, Volume 4, Issue 3, pp 63–70 | Cite as

Context conditioning in virtual reality as a model for pathological anxiety

  • E. Glotzbach-Schoon
  • M. Andreatta
  • A. Mühlberger
  • P. Pauli
Review article


Phobic fear which is triggered by specific stimuli can be modeled experimentally through cue conditioning. In contrast, context conditioning may serve as a model for anxiety which is longer lasting and unrelated to cues. Such context conditioning can be studied in humans in analogy to animal studies by using virtual reality (VR). Our VR context conditioning paradigm uses virtual offices as contexts. One office becomes the anxiety context since participants receive unpredictable mildly painful electric stimulations. The other office becomes the safety context because no aversive stimulation is delivered while participants explore this office. The validity of the paradigm is indicated in the findings that after conditioning participants rate the virtual anxiety context as anxiety eliciting, avoid this context, and show startle potentiation in this context. Our studies further revealed that known risk factors for anxiety disorders affect context conditioning. We found that enhanced trait anxiety facilitates contextual fear conditioning. In addition, we observed that individuals with genetic risks for anxiety disorders learn context conditioning very effectively as shown in startle potentiation. These findings suggest that in individuals vulnerable to anxiety disorders such as panic disorder or posttraumatic stress disorder, context conditioning may have contributed to the development of these disorders.


Fear Anxiety Conditioning Virtual reality 



The original German article was translated by Dr. Preeti Sareen from the Department of Psychology I, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Germany.

Compliance with ethical guidelines

Conflict of interest. E. Glotzbach-Schoon, M. Andreatta, A. Mühlberger, and P. Pauli state that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.


