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Original Article

Challenges of Fear Conditioning Research in the Age of RDoC

Published Online:https://doi.org/10.1027/2151-2604/a000303

Abstract. As the criticism of the definition of the phenotype (i.e., clinical diagnosis) represents the major focus of the Research Domain Criteria (RDoC) initiative, it is somewhat surprising that discussions have not yet focused more on specific conceptual and procedural considerations of the suggested RDoC constructs, sub-constructs, and associated paradigms. We argue that we need more precise thinking as well as a conceptual and methodological discussion of RDoC domains and constructs, their interrelationships as well as their experimental operationalization and nomenclature. The present work is intended to start such a debate using fear conditioning as an example. Thereby, we aim to provide thought-provoking impulses on the role of fear conditioning in the age of RDoC as well as conceptual and methodological considerations and suggestions to guide RDoC-based fear conditioning research in the future.

References

  • Alvarez, R. P., Chen, G., Bodurka, J., Kaplan, R. & Grillon, C. (2011). Phasic and sustained fear in humans elicits distinct patterns of brain activity. NeuroImage, 55, 389–400. https://doi.org/10.1016/j.neuroimage.2010.11.057 First citation in articleCrossrefGoogle Scholar

  • Baas, J. M. P., van Ooijen, L., Goudriaan, A. & Kenemans, J. L. (2008). Failure to condition to a cue is associated with sustained contextual fear. Acta Psychologica, 127, 581–592. https://doi.org/10.1016/j.actpsy.2007.09.009 First citation in articleCrossrefGoogle Scholar

  • Bach, D. R., Friston, K. J. & Dolan, R. J. (2013). An improved algorithm for model-based analysis of evoked skin conductance responses. Biological Psychology, 94, 490–497. https://doi.org/10.1016/j.biopsycho.2013.09.010 First citation in articleCrossrefGoogle Scholar

  • Benedek, M. & Kaernbach, C. (2010a). A continuous measure of phasic electrodermal activity. Journal of Neuroscience Methods, 190, 80–91. https://doi.org/10.1016/j.jneumeth.2010.04.028 First citation in articleCrossrefGoogle Scholar

  • Benedek, M. & Kaernbach, C. (2010b). Decomposition of skin conductance data by means of nonnegative deconvolution. Psychophysiology, 47, 647–658. https://doi.org/10.1111/j.1469-8986.2009.00972.x First citation in articleGoogle Scholar

  • Birbaumer, N., Veit, R., Lotze, M., Erb, M., Hermann, C., Grodd, W. & Flor, H. (2005). Deficient fear conditioning in psychopathy: A functional magnetic resonance imaging study. Archives of General Psychiatry, 62, 799–805. https://doi.org/10.1001/archpsyc.62.7.799 First citation in articleCrossrefGoogle Scholar

  • Bonanno, G. A. (2004). Loss, trauma, and human resilience: Have we underestimated the human capacity to thrive after extremely aversive events? The American Psychologist, 59, 20–28. https://doi.org/10.1037/0003-066X.59.1.20 First citation in articleCrossrefGoogle Scholar

  • Bouton, M. E. (2004). Context and behavioral processes in extinction. Learning & Memory, 11, 485–494. https://doi.org/10.1101/lm.78804 First citation in articleCrossrefGoogle Scholar

  • Bradley, M. M., Cuthbert, B. N. & Lang, P. J. (1999). Affect and the startle reflex. In M. E. DawsonA. M. SchellA. H. BöhmeltEds., Startle modification: Implications for neuroscience, cognitive science, and clinical science (pp. 157–183). Cambridge, UK: Cambridge University Press. https://doi.org/10.1017/CBO9780511665523 First citation in articleGoogle Scholar

  • Cichy, R. M., Pantazis, D. & Oliva, A. (2014). Resolving human object recognition in space and time. Nature Neuroscience, 17, 455–462. https://doi.org/10.1038/nn.3635 First citation in articleCrossrefGoogle Scholar

  • Cross-Disorder Group of the Psychiatric Genomics Consortium. (2013). Identification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet, 381, 1371–1379. https://doi.org/10.1016/S0140-6736(12)62129-1 First citation in articleCrossrefGoogle Scholar

  • Cuthbert, B. N. (2014). The RDoC framework: Facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology: Forum – The Research Domain Criteria Project. World Psychiatry, 13, 28–35. https://doi.org/10.1002/wps.20087 First citation in articleCrossrefGoogle Scholar

