Hou XF, Mei BH, Wang X, Zhao FT, He L, Chen QY, Zang C, Wang C, Tang YF, Li XX, Zhang HF, Wang N, Cao B. Abnormal regional spontaneous brain activity in major depressive disorder with obesity comorbidity: A resting-state functional magnetic resonance imaging study. World J Psychiatry 2026; 16(1): 113064 [DOI: 10.5498/wjp.v16.i1.113064]
Corresponding Author of This Article
Xiao-Fang Hou, Department of Magnetic Resonance Imaging, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, No. 51 East Section of Xuesong Road, Yicheng District, Zhumadian 463000, Henan Province, China. hxf758@126.com
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Neurosciences
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Observational Study
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Jan 19, 2026 (publication date) through Dec 31, 2025
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World Journal of Psychiatry
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Hou XF, Mei BH, Wang X, Zhao FT, He L, Chen QY, Zang C, Wang C, Tang YF, Li XX, Zhang HF, Wang N, Cao B. Abnormal regional spontaneous brain activity in major depressive disorder with obesity comorbidity: A resting-state functional magnetic resonance imaging study. World J Psychiatry 2026; 16(1): 113064 [DOI: 10.5498/wjp.v16.i1.113064]
World J Psychiatry. Jan 19, 2026; 16(1): 113064 Published online Jan 19, 2026. doi: 10.5498/wjp.v16.i1.113064
Abnormal regional spontaneous brain activity in major depressive disorder with obesity comorbidity: A resting-state functional magnetic resonance imaging study
Xiao-Fang Hou, Qian-Yu Chen, Chen Zang, Yu-Feng Tang, Xiao-Xin Li, Hui-Fang Zhang, Department of Magnetic Resonance Imaging, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, Zhumadian 463000, Henan Province, China
Bo-Hui Mei, Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Xia Wang, Department of Otorhinolaryngology, Traditional Chinese Medicine Hospital of Zhumadian, Zhumadian 463000, Henan Province, China
Fu-Tao Zhao, Department of Psychiatry, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, Zhumadian 463000, Henan Province, China
Lei He, Department of Psychology III, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, Zhumadian 463000, Henan Province, China
Chong Wang, Department of Addiction Medicine, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, Zhumadian 463000, Henan Province, China
Na Wang, Bing Cao, Faculty of Psychology, Southwest University, Chongqing 400715, China
Co-corresponding authors: Xiao-Fang Hou and Bing Cao.
Author contributions: Hou XF and Mei BH conceived and designed the study, made equal contributions as co-first authors; Hou XF, Zhao FT, Zang C, Wang C, Tang YF, Zhang HF, Wang N, and He L collected the data and performed the statistical analysis; Cao B, Wang X, Wang N, and Mei BH contributed to the discussion; Cao B and Hou XF made equal contributions as co-corresponding authors; all authors have read and approved the final version of this article.
Supported by Provincial Key Research Project of Henan Province, No. 232102310081.
Institutional review board statement: This study was approved by the Institutional Review Board of Zhumadian Second People’s Hospital, No. IRB-2023-002-01.
Informed consent statement: All participants were informed of the study requirements, provided written informed consent voluntarily, and received financial compensation based on task completion.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Fang Hou, Department of Magnetic Resonance Imaging, The Affiliated Brain Hospital of Zhengzhou University, The Second People’s Hospital of Zhumadian, No. 51 East Section of Xuesong Road, Yicheng District, Zhumadian 463000, Henan Province, China. hxf758@126.com
Received: August 14, 2025 Revised: September 2, 2025 Accepted: October 28, 2025 Published online: January 19, 2026 Processing time: 139 Days and 10.8 Hours
Abstract
BACKGROUND
Major depressive disorder (MDD) and obesity (OB) are bidirectionally comorbid conditions with common neurobiological underpinnings. However, the neurocognitive mechanisms of their comorbidity remain poorly understood.
AIM
To examine regional abnormalities in spontaneous brain activity among patients with MDD-OB comorbidity.
METHODS
This study adopted a regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging. The study included 149 hospital patients divided into four groups: Patients experiencing their first episode of drug-naive MDD with OB, patients with MDD without OB, and age- and sex-matched healthy individuals with and without OB. Whole-brain ReHo analysis was conducted using SPM12 software and RESTplus toolkits, with group comparisons via ANOVA and post-hoc tests. Correlations between ReHo values and behavioral measures were examined.
