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An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent
Abstract
Although disrupting the process of memory reconsolidation has a great potential for clinical practice, the fear-amnesic effects are typically demonstrated through Pavlovian conditioning. Given that older and stronger memories are generally more resistant to change, we tested whether disrupting reconsolidation would also diminish fear in individuals who had developed a persistent spider fear outside the laboratory.
Spider-fearful participants received a single dose of 40 mg of the noradrenergic β-blocker propranolol (n = 15), double-blind and placebo-controlled (n = 15), after a short 2-min exposure to a tarantula. To test whether memory reactivation was necessary to observe a fear-reducing effect, one additional group of spider-fearful participants (n = 15) received a single dose of 40 mg propranolol without memory reactivation.
Disrupting reconsolidation of fear memory transformed avoidance behavior into approach behavior in a virtual binary fashion-an effect that persisted at least 1 year after treatment. Interestingly the β-adrenergic drug did initially not affect the self-declared fear of spiders but instead these reports followed the instant behavioral transformation several months later.
Our findings are in sharp contrast with the currently pharmacological and cognitive behavioral treatments for anxiety and related disorders. The β-adrenergic blocker was only effective when the drug was administered upon memory reactivation, and a modification in cognitive representations was not necessary to observe a change in fear behavior. A new wave of treatments that pharmacologically target the synaptic plasticity underlying learning and memory seems to be within reach.
Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
... This can potentially lead to relapse. Memory reconsolidation interventions are an exciting alternative to exposure therapy because they are assumed to directly modify the affective value of a fear memory and could thereby prevent relapse [7][8][9][10]. Yet, results regarding the translational value of reconsolidation interventions in (sub-)clinical phobias are mixed [7,[11][12][13]. ...
... Yet, results regarding the translational value of reconsolidation interventions in (sub-)clinical phobias are mixed [7,[11][12][13]. We aimed to better understand the mechanism of change in reconsolidation interventions by shedding light on the dissociation between the different aspects of fear memory expression that was previously observed after reconsolidation interference [8,9,14]. ...
... This process, referred to as reconsolidation interference, is thought to directly weaken the (affective value of the) fear memory [10,19]. As a result, there is an abrupt change in the defensive response (e.g., avoidance behaviour) when confronted with the feared situation after a night of sleep [9,10,20]. In contrast, a gradual decline of avoidance behaviour is typically observed over the course of multiple exposure therapy sessions [1,21], after maladaptive thoughts and threat expectations have been challenged [22,23]. ...
Memory reconsolidation interventions offer an exciting alternative to exposure treatment because they may target fear memories directly, thereby preventing relapse. A previous reconsolidation intervention for spider fear abruptly reduced avoidance behaviour, whereas changes in self-reported fear followed later. In this pre-registered placebo-controlled study, we first aimed to conceptually replicate these effects in spider phobia. Second, we investigated whether re-encountering the phobic cue after the reconsolidation intervention is necessary for changes in self-reported fear to occur. Third, we tested whether the window to trigger such changes is time limited. Individuals with spider phobia (N = 69) were randomized into three groups and underwent a memory reactivation procedure with a tarantula, followed immediately by propranolol (reconsolidation intervention) or placebo. One reconsolidation intervention group and the placebo group re-encountered spiders two days after treatment in behavioural approach tasks, whereas another reconsolidation intervention group re-encountered spiders after four weeks. Changes in spider avoidance behaviour and self-reported fear were followed for one year. In the short term, the reconsolidation intervention was not more effective than placebo: both conditions benefited from the intervention. In the long term, the reconsolidation intervention was more effective than placebo, but only when the phobic stimulus was re-encountered within days after treatment. Specifically, we found less tarantula avoidance behaviour and self-reported fear over the course of one year when spiders were re-encountered two days after the reconsolidation intervention, but not when the behavioural test was conducted four weeks after the intervention. These findings challenge the idea that a reconsolidation-inspired intervention alone is sufficient to treat clinical fears: Experiencing the behavioural change during the re-encounter within days after the reconsolidation window has closed seems crucial to observe a lasting fear reduction.
... Studies in humans have consistently demonstrated that a conditioned fear response, as measured by fear potentiated startle (FPS), can be eliminated if reactivation is paired with oral administration of propranolol [4,7,8,9], though a few studies have failed to replicate this effect [10,11]. These findings have also been replicated for traumatic memories in individuals diagnosed with posttraumatic stress disorder [12,13,14]. ...
... Additionally, reconsolidation has also been incorporated in treatment of the specific phobia of spiders using propranolol. Soeter and Kindt [9] examined if blocking reconsolidation in individuals with high levels of spider fear would inhibit the return of fear following reinstatement using a behavioural approach test (BAT) as a measure of fear. Participants who had their memory reactivated (i.e., by focusing on their fears) followed by an oral dose of propranolol displayed greater approach behaviour during a BAT than participants who received a placebo or did not have their memory reactivated. ...
... Researchers have suggested that SCR reflects a cognitive representation of arousal and is more difficult to reconsolidate [4,7,8]. In contrast, FPS is believed to represent an automatic emotional fear response and has been more successfully reconsolidated [7,8,4,9]. It is notable that in studies where both SCR and FPS are measured, evidence of reconsolidation was found for FPS but not for SCR [4,21], with the exception of one study which found that SCR did not interfere with the measurement of FPS [20]. ...
Objective
The present study examined if the expectation for learning enhances reconsolidation of conditioned fear memories using the post-retrieval extinction paradigm in an undergraduate sample (n = 48).
Methods
The study took place over three consecutive days. The expectation for learning was manipulated through oral instructions prior to memory reactivation. On day one, participants underwent differential fear conditioning to two spider images (CS+ and CS-). On day two, participants were assigned to either a reactivation with expectation for learning group, a reactivation with no expectation for learning group, or a no reactivation group. On day three, return of fear in response to the CS+ spider image was measured following reinstatement (i.e., four shocks). Fear potentiated startle (FPS) and skin conductance response (SCR) were taken as measures of fear.
Results
The study found evidence that the expectation for learning may enhanced reconsolidation with FPS as a measure of fear as it was only the expectation for learning group in which FPS to the CS+ remained stable following reinstatement, however this effect was small and non-robust. In contrast, no evidence of reconsolidation was observed for SCR, as all participants exhibited a return of fear following reinstatement.
Implications
These findings suggest that a verbal manipulation of the expectation for learning may not be salient enough to induce reconsolidation as measured by SCR but may be sufficient as measured by FPS. Additionally, given in the inconsistent findings between SCR and FPS, the study’s results bring into question whether the post-retrieval extinction paradigm is appropriate to investigate reconsolidation using both physiological measures concurrently.
... In humans, the unconditioned stimulus-based memory retrieval interference procedure with propranolol can permanently reduce the fear response and prevent the return of fear for all CSs [57]. Numerous follow-up studies of propranolol administration after reactivation in humans convincingly confirmed attenuated emotional responses while also demonstrating that it preserved declarative memory, i.e., knowledge of CS-US contingencies remained unaffected [72][73][74][75][76][77][78]. A case series found that providing 40 mg of propranolol shortly after reactivation decreased PTSD symptoms [79]. ...
... Propranolol has been demonstrated to be effective in reducing anxiety in patients with dental phobia [101] and arachnophobia [74]. ...
... Soeter and Kindt [74] used a live tarantula to reactivate a naturalistic fear memory in subjects who were afraid of spiders. This 'memory reactivation' was promptly followed by oral propranolol administration. ...
Propranolol, a non-cardioselective β1,2 blocker, is most commonly recognised for its application in the therapy of various cardiovascular conditions, such as hypertension, coronary artery disease, and tachyarrhythmias. However, due to its ability to cross the blood–brain barrier and affinity towards multiple macromolecules, not only adrenoreceptors, it has also found application in other fields. For example, it is one of the very few medications successfully applied in the treatment of stage fright. This review focuses on the application of propranolol in the treatment of various types of anxiety and stress, with particular reference to stage fright and post-traumatic stress disorder (PTSD). Both mechanisms of action as well as comparison with other therapies are presented. As those indications for propranolol are, in most countries, considered off-label, this review aims to gather information that can be useful while making a decision about the choice of propranolol as a drug in the treatment of those mental conditions.
... Although much of the initial research on reconsolidation was conducted in animals using pharmacological agents, more recent pharmacological studies have been performed on humans using the beta-adrenergic receptor blocker propranolol [7]. Such studies in humans have demonstrated that a conditioned fear response, as measured by fear potentiated startle (FPS), can be eliminated if reactivation is paired with oral administration of propranolol [4,[8][9][10], though some studies have failed to replicate this effect [11][12][13]. Of clinical relevance, Brunet et al. [14] demonstrated that physiological responding (i.e., heart rate and skin conductance responses (SCR)) to personalized script driven trauma imagery was reduced one week after the administration of propranolol post recall of the traumatic event compared to a placebo group. ...
... Reconsolidation has also been incorporated into the treatment of the specific phobia of spiders using propranolol. Soeter and Kindt [10] examined if blocking reconsolidation in individuals with high levels of spider fear would inhibit the return of fear following reinstatement using a behavioural approach test (BAT) as a measure of fear. Participants who had their memory reactivated (i.e., by focusing on their fears) followed by an oral dose of propranolol displayed greater approach behaviour during a BAT than participants who received a placebo or did not have their memory reactivated. ...
... Differences between these groups were exhibited at all follow-up periods (i.e., 16 days, three months, and 1 year later) demonstrating that the reduction of fear following reconsolidation persisted long-term. The above studies [4,[8][9][10][14][15][16] illustrate that reconsolidation of memories can be blocked by the administration of propranolol followed by reactivation of the memory and this process might be beneficial in the treatment of anxiety based psychological disorders. ...
Objectives
Pharmacological studies using propranolol suggest that if reactivation signals that new information will be learned (i.e., there is an expectation for learning) reconsolidation can be enhanced. We examined if the verbal instructions to expect new learning will enhance reconsolidation of fear memories using the post-retrieval extinction paradigm.
Methods
On day one, participants (n = 48) underwent differential fear conditioning to two images (CS+ and CS-). On day two, participants were randomly assigned to one of three groups; groups one and two had their memory for the CS+ reactivated (i.e., a single presentation of the CS+) 10 minutes prior to extinction, whereas group three did not have their memory reactivated but went right to extinction (no reactivation group). One reactivation group was told that they would learn something new about the images (expectation for learning group), and the other group was told that they would not learn anything new (no expectation for learning group). On day three, return of fear was measured following reinstatement (i.e., four shocks). Fear potentiated startle (FPS) and skin conductance response (SCR) were measured throughout.
Results
There was evidence of fear acquisition for participants for SCR but not FPS. With regards to reconsolidation, SCR increased for the CS+ and CS-in all groups from the end of extinction to the beginning of re-extinction (i.e., return of fear). For FPS, post-hoc tests conducted on the sub-group of participants showing fear learning showed that FPS remained stable in the two reactivation groups, but increased to the CS+, but not the CS- in the no reactivation group.
Implications
These findings suggest that a verbal manipulation of the expectation for learning may not be salient enough to enhance reconsolidation. Results are discussed in relation to theories on differences in between SCR, as a measure of cognitive awareness, and FPS, as a measure of fear.
... Yet even working with such simple associations, there have been failures to replicate the reconsolidation effect [8][9][10]. Almost all previous studies on clinical and pre-clinical reconsolidation interventions have used study-specific reactivation procedures combined with an amnesic agent or a placebo to determine whether that particular reactivation procedure triggered reconsolidation [11][12][13][14]. The inconsistency in the results is unsurprising given the substantial variation in the procedures employed (e.g., Elsey & Kindt, 2021 [15]; see Walsh et al. [16] for a review), and that the window to target the process of memory reconsolidation seems to be small and easy to miss [17]. ...
... In extinction new emotionally neutral memory traces are formed and compete with the fear memory, thus disrupting extinction results in continued fear expression [24,25]. In reconsolidation new information is incorporated into the existing memory trace [2,22], therefore disruption achieves the opposite effect, reducing the emotional valence and behavioural expression of the existing fear memory after sleep [2,14,26]. Such pharmacological agents do not affect subsequent fear-memory expression when applied during the limbo-state [22], the phase between reconsolidation and extinction. ...
