In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradigms with a learning element. We illustrate this empirically ...through case examples from human fear conditioning research, in which the exclusion of 'non-learners' and 'non-responders' is common - despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria identified in a systematic literature search and highlight the potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. On the basis of these studies, we propose a consensus on evidence-based rather than idiosyncratic criteria, including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element.
•Originates from discussions on replicability and researcher’s degrees of freedom.•Aims at stimulating discussions on methods applied in fear conditioning research.•Addresses critical issues on ...terminology, design, methods, analysis.•Serves as comprehensive compendium and critical evaluation of read-out measures.•Highlights methodological considerations when studying individual differences.
The so-called ‘replicability crisis’ has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe.
This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence-based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.
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•Glucocorticoids have a critical role in emotional memory reconsolidation.•Their effect is mediated by glucocorticoids receptors in the amygdala and hippocampus.•Glucocorticoid ...receptor antagonists might be useful to disrupt unwanted memories.
Glucocorticoids are secreted following exposure to stressful events. Their modulating role on memory reconsolidation, a post-retrieval process of re-stabilization, has been investigated only recently, at times with conflicting results. The goal of this review is twofold. First, to establish the modulating role of glucocorticoids on memory reconsolidation. Second, to point the potential factors and confounds that might explain the seemingly paradoxical findings. Here we review recent pharmacological studies, conducted in rodents and humans, which suggest a critical role of glucocorticoids in this post-retrieval process. In particular, the activation of glucocorticoid receptors in the amygdala and hippocampus is suggested to be involved in emotional memories reconsolidation, pointing to a similarity between post-retrieval reconsolidation and initial memory consolidation. In addition, based on the general reconsolidation literature, we suggest several factors that might play a role in determining the direction and strength of the reconsolidation effect following glucocorticoids treatment: memory-related factors, manipulation-related factors, and individual differences. We conclude that only when taking these additional factors into account can the paradox be resolved.
•Considers methodological comparability of translational research in fear conditioning in rodents and humans.•Equips researchers with practical and methodological considerations across species to ...foster translational behavioural neuroscience.•Aid designing of future experiments that employ more comparable processes in human participants and laboratory rodents in fear conditioning protocols.•Originates from discussions about fear conditioning protocols used in rodents and humans.
Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.
The return of conditioned fear after successful extinction (eg, following exposure therapy) is a significant problem in the treatment of anxiety disorders and posttraumatic stress disorder (PTSD). ...Targeting the reconsolidation of fear memories may allow a more lasting effect as it intervenes with the original memory trace. Indeed, several pharmacological agents and behavioral interventions have been shown to alter (enhance, impair, or otherwise update) the reconsolidation of reactivated memories of different types. Cortisol is a stress hormone and a potent modulator of learning and memory, yet its effects on fear memory reconsolidation are unclear. To investigate whether cortisol intervenes with the reconsolidation of fear memories in healthy males and how specific this effect might be, we built a 3-day reconsolidation design with skin conductance response (SCR) as a measure of conditioned fear: Fear acquisition on day 1; reactivation/no-reactivation of one conditioned stimulus and pharmacological intervention on day 2; extinction learning followed by reinstatement and reinstatement test on day 3. The groups differed only in the experimental manipulation on day 2: Reactivation+Cortisol Group, Reactivation+Placebo Group, or No-reactivation+Cortisol Group. Our results revealed an enhancing effect of cortisol on reconsolidation of the reactivated memory. The effect was highly specific, strengthening only the memory of the reactivated conditioned stimulus and not the non-reactivated one. Our findings are in line with previous findings showing an enhancing effect of behavioral stress on the reconsolidation of other types of memories. These results have implications for the understanding and treatment of anxiety disorders and PTSD.
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•Extinction learning is the most important underlying mechanism of exposure therapy.•Recent studies show that glucocorticoids, e.g. cortisol, can affect extinction.•However, the ...direction of effects depends on timing of stress/cortisol treatment.•Our model illustrates timing-depending effects of stress/cortisol on extinction.•We discuss theoretical and clinical implications of the model.
