Elsevier

Psychoneuroendocrinology

Volume 37, Issue 11, November 2012, Pages 1769-1779
Psychoneuroendocrinology

Erasing fear for an imagined threat event

https://doi.org/10.1016/j.psyneuen.2012.03.011Get rights and content

Summary

Although memory for emotionally arousing and stressful experiences is strong and resistant to change, recent years have witnessed rapidly emerging evidence for the plasticity of fear memories. Upon retrieval a memory may be rendered labile and vulnerable to the disruptive effects of amnestic agents. This process is referred to as “disrupting reconsolidation” and may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However, the fear-reducing effects are thus far only demonstrated for freezing reactions in rodents and autonomic fear responding in humans. If disrupting reconsolidation will be of value for clinical practice, it should also target the subjective feelings of anxiety. Using an instructed fear-learning paradigm in humans, we here tested whether disrupting reconsolidation would diminish the subjective feelings of anxiety for a noxious event that was anticipated but never actually experienced. Beta-adrenergic receptor blockade during reconsolidation strongly diminished the behavioral expression of the instructed fear memory (i.e., startle responding) as well as the subjective feelings of anxiety 24 h later, yet without affecting both the physiological and cognitive component of the anticipation of threat (i.e., skin conductance responding, expectancy ratings). Together, the present findings suggest that the various memory traces of a learned fear association do not necessarily undergo reconsolidation in harmony. Considering that patients with anxiety disorders (1) often fear objects and situations that they have never actually experienced, and (2) primarily suffer from the subjective feelings of anxiety, the present findings may have important ramifications for psychotherapy.

Introduction

Recent insights into the neurobiological underpinnings of fear memory suggest novel strategies to improve therapeutic interventions for anxiety disorders (Nader, 2003). Specifically, a substantial body of animal and human research now indicates that a permanent reduction of fear may be realized through targeting the process of “reconsolidation” (Nader et al., 2000, Kindt et al., 2009). This protein-synthesis dependent restabilization of a memory upon retrieval enables the modification of the original fear memory representation through either pharmacological (Nader et al., 2000, Kindt et al., 2009) or behavioral manipulations (Monfils et al., 2009, Schiller et al., 2010). Even though disrupting reconsolidation may thus point to a promising therapeutic tool providing long-term cure for patients suffering from anxiety disorders, the fear reducing effects are thus far only demonstrated for the behavioral expression of fear memories (e.g., freezing in rodents or autonomic fear responding in humans) (Nader et al., 2000, Brunet et al., 2008, Kindt et al., 2009, Monfils et al., 2009, Schiller et al., 2010, Soeter and Kindt, 2010, Soeter and Kindt, 2011a, Soeter and Kindt, 2011b). For the feasibility of reconsolidation in psychotherapy, disrupting reconsolidation should also diminish the subjective feelings of anxiety.

The phenomenon of “fear” memory reconsolidation is traditionally investigated for a learned association between a visual or auditory stimulus (i.e., conditioned stimulus, CS) (e.g., pictures, tones) and a noxious event (i.e., unconditioned stimulus, US) (e.g., electric stimulus). Pavlovian fear conditioning is in fact a valuable experimental model to test novel procedures for diminishing acquired fears and anxiety. Using such a differential fear conditioning paradigm in humans, we previously demonstrated that disrupting reconsolidation specifically targeted the startle fear responding without affecting the subjective feelings of distress (Soeter and Kindt, 2011a). This finding that memories may undergo reconsolidation at one level, while leaving other aspects of the fear memory untouched, may be interpreted from a functional perspective on reconsolidation (Lee, 2009). That is, reconsolidation may be viewed as a fundamental process in the ongoing modification and storage of memories, which seems potentially adaptive in terms of maintaining a memory's relevance in guiding future behavior (Dudai, 2006, Dudai, 2009, Lee, 2009). Indeed, labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned (i.e., informational value) during memory retrieval (Pedreira et al., 2004, Forcato et al., 2009, Lee, 2009). A violation based upon prior learning is supposed to be a necessary condition for reconsolidation, meaning that the magnitude of the outcome or the outcome itself in not being fully predicted (i.e., prediction error) (Pedreira et al., 2004, Forcato et al., 2009, Lee, 2009). Traditional human fear conditioning paradigms seem not to be suitable for targeting the subjective component of fear memory given that the repeated pairing of the CS with the “experience” of a relatively mild noxious event (e.g., electric stimulus) makes the aversiveness of the outcome very “predictable” (Lee, 2009, Soeter and Kindt, 2011a). In general, humans tend to fear objects and situations that either were so aversive that they fear a re-exposure or that they have never really experienced (Rachman, 1977). We hypothesized that disrupting reconsolidation may target the subjective feelings of anxiety when participants fear something that they never actually experienced.

