) was considered as the independent variable, and depression severity (HAMD scores) was considered as the dependent variable. In the moderation analysis, we used data only from patients with MDD. Figure 4 depicts the outcomes of the moderating effect for the high, medium, and low dynamic functional connectivity groups. Table 4 details the results of the multilevel models of MDD severity by childhood trauma. We found that the dynamic functional connectivity between the right anterior globus pallidus and right superior frontal gyrus, as well as between the left anterior globus pallidus and right precentral gyrus, both played a moderating role in the relationship between childhood trauma and the severity of MDD.
Abnormal dynamic functional connectivity (dFC) as a moderator of the relationship between childhood abuse (independent variable) and depression severity (dependent variable), at 3 levels of the moderating variable (high: above mean dFC + 0.5 standard deviation [SD], medium: mean dFC – 0.5 SD to mean dFC + 0.5 SD, low: below mean – 0.5 SD) for (A) dFC between the right anterior globus pallidus (aGP) and the right superior frontal gyrus and (B) dFC between the left aGP and right precentral gyrus. Full model results are presented in Table 5.
Variability in dynamic functional connectivity (dFC) as a moderator in the relationship between childhood trauma and the severity of depression
To further explore the interaction effect of childhood trauma and abnormalities in dynamic functional connectivity on MDD severity, we performed multiple linear regressions in each of the 3 subgroups of dynamic functional connectivity. In multilevel models, MDD severity was the dependent variable and childhood trauma was the independent variable, with sex, age, and education as covariates. In a model with dynamic functional connectivity between the right anterior globus pallidus and the right superior frontal gyrus as the moderating variable, the group with low dynamic functional connectivity included patients with dynamic functional connectivity below 1.435, the moderate group included patients with dynamic functional connectivity between 1.435 and 1.747, and the group with high dynamic functional connectivity included patients with dynamic functional connectivity greater than 1.747. As shown in Model A of Table 5, childhood trauma was significantly associated with MDD severity only in the group with low dynamic functional connectivity, which showed that severity of childhood trauma was negatively associated with MDD severity.
Multilevel models of severity of major depressive disorder by childhood abuse by degree of abnormal dynamic functional connectivity (dFC)
Model B used the dynamic functional connectivity between the left anterior globus pallidus and right precentral gyrus as the moderating variable (low: dynamic functional connectivity < 1.429; moderate: dynamic functional connectivity 1.429–1.749; high: dynamic functional connectivity > 1.749). Childhood trauma was significantly positively associated with the severity of MDD in the high dynamic functional connectivity group only.
Results from univariate ANOVAs are provided in Appendix 1, Table S4 and Table S5.
Validation analysis
We conducted supplementary analyses that employed different sliding window lengths (70 TR and 30 TR) to validate the robustness of our findings. Most results were consistent with our main analyses. This congruence serves to emphasize the reliability and stability of our findings. Compared with patients with MDD without childhood trauma, those with both MDD and childhood trauma had lower dynamic functional connectivity between the right posterior globus pallidus and right precentral gyrus with window lengths of 30 TR, 50 TR, and 70 TR, and between the left posterior globus pallidus and left thalamus with window lengths of 50 TR and 70 TR. Conversely, there was higher dynamic functional connectivity between the left anterior globus pallidus and right middle frontal gyrus among patients with MDD and childhood trauma than among those without childhood trauma with window lengths of 30 TR and 50 TR. We observed lower dynamic functional connectivity between the left anterior globus pallidus and right precentral gyrus among patients with MDD and childhood trauma than among those without childhood trauma with window lengths of 30 TR and 50 TR. Detailed results with window lengths of 30 TR and 70 TR are provided in Appendix 1.
