Pre-encoding stress induced changes in perceived stress, blood pressure and cortisol are differentially associated with recollection and familiarity.

Stress before encoding is often linked to impaired memory. Further influences of stress on memory are arousal of the to be learned material and memory retrieval type (free recall vs. recognition). In the current study we tested the influence of stress on memory encoding for neutral and negative arousing pictures in healthy young adults. A total of 80 participants (40 men) were subjected either to the socially evaluated cold pressure test or a control condition before encoding of arousing and neutral pictures. One day later participants underwent a recognition test. Results show different relationships between the obtained stress markers and recognition memory. Higher perceived stress ratings predicted poorer overall accuracy for arousing material. Lower perceived stress ratings and larger blood pressure increase predicted higher recollection values for arousing material. In contrast, a larger cortisol increase predicted lower familiarity values for arousing material. Concluding, activity of the sympathetic nervous system (SNS) and a lower feeling of perceived stress predict better recollection. HPA axis activity predicts lower familiarity. Pre-encoding induced changes in the perceived feeling of stress, activity of the SNS, and activity of the HPA axis show specific and distinct relationships to recognition memory.

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

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learning, the individual learns that a previously acquired association (e.g. between a threat and its predictor) is no longer valid.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.

Cortisol effects on fear memory reconsolidation in women.

RATIONALE: Previous 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. OBJECTIVES: The 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: The 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.

Immediate extinction promotes the return of fear.

Accumulating evidence indicates that immediate extinction is less effective than delayed extinction in attenuating the return of fear. This line of fear conditioning research impacts the proposed onset of psychological interventions after threatening situations. In the present study, forty healthy men were investigated in a differential fear conditioning paradigm with fear acquisition in context A, extinction in context B, followed by retrieval testing in both contexts 24h later to test fear renewal. Differently coloured lights served as conditioned stimuli (CS): two CS (CS+) were paired with an electrical stimulation that served as unconditioned stimulus, the third CS was never paired (CS-). Extinction took place immediately after fear acquisition or 24h later. One CS+ was extinguished whereas the second CS+ remained unextinguished to control for different time intervals between fear acquisition and retrieval testing. Immediate extinction led to larger skin conductance responses during fear retrieval to both the extinguished and unextinguished CS relative to the CS-, indicating a stronger return of fear compared to delayed extinction. Taken together, immediate extinction is less potent than delayed extinction and is associated with a stronger renewal effect. Thus, the time-point of psychological interventions relative to the offset of threatening situations needs to be carefully considered to prevent relapses.

Enhanced emotional empathy after psychosocial stress in young healthy men.

Empathy is a core prerequisite for human social behavior. Relatively, little is known about how empathy is influenced by social stress and its associated neuroendocrine alterations. The current study was designed to test the impact of acute stress on emotional and cognitive empathy. Healthy male participants were exposed to a psychosocial laboratory stressor (trier social stress test, (TSST)) or a well-matched control condition (Placebo-TSST). Afterwards they participated in an empathy test measuring emotional and cognitive empathy (multifaceted empathy test, (MET)). Stress exposure caused an increase in negative affect, a rise in salivary alpha amylase and a rise in cortisol. Participants exposed to stress reported more emotional empathy in response to pictures displaying both positive and negative emotional social scenes. Cognitive empathy (emotion recognition) in contrast did not differ between the stress and the control group. The current findings provide initial evidence for enhanced emotional empathy after acute psychosocial stress.

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.

Stress following extinction learning leads to a context-dependent return of fear.

It has been suggested that extinction-based therapy benefits from administration of the stress hormone cortisol. However, it is unclear whether similar effects can be obtained by inducing stress instead of administering cortisol, and whether the effects also persist if memory is tested in a different context (renewal test) or after exposure to an aversive stimulus (reinstatement). The present study therefore applied a fear conditioning (context A, day 1) and extinction (context B, day 2) paradigm in healthy men. After fear extinction, participants were exposed to a stress or control procedure (n = 20 each). Fear retrieval was tested in contexts A and B on day 3. Postextinction stress increased skin conductance responses to the extinguished stimulus in the retrieval and reinstatement test especially in the acquisition context. The context-dependent return of fear may reflect enhancing effects of stress on the consolidation of contextual cues.

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.

Exposure to stress attenuates fear retrieval in healthy men.

