Theories of Everything with Curt Jaimungal - Merel Kindt on Eliminating Phobias / PTSD enduringly

Episode Date: October 20, 2020

Patreon for conversations on Theories of Everything, Consciousness, Free Will, and God: https://patreon.com/curtjaimungal Help support conversations like this via PayPal: https://bit.ly/2EOR0M4 Twitter: https://twitter.com/TOEwithCurt iTunes: https://podcasts.apple.com/ca/podcast/better-left-unsaid-with-curt-jaimungal/id1521758802 Pandora: https://pdora.co/33b9lfP Spotify: https://open.spotify.com/show/4gL14b92xAErofYQA7bU4e Google Podcasts: https://play.google.com/music/listen?u=0#/ps/Id3k7k7mfzahfx2fjqmw3vufb44DOCUMENTARY SERIES: https://www.youtube.com/watch?v=pM3G6kITdYk MEREL'S WEBSITE: https://kindtclinics.com/en/ [1]: Beyond extinction: erasing human fear responses and preventing the return of fear [2]: MissingINTERVIEWERS: Peter Glinos, Faraz Honarvar, Curt Jaimungal EDITED BY: Efron Monsanto TIMESTAMPS BY: Prof. Joe Velikovsky00:00 Introduction to fear extinction 14:07 ​Propranolol & the blood/brain barrier 18:32 ​Epigenetics & inherited fears (vs irrational/phobic fears) 26:33 ​Removing the fear of Public Speaking 30:36 ​PTSD 33:45 Using ​psychedelics / MDMA to enhance self-treatment 37:29 ​Pilot study with cigarette addiction 42:31 Should we get rid of fear? What are the consequences? 43:13 ​MDMA vs LSD vs Psilocybin 48:07 Fear of ​silverfish 50:13 ​Phobias don't always come from trauma, they can be from modelling someone else's behavior 54:37 ​Prof. Kindt's groundbreaking 2009 paper, and memory engrams [1] 55:34 Prof. Kindt's 2019 paper [2] 58:02 ​Imagery scripting 59:35 What about disgust-removal? 1:00:36 ​How beta-blockers work 1:02:04 The necessity of sleep for memory transcription and re-consolidation 1:03:33 Prof. Kindt measures the startle reflex (emanating from the amygdala) when someone's threatened 1:06:07 Testing a different beta-blocker (but it didn't pass the blood/brain barrier) 1:07:12 ​Future challenges & limitations (re: fear extinction)* * *Subscribe if you want more conversations on Theories of Everything, Consciousness, Free Will, God, and the mathematics / physics of each.* * *I'm producing an imminent documentary Better Left Unsaid http://betterleftunsaidfilm.com on the topic of "when does the left go too far?" Visit that site if you'd like to contribute to getting the film distributed (in 2020) and seeing more conversations like this.

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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 Drachma Institute, where we interview postdocs, 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 Drachma 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 Merel Kint of the University of Amsterdam, and she is a professor in fear extinction, if I'm not mistaken.

Or at least that's what she studies. So, Professor, can you give us an overview of your fear extinction research? This is a long story, so I don't know how much time you have, but I think I have to give you a bit of background information, otherwise it's really difficult to understand the research programme and why we changed 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 behavioural 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 the yeah the what is really a problem is the high relapse rate so even after successful treatment there are many patients that yeah show a relapse

and um yeah this this idea of relapse after cognitive behavioral treatment can be 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 rat? Can you go nine meters? And then they're like, that's, that's the most you'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 some, and that takes weeks and weeks and weeks. And what you're saying is there are a couple of 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 um uh model to understand um exposure treatment or cognitive behavior treatment and and this is so we can learn

for instance rats um by presenting a neutral stimulus a tone which is followed by painful stimulus a shock and then after a couple of learning trials they so they if we only present them the new originally neutral throne they react with a freezing response so that means that a what we call a fear memory has been formed which is a 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 are 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 the 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 it's a very effective procedure to reduce the learned fear responsees 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 the, yeah, around the, well, 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 behavior 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 post-traumatic stress disorder. I was well known with the literature, also with the neuroscience literature. And I was 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 three three indeed because that was the year that the paper of Grimnader appeared the paper by Krimnader 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 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 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, well, if there is memory of what they learned, there is a short-term memory. And in order to transfer the 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 there is 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 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 Grimnader showed that it may be possible even after memory consolidation to change the original memory trace and that if you reactivate the 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, or inhibits this protein in some way, the one that would re 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 labeled so if you retrieve a memory it's not always the case that the memory trace is becomes in a sort of label or destabilized phase but if so then after destabilization it requires

protein synthesis to be restabilized 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 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 is that it is a sort of, well, it makes us very adaptive

because it helps us 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 higher relapse rate. But the anisomycin, the protein synthesis can clearly not be used in humans. This is very toxic. And also what we can do is inject the drug directly into the brain, into the amygdala, the fear center of the brain. And that is what, for instance,