... Contrastingly, for the older and stronger memories targeted in clinical practice, reconsolidation interventions include a reactivation procedure of minutes (e.g., refs. [14,30]), and exposure therapy, where the underlying memory process is thought to be extinction, typically lasts 2-3 h across single or multiple sessions (e.g., refs. [31,32]). ...
Pharmacologically disrupting fear memory reconsolidation dramatically reduces fear behaviour. For example, 2–3 min of tarantula exposure followed by 40 mg of propranolol HCl (i.e., a reconsolidation intervention) abruptly decreased spider avoidance, an effect that persisted one year later. However, the success of reconsolidation interventions is not guaranteed: Pavlovian fear-conditioning research shows that the window to target memory reconsolidation is small and easy to miss. If exposure is too long to trigger reconsolidation, but too short for extinction learning, an inactive transitional limbo state occurs, rendering the fear memory unchanged and insensitive to amnesic agents. In this pre-registered study, we aimed to find this behaviourally-controlled boundary condition. Spider-fearful participants underwent a ~3 min (n = 23) or ~14 min (n = 20) exposure to a tarantula, intended to trigger reconsolidation or the limbo state respectively, followed by 40 mg of propranolol. We expected greater spider fear reduction after 3 than 14 min of exposure. Unexpectedly, there were no group differences on any outcome measures. In both groups, Bayesian analysis revealed a marked reduction in fear behaviour towards a generalisation stimulus (a house spider) accompanied by lower self-reported distress, with a sharp decline in spider fear scores two days after treatment that persisted one year later. Possible explanations include that the boundary conditions of reconsolidation are wider in older and stronger memories than experimentally-induced fears, or that alternative processes caused the treatment effects. Although the mechanism is unclear, these results carry a tentative promising message for the potential of brief reconsolidation-targeting interventions to mitigate irrational fears.
... 23,24 Similar protocols that elicit memory retrieval (reactivation) using videos, words or in vivo exposure to substance cues or fearful stimuli have also shown efficacy. 7,25,26 However, some studies have failed to find such effects. 27,28 One metaanalysis examined the reconsolidation of naturalistic memories in clin ical and subclinical samples; although the auth ors reported promising results, they concluded that heterogeneity among studies limited the strength of the findings. ...
... Thus, across 24 publications, 26 studies were included in the metaanalysis: 14 involving healthy sam ples [37][38][39][40][41][42][43][44][45][46][47][48]50 and 12 involving clinical samples. 7,23,24,[26][27][28][52][53][54]56,58 Qualitative results Table 1 summarizes the characteristics of the studies included in the qualitative synthesis, but not in the metaanalysis. Table 2 and Table 3 summarize the characteristics of the healthy adult and clinical studies, respectively, that were included in the quantitative synthesis. ...
... 27,28,57 Finally, for 5 of the 6 clin ical studies that implemented other exposurebased meth ods and the studies that used a word list or pictures, propranolol paired with reactivation improved clinical symptoms compared to placebo paired with reactivation at the posttreatment test phase. 7,25,26,53,59 The remaining study did not find an effect for propranolol. 54 ...
Background:
Reconsolidation impairment using propranolol is a novel intervention for mental disorders with an emotional memory at their core. In this systematic review and meta-analysis, we examined the evidence for this intervention in healthy and clinical adult samples.
Methods:
We searched 8 databases for randomized, double-blind studies that involved at least 1 propranolol group and 1 placebo group. We conducted a meta-analysis of 14 studies (n = 478) in healthy adults and 12 studies in clinical samples (n = 446).
Results:
Compared to placebo, reconsolidation impairment under propranolol resulted in reduced recall of aversive material and cue-elicited conditioned emotional responses in healthy adults, as evidenced by an effect size (Hedges g) of -0.51 (p = 0.002, 2-tailed). Moreover, compared to placebo, reconsolidation impairment under propranolol alleviated psychiatric symptoms and reduced cue-elicited reactivity in clinical samples with posttraumatic stress disorder, addiction or phobia (g = -0.42, p = 0.010).
Limitations:
Methodological differences between studies posed an obstacle for identifying sources of heterogeneity.
Conclusion:
Reconsolidation impairment is a robust, well-replicated phenomenon in humans. Its clinical use is promising and deserves further controlled investigation.
... A more recent study also aimed to tackle a naturalistic fear of public speaking using a reconsolidation-based approach, but found that propranolol + reactivation did not outperform placebo + reactivation [ (20); throughout, we use the term "reconsolidationbased" to refer to the ideas underpinning such treatments, but not as a conclusive statement that reconsolidation necessarily underpins any observed effects]. Perhaps the most convincing demonstration of the prospect of harnessing reconsolidation to tackle naturalistic fears was a placebo-controlled study of participants with a subclinical fear of spiders (21). In Soeter and Kindts' study, participants were briefly exposed to a tarantula to reactivate their fear, after which they received 40 mg oral propranolol or a placebo. ...
... In the present experiments, we sought to exploratorily pilot several possible means of reactivating the fears of arachnophobic patients. These patients differed from those who participated in Soeter and Kindt (21) in that they were required to meet full criteria for a specific phobia, whereas those in Soeter and Kindt (21) did not need to experience interference in their lives due to their phobia. These patients were recruited on the basis of either contacting a clinical center at the University of Amsterdam that offers reconsolidation-based interventions, or through responding to an advertisement offering participation in a trial of such treatments. ...
... In the present experiments, we sought to exploratorily pilot several possible means of reactivating the fears of arachnophobic patients. These patients differed from those who participated in Soeter and Kindt (21) in that they were required to meet full criteria for a specific phobia, whereas those in Soeter and Kindt (21) did not need to experience interference in their lives due to their phobia. These patients were recruited on the basis of either contacting a clinical center at the University of Amsterdam that offers reconsolidation-based interventions, or through responding to an advertisement offering participation in a trial of such treatments. ...
The idea that maladaptive memories may be rendered susceptible to interference after reactivation raises the possibility of reactivating and neutralizing clinically-relevant emotional memories. In this study, we sought to investigate the feasibility of such a “reconsolidation-based” intervention for arachnophobia, drawing upon previous research that successfully reduced fear of spiders in a subclinical sample. In Experiment 1, we piloted several reactivation procedures for conducting a reconsolidation-based treatment for arachnophobic individuals. All procedures involved some form of brief exposure to a fear-provoking spider, followed by the administration of 40 mg propranolol. In Experiment 2, we conducted a double-blind, placebo-controlled assessment of one procedure tested in Experiment 1. In Experiment 1, we found that most reactivation procedures produced drops in self-reported fear of spiders from pre- to post-treatment, including fear declines that were apparent up to 6- and even 14-months later. However, in Experiment 2, we found no evidence that the participants receiving propranolol were better off than those who received placebo. While our findings are limited by the small sample sizes used, they nevertheless show a different pattern of responses than was observed in a previous reconsolidation-based intervention for subclinical spider fearful participants. Alterations to the protocol made to accommodate the clinical participants may have led to greater opportunities for non-specific effects (e.g., exposure, placebo effects) to drive change in the participants. Our findings highlight both the challenges of translating reconsolidation-based procedures into clinical interventions, as well as the importance of controls for non-specific effects in reconsolidation-based research.
... After such memory updating, mice show preference for the initially feared context instead of avoiding it or freezing. While these studies help to understand and treat simple associative fear memories that are relevant for some anxiety disorders such as specific phobias (Soeter & Kindt, 2015), it is unclear whether their findings translate to more complex episodic memories that are relevant in different mental disorders and involve other emotions than threat and fear (Everaert et al., 2022;Holmes et al., 2016). ...
... The finding that the affective tone of episodic memories does not change profoundly after memory updating challenges the clinical utility of therapeutics that aim at altering sad or happy episodic memories (Elsey & Kindt, 2016. The observed changes of episodic memory emotionality are also small in comparison to some of the drastic changes observed in conditioning studies (e.g., Kindt et al., 2009) and reconsolidation interventions for phobic fear memories (e.g., Soeter & Kindt, 2015). However, the magnitude of changes in affect may depend critically on the operationalization of the updating manipulation. ...
... After such memory updating, mice show preference for the initially feared context instead of avoiding it or freezing. While these studies help to understand and treat simple associative fear memories that are relevant for some anxiety disorders such as specific phobias (Soeter & Kindt, 2015), it is unclear whether their findings translate to more complex episodic memories that are relevant in different mental disorders and involve other emotions than threat and fear (Everaert et al., 2022;Holmes et al., 2016). ...
... The finding that the affective tone of episodic memories does not change profoundly after memory updating challenges the clinical utility of therapeutics that aim at altering sad or happy episodic memories (Elsey & Kindt, 2016. The observed changes of episodic memory emotionality are also small in comparison to some of the drastic changes observed in conditioning studies (e.g., Kindt et al., 2009) and reconsolidation interventions for phobic fear memories (e.g., Soeter & Kindt, 2015). However, the magnitude of changes in affect may depend critically on the operationalization of the updating manipulation. ...
Maladaptive emotional memories are a transdiagnostic feature of mental health problems. Therefore, understanding whether and how emotional memories can change might help to prevent and treat mental disorders. We tested whether neutral memories of naturalistic events can retroactively acquire positive or negative affect, in a preregistered three-day Modification of Valence in Episodes (MOVIE) paradigm. On Day 1, participants (N = 41) encoded memories of neutral movie scenes, representing lifelike naturalistic experiences. On Day 2, they retrieved each episode before viewing a happy, sad, or neutral scene from the same movie (resulting in a neutral-negative, neutral-positive, and neutral-neutral condition). On Day 3, participants again retrieved each memory from Day 1. We assessed the affective tone of episodes through facial expressions of positive and negative affect and through self-reported feelings. Positive updating of neutral episodes led to increased expressions of positive affect, whereas negative updating led to increased self-reported negative feelings. These results suggest that complex neutral episodic memories can retroactively acquire an affective tone, but the effects were modest and inconsistent across affect readouts. Future research should investigate alternative approaches to updating emotional memories that produce more profound changes in the valence of memories.
... Brunet et al. (2018) recently showed that six 25-min sessions of trauma reactivation under propranolol alleviated PTSD symptoms compared to the same reactivation procedure under placebo. Further evidence of its therapeutic potential comes from studies of spider phobia (Soeter and Kindt, 2015), substance dependence (Lonergan et al., 2016), and meta-analyses examining memory reactivation under propranolol vs. placebo in healthy volunteers and clinical samples (Lonergan et al., 2013;Pigeon et al., 2022). ...
... A rapid reduction in specific event-related symptom clusters (intrusions, avoidance, hypervigilance), as well as general anxiodepressive symptoms, was also observed. These findings align with prior research suggesting that a single reactivation session under propranolol can produce notable decreases in emotional responses to stressors (Brunet et al., 2008;Soeter and Kindt, 2015), and additional sessions may have additive effects (Brunet et al., 2018). The treatment protocol was well tolerated as documented by a low drop-out rate, and treatment gains were maintained at the follow-up, suggesting a sustained effect lasting up to at least 4-months even after treatment is discontinued. ...
Objectives
In a sustained relationship, romantic betrayal is a catastrophic event that can precipitate an adjustment disorder (AD). Surprisingly, there exists no empirically validated treatment for AD, despite its high prevalence in clinical practice. Considering the promise of memory reactivation under propranolol (i.e., reconsolidation interference) for treating posttraumatic stress disorder, we sought to extend this finding to AD, given that in both disorders, symptoms stem from an identified stressor.
Method
A single-blind interrupted time series design was used to examine the efficacy of memory reactivation under propranolol to alleviate symptoms of AD. After being placed on a 4-week waitlist, sixty-one participants received 5 weekly 25-min treatments during which they recalled the betrayal event, 1 h after having orally ingested the beta-blocker propranolol.
Results
Segmented regression analyses on the intent-to-treat sample revealed that AD symptoms significantly decreased during the treatment phase (pre/post Cohen's d = 1.44), compared to the waitlist phase (d = 0.01). Significant pre/post reductions in anxio-depressive symptomatology were also found. Improvement was maintained at the 4-month follow-up on all outcomes.
Conclusion
Memory reactivation under propranolol shows promise in reducing symptoms of AD. This study provides the theoretical framework and necessary effect sizes to inform larger, double-blind, placebo-controlled clinical trials.
