Keeping emotional memories at bay: From molecule to patient
by Jorn Hövels
Long-term memory is less unerasable than scientists have always thought, according to recent research. Negative emotional memories can be influenced shortly after they have been reactivated. This creates new opportunities for the treatment of anxiety disorders and post-traumatic stress disorder (PTSD).
Among other things, these opportunities are being explored in the research program Keeping emotional memories at bay: from molecule to patient, one of four projects awarded in the university research priority program Brain and Cognition. The project is jointly led by Merel Kindt, professor of experimental clinical psychology; Marian Joëls, professor of neurobiology; and Miranda Olff, head of the AMC's psychotrauma research program. The goal is to better understand the emotional memory and find out how unwanted emotional memories can be weakened in patients with an anxiety disorder or PTSD. The ambitious research project needs to bridge different disciplines. Using animal research, Joëls' research group primarily studies the fundamental neurobiological principles of memory. Kindt's program group focuses on, among others, the emotional memory functions of healthy volunteers. Olff predominantly focuses her research on the potential applications for the treatment of patients.
‘This joint project is a unique collaboration,' Kindt says. ‘Take Joëls' research. She has the opportunity to inject the substances propranolol and cortisol-both of which influence the emotional memory-directly into the amygdala or hippocampus of rat brains. Such animal experiments, which are not within my reach, yield a variety of new insights for us. This advantage also goes the other way around. In our research with healthy volunteers and patients, Olff and I can differentiate between different types of memory. Moreover, it's important to eventually test findings from animal models in humans.'
Since the nineteenth century psychologists and psychiatrists have tried to change unwanted, fearful memories with therapies and drugs. Until recently, their efforts were in vain-memories appeared to be permanently fixed in long-term memory. The assumption was that fears of patients with anxiety disorders or PTSD had also been inerasably fixed in their memory.
Right now, the most common and effective treatment for patients with an anxiety disorder is cognitive behavioral therapy. For anxiety disorders, this consists of exposure-the repeated confrontation of patients with fear-inducing stimuli such as a spider, a dog or air travel. This gradual and repeated confrontation causes the fear response to eventually weaken or even extinguish. This is because this treatment enables patients to experience time and again that feared consequences fail to occur: the spider does not attack; the dog is strokable; the plane lands safely.
Exposure treatments are quite effective. However, if a patient has rather complicated or severe traumas, the anxiety symptoms-such as insomnia, flashback episodes, nightmares, problems focusing-can return in time. Kindt: During exposure treatment, patients create a new memory pathway that suppresses the old one. But the old fear memory stays intact and can eventually start to dominate again.'
The three scientists are therefore looking for ways to actually change fear memory; ways to "overwrite" the old memory instead of suppressing it. Olff: ‘We're striving for an anxiety treatment with one hundred percent results. But I do want to emphasize that our project involves basic research. Our primary focus is to better understand the emotional brain. Who knows-we may eventually come to an ideal anxiety treatment and develop a treatment that works faster or is easier to provide than cognitive behavioral therapy. Anything we can do to relieve patients of their nasty post-traumatic stress complaints either sooner or more efficiently is worth the effort.'
The most important reason to apply for research funds for this ambitious project was earlier research by Kindt and her doctoral student Marieke Soeter, which they published in the journal Nature Neuroscience in 2009. This research showed that subjects' emotional fear response disappears permanently if they are given the beta blocker propranolol just prior to the reactivation of their fear memories. This is a drug that is normally prescribed for high blood pressure and heart disease. Various artists also use it (in low doses) for stage fright.
Kindt: ‘Contrary to what has long been thought, neuroscientists are finding more and more clues that raking up old memories again plunges the memory pathway back into an "unstable condition." This memory pathway can subsequently be consolidated again. This process is also referred to as reconsolidation. The beauty of this is that during this short time-this supposed reconsolidation phase-we can intervene in the memory pathway. You can strengthen the old memory pathway, something new can be learned, and fear memories can be weakened.'
While disrupting the reconsolidation it is important that it is the emotional fear responses that change and not the memories themselves-those are stored in the declarative memory. People need to still be able to remember, for example, that some dogs are dangerous, or that it is risky to be sent to Afghanistan as a soldier. That's why it's quite possible that, in the future, patients will be faced with a difficult choice: do I want to get rid of my anxiety, or do I want to save all the details of my memory? Kindt: ‘There are studies that show that propranolol also affects the declarative memory. That makes sense-when emotions dull down, people remember details less vividly.'
With her animal models, neuroscientist Joëls studies the fundamental neurological mechanisms that play a role in the stirring up and weakening of fear memories. Her research group focuses on, among others, the influence of stress hormones such as cortisol on memory storage. The effect of the stimulating neurotransmitter glutamate on the extinguishing of fear memories is also being studied more closely by her group.
Joëls: ‘We want to know how different drugs can intervene in the fear memory. In animal models we can intervene very precisely in parts of the memory process and discover which steps are essential in that process. That gives us new ideas for treatment that we can subsequently test in humans.'
In collaboration with the sleep lab of researcher Lucia Talamini of the psychonomics program group, Olff's research group will look into how sleep is disrupted in PTSD patients. During the night, many patients with PTSD are still fleeing things that once happened. They have nightmares, repeatedly wake up with a start, and experience flashback episodes. Olff: ‘We don't yet exactly know what effect that has on memory, but we suspect that in addition to the trauma disrupting sleep, sleep patterns also influence the ability to cope with trauma.'
It has been known that after exposure therapy or after taking medication the brain activity of PTSD patients during sleep is different than before. Olff: ‘If we can discover how we can improve the sleep of PTSD patients, that would already be quite something. Or, the other way around, that improved sleep allows them to better cope with the trauma. We'll have to research that, too.'
Kindt, Joëls and Olff are not the only researchers looking at anxiety. Agnes van Minnen, endowed professor of anxiety regulation at the Radboud University in Nijmegen, has previously done research on exposure therapy for PTSD patients in combination with d-cycloserine, a drug that is being thought to have a facilitating effect on extinction. After taking d-cycloserine as part of exposure therapy, patients are said to remember even better that they don't have to be afraid of fear-inducing stimuli.
Beside the fact that Kindt thinks treatment results with d-cycloserine are disappointing, she is especially worried about the (too) rapid application of new treatment methods. ‘D-cycloserine is a dangerous drug. When you rake up an emotional fear memory, you run the risk of strengthening the old fear memory, instead of the newly learned.'
Such risks also apply to a drug like propranolol. Still, patients are already being treated with it abroad. ‘I wouldn't feel comfortable doing that yet,' Kindt says. ‘While we're using the drug to weaken the old memory, in the case of propranolol it could also happen that during the treatment the newly learned is accidentally being weakened. The drug would then have the opposite effect. You have to be very careful with such drugs and should not use them to treat people right away.'
Prof. dr. Merel Kindt (Psychology)
Dr. Miranda Olff (AMC)
Prof. dr. Marian Joëls (SILS)
The following institutes participate: