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Merel Kindt on Eliminating Phobias / PTSD enduringly
October 20, 2020
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Part of the goal of this channel is to go in depth with intellectuals not particularly concerned with whether or not the audience will follow along because I believe that it's more interesting at the edges of the fractal than it is in the simple middle. Because of that, as well as the fact that there are certain academics that don't get as much press as we think that they should, my colleagues and I started a non-profit called the Drakma Institute where we interview post-docs, PhDs, as well as professors,
transcribe the interviews, put in the requisite citations, and then subsequently get it published in a peer-reviewed journal. The following is an interview with Professor Meryl Kint, who I think is revolutionizing her field by developing a treatment for treatment-resistant phobias and PTSD, which effectively utilizes a common beta blocker in just one or two sessions, and the effects seem to be permanent.
Again, please subscribe to the Drakma Institute if you'd like more videos like this. This is just a reposting from that channel. The next interview would likely be with someone named Peter Gray who's an evolutionary psychologist on the concept of unschooling. Enjoy. We're here with Merrill Kint of
This is a long story, so I don't know how much time you have.
I think I have to give you a bit of a background information, otherwise it's really difficult to understand the research program and why we changed actually our approach from the traditional approach that is taken to tackle irrational fears. For fear and anxiety disorders and also post-traumatic stress disorder cognitive behaviour therapy is the most
effective treatment. And even though it is effective, there are also many patients that do not profit from the treatment. But what is really a problem is the high relapse rate. So even after successful treatment, there are many patients that show a relapse. And
Yeah, this idea of relapse after cognitive behavioral treatment can be understood by behavioral neuroscience research. So I will briefly explain that. So to understand the mechanisms of change,
and also cognitive behavior therapy. We use the fear conditioning paradigm. This is laboratory research that can be done in rodents but also in humans. So please interrupt me if you don't understand me. So cognitive behavioral therapy as far as I know is something like you're afraid of a stimulus. Let's say it's rats or mice.
then you have progressive exposure over the course of weeks maybe even months so that is how far can you go to a ramp can you go nine meters and then they're like that's that's the most they're like how about 8.5 like ah okay great great job great job next day it's like can you do eight meters instead of 8.5 they're like okay and then and then somewhere and that takes weeks and weeks and weeks yeah
And what you're saying is there are a couple downsides to this cognitive, the traditional cognitive behavioral therapy. One is that the long amount of time it takes. And then two is that even when you're supposedly cured, something traumatic can happen again that can trigger you back to being at baseline, baseline fear level where you were before. Okay.
So this was very well explained and the so the idea is that we know from so we have an experimental model to understand exposure treatment or cognitive behaviour treatments and and this is so we can learn for instance rats
by presenting a neutral stimulus, a tone, which is followed by a painful stimulus, a shock. And then after a couple of learning trials, if we only present them the originally neutral tone, they react with a freezing response. So that means that what we call a fear memory has been formed, which is an association between the originally neutral stimulus, the tone, and the shock.
And that when they are only presented to the tone, they respond as if they're also presented, they expect also to be presented to a shock, even though they are not exposed to a shock anymore. And then you can also extinguish your fear by repeatedly exposing them to the
tone without a shock and then after many many tries you see a gradual decline of fear but then if you just wait a couple of weeks or you change the context then it's very easy to trigger the fear response again so you see very easily a return of fear.
And we know from the animal research that this can be explained that extinction learning, even though is a very effective procedure to reduce the learned fear response, it does not erase the original fear memory. So the fear memory remains intact.
and a new sort of extinction memory is formed that competes for behavioral control with the original fear memory but the original fear memory is extremely strong and very often wins from the extinction memory and this explains actually the return of fear.
So until around 2000 or so it was a sort of accepted view that we can never change the fear memory and the best thing that we can do is actually forming a new extinction memory and all the new approaches that tries to improve the cognitive behaviour treatment was actually aimed to strengthen or enhance the extinction memory.
So after my PhD at the University of Amsterdam, I moved to Maastricht University and did also my clinical training. So I saw many patients with fear and phobias and posttraumatic stress disorder. I was well known with the literature also with the neuroscience literature and I
But sort of for years thinking, well, how can we somehow mislead our brain and sort of weaken the fear memory itself? Would that be possible? And then I discovered early, I think, in 2002 or 2003, indeed, because it was the year that the paper of Grimnader appeared. The paper by Grimnader showing that it might be possible to change the underlying or to weaken the underlying fear memory.
And so what they did in rodents, they first learned this fear by presenting the rodents with a tone and a shock and then testing them a couple of days later, you see an expression of the fear memory by freezing a response if they are only presented to the tone. And what they did is instead of an extinction procedure, they reactivated the fear memory by presenting them to a single tone.
And then injected the animals with a protein synthesis inhibitor, anisomycin, a very toxic drug, which you cannot use in humans, but they did so in the rodents. And then if they tested the animals a couple of hours later, there was still a very strong expression of the fear memory. But then 24 hours later, the fear was almost gone, as if there was no longer an expression of the fear memory.
Yeah, this was really sort of this changed our whole idea of memory, because until then, we thought that after memory is consolidated, so maybe can dive a little bit into the basics of neuroscience on memory. So if if organisms learn something and you test them, for instance, within an hour, we speak of short term memory. So if they have learned and memorized what they if there is memory of what they learned is a short term memory.
And in order to transfer the short-term memory into a long-term memory, protein synthesis is necessary. And if you block the protein synthesis, it is not possible to form a long-term memory. So then if you test the animals, for instance, 24 hours later, you don't see any expression anymore. But the sort of accepted view or dominant view in the memory
literature was that after memory has been consolidated, we cannot change the original memory trace. So the only way to change our memory is by forming new memory traces that interfere with the original memory trace.
So this seminal study by Krimnader showed that it may be possible even after memory consolidation to change the original memory trace and that if you reactivate memory that the resaving of the memory requires again protein synthesis and this means that if you interfere with these processes with the protein synthesis
required for the rewriting of the previously formed memory, then we may be able to change fear memory itself. Right, and just to interrupt, if I'm understanding correctly, you make a mouse or rat or whatever it is, extremely afraid of some stimulus, let's call it a tone in this case, then you can make it afraid again by
repeating the stimulus, and afterwards you inject it with a neurotoxic, I believe it's just toxic in general, but I don't know, neurotoxic chemical at least, that prevents this protein from synthesizing or inhibits this protein in some way, the one that would entrench this memory, and then it would eliminate the fear response because that memory is no longer being fortified. Is that correct?
Yeah, almost. So what happens is if you, and I can come later to that, because it really depends on very specific circumstances, whether the memory trace is labelized. So if you retrieve a memory, it's not always the case that the memory trace becomes in a sort of label or destabilized phase. But if so, then after destabilization, it requires protein synthesis to be re-stabilized again.
and normally that is what happens so memory reconsolidation is a way of updating the memory so if the memory should
stay the same should should be kept if the environment does not change but if the environment changes the memory should be changed a bit because while the whole idea of memory said it is a sort of well it makes us very adaptive because it helps us to to better respond to the environment so if the environment does not change the memory should also not change if it changes then the memory can either be changed by forming new memory traces or by
updating the original memory trace. Would you please elaborate a little bit on how you arrived at the idea that taking these beta blockers after being exposed to the stimulus is what's efficacious as opposed to before? So after reading this seminal study by Grimnader that appeared in 2000, so at the turn of the century, I became really thrilled because I thought if we can translate this finding to the human field, this might sort of implicate that we really
can sort of treat people with irrational fears and anxiety disorders and maybe also with post-traumatic stress disorder which are much more effective intervention and this could be a solution for the high relapse rate. But the anisomyosin, the protein synthesis can clearly not be used in humans. This is very toxic and also what we can do is
Injected drug directly into the brain, into the amygdala, the fear center of the brain, and that is what for instance, many other animal researches.
But in 2004 and also a little bit before that year, there were a couple of studies testing the same ID, but then with propanolol, the noragenergic beta blocker. So we only give 14 milligrams and only once is not very clearly not very toxic for humans.
In our first study we gave propanolol actually before the memory reactivation and not to dampen the fear response but we reasoned that if you reactivate the fear memory then the processes of memory destabilization and restabilization probably start immediately following the memory retrieval and it takes between one and two hours before propanolol
has passed the blood-brain barrier and reaches a peak level. So we thought if we give it afterwards, we may miss the window. But then, of course, if you give it before memory reactivation, you never know whether it somehow interferes with the retrieval. So that was why in later studies, so it worked very well, and then in later studies we always now give it after the memory reactivation. But we don't use it
to dampen the fear response but noradrenaline as a neurotransmitter is indirectly involved in the protein synthesis necessary for memory consolidation and also for memory reconsolidation. So this is the reason why we can also work with propanolol instead of working with protein synthesis blockers.
Would you say then that the difference between your approach and cognitive behavioral therapy is the focus on the recollection of memory and the destruction of the initial fear memory, as opposed to trying to build barrier memories that would inhibit that original fear response? Yeah, indeed. The difference is that instead of building new memories or trying to control the emotional memory and emotional responses, we try to
to mitigate the root of the disorder, so to weaken the fear memory itself. Procedurally, it's also very different because exposure treatment, yeah, the idea is that it actually targets more the cognitive processes, so the expectancies, it's a longer process, so by repeatedly people exposing to the fear cue, they gradually learn
that what they fear is irrational, whereas we expose our participants only very briefly between two and five minutes to the feared queue. So we don't target the cognitive system.
And what is interesting what we see is first we see a behavior change. So we shall we reduce the defensive reflex or in phobics we change the avoidance behavior.
When you say first, do you see the change? Are you talking about after you give the beta blocker and then you wait 20 minutes? Are you talking about that or the next day? Actually, we published that paper in 2018. When you test them 12 hours later on the same day, you still see the same fear expression, but only after a night of sleep.
we see the sudden, very abrupt reduction of fear. So instead of the gradual decline of the fear response, it's delayed, so after 24 hours, but very abrupt. And that, especially when I treat patients and it is a successful treatment, it's every time feels like magic because
Yeah, normally you see a sort of you are there when you see a sort of gradual change in behavior and now first you see during the exposure that people are really has an intense fear response are sometimes crying and panicking and then if they come back 24 hours later they are able to it's not that they're entirely relaxed but yeah this such a huge difference so that
I'm curious, you had mentioned the relationship between protein synthesis and fear. It is known that for protein synthesis that this is deeply tied with our genetics, the sort of manuscript for the creation of all of our proteins. Do you think it is for this reason that one finds that in epigenetics that there are inherited fears? Does that have a connection to your research?
Yeah, no, what do you mean with inherited fears? Because I'm a bit, I mean, that was also one of the questions that the fear of snakes, I mean, the fears that we treat are the irrational fears. So not, I mean, of course, I mean, snakes can be dangerous, but there's no reason to be really phobic in the sense that you
that people avoid several places because there could be a snake, whereas there is no snake. So that is the kind of fear that we treat. There was an article published on, it was an epigenetic study where they, I believe they induced a fear response to rodents at the sound of a bell and they made a very visceral pain
for the rodents at the sound of that bell. They then allowed the rodents to have their next generation of offspring and then gave them the sound of that bell. Apparently the rodents were afraid, although never hearing the bell before or feeling tortured at this hearing of the bell, were afraid at the sound of the bell. What is even more amazing is that the generation after the grandchildren
They then gave the sound of the bell and had these rodents afraid. So I'm curious if this link of fear, this inheritance of fear, has something to do with epigenetic mechanisms on DNA, considering that you were speaking of the relation between protein synthesis and fear.
I don't know if this is a topic that is explored. I'm very curious to read. Do you remember the authors of the paper? I can find it and send it. Yeah, please. I don't know, but somehow as if there is indeed a memory of the fear that is transgressed to the next generation. By the way, does this only work on fear memories?
post-traumatic stress disorder, or can it work on people who have innate fears, like we were mentioning before, some people are afraid of snakes innately, some people are afraid of blood, that's more discussed. No, yeah, well, we tested that because in a fear conditioning procedure, so what we do is we work with pictures and electric stimulus administered to the wrist, so painful stimulus. So we also use the fear conditioning model in the laboratory.
