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Episode 21: Pain perception and treatment: Guest Mike Trujillo
13 Plays5 years ago
Guest Dr. Michael Trujillo of Karuna Labs talks to us about pain perception and recent research on the management of pain. We discuss a recent article (Hird et al.) exploring the degree to which expectation can alter the perception of pain, as well as Trujillo's work in using Virtual Reality in pain management.
Boundary effects of expectation in human pain perception (2019) by Hird, Charalambous, El-Deredy, Jones, & Talmi
Shout out to Gareth Thompson of Digitimer
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Transcript
Introduction and Guest Overview
00:00:10
Speaker
Welcome to Cognation. This is your host, Rolf Nelson. And me, Joe Hardy. Welcome to the show. On this week's episode, we're going to be talking about pain. And we have a special guest, Dr. Michael Trujillo. Mike is a PhD neuroscientist who has got his degree at UC Riverside. He is currently the vice president for clinical affairs and data science at Corona Labs.
Virtual Reality in Pain Treatment
00:00:36
Speaker
And they're working on a variety of topics, but I think the
00:00:40
Speaker
I think we're going to be focusing on today is pain. So, uh, we can talk a little bit about that. Mike, do you want to say a little bit about, uh, yourself and what you're doing these days? Sure. Um, so, uh, happy to be on with you, uh, Joe and Ralph. Uh, yeah. So, uh, as Joe mentioned, I'm the vice president for clinical affairs at Corona labs, uh, at, at Corona, we create, um, virtual reality tools to treat chronic pain.
00:01:11
Speaker
And the way that we do that is we use a concept known as virtual embodiment combined with functional rehabilitation exercises to treat chronic pain. I got into this type of work several years after my PhD working with in vitro diagnostics, such as in vitro electrophysiology on stem cell derived cells in safety pharmacology and toxicology.
00:01:41
Speaker
I was really interested in the way that pain itself is very complicated and is a very interesting thing to study right now because there is a lot of things that can be done with respect to the way that pain is modulated.
Personal and Professional Insights
00:02:00
Speaker
I would mention also that Mike and I know each other from way back now. We worked together at Posit Science over 10 years ago now.
00:02:10
Speaker
Almost 20. Oh, wow. Yeah. So a lot more than 10. That's giving away a little too much information. But yeah, so we've been able to keep in touch. And so I'm super glad to have him on the show today. And I think I think we've got a really good topic.
00:02:25
Speaker
Yeah, great. So I am really looking forward to this. And Mike, this is the first time I'm meeting you. So pleasure to talk with you on this show. And I think this is a great, interesting topic to get into.
The Influence of Expectations on Pain Perception
00:02:37
Speaker
So the paper that we're using as a sort of guide for this episode is one that came out fairly recently in June of this year. And it is called Boundary Effects of Expectation in Human Pain Perception.
00:02:55
Speaker
And it's by E.J. Hurd and his colleagues in the United Kingdom at Manchester.
00:03:03
Speaker
And just a basic overview of this paper. The basic idea is that expectations can temper the way that we experience pain. So maybe let's just dive into this paper. So Mike and Joe, feel free to jump in. What did you think about this? Maybe we can go over some of the. Yeah, so to take kind of the 32,000 foot view.
00:03:33
Speaker
This is one of those things within pain research that people have thought existed for a long time, that you can modulate your experience to pain, or you can modulate the perception of how discomforting pain is to you. And I thought this paper was pretty interesting because they had a pretty straightforward and simple way to test whether you can modulate your perception to the intensity of pain.
00:04:03
Speaker
Yeah, I mean, it seems like it's the kind of thing that makes sense. So for example, if you're expecting something to be very painful and then something happens, you're going to maybe feel like that's more painful than if you were expecting it to just be not very painful at all.
Personal Stories and Pain Perception
00:04:23
Speaker
And that's the general idea. So it's sort of like a placebo effect or a no-cebo effect if it's more painful than you're expecting. And I will make the claim that this is significantly worse in young children because
00:04:40
Speaker
I was a couple of weeks ago, I took my kid to the emergency room because he had a cut on his chin and he needed stitches. And as it turned out, actually getting the stitches was not that bad. And he wasn't even wasn't even that bad when he was getting it. But the anticipation for it was just killing him, especially he didn't know what he was getting. He thought he was he thought this was it. This is the end of it. And he was just screaming bloody murder. This to me is sort of at the at the one end of how expectations can affect
00:05:11
Speaker
How old's your kid, your kid, Rolf? He is eight years old right now. Oh, okay. I've got an eight year old, too. Oh, okay. So maybe it's something that you've seen before, too. Oh, yeah. Jackson's about to turn eight. Yeah. Yeah. Yeah. Yeah. I heard this real interesting kind of, I guess, wisdom once is that children learn to deal with pain and adversity based on how their parents react when they fall down. So I try to ignore them when they get hurt.
00:05:40
Speaker
Yeah. That's definitely part of it. There is some sense to that. There is some intuitive sense to that as a parent, I think.
Pain Tolerance and Perception Differences
00:05:50
Speaker
But it's funny how the pain thing is interesting from the perspective of just that there are psychological effects. There are things that you can do to modulate pain. We all know that. I think the fun thing about this particular work is that they really do some
00:06:10
Speaker
careful exploration of the space of how much and under one conditions you can modulate pain. Uh, the paper as we will get into is not perfect, but it's some pretty, there's a pretty cool stuff in here and it's interesting. So, you know, pain perception itself is a, is a super interesting topic for me because there, there's a very wide spectrum for pain tolerance itself. You know, some people can deal with pain very well.
