Translational fear inhibition models as indices of trauma-related psychopathology
Abstract
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that arises from exposure to a traumatic event such as combat exposure, a vehicular accident, or an act of violence. The symptom clusters of PTSD include hyperarousal and re-experiencing of the traumatic event when exposed to trauma reminders, as well as avoidance of such reminders. The fear-and anxiety-related symptoms of PTSD can be conceptualized, and subsequently modeled, as the result of fear conditioning such that the traumatic event serves as an unconditioned stimulus and the environmental cues present at the time of the trauma serve as conditioned stimuli that can ultimately elicit conditioned fear responses (i.e., clinical symptoms) long after the trauma has occurred. Many of the most successful treatments for anxiety disorders such as PTSD are based on the principles of fear extinction in which the repeated presentation of a conditioned stimulus, without noxious consequences, reduces the frequency and intensity of a conditioned response. In the current review, we discuss the most widely employed psychophysiological protocols that have been used to study fear processing in human populations, both psychiatrically healthy and with PTSD. Special emphasis is placed on how translational clinical research can inform clinical practices and vice versa. Keywords: Anxiety, fear, posttraumatic stress disorder, psychophysiology, translation, treatment outcome, heuristics, co-morbid PTSD, neutral cue, hyperventilation, trauma-exposed, psychophysiological measures, progesterone
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The authors previously showed that a predominately male population of combat veterans with PTSD did not show 'fear load,' but rather impaired within-session extinction learning characterized by a 'persistence of fear'.
“As an example, we previously showed that a predominately male population of combat veterans with PTSD did not show “fear load,” but rather impaired within-session extinction learning characterized by a “persistence of fear” (40).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [40]
Cites
Trauma and Posttraumatic Stress Disorder in the Community: The 1996 Detroit Area Survey of Trauma
Breslau, N., Kessler, R. C., Chilcoat, H. D., Schultz, L. R., Davis, G. C., & Andreski, P. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.7.626 · Cited by 2,407 · see citing works
Phelps, E. A., Delgado, M. R., Nearing, K. I., & LeDoux, J. E. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.042 · Cited by 1,753 · see citing works
Behavioral/cognitive conceptualizations of post-traumatic stress disorder
Foa, E. B., Steketee, G., & Rothbaum, B. O. (1989) · Behavior Therapy · doi:10.1016/s0005-7894(89)80067-x · Cited by 1,518 · see citing works
Posttraumatic stress disorder: the burden to the individual and to society.
Kessler, R. C. (2000) · PubMed · Cited by 1,443 · see citing works
Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder
Milad, M. R., Pitman, R. K., Ellis, C. B., Gold, A. L., Shin, L. M., Lasko, N. B., Zeidan, M. A., Handwerger, K., Orr, S. P., & Rauch, S. L. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.06.026 · Cited by 1,339 · see citing works
Preventing the return of fear in humans using reconsolidation update mechanisms
Schiller, D., Monfils, M.-H., Raio, C. M., Johnson, D. C., LeDoux, J. E., & Phelps, E. A. (2010) · Nature · doi:10.1038/nature08637 · Cited by 1,248 · see citing works
Milad, M. R., Wright, C. I., Orr, S. P., Pitman, R. K., Quirk, G. J., & Rauch, S. L. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.10.011 · Cited by 1,197 · see citing works
Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E., Hodges, L., & Davis, M. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.11.1136 · Cited by 1,063 · see citing works
Emotion, motivation, and anxiety: brain mechanisms and psychophysiology
Lang, P. J., Bradley, M. M., & Cuthbert, B. N. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00275-3 · Cited by 1,043 · see citing works
Extinction-Reconsolidation Boundaries: Key to Persistent Attenuation of Fear Memories
Monfils, M.-H., Cowansage, K. K., Klann, E., & LeDoux, J. E. (2009) · Science · doi:10.1126/science.1167975 · Cited by 960 · see citing works
Behavioral and Neural Analysis of Extinction
Myers, K. M., & Davis, M. (2002) · Neuron · doi:10.1016/s0896-6273(02)01064-4 · Cited by 918 · see citing works
Miserendino, M. J. D., Sananes, C. B., Melia, K. R., & Davis, M. (1990) · Nature · doi:10.1038/345716a0 · Cited by 824 · see citing works
Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02343.2002 · Cited by 815 · see citing works
Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor
Ressler, K. J., Mercer, K. B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S. D., Kilaru, V., Smith, A. K., Myers, A. J., et al. (2011) · Nature · doi:10.1038/nature09856 · Cited by 800 · see citing works
Self-citationBouton, M. E., & King, D. A. (1983) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.9.3.248 · Cited by 771 · see citing works
Reinstatement of fear to an extinguished conditioned stimulus.
