, Volume 236, Issue 1, pp 407–414 | Cite as

The emerging neuroscience of appetitive and drug cue extinction in humans

  • Anna B. KonovaEmail author
  • Rita Z. GoldsteinEmail author


Fear extinction has been extensively studied in both humans and non-human animals, and this work has contributed greatly to our understanding and treatment of anxiety disorders. Yet other psychopathologies like addiction might be associated with impairments selectively in extinction of non-fear based, appetitive and drug cue associations, and these processes have been underexplored in clinical translational neuroscience. Important questions regarding similarities and differences in the neurobiological mechanisms underlying aversive and appetitive extinction remain unanswered, particularly those pertaining to cross-species evidence for the role of the ventromedial prefrontal cortex and, to some extent, the striatum. Here, we aim to draw attention to the paucity of studies investigating non-fear based extinction in humans, summarize emerging findings from the available literature, and highlight important directions for future research. We argue that closing these gaps in our understanding could help inform the development of more targeted, and perhaps more durable, forms of extinction-based treatments for addiction and related psychopathologies characterized by abnormally persistent appetitive and drug cue associations.


Funding information

The authors were supported by grants from the National Institute on Drug Abuse (F32DA039648 to A.B.K. and R01DA041528 and R21DA020626 to R.Z.G.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. Balleine BW, O'Doherty JP (2010) Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 35:48–69CrossRefGoogle Scholar
  2. Bartra O, McGuire JT, Kable JW (2013) The valuation system: a coordinate-based meta-analysis of BOLD fMRI experiments examining neural correlates of subjective value. Neuroimage 76:412–427CrossRefGoogle Scholar
  3. Bossert JM, Stern AL, Theberge FR, Cifani C, Koya E, Hope BT, Shaham Y (2011) Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin. Nat Neurosci 14:420–422CrossRefGoogle Scholar
  4. Bossert JM, Stern AL, Theberge FR, Marchant NJ, Wang HL, Morales M, Shaham Y (2012) Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci 32:4982–4991CrossRefGoogle Scholar
  5. Bouton ME (2004) Context and behavioral processes in extinction. Learn Mem 11:485–494CrossRefGoogle Scholar
  6. Bouton ME (2011) Learning and the persistence of appetite: extinction and the motivation to eat and overeat. Physiol Behav 103:51–58CrossRefGoogle Scholar
  7. Bray S, Rangel A, Shimojo S, Balleine B, O'Doherty JP (2008) The neural mechanisms underlying the influence of Pavlovian cues on human decision making. J Neurosci 28:5861–5866CrossRefGoogle Scholar
  8. Conklin CA, Tiffany ST (2002) Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97:155–167CrossRefGoogle Scholar
  9. Delgado MR, Beer JS, Fellows LK, Huettel SA, Platt ML, Quirk GJ, Schiller D (2016) Viewpoints: dialogues on the functional role of the ventromedial prefrontal cortex. Nat Neurosci 19:1545–1552CrossRefGoogle Scholar
  10. Do-Monte FH, Manzano-Nieves G, Quinones-Laracuente K, Ramos-Medina L, Quirk GJ (2015) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35:3607–3615CrossRefGoogle Scholar
  11. Ebrahimi C, Koch SP, Friedel E, Crespo I, Fydrich T, Strohle A, Heinz A, Schlagenhauf F (2017) Combining D-cycloserine with appetitive extinction learning modulates amygdala activity during recall. Neurobiol Learn Mem 142:209–217CrossRefGoogle Scholar
  12. Fullana MA, Harrison BJ, Soriano-Mas C, Vervliet B, Cardoner N, Avila-Parcet A, Radua J (2016) Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Mol Psychiatry 21:500–508CrossRefGoogle Scholar
