Dataset Information

The functional and structural associations of aberrant microglial activity in major depressive disorder.

ABSTRACT:

Background

Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [¹⁸F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([¹⁸F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes.

Methods

Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [¹⁸F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [¹⁸F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale.

Results

We found significantly increased [¹⁸F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [¹⁸F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle. [¹⁸F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale.Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings.

Conclusion

We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

SUBMITTER: Cakmak JD

PROVIDER: S-EPMC9343118 | biostudies-literature | 2022 May-Jun

REPOSITORIES: biostudies-literature

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Publications

The functional and structural associations of aberrant microglial activity in major depressive disorder.

Cakmak Jasmine D JD Liu Linshan L Poirier Stefan E SE Schaefer Betsy B Poolacherla Raju R Burhan Amer M AM Sabesan Priyadharshini P St Lawrence Keith K Théberge Jean J Hicks Justin W JW Finger Elizabeth E Palaniyappan Lena L Anazodo Udunna C UC

Journal of psychiatry & neuroscience : JPN 20220501 3

<h4>Background</h4>Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [<sup>18</sup>F]N-2-(fluoroethoxyl)be ...[more]

PMID: 35654450

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Project description:Thalamocortical circuitry has a substantial impact on emotion and cognition. Previous studies have demonstrated alterations in thalamocortical functional connectivity (FC), characterized by region-dependent hypo- or hyper-connectivity, among individuals with major depressive disorder (MDD). However, the dynamical reconfiguration of the thalamocortical system over time and potential abnormalities in dynamic thalamocortical connectivity associated with MDD remain unclear. Hence, we analyzed dynamic FC (dFC) between ten thalamic subregions and seven cortical subnetworks from resting-state functional magnetic resonance images of 48 patients with MDD and 57 healthy controls (HCs) to investigate time-varying changes in thalamocortical FC in patients with MDD. Moreover, dynamic laterality analysis was conducted to examine the changes in functional lateralization of the thalamocortical system over time. Correlations between the dynamic measures of thalamocortical FC and clinical assessment were also calculated. We identified four dynamic states of thalamocortical circuitry wherein patients with MDD exhibited decreased fractional time and reduced transitions within a negative connectivity state that showed strong correlations with primary cortical networks, compared with the HCs. In addition, MDD patients also exhibited increased fluctuations in functional laterality in the thalamocortical system across the scan duration. The thalamo-subnetwork analysis unveiled abnormal dFC variability involving higher-order cortical networks in the MDD cohort. Significant correlations were found between increased dFC variability with dorsal attention and default mode networks and the severity of symptoms. Our study comprehensively investigated the pattern of alteration of the thalamocortical dFC in MDD patients. The heterogeneous alterations of dFC between the thalamus and both primary and higher-order cortical networks may help characterize the deficits of sensory and cognitive processing in MDD.

Project description:Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. In contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. One hundred and eighty-two MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) to resting-state functional magnetic resonance imaging (fMRI) data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Network properties including global efficiency, local efficiency, node strength and harmonic centrality, were calculated for each subject. Five dynamic functional states were identified, three of which demonstrated significant group differences in their percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly-connected State 2, which includes regions previously associated with self-focused thinking, a representative feature of depression. In addition, the FNCs in MDD were connected differently in different states, especially among prefrontal, sensorimotor, and cerebellum networks. MDD patients exhibited significantly reduced harmonic centrality primarily involving parietal lobule, lingual gyrus and thalamus. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, and also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in MDD in a Chinese population using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder.

Project description:BackgroundAs one of the most common diseases, major depressive disorder (MDD) has a significant adverse impact on the li of patients. As a mild form of depression, subclinical depression (SD) serves as an indicator of progression to MDD. This study analyzed the degree centrality (DC) for MDD, SD, and healthy control (HC) groups and identified the brain regions with DC alterations.MethodsThe experimental data were composed of resting-state functional magnetic resonance imaging (rs-fMRI) from 40 HCs, 40 MDD subjects, and 34 SD subjects. After conducting a one-way analysis of variance, two-sample t-tests were used for further analysis to explore the brain regions with changed DC. Receiver operating characteristic (ROC) curve analysis of single index and composite index features was performed to analyze the distinguishable ability of important brain regions.ResultsFor the comparison of MDD vs. HC, increased DC was found in the right superior temporal gyrus (STG) and right inferior parietal lobule (IPL) in the MDD group. For SD vs. HC, the SD group showed a higher DC in the right STG and the right middle temporal gyrus (MTG), and a smaller DC in the left IPL. For MDD vs. SD, increased DC in the right middle frontal gyrus (MFG), right IPL, and left IPL, and decreased DC in the right STG and right MTG was found in the MDD group. With an area under the ROC (AUC) of 0.779, the right STG could differentiate MDD patients from HCs and, with an AUC of 0.704, the right MTG could differentiate MDD patients from SD patients. The three composite indexes had good discriminative ability in each pairwise comparison, with AUCs of 0.803, 0.751, and 0.814 for MDD vs. HC, SD vs. HC, and MDD vs. SD, respectively.ConclusionAltered DC in the STG, MTG, IPL, and MFG were identified in depression groups. The DC values of these altered regions and their combinations presented good discriminative ability between HC, SD, and MDD. These findings could help to find effective biomarkers and reveal the potential mechanisms of depression.

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.

Dataset Information

The functional and structural associations of aberrant microglial activity in major depressive disorder.

Background

Methods

Results

Conclusion

Publications

The functional and structural associations of aberrant microglial activity in major depressive disorder.

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