Abnormal Amygdala-Prefrontal Effective Connectivity to Happy Faces Differentiates Bipolar from Major Depression

Jorge Renner Cardoso de Almeida, Amelia Versace, Andrea Mechelli, Stefanie Hassel, Karina Quevedo, David Jerome Kupfer, Mary Louise Phillips

Research output: Contribution to journalArticlepeer-review

211 Scopus citations


Background: Bipolar disorder is frequently misdiagnosed as major depressive disorder, delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation might therefore help discriminate bipolar from major depressive disorder. Methods: Thirty-one depressed individuals-15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, ages 18-55 years, matched for age, age of illness onset, illness duration, and depression severity-and 16 age- and gender-matched healthy control subjects performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right- and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC). Results: During classification of happy faces, we found profound and asymmetrical differences in EC between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects. Conclusions: Abnormal, left-sided, top-down OMPFC-amygdala and right-sided, bottom-up, amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.

Original languageEnglish (US)
Pages (from-to)451-459
Number of pages9
JournalBiological psychiatry
Issue number5
StatePublished - Sep 1 2009

Bibliographical note

Funding Information:
Dr. Phillips reports having support from National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award and 5R01 MH076971-01. Dr. Almeida reports having support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Foundation (#190105-2). Dr. Hassel reports having support from NARSAD. Dr. Mechelli, Dr. Versace, Dr. Quevedo and Dr. Kupfer reported no biomedical financial interests or potential conflicts of interest.


  • Amygdala
  • bipolar disorder
  • dynamic causal modeling
  • fMRI
  • major depression disorder
  • orbitomedial prefrontal cortex


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