... Drugs that manipulate adrenergic signaling have been used to manipulate either the reactivation, the reconsolidation, and/or the extinction processes involved in the weakening of a fearful memory (Taylor et al., 2008;Lonergan et al., 2013;McGuire et al., 2014;Belkin and Schwartz, 2015). The non-selective β-adrenergic antagonist propranolol (P), in particular, has been used for several decades in anxiety disorders including performance anxiety (Tyrer, 1988;Liu et al., 1991;Soeter and Kindt, 2015) and generalized anxiety disorder (GAD) (Fagerström et al., 1985;Tyrer, 1988;Grillon et al., 2004). Propranolol has also been used to aid in the treatment of phobias and in exposure therapies for PTSD (Grillon et al., 2004;Soeter and Kindt, 2015;Kroes et al., 2016). ...
... The non-selective β-adrenergic antagonist propranolol (P), in particular, has been used for several decades in anxiety disorders including performance anxiety (Tyrer, 1988;Liu et al., 1991;Soeter and Kindt, 2015) and generalized anxiety disorder (GAD) (Fagerström et al., 1985;Tyrer, 1988;Grillon et al., 2004). Propranolol has also been used to aid in the treatment of phobias and in exposure therapies for PTSD (Grillon et al., 2004;Soeter and Kindt, 2015;Kroes et al., 2016). ...
Altered fear learning is a strong behavioral component of anxiety disorders such as post-traumatic stress disorder (PTSD). Recent efforts have attempted to combine exposure therapies with drugs that target fear memory retrieval and memory reconsolidation, in order to improve treatment efficacy. The noradrenergic (NA) signaling system is of particular interest, due to its role in regulating the stress response and its involvement in fear and learning processes. Importantly, propranolol (P), a non-selective β-adrenergic antagonist, has shown the potential in decreasing exaggerated fear in both humans and animal models. In a previous study, we utilized an activity-dependent tagging murine model to determine the neural mechanisms by which propranolol attenuates learned fear. We found that propranolol acutely decreased memory trace reactivation specifically in the dorsal dentate gyrus (dDG), but not in CA3 or CA1. Here, we extended our previous study by investigating whether propranolol additionally altered activity in the hilus, a polymorphic layer that consists of neurons, mossy cells, and GABAergic interneurons. We found that propranolol acutely reduced overall hilar activity in both the dorsal and ventral hilus. Moreover, we report that propranolol significantly altered the activity of parvalbumin (PV)+ cells in the ventral (vDG), but not dorsal DG (dDG). Together, these results suggest that a β-adrenergic blockade may affect the activity of excitatory and inhibitory cell types in the hilar layer of the DG, and that these alterations may contribute to manipulating fear memory traces.
... To evaluate the existence of memory consolidation/reconsolidation, amnesic agents such as electroconvulsive shock (ECS, [34][35][36][37]), protein synthesis and gene expression inhibitors [38,39] and β-blockers [40][41][42] have been administered after learning/reactivation. However, a more ecological way is to use other learnings [4,5,7,8,[43][44][45][46][47]. ...
... Thus, considering that consolidation and reconsolidation share similar molecular mechanisms it would be of great interest for the clinical field to study this short time window where the memory is protected against interference. In the last few years, lots of studies have proposed the possibility of using reconsolidation as a therapeutic tool for the intervention of maladaptive memories [42,[58][59][60][61][62][63][64]. That is, to reactivate a maladaptive memory and update its content. ...
After encoding, memories go through a labile state followed by a stabilization process known as consolidation. Once consolidated they can enter a new labile state after the presentation of a reminder of the original memory, followed by a period of re-stabilization (reconsolidation). During these periods of lability the memory traces can be modified. Currently, some studies show a rapid stabilization after 30 min, while others show that stabilization occurs after longer periods (e.g. > 6 h). Here we investigate the effect of an interference treatment on declarative memory consolidation, comparing distinct time intervals after acquisition. On day 1, participants learned a list of non- syllable pairs (List 1). 5 min, 30 min, 3 h or 8 h later, they received an interference list (List 2) that acted as an amnesic agent. On day 2 (48 h after training) participants had to recall List 1 first, followed by List 2. We found that the List 1 memory was susceptible to interference when List 2 was administered 5 min or 3 h after learning but not when it was administered 30 min or 8 h after. We propose the possibility that this rapid memory protection could be induced by a fast and transient neocortical integration. Our results open a discussion about the contribution of molecular and systemic aspects to memory consolidation.
... Importantly, noradrenergic hyperarousal may impede therapeutic interventions, such as prolonged exposure therapy, that rely upon extinction learning to reduce pathological fear (McCurry et al., 2020). There is evidence that treatment with propranolol after reactivating trauma memory can reduce symptom severity in patients with PTSD (Vaiva et al., 2003;Hoge et al., 2012;Brunet et al., 2018) or specific phobias (Soeter and Kindt, 2015). Potential mechanisms for these effects include the suppression of fear expression, facilitation of extinction, or impaired reconsolidation of fear memories (Grillon et al., 2004;Kindt et al., 2009;Kroes et al., 2010Kroes et al., , 2016Maren, 2011;Soeter and Kindt, 2015;Chalkia et al., 2019). ...
... There is evidence that treatment with propranolol after reactivating trauma memory can reduce symptom severity in patients with PTSD (Vaiva et al., 2003;Hoge et al., 2012;Brunet et al., 2018) or specific phobias (Soeter and Kindt, 2015). Potential mechanisms for these effects include the suppression of fear expression, facilitation of extinction, or impaired reconsolidation of fear memories (Grillon et al., 2004;Kindt et al., 2009;Kroes et al., 2010Kroes et al., , 2016Maren, 2011;Soeter and Kindt, 2015;Chalkia et al., 2019). Preclinical work on the IED suggests that propranolol might be most effective in patients with noradrenergic hyperarousal, particularly when combined with cognitive-behavioral therapy. ...
Therapeutic interventions for disorders of fear and anxiety rely on behavioral approaches that reduce pathological fear memories. For example, learning that threat-predictive stimuli are no longer associated with aversive outcomes is central to the extinction of conditioned fear responses. Unfortunately, fear memories are durable, long-lasting, and resistant to extinction, particularly under high levels of stress. This is illustrated by the “immediate extinction deficit,” which is characterized by a poor long-term reduction of conditioned fear when extinction procedures are attempted within hours of fear conditioning. Here, I will review recent work that has provided new insight into the neural mechanisms underlying resistance to fear extinction. Emerging studies reveal that locus coeruleus norepinephrine modulates amygdala-prefrontal cortical circuits that are critical for extinction learning. These data suggest that stress-induced activation of brain neuromodulatory systems biases fear memory at the expense of extinction learning. Behavioral and pharmacological strategies to reduce stress in patients undergoing exposure therapy might improve therapeutic outcomes.
... Appropriate and efficient interventions for maladaptive memory to prevent the development of severe mental illnesses are in need. There are pieces of evidence showing pharmacological manipulations like adrenergic receptor antagonist (Lonergan, Brunet, Olivera-Figueroa, & Pitman, 2013;Soeter & Kindt, 2015), and electroconvulsive therapy (ECT) might interference with aversive memories (Kroes et al., 2014;Misanin, Miller, & Lewis, 1968). However, these methods are limited for applications due to their invasive nature. ...
... Besides the memory contents, the subjective emotional feeling is a vital component of emotional episodic memory, and it is also a crucial indicator to evaluate therapeutic modifications (Lane, Ryan, Nadel, & Greenberg, 2015). Ample studies have successfully reduced the individual's negative feelings (e.g., fear) through memory updating operations (Sandkühler & Lee, 2013;Soeter & Kindt, 2015). However, to our knowledge, there is no study yet to investigate how updating with positive emotion reshapes previously acquired aversive memories with either impaired or distorted outcomes, and even less is known how this procedure alters the emotional arousal of original memory representation. ...
Aversive memories are long-lasting and prone to burden our emotional wellbeing and mental health. Yet, how to remedy the maladaptive effects of aversive memories remains elusive. Using memory reactivation and emotional updating manipulations, we investigated how positive and neutral emotion may update aversive memories for reconsolidation in humans. We found that positive updating after reactivation was equivalent to neutral updating in impairing true memories of a previous aversive event after a 12-hour wakeful delay, but induced more false memory. Moreover, additional 12-hour delay with overnight sleep did not further enlarge true memory differences, but attenuated the effect of reactivation and updating on false memory. Interestingly, the neutral rather than the positive updating reduced the emotional arousal of the aversive memory 24 hours later. Our findings could serve as references for real-world therapeutic applications regarding how positive and neutral updating may reshape aversive memories, especially when taking wake- and sleep-filled reconsolidation into account.
... Based on an a-priori power analysis [50,51] and previous work that indicated large effect sizes by taVNS on the inhibition of fear [31,32], this sample size was sufficiently powered (i.e., ≥ 0.80) [52] to detect large effects throughout exposures in vitro and in vivo 1 . Furthermore, this sample size is also comparable to previous studies, that tested neurosciencebased adjuncts to exposure therapy [54]. ...
Recent laboratory research showed that vagus nerve stimulation promotes fear extinction, the inhibitory core mechanism of exposure treatment, presumably via activation of the noradrenergic brain system. However, a translation of this stimulation technique to clinical practice is lacking. We therefore investigated the potential of vagal stimulation to inhibit excessive fear responses and facilitate responding to in-vivo and laboratory exposure in individuals with specific phobia. Spider-phobic participants were subjected to three standardized in-vivo exposures towards a living tarantula, complemented by an exposure in vitro (between exposure in vivo I and II). Transcutaneous auricular vagus nerve stimulation (taVNS) was applied during in-vitro exposure, presenting pictures of the exposed tarantula, other spiders and neutral tools in the laboratory. Fear was assessed by self-reports and behavioral avoidance (in-vivo exposures), and amygdala-mediated autonomic and behavioral fear components (exposure in vitro). Vagal stimulation facilitated the reduction of behavioral avoidance across repeated in-vivo exposures. During laboratory exposure, taVNS inhibited fear tachycardia and corrugator muscle activity specifically in response to pictures of the previously exposed tarantula – an effect that became stronger with increasing stimulation duration. Psychophysiological indices of noradrenergic transmission in the basolateral amygdala were elevated during taVNS and correlated to subsequent attenuation of behavioral avoidance. Our results suggest, that taVNS exerts stimulus-specific and dose-dependent inhibition of multiple automatic response components of excessive fear, highlighting taVNS as a valuable adjunct to exposure-based treatment. A translational mechanism of action is supported, proposing that taVNS exhibits its effects by noradrenergic activation of fear extinction circuitry, particularly targeting the basolateral amygdala.
... Propranolol: Reflecting the very broad impact of the noradrenergic system, this drug is indicated for various anxiety and stress-related conditions, including stage fright, posttraumatic stress disorder (PTSD), arachnophobia, and autism spectrum disorder [e.g., [44][45][46][47][48]. ...
Humans and animals use multiple control systems for decision-making. This involvement is subject to meta-cognitive regulation – as a form of control over control or meta-control. However, the nature of this meta-control is unclear. For instance, Model-based (MB) control may be boosted when decision-makers generally lack confidence as it is more statistically efficient; or it may be suppressed, since the MB controller can correctly assess its own unreliability. Since control and metacontrol are themselves subject to the influence of neuromodulators, we examined the effects of perturbing the noradrenergic (NE) and dopaminergic (DA) systems with propranolol and L-DOPA, respectively. We first administered a simple perceptual task to examine the effects of the manipulations on meta-cognitive ability. Using Bayesian analyses, we found that 81% of group M-ratio samples were lower under propranolol relative to placebo, suggesting a decrease of meta-cognitive ability; and 60% of group M-ratio samples were higher under L-DOPA relative to placebo, considered as no effect of L-DOPA on meta-cognitive ability . We then asked subjects to provide choices and confidence ratings in a two-outcome decision-making task that has been used to dissociate Model-free (MF) and MB control. MB behavior was enhanced by propranolol, while MF behavior was not significantly affected by either drug. The interaction between confidence and MF/MB behavior was highly variable under propranolol, but under L-DOPA, the interaction was significantly lower/higher relative to placebo. Our results suggest a decrease in metacognitive ability under the influence of propranolol and an enhancement of MB behavior and meta-control under the influence of propranolol and L-DOPA, respectively. These findings shed light on the role of NE and DA in different aspects of control and meta-control and suggest potential avenues for mitigating dysfunction.
