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Background: Growing evidence points to the pivotal role of vitamin D in the pathophysiology and treatment of major depressive disorder (MDD). However, there is a paucity of longitudinal research investigating the effects of vitamin D supplementation on the brain of MDD patients., Methods: We conducted a double-blind randomized controlled trial in 46 MDD patients, who were randomly allocated into either VD (antidepressant medication + vitamin D supplementation) or NVD (antidepressant medication + placebos) groups. Data from diffusion tensor imaging, resting-state functional MRI, serum vitamin D concentration, and clinical symptoms were obtained at baseline and after an average of 7 months of intervention., Results: Both VD and NVD groups showed significant improvement in depression and anxiety symptoms but with no significant differences between the two groups. However, a greater increase in serum vitamin D concentration was found to be associated with greater improvement in depression and anxiety symptoms in VD group. More importantly, neuroimaging data demonstrated disrupted white matter integrity of right inferior fronto-occipital fasciculus along with decreased functional connectivity between right frontoparietal and medial visual networks after intervention in NVD group, but no changes in VD group., Conclusions: These findings suggest that vitamin D supplementation as adjunctive therapy to antidepressants may not only contribute to improvement in clinical symptoms but also help preserve brain structural and functional connectivity in MDD patients.

Background: Sleep disturbance is one of the most frequent somatic symptoms in major depressive disorder (MDD), but the neural mechanisms behind it are not well understood. Sleep efficiency (SE) is a good indicator of early awakening and difficulty falling asleep in MDD patients. Our study aimed to investigate the relationship between sleep efficiency and brain function in MDD patients., Methods: We recruited 131 MDD patients from the Fourth People's Hospital in Hefei, and 71 well-matched healthy controls who were enrolled from the community. All subjects underwent resting-state functional MRI. Brain function was measured using the fractional amplitude of low-frequency fluctuation (fALFF), sleep efficiency was objectively measured by polysomnography (PSG), and clinical scales were used to evaluate depressive symptoms and sleep status. Multivariate regression analysis was performed to assess the relationship between the amplitude of the low frequency fluctuation fraction and sleep efficiency., Result: Three brain regions with relevance to sleep efficiency in MDD patients were found: inferior occipital gyrus (Number of voxels = 25, peak MNI coordinate x/y/z = -42/-81/-6, Peak intensity = 4.3148), middle occipital gyrus (Number of voxels = 55, peak MNI coordinate x/y/z = -30/-78/18, Peak intensity = 5.111), and postcentral gyrus (Number of voxels = 26, peak MNI coordinate x/y/z = -27/-33/60, Peak intensity = 4.1263). But there was no significant relationship between fALFF and SE in the healthy controls., Conclusion: The reduced sleep efficiency in MDD may be related to their lower neural activity in the inferior occipital gyrus, middle occipital gyrus, and postcentral gyrus. The findings may provide a potential neuroimaging basis for the clinical intervention in patients with major depressive disorder with sleep disturbances., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Major depressive disorder (MDD) is a heterogeneous syndrome, and understanding its neural mechanisms is crucial for the advancement of personalized medicine. However, conventional subtyping studies often categorize MDD patients into a single subgroup, neglecting the continuous interindividual variations. This implies a pressing need for a dimensional approach. 230 first-episode drug-naïve MDD patients and 395 healthy controls were obtained from 5 sites via the Rest-meta-MDD project. A Bayesian model was used to decompose the resting-state functional connectivity (RSFC) into multiple distinct RSFC patterns (refer to as "factors"), and each individual was allowed to express multiple factors to varying degrees (dimensional subtyping). The associations between demographic and clinical variables with the identified factors were calculated. We identified three latent factors with distinct but partially overlapping hypo- and hyper-RSFC patterns. Most participants co-expressed multiple latent factors. All factors shared abnormal RSFC involving the default mode network and frontoparietal network, but the directionality partially differed across factors. All factors were not significantly associated with demographic and clinical variables. These findings shed light on the interindividual variability in MDD and could form the basis for developing novel therapeutic approaches that capitalize on the heterogeneity of MDD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Vitamin