Episode Transcript hideshow
**Voice-over:** *I try to imagine a fellow smarter than myself, then I try to think - What would he do?*
**Announcer:** *Charge up your axons, ready your receptors and shift your lobes in to upper beta phase. You're listening to Smart Drug Smarts - the podcast dedicated to helping you optimize your brain with the latest breakthroughs in neuroscience, nootropics and psychopharmocology.*
**Jesse:** Hello and welcome to Smart Drug Smarts, I'm your host Jesse Lawler happy to bring you the 50th episode and a special Halloween edition of Smart Drug Smarts. So I was talking with Rhiannan who is the woman that gets us guests on the show and Anushtup our editor and we were kind of racking our brains like, "What's a good Halloween brain related Smart Drugs related thing?" And what we wound up settling on is that we were thinking about, "What about phantom limb pain?" We've got a pain specific episode. We've actually got one of the world's leading researchers on pain, Professor Lorimer Moseley of the University of South Australia. We're going to be talking with him about phantom limb pain. The differences between useful pain and maladaptive pain, pain that would be chronic ongoing and not necessarily helpful to us. The future of pain. Fair warning that this will not be a particularly nootropics heavy episode but for those of you who like something a little bit different, I hereby present to you our first holiday themed episode.
Keeping with the theme, in our Ruthless Listener Retention Gimmick I'm going to tell you how your cat might be driving you crazy. Whether it is a black witches cat or a white, perpetually sleepy, fairly useless cat like mine. But before we get into any of that let's do This week in Neuroscience.
**Voice-over:** *Smart Drug Smarts - This week in Neuroscience!*
**Jesse:** Okay. So, this is a little bit spooky also. Researchers at the Lund University in Sweden have done a study which proves pretty convincingly that people are not actually aware of what we're saying before we say it sometimes. That, even though it seems like you must be planning your speech out in advance of speaking the words, people are actually getting feedback by listening to themselves speak and learning what they say, after the fact. They did this study by basically flashing different colors in front of a bunch of people and recording their verbal cues to - "Okay, that color is green, this color is grey, that color is red." They did that enough times where they were able to record a bunch of responses. So you got a lot of people saying "red", a lot of people saying "blue", a lot of people saying whatever, and understanding how long it normally takes between when the cue is presented and for the person to repeat it back to them. They had these people with headphones, who were recording these things and all the rest. Then, after a while, they started showing color and playing through the earphones, the person saying the wrong word. So, a person might be speaking the word but because of the way that the earphones were set up because of the noise cancellation and things like that, they couldn't actually hear their own voice except through the earphones and the audio feedback coming back was their own voice, but it was the pre-recorded sound of their own voice saying a different color. So, people would hear themselves making mistakes even though they hadn't necessarily really made a mistake. And this sort of switch passed undetected by the participants over 2/3rds of the time. So, they would hear themselves say something different than what they'd actually said and would be completely unaware of it. So, yet another strange, counter intuitive thing about the way the human brain works that, apparently, when we are speaking, we are somewhat on auto-pilot - we're not consciously choosing our words and, to a large degree, are learning what we have to say after we've already said it.
**Voice-over:** *Smart Drugs Smarts.*
**Jesse:** So as I mentioned Professor Lorimer Moseley is one of the world's leading authorities on the study of pain. He's made a career out of it, actually still making a career out of it. He's not a terribly old guy. He has membership's in societies with ominous names like, The Australian Pain Society and The International Association For The Study Of Pain. But is also a heck of a nice guy. Been published all over the place. He's got about a 150 papers to his name and is responsible for about 11.5 million in competitive grant funding. Has given over 50 keynote talks at big international meetings and is definitely just a heavy hitter in this whole area of pain studies. We talked for a long time. Sort of started with a general conversation about what the brain is doing as it creates the sensation of pain for us before getting into a little bit more of a detailed talk phantom limb pain and some of the things that are going on there when the brain is tricking us and making feel pain that we don't deserve. But with no further adieu let's dive in.
**Jesse:** I would love to hear about your research into pain and chronic pain and just some of the things that most people don't know about what's going on within the brain, when we feel pain.