RESULTS
ANOVA revealed significant whole-brain ReHo differences among the four groups in four key regions: The left middle temporal gyrus (MTG.L), right cuneus, left precuneus, and left thalamus. Post-hoc analyses confirmed pairwise differences between all groups across these regions (P < 0.05). OB was associated with ReHo alterations in the MTG.L, right cuneus, and left thalamus, whereas abnormalities in the precuneus suggested synergistic pathological mechanisms between MDD and OB. Statistically significant correlations were found between the drive and fun-seeking dimensions of the behavioral activation system, as well as behavioral inhibition and the corresponding ReHo values.
CONCLUSION
Our findings provide novel evidence for the neuroadaptive mechanisms underlying the MDD-OB comorbidity. Further validation could lead to personalized interventions targeting MTG.L hyperactivity and targeting healthy food cues.
Core Tip: This study used resting-state functional magnetic resonance imaging and regional homogeneity analysis to investigate spontaneous brain activity in patients with comorbid major depressive disorder and obesity. Significant regional homogeneity alterations were found in the left middle temporal gyrus, right cuneus, left precuneus, and left thalamus. These findings suggest shared and synergistic neurobiological mechanisms underlying major depressive disorder-obesity comorbidity and highlight potential targets, such as left middle temporal gyrus hyperactivity, for personalized interventions aimed at improving emotional regulation and food-related cue processing in affected individuals.
Citation: Hou XF, Mei BH, Wang X, Zhao FT, He L, Chen QY, Zang C, Wang C, Tang YF, Li XX, Zhang HF, Wang N, Cao B. Abnormal regional spontaneous brain activity in major depressive disorder with obesity comorbidity: A resting-state functional magnetic resonance imaging study. World J Psychiatry 2026; 16(1): 113064
Major depressive disorder (MDD), a complex and multidimensional psychiatric condition characterized by psychological impairments (e.g., persistent low mood, anhedonia, and cognitive deficits) and systemic dysregulation (e.g., sleep disturbances, metabolic abnormalities, and appetite dysregulation)[1,2], exhibits a strong bidirectional comorbidity with obesity (OB)[3]. Epidemiological studies have reported a 55% elevated risk of depression in individuals with OB and a 58% higher OB risk in individuals with depression, as compared to the general populations[4]. Metabolic comorbidities (e.g., type 2 diabetes) further complicate MDD and OB (MDD-OB) treatment efficacy[5,6]. MDD-OB, along with their comorbidity, are estimated to impose a substantial global economic burden of trillions of United States dollars annually, and their public health impact is expected to intensify over the next decade[7,8].
Emerging evidence suggests that the bidirectional association between MDD-OB may be mediated by shared psychological and neurocognitive mechanisms[9,10]. From a psychological perspective, OB may exacerbate depressive self-perception and social withdrawal, while depression reciprocally promotes obesogenic behaviors (e.g., hyperphagia and sedentary lifestyles) through maladaptive dietary preferences and reduced physical activity[11]. Neurophysiological findings implicate genetic predisposition, early life adversity, and neuroendocrine dysregulation (e.g., hypothalamic-pituitary-adrenal axis hyperactivity) in remodeling cognitive neural networks, which could partially account for the MDD-OB interplay[10,12]. However, current research predominantly adopts epidemiological or endocrine-metabolic frameworks, with a paucity of systematic investigations into the neurocognitive underpinnings of MDD-OB comorbidity.
Resting-state functional magnetic resonance imaging (rs-fMRI) is a widely used neuroimaging technique[13]. Among its analytical approaches, regional homogeneity (ReHo), which is a measurement of the blood oxygen level-dependent signal, can quantify the similarity of time-series signals between a given voxel and its adjacent neighbors, reflecting localized neural synchronization[14]. The ReHo method has been validated as a robust and replicable biomarker for detecting cerebral abnormalities in psychiatric and neurological disorders such as Alzheimer’s disease, MDD, schizophrenia, and attention deficit hyperactivity disorder[15,16]. Accumulating evidence has reported abnormal ReHo in individuals with MDD as compared with controls, which is commonly interpreted as a deficit in local neural activity or connectivity[17]. A study with five cohorts involving 1434 participants [709 patients with MDD and 725 healthy controls (HCs)] in China found that patients with MDD had significantly lower functional activities (ReHo values) in the right postcentral gyrus, bilateral orbitofrontal cortices, and bilateral middle and inferior occipital gyri than HCs[18]. Liang et al[19] also found lower ReHo values in the calcarine/Lingual gyrus, right temporal superior gyrus, and right precentral/postcentral gyrus in their MDD group. Moreover, a study on severe OB with comorbid meibomian gland dysfunction revealed increased ReHo values in the patient group compared to HCs across various brain regions, such as the left cerebellum, right fusiform gyrus, left rectus gyrus, and left insula. Notably, the right fusiform gyrus ReHo values demonstrated a significant positive correlation with depression scores (r = 0.676, P = 0.016)[20].
