disrupting-reconsolidation-fear-memory-humans-noradrenergic

Disrupting Reconsolidation of Fear Memory in Humans by a Noradrenergic &#946;-Blocker

The basic design used in our human fear-conditioning studies on disrupting reconsolidation includes testing over different phases across three consecutive ...

University of Amsterdam

Cognitive behavioural treatment (CBT) is highly effective in treating post-traumatic stress disorder (PTSD). However, the mechanisms of change are still poorly understood. The aim of the present study was to investigate trauma processing during and after CBT for PTSD. Treatment consisted of imaginal exposure combined with rescripting. The rationale of this treatment is that dysfunctional interpretations may best be corrected by inducing new perspectives on what happened during trauma by experiencing new views and new emotions. In twenty-five chronic patients with PTSD, we tested whether an initial increase of perceptual processing and a subsequent increase of conceptual processing predicted treatment outcome. Possible changes in perceptual/conceptual processing during and after treatment were inferred from changes in trauma memories from pre- to post-treatment and from post- to 1-month follow-up. These memory parameters were assessed by analysing trauma narratives that were produced before the first treatment session, after the last treatment session and at follow-up. Consistent with predictions, a relative increase of conceptual processing after treatment predicted treatment outcome levels for both PTSD symptoms and general psychopathology at 1-month follow-up. Although a relative increase of perceptual processing during treatment also predicted treatment outcome, this effect was explained by the beneficial effect of a subsequent increase of conceptual processing. But an increase of perceptual processing during treatment was strongly related to an increase of conceptual processing after treatment. The results suggest that imaginal reliving during CBT is not crucial for symptom reduction, but it may promote conceptual processing, which in itself predicts a better treatment outcome.

Perceptual and conceptual processing as predictors of treatment outcome in PTSD.

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

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

In addition to the extensive evidence in animals, we previously showed that disrupting reconsolidation by noradrenergic blockade produced amnesia for the original fear response in humans. Interestingly, the declarative memory for the fear association remained intact. These results asked for a solid replication. Moreover, given the constructive nature of memories, the intact recollection of the fear association could eventually 'rebuild' the fear memory, resulting in the spontaneous recovery of the fear response. Yet, perseverance of the amnesic effects would have substantial clinical implications, as even the most effective treatments for psychiatric disorders display high percentages of relapse. Using a differential fear conditioning procedure in humans, we replicated our previous findings by showing that administering propranolol (40mg) prior to memory reactivation eliminated the startle fear response 24h later. But most importantly, this effect persisted at one month follow-up. Notably, the propranolol manipulation not only left the declarative memory for the acquired contingency untouched, but also skin conductance discrimination. In addition, a close association between declarative knowledge and skin conductance responses was found. These findings are in line with the supposed double dissociation of fear conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. They support the view that skin conductance conditioning primarily reflects contingency learning, whereas the startle response is a rather specific measure of fear. Furthermore, the results indicate the absence of a causal link between the actual knowledge of a fear association and its fear response, even though they often operate in parallel. Interventions targeting the amygdalar fear memory may be essential in specifically and persistently dampening the emotional impact of fear. From a clinical and ethical perspective, disrupting reconsolidation points to promising interventions persistently erasing fear responses from trauma memory without affecting the actual recollection.

Dissociating response systems: erasing fear from memory.

We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment I(b), we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not "erase" the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, β-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.

Disrupting reconsolidation: pharmacological and behavioral manipulations.

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.

Noradrenergic enhancement of associative fear memory in humans.

Disrupting reconsolidation seems to be a promising approach to dampen the expression of fear memory. Recently, we demonstrated that disrupting reconsolidation by a pharmacological manipulation specifically targeted the emotional expression of memory (i.e., startle response). Here we test in a human differential fear-conditioning paradigm with fear-relevant stimuli whether the spacing of a single unreinforced retrieval trial relative to extinction learning allows for "rewriting" the original fear association, thereby preventing the return of fear. In contrast to previous findings reported by Schiller et al. (2010), who used a single-method for indexing fear (skin conductance response) and fear-irrelevant stimuli, we found that extinction learning within the reconsolidation window did not prevent the recovery of fear on multiple indices of conditioned responding (startle response, skin conductance response and US-expectancy). These conflicting results ask for further critical testing given the potential impact on the field of emotional memory and its application to clinical practice.

Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism.

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 α(2)-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.

Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation.

Although memory for emotionally arousing and stressful experiences is strong and resistant to change, recent years have witnessed rapidly emerging evidence for the plasticity of fear memories. Upon retrieval a memory may be rendered labile and vulnerable to the disruptive effects of amnestic agents. This process is referred to as "disrupting reconsolidation" and may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However, the fear-reducing effects are thus far only demonstrated for freezing reactions in rodents and autonomic fear responding in humans. If disrupting reconsolidation will be of value for clinical practice, it should also target the subjective feelings of anxiety. Using an instructed fear-learning paradigm in humans, we here tested whether disrupting reconsolidation would diminish the subjective feelings of anxiety for a noxious event that was anticipated but never actually experienced. Beta-adrenergic receptor blockade during reconsolidation strongly diminished the behavioral expression of the instructed fear memory (i.e., startle responding) as well as the subjective feelings of anxiety 24h later, yet without affecting both the physiological and cognitive component of the anticipation of threat (i.e., skin conductance responding, expectancy ratings). Together, the present findings suggest that the various memory traces of a learned fear association do not necessarily undergo reconsolidation in harmony. Considering that patients with anxiety disorders (1) often fear objects and situations that they have never actually experienced, and (2) primarily suffer from the subjective feelings of anxiety, the present findings may have important ramifications for psychotherapy.