Discussion
We employed analyses involving static and dynamic functional connectivity, using subregions of the globus pallidus as the seeds, to investigate abnormal functional connectivity patterns between patients with MDD with or without childhood trauma and healthy controls with or without childhood trauma. This study provides insights into the relationship between MDD, childhood trauma, and dysfunction in specific globus pallidus subregions, shedding light on the neurobiological basis of MDD susceptibility. Among patients with MDD and childhood trauma, dynamic functional connectivity decreased between the posterior globus pallidus and several brain regions, including the postcentral gyrus, precentral gyrus, and thalamus. Conversely, dynamic functional connectivity increased between the anterior globus pallidus and the middle frontal gyrus (medial orbital). Furthermore, among controls with childhood trauma, dynamic functional connectivity increased between the anterior globus pallidus and the precuneus, superior frontal gyrus, and postcentral gyrus. Similarly, dynamic functional connectivity increased between the posterior globus pallidus and the postcentral gyrus and thalamus. Moreover, abnormal dynamic functional connectivity between the anterior globus pallidus and several brain regions (such as the precuneus and the superior frontal gyrus) was significantly associated with childhood trauma. Abnormal dynamic functional connectivity between the anterior globus pallidus and the superior frontal gyrus, and between the anterior globus pallidus and the precentral gyrus, moderated the relationship between childhood abuse and the severity of depression. This further elucidates the intricate relationship between childhood trauma, dysfunction in subregions of the globus pallidus, and MDD.
Altered dynamic functional connectivity with the anterior globus pallidus
We observed alterations in the functional connectivity of the anterior globus pallidus with several brain regions, including the precuneus, superior frontal gyrus, middle frontal gyrus, postcentral gyrus, and precentral gyrus. The anterior globus pallidus is considered to play a crucial role in motivation (i.e., reward-seeking and aversive avoidance) and cognitive processing (i.e., goal decisions and action selection).23,53,54 The anterior part of the precuneus is a central hub of the default mode network and is believed to facilitate theory of mind and self-referential thinking.55,56 On the other hand, the posterior default mode network, which includes the superior frontal gyrus and the posterior cingulate cortex, is associated with episodic memory and visual–spatial imagery processing.55,57 We speculate that abnormal dynamic functional connectivity in these areas is linked to motivation deficits, reduced reward processing, and aberrant episodic memory processing among patients with MDD and childhood trauma. In alignment with our speculation, Tozzi and colleagues58 illustrated that high severity of childhood trauma, represented by concurrent childhood neglect and abuse, was strongly associated with reduced thickness in the precuneus, and that patients with MDD had lower activation of the right precuneus compared with controls, impairing the procession of episodic memory. Zhang and colleagues55 also found that increased spontaneous neural activity in the right precuneus in subclinical depression may cause cognition and sensory dysfunction. Our findings confirm the important role of the anterior globus pallidus–precuneus in MDD with childhood trauma.
Previous research has shown that childhood trauma exerts profound influences on motivation and reward systems.5,34,59 This effect manifests in several distinct ways. People with childhood trauma often have anhedonia, with difficulty in deriving satisfaction from pleasurable experiences, which is highly associated with dysfunction in the brain’s reward circuitry.60 Fan and colleagues34 reported that physical, social, and anticipatory (but not consummatory) anhedonia of the reward system could be persistently affected by childhood traumatic experiences. Childhood trauma frequently hampers motivation, making it challenging to establish goals, pursue happiness, and actively seek rewards.59 Finally, people with childhood trauma may resort to self-punishing behaviours — such as substance abuse, self-harm, or other self-destructive actions — as a means of coping with their traumatic past.5 Paradoxically, these behaviours can be interpreted as a form of reward as they serve to alleviate emotional distress. Our findings support the idea that childhood trauma can have profound effects on motivation and reward systems.