**Lorimer Moseley:** Maybe the best way to approach that question is to really focus on what I understand best and that is, I guess the principles of what happens in the brain. It's really how to work out what happens in the brain because all we've got is brain imaging data. Your listeners would be, I imagine very familiar with the different types of brain imaging. Which is dominated by Functional Magnetic Resonance Imaging (FMRI) but also PEG and MEG which look at electrical or magnetic field propagation. So you do something to the human and then you look at what areas of their brain are involved in that and when those areas are involved. In order to experience pain your brain must evaluate every single piece of relevant evidence. Now a really important and real-time piece of evidence is the sensory information that's coming from your body and there are a whole class of neurons that we call Nociceptors, which mean danger detectors or danger receptors. And those neurons respond to things that evolution has taught us as an animal, are potentially dangerous to our physical self. Those messages of danger come up the system and will usually reach the brain and then the brain almost asks the question, "How dangerous is this really? What other information have I got, that can help me to make the best prediction here?" Because it is an uncertain situation. And the brain may very well produce pain. For example someone was putting a very hot thermite on my leg and I get danger messages from that, then my brain would normally make that area of skin hurt. So the brain produces pain that is filled in that area of skin but it's an entire illusion. You know it doesn't do anything to that area of skin, it just makes it feel pain there. But let's say exactly the same scenario, but I was a sadomasochist and I had a mistress putting exactly that same stimulus, then exactly the same message arrives at the brain. But now, the brain has a different bunch of information to solve the problem and decides that, "This is good and I will make you experience pleasure." So the difference there is not in the stimulus, the difference is in the context and in the previous history if you like. Not to imply that I would like anyone to put a hot thermite on my leg, whether they are a mistress or not. But I know that there are people who would get pleasure out of that in the right context.
**Jesse:** Yeah, that's a really interesting problem. It seems like different people have very very different pain thresholds and of course that can probably be altered with all sorts of biochemistry. Like women and child-birth. If it wasn't for the hormones that there body was releasing at the time it would hurt even more than it already does and such things. But why do you think that there's such a wide range of pain thresholds among the standard populace?
**Lorimer Moseley:** I love that question, I love that example Jesse of the labor and the potential impact that hormones etc are having. The endocrine system is having in that situation. But I would submit that actually we've got far more clues by looking outside of the body for modulators. For examples labor pain. There's quite a famous condition or manifestation of cultural importance. I think it's named after the anthropologist who first described it but the name is Couvade syndrome. And it describes the symptoms of pregnancy and labor in the father of the child. There were villages or communities I think in South or Central america where this was such a profound influence on pain, that not only did the father experience the pain of labor, but the mother did not. And when you learn about these communities, the entire structure of the community is that the chief of the village is the man who has had the most children and has suffered the most. So the way I interpret that is the cultural mediators convince the brain, "Don't make this hurt, there is no biological advantage in making this hurt." And if we take that out of this extreme cultural situation, I think your example of pain thresholds is very applicable to labor. Some women describe labor as "Not painful." Some women describe it as "Excruciating." And the difference between those women is almost certainly not in the danger messages that are sent from their muscles that the baby has to come out of. The difference between those women exists elsewhere, not in the danger detection and danger transmission system.
If we go to pain thresholds, which we touched on. Actually we do a lot of experiments in our lab where we mean to determine pain thresholds and the variability in pain thresholds in a laboratory with very controlled context, people in the room and all those sorts of things, is actually really consistent. There is not a lot of variability in the people that we look at there. The variability emerges once you put them into the real world.
**Jesse:** There's such a wide range of when pain is appropriate for us to feel and perceive and have an emotional response to and when there isn't, it's hard to give a blanket answer to this - but what is technology, both external gadgetry, internally implanted gadgetry, pharmaceutical technology all these things. What is it going to be doing in the next 5 - 10 -15 - 20 years as far as giving us the ability to essentially turn off our pain response when we want to?
**Lorimer Moseley:** I would speculate on the grounds of I guess what I see to be developments in those fields that you talked about. Pharmacologically the challenges that we face are that most of our drugs will go all over the body. So anything taken orally or put in to the system will act on receptors for that drug wherever they are. And there are really not a lot of targets. Now I'm no pharmacologist but there's not a lot of potential targets where we could selectively tamper with receptors and processes that are just danger specific. There are a couple of exceptions to that rule. So there are search groups who are doing really exciting things that seem to be limiting their impact to the danger detectors in the tissues of the body - so these Nociceptors. They are quite sophisticated manipulations of genetic expression and inter-cellular mechanisms. And I would say that in 20 years we'll know if it was worth getting excited about I guess and there's a possibility that it is.
