Advertisement

Contingency awareness as a prerequisite for differential contextual fear conditioning

  • Christian Baeuchl
  • Michael Hoppstädter
  • Patric Meyer
  • Herta Flor
Article
  • 3 Downloads

Abstract

Contingency awareness during conditioning describes the phenomenon of becoming consciously aware of the association between a conditioned stimulus (CS) and an unconditioned stimulus (US). Despite the fact that contingency awareness is necessary for associative learning in some conditioning paradigms, its role in contextual fear conditioning, a variant that uses a context-CS (CTX) instead of a cue, has not been characterized thus far. We investigated if contingency awareness is a prerequisite for contextual fear conditioning and if subjects classified as aware differ from unaware subjects on a hemodynamic, autonomic, and behavioral level. We used a computer-generated picture context as CTX and slightly painful electric stimulation as US while we recorded brain responses by functional magnetic resonance imaging (fMRI), and obtained skin conductance responses (SCR) and verbal ratings of emotional valence and arousal. SCR analyses revealed that only aware subjects became conditioned to the US-associated CTX (CTX+). Brain activity related to the CTX+ was more strongly pronounced in fear-associated areas like the insula in the aware relative to the unaware group. Finally, the hippocampus was functionally connected to the cingulate cortex and posterior medial frontal gyrus in aware subjects relative to unaware subjects. These task-related differential connectivity patterns suggest that information exchange between the hippocampus and regions involved in the expression of conditioned fear and decision uncertainty is crucial for the acquisition of contingency knowledge. This study demonstrates the importance of contingency awareness for contextual fear conditioning and points to the hippocampus as a potential mediator for contingency learning in contextual learning.

Keywords

Contextual fear conditioning Contingency awareness fMRI Hippocampus Neuropsychological testing Functional connectivity 

Notes

Acknowledgements

This work was funded by a grant from the German Ministry of Education and Research (BMBF, 01GQ1003B).