We observed abnormal functional connectivity between the anterior globus pallidus and the precentral gyrus and postcentral gyrus. This could be related to the motor and emotional regulatory functions, as well as the sensory and emotional regulatory functions, of these brain regions.61–63 The precentral gyrus is primarily associated with muscle movement and motor execution.61 Although not directly related to emotional regulation, it has been shown that physical activity and sports can have a positive impact on emotional states.64,65 Physical activity promotes the release of neurotransmitters in the brain, such as dopamine and endorphins, which are associated with emotional regulation.66 Therefore, the precentral gyrus may be indirectly involved in emotional regulation through exercise and physical activities. In addition, patients with somatic symptom disorder involving demonstrated pain symptoms have shown abnormal regional homogeneity in the left precentral gyrus, indicating the role of the precentral gyrus in the perception of pain, similar to symptoms of unexplained physical pain among people with depression.62 The postcentral gyrus is part of the somatosensory cortex and is mainly related to the reception and processing of sensory information. Emotional regulation often involves interpretation and response to sensory information from both the self and the external environment.63 Consistent with our findings, the rs-fMRI study conducted by Liu and colleagues67 revealed that abnormalities in brain regions associated with somatic symptoms (precentral gyrus and paracentral gyrus) were also significantly associated with depressive symptoms. Furthermore, depressive symptoms may influence somatic symptoms, just as depression may influence or amplify somatic sensations associated with depression.67 Therefore, the postcentral gyrus may play a role in emotional perception and emotional regulation by interpreting and replying to specific sensory information.
Altered dynamic functional connectivity with the posterior globus pallidus
We detected alterations in dynamic functional connectivity between the posterior globus pallidus and several brain regions, including the superior frontal gyrus, thalamus, postcentral gyrus, and inferior parietal lobe. The posterior globus pallidus is primarily involved in regulating motor functions (i.e., action preparation and execution),53 especially precise grasping movements.23,68 The superior frontal gyrus plays a crucial role in emotion regulation, cognitive control, and decision-making.69,70 The abnormal dynamic functional connectivity between the posterior globus pallidus and the superior frontal gyrus may lead to decreased cognitive flexibility, making it challenging for patients to adapt to changes and adversities in life. In their study of people with subclinical depression, Zhang and colleagues55 found that increased spontaneous neural activity in both the left middle frontal gyrus (especially in the inferior frontal junction) and the left superior frontal gyrus may serve as neuroimaging markers for the diagnosis of depressive disorder. Moreover, the close association of the superior frontal gyrus with emotion regulation suggests that its dysfunction may contribute to emotional instability, increased negative emotions, and decreased positive emotions leading by negative bias, which are typical symptoms of depression. Noll-Hussong and colleagues71 found that higher activation of the lateral and medial superior frontal gyrus among patients with childhood experiences of sexual abuse may reflect an increased negativity bias.
The thalamus serves as a pivotal relay station for sensory information by receiving signals from sensory organs and transmitting them to other parts of the brain.72 Patients with MDD and childhood trauma exhibit altered responses to sensory information, including overinterpretation of emotional cues or heightened sensory sensitivity.73 This phenomenon may be linked to the role of the thalamus in sensory processing. Furthermore, the thalamus is closely associated with emotional processing and the regulation of emotional processing across psychiatric disorders, as confirmed by a meta-analysis.74 Emotional disturbances — such as emotional dysregulation, depression, and anxiety — are serious concerns among people with childhood trauma–related depression, and the thalamus may play a vital role in the neural circuitry of emotional regulation.74,75 In addition, dysfunction and structural disruptions in the thalamus can lead to an amnestic syndrome; impairments in recall and recognition may explain the phenomenon of memory loss among people with MDD.76
The inferior parietal lobe is involved in the perception and processing of self-identity and body image.74 Patients with MDD and childhood trauma often report distorted perceptions of their self-image, as shown in a study from northeast India, which showed a strong association between body image and depression and anxiety among college students, which may be related to the dysfunction of the inferior parietal lobe.77 People with childhood trauma–related depression may exhibit an attention bias toward negative emotional information in their cognitive processes; a dysfunctional inferior parietal lobe may contribute to this attention bias, increasing sensitivity to negative stimuli.58,71 Skokauskas and colleagues78 suggested that, with the contrast judgment of emotion minus judgment of geometry following emotional negative stimuli, participants with MDD and sexual abuse showed significantly higher activation in the area of the left inferior parietal lobe, further unveiling how the dysfunction between the posterior globus pallidus and the inferior parietal lobe impaired cognitive processing, as well as the predisposition to a negative bias.
The postcentral gyrus is a part of the somatosensory cortex primarily associated with touch, pain, and proprioception (perception of body position).62,63 Patients with MDD may show heightened sensory perception, particularly in terms of perceiving pain or discomfort, which may be related to dysfunction in the posterior postcentral gyrus.62 Furthermore, those exposed to traumatic experiences in childhood may occasionally report alterations in their state of consciousness, including feeling sluggish, experiencing difficulty concentrating, a sense of detachment from reality, or depersonalization.79 Dysfunction in the postcentral gyrus could influence these consciousness-related issues. Our findings highlight the role of abnormal functional connectivity in the posterior globus pallidus in the emotional and cognitive dysregulation of patients with MDD and childhood trauma.
The relationship between dynamic functional connectivity abnormalities and childhood trauma
We found a positive correlation between childhood trauma and dynamic functional connectivity with the anterior globus pallidus as the region of interest. Childhood trauma often leads to difficulties in emotional regulation and heightened stress responses.80 The anterior portion of the globus pallidus plays a critical role in motivation processing involving reward-seeking and aversive avoidance, as well as cognitive processing, including goal decision-making and action selection.23,53,54 Hence, functional abnormalities may result in reduced reward-seeking, more frequent avoidance behaviours, and tougher goal decision-making and action selection. The dynamic functional connectivity of the anterior globus pallidus modulated the relationship between childhood abuse and the severity of depression. This provides new evidence for the long-term effect of childhood trauma on the development of MDD via impairment of the reward system.2,4
Limitations
As the CTQ is a self-reported and retrospective questionnaire, the assessment of childhood trauma is susceptible to individual subjectivity and recall bias. Given the cross-sectional nature of the study, causal relationships between variables are challenging to infer. Future research should consider factors beyond sex, age, and education — such as family composition, household income, and social support — in understanding the effect of childhood trauma on depression outcomes. Future research could also investigate the effects of specific subtypes of childhood trauma on abnormal functional connectivity in MDD or other depressive subtypes. Compared with the large sample size of previous studies,81,82 the limited sample size in our study undermines its statistical validity, necessitating a more extensive sample to either confirm or refute the present findings. Previous studies have indicated the basal ganglia play a crucial role in producing psychomotor symptoms.83,84 We did not examine psychomotor abnormalities and will address this aspect in the future.
Conclusion
We explored the relationship between childhood trauma, MDD, and dysfunctional reward circuitry centred on subregions of the globus pallidus. Our findings support childhood trauma as a risk factor for MDD. Patients with MDD and childhood trauma exhibit pronounced abnormalities in the reward circuitry. These abnormalities involve various brain regions, including the postcentral gyrus, precentral gyrus, inferior parietal lobe, precuneus, superior frontal gyrus, thalamus, and middle frontal gyrus. Our findings offer new insights into identifying neurobiological markers for patients with MDD and childhood trauma.
Footnotes
↵* Jinrou Xia and Xiaohui Lin contributed to this work equally.
Competing interests: None declared.
Contributors: Qianyi Luo and Hongjun Peng conceived and designed the study. Xiaohui Lin, Tong Yu, Huiwen Yu, and Yurong Zou acquired the data. Jinrou Xia and Qianyi Luo analyzed and interpreted the data. Jinrou Xia, Xiaohui Lin, Tong Yu, Huiwen Yu, and Yurong Zou drafted the manuscript. All of the authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Funding: This work was supported by the Guangdong Natural Science Foundation, China (no. 2015A030313800 to Hongjun Peng) and the Guangzhou Municipal Key Discipline in Medicine for Guangzhou Brain Hospital (no. GBH2014-ZD04 to Hongjun Peng). The funders had no role in the study design, analysis or interpretation of data, or in the preparation of the report or decision to publish.
- Received February 19, 2024.
- Revision received April 18, 2024.
- Accepted May 3, 2024.
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