Altered resting state functional connectivity of fear and reward circuitry in comorbid PTSD and major depression

Xi Zhu, Liat Helpman, Santiago Papini, Franklin Schneier, John C. Markowitz, Page E. Van Meter, Martin A. Lindquist, Tor D. Wager, Yuval Neria

Research output: Contribution to journalArticlepeer-review


Background: Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD-MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD-MDD is associated with different network connectivity abnormalities than PTSD alone. Methods: We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs-FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD-alone (n = 27), PTSD-MDD (n = 21), and trauma-exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc). Results: Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA-orbitalfrontal cortex (OFC) and CMA-thalamus pathways, key to fear processing, and fear expression, respectively. PTSD-MDD, compared to PTSD-alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal-subcortical pathways: BLA-OFC, NAcc-thalamus, and NAcc-hippocampus. Further, while both the BLA-OFC and the NAcc-thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA-OFC; CMA-thalamus) only. Conclusions: Comorbid PTSD-MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed.

Original languageEnglish
Pages (from-to)641-650
Number of pages10
JournalDepression and Anxiety
Issue number7
StatePublished - Jul 2017
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by grant R01MH072833 and R01MH105355 from the National Institute of Mental Health (Dr. Neria, Principal Investigator), and the New York State Psychiatric Institute. Dr. Helpman's work is supported by grant T32 MH096724 from the National Institute of Mental Health (Wainberg, Oquendo Principal Investigators). Mr. Papini's work was supported by funding from the Donald D. Harrington Fellows Program. Dr. Markowitz has received book royalties from American Psychiatric Publishing, Basic books and Oxford University Press and receives an editorial stipend from Elsevier Press. Dr. Neria has received royalties from Cambridge University Press, Stand for the troops, and the Mack Foundation. Dr. Schneier has received royalties from Cambridge University Press, Guilford and Uptodate, research support from Forest Labs, honorarium from Elsevier and consulting income from Genentech. Drs. Zhu, Helpman, Van Meter, Lindquist, Wager, and Mr. Papini, report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.


  • MDD
  • PTSD
  • amygdala
  • depression
  • fear processing
  • nucleus accumbens
  • resting state functional connectivity
  • reward processing

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Clinical Psychology


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