References

  1. Alvarez, R. P., Biggs, A., Chen, G., Pine, D. S., & Grillon, C. (2008). Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J Neurosci, 28(24), 6211-6219.  https://doi.org/10.1523/JNEUROSCI.1246-08.2008 Google Scholar
  2. Andreatta, M., Glotzbach-Schoon, E., Muhlberger, A., Schulz, S. M., Wiemer, J., & Pauli, P. (2015). Initial and sustained brain responses to contextual conditioned anxiety in humans. Cortex, 63, 352-363.  https://doi.org/10.1016/j.cortex.2014.09.014 Google Scholar
  3. Baeuchl, C., Meyer, P., Hoppstädter, M., Diener, C., & Flor, H. (2015). Contextual fear conditioning in humans using feature-identical contexts. Neurobiology of Learning and Memory, 121, 1-11.  https://doi.org/10.1016/j.nlm.2015.03.001 Google Scholar
  4. Bechara, A., Tranel, D., Damasio, H., Adolphs, R., Rockland, C., & Damasio, A. R. (1995). Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science, 269(5227), 1115-1118.Google Scholar
  5. Benedek, M., & Kaernbach, C. (2010). A continuous measure of phasic electrodermal activity. J Neurosci Methods, 190(1), 80-91.  https://doi.org/10.1016/j.jneumeth.2010.04.028 Google Scholar
  6. Benjamini, Y., & Hochberg, J. (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. Series B (Methodological). 57(1), 289-300.Google Scholar
  7. Buchel, C., & Dolan, R. J. (2000). Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol, 10(2), 219-223.Google Scholar
  8. Büchel, C., Dolan, R. J., Armony, J. L., & Friston, K. J. (1999). Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging. J Neurosci, 19(24), 10869-10876.Google Scholar
  9. Büchel, C., Morris, J., Dolan, R. J., & Friston, K. J. (1998). Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron, 20(5), 947-957.Google Scholar
  10. Burns, B. D., & Corpus, B. (2004). Randomness and inductions from streaks: "gambler's fallacy" versus "hot hand". Psychon Bull Rev, 11(1), 179-184.Google Scholar
  11. Cannon, T. D., Sun, F., McEwen, S. J., Papademetris, X., He, G., van Erp, T. G. M., … Toga, A. W. (2014). Reliability of neuroanatomical measurements in a multisite longitudinal study of youth at risk for psychosis. Human Brain Mapping, 35(5), 2424-2434.  https://doi.org/10.1002/hbm.22338 Google Scholar
  12. Carter, R. M., Hofstotter, C., Tsuchiya, N., & Koch, C. (2003). Working memory and fear conditioning. Proc Natl Acad Sci U S A, 100(3), 1399-1404.  https://doi.org/10.1073/pnas.0334049100 Google Scholar
  13. Carter, R. M., O'Doherty, J. P., Seymour, B., Koch, C., & Dolan, R. J. (2006). Contingency awareness in human aversive conditioning involves the middle frontal gyrus. Neuroimage, 29(3), 1007-1012.  https://doi.org/10.1016/j.neuroimage.2005.09.011 Google Scholar
  14. Chen, J. Y., Liu, J. Y., Calhoun, V. D., Arias-Vasquez, A., Zwiers, M. P., Gupta, C. N., … Turner, J. A. (2014). Exploration of scanning effects in multi-site structural MRI studies. Journal of Neuroscience Methods, 230, 37-50.  https://doi.org/10.1016/j.jneumeth.2014.04.023 Google Scholar
  15. Clark, R. E., Manns, J. R., & Squire, L. R. (2002). Classical conditioning, awareness, and brain systems. Trends Cogn Sci, 6(12), 524-531.Google Scholar
  16. Clark, R. E., & Squire, L. R. (1998). Classical conditioning and brain systems: the role of awareness. Science, 280(5360), 77-81.Google Scholar
  17. Cosand, L. D., Cavanagh, T. M., Brown, A. A., Courtney, C. G., Rissling, A. J., Schell, A. M., & Dawson, M. E. (2008). Arousal, working memory, and conscious awareness in contingency learning. Conscious Cogn, 17(4), 1105-1113.  https://doi.org/10.1016/j.concog.2008.04.007 Google Scholar
  18. Critchley, H. D., Mathias, C. J., Josephs, O., O'Doherty, J., Zanini, S., Dewar, B. K., … Dolan, R. J. (2003). Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain, 126(Pt 10), 2139-2152.  https://doi.org/10.1093/brain/awg216 Google Scholar
  19. Eichenbaum, H. (2004). Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron, 44(1), 109-120.  https://doi.org/10.1016/j.neuron.2004.08.028 Google Scholar
  20. Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., Amunts, K., & Zilles, K. (2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage, 25(4), 1325-1335.  https://doi.org/10.1016/j.neuroimage.2004.12.034 Google Scholar
