Review
Nature and causes of the immediate extinction deficit: A brief review

https://doi.org/10.1016/j.nlm.2013.10.012Get rights and content

Highlights

  • The timing of extinction after conditioning determines the magnitude and longevity of response loss.

  • Delivering extinction trials minutes to hours after conditioning often leads to an ‘immediate extinction deficit’.

  • The ‘immediate extinction deficit’ may be mediated by stress-induced impairments in medial prefrontal cortical function.

Abstract

Recent data in both rodents and humans suggests that the timing of extinction trials after conditioning influences the magnitude and duration of extinction. For example, administering extinction trials soon after Pavlovian fear conditioning in rats, mice, and humans results in minimal fear suppression – the so-called immediate extinction deficit. Here I review recent work examining the behavioral and neural substrates of the immediate extinction deficit. I suggest that extinction is most effective at some delay after conditioning, because brain systems involved in encoding and retrieving extinction memories function sub-optimally under stress.

Introduction

Behavioral interventions for pathological fear often involve exposure therapy in which cues or reminders of trauma-related events are used to evoke fear memories in a safe and controlled setting. It is widely believed that exposure therapy relies, at least in part, on extinction learning (Bouton et al., 2001, Craske et al., 2008, Rothbaum and Davis, 2003). In this form of learning, subjects learn that once fearful cues no longer predict an aversive consequence. Extinction procedures do not erase fear memories, but result in new inhibitory associations between the now safe cue and its formerly aversive outcome (Bouton, 1993). The inhibitory associations acquired during exposure therapy lead to a reduction of fear and have considerable therapeutic benefits. Not surprisingly, extinction learning has become an important translational model for developing behavioral interventions for fear and anxiety disorders (Milad & Quirk, 2012).

Curiously, recent data in both rodents and humans suggests that the timing of extinction relative to fear conditioning influences the magnitude of fear reduction after extinction (Golkar and Öhman, 2012, Huff et al., 2009, Maren and Chang, 2006, Myers et al., 2006, Norrholm et al., 2008). In many cases, administering extinction trials soon after fear conditioning results in no long-term fear suppression at all – the so-called immediate extinction deficit (Chang et al., 2010, Chang and Maren, 2009, Chang and Maren, 2011, Kim et al., 2010, MacPherson et al., 2013, Maren and Chang, 2006). Interestingly, the administration of extinction trials soon after fear conditioning often produces within-session decrements in fear, but this is not maintained over long retention intervals resulting in the spontaneous recovery of fear. The clinical implications of this finding are clear: widely practiced early interventions after psychological trauma may be ineffective in producing long-term fear reduction. Indeed, a review of several studies of early intervention after trauma finds that they are largely ineffective at reducing post-traumatic stress and other anxiety disorders (Bryant, 2002, McNally et al., 2003). Because of the difficult clinical problem of fear relapse after behavioral therapies, the last several years have witnessed a swell of interest in understanding the factors, including the acquisition–extinction interval, that regulate the recovery of fear after extinction (Maren, 2011).

Here I review recent work in rodents and humans examining the influence of the timing of extinction relative to conditioning on the subsequent suppression of fear. In many cases, delivering extinction trials soon after conditioning produces weak long-term extinction, which, in the case of fear conditioning, is associated with a rapid return of fear responses. I suggest that extinction is most effective at some delay after conditioning, because the severe stress that accompanies trauma engages brain systems involved in acquiring fear memories, and these systems in turn inhibit those involved in fear extinction.

Section snippets

Nature of the immediate extinction deficit

In an extinction procedure, subjects receive non-reinforced presentations of a conditioned stimulus (CS), which ultimately yield suppression of the conditional response (CR). The loss of conditional responding that occurs after extinction is both temporary and context-dependent (Bouton, 1993, Delamater, 2004). That is, extinguished CRs return with the passage of time (i.e., spontaneous recovery) and with changes in context (i.e., renewal). Clearly, spontaneous recovery indicates that the

Causes of the immediate extinction deficit

Two general classes of explanations have been offered to account for the spontaneous recovery of conditional responding after immediate extinction (Maren & Chang, 2006). Importantly, these explanations are not mutually exclusive. One class of explanation appeals to the interference of acquisition and extinction memories during memory retrieval at the time of retention testing. The notion that the resolution of interference between competing memories has had considerable success in accounting

Neural mechanisms underlying the immediate extinction deficit

Neurobiological investigation of the immediate extinction deficit has focused on the medial prefrontal cortex (mPFC) given its prominent role in the encoding and retrieval of extinction memories (Herry et al., 2010, Milad and Quirk, 2012, Orsini and Maren, 2012, Quirk and Mueller, 2008). The initial studies to investigate the phenomenon used Fos immunohistochemistry (Kim et al., 2010) and single-unit recording methods (Chang et al., 2010) to examine neuronal activity in the mPFC after immediate

Conclusions

A considerable body of evidence now suggests that the timing of extinction after conditioning influences the durability of extinction memory. Short intervals between fear conditioning and extinction result in the spontaneous recovery of fear within 24 h after extinction. Although the precise mechanisms underlying this effect are under active investigation, mounting evidence suggests that the arousal of fear before extinction may interfere with the brain systems involved in encoding and

Acknowledgment

Supported by the National Institutes of Health (R01MH065961).

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