Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Fear reduction without fear through reinforcement of neural activity that bypasses conscious exposure

Nature Human Behaviour volume 1, Article number: 0006 (2017) Cite this article

Subjects

Abstract

Fear conditioning is a fundamentally important and preserved process across species1,2. In humans it is linked to fear-related disorders such as phobias and post-traumatic stress disorder (PTSD)3,4. Fear memories can be reduced by counter-conditioning, in which fear conditioned stimuli (CS+s) are repeatedly reinforced with reward5 or with novel non-threatening stimuli6. However, this procedure involves explicit presentations of CS+s, which is itself aversive before fear is successfully reduced. This aversiveness may be a problem when trying to translate such experimental paradigms into clinical settings7. It also raises the fundamental question as to whether explicit presentations of feared objects is necessary for fear reduction1,8. Although learning without explicit stimulus presentation has been previously demonstrated9–12, whether fear can be reduced while avoiding explicit exposure to CS+s remains largely unknown. One recently developed approach employs an implicit method to induce learning by reinforcing stimulus-specific neural representations using real-time decoding of multivariate functional magnetic resonance imaging (fMRI) signals13–15 in the absence of stimulus presentation; that is, pairing rewards with the occurrences of multi-voxel brain activity patterns matching a specific stimulus (decoded fMRI neurofeedback (DecNef)13,15). It has been shown that participants exhibit perceptual learning for a specific visual stimulus feature through DecNef, without being given any strategy for the induction of specific neural representations, and without awareness of the content of reinforced neural representations13. Here we examined whether a similar approach could be applied to counter-conditioning of fear. We show that we can reduce fear towards CS+s by pairing rewards with the activation patterns in visual cortex representing a CS+, while participants remain unaware of the content and purpose of the procedure. This procedure may be an initial step towards novel treatments for fear-related disorders such as phobia and PTSD, via unconscious processing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall experimental design.
Figure 2: Reduction of fear response as measured by SCR.
Figure 3: Brain activity in the amygdala and VMPFC.
Figure 4: Engagement of striatum and disengagement of VMPFC during neural reinforcement.

Similar content being viewed by others

References

  1. LeDoux, J. Anxious (Oneworld Publications, 2015).

    Google Scholar 

  2. Schiller, D. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Lissek, S. et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behav. Res. Ther. 43, 1391–1424 (2005).

    Article  PubMed  Google Scholar 

  4. Yehuda, R. & LeDoux, J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56, 19–32 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Dickinson, A. & Dearing, M. in Mechanisms of Learning and Motivation (eds Dickinson, A. & Boakes, R. A. ) Ch. 8 (Psychology Press, 1979).

    Google Scholar 

  6. Dunsmoor, J. E., Campese, V. D., Ceceli, A. O., LeDoux, J. E. & Phelps, E. A. Novelty-facilitated extinction: providing a novel outcome in place of an expected threat diminishes recovery of defensive responses. Biol. Psychiatry 78, 203–209 (2015).

    Article  PubMed  Google Scholar 

  7. Schnurr, P. P. et al. Cognitive behavioral therapy for posttraumatic stress disorder in women: a randomized controlled trial. JAMA 297, 820–830 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Siegel, P. & Weinberger, J. Less is more: the effects of very brief versus clearly visible exposure. Emotion 12, 394–402 (2012).

    Article  PubMed  Google Scholar 

  9. Esteves, F., Parra, C., Dimberg, U. & Ohman, A. Nonconscious associative learning: Pavlovian conditioning of skin conductance responses to masked fear-relevant facial stimuli. Psychophysiology 31, 375–385 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Knight, D. C., Nguyen, H. T. & Bandettini, P. A. Expression of conditional fear with and without awareness. Proc. Natl Acad. Sci. USA 100, 15280–15283 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Raio, C. M., Carmel, D., Carrasco, M. & Phelps, E. A. Nonconscious fear is quickly acquired but swiftly forgotten. Curr. Biol. 22, R477–R479 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Redondo, R. L. et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shibata, K., Watanabe, T., Sasaki, Y. & Kawato, M. Perceptual learning incepted by decoded fMRI neurofeedback without stimulus presentation. Science 334, 1413–1415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. deBettencourt, M. T., Cohen, J. D., Lee, R. F., Norman, K. A. & Turk-Browne, N. B. Closed-loop training of attention with real-time brain imaging. Nat. Neurosci. 18, 470–475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Amano, K., Shibata K., Kawato, M., Sasaki, Y. & Watanabe, T. Learning to associate orientation with color in early visual areas by associative decoded fMRI neurofeedback. Curr. Biol 26, 1861–1866 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bouton, M. E. Context and behavioral processes in extinction. Learn. Mem. 11, 485–494 (2004).