Rescorla, R. A., & Heth, C. D. (1975) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.1.1.88 · Cited by 768 · see citing works
Effectiveness of computer-generated (virtual reality) graded exposure in the treatment of acrophobia
(1995) · American Journal of Psychiatry · doi:10.1176/ajp.152.4.626 · Cited by 694 · see citing works
A cognitive neuroscience account of posttraumatic stress disorder and its treatment
Brewin, C. R. (2001) · Behaviour Research and Therapy · doi:10.1016/s0005-7967(00)00087-5 · Cited by 588 · see citing works
Augmentation of Exposure Therapy With D-Cycloserine for Social Anxiety Disorder
Hofmann, S. G., Meuret, A. E., Smits, J. A. J., Simon, N. M., Pollack, M. H., Eisenmenger, K., Shiekh, M., & Otto, M. W. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.3.298 · Cited by 560 · see citing works
The stressor criterion in DSM-IV posttraumatic stress disorder: an empirical investigation
Breslau, N., & Kessler, R. C. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01167-2 · Cited by 526 · see citing works
Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study
Milad, M. R., Orr, S. P., Lasko, N. B., Chang, Y., Rauch, S. L., & Pitman, R. K. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.01.017 · Cited by 512 · see citing works
Effects of D-Cycloserine on Extinction: Translation From Preclinical to Clinical Work
Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.084 · Cited by 498 · see citing works
Role of conditioned contextual stimuli in reinstatement of extinguished fear.
Bouton, M. E., & Bolles, R. C. (1979) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037//0097-7403.5.4.368 · Cited by 481 · see citing works
Blechert, J., Michael, T., Vriends, N., Margraf, J., & Wilhelm, F. H. (2007) · Behaviour Research and Therapy · doi:10.1016/j.brat.2007.02.012 · Cited by 479 · see citing works
Sleep states and memory processes
Smith, C. (1995) · Behavioural Brain Research · doi:10.1016/0166-4328(95)00024-n · Cited by 473 · see citing works
Impaired fear inhibition is a biomarker of PTSD but not depression
Jovanovic, T., Norrholm, S. D., Blanding, N. Q., Davis, M., Duncan, E., Bradley, B., & Ressler, K. J. (2010) · Depression and Anxiety · doi:10.1002/da.20663 · Cited by 444 · see citing works
How the Neurocircuitry and Genetics of Fear Inhibition May Inform Our Understanding of PTSD
Jovanović, T., & Ressler, K. J. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09071074 · Cited by 441 · see citing works
Stimulus selection in animal discrimination learning.
Wagner, A. R., Logan, F. A., & Haberlandt, K. F. (1968) · Journal of Experimental Psychology · doi:10.1037/h0025414 · Cited by 425 · see citing works
Norrholm, S. D., Jovanovic, T., Olin, I. W., Sands, L. A., Karapanou, I., Bradley, B., & Ressler, K. J. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.013 · Cited by 397 · see citing works
Effects of D-cycloserine on extinction of conditioned freezing.