These findings suggest that comorbid OB may augment the complexity of functional neural connectivity in individuals with MDD. Although many studies have confirmed robust and replicable abnormalities in neural activity based on ReHo in patients with MDD, only a few have explored the functional changes associated with OB. To the best of our knowledge, the current study is the first that has primarily focused on localized brain regions or individual neural connections, and limited studies have been conducted with comprehensive ReHo analyses of broader neural networks or multivariate interactions in patients with MDD-OB. This hypothesis-free study aimed to investigate whole-brain fractional ReHo alterations across four groups: (1) Patients experiencing their first episode of drug-naive with MDD-OB (MDD-OB group); (2) Patients with MDD without OB (MDD group); (3) HCs with OB (OB group); and (4) HCs without OB (HC group). Furthermore, we examined the potential associations between aberrant ReHo patterns and behavioral activation and inhibition in all participants.
MATERIALS AND METHODS
Ethical approval
The authors affirm that all research procedures involving human participants complied with both the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as its 2008 revisions. Formal ethical approval for this study was obtained from the Institutional Review Board of Zhumadian Second People’s Hospital, No. IRB-2023-002-01. Written informed consent was secured from all participants prior to any study-related procedures.
Study design and participants
This study employed a cross-sectional observational design and included 149 participants. All participants were enrolled at the Zhumadian Second People’s Hospital in Henan, China, from March 2024 to September 2024. All participants with MDD were recruited from outpatient psychiatric units, whereas age- and sex-matched HCs were enrolled in the health-screening clinic of the same hospital. Ten participants with MDD and 19 HCs were excluded because of maximum head motion exceeding 2 mm or 2 degrees. The final sample comprised 23 patients with MDD-OB, 47 patients with MDD without OB, 42 HCs with OB, and 37 HCs without OB. The inclusion and exclusion criteria for each group are presented in Table 1.
Table 1 The inclusion criteria and exclusion criteria of each group.
Group
Inclusion criteria
Exclusion criteria
MDD-OB
(1) Outpatients meeting DSM-5 diagnostic criteria for MDD, with current MDE confirmed through the M.I.N.I 5.0 by trained psychiatrists; (2) HAMD-24 score ≥ 20; (3) First-episode, antidepressant-naive status at enrollment; and (4) BMI1 ≥ 28 kg/m2
(1) Presence of organic brain diseases; (2) Severe systemic diseases; (3) Intellectual disability (or: Mental retardation); (4) History of alcohol or substance abuse; (5) Visual or auditory impairments; (6) History of clinically diagnosed neurological disorders; and (7) Pregnant or lactating women
MDD
(1) Outpatients meeting DSM-5 diagnostic criteria for MDD, with current MDE confirmed through the M.I.N.I 5.0 by trained psychiatrists; (2) HAMD-24 score ≥ 20; (3) First-episode, antidepressant-naive status at enrollment; and (4) 18.5 ≤ BMI < 24 kg/m2
OB
(1) BMI ≥ 28 kg/m2; and (2) Exclusion of MDD and other conditions meeting exclusion criteria
HC
(1) 18.5 ≤ BMI < 24 kg/m2; and (2) Exclusion of MDD and other conditions meeting exclusion criteria
All participant groups
(1) Minimum education level: Completion of elementary school or higher; (2) Aged 18-60 years, irrespective of gender; and (3) Voluntary participation with written informed consent obtained after full explanation of study procedures
Trained healthcare workers collected the demographic information of all the participants. The Hamilton Depression Rating Scale (HAM-D24) was employed to quantify the severity of psychiatric symptoms. The Behavioral Inhibition System (BIS)/Behavioral Approach System (BAS) scales[21], validated for the Chinese population[22], were used to assess individual differences in BIS and BAS sensitivity. This 18-item instrument comprises a 5-item BIS scale and a 13-item BAS scale. The BAS includes three subscales: Drive (four items), reward responsiveness (five items), and fun-seeking (four items). All items were rated on a 4-point Likert scale ranging from 1 (strongly disagree) to 4 (strongly agree).