When you talk about stimulation paradigms. So there's a lot of excitement at the moment in some areas, in some search groups on the potential role of Transcranial Direct Current Stimulation and along side of that is Repetitive Transcranial Magnetic Stimulation, which is a far more brutal sort of stimulation. That's a magnetic field and if you've ever been a participant in one of those experiments, you really know when you're getting the real treatment because it jolts you. Whereas tDCS supposedly you can blind that, you can mask it. So people don't realize whether they're getting the active or the inactive intervention. So you know the neuro modulation stuff - my prediction is that in 20 years we would either have developed new stimulation paradigms that show more promise than what we've currently got or we've dropped tDCS. We maybe able to get better methods of modulating brain activity with regards to pain.
What else will we be doing? I think you might have mentioned prosthetics and stuff like that. One of the big barriers that we face in rehabilitation with people with persistent pain is the conviction that something will be dangerous, so that I do it and it's almost like an inverse learning and if we decide not to do something and you remain pain-free that implies in a perverse sort of way that if you had done it you would've hurt.
**Jesse:** Right, that's the confirmation bias.
**Lorimer Moseley:** Exactly. So one of the things that we try to do is expose people to the things that I think will be painful and hopefully not evoke the pain they're expected to get. And I think there are some really exciting developments going on with virtual reality, those sort of applications. Or people with phantom limb pain. I guess the compelling nature of their prosthesis probably remains the best way of modulating the phantom limb pain.
**Jesse:** Could go into detail on prosthetics, phantom limb pain; how all these things tie together?
**Lorimer Moseley:** This line of inquiry was triggered by a German research group - Martin Lotze. He's a collaborator of mine and an exceptional neurologist and scientist. Published a paper comparing amputees, comparing them using a functional prosthesis. So one that responded to commands and normally that would be prosthesis that moves when you contract a muscle. So they would have recording electrodes on muscles in the remaining part of the limb and they would then feed into this prosthesis, let's say for the hand, and the person would learn how to maneuver their hand and basic movements by muscle commands. All this could have been 20 years ago Jesse. It's not a brand new finding by any means. But that was a really potent modulator of the phantom limb pain and we know that the earlier you get your prosthesis the less likely you're to have phantom limb pain. And we know how well you integrate that prosthesis into your body schemer, till you can start to consider it a part of you and that sorts of things, the less likely you're to have phantom limb pain. So I think that the developments in that way will focus more and more on prosthesis that look, feel and interact with the human in a way that's as close as possible to the missing body parts.
A more recent study from a group out of Oxford who showed that the amputees with phantom limb pain showed a more normal activation in their sensory cortex to imagine movements than the amputees without. So that's a really really interesting finding because it implies that on the one hand there is more real estate being devoted to adjacent areas of the brain or adjacent areas of skin, in this case to the face which encroaches on the hand, but the brain is maintaining activation of those neurons in response to imagined movements or movement commands. So now you're moving your hand but you're activating brain cells that are otherwise involved in your face.
Potentially citing direction at the moment with regard to brain function is actually developments in our understanding of the interaction between immune regulation and inflammatory mechanisms and neuro function. I think that we really are a single unit as a human so we probably can't mess with one thing without having an effect in the other systems. We did an experiment where we convinced someone that a rubber hand replaced their normal hand. That's a really recognized experiment, it's called the rubber hand illusion and it's been done for 15 years. But what we looked at was histamine reactivity in the limb that's been replaced and simply that quality of illusion, which is purely brain illusion, changes the response to histamine in the arm that's been replaced. But simultaneously not in the other arm. So it's a body part specific change in inflammatory response.
**Jesse:** What are you currently studying and what study would you love to get funding for that maybe you've had a hard time finding the resources or political will behind?
**Lorimer Moseley:** My research group is currently working on 3 broad streams of inquiry and I'll try to summarize them quickly for you.