  13. Fullana MA, Albajes-Eizagirre A, Soriano-Mas C, Vervliet B, Cardoner N, Benet O, Radua J, Harrison BJ (2018) Fear extinction in the human brain: a meta-analysis of fMRI studies in healthy participants. Neurosci Biobehav Rev 88:16–25CrossRefGoogle Scholar
  14. Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652–669CrossRefGoogle Scholar
  15. Graham BM, Milad MR (2011) The study of fear extinction: implications for anxiety disorders. Am J Psychiatry 168:1255–1265CrossRefGoogle Scholar
  16. Haber SN, Knutson B (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4–26CrossRefGoogle Scholar
  17. Harrison BJ, Fullana MA, Via E, Soriano-Mas C, Vervliet B, Martinez-Zalacain I, Pujol J, Davey CG, Kircher T, Straube B, Cardoner N (2017) Human ventromedial prefrontal cortex and the positive affective processing of safety signals. Neuroimage 152:12–18CrossRefGoogle Scholar
  18. Hartley CA, Fischl B, Phelps EA (2011) Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear. Cereb Cortex 21:1954–1962CrossRefGoogle Scholar
  19. Jansen A, Schyns G, Bongers P, van den Akker K (2016) From lab to clinic: extinction of cued cravings to reduce overeating. Physiol Behav 162:174–180CrossRefGoogle Scholar
  20. Jin J, Zelano C, Gottfried JA, Mohanty A (2015) Human amygdala represents the complete spectrum of subjective valence. J Neurosci 35:15145–15156CrossRefGoogle Scholar
  21. Kalisch R, Korenfeld E, Stephan KE, Weiskopf N, Seymour B, Dolan RJ (2006) Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. J Neurosci 26:9503–9511CrossRefGoogle Scholar
  22. Konova AB, Goldstein RZ (2015) Addiction and addiction treatment. The Wiley handbook on the cognitive neuroscience of addiction: 109Google Scholar
  23. Konova AB, Parvaz MA, Bernstein V, Zilverstand A, Moeller SJ, Delgado MR, Alia-Klein N, Goldstein RZ (2017) Neural mechanisms of extinguishing drug and pleasant cue associations in human addiction: role of the VMPFC. Addict BiolGoogle Scholar
  24. Kroes MCW, Dunsmoor JE, Mackey WE, McClay M, Phelps EA (2017) Context conditioning in humans using commercially available immersive virtual reality. Sci Rep 7:8640CrossRefGoogle Scholar
  25. Kruse O, Tapia Leon I, Stark R, Klucken T (2017) Neural correlates of appetitive extinction in humans. Soc Cogn Affect Neurosci 12:106–115CrossRefGoogle Scholar
  26. LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem 17:168–175CrossRefGoogle Scholar
  27. Liljeholm M, O'Doherty JP (2012) Contributions of the striatum to learning, motivation, and performance: an associative account. Trends Cogn Sci 16:467–475CrossRefGoogle Scholar
  28. Lonsdorf TB, Menz MM, Andreatta M, Fullana MA, Golkar A, Haaker J, Heitland I, Hermann A, Kuhn M, Kruse O, Meir Drexler S, Meulders A, Nees F, Pittig A, Richter J, Romer S, Shiban Y, Schmitz A, Straube B, Vervliet B, Wendt J, Baas JMP, Merz CJ (2017) Don’t fear ‘fear conditioning’: methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neurosci Biobehav Rev 77:247–285CrossRefGoogle Scholar
  29. Mackey S, Petrides M (2014) Architecture and morphology of the human ventromedial prefrontal cortex. Eur J Neurosci 40:2777–2796CrossRefGoogle Scholar
  30. Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129–151CrossRefGoogle Scholar
  31. Milad MR, Quinn BT, Pitman RK, Orr SP, Fischl B, Rauch SL (2005) Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc Natl Acad Sci U S A 102:10706–10711CrossRefGoogle Scholar
  32. Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71CrossRefGoogle Scholar
  33. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL (2007) Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 62:446–454CrossRefGoogle Scholar