And an innate fear is not the fear what we call to the learned stimulus or the picture followed by the shock, but actually the response to the shock itself. And that didn't change. So it's not that we in that sense dampen the, that is what you could expect if you dampen your whole fear system, that people or animals don't respond anymore to intrinsically
And you mentioned that what's required is a night's rest in order for your treatment to be effective. Have you measured the quality of someone's sleep to the extinction of the fear?
This is what we are currently testing, but unfortunately the study, we had to stop with the data collection due to COVID-19. So hopefully we can proceed with our study after the summer. But so this is, so what we did is we controlled for the, for the hours. So because from the animal literature, we learned that is that reconsolidation is time dependent.
So we started first with a pilot study and then we discovered that yeah when you wait five or six hours that there was still such a strong fear expression and we always in all our previous studies we always tested the next day.
for the effect. And it takes also, well, propanol has a five hour half time value. So after 12 hours, it's almost completely out of the body. And especially the next day, it's completely gone. So then you are also sure that what you measure can no longer be a propanol effect. And so we piloted first and tested five hours. And then a certain moment, I
ask my postdoc, maybe you could test also 12 hours later on the same day and we still found such a strong fear response and then we decided to study where we either did the treatment in the morning, tested them 12 hours later on the same day and then again the next day or we treated them in the evening, also waited 12 hours but with a night of sleep in between and then the next day and we really saw that it was not the time but the night of sleep.
But we did not register the sleep quality. We don't know which phase of the sleep is important. So these are very interesting next steps. We also tested the time window during which we can actually give propanolol. So it was possible to give it one hour after memory activation, and it still works. But two hours after memory retrieval, then it's really too late. So that also shows that it's a really
specific time we know that you can target these processes and otherwise you are too late. Can fear extinction work on relatively minor fears? So for example, if someone were nervous speaking in front of others, could they use this treatment to get rid of those minor fears?
Social fears are in that sense not so easy because we did a study in people who have a fear of public speaking and there the treatment was not effective and the problem in research is done that you, for instance, work with a standard protocol that is already quite difficult for people who suffer from social fears because these fears are generally very idiosyncratic.
but especially with social fears people very often they their fears actually what other people think for instance and it is really hard to to expose people to that and our issue is that the threat or the anticipated catastrophe does not necessarily happen in a specific time window so if what people fear can happen for instance a year later then the treatment
Cannot be applied because it really should be in the moment that you trigger the memory and then something they can learn something from from their environment With respect to their fear and there are also many fears I mean when people are afraid of dying very often that that it's not something that that's the thing will happen in the near future, but maybe in a year or so So for the kind of fears the treatment is not suitable
It seems to me that this is almost like a surgical knife, cognitively speaking, that you are removing sectors of fear and of memory, and the more clean cut and defined those fears are, the better they can be removed. Are there other complicating factors in this mental surgery? Yeah.
Yeah, I agree. I also have called it once in a paper kind of sort of as a metaphor neurosurgery or so it is that sounds very different from psychotherapy. Yeah, it is one of your I think last questions.
So we first showed this effect in the laboratory in dozens of studies, which is a sort of proof of principle. Then we tested it in people with fear of spiders. And then, of course, I received many questions from people who were suffering from crippling fear. So if it's so easy, I can also do it myself, expose myself to the cue, take the pill, and then the fear is gone.
But yeah, unfortunately it's not easy because there are many boundary conditions and this has to do with the idea that if you are exposed to the feared cue, it's not necessarily so that the memory is destabilized.
And if the exposure for instance is too, so either it is not, there's nothing new to be learned, then it's a sort of passive retrieval. It could also be that a situation is too new or too different from their original fear. And then this is a sort of, yeah, sort of initiation of the formation of a new memory or of an extinction memory.
And whether you target the process of memory reconsolidation is really in between a sort of passive retrieval process and the formation of a new memory. And the problem is that we do not have a sort of index that we can use to know what is happening in the brain during the memory activation. So we only have the behavior, the readout of memory, but the fear reaction is not
informative on what happens actually in the brain, on whether it's only a passive retrieval process or whether the memory reconsolidation is triggered. So this is a huge challenge and our current research is trying to tackle this problem, especially in translating to the clinical practice. So what we do now, so I'm now sitting here in
In my clinic, we opened a clinic a year ago, where we treat many people with suffering from fears and phobias. So what we do now is, partly intuitively, to decide when do we stop? So you expose people to the fear cue. It could be a dog, a kitten, a spider, heights, whatever. How long should the exposure be?
Something I was thinking about, there are people with childhood traumas and various other anxieties, and I was wondering, well, instead of exposing them to whatever stimulus would cause them to feel the extreme fear, given that sometimes that's impractical, especially now during COVID,
Can they, with tremendous effort, concerted mental effort, just think about that stimulus to hallucinate, in a sense, their fear, and instead of bringing their fear response up to 10 out of 10, which is what you try to do in your practice, bring it up to 4 out of 10, because obviously it's not the same as having, let's say, a masked murderer in front of you and you imagining a masked murderer.
Or a person in a mask. Let's say they're afraid of the scream mask from that 90s movie. So they imagine the scream mask. Okay. They imagine it and they're triggering themselves up to four out of 10. Then they take the beta blocker. Now imagine they do that. Well, first of all, would that work at all? And second of all, if let's say it doesn't work, do you imagine it would work if they did that a few times? Your treatment is like one extinction event.
Eradicate that memory from one treatment, but you imagine this four out of ten progressively over the course of two weeks, let's say could bring it down to Remove that memory at least the fear associated with yeah First of all, we of course it is not necessarily so that even if it works that it is I Mean memory emotional memory that underlies anxiety disorders and especially post-traumatic stress disorder is not a sort of single memory trace, but it is a network and
So you could imagine that for PTSD that you even if it works that you weaken the network but that you need more treatment sessions to really dismantle the underlying emotional memory. We have applied the reconciliation intervention already to people suffering from post-traumatic stress disorder and this is in general the way also
Yeah, if you use the standard cognitive behaviour treatment, you always work with imaginary exposure. And the idea is that the trauma memory is actually the trigger, like in dog phobia, the dog trauma memory triggers overwhelming emotional responses and people are afraid of being overwhelmed by their emotional responses and they feel like they cannot handle it, they will become crazy, losing control, whatever.
So the reason to go back to the trauma is actually usually when people have intrusive memories they try to avoid it because they don't want to expose themselves to the trauma memory because it triggers very intense difficult emotions and what you do in treatment then is you try to do that of course supporting the patient and if you do
right then it triggers indeed very strong emotional reactions and then they can experience that they do hear that sound
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not die or that they are not going crazy over there. So this is then the sort of prediction error or new experience that may
destabilize the trauma memory and and then a propanolol could work. There is a in one of the I don't know whether you have seen the documentary by Lana Wilson a cure for fear so one of the four parts is a night in Kabul and this was a trauma treatment.
and there we used to strengthen the memory reactivation also a virtual reality environment to make it a bit stronger, so to present him with some cues that could sort of enhance the reactivation of the specific
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Do you think psychedelics could have any role in all this? Do you think it can perhaps enhance the effect?
get enhanced and that way maybe we can do something about it, reactivating that memory, or is it too much of a novel experience for someone who maybe hasn't done psychedelics before? What are your speculations on that? Well, there are some promising studies using MDMA, for instance, so I think the idea, what is important, of course, is that the researcher has a sort of
at least plausible hypothesis on the working mechanism that's in my view important and whereas you very often see in in this field is that sort of drugs are just tested and so see just observe whether it has an effect or not about it's not the way I like to work but there are I mean psychedelics could work by they could help to destabilize the memory and yeah
So, and then it is easier to, yeah, to either, and then maybe not, I don't think that you should then work maybe with propanolol, because then it could be also an interaction between the two, at least you should make sure that it is not problematic. But there are also behavior, of course, imagery re-scripting is a good way to change a trauma memory. And you could do that in combination with... Yes, I wouldn't ask a question, but...
Yeah, right. It will be really interesting to do something in conjunction. So perhaps we can maybe talk a little bit about that down the road. That would be great. Yeah, but then the difference is because sometimes, I mean, cognitive behaviour treatment is just combined with drugs, but then it's only, I mean, drugs that also dampen the emotional response, whereas the
Intriguing aspect here is that we use a drug not to dampen the emotional response, but to really interfere with the learning and memory processes, which is a very different way of using a drug. How far do these unlearning processes go? Is it possible to remove disgust or happiness, for example, or let's say fond memory of something, the opposite of fear?
Certainly not limited to fears and phobias because it has also been tested in the area of addiction.
Also with propanolol, by the way, in animals. We got to explore that. Can you explain how do you test this with addiction? You expose someone to something they're addicted to and then give them the propanololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololol
So there's a cue and an approach behavior because the animal is addicted to it. And so in fears we aim to change the afforded behavior and in addiction you, yeah, then you should try to change the approach behavior. So the other way. And that is possible. It is, I think, but it has not been, I mean,
We are now in a pilot phase testing people who are addicted to cigarettes. But yeah. Okay, can you explain to me how? So let's say someone's addicted to cigarettes or cocaine.
If they see the stimulus, the cigarettes or the cocaine, it triggers them. They want to smoke or they want to have cocaine again. Now, if we're making an analog to the fear response, the fear response situation is you provoke them intensely and then give them the beta blocker. Now in the addiction response, do you get them to smoke the cigarettes intensely and then the cocaine or the cocaine intensely? And then, well, obviously that's illegal. And then the beta blocker, you just make them feel like, Oh, I need to be, I want to have this so much. Then remove it. Take the beta blocker.
It's this last and that makes it very hard. So the because so we first years ago we already tested this with students that wanted to quit smoking and then we so we asked them to bring their favorite cigarettes to the lab and they thought well I'm smoking my last cigarette and then they had to give the cigarette to the experimenter and we were a bit afraid that
that the participants would sort of clap the experimenter in his face or whatever but that didn't happen but the treatment also didn't work and we realized afterwards yeah because then it is a sort of passive process in terms of the memory because someone else decide for you even though the participants were motivated to quit the
It was not that they, I mean the experimenter decided that they were not allowed to smoke their own cigarettes. So we think indeed what you said, somehow we have to trigger the urge to smoke and then they have to decide themselves, so they really should be engaged in it. Okay, now I stop. See, this is why it's Nobel Prize winning, because if this works, this can work for
Addiction is a huge, huge topic. This can work for porn addiction or drug addiction or any form of addiction. That's true. I don't know. I don't know the limitations, but I've just surmised it. I mean, the translation is so difficult. And there are so, I mean, it really depends on so many subtle factors, whether it works or not. That is, I mean, as a scientist, that is really, I mean, I love that because it will never be boring.
But I'm working at two sites. So I'm a neuroscientist, but I'm also working in clinical science. So I also see the, yeah, how difficult it is to bridge these two fields. And yeah, we are working on it with a team of PhD students and postdocs. There are also, I mean, there are several labs in the world that basically work with animal models.
We can learn a lot from them because they can do things that we can't do. I mean, they really study the microbiology in the brain and we can't study that in humans. But yeah, it looks easier, I think, than it is. And this really has to do so because these memories, these emotional memories are so strong also for addiction and they're
I mean, if an emotional memory in general is already strong, and then they are engraved almost in the physical architecture of the brain, especially because people are addicted for years, they have experienced their addiction in many different contexts. So it's not easy to destabilize the memory. But yeah, now that we are on the road, then we should be able to change it.
Now that we are on the cusp of removing fears, I think it might be important to ask, is there an important reason why people feel fear? What would be the ramifications of a society that has gone through with this research and eliminated not only fear, but as you have mentioned, addiction, disgust, even pleasure towards certain things that are otherwise unsavoury, what would the ramifications be?
I think that fear is one of the most important emotions across species, because it definitely helped us to survive, so not only is it crucial for the survival of the individual, but also for our group. It has also been, I like that phrase, sorry?
I was going to ask as a follow-up to that, how far down the phylogenetic tree does fear go? How conserved is this emotion? Yeah, well, it depends a bit on the definition of fear, but if we consider defensive reflexes as a sign of fear, then all animals, I think, exhibits a sign of fear. But I would say a society without fear, well, would not be a society anymore.
it's also for instance and and the fear of losing your offspring it's very fundamental for our intense tendency to care for our babies but without fear i mean people see i i mean i think social behavior is also dependent on on fear sorry if i may if i just
Briefly go back to the idea of psychedelics because that area really fascinates me overall. Is there a particular reason you brought up MDMA specifically as opposed to let's say the other ones such as LSD, mushrooms? Do you identify anything specifically unique to MDMA that is not present in the others?
