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

Horn Horn

doi:10.3389/fnsys.2010.00033

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.

Highlights

Major depressive disorder (MDD) is characterized by persistent negative feelings of sadness, guilt, and worthlessness and further by ruminating thoughts, cognitive impairments, and somatic complaints
Because of their hypothesized role in depression we investigated the functional connectivity between pregenual anterior cingulate cortex (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
Reduced BOLD amplitudes during task were further related to abnormal glutamate concentrations in the same region. This finding is compatible with the hypothesis that the extent of functional responses that appear on top of baseline neuronal activity depends on the metabolic baseline level of the involved neuronal–astroglial unit and the degree of anaerobic glucose consumption (Raichle and Mintun, 2006). In this first combined resting-state functional magnetic resonance imaging (fMRI)–magnetic resonance spectroscopy (MRS) study in major depressive disorder (MDD), we extend previous work (Walter et al, 2009) that relates the amplitudes of negative BOLD responses in pgACC to regional GABA ratios

Summary

Introduction

Major depressive disorder (MDD) is characterized by persistent negative feelings of sadness, guilt, and worthlessness and further by ruminating thoughts, cognitive impairments, and somatic complaints These various symptoms are accompanied by abnormal activity in several brain regions as observed in a number of imaging studies. The medial prefrontal cortex and the anterior cingulate cortex (ACC) have been identified as key structures for MDD, with abnormalities in fMRI activation and in baseline metabolism or perfusion In accordance with these in vivo findings, post mortem investigations in MDD have revealed reductions in neuronal and glial cell densities, size, and arborization (Ongür et al, 1998; Cotter et al, 2001; Manji et al, 2001). During the past few years, the hypothesis of a complex metabolic abnormality in the ACC has been developed which links psychological abnormalities in MDD to abnormal baseline metabolism in astrocytes and neurons and even to disease related immunological processes in microglia (Dantzer et al, 2008)

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