Primary functional brain connections associated with melancholic major depressive disorder and modulation by antidepressants.
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ABSTRACT:
SUBMITTER: Ichikawa N
PROVIDER: S-EPMC7044159 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Primary functional brain connections associated with melancholic major depressive disorder and modulation by antidepressants.
Ichikawa Naho N Lisi Giuseppe G Yahata Noriaki N Okada Go G Takamura Masahiro M Hashimoto Ryu-Ichiro RI Yamada Takashi T Yamada Makiko M Suhara Tetsuya T Moriguchi Sho S Mimura Masaru M Yoshihara Yujiro Y Takahashi Hidehiko H Kasai Kiyoto K Kato Nobumasa N Yamawaki Shigeto S Seymour Ben B Kawato Mitsuo M Morimoto Jun J Okamoto Yasumasa Y
Scientific reports 20200226 1
The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by o ...[more]
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Project description:Background: Melancholic depression has been viewed as one severe subtype of major depressive disorder (MDD). However, it is unclear whether melancholic depression has distinct changes in brain imaging. We aimed to explore specific or distinctive alterations in melancholic MDD and whether the alterations could be used to separate melancholic MDD from non-melancholic MDD or healthy controls. Materials and Methods: Thirty-one outpatients with melancholic MDD and thirty-three outpatients with non-melancholic MDD and thirty-two age- and gender-matched healthy controls were recruited. All participants were scanned by resting-state functional magnetic resonance imaging (fMRI). Imaging data were analyzed with the regional homogeneity (ReHo) and support vector machine (SVM) methods. Results: Melancholic MDD patients exhibited lower ReHo in the right superior occipital gyrus/middle occipital gyrus than non-melancholic MDD patients and healthy controls. Merely for non-melancholic MDD patients, decreased ReHo in the right middle frontal gyrus was negatively correlated with the total HRSD-17 scores. SVM analysis results showed that a combination of abnormal ReHo in the right fusiform gyrus/cerebellum Crus I and the right superior occipital gyrus/middle occipital gyrus exhibited the highest accuracy of 83.05% (49/59), with a sensitivity of 90.32% (28/31), and a specificity of 75.00% (21/28) for discriminating patients with melancholic MDD from patients with non-melancholic MDD. And a combination of abnormal ReHo in the right fusiform gyrus/cerebellum VI and left postcentral gyrus/precentral gyrus exhibited the highest accuracy of 98.41% (62/63), with a sensitivity of 96.77% (30/31), and a specificity of 100.00%(32/32) for separating patients with melancholic MDD from healthy controls. Conclusion: Our findings showed the distinctive ReHo pattern in patients with melancholic MDD and found brain area that may be associated with the pathophysiology of non-melancholic MDD. Potential imaging markers for discriminating melancholic MDD from non-melancholic MDD or healthy controls were reported.
| S-EPMC7928375 | biostudies-literature
Project description:BackgroundNeuroimaging studies have provided valuable insights into the macroscale impacts of antidepressants on brain functions in patients with major depressive disorder. However, the findings of individual studies are inconsistent. Here, we aimed to provide a quantitative synthesis of the literature to identify convergence of the reported findings at both regional and network levels and to examine their associations with neurotransmitter systems.MethodsThrough a comprehensive search in PubMed and Scopus databases, we reviewed 5258 abstracts and identified 36 eligible functional neuroimaging studies on antidepressant effects in major depressive disorder. Activation likelihood estimation was used to investigate regional convergence of the reported foci of antidepressant effects, followed by functional decoding and connectivity mapping of the convergent clusters. Additionally, utilizing group-averaged data from the Human Connectome Project, we assessed convergent resting-state functional connectivity patterns of the reported foci. Next, we compared the convergent circuit with the circuits targeted by transcranial magnetic stimulation therapy. Last, we studied the association of regional and network-level convergence maps with selected neurotransmitter receptors/transporters maps.ResultsNo regional convergence was found across foci of treatment-associated alterations in functional imaging. Subgroup analysis in the Treated > Untreated contrast revealed a convergent cluster in the left dorsolateral prefrontal cortex, which was associated with working memory and attention behavioral domains. Moreover, we found network-level convergence of the treatment-associated alterations in a circuit more prominent in the frontoparietal areas. This circuit was co-aligned with circuits targeted by "anti-subgenual" and "Beam F3" transcranial magnetic stimulation therapy. We observed no significant correlations between our meta-analytic findings with the maps of neurotransmitter receptors/transporters.ConclusionOur findings highlight the importance of the frontoparietal network and the left dorsolateral prefrontal cortex in the therapeutic effects of antidepressants, which may relate to their role in improving executive functions and emotional processing.