00:06:40
Speaker
Uh, other people, you know, just the slightest bit of pain is, is very discomforting to them. And, uh, and, and it hurts, you know, so, um, one of the ways I like to think about it is like kind of extremes. Um, so if you take fighters, for example, you know, like a boxer, MMA boxer, MMA fighter, even, you know, wrestlers or, or football players, you know, who are just takes a ton of punishment.
00:07:07
Speaker
Exactly. So, you know, they, they go into these things knowing that, you know, I may break my hand in the middle of a fight and you see these, these fighters who, you know, will break their hand and let's say the first round of a boxing match and then continue 11 more rounds. And what should be under excruciating pain, you know, if, if I broke my hand at work, I'm not finishing the day I'm going home. Yeah. Yeah. I'm going home. But, you know, for, for some reason, there's these people, you know, like, like,
00:07:34
Speaker
like fighters at a high level that can endure that pain long enough to get through another 30 minutes of a fight. So there's a, go ahead. Now, someone like that who has a really high tolerance for pain, is that, this is something I don't know so much about. So is this on a continuum with people who experience no pain? So people who actually have fibers cut so that they're, or that have a congenital inability to feel pain?
00:08:05
Speaker
So the inability to feel pain is not, it would not be on the same continuum. That's a disorder. And that's clearly, and I know that that's clearly, I mean, it's a huge disability too, because if you're not getting that feedback, you can really damage your, you can damage just about everything in your body because you curl up and you have no, you have nothing to tell you that it's a painful position that you're in.
00:08:33
Speaker
Exactly. Yeah. Yeah. You put yourself in danger, you know, and that's, you know, the way that pains are often framed is that it's your body's warning system that you are in danger, you know, so you'll take yourself back to introductory psychology when they're talking about reflexes. And they always give the example of when you touch a hot stove, you withdraw from that hot stove before you even perceive that you are damaging your skin from touching the hot stove. So there's multiple mechanisms that work there, you know,
00:09:01
Speaker
from subcortical, which would be largely out of our conscious awareness, all the way down to the level of the spinal cord where if a stimulus is so dangerous and so damaging to your well-being that, hey, we're not even going to give the brain a second to figure out if this is good or bad. The spinal cord is just going to take care of it and withdraw from that stimulus.
Complexity of Chronic Pain Perception
00:09:25
Speaker
But as far as the question about the continuum goes,
00:09:28
Speaker
You can think of the continuum of these fighters or professional football players or somebody who can endure a large amount of pain and still push through that pain to finish whatever task they're on. On the other end of the continuum would actually probably be people who suffer from chronic pain. Not to say that people who suffer from chronic pain are somehow less tough or less able to deal with their pain.
00:09:57
Speaker
their nervous system has adapted in such a way that it's made pain processing kind of at the forefront of their existence. So they constantly attend towards this pain that may or may not be due to some kind of a warning or some kind of damage that they may incur. You know, so to give an example, there's a condition known as complex regional pain syndrome.
00:10:24
Speaker
which is very mysterious. There's not a lot known about the mechanisms of it, but symptomatically, it occurs when somebody has, let's say, an initial injury such as a sprained ankle that six months, one year, several years down the line, after the tissue from the sprained ankle has healed, they still perceive the ankle as painful. So there's some maladaptive plasticity that's occurred where either their pain tolerance has shifted
00:10:53
Speaker
to the point where something that should not be perceived as painful is perceived as painful, or there's some kind of maladaptive mechanism within the central nervous system, up in the brain itself, that is creating this reaction to the previously damaged area in kind of a protective mechanism. And the way that psychologists will refer to this, or pain psychologists, is hurt versus harm.
00:11:23
Speaker
So the initial, the initial reaction for pain is that I want to avoid something that's going to harm my body, but it continues for people in chronic pain because they now perceive it as every time it hurts, I need to protect that. So I don't harm it. Uh, but that's not necessarily the case. That's a super interesting distinction there between hurt and harm. I think it, you know, I was thinking about that from the perspective as you were talking.
00:11:54
Speaker
about pain tolerance because in some sense it's pain tolerance is a question because if I'm experiencing something you know that's like I say a six on a scale of zero to ten like let's say it's a shock for example like an electrical shock like we're going to talk about in this in this paper the same level of voltage I might experience as a six you might experience as an eight
00:12:22
Speaker
You have, you're having more pain than I'm having or reporting more pain than I'm reporting. But is that because I have a higher tolerance for pain or is it actually just that I'm, I experienced less pain for the same amount of harm or experience pain or even experience differently? Yeah. So it's, it's, it's difficult to talk about that. I feel like the language kind of fails us a little bit when we start to talk about pain as such, because it is a psych, you know, it is a,
Neurological Basis of Pain Perception
00:12:50
Speaker
A conscious experience, it's a subjective conscious experience. It's hard for us to compare. It's very subjective and also very categorical. There's also situations. One way to think about it is to look at the extreme. Somebody can tolerate pain versus somebody who has a low tolerance for pain. But another way to think about it is within an individual, they can handle pain differently depending on the context they're in.
00:13:20
Speaker
So to give an example, from what my wife tells me, childbirth is very painful. I can only assume that it is. But that most women can tolerate it because it's this context where you understand that there's going to be some pain that presumably is followed up by this joyous moment of having a child. And evolutionary can think of it that there's built-in mechanisms that help women
00:13:47
Speaker
deal with that type of pain in a way that is not going to damage them long-term, because it's obviously very painful, but that can continue the evolutionary line so that they can have children. Yeah, that's a very interesting example.
