Human fear conditioning: From neuroscience to the clinic.

Both clinicians and neuroscientists have been long interested in the topic of fear conditioning, with recent advances in neuroscience, in particular, igniting a shared interest in further translation between these domains. Here, we review some historical aspects of this relationship and the progress that has been made in translating the neuroscientific study of fear conditioning to the conceptualization and treatment of mental disorders, especially anxiety-related disorders. We also address some conceptual and methodological challenges faced by this research, and offer some suggestions to support future progress in the field.

Common and distinct neural correlates of fear extinction and cognitive reappraisal: A meta-analysis of fMRI studies.

Cognitive reappraisal and fear extinction learning represent two different approaches to emotion regulation. While their respective neural correlates have been widely studied with functional magnetic resonance imaging (fMRI), few direct comparisons between these processes have been conducted. We conducted a meta-analysis of fMRI studies of reappraisal and fear extinction, with the aim of examining both commonalities and differences in their neural correlates. We also conducted independent analyses that focused on specific reappraisal strategies (reinterpretation, distancing). Overall, we observed that the dorsal anterior cingulate cortex (dACC) and the bilateral anterior insular cortex (AIC) were similarly consistently engaged by reappraisal and extinction. Extinction was more consistently linked to activation of sensory and emotion processing regions, whereas reappraisal was more consistently associated with activation of a dorsal fronto-parietal network. Interestingly, the amygdala was preferentially deactivated by distancing. These results suggest that the dACC and the AIC are involved in domain-general regulatory networks. Differences between extinction and reappraisal could be explained by their relative processing demands on visual perceptual versus higher cognitive neural systems.

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

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.