... The last decade has seen a large number of translational studies testing immediate symptom reduction based on either a behavioral or a pharmacological paradigm and the sustainability of these effects. For example, Soeter and Kindt (2015) describe how the application of propranolol after fearmemory retrieval in patients with spider phobia resulted in a greater symptom improvement compared to a placebo that persisted for at least one year after the procedure. However, the benefits of the propranolol reconsolidation paradigm have not been equally observed in all translational studies (Elsey et al., 2020;Steenen et al., 2016). ...
Return of fear after successful exposure therapy for phobia is a common clinical challenge. A previous study on mice demonstrated that the persistent attenuation of remote fear memories can be achieved by combining histone deacetylase inhibitors (HDACis) with fear-memory retrieval prior to extinction training. To evaluate the translational potential of this approach, we conducted a randomized, double-blind placebo-controlled trial. Forty-eight individuals with DSM-IV spider phobia received either HDACi valproic acid (VPA, 500 mg) or a placebo prior to the retrieval of fear memory followed by exposure therapy in virtual reality. No significant group difference was found in terms of behavioral change on the behavioral approach test at 3 months follow-up and baseline (primary outcome). However, the VPA group displayed significantly reduced fear in two self-report questionnaires related to spider phobia (Fear of Spider Questionnaire; Spider Phobia Beliefs Questionnaire) as compared to the placebo group. No group differences were observed for psychophysiological indicators of fear. The favorable impact of a single administration of VPA in combination with fear-memory retrieval prior to exposure therapy suggests that it might be an effective way to enhance symptom improvement at the subjective level in the treatment of phobias. Further studies need to investigate the conditions under which an improvement on the physiological and behavioral levels can be achieved as well.
... In developing interventions to treat PTSD, there has been considerable interest in targeting post-encoding processes that alter memory expression, such as extinction, reconsolidation, and extinction-reconsolidation [60,61]. For example, drugs that enhance extinction [62] or impair reconsolidation [63,64] may be useful pharmacotherapeutic adjuncts in prolonged exposure therapy. The current experiments indicate that targeting another post-encoding memory process-forgetting-offers promise for treatment of hypermnesic conditions such as PTSD and addiction. ...
Post-traumatic stress disorder (PTSD) is a hypermnesic condition that develops in a subset of individuals following exposure to severe trauma. PTSD symptoms are debilitating, and include increased anxiety, abnormal threat generalization, and impaired extinction. In developing treatment strategies for PTSD, preclinical studies in rodents have largely focused on interventions that target post-encoding memory processes such as reconsolidation and extinction. Instead, here we focus on forgetting, another post-encoding process that regulates memory expression. Using a double trauma murine model for PTSD, we asked whether promoting neurogenesis-mediated forgetting can weaken trauma memories and associated PTSD-relevant behavioral phenotypes. In the double trauma paradigm, consecutive aversive experiences lead to a constellation of behavioral phenotypes associated with PTSD including increases in anxiety-like behavior, abnormal threat generalization, and deficient extinction. We found that post-training interventions that elevate hippocampal neurogenesis weakened the original trauma memory and decreased these PTSD-relevant phenotypes. These effects were observed using multiple methods to manipulate hippocampal neurogenesis, including interventions restricted to neural progenitor cells that selectively promoted integration of adult-generated granule cells into hippocampal circuits. The same interventions also weakened cocaine place preference memories, suggesting that promoting hippocampal neurogenesis may represent a broadly useful approach in hypermnesic conditions such as PTSD and substance abuse disorders.
... A paradigmatic example of these novel interventions is propranolol. Administering the beta-adrenergic receptor antagonist upon spider memory reactivation in subclinical spider phobic participants reduced fear to spiders for at least one year [91]. However, this intervention showed contrasting results when used to target spider phobia in clinical participants, where placebo-treated participants showed as much benefit as those receiving propranolol [92]. ...
Memory persistence is a double edge sword. Persistence of adaptive memories is essential for survival and even determines who we are. Neurodegenerative conditions with significant memory loss such as Alzheimer’s disease, testify how defects of memory persistence have severe and irreversible effects on personality, among other symptoms. Yet, maintenance of overly strong maladaptive memories underlies highly debilitating psychiatric conditions including post-traumatic stress disorder, specific phobia, substance dependence and binge eating disorder. Here we review the neurobiological mechanisms supporting memory formation, persistence, inhibition and forgetting. We then shift the focus to how such mechanisms have been exploited to alter the persistence of laboratory-generated memories in human healthy volunteers as a proof of concept. Finally, we review the effect of behavioural and pharmacological interventions in anxiety and addiction disorder patients, highlighting key findings, gaps, and future directions for basic and translational research.
... The crucial role of central noradrenergic signaling in the process cascade (41) suggests that the β-adrenergic blocker propranolol is a viable option for effectively interfering with memory reconsolidation in humans. Indeed, preclinical research has compellingly shown that β-adrenergic blockade during reconsolidation can disrupt fear memories in healthy individuals (e.g., (42); see for a review (43)) and in people with a fear of spiders ( (44,45); but see (46)). Even though these findings point to a revolutionary new treatment for emotional memory disorders, the success of reconsolidation interventions is not guaranteed (47). ...
Introduction
Despite the positive outcomes observed in numerous individuals undergoing trauma-focused psychotherapy for PTSD, veterans with this condition experience notably diminished advantages from such therapeutic interventions in comparison to non-military populations.
Methods
In a preliminary study we investigated the efficacy of an innovative treatment approach in a small sample of veterans (n = 7). Recognizing that accessing and targeting trauma memory in veterans with PTSD may be more challenging compared to other patient populations, we employed unique and personalized retrieval cues that engaged multiple senses and were connected to the context of their trauma. This was followed by a session focused on memory reconsolidation, which incorporated both psychological techniques (i.e., imagery rescripting) and a pharmacological component (i.e., 40 mg of propranolol).
Results
The findings from this small-scale case series cautiously indicate that this brief intervention, typically consisting of only one or two treatment sessions, shows promise in producing significant effects on symptoms of PTSD, distress and quality of life.This is particularly noteworthy given the complex symptomatology experienced by the veterans in this study.
Conclusion
To summarize, there are grounds for optimism regarding this brief treatment of combat-related PTSD. It appears that the potential for positive outcomes is far greater than commonly believed, as demonstrated by the encouraging results of this pilot study.
... In spider phobia, repeated exposure to a spider image after fear reactivation attenuated amygdala response to that image 24 h later [38]. Administering propranolol (a β-blocker) after reactivation of fear of spiders resulted in decreased avoidance response and increased approach behavior in spider-fearful people [39]. Lastly, administration of propranolol before exposure therapy yielded a steeper decline in PTSD symptoms at follow-up [40]. ...
NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, post-treatment, ketamine recipients showed a lower amygdala (−0.33, sd = 0.13, 95%HDI [−0.56,−0.04]) and hippocampus (−0.3 (sd = 0.19), 95%HDI [−0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (−0.28, sd = 0.11, 95%HDI [−0.46, −0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: −0.01108, 95% HDI [−0.0184,−0.003]; follow-up: −0.0183, 95% HDI [−0.02719,−0.0107]; left: post-treatment: −0.019, 95% HDI [−0.028,−0.011]; follow-up: −0.017, 95% HDI [−0.026,−0.007]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.
... The experiment concluded that this treatment is able to weaken the fear memory, which is actually not permanent how it was previously considered. This is however an experimental approach that has several disadvantages and requires further research [11]. ...
The current paper presents a survey on virtual reality applications and analyses their utility as tools for learning how to overcome phobias, thus improving one's quality of life. Nowadays, phobias do not have a universal treatment, even though medicine is a constantly evolving field. There are hundreds of well-known phobias, such as Arachnophobia (fear of spiders), Agoraphobia (fear of open spaces), Claustrophobia (fear of closed spaces), as well as bizarre ones, such as Coulrophobia (fear of clowns). In some cases, specialists consider that avoiding the phenomenon which causes the phobia is the sufficient treatment; in others, the exact opposite, being gradually exposed to the object of fear may lead to a cure. We have to start looking for other psychotherapeutic methods, innovative ones, in order to help people surpass their immense fears and improve their life quality. Virtual Reality (VR) is a major current trend, a technology which creates a realistic artificial environment that can have a lot of day-to-day applications. Using IT-based solutions for treating real-life problems, especially medical conditions, can be viewed as controversial and provoke scepticism. The current methods of dealing with phobias will be reviewed, as well as the computer-based or VR-based tools used for this genre of treatment. We will analyse the existent VR applications, the concept behind their mechanism and the possibility of exploiting them in a medical environment. There are a lot of challenges coming from such an innovative field, therefore the paper debates whether these IT instruments are useful, difficult to implement or if they can be tested on real subjects. Based on the results of the survey, we will propose a model of a virtual reality application containing some phobias that it should treat, as well as the principle on which it is based.
... As mentioned before, cortisol does not seem to exert beneficial effects on reconsolidation processes (Meir Drexler et al., 2020;Meir Drexler and Wolf, 2016), but beta-blockers effectively reduced fear reconsolidation (Elsey et al., 2018;Kindt et al., 2009;Kroes et al., 2016a). On the one hand, the first translation attempts to the clinic revealed that spider fearful participants profited from the beta-blocker/reactivation approach (Soeter and Kindt, 2015). On the other hand, attempts to reduce posttraumatic stress disorder symptoms by combining a beta-blocker with reactivation have been less successful (Raut et al., 2022; but see Brunet et al., 2018). ...
Stress hormones influence the processing of fear, anxiety, and related memory mechanisms. For example, they modulate consolidation and retrieval processes associated with emotional episodic memory, fear and extinction learning. In this review, we summarize recent laboratory findings on the timing-dependent effects of stress on extinction learning and extinction retrieval. Furthermore, we relate these experiments to clinical intervention approaches relying on extinction processes such as exposure therapy, for which beneficial effects of the administration of the stress hormone cortisol have been observed. The modulation of extinction-based interventions differs from findings obtained with reconsolidation manipulation procedures utilizing the restabilization of retrieved (or reactivated) memories. In this case, blockade of adrenergic beta-receptors during reconsolidation of the fearful stimulus might represent a promising intervention. The substantial progress made in the understanding of the interaction of stress hormones with memory processes associated with fear and anxiety has the potential to enhance therapeutic success and prevent relapse in the long run.
... In the past two decades, memory reconsolidation blockade interventions have shown promise as treatments for stress and anxiety related disorders [21][22][23][24][25]. These interventions have typically used pharmacological agents to impair reconsolidation and weaken memory associations. ...
Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessation aids show only modest efficacy, new interventions are needed. Given the evidence that stress is a potent trigger for smoking, the present randomized clinical trial tested whether stress could augment the effects of a memory updating (retrieval-extinction) intervention. Non-treatment seeking smokers ( n = 76) were assigned to one of four conditions composed of either a stressful or non-stressful psychosocial challenge followed by either smoking or neutral cues. Ten minutes after this manipulation, all underwent a 60-minute extinction procedure during which they viewed smoking-related videos and images and manipulated smoking paraphernalia. Compared to participants who were not exposed to the laboratory stressor, the stressor-exposed groups exhibited greater psychophysiological responses during their intervention and greater decreases in cigarette use at two- and six-weeks follow-up independent of smoking cue exposure. Together, these findings suggest that the ability of stress to activate cigarette seeking processes can be exploited to decrease cigarette use. With replication, the stress-based intervention could become a novel strategy for decreasing cigarette use in non-treatment seeking smokers.
Clinicaltrials.gov identifier: NCT04843969.
... Aikins 11 Brunet et al. 4 Elsey and Kindt 9 Elsey et al. 5 Orr 12 Roullet et al. 6 Saladin 13 Soeter and Kindt 7 Risk of bias legend A) Random sequence generation (selection bias) B) Allocation concealment (selection bias) C) Blinding of participants and personnel (performance bias) D) Blinding of outcome assessment (detection bias) E) Incomplete outcome data (attrition bias) F) Selective reporting (reporting bias) G) Other bias + + + + + + + + + + + ? + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ...
