Periodic Reporting for period 3 - ErasingFear (Understanding the Stability and Plasticity of Emotional Memory)
Reporting period: 2021-01-01 to 2022-06-30
Since the time of the ancient Greeks, people have imagined memories to be a stable form of information, as if they are indelible portraits of our past. The metaphors for this persistence have changed over time: from impressions in a wax tablet by Plato, to computer analogies that are still popular today. The most widely accepted view in science was that memories were only initially labile and sensitive to disruption (short-term memory), after which they became fixed or ‘consolidated’ into the physical architecture of the brain (long-term memory). At the turn of this century, a major breakthrough in neuroscience was achieved with the (re)discovery that fear memory is not inevitably permanent but can change when retrieved. Upon a reminder cue, previously formed memories may return to a labile state, requiring a cascade of brain processes for restabilisation in order to persist. This process is now referred to as ‘memory reconsolidation’ and offers a window of opportunity for targeting fear memories with amnestic agents. Over the past decade, evidence for persistently reducing fear response by pharmacologically interfering with the process of memory reconsolidation progressed from animals to humans. In a series of laboratory experiments, we have convincingly demonstrated that disrupting the process of memory reconsolidation with a drug neutralized the affective expression of a fear memory without changing the actual recollection of the threatening event. A technology that instantaneously dampens the emotional impact of unduly intense fear memories would signify a true paradigm shift in the practice of psychotherapy. Instead of multiple sessions of cognitive behavioural treatment or daily drug intake with a gradual and often temporary decline of symptoms, it involves one single instance of treatment that leads to a sudden - albeit delayed - decline in fear. Although these findings suggest the possibility of a paradigm shift in clinical practice, a reconsolidation intervention for horrific or otherwise undesirable memories has not left the hypothetical arena. Until now, an abrupt reduction in fear response using a single amnestic drug administered upon memory reactivation has only been reliably demonstrated for very specific fears, which are typically induced in the laboratory, and more recently in a subclinical sample of people with spider fear. Irrespective of these dramatic effects (i.e. proof of principle), the results of the reconsolidation intervention for more severe emotional memory disorders such as chronic PTSD and fear of public speaking are both promising and disappointing. It is worth noting, however, that the swift translation from basic to clinical science could easily bypass several important steps. Laboratory experiments in animals and humans illustrate that the effect of the reconsolidation intervention depends on subtle differences in the reactivation procedure in interaction with the learning history, while these experimental parameters cannot be easily controlled in clinical practice (see figure 1 in Question 5). In harnessing the clinical potential of memory reconsolidation as an alternative treatment for emotional memory disorders, a bi-directional translational approach is proposed. Not only are fundamental insights on the principles of learning and memory from the animal and human literature indispensable, clinical observations need to be considered as well. These insights and observations provide operational tools for testing novel hypotheses on different levels of analysis: from behavioural neuroscience to clinical science, and vice versa.
The key objective of the proposal is to gain an in-depth, comprehensive understanding of the dynamic balance between the stability and malleability of emotional memory, and consequently develop a revolutionary theory-driven treatment for people suffering from emotional memory disorders.
Why Research on Emotional Memory and Therapeutic Forgetting?
Anxiety Disorders are very common (60 million in Europe), so common that we almost forget the high burden of these disorders. The fears range from very broad anxieties to specific fears and phobias,
but also, specific fears (spider phobia, fear of dogs, heights or small spaces) are sometimes very complex and can be devastating and interfering with people’s daily life. Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. Disrupting the process of memory reconsolidation has the potential to fundamentally advance the treatment for fears and anxiety disorders.
Figure 1. Dynamic balance between the stability and malleability of emotional memory
Boundary conditions that affect the post reactivation fate of memory: Behavioral expression of fear during memory reactivation is not necessary or sufficient to trigger post-reactivation mnemonic processes. However, a match/mismatch based on prior learning, introduced during a reactivation trial, results in prediction error that is necessary for destabilization of memory. Depending on the number of errors generated during memory reactivation, as well as the nature of the original learning trial, memories may enter one of several states, namely; sole retrieval, reconsolidation, an intermediate limbo state or extinction. In our ongoing studies we aim to delineate the transition between these different states in humans, both in healthy participants who acquire a specific in the laboratory (i.e. fear-conditioning studies) and in clinical trials (i.e. patients suffering specific fears and phobias).
The key objective of the proposal is to gain an in-depth, comprehensive understanding of the dynamic balance between the stability and malleability of emotional memory, and consequently develop a revolutionary theory-driven treatment for people suffering from emotional memory disorders.
Why Research on Emotional Memory and Therapeutic Forgetting?
Anxiety Disorders are very common (60 million in Europe), so common that we almost forget the high burden of these disorders. The fears range from very broad anxieties to specific fears and phobias,
but also, specific fears (spider phobia, fear of dogs, heights or small spaces) are sometimes very complex and can be devastating and interfering with people’s daily life. Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. Disrupting the process of memory reconsolidation has the potential to fundamentally advance the treatment for fears and anxiety disorders.
