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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    • "Excitatory activation gradients – peaking at the CS+ with a decline as dissimilarity from the CS increases ‐ have been observed within the insula, thalamus, cingulate cortex and striatum (Dunsmoor et al., 2011), dorsomedial prefrontal cortex (Lissek et al., 2014a), supplementary motor area, the caudate nucleus (Greenberg et al., 2013a) and the ventral tegmental area (Cha et al., 2014). The opposite, an inhibitory gradient peaking at the CS‐ has been found in the vmPFC (Dunsmoor et al., 2011; A c c e p t e d M a n u s c r i p t 5 | D i e t e r S t r u y f experimental and clinical work, generalization has attained a central role in contemporary anxiety theories, as it is considered a key pathogenic mechanism in the etiology of anxiety disorders (Kindt, 2014; Lissek and Grillon, 2010). For example, overgeneralization of fear responses has been associated with both panic disorder as well as generalized anxiety disorder (GAD) (Lissek et al., 2014b, 2010). "
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    • "Conversely, activation of dACC appears involved in the acquisition of threat-related learning [Phelps et al., 2004] and anxiety [Kim et al., 2011; Milad et al., 2009]. In addition to connections between amygdala and prefrontal cortex, research has found that enhanced functional connectivity between amygdala and perceptual regions during feargeneralization is positively correlated with trait anxiety [Dunsmoor et al., 2011]. One possibility is that high trait anxiety is associated with enhanced structural connectivity between amygdala and regions involved in perceptual and semantic processing. "
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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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