Well, at least I know, I'm not so familiar with all the studies. I know that there are a couple of studies that used MDMA successfully in PTSD and it targets the NMDA receptors and NMDA receptors are involved in the memory destabilization. So that was actually the reason that I mentioned MDMA. As far as I can understand, the MDMA would be more
for the cognitive behavioral therapy route where you just get them to relive their memory. And then now with the MDMA, they can't feel the fear as much. In fact, they might attach positive emotions to it. Whereas with your treatment, it's like, please don't attach any positive emotions, feel the fear. So that's why with LSD, that's completely different. LSD is not like you're only experiencing euphoria. If you're, you can have the most intense anxiety attacks of your entire life.
so do you imagine the treatment with lsd would be i would imagine it'd be much different than mdma i would imagine that lsd or mushrooms would be more in line with your treatment rather than mdma which is cognitive behavioral therapy a cognitive behavioral therapy accelerator is mdma your treatment accelerator might be lsd that's what i surmise but i want to know what you think
Yeah, I agree. Because, yeah, because MDMA also triggers, I think, an oxytocin release if I, yeah. So it could be sort of somehow inhibits the, yeah, it could- You're allowed to speculate. Don't worry. It could work in two directions because it could also help
If you feel safe and attached, for instance, to your therapist, it could also help to dive into your trauma memory and into the more difficult emotions. So in that sense, MDMA would also work. Because if the emotions are too strong, it could also, at a certain point, inhibit of really going into it and feeling it.
The documentary you mentioned is called Cure of Fear, is that correct? Yeah. Okay, I recommend everyone watch this. This I watched. I found it endlessly fascinating. It's what turned me on to your research to begin with. Is there something else you do afterwards, after the post fear stimulus, other than just give them the beta blocker? Do you talk them down? You say everything will be okay? Or is it as simple as expose yourself to the fear, 10 out of 10, take the beta blocker five minutes after that, or pretty much immediately after that?
Go along with your day. Have a nice rest. Is there something else that's missing? No, so I mean the exposure is not so easy. I mean that is really difficult. People are generally not able to do it themselves because they really need support.
to actually do it because the fear response itself triggers an avoidance response so they want to to escape the situation of course but if they have done so no then they go to a room what we do is only i mean i briefly reinforce them for what they did so far and then they wait for two hours they relax because we want to make sure that they
Don't have another stressful experience that could trigger another nor adrenaline response that could interfere with the effect of the beta blocker. Okay, so and then after two hours they go home have a night of sleep and then they come back for a test. So you're there.
in part to make sure that they don't have another traumatic experience that worsens it completely because I would imagine that this could drive someone insane if they're exposed to 10 out of 10 fear on something that they're already extremely afraid of. Yeah, so we try to make sure that they are not re-exposed to the feared cue and sometimes it's difficult for instance we also treat people with fear of dogs and then when they go outside it could be that they will meet a dog again and
Yeah, because then, because we know that, I mean, that could trigger again the fear memory. And we don't know, but it makes sense that it then interferes with the treatment effect. So we always make sure if that is the case, that someone will pick them up in the car, that they don't meet a dog until a night of sleep and then the next day. So we also once treated a woman with a fear of silverfish.
And they were at her house so she was not allowed to sleep in her own house. She booked a hotel and then came back for the test and then after this first night she could go home again to expose herself to the silverfish when she was removed from the fear.
Now, in this case of the silverfish, was there a traumatic event that happened that made her afraid of the silverfish to begin with? Because I'll give you an excuse me for seeming imbecilic or asinine. My fear, I have a fear, and it's of flying insects. I despise flying insects. Like, I like dragonflies. It's the only kind, but mosquitoes and bees and blackflies. I can't even go into the wilderness because of it. So, so practically speaking, I don't have access to you. I'm not in Amsterdam. What can I do?
Here in Toronto, alone in my condo, and other people who have fears similar to mine, maybe not flying insects, but what can they do? Obviously, this is not medical advice, but what would you, if you could take, no one's going to sue you, what would you do? Yeah, what I would do is expose you, then I would first ask you which, if there is an insect that you fear most, and then order, yeah, a couple of them, or sometimes dozens,
and then so very often fears so first of all your first question was actually is it necessary to have a traumatic experience with the cue that you fear no the idea so at least it is our conceptualization of fear and anxiety disorders that there isn't we call a fear memory or associate memory that analyzed the fear response and the fear memory is formed either through direct traumatic experiences but also very often
in an indirect way just by modeling because you have seen other people that are afraid of dogs or insects or information or sometimes people really don't know how they developed it but it is just there. Then if you have a fear some people have some sort of traumatic experience because if you have a fear of a specific animal and then you are exposed to the animal that can be experienced as a trauma.
For your treatment, then, yeah, I would say, well, we should try to, I mean, first, I should do a sort of interview to know exactly what kind of situation would be terrifying for you.
like being in a small room, for instance, with insects or that they are on your skin or on your feet or whatever. I'm not claustrophobic, but yes, if I was in a room that's trapped with a thousand mosquitoes, I would know. I also dislike the buzzing around my ears. So I imagine maybe I can't order mosquitoes. I don't even know how you could do that. Maybe I could just find a YouTube video of mosquitoes around a microphone, put that on, try to imagine myself in a room full of mosquitoes.
No, I don't think so. It's not enough, I think, just hearing it and not being exposed to the real threat. Yeah. And it has probably to do something because most of the fears have to do with not being able to predict, for instance, the cue that you fear and with not being able to control it.
So with uncontrollability and with unpredictability and that's why these insects moving fast and somehow, yeah, you feel probably like I want to control them, I want to control the noise or that they come to me and you can't. So this is really then what you need in the treatment to feel that in order to target your fear memory.
So what compelled you to make this documentary, the Cure to Fear documentary? Yeah, first of all, the documentary. There are more documentaries. So first, the Memory Hackers. There's a treatment. It was a NOFA documentary. And then there's The Science of Fear by Roberto Fredecchia. That is Be Afraid, The Science of Fear. That was broadcasted in Canada, actually.
CBS. They approached me, so not vice versa. And the same for Lana Wilson. But yeah, I think
First, to educate people that there are millions of people that suffer from crippling fears and phobias. So to teach people that they are not weak or crazy, that they have these fears, that is very important, but also to educate them about all the mysteries of emotional memory, which is, I think, for everyone a very relevant and intriguing topic.
Great. I'd like to ask a couple of technical questions, if I may, regarding your research. In your illuminating 2009 paper, you briefly discussed two theories, namely, there was the storage theory as well as the retrieval theory, one of which you surmised may have caused fear of memory extinction. However, at the time, it was not clear which one was the cause. Would you please
a little bit elaborate on these theories and furthermore tell us whether 11 years later now in 2020 do we have a better understanding of the mechanism behind memory extinction from a let's say theoretical perspective or is it still largely a mystery overall? No well if you only study humans it is almost at least very hard and almost impossible to to disentangle between a retrieval
problem or storage problem, whether you really change the underlying memory trace or whether it's difficult, it's more difficult to retrieve it, but maybe it's still there, but you can't just retrieve it. And clinically, I mean, if the retrieval difficulty is so huge that you can never retrieve it anymore, then it doesn't
make any difference, but theoretically is of course very interesting. From the animal literature, well, now that we are more and more able to find actually the memory engram in the brain by optogenetics and so on, and that means that you can turn on and off the fear memory
They also showed that the reconsolidation intervention really changed the memory engram and this suggests at least that it affects the storage of the fear memory and that it is not just a retrieval issue. Okay, so from the animal side then it's more geared toward the storage aspect. Yeah, purely based on human research I read that it is actually, yeah,
impossible to disentangle the two conceptual frameworks. Yeah, right. Yes, there are limitations, unfortunately. And going back to the imagery rescripting phenomenon that you had, you I think you delve deep into it into a recent 2019 paper, where you discuss, you know, the role of imagery rescripting in emotional memory. Now, maybe if we can just briefly talk about this a little more, just to see whether you know, we could
utilize imagery rescripting in conjunction with let's say propranolol to extend the impact of modifying fear in various settings, for example, online therapies, like is that a possibility you think? I mean, I know we briefly talked about how the fear has to be, we have to be in a controlled environment where this has to be properly conducted, but with the introduction of imagery rescripting, do you think we can do anything in that regard or no, we still have certain
I think that, for instance, when we use the procedure in specific fears and phobias, we actually ask the participant to approach, for instance, the spider or the dog.
You see they would sort of run away because I think if I approach it then something very bad happens and then they experience that it doesn't happen. So this is sort of new something new is a new experience and that's the idea that this is necessary to open up the memory trace.
And for trauma memory, it could be that especially sometimes you see traumatized people and they went over and over the trauma memory in a trauma story. And then it's really hard just by going back to open up the memory trace. And then when we do a little bit of rescripting, that could help to destabilize the memory.
Right, so in a sense it is possible then to do something in conjunction, because I know in that study you did not introduce beta blockers, right? It was purely... Yeah, well, so we did it, I did this already a couple of times, then it's only one session, but I also supervised several, so a recent huge trial and also in the past trial,
My question on disgust is, is it possible to
Yeah. Um,
I don't know, I don't think sometimes we see people with a fear of spiders, but sometimes they also find the spiders very disgusting. And we have the idea, but we never really tested it, that the treatment then reduces the fear response, but that the disgust remains intact. I can imagine, though,
that if they disgust is that sometimes if for instance disgust is so strong that people are yeah are afraid of the disgusts I mean that to a degree some people have a sort of cheese aversion or so or milk aversion so they have sort of disgust for some smells or and so on and I think by I don't think that we can treat that but then if people really fear that if they are exposed
to something that would trigger such a strong disgust feeling that they will faint or whatever, we could treat that. So then the disgust is more like what a spider or a dog is for people with a animal phobia. I see, thank you. Now before we wrap up, I have an analogy that I made that I think is completely naive and but but please I want you to correct it because I cannot figure out another a better way of
conceptualizing your research as to why beta blockers afterwards works rather than before. So the way that I see it is when you get exposed to a fearful stimuli, it's as if imagine you have a cabinet behind you and this is an oversimplification and each one of the drawers in the cabinet is a memory. It's as if what you've done in the fear example is you've opened up that drawer. However, if you take the beta blockers before because memory
I believe memory consolidation is highly dependent on beta receptors in your brain that if you take beta blockers that actually interferes with you, you're formulating memories. So if you were to take the beta blocker before it would be as if you can you maybe you open up that drawer, but the rewrite capabilities are not there because the beta receptors for some reason need to be active for the rewrite abilities to be
available. Okay, then you take the beta blockers afterwards because it's not as if the memory gets rewrote. I thought this is so convoluted. It's not as if the memory gets rewritten right then it gets rewritten about two hours later or one hour later. So it's like fierce stimuli, fear, experience stimuli, open up that drawer.
don't rewrite in it wait one hour then the bot then the brain is going to rewrite it but the brain at one hour for now looks to the body how are you feeling are you afraid and then it will rewrite based on that so that's why if you take a beta blocker afterwards and you're calm it's like okay we're about to rewrite but now i see your calm let's rewrite it and say
Calmness. Let's put the hashtag calm on it. What's wrong with that? I'm sure there's many that's much less wrong with it. You said a lot. First of all, I think that the actual writing takes place during sleep. And there's probably more work on that.
Probably the phase where when there is no new incoming information it's sort of that for the brain that is probably sort of best phase to decide if this is the information that should be kept and this can be forgotten. So that makes sense to do that when there is no new incoming information that is during the night. But there are of course several important steps in this whole process of resaving. So the
What we have shown is that you should give the beta blocker up to one hour after memory retrieval and not two hours is probably because in this brief window, time window, the beta-agenetic receptors are involved. But there are of course many other steps in this whole cascade of memory resaving. But the actual rewriting probably happens there.