  1. 1.
    Alvarez RP, Biggs A, Chen G et al (2008) Contextual fear conditioning in humans: cortical–hippocampal and amygdala contributions. J Neurosci 28:6211–6219PubMedCrossRefGoogle Scholar
  2. 2.
    Alvarez RP, Chen G, Bodurka J et al. (2011) Phasic and sustained fear in humans elicits distinct patterns of brain activity. NeuroImage 55: 389–400PubMedCrossRefGoogle Scholar
  3. 3.
    Baas JMP (2013) Individual differences in predicting aversive events and modulating contextual anxiety in a context and cue conditioning paradigm. Biol Psychology 1: 17–25CrossRefGoogle Scholar
  4. 4.
    Baas JM, Nugent M, Lissek S et al (2004) Fear conditioning in virtual reality contexts: a new tool for the study of anxiety. Biol Psychiatry 55:1056–1060PubMedCrossRefGoogle Scholar
  5. 5.
    Baas JMP, van Ooijen L, Goudriaan A, Kenemans JL (2008) Failure to condition to a cue is associated with sustained contextual anxiety. Acta Psychologica 127: 581–592PubMedCrossRefGoogle Scholar
  6. 6.
    Bechara A, Tranel D, Damasio H et al (1995) Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269: 1115–1118PubMedCrossRefGoogle Scholar
  7. 7.
    Blascovich J, Beall AC, Loomis JM, et al (2002) Interpersonal distance in immersive virtual environments. Personality and Social Psychology Bulletin 29: 1–15Google Scholar
  8. 8.
    Blumenthal TD, Cuthbert BN, Filion DL et al (2005) Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42: 1–15PubMedCrossRefGoogle Scholar
  9. 9.
    Büchel C, Morris J, Dolan RJ, Friston KJ (1998) Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 20:947–957PubMedCrossRefGoogle Scholar
  10. 10.
    Chambers JA, Power KG, Durham RC (2004) The relationship between trait vulnerability and anxiety and depressive diagnoses at long-term follow-up of generalized anxiety disorder. J Anxiety Disorders 18: 587–607CrossRefGoogle Scholar
  11. 11.
    Dannlowski U, Konrad C, Kugel H et al (2010) Emotion specific modulation of automatic amygdala responses by 5-HTTLPR genotype. NeuroImage 53: 893–898PubMedCrossRefGoogle Scholar
  12. 12.
    Dannlowski U, Kugel H, Franke F et al (2011) Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli. Neuropsychopharmacology 36: 1879–1885PubMedCrossRefGoogle Scholar
  13. 13.
    Davis M, Walker DL, Miles L, Grillon C (2010) Phasic vs. sustained fear in rats and humans: role of the extended amygdala in fear vs. anxiety. Neuropsychopharmacology 35:105–135PubMedCrossRefGoogle Scholar
  14. 14.
    Domschke K, Reif A, Weber H et al (2011) Neuropeptide S receptor gene—converging evidence for a role in panic disorder. Mol Psychiatry 16:938–948PubMedCrossRefGoogle Scholar
  15. 15.
    Fanselow MS (1994) Neural organization of the defensive behavior system responsible for fear. Psychon Bull Rev 1:429–438CrossRefGoogle Scholar
  16. 16.
    Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760PubMedCrossRefGoogle Scholar
  17. 17.
    Glotzbach E, Ewald H, Andreatta M et al (2012) Contextual fear conditioning predicts subsequent avoidance behaviour in a virtual reality environment. Cogn Emot 26:1256–1272PubMedCrossRefGoogle Scholar
  18. 18.
    Glotzbach-Schoon E, Tadda R, Andreatta M et al (2013) Enhanced discrimination between threatening and safe contexts in high-anxious individuals. Biol Psychol 93:159–166PubMedCrossRefGoogle Scholar
  19. 19.
    Glotzbach-Schoon E, Andreatta M, Reif A et al (2013) Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle. Front Behav Neurosci 7:31. doi:10.3389/fnbeh.2013.00031PubMedCrossRefGoogle Scholar
  20. 20.
    Grillon C (2002) Startle reactivity and anxiety disorders: aversive conditioning, context, and neurobiology. Biol Psychiatry 52: 958–975PubMedCrossRefGoogle Scholar
  21. 21.
    Grillon C (2008) Models and mechanisms of anxiety: evidence from startle studies. Psychopharmacology 199: 421–437PubMedCrossRefGoogle Scholar
  22. 22.
    Grillon C, Lissek S, Rabin S et al (2008) Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am J Psychiatry 165: 898–904PubMedCrossRefGoogle Scholar
  23. 23.
    Grillon C, Pine DS, Lissek S et al (2009) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66: 47–53PubMedCrossRefGoogle Scholar
  24. 24.
    Grillon C, Baas JMP, Cornwell B, Johnson L (2006) Context conditioning and behavioral avoidance in a virtual reality environment: effect of predictability. Biol Psychiatry 60:752–759PubMedCrossRefGoogle Scholar
  25. 25.
    Hariri AR, Mattay VS, Tessitore A et al (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297: 400–403PubMedCrossRefGoogle Scholar
  26. 26.
    Heitland I, Klumpers F, Oosting RS et al (2012) Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Translational Psychiatry 2: e162. doi:10.1038/tp.2012.90PubMedCrossRefGoogle Scholar
  27. 27.
    Indovina I, Robbins TW, Nú˜nez-Elizalde AO et al (2011) Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans. Neuron 69: 563–571PubMedCrossRefGoogle Scholar
  28. 28.
    Kalisch R, Korenfeld E, Stephan KE et al (2006) Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. The Journal of Neuroscience 26: 9503–9511PubMedCrossRefGoogle Scholar
  29. 29.