00:14:04
Speaker
So in maybe a simplistic way that I think about this, and maybe you have a better conception of it, is I think about when you're getting the pain signal from the actual, there's the actual thing in the world that transduces a pain signal that goes up your spinal cord into your brain. And I think about part of the rest of the pain system as being an interpretation of what that means.
00:14:31
Speaker
You do have something physical, but it can be highly modulated by all kinds of context, if meditation can help pain, or a lot of treatments that aren't directly addressing the initial shot of pain up through the nervous system. All of that stuff is trying to modulate it at a higher level. And as you mentioned, pain is a subjective phenomena. It's entirely a personal experience, so we can't know exactly what pain another person is feeling.
00:15:00
Speaker
I wonder if this is a framework that seems helpful or maybe you could update it with better terminology. Well, you know, there's a word that you touched on there that throughout the pain research literature, this will always come up. That's the word perception, right? So I know Joe has a background of perceptual psychophysics. Ralph, you studied with Joe, so you may have... Yeah, and that's a lot of my area, too, is in perceptual psychophysics.
00:15:29
Speaker
Yeah, so if you think within the visual system, for example, let's say you have these neurons, these circuits within, let's say, the primary visual cortex that are very, very good at responding to angles or straight lines. So your brain, when the signal comes in from your eyes, it sends a signal back and there's this neuron that its job is to say, I saw a straight line.
00:15:56
Speaker
When you see an object, you're not thinking about, wow, it's just sliding straight, slightly angled at 25 degrees, slightly angled at negative 25 degrees. So you're not thinking that, but you have this perception of something you saw. So pain is similar in that there is a signal coming in that there may be damage to your body or your organism. But the perception of it is kind of higher order.
00:16:24
Speaker
similar to how you have this visual perception where you have these, these primary sensory modalities that are processing a signal. But the actual interpretation of that signal is it happens at a, at a higher level within the organization of the brain. And because it happens at this higher level, there's a lot of things that can come into play with the way that you actually do perceive that painless painful stimuli.
00:16:53
Speaker
And it's very complex, very complicated. And for the most part, the exact mechanisms by which pain perception occur within the higher centers within the brain is not very well understood. There's a lot of things like fMRI studies that say, well, there are certain areas within the brain that are active when you're experiencing pain.
00:17:21
Speaker
So one of those, of course, is, as I'm sure you could guess, the amygdala, right? Because the amygdala is very involved in threat detection as well as emotional response to things. Another one that's actually pretty interesting is the anterior cingulate cortex, which is involved in a lot of attentional processing. You know, this is kind of an area that is active when you're choosing to pay attention to one thing versus another. And also, you know,
00:17:49
Speaker
with these fMRI studies, they say, oh, the hippocampus is also active. But show me when the hippocampus isn't active. Right. That's not telling you a lot. Right. But I mean, even the anterior cingulate now is like in all of these fMRI studies, it feels like that's always one that comes up. Yeah. And there's animal models of chronic pain, rodent models, that show a lot of interesting changes within all these circuits.
00:18:21
Speaker
Professor Zhao up at University of Toronto has shown a long-term plasticity within the anterior cingulate cortex and a rodent model of chronic pain. But as you both know, the rodent models can tell us a lot, but it's very hard to ask a mouse or a rat to subjectively rate their pain.
00:18:41
Speaker
If you're translating from a mouse or a rat model, if you're developing a drug or something like that that may have a particular effect on a mouse behavior or certain circuitry, you don't know how analogous that is to human behavior or human circuitry. So it's, again, since pain is this intense subjective feeling, it's difficult to know how pain for a mouse translates into pain for a human and what aspect of pain you might be addressing.
00:19:12
Speaker
That's right. Maybe it makes sense to jump into talking about how we do sometimes measure pain perception, maybe in the context of the paper and how the technique that they use for rating pain.
Methodology of Pain Perception Studies
00:19:31
Speaker
While in the paper, it's a scientific report, so the methods come last, I think it's actually probably a great place to start to talk about how
00:19:41
Speaker
people actually are experiencing pain and rating their pain in this paper. So in this paper, they use a very, very standard method of rating pain, which is a numerical scale. It's usually typically on a scale of one to 10, you know, rate how intense the pain you're perceiving is. Typically people will use that or something that's called a visual analog scale, where you'll have a 10 centimeter line.
00:20:08
Speaker
And you have to kind of put an X on that line where you, you have how you perceive the intensity or pain, but with these types of scales, it's kind of difficult to, uh, kind of tease out the meaningfulness of their rating. So if it's a scale of one to 10, 10 is supposed to represent pain that's absolutely unbearable, which is difficult, you know, difficult to measure within a laboratory setting. So with this, with this paper, what they did is they kind of.
00:20:36
Speaker
prime the participants to rate the pain at a level that was scientifically, at least as part of the study goes itself, attainable. So they kind of normalize them to rate a certain intensity of stimulation to the back of their hand as a certain number. And if they couldn't do that initially, they had to renormalize them until they said, this is the intensity
00:21:04
Speaker
That should be given an eight, for example. Right. They, in this case, they, they were zapping them with electricity, right? Right. There was some sort of an electro that they had on the, they put on their back of their hand and they were increasing the voltage and giving them more and more.