1) So one is on the back of 15 years of looking at how we can teach people in pain about pain. In a way that makes them understand that their pain is not a major tissue damage. The field is now called "Explaining pain" and currently explaining pain is about as effective as anything we can do with persistent pain. Just giving them an understanding that their pain equals credible evidence of safety versus credible evidence of danger. And that credible evidence can come from anything that places your body under potential threat. In people with persistent pain that's really important because the danger detecting and transmission system really doesn't explain the vast majority of chronic pain cases. So and people get a great deal of advantage out of realizing that their thoughts, their beliefs, their behaviors, their activities, people around them, the things they see, the things they say, the things they hear, all those sorts of things can modulate their perception of threat and therefore their pain.
2) Another line of research that we're working on is, what I would describe as a really novel approach to the problem of chronic widespread pain, a bit like fibromyalgia if you like. We proposed a theory where adaptations in parts of the nervous system including the brain that process the non-danger aspects of the package are important in developing chronic pain. So for the last 50 years our attention has been focused on the danger transmission systems, so the nociceptive system and we're testing whether the non-nociceptive system might be or has more important in that transition.
3) We're also very interested in the mapping of space and what we're proposing is that in anatomically confined chronic pains eg limb pain, back pain, neck pain - the transition from an acute severely painful highly inflammatory state into chronic, maladaptive, cruddy, scary pain, might involve a really simple neuroplasticity effect, in the monitoring of the body and space and movement.
Your question was really about what would I most like to solve if someone said, "Here's 5 million bucks to solve a problem." I would love to find out the best way that we could convince anyone; well if I was to be super speculative and not a scientist. If I took off my scientist hat and put on my normal human in relationships hat. I reckon if we could convince everyone that they are both loved and are loving, we would drastically reduce stuff like chronic pain. To love and be loved I reckon is probably the strongest biological drive I would imagine. Any human who is absolutely convinced that they are physically safe from everything will not experience pain. How can we capture that sort of stuff? How can we capture the fact that some people, you give them a really dangerous stimulus and if they think it's from a mistress, it doesn't hurt. Or if they're in the right context, hanging from a ceiling, a suspension artist with hooks through the muscles of their back, it doesn't hurt. This excites me because it makes me think there's a potential there to grab whatever it is and teach it or deliver it to people who are on the edges of our society because of their persistent pain. They're misunderstood, they're stigmatized, they can't work, they can't go to school, they can't cook for the family, they can't have sex with their wife, whatever it is. There is a capacity in the human to solve this problem, I'd just really love to see that.
**Voice-over:** *Smart Drugs Smarts.*
**Jesse:** So thank you very much Dr. Moseley for sharing all of his insights on pain. pain is obviously almost like the exact opposite of a smart drug. If you're in pain you're going to have distractions and not be focusing fully on whatever it is that you wish you were putting all your smarts towards. So gaining insight into pain is one of our main cognitive nemesis is something that we're fully behind. And thinking ahead to next years Halloween - Halloween 2015 - if anybody has any ideas for another neurologically relevant and yet Halloween specific episode, definitely let us know. We've got a lot of time to plan for it but would love to come up with something equally interesting next year. And now the Ruthless Listener Retention Gimmick.
