Program: Mapping the brain using the placebo effect

Preeya Alexander: You've been around for a while, Norman, in a good way…

Norman Swan: Yeah, like 10 minutes, you know.

Preeya Alexander: What's one of the most surprising things you've come across?

Norman Swan: Very early on, I remember reading this research into people who were addicted to heroin, and when they studied these people, they discovered they actually weren't on heroin, they were on something else which wasn't addictive. It was either powder or basically another substance; they'd been sold something by the dealers that wasn't actually heroin.

Preeya Alexander: That they thought was heroin, though?

Norman Swan: That's right. And when they were told that it wasn't heroin, they went into full withdrawal. 

Preeya Alexander: Wow!

Norman Swan: The power of the brain. And since then, I've been fascinated by the placebo effect, because they thought they were on heroin.

Preeya Alexander: And the placebo effect is real. Patients often say to me, 'What do you think about me taking this? I'm taking it for my leg pain or my cramping,' and I say there's not much evidence to support it, but I say, look, there's limited harm if you're happy to spend the pennies. And there is some power in placebo.

Norman Swan: It's a lot of power; 40% of the effect of any drug is probably placebo.

Preeya Alexander: So that's one of the things coming up on the Health Report today, we're looking at a study showing how the brain has a map when it comes to pain and where the placebo effect comes in. 

Norman Swan: I'm Norman Swan on Gadigal land.

Preeya Alexander: And I'm Preeya Alexander on Wurundjeri land.

Norman Swan: So on the show today we've actually got a bit of a theme going, Preeya, haven't we, where there are conditions which are being under-diagnosed or misdiagnosed and really need to be redefined.

Preeya Alexander: So in the dementia space, lots of people get diagnosed with Alzheimer's, but there's another diagnosis, frontotemporal dementia, and there are calls for the diagnostic criteria to be changed.

Norman Swan: And also young people with complex and unusual mental health issues which are being labelled all sorts of things, but turn out to be autoimmune and treatable with immunotherapy.

So, what have we got in the news?

Preeya Alexander: We're back to the US, interestingly, where yet again there's more developments in the vaccination space, and they're not good ones. So in Florida, the State Surgeon General, Dr Joseph Ladapo, has announced the decision to eliminate all vaccine mandates in the state.

Norman Swan: Yeah, he's got form. God knows how he passed his medical exams. He was anti-mask in Covid, and you could actually call him an anti-vaxxer. As a public health physician, you just wonder what he stands for. 

Preeya Alexander: Well, he's undermining public health initiatives, is what it seems like. At the moment there are requirements for schools, just like there are here for people to show vaccination status of their children, and he has described them as immoral intrusions on people's rights and that they hamper a parent's ability to make health decisions for their child. 

Now, there's a lot that's been happening, and we've covered a lot with RFK, Covid vaccines, the schedule has been changed, and a lot has happened in the last week where nine former directors of the CDC, the Centres for Disease Control in the US, have published an op ed in the New York Times, and they have said some very significant things about the current health administration and possible dangers.

Norman Swan: And this comes in the light of the Director of the CDC, Susan Monarez, being sacked. Well, first of all RFK sacked her, she refused to go, and then it took the President to sack her because she'd been appointed by Congress, and that was because she refused to follow his directives, particularly in relation to vaccines because they've changed the Vaccine Advisory Committee. I mean, the place is in a mess. And, as you say, a significant number of people have left, a significant number of people have been sacked. They're talking about reorganising, moving prevention to another agency. And the worry is that if there is an outbreak of a new pandemic, America will not be able to cope. But we could suffer from that, because we need countries around the world to identify new organisations that are appearing, so if they appear on our doorstep we'll know what's going on. And America is going to be flying blind if the predictions of these former CDC leaders are right.

Preeya Alexander: The American Medical Association, in response to this decision in Florida, have said that this would undermine decades of public health progress. We need to remember there's robust evidence showing that particularly the childhood vaccination schedule really does protect the individual, it protects other children, it protects staff. And I think a lot of people, Norman, still think, oh well, it's just chicken pox, it's just a viral infection, it's only whooping cough, but a lot of these conditions can be fatal and have significant flow-on effects and negative consequences.

