title: Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression.
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.
  
  
  METHODS
  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.
authors.affiliation: Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Macoveanu
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: U
authors.initials: U
authors.lastname: Knorr
authors.affiliation: Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Skimminge
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: M G
authors.initials: MG
authors.lastname: Søndergaard
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Jørgensen
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Fauerholdt-Jepsen
authors.affiliation: Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark.
authors.forename: O B
authors.initials: OB
authors.lastname: Paulson
authors.affiliation: Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: G M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark.
authors.forename: H R
authors.initials: HR
authors.lastname: Siebner
authors.affiliation: Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: L V
authors.initials: LV
authors.lastname: Kessing
mesh_terms: D000328:Adult; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D004311:Double-Blind Method; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010919:Placebos; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D012201:Reward; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D010919:Placebos; D017367:Selective Serotonin Reuptake Inhibitors