Figure 1. Dynamic balance between the stability and malleability of emotional memory
Boundary conditions that affect the post reactivation fate of memory: Behavioral expression of fear during memory reactivation is not necessary or sufficient to trigger post-reactivation mnemonic processes. However, a match/mismatch based on prior learning, introduced during a reactivation trial, results in prediction error that is necessary for destabilization of memory. Depending on the number of errors generated during memory reactivation, as well as the nature of the original learning trial, memories may enter one of several states, namely; sole retrieval, reconsolidation, an intermediate limbo state or extinction. In our ongoing studies we aim to delineate the transition between these different states in humans, both in healthy participants who acquire a specific in the laboratory (i.e. fear-conditioning studies) and in clinical trials (i.e. patients suffering specific fears and phobias).
We have witnessed considerable progress in understanding the critical conditions to trigger and observe memory reconsolidation in humans. While promising, these insights are largely restricted to either the context of Pavlovian fear-conditioning experiments or to clinical intuition. The success of the reconsolidation intervention depends on subtle differences in the reactivation procedure, and the window to actually target the process of memory reconsolidation is specific and relatively small. The induction of reconsolidation is a subtle process: prediction error appears to be required for memory labilization, but with extended reactivation and/or multiple prediction errors, the window to target the fear memory may already be missed. Understanding the critical conditions for triggering reconsolidation in clinical practice is further complicated by the absence of a single universally effective procedure to induce memory reconsolidation. Whether any given reactivation triggers memory reconsolidation depends not only on the reactivation procedure itself, but also on individual differences in learning history and temperament. Irrespective of the great advances that have been made in understanding memory reconsolidation in the clinic, the critical parameters governing the persistent mitigation of emotional memory in clinical practice remain unknown. One way through which these difficulties might be alleviated would be if it were possible to develop a real-time marker of prediction error, or some other process, that might predict the successful induction of reconsolidation. Ideally, a real-time marker – cognitive, behavioural or physiological – for whether reconsolidation was likely to be triggered by a particular reactivation could be consulted during reactivation, so that the experimenter or clinician knows when reactivation is most likely to have been sufficient. Future research from our lab aims to investigate whether such a real-time marker of successful reactivation can be developed. With such a tool, reactivation sessions could be adapted in real time, with the clinician determining whether an exposure task should be prolonged or terminated. This is, however, likely to be a difficult process, as we have already seen how determining whether reconsolidation is likely to occur presents challenges even in relatively simplistic settings. Continued translation of findings from experimental to clinical work and back again will likely be required. In our ongoing and future studies, we aim to unravel the unravel potential boundary and optimal conditions for targeting the process of memory reconsolidation in a range of fears and anxiety disorders. Translating research on memory reconsolidation from basic science into effective reconsolidation-based therapies is an exciting prospect, with the potential to signify a paradigm shift in the treatment of emotional memory disorders.
The reconsolidation intervention is not only procedurally in stark contrast with cognitive behavioural therapy (CBT), the dominant treatment for disorders of emotional memory, but also with a fundamental tenet of CBT. The CBT-model postulates that a change in cognitive processes (i.e. a shift in faulty or dysfunctional threat beliefs or thinking) is the mode of action and even a condition sine qua non for obtaining a treatment effect, while a cognitive change is not required for the reconsolidation intervention. In contrast, when a cognitive change takes place during the reconsolidation intervention, this actually poses a boundary condition for the treatment. But the instantaneous reduction in fear responding and the transformation from avoidance to approach behaviour seems to create a discrepancy between the “remembering self” (i.e. I’m a phobic person) and the “experiencing self” (I’m able to approach the phobic object)* Instead of multiple sessions of cognitive behavioural treatment or daily drug intake with a gradual and often temporary decline of symptoms, it involves one single instance of treatment that leads to a sudden - albeit delayed, after a night of sleep - decline in fear. The reconsolidation intervention also represents a shift in the use of pharmacological agents to alleviate symptoms. It involves just one single administration of a very common drug (i.e. 40 mg propranolol HCl) administered during a specific time window. Given that the fear reduction has only been observed after a night of sleep, when the drug has been washed, demonstrates that mode of action is very different from other pharmacological treatments. Instead of a general fear dampening effect it targets the expression of specific fear memories. We are currently testing whether a daytime nap or a night of sleep is required to observe the transformation in fear behaviour.
Clearly, this research has huge implications for the clinical field, with the possibility of novel and effective treatments requiring minimal time or cost. Inspired by the novel insights on how to change unduly intense fears, dr Kindt has established an outpatient clinic for phobias and anxiety disorders (Kindt Clinics https://kindtclinics.com/) where she is the founder and scientific director. Kindt Clinics applies the scientific advancements of the ErasingFear project to treat individuals with severe fear and anxiety disorders, with 80% of clients overcoming their fear or phobia basically within one day.
Clearly, this research has huge implications for the clinical field, with the possibility of novel and effective treatments requiring minimal time or cost. Inspired by the novel insights on how to change unduly intense fears, dr Kindt has established an outpatient clinic for phobias and anxiety disorders (Kindt Clinics https://kindtclinics.com/) where she is the founder and scientific director. Kindt Clinics applies the scientific advancements of the ErasingFear project to treat individuals with severe fear and anxiety disorders, with 80% of clients overcoming their fear or phobia basically within one day.