Image acquisition and processing
Structural and functional images of each participant were obtained using a GE Signa HDXT 3.0T scanner. Rs-fMRI images were acquired using a gradient echo-planar imaging sequence. The sequence parameters were as follows: Repetition time = 1500 millisecond; echo time = 29 millisecond; flip angle = 90°; field of view = 192 mm × 192 mm; matrix size = 64 × 64 pixels; 33 slices, slice thickness = 4 mm; isotropic voxel size = 3 mm × 3 mm × 5.5 mm. During the scans, each participant was instructed to close their eyes, but remain awake. Participants were also encouraged to avoid active thinking.
Rs-fMRI data were processed using the DPABI toolbox (version 4.3; http://rfmri.org/dpabi) in MATLAB (R2021a; MathWorks). The first 10 volumes were removed to adapt to scanning noise. The remaining volumes were processed per the following seven steps: (1) Slice-timing; (2) Realignment of head-motion; (3) Spatial normalization, which was performed using the Montreal Neurological Institute coordinate space with 3 mm × 3 mm × 3 mm; (4) Linear detrending to reduce the influence of magnetic resonance imaging equipment; (5) Temporal band-pass filtering (0.01-0.08 Hz); and (6) The use of white matter signal, cerebrospinal fluid, and head motion scrubbing regressors as covariates.
The ReHo analysis was performed using the RESTplus toolkit (version 1.28; http://www.restfmri.net/forum/) on filtered data that had not undergone smoothing. The Kendall’s coefficient of concordance value for each voxel was subtracted from the mean of all voxels in the whole brain and then divided by the standard deviation to complete data standardization. Subsequently, spatial smoothing was applied to the ReHo values using a smoothing kernel of 6 mm × 6 mm × 6 mm to obtain the szReHo (smooth z-score ReHo) for statistical analysis[23].
Statistical analysis
IBM SPSS Statistics (version 23.0; Statistical Package for Social Sciences) was used to conduct the statistical analyses. When evaluating the data, continuous variables were summarized using either the mean or SD, and categorical variables were summarized using n (%). One-way analysis of variance was performed to determine differences in continuous variables. Group sex differences were compared using the χ2 test. The threshold of statistical significance was set at P < 0.05 (two-tailed).
Whole-brain ReHo maps were compared using an ANOVA model in SPM12, and any abnormalities among the four groups were documented. Post-hoc t-tests were used to determine the differences between each pair of groups using SPSS. Significant voxels and clusters were identified based on family-wise error rate correction (voxel P < 0.001, cluster P < 0.05). Subsequently, we obtained the mean ReHo values for these abnormal clusters, and Pearson’s correlation analyses were used to calculate the correlation coefficients between the abnormal clusters and clinical symptoms.
A voxel-based ANOVA was performed on the ReHo values of each group, with age, sex, and head motion parameters as covariates in SPM12. The analysis identified voxels and clusters with significant differences, and the results were corrected using family-wise error rate corrections at both the cluster and voxel levels. Statistical thresholds were set as follows: Voxel level P < 0.001, cluster level P < 0.05, and cluster size > 20 voxels. Pearson’s correlation analysis and post-hoc t-tests were then conducted between the ReHo values of the significant voxels and clusters and the BAS/BIS data. P < 0.05 (uncorrected P value) was considered statistically significant.
RESULTS
Demographic characteristics of participants
In total, 149 participants were included in the final analysis. There were significant group differences in body mass index (BMI) (F = 61.01, P < 0.001) and depression severity as measured using the HAM-D24 (F = 93.83, P < 0.001). Post-hoc analyses confirmed higher BMI in the OB and MDD-OB groups than in the HC and MDD groups and elevated HAM-D24 scores in the MDD and MDD-OB groups than in the HC and OB groups. The BIS and BAS scales also showed significant intergroup differences in reward responsiveness (BAS-R), drive (BAS-D), fun-seeking (BAS-F), and behavioral inhibition (all P < 0.001). Participants’ demographic and clinical characteristics are presented in Table 2.
Table 2 Demographic features of participants in the study, n (%).
