Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress

Abstract

The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by an unusual degree of coordination between rodent and human researchers examining fear extinction. This successful research program could serve as a model for translational research in other areas of behavioral neuroscience. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction.

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

“…In addition to the engagement of the amygdala, functional magnetic resonance imaging (fMRI) studies of fear conditioning commonly report CS-evoked increases in blood oxygen level-dependent (BOLD) activation in the dorsal anterior cingulate cortex (dACC). CS-evoked BOLD activation as well as cortical thickness in this region correlates positively with the magnitude of conditioned fear expression, motivating the suggestion that this region may be a human homologue of the rodent PL (Hartley and Phelps, 2013;Milad et al, 2007a;Milad and Quirk, 2012). Human imaging studies that dissociate neural responses to conditioned cues and contexts corroborate the involvement of the hippocampus in contextual fear learning (Alvarez et al, 2008;Marschner et al, 2008).…”

“…Both the magnitude of vmPFC BOLD signal as well as the thickness of the cortex in this region have been found to correlate with the degree of extinction retrieval (Hartley et al, 2011;Milad et al, 2005;Milad et al, 2007b). On the basis of these findings, the subgenual vmPFC region has been proposed to be a potential human homologue of the rodent IL region (Hartley and Phelps, 2013;Milad et al, 2007a;Milad and Quirk, 2012), and may diminish fear expression via its projections to the amygdala. Context-dependent retrieval of extinction is associated with increased BOLD activation in the hippocampus (Kalisch et al, 2006;Milad et al, 2007b), and hippocampal lesions impair context-dependent fear reinstatement (LaBar and Phelps, 2005), a finding that parallels observations in rodents (Wilson et al, 1995).…”

Prepared stimuli enhance aversive learning without weakening the impact of verbal instructions

“…Work in nonhuman primates suggests that innate responses to fear-relevant stimuli are mediated by the amygdala and orbitofrontal cortex (Meunier et al 1999;Kalin et al 2001;Murray and Izquierdo 2007). These structures play crucial roles in fear acquisition (Davis 1992; Maren 2001), extinction (Schiller andDelgado 2010;Milad and Quirk 2012), and value-based learning (Schoenbaum et al 1998;Holland and Gallagher 2004), and thus their preferential recruitment by prepared stimuli might enhance dynamic aversive learning.Second, a distinct literature indicates that fear-relevant stimuli may be less responsive to instructions about safety. Studies of instructed extinction (Hugdahl and Ohman 1977;Hugdahl 1978) indicate that when individuals are informed that shocks will no longer be delivered following standard Pavlovian conditioning, conditioned responses are abolished immediately in people exposed to neutral stimuli, whereas conditioned responses remain elevated in those conditioned with biologically prepared stimuli.…”

Reductions in Children’s Vicariously Learnt Avoidance and Heart Rate Responses Using Positive Modeling

“…Extinction is a well-established behavioral phenomenon in which repeated exposure to a CS alone, in the absence of its associated aversive US, leads to the gradual diminishing of the previously established fear CR (e.g., Bouton, 2004;Craske et al, 2008;Milad & Quirk, 2012;Myers & Davis, 2007). For example, following the contiguous presentation of a tone (CS) and shock (US), the tone will come to evoke a fear response (CR) in the absence of the shock.…”