Here, we addressed this issue by using an instructed fear learning paradigm in which the aversiveness of the US is imagined and thereby “unpredictable” as the US is anticipated but never really felt. Testing included different phases across three consecutive days each separated by 24 h. Prior to fear acquisition (day1), the participants were instructed which out of two fear-relevant stimuli (CS1) would at times be followed by a very unpleasant electric stimulus (US) delivered to the wrist of the unpreferred hand. The US was never administered. After the reactivation of the CS1 stimulus (day2), the participants received double blind an oral dose of placebo pill or 40 mg of propranolol HCl, a β-adrenergic receptor antagonist known to disrupt reconsolidation (Dębiec and LeDoux, 2004, Kindt et al., 2009, Soeter and Kindt, 2010, Soeter and Kindt, 2011a, Soeter and Kindt, 2011b). The retention of the memory (CS1 vs. CS2) was tested 24 h later (day3). Given that a context switch offers a potent means to trigger the original fear memory (Bouton, 2002), we presented renewal stimuli (CS1R, CS2R) to assess the generalization of fear reduction across contexts. The fear response was measured as potentiation of the eyeblink startle reflex to a loud noise by electromyography of the right orbicularis oculi muscle. Startle potentiation is considered a reliable and specific index of fear (Hamm and Weike, 2005), which is directly connected with and modulated by the amygdala (Davis, 2006). The subjective feelings of distress (i.e., anxiety, tension or nervousness) were measured through online ratings during each stimulus presentation. We further obtained skin conductance responding and retrospective US expectancy ratings to assess the physiological and subjective level of threat anticipation, respectively (Weike et al., 2007). Salivary alpha amylase and blood pressure levels were determined to ensure the drug manipulation exerted its intended physiological effect (Stegeren et al., 2006). We hypothesized that targeting the reconsolidation of the instructed fear memory would allow for the updating and hence weakening of the behavioral expression of fear (i.e., startle fear responding) as well as the subjective feelings of anxiety. In line with our previous findings (Kindt et al., 2009, Soeter and Kindt, 2010, Soeter and Kindt, 2011a, Soeter and Kindt, 2011b), we did – on the other hand – not expect any effects of the propranolol HCl manipulation on skin conductance discrimination and the US expectancy ratings given that the instructed fear learning paradigm would prevent any learning about the “contingency” at the time of memory retrieval.

Section snippets

Participants

Twenty-four1 undergraduate students (3 men, 21 women) from the University of Amsterdam ranging in the age of 18–30 years (mean ± SD age, 20.9 ± 3.5 years) participated in the study. All participants were assessed to be free from any current or previous medical or psychiatric condition that would contraindicate taking a single 40 mg dose of propranolol HCl

Manipulation check propranolol HCl

Analysis of the effect of the propranolol HCl manipulation on blood pressure and sAA level during memory reactivation (i.e., day 2) revealed the expected decrease in both systolic and diastolic blood pressure [moment × condition, F(1,22) = 38.76, p < 0.001, ηp2=.64; F(1,22) = 5.74, p < 0.05, ηp2=.21, respectively] as well as salivary alpha amylase [moment × condition, F(1,19) = 5.11, p < 0.05, ηp2=.21] (Stegeren et al., 2006) in comparison to placebo pill, indicating that the drug manipulation exerted its

Discussion

Here, we demonstrate that β-adrenergic receptor blockade during reconsolidation strongly attenuated the behavioral expression of the instructed fear memory (i.e., startle fear responding) as well as the subjective feelings of anxiety. The propranolol HCl drug seemed to be highly effective in weakening the fearful aspects of the memory 24 h later as one of the hallmark recovery phenomena (i.e., renewal testing) failed to uncover any fear responding (i.e., startle fear responding, subjective

Role of funding source

This work was supported by a Vici grant (Merel Kindt) from the Netherlands Organization for Scientific Research.

Conflict of interest

Both authors declare that they do not have any conflicts of interest.

Acknowledgments

The authors thank B. Molenkamp for technical assistance.

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