I think in the lab, when we did the fear conditioning, and we do not measure freezing, what they do in rodents, but we measure the starter reflex, this is an eye-blink reflex. So this is, yeah, you cannot control this reflex, it's a defensive reflex initiated in the amygdala, and that is typically potentiated when people anticipate something threatening.
So when they are in a fearful state, you see an enhanced startle reflex, startle potentiation. This defensive fear behavior was not suppressed when we gave propanolol before memory retrieval. So we gave it before and it was still a fear response and
And it apparently targets the beta-agenetic receptors in the phase where it should. If you give propanolol to people that suffer from a phobia, the fear response itself is part of the, the subjective fear is part of the emotional memory. So if you suppress that, I also think that it doesn't work because this
information feedbacks and is part of the reactivation of the fear memory. So for that reason, I also would not give it before and would not suppress the fear response in people with fears and phobias. Okay, you said that you can also give beta blockers to people in the morning. But beta blockers have a half life of about five hours. So that means 12 hours from now, it's almost gone from your system. Why is it that then
the memory rewriting that happens at night time when you sleep is affected by the beta blockers earlier? Does like what I'm asking is like does the brain when you're sleeping does it look at the current? Why does the beta blocker have an effect if it's gone by the time that you're rewriting your memories when you're sleeping? Because the effect of the beta blockers is it's not that it's sort of
I mean beta blockers, we also have, it blocks the beta-agenetic receptors, they're in the brain but also in the heart. So if you take a beta blocker in a situation where you're normally stressful, you feel that because peripherally you don't have the bodily response that you normally would have in a stressful situation.
but by the way we tested also another beta blocker nadolol which has the same bodily effect but does not pass the blood-brain barrier and there it doesn't work so it's really the central effect in the brain that explains the fear reduction so the beta blocker does not work by suppressing the peripheral the bodily fear response it works because in a specific time window it's
It blocks the beta adrenerotic receptors and therefore the noradrenaline as a neurotransmitter in the brain cannot signal other cells that are necessary to synthesize the proteins which are normally used for the resafing of the memory. Okay, I see. And even though the protein synthesis may take
place later. It does not mean that all these neurobiological processes take place at the same time. They have, in that sense, probably their own time window. I see. So I'm pretty much wrapped with my questions to Faraz and Peter. Do you have any follow ups? Just maybe if you could, as my final question, if you could briefly maybe talk about the future challenges and limitations in determining the exact role and impact of a proper analog, if you want to summarize that.
We are currently working on what is important is that there is no, I think I haven't said that, so what makes it so difficult is that there is not a single
exposure or in the laboratory memory reactivation procedure that always triggers the process of memory reconsolidation. So whether a brief exposure destabilizes the memory depends both on the learning history, so on the memory representation itself and on the retrieval or on the exposure.
So this is the interaction between these two, and this makes it quite a challenge. It means that for instance, a stronger memory requires sometimes a longer exposure than a weaker memory. But yeah.
but yeah i mean the memory is a theoretical construct so we can only observe the behavior and we cannot say on basis of the behavior this is a strong memory and this is a weak memory and this is for this strong memory you need a one minute exposure and for this memory is three minutes so so
So we are actually because of this interaction and in the lab we can really control that and we did so. So we changed we can really play around with the learning history in the lab is the fear conditioning and then and then see okay we can control if if we then expose them to one or two trials
It's it's it works and then to a bit more than it doesn't work anymore and we understand why in Clinical practice when we work with people with a phobia we we have we don't nothing about the learning history this very often there are many many Experiences or it can be very implicit learning or indirect. We don't know so we have to guess what is actually necessary to destabilize the memory and this is what we Yeah, we try to
to do in our current research to understand it better so that we can better control what the boundary and necessary conditions are when we translate our findings to clinical practice. Doctor, speaking of your current research, where can our audience find out more about you and are there ways that they can support you in your work? And that I believe will be our final question.
Yeah, well I can also send my links of course to the UVA, the University of Amsterdam and also the link to the clinic. Thank you very much. Thank you so much, appreciate it.
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"text": " The Economist covers math, physics, philosophy, and AI in a manner that shows how different countries perceive developments and how they impact markets. They recently published a piece on China's new neutrino detector. They cover extending life via mitochondrial transplants, creating an entirely new field of medicine. But it's also not just science they analyze."
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"text": " Think Verizon, the best 5G network is expensive? Think again. Bring in your AT&T or T-Mobile bill to a Verizon store today and we'll give you a better deal. Now what to do with your unwanted bills? Ever seen an origami version of the Miami Bull?"
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"text": " Jokes aside, Verizon has the most ways to save on phones and plans where you can get a single line with everything you need. So bring in your bill to your local Miami Verizon store today, and we'll give you a better deal. Rankings based on root metrics, root score, part data to 1H2025, your results may vary. Must provide a post-paid consumer mobile bill dated within the past 45 days. Bill must be in the same name as the person who made the deal. Additional terms apply. All right. Hello, toll listeners. Kurt here. That silence is missed sales. Now, why? It's because you haven't met Shopify, at least until now."
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"text": " Now that's success. As sweet as a solved equation. Join me in trading that silence for success with Shopify. It's like some unified field theory of business. Whether you're a bedroom inventor or a global game changer, Shopify smooths your path. From a garage-based hobby to a bustling e-store, Shopify navigates all sales channels for you. With Shopify powering 10% of all US e-commerce and fueling your ventures in over"
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"text": " One hundred and seventy countries, your business has global potential and their stellar support is as dependable as a law of physics. So don't wait. Launch your business with Shopify. Shopify has award winning service and has the Internet's best converting checkout. Sign up for a one dollar per month trial period at Shopify dot com slash theories. All lowercase that's Shopify dot com slash theories."
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"text": " Part of the goal of this channel is to go in depth with intellectuals not particularly concerned with whether or not the audience will follow along because I believe that it's more interesting at the edges of the fractal than it is in the simple middle. Because of that, as well as the fact that there are certain academics that don't get as much press as we think that they should, my colleagues and I started a non-profit called the Drakma Institute where we interview post-docs, PhDs, as well as professors,"
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"text": " transcribe the interviews, put in the requisite citations, and then subsequently get it published in a peer-reviewed journal. The following is an interview with Professor Meryl Kint, who I think is revolutionizing her field by developing a treatment for treatment-resistant phobias and PTSD, which effectively utilizes a common beta blocker in just one or two sessions, and the effects seem to be permanent."
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"text": " Again, please subscribe to the Drakma Institute if you'd like more videos like this. This is just a reposting from that channel. The next interview would likely be with someone named Peter Gray who's an evolutionary psychologist on the concept of unschooling. Enjoy. We're here with Merrill Kint of"
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"text": " I think I have to give you a bit of a background information, otherwise it's really difficult to understand the research program and why we changed actually our approach from the traditional approach that is taken to tackle irrational fears. For fear and anxiety disorders and also post-traumatic stress disorder cognitive behaviour therapy is the most"
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"text": " effective treatment. And even though it is effective, there are also many patients that do not profit from the treatment. But what is really a problem is the high relapse rate. So even after successful treatment, there are many patients that show a relapse. And"
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"text": " and also cognitive behavior therapy. We use the fear conditioning paradigm. This is laboratory research that can be done in rodents but also in humans. So please interrupt me if you don't understand me. So cognitive behavioral therapy as far as I know is something like you're afraid of a stimulus. Let's say it's rats or mice."
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"text": " then you have progressive exposure over the course of weeks maybe even months so that is how far can you go to a ramp can you go nine meters and then they're like that's that's the most they're like how about 8.5 like ah okay great great job great job next day it's like can you do eight meters instead of 8.5 they're like okay and then and then somewhere and that takes weeks and weeks and weeks yeah"
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"text": " And what you're saying is there are a couple downsides to this cognitive, the traditional cognitive behavioral therapy. One is that the long amount of time it takes. And then two is that even when you're supposedly cured, something traumatic can happen again that can trigger you back to being at baseline, baseline fear level where you were before. Okay."
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"text": " So this was very well explained and the so the idea is that we know from so we have an experimental model to understand exposure treatment or cognitive behaviour treatments and and this is so we can learn for instance rats"
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"text": " by presenting a neutral stimulus, a tone, which is followed by a painful stimulus, a shock. And then after a couple of learning trials, if we only present them the originally neutral tone, they react with a freezing response. So that means that what we call a fear memory has been formed, which is an association between the originally neutral stimulus, the tone, and the shock."
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"text": " And that when they are only presented to the tone, they respond as if they're also presented, they expect also to be presented to a shock, even though they are not exposed to a shock anymore. And then you can also extinguish your fear by repeatedly exposing them to the"
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"text": " tone without a shock and then after many many tries you see a gradual decline of fear but then if you just wait a couple of weeks or you change the context then it's very easy to trigger the fear response again so you see very easily a return of fear."
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"text": " And we know from the animal research that this can be explained that extinction learning, even though is a very effective procedure to reduce the learned fear response, it does not erase the original fear memory. So the fear memory remains intact."
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"text": " and a new sort of extinction memory is formed that competes for behavioral control with the original fear memory but the original fear memory is extremely strong and very often wins from the extinction memory and this explains actually the return of fear."
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"text": " So until around 2000 or so it was a sort of accepted view that we can never change the fear memory and the best thing that we can do is actually forming a new extinction memory and all the new approaches that tries to improve the cognitive behaviour treatment was actually aimed to strengthen or enhance the extinction memory."
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"text": " So after my PhD at the University of Amsterdam, I moved to Maastricht University and did also my clinical training. So I saw many patients with fear and phobias and posttraumatic stress disorder. I was well known with the literature also with the neuroscience literature and I"
},
{
"end_time": 586.766,
"index": 25,
"start_time": 556.766,
"text": " But sort of for years thinking, well, how can we somehow mislead our brain and sort of weaken the fear memory itself? Would that be possible? And then I discovered early, I think, in 2002 or 2003, indeed, because it was the year that the paper of Grimnader appeared. The paper by Grimnader showing that it might be possible to change the underlying or to weaken the underlying fear memory."
},
{
"end_time": 617.705,
"index": 26,
"start_time": 588.285,
"text": " And so what they did in rodents, they first learned this fear by presenting the rodents with a tone and a shock and then testing them a couple of days later, you see an expression of the fear memory by freezing a response if they are only presented to the tone. And what they did is instead of an extinction procedure, they reactivated the fear memory by presenting them to a single tone."
},
{
"end_time": 647.5,
"index": 27,
"start_time": 618.046,
"text": " And then injected the animals with a protein synthesis inhibitor, anisomycin, a very toxic drug, which you cannot use in humans, but they did so in the rodents. And then if they tested the animals a couple of hours later, there was still a very strong expression of the fear memory. But then 24 hours later, the fear was almost gone, as if there was no longer an expression of the fear memory."
},
{
"end_time": 677.295,
"index": 28,
"start_time": 648.2,
"text": " Yeah, this was really sort of this changed our whole idea of memory, because until then, we thought that after memory is consolidated, so maybe can dive a little bit into the basics of neuroscience on memory. So if if organisms learn something and you test them, for instance, within an hour, we speak of short term memory. So if they have learned and memorized what they if there is memory of what they learned is a short term memory."
},
{
"end_time": 704.804,
"index": 29,
"start_time": 677.688,
"text": " And in order to transfer the short-term memory into a long-term memory, protein synthesis is necessary. And if you block the protein synthesis, it is not possible to form a long-term memory. So then if you test the animals, for instance, 24 hours later, you don't see any expression anymore. But the sort of accepted view or dominant view in the memory"
},
{
"end_time": 721.664,
"index": 30,
"start_time": 704.974,
"text": " literature was that after memory has been consolidated, we cannot change the original memory trace. So the only way to change our memory is by forming new memory traces that interfere with the original memory trace."