Whole-brain ANOVA of ReHo values revealed significant differences among the four groups in four regions (Table 3): The left middle temporal gyrus (MTG.L; F = 24.67), right cuneus (F = 28.39), left precuneus (F = 29.60), and left thalamus (F = 25.05) (voxel P < 0.001, cluster P < 0.05). Post-hoc analyses revealed distinct spatial patterns; For the MTG.L, ReHo values progressively increased from the HC to MDD to OB groups, with the comorbid MDD-OB group matching the OB group. The right cuneus ReHo decreased from the HC to the MDD to OB groups, with the MDD-OB group being equivalent to the OB group. The left precuneus ReHo remained comparable between the HC and MDD groups, but significantly decreased in the OB group and was even significantly lower in the MDD-OB group. The left thalamus showed divergent directional effects: MDD increased ReHo vs HC, while OB decreased it, with comorbid MDD-OB resembling the OB group (Figure 1).
Figure 1 Brain regions showing differences among the healthy control, obesity, major depressive disorder, and comorbid major depressive disorder-obesity groups.
A: Left middle temporal gyrus; B: Right cuneus; C: Left precuneus; D: Left thalamus. Corrected for multiple comparisons using family-wise error rate cluster-wise corrected. MDD: Major depressive disorder; HC: Healthy control; OB: Obesity; Cuneus.R: Cuneus right; Precuneus.L: Precuneus left; Thalamus.L: Thalamus left; Gyrus.L: Gyrus left. aP < 0.05, bP < 0.01, and cP < 0.001.
Table 3 Brain areas with significantly different regional homogeneity values among healthy control, obesity, major depressive disorder, and comorbid major depressive disorder-obesity groups.
Correlations between ReHo and clinical characteristics
Significant associations were observed between ReHo values and behavioral measures (details are shown in Figure 2). Increased ReHo in the MTG.L showed moderate positive correlations with higher BAS-D (r = 0.223, P < 0.01), BAS-F (r = 0.255, P < 0.01), and BIS (r = 0.365, P < 0.01). Conversely, reduced ReHo in the right cuneus was associated with higher BAS-D (r = -0.254, P < 0.01), BAS-F (r = -0.292, P < 0.01), and BIS (r = -0.279, P < 0.01). Lower ReHo in the left precuneus was correlated with increased BIS (r = -0.215, P < 0.01). For the left thalamus, decreased ReHo was linked to elevated BAS-D (r = -0.174, P < 0.05) and BAS-F (r = -0.225, P < 0.01). No significant correlations were found between any ReHo measures and BAS-R.
Figure 2 The Person correlation between regional homogeneity value of the differential brain areas and clinical features.
Green: Healthy control group; Orange color: Obesity group; Blue color: Major depressive disorder group; Red color: Major depressive disorder-obesity group. BASR: Behavioral activation system-reward responsiveness; BASD: Behavioral activation system-drive; BASF: Behavioral activation system-fun seeking; BIS: Behavioral inhibition/system; MTGL: Left middle temporal gyrus; Cuneus.R: Cuneus right; Precuneus.L: Precuneus left; Thalamu.L: Thalamus left. aP < 0.05, bP < 0.01, and cP < 0.001.
DISCUSSION
To the best of our knowledge, this study is the first rs-fMRI study to employ ReHo analysis to investigate functional connectivity differences among individuals with OB, MDD, comorbid MDD-OB, and HCs. The post-hoc analyses revealed that individuals with comorbid MDD-OB exhibited significant ReHo differences compared to HCs in all four brain regions (the MTG.L, right cuneus, left precuneus, and left thalamus). Critically, the comorbid group exhibited a divergent pattern of neural alterations that did not perfectly align with the MDD or OB group. Our results suggest that ReHo alterations in the MTG.L, right cuneus, and left thalamus among comorbid individuals may be mainly associated with OB, whereas the changes in the left thalamus are more complex. Further correlational analyses indicated that the observed ReHo alterations in these regions were associated with group differences in behavioral inhibition/activation. These findings suggest that the neuropathology of comorbid MDD-OB may involve unique neuroadaptive mechanisms beyond the simple additive effects of the individual conditions. The correlational nature of these findings precludes causal inference; however, they preliminarily establish a link between altered ReHo in brain regions and behavioral inhibition/activation.
