title: Dissociating pathomechanisms of depression with fMRI: bottom-up or top-down dysfunctions of the reward system.
abstract: Depression is a debilitating psychiatric disorder characterized among other aspects by the inability to properly experience or respond to reward. However, it remains unclear whether patients with depression present impaired reward system due to abnormal modulatory mechanisms. We investigated the activation of the nucleus accumbens (NAcc), a crucial region involved in reward processing, with functional magnetic resonance imaging using the desire-reason-dilemma paradigm. This task allows tracking the activity of the NAcc during the acceptance or the rejection of previously conditioned reward stimuli. Patients were assigned into subgroups of lower (LA) or higher (HA) NAcc activation according to beta weights. LA patients presented significant hypoactivation in the ventral tegmental area in addition to bilateral ventral striatum, confirming impairments in the bottom-up input to the NAcc. Conversely, HA patients presented significant hyperactivation in prefrontal areas such as the rostral anterior cingulate cortex and the anterior ventral prefrontal cortex in addition to bilateral ventral striatum, suggesting disturbances in the top-down regulation of the NAcc. Demographic and clinical differences explaining the abnormal co-activations of midbrain and prefrontal regions were not identified. Therefore, we provide evidence for dysfunctional bottom-up processing in one potential neurobiological subtype of depression (LA) and dysfunctional top-down modulation in another subtype (HA). We suggest that the midbrain and prefrontal regions are more specific pathophysiological substrates for each depression subtype. Above all, our results encourage the segregation of patients by similar dysfunctional mechanisms of the dopaminergic system, which would finally contribute to disentangle more specific pathogeneses and guide the development of more personalized targets for future therapies.
authors.affiliation: Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Georg August University, Göttingen, Germany, roberto.goya@med.uni-goettingen.de.
authors.forename: Roberto
authors.initials: R
authors.lastname: Goya-Maldonado
authors.forename: Kristina
authors.initials: K
authors.lastname: Weber
authors.forename: Sarah
authors.initials: S
authors.lastname: Trost
authors.forename: Esther
authors.initials: E
authors.lastname: Diekhof
authors.forename: Maria
authors.initials: M
authors.lastname: Keil
authors.forename: Peter
authors.initials: P
authors.lastname: Dechent
authors.forename: Oliver
authors.initials: O
authors.lastname: Gruber
mesh_terms: D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D003865:Major Depressive Disorder / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012201:Reward; D017557:Ventral Tegmental Area / Q000503:physiopathology; D055815:Young Adult