},
{
"end_time": 749.684,
"index": 31,
"start_time": 722.056,
"text": " So this seminal study by Krimnader showed that it may be possible even after memory consolidation to change the original memory trace and that if you reactivate memory that the resaving of the memory requires again protein synthesis and this means that if you interfere with these processes with the protein synthesis"
},
{
"end_time": 777.005,
"index": 32,
"start_time": 750.572,
"text": " required for the rewriting of the previously formed memory, then we may be able to change fear memory itself. Right, and just to interrupt, if I'm understanding correctly, you make a mouse or rat or whatever it is, extremely afraid of some stimulus, let's call it a tone in this case, then you can make it afraid again by"
},
{
"end_time": 803.148,
"index": 33,
"start_time": 777.619,
"text": " repeating the stimulus, and afterwards you inject it with a neurotoxic, I believe it's just toxic in general, but I don't know, neurotoxic chemical at least, that prevents this protein from synthesizing or inhibits this protein in some way, the one that would entrench this memory, and then it would eliminate the fear response because that memory is no longer being fortified. Is that correct?"
},
{
"end_time": 831.22,
"index": 34,
"start_time": 803.626,
"text": " Yeah, almost. So what happens is if you, and I can come later to that, because it really depends on very specific circumstances, whether the memory trace is labelized. So if you retrieve a memory, it's not always the case that the memory trace becomes in a sort of label or destabilized phase. But if so, then after destabilization, it requires protein synthesis to be re-stabilized again."
},
{
"end_time": 842.073,
"index": 35,
"start_time": 831.732,
"text": " and normally that is what happens so memory reconsolidation is a way of updating the memory so if the memory should"
},
{
"end_time": 870.691,
"index": 36,
"start_time": 842.602,
"text": " stay the same should should be kept if the environment does not change but if the environment changes the memory should be changed a bit because while the whole idea of memory said it is a sort of well it makes us very adaptive because it helps us to to better respond to the environment so if the environment does not change the memory should also not change if it changes then the memory can either be changed by forming new memory traces or by"
},
{
"end_time": 900.316,
"index": 37,
"start_time": 871.323,
"text": " updating the original memory trace. Would you please elaborate a little bit on how you arrived at the idea that taking these beta blockers after being exposed to the stimulus is what's efficacious as opposed to before? So after reading this seminal study by Grimnader that appeared in 2000, so at the turn of the century, I became really thrilled because I thought if we can translate this finding to the human field, this might sort of implicate that we really"
},
{
"end_time": 923.148,
"index": 38,
"start_time": 900.316,
"text": " can sort of treat people with irrational fears and anxiety disorders and maybe also with post-traumatic stress disorder which are much more effective intervention and this could be a solution for the high relapse rate. But the anisomyosin, the protein synthesis can clearly not be used in humans. This is very toxic and also what we can do is"
},
{
"end_time": 936.903,
"index": 39,
"start_time": 923.882,
"text": " Injected drug directly into the brain, into the amygdala, the fear center of the brain, and that is what for instance, many other animal researches."
},
{
"end_time": 958.951,
"index": 40,
"start_time": 937.278,
"text": " But in 2004 and also a little bit before that year, there were a couple of studies testing the same ID, but then with propanolol, the noragenergic beta blocker. So we only give 14 milligrams and only once is not very clearly not very toxic for humans."
},
{
"end_time": 983.575,
"index": 41,
"start_time": 959.326,
"text": " In our first study we gave propanolol actually before the memory reactivation and not to dampen the fear response but we reasoned that if you reactivate the fear memory then the processes of memory destabilization and restabilization probably start immediately following the memory retrieval and it takes between one and two hours before propanolol"
},
{
"end_time": 1009.121,
"index": 42,
"start_time": 983.575,
"text": " has passed the blood-brain barrier and reaches a peak level. So we thought if we give it afterwards, we may miss the window. But then, of course, if you give it before memory reactivation, you never know whether it somehow interferes with the retrieval. So that was why in later studies, so it worked very well, and then in later studies we always now give it after the memory reactivation. But we don't use it"
},
{
"end_time": 1031.783,
"index": 43,
"start_time": 1009.582,
"text": " to dampen the fear response but noradrenaline as a neurotransmitter is indirectly involved in the protein synthesis necessary for memory consolidation and also for memory reconsolidation. So this is the reason why we can also work with propanolol instead of working with protein synthesis blockers."
},
{
"end_time": 1062.534,
"index": 44,
"start_time": 1032.568,
"text": " Would you say then that the difference between your approach and cognitive behavioral therapy is the focus on the recollection of memory and the destruction of the initial fear memory, as opposed to trying to build barrier memories that would inhibit that original fear response? Yeah, indeed. The difference is that instead of building new memories or trying to control the emotional memory and emotional responses, we try to"
},
{
"end_time": 1091.22,
"index": 45,
"start_time": 1063.183,
"text": " to mitigate the root of the disorder, so to weaken the fear memory itself. Procedurally, it's also very different because exposure treatment, yeah, the idea is that it actually targets more the cognitive processes, so the expectancies, it's a longer process, so by repeatedly people exposing to the fear cue, they gradually learn"
},
{
"end_time": 1108.797,
"index": 46,
"start_time": 1091.425,
"text": " that what they fear is irrational, whereas we expose our participants only very briefly between two and five minutes to the feared queue. So we don't target the cognitive system."
},
{
"end_time": 1122.517,
"index": 47,
"start_time": 1109.189,
"text": " And what is interesting what we see is first we see a behavior change. So we shall we reduce the defensive reflex or in phobics we change the avoidance behavior."
},
{
"end_time": 1144.087,
"index": 48,
"start_time": 1122.961,
"text": " When you say first, do you see the change? Are you talking about after you give the beta blocker and then you wait 20 minutes? Are you talking about that or the next day? Actually, we published that paper in 2018. When you test them 12 hours later on the same day, you still see the same fear expression, but only after a night of sleep."
},
{
"end_time": 1172.125,
"index": 49,
"start_time": 1144.633,
"text": " we see the sudden, very abrupt reduction of fear. So instead of the gradual decline of the fear response, it's delayed, so after 24 hours, but very abrupt. And that, especially when I treat patients and it is a successful treatment, it's every time feels like magic because"
},
{
"end_time": 1201.954,
"index": 50,
"start_time": 1172.688,
"text": " Yeah, normally you see a sort of you are there when you see a sort of gradual change in behavior and now first you see during the exposure that people are really has an intense fear response are sometimes crying and panicking and then if they come back 24 hours later they are able to it's not that they're entirely relaxed but yeah this such a huge difference so that"
},
{
"end_time": 1232.637,
"index": 51,
"start_time": 1202.79,
"text": " I'm curious, you had mentioned the relationship between protein synthesis and fear. It is known that for protein synthesis that this is deeply tied with our genetics, the sort of manuscript for the creation of all of our proteins. Do you think it is for this reason that one finds that in epigenetics that there are inherited fears? Does that have a connection to your research?"
},
{
"end_time": 1255.418,
"index": 52,
"start_time": 1233.797,
"text": " Yeah, no, what do you mean with inherited fears? Because I'm a bit, I mean, that was also one of the questions that the fear of snakes, I mean, the fears that we treat are the irrational fears. So not, I mean, of course, I mean, snakes can be dangerous, but there's no reason to be really phobic in the sense that you"
},
{
"end_time": 1285.418,
"index": 53,
"start_time": 1256.067,
"text": " that people avoid several places because there could be a snake, whereas there is no snake. So that is the kind of fear that we treat. There was an article published on, it was an epigenetic study where they, I believe they induced a fear response to rodents at the sound of a bell and they made a very visceral pain"
},
{
"end_time": 1314.77,
"index": 54,
"start_time": 1285.606,
"text": " for the rodents at the sound of that bell. They then allowed the rodents to have their next generation of offspring and then gave them the sound of that bell. Apparently the rodents were afraid, although never hearing the bell before or feeling tortured at this hearing of the bell, were afraid at the sound of the bell. What is even more amazing is that the generation after the grandchildren"
},
{
"end_time": 1339.036,
"index": 55,
"start_time": 1315.333,
"text": " They then gave the sound of the bell and had these rodents afraid. So I'm curious if this link of fear, this inheritance of fear, has something to do with epigenetic mechanisms on DNA, considering that you were speaking of the relation between protein synthesis and fear."
},
{
"end_time": 1365.794,
"index": 56,
"start_time": 1339.804,
"text": " I don't know if this is a topic that is explored. I'm very curious to read. Do you remember the authors of the paper? I can find it and send it. Yeah, please. I don't know, but somehow as if there is indeed a memory of the fear that is transgressed to the next generation. By the way, does this only work on fear memories?"
},
{
"end_time": 1396.305,
"index": 57,
"start_time": 1366.852,
"text": " post-traumatic stress disorder, or can it work on people who have innate fears, like we were mentioning before, some people are afraid of snakes innately, some people are afraid of blood, that's more discussed. No, yeah, well, we tested that because in a fear conditioning procedure, so what we do is we work with pictures and electric stimulus administered to the wrist, so painful stimulus. So we also use the fear conditioning model in the laboratory."
},
{
"end_time": 1424.172,
"index": 58,
"start_time": 1396.766,
"text": " And an innate fear is not the fear what we call to the learned stimulus or the picture followed by the shock, but actually the response to the shock itself. And that didn't change. So it's not that we in that sense dampen the, that is what you could expect if you dampen your whole fear system, that people or animals don't respond anymore to intrinsically"
},
{
"end_time": 1447.329,
"index": 59,
"start_time": 1424.582,
"text": " And you mentioned that what's required is a night's rest in order for your treatment to be effective. Have you measured the quality of someone's sleep to the extinction of the fear?"
},
{
"end_time": 1471.493,
"index": 60,
"start_time": 1448.08,
"text": " This is what we are currently testing, but unfortunately the study, we had to stop with the data collection due to COVID-19. So hopefully we can proceed with our study after the summer. But so this is, so what we did is we controlled for the, for the hours. So because from the animal literature, we learned that is that reconsolidation is time dependent."
},
{
"end_time": 1485.009,
"index": 61,
"start_time": 1471.817,
"text": " So we started first with a pilot study and then we discovered that yeah when you wait five or six hours that there was still such a strong fear expression and we always in all our previous studies we always tested the next day."
},
{
"end_time": 1514.855,
"index": 62,
"start_time": 1485.828,
"text": " for the effect. And it takes also, well, propanol has a five hour half time value. So after 12 hours, it's almost completely out of the body. And especially the next day, it's completely gone. So then you are also sure that what you measure can no longer be a propanol effect. And so we piloted first and tested five hours. And then a certain moment, I"
},
{
"end_time": 1541.459,
"index": 63,
"start_time": 1515.213,
"text": " ask my postdoc, maybe you could test also 12 hours later on the same day and we still found such a strong fear response and then we decided to study where we either did the treatment in the morning, tested them 12 hours later on the same day and then again the next day or we treated them in the evening, also waited 12 hours but with a night of sleep in between and then the next day and we really saw that it was not the time but the night of sleep."
},
{
"end_time": 1571.152,
"index": 64,
"start_time": 1541.834,
"text": " But we did not register the sleep quality. We don't know which phase of the sleep is important. So these are very interesting next steps. We also tested the time window during which we can actually give propanolol. So it was possible to give it one hour after memory activation, and it still works. But two hours after memory retrieval, then it's really too late. So that also shows that it's a really"
},
{
"end_time": 1592.722,
"index": 65,
"start_time": 1571.544,
"text": " specific time we know that you can target these processes and otherwise you are too late. Can fear extinction work on relatively minor fears? So for example, if someone were nervous speaking in front of others, could they use this treatment to get rid of those minor fears?"
},
{
"end_time": 1619.224,
"index": 66,
"start_time": 1593.37,
"text": " Social fears are in that sense not so easy because we did a study in people who have a fear of public speaking and there the treatment was not effective and the problem in research is done that you, for instance, work with a standard protocol that is already quite difficult for people who suffer from social fears because these fears are generally very idiosyncratic."
},
{
"end_time": 1646.647,
"index": 67,
"start_time": 1619.667,
"text": " but especially with social fears people very often they their fears actually what other people think for instance and it is really hard to to expose people to that and our issue is that the threat or the anticipated catastrophe does not necessarily happen in a specific time window so if what people fear can happen for instance a year later then the treatment"
},
{
"end_time": 1675.964,
"index": 68,
"start_time": 1647.073,
"text": " Cannot be applied because it really should be in the moment that you trigger the memory and then something they can learn something from from their environment With respect to their fear and there are also many fears I mean when people are afraid of dying very often that that it's not something that that's the thing will happen in the near future, but maybe in a year or so So for the kind of fears the treatment is not suitable"
},
{
"end_time": 1699.07,
"index": 69,
"start_time": 1676.732,
"text": " It seems to me that this is almost like a surgical knife, cognitively speaking, that you are removing sectors of fear and of memory, and the more clean cut and defined those fears are, the better they can be removed. Are there other complicating factors in this mental surgery? Yeah."