  • Cuthbert, B. N. (2015). Research Domain Criteria: Toward future psychiatric nosologies. Dialogues in Clinical Neuroscience, 17, 89–97. https://doi.org/10.1016/j.ajp.2013.12.007 First citation in articleGoogle Scholar

  • Cuthbert, B. N. & Insel, T. R. (2013). Toward the future of psychiatric diagnosis: The seven pillars of RDoC. BMC Medicine, 11, 126. https://doi.org/10.1186/1741-7015-11-126 First citation in articleCrossrefGoogle Scholar

  • Davis, M., Walker, D. L., Miles, L. & Grillon, C. (2010). Phasic vs. sustained fear in rats and humans: Role of the extended amygdala in fear vs. anxiety. Neuropsychopharmacology, 35, 105–135. https://doi.org/10.1038/npp.2009.109 First citation in articleCrossrefGoogle Scholar

  • Dawson, M. E., Schell, A. M. & Filion, D. L. (2007). The electrodermal system. In J. T. CacioppoL. G. TassinaryG. G. BerntsonEds., Handbook of psychophysiology (3rd ed., pp. 159–181). Cambridge, UK: Cambridge University Press. https://doi.org/10.1017/9781107415782 First citation in articleGoogle Scholar

  • Duits, P., Cath, D. C., Lissek, S., Hox, J. J., Hamm, A. O., Engelhard, I. M., … Baas, J. M. P. (2015). Updated meta-analysis of classical fear conditioning in the anxiety disorders. Depression and Anxiety, 32, 239–253. https://doi.org/10.1002/da.22353 First citation in articleCrossrefGoogle Scholar

  • Duits, P., Richter, J., Baas, J. M. P., Engelhard, I. M., Limberg-Thiesen, A., Heitland, I., … Cath, D. C. (2017). Enhancing effects of contingency instructions on fear acquisition and extinction in anxiety disorders. Journal of Abnormal Psychology, 126, 378–391. https://doi.org/10.1037/abn0000266 First citation in articleCrossrefGoogle Scholar

  • Dymond, S., Dunsmoor, J. E., Vervliet, B., Roche, B. & Hermans, D. (2015). Fear generalization in humans: Systematic review and implications for anxiety disorder research. Behavior Therapy, 46, 561–582. https://doi.org/10.1016/j.beth.2014.10.001 First citation in articleCrossrefGoogle Scholar

  • Flor, H., Birbaumer, N., Hermann, C., Ziegler, S. & Patrick, C. J. (2002). Aversive Pavlovian conditioning in psychopaths: Peripheral and central correlates. Psychophysiology, 39, 505–518. https://doi.org/10.1017.S0048577202394046 First citation in articleCrossrefGoogle Scholar

  • Galatzer-Levy, I. R., Bonanno, G. A., Bush, D. E. A. & LeDoux, J. E. (2013). Heterogeneity in threat extinction learning: Substantive and methodological considerations for identifying individual difference in response to stress. Frontiers in Behavioral Neuroscience, 7, 55. https://doi.org/10.3389/fnbeh.2013.00055 First citation in articleCrossrefGoogle Scholar

  • Gazendam, F. J., Kamphuis, J. H., Eigenhuis, A., Huizenga, H. M. H., Soeter, M., Bos, M. G. N., … Kindt, M. (2014). Personality predicts individual variation in fear learning a multilevel growth modeling approach. Clinical Psychological Science, 3, 175–188. https://doi.org/10.1177/2167702614535914 First citation in articleCrossrefGoogle Scholar

  • Hahn, T., Kircher, T., Straube, B., Wittchen, H.-U., Konrad, C., Ströhle, A., … Lueken, U. (2015). Predicting treatment response to cognitive behavioral therapy in panic disorder with agoraphobia by integrating local neural information. JAMA Psychiatry, 72, 68–74. https://doi.org/10.1001/jamapsychiatry.2014.1741 First citation in articleCrossrefGoogle Scholar

  • Hamm, A. O., Richter, J., Pané-Farré, C., Westphal, D., Wittchen, H.-U., Vossbeck-Elsebusch, A. N., … Deckert, J. (2016). Panic disorder with agoraphobia from a behavioral neuroscience perspective: Applying the research principles formulated by the Research Domain Criteria (RDoC) initiative. Psychophysiology, 53, 312–322. https://doi.org/10.1111/psyp.12553 First citation in articleCrossrefGoogle Scholar

