Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

Ra, Morey; Je, Dunsmoor; Haswell, CC; Brown, Vanessa M.; Vora, A; Weiner, Jonathan Z; Stjepanović, Daniel; Wagner, H. Ryan; Workgroup, VA Mid-Atlantic Mirecc; LaBar, KS

doi:10.1038/tp.2015.196

Cited by 184 publications

(138 citation statements)

References 65 publications

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“…In a similar way, the mere instruction that a stimulus will be paired with shock is enough to induce increases in sympathetic arousal and amygdala activity (Olsson & Phelps, 2007). This explanation is also in line with clinical literature showing that the subjective perception of the level of harm posed by a threat mediates the development of PTSD (King, King, Vogt, Knight, & Samper, 2006; Rubin, Berntsen, & Bohni, 2008; Solomon, Mikulincer, & Benbenishty, 1989; van Wingen, Geuze, Vermetten, & Fernández, 2011), and drives emotion-related brain activations in PTSD (Morey et al, 2015; van Wingen et al, 2011) more than the actual level of harm.…”

Section: Discussionsupporting

confidence: 88%

Threat intensity widens fear generalization gradients.

Dunsmoor

Kroes

Braren

et al. 2017

Behavioral Neuroscience

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Research in non-human animals reveals threat-sensitive generalization of defensive behavior that favors widespread generalization when threat intensity is high and limited generalization (i.e., specificity) when threat intensity is low. Here, we used Pavlovian fear-conditioning to systematically investigate whether threat intensity widens behavioral generalization gradients to stimuli that decreasingly resemble a learned threat cue. Using a between-subjects design, volunteers underwent fear-conditioning with a tone paired with either a high-intensity or low-intensity aversive stimulus prior to a test of fear-generalization to novel tones. Results showed no effect of threat intensity on initial acquisition of conditioned fear. However, volunteers who underwent fear-conditioning with a high-intensity aversive stimulus exhibited widespread generalization of autonomic arousal (skin conductance responses) as compared to volunteers who received a low-intensity aversive stimulus. These results show a transition from normal (selective) to overgeneralized fear as threat intensity increases, and have implications for understanding overgeneralization characteristic of trauma- and stress-related disorders.

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Section: Discussionsupporting

confidence: 88%

Threat intensity widens fear generalization gradients.

Dunsmoor

Kroes

Braren

et al. 2017

Behavioral Neuroscience

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“…In humans, a single episode of acute stress can impair retrieval of cued threat extinction after a delay (14), consistent with studies of patients with PTSD showing deficits in the ability to retain extinction memories following standard extinction procedures (15). Notably, PTSD is also characterized by difficulty discriminating between a dangerous CS and a safe CS (16,17) and overgeneralization of amygdala activity to a variety of cues that resemble a learned threat (18). Whether a single episode of acute stress affects the ability to behaviorally discriminate between threat cues and similar, but harmless cues-thereby leading to overgeneralization-has to our knowledge remained unexplored in humans and in other species (see ref.…”

supporting

confidence: 71%

Stress promotes generalization of older but not recent threat memories

Dunsmoor

Otto

Phelps

2017

Proc. Natl. Acad. Sci. U.S.A.

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Stress broadly affects the ability to regulate emotions and may contribute to generalization of threat-related behaviors to harmless stimuli. Behavioral generalization also tends to increase over time as memory precision for recent events gives way to more gist-like representations. Thus, acute stress coupled with a delay in time from a negative experience may be a strong predictor of the transition from normal to generalized fear expression. Here, we investigated the effect of a single-episode acute stressor on generalization of aversive learning when stress is administered either immediately after an aversive learning event or following a delay. In a betweensubjects design, healthy adult volunteers underwent threat (fear) conditioning using a tone-conditioned stimulus paired with an electric shock to the wrist and another tone not paired with shock. Behavioral generalization was tested to a range of novel tones either on the same day (experiment 1) or 24 h later (experiment 2) and was preceded by either an acute stress induction or a control task. Anticipatory sympathetic arousal [i.e., skin conductance responses (SCRs)] and explicit measures of shock expectancy served as dependent measures. Stress administered shortly after threat conditioning did not affect behavioral generalization. In contrast, stress administered following a delay led to heightened arousal and increased generalization of SCRs and explicit measures of shock expectancy. These findings show that acute stress increases generalization of older but not recent threat memories and have clinical relevance to understanding overgeneralization characteristics of anxiety and stress-related disorders.stress | Pavlovian conditioning | associative learning | generalization | memory A number of anxiety and stress-related disorders can be characterized by an inability to discriminate threat from safety. For instance, a core symptom of trauma-and stressrelated disorders [e.g., posttraumatic stress disorder (PTSD)] is persistent and widespread fear and avoidance of myriad harmless cues that act as reminders of the trauma, often referred to as overgeneralization (1). A key component of overgeneralization in anxiety and stress-related disorders may hinge on stress-induced changes in neural circuitry underlying the ability to discriminate threat from safety and regulate emotional responses (2-4). Behavioral generalization also tends to increase over time, as memory precision for recent events gives way to more gist-like representations (5, 6). It then follows that stress-induced impairments in discriminating threat from safety coupled with a loss of memory precision might jointly influence the transition away from normal fear (i.e., highly specific to a known threat) toward overgeneralized fear. Here, we investigate how acute stress and the time between learning and test impacts fear generalization in humans.The effects of stress on the ability to regulate defensive behaviors have been detailed using Pavlovian threat (fear) conditioning tasks in humans and labo...

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“…Given that vmPFC-mediated inhibition of the amygdala is thought to be necessary for fear extinction 31 , these changes could offer a mechanistic basis for the decrements in extinction retention observed in PTSD subjects. There is also some evidence to support the idea that patients with PTSD might exhibit an increased capacity for fear conditioning itself 44 or a greater propensity for increased fear generalization 45–47 ; however, there have been no longitudinal studies of these traits in patients at risk of developing PTSD, making it unclear whether these characteristics are a cause or an effect of developing PTSD.…”

Section: Intrusion Symptomsmentioning

confidence: 99%

Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

et al. 2018

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Post-traumatic stress disorder (PTSD) is a prevalent, debilitating and sometimes deadly consequence of exposure to severe psychological trauma. Although effective treatments exist for some individuals, they are limited. New approaches to intervention, treatment and prevention are therefore much needed. In the past few years, the field has rapidly developed a greater understanding of the dysfunctional brain circuits underlying PTSD, a shift in understanding that has been made possible by technological revolutions that have allowed the observation and perturbation of the macrocircuits and microcircuits thought to underlie PTSD-related symptoms. These advances have allowed us to gain a more translational knowledge of PTSD, have provided further insights into the mechanisms of risk and resilience and offer promising avenues for therapeutic discovery.

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Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

Cited by 184 publications

References 65 publications

Threat intensity widens fear generalization gradients.

Threat intensity widens fear generalization gradients.

Stress promotes generalization of older but not recent threat memories

Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

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