Although MDD alone elevated ReHo in the MTG.L group, this increase was more pronounced in the OB group. When MDD co-occurred with OB, the ReHo values of the MTG.L group were similar to those of the OB group. This suggests that OB may exert a more substantial facilitative effect on local synchrony in this region, irrespective of comorbid MDD. In contrast, the impact of MDD alone appears to be comparatively weaker. The middle temporal gyrus is involved in diverse functions and plays a critical role in emotional perception, memory, and social cognition[24,25]. Through its connections with prefrontal regions, it also contributes to impulse regulation during inhibitory control[24]. Thus, elevated MTG.L ReHo in both the MDD and OB groups may reflect altered local neural synchrony, which could be linked to the sustained recruitment of cognitive resources related to emotional and/or food-related impulses. Our correlation analysis also revealed a significant positive association between MTG.L ReHo and behavioral inhibition (BIS: r = 0.365, P < 0.01). This moderate correlation suggests that increased synchrony in the MTG.L may be one of several neural factors contributing to increased behavioral inhibition, consistent with its role in cognitive control and conflict monitoring[26]. Consistent with our findings, a longitudinal study reported that compared with patients with a first episode of MDD, remitted individuals showed significantly lower ReHo values in the MTG.L[27]. A recent study also found that obese children aged 7-15 years exhibited increased ReHo in the left inferior temporal gyrus. This aligns with our observations and implies that altered neural synchrony in temporal regions may be associated with hedonic food-related impulses that outweigh weight management capacity, in a manner similar to the mechanism of addiction[28]. The MTG.L and inferior temporal gyrus, though both temporal regions, have distinct functional roles (e.g., MTG.L in emotion perception vs inferior temporal gyrus in object recognition).
The cuneus serves as a core component of the visual cortex and maintains extensive neural connections with the primary visual cortex and other higher-order visual areas (e.g., the lateral occipital cortex)[29,30]. Abnormal ReHo values in the cuneus are frequently observed in populations with visual dysfunction and may reflect altered local neural synchrony related to visual input processing and potential disruptions in neural transmission[31]. In addition to its critical role in visual attention, the cuneus participates in complex cognitive tasks, such as visuospatial memory[32]. Our findings demonstrate that OB (irrespective of MDD) exerts a robust reducing effect on ReHo in the right cuneus, whereas MDD alone also reduces ReHo to a lesser degree than OB. Alterations of the cuneus in MDD have been investigated in multiple studies, and a meta-analysis found a robust ReHo reduction in the left cuneus in MDD, suggesting that cuneus dysfunction may be associated with emotional regulation and cognitive dysfunction[33,34]. Our findings suggest that OB may have a greater influence, lowering the ReHo in the right cuneus of the comorbid group to levels comparable to those in obese individuals.
Similar to the cuneus, the precuneus is involved in visual information processing and is among the first regions to respond within the occipital lobe[35]. ReHo in the left precuneus remained comparable between patients with MDD only and HCs. However, OB (irrespective of comorbid MDD) significantly reduced ReHo values in this region. Thus, the comorbidity group may have exhibited a combined negative effect in this area. Furthermore, the precuneus is a densely connected hub region in the human cerebrum, accounting for approximately 35% of glucose metabolism within the default mode network areas[36]. Altered neural activity in the precuneus may be linked to metabolic disturbances such as OB-related disorders[37]. We further hypothesize that comorbid MDD-OB may be associated with exacerbated blood-brain barrier disruption and neuroinflammation, which could potentially amplify the alterations observed in this region. The modest negative correlations observed between the ReHo of the cuneus and precuneus and behavioral measures (e.g., BAS-D, BAS-F, BIS), while modest, align with the emerging understanding of the visual cortex’s role in attentional and cognitive processes beyond basic visual perception, potentially indicating that reduced neural synchrony in this region may impair visual attention toward motivationally relevant stimuli[38].
The thalamus serves as a central hub in cognitive networks, including memory and executive functions such as attention and information processing[39]. Our results revealed a distinctive pattern in the left thalamus across the four groups: MDD-OB exerted divergent directional effects on thalamic regional activity (i.e., MDD increased ReHo, whereas OB decreased it). Notably, the comorbid MDD-OB group exhibited alterations that closely resembled those in the OB group. Our findings suggest that these two conditions may be associated with disruptions in core thalamic function through distinct mechanisms, with complex interactions occurring in comorbidity. A recent longitudinal United Kingdom Biobank study demonstrated reduced bilateral thalamic subcortical volumes in moderate-stable and high-stability OB groups compared with a low-stability OB group[40]. Volumetric changes may be associated with alterations in reward processing and executive function, which may influence cognitive and aging trajectories[41]. We also observed a negative correlation between left thalamic ReHo and BAS-fun seeking, further suggesting an association between decreased ReHo in the left thalamus and executive control, as well as impulsive decision-making. In contrast to prior studies reporting decreased left thalamic ReHo in MDD patients[42,43], differences in sample characteristics (e.g., first-episode vs chronic MDD, medication status), ReHo processing pipelines (e.g., smoothing kernel size, covariate adjustment), or thalamic subregions may contribute to the results. Our findings highlight the necessity to further investigate thalamic functional differences between comorbid MDD-OB and MDD-only groups.