Ledgerwood, L., Richardson, R., & Cranney, J. (2003) · Behavioral Neuroscience · doi:10.1037/0735-7044.117.2.341 · Cited by 388 · see citing works
Enhancing Cannabinoid Neurotransmission Augments the Extinction of Conditioned Fear
Chhatwal, J. P., Davis, M., Maguschak, K. A., & Ressler, K. J. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300655 · Cited by 376 · see citing works
Quirk, G. J. (2002) · Learning & Memory · doi:10.1101/lm.49602 · Cited by 360 · see citing works
The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction
Walker, D. L., & Davis, M. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00698-0 · Cited by 356 · see citing works
Sleep states and memory processes in humans: procedural versus declarative memory systems
Smith, C. (2001) · Sleep Medicine Reviews · doi:10.1053/smrv.2001.0164 · Cited by 355 · see citing works
Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder
Peri, T., Ben‐Shakhar, G., Orr, S. P., & Shalev, A. Y. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00144-4 · Cited by 349 · see citing works
A learning theory perspective on lapse, relapse, and the maintenance of behavior change.
Bouton, M. E. (2000) · Health Psychology · doi:10.1037/0278-6133.19.suppl1.57 · Cited by 341 · see citing works
Wessa, M., & Flor, H. (2007) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2007.07030525 · Cited by 323 · see citing works
A synaptic basis for memory storage in the cerebral cortex
Bear, M. F. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13453 · Cited by 315 · see citing works
Jovanovic, T., Norrholm, S. D., Fennell, J. E., Keyes, M., Fiallos, A. M., Myers, K. M., Davis, M., & Duncan, E. J. (2009) · Psychiatry Research · doi:10.1016/j.psychres.2007.12.014 · Cited by 315 · see citing works
Amygdalar NMDA Receptors are Critical for New Fear Learning in Previously Fear-Conditioned Rats
Lee, H. J., & Kim, J. J. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08444.1998 · Cited by 310 · see citing works
Context modulation of memory for fear extinction in humans.
Milad, M., Orr, S., Pitman, R., & Rauch, S. (2005) · Psychophysiology · doi:10.1111/j.1469-8986.2005.00302.x · Cited by 289 · see citing works
Hippocampal synaptic plasticity and NMDA receptors: a role in information storage?
Morris, R., Davis, S., & Butcher, S. P. (1990) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1990.0164 · Cited by 265 · see citing works
NMDA receptor regulation of memory and behavior in humans
Newcomer, J. W., & Krystal, J. (2001) · Hippocampus · doi:10.1002/hipo.1069 · Cited by 258 · see citing works
Ledgerwood, L., Richardson, R., & Cranney, J. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.01.023 · Cited by 243 · see citing works
Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301605 · Cited by 224 · see citing works
Gewirtz, J. C., Falls, W. A., & Davis, M. E. (1997) · Behavioral Neuroscience · doi:10.1037//0735-7044.111.4.712 · Cited by 222 · see citing works
Lu, K., Walker, D. L., & Davis, M. E. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-16-j0005.2001 · Cited by 222 · see citing works
Sleep and memory: a molecular perspective
Graves, L. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01744-6 · Cited by 216 · see citing works
Sleep Promotes Generalization of Extinction of Conditioned Fear
(2009) · Sleep · doi:10.5665/sleep/32.1.19 · Cited by 196 · see citing works
Quartermain, D., Mower, J., Rafferty, M. F., Herting, R. L., & Lanthorn, T. H. (1994) · European Journal of Pharmacology · doi:10.1016/0014-2999(94)90687-4 · Cited by 190 · see citing works
Ledgerwood, L., Richardson, R., & Cranney, J. (2004) · Behavioral Neuroscience · doi:10.1037/0735-7044.118.3.505 · Cited by 190 · see citing works