Erasing fear for an imagined threat event.

There is a tendency to substitute frequently used, but relatively hazardous brominated flame retardants (BFRs) with halogen-free flame retardants (HFFRs). Consequently, information on the persistence, bioaccumulation and toxicity (PBT) of these HFFRs is urgently needed, but large data gaps and inconsistencies exist. Therefore, in the present study the toxicity of a wide range of HFFRs to the water flea Daphnia magna was investigated. Our results revealed that four HFFRs were showing no effect at their Sw (saturated water concentration) and three had a low toxicity (EC50>10 mg L(-1)), suggesting that these compounds are not hazardous. Antimony trioxide had a moderate toxicity (EC50=3.01 mg L(-1), 95% CL: 2.76-3.25) and triphenyl phosphate and the brominated reference compound tetra bromobisphenol A were highly toxic to D. magna (EC50=0.55 mg L(-1), 95% CL: 0.53-0.55 and EC50=0.60 mg L(-1), 95% CL: 0.24-0.97 respectively). Aluminum trihydroxide and bisphenol A bis(diphenyl phosphate) caused limited mortality at Sw (26 and 25% respectively) and have a low solubility (<10 mg L(-1)). Hence, increased toxicity of these compounds may be observed when for instance decreasing pH could increase solubility. By testing all compounds under identical conditions we provided missing insights in the environmental hazards of new generation flame retardants and propose as best candidates for BFR replacements: APP, ALPI, DOPO, MHO, MPP, ZHS and ZS.

Toxicity of new generation flame retardants to Daphnia magna.

Suspended particles are a major constituent of municipal wastewater and generally contain high levels of bacteria, including human pathogens. Discharge of these particles of anthropogenic nature can have profound effects on receiving aquatic ecosystems and mitigation of these effects requires additional polishing of treated municipal wastewater. Previously it was shown that surface flow constructed wetlands are effective in improving water quality by reducing the numbers of fecal indicator organisms. However, fecal indicator organisms represent only a minor fraction of the total planktonic bacterial community and knowledge on the effects of these constructed wetlands on the composition and functioning of the entire planktonic bacterial community is limited. The aim of this descriptive study was therefore to identify changes in the planktonic bacterial community during residence of secondary treated municipal wastewater in a full-scale surface flow constructed wetland. To this purpose water samples were taken in which the bacterial community composition and functioning were analyzed using FISH, DGGE and BIOLOG. Surprisingly, the bacterial abundance at the inflow of the constructed wetland was relatively low compared with more natural surface waters. However, the inflowing bacterial community showed high metabolic activity and functional diversity. During residence in the surface flow constructed wetland the bacterial abundance doubled, but decreased in metabolic activity and functional diversity. Shifts in the community composition indicate that these changes are related to turn-over of the bacterial community. The planktonic bacterial community in the effluent of the constructed wetland closely resembled natural bacterial communities in urban and agricultural ditches. Based on these observations we conclude that constructed wetlands are capable to mitigate possible impacts of the particle load in treated wastewaters by transforming the anthropological bacterial community to a bacterial community resembling more "natural" surface waters.

Changes in the planktonic microbial community during residence in a surface flow constructed wetland used for tertiary wastewater treatment.

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.

High trait anxiety: a challenge for disrupting fear memory reconsolidation.

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. 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 or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

Article	Year
Perceptual and conceptual processing as predictors of treatment outcome in PTSD. Journal of behavior therapy and experimental psychiatry\| PubMed ID: 18037392	2007
Beyond extinction: erasing human fear responses and preventing the return of fear. Nature neuroscience\| PubMed ID: 19219038	2009
Dissociating response systems: erasing fear from memory. Neurobiology of learning and memory\| PubMed ID: 20381628	2010
Disrupting reconsolidation: pharmacological and behavioral manipulations. Learning & memory (Cold Spring Harbor, N.Y.)\| PubMed ID: 21576515	2011
Noradrenergic enhancement of associative fear memory in humans. Neurobiology of learning and memory\| PubMed ID: 21624479	2011
Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism. Biological psychology\| PubMed ID: 21986472	2013
Stimulation of the noradrenergic system during memory formation impairs extinction learning but not the disruption of reconsolidation. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 22169947	2012
Erasing fear for an imagined threat event. Psychoneuroendocrinology\| PubMed ID: 22503387	2012
Toxicity of new generation flame retardants to Daphnia magna. The Science of the total environment\| PubMed ID: 23886749	2013
Changes in the planktonic microbial community during residence in a surface flow constructed wetland used for tertiary wastewater treatment. The Science of the total environment\| PubMed ID: 23973550	2014
High trait anxiety: a challenge for disrupting fear memory reconsolidation. PloS one\| PubMed ID: 24260096	2013
Fear inhibition in high trait anxiety. PloS one\| PubMed ID: 24454969	2014

Marieke Soeter

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