},
{
"end_time": 1716.937,
"index": 70,
"start_time": 1699.889,
"text": " Yeah, I agree. I also have called it once in a paper kind of sort of as a metaphor neurosurgery or so it is that sounds very different from psychotherapy. Yeah, it is one of your I think last questions."
},
{
"end_time": 1745.196,
"index": 71,
"start_time": 1718.114,
"text": " So we first showed this effect in the laboratory in dozens of studies, which is a sort of proof of principle. Then we tested it in people with fear of spiders. And then, of course, I received many questions from people who were suffering from crippling fear. So if it's so easy, I can also do it myself, expose myself to the cue, take the pill, and then the fear is gone."
},
{
"end_time": 1765.282,
"index": 72,
"start_time": 1745.196,
"text": " But yeah, unfortunately it's not easy because there are many boundary conditions and this has to do with the idea that if you are exposed to the feared cue, it's not necessarily so that the memory is destabilized."
},
{
"end_time": 1795.555,
"index": 73,
"start_time": 1766.237,
"text": " And if the exposure for instance is too, so either it is not, there's nothing new to be learned, then it's a sort of passive retrieval. It could also be that a situation is too new or too different from their original fear. And then this is a sort of, yeah, sort of initiation of the formation of a new memory or of an extinction memory."
},
{
"end_time": 1823.08,
"index": 74,
"start_time": 1796.015,
"text": " And whether you target the process of memory reconsolidation is really in between a sort of passive retrieval process and the formation of a new memory. And the problem is that we do not have a sort of index that we can use to know what is happening in the brain during the memory activation. So we only have the behavior, the readout of memory, but the fear reaction is not"
},
{
"end_time": 1850.538,
"index": 75,
"start_time": 1824.582,
"text": " informative on what happens actually in the brain, on whether it's only a passive retrieval process or whether the memory reconsolidation is triggered. So this is a huge challenge and our current research is trying to tackle this problem, especially in translating to the clinical practice. So what we do now, so I'm now sitting here in"
},
{
"end_time": 1880.811,
"index": 76,
"start_time": 1851.288,
"text": " In my clinic, we opened a clinic a year ago, where we treat many people with suffering from fears and phobias. So what we do now is, partly intuitively, to decide when do we stop? So you expose people to the fear cue. It could be a dog, a kitten, a spider, heights, whatever. How long should the exposure be?"
},
{
"end_time": 1911.408,
"index": 77,
"start_time": 1881.681,
"text": " Something I was thinking about, there are people with childhood traumas and various other anxieties, and I was wondering, well, instead of exposing them to whatever stimulus would cause them to feel the extreme fear, given that sometimes that's impractical, especially now during COVID,"
},
{
"end_time": 1936.425,
"index": 78,
"start_time": 1911.8,
"text": " Can they, with tremendous effort, concerted mental effort, just think about that stimulus to hallucinate, in a sense, their fear, and instead of bringing their fear response up to 10 out of 10, which is what you try to do in your practice, bring it up to 4 out of 10, because obviously it's not the same as having, let's say, a masked murderer in front of you and you imagining a masked murderer."
},
{
"end_time": 1961.408,
"index": 79,
"start_time": 1936.852,
"text": " Or a person in a mask. Let's say they're afraid of the scream mask from that 90s movie. So they imagine the scream mask. Okay. They imagine it and they're triggering themselves up to four out of 10. Then they take the beta blocker. Now imagine they do that. Well, first of all, would that work at all? And second of all, if let's say it doesn't work, do you imagine it would work if they did that a few times? Your treatment is like one extinction event."
},
{
"end_time": 1989.445,
"index": 80,
"start_time": 1961.817,
"text": " Eradicate that memory from one treatment, but you imagine this four out of ten progressively over the course of two weeks, let's say could bring it down to Remove that memory at least the fear associated with yeah First of all, we of course it is not necessarily so that even if it works that it is I Mean memory emotional memory that underlies anxiety disorders and especially post-traumatic stress disorder is not a sort of single memory trace, but it is a network and"
},
{
"end_time": 2015.247,
"index": 81,
"start_time": 1989.838,
"text": " So you could imagine that for PTSD that you even if it works that you weaken the network but that you need more treatment sessions to really dismantle the underlying emotional memory. We have applied the reconciliation intervention already to people suffering from post-traumatic stress disorder and this is in general the way also"
},
{
"end_time": 2043.626,
"index": 82,
"start_time": 2015.759,
"text": " Yeah, if you use the standard cognitive behaviour treatment, you always work with imaginary exposure. And the idea is that the trauma memory is actually the trigger, like in dog phobia, the dog trauma memory triggers overwhelming emotional responses and people are afraid of being overwhelmed by their emotional responses and they feel like they cannot handle it, they will become crazy, losing control, whatever."
},
{
"end_time": 2068.08,
"index": 83,
"start_time": 2043.626,
"text": " So the reason to go back to the trauma is actually usually when people have intrusive memories they try to avoid it because they don't want to expose themselves to the trauma memory because it triggers very intense difficult emotions and what you do in treatment then is you try to do that of course supporting the patient and if you do"
},
{
"end_time": 2077.227,
"index": 84,
"start_time": 2068.49,
"text": " right then it triggers indeed very strong emotional reactions and then they can experience that they do hear that sound"
},
{
"end_time": 2104.258,
"index": 85,
"start_time": 2078.097,
"text": " That's the sweet sound of success with Shopify. Shopify is the all-encompassing commerce platform that's with you from the first flicker of an idea to the moment you realize you're running a global enterprise. Whether it's handcrafted jewelry or high-tech gadgets, Shopify supports you at every point of sale, both online and in person. They streamline the process with the internet's best converting checkout, making it 36% more effective than other leading platforms."
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"end_time": 2176.34,
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"text": " not die or that they are not going crazy over there. So this is then the sort of prediction error or new experience that may"
},
{
"end_time": 2197.517,
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"text": " destabilize the trauma memory and and then a propanolol could work. There is a in one of the I don't know whether you have seen the documentary by Lana Wilson a cure for fear so one of the four parts is a night in Kabul and this was a trauma treatment."
},
{
"end_time": 2219.155,
"index": 90,
"start_time": 2198.217,
"text": " and there we used to strengthen the memory reactivation also a virtual reality environment to make it a bit stronger, so to present him with some cues that could sort of enhance the reactivation of the specific"
},
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"text": " Razor blades are like diving boards. The longer the board, the more the wobble, the more the wobble, the more nicks, cuts, scrapes. A bad shave isn't a blade problem, it's an extension problem. Henson is a family-owned aerospace parts manufacturer that's made parts for the International Space Station and the Mars Rover."
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"end_time": 2327.944,
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"text": " Do you think psychedelics could have any role in all this? Do you think it can perhaps enhance the effect?"
},
{
"end_time": 2351.51,
"index": 96,
"start_time": 2328.712,
"text": " get enhanced and that way maybe we can do something about it, reactivating that memory, or is it too much of a novel experience for someone who maybe hasn't done psychedelics before? What are your speculations on that? Well, there are some promising studies using MDMA, for instance, so I think the idea, what is important, of course, is that the researcher has a sort of"
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{
"end_time": 2381.408,
"index": 97,
"start_time": 2351.92,
"text": " at least plausible hypothesis on the working mechanism that's in my view important and whereas you very often see in in this field is that sort of drugs are just tested and so see just observe whether it has an effect or not about it's not the way I like to work but there are I mean psychedelics could work by they could help to destabilize the memory and yeah"
},
{
"end_time": 2409.155,
"index": 98,
"start_time": 2381.937,
"text": " So, and then it is easier to, yeah, to either, and then maybe not, I don't think that you should then work maybe with propanolol, because then it could be also an interaction between the two, at least you should make sure that it is not problematic. But there are also behavior, of course, imagery re-scripting is a good way to change a trauma memory. And you could do that in combination with... Yes, I wouldn't ask a question, but..."
},
{
"end_time": 2434.821,
"index": 99,
"start_time": 2409.684,
"text": " Yeah, right. It will be really interesting to do something in conjunction. So perhaps we can maybe talk a little bit about that down the road. That would be great. Yeah, but then the difference is because sometimes, I mean, cognitive behaviour treatment is just combined with drugs, but then it's only, I mean, drugs that also dampen the emotional response, whereas the"
},
{
"end_time": 2464.718,
"index": 100,
"start_time": 2435.538,
"text": " Intriguing aspect here is that we use a drug not to dampen the emotional response, but to really interfere with the learning and memory processes, which is a very different way of using a drug. How far do these unlearning processes go? Is it possible to remove disgust or happiness, for example, or let's say fond memory of something, the opposite of fear?"
},
{
"end_time": 2484.326,
"index": 101,
"start_time": 2465.111,
"text": " Certainly not limited to fears and phobias because it has also been tested in the area of addiction."
},
{
"end_time": 2514.087,
"index": 102,
"start_time": 2485.196,
"text": " Also with propanolol, by the way, in animals. We got to explore that. Can you explain how do you test this with addiction? You expose someone to something they're addicted to and then give them the propanololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololololol"
},
{
"end_time": 2541.135,
"index": 103,
"start_time": 2514.48,
"text": " So there's a cue and an approach behavior because the animal is addicted to it. And so in fears we aim to change the afforded behavior and in addiction you, yeah, then you should try to change the approach behavior. So the other way. And that is possible. It is, I think, but it has not been, I mean,"
},
{
"end_time": 2559.258,
"index": 104,
"start_time": 2542.073,
"text": " We are now in a pilot phase testing people who are addicted to cigarettes. But yeah. Okay, can you explain to me how? So let's say someone's addicted to cigarettes or cocaine."
},
{
"end_time": 2587.363,
"index": 105,
"start_time": 2559.787,
"text": " If they see the stimulus, the cigarettes or the cocaine, it triggers them. They want to smoke or they want to have cocaine again. Now, if we're making an analog to the fear response, the fear response situation is you provoke them intensely and then give them the beta blocker. Now in the addiction response, do you get them to smoke the cigarettes intensely and then the cocaine or the cocaine intensely? And then, well, obviously that's illegal. And then the beta blocker, you just make them feel like, Oh, I need to be, I want to have this so much. Then remove it. Take the beta blocker."
},
{
"end_time": 2612.807,
"index": 106,
"start_time": 2588.387,
"text": " It's this last and that makes it very hard. So the because so we first years ago we already tested this with students that wanted to quit smoking and then we so we asked them to bring their favorite cigarettes to the lab and they thought well I'm smoking my last cigarette and then they had to give the cigarette to the experimenter and we were a bit afraid that"
},
{
"end_time": 2635.52,
"index": 107,
"start_time": 2613.422,
"text": " that the participants would sort of clap the experimenter in his face or whatever but that didn't happen but the treatment also didn't work and we realized afterwards yeah because then it is a sort of passive process in terms of the memory because someone else decide for you even though the participants were motivated to quit the"
},
{
"end_time": 2665.52,
"index": 108,
"start_time": 2636.476,
"text": " It was not that they, I mean the experimenter decided that they were not allowed to smoke their own cigarettes. So we think indeed what you said, somehow we have to trigger the urge to smoke and then they have to decide themselves, so they really should be engaged in it. Okay, now I stop. See, this is why it's Nobel Prize winning, because if this works, this can work for"
},
{
"end_time": 2693.046,
"index": 109,
"start_time": 2666.169,
"text": " Addiction is a huge, huge topic. This can work for porn addiction or drug addiction or any form of addiction. That's true. I don't know. I don't know the limitations, but I've just surmised it. I mean, the translation is so difficult. And there are so, I mean, it really depends on so many subtle factors, whether it works or not. That is, I mean, as a scientist, that is really, I mean, I love that because it will never be boring."
},
{
"end_time": 2718.183,
"index": 110,
"start_time": 2693.404,
"text": " But I'm working at two sites. So I'm a neuroscientist, but I'm also working in clinical science. So I also see the, yeah, how difficult it is to bridge these two fields. And yeah, we are working on it with a team of PhD students and postdocs. There are also, I mean, there are several labs in the world that basically work with animal models."