In recent years, various research groups aimed to augment extinction learning (the most important underlying mechanism of exposure therapy) using glucocorticoids (GCs), in particular the stress hormone cortisol. In this review, we introduce the STaR (Stress Timing affects Relapse) model, a theoretical model of the timing-dependent effects of stress/GCs treatment on extinction and relapse. In particular, we show that (1) pre-extinction stress/GCs promote memory consolidation in a context-independent manner, making extinction memory more resistant to relapse following context change. (2) Post-extinction stress also enhances extinction consolidation, but in a context-bound manner. These differences may result from the timing-dependent effects of cortisol on emotional memory contextualization. At the neural level, extinction facilitation is reflected in alterations in the amygdala-hippocampal-prefrontal cortex network. (3) Stress/GCs before a retrieval test impair extinction retrieval and promote relapse. This may result from strengthening amygdala signaling or disruption of the inhibitory functioning of the prefrontal cortex. The STaR model can contribute to the understanding and prevention of relapse processes.
During the postretrieval reconsolidation "window", memories can be disrupted, strengthened, or updated using various pharmacological and behavioral manipulations. Behavioral manipulations are more ...ecologically valid, thus allowing better understating of memory modification under natural conditions, but they can also be less potent compared to pharmacological interventions. In this review we present the current human and animal literature, aiming to understand the modulatory factors (i.e., task relevance, complexity, intensity) that promote reconsolidation disruption in purely behavioral means. The reviewed studies have suggested that both very simple tasks and more complex learning paradigms can be used to disrupt or update memory reconsolidation, even of stronger emotional memories. Stress exposure is a possible interference task, yet the conflicting results leave many open questions regarding its required timing and intensity. Going from bench to bedside and back again, we point to the need for more research in clinical populations to establish the therapeutic potential of reconsolidation-based treatments. Several findings from outside the laboratory offer promising leads for future research.
Extinction training creates a second inhibitory memory trace and effectively reduces conditioned responding. However, acute stress inhibits the retrieval of this extinction memory trace. It is not ...known whether this also applies to other forms of associative learning such as instrumental counterconditioning, where previously learned associations are reversed and paired with the opposite valence. Therefore, the current preregistered study investigates whether stress decreases the retrieval of instrumental counterconditioning memories with aversive and appetitive consequences. Fifty-two healthy men were randomly assigned to either a stress or control group and took part in a two-day instrumental learning paradigm. During a first phase, participants learned that pressing specific buttons in response to the presentation of four neutral stimuli either leads to gaining or losing money. During a second phase, two stimuli reversed their contingencies (counterconditioning). One day later, participants were exposed to acute stress or a control condition prior to the same task, which no longer included feedback about gains or losses. Stressed participants showed more approach behavior towards appetitive and less avoidance behavior towards aversive stimuli as compared to non-stressed participants. Our findings indicate that stress effects on memory retrieval differ depending on the associative learning approach in men. These differences might be related to stress effects on decision making and different motivational systems involved.
Reconsolidation is the post-retrieval stabilization of memories, a time-limited process during which reactivated (i.e., retrieved) memories can be updated with new information, become stronger or ...weaker, depending on the specific treatment. We have previously shown that the stress hormone cortisol has an enhancing effect on the reconsolidation of fear memories in men. This effect was specific, i.e., limited to the conditioned stimulus (CS) that was reactivated, and did not generalize to other previously reinforced, but not reactivated, CS. Based on these results, we suggested that cortisol plays a critical role in the continuous strengthening of reactivated emotional memories, contributing to their persistence and robustness. In the current study, we aimed to achieve a more generalized reconsolidation enhancement using an alternative reactivation method, i.e., by low-intensity unconditioned stimulus (UCS) presentation instead of the more common unreinforced CS presentation. In previous studies, UCS reactivation was shown to lead to a more generalized reconsolidation effect. Therefore, we hypothesized that the combination of cortisol treatment and UCS reactivation would lead to an enhanced fear memory reconsolidation, which would generalize from previously reinforced CS to stimuli that resemble it. We tested 75 men in a three-day fear conditioning paradigm: fear acquisition training on day 1; UCS reactivation/no reactivation and pharmacological treatment (20mg hydrocortisone/placebo) on day 2; extinction training, reinstatement and test (of original and modified stimuli) on day 3. In contrast to our hypothesis, UCS reactivation prevented the return of fear (observed in skin conductance responses) regardless of the pharmacological manipulation: while reinstatement to the original CS was found in the no-reactivation group, both reactivation groups (cortisol and placebo) showed no reinstatement. As the only methodological difference between our previous study and the current one was the reactivation method, we focus on UCS reactivation as the main explanation for these unexpected findings. We suggest that the robust prediction error generated by this UCS reactivation method (as opposed to CS reactivation) can by itself lead to memory reconsolidation impairment. We call for future research to support these findings and to examine the potential of this reactivation method, or variations thereof, as a tool for therapeutic use.
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