00:21:21
Speaker
juice until they, they reached a level where it was, you know, just tolerable. I think that was the way they described the highest level. They was like just tall. Yeah. So they, they gave, they gave the constant current stimulation and I, I feel the need to give a shout out to my friends at digit timer because I'm very, I know the guys who produce the, uh, the actual equipment that they use. So give a shout out to Gareth Thompson at digit timer. Uh, but yeah, it's a, it's a constant current stimulation. Yeah. Well, I mean,
00:21:51
Speaker
They didn't design it with that in mind, but it's very useful for giving any stimulation. I have to say, I noticed here that they receive, okay, so this is in, this is in Britain. So they're receiving pounds. They get 15 pounds of compensation. I don't know if I would volunteer for an experiment, 15 pounds for that level of pain. I think it depends on what the exchange rate is. The pound for pain ratio is a little bit off. Yeah.
00:22:21
Speaker
They're also all undergrads. So I wonder if they're getting course credits for it as well, maybe, or something like that. I guess so. But that seems low. I feel like you should have to pay paying people, paying subjects a little extra. Absolutely.
Challenges in Chronic Pain Treatment
00:22:40
Speaker
But then, of course, you get into the whole question of is the amount of money so much that it's causing people to take on this
00:22:50
Speaker
this experiment when they maybe don't want to or don't feel comfortable. Yes, that's probably true. Coercion is the word I was looking for. So you don't want to be coercive in the amount of money that you give out. That's actually one of the things they always make you talk about when you do your human subjects. I just want to know the rate at which people decided it was worth it to go through the experiment or how much resentment they got afterwards. Yeah, they don't report how many people dropped out of the experiment.
00:23:18
Speaker
Right. No, they didn't talk about that at all. Yeah. But you know, but I mean, there's, there's cognitive dissonance at work here too. And that's a whole other episode, but yeah. You know, so, uh, so with my work at Karuna, what's, what's actually been pretty interesting to me is that, uh, there's people that contact, contact us on almost a daily basis who've been suffering from chronic pain for a long time, like, you know, sometimes years who say, I'm willing to try out anything and pay whatever it takes, uh, to receive
00:23:49
Speaker
some kind of relief. What a horrible life that must be. For some people it is. Yeah. Um, and so one of the, one of the approaches that's been most successful in the treatment for chronic pain is something, something's called a functional restoration program. Um, and the functional restoration programs approach chronic pain holistically. So they're not, not approaching it like a typical, like you're a physician would.
00:24:15
Speaker
where they're saying, okay, well, if you have pain, let's give you some, some pain medicine, some medicine to help you with coping with the pain, um, which can have a temporary relief. You know, so the common thing is opioids. And of course we're in the middle of the opioid crisis now because it's been over prescribed for things like chronic pain. Opioids were never really designed to be used long-term. It's more of a temporary solution to something like recovering from a surgery where you know that you're going to have some pain that should subside within a given period of time.
00:24:45
Speaker
But to bring up the point about paying subjects, sometimes patients will contact us at Caruna and say, can I pay to be a part of a clinical trial? But that's unethical because then if you make paying part of the exclusion criteria of being part of a clinical trial, you're potentially excluding some percentage of the population you can't afford to pay.
00:25:11
Speaker
Right. No. So yeah, you can't, you can't have people pay to participate. Yeah. But that's it. You know, the, uh, the technique is interesting. So they, they're basically shocking the person's back of their hand.
The Placebo Effect and Expectations
00:25:24
Speaker
And then they rate on a scale of, is it zero to 10 or one to 10, one to 10 pain scale, uh, you know, how painful it is. But they, they, they, they prime them first. So they, they let them know this is what you can expect the intensity to be.
00:25:42
Speaker
Right. So they're kind of giving them a range of expectation. And then in the training, they actually do even more than that, right? They actually go through and have them rate the different levels and intensities and they have to get them quote unquote correct. So they have to map their two, you know, pain rating to the two on the dial at 75% correct to participate in the study.
00:26:10
Speaker
So there's a decent amount of training at the beginning part to like kind of map it out. So what might, what thought I had there was how much of this is you're just learning to represent the sensation as a, as a number versus like the, the actually feeling that much quote unquote, that much pain was painted, you know, as we, as we just discussed pain is subjective. So, you know, whatever we tell you, it should be, you know, as, as, say, as an experimenter, you know, talking to a participant.
00:26:39
Speaker
Whatever we tell you it should be is what it should be because it is subjective and contextual. And it is a very acute stimulation paradigm in the sense that the amount of time that you're actually receiving the stimulus is very short. I think it's five, what did I say, five milliseconds? So the way that people sometimes measure this is you have to get it correct for the stimulation to stop.
00:27:08
Speaker
And they'd probably be much more accurate if they had, especially on the high end, if they had to get it right for the pain to stop. The, the point here for the paper is, you know, of course the ratings, but the real idea is to see if they can modulate the expectations of pain and to see if that affects how much pain people are reporting and then
00:27:35
Speaker
to go even one step further to see if there's a limit to how much you can do there, how much of this a placebo effect you can create. The hypothesis that they had was that there would be a tipping point where, let's say if you are told that there's going to be a six, the pain on this trial is going to be a six, you're going to feel that eight may be as closer to a seven.