... For instance, a number of clinical trials have claimed to test reconsolidation blockade in people with (sub)clinical anxiety, mainly phobias and post-traumatic stress disorder (PTSD). Some of these studies have found clinically significant beneficial effects of a reminder combined with an amnestic intervention like, for example, propranolol (e.g., Brunet et al., 2018;Soeter & Kindt, 2015), while other studies showed mixed findings (e.g., Bolsoni et al., 2022;Brunet et al., 2008;Roullet et al., 2021;Surís et al., 2010), and yet others found no effects (e.g., Elsey et al., 2020;Elsey & Kindt, 2021;Raut et al., 2022;Surís et al., 2013;Tang et al., 2021;Wood et al., 2015). Of note, Brunet et al. (2008) found statistically significant effects for physiological measures (skin conductance and heart rate) during traumatic imagery, but not for actual PTSD symptoms (Brunet et al., 2011). ...
Re-exposure to elements of prior experiences can create opportunities for inducing amnesia for those events. The dominant theoretical framework posits that such re-exposure can result in memory destabilization, making the memory representation temporarily sensitive to disruption while it awaits reconsolidation. If true, such a mechanism that allows for memories to be permanently changed could have important implications for the treatment of several forms of psychopathology. However, there have been contradictory findings and elusive occurrences of replication failures within the “reconsolidation” field. Considering its potential relevance for clinical applications, the fact that this “hot” research area is being dominated by a single mechanistic theory, and the presence of unexplainable contradictory findings, we believe that it is both useful and timely to critically evaluate the reconsolidation framework. We discuss potential issues that may arise from how reconsolidation interference has typically been deducted from behavioral observations, and provide a principled assessment of reconsolidation theory that illustrates that the theory and its proposed boundary conditions are vaguely defined, which has made it close to impossible to refute reconsolidation theory. We advocate for caution, encouraging researchers not to blindly assume that a reconsolidation process must underlie their findings, and pointing out the risks of doing so. Finally, we suggest concrete theoretical and methodological advances that can promote a fruitful translation of reminder-dependent amnesia into clinical treatment.
... We conducted a tarantula BAT (TBAT; adult female Grammostola porteri, ~10 cm) and a house spider BAT (HBAT; Eratigena atrica, ~ 3 cm) to assess participants' spider avoidance behaviour, modified from Soeter and Kindt (2015). The TBAT consisted of eight steps, ranging from standing in front of the terrarium (1), touching the tarantula (5), to placing one's hand on the terrarium's floor with the eyes closed while the spider is being sprayed with water (8). ...
Spider fear is an excellent model to experimentally study processes in the maintenance and treatment of long-lasting fears. A valid, reliable, and practical tool to assess spider-related distress dimensionally, and to differentiate between spider-related fear and disgust in a time-sensitive manner, may help to better understand individual differences in these two emotions and to tailor treatments accordingly. We developed a concise self-report questionnaire, the Spider Distress Scale (SDS), that combines the strengths of established spider fear questionnaires and addresses their shortcomings. We explored (study 1 and 2) and confirmed (study 3) a two-factor structure of the SDS in samples from the general population (n=370; n=360; n=423), recruited online via Prolific Academic from the United Kingdom, the Netherlands, and the United States. The fear and disgust factors of the SDS are highly internally consistent and the SDS has excellent test-retest reliability. We found good convergent and discriminant validity, based on self-report measures and spider behavioural approach tasks, and the SDS successfully differentiated between individuals with and without spider fear (study 4, n=75). Our series of studies suggests that fear and disgust are functionally related, but that disgust towards spiders can be differentially assessed when focussing on unique elements of disgust-related information.
... Translation of these findings to real-life anxiety disorders and posttraumatic stress disorder remains a great challenge (Kindt, 2014). At present, both promising (Brunet et al., 2008(Brunet et al., , 2011(Brunet et al., , 2018Soeter and Kindt, 2015a;Kindt and van Emmerik, 2016) as well as disappointing (Wood et al., 2015;Elsey et al., 2020;Roullet et al., 2021) results have been reported to treat real-life fears that have been acquired outside the laboratory. These relatively mixed observations have often been attributed to the subtle conditions under which amnestic agents interfere with fear memories (Elsey et al., 2018(Elsey et al., , 2020. ...
Post-reactivation amnesia of contextual fear memories by blockade of noradrenergic signaling has been shown to have limited replicability in rodents. This is usually attributed to several boundary conditions that gate the destabilization of memory during its retrieval. How these boundary conditions can be overcome, and what neural mechanisms underlie post-reactivation changes in contextual fear memories remain largely unknown. Here, we report a series of experiments in a contextual fear-conditioning paradigm in mice, that were aimed at solving these issues. We first attempted to obtain a training paradigm that would consistently result in contextual fear memory that could be destabilized upon reactivation, enabling post-retrieval amnesia by the administration of propranolol. Unexpectedly, our attempts were unsuccessful to this end. Specifically, over a series of experiments in which we varied different parameters of the fear acquisition procedure, at best small and inconsistent effects were observed. Additionally, we found that propranolol did not alter retrieval-induced neural activity, as measured by the number of c-Fos+ cells in the hippocampal dentate gyrus. To determine whether propranolol was perhaps ineffective in interfering with reactivated contextual fear memories, we also included anisomycin (i.e., a potent and well-known amnesic drug) in several experiments, and measures of synaptic glutamate receptor subunit GluA2 (i.e., a marker of memory destabilization). No post-retrieval amnesia by anisomycin and no altered GluA2 expression by reactivation was observed, suggesting that the memories did not undergo destabilization. The null findings are surprising, given that the training paradigms we implemented were previously shown to result in memories that could be modified upon reactivation. Together, our observations illustrate the elusive nature of reactivation-dependent changes in non-human fear memory.
... The lack of reconsolidation disruption in the value-PE group does, however, make an interpretation of the results in the identity-PE group difficult. Our results do not confirm previous results of successful disruption of fear memory reconsolidation with propranolol [6][7][8][9][10][11][12]25,30,41 but are rather in line with a small number of studies that could not replicate the effect [42][43][44] . A potential explanation for the lack of reconsolidation disruption in the value-PE group may be their lack of certainty about the CS-US contingency. ...
Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.
... Similarly, beta-adrenergic receptor blocker propranolol has been shown to be effective in ameliorating post-traumatic stress disorder (PTSD) related memories [114,115]. Propranolol was shown to also interfere with memory reconsolidation processes when administered after exposure to stressful stimuli in animals [116] and in humans [117]. This is possibly due to the blockade of noradrenergic activity in the amygdala during the reconsolidation process which is responsible for the encoding of emotionally enhanced memories associated with PTSD [118,119]. ...
Epileptogenesis is a complex and not well understood phenomenon. Here, we explore the hypothesis that epileptogenesis could be “hijacking” normal memory processes, and how this hypothesis may provide new directions for epilepsy treatment. First, we review similarities between the hypersynchronous circuits observed in epilepsy and memory consolidation processes involved in strengthening neuronal connections. Next, we describe the kindling model of seizures and its relation to long-term potentiation model of synaptic plasticity. We also examine how the strengthening of epileptic circuits is facilitated during the physiological slow wave sleep, similarly as episodic memories. Furthermore, we present studies showing that specific memories can directly trigger reflex seizures. The neuronal hypersynchrony in early stages of Alzheimer's disease, and the use of anti-epileptic drugs to improve the cognitive symptoms in this disease also suggests a connection between memory systems and epilepsy. Given the commonalities between memory processes and epilepsy, we propose that therapies for memory disorders might provide new avenues for treatment of epileptic patients.
... Disrupting memory reconsolidation with propranolol is believed to be a promising new method to reduce automatic fear responses in humans 5,6,8,10,11,35 . However, in line with the results presented here, many others have not been able to replicate effects of interfering with memory reconsolidation [15][16][17][18]36 . ...
Disrupting memory reconsolidation provides an opportunity to abruptly reduce the behavioural expression of fear memories with long-lasting effects. The success of a reconsolidation intervention is, however, not guaranteed as it strongly depends on the destabilization of the memory. Identifying the necessary conditions to trigger destabilization remains one of the critical challenges in the field. We aimed to replicate a study from our lab, showing that the occurrence of a prediction error (PE) during reactivation is necessary but not sufficient for destabilization. We tested the effectiveness of a reactivation procedure consisting of a single PE, compared to two control groups receiving no or multiple PEs. All participants received propranolol immediately after reactivation and were tested for fear retention 24 h later. In contrast to the original results, we found no evidence for a reconsolidation effect in the single PE group, but a straightforward interpretation of these results is complicated by the lack of differential fear retention in the control groups. Our results corroborate other failed reconsolidation studies and exemplify the complexity of experimentally investigating this process in humans. Thorough investigation of the interaction between learning and memory reactivation is essential to understand the inconsistencies in the literature and to improve reconsolidation interventions.
In the years following publication of the DSM-5, the field of psychiatry has seen vigorous debate between the DSM’s more traditional, diagnosis-oriented approach and the NIMH’s more biological, dimension-based RDoC approach. Charney & Nestler’s Neurobiology of Mental Illness is an authoritative foundation for translating information from the laboratory to clinical treatment, and this edition extends beyond its reference function to acknowledge and examine the controversies and thoughts on the future of psychiatric diagnosis. In this wider context, this book provides information from numerous levels of analysis including molecular biology and genetics, cellular physiology, neuroanatomy, neuropharmacology, epidemiology, and behavior. Section I, which reviews the methods used to examine the biological basis of mental illness in animal and cell models and in humans, has been expanded to reflect important technical advances in complex genetics, epigenetics, stem cell biology, optogenetics, neural circuit functioning, cognitive neuroscience, and brain imaging. These established and emerging methodologies offer groundbreaking advances in our ability to study the brain and breakthroughs in our therapeutic toolkit. Sections II through VII cover the neurobiology and genetics of major psychiatric disorders: psychoses, mood disorders, anxiety disorders, substance use disorders, dementias, and disorders of childhood onset. Also covered within these sections is a summary of current therapeutic approaches for these illnesses as well as the ways in which research advances are now guiding the search for new treatments. The last section, Section VIII, focuses on diagnostic schemes for mental illness. This includes an overview of the unique challenges that remain in diagnosing these disorders given our still limited knowledge of disease etiology and pathophysiology. The section then provides reviews of DSM-5 and RDoC. Also included are chapters on future efforts toward precision and computational psychiatry, which promise to someday align diagnosis with underlying biological abnormalities.
Klasik korku koşullaması, klinik öncesi çalışmalarda travma sonrası stres bozukluğunu (TSSB) modellemede kullanılmaktadır. Yeniden-bütünleştirme sürecinde bellek reaktif hale geldiğinde kararsız bir duruma gelir ve müdahale edilmeye uygundur. Koşullu uyarana (CS) maruz bırakma ile tetiklenen yeniden-bütünleştirme sürecindeki müdahalelerin sadece maruz bırakılan CS’in indüklediği korku tepkisinde azalmaya neden olduğu, korku ile ilişkili diğer ipuçlarına genellenmediği gözlenmiştir. Ancak günlük yaşamda, birden çok CS, korku uyandıran olayla ilişkilendirilebilir. Bu nedenle, son çalışmalarda tüm korku belleğinin yeniden-bütünleştirme sürecine girmesine yol açtığı düşünülen, koşulsuz uyaran (US) ile geri çağırma prosedürüne odaklanılmıştır. US ile geri-çağırma ile tetiklenen yeniden-bütünleştirme sürecinde uygulanan müdahalelerin daha etkili olduğu düşünülmektedir. Bu derleme çalışmasında, CS veya US ile aktive edilmiş korku belleği çalışmalara atıfta bulunularak, edinilmiş korkunun davranışsal ve farmakolojik müdahalelerle nasıl söndürülebileceğinden bahsedilmektedir. Ayrıca, korku belleğinde rol oynayan beyin bölgeleri ve cinsiyet farklılıklarının etkisi de ele alınmıştır. Bu derlemenin amacı, korku bozukluklarının daha etkili tedavi yaklaşımlarıyla nasıl çözülebileceğine yönelik alana katkıda bulunmaktır.