  • Hamm, A. O. & Vaitl, D. (1996). Affective learning: Awareness and aversion. Psychophysiology, 33, 698–710. https://doi.org/10.1111/j.1469-8986.1996.tb02366.x First citation in articleCrossrefGoogle Scholar

  • Hamm, A. O. & Weike, A. I. (2005). The neuropsychology of fear learning and fear regulation. International Journal of Psychophysiology, 57, 5–14. https://doi.org/10.1016/j.ijpsycho.2005.01.006 First citation in articleCrossrefGoogle Scholar

  • Hogervorst, M. A., Brouwer, A.-M. & van Erp, J. B. F. (2014). Combining and comparing EEG, peripheral physiology and eye-related measures for the assessment of mental workload. Neuroprosthetics, 8, 322. https://doi.org/10.3389/fnins.2014.00322 First citation in articleGoogle Scholar

  • Holt, D. J., Coombs, G., Zeidan, M. A., Goff, D. C. & Milad, M. R. (2012). Failure of neural responses to safety cues in schizophrenia. Archives of General Psychiatry, 69, 893–903. https://doi.org/10.1001/archgenpsychiatry.2011.2310 First citation in articleCrossrefGoogle Scholar

  • Insel, T. R. (2014). The NIMH Research Domain Criteria (RDoC) Project: Precision medicine for psychiatry. The American Journal of Psychiatry, 171, 395–397. https://doi.org/10.1176/appi.ajp.2014.14020138 First citation in articleCrossrefGoogle Scholar

  • Insel, T. R. & Cuthbert, B. N. (2009). Endophenotypes: Bridging genomic complexity and disorder heterogeneity. Biological Psychiatry, 66, 988–989. https://doi.org/10.1016/j.biopsych.2009.10.008 First citation in articleCrossrefGoogle Scholar

  • Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D. S., Quinn, K., … Wang, P. (2010). Research Domain Criteria (RDoC): Toward a new classification framework for research on mental disorders. The American Journal of Psychiatry, 167, 748–751. https://doi.org/10.1176/appi.ajp.2010.09091379 First citation in articleCrossrefGoogle Scholar

  • Kozak, M. J. & Cuthbert, B. N. (2016). The NIMH Research Domain Criteria Initiative: Background, issues, and pragmatics. Psychophysiology, 53, 286–297. https://doi.org/10.1111/psyp.12518 First citation in articleCrossrefGoogle Scholar

  • Kuhn, M., Mertens, G. & Lonsdorf, T. B. (2016). State anxiety modulates the return of fear. International Journal of Psychophysiology, 110, 194–199. https://doi.org/10.1016/j.ijpsycho.2016.08.001 First citation in articleCrossrefGoogle Scholar

  • Lilienfeld, S. O. (2014). The Research Domain Criteria (RDoC): An analysis of methodological and conceptual challenges. Behaviour Research and Therapy, 62, 129–139. https://doi.org/10.1016/j.brat.2014.07.019 First citation in articleCrossrefGoogle Scholar

  • Lindner, K., Neubert, J., Pfannmöller, J., Lotze, M., Hamm, A. O. & Wendt, J. (2015). Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction. International Journal of Psychophysiology, 98, 535–545. https://doi.org/10.1016/j.ijpsycho.2015.02.025 First citation in articleCrossrefGoogle Scholar

  • Lipp, O. V. & Purkis, H. M. (2005). No support for dual process accounts of human affective learning in simple Pavlovian conditioning. Cognition & Emotion, 19, 269–282. https://doi.org/10.1080/02699930441000319 First citation in articleCrossrefGoogle Scholar

  • Lissek, S., Powers, A. S., McClure, E. B., Phelps, E. A., Woldehawariat, G., Grillon, C. & Pine, D. S. (2005). Classical fear conditioning in the anxiety disorders: A meta-analysis. Behaviour Research and Therapy, 43, 1391–1424. https://doi.org/10.1016/j.brat.2004.10.007 First citation in articleCrossrefGoogle Scholar

  • Lonsdorf, T. B., Haaker, J. & Kalisch, R. (2014). Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: A reinstatement study in two independent samples. Social Cognitive and Affective Neuroscience, 9, 1973–1983. https://doi.org/10.1093/scan/nsu018 First citation in articleCrossrefGoogle Scholar

  • Lonsdorf, T. B., Menz, M. M., Andreatta, M., Fullana, M. A., Golkar, A., Haaker, J., … Merz, C. J. (2017). Don’t fear “fear conditioning”: Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear. Neuroscience and Biobehavioral Reviews, 77, 247–285. https://doi.org/10.1016/j.neubiorev.2017.02.026 First citation in articleCrossrefGoogle Scholar