    Article  PubMed  Google Scholar 

  17. Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

    Article  PubMed  Google Scholar 

  19. Phelps, E. A., Delgado, M. R., Nearing, K. I. & LeDoux, J. E. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Do-Monte, F. H., Manzano-Nieves, G., Quiñones-Laracuente, K., Ramos-Medina, L. & Quirk, G. J. Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J. Neurosci. 35, 3607–3615 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schiller, D., Kanen, J. W., LeDoux, J. E., Monfils, M.-H. & Phelps, E. A. Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proc. Natl Acad. Sci. USA 110, 20040–20045 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kriegeskorte, N., Goebel, R. & Bandettini, P. Information-based functional brain mapping. Proc. Natl Acad. Sci. USA 103, 3863–3868 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Haruno, M. & Kawato, M. Different neural correlates of reward expectation and reward expectation error in the putamen and caudate nucleus during stimulus-action-reward association learning. J. Neurophysiol. 95, 948–959 (2006).

    Article  PubMed  Google Scholar 

  24. O’Doherty, J. et al. Dissociable roles of ventral and dorsal striatum in instrumental conditioning. Science 304, 452–454 (2004).

    Article  PubMed  Google Scholar 

  25. Friston, K. J. et al. Psychophysiological and modulatory interactions in neuroimaging. Neuroimage 6, 218–229 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Sarrazin, J.-C., Cleeremans, A. & Haggard, P. How do we know what we are doing? Time, intention and awareness of action. Conscious. Cogn. 17, 602–615 (2008).

    Article  PubMed  Google Scholar 

  27. Koenigs, M. et al. Focal brain damage protects against post-traumatic stress disorder in combat veterans. Nat. Neurosci. 11, 232–237 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Kim, J. H., Hamlin, A. S. & Richardson, R. Fear extinction across development: the involvement of the medial prefrontal cortex as assessed by temporary inactivation and immunohistochemistry. J. Neurosci. 29, 10802–10808 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Emmert, K. et al. Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: how is brain regulation mediated? Neuroimage 124, 806–812 (2016).

    Article  PubMed  Google Scholar 

  30. Brooks, D. C., Beth, H., Nelson, J. B. & Bouton, M. E. Reinstatement after counterconditioning. Anim. Learn. Behav. 23, 383–390 (1995).

    Article  Google Scholar 

  31. LaBar, K. S. & Phelps, E. A. Reinstatement of conditioned fear in humans is context dependent and impaired in amnesia. Behav. Neurosci. 119, 677–686 (2005).

    Article  PubMed  Google Scholar 

  32. Norrholm, S. D. et al. Conditioned fear extinction and reinstatement in a human fear-potentiated startle paradigm. Learn. Mem. 13, 681–685 (2006).

    Article  PubMed  Google Scholar 

  33. Hermans, D. et al. Reinstatement of fear responses in human aversive conditioning. Behav. Res. Ther. 43, 533–551 (2005).

    Article  PubMed  Google Scholar 

  34. Haxby, J. V. et al. A common, high-dimensional model of the representational space in human ventral temporal cortex. Neuron 72, 404–416 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Engel, S. A., Glover, G. H. & Wandell, B. A. Retinotopic organization in human visual cortex and the spatial precision of functional MRI. Cereb. Cortex 7, 181–192 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Yamashita, O., Sato, M.-A., Yoshioka, T., Tong, F. & Kamitani, Y. Sparse estimation automatically selects voxels relevant for the decoding of fMRI activity patterns. Neuroimage 42, 1414–1429 (2008).