  21. Etkin, A., Egner, T., & Kalisch, R. (2011). Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci, 15(2), 85-93.  https://doi.org/10.1016/j.tics.2010.11.004 Google Scholar
  22. Ewers, M., Teipel, S. J., Dietrich, O., Schonberg, S. O., Jessen, F., Heun, R., … Hampel, H. (2006). Multicenter assessment of reliability of cranial MRI. Neurobiology of Aging, 27(8), 1051-1059.  https://doi.org/10.1016/j.neurobiolaging.2005.05.032 Google Scholar
  23. Friston, K. J., Buechel, C., Fink, G. R., Morris, J., Rolls, E., & Dolan, R. J. (1997). Psychophysiological and modulatory interactions in neuroimaging. Neuroimage, 6(3), 218-229.  https://doi.org/10.1006/nimg.1997.0291 Google Scholar
  24. Friston, K. J., Williams, S., Howard, R., Frackowiak, R. S., & Turner, R. (1996). Movement-related effects in fMRI time-series. Magn Reson Med, 35(3), 346-355.Google Scholar
  25. Fullana, M. A., Harrison, B. J., Soriano-Mas, C., Vervliet, B., Cardoner, N., Avila-Parcet, A., & Radua, J. (2015). Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Molecular Psychiatry, 21(4), 500-508.  https://doi.org/10.1038/mp.2015.88 Google Scholar
  26. Gitelman, D. R., Penny, W. D., Ashburner, J., & Friston, K. J. (2003). Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution. Neuroimage, 19(1), 200-207.Google Scholar
  27. Greco, J. A., & Liberzon, I. (2016). Neuroimaging of Fear-Associated Learning. Neuropsychopharmacology, 41(1), 320-334.  https://doi.org/10.1038/npp.2015.255 Google Scholar
  28. Grillon, C., Baas, J. P., Lissek, S., Smith, K., & Milstein, J. (2004). Anxious responses to predictable and unpredictable aversive events. Behavioral Neuroscience, 118(5), 916-924.  https://doi.org/10.1037/0735-7044.118.5.916 Google Scholar
  29. Hamm, A. O., Greenwald, M. K., Bradley, M. M., & Lang, P. J. (1993). Emotional Learning, Hedonic Change, and the Startle Probe. Journal of Abnormal Psychology, 102(3), 453-465.  https://doi.org/10.1037/0021-843x.102.3.453 Google Scholar
  30. Härting, C., Markowitsch, H.-J., Neufeld, H., Calabrese, P., Seisinger, K., & Kessler, J. (2000). Wechsler Memory Scale - Revised Edition, German Edition. Manual. Bern: Huber.Google Scholar
  31. Jovicich, J., Czanner, S., Greve, D., Haley, E., van der Kouwe, A., Gollub, R., … Dale, A. (2006). Reliability in multi-site structural MRI studies: Effects of gradient non-linearity correction on phantom and human data. Neuroimage, 30(2), 436-443.  https://doi.org/10.1016/j.neuroimage.2005.09.046 Google Scholar
  32. Kass, R. E., & Raftery, A. E. (1995). Bayes factors. J Am Stat Assoc, 90(430), 773-795.Google Scholar
  33. Klucken, T., Kagerer, S., Schweckendiek, J., Tabbert, K., Vaitl, D., & Stark, R. (2009a). Neural, Electrodermal and Behavioral Response Patterns in Contingency Aware and Unaware Subjects during a Picture-Picture Conditioning Paradigm. Neuroscience, 158(2), 721-731.  https://doi.org/10.1016/j.neuroscience.2008.09.049 Google Scholar
  34. Klucken, T., Tabbert, K., Schweckendiek, J., Merz, C. J., Kagerer, S., Vaitl, D., & Stark, R. (2009b). Contingency learning in human fear conditioning involves the ventral striatum. Human Brain Mapping, 30(11), 3636-3644.  https://doi.org/10.1002/hbm.20791 Google Scholar
  35. Knight, D. C., Cheng, D. T., Smith, C. N., Stein, E. A., & Helmstetter, F. J. (2004). Neural substrates mediating human delay and trace fear conditioning. J Neurosci, 24(1), 218-228.  https://doi.org/10.1523/JNEUROSCI.0433-03.2004 Google Scholar
  36. Knight, D. C., Waters, N. S., & Bandettini, P. A. (2009). Neural substrates of explicit and implicit fear memory. Neuroimage, 45(1), 208-214.  https://doi.org/10.1016/j.neuroimage.2008.11.015 Google Scholar
  37. Knuttinen, M. G., Power, J. M., Preston, A. R., & Disterhoft, J. F. (2001). Awareness in classical differential eyeblink conditioning in young and aging humans. Behavioral Neuroscience, 115(4), 747-757.Google Scholar
  38. LaBar, K. S., & Disterhoft, J. F. (1998). Conditioning, awareness, and the hippocampus. Hippocampus, 8(6), 620-626.  https://doi.org/10.1002/(SICI)1098-1063(1998)8:6<620::AID-HIPO4>3.0.CO;2-6 Google Scholar
  39. LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E., & Phelps, E. A. (1998). Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron, 20(5), 937-945.Google Scholar