| S-EPMC11746144 | biostudies-literature
Project description:BackgroundThe efficacy and prognosis of major depressive disorder (MDD) are limited by its heterogeneity. MDD with melancholic features is an important subtype of MDD. The present study aimed to reveal the white matter (WM) network changes in melancholic depression.Materials and methodsTwenty-three first-onset, untreated melancholic MDD, 59 non-melancholic MDD patients and 63 health controls underwent diffusion tensor imaging (DTI) scans. WM network analysis based on graph theory and support vector machine (SVM) were used for image data analysis.ResultsCompared with HC, small-worldness was reduced and abnormal node attributes were in the right orbital inferior frontal gyrus, left orbital superior frontal gyrus, right caudate nucleus, right orbital superior frontal gyrus, right orbital middle frontal gyrus, left rectus gyrus, and left median cingulate and paracingulate gyrus of MDD patients. Compared with non-melancholic MDD, small-worldness was reduced and abnormal node attributes were in right orbital inferior frontal gyrus, left orbital superior frontal gyrus and right caudate nucleus of melancholic MDD. For correlation analysis, the 7th item score of the HRSD-17 (work and interest) was positively associated with increased node betweenness centrality (aBC) values in right orbital inferior frontal gyrus, while negatively associated with the decreased aBC in left orbital superior frontal gyrus. SVM analysis results showed that abnormal aBC in right orbital inferior frontal gyrus and left orbital superior frontal gyrus showed the highest accuracy of 81.0% (69/83), the sensitivity of 66.3%, and specificity of 85.2% for discriminating MDD patients with or without melancholic features.ConclusionThere is a significant difference in WM network changes between MDD patients with and without melancholic features.
| S-EPMC9046786 | biostudies-literature
Project description:BackgroundSubanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized.MethodsData-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status.ResultsSignificant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern.ConclusionResults support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.
| S-EPMC9647551 | biostudies-literature
Project description:Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an ex vivo model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs.
| S-EPMC8558816 | biostudies-literature
Project description:BackgroundInsomnia is considered one of the manifestations of sleep disorders, and its intensity is linked to the treatment effect or suicidal thoughts. Major depressive disorder (MDD) is classified into various subtypes due to heterogeneous symptoms. Melancholic MDD has been considered one of the most common subtypes with special sleep features. However, the brain functional mechanisms in melancholic MDD with insomnia remain unclear.Materials and methodsMelancholic MDD and healthy controls (HCs, n = 46) were recruited for the study. Patients were divided into patients with melancholic MDD with low insomnia (mMDD-LI, n = 23) and patients with melancholic MDD with high insomnia (mMDD-HI, n = 30), according to the sleep disturbance subscale of the 17-item Hamilton Depression Rating Scale. The dynamic amplitude of low-frequency fluctuation was employed to investigate the alterations of brain activity among the three groups. Then, the correlations between abnormal dALFF values of brain regions and the severity of symptoms were investigated.ResultsLower dALFF values were found in the mMDD-HI group in the right middle temporal gyrus (MTG)/superior temporal gyrus (STG) than in the mMDD-LI (p = 0.014) and HC groups (p < 0.001). Melancholic MDD groups showed decreased dALFF values than HC in the right middle occipital gyri (MOG)/superior occipital gyri (SOG), the right cuneus, the bilateral lingual gyrus, and the bilateral calcarine (p < 0.05). Lower dALFF values than HC in the left MOG/SOG and the left cuneus in melancholic MDD groups were found, but no significant difference was found between the mMDD-LI group and HC group (p = 0.079). Positive correlations between the dALFF values in the right MTG/STG and HAMD-SD scores (the sleep disturbance subscale of the HAMD-17) in the mMDD-HI group (r = 0.41, p = 0.042) were found. In the pooled melancholic MDD, the dALFF values in the right MOG/SOG and the right cuneus (r = 0.338, p = 0.019), the left MOG/SOG and the left cuneus (r = 0.299, p = 0.039), and the bilateral lingual gyrus and the bilateral calcarine (r = 0.288, p = 0.047) were positively correlated with adjusted HAMD scores.ConclusionThe occipital cortex may be related to depressive symptoms in melancholic MDD. Importantly, the right MTG/STG may play a critical role in patients with melancholic MDD with more severe insomnia.
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Project description:Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.
| S-EPMC8873016 | biostudies-literature
Project description:Brain function relies on efficient communications between distinct brain systems. The pathology of major depressive disorder (MDD) damages functional brain networks, resulting in cognitive impairment. Here, we reviewed the associations between brain functional connectome changes and MDD pathogenesis. We also highlighted the utility of brain functional connectome for differentiating MDD from other similar psychiatric disorders, predicting recurrence and suicide attempts in MDD, and evaluating treatment responses. Converging evidence has now linked aberrant brain functional network organization in MDD to the dysregulation of neurotransmitter signaling and neuroplasticity, providing insights into the neurobiological mechanisms of the disease and antidepressant efficacy. Widespread connectome dysfunctions in MDD patients include multiple, large-scale brain networks as well as local disturbances in brain circuits associated with negative and positive valence systems and cognitive functions. Although the clinical utility of the brain functional connectome remains to be realized, recent findings provide further promise that research in this area may lead to improved diagnosis, treatments, and clinical outcomes of MDD.
| S-EPMC8513388 | biostudies-literature
Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.
2011-10-04 | E-GEOD-19738 | biostudies-arrayexpress
Project description:Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist-antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.
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