Glutamatergic and Resting-State Functional Connectivity Correlates of Severity in Major Depression – The Role of Pregenual Anterior Cingulate Cortex and Anterior Insula

Glutamatergic mechanisms and resting-state functional connectivity alterations have been recently described as factors contributing to major depressive disorder (MDD). Furthermore, the pregenual anterior cingulate cortex (pgACC) seems to play an important role for major depressive symptoms such as anhedonia and impaired emotion processing. We investigated 22 MDD patients and 22 healthy subjects using a combined magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (fMRI) approach. Severity of depression was rated using the 21-item Hamilton depression scale (HAMD) and patients were divided into severely and mildly depressed subgroups according to HAMD scores. Because of their hypothesized role in depression we investigated the functional connectivity between pgACC and left anterior insular cortex (AI). The sum of Glutamate and Glutamine (Glx) in the pgACC, but not in left AI, predicted the resting-state functional connectivity between the two regions exclusively in depressed patients. Furthermore, functional connectivity between these regions was significantly altered in the subgroup of severely depressed patients (HAMD > 15) compared to healthy subjects and mildly depressed patients. Similarly the Glx ratios, relative to Creatine, in the pgACC were lowest in severely depressed patients. These findings support the involvement of glutamatergic mechanisms in severe MDD which are related to the functional connectivity between pgACC and AI and depression severity

Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus--a DTI study in major depressive disorder

BACKGROUND: Depression is commonly conceptualized as corticolimbic dysregulation. Due to insufficient studies in normal aged populations especially subcortical sources of disconnection are unclear in contrast to potentially general parietal white matter (WM) deficits. This may be due to important influences of variable patient characteristics, most importantly episode severity. Especially thalamic disconnections have been functionally revealed, however, their structural correlates have not been distinctly investigated for its highly diverse subnuclei. METHODS: We compared 20 major depressive disorder (MDD) patients with mixed Hamilton depression rating scale (HAMD) severity to matched controls in fractional anisotropy (FA) derived from diffusion tensor imaging (DTI). Robust acquisition of 4 repetitions restricted to twelve directions, also to match the same parameters used by Eckert et al. (2011) who described a preferential architecture of centromedian (CM) and mediodorsal (MD) thalamic connections. Second to whole brain analysis, we tested for group differences within the preferred structural network of these two nuclei using a tract of interest (TOI) approach. RESULTS: Significant FA deficits in a whole brain analysis were only found in right parietal WM (p<0.05, corrected). Effects of severity were found for increasing thalamic FA. Post hoc analysis revealed this effect to be restricted to CM specific tracts. In contrast, we found MD to dorsolateral prefrontal cortex (DLPFC) tracts to be decreased in FA. Unspecific decreases between MD and CM towards amygdala were paralleled by primary amygdala FA reductions. LIMITATIONS: Specificity of the TOI approach and heterogenous sample. CONCLUSIONS: Robust parietal FA reductions, controlled for age effects were found in MDD. Further we revealed subcortical disease state dependency of FA in thalamic tracts, specific to predescribed preferential connections