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Martin Walter, MD; Anke Henning, PhD; Simone Grimm, PhD; Rolf F. Schulte, PhD; Johannes Beck, MD; Ulrike Dydak, PhD; Betina Schnepf, Dipl Inf Med; Heinz Boeker, MD; Peter Boesiger, PhD; Georg Northoff, MD, PhD

Arch Gen Psychiatry. 2009;66(5):478-486.

Context  Major depressive disorder (MDD) is characterized by diverse metabolic and functional abnormalities that occur in, among other regions, the pregenual anterior cingulate cortex (pgACC), a cortical region linked to anhedonia.

Objectives  To contextualize metabolic, functional, and clinical parameters and thus to reveal cellular mechanisms related to anhedonia.

Design  The pgACC was investigated using a combined functional magnetic resonance imaging and magnetic resonance spectroscopic approach. Negative blood oxygenation level–dependent (BOLD) activations in the pgACC were assessed during emotional stimulation. Quantitative J-resolved magnetic resonance spectroscopy in the pgACC enabled simultaneous determination of glutamine, glutamate, N-acetylaspartate, glucose, and -aminobutyric acid concentrations. Subjective emotional intensity ratings as well as various clinical parameters were determined.

Setting  The patients were recruited and evaluated in the Department of Psychiatry, University of Zurich, while the measurements were performed in the Institute of Biomedical Engineering, University of Zurich and the Technical University Zurich.

Participants  Nineteen unmedicated patients with MDD and 24 healthy subjects.

Main Outcome Measures  Reduced glutamine levels and lower functional responses in pgACC in anhedonic depressed patients were expected to be the predominant effect of abnormal glutamatergic transmission. It was further tested if, among patients, the ratings of emotional intensity on visual stimulation predicted the amount of metabolic and functional alterations in terms of reduced relative metabolite concentrations and BOLD changes.

Results  Patients with highly anhedonic MDD show decreased glutamine but normal glutamate and -aminobutyric acid concentrations, with glutamine concentrations being dissociated from glucose concentrations. Glutamate and N-acetylaspartate concentrations in pgACC correlate with negative BOLD responses induced by emotional stimulation in MDD; whereas in healthy subjects, negative BOLD responses correlate with -aminobutyric acid instead. Negative BOLD responses as well as glutamate and N-acetylaspartate concentrations correlate with emotional intensity ratings, an anhedonia surrogate, in those with MDD but not in healthy subjects.

Conclusion  Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

Author Affiliations: Department of Psychiatry, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany (Drs Walter and Northoff); Institute for Biomedical Engineering, University of Zurich and the Technical University Zurich, Zurich, Switzerland (Drs Henning, Schulte, Dydak, and Boesiger, and Ms Schnepf); Department of Psychiatry, University of Zurich, Zurich (Drs Grimm, Beck, and Boeker). Dr Schulte is now with GE Global Research, Munich, Germany; Dr Beck is now with the Department of Psychiatry, University of Basel, Basel, Switzerland; Dr Dydak is now with the School of Health Sciences, Purdue University, West Lafayette, Indiana, and the Department of Radiology, Indiana University, Bloomington; and Dr Northoff is now with the Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada.

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