  • Lonsdorf, T. B. & Merz, C. (2017). More than just noise: Inter-individual differences in fear acquisition, extinction and return of fear in humans – Biological, experiential, tem-peramental factors, and methodological pitfalls. Neuroscience & Biobehavioral Reviews, 80, 703–728. https://doi.org/10.1016/j.neubiorev.2017.07.007 First citation in articleCrossrefGoogle Scholar

  • Lovibond, P. F. (2004). Cognitive processes in extinction. Learning & Memory (Cold Spring Harbor, N.Y.), 11, 495–500. https://doi.org/10.1101/lm.79604 First citation in articleCrossrefGoogle Scholar

  • Lovibond, P. F. & Shanks, D. R. (2002). The role of awareness in Pavlovian conditioning: Empirical evidence and theoretical implications. Journal of Experimental Psychology. Animal Behavior Processes, 28, 3–26. https://doi.org/10.1037/0097-7403.28.1.3 First citation in articleCrossrefGoogle Scholar

  • Löw, A., Lang, P. J., Smith, J. C. & Bradley, M. M. (2008). Both predator and prey: Emotional arousal in threat and reward. Psychological Science, 19, 865–873. https://doi.org/10.1111/j.1467-9280.2008.02170.x First citation in articleCrossrefGoogle Scholar

  • Löw, A., Weymar, M. & Hamm, A. O. (2015). When threat is near, get out of here: Dynamics of defensive behavior during freezing and active avoidance. Psychological Science, 26, 1706–1716. https://doi.org/10.1177/0956797615597332 First citation in articleCrossrefGoogle Scholar

  • Lueken, U., Zierhut, K. C., Hahn, T., Straube, B., Kircher, T., Reif, A., … Domschke, K. (2016). Neurobiological markers predicting treatment response in anxiety disorders: A systematic review and implications for clinical application. Neuroscience and Biobehavioral Reviews, 66, 143–162. https://doi.org/10.1016/j.neubiorev.2016.04.005 First citation in articleCrossrefGoogle Scholar

  • MacNamara, A. & Phan, K. L. (2016). Psychobiological operationalization of RDoC constructs: Methodological and conceptual opportunities and challenges. Psychophysiology, 53, 406–409. https://doi.org/10.1111/psyp.12587 First citation in articleCrossrefGoogle Scholar

  • Maren, S. (2014). Nature and causes of the immediate extinction deficit: A brief review. Neurobiology of Learning and Memory, 113, 19–24. https://doi.org/10.1016/j.nlm.2013.10.012 First citation in articleCrossrefGoogle Scholar

  • Marin, M.-F., Zsido, R. G., Song, H., Lasko, N. B., Killgore, W. D. S., Rauch, S. L., … Milad, M. R. (2017). Skin conductance responses and neural activations during fear conditioning and extinction recall across anxiety disorders. JAMA Psychiatry, 74, 622–631. https://doi.org/10.1001/jamapsychiatry.2017.0329 First citation in articleCrossrefGoogle Scholar

  • Marschner, A., Kalisch, R., Vervliet, B., Vansteenwegen, D. & Büchel, C. (2008). Dissociable roles for the hippocampus and the amygdala in human cued versus context fear conditioning. The Journal of Neuroscience, 28, 9030–9036. https://doi.org/10.1523/JNEUROSCI.1651-08.2008 First citation in articleCrossrefGoogle Scholar

  • Mineka, S. & Ohman, A. (2002). Phobias and preparedness: The selective, automatic, and encapsulated nature of fear. Biological Psychiatry, 52, 927–937. https://doi.org/10.1016/S0006-3223(02)01669-4 First citation in articleCrossrefGoogle Scholar

  • Mineka, S. & Zinbarg, R. (2006). A contemporary learning theory perspective on the etiology of anxiety disorders: It’s not what you thought it was. The American Psychologist, 61, 10–26. https://doi.org/10.1037/0003-066X.61.1.10 First citation in articleCrossrefGoogle Scholar

  • Mobbs, D., Petrovic, P., Marchant, J. L., Hassabis, D., Weiskopf, N., Seymour, B., … Frith, C. D. (2007). When fear is near: Threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science (New York, NY), 317, 1079–1083. https://doi.org/10.1126/science.1144298 First citation in articleCrossrefGoogle Scholar