  40. Lang, S., Kroll, A., Lipinski, S. J., Wessa, M., Ridder, S., Christmann, C., … Flor, H. (2009). Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex. Eur J Neurosci, 29(4), 823-832.  https://doi.org/10.1111/j.1460-9568.2009.06624.x Google Scholar
  41. Lehrl, S. (2005). Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B). Balingen: Spitta Verlag.Google Scholar
  42. Lemmin, T., Ganesh, G., Gassert, R., Burdet, E., Kawato, M., & Haruno, M. (2010). Model-based attenuation of movement artifacts in fMRI. J Neurosci Methods, 192(1), 58-69.  https://doi.org/10.1016/j.jneumeth.2010.07.013 Google Scholar
  43. Lovibond, P. F., Liu, J. C., Weidemann, G., & Mitchell, C. J. (2011). Awareness is necessary for differential trace and delay eyeblink conditioning in humans. Biol Psychol, 87(3), 393-400.  https://doi.org/10.1016/j.biopsycho.2011.05.002 Google Scholar
  44. Lovibond, P. F., & Shanks, D. R. (2002). The role of awareness in Pavlovian conditioning: empirical evidence and theoretical implications. J Exp Psychol Anim Behav Process, 28(1), 3-26.Google Scholar
  45. Lund, T. E., Norgaard, M. D., Rostrup, E., Rowe, J. B., & Paulson, O. B. (2005). Motion or activity: their role in intra- and inter-subject variation in fMRI. Neuroimage, 26(3), 960-964.  https://doi.org/10.1016/j.neuroimage.2005.02.021 Google Scholar
  46. Manns, J. R., Clark, R. E., & Squire, L. R. (2002). Standard delay eyeblink classical conditioning is independent of awareness. J Exp Psychol Anim Behav Process, 28(1), 32-37.Google Scholar
  47. Maren, S., Phan, K. L., & Liberzon, I. (2013). The contextual brain: implications for fear conditioning, extinction and psychopathology. Nature Reviews Neuroscience, 14(6), 417-428.  https://doi.org/10.1038/nrn3492 Google Scholar
  48. Marschner, A., Kalisch, R., Vervliet, B., Vansteenwegen, D., & Buchel, C. (2008). Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning. J Neurosci, 28(36), 9030-9036.  https://doi.org/10.1523/JNEUROSCI.1651-08.2008 Google Scholar
  49. McIntosh, A. R., Rajah, M. N., & Lobaugh, N. J. (1999). Interactions of prefrontal cortex in relation to awareness in sensory learning. Science, 284(5419), 1531-1533.Google Scholar
  50. McIntosh, A. R., Rajah, M. N., & Lobaugh, N. J. (2003). Functional connectivity of the medial temporal lobe relates to learning and awareness. J Neurosci, 23(16), 6520-6528.Google Scholar
  51. Mechias, M. L., Etkin, A., & Kalisch, R. (2010). A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. Neuroimage, 49(2), 1760-1768.  https://doi.org/10.1016/j.neuroimage.2009.09.040 Google Scholar
  52. Milad, M. R., Quirk, G. J., Pitman, R. K., Orr, S. P., Fischl, B., & Rauch, S. L. (2007). A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry, 62(10), 1191-1194.  https://doi.org/10.1016/j.biopsych.2007.04.032 Google Scholar
  53. Mitchell, C. J., De Houwer, J., & Lovibond, P. F. (2009). The propositional nature of human associative learning. Behav Brain Sci, 32(2), 183-198; discussion 198-246.  https://doi.org/10.1017/S0140525X09000855 Google Scholar
  54. Moses, S. N., & Ryan, J. D. (2006). A comparison and evaluation of the predictions of relational and conjunctive accounts of hippocampal function. Hippocampus, 16(1), 43-65.  https://doi.org/10.1002/hipo.20131 Google Scholar
  55. Nieuwenhuis, S., Forstmann, B. U., & Wagenmakers, E. J. (2011). Erroneous analyses of interactions in neuroscience: a problem of significance. Nat Neurosci, 14(9), 1105-1107.  https://doi.org/10.1038/nn.2886 Google Scholar
  56. Oldfield, R. C. (1971). The Assessment and Analysis of Handedness: The Edinburgh Inventory. Neuropsychologia, 9(1), 97-113.  https://doi.org/10.1016/0028-3932(71)90067-4 Google Scholar
  57. Pavlov, I. P. (1927). Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford, England: Oxford University Press.Google Scholar
  58. Perusini, J. N., & Fanselow, M. S. (2015). Neurobehavioral perspectives on the distinction between fear and anxiety. Learning & Memory, 22(9), 417-425.  https://doi.org/10.1101/lm.039180.115 Google Scholar
  59. Ploghaus, A., Tracey, I., Gati, J. S., Clare, S., Menon, R. S., Matthews, P. M., & Rawlins, J. N. (1999). Dissociating pain from its anticipation in the human brain. Science, 284(5422), 1979-1981.Google Scholar
