Impaired safety signal learning may be a biomarker of PTSD
Open accessAbstract
A dysregulated fear response is one of the hallmark clinical presentations of patients suffering from posttraumatic stress disorder (PTSD). These patients show over-generalization of fear and in tandem an inability to inhibit fear responses in the presence of safety. Here, we summarize our recent findings using a conditional discrimination paradigm, which assesses safety signal processing (AX+/BX-) in combat and civilian PTSD populations. Overall, PTSD subjects demonstrate a lack of safety signal learning and an inability to modulate the fear responses with safety cues. We then review studies of the neurobiology of fear expression and inhibition in humans and non-humans, in order to provide a background for preliminary studies using reverse translation procedures in which the same AX+/BX- paradigm was used in rhesus macaques. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
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Elevated CRP is associated with impaired inhibition of fear-potentiated startle in the presence of a safety signal.
“Furthermore, elevated CRP is also associated with impaired inhibition of fear-potentiated startle in the presence of a safety signal, a well-characterized biomarker of PTSD (Jovanovic et al, 2012).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Jovanovic et al, 2012
Section 1.5 (page unavailable) describes impaired safety-signal learning and fear inhibition as specific markers of PTSD symptoms, supporting the biomarker description. It presents biomarker status as a suggestion rather than an established fact. The paper does not address the sentence’s association with elevated CRP. (LLM, conf=0.83)
Experimental — accuracy not yet measuredPTSD patients have difficulty learning safety discrimination.
“as well as difficulty learning safety discrimination, another form of inhibitory learning where the subjects are trained to differentiate between a safe versus dangerous cue or context (Jovanovic, Kazama, Bachevalier, & Davis, 2012; Jovanovic et al., 2010, 2009; Lissek et al., 2005; for a review, see Christianson et al., 2012).”
From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Jovanovic et al., 2012
PTSD patients have shown increased fear responses to cues that they subjectively report as safe.
“For example, PTSD patients have shown increased fear responses to cues that they subjectively report as safe (28).”
From Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors (2014) · cites this paper as [28]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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Role of the Primate Orbitofrontal Cortex in Mediating Anxious Temperament
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Fear potentiation is associated with hypothalamic–pituitary–adrenal axis function in PTSD
Jovanović, T., Norrholm, S. D., Blanding, N. Q., Phifer, J. E., Weiss, T., Davis, M., Duncan, E., Bradley, B., & Ressler, K. J. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.11.009 · Cited by 112 · see citing works
Self-citationConditioned inhibition of fear-potentiated startle and skin conductance in humans
Grillon, C., & Ameli, R. (2001) · Psychophysiology · doi:10.1111/1469-8986.3850807 · Cited by 102 · see citing works
Izquierdo, A., & Murray, E. A. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04434.x · Cited by 96 · see citing works
Myers, K. M., & Davis, M. E. (2004) · Learning & Memory · doi:10.1101/lm.74704 · Cited by 87 · see citing works
Self-citationMeasuring cortisol and DHEA in fingernails: A pilot study
Seo (2009) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s8307 · Cited by 80 · see citing works
Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm.
Jovanović, T., Norrholm, S. D., Keyes, M. D., Fiallos, A. M., Jovanovic, S., Myers, K. M., Davis, M., & Duncan, E. (2006) · Behavioral Neuroscience · doi:10.1037/0735-7044.120.5.995 · Cited by 73 · see citing works
Self-citationDorsal anterior cingulate function in posttraumatic stress disorder
Shin, L. M., Bush, G., Whalen, P. J., Handwerger, K., Cannistraro, P. A., Wright, C. I., Martis, B., Macklin, M. L., Lasko, N. B., Orr, S. P., et al. (2007) · Journal of Traumatic Stress · doi:10.1002/jts.20231 · Cited by 72 · see citing works
Posttraumatic stress disorder in rape victims: Autonomic habituation to auditory stimuli
ROTHBAUM, B. O., Kozak, M. J., Foa, E. B., & Whitaker, D. J. (2001) · Journal of Traumatic Stress · doi:10.1023/a:1011160800958 · Cited by 71 · see citing works
Antoniadis, E. A., Winslow, J., Davis, M., & Amaral, D. G. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5643-06.2007 · Cited by 70 · see citing works
Self-citationChudasama, Y., Wright, K. S., & Murray, E. A. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.11.012 · Cited by 65 · cited 1× · see citing works
“First, studies investigating the role of the hippocampus in defensive behaviors have demonstrated that lesions of the hippocampus blunted emotional reactivity in response to threatening stimuli (Chudasama et al., 2008; Machado et al., 2009).”