Nader did and also 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 neuro-adrenergic beta blocker. So we only give 14 milligrams and only once. It's clearly not very toxic for humans. In our first study, we gave propranolol 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 the emotional responses we try to to yeah mitigate the uh 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 it's a longer process so by repeatingly people exposing to the feared cue they gradually learn that what they fear is

is irrational whereas we expose our participants only very briefly between two and five minutes to the third cue. So we don't target the cognitive system and what is interesting what we see is first we see a behavior change so we reduce the defensive reflex or in phobics we change the avoidance behavior and when you say first you see the change are you talking about after you give the beta blocker and then you wait 20 minutes or talking about that or the next day we actually we found and we published that paper in 2018 and when you test them 12 hours later on the same day you still see them 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 And that, especially when I treat patients

and it is a successful treatment, it's every time feels like magic because normally you are there when you see a 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 and panicking and then if they come back 24 hours later they are able to it's not that they're entirely relaxed uh but yeah there's such a huge difference so that really feels like it cannot be true i'm curious you had mentioned the relationship between protein synthesis and fear it is known

that 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 i i'm 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 is of is 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 a sense that you that people avoid several places because there could be a snake whereas there is no snake or so that is the kind of fear that we treat um there was an article uh published on it was an epigenetic study

where they i believe they induced a fear response they 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 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 for 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... curious to 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 um indeed a memory of the fear that is transgressed to the next generation. By the way, does this only work on fear memories like 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 an electric stimulus administered to the wrist so painful stimulus so we also use the fear conditioning model in the laboratory and and an innate fear is not the fear but 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 the whole fear system that people or or animals don't respond anymore to intrinsically uh threatening stimuli like pain or uh or a threatening animal and that's that this is not what happens it's really to the learned fears 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 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 it 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 and it takes also um well propanolol has a five hour half time value so after 12 hours it's almost completely out of the body and especially the next next day, it's completely gone. So then you are also sure that what you measure can no longer be a propanolol effect. And so we piloted first and tested five hours. And then a certain moment, I asked 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 designed a 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 test 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 a memory activation and

it still works but two hours after memory retrieval then it's really too late so that also shows that there's a really specific time window 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 to approach, 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 people, we did a study in people who have a fear of um 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, their fear is actually what other people think, for instance. And it is really hard to expose people to that. And another 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 a treatment cannot be applied

because it really should be in the moment that you trigger the memory and then they can learn something from their environment with respect to their fear. And there are also many fears. I mean, when people are afraid of dying, very often this is not something that the thing will happen in the near future, but maybe in a year or so. So for that kind of fear, 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? whole 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 in that sense very different from psychotherapy yeah it is in one of your i think last questions um because after so we first showed this effect in the laboratory in dozens of studies, which is a sort of principle. Then we tested it in people with fear of spiders. And then, of course, I received many questions from people who are 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 to so either it is not there's nothing new to be learned then it is 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 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 reactivation. 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 this problem especially in translating to 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, so to decide when do we stop. So you expose people to the feared cue. It could be a dog, a kitten, a spider, heights, whatever. And then you have to determine, okay, how long should the exposure be such that we trigger the, so we destabilize the memory, but that it's not too long such that it becomes already an exposure treatment. And that is, yeah, really a challenge.

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

four 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.

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 do you imagine this four out of 10 progressively over the course of two weeks, let's say, could bring it down to almost remove that memory, at least the fear associated with it? Yeah. First of all, of course it is not necessary 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. 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 behavior 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 and if you do it right then it triggers indeed the and yeah very strong emotional reactions and then they can experience that they do not die or that they are not going crazy or whatever so this is then a sort of prediction error or new experience that may destabilize the trauma memory, and then the propranolol 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 Night in Kabul. And this was a trauma treatment. And there we used to strengthen the memory activation 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 trauma memory. But this is not always necessary. Sometimes people are very good in remembering the trauma. Razor blades are like diving boards. The longer the board,

