Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study

Christian A. Webb, Daniel G. Dillon, Pia Pechtel, Franziska K. Goer, Laura Murray, Quentin J.M. Huys, Maurizio Fava, Patrick J. McGrath, Myrna Weissman, Ramin Parsey, Benji T. Kurian, Phillip Adams, Sarah Weyandt, Joseph M. Trombello, Bruce Grannemann, Crystal M. Cooper, Patricia Deldin, Craig Tenke, Madhukar Trivedi, Gerard BruderDiego A. Pizzagalli

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)454-463
Number of pages10
Issue number2
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


Dive into the research topics of 'Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study'. Together they form a unique fingerprint.

Cite this