Neurobehavioral mechanisms of human fear generalization

Center for Cognitive Neuroscience, Duke University, Durham, NC 27708-0999, USA.
NeuroImage (Impact Factor: 6.36). 04/2011; 55(4):1878-88. DOI: 10.1016/j.neuroimage.2011.01.041
Source: PubMed


While much research has elucidated the neurobiology of fear learning, the neural systems supporting the generalization of learned fear are unknown. Using functional magnetic resonance imaging (fMRI), we show that regions involved in the acquisition of fear support the generalization of fear to stimuli that are similar to a learned threat, but vary in fear intensity value. Behaviorally, subjects retrospectively misidentified a learned threat as a more intense stimulus and expressed greater skin conductance responses (SCR) to generalized stimuli of high intensity. Brain activity related to intensity-based fear generalization was observed in the striatum, insula, thalamus/periacqueductal gray, and subgenual cingulate cortex. The psychophysiological expression of generalized fear correlated with amygdala activity, and connectivity between the amygdala and extrastriate visual cortex was correlated with individual differences in trait anxiety. These findings reveal the brain regions and functional networks involved in flexibly responding to stimuli that resemble a learned threat. These regions may comprise an intensity-based fear generalization circuit that underlies retrospective biases in threat value estimation and overgeneralization of fear in anxiety disorders.

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Available from: Steve E Prince, Oct 06, 2015
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    • "If one interprets the vmPFC as reflecting a relative 'safety signaling' mechanism that supports extinction recall, then the results are consistent across the majority of studies. Other studies have found greater vmPFC activity to the CS− relative to the CS+ during acquisition, extinction , and/or generalization testing (e.g., Phelps et al., 2004; Schiller et al., 2008; Dunsmoor et al., 2011; Apergis-Schoute et al., 2014; Dunsmoor et al., 2014b; Lissek et al., 2014; Icenhour et al., 2015), and Schiller et al. (2008) reported that the vmPFC activation patterns to a CS+ and CS− flip during reversal learning. Theoretically, safety signaling can support extinction recall by modifying the CS −/US, CS −/ context, or CS−/CS+ associations, which, in turn, can affect the CS+/ US and CS+/context associations. "
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    ABSTRACT: The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 07/2015; 122. DOI:10.1016/j.neuroimage.2015.07.051 · 6.36 Impact Factor
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    • "For example, using functional magnetic resonance imaging (fMRI) and skin conductance response measures, Dunsmoor et al. (2011) generated a generalization gradient along a continuum of fearful-to-neutral faces. In that study, generalization of fear responses occurred in the presence of faces one unit of differentiation removed from the previously reinforced CS+ and this heightened fear response was correlated with neural activity in the amygdala, striatum, insula, thalamus, and periaqueductal gray (Dunsmoor et al., 2011); brain regions that are critical for the expression of learned fear as well as for adaptation to changes in CS-US contingencies (LeDoux et al., 1988; LeDoux, 1996; Berns et al., 2006; Dunsmoor et al., 2007; Delgado et al., 2008; Schiller and Delgado, 2010). In another similar set of experiments using faces as conditioned stimuli, Glenn and colleagues developed a paradigm that gradually morphed one individual into a different individual, both of which had an emotionally neutral expression (Glenn et al., 2012). "
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    ABSTRACT: Intense fear responses observed in trauma-, stressor-, and anxiety-related disorders can be elicited by a wide range of stimuli similar to those that were present during the traumatic event. The present study investigated the experimental utility of fear-potentiated startle paradigms to study this phenomenon, known as stimulus generalization, in healthy volunteers. Fear-potentiated startle refers to a relative increase in the acoustic startle response to a previously neutral stimulus that has been paired with an aversive stimulus. Specifically, in Experiment 1 an auditory pure tone (500 Hz) was used as the conditioned stimulus (CS+) and was reinforced with an unconditioned stimulus (US), an airblast to the larynx. A distinct tone (4000 Hz) was used as the nonreinforced stimulus (CS-) and was never paired with an airblast. Twenty-four hours later subjects underwent Re-training followed by a Generalization test, during which subjects were exposed to a range of generalization stimuli (GS) (250, 1000, 2000, 4000, 8000 Hz). In order to further examine the point at which fear no longer generalizes, a follow-up experiment (Experiment 2) was performed where a 4000 Hz pure tone was used as the CS+, and during the Generalization test, 2000 and 8000 Hz were used as GS. In both Experiment 1 and 2 there was significant discrimination in US expectancy responses on all stimuli during the Generalization Test, indicating the stimuli were perceptually distinct. In Experiment 1, participants showed similar levels of fear-potentiated startle to the GS that were adjacent to the CS+, and discriminated between stimuli that were 2 or more degrees from the CS+. Experiment 2 demonstrated no fear-potentiated startle generalization. The current study is the first to use auditory cues to test generalization of conditioned fear responses; such cues may be especially relevant to combat posttraumatic stress disorder (PTSD) where much of the traumatic exposure may involve sounds.
    Frontiers in Behavioral Neuroscience 10/2014; 8:361. DOI:10.3389/fnbeh.2014.00361 · 3.27 Impact Factor
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    • "Consistent with the work conducted in rodents, functional imaging studies of fear generalization in humans using Pavlovian conditioning procedures have found that the medial prefrontal cortex (Dunsmoor et al., 2011; Greenberg et al., 2013a; Lissek et al., 2013a; Cha et al., 2014b) and hippocampus (Lissek et al., 2013a) show response gradients that are consistent with a fear generalization phenomenon. Similar gradients have also been detected in the responses of regions known to be important in salience detection and fear production, such as the insula (Dunsmoor et al., 2011; Greenberg et al., 2013a; Lissek et al., 2013a), striatum (Dunsmoor et al., 2011; Greenberg et al., 2013a) and ventral tegmental area (Cha et al., 2014a). "
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    ABSTRACT: Fear generalization is the production of fear responses to a stimulus that is similar – but not identical - to a threatening stimulus. Although prior studies have found that fear generalization magnitudes are qualitatively related to the degree of perceptual similarity to the threatening stimulus, the precise relationship between these two functions has not been measured systematically. Also, it remains unknown whether fear generalization mechanisms differ for social and non-social information. To examine these questions, we measured perceptual discrimination and fear generalization in the same subjects, using images of human faces and non-face control stimuli (“blobs”) that were perceptually matched to the faces. First, each subject’s ability to discriminate between pairs of faces or blobs was measured. Each subject then underwent a Pavlovian fear conditioning procedure, in which each of the paired stimuli were either followed (CS+) or not followed (CS-) by a shock. Skin conductance responses (SCRs) were also measured. Subjects were then presented with the CS+, CS- and five levels of a CS+-to-CS- morph continuum between the paired stimuli, based on individual discrimination thresholds. Finally, subjects rated the likelihood that each stimulus had been followed by a shock. Subjects showed both autonomic (SCR-based) and conscious (ratings-based) fear responses to morphs that they could not discriminate from the CS+ (generalization). For both faces and non-face objects, fear generalization was not found above discrimination thresholds. However, subjects exhibited greater fear generalization in the shock likelihood ratings compared to the SCRs, particularly for faces. These findings reveal that autonomic threat detection mechanisms in humans are highly sensitive to small perceptual differences between stimuli. Also, the conscious evaluation of threat shows broader generalization than autonomic responses, biased towards labeling a stimulus as threatening.
    Frontiers in Human Neuroscience 09/2014; 8:624. DOI:10.3389/fnhum.2014.00624 · 2.99 Impact Factor
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