Vansteenwegen, D., Hermans, D., Vervliet, B., Francken, G., Beckers, T., Baeyens, F., & Eelen, P. (2005) · Behaviour Research and Therapy · doi:10.1016/j.brat.2004.01.001 · Cited by 188 · see citing works
Pilot controlled trial of d-serine for the treatment of post-traumatic stress disorder
Heresco‐Levy, U., Vass, Á., Bloch, B., Wolosker, H., Dumin, E., Balan, L., Deutsch, L., & Kremer, I. (2009) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709000339 · Cited by 171 · see citing works
Gewirtz, J. C., & Davis, M. E. (2000) · Learning & Memory · doi:10.1101/lm.35200 · Cited by 168 · see citing works
Conditioned fear extinction and reinstatement in a human fear-potentiated startle paradigm
Norrholm, S. D., Jovanovic, T., Vervliet, B., Myers, K. M., Davis, M., Rothbaum, B. O., & Duncan, E. J. (2006) · Learning & Memory · doi:10.1101/lm.393906 · Cited by 167 · see citing works
Timing of extinction relative to acquisition: a parametric analysis of fear extinction in humans
Norrholm, S. D., Vervliet, B., Jovanovic, T., Boshoven, W., Myers, K. M., Davis, M., Rothbaum, B., & Duncan, E. J. (2008) · Behavioral Neuroscience · doi:10.1037/a0012604 · Cited by 120 · see citing works
Neural Systems Involved in Fear Inhibition: Extinction and Conditioned Inhibition
Davis, M., Falls, W., & Gewirtz, J. C. (2000) · Neurobiological foundation of aberrant behaviors · doi:10.1007/978-1-4757-4860-4_8 · Cited by 115 · see citing works
Post-Traumatic Stress Disorder, Conditioning, and Network Theory
Pitman, R. K. (1988) · Psychiatric Annals · doi:10.3928/0048-5713-19880301-11 · Cited by 114 · see citing works
Alvarez, R. P., Johnson, L., & Grillon, C. (2007) · Learning & Memory · doi:10.1101/lm.493707 · Cited by 110 · see citing works
Myers, K. M., & Davis, M. E. (2004) · Learning & Memory · doi:10.1101/lm.74704 · Cited by 87 · see citing works
Chhatwal, J. P., Gutman, A. R., Maguschak, K. A., Bowser, M. E., Yang, Y., Davis, M., & Ressler, K. J. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.97 · Cited by 80 · see citing works
Considering PTSD from the perspective of brain processes: A psychological construction approach
Suvak, M. K., & Barrett, L. F. (2011) · Journal of Traumatic Stress · doi:10.1002/jts.20618 · Cited by 76 · see citing works
Test–Retest Reliability during Fear Acquisition and Fear Extinction in Humans
Zeidan, M. A., Lebrón‐Milad, K., Thompson‐Hollands, J., Im, J. J. Y., Dougherty, D. D., Holt, D. J., Orr, S. P., & Milad, M. R. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2011.00238.x · Cited by 64 · see citing works
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Huckins, L. M., Chatzinakos, C., Breen, M. S., Hartmann, J., Klengel, T., Almeida, A. C. D. S., Dobbyn, A. L., Girdhar, K., Hoffman, G. E., Klengel, C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107716 · Cited by 67 · see citing works
Warren, V. T., Anderson, K. M., Kwon, C., Bosshardt, L., Jovanovic, T., Bradley, B., & Norrholm, S. D. (2014) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.10.014 · Cited by 62 · see citing works
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- Authors
- D. Norrholm, S., & Jovanovic, T.
- Venue
- Current Psychiatry Reviews
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2011-08-01
- Volume
- 7
- Issue
- 3
- Pages
- 194-204
- ISSN
- 1573-4005 (ISSN-L)
- OpenAlex
- W2329975296
- Cited by
- 17
- References
- 63
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2020: 3 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Psychiatry Reviews (publishedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Keywords
- post-traumatic stress disorder, fear conditioning, fear extinction, fear inhibition, psychophysiological measures, trauma exposure, anxiety, hyperarousal, avoidance, progesterone, translational research, treatment outcomes, trauma-related psychopathology
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