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Just as a follow-up question, do you think psychedelics could have any role in all this? Do you think it can perhaps enhance the effect? Let's say if the memory is at the level of, let's say, four out of 10, perhaps with a psychedelic experience, this can get enhanced and that way, maybe we can do something about it,

reactivating that memory or is it too too much of a novel experience for someone who maybe hasn't done psychedelics before what are your speculations yeah well there are some some promising studies using mdma for instance so i think the idea what is important of course is that 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 well that's not the way i like to work but there are i mean psychedelics could work by um they could help to destabilize the memory and yeah so and then it is easier to yeah to to either

and then maybe not i 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 scripting is a good way to to change the trauma memory and you could do that in combination with yes I would ask the question about the memory yeah yeah right it would be really interesting to to do something in conjunction so perhaps we can maybe talk a little bit about that down the road it'll be great yeah but but then the difference is because sometimes i mean cognitive behavioral treatment is just combined with um with drugs but then it's only i mean drugs that also dampen the emotion response whereas the

intriguing aspect here is that we use a drug uh not to dampen the emotion response but to really interfere with the yeah 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 a fond memory of something, the opposite of fear. Are these future paths for this research or is it limited only within the scope of the phobic? Certainly not limited to fears and phobias because it has also been tested for in the area of addiction. Also with propranolol by the way in animals. Okay 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 propranolol propranolol

well there are not many studies uh in in successful studies in humans but in animals it is possible that you can yeah first learn animals to become addicted to cocaine or other uh other drugs so addiction is also an associative memory like fears so there's a cue and an and an um yeah approach behavior because the animal is addicted to it and um so in fears we aim to change the affordance behavior and in addiction you yeah then you should try to to change the approachance behavior and in addiction you, yeah, then you should try to, 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, uh, testing, um,

people who are addicted to, uh, cigarettes. Uh, but yeah. Okay. Can you, 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 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 give them

the beta blocker or 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 uh 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 decided for you even though the participants were motivated to quit that 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 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 it's true i don't know i don't know the limitations but i'm just surmising huge topic this can work for porn addiction or drug addiction or any form of addiction it's true i don't know i don't know the limitations but i'm just surmising i mean the translation is so difficult so uh 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's it will never be boring uh but i'm i'm working at two sides 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 psd 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 uh yeah the the it looks easier i think than it is and this really has to do so so because these memories

these emotional memories are so strong also for addiction and they are um um 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...

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 unsavory, what would the ramifications be? I think that fear is one of the most important emotions across species because it's yeah 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... How far down... 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 the fear of losing your offspring, it's very fundamental for our intense tendency to care for our babies. for our babies but without fear I mean people see 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 that area really fascinates me overall and is there a particular reason you brought up MDMA specifically as opposed to let's say the other ones such as you know LSD mushrooms is are there

any you do identify anything specifically unique to MDMA that is not present in the others or well at least I know I'm 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 accelerators MDMA, your treatment accelerator might be LSD. That's what I surmise, but I want to know what you think. Yeah, I agree. Uh, because, uh, yeah, because MDMA, uh, also triggers and I think an oxytocin release if I, uh, yeah. Um, oxytocin release if i uh yeah um so it could be sort of somehow inhibits the um 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 also in into the trauma memory and into the more difficult emotions so in that sense MDMA would also work because if you are too if the emotions are too strong it could also at a certain point sort of inhibits 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 it. 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 is there or is it as is it as simple as expose yourself to the fear 10 out of 10 take the beta blocker five minutes after that or or pretty much immediately after that and go along with your day have a night's rest is there something

else that's missing no so so i mean 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 escape the situation, of course. But if they have done so, no, then 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 noradrenaline response that could interfere with the effect of the beta blocker. Okay. And then after two hours, they go home, have a night of sleep, and then they come back for a test. 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 um so we 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 she booked a hotel and then came back for the test and then after this first night she could go home again to to expose herself

to the silverfish fish when she was removed from the fear now 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 and stonemasons, but mosquitoes and bees and black flies, I can't even go into the wilderness because of it. 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 what would you if you could take no one's going to sue you what would you what would you do yeah what i would do is expose you then i would first ask you which if if there is an insect that you um fear most and then order um yeah a couple of them or sometimes dozens and then um 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 is, or at least it is our conceptualization of fear and anxiety disorders, that there isn't, we call it fear memory or associative memory that analyzes the fear response. 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 um for your treatment then yeah i would say well we should try to i mean i at 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 that they that you that they are on your skin or on your feet or whatever so I'm not claustrophobic but yes if I was in a room that's trapped with a thousand mosquitoes, I would not, I don't, I also desperately, I 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, make my fear response four out of 10, because that's probably the best I could do. Then take the beta blocker. Do you imagine something like that would work? 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 is 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 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 that cure to fear documentary

