Preventing the return of fear in humans using reconsolidation update mechanisms

An Addendum to this article was published on 26 July 2018

Abstract

Recent research on changing fears has examined targeting reconsolidation. During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting that they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic. Here we introduce a non-invasive technique to target the reconsolidation of fear memories in humans. We provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. As a consequence, fear responses are no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others. These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Extinction during reconsolidation prevents spontaneous recovery of extinguished fear.
Figure 2: Blockade of the return of fear persists one year later.
Figure 3: Blockade of the return of fear is specific to reactivated memories.

References

  1. 1

    Miracle, A. D., Brace, M. F., Huyck, K. D., Singler, S. A. & Wellman, C. L. Chronic stress impairs recall of extinction of conditioned fear. Neurobiol. Learn. Mem. 85, 213–218 (2006)

    Article  Google Scholar 

  2. 2

    Misanin, J. R., Miller, R. R. & Lewis, D. J. Retrograde amnesia produced by electro-convulsive shock after reactivation of a consolidated memory trace. Science 160, 554–555 (1968)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Alberini, C. M. Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci. 28, 51–56 (2005)

    CAS  Article  Google Scholar 

  4. 4

    Nader, K., Schafe, G. E. & LeDoux, J. E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Dudai, Y. Reconsolidation: the advantage of being refocused. Curr. Opin. Neurobiol. 16, 174–178 (2006)

    CAS  Article  Google Scholar 

  6. 6

    Sara, S. J. & Hars, B. In memory of consolidation. Learn. Mem. 13, 515–521 (2006)

    Article  Google Scholar 

  7. 7

    Hupbach, A., Gomez, L., Hardt, O. & Nadel, R. Reconsolidation of episodic memories: a subtle reminder triggers integration of new information. Learn. Mem. 14, 47–53 (2007)

    Article  Google Scholar 

  8. 8

    Monfils, M.-H., Cowansage, K. K., Klann, E. & LeDoux, J. E. Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324, 951–955 (2009)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Squire, L. R. & Davis, H. P. The pharmacology of memory: a neurobiological perspective. Annu. Rev. Pharmacol. Toxicol. 21, 323–356 (1981)

    CAS  Article  Google Scholar 

  10. 10

    McGaugh, J. L. Memory—a century of consolidation. Science 287, 248–251 (2000)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Duvarci, S. & Nader, K. Characterization of fear memory reconsolidation. J. Neurosci. 24, 9269–9275 (2004)

    CAS  Article  Google Scholar 

  12. 12

    Alberini, C. M., Milekic, M. H. & Tronel, S. Memory: mechanisms of memory stabilization and de-stabilization. Cell. Mol. Life Sci. 63, 999–1008 (2006)

    CAS  Article  Google Scholar 

  13. 13

    Lee, J. L., Milton, A. L. & Everitt, B. J. Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J. Neurosci. 26, 10051–10056 (2006)

    CAS  Article  Google Scholar 

  14. 14

    Doyère, V., Debiec, J., Monfils, M. H., Schafe, G. E. & LeDoux, J. E. Synapse-specific reconsolidation of distinct fear memories in the lateral amygdala. Nature Neurosci. 10, 414–416 (2007)

    Article  Google Scholar 

  15. 15

    Myers, K. M., Ressler, K. J. & Davis, M. Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learn. Mem. 13, 216–223 (2006)

    Article  Google Scholar 

  16. 16

    Alvarez, R. P., Johnson, L. & Grillon, C. Contextual-specificity of short-delay extinction in humans: renewal of fear-potentiated startle in a virtual environment. Learn. Mem. 14, 247–253 (2007)

    Article  Google Scholar 

  17. 17

    Schiller, D. et al. Evidence for recovery of fear following immediate extinction in rats and humans. Learn. Mem. 15, 394–402 (2008)

    Article  Google Scholar 

  18. 18

    Walker, M. P., Brakefield, T., Hobson, J. A. & Stickgold, R. Dissociable stages of human memory consolidation and reconsolidation. Nature 425, 616–620 (2003)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Forcato, C. et al. Reconsolidation of declarative memory in humans. Learn. Mem. 14, 295–303 (2007)

    Article  Google Scholar 

  20. 20

    Squire, L. H. & Knowlton, B. J. in The New Cognitive Neurosciences (ed. Gazzaniga, M. S.) 765–780 (MIT Press, 2000)

    Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  23. 23

    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  Google Scholar 

  24. 24

    LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)

    CAS  Article  Google Scholar 

  25. 25

    Bouton, M. E. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol. Psychiatry 52, 976–986 (2002)

    Article  Google Scholar 

  26. 26

    Quirk, G. J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008)

    Article  Google Scholar 

  27. 27

    Foa, E. B., Franklin, M. E. & Moser, J. Context in the clinic: how well do cognitive-behavioral therapies and medications work in combination. Biol. Psychiatry 52, 987–997 (2002)

    Article  Google Scholar 

  28. 28

    Rauch, S. L., Shin, L. M. & Phelps, E. A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present and future. Biol. Psychiatry 60, 376–382 (2006)

    Article  Google Scholar 

  29. 29

    Kindt, M., Soeter, M. & Vervliet, B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nature Neurosci. 12, 256–258 (2009)

    CAS  Article  Google Scholar 

  30. 30

    Brunet, A. et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42, 503–506 (2008)

    ADS  Article  Google Scholar 

  31. 31

    Tollenaar, M. S., Elzinga, B. M., Spinhoven, P. & Everaerd, W. Psychophysiological responding to emotional memories in healthy young men after cortisol and propranolol administration. Psychopharmacology (Berl.) 203, 793–803 (2009)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Acknowledgement We thank K. Doelling for assistance with data collection and discussions on the revised version of the manuscript. We also thank Y. Niv and M. Milad for advice on the experimental protocols. This study was funded by the James S. McDonnell Foundation and National Institutes of Health (NIH) grant R21 MH072279 (E.A.P.), NIH grants R37 MH038774, P50 MH058911, RO1 MH046516 and K05 MH067048 (J.E.L.), Postdoctoral fellowships NSERC, CIHR and AHFMR (M.-H.M.), and a Fulbright award (D.S.).

Author Contributions D.S. designed the experiments, collected and analysed data, interpreted the data and wrote the first draft of the manuscript; C.M.R. and D.C.J. collected the data and contributed to experimental design, analysis, interpretation and the final version of the manuscript; M.-H.M., J.E.L. and E.A.P. contributed to experimental design, data interpretation, and the final version of the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Elizabeth A. Phelps.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Data and Supplementary Figures 1-3 with Legends. (PDF 255 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schiller, D., Monfils, MH., Raio, C. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010). https://doi.org/10.1038/nature08637

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

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