Glutamatergic and resting-state functional connectivity correlates of severity in major depression - the role of pregenual anterior cingulate cortex and anterior insula

Dorothea I Horn, Chunshui Yu, Johann Steiner, Julia Buchmann, Joern Kaufmann, Annemarie Osoba, Ulf Eckert, Kathrin C Zierhut, Kolja Schiltz, Huiguang He, Bharat Biswal, Bernhard Bogerts, Martin Walter, Dorothea I Horn, Chunshui Yu, Johann Steiner, Julia Buchmann, Joern Kaufmann, Annemarie Osoba, Ulf Eckert, Kathrin C Zierhut, Kolja Schiltz, Huiguang He, Bharat Biswal, Bernhard Bogerts, Martin Walter

Abstract

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.

Keywords: anterior insula; functional connectivity; functional magnetic resonance imaging; glutamate; magnetic resonance spectroscopy; major depressive disorder; pregenual anterior cingulate cortex; resting state.

Figures

Figure 1
Figure 1
Positioning of the spectroscopy voxels (A: pgACC, B: AI) and a representative spectrum of pgACC (C).
Figure 2
Figure 2
Correlation of functional connectivity between pgACC and AI and Glx/Cr ratios for depressed patients (A) and healthy controls (B) ratios was found in our samples of either patients or controls.
Figure 3
Figure 3
Correlation of clinical severity of depression with RSFC (A) as well as with Glx/Cr ratios in pgACC (B).
Figure 4
Figure 4
Severely depressed patients with altered functional connectivity between pgACC and AI (box plot showing median, interquartile range, sample minimum and maximum;*P < 0. 05, **P < 0.01, n.s.: not significant.
Figure 5
Figure 5
Mean levels of the sum value of Glu and Gln (Glx), glutamate (Glu) and NAA relative to creatine (Cr) in pgACC (box plot showing median, interquartile range, sample minimum and maximum).

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