yeah first of all the, there are more documentaries. So first, the Memory Hackers, there's a treatment, was a NOVA documentary. And then there's the Science of Fear by Roberto Verdeckia. That is Be Afraid, the Science of Fear. That was broadcast in Canada, actually, CBS. They they approached me so not Pfizer for SF and the same old for Lana Wilson but yeah I think to 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, you know, 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? 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 disentangle between a retrieval problem or a 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 retrievalval difficulty is so huge that you can never retrieve it anymore, then it doesn't make any difference. But theoretically, it's, 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 it's more geared toward the storage aspect yeah very purely based on human uh research i agree that it is actually yeah impossible to uh this entangle the two uh conceptual frameworks yeah right

yes there are limitations unfortunately and um going back to the imagery rescripting phenomenon that you had you i think you delved deep into it into a recent 2019 paper where you discussed 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 re-scripting 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, do you think?

I mean, I know we briefly talked about how the fear has to you we have to be in a controlled environment where this has to be properly conducted but with the introduction of imagery re-scripting do you think we can do anything in that regard or or no we still have certain hard limitations yeah i think that for instance in for if when we um use the uh procedure in specific fears and phobias but we actually ask the participant to approach for instance the spider or the dog and and then I mean usually they would sort of run away because they 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 is that this is necessary to open up the memory trace.

And for trauma memory, it could be that especially sometimes we see traumatized people and they went over and over the trauma memory and the 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 with, because I know in that study you did not introduce beta blockers, right? It was purely... Yeah, yeah well or so then

so we we did it we already did this already so a couple of times then it's only one session but i also supervised several uh um so a recent uh huge trial and also in the in the past trial uh where we only did imagery scripting but then it's more like a traditional cognitive behavior treatment. And you do sort of weekly sessions, many sessions in a row. Right, right, right.

Yeah. My question on disgust is, is it possible to have a technique for disgust that would eliminate it and mirror the would it be the same process except as as fear removal but instead with the disgust stimulus uh stimulus so for example uh if someone is completely grossed out by my blood or by public toilets uh how would they overcome this this disg? Would they do it the same format? Yeah. 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. they also find the spiders very disgusting and we have the idea but we never really tested it that that's the treatment then reduces the fear response but that the disgust remains intact I can imagine though that if the disgust is that sometimes if for instance disgust is so strong that people are yeah are afraid of the disgust i mean that to 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 well 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 animal phobia. I see. Thank you. Before we wrap up, I have an analogy that I made that I think is completely naive. But please, I want you to correct it because I cannot figure out a better way of conceptualizing your research as to why beta blockers afterwards works rather than before.

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, it actually interferes with you formulating memories. So if you were to take the beta blockers before, it would be as if 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 know 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 like fierce, extimulate, fear, fear, stimuli, open up that drawer. Don't rewrite in it. Wait one hour. Then the, then the brain is going to rewrite it. But the brain at one hour from 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 let's put the hashtag calm on it now is what's wrong with that i'm sure that there's some there's many of it's much better but yeah you said a lot uh first of

all i think that the the actual rewriting takes place during sleep um and that's probably there's more work on that probably the face where when there is no new incoming information it's sort of that for the brain that is probably sort of best face 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 what we have shown is that you should give the beta blocker up to one hour after memory retrieval and not two hours. It's probably because in this brief window, time window, the beta-adrenergic 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 eye blink reflex so um this is a yeah you cannot control this reflex it's a defensive reflex um 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 propranolol before memory retrieval. So we gave it before and it was still a fear response. And it apparently targeted the beta-agenetic receptors in the phase where it should. receptors in in the phase where it should if you do it if you give propanolol um to people that suffer from that that suffer from a phobia um 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 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 nighttime 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 um yeah because um the effect of the beta blockers is it's not that it's sort of

i mean beta blockers i mean you also have um it blocks the beta-agenetic receptors. They are in the brain, but also in the heart. So if you take a beta blocker in a situation where you are 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 blocks the beta-adrenergic 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 resaving 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 or 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 proper analog if you want to summarize that um in terms with regards to fear extinction that would be great but other than that yes it was was great yeah we um we are currently working on so 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

that 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 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 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 try 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