Marieke Soeter

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.

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.

An Abrupt Transformation of Phobic Behavior After a Post-Retrieval Amnesic Agent

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Noradrenergic enhancement of associative fear memory in humans

Ample evidence in animals and humans supports the noradrenergic modulation in the formation of emotional memory. However, in humans the effects of stress on emotional memory are traditionally investigated by declarative memory tests (e.g., recall, recognition) for non-associative emotional stimuli (e.g., stories, pictures). Given that anxiety disorders are thought to originate from associative learning processes and are characterized by distressing emotional responses, the existing literature seems to be inconclusive for the understanding of these disorders. Here, we tested whether noradrenaline strengthens the emotional expression of associative fear memory by using a differential fear conditioning procedure in humans. Stimulation of the noradrenergic system by the administration of yohimbine HCl (20mg) during memory formation did not directly augment the differential startle fear response 48 h later. Yet, the other retention tests uncovered that the administration of yohimbine HCl contrary to placebo pill extensively delayed the process of extinction learning and generated a superior recovery of fear (i.e., reinstatement and reacquisition). Conversely, the yohimbine HCl manipulation did not affect the skin conductance responding and the US expectancy ratings, emphasizing the concept of multiple memory systems. To our knowledge this is the first demonstration in humans that increased noradrenaline release during or shortly after a stressful event strengthens the formation of associative fear memory traces. The present findings suggest that noradrenaline may play an important role in the etiology and maintenance of anxiety disorders.

High Trait Anxiety: A Challenge for Disrupting Fear Memory Reconsolidation

Disrupting reconsolidation may be promising in the treatment of anxiety disorders but the fear-reducing effects are thus far solely demonstrated in the average organism. A relevant question is whether disrupting fear memory reconsolidation is less effective in individuals who are vulnerable to develop an anxiety disorder. By collapsing data from six previous human fear conditioning studies we tested whether trait anxiety was related to the fear-reducing effects of a pharmacological agent targeting the process of memory reconsolidation - n = 107. Testing included different phases across three consecutive days each separated by 24 h. Fear responding was measured by the eye-blink startle reflex. Disrupting the process of fear memory reconsolidation was manipulated by administering the β-adrenergic receptor antagonist propranolol HCl either before or after memory retrieval. Trait anxiety uniquely predicted the fear-reducing effects of disrupting memory reconsolidation: the higher the trait anxiety, the less fear reduction. Vulnerable individuals with the propensity to develop anxiety disorders may need higher dosages of propranolol HCl or more retrieval trials for targeting and changing fear memory. Our finding clearly demonstrates that we cannot simply translate observations from fundamental research on fear reduction in the average organism to clinical practice.

Fear inhibition in high trait anxiety.

Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear [1]. Sixty undergraduate students participated in the study - High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms [2] or with current anxiety symptoms [3], we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience

Disrupting the process of memory reconsolidation may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However both in animal and human studies the retrieval cue typically involves a re-exposure to the original fear-conditioned stimulus (CS). A relevant question is whether abstract cues not directly associated with the threat event also trigger reconsolidation, given that anxiety disorders often result from vicarious or unobtrusive learning for which no explicit memory exists. Insofar as the fear memory involves a flexible representation of the original learning experience, we hypothesized that the process of memory reconsolidation may also be triggered by abstract cues. We addressed this hypothesis by using a differential human fear-conditioning procedure in two distinct fear-learning groups. We predicted that if fear learning involves discrimination on basis of perceptual cues within one semantic category (i.e., the perceptual-learning group, n = 15), the subsequent ambiguity of the abstract retrieval cue would not trigger memory reconsolidation. In contrast, if fear learning involves discriminating between two semantic categories (i.e., categorical-learning group, n = 15), an abstract retrieval cue would unequivocally reactivate the fear memory and might subsequently trigger memory reconsolidation. Here we show that memory reconsolidation may indeed be triggered by another cue than the one that was present during the original learning occasion, but this effect depends on the learning history. Evidence for fear memory reconsolidation was inferred from the fear-erasing effect of one pill of propranolol (40 mg) systemically administered upon exposure to the abstract retrieval cue. Our finding that reconsolidation of a specific fear association does not require exposure to the original retrieval cue supports the feasibility of reconsolidation-based interventions for emotional disorders.

Personality predicts individual variation in fear learning: a multilevel growth modeling approach

Although fear-learning research has tended to focus on typical responses, there is substantial individual variation in response to threat. Here, we investigated how personality is related to variability in associative fear learning. We used multilevel growth curve modeling to examine the unique and interactive effects of Stress Reaction (SR) and Harmavoidance (HA; Multidimensional Personality Questionnaire scales) and their corresponding higher-order factors on differential fear conditioning (n = 225) and extinction (n = 109; 24–48 hr later). Fear was indexed by fear potentiation of the eyeblink startle reflex. Our findings demonstrated weaker discrimination between threat and safety with high levels of SR. Subsequently, both retention of differential fear acquisition and extinction were weaker with high levels of SR and HA, thereby indicating maladaptive fear learning, whereas they were stronger with low levels of SR and high levels of HA, which suggests efficient fear learning. These findings illustrate how specific personality traits may operate to confer vulnerability or resilience for anxiety disorders.

Disrupting reconsolidation of fear memory in humans by a noradrenergic β-blocker

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive days. On day 1 - the fear acquisition phase, healthy participants are exposed to a series of picture presentations. One picture stimulus (CS1+) is repeatedly paired with an aversive electric stimulus (US), resulting in the acquisition of a fear association, whereas another picture stimulus (CS2-) is never followed by an US. On day 2 - the memory reactivation phase, the participants are re-exposed to the conditioned stimulus without the US (CS1-), which typically triggers a conditioned fear response. After the memory reactivation we administer an oral dose of 40 mg of propranolol HCl, a β-adrenergic receptor antagonist that indirectly targets the protein synthesis required for reconsolidation by inhibiting the noradrenaline-stimulated CREB phosphorylation. On day 3 - the test phase, the participants are again exposed to the unreinforced conditioned stimuli (CS1- and CS2-) in order to measure the fear-reducing effect of the manipulation. This retention test is followed by an extinction procedure and the presentation of situational triggers to test for the return of fear. Potentiation of the eye blink startle reflex is measured as an index for conditioned fear responding. Declarative knowledge of the fear association is measured through online US expectancy ratings during each CS presentation. In contrast to extinction learning, disrupting reconsolidation targets the original fear memory thereby preventing the return of fear. Although the clinical applications are still in their infancy, disrupting reconsolidation of fear memory seems to be a promising new technique with the prospect to persistently dampen the expression of fear memory in patients suffering from anxiety disorders and other psychiatric disorders.