As discussed in this chapter, there have been enormous advances in our understanding of how anxiety disorders develop, are maintained, and can be treated. Many of these advances have been the result of translational studies using fear conditioning and extinction models. Despite these successes, we recognize, as a field, that there are important limitations in the extent to which extinction can explain how anxiety disorders and behaviors remit. Clinically speaking, the outstanding challenge for treatment of anxiety disorders is to improve the current suboptimal success rates. Over the past 30 years, we have not improved our treatment success rates despite employing many pharmacological and pharmacological strategies. While extinction and related fear circuitry mechanisms most certainly appear to play a role in treatment of anxiety disorders, they are also apparently insufficient to fully accommodate the varied responses individuals exhibit with this treatment approach. Increasingly diverse and innovative approaches are needed that accommodate the multitude of change mechanisms involved in treating anxiety. However, this is not to suggest ignoring the key role that extinction and memory updating processes play in overcoming anxiety.
Reconsolidation results in the restabilisation, and thus persistence, of a memory made labile by retrieval, and interfering with this process is thought to enable modification or weakening of the original trace. As such, reconsolidation-blockade has been a focus of research aiming to target the maladaptive memories underlying mental health disorders, including post-traumatic stress disorder and drug addiction. Current first-line therapies are not effective for all patients, and a substantial proportion of those for whom therapies are effective later relapse. A reconsolidation-based intervention would be invaluable as an alternative treatment for these conditions. However, the translation of reconsolidation-based therapies to the clinic presents a number of challenges, with arguably the greatest being the overcoming of the boundary conditions governing the opening of the reconsolidation window. These include factors such as the age and strength of memory, and can broadly be divided into two categories: intrinsic features of the targeted memory itself, and parameters of the reactivation procedure used. With maladaptive memory characteristics inevitably varying amongst individuals, manipulation of the other limitations imposed by procedural variables have been explored to circumvent the boundary conditions on reconsolidation. Although several apparently discrepant results remain to be reconciled and these limitations yet to be truly defined, many studies have produced successful results which encouragingly demonstrate that boundary conditions may be overcome using various proposed strategies to enable translation of a reconsolidation-based intervention to clinical use.
Experiments demonstrating post-reactivation amnesia for learned fear in animals have generated a novel and influential hypothesis on the plasticity of memory, usually referred to as memory reconsolidation. The clinical potential of pharmacologically disrupting the process of memory reconsolidation has sparked a wave of interest into whether this phenomenon can also be demonstrated in humans, and ultimately harnessed for therapeutic purposes. In this essay we outline how the work of Karim Nader and colleagues has moved the field forward from a focus on extinction learning to the prospect of disrupting memory reconsolidation. We then review some promising findings on the necessary conditions, as well as potential boundary conditions, of pharmacologically disrupting the process of memory reconsolidation obtained in our laboratory. Even though laboratory experiments in animals and humans suggest that we may be at the brink of a breakthrough in fundamentally changing emotional memories, the necessary and sufficient conditions for targeting and disrupting memory reconsolidation in clinical practice are largely unknown. There is likely no universally effective reactivation procedure for triggering the reconsolidation of clinically significant emotional memories, and the impact of subtle boundary conditions observed in basic experiments compounds this issue. Notwithstanding these challenges, the discovery of changing emotional memory through disrupting the process of memory reconsolidation has unquestionably invigorated the field.
This commentary is part of a special issue honoring Karim Nader and his focal role in igniting the reconsolidation field. The commentary describes in broad strokes the evolution of the field, its branches, major challenges, and future endeavors.
In recent years, a controversial approach to the high rate of relapse in exposure therapy has resurfaced. Theoretically, the recovery of an already treated fear can be explained due to the competition that seems to take place between initial excitatory learning and a new inhibitory learning (produced by training in extinction) in which the former is shown superior. To address this matter, the weakening of the original learning is proposed by means of reactivating it and blocking its reconsolidation through pharmacological or behavioural methods. The great variability and inconsistency of methods and results that characterize this paradigm is shown in this work, which, on the one hand, invites to continue the research aimed at reaching firm conclusions and, on the other hand, questions the applicability of this strategy for the treatment of different psychopathologies.
Beliefs can be highly resilient in the sense that they are not easily abandoned in the face of counterevidence. This has the advantage of guiding consistent behavior and judgments but may also have destructive consequences for individuals, nature, and society. For instance, pathological beliefs can sustain psychiatric disorders, the belief that rhinoceros horn is an aphrodisiac may drive a species extinct, beliefs about gender or race may fuel discrimination, and belief in conspiracy theories can undermine democracy. Here, we present a unifying framework of how self-amplifying feedbacks shape the inertia of beliefs on levels ranging from neuronal networks to social systems. Sustained exposure to counterevidence can destabilize rigid beliefs but requires organized rational override as in cognitive behavioral therapy for pathological beliefs or institutional control of discrimination to reduce racial biases. Black-and-white thinking is a major risk factor for the formation of resilient beliefs associated with psychiatric disorders as well as prejudices and conspiracy thinking. Such dichotomous thinking is characteristic of a lack of cognitive resources, which may be exacerbated by stress. This could help explain why conspiracy thinking and psychiatric disorders tend to peak during crises. A corollary is that addressing social factors such as poverty, social cleavage, and lack of education may be the most effective way to prevent the emergence of rigid beliefs, and thus of problems ranging from psychiatric disorders to prejudices, conspiracy theories, and posttruth politics.
Background
Preclinical experiments with rodents demonstrate that cannabidiol (CBD), the non-psychotomimetic constituent of the Cannabis sativa plant, disrupts reconsolidation of aversive memories conditioned in the laboratory when administered within the memory reconsolidation window (< 6 h. post-retrieval) by indirectly activating cannabinoid type-1 (CB1) receptors in the dorsal anterior cingulate cortex (dACC). Based on these findings, we aim to test whether administration of 300 mg CBD-rich hemp extract oil following fear reactivation of an aversive interoceptive threat memory can disrupt reconsolidation of naturalistic aversive memories in humans. More specifically, naturalistic interoceptive aversive memories, a form of transdiagnostic fear memory that contributes to the pathogenesis of fear-related disorders such as panic disorder, posttraumatic stress disorder (PTSD), and illness anxiety disorder.
Methods
For this proof-of-concept, placebo-controlled double-blind trial, volunteers (n = 99) reporting elevated fears of somatic sensations will be stratified on biological sex and randomized to one of three intervention arms: (a). CBD-rich oil administered within the reconsolidation window, (b) Placebo oil administered within the reconsolidation window; or (c) CBD-rich oil administered outside of the reconsolidation window. Change in emotional reactivity to a 35% CO2 challenge from baseline to two-week follow-up will serve as our primary outcome.
Conclusion
Study findings may contribute towards the development of a novel brief transdiagnostic intervention guided by reconsolidation theory for individuals prone to fear-related psychiatric disorders.
Trial Registration: ClinicalTrials.gov Identifier: NCT04726475.
Systematic investigation of reactivation-induced memory updating began in the 1960s, and a wave of research in this area followed the seminal articulation of “reconsolidation” theory in the early 2000s. Myriad studies indicate that memory reactivation can cause previously consolidated memories to become labile and sensitive to weakening, strengthening, or other forms of modification. However, from its nascent period to the present, the field has been beset by inconsistencies in researchers’ abilities to replicate seemingly established effects. Here we review these many studies, synthesizing the human and nonhuman animal literature, and suggest that these failures-to-replicate reflect a highly complex and delicately balanced memory modification system, the substrates of which must be finely tuned to enable adaptive memory updating while limiting maladaptive, inaccurate modifications. A systematic approach to the entire body of evidence, integrating positive and null findings, will yield a comprehensive understanding of the complex and dynamic nature of long-term memory storage and the potential for harnessing modification processes to treat mental disorders driven by pervasive maladaptive memories.
The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though, that studies reporting no effect of propranolol on memory reconsolidation could be due to a failure to engage the memory destabilisation process, which is necessary for the memory to become susceptible to disruption with amnestic agents. Demonstrating that memory destabilisation has not been engaged is challenging when only using behavioural measures, but there are molecular correlates of memory destabilisation that can be used to determine whether memory lability has been induced. Here, we attempted to replicate the classic finding that systemic administration of propranolol disrupts the reconsolidation of a pavlovian auditory fear memory. Following a failure to replicate, we manipulated the parameters of the memory reactivation session to enhance prediction error in an attempt to overcome the boundary conditions of reconsolidation. On finding no disruption of memory despite these manipulations, we examined the expression of the post-synaptic density protein Shank in the basolateral amygdala. Degradation of Shank has been shown to correlate with the induction of memory lability, but we found no effect on Shank expression, consistent with the lack of observed behavioural effects.
Post-reactivation amnesia of contextual fear memories by blockade of noradrenergic signaling has been shown to have limited replicability in rodents. This is usually attributed to several boundary conditions that gate the destabilization of memory during its retrieval. However, how these boundary conditions can be overcome, and what neural mechanisms underlie post-reactivation changes in contextual fear memory remain largely unknown. Here, we report a series of experiments in a contextual fear conditioning paradigm in mice, that were aimed at elucidating these matters. Towards this overarching goal, we first attempted to obtain a training paradigm that would consistently result in a contextual fear memory that could be destabilized upon reactivation, enabling robust amnesia by administration of propranolol. Unexpectedly, our attempts were unsuccessful to this end. Specifically, over a series of 11 experiments (including replicates) in which we varied different parameters of the fear acquisition procedure and administered propranolol or anisomycin, at best small and inconsistent effects were observed. These null findings are surprising, given that the training paradigms we implemented were previously shown to be vulnerable to post-reactivation amnestic agents. Additionally, we found that propranolol did not alter memory retrieval-induced neural activity, as measured by the number of c-Fos+ cells in the hippocampal dentate gyrus. Together, our findings illustrate the elusive nature of reactivation-dependent changes of non-human fear memory and underscore the need for better control over genetic and environmental factors that may influence behavioral outcomes of commonly used mouse strains.
The long-term prevention of relapse is one of the most challenging aspects of treating drug addiction. Relapse can be precipitated by environmental cues previously associated with the drug high in a pavlovian manner. These drug-associated conditioned stimuli (CSs) become maladaptive emotional memories that interact with instrumental drug-seeking and drug-taking memories to enhance drug use, and these memories can persist for a lifetime.
Posttraumatic stress disorder (PTSD) is a common reaction to traumatic events. Many people recover in the ensuing months, but in a significant subgroup the symptoms persist, often for years. A cognitive model of persistence of PTSD is proposed. It is suggested that PTSD becomes persistent when individuals process the trauma in a way that leads to a sense of serious, current threat. The sense of threat arises as a consequence of: (1) excessively negative appraisals of the trauma and/or ist sequelae and (2) a disturbance of autobiographical memory characterised by poor elaboration and contextualisation, strong associative memory and strong perceptual priming. Change in the negative appraisals and the trauma memory are prevented by a series of problematic behavioural and cognitive strategies. The model is consistent with the main clinical features of PTSD, helps explain several apparently puzzling phenomena and provides a framework for treatment by identifying three key targets for change. Recent studies provided preliminary support for several aspects of the model.
Although disrupting reconsolidation is promising in targeting emotional memories, the conditions under which memory becomes labile are still unclear. The current study showed that post-retrieval changes in expectancy as an index for prediction error may serve as a read-out for the underlying processes engaged by memory reactivation. Minor environmental changes define whether retrieval induces memory reconsolidation or the initiation of a new memory trace even before fear extinction can be observed.
Memory persistence is critically influenced by retrieval. In rats, a single presentation of a conditioned fear stimulus induces memory reconsolidation and fear memory persistence, while repeated fear cue presentations result in loss of fear through extinction. These two opposite behavioral outcomes are operationally linked by the number of cue presentations at memory retrieval. However, the behavioral properties and mechanistic determinants of the transition have not yet been explored; in particular, whether reconsolidation and extinction processes coexist or are mutually exclusive, depending on the exposure to non-reinforced retrieval events. We characterized both behaviorally and molecularly the transition from reconsolidation to extinction of conditioned fear and showed that an increase in calcineurin (CaN) in the basolateral amygdala (BLA) supports the shift from fear maintenance to fear inhibition. Gradually increasing the extent of retrieval induces a gradual decrease in freezing responses to the conditioned stimulus and a gradual increase in amygdala CaN level. This newly synthesized CaN is required for the extinction, but not the reconsolidation, of conditioned fear. During the transition from reconsolidation to extinction, we have revealed an insensitive state of the fear memory where NMDA-type glutamate receptor agonist and antagonist drugs are unable either to modulate CaN levels in the BLA or alter the reconsolidation or extinction processes. Together, our data indicate both that reconsolidation and extinction are mutually exclusive processes and also reveal the presence of a transitional, or "limbo," state of the original memory between these two alternative outcomes of fear memory retrieval, when neither process is engaged.
