title: Disrupted habenula function in major depression.
abstract: The habenula is a small, evolutionarily conserved brain structure that plays a central role in aversive processing and is hypothesised to be hyperactive in depression, contributing to the generation of symptoms such as anhedonia. However, habenula responses during aversive processing have yet to be reported in individuals with major depressive disorder (MDD). Unmedicated and currently depressed MDD patients (N=25, aged 18-52 years) and healthy volunteers (N=25, aged 19-52 years) completed a passive (Pavlovian) conditioning task with appetitive (monetary gain) and aversive (monetary loss and electric shock) outcomes during high-resolution functional magnetic resonance imaging; data were analysed using computational modelling. Arterial spin labelling was used to index resting-state perfusion and high-resolution anatomical images were used to assess habenula volume. In healthy volunteers, habenula activation increased as conditioned stimuli (CSs) became more strongly associated with electric shocks. This pattern was significantly different in MDD subjects, for whom habenula activation decreased significantly with increasing association between CSs and electric shocks. Individual differences in habenula volume were negatively associated with symptoms of anhedonia across both groups. MDD subjects exhibited abnormal negative task-related (phasic) habenula responses during primary aversive conditioning. The direction of this effect is opposite to that predicted by contemporary theoretical accounts of depression based on findings in animal models. We speculate that the negative habenula responses we observed may result in the loss of the capacity to actively avoid negative cues in MDD, which could lead to excessive negative focus.
authors.affiliation: Institute of Cognitive Neuroscience, University College London, London, UK.|Wellcome Trust Centre for Neuroimaging, University College London, London, UK.
authors.forename: R P
authors.initials: RP
authors.lastname: Lawson
authors.affiliation: Institute of Cognitive Neuroscience, University College London, London, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Nord
authors.affiliation: Computational and Biological Learning Lab, University of Cambridge, Cambridge, UK.|Centre for Information and Neural Networks, National Institute for Information and Communications Technology, Osaka, Japan.
authors.forename: B
authors.identifier: 0000-0003-1724-5832
authors.initials: B
authors.lastname: Seymour
authors.affiliation: Department of Brain Repair and Rehabilitation, University College London, London, UK.
authors.forename: D L
authors.initials: DL
authors.lastname: Thomas
authors.affiliation: Gatsby Computational Neuroscience Unit, University College London, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Dayan
authors.affiliation: Research Department of Clinical, Educational and Health Psychology, University College London, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Pilling
authors.affiliation: Institute of Cognitive Neuroscience, University College London, London, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Roiser
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect / Q000502:physiology; D059445:Anhedonia / Q000502:physiology; D016022:Case-Control Studies; D003198:Computer Simulation; D003214:Conditioning, Classical; D003463:Cues; D003863:Depression / Q000378:metabolism / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D019262:Habenula / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D013329:Structure-Activity Relationship