00:28:05
Speaker
because you have that expectation of a six going into it. And that's coloring your experience or perception of the pain. But if you're told that it's going to be a two and you get a 10, maybe the expectation effect is not gonna be so direct because the discrepancy, the prediction error is so large
00:28:32
Speaker
that it doesn't make sense to modulate the pain perception based on that expectation anymore. Yeah, it seems as though only their prediction and findings are that only when it's within a certain range of what the actual pain is, do you get the strongest effects of modulation, right? Yeah. That's right. So they term this a boundary effect, which it definitely is. But it's similar to, you know,
00:29:01
Speaker
and other perceptual psychophysics domains, kind of like an envelope effect, where there's a certain threshold that you have to interpret whether two signals are actually different from each other. And that threshold, as things are more similar, it becomes more difficult to tell them apart. So in one way, you can interpret these results as similar to maybe their pain thresholds, where if something is close to what they're expecting,
00:29:30
Speaker
It's close enough to whether to where they can not tell whether their expert expectations differ from what they, the stimulus they've received. But if it's so large, like if you tell me it's a two and it's a 10, I know you're tricking me there. You know, that's not right.
00:29:49
Speaker
So they probably rate it much higher. I had a similar way of thinking about it. I was thinking about it in vision. If we want to test out, say, the relative strength of vision versus audition, sometimes vision dominates and maybe you get something like ventriloquism because you see the mouth moving and that overtakes your sense of hearing.
00:30:13
Speaker
or like the McGurk effect exactly yeah yeah so you have two different sources of information you have you have vision and audition and in the pain experiment here you have two sources of information you have the expectation that's given to you and you have the actual zap that you get and you have to sort of decide which of those is more reliable
00:30:38
Speaker
And if they're close together, you might have some confusion about them. But again, if it's far apart, if it's a 2 versus a 10, then you wouldn't really be fooled by the prediction of a 10. You'd have a strong sense of what that signal is. Yeah. And the other interesting thing, too, about their model is that you have this double asymptote. So they use a polynomial fit.
00:31:07
Speaker
And the reason they're using a polynomial fit is because they expect a double asymptote. They expect that if the stimulus is orders of magnitude larger on the expectation, then you expect that there will asymptote up to this point where there'll be an optimal level or what they call the tipping point where you will be able to change your perception to that pain stimulus based on what you expect.
00:31:36
Speaker
But they also see it negatively, which is also interesting. Because with these types of scales, they should be nonlinear, really. Because you can imagine, if you have a pain, if you're experiencing pain so intense that you rate it an 8 out of 10, and keep in mind that that 10 is absolutely unbearable. That's the limit, yeah. That's the limit. And then you change it by two points. That change from an 8 to 6 is probably very, very significant.
00:32:05
Speaker
but it's a very low percentage, but you're changing it at the high end where it's almost unbearable. But then if you're at a four, it's like, oh, that's a little bit uncomfortable, but then you change it to a two from a little bit uncomfortable to mildly annoying. It's still a change of two, but the magnitude of change is probably much less significant than changing it from an eight to a six. Yeah, that was an interesting aspect to the scale thing. The other thing about the scale,
00:32:35
Speaker
the use of the scale and the queuing that they did in this study was that I kind of thought about it almost like a game, you know, you're kind of playing a game.
Training and Perception Modulation
00:32:46
Speaker
They're saying this is going to be a two or this is going to be a six or this is going to be an eight. And then you're trying to get it, quote unquote, correct, based on your experience of the stimulus. So you're because you were trained to correctly, you know, indicate the the
00:33:06
Speaker
stimulation level in the first part of the experiment. The second part of the experiment, you're probably taking the same mentality into it. You're trying to get the correct answer. And you realize that some of the time or maybe you don't realize that they didn't really get into whether the people were aware of what was going on or not. But you may be aware that sometimes the number is right on and sometimes it's not. And to your point of the just noticeable difference,
00:33:35
Speaker
when it's close enough to where it's within that couple of points, you're not sure if it's actually, they're trying to trick you or if it's correct, a veridical cue in that case. So that's where you could get the same basic effect across the board here and not have, in other words, it could be completely artifactual.
00:34:05
Speaker
in a way based on the demand characteristics of the study. So people could be reporting not their subjective level of pain, but rather a guess that's meant to match it up to what the experimenters are, what their measure is. And so your whole mentality goes towards getting this answer correct.
00:34:30
Speaker
So in some ways you're, you can imagine the person's mind is going in this direction of, Oh, I'm going to interpret this signal to try to basically guess or, or indicate which, you know, what level of stimulation I got on that particular trial. But there's an, there's an additional component in that pain is multimodal. Whereas something like auditory and visual is you can isolate your, your visual from the auditory with pain.
00:34:58
Speaker
It's difficult to isolate something from, from pain or just simple. I felt something on my hand. I had a somatosensation. I sense something stimulating my skin. So it may not even necessarily be that they're rating pain on the lower levels rather than the rating that they detected something. And what's interesting is in, so in, in figure two where they actually show the, um,
00:35:28
Speaker
the numerical scale rating versus the stimulus intensity, at the lower levels, what you see is that if your cue is less than the stimulus, so if they're cueing you to less, you actually don't see a difference between the stimulus intensity and their rating score. So it's almost like a floor effect where the pain is not so severe that I think that cueing it is going to make it less severe.
00:35:56
Speaker
So if you, if they say you're going to get a two and you get a three, you're still saying three. Right. Or you're still saying two or it's close enough or more like, um, they say you're going to get a, a five, but then they gave you a three. Well, the, the three's not really that painful. So you're, you're, you're, you're probably going to gauge it within that, that, that range of where you're three. But if they say they're going to give you a five and give you an eight.