D is engaged in various neural processes, with low vitamin D linked to depression and cognitive dysfunction. There are gender differences in depression and vitamin D level. However, the relationship between depression, gender, vitamin D, cognition, and brain function has yet to be determined., Methods: One hundred and twenty-two patients with major depressive disorder (MDD) and 119 healthy controls underwent resting-state functional MRI and fractional amplitude of low-frequency fluctuations (fALFF) was calculated to assess brain function. Serum concentration of vitamin D (SCVD) and cognition (i.e. prospective memory and sustained attention) were also measured., Results: We found a significant group-by-gender interaction effect on SCVD whereby MDD patients showed a reduction in SCVD relative to controls in females but not males. Concurrently, there was a female-specific association of SCVD with cognition and MDD-related fALFF alterations in widespread brain regions. Remarkably, MDD- and SCVD-related fALFF changes mediated the relation between SCVD and cognition in females., Conclusion: Apart from providing insights into the neural mechanisms by which low vitamin D contributes to cognitive impairment in MDD in a gender-dependent manner, these findings might have clinical implications for assignment of female patients with MDD and cognitive dysfunction to adjuvant vitamin D supplementation therapy, which may ultimately advance a precision approach to personalized antidepressant choice.

Background: Despite remarkable success in identifying genetic risk factors for depression, there are still open questions about the exact genetic mechanisms underlying certain disease phenotypes, such as brain structural and functional impairments., Methods: Comprehensive multi-modal neuroimaging meta-analyses were conducted to examine changes in brain structure and function in drug-naive first-episode patients with major depressive disorder (DF-MDD). Combined with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial association analyses were performed to identify genes whose expression related to these brain structural and functional changes, followed by a range of gene functional signature analyses., Results: Meta-analyses revealed gray matter atrophy in the insula, temporal pole, cerebellum and postcentral gyrus, and a complex pattern of hyper-function in the temporal pole and hypo-function in the cuneus/precuneus, angular gyrus and lingual gyrus in DF-MDD. Moreover, these brain structural and functional changes were spatially associated with the expression of 1194 and 1733 genes, respectively. Importantly, there were commonalities and differences in the two gene sets and their functional signatures including functional enrichment, specific expression, behavioral relevance, and constructed protein-protein interaction networks., Limitations: The results merit further verification using a large sample of DF-MDD., Conclusions: Our findings not only corroborate the polygenic nature of depression, but also suggest common and distinct genetic modulations of brain structural and functional impairments in this disorder., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Low vitamin D is linked to major depressive disorder (MDD) through affecting the brain. Gender difference is apparent in MDD and vitamin D level. We aimed to examine the association between gender, vitamin D, clinical presentations, and brain functional connectivity in a large cohort of MDD patients and comparison subjects. Resting-state functional MRI data from 122 patients and 119 controls were collected to perform a combined analysis of functional connectivity density (FCD) and seed-based functional connectivity (FC). Peripheral venous blood samples were obtained to measure serum concentration of vitamin D (SCVD). Clinical presentations (symptoms profiles and cognition) were also assessed. We found an interaction of group and gender on SCVD in which MDD patients demonstrated lower SCVD than controls in females rather than males. Concurrently, lower SCVD was associated with worse cognitive performance (prospective memory and sustained attention). Compared with controls, female MDD patients showed reduced FCD and FC of the left middle frontal gyrus, which were related to lower SCVD. Importantly, these FCD and FC changes mediated the relationship between lower SCVD and cognitive dysfunction. Our findings suggest that functional connectivity abnormalities may serve as neural substrates underlying the associations between low vitamin D and cognitive impairments in female MDD patients, providing unique insight into treatment and prevention of MDD and its related cognitive dysfunction from the perspective of regulating circulating vitamin D., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Functional stability is a newly developed dynamic functional connectivity approach. The objective of this study was to adopt functional stability to investigate diagnosis-associated abnormalities (patients vs. controls) and status-related changes (acute vs. remitted status) in brain function in major depressive disorder (MDD). 