  34. Milad MR, Rosenbaum BL, Simon NM (2014) Neuroscience of fear extinction: implications for assessment and treatment of fear-based and anxiety related disorders. Behav Res Ther 62:17–23CrossRefGoogle Scholar
  35. Millan EZ, Marchant NJ, McNally GP (2011) Extinction of drug seeking. Behav Brain Res 217:454–462CrossRefGoogle Scholar
  36. Moorman DE, Aston-Jones G (2014) Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking. J Neurosci 34:10234–10246CrossRefGoogle Scholar
  37. Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053CrossRefGoogle Scholar
  38. Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279–288CrossRefGoogle Scholar
  39. Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004) Extinction learning in humans: role of the amygdala and VMPFC. Neuron 43:897–905CrossRefGoogle Scholar
  40. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72CrossRefGoogle Scholar
  41. Raczka KA, Mechias ML, Gartmann N, Reif A, Deckert J, Pessiglione M, Kalisch R (2011) Empirical support for an involvement of the mesostriatal dopamine system in human fear extinction. Transl Psychiatry 1:e12CrossRefGoogle Scholar
  42. Rhodes SE, Killcross S (2004) Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response. Learn Mem 11:611–616CrossRefGoogle Scholar
  43. Rhodes SE, Killcross AS (2007) Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding. Eur J Neurosci 25:2498–2503CrossRefGoogle Scholar
  44. Schiller D, Delgado MR (2010) Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cogn Sci 14:268–276CrossRefGoogle Scholar
  45. Schneider B, Koenigs M (2017) Human lesion studies of ventromedial prefrontal cortex. Neuropsychologia 107:84–93CrossRefGoogle Scholar
  46. Sehlmeyer C, Schoning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V, Konrad C (2009) Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS One 4:e5865CrossRefGoogle Scholar
  47. Stuber GD, Sparta DR, Stamatakis AM, van Leeuwen WA, Hardjoprajitno JE, Cho S, Tye KM, Kempadoo KA, Zhang F, Deisseroth K, Bonci A (2011) Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475:377–380CrossRefGoogle Scholar
  48. Taschereau-Dumouchel V, Cortese A, Chiba T, Knotts JD, Kawato M, Lau H (2018) Towards an unconscious neural reinforcement intervention for common fears. Proc Natl Acad Sci U S A 115:3470–3475CrossRefGoogle Scholar
  49. Taylor JR, Olausson P, Quinn JJ, Torregrossa MM (2009) Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction. Neuropharmacology 56(Suppl 1):186–195CrossRefGoogle Scholar
  50. Torregrossa MM, Taylor JR (2013) Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology 226:659–672CrossRefGoogle Scholar
  51. Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17CrossRefGoogle Scholar
  52. Van den Oever MC, Rotaru DC, Heinsbroek JA, Gouwenberg Y, Deisseroth K, Stuber GD, Mansvelder HD, Smit AB (2013) Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory. J Neurosci 33:18225–18233CrossRefGoogle Scholar
  53. Wassum KM, Izquierdo A (2015) The basolateral amygdala in reward learning and addiction. Neurosci Biobehav Rev 57:271–283CrossRefGoogle Scholar
  54. Winecoff A, Clithero JA, Carter RM, Bergman SR, Wang L, Huettel SA (2013) Ventromedial prefrontal cortex encodes emotional value. J Neurosci 33:11032–11039CrossRefGoogle Scholar
  55. Zhang Z, Mendelsohn A, Manson KF, Schiller D, Levy I (2015) Dissociating value representation and inhibition of inappropriate affective response during reversal learning in the ventromedial prefrontal cortex. eNeuro 2:1–16Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Psychiatry and University Behavioral Health Care (UBHC)Rutgers University–New BrunswickPiscatawayUSA
  2. 2.Departments of Psychiatry and NeuroscienceIcahn School of Medicine at Mount Sinai, The Leon and Norma Hess Center for Science and MedicineNew YorkUSA

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