Neural mechanisms of extinguishing drug and pleasant cue associations in human addiction: role of the VMPFC

Anna B. Konova, Muhammad A. Parvaz, Vladimir Bernstein, Anna Zilverstand, Scott J. Moeller, Mauricio R. Delgado, Nelly Alia-Klein, Rita Z. Goldstein

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The neurobiological mechanisms that underlie the resistance of drug cue associations to extinction in addiction remain unknown. Fear extinction critically depends on the ventromedial prefrontal cortex (VMPFC). Here, we tested if this same region plays a role in extinction of non-fear, drug and pleasant cue associations. Eighteen chronic cocaine users and 15 matched controls completed three functional MRI scans. Participants first learned to associate an abstract cue (the conditioned stimulus, CS) with a drug-related (CS D+ ) or pleasant (CS P+ ) image. Extinction immediately followed where each CS was repeatedly presented without the corresponding image. Participants underwent a second identical session 24 hours later to assess retention of extinction learning. Results showed that like fear extinction, non-fear-based extinction relies on the VMPFC. However, extinction-related changes in the VMPFC differed by cue valence and diagnosis. In controls, VMPFC activation to the CS D+ (which was unpleasant for participants) gradually increased as in fear extinction, while it decreased to the CS P+ , consistent with a more general role of the VMPFC in flexible value updating. Supporting a specific role in extinction retention, we further observed a cross-day association between VMPFC activation and skin conductance, a classic index of conditioned responses. Finally, cocaine users showed VMPFC abnormalities for both CSs, which, in the case of the CS D+ , correlated with craving. These data suggest a global deficit in extinction learning in this group that may hinder extinction-based treatment efforts. More broadly, these data show that the VMPFC, when functionally intact, supports extinction learning in diverse contexts in humans.

Original languageEnglish (US)
Pages (from-to)88-99
Number of pages12
JournalAddiction Biology
Issue number1
StatePublished - Jan 2019

Bibliographical note

Funding Information:
This research was supported by grants from the National Institute on Drug Abuse (1F32DA039648 to A.B.K.; 5F32DA033088 to M.A.P.; 1K01DA037452 to S.J.M.; and 5R21DA020626, 2R21DA034954-01 and 5R01DA023579 to R.Z.G.) and the Netherlands Organization for Scientific Research (Rubicon 446-14-015 to A.Z.). The authors would like to thank Thomas Maloney, Daniel Carrero and Xufeng Han for help with data collection and analysis and Patricia A. Woicik for help with participant recruitment. The authors would also like to thank Elizabeth A. Phelps and Candace M. Raio for helpful discussions on the study design and early versions of the manuscript.

Publisher Copyright:
© 2017 Society for the Study of Addiction

Copyright 2019 Elsevier B.V., All rights reserved.


  • cocaine
  • craving
  • extinction
  • functional magnetic resonance imaging
  • reward
  • ventromedial prefrontal cortex

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural


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