DOI QR코드

DOI QR Code

A Review of Brain Imaging Studies on Classical Fear Conditioning and Extinction in Healthy Adults

건강한 성인에서의 고전적 공포 조건화 및 소거에 연관된 뇌 영역에 대한 뇌영상 연구 고찰

  • 강일향 (이화여자대학교 뇌융합과학연구원) ;
  • 서채원 (이화여자대학교 뇌융합과학연구원) ;
  • 윤수정 (이화여자대학교 뇌융합과학연구원) ;
  • 김정윤 (이화여자대학교 뇌융합과학연구원)
  • Received : 2021.06.01
  • Accepted : 2021.07.05
  • Published : 2021.10.31

Abstract

Fear conditioning and extinction, which are adaptive processes to learn and avoid potential threats, have essential roles in the pathophysiology of anxiety disorders. Experimental fear conditioning and extinction have been used to identify the mechanism of fear and anxiety in humans. However, the brain-based mechanisms of fear conditioning and extinction are yet to be established. In the current review, we summarized the results of neuroimaging studies that examined the brain changes-functional activity and structures-regarding fear conditioning or extinction in healthy individuals. The functional activity of the amygdala, insula, anterior cingulate gyrus, ventromedial prefrontal cortex, and hippocampus changed dynamically with both fear conditioning and extinction. This review may provide an up-to-date summary that may broaden our understanding of pathophysiological mechanisms of anxiety disorder. In addition, the brain regions that are involved in the fear conditioning and extinction may be considered as potential treatment targets in the future studies.

Keywords

Acknowledgement

This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1A6A1A03043528 and NRF-2019R1I1A1A01045872).