The stress hormone cortisol reduces retrieval of emotional memories, which has been suggested to support the treatment of psychiatric disorders characterized by exaggerated fear-related memories. Indeed, studies in patients with anxiety disorders have indicated that the success of exposure therapy can be enhanced with accompanying cortisol administration. Fear renewal refers to the clinically relevant phenomenon that successfully extinguished fear can return after a context change. It remains to be investigated whether the effects of stress hormones on fear retrieval also generalize across different contexts. Healthy men were exposed to a fear renewal design with fear acquisition in context A and extinction in context B. Pictures of rooms served as contexts, coloured lights were introduced as conditioned stimuli (CS), and an electrical stimulation served as the unconditioned stimulus (UCS). On the next day, participants were randomly assigned to a stress (Socially Evaluated Cold Pressor Test) or a control condition (n=20 each). We tested for fear retrieval in contexts A and B during peak cortisol concentrations after stress induction. Overall, a context×stress interaction occurred, revealing that stress attenuated skin conductance responses in the extinction context B. Stress also reduced UCS expectancy in context B. Additionally, stress abolished the renewal effect (differentiation between CS in context A) at the electrodermal level. These results demonstrate a decreased return of fear after acute exposure to stress. Stress interferes with the retrieval of the original fear memory which in turn affects extinction responding. Thus, acute stress reduces rather than promotes the return of fear.

Stress enhances the consolidation of extinction memory in a predictive learning task.

Extinction is not always permanent, as indicated by several types of recovery effects, such as the renewal effect, which may occur after a context change and points towards the importance of contextual cues. Strengthening the retrieval of extinction memory is a crucial aim of extinction-based psychotherapeutic treatments of anxiety disorders to prevent relapse. Stress is known to modulate learning and memory, with mostly enhancing effects on memory consolidation. However, whether such a consolidation-enhancing effect of acute stress can also be found for extinction memory has not yet been examined in humans. In this study, we investigated the effect of stress after extinction learning on the retrieval of extinction memory in a predictive learning renewal paradigm. Participants took the part of being the doctor of a fictitious patient and learned to predict whether certain food stimuli were associated with "stomach trouble" in two different restaurants (contexts). On the first day, critical stimuli were associated with stomach trouble in context A (acquisition phase). On the second day, these associations were extinguished in context B. Directly after extinction, participants were either exposed to a stressor (socially evaluated cold pressor test; n = 22) or a control condition (n = 24). On the third day, we tested retrieval of critical associations in contexts A and B. Participants exposed to stress after extinction exhibited a reduced recovery of responding at test in context B, suggesting that stress may context-dependently enhance the consolidation of extinction memory. Furthermore, the increase in cortisol in response to the stressor was negatively correlated with the recovery of responding in context A. Our findings suggest that in parallel to the known effects of stress on the consolidation of episodic memory, stress also enhances the consolidation of extinction memory, which might be relevant for potential applications in extinction-based psychotherapy.

What we remember from a stressful episode.

A stressful episode is thought to be consolidated better because of a stress-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis. However, human experimental studies addressing this hypothesis directly are lacking. Thus, we investigated memories of the stressful episode itself. Furthermore, we aimed to determine the influence of stress on recollection and familiarity processes. Participants (n=63) were subjected to a psychosocial stressor (Trier Social Stress Test, TSST) or a newly developed non-stressful control condition (friendly-TSST). During both conditions, they were exposed to a committee and visual stimuli, either bound to the situation (central) or not (peripheral). The next day, participants engaged in unexpected recognition tasks. Negative affect and salivary cortisol concentration increased in stressed but not in control participants. The following day, stressed participants recognized central objects and the committees' faces better than control participants. Furthermore, recollection contributed significantly more to memory performance in stressed than in control participants. Our findings are congruent with the idea of enhanced memory binding under stress combined with enhanced memory consolidation of information acquired during stress. What we remember from a stressful episode appears to be determined by the strength of the association between the stressor and the material to be remembered.

Stress impairs retrieval of extinguished and unextinguished associations in a predictive learning task.

Recovery effects which can frequently be observed after a seemingly successful extinction procedure indicate that extinction does not lead to an erasure of the memory trace. Investigating factors which modulate the retrieval of extinction memory is highly relevant for basic science and clinical applications alike. This study investigated the effect of stress on the retrieval of extinguished and unextinguished stimulus-outcome associations in a predictive learning task. In this task, participants had to imagine being the doctor of a patient who sometimes suffers from stomach trouble after meals in his favorite restaurants. They were presented with different food stimuli while having to predict the occurrence or non-occurrence of stomach trouble. As extinction memory is modulated by context, we manipulated contextual cues so that initial acquisition of critical associations occurred in context (restaurant frame) A on day one, whereas associations were reversed in context B (extinction, day two). On the third day, participants were either stressed (exposed to the socially evaluated cold pressor task (SECPT); n=21) or subjected to a control condition (n=21) shortly before extinction memory retrieval was tested (in contexts A and B). Salivary cortisol and blood pressure measures as well as subjective ratings indicated that stress induction was successful. When retrieval of extinguished associations was tested on day three, participants' predictions reflected a renewal effect, as indicated by stronger recovery of responding in the acquisition context compared to the extinction context. Compared to controls, stressed participants showed impaired retrieval of extinguished and unextinguished associations. Contextual cues abolished the stress-induced memory impairment for unextinguished but not for extinguished associations. These findings might help to explain why stress leads to the reoccurrence of symptoms in affective disorders.