Program: Mapping pain in the brain — and the placebo effect

Preeya Alexander: So we're going to talk about the brain again, and it does feel a lot like a brain show…

Norman Swan: Nothing wrong with that.

Preeya Alexander: Nothing wrong with that.

Norman Swan: I like things that stimulate my brain.

Preeya Alexander: But also we should acknowledge that all of the experts on the show are also from the University of Sydney.

Norman Swan: Purely by coincidence.

Preeya Alexander: Coincidence. But it is a brain show…

Norman Swan: So piss off everybody at the University of Melbourne where they think they're the leaders in neuroscience in Australia, nah nah nah-nah nah!

Preeya Alexander: Norman, you can be so inflammatory, and I get put in the basket with you. 

Norman Swan: You can just complain about me when the University of Melbourne phones you up. 

Preeya Alexander: I live here, I might run into them. When it comes to chronic pain, we often talk about the brain's involvement, and I think everyone now knows that the brain plays a very important role in any pain signalling, how we perceive pain. But there's new research showing that the brain stem has a map-like system that activates depending on where the pain is in the body. And they've used functional MRIs, this is incredibly interesting, and they've used the placebo effect, and we talk about how powerful that is and how they've used it to actually find this brain map. And I spoke to one of the authors of the study, Dr Lewis Crawford, who's a postdoctoral researcher…

Norman Swan: Now, don't let me interrupt you, let me guess, he said the Brain and Mind Centre at the University of Sydney, is that right?

Preeya Alexander: That's right. Thank you, Norman Swan.

Lewis Crawford: The study basically works by a magic trick. So we trick people into thinking that a cream, we tell them it holds the properties of an analgesic, it's going to work to reduce your pain, relative to a separate cream we also put either on the arm, the face or the leg. You can imagine you've got these two creams sitting on those three parts of your body, either the control cream, we'll call it, or the fake analgesic. And that one looks like it's going to work. We do things like add a label to it that looks like something you'd get from a chemist, or we put some food colouring in it so it kind of looks like it's got some property to it. 

Preeya Alexander: Wow, so it's really convincing people this is the real deal.

Lewis Crawford: Exactly. And this whole effect, so the whole placebo effect works by belief principles. So there's a few ways to trigger it. You can get it through conditioning. You can imagine Pavlov's dogs, when they used to ring the bell and the dogs would salivate, there's conditioning principles. There's expectancy modulation, so I tell you that it has some property, and you believe me, because either you think I'm trustworthy or I've made the cream look believable enough to you that you think it's going to have some effect. Or there are environmental things. So certain people with different histories or backgrounds or interactions with clinicians in the past will show some different amount of a placebo response. 

But this particular experiment worked through conditioning. So we had these two creams, and then on an initial day we brought people into the MRI area had those creams there, and we told them that both the creams, so that one that is just Vaseline and the one that was the fake analgesic, would be given the same temperature. And we had this, you can think of it as a little black box that heats up, connects to a computer and we program it to go to different temperatures. We told them that both creams would get the same temperature. But in reality, without telling them we were turning down the amount of heat that was going on to that fake analgesic. So they start building that belief that that cream was working to reduce their pain.

Preeya Alexander: So you're trying to condition people that this cream is working, but the probe is actually not as hot.

Lewis Crawford: Correct. We'd move the probe around to the different cream sites, and they'd go away for a day, they'd come back the next day, and at this point we stopped tricking them. We do give the same temperature to both the creams, but now if they rate their pain differently, or if they feel any difference in pain between the two sides, that's encoding a placebo effect; because now both creams are receiving identical input, any difference in perception is due only to the conditioning or their belief systems or some action of the brainstem, which is what we show.

Preeya Alexander: So on the next day they're getting the same temperature on all the areas?

Lewis Crawford: Correct. 

Preeya Alexander: Okay, and so what did you find? What are the results from the study?

Lewis Crawford: What we can do is isolate the brainstem, which is a bit tricky. It's a little area of the image space, because most of the image is taken up by the main brain. You've got the big walnut so your big cortex up top, and then the spinal cord runs all the way down your back, but then between those two things sits the brainstem, but it is really small and it's hard to look at, so we have ways to kind of segment that area out and look exactly at where we're seeing changes in activation. And when we say activation, we talk about changes in blood flow. So there's no real way in humans to see certainly if there's neurons that are firing or changing in how they're signalling, but you can infer it by blood flow. And so, yeah, that's what we did, we looked at two areas of the brainstem that we know are really important for both pain perception and modulation.

Preeya Alexander: And so you found that different parts of the brainstem were activated depending on where the pain was.