References

  1. Sehlmeyer C, Schoning S, Zwitserlood P, Pfleiderer B, Kircher T, Arolt V, et al. Human fear conditioning and extinction in neuroimaging: a systematic review. PLoS One 2009;4:e5865. https://doi.org/10.1371/journal.pone.0005865
  2. Fullana MA, Albajes-Eizagirre A, Soriano-Mas C, Vervliet B, Cardoner N, Benet O, et al. Fear extinction in the human brain: a metaanalysis of fMRI studies in healthy participants. Neurosci Biobehav Rev 2018;88:16-25. https://doi.org/10.1016/j.neubiorev.2018.03.002
  3. Mineka S, Oehlberg K. The relevance of recent developments in classical conditioning to understanding the etiology and maintenance of anxiety disorders. Acta Psychol (Amst) 2008;127:567-580. https://doi.org/10.1016/j.actpsy.2007.11.007
  4. Maren S. Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 2001;24:897-931. https://doi.org/10.1146/annurev.neuro.24.1.897
  5. Dunsmoor JE, Paz R. Fear generalization and anxiety: behavioral and neural mechanisms. Biol Psychiatry 2015;78:336-343. https://doi.org/10.1016/j.biopsych.2015.04.010
  6. Myers KM, Davis M. Behavioral and neural analysis of extinction. Neuron 2002;36:567-584. https://doi.org/10.1016/S0896-6273(02)01064-4
  7. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000;23:155-184. https://doi.org/10.1146/annurev.neuro.23.1.155
  8. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 2012;63:129-151. https://doi.org/10.1146/annurev.psych.121208.131631
  9. Fullana MA, Dunsmoor JE, Schruers KRJ, Savage HS, Bach DR, Harrison BJ. Human fear conditioning: from neuroscience to the clinic. Behav Res Ther 2020;124:103528. https://doi.org/10.1016/j.brat.2019.103528
  10. Fullana MA, Harrison BJ, Soriano-Mas C, Vervliet B, Cardoner N, Avila-Parcet A, et al. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Mol Psychiatry 2016;21:500-508. https://doi.org/10.1038/mp.2015.88
  11. Andreatta M, Fendt M, Muhlberger A, Wieser MJ, Imobersteg S, Yarali A, et al. Onset and offset of aversive events establish distinct memories requiring fear and reward networks. Learn Mem 2012;19:518-526. https://doi.org/10.1101/lm.026864.112
  12. Apergis-Schoute AM, Schiller D, LeDoux JE, Phelps EA. Extinction resistant changes in the human auditory association cortex following threat learning. Neurobiol Learn Mem 2014;113:109-114. https://doi.org/10.1016/j.nlm.2014.01.016
  13. Feng P, Feng T, Chen Z, Lei X. Memory consolidation of fear conditioning: bi-stable amygdala connectivity with dorsal anterior cingulate and medial prefrontal cortex. Soc Cogn Affect Neurosci 2014;9:1730-1737. https://doi.org/10.1093/scan/nst170
  14. Bach DR, Weiskopf N, Dolan RJ. A stable sparse fear memory trace in human amygdala. J Neurosci 2011;31:9383-9389. https://doi.org/10.1523/JNEUROSCI.1524-11.2011
  15. Dunsmoor JE, Kroes MCW, Li J, Daw ND, Simpson HB, Phelps EA. Role of human ventromedial prefrontal cortex in learning and recall of enhanced extinction. J Neurosci 2019;39:3264-3276. https://doi.org/10.1523/jneurosci.2713-18.2019
  16. Goodman AM, Harnett NG, Wheelock MD, Hurst DR, Orem TR, Gossett EW, et al. Anticipatory prefrontal cortex activity underlies stress-induced changes in Pavlovian fear conditioning. Neuroimage 2018;174:237-247. https://doi.org/10.1016/j.neuroimage.2018.03.030
  17. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005;48:175-187. https://doi.org/10.1016/j.neuron.2005.09.025
  18. Hermans EJ, Kanen JW, Tambini A, Fernandez G, Davachi L, Phelps EA. Persistence of amygdala-hippocampal connectivity and multi-voxel correlation structures during awake rest after fear learning predicts long-term expression of fear. Cereb Cortex 2017;27:3028-3041. https://doi.org/10.1093/cercor/bhw145
  19. Klucken T, Schweckendiek J, Blecker C, Walter B, Kuepper Y, Hennig J, et al. The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity. Soc Cogn Affect Neurosci 2015;10:700-707. https://doi.org/10.1093/scan/nsu108
  20. Klucken T, Kruse O, Schweckendiek J, Kuepper Y, Mueller EM, Hennig J, et al. No evidence for blocking the return of fear by disrupting reconsolidation prior to extinction learning. Cortex 2016;79:112-122. https://doi.org/10.1016/j.cortex.2016.03.015
  21. Schiller D, Kanen JW, LeDoux JE, Monfils MH, Phelps EA. Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proc Natl Acad Sci U S A 2013;110:20040-20045. https://doi.org/10.1073/pnas.1320322110
  22. Sehlmeyer C, Dannlowski U, Schoning S, Kugel H, Pyka M, Pfleiderer B, et al. Neural correlates of trait anxiety in fear extinction. Psychol Med 2011;41:789-798. https://doi.org/10.1017/s0033291710001248
  23. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297:400-403. https://doi.org/10.1126/science.1071829
  24. Munafo MR, Brown SM, Hariri AR. Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 2008;63:852-857. https://doi.org/10.1016/j.biopsych.2007.08.016
  25. Delgado MR, Olsson A, Phelps EA. Extending animal models of fear conditioning to humans. Biol Psychol 2006;73:39-48. https://doi.org/10.1016/j.biopsycho.2006.01.006