**Voice-over:** *Smart Drug Smarts - Ruthless Listener Retention Gimmick!!!*
**Jesse:** Okay, so for this one, thanks off the bat to my friend Dan Sola, who sent me an article about 6 months ago that I saved for just a proper occasion which was this Halloween episode about how your cat might be driving you crazy. This is actually a really long article from The Atlantic magazine and I am just going to go over the highlights of it here, but it's really worth a read if somebody wants to devote, maybe, 20-25 minutes reading the full article. Essentially, there is a parasite, the primary host of which, is cats. It's called Toxoplasma Gondii or Toxo for short and this little single-cell protozoan parasite basically reproduces inside the cat - it lays eggs that get deposited into the cat's feces and some of those get eaten by other things, picked up by rats, whatever, and their life cycle includes other animals that eventually make their way back to the cat but they need to get re-ingested by a cat if they are ever going to have sex and reproduce more little protozoans. But, here's where it gets amazing, is that rats, needless to say, are pretty inextricably linked with the cat as far as being a major food source and the way that a Toxo infected rat behaves is radically different from a normal rat. The low level infection that a rat gets alters the rat's behavior in such a way that it basically makes the rat less shy about threats and more likely to put itself in harm's way with a cat. Cats are attracted to fast-moving objects, infected rats tend to run around more and be more lively. Even more amazing, male rats who are infected with this protozoan are sexually aroused by the smell of cat urine. So, all the normal warning signs that should be going on in a rat's brain saying, "Hey if any of you see a cat or anything to do with it get the hell out of there", are very strategically flipped on their axis by this protozoan which makes it more likely that that particular rat is going to get eaten by a cat and the protozoan is going to be able to continue its little protozoan life cycle. An inter-evolutionary biologist from Charles University in Prague, Jaroslav Flegr, this Czech scientist is probably one of the leading authorities on Toxoplasma Gondii, at this point. He's been studying it for decades, he's infected with it himself. And starting in the early 1990s, he began to suspect that the protozoan that was infecting him might be subtly manipulating his personality in strange and sometime self-destructive ways. Now, what's really interesting is that up to a third of all humans are probably infected with this parasite. For people who have been infected, sometimes, there is flu-like symptoms at the beginning, but, if you are a healthy individual, it's not going to kill you, it goes into what they have always thought was a long-term dormant period inside the human body. But, not so, says Flegr. He's done studies that have shown that there are distinct psychological differences that can be seen if you have a broad-enough population sample between humans who are or aren't infected with this parasite. One of the effects was a slower reaction timing and he thinks that people who are infected with this disease might be more dangerous drivers, basically, that this parasitic infestation might lead to tens or hundreds or thousands of traffic deaths worldwide, per year, that might not otherwise be happening. One of the other really interesting things is that there is major sex-specific differences in the changes in personality. Compared with uninfected males, males who had the parasite, were more introverted, suspicious and oblivious to other people's opinions of them and inclined to disregard rules. Infected women, on the other hand, were more outgoing, more trusting, more image conscious and more rule-abiding than uninfected women. Findings were so weird that Flegr initially thought that his data must be flawed but what he came to realize after consulting psychological literature is that heightened anxiety might be the common denominator underlying the differences in responses between the sexes. While under emotional strain, women seek solace through social bonding and nurturing and are inclined to tend and befriend. Whereas anxious men typically respond by withdrawing and becoming hostile or anti-social. So, maybe he was looking at two flip sides of the same coin in increased anxiety for people that have the Toxo parasite inside them. So, before you run out and get rid of the cat you own, the scientists who studied this are thinking it may be a bit premature. For one thing, it's not really a danger if you have an indoor cat. If you have an outdoor cat, it's still not as much of a threat as you might think. Outdoor cats only shed the parasite during three weeks of their life, typically, when they are young and they've just begun hunting. During that brief period Flegr recommends taking care to keep the kitchen counters and tables wiped clean. It is probably much more important for preventing exposure to Toxo, he says, is to scrub vegetables thoroughly and avoid drinking water that has not been properly purified. This is especially true in the developing world, where infection rates can reach 95 percent in some places. Infection rates seem to be around a third of humans in Europe and somewhat lower in the United States where its about 10-20% of the people. But, really, it is a significant chunk of the entire human population. We are talking over 2 billion people that are infected by this thing. It is fascinating to think that, although subtle, there are distinct personality differences that do result, apparently, from the presence of this protozoan in our bodies and brains. So, if you want a weird mind-bending article, the link for this will be on the Smart Drug Smarts website, of course. And my personal kudos to Kathleen McAuliffe for some really interesting journalism.
**Voice-over:** *Smart Drug Smarts - The podcast so smart, we have smart in our title, twice!!*
**Jesse:** You heard it that is the episode. 50 episodes in the can now. I must admit I'm a wee bit pleased with myself that we finally made it to 50. Not quite as quickly as I would have hoped but nevertheless nice to be here. If you liked what you heard please recommend this podcast to your friends and or leave us a review on iTunes. The show notes for this episode will be online at [www.smartdrugsmarts.com](http:/smartdrugsmarts.com//) including the links to all the stuff we talked about here. I'll be back at you next week. Can't promise that I'll have a Thanksgiving themed episode for Smart Drug Smarts but maybe there's like an l-tryptophan or something like that. Who knows what we can do next. Have a great week and stay smart.
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