Erasing fear for an imagined threat event
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, ; F(1,22) = 5.74, p < 0.05, , respectively] as well as salivary alpha amylase [moment × condition, F(1,19) = 5.11, p < 0.05, ] (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.
References (40)
Context, ambiguity, and unlearning: sources of relapse after behavioral extinction
Biol. Psychiatry
(2002)- et al.
Effect of post-retrieval propranolol on psychophysiological responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder
J. Psychiatr. Res.
(2008) - et al.
Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala
Neuroscience
(2004) Reconsolidation: the advantage of being refocused
Curr. Opin. Neurobiol.
(2006)- et al.
Contextual control of human fear associations in a renewal paradigm
Behav. Res. Ther.
(2007) - et al.
Human reconsolidation does not always occur when a memory is retrieved: the relevance of the reminder structure
Neurobiol. Learn. Mem.
(2009) - et al.
The effect of propranolol on anxiety
Lancet
(1966) - et al.
The neuropsychology of fear learning and fear regulation
Int. J. Psychophysiol.
(2005) - et al.
Psychometric description of some specific fear questionnaires
Behav. Ther.
(1974) Reconsolidation: maintaining memory relevance
Trends Neurosci.
(2009)