    Kim JJ, Jung MW (2006) Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review. Neurosci Biobehav Rev 30:88–202CrossRefGoogle Scholar
  30. 30.
    Koch M (1999) The neurobiology of startle. Progress in Neurobiology 59: 107–128PubMedCrossRefGoogle Scholar
  31. 31.
    Kolassa I-T, Ertl V, Eckart C et al (2010) Association study of trauma load and SLC6A4 promoter polymorphism in posttraumatic stress disorder: evidence from survivors of the Rwandan genocide. Journal of Clinical Psychiatry 71: 543–547PubMedCrossRefGoogle Scholar
  32. 32.
    LaBar KS, Gatenby JC, Gore JC et al (1998) Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 20: 937–945PubMedCrossRefGoogle Scholar
  33. 33.
    Lang PJ, Bradley MM, Cuthbert BN (1990) Emotion, attention, and the startle reflex. Psychological Review 97: 377–395PubMedCrossRefGoogle Scholar
  34. 34.
    Lang S, Kroll A, Lipinski SJ et al (2009) Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex. The European Journal of Neuroscience 29: 823–832PubMedCrossRefGoogle Scholar
  35. 35.
    LeDoux JE (2000) Emotion circuits in the brain. Annual Review of Neuroscience 23: 155–184PubMedCrossRefGoogle Scholar
  36. 36.
    Lesch KP, Bengel D, Heils et al (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274: 1527–1531PubMedCrossRefGoogle Scholar
  37. 37.
    Lonsdorf TB, Weike AI, Nikamo P et al (2009) Genetic gating of human fear learning and extinction: possible implications for gene–environment interaction in anxiety disorder. Psychol Sci 20:198–206PubMedCrossRefGoogle Scholar
  38. 38.
    Luyten L, Vansteenwegen D, Kuyck K van et al (2011) Optimization of a contextual conditioning protocol for rats using combined measurements of startle amplitude and freezing: the effects of shock intensity and different types of conditioning. J Neurosci Methods 194:305–311PubMedCrossRefGoogle Scholar
  39. 39.
    Meyerbröker K, Emmelkamp PMG (2010) Virtual reality exposure therapy in anxiety disorders: a systematic review of process-and-outcome studies. Depression and Anxiety 27: 933–944PubMedCrossRefGoogle Scholar
  40. 40.
    Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420: 70–74PubMedCrossRefGoogle Scholar
  41. 41.
    Mineka S, Oehlberg K (2008) The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. Acta Psychologica 127: 567–580PubMedCrossRefGoogle Scholar
  42. 42.
    Mineka S, Öhman A (2002) Phobias and preparedness: the selective, automatic, and encapsulated nature of fear. Biological Psychiatry 52: 927–937PubMedCrossRefGoogle Scholar
  43. 43.
    Mineka S, Zinbarg R (2006) A contemporary learning theory perspective on the etiology of anxiety disorders: it’s not what you thought it was. Am Psychol 61:10–26PubMedCrossRefGoogle Scholar
  44. 44.
    Mühlberger A, Pauli P (2011) Virtuelle Realität in der Psychotherapie. Psychotherapie im Dialog 12: 143–147CrossRefGoogle Scholar
  45. 45.
    O’Keefe J, Nadel L (1978) The hippocampus as a cognitive map. Oxford: Oxford University PressGoogle Scholar
  46. 46.
    Pavlov I (1927) Conditioned Reflexes. New York: Oxford University PressGoogle Scholar
  47. 47.
    Phillips RG, LeDoux JE (1994) Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learning & Memory 1: 34–44Google Scholar
  48. 48.
    Schinka JA, Busch RM, Robichaux-Keene N (2004) A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry 9:197–202PubMedCrossRefGoogle Scholar
  49. 49.
    Seligman ME (1968) Chronic fear produced by unpredictable electric shock. Journal of Comparative and Physiological Psychology 66: 402–411PubMedCrossRefGoogle Scholar
  50. 50.
    Seligman MEP, Binik YM (1977) The safety signal hypothesis. In: Davis H, Hurwitz HMB (eds) Operant-Pavlovian Interactions. Hillsdale, NJ: Erlbaum, pp 165–188Google Scholar
  51. 51.
    Spielberger CD, Gorsuch RL, Edward LR (1970) STAI manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists PressGoogle Scholar
  52. 52.
    Tarr MJ, Warren WH (2002) Virtual reality in behavioral neuroscience and beyond. Nature Neuroscience 5: 1089-1092PubMedCrossRefGoogle Scholar
  53. 53.
    Tröger C, Ewald H, Glotzbach E et al (2012) Does pre-exposure inhibit fear context conditioning? A virtual reality study. J Neural Transm 119:709–719PubMedCrossRefGoogle Scholar
  54. 54.
    Vansteenwegen D, Iberico C, Vervliet B et al (2008) Contextual fear induced by unpredictability in a human fear conditioning preparation is related to the chronic expectation of a threatening US. Biol Psychol 77:39–46PubMedCrossRefGoogle Scholar
  55. 55.
    Wang Z, Baker DG, Harre, J et al (2011) The relationship between combat-related posttraumatic stress disorder and the 5-HTTLPR/rs25531 polymorphism. Depression and Anxiety 28: 1067–1073PubMedCrossRefGoogle Scholar
  56. 56.
    Wittchen H-U, Wunderlich U, Gruschwitz S, Zaudig M (1997) Skid. Strukturiertes klinisches Interview für DSM-IV. Göttingen: HogrefeGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Psychology I, Biological Psychology, Clinical Psychology, and PsychotherapyUniversity of WürzburgWürzburgGermany
  2. 2.Department of Clinical Psychology, and PsychotherapyUniversity of RegensburgRegensburgGermany

Personalised recommendations