Lewis Crawford: Yeah. So, like I said, we had the creams on either the cheek, so the face, the forearm, the arm, upper limb, and then the shin of the leg, so the lower leg. And the reason for that is we know that there's some sort of arrangement to enable pain behaviours or analgesic effects, depending on where you may encounter a threat. So either your face, your upper or lower limbs, and that sort of organisation lets you mount the correct behaviour in order to escape that, we just had never been able to show that in humans at this level. And so yeah, for the face, we found it relatively higher, for the upper limb a bit lower, and for the lower limb even lower than that.

Preeya Alexander: And what did you find in terms of the placebo effect in the study?

Lewis Crawford: Not everyone shows a placebo response. It's about 50% in our sample. That's pretty similar to what others see. There's a bunch of reasons you can posit why some people do and some people don't show it, but we do know it's not an expectancy thing. So even those that didn't show the response had a belief that the cream would work to reduce their pain. And that means that we're more inclined to believe that it's something going on with their brain or brainstem that might be driving this more significant analgesic response in some people.

Preeya Alexander: So it's not just about the belief alone that it's going to work.

Lewis Crawford: Correct, yeah. 

Preeya Alexander: So you've essentially uncovered or confirmed that there's a map-like system in the brainstem that controls pain differently depending on where it's felt in the body. What does it mean, Lewis, for people living with chronic pain, and for therapies in the future?

Lewis Crawford: There's a lot of new work coming out that looks at different ways we might be able to change the way the brain is acting through paradigms like non-invasive stimulation, focused ultrasound, and these are techniques that target a really specific area of the brain to cause some change in either activity or communication. So what we've done here is map out the brainstem areas that seem to be able to downregulate someone's pain without giving someone a true pharmacological agent. If we know then where these areas are talking to in the higher brain, it's possible, I think or I hope, that we could seek to target these areas to activate these areas of the brainstem and trigger some sort of pain relief. So I guess the really important thing about this work is that these areas we showed were dependent on the body location where we were conditioning. So you can imagine chronic pain is not often felt across the whole body. You have people with fibromyalgia, they might have their pain localised to their wrists or their arms, and you have people with migraine that have it in the head. So what we're suggesting, I guess, is that there might be a more optimal site to target to relieve pain in a specific body site.

Preeya Alexander: So what are the next steps for you in terms of research? Where are you headed next?

Lewis Crawford: This whole study, I think it's wonderful, but it was done in people that weren't experiencing pain, and we know that people with chronic pain, they show changes in the way the brain is functioning. So I can't go out and say that my results are also true for someone that is experiencing pain in their life. And it would be really nice to be able to test what we've found in people like that.

Preeya Alexander: So you've just mentioned the brain in chronic pain can be different. Can you just talk us through what kind of changes can happen?

Lewis Crawford: You can get a reorganisation of where certain parts of the body are represented in the primary somatosensory cortex. So that's an area which essentially, like this study, it maps parts of the body to certain parts of this area of the brain, and typically you'll see an enlargement for areas like the face and the lips and the fingers, so areas where it's more sensitive than others, right? In those with certain types of chronic pain we see these body map areas shift in space. They can either enlarge, they can shrink. And we think that might in some way relate to how that pain is encoded and persisted.

Preeya Alexander: You were talking about the homunculus then, weren't you?

Lewis Crawford: Correct.

Preeya Alexander: Oh my God, I love the homunculus. 

Lewis Crawford: Me too.

Preeya Alexander: For people listening, it's how parts of the body are represented on the brain in terms of pain. So some areas have much more sensitivity (like the lips) than others, and so when this is represented as a graphic, it really does look like quite a bizarre human. You've got large lips and large other parts of the body and a smaller kind of abdomen, but it is a human and how they perceive pain.

Lewis Crawford: Yeah, well, I mean, this whole work was kind of a mash-up between what we knew about the human homunculus, human sensory systems, and then pre-clinical evidence of rodent brainstem. So I guess it was motivated by an understanding that, yes, the human brain and brainstem can be organised in this manner, it just hasn't been shown yet, and so that's what drove us to trying to answer this question in the first place, really, homunculus for the win.

Preeya Alexander: That was Dr Lewis Crawford, who's a postdoctoral researcher at the Brain and Mind Centre at the University of Sydney. So Norman, do you remember the homunculus?

Norman Swan: I do, and it used to give me nightmares, because it's this kind of ghastly human figure creeping all over the brain…

Preeya Alexander: Big lips…

Norman Swan: That's right, the sensitive parts of the body, but probably not all the sensitive parts of the body accurately represented. I think it was sort of edited for proprietary reasons. But yes, I do remember the homunculus.

On ABC Radio National, you're with the Health Report.