},
{
"end_time": 2745.691,
"index": 111,
"start_time": 2718.507,
"text": " We can learn a lot from them because they can do things that we can't do. I mean, they really study the microbiology in the brain and we can't study that in humans. But yeah, it looks easier, I think, than it is. And this really has to do so because these memories, these emotional memories are so strong also for addiction and they're"
},
{
"end_time": 2772.568,
"index": 112,
"start_time": 2746.186,
"text": " I mean, if an emotional memory in general is already strong, and then they are engraved almost in the physical architecture of the brain, especially because people are addicted for years, they have experienced their addiction in many different contexts. So it's not easy to destabilize the memory. But yeah, now that we are on the road, then we should be able to change it."
},
{
"end_time": 2796.22,
"index": 113,
"start_time": 2773.302,
"text": " Now that we are on the cusp of removing fears, I think it might be important to ask, is there an important reason why people feel fear? What would be the ramifications of a society that has gone through with this research and eliminated not only fear, but as you have mentioned, addiction, disgust, even pleasure towards certain things that are otherwise unsavoury, what would the ramifications be?"
},
{
"end_time": 2825.282,
"index": 114,
"start_time": 2798.763,
"text": " I think that fear is one of the most important emotions across species, because it definitely helped us to survive, so not only is it crucial for the survival of the individual, but also for our group. It has also been, I like that phrase, sorry?"
},
{
"end_time": 2855.913,
"index": 115,
"start_time": 2827.312,
"text": " I was going to ask as a follow-up to that, how far down the phylogenetic tree does fear go? How conserved is this emotion? Yeah, well, it depends a bit on the definition of fear, but if we consider defensive reflexes as a sign of fear, then all animals, I think, exhibits a sign of fear. But I would say a society without fear, well, would not be a society anymore."
},
{
"end_time": 2884.974,
"index": 116,
"start_time": 2856.63,
"text": " it's also for instance and and the fear of losing your offspring it's very fundamental for our intense tendency to care for our babies but without fear i mean people see i i mean i think social behavior is also dependent on on fear sorry if i may if i just"
},
{
"end_time": 2906.749,
"index": 117,
"start_time": 2885.282,
"text": " Briefly go back to the idea of psychedelics because that area really fascinates me overall. Is there a particular reason you brought up MDMA specifically as opposed to let's say the other ones such as LSD, mushrooms? Do you identify anything specifically unique to MDMA that is not present in the others?"
},
{
"end_time": 2931.22,
"index": 118,
"start_time": 2907.363,
"text": " Well, at least I know, I'm not so familiar with all the studies. I know that there are a couple of studies that used MDMA successfully in PTSD and it targets the NMDA receptors and NMDA receptors are involved in the memory destabilization. So that was actually the reason that I mentioned MDMA. As far as I can understand, the MDMA would be more"
},
{
"end_time": 2957.295,
"index": 119,
"start_time": 2931.681,
"text": " for the cognitive behavioral therapy route where you just get them to relive their memory. And then now with the MDMA, they can't feel the fear as much. In fact, they might attach positive emotions to it. Whereas with your treatment, it's like, please don't attach any positive emotions, feel the fear. So that's why with LSD, that's completely different. LSD is not like you're only experiencing euphoria. If you're, you can have the most intense anxiety attacks of your entire life."
},
{
"end_time": 2977.073,
"index": 120,
"start_time": 2957.688,
"text": " so do you imagine the treatment with lsd would be i would imagine it'd be much different than mdma i would imagine that lsd or mushrooms would be more in line with your treatment rather than mdma which is cognitive behavioral therapy a cognitive behavioral therapy accelerator is mdma your treatment accelerator might be lsd that's what i surmise but i want to know what you think"
},
{
"end_time": 3004.309,
"index": 121,
"start_time": 2979.155,
"text": " Yeah, I agree. Because, yeah, because MDMA also triggers, I think, an oxytocin release if I, yeah. So it could be sort of somehow inhibits the, yeah, it could- You're allowed to speculate. Don't worry. It could work in two directions because it could also help"
},
{
"end_time": 3034.258,
"index": 122,
"start_time": 3004.701,
"text": " If you feel safe and attached, for instance, to your therapist, it could also help to dive into your trauma memory and into the more difficult emotions. So in that sense, MDMA would also work. Because if the emotions are too strong, it could also, at a certain point, inhibit of really going into it and feeling it."
},
{
"end_time": 3064.411,
"index": 123,
"start_time": 3034.667,
"text": " The documentary you mentioned is called Cure of Fear, is that correct? Yeah. Okay, I recommend everyone watch this. This I watched. I found it endlessly fascinating. It's what turned me on to your research to begin with. Is there something else you do afterwards, after the post fear stimulus, other than just give them the beta blocker? Do you talk them down? You say everything will be okay? Or is it as simple as expose yourself to the fear, 10 out of 10, take the beta blocker five minutes after that, or pretty much immediately after that?"
},
{
"end_time": 3081.596,
"index": 124,
"start_time": 3064.804,
"text": " Go along with your day. Have a nice rest. Is there something else that's missing? No, so I mean the exposure is not so easy. I mean that is really difficult. People are generally not able to do it themselves because they really need support."
},
{
"end_time": 3111.596,
"index": 125,
"start_time": 3082.073,
"text": " to actually do it because the fear response itself triggers an avoidance response so they want to to escape the situation of course but if they have done so no then they go to a room what we do is only i mean i briefly reinforce them for what they did so far and then they wait for two hours they relax because we want to make sure that they"
},
{
"end_time": 3134.121,
"index": 126,
"start_time": 3112.295,
"text": " Don't have another stressful experience that could trigger another nor adrenaline response that could interfere with the effect of the beta blocker. Okay, so and then after two hours they go home have a night of sleep and then they come back for a test. So you're there."
},
{
"end_time": 3162.005,
"index": 127,
"start_time": 3134.599,
"text": " in part to make sure that they don't have another traumatic experience that worsens it completely because I would imagine that this could drive someone insane if they're exposed to 10 out of 10 fear on something that they're already extremely afraid of. Yeah, so we try to make sure that they are not re-exposed to the feared cue and sometimes it's difficult for instance we also treat people with fear of dogs and then when they go outside it could be that they will meet a dog again and"
},
{
"end_time": 3186.152,
"index": 128,
"start_time": 3162.312,
"text": " Yeah, because then, because we know that, I mean, that could trigger again the fear memory. And we don't know, but it makes sense that it then interferes with the treatment effect. So we always make sure if that is the case, that someone will pick them up in the car, that they don't meet a dog until a night of sleep and then the next day. So we also once treated a woman with a fear of silverfish."
},
{
"end_time": 3206.476,
"index": 129,
"start_time": 3186.51,
"text": " And they were at her house so she was not allowed to sleep in her own house. She booked a hotel and then came back for the test and then after this first night she could go home again to expose herself to the silverfish when she was removed from the fear."
},
{
"end_time": 3236.271,
"index": 130,
"start_time": 3206.971,
"text": " Now, in this case of the silverfish, was there a traumatic event that happened that made her afraid of the silverfish to begin with? Because I'll give you an excuse me for seeming imbecilic or asinine. My fear, I have a fear, and it's of flying insects. I despise flying insects. Like, I like dragonflies. It's the only kind, but mosquitoes and bees and blackflies. I can't even go into the wilderness because of it. So, so practically speaking, I don't have access to you. I'm not in Amsterdam. What can I do?"
},
{
"end_time": 3265.555,
"index": 131,
"start_time": 3236.749,
"text": " Here in Toronto, alone in my condo, and other people who have fears similar to mine, maybe not flying insects, but what can they do? Obviously, this is not medical advice, but what would you, if you could take, no one's going to sue you, what would you do? Yeah, what I would do is expose you, then I would first ask you which, if there is an insect that you fear most, and then order, yeah, a couple of them, or sometimes dozens,"
},
{
"end_time": 3292.346,
"index": 132,
"start_time": 3265.776,
"text": " and then so very often fears so first of all your first question was actually is it necessary to have a traumatic experience with the cue that you fear no the idea so at least it is our conceptualization of fear and anxiety disorders that there isn't we call a fear memory or associate memory that analyzed the fear response and the fear memory is formed either through direct traumatic experiences but also very often"
},
{
"end_time": 3321.084,
"index": 133,
"start_time": 3292.346,
"text": " in an indirect way just by modeling because you have seen other people that are afraid of dogs or insects or information or sometimes people really don't know how they developed it but it is just there. Then if you have a fear some people have some sort of traumatic experience because if you have a fear of a specific animal and then you are exposed to the animal that can be experienced as a trauma."
},
{
"end_time": 3336.527,
"index": 134,
"start_time": 3322.278,
"text": " For your treatment, then, yeah, I would say, well, we should try to, I mean, first, I should do a sort of interview to know exactly what kind of situation would be terrifying for you."
},
{
"end_time": 3366.493,
"index": 135,
"start_time": 3336.954,
"text": " like being in a small room, for instance, with insects or that they are on your skin or on your feet or whatever. I'm not claustrophobic, but yes, if I was in a room that's trapped with a thousand mosquitoes, I would know. I also dislike the buzzing around my ears. So I imagine maybe I can't order mosquitoes. I don't even know how you could do that. Maybe I could just find a YouTube video of mosquitoes around a microphone, put that on, try to imagine myself in a room full of mosquitoes."
},
{
"end_time": 3394.906,
"index": 136,
"start_time": 3367.381,
"text": " No, I don't think so. It's not enough, I think, just hearing it and not being exposed to the real threat. Yeah. And it has probably to do something because most of the fears have to do with not being able to predict, for instance, the cue that you fear and with not being able to control it."
},
{
"end_time": 3421.254,
"index": 137,
"start_time": 3395.265,
"text": " So with uncontrollability and with unpredictability and that's why these insects moving fast and somehow, yeah, you feel probably like I want to control them, I want to control the noise or that they come to me and you can't. So this is really then what you need in the treatment to feel that in order to target your fear memory."
},
{
"end_time": 3451.493,
"index": 138,
"start_time": 3422.944,
"text": " So what compelled you to make this documentary, the Cure to Fear documentary? Yeah, first of all, the documentary. There are more documentaries. So first, the Memory Hackers. There's a treatment. It was a NOFA documentary. And then there's The Science of Fear by Roberto Fredecchia. That is Be Afraid, The Science of Fear. That was broadcasted in Canada, actually."
},
{
"end_time": 3465.913,
"index": 139,
"start_time": 3452.125,
"text": " CBS. They approached me, so not vice versa. And the same for Lana Wilson. But yeah, I think"
},
{
"end_time": 3497.022,
"index": 140,
"start_time": 3467.176,
"text": " First, to educate people that there are millions of people that suffer from crippling fears and phobias. So to teach people that they are not weak or crazy, that they have these fears, that is very important, but also to educate them about all the mysteries of emotional memory, which is, I think, for everyone a very relevant and intriguing topic."
},
{
"end_time": 3526.442,
"index": 141,
"start_time": 3500.606,
"text": " Great. I'd like to ask a couple of technical questions, if I may, regarding your research. In your illuminating 2009 paper, you briefly discussed two theories, namely, there was the storage theory as well as the retrieval theory, one of which you surmised may have caused fear of memory extinction. However, at the time, it was not clear which one was the cause. Would you please"
},
{
"end_time": 3554.838,
"index": 142,
"start_time": 3526.732,
"text": " a little bit elaborate on these theories and furthermore tell us whether 11 years later now in 2020 do we have a better understanding of the mechanism behind memory extinction from a let's say theoretical perspective or is it still largely a mystery overall? No well if you only study humans it is almost at least very hard and almost impossible to to disentangle between a retrieval"
},
{
"end_time": 3577.91,
"index": 143,
"start_time": 3555.265,
"text": " problem or storage problem, whether you really change the underlying memory trace or whether it's difficult, it's more difficult to retrieve it, but maybe it's still there, but you can't just retrieve it. And clinically, I mean, if the retrieval difficulty is so huge that you can never retrieve it anymore, then it doesn't"
},
{
"end_time": 3598.643,
"index": 144,
"start_time": 3578.37,
"text": " make any difference, but theoretically is of course very interesting. From the animal literature, well, now that we are more and more able to find actually the memory engram in the brain by optogenetics and so on, and that means that you can turn on and off the fear memory"
},
{
"end_time": 3629.189,
"index": 145,
"start_time": 3599.343,
"text": " They also showed that the reconsolidation intervention really changed the memory engram and this suggests at least that it affects the storage of the fear memory and that it is not just a retrieval issue. Okay, so from the animal side then it's more geared toward the storage aspect. Yeah, purely based on human research I read that it is actually, yeah,"
},
{
"end_time": 3656.357,
"index": 146,
"start_time": 3629.48,
"text": " impossible to disentangle the two conceptual frameworks. Yeah, right. Yes, there are limitations, unfortunately. And going back to the imagery rescripting phenomenon that you had, you I think you delve deep into it into a recent 2019 paper, where you discuss, you know, the role of imagery rescripting in emotional memory. Now, maybe if we can just briefly talk about this a little more, just to see whether you know, we could"
},
{
"end_time": 3685.657,
"index": 147,
"start_time": 3656.8,
"text": " utilize imagery rescripting in conjunction with let's say propranolol to extend the impact of modifying fear in various settings, for example, online therapies, like is that a possibility you think? I mean, I know we briefly talked about how the fear has to be, we have to be in a controlled environment where this has to be properly conducted, but with the introduction of imagery rescripting, do you think we can do anything in that regard or no, we still have certain"
},
{
"end_time": 3713.183,
"index": 148,
"start_time": 3686.169,
"text": " I think that, for instance, when we use the procedure in specific fears and phobias, we actually ask the participant to approach, for instance, the spider or the dog."
},
{
"end_time": 3731.766,
"index": 149,
"start_time": 3713.882,
"text": " You see they would sort of run away because I think if I approach it then something very bad happens and then they experience that it doesn't happen. So this is sort of new something new is a new experience and that's the idea that this is necessary to open up the memory trace."
},
{
"end_time": 3757.978,
"index": 150,
"start_time": 3733.2,
"text": " And for trauma memory, it could be that especially sometimes you see traumatized people and they went over and over the trauma memory in a trauma story. And then it's really hard just by going back to open up the memory trace. And then when we do a little bit of rescripting, that could help to destabilize the memory."
},
{
"end_time": 3788.609,
"index": 151,
"start_time": 3761.442,
"text": " Right, so in a sense it is possible then to do something in conjunction, because I know in that study you did not introduce beta blockers, right? It was purely... Yeah, well, so we did it, I did this already a couple of times, then it's only one session, but I also supervised several, so a recent huge trial and also in the past trial,"
},
{
"end_time": 3807.585,
"index": 152,
"start_time": 3789.155,
"text": " My question on disgust is, is it possible to"
},
{
"end_time": 3837.671,
"index": 153,
"start_time": 3808.456,
"text": " Yeah. Um,"
},
{
"end_time": 3867.688,
"index": 154,
"start_time": 3840.282,
"text": " I don't know, I don't think sometimes we see people with a fear of spiders, but sometimes they also find the spiders very disgusting. And we have the idea, but we never really tested it, that the treatment then reduces the fear response, but that the disgust remains intact. I can imagine, though,"
},
{
"end_time": 3897.142,
"index": 155,
"start_time": 3868.285,
"text": " that if they disgust is that sometimes if for instance disgust is so strong that people are yeah are afraid of the disgusts I mean that to a degree some people have a sort of cheese aversion or so or milk aversion so they have sort of disgust for some smells or and so on and I think by I don't think that we can treat that but then if people really fear that if they are exposed"
},
{
"end_time": 3925.759,
"index": 156,
"start_time": 3897.568,
"text": " to something that would trigger such a strong disgust feeling that they will faint or whatever, we could treat that. So then the disgust is more like what a spider or a dog is for people with a animal phobia. I see, thank you. Now before we wrap up, I have an analogy that I made that I think is completely naive and but but please I want you to correct it because I cannot figure out another a better way of"
},
{
"end_time": 3953.865,
"index": 157,
"start_time": 3926.459,
"text": " conceptualizing your research as to why beta blockers afterwards works rather than before. So the way that I see it is when you get exposed to a fearful stimuli, it's as if imagine you have a cabinet behind you and this is an oversimplification and each one of the drawers in the cabinet is a memory. It's as if what you've done in the fear example is you've opened up that drawer. However, if you take the beta blockers before because memory"
},
{
"end_time": 3978.626,
"index": 158,
"start_time": 3955.862,
"text": " I believe memory consolidation is highly dependent on beta receptors in your brain that if you take beta blockers that actually interferes with you, you're formulating memories. So if you were to take the beta blocker before it would be as if you can you maybe you open up that drawer, but the rewrite capabilities are not there because the beta receptors for some reason need to be active for the rewrite abilities to be"
},
{
"end_time": 3996.169,
"index": 159,
"start_time": 3979.667,
"text": " available. Okay, then you take the beta blockers afterwards because it's not as if the memory gets rewrote. I thought this is so convoluted. It's not as if the memory gets rewritten right then it gets rewritten about two hours later or one hour later. So it's like fierce stimuli, fear, experience stimuli, open up that drawer."
},
{
"end_time": 4013.319,
"index": 160,
"start_time": 3996.51,
"text": " don't rewrite in it wait one hour then the bot then the brain is going to rewrite it but the brain at one hour for now looks to the body how are you feeling are you afraid and then it will rewrite based on that so that's why if you take a beta blocker afterwards and you're calm it's like okay we're about to rewrite but now i see your calm let's rewrite it and say"
},
{
"end_time": 4035.179,
"index": 161,
"start_time": 4013.643,
"text": " Calmness. Let's put the hashtag calm on it. What's wrong with that? I'm sure there's many that's much less wrong with it. You said a lot. First of all, I think that the actual writing takes place during sleep. And there's probably more work on that."
},
{
"end_time": 4059.906,
"index": 162,
"start_time": 4035.418,
"text": " Probably the phase where when there is no new incoming information it's sort of that for the brain that is probably sort of best phase to decide if this is the information that should be kept and this can be forgotten. So that makes sense to do that when there is no new incoming information that is during the night. But there are of course several important steps in this whole process of resaving. So the"
},
{
"end_time": 4084.599,
"index": 163,
"start_time": 4060.196,
"text": " What we have shown is that you should give the beta blocker up to one hour after memory retrieval and not two hours is probably because in this brief window, time window, the beta-agenetic receptors are involved. But there are of course many other steps in this whole cascade of memory resaving. But the actual rewriting probably happens there."
},
{
"end_time": 4114.462,
"index": 164,
"start_time": 4085.469,
"text": " I think in the lab, when we did the fear conditioning, and we do not measure freezing, what they do in rodents, but we measure the starter reflex, this is an eye-blink reflex. So this is, yeah, you cannot control this reflex, it's a defensive reflex initiated in the amygdala, and that is typically potentiated when people anticipate something threatening."
},
{
"end_time": 4143.336,
"index": 165,
"start_time": 4114.889,
"text": " So when they are in a fearful state, you see an enhanced startle reflex, startle potentiation. This defensive fear behavior was not suppressed when we gave propanolol before memory retrieval. So we gave it before and it was still a fear response and"
},
{
"end_time": 4171.834,
"index": 166,
"start_time": 4143.695,
"text": " And it apparently targets the beta-agenetic receptors in the phase where it should. If you give propanolol to people that suffer from a phobia, the fear response itself is part of the, the subjective fear is part of the emotional memory. So if you suppress that, I also think that it doesn't work because this"
},
{
"end_time": 4199.974,
"index": 167,
"start_time": 4172.125,
"text": " information feedbacks and is part of the reactivation of the fear memory. So for that reason, I also would not give it before and would not suppress the fear response in people with fears and phobias. Okay, you said that you can also give beta blockers to people in the morning. But beta blockers have a half life of about five hours. So that means 12 hours from now, it's almost gone from your system. Why is it that then"
},
{
"end_time": 4226.186,
"index": 168,
"start_time": 4200.299,
"text": " the memory rewriting that happens at night time when you sleep is affected by the beta blockers earlier? Does like what I'm asking is like does the brain when you're sleeping does it look at the current? Why does the beta blocker have an effect if it's gone by the time that you're rewriting your memories when you're sleeping? Because the effect of the beta blockers is it's not that it's sort of"
},
{
"end_time": 4249.787,
"index": 169,
"start_time": 4227.858,
"text": " I mean beta blockers, we also have, it blocks the beta-agenetic receptors, they're in the brain but also in the heart. So if you take a beta blocker in a situation where you're normally stressful, you feel that because peripherally you don't have the bodily response that you normally would have in a stressful situation."
},
{
"end_time": 4279.206,
"index": 170,
"start_time": 4250.179,
"text": " but by the way we tested also another beta blocker nadolol which has the same bodily effect but does not pass the blood-brain barrier and there it doesn't work so it's really the central effect in the brain that explains the fear reduction so the beta blocker does not work by suppressing the peripheral the bodily fear response it works because in a specific time window it's"
},
{
"end_time": 4307.722,
"index": 171,
"start_time": 4279.599,
"text": " It blocks the beta adrenerotic receptors and therefore the noradrenaline as a neurotransmitter in the brain cannot signal other cells that are necessary to synthesize the proteins which are normally used for the resafing of the memory. Okay, I see. And even though the protein synthesis may take"
},
{
"end_time": 4337.09,
"index": 172,
"start_time": 4308.029,
"text": " place later. It does not mean that all these neurobiological processes take place at the same time. They have, in that sense, probably their own time window. I see. So I'm pretty much wrapped with my questions to Faraz and Peter. Do you have any follow ups? Just maybe if you could, as my final question, if you could briefly maybe talk about the future challenges and limitations in determining the exact role and impact of a proper analog, if you want to summarize that."
},
{
"end_time": 4360.981,
"index": 173,
"start_time": 4337.722,
"text": " We are currently working on what is important is that there is no, I think I haven't said that, so what makes it so difficult is that there is not a single"
},
{
"end_time": 4389.206,
"index": 174,
"start_time": 4364.275,
"text": " exposure or in the laboratory memory reactivation procedure that always triggers the process of memory reconsolidation. So whether a brief exposure destabilizes the memory depends both on the learning history, so on the memory representation itself and on the retrieval or on the exposure."
},
{
"end_time": 4410.35,
"index": 175,
"start_time": 4389.531,
"text": " So this is the interaction between these two, and this makes it quite a challenge. It means that for instance, a stronger memory requires sometimes a longer exposure than a weaker memory. But yeah."
},
{
"end_time": 4430.043,
"index": 176,
"start_time": 4410.981,
"text": " but yeah i mean the memory is a theoretical construct so we can only observe the behavior and we cannot say on basis of the behavior this is a strong memory and this is a weak memory and this is for this strong memory you need a one minute exposure and for this memory is three minutes so so"
},
{
"end_time": 4448.695,
"index": 177,
"start_time": 4430.452,
"text": " So we are actually because of this interaction and in the lab we can really control that and we did so. So we changed we can really play around with the learning history in the lab is the fear conditioning and then and then see okay we can control if if we then expose them to one or two trials"
},
{
"end_time": 4475.93,
"index": 178,
"start_time": 4448.695,
"text": " It's it's it works and then to a bit more than it doesn't work anymore and we understand why in Clinical practice when we work with people with a phobia we we have we don't nothing about the learning history this very often there are many many Experiences or it can be very implicit learning or indirect. We don't know so we have to guess what is actually necessary to destabilize the memory and this is what we Yeah, we try to"
},
{
"end_time": 4505.23,
"index": 179,
"start_time": 4476.698,
"text": " to do in our current research to understand it better so that we can better control what the boundary and necessary conditions are when we translate our findings to clinical practice. Doctor, speaking of your current research, where can our audience find out more about you and are there ways that they can support you in your work? And that I believe will be our final question."
},
{
"end_time": 4521.101,
"index": 180,
"start_time": 4505.998,
"text": " Yeah, well I can also send my links of course to the UVA, the University of Amsterdam and also the link to the clinic. Thank you very much. Thank you so much, appreciate it."
}
]
}No transcript available.