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Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression

Published online by Cambridge University Press:  19 July 2013

J. Macoveanu ,
U. Knorr ,
A. Skimminge ,
M. G. Søndergaard ,
A. Jørgensen ,
M. Fauerholdt-Jepsen ,
O. B. Paulson ,
G. M. Knudsen ,
H. R. Siebner  and
L. V. Kessing
J. Macoveanu*
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark
U. Knorr
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
A. Skimminge
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark
M. G. Søndergaard
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
A. Jørgensen
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
M. Fauerholdt-Jepsen
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
O. B. Paulson
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Denmark
G. M. Knudsen
Affiliation:
Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Denmark
H. R. Siebner
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark
L. V. Kessing
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
*
* Address for correspondence: J. Macoveanu, Ph.D., Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. (Email: julianm@drcmr.dk)
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Abstract

Background

Healthy first-degree relatives of patients with major depression (rMD+) show brain structure and functional response anomalies and have elevated risk for developing depression, a disorder linked to abnormal serotonergic neurotransmission and reward processing.

Method

In a two-step functional magnetic resonance imaging (fMRI) investigation, we first evaluated whether positive and negative monetary outcomes were differentially processed by rMD+ individuals compared to healthy first-degree relatives of control probands (rMD−). Second, in a double-blinded placebo-controlled randomized trial we investigated whether a 4-week intervention with the selective serotonergic reuptake inhibitor (SSRI) escitalopram had a normalizing effect on behavior and brain responses of the rMD+ individuals.

Results

Negative outcomes increased the probability of risk-averse choices in the subsequent trial in rMD+ but not in rMD− individuals. The orbitofrontal cortex (OFC) displayed a stronger neural response when subjects missed a large reward after a low-risk choice in the rMD+ group compared to the rMD− group. The enhanced orbitofrontal response to negative outcomes was reversed following escitalopram intervention compared to placebo. Conversely, for positive outcomes, the left hippocampus showed attenuated response to high wins in the rMD+ compared to the rMD− group. The SSRI intervention reinforced the hippocampal response to large wins. A subsequent structural analysis revealed that the abnormal neural responses were not accounted for by changes in gray matter density in rMD+ individuals.

Conclusions

Our study in first-degree relatives of depressive patients showed abnormal brain responses to aversive and rewarding outcomes in regions known to be dysfunctional in depression. We further confirmed the reversal of these aberrant activations with SSRI intervention.

Keywords

Decision makingdepressionescitaloprampharmacological MRIrewardSSRI
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 6 , April 2014 , pp. 1183 - 1195
Copyright
Copyright © Cambridge University Press 2013 

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