    Article  PubMed  Google Scholar 

  37. Kobayashi, S. et al. Influences of rewarding and aversive outcomes on activity in macaque lateral prefrontal cortex. Neuron 51, 861–870 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Bray, S., Shimojo, S. & O’Doherty, J. P. Direct instrumental conditioning of neural activity using functional magnetic resonance imaging-derived reward feedback. J. Neurosci. 27, 7498–7507 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lonsdorf, T. B., Haaker, J. & Kalisch, R. Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: a reinstatement study in two independent samples. Soc. Cogn. Affect. Neurosci. 9, 1973–1983 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kalisch, R. et al. Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. J. Neurosci. 26, 9503–9511 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tziortzi, A. C. et al. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy. Neuroimage 54, 264–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Nichols, T. E. & Holmes, A. P. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum. Brain Mapp. 15, 1–25 (2002).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Nakamura for her help in scheduling and conducting the experiment, N. Hiroe for assistance with equipment, Y. Shimada and A. Nishikido for operating the fMRI scanner, H. Ban for technical advice, and M. Craske, M. Treanor, M. Sun, A. Izquierdo and F. Krasne for their comments on the manuscript. The study was conducted in the ImPACT Program of Council for Science, Technology and Innovation (Cabinet Office, Government of Japan). This work was partially supported by ‘Brain Machine Interface Development’ under the Strategic Research Program for Brain Sciences supported by the Japan Agency for Medical Research and Development (AMED), the ATR entrust research contract from the National Institute of Information and Communications Technology, and the US National Institute of Neurological Disorders and Stroke of the National Institutes of Health (grant no. R01NS088628 to H.L.). B.S. is funded by the Wellcome Trust, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Ai Koizumi, Kaoru Amano and Aurelio Cortese: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Decoded Neurofeedback, ATR Computational Neuroscience Laboratories, 2-2-2, Hikaridai, Seika-cho, Sorakugun, 619-0288, Kyoto, Japan

    Ai Koizumi, Aurelio Cortese, Kazuhisa Shibata & Mitsuo Kawato

  2. Department of Psychology, Columbia University, 1190 Amsterdam Avenue 370 Schermerhorn Extension MC:5501, New York, 10027, USA

    Ai Koizumi & Hakwan Lau

  3. Center for Information and Neural Networks (CiNet), NICT, 1-4 Yamadaoka, Suita City, 565-0871, Osaka, Japan

    Ai Koizumi, Kaoru Amano, Aurelio Cortese, Wako Yoshida, Ben Seymour & Mitsuo Kawato

  4. Graduate School of Information Science, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma Nara, 630-0192, Japan

    Aurelio Cortese & Mitsuo Kawato

  5. Department of Psychology, UCLA, Box 951563, Los Angeles, 90095-1563, California, USA

    Aurelio Cortese & Hakwan Lau

  6. Department of Psychology, Graduate School of Environmental Studies, Nagoya University, Furo-cho, Chikusa-ku, 464-8601, Nagoya, Japan

    Kazuhisa Shibata

  7. Department of Neural Computation for Decision-making, ATR Cognitive Mechanisms Laboratories, 2-2-2, Hikaridai, Seika-cho, Sorakugun, 619-0288, Kyoto, Japan

    Wako Yoshida & Ben Seymour

  8. Department of Engineering, University of Cambridge, Trumpington Street, Cambridge, CB2 1PZ, UK

    Wako Yoshida & Ben Seymour

  9. Brain Research Institute, UCLA, Box 951761, Los Angeles, 90095-1761, California, USA

    Hakwan Lau

Authors
  1. Ai Koizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaoru Amano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aurelio Cortese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kazuhisa Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wako Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ben Seymour
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mitsuo Kawato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hakwan Lau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.K., H.L., B.S. and M.K. designed the study while actively discussing with other co-authors, A.K., K.A. and A.C. implemented the experiment, A.K. conducted the experiment, A.K., K.S., A.C., H.L. and M.K. analysed the results with the support of K.A. and W.Y. A.K., B.S., H.L. and M.K. wrote the manuscript.

Corresponding authors

Correspondence to Ben Seymour, Mitsuo Kawato or Hakwan Lau.

Ethics declarations

Competing interests

K.S. and M.K. are the inventors of patents related to the DecNef method used in this study, and the original assignee of the patents is ATR, with which some of the authors are affiliated.

Supplementary information

Supplementary information

Supplementary Figures 1–7, Supplementary Methods, Supplementary Table 1, Supplementary References. (PDF 1142 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koizumi, A., Amano, K., Cortese, A. et al. Fear reduction without fear through reinforcement of neural activity that bypasses conscious exposure. Nat Hum Behav 1, 0006 (2017). https://doi.org/10.1038/s41562-016-0006

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41562-016-0006

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing