Adversity-induced relapse of fear: neural mechanisms and implications for relapse prevention from a study on experimentally induced return-of-fear following fear conditioning and extinction.

T B Lonsdorf,M Menz,R Scharfenort

doi:10.1038/tp.2016.126

T B Lonsdorf, M Menz + Show 1 more

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https://doi.org/10.1038/tp.2016.126

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Abstract

The efficacy of current treatments for anxiety disorders is limited by high relapse rates. Relapse of anxiety disorders and addiction can be triggered by exposure to life adversity, but the underlying mechanisms remain unexplored. Seventy-six healthy adults were a priori selected for the presence or absence of adverse experiences during childhood (CA) and recent past (RA; that is, past 12 months). Participants underwent fear conditioning (day 1) and fear extinction and experimental return-of-fear (ROF) induction through reinstatement (a model for adversity-induced relapse; day 2). Ratings, autonomic (skin conductance response) and neuronal activation measures (functional magnetic resonance imaging (fMRI)) were acquired. Individuals exposed to RA showed a generalized (that is, not CS− specific) fear recall and ROF, whereas unexposed individuals showed differential (that is, CS+ specific) fear recall and ROF on an autonomic level despite no group differences during fear acquisition and extinction learning. These group differences in ROF were accompanied by corresponding activation differences in brain areas known to be involved in fear processing and differentiability/generalization of ROF (that is, hippocampus). In addition, dimensional measures of RA, CA and lifetime adversity were negatively correlated with differential skin conductance responses (SCRs) during ROF and hippocampal activation. As discriminating signals of danger and safety, as well as a tendency for overgeneralization, are core features in clinically anxious populations, these deficits may specifically contribute to relapse risk following exposure to adversity, in particular to recent adversity. Hence, our results may provide first and novel insights into the possible mechanisms mediating enhanced relapse risk following exposure to (recent) adversity, which may guide the development of effective pre- and intervention programs.

Highlights

Anxiety- and stress-related disorders are highly prevalent and tend to be persistent.[1]
Consent to the protocol approved by the local ethics committee Contrasts of interest (CS+4CS − ; conditioned stimulus (CS)+o CS − ) were estimated on the first (Ärztekammer Hamburg (General Medical Council Hamburg)) and the level and taken to the second-level analyses employing two-sample t-tests study was conducted in accordance with the Declaration of Helsinki
Significant group differences in CS discrimination total, 84 participants were recruited from a large pool of 392 participants. (CS+4CS − ) at a neural level were further tested by separate analyses for

Summary

Introduction

Anxiety- and stress-related disorders are highly prevalent and tend to be persistent.[1]. Relapse can be experimentally modeled in classical conditioning paradigms through the induction of return-of-fear (ROF) following successful extinction training in both animals and humans.[9,10] Thereby, during differential conditioning, one of two neural cues (the CS+) reliably predicts an aversive event (unconditioned stimulus, US), whereas a second one (CS − ) does not. During extinction, both the CS+ and the CS − are presented without the US, leading to a waning of the acquired fear response. Thereby, RI-induced ROF (for a review in humans[13] in animals11) serves as an experimental model of adversity-induced relapse of fear in which an adverse laboratory event induces ROF

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