BackgroundAntoniadis, E. A., Winslow, J., Davis, M., & Amaral, D. G. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.07.007 · Cited by 65 · see citing works
Self-citationNeurophysiological correlates of habituation during exposure in spider phobia.
Veltman, D., Tuinebreijer, W., Winkelman, D. L. B., Lammertsma, A., Witter, M., Dolan, R., & Emmelkamp, P. (2004) · Psychiatry Research · doi:10.1016/j.pscychresns.2004.09.001 · Cited by 61 · see citing works
Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters
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Self-citationContextual fear‐potentiated startle conditioning in humans: Replication and extension
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A prospective assessment of auditory startle alterations in rape and physical assault survivors
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In dubio pro defensio: Initial activation of conditioned fear is not cue specific.
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AX+/BX− discrimination learning in the fear-potentiated startle paradigm in monkeysPreprint
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Self-citationPrevention of Psychiatric Problems among Military Personnel and Their Spouses
Friedman, M. J. (2010) · New England Journal of Medicine · doi:10.1056/nejme0911108 · Cited by 16 · see citing works
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- Pavlov IP Conditioned Reflexes Oxford University Press 1927
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The sleep-deprived human brain
Krause, A. J., Simon, E. B., Mander, B. A., Greer, S. M., Saletin, J. M., Goldstein-Piekarski, A. N., & Walker, M. P. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2017.55 · Cited by 1,200 · see citing works
The role of sleep in emotional brain function
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“…PTSD not only include hyperarousal and an increased startle response, but also a generalization of the fear response to commonly non-threatening stimuli; the former two indicative of heightened sensitivity, the latter of decreased emotional specificity (Jovanovic et al 2012, Jovanovic et al 2009).”
BackgroundInflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond
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Self-citationPrefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety
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“…external cues in the absence of any actual danger, and often include an inability to extinguish learned fear and to show adequate safety learning [(Jovanovic et al., 2012; Michael et al., 2007; Milad et al., 2009; Milad et al., 2013; Wessa & Flor, 2007) reviewed in (Holmes & Singewald, 2013) and…”
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Self-citationOptimizing exposure therapy with an inhibitory retrieval approach and the OptEx Nexus
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Atypical interoception as a common risk factor for psychopathology: A review
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The neurobiological basis of sex differences in learned fear and its inhibition
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Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders
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Resting heart rate variability is associated with inhibition of conditioned fear
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Expanding the canon: An inclusive neurobiology of thalamic and subthalamic fear circuits
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Cognitive inflexibility, obsessive-compulsive symptoms and traits and poor post-pandemic adjustment
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Layer-specific input to medial prefrontal cortex is linked to stress susceptibility
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- Authors
- Jovanovic, T., Kazama, A., Bachevalier, J., & Davis, M.
- Affiliations
- Emory National Primate Research Center (US)
- Emory University (US)
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 62
- Issue
- 2
- Pages
- 695-704
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3146576
- OpenAlex
- W2066642195
- Cited by
- 473
- References
- 121
- Citations by year
- 2026: 14 · 2025: 30 · 2024: 33 · 2023: 32 · 2022: 50 · 2021: 39 · 2020: 47 · 2019: 47 · 2018: 41 · 2017: 28 · 2016: 32 · 2015: 29 · 2014: 24 · 2013: 18 · 2012: 7
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000454)
- National Institute of Mental Health (R01MH058846, MH-086947, R37MH47840, F32MH070129, R37MH047840, R33MH086947, R21MH086947, R21MH092576, MH 58846)
- National Center for Research Resources (UL1RR025008)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD035471, HD35471)
- 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 extinction, fear inhibition, conditional discrimination, fear expression, rhesus monkeys, reverse translation, biomarkers
- MeSH terms
- Association Learning, Conditioning, Psychological, Extinction, Psychological, Fear, Humans, Stress Disorders, Post-Traumatic
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