Search

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD., (© 2024. The Author(s).)

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.)

Introduction: Prior studies have discussed rapid eye movement (REM) sleep disturbance as a potential endophenotype of major depressive disorder (MDD). However, the neural substrates underlying the percentage of REM sleep duration (REM%) and its association with disease progression in MDD remain unclear., Methods: One hundred and fourteen MDD patients and 74 healthy controls (HCs) underwent resting-state functional and perfusion magnetic resonance imaging (MRI) scans as well as overnight polysomnography examination to assess brain function and REM%, with 48 patients completing follow-up visits. Correlation and mediation analyses were conducted to investigate the associations among baseline REM%, multimodal brain imaging measures, and the improvement of depressive symptoms at follow-up in MDD., Results: We found voxel-wise correlations between baseline REM% and multimodal brain imaging metrics in many brain regions involved in sensorimotor, visual processing, emotion, and cognition in patients with MDD. Moreover, the baseline REM% was correlated with the improvement of depressive symptoms from acute to remitted status in patients through regulating brain activity in the left inferior temporal gyrus and cerebral blood flow in the bilateral paracentral lobule., Conclusion: Our findings help to identify the neural underpinnings of REM% in depression and highlight REM% as a potential prognostic biomarker to predict disease progression. These may inform future novel interventions of MDD from the perspective of regulating REM sleep., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.)

Several behavioral and neuroimaging markers could be used to predict eventual antidepressant medication (ADM) outcomes in patients with major depressive disorder (MDD). However, these predictors are either subjective or complex, which has limited their clinical use. Thus, we aimed to identify an objective and easy-to-get marker to predict early therapeutic efficacy. Forty-seven drug-naïve patients with MDD and 47 age-, gender- and education-matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scans. We calculated the variable coefficient (VC) of the global signal for each subject. Baseline Hamilton Rating Scale for Depression (HRSD) score and that after 2 weeks of ADM were assessed for patients. Although there was no difference in VC between patients with MDD and healthy controls, we found a significant positive correlation between the VC and the decline rate of HRSD scores in the patients. Compared with the non-responding depression (NRD) group, the treatment-responsive depression (TRD) group had a higher VC. Receiver operator characteristic curve analysis revealed that the VC exhibited a good ability to differentiate TRD from NRD. In addition, the linear and logistic regression analyses showed that the VC was a significant predictor of the decline rate of HRSD scores and the antidepressant treatment response. These findings suggest that variance of the global signal may serve as a useful marker to help clinicians find an appropriate drug for individuals with MDD at the earliest opportunity and then further to facilitate personalized therapy.

Background: Patients with major depressive disorder (MDD) have shown altered resting-state functional connectivity (rsFC) of the precuneus; however, it is unknown whether rsFC of the precuneus subregions is differentially affected in this disorder., Methods: In this study, we aimed to clarify this issue by comparing rsFC of each precuneus subregion between patients with MDD and healthy controls. Forty-seven drug-naive patients with MDD and 47 sex-, age- and education-matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI). The precuneus was divided into PCun-1 (dorsal-central portion; medial area 7), PCun-2 (dorsal-anterior portion; medial area 5), PCun-3 (dorsal-posterior portion; dorsomedial parietooccipital sulcus) and PCun-4 (ventral portion; area 31). The rsFC of each precuneus subregion was compared between the two groups., Results: Compared with healthy controls, patients with MDD exhibited increased rsFC between the left PCun-2 and the right fusiform gyrus, lateral prefrontal cortex, sensorimotor cortex and supramarginal gyrus. No significant inter-group difference was observed in the rsFC of other precuneus subregions. In addition, there was no difference in gray matter volume of all the precuneus subregions between patients with MDD and healthy controls., Limitations: Some of the patients had chronic MDD and relevant neuropsychological data were not collected., Conclusions: These findings suggest a selective functional dysconnectivity of the precuneus subregions in drug-naive MDD, characterized by the hyperconnnectivity between the dorsal-anterior subregion and regions involved in visual, executive control, sensorimotor and bottom-up attention functions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Previous studies using resting-state functional magnetic resonance imaging (fMRI) have found abnormal functional connectivity in patients with major depressive disorder (MDD). Yet, effect of distance thresholds on local functional connectivity changes in MDD is largely unknown. Here, we used resting-state fMRI data and functional connectivity strength (FCS) method to test local functional connectivity differences at different distance thresholds between 47 drug-naive patients with MDD and 47 healthy controls. For the distribution of functional brain hubs with high local FCS, the overall changing trend from distance thresholds of 10mm to 100mm was from lateral to medial. Compared to controls, MDD patients exhibited decreased local FCS independent of distance threshold in the sensorimotor system (postcentral gyrus, paracentral lobule, and supplementary motor area). MDD Patients exhibited increased local FCS in the inferior temporal gyrus at two lower distance thresholds (20mm and 30mm) and a higher distance threshold (100mm). In addition, MDD patients showed increased local FCS in the putamen at higher distance thresholds (80-100mm). These findings suggest that local functional connectivity abnormalities in MDD are dependent on distance thresholds and that future studies should take the distance thresholds into account when measuring local functional connectivity in MDD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Alterations in grey matter structure and functional connectivity (FC) are pathological features of major depressive disorder (MDD). However, the relationship between brain structural and functional impairments in MDD remains uncertain. Thus, the aim of this study was to investigate the relationship between alterations in grey matter volume (GMV) and resting-state global functional connectivity density (rs-gFCD) in MDD. Forty-five patients with MDD and 48 healthy controls underwent structural and resting-state functional magnetic resonance imaging (fMRI). GMV and rs-gFCD maps of each subject were created, and the intergroup differences in these neuroimaging metrics were evaluated. Compared to healthy controls, patients with MDD displayed reduced GMV in the left insula, putamen, amygdala and hippocampus (mainly in the limbic system). In contrast, decreased rs-gFCD was observed in the left postcentral and precentral gyri, right fusiform gyrus and lingual gyrus (mainly in the sensory system). Furthermore, we found no significant correlations between GMV and rs-gFCD in these brain regions. Finally, overlap ratio analysis demonstrated that the spatial distribution patterns of intergroup differences on the GMV and rs-gFCD maps were distinct. Our findings suggest that the presence of distinct spatial distribution patterns of brain atrophy and global FC impairments might be pathological features of MDD.