  60. Pohlack, S. T., Nees, F., Ruttorf, M., Schad, L. R., & Flor, H. (2012). Activation of the ventral striatum during aversive contextual conditioning in humans. Biol Psychol, 91(1), 74-80.  https://doi.org/10.1016/j.biopsycho.2012.04.004 Google Scholar
  61. Power, J. D., Barnes, K. A., Snyder, A. Z., Schlaggar, B. L., & Petersen, S. E. (2012). Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage, 59(3), 2142-2154.  https://doi.org/10.1016/j.neuroimage.2011.10.018 Google Scholar
  62. Quirk, G. J., Armony, J. L., & LeDoux, J. E. (1997). Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala. Neuron, 19(3), 613-624.Google Scholar
  63. Ridderinkhof, K. R., Ullsperger, M., Crone, E. A., & Nieuwenhuis, S. (2004). The role of the medial frontal cortex in cognitive control. Science, 306(5695), 443-447.  https://doi.org/10.1126/science.1100301 Google Scholar
  64. Rudy, J. W. (2009). Context representations, context functions, and the parahippocampal-hippocampal system. Learn Mem, 16(10), 573-585.  https://doi.org/10.1101/lm.1494409 Google Scholar
  65. Rudy, J. W., & Sutherland, R. J. (1995). Configural association theory and the hippocampal formation: an appraisal and reconfiguration. Hippocampus, 5(5), 375-389.  https://doi.org/10.1002/hipo.450050502 Google Scholar
  66. Schultz, D. H., & Helmstetter, F. J. (2010). Classical conditioning of autonomic fear responses is independent of contingency awareness. J Exp Psychol Anim Behav Process, 36(4), 495-500.  https://doi.org/10.1037/a0020263 Google Scholar
  67. Simon, O., Kherif, F., Flandin, G., Poline, J. B., Riviere, D., Mangin, J. F., … Dehaene, S. (2004). Automatized clustering and functional geometry of human parietofrontal networks for language, space, and number. Neuroimage, 23(3), 1192-1202.  https://doi.org/10.1016/j.neuroimage.2004.09.023 Google Scholar
  68. Smith, C. N., Clark, R. E., Manns, J. R., & Squire, L. R. (2005). Acquisition of differential delay eyeblink classical conditioning is independent of awareness. Behavioral Neuroscience, 119(1), 78-86.  https://doi.org/10.1037/0735-7044.119.1.78 Google Scholar
  69. Stout, D. M., Glenn, D. E., Acheson, D. T., Spadoni, A. D., Risbrough, V. B., & Simmons, A. N. (2018). Neural measures associated with configural threat acquisition. Neurobiology of Learning and Memory, 150, 99-106.  https://doi.org/10.1016/j.nlm.2018.03.012 Google Scholar
  70. Tabbert, K., Merz, C. J., Klucken, T., Schweckendiek, J., Vaitl, D., Wolf, O. T., & Stark, R. (2011). Influence of contingency awareness on neural, electrodermal and evaluative responses during fear conditioning. Social Cognitive and Affective Neuroscience, 6(4), 495-506.  https://doi.org/10.1093/scan/nsq070 Google Scholar
  71. Tabbert, K., Stark, R., Kirsch, P., & Vaitl, D. (2006). Dissociation of neural responses and skin conductance reactions during fear conditioning with and without awareness of stimulus contingencies. Neuroimage, 32(2), 761-770.  https://doi.org/10.1016/j.neuroimage.2006.03.038 Google Scholar
  72. Tovote, P., Fadok, J. P., & Luthi, A. (2015). Neuronal circuits for fear and anxiety. Nature Reviews Neuroscience, 16(6), 317-331.  https://doi.org/10.1038/nrn3945 Google Scholar
  73. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., … Joliot, M. (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage, 15(1), 273-289.  https://doi.org/10.1006/nimg.2001.0978 Google Scholar
  74. Van Dijk, K. R., Sabuncu, M. R., & Buckner, R. L. (2012). The influence of head motion on intrinsic functional connectivity MRI. Neuroimage, 59(1), 431-438.  https://doi.org/10.1016/j.neuroimage.2011.07.044 Google Scholar
  75. Watson, J. B., & Rayner, R. (1920). Conditioned emotional reactions. Journal of Experimental Psychology, 3, 1-14.  https://doi.org/10.1037/h0069608 Google Scholar
  76. Weidemann, G., Best, E., Lee, J. C., & Lovibond, P. F. (2013). The role of contingency awareness in single-cue human eyeblink conditioning. Learn Mem, 20(7), 363-366.  https://doi.org/10.1101/lm.029975.112 Google Scholar

Copyright information

© Psychonomic Society, Inc. 2018

Authors and Affiliations

  • Christian Baeuchl
    • 1
    • 2
  • Michael Hoppstädter
    • 1
    • 2
  • Patric Meyer
    • 1
    • 2
  • Herta Flor
    • 1
    • 2
  1. 1.Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
  2. 2.Bernstein Center for Computational Neuroscience Heidelberg/MannheimMannheimGermany

Personalised recommendations