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The emerging neuroscience of appetitive and drug cue extinction in humans

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Abstract

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.

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References

  • Balleine BW, O'Doherty JP (2010) Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. Neuropsychopharmacology 35:48–69

    Article  Google Scholar 

  • 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 76:412–427

    Article  Google Scholar 

  • 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 14:420–422

    Article  CAS  Google Scholar 

  • 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 32:4982–4991

    Article  CAS  Google Scholar 

  • Bouton ME (2004) Context and behavioral processes in extinction. Learn Mem 11:485–494

    Article  Google Scholar 

  • Bouton ME (2011) Learning and the persistence of appetite: extinction and the motivation to eat and overeat. Physiol Behav 103:51–58

    Article  CAS  Google Scholar 

  • 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 28:5861–5866

    Article  CAS  Google Scholar 

  • Conklin CA, Tiffany ST (2002) Applying extinction research and theory to cue-exposure addiction treatments. Addiction 97:155–167

    Article  Google Scholar 

  • 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 19:1545–1552

    Article  CAS  Google Scholar 

  • 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 35:3607–3615

    Article  CAS  Google Scholar 

  • 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 142:209–217

    Article  CAS  Google Scholar 

  • 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 21:500–508

    Article  CAS  Google Scholar 

  • 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 88:16–25

    Article  Google Scholar 

  • Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652–669

    Article  CAS  Google Scholar 

  • Graham BM, Milad MR (2011) The study of fear extinction: implications for anxiety disorders. Am J Psychiatry 168:1255–1265

    Article  Google Scholar 

  • Haber SN, Knutson B (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4–26

    Article  Google Scholar 

  • 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 152:12–18

    Article  Google Scholar 

  • Hartley CA, Fischl B, Phelps EA (2011) Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear. Cereb Cortex 21:1954–1962

    Article  Google Scholar 

  • Jansen A, Schyns G, Bongers P, van den Akker K (2016) From lab to clinic: extinction of cued cravings to reduce overeating. Physiol Behav 162:174–180

    Article  CAS  Google Scholar 

  • Jin J, Zelano C, Gottfried JA, Mohanty A (2015) Human amygdala represents the complete spectrum of subjective valence. J Neurosci 35:15145–15156

    Article  CAS  Google Scholar 

  • 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 26:9503–9511

    Article  CAS  Google Scholar 

  • Konova AB, Goldstein RZ (2015) Addiction and addiction treatment. The Wiley handbook on the cognitive neuroscience of addiction: 109

  • 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 Biol

  • Kroes MCW, Dunsmoor JE, Mackey WE, McClay M, Phelps EA (2017) Context conditioning in humans using commercially available immersive virtual reality. Sci Rep 7:8640

    Article  Google Scholar 

  • Kruse O, Tapia Leon I, Stark R, Klucken T (2017) Neural correlates of appetitive extinction in humans. Soc Cogn Affect Neurosci 12:106–115

    Article  Google Scholar 

  • LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem 17:168–175

    Article  CAS  Google Scholar 

  • Liljeholm M, O'Doherty JP (2012) Contributions of the striatum to learning, motivation, and performance: an associative account. Trends Cogn Sci 16:467–475

    Article  Google Scholar 

  • 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 77:247–285

    Article  Google Scholar 

  • Mackey S, Petrides M (2014) Architecture and morphology of the human ventromedial prefrontal cortex. Eur J Neurosci 40:2777–2796

    Article  Google Scholar 

  • Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129–151

    Article  Google Scholar 

  • 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 102:10706–10711

    Article  CAS  Google Scholar 

  • Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71

    Article  Google Scholar 

  • 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 62:446–454

    Article  Google Scholar 

  • 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 62:17–23

    Article  Google Scholar 

  • Millan EZ, Marchant NJ, McNally GP (2011) Extinction of drug seeking. Behav Brain Res 217:454–462

    Article  CAS  Google Scholar 

  • Moorman DE, Aston-Jones G (2014) Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking. J Neurosci 34:10234–10246

    Article  CAS  Google Scholar 

  • Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053

    Article  CAS  Google Scholar 

  • Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16:279–288

    Article  Google Scholar 

  • Phelps EA, Delgado MR, Nearing KI, LeDoux JE (2004) Extinction learning in humans: role of the amygdala and VMPFC. Neuron 43:897–905

    Article  CAS  Google Scholar 

  • Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72

    Article  Google Scholar 

  • 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:e12

    Article  CAS  Google Scholar 

  • Rhodes SE, Killcross S (2004) Lesions of rat infralimbic cortex enhance recovery and reinstatement of an appetitive Pavlovian response. Learn Mem 11:611–616

    Article  Google Scholar 

  • Rhodes SE, Killcross AS (2007) Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding. Eur J Neurosci 25:2498–2503

    Article  CAS  Google Scholar 

  • Schiller D, Delgado MR (2010) Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cogn Sci 14:268–276

    Article  Google Scholar 

  • Schneider B, Koenigs M (2017) Human lesion studies of ventromedial prefrontal cortex. Neuropsychologia 107:84–93

    Article  Google Scholar 

  • 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:e5865

    Article  Google Scholar 

  • 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 475:377–380

    Article  CAS  Google Scholar 

  • 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 115:3470–3475

    Article  CAS  Google Scholar 

  • 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):186–195

    Article  CAS  Google Scholar 

  • Torregrossa MM, Taylor JR (2013) Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacology 226:659–672

    Article  CAS  Google Scholar 

  • Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17

    Article  Google Scholar 

  • 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 33:18225–18233

    Article  Google Scholar 

  • Wassum KM, Izquierdo A (2015) The basolateral amygdala in reward learning and addiction. Neurosci Biobehav Rev 57:271–283

    Article  Google Scholar 

  • Winecoff A, Clithero JA, Carter RM, Bergman SR, Wang L, Huettel SA (2013) Ventromedial prefrontal cortex encodes emotional value. J Neurosci 33:11032–11039

    Article  CAS  Google Scholar 

  • 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 2:1–16

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Funding

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.).

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Authors and Affiliations

  1. Department of Psychiatry and University Behavioral Health Care (UBHC), Rutgers University–New Brunswick, 671 Hoes Lane West, Piscataway, NJ, 08854, USA

    Anna B. Konova

  2. Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, The Leon and Norma Hess Center for Science and Medicine, 1470 Madison Ave., New York, NY, 10029, USA

    Rita Z. Goldstein

Authors
  1. Anna B. Konova
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  2. Rita Z. Goldstein
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Correspondence to Anna B. Konova or Rita Z. Goldstein.

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This article belongs to a Special Issue on Psychopharmacology of Extinction.

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Konova, A.B., Goldstein, R.Z. The emerging neuroscience of appetitive and drug cue extinction in humans. Psychopharmacology 236, 407–414 (2019). https://doi.org/10.1007/s00213-018-5098-y

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  • DOI: https://doi.org/10.1007/s00213-018-5098-y

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