Shira Meir Drexler

Don’t fear ‘fear conditioning’: Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear

HighlightsOriginates from discussions on replicability and researchers 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. ABSTRACT 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.

Effects of Cortisol on Reconsolidation of Reactivated Fear Memories

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.

Effects of postretrieval-extinction learning on return of contextually controlled cued fear.

Reactivation of an already consolidated memory makes it labile for a period of several hrs, which are required for its reconsolidation. Evidence suggests that the return of conditioned fear through spontaneous recovery, reinstatement, or renewal can be prevented by blockading this reconsolidation process using pharmacological or behavioral interventions. Postretrieval-extinction learning has been shown to prevent the return of cued fear in humans using fear-irrelevant stimuli, as well as cued and contextual fear in rodents. The effects of postretrieval extinction on human contextually controlled cued fear to fear-relevant stimuli remain unknown, and are the focus of the present study. The experimental design was based on 3 consecutive days: acquisition, reactivation and extinction, and re-extinction. For the fear conditioning, 2 zoo frames served as different contexts, 5 fear-relevant stimuli (aversive animal pictures) served as conditioned stimuli (CS), electric shocks served as unconditioned stimuli (UCS). Expectancy ratings and skin-conductance response (SCR) were used as measures of fear responses; spontaneous recovery and renewal were used as indicators of the return of fear. The expectancy ratings and SCR results indicated spontaneous recovery on the third day, regardless of retrieval prior to extinction. No robust renewal effect was seen. It is suggested that the use of fear-relevant stimuli, the context salience, or reactivation context may explain the lack of reconsolidation effect. Our study indicates that the beneficial effects of postretrieval-extinction learning are sensitive to subtle methodological changes.

Stress disrupts the reconsolidation of fear memories in men

Reconsolidation is a post-retrieval process of restabilization of the memory trace. Previous findings from our group suggest that cortisol, a glucocorticoid hormone secreted in response to stress, enhances the reconsolidation of fear memories in healthy men. Cortisol effect was found to be very specific, enhancing only the fear memory that was reactivated (i.e. retrieved), but not the non-reactivated memory. In the current study we aimed to investigate the effects of psychosocial stress, a more ecologically valid intervention, on fear memory reconsolidation in men. Using a similar design, we expected stress induction to have comparable effects to those of cortisol intake. During the three testing days, the participants went through (1) fear acquisition, (2) stress induction and memory reactivation (or the corresponding control conditions), (3) fear extinction, reinstatement and reinstatement test. Salivary cortisol, blood pressure measures and subjective ratings confirmed the success of the stress induction. Skin conductance response, serving as a measure of conditioned fear, confirmed acquisition, fear retrieval, and extinction in all groups. In the three control groups (where either reactivation, stress, or both components were missing) reinstatement effects were seen as expected. Yet in contrast to the hypothesis, the target group (i.e. combining reactivation and stress) showed no reinstatement to any of the stimuli. Stress induction is thus suggested to have a general impairing effect on the reconsolidation of fear memories. The unique characteristic of the stress response and experience compared to a pharmacological intervention are proposed as possible explanations to the findings. This disruptive effect of stress on fear memory reconsolidation may have potential therapeutic implications.

Cortisol effects on fear memory reconsolidation in women

RationalePrevious work from our group has shown that cortisol enhances fear reconsolidation in men. Whether similar effects can be observed in women remains an open question.ObjectivesThe effects of cortisol on the reconsolidation of fear memories were investigated in women. Based on results in men, we expected a specific enhancing effect of cortisol administration on the reactivated fear memory. In addition, possible interactions with oral contraceptive use were tested.MethodsWe incorporated a differential fear conditioning paradigm in a 3-day reconsolidation design. A fear memory, which was created on the first day, was reactivated on the second day following cortisol administration in the target group. One control group was given cortisol without reactivation, and the other participated in the reactivation session following placebo intake. On the third day, the return of fear for all stimuli following reinstatement was tested. Skin conductance response served as measure of conditioned response.ResultsIn contrast to the hypothesis, cortisol in combination with reactivation did not enhance fear reconsolidation. No differences between the three experimental groups were apparent. In addition, hormonal contraceptive use had no effect on any of the learning phases and did not interact with the cortisol manipulation.ConclusionsThe lack of an effect in women might be the result of alternating concentrations of sex hormones during different phases of the menstrual cycle or following oral contraceptive use. Considering the higher vulnerability of women to stress-related mental disorders, further investigations in women are of great importance for both theory and treatment.

