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Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder.

ABSTRACT: Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently depressed MDD subjects extend to or persist in patients who experience prolonged remission. The aim of the present study was to investigate gray matter (GM) differences in unmedicated, currently-depressed participants (dMDD) and unmedicated, currently-remitted (rMDD) participants with MDD compared to healthy controls (HC). The GM density and volume were compared across groups using voxel-based morphometry, a quantitative neuroanatomical technique, and high-resolution MRI images from 107 HC, 58 dMDD and 27 rMDD subjects. Relative to the HC group the dMDD group had reduced GM in the dorsal anterolateral (DALPFC), the dorsomedial (DMPFC) and the ventrolateral prefrontal cortex (VLPFC). Relative to the rMDD group the dMDD group showed reduced GM in the DALPFC, the VLPFC, the anterior cingulate cortex (ACC), the precuneus and the inferior parietal lobule. No regions were identified in which the rMDD group showed significantly lower GM compared to the HC group after p-values were corrected for the number of comparisons performed. In unmedicated patients in the depressed phase of MDD, we found evidence of morphometric abnormalities in DALPFC and in medial prefrontal cortical regions belonging to the visceromotor network. These findings, along with the absence of GM abnormalities in the remitted sample imply a possible link between greater GM tissue and better clinical outcome. Consistent with other neuroimaging and post-mortem neuropathological studies of MDD, we also found evidence of decreased white matter in patients with dMDD and rMDD.

SUBMITTER: Salvadore G

PROVIDER: S-EPMC3020249 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder.

Salvadore Giacomo G Nugent Allison C AC Lemaitre Herve H Luckenbaugh David A DA Tinsley Ruth R Cannon Dara M DM Neumeister Alexander A Zarate Carlos A CA Drevets Wayne C WC

NeuroImage 20101110 4

Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently ...[more]

PMID: 21073959

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Project description:Background: Despite their high lifetime prevalence, major depressive disorder (MDD) is often difficult to diagnose, and there is a need for useful biomarkers for the diagnosis of MDD. Eye movements are considered a non-invasive potential biomarker for the diagnosis of psychiatric disorders such as schizophrenia. However, eye movement deficits in MDD remain unclear. Thus, we evaluated detailed eye movement measurements to validate its usefulness as a biomarker in MDD. Methods: Eye movements were recorded from 37 patients with MDD and 400 healthy controls (HCs) using the same system at five University hospitals. We administered free-viewing, fixation stability, and smooth pursuit tests, and obtained 35 eye movement measurements. We performed analyses of covariance with group as an independent variable and age as a covariate. In 4 out of 35 measurements with significant group-by-age interactions, we evaluated aging effects. Discriminant analysis and receiver operating characteristic (ROC) analysis were conducted. Results: In the free-viewing test, scanpath length was significantly shorter in MDD (p = 4.2 × 10-3). In the smooth pursuit test, duration of saccades was significantly shorter and peak saccade velocity was significantly lower in MDD (p = 3.7 × 10-3, p = 3.9 × 10-3, respectively). In the fixation stability test, there were no significant group differences. There were significant group differences in the older cohort, but not in the younger cohort, for the number of fixations, duration of fixation, number of saccades, and fixation density in the free-viewing test. A discriminant analysis using scanpath length in the free-viewing test and peak saccade velocity in the smooth pursuit showed MDD could be distinguished from HCs with 72.1% accuracy. In the ROC analysis, the area under the curve was 0.76 (standard error = 0.05, p = 1.2 × 10-7, 95% confidence interval = 0.67-0.85). Conclusion: These results suggest that detailed eye movement tests can assist in differentiating MDD from HCs, especially in older subjects.

Project description:Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0.05). Consistent with our previous findings in an overlapping sample, the KynA/3HK ratio and the log KynA/QA were reduced in the MDD group relative to the HC group (p's<0.05) and symptoms of anhedonia were negatively correlated with log KynA/QA in the MDD group (p<0.05). Both KynA/3HK and log KynA/QA at least partially mediated the relationship between diagnosis and cortical thickness of right BA32 (p's<0.05). CRP was inversely associated with BA32 thickness (p<0.01) and KynA/3HK partially mediated the relationship between CRP and the thickness of right BA32 (p<0.05). The results raise the possibility that the relative imbalance between KynA and neurotoxic kynurenine metabolites may partially explain the reductions in mPFC thickness observed in MDD, and further that these changes are more strongly linked to the putative effects of neuroactive kynurenine metabolites than those of inflammatory mediators.

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

Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder.

Publications

Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder.

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