00:36:24
Speaker
then you're much more likely to say, that's more painful than you queued me. But on the other side, it makes it kind of strange that they see this effect where if the stimulus is less painful than they're queued, it's strange that they can detect that difference at all. Yeah, so the first order effects of the study are interesting in themselves. And I think we can think about whether or not
00:36:53
Speaker
we believe in those. And then there's these higher order effects. When I say the higher order effects, what I mean is what's so-called boundary effects.
Subjectivity and Bias in Pain Reporting
00:37:04
Speaker
In other words, is there a point, a tipping point at which the difference in perception of the pain is not as great as you would expect due to cueing because there's just such a discrepancy. That's like the higher order effects.
00:37:21
Speaker
Even their effect size for that was pretty small. And there's some indication that there was something in that direction. But the first order effects are themselves interesting, which is just that if you queue a lower value, generally speaking, you are reporting subjectively less pain. And if you queue a higher value, you're generally speaking reporting more pain. Right.
00:37:52
Speaker
But even there, I mean, again, to the idea of it's difficult to separate out, is that the fact that they're actually experiencing less pain, or they're taking that information into account when they're trying to correctly identify the stimulation level? Well, that's a hard one, because at some point, with a subjective measure like this, you almost have to just
00:38:22
Speaker
I mean, you can ask them if they feel like they're trying to please the experimenter, or if they're engaging in some sort of deception. But you almost have to take their word for it on a subjective measure, because you just don't have anything else. Yeah. You could do a thing where you modulate the probability of a veridical queue versus a non-veridical queue.
00:38:49
Speaker
Right, so the trustworthiness of the queues. Correct, correct. So what you should see is that if they are, unfortunately, it won't pull apart so perfectly. Because you can imagine that either way, the more reliable the queue is, the more they're going to wait that. It even goes a step further.
00:39:20
Speaker
uh, inverse to that. Um, there's, there's people themselves, human beings are, you know, there's individual variation across people on how reliable they are at rating pain. So in, in pain research, uh, there's two types of patients that you don't really want in your study. Uh, the one patient is every time you ask them to rate their pain, they give you the same answer. So it's always six, six, six, six. So in the research, those, those patients are very hard to move.
00:39:50
Speaker
clinically. It's very hard to change their interpretation of their pain intensity. The other one that you don't want is one that's all over the board. That they're like two, eight, you know, two one day, eight one another day, four another day, 10 another day. Those patients who are highly variable are also very hard to move. What you want is a, you know, is in these pain research is the type of patient who is representative of kind of the population and that they kind of have an understanding of where their pain is.
00:40:18
Speaker
So in addition to making it predictable or non-predictable of the stimulus intensity, there's also that individual variation where some people, some of these participants were probably pretty variable in their responses to, let's say a two or a six. Maybe we can take a little break here and get back at some of this stuff. Sounds good.
00:40:44
Speaker
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00:41:15
Speaker
All right, we're back. So just wrapping up discussion on this paper. I don't know if there's anything else either of you wanted to put in about this, but very nifty result and a nice demonstration of the kinds of effects you can have from context on pain. And you can get a nice good grip on how some of this stuff works. So anything else either of you wanted to add to this? I would just mention that it's very interesting that they see
00:41:44
Speaker
you know, these clear indications of modulation of pain perception with cues. I don't necessarily buy the higher order sort of effects that they are purporting to see in this study. I think the effect sizes are kind of small. They're doing a lot of math. They're doing a lot of analysis for the number of subjects that they have, 30 in each of two data sets. So I think they may be overstepping the data here with their analysis, which is,
00:42:14
Speaker
Yeah, normal, especially because the two data sets don't replicate each other perfectly. Another general thing. So the first order effect that there is this, if you have a lower queue, you're going to report less pain. Or if you have a higher queue, you're going to report more pain. That seems to be pretty solid and pretty robust. And the techniques that they're using are interesting and relatively convincing. But I don't really necessarily buy the higher order stuff.
00:42:41
Speaker
Yeah, I would second that. This is one of those things in pain research that has kind of been agreed upon for a long time, that pain is very subjective, very contextual, and can be modulated. But they had a really nice way of testing that and showing that empirically. So I like those first order results.
00:43:07
Speaker
Awesome. Okay. Um, let's move on and, uh, maybe we can talk a little bit about, uh, pain treatment in general and Mike, you could say something about your experiences in the pain treatment world and then, uh, something about the approach that you have right now in virtual reality. Sure.
Chronic vs. Acute Pain
00:43:27
Speaker
So, you know, with, with chronic pain.
00:43:30
Speaker
It's a little bit different than either, in the pain research, we'd refer to a study like this as experimentally induced pain, where they're actually inducing a predictable stimulus that they can measure a pain response from versus acute pain, which is pain out. I sprained my ankle. There should be some pain there, and the pain is thought of as the body's warning system that
00:43:59
Speaker
Hey, let's not run on this right now. We need the tissue to heal. And so the function of the pain is to protect the body so that it has sufficient time to heal so that, you know, we'll recover normally and you won't have any additional injury in addition to the initial insult. So where I'm working right now is in the realm of chronic pain, pain that lasts longer than three to six months.
00:44:25
Speaker
It's a really big problem in that chronic pain by definition is treatment resistant. You have chronic pain because the methods that are used to treat things like acute pain are generally not good enough or don't have long lasting benefits to where the pain subsides over time. They have it for a long time.