Stress before extinction learning enhances and generalizes extinction memory in a predictive learning task

HIGHLIGHTSThe context‐specificity of extinction memory often leads to renewal.Yet stress prior to learning can impair the integration of contextual cues.Our results show that pre‐extinction stress enhances and generalizes extinction.The results have implications for the use of glucocorticoids in exposure therapy. ABSTRACT In extinction learning, the individual learns that a previously acquired association (e.g. between a threat and its predictor) is no longer valid. This learning is the principle underlying many cognitive‐behavioral psychotherapeutic treatments, e.g. ‘exposure therapy’. However, extinction is often highly‐context dependent, leading to renewal (relapse of extinguished conditioned response following context change). We have previously shown that post‐extinction stress leads to a more context‐dependent extinction memory in a predictive learning task. Yet as stress prior to learning can impair the integration of contextual cues, here we aim to create a more generalized extinction memory by inducing stress prior to extinction. Forty‐nine men and women learned the associations between stimuli and outcomes in a predictive learning task (day 1), extinguished them shortly after an exposure to a stress/control condition (day 2), and were tested for renewal (day 3). No group differences were seen in acquisition and extinction learning, and a renewal effect was present in both groups. However, the groups differed in the strength and context‐dependency of the extinction memory. Compared to the control group, the stress group showed an overall reduced recovery of responding to the extinguished stimuli, in particular in the acquisition context. These results, together with our previous findings, demonstrate that the effects of stress exposure on extinction memory depend on its timing. While post‐extinction stress makes the memory more context‐bound, pre‐extinction stress strengthens its consolidation for the acquisition context as well, making it potentially more resistant to relapse. These results have implications for the use of glucocorticoids as extinction‐enhancers in exposure therapy.

Behavioral disruption of memory reconsolidation: From bench to bedside and back again.

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.

Stress and Memory Consolidation

This chapter presents stress modulation of learning and memory processes, focusing on the consolidation (and reconsolidation) of emotional memories in health and disease. A stressor is any kind of condition, which presents an environmental demand that exceeds the natural regulatory capacity of the individual. A stressor can be of a physical or psychological nature, tangible or mentally evoked. The subjective state of sensing these possibly adverse conditions is termed ‘stress’ and it leads to the activation of two systems: the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Their end-products of (nor)adrenaline and glucocorticoids mediate different functions but also work in concert to promote an adaptive physiological and behavioral response to the challenge. Stress can either enhance or impair memory, and the timing of the stress relative to the task plays a major role in determining the direction of these effects. The adaptive stress response prioritizes consolidation of potentially dangerous events, therefore while consolidation is enhanced, retrieval is usually impaired. Additional factors, such as stimulus and context characteristics (e.g. emotionality and arousal), stress intensity and duration, also play a role. While in several circumstances can stress hormones lead to strong and persistent maladaptive or traumatic memories, their memory-enhancing and retrieval-impairing properties also make them potential adjuvants for treatment, e.g. in extinction-learning based therapies.

The impact of stress and glucocorticoids on extinction and reconsolidation of emotional memories

Studies on episodic long-term memory have established the notion that the stress-induced increase in glucocorticoids (GCs) has a phase specific effect on memory. GCs enhance memory consolidation while memory retrieval is compromised. The relevance of these findings for the impact of GCs on extinction (and its retrieval) as well as on reconsolidation remains largely unknown. In the present overview I will summarize our recent work addressing these issues. For extinction consolidation, we observed that post-extinction stress made the extinction memory trace more context-dependent, leading to a stronger renewal effect. For extinction retrieval, the impact of stress depended on the emotionality of the original memory trace. In a fear-conditioning paradigm, stress prior to extinction retrieval caused a reduced return of the original fear memory. The opposite result pattern was observed when investigating a neutral predictive learning task. Influencing fear memory reconsolidation appears to be an attractive alternative when trying to eliminate fear memories. While the power of beta blockers to abolish fear memory reconsolidation has been shown convincingly, studies testing the impact of GCs on fear memory reconsolidation in humans were lacking. In a first experiment we could demonstrate that cortisol enhances fear memory reconsolidation as indicated by a stronger return of fear. Together, these studies provide a more elaborate view on the influence of GCs on the modulation of an existing memory trace using extinction or reconsolidation based approaches.