  • Myers, K. M. & Davis, M. (2007). Mechanisms of fear extinction. Molecular Psychiatry, 12, 120–150. https://doi.org/10.1038/sj.mp.4001939 First citation in articleCrossrefGoogle Scholar

  • Nees, F., Heinrich, A. & Flor, H. (2015). A mechanism-oriented approach to psychopathology: The role of Pavlovian conditioning. International Journal of Psychophysiology, 98, 351–364. https://doi.org/10.1016/j.ijpsycho.2015.05.005 First citation in articleCrossrefGoogle Scholar

  • Ohman, A. & Soares, J. J. (1998). Emotional conditioning to masked stimuli: Expectancies for aversive outcomes following nonrecognized fear-relevant stimuli. Journal of Experimental Psychology. General, 127, 69–82. First citation in articleCrossrefGoogle Scholar

  • Parra, C., Esteves, F., Flykt, A. & Öhman, A. (1997). Pavlovian conditioning to social stimuli. European Psychologist, 2, 106–117. https://doi.org/10.1027/1016-9040.2.2.106 First citation in articleLinkGoogle Scholar

  • Rachman, S. (1989). The return of fear: Review and prospect. Clinical Psychology Review, 9, 147–168. https://doi.org/10.1016/0272-7358(89)90025-1 First citation in articleCrossrefGoogle Scholar

  • Richter, J., Hamm, A. O., Pané-Farré, C. A., Gerlach, A. L., Gloster, A. T., Wittchen, H.-U., … Arolt, V. (2012). Dynamics of defensive reactivity in patients with panic disorder and agoraphobia: Implications for the etiology of panic disorder. Biological Psychiatry, 72, 512–520. https://doi.org/10.1016/j.biopsych.2012.03.035 First citation in articleCrossrefGoogle Scholar

  • Rothemund, Y., Ziegler, S., Hermann, C., Gruesser, S. M., Foell, J., Patrick, C. J. & Flor, H. (2012). Fear conditioning in psychopaths: Event-related potentials and peripheral measures. Biological Psychology, 90, 50–59. https://doi.org/10.1016/j.biopsycho.2012.02.011 First citation in articleCrossrefGoogle Scholar

  • Sevenster, D., Beckers, T. & Kindt, M. (2012). Instructed extinction differentially affects the emotional and cognitive expression of associative fear memory. Psychophysiology, 49, 1426–1435. https://doi.org/10.1111/j.1469-8986.2012.01450.x First citation in articleCrossrefGoogle Scholar

  • Shankman, S. A. & Gorka, S. M. (2015). Psychopathology research in the RDoC era: Unanswered questions and the importance of the psychophysiological unit of analysis. International Journal of Psychophysiology, 98, 330–337. https://doi.org/10.1016/j.ijpsycho.2015.01.001 First citation in articleCrossrefGoogle Scholar

  • Sjouwerman, R., Niehaus, J., Kuhn, M. & Lonsdorf, T. B. (2016). Don’t startle me – Interference of startle probe presentations and intermittent ratings with fear acquisition. Psychophysiology, 53, 1889–1899. https://doi.org/10.1111/psyp.12761 First citation in articleCrossrefGoogle Scholar

  • Tovote, P., Fadok, J. P. & Lüthi, A. (2015). Neuronal circuits for fear and anxiety. Nature Reviews Neuroscience, 16, 317–331. https://doi.org/10.1038/nrn3945 First citation in articleCrossrefGoogle Scholar

  • van Well, S., Visser, R. M., Scholte, H. S. & Kindt, M. (2012). Neural substrates of individual differences in human fear learning: Evidence from concurrent fMRI, fear-potentiated startle, and US-expectancy data. Cognitive, Affective & Behavioral Neuroscience, 12, 499–512. https://doi.org/10.3758/s13415-012-0089-7 First citation in articleCrossrefGoogle Scholar

  • Veit, R., Konicar, L., Klinzing, J. G., Barth, B., Yilmaz, Ö. & Birbaumer, N. (2013). Deficient fear conditioning in psychopathy as a function of interpersonal and affective disturbances. Frontiers in Human Neuroscience, 7, 706. https://doi.org/10.3389/fnhum.2013.00706 First citation in articleCrossrefGoogle Scholar

  • Vervliet, B., Craske, M. G. & Hermans, D. (2013). Fear extinction and relapse: State of the art. Annual Review of Clinical Psychology, 9, 215–248. https://doi.org/10.1146/annurev-clinpsy-050212-185542 First citation in articleCrossrefGoogle Scholar