00:44:51
Speaker
interesting, both the interesting things scientifically, but also the unfortunate thing from, for individuals is there's a lot of maladaptive neuroplasticity that occurs in people with chronic pain. So, you know, you can imagine from your, from your guys's work in, in perceptual psychophysics, the things that a person attends to or devotes attentional resources to typically gets a priority in the processing of, of what's going on in, you know, around them in their world.
00:45:19
Speaker
So when people with chronic pain, what they have is this constant attending towards their pain. And that does two things. Number one, it actually decreases their pain threshold. So then they will perceive things that shouldn't be perceived as painful as painful. So if somebody has, for example, complex regional pain syndrome of their right hand, they may perceive something as light as just a hand brushing their hand as painful.
Virtual Reality and Chronic Pain Therapy
00:45:50
Speaker
Whereas a normal, if you're, not to say that they're abnormal, but people who are not suffering from chronic pain, if you brush across a hand, they perceive that, oh, something brushed across my hand. So it shifts pain thresholds, but also they have an increased anticipation for painful events. So at Karuna, what we work with a lot is movement-induced pain. So for example, if somebody has chronic shoulder pain,
00:46:19
Speaker
They begin to associate, if I move, then I will experience pain. That movement equals pain. And so what we do at Karuna is we provide virtual reality tools to help people overcome that pain. Virtual reality itself actually has some analgesic benefits or it's pain relieving in that it can distract people temporarily
00:46:47
Speaker
from whatever they're experiencing. So there's a lot of research actually in burn victims. He uses this application called Cool World, which has, you put virtual reality goggles on and you experience something that's cool like these glaciers with penguins playing around. And it's a very cooling kind of experience. And people with burn pain report their pain as less severe
00:47:17
Speaker
when they are in that experience. And this is known as distraction therapy. So at Caruna, we take it beyond distraction therapy in that while patients are temporarily given some relief from their pain from being in the virtual reality setting, we provide functional rehabilitation exercises for them so that their body can move in a way that does not associate the movement with pain, or they can reach beyond their
00:47:47
Speaker
pain-free range of motion, so that we can gradually move them back into a spot where they don't have this fear of movement, this kinesiophobia, where they're afraid to move because if they move, they'll experience pain. Now within the virtual reality setting, they're experiencing movement differently, so we can potentially break that association between movement and pain. And we take a bio-psycho-social approach
00:48:13
Speaker
which has been shown to be very effective within chronic pain treatments, at least the most effective so far. Still not meeting the mark of completely effective, but people use things like a concept known as graded motor imagery, where you gradually recontextualize the way that people move so that you can break that association between movement and pain. And what we do is we bundle that into a virtual embodiment experience
00:48:43
Speaker
where patients in the VR setting will perceive the movements of a virtual avatar as their own. So we can do some unique manipulations such as mirroring, where if I have unilateral chronic shoulder pain, for example, I can perform exercise with my opposite side, which presumably does not experience pain, but in the virtual world, I can show my painful side moving, even though my non-painful side is controlling the movement,
00:49:13
Speaker
I could perceive the painful side moving and theoretically what you can do is you can gradually break up that, that, um, association between pain and movement. Interesting. So that's a, I mean, it's a little bit similar to, uh, mirror boxes for Phantom limbs. Yeah. What we like to say is actually it's, it's like mirror box on steroids. Right. Because you're going to be getting a lot better representation.
00:49:42
Speaker
Yeah. Yeah. And we just, so we just, um, we just presented this poster a few, few months ago at a big conference called pain week, which is kind of the, the big conference for people who work in pain where, um, we actually wanted to test whether. Uh, mirroring, or if you move your non-affected side, but mirror it onto your affected side and you see some kind of difference. And what we were hoping to see is that if you move the painful side,
00:50:12
Speaker
but you mirror it so that you, in the virtual reality setting, it looks like your non-painful side is moving. We were hoping that we could increase the range of motion of the painful side. Unfortunately, we didn't see that. And there could be a lot of reasons. These were chronic pain patients of longer than six months. Some of them had chronic pain for years. So there could be some just physical limitation to how far they can move their painful side. But we saw something really interesting and really unexpected.
00:50:41
Speaker
When their non-painful side, which has complete and full range of motion, if it's mirrored onto their painful side, they reduce how much they move, even though their non-painful side has complete and full range of motion. So this suggests that the mirroring is really having an effect on how they perceive themselves moving. So what our hope is is that we can use that to build these exercises that can break that association between pain and movement.
00:51:10
Speaker
That sounds very promising. That's really cool stuff. Yeah, that is interesting. I mean, thinking about the paper we were talking about before, are people doing things like trying to just work on your expectation for pain? So just trying to get people to expect to have less pain or understand that they don't need to be afraid of having movement in certain directions, things like that.
00:51:40
Speaker
Yeah, so one of the most actually effective treatments right now for chronic pain is actually just what they call a neuroscience pain education. So if they educate patients on what pain processing is and what its function actually is in pain neuroscience education, they use that term hurt not harm. So you get this kind of snowball effect with people with chronic pain
00:52:07
Speaker
They think, oh, my shoulder hurts again. I must have injured it again. So if you begin to understand that just because you're experiencing the pain doesn't mean you're necessarily harming the tissue or the joint or the muscle or whatever it is around there, that patients can actually recover some of their function after just learning that this movement doesn't necessarily mean I've re-injured my shoulder, to give an example.