132 MDD patients and 102 healthy controls underwent resting-state functional MRI as well as clinical and cognitive assessment at baseline, with 48 patients completing follow-up examinations at an average of 7 months. Results showed no group differences in baseline functional stability and no longitudinal functional stability changes from acute to remitted status in patients. However, we found that baseline functional stability in the dorsal and ventral anterior cingulate cortex, calcarine sulcus, and middle occipital gyrus could predict improvement in depressive symptoms from acute to remitted status in MDD patients, with longitudinal functional stability changes in these regions related to the degree of symptom improvement. In addition, lower baseline functional stability in the inferior temporal gyrus could predict a greater improvement in sustained attention, which was associated with a greater functional stability increase in this region. Our findings highlight functional stability as a potential prognostic biomarker to predict and track disease progression or stratify MDD patients for optimizing disease management and treatment strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There is evidence that major depressive disorder (MDD) is related to serum lipid level alterations. However, the neural correlates underlying this association remain poorly understood. Forty-nine patients with MDD and fifty healthy controls (HCs) underwent structural, resting-state functional and diffusion magnetic resonance imaging scans. Voxel-based morphometry, functional connectivity (FC) and tract-based spatial statistics analyses were performed to assess brain structure and function, respectively. Blood samples were collected to measure serum levels of lipid variables including total cholesterol, triglyceride and high density lipoprotein cholesterol (HDL-C). Correlation and mediation analyses were conducted to investigate the associations of serum lipid levels with brain imaging measures in MDD patients and HCs, respectively. We found that the serum HDL-C level in MDD patients was lower than that in HCs. The lower serum HDL-C level was associated with lower gray matter volume (GMV) in ventromedial prefrontal cortex (VMPFC), higher within-network FC of the default mode network, and lower micro-structural integrity in multiple white matter regions in MDD patients. Moreover, the within-default mode network FC mediated the relationship between GMV in VMPFC and serum HDL-C level; white matter integrity in genu of corpus callosum mediated the relationship between serum HDL-C level and depressive symptom severity. However, we did not observe any correlations between serum lipids and brain imaging parameters in HCs. These findings help to identify neural correlates underlying the association between depression and serum HDL-C change, which may provide new insight into intervention, treatment and prevention of depression from the perspective of regulating serum lipids., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The cerebellum plays an important role in the neural mechanism of depression and its static functional connectivity (FC) with the cerebrum is disrupted in patients with major depressive disorder (MDD). However, cerebellar-cerebral dynamic FC alterations in MDD remain largely unknown., Methods: 50 patients with MDD and 36 well-matched healthy controls underwent resting-state functional magnetic resonance imaging. Cerebellar-cerebral dynamic FC analyses were performed using the cerebellar seeds previously identified as being involved in the executive, default-mode, affective-limbic, and motor networks. Inter-group differences in the cerebellar dynamic FC and their associations with clinical and cognitive variables were examined., Results: Compared to healthy controls, patients with MDD had decreased cerebellar-cerebral dynamic FC of the cerebellar subregions connecting with the executive, default-mode and affective-limbic networks. The dynamic FC of the cerebellar subregion connecting with the affective-limbic network was related to severity of depression and anxiety symptoms in MDD patients. The dynamic FC of the cerebellar subregions connecting with the default-mode and affective-limbic networks were related to sustained attention and prospective memory in controls, while the correlations were inverse or non-significant in patients., Limitations: The fairly modest sample size and potential medication effect may increase the instability of the results., Conclusions: Our findings provide further evidence for the pivotal role of the cerebellum in the neuropathology of depression, pointing to potential targets of cerebellar-cerebral pathways for alternative intervention or monitoring therapeutic responses., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020. Published by Elsevier B.V.)