Our findings provide novel mechanistic insights into the neuroimaging correlations between MDD-OB. These results suggest that clinicians may consider neurofeedback training as a potential approach to reduce MTG.L ReHo, which might help alleviate impulse/conflict sensitivity. Furthermore, enhanced visual mindfulness training (e.g., focusing attention on healthy food cues) could theoretically aim to modulate the low ReHo observed in the cuneus and precuneus in individuals with OB and comorbid conditions[44]. These suggestions are based on the implications of our findings and would require validation in future interventional studies.
Limitations
Our findings must be interpreted with caution owing to some inherent methodological limitations. First, the recruitment of first-episode patients with comorbid conditions was challenging, suggesting that some comorbidities may be secondary to medication interventions, which requires further investigation. Second, all participants were recruited from a single-center institution, and the sample size was relatively small, which limits population representativeness and necessitates cautious generalization. Third, the reliance on self-administered questionnaires might have introduced potential self-report biases. Our research did not find valuable explanatory results for brain regions closely related to emotional health, such as the prefrontal limbic system, which also requires further verification with large samples. Fourthly, we did not assess key metabolic and inflammatory biomarkers (e.g., insulin resistance, lipid profiles, inflammatory cytokines) which are known to mediate MDD-OB comorbidity and could confound brain-behavior relationships. Future studies incorporating these measures are essential to clarify the specific physiological mechanisms underlying the ReHo alterations. Moreover, the use of an Asian-specific BMI classification (≥ 28 kg/m2) may affect the generalizability of our findings to non-Asian populations and limit direct comparability with studies applying World Health Organization criteria (≥ 30 kg/m2). Furthermore, although alterations in visual regions (i.e., cuneus, precuneus) were identified, this study did not control for potential ophthalmic or visual confounds (e.g., visual acuity, ophthalmic diseases), which should be carefully considered in future studies to clarify the specificity of these findings. The findings from the uncorrected correlation analyses must be interpreted with caution, as the possibility of false-positive results cannot be ruled out. The association analysis between neuroimaging features and clinical behavioral scores in this study employed a univariate approach, which cannot capture the complex relationships where multiple brain regions collectively correlate with behavior in a combined pattern[45,46]. Future studies need to employ more rigorous cross-validation/independent validation protocols to obtain more reliable and unbiased estimates of brain-behavior associations. In addition to regional spontaneous activity, future studies could incorporate analyses of both static and dynamic functional connectivity to provide a mechanistic framework for understanding functional network deficits in MDD-OB.
CONCLUSION
The MDD-OB comorbidity exhibits distinct neural activity patterns, with altered brain functions that differ from the simple summation of MDD-OB alone. Our findings provide novel evidence for the neuroadaptive mechanisms underlying comorbidities. MDD-OB may be associated with functional changes in brain regions linked to emotion regulation (MTG.L), visual processing (cuneus/precuneus), and cognitive integration (thalamus). OB is associated with ReHo alterations in the MTG.L, right cuneus, and left thalamus, whereas abnormalities in the precuneus suggest a synergistic pathological mechanism between these two conditions. If our findings are validated through large-sample longitudinal studies, personalized interventions such as neurofeedback training targeting middle temporal gyrus hyperactivity and/or enhanced visual mindfulness training targeting healthy food cues may be explored for individuals with comorbidities.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B
Novelty: Grade B, Grade B, Grade B
Creativity or Innovation: Grade B, Grade B, Grade B
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Li F, MD, PhD, Associate Professor, China; Zhang JW, PhD, Professor, China S-Editor: Wu S L-Editor: A P-Editor: Zhang YL
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Li Q, Wang X, Yang M. [Study on rs-fMRI in different degrees of obesity children aged 7-15 years based on ReHo].Nanjing Yike Daxue Xuebao. 2024;44:1257-1261.
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