00:52:35
Speaker
How does this stuff fit in with an evolutionary description of what pain is for? Because, I mean, I guess you already mentioned this, you know, you sort of hinted at this, but obviously pain serves a valuable role in our lives because we need to know when we're hurt and we need to take care of ourselves when we're hurt.
00:52:58
Speaker
But in some of these cases with chronic pain, you're getting a clearly maladaptive response where there is no external danger, but you're still responding as though there is. One of the things that we see in this paper that we're looking at now is that expectation or the prediction of pain seems to have a lot to do with how that perception eventually arises.
00:53:24
Speaker
I wonder if this might be part of the reason why we have this really contextual system for pain, that it is so flexible and it isn't just a straight response to something that hits us or lights us on fire or something that we're sensitive to other aspects of it.
Evolutionary Role of Pain and Maladaptation
00:53:46
Speaker
The evolutionary purpose of just about anything, if anything that's valuable is to get you away from danger and not get killed. So the predictive value seems to be built into a lot of these expectations about pain that seem to go so badly wrong in people with chronic pain. And I'm wondering if that's in line with the way that you might think about it too. Yeah.
00:54:15
Speaker
with this Darwinian approach of evolution is that animals want to survive, according to Darwin, live long enough to reproduce. But with humans, we have the ability to contextualize our environment. Other animals may have that ability too, but we can't ask them. We can't ask a lab mouse, what did you think about today's experiment? Humans can contextualize it.
00:54:45
Speaker
And there's a lot of comorbid features of people suffering from chronic pain, such as the tendency for high anxiety. There's also people with chronic pain tend to have less quality sleep. The quality of sleep is not as good. So there's these other co-morbid factors. But aside from the evolutionary part of it,
00:55:14
Speaker
The way that I like to think of it about it is there's really kind of two types of neuroplasticity, at least generally, if you can categorize them. One is the classic, what is referred to as Hebbian plasticity, the cells that fire together wire together. And that can explain kind of the strengthening at the synaptic level, the strengthening between two cells that share a synapse. But there's another
00:55:42
Speaker
form of plasticity, it's called homeostatic plasticity, which is really meant to kind of control the gain of neural circuits, to make sure that the noise within the signal is dampen enough that you can extract the signal from the noise. So there's these rodent models in auditory neurophysiology where if you expose them to, let's say, white noise and make that white noise meaningful,
00:56:12
Speaker
Every time they hear this white noise, they'll have a foot shock. You can disrupt the organization within the auditory cortex to where it's not quite as organized. Therefore, the noise within the system is amplified. With homeostatic plasticity, you'd have increases in the inhibitory connections within the circuit to dampen the noise. And so with chronic pain, if you think about it more, instead of like an evolutionarily
00:56:43
Speaker
driven thing but more of a an artifact of our our ability for our nervous system to remain plastic throughout life that this kind of like this this runaway maladaption in homeostatic plasticity because the pain signal is so crucial to the survival of the organism it's the thing that the organism should pay attention to because if you don't you know you're going to
00:57:11
Speaker
burn your hand instead of withdrawing it from the hot pan. So because the pain is constantly coming in, the thought is that the inhibitory part of that or the homeostatic plastic part of that is actually decreasing because the pain is signaling something that should be paid attention to. That's an extremely helpful way of thinking about it. I like that description.
00:57:41
Speaker
Yeah, that's, that makes a lot of sense to me as well. Good. So in terms of, uh, you know, next steps are going forward. What do you, you know, and maybe we can take it out with this. What do you think is really exciting in, in this, in this area of research? Like what, what are some,
00:58:10
Speaker
What are one or two really exciting things that you're just pumped about right now?
Holistic Approaches to Pain Management
00:58:17
Speaker
So the primary thing is actually taking advantage of this so-called placebo effect. I say so-called because the dogma of the placebo effect is that, oh, it's not really real, right? So there is a study released a couple of years ago
00:58:38
Speaker
uh, where, where patients were chronic migraine pain patients. And they were testing a new drug and they, they, when patients would come in with their migraine pain, they'd give them one of four cards. One card had the name of the drug and had the drug on it. One card said placebo, but had the drug on it. The third, the third card said the name of the drug, but had the placebo and the fourth card
00:59:06
Speaker
said placebo on it and had the placebo. Can you guys guess what happened with the placebo? Still worked. Even when patients know they're receiving a placebo, they perceive that it has benefits for them. I love that. That's a great finding. I wish I could, I would take any placebo effects that I can get. I try not to learn anything about medication so that I can get all the placebo effects I can. Yeah.
00:59:34
Speaker
So, but I think that the placebo effect is going beyond just something of just tricking somebody. It's really showing the power of the mind to have a top-down influence on the sensory perception of pain. And with virtual reality, or at least with Karuna virtual embodiment training, what we're providing is a holistic approach. We're trying to reframe holistically the way that chronic pain patients
01:00:04
Speaker
cope with their pain. And we're doing that through functional rehabilitation exercises. But we also add things like guided meditation, pain neuroscience education, and with our home unit that should be released in the next couple months, we're actually going to bundle pain coaching with it, where patients will interact with a pain coach remotely
01:00:31
Speaker
to help them overcome or help them with coping mechanisms and dealing with their pain and also staying with their plan of care. Well, that's very cool. I think that sounds like maybe a great place to stop and wrap it
Episode Conclusion
01:00:44
Speaker
up. But yeah, Mike, thank you so much for being on the show today. I think I learned a lot and I enjoyed it. Mike, what a pleasure to have you on. This is a really great conversation. Thanks for stopping by. Sure. My pleasure.