title: Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study.
abstract: Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5-44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5-8 Hz) and alpha2 (10.5-12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Webb
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Dillon
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Pechtel
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Franziska K
authors.identifier: http://orcid.org/0000-0002-4641-9945
authors.initials: FK
authors.lastname: Goer
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Murray
authors.affiliation: Centre for Addiction Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Hospital of Psychiatry, University of Zurich, Switzerland.|Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Switzerland.
authors.forename: Quentin J M
authors.initials: QJ
authors.lastname: Huys
authors.affiliation: Clinical Research Program, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fava
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McGrath
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Myrna
authors.initials: M
authors.lastname: Weissman
authors.affiliation: Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Parsey
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Benji T
authors.initials: BT
authors.lastname: Kurian
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Adams
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weyandt
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Trombello
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Grannemann
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Cooper
authors.affiliation: Department of Psychiatry, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Deldin
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Tenke
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Madhukar
authors.initials: M
authors.lastname: Trivedi
authors.affiliation: Department of Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Bruder
authors.affiliation: Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, MA, USA.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Pizzagalli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001008:Anxiety Disorders / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D003865:Major Depressive Disorder / Q000503:physiopathology* / Q000523:psychology*; D004569:Electroencephalography / Q000379:methods; D058068:Endophenotypes; D006801:Humans; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D009483:Neuropsychological Tests; D000075384:Neuroticism; D011569:Psychiatric Status Rating Scales; D011930:Reaction Time; D012146:Rest; D012201:Reward; D014054:Tomography / Q000379:methods; D055815:Young Adult