Significance
Research on Pavlovian fear conditioning has been very successful in revealing what has come to be called the brain’s fear system. The field has now matured to the point where a sharper conceptualization of what is being studied could be very useful as we go forward. Terms like “fear conditioning” and “fear system” blur the distinction between processes that give rise to conscious feelings of fear and nonconscious processes that control defense responses elicited by threats. These processes interact but are not the same. Using terms that respect the distinction will help focus future animal research on brain circuits that detect and respond to threats, and should also help clarify the implications of this work for understanding how normal and pathological feelings of fear come about in the human brain.
In this article I review research and theory on the "interference paradigms" in Pavlovian learning. In these situations (e.g., extinction, counterconditioning, and latent inhibition), a conditioned stimulus (CS) is associated with different unconditioned stimuli (USs) or outcomes in different phases of the experiment; retroactive interference, proactive interference, or both are often observed. In all of the paradigms, contextual stimuli influence performance, and when information is available, so does the passage of time. Memories of both phases are retained, and performance may depend on which is retrieved. Despite the similarity of the paradigms, conditioning theories tend to explain them with separate mechanisms. They also do not provide an adequate account of the context's role, fail to predict the effects of time, and overemphasize the role of learning or storage deficits. By accepting 4 propositions about animal memory (i.e., contextual stimuli guide retrieval, time is a context, different memories are differentially dependent on context, and interference occurs at performance output), a memory retrieval framework can provide an integrated account of context, time, and performance in the various paradigms.
Overwriting Human Memory
A consolidated fear memory can enter a transient labile phase upon its reactivation. Pharmacological blockade of the subsequent protein synthesis-dependent restabilization produces a memory deficit. Sevenster et al. (p. 830 ) found that prediction error (a discrepancy between actual and expected events) is a necessary condition for reconsolidation of a fear memory in human subjects. Retrieval cued by a negative prediction error, for example, like a conditioned stimulus presented in the absence of the unconditioned stimulus, resulted in labilization and subsequent reconsolidation was blocked by the drug propranolol. However, if there was no prediction error because the conditioned stimulus and the aversive unconditioned stimulus were presented simultaneously, the memory did not enter a labile state and its reconsolidation could not be blocked.
In this article we propose mechanisms that govern the processing of emotional information, particularly those involved in fear reduction. Emotions are viewed as represented by information structures in memory, and anxiety is thought to occur when an information structure that serves as program to escape or avoid danger is activated. Emotional processing is defined as the modification of memory structures that underlie emotions. It is argued that some form of exposure to feared situations is common to many psychotherapies for anxiety, and that confrontation with feared objects or situations is an effective treatment. Physiological activation and habituation within and across exposure sessions are cited as indicators of emotional processing, and variables that influence activation and habituation of fear responses are examined. These variables and the indicators are analyzed to yield an account of what information must be integrated for emotional processing of a fear structure. The elements of such a structure are viewed as cognitive representations of the stimulus characteristic of the fear situation, the individual's responses in it, and aspects of its meaning for the individual. Treatment failures are interpreted with respect to the interference of cognitive defenses, autonomic arousal, mood state, and erroneous ideation with reformation of targeted fear structures. Applications of the concepts advanced here to therapeutic practice and to the broader study of psychopathology are discussed.
Fear conditioning is one of the prime paradigms of behavioural neuroscience and a source of tremendous insight in the fundamentals of learning and memory and the psychology and neurobiology of emotion. It is also widely regarded as a model for the pathogenesis of anxiety disorders in a diathesis-stress model of psychopathology. Starting from the apparent paradox between the adaptive nature of fear conditioning and the dysfunctional nature of pathological anxiety, we present a critique of the human fear conditioning paradigm as an experimental model for psychopathology. We discuss the potential benefits of expanding the human fear conditioning paradigm by (1) including action tendencies as an important index of fear and (2) paying more attention to "weak" (i.e., ambiguous) rather than "strong" fear learning situations (Lissek et al., 2006), such as contained in selective learning procedures. We present preliminary data that illustrate these ideas and discuss the importance of response systems divergence in understanding individual differences in vulnerability for the development of pathological anxiety.
The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.
Although the lateral nucleus of the amygdala (LA) is essential for conditioned auditory fear memory, an emerging theme is that plasticity in multiple brain regions contributes to fear memory formation. The LA receives direct projections from the auditory thalamus, specifically the medial division of the medial geniculate nucleus (MGm) and adjacent posterior intralaminar nucleus (PIN). While traditionally viewed as a simple relay structure, mounting evidence implicates the thalamus in diverse cognitive processes. We investigated the role of plasticity in the MGm/PIN in auditory fear memory. First we found that auditory fear conditioning (but not control manipulations) increased the levels of activated CREB in both the MGm and PIN. Next, using viral vectors, we showed that exogenously increasing CREB in this region specifically enhanced formation of an auditory conditioned fear memory without affecting expression of an auditory fear memory, formation of a contextual fear memory, or basic auditory processing. Interestingly, mice with increased CREB levels in the MGm/PIN also showed broad auditory fear generalization (in contrast to control mice, they exhibited fear responses to tones of other frequencies). Together, these results implicate CREB-mediated plasticity in the MGm/PIN in both the formation and generalization of conditioned auditory fear memory. Not only do these findings refine our knowledge of the circuitry underlying fear memory but they also provide novel insights into the neural substrates that govern the degree to which acquired fear of a tone generalizes to other tones.
We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment I(b), we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not "erase" the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, β-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.
Consolidated memories can re-enter states of transient instability following reactivation, from which they must again stabilize in order to persist, contradicting the previously dominant view that memory and its associated plasticity mechanisms progressively and irreversibly decline with time. We witness exciting times, as neuroscience begins embracing a position, long-held in cognitive psychology, that recognizes memory as a principally dynamic process. In light of remaining controversy, we here establish that the same operational definitions and types of evidence underpin the deduction of both reconsolidation and consolidation, thus validating the extrapolation that post-retrieval memory plasticity reflects processes akin to those that stabilized the memory following acquisition.
Animal studies have shown that fear memories can change when recalled, a process referred to as reconsolidation. We found that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear. Disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders.
Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.
Memory retrieval is not a passive phenomenon. Instead, it triggers a number of processes that either reinforce or alter stored information. Retrieval is thought to activate a second memory consolidation cascade (reconsolidation) that requires protein synthesis. Here, we show that the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger and weaker memories are more easily reconsolidated than older and stronger memories. We also report that reconsolidation and extinction, two opposing processes triggered by memory retrieval, have distinct biochemical signatures: pharmacological antagonism of either cannabinoid receptor 1 or L-type voltage-gated calcium channels blocks extinction but not reconsolidation. These studies demonstrate the dynamic nature of memory processing after retrieval and represent a first step toward a molecular dissection of underlying mechanisms.
Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the β-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non-reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Over the past decades, behaviour and cognitive psychology have produced fruitful and mutually converging theories from which hypotheses could be derived on the nature and origin of fear and anxiety disorders. Notwithstanding the emergence of effective treatments, there are still many questions that remain to be answered. Here, I will argue that the burgeoning field of behavioural neuroscience may advance our understanding of fear, anxiety disorders and its treatments. Decades of fear-conditioning research across species have begun to elucidate the neurobiological mechanisms underlying associative fear learning and memory. The fear-conditioning paradigm provides a well-controlled and fine-grained research platform to examine these processes. Although the traditional fear conditioning paradigm was originally designed to unveil general principles of fear (un)learning, it is well-suited to understand the transition from normal fear to pathological fear and the mechanisms of change. This paper presents 1) a selection of fear conditioning studies on the generalization and persistence of associative fear memory as intermediate phenotypes of fear and anxiety disorders, and 2) insights from neuroscience on the malleability of fear memory with the potential to provide a long-term cure for anxiety and related disorders.
Current exposure-based therapies aimed to reduce pathological fear and anxiety are now amongst the most effective interventions for trauma and anxiety related disorders. Nevertheless, they can be further improved to enhance initial and long-term outcomes. It is now widely accepted that a greater understanding of the neurobiological mechanisms of fear extinction is needed to further develop and identify novel effective targeted treatments as well as prevention strategies for fear-based and anxiety-related disorders. Guided by elegant mechanistic, cellular, and molecular preclinical reports, data from imaging studies are beginning to shape our understanding of how fear is quelled in the human brain. In this article, we briefly review the neural circuits underlying fear extinction in rodents and healthy humans. We then review how these circuits may fail to extinguish fear in patients with anxiety disorders. We end with a discussion examining how fear extinction research may lead to significant advances of current therapeutics for anxiety disorders.
In recent years the gap between psychological and psychiatric research and practice has lessened. In turn, greater attention has been paid toward how psychological and pharmacological treatments interact. Unfortunately, the majority of research has indicated no additive effect of anxiolytics and antidepressants when combined with psychological treatments, and in many cases pharmacological treatments attenuate the effectiveness of psychological treatments. However, as psychology and psychiatry have come closer together, research has started to investigate the neural and molecular mechanisms underlying psychological treatments. Such research has utilised preclinical models of psychological treatments, such as fear extinction, in both rodents and humans to determine multiple neural and molecular changes that may be responsible for the long-term cognitive and behavioural changes that psychological treatments induce. Currently, researchers are attempting to identify pharmacological agents that directly augment these neural/molecular changes, and which may be more effective adjuncts to psychological treatments than traditional anxiolytics and antidepressants. In this review we describe the research that has led to this new wave of thinking about combined psychological/pharmacological treatments. We also argue that an increased emphasis on identifying individual difference factors that predict the effectiveness of pharmacological adjuncts is critical in facilitating the translation of this preclinical research into clinical practice.
Infusion of a beta-adrenoceptor antagonist into the basolateral nucleus of the amygdala (BLA) blocks memory enhancement induced by systemic or intra-BLA administration of a glucocorticoid receptor (GR) agonist. As there is evidence that glucocorticoids interact with the noradrenergic signalling pathway in activating adenosine 3prime prime or minute,5prime prime or minute-cyclic monophosphate (cAMP), the present experiments examined whether glucocorticoids influence the beta-adrenoceptor--cAMP system in the BLA in modulating memory consolidation. Male, Sprague--Dawley rats received bilateral infusions of atenolol (a beta-adrenoceptor antagonist), prazosin (an alpha1-adrenoceptor antagonist) or Rp-cAMPS (a protein kinase A inhibitor) into the BLA 10 min before inhibitory avoidance training and immediate post-training intra-BLA infusions of the GR agonist, RU 28362. Atenolol and Rp-cAMPS, but not prazosin, blocked 48-h retention enhancement induced by RU 28362. A second series of experiments investigated whether a GR antagonist alters the effect of noradrenergic activation in the BLA on memory consolidation. Bilateral intra-BLA infusions of the GR antagonist, RU 38486, administered 10 min before inhibitory avoidance training completely blocked retention enhancement induced by alpha1-adrenoceptor activation and attenuated the dose--response effects of post-training intra-BLA infusions of clenbuterol (a beta-adrenoceptor agonist). However, the GR antagonist did not alter retention enhancement induced by post-training intra-BLA infusions of 8-Br-cAMP (a synthetic cAMP analogue). These findings suggest that glucocorticoids influence the efficacy of noradrenergic stimulation in the BLA on memory consolidation via an interaction with the beta-adrenoceptor--cAMP cascade, at a locus between the membrane-bound beta-adrenoceptor and the intracellular cAMP formation site.
This paper deals with questionnaires tapping fears of snakes, spiders, mutilation, and public speaking. Psychometric description of the scales across several samples indicated consistent distribution characteristics. In addition, consistently high reliability estimates were obtained; available results on test-retest reliability and validity were also encouraging. Correlations of these tests with one another and with general measures of anxiety indicated little shared variance. Inclusion of these scales in fear assessment procedures is suggested to promote standardization of evaluation and comparability of results across samples and laboratories.
