Merel Kindt

Beyond extinction: erasing human fear responses and preventing the return of fear

Animal studies have shown that fear memories can change when recalled, a process referred to as reconsolidation. We found that oral administration of the β-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.

Autobiographical memories become less vivid and emotional after eye movements.

OBJECTIVES To test (1) whether eye movements during retrieval of emotional memories are followed by less vividness and less emotionality of future recollections, (2) whether this effect, if present, is stronger than the effects of a control activity (finger tapping), (3) whether the alleged effects of tapping and eye movements are stronger than a no-movement, control condition (mere imagery), (4) whether reductions in vividness and emotionality after eye movements (and finger tapping) are specific to negative memories or also occur in the case of positive memories. METHOD Sixty healthy volunteers recalled either positive or negative memories and scored the vividness and emotionality of the recollections. Next, memories were recalled whilst the participant was performing rapid eye movements, finger tapping, or not performing a dual task. Then participants were asked to recall the event again and to rate its vividness and emotionality. RESULTS Compared to finger tapping and the no-dual-task condition, recollections after eye movements made future recollections less vivid. After eye movements, but not after the other interventions, negative memories became less negative, and positive memories became less positive. CONCLUSION The findings show that eye movements not only reduce vividness and emotionality of memories during the eye moving, but also affect future recollections, during which no eye movements are made. Some theoretical explanations are discussed. As to clinical implications, it is suggested that if there is a role for eye-movement-based treatments, it is very limited.

Prediction error governs pharmacologically induced amnesia for learned fear

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. Human fear memory labilization can be assessed noninvasively, independent of whether reconsolidation occurs. Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.

Salivary alpha amylase and cortisol responses to different stress tasks: Impact of sex

Neuro-endocrine markers such as salivary alpha amylase (sAA) and cortisol (CORT) play an important role in establishing human responses to stressful events. Whereas sAA levels reflect sympathetic system activity, salivary cortisol appears to be a valid measure for HPA axis activity. Although many studies looked at either sAA or CORT responses in reaction to stress, work still has to be done to look at the way these systems interact, especially when both systems are activated. Additionally, sex effects in CORT responses have been investigated relatively often, but possible sex differences in sAA levels and responses, or the way both systems interact has not been the focus of sufficient studies to yield a univocal conclusion. In this study we presented a group of healthy participants (n=80) with two mildly stressful tasks, consisting of an aversive picture rating task and a cold pressor stress (CPS) task. The second task was compared with a control task. We expected a rise in sAA level in response to the first task and sAA as well as CORT responses on the second task and explored the interaction between the two responses. Results indicate that sAA is indeed a sensitive marker in both psychologically and physically induced arousal paradigms, whereas a cortisol response was only observed in the CPS task. Men had higher sAA levels than women during the complete course of the study, but men and women were comparable in their responsivity to the tasks. No strong correlations between sAA and CORT responses were found.

Retrieval per se is not sufficient to trigger reconsolidation of human fear memory

Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not necessarily affect the cognitive component and vice versa. Second, mere retrieval of the fear memory is not sufficient to induce its labilization and reconsolidation.

Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding

Emotionally arousing experiences are usually well retained, an effect that depends on the release of adrenal stress hormones. Animal studies have shown that corticosterone and noradrenaline - representing the two main stress hormone systems - act in concert to enhance memory formation by actions involving the amygdala, hippocampus and prefrontal cortex (PFC). Here we test whether interactions between these two stress hormone systems also affect human memory formation as well as the associated pattern of brain activation. To this end, forty-eight male human subjects received hydrocortisone, yohimbine or both before presentation of emotional and neutral pictures. Activity in the amygdala, hippocampus and PFC was monitored with functional Magnetic Resonance Imaging (fMRI) during encoding of these stimuli, when hormonal levels were elevated. Memory performance was tested 1 week later. We investigated whether an increased level of one of the two hormone systems would lead to differential effects compared to the combined application of the drugs on brain activation and memory performance. We report that the application of cortisol led to an overall enhancing effect on recognition memory, with no significant additional effect of yohimbine. However, during encoding the brain switched from amygdala/hippocampus activation with either hormone alone, to a strong deactivation of prefrontal areas under the influence of the combination of both exogenous hormones. Although we did not find evidence that exogenous stimulation of the noradrenergic and corticosteroid systems led to significant interaction effects on memory performance in this experiment, we conclude that stress hormone levels during encoding did differentially determine the activation pattern of the brain circuits here involved.

Peritraumatic dissociation and posttraumatic stress after pregnancy loss: a prospective study

This study examined (1). predictors for peritraumatic dissociation, (2). its relations with acute and chronic symptoms of posttraumatic stress disorder (PTSD), and (3). pathways regarding these relations in response to pregnancy loss. In early pregnancy, about 1370 women volunteers completed questionnaires for neuroticism, control over emotions, dissociative tendencies, absorption, and prior life events. Of these, 126 subsequently experienced pregnancy loss and most of them completed measures 1 month (N = 118) and 4 months (N = 104) later. At 1 month, peritraumatic dissociation, memory of pregnancy loss (degree of fragmentation, sensory impressions, and emotional intensity), thought suppression, and PTSD symptoms were assessed, and at 4 months, PTSD symptoms were re-assessed. Peritraumatic dissociation was predicted by prior low control over emotions, dissociative tendencies, and lower education. It was not predicted by neuroticism, absorption, and prior life events. Peritraumatic dissociation was related to acute PTSD symptoms and LISREL analyses indicated that self-reported memory fragmentation and thought suppression of pregnancy loss mediated this relation. It also predicted chronic PTSD symptoms, and this relation was mediated by acute PTSD symptoms.

Stimulation of the Noradrenergic System during Memory Formation Impairs Extinction Learning but not the Disruption of Reconsolidation

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 α2-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.

Responding to subliminal threat cues is related to trait anxiety and emotional vulnerability: a successful replication of Macleod and Hagan (1992)

Macleod and Hagan (1992) [Behaviour Research and Therapy, 30, 151-161] reported that threat-relevant interference on a masked Stroop task, where neutral and negative words cannot be consciously perceived, is positively correlated with trait anxiety and emotional vulnerability to stressful life events. Their findings were obtained from subjects who were currently stressed. The aim of the present study was to determine whether the Macleod and Hagan findings could be replicated in a sample that was not currently stressed. Using a sample of 32 volunteers, we found a significant correlation between trait anxiety and threat-relevant interference on a masked Stroop. Furthermore, it was found that the single best predictor of vulnerability to life stress was the interference on the masked Stroop. The findings of the present study correspond quite closely to those reported by Macleod and Hagan (1992).

Phobia-related cognitive bias for pictorial and linguistic stimuli.

The purpose of this study was to examine whether anxiety-related cognitive bias for threat is stronger for threatening pictures than for threatening words. Spider-phobic participants (n = 31) and control participants (n = 33) performed a pictorial and linguistic spider Stroop task. Spider-phobic participants showed a marked bias for threat. However, this bias was similar for pictures and for words, although the spider-phobic group evaluated the pictures as being more aversive. The results suggest that automatic processing of threatening information in people with phobias is triggered in an on-off fashion, independent of subjective threat of the stimuli. This lack of distinction in automatic processing of weak and strong predictors of danger may be fundamental to the irrational nature of anxiety disorders.