  26. Schweckendiek J, Klucken T, Merz CJ, Tabbert K, Walter B, Ambach W, et al. Weaving the (neuronal) web: fear learning in spider phobia. Neuroimage 2011;54:681-688. https://doi.org/10.1016/j.neuroimage.2010.07.049
  27. van Well S, Visser RM, Scholte HS, Kindt M. Neural substrates of individual differences in human fear learning: evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data. Cogn Affect Behav Neurosci 2012;12:499-512. https://doi.org/10.3758/s13415-012-0089-7
  28. Cacciaglia R, Pohlack ST, Flor H, Nees F. Dissociable roles for hippocampal and amygdalar volume in human fear conditioning. Brain Struct Funct 2015;220:2575-2586. https://doi.org/10.1007/s00429-014-0807-8
  29. Mechias ML, Etkin A, Kalisch R. A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. Neuroimage 2010;49:1760-1768. https://doi.org/10.1016/j.neuroimage.2009.09.040
  30. Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol 2000;10:219-223. https://doi.org/10.1016/S0959-4388(00)00078-7
  31. Phelps EA, O'Connor KJ, Gatenby JC, Gore JC, Grillon C, Davis M. Activation of the left amygdala to a cognitive representation of fear. Nat Neurosci 2001;4:437-441. https://doi.org/10.1038/86110
  32. Dunsmoor JE, Prince SE, Murty VP, Kragel PA, LaBar KS. Neurobehavioral mechanisms of human fear generalization. Neuroimage 2011;55:1878-1888. https://doi.org/10.1016/j.neuroimage.2011.01.041
  33. Haritha AT, Wood KH, Ver Hoef LW, Knight DC. Human trace fear conditioning: right-lateralized cortical activity supports traceinterval processes. Cogn Affect Behav Neurosci 2013;13:225-237. https://doi.org/10.3758/s13415-012-0142-6
  34. MacNamara A, Rabinak CA, Fitzgerald DA, Zhou XJ, Shankman SA, Milad MR, et al. Neural correlates of individual differences in fear learning. Behav Brain Res 2015;287:34-41. https://doi.org/10.1016/j.bbr.2015.03.035
  35. Visser RM, Scholte HS, Beemsterboer T, Kindt M. Neural pattern similarity predicts long-term fear memory. Nat Neurosci 2013;16:388-390. https://doi.org/10.1038/nn.3345
  36. Hartley CA, Fischl B, Phelps EA. Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear. Cereb Cortex 2011;21:1954-1962. https://doi.org/10.1093/cercor/bhq253
  37. Schiller D, Delgado MR. Overlapping neural systems mediating extinction, reversal and regulation of fear. Trends Cogn Sci 2010;14:268-276. https://doi.org/10.1016/j.tics.2010.04.002
  38. Harrison BJ, Fullana MA, Via E, Soriano-Mas C, Vervliet B, Martinez-Zalacain I, et al. Human ventromedial prefrontal cortex and the positive affective processing of safety signals. Neuroimage 2017;152:12-18. https://doi.org/10.1016/j.neuroimage.2017.02.080
  39. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 2000;4:215-222. https://doi.org/10.1016/S1364-6613(00)01483-2
  40. Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL. A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry 2007;62:1191-1194. https://doi.org/10.1016/j.biopsych.2007.04.032
  41. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 1996;22:229-244. https://doi.org/10.1016/S0165-0173(96)00011-2
  42. Ongur D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 2000;10:206-219. https://doi.org/10.1093/cercor/10.3.206
  43. Sanders MJ, Wiltgen BJ, Fanselow MS. The place of the hippocampus in fear conditioning. Eur J Pharmacol 2003;463:217-223. https://doi.org/10.1016/S0014-2999(03)01283-4
  44. Morriss J, Christakou A, van Reekum CM. Intolerance of uncertainty predicts fear extinction in amygdala-ventromedial prefrontal cortical circuitry. Biol Mood Anxiety Disord 2015;5:4. https://doi.org/10.1186/s13587-015-0019-8
  45. Feng P, Zheng Y, Feng T. Resting-state functional connectivity between amygdala and the ventromedial prefrontal cortex following fear reminder predicts fear extinction. Soc Cogn Affect Neurosci 2016;11:991-1001. https://doi.org/10.1093/scan/nsw031
  46. Carlson JM, Greenberg T, Rubin D, Mujica-Parodi LR. Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation. Soc Cogn Affect Neurosci 2011;6:74-81. https://doi.org/10.1093/scan/nsq017
  47. Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol 2004;14:198-202. https://doi.org/10.1016/j.conb.2004.03.015
  48. Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;106:274-285. https://doi.org/10.1037/0735-7044.106.2.274
  49. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007;62:446-454. https://doi.org/10.1016/j.biopsych.2006.10.011
  50. Feng P, Zheng Y, Feng T. Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI. Sci Rep 2015;5:16701. https://doi.org/10.1038/srep16701
  51. Martynova O, Tetereva A, Balaev V, Portnova G, Ushakov V, Ivanitsky A. Longitudinal changes of resting-state functional connectivity of amygdala following fear learning and extinction. Int J Psychophysiol 2020;149:15-24. https://doi.org/10.1016/j.ijpsycho.2020.01.002
  52. Sevenster D, Visser RM, D'Hooge R. A translational perspective on neural circuits of fear extinction: current promises and challenges. Neurobiol Learn Mem 2018;155:113-126. https://doi.org/10.1016/j.nlm.2018.07.002
  53. Herry C, Johansen JP. Encoding of fear learning and memory in distributed neuronal circuits. Nat Neurosci 2014;17:1644-1654. https://doi.org/10.1038/nn.3869