In this paper I discuss five basic principles that make Beck's cognitive therapy (CT) a distinctive school of psychotherapy. In light of these principles, four major criticisms of Beck's standard cognitive theory and practice are considered. These include: (a) standard CT has a limited view of emotion; (b) CT has an inadequate view of interpersonal factors; (c) CT ignores the therapeutic alliance; and (d) CT overemphasizes conscious controlled processing. Each of these criticisms are evaluated on whether they can be accommodated within the standard CT approach advocated by Beck thereby leading to refinement of his theory and therapy, or whether efforts at revision and/or integration with other schools of psychotherapy result in a transformation so radical as to threaten the distinctiveness of Beck's therapy.
Posttraumatic stress disorder (PTSD) is a well recognized reaction to traumatic events, such as assault, disasters, and severe accidents. The symptoms include involuntary reexperiencing of aspects of the event, hyperarousal, emotional numbing, and avoidance of stimuli that could serve as reminders of the event. Many people experience at least some of these symptoms in the immediate aftermath of a traumatic event. A large proportion recover in the ensuing months or years, but in a significant subgroup the symptoms persist, often for many years (Ehlers, Mayou, & Bryant, 1998; Rothbaum, Foa, Riggs, Murdock, & Walsh, 1992; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995). This raises the question of why PTSD persists in some individuals and how the condition can be treated. The present chapter overviews our group's cognitive approach to these questions. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Evaluated a scale for measuring anxiety sensitivity (i.e., the belief that anxiety symptoms have negative consequences), the Child Anxiety Sensitivity Index (CASI), in 76 7th–9th graders and 33 emotionally disturbed children (aged 8–15 yrs). The CASI had sound psychometric properties for both samples. The view that anxiety sensitivity is a separate concept from that of anxiety frequency and that it is a concept applicable with children was supported. The CASI correlated with measures of fear and anxiety and accounted for variance on the Fear Survey Schedule for Children—Revised and the State-Trait Anxiety Inventory for Children (Trait form) that could not be explained by a measure of anxiety frequency. The possible role of anxiety sensitivity as a predisposing factor in the development of anxiety disorder in children is discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The conditioning theory of fear-acquisition is outlined and the supporting evidence and arguments presented. It is argued that the theory lacks comprehensiveness and is also inadequate in other respects.Six arguments against acceptance of the theory are advanced. People fail to acquire fears in what are theoretically fear-evoking situations (e.g. air raids). It is difficult to produce conditioned fear reactions in human subjects in the laboratory. The theory rests on the untenable equipotentiality premise. The distribution of human fears is not consistent with the theory. Many phobic patients recount histories inconsistent with the theory. Lastly, fears can be acquired indirectly, contrary to the demands of the conditioning theory. It is suggested that fears can be acquired by three pathways: conditioning, vicarious exposures and by the transmission of information and instruction. Vicarious and informational transmission of fears can take place in the absence of direct contact with the fear stimuli.
Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.
In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising interventions persistently erasing fear responses from trauma memory without affecting the actual recollection.
Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance-dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients.
Yohimbine's effects were assessed in rats using the five-choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein-a transcription factor implicated in the stress response-in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB.
Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbine's effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine.
These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations.
The retrieval of a memory places it into a plastic state, the result of which is that the memory can be disrupted or even enhanced by experimental treatment. This phenomenon has been conceptualised within a framework of memories being reactivated and then reconsolidated in repeated rounds of cellular processing. The reconsolidation phase has been seized upon as crucial for the understanding of memory stability and, more recently, as a potential therapeutic target in the treatment of disorders such as post-traumatic stress and drug addiction. However, little is known about the reactivation process, or what might be the adaptive function of retrieval-induced plasticity. Reconsolidation has long been proposed to mediate memory updating, but only recently has this hypothesis been supported experimentally. Here, the adaptive function of memory reconsolidation is explored in more detail, with a strong emphasis on its role in updating memories to maintain their relevance.
Based on a critical review of the literature, Davey (1994) [Behaviour Research and Therapy, 32, 291-299] concludes that there is no sufficient evidence to support the theoretical position that evaluative conditioning is a qualitatively different form of classical conditioning. In the present manuscript, we will try to show that Davey's conclusion is biased by: (a) an overemphasis on what he believes to be problematic procedural aspects of previous evaluative conditioning studies; and (b) a selective reading of the available evidence. Finally, an attempt is made to characterize evaluative conditioning phenomena as the output of a Referential Learning System, which can be distinguished from an Expectancy Learning System.
In this article I review research and theory on the "interference paradigms" in Pavlovian learning. In these situations (e.g., extinction, counterconditioning, and latent inhibition), a conditioned stimulus (CS) is associated with different unconditioned stimuli (USs) or outcomes in different phases of the experiment; retroactive interference, proactive interference, or both are often observed. In all of the paradigms, contextual stimuli influence performance, and when information is available, so does the passage of time. Memories of both phases are retained, and performance may depend on which is retrieved. Despite the similarity of the paradigms, conditioning theories tend to explain them with separate mechanisms. They also do not provide an adequate account of the context's role, fail to predict the effects of time, and overemphasize the role of learning or storage deficits. By accepting 4 propositions about animal memory (i.e., contextual stimuli guide retrieval, time is a context, different memories are differentially dependent on context, and interference occurs at performance output), a memory retrieval framework can provide an integrated account of context, time, and performance in the various paradigms.
The present studies compared the psychometric properties of two self-report measures of spider fear: Fear of Spiders Questionnaire (FSQ) and Spider Phobia Questionnaire (SPQ). In the first study, adequate test-retest stability and internal consistency was found for both FSQ and SPQ. In the second study, both instruments were able to differentiate between phobic and non-phobic subjects. Furthermore, FSQ as well as SPQ were sensitive to therapeutic change and correlated in a meaningful way with other subjective and behavioral indices of spider fear. Data suggest that the FSQ is superior to the SPQ in measuring fear in the non-phobic range. Also, the FSQ taps a somewhat different aspect of subjective spider fear (i.e., fear of harm) and, consequently, may provide additional information.
Context-specificity of fear extinction was tested among 65 participants who were fearful of spiders by manipulating the contexts used for exposure treatment and two-week follow-up assessment. Context was defined by both meaningful (presence of a particular therapist) and incidental (room location and furnishings) environmental cues. Distinct phobic stimuli were used to examine interactions of context with stimulus. Physiological, behavioral and verbal indices of fear were measured. Results provided modest support for context-specific return of fear. With one stimulus, participants assessed in a non-treatment context at follow-up exhibited greater returns in heart rate levels. In addition, three of four participants who could not touch the stimulus at follow-up had been tested in a non-treatment context. Future investigations may benefit from greater distinctions between contexts or manipulation of contextual features more directly relevant to fear. Finally, post hoc analyses identified high trait anxiety, slow treatment response, recovery of phobic cognitions and long duration/high intensity phobic encounters post-treatment as significant predictors of increased return of fear.
Posttraumatic stress disorder (PTSD) is a common reaction to traumatic events. Many people recover in the ensuing months, but in a significant subgroup the symptoms persist, often for years. A cognitive model of persistence of PTSD is proposed. It is suggested that PTSD becomes persistent when individuals process the trauma in a way that leads to a sense of serious, current threat. The sense of threat arises as a consequence of: (1) excessively negative appraisals of the trauma and/or its sequelae and (2) a disturbance of autobiographical memory characterised by poor elaboration and contextualization, strong associative memory and strong perceptual priming. Change in the negative appraisals and the trauma memory are prevented by a series of problematic behavioural and cognitive strategies. The model is consistent with the main clinical features of PTSD, helps explain several apparently puzzling phenomena and provides a framework for treatment by identifying three key targets for change. Recent studies have provided preliminary support for several aspects of the model.
'New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after conditioning. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolidation, delay of the infusion until six hours after memory reactivation produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These findings are not predicted by traditional theories of memory consolidation.
At least two temporally and mechanistically distinct forms of memory are conserved across many species: short-term memory that persists minutes to hours after training and long-term memory (LTM) that persists days or longer. In general, repeated training trials presented with intervening rest intervals (spaced training) is more effective than massed training (the same number of training trials presented with no or short intervening rest intervals) in producing LTM. LTM requires de novo protein synthesis, and cAMP response element-binding protein (CREB) may be one of the transcription factors regulating the synthesis of new proteins necessary for the formation of LTM. Here we show that rats given massed fear conditioning training show no or weak LTM, as measured by fear-potentiated startle, compared with rats given the same amount of training but presented in a spaced manner. Increasing CREB levels specifically in the basolateral amygdala via viral vector-mediated gene transfer significantly increases LTM after massed fear training. The enhancing effect of CREB overexpression on LTM formation is shown to be specific in terms of biochemistry, anatomy, time course, and the training procedure used. These results suggest that CREB activity in the amygdala serves as a molecular switch for the formation of LTM in fear conditioning.
It has been argued that in classical conditioning two processes might be operative. First, one may learn that the conditioned stimulus (CS+) is a valid predictor for the occurrence of the biologically negative or positive event (US; expectancy-learning). Second, one may learn to perceive the conditioned stimulus itself as a negative or positive stimulus, depending on the valence of the event it has been associated with (evaluative learning). Until the present, however, both forms of learning have been investigated using rather different conditioning procedures. Using a differential aversive conditioning preparation with pictures of human faces as CSs and an electrocutaneous stimulus as US, we were able to demonstrate that both forms of learning can co-occur. Moreover, the extent of evaluative learning in this aversive conditioning procedure did not significantly differ from the amount of evaluative learning in an evaluative conditioning procedure with positive and negative adjectives as USs, which was administered to the same participants. In the present study evaluative learning was not only indexed by direct evaluative ratings, but we introduced affective priming as an indirect and unobtrusive, reaction time based measure of stimulus valence. Finally, imagery instructions during acquisition did not facilitate expectancy-learning nor evaluative learning.
Infusion of a beta-adrenoceptor antagonist into the basolateral nucleus of the amygdala (BLA) blocks memory enhancement induced by systemic or intra-BLA administration of a glucocorticoid receptor (GR) agonist. As there is evidence that glucocorticoids interact with the noradrenergic signalling pathway in activating adenosine 3prime prime or minute,5prime prime or minute-cyclic monophosphate (cAMP), the present experiments examined whether glucocorticoids influence the beta-adrenoceptor--cAMP system in the BLA in modulating memory consolidation. Male, Sprague--Dawley rats received bilateral infusions of atenolol (a beta-adrenoceptor antagonist), prazosin (an alpha1-adrenoceptor antagonist) or Rp-cAMPS (a protein kinase A inhibitor) into the BLA 10 min before inhibitory avoidance training and immediate post-training intra-BLA infusions of the GR agonist, RU 28362. Atenolol and Rp-cAMPS, but not prazosin, blocked 48-h retention enhancement induced by RU 28362. A second series of experiments investigated whether a GR antagonist alters the effect of noradrenergic activation in the BLA on memory consolidation. Bilateral intra-BLA infusions of the GR antagonist, RU 38486, administered 10 min before inhibitory avoidance training completely blocked retention enhancement induced by alpha1-adrenoceptor activation and attenuated the dose--response effects of post-training intra-BLA infusions of clenbuterol (a beta-adrenoceptor agonist). However, the GR antagonist did not alter retention enhancement induced by post-training intra-BLA infusions of 8-Br-cAMP (a synthetic cAMP analogue). These findings suggest that glucocorticoids influence the efficacy of noradrenergic stimulation in the BLA on memory consolidation via an interaction with the beta-adrenoceptor--cAMP cascade, at a locus between the membrane-bound beta-adrenoceptor and the intracellular cAMP formation site.
There is now ample evidence that extinction, the loss of learned performance that occurs when a Pavlovian signal or an instrumental action is repeatedly presented without its reinforcer, does not reflect a destruction of the original learning. This article summarizes the evidence and extends and updates earlier reviews. The main alternative to "unlearning" is the idea that extinction (as well as other retroactive interference processes, including counterconditioning) involves new learning that is stored along with the old. One consequence is that the Pavlovian signal or instrumental action has two available "meanings" and thus has the properties of an ambiguous word: its current meaning (and the resulting behavioral output) depends on what the current context retrieves. Contexts can be provided by a variety of background stimuli, including the physical environment, internal drug state, and time. The second thing learned (e.g., extinction, counterconditioning) seems especially dependent on the context for retrieval. A variety of evidence is consistent with this analysis, which highlights several important sources of relapse after extinction. The article concludes with several issues for future research, among them the question of how we can optimize extinction and other putative "unlearning" treatments so as to prevent the various forms of relapse discussed here.