Background: Sleep disturbance is a common and key symptom that affects most of patients with major depressive disorder (MDD). However, neural substrates underlying sleep disturbance and their clinical relevance in depression remain unclear., Methods: Ninety-six MDD patients underwent resting-state functional MRI. Fractional amplitude of low-frequency fluctuation (fALFF) and resting-state functional connectivity (rsFC) were used to measure brain function. Overnight polysomnography was performed to objectively measure sleep efficiency (SE), which was used to classify patients into normal sleep efficiency (NSE) and low sleep efficiency (LSE) groups. Between-group differences in fALFF and rsFC were examined using two-sample t-tests. Moreover, correlation and mediation analyses were conducted to test for potential associations between SE, brain functional changes, and clinical variables., Results: LSE group showed decreased fALFF in right cuneus, thalamus, and middle temporal gyrus compared to NSE group. MDD patients with low SE also exhibited lower rsFC of right cuneus to right lateral temporal cortex, which was associated with more severe depression and anxiety symptoms. More importantly, mediation analyses revealed that the relationships between SE and severity of depression and anxiety symptoms were significantly mediated by the altered rsFC. In addition, these low SE-related brain functional alterations were not affected by antidepressant medication and were independent of structural changes., Limitations: The lack of healthy controls because of "first-night effect"., Conclusion: These findings not only may expand existing knowledge about neuropathology of sleep disturbance in depression, but also may inform real-world clinical practice by improving depression and anxiety symptoms through sleep regulation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients with major depressive disorder (MDD) often have circadian rhythm alteration and sleep disturbance. The pineal gland regulates the circadian rhythm and sleep by the secretion of melatonin neurohormone. However, the relationship between pineal abnormality and MDD remains elusive. 50 patients with MDD and 35 gender- and age-matched healthy controls underwent high-resolution structural MRI. Pineal parenchymal volume (PPV) was measured manually. Inter-group differences in prevalence of pineal cyst and PPV were examined. In addition, we investigated the correlations between PPV and symptom severity as well as sleep variables in the patient group. Compared to healthy controls, patients with MDD had a higher prevalence of pineal cyst. Moreover, patients had significantly decreased PPV relative to controls. However, no significant correlations were observed between PPV and symptom severity as well as sleep variables. Our findings suggest that pineal abnormality may play a critical role in depression., (Copyright © 2019. Published by Elsevier B.V.)

Background: A variety of functional metrics derived from resting-state functional magnetic resonance imaging (rs-fMRI) have been employed to explore spontaneous brain activity changes in major depressive disorder (MDD) and have enjoyed significant success in unraveling the neurobiological mechanisms underlying this disorder. However, it is unclear whether spatial and temporal coupling relationships among these rs-fMRI metrics are altered in MDD., Methods: 50 patients with MDD and 36 well-matched healthy controls underwent rs-fMRI scans. A dynamic analysis was applied to compute multiple frequently used metrics including fractional amplitude of low frequency fluctuations, regional homogeneity, voxel-mirrored homotopic connectivity, degree centrality and global signal connectivity. Kendall's W was used to calculate volume-wise (across voxels) and voxel-wise (across time windows) concordance among these metrics. Inter-group differences in the concordance and their associations with clinical and cognitive variables were tested., Results: Compared to healthy controls, patients with MDD showed decreased whole gray matter volume-wise concordance. Despite similar spatial distributions, quantitative comparison analysis revealed that MDD patients exhibited reduced voxel-wise concordance in multiple cortical and subcortical regions. Moreover, the lower concordance was associated with worse performances in prospective memory and sustained attention in the MDD group., Limitations: The study design of fairly modest sample size did not allow us to perform a full analysis of the potential effects of medication and illness duration., Conclusions: Our findings suggest that spatial and temporal decoupling of multiple resting-state brain activity metrics may help elucidate the neural mechanisms of cognitive deficits in depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)