Norman Swan: And we can't be complacent. I mean, in New South Wales a group of people are wanting to have another demonstration crossing the Harbour Bridge. This time it's supposedly under the rubric of against government corruption, but there are sovereign citizens and anti-vaxxers involved there. So the anti-vax movement is still not huge, it's overstated how big it is in Australia, but it's there, and we can't be complacent. When it comes to vaccines there's something to celebrate this week in terms of Australian research.

Preeya Alexander: There is. So the Eureka Awards have come out, and the prize for Infectious Diseases Research has gone to a group who've shown that vaccination against meningococcal B offers cross-protection against gonorrhoea.

Norman Swan: It's the same family of organisms, so it's called Neisseria. So the meningococcal bug is called Neisseria meningitidis, and the gonorrhoea bug is also a part of the Neisseria family, and they cross-react, which is amazing because gonorrhoea is a global infection with huge antibiotic resistance.

Preeya Alexander: And also when it comes to meningococcal B and gonorrhoea, these are two infections that disproportionately impact First Nations people. So this could have very significant public health consequences if there was widespread vaccination against meningococcal B rolled out, but at the moment most of my patients pay for it privately, and only some people can receive a funded vaccine from the government.

Norman Swan: And it leads the advisory committee ATAGI to approve it, and then the government to approve that. And we'll come back to that in a future episode of the Health Report.

Preeya Alexander: We've talked a lot about GLP-1 on the show.

Norman Swan: The Ozempic kind of drugs, Wegovy, Mounjaro, et cetera.

Preeya Alexander: Injectable medications which are used in type 2 diabetes which have also developed a lot of benefit in the weight management space. And we've done several interviews on the Health Report so people can go back and listen to them, but we spoke to Associate Professor Samantha Hocking, an endocrinologist, about the medications' potential side effects, like nausea. We also did a follow-up with Dr Sarah Trobe from the National Eating Disorders Collaboration about the need for people to be screened in any body size for eating disorders before these medications are dispensed.

Norman Swan: And before you go on, we will have links to those interviews in our show notes.

Preeya Alexander: Now, we talk a lot about the benefits of the medications, and I think we must acknowledge that for some people living with overweight or obesity, for people with insulin resistance in diagnoses like polycystic ovarian syndrome, these medications have changed the game for some. However, we are starting to see, and I say 'we' because I'm speaking to colleagues on the ground, and I started to notice some things, and I've spoken to pharmacists, endocrinologists, psychologists, dietitians, people that I work with, about the fact that we're starting to see people with no clear medical indication using these medications.

Norman Swan: Well, they're getting some of it on telehealth consultations…

Preeya Alexander: I think through online telehealth services and probably face to face. And I think this raises the question of how widely is this occurring. Some patients have told me honestly; 'I really appreciate the transparency, Preeya, I knew you weren't going to give it to me, but I'm just letting you know that people have told me that if I just lie about my weight, my height, I can attain it from this particular service.' And I just wonder how widespread it is, if there are other people in the community noticing this, if there are health professionals in any capacity noticing it, and what is the duty of care here? Because I take the role of writing a script and giving someone something quite seriously and doing no harm. 

Norman Swan: So what we're talking about here is, well, it could create an eating disorder, you could get a nutritional deficiency, you could go seriously underweight, and you could have muscle wasting. So I mean, there's a whole series of things that could actually be a problem. And there are rare eye side effects, which we've talked about on the show before. No drug is harmless, and these are not harmless drugs.

Preeya Alexander: And if you prescribe these medications…so most clinicians, I think, like me, will offer allied health support, exercise physiology, because people should be doing more resistance training, because you lose muscle mass. A dietitian should be seen because you need to increase your protein intake. A lot of support is required for these patients, and if they're not getting it…and all the harms you've just discussed, but if this is now a tool in the beast of diet culture, which it potentially is, then I think we need to try and prevent harm.

Norman Swan: So we've approached AHPRA, which is the regulatory agency for health practitioners, particularly doctors, but also other practitioners as well, to see what they're doing about it, because it's a major issue in terms of regulation. If it's a concern for you, or you disagree with us, why don't you contact us at healthreport@abc.net.au.

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

The next story is on immunotherapy, but not in the space that we usually think of, this is mental health.

Norman Swan: Yeah, and it's not the same immunotherapy drugs that are used in cancer, which we talk about all the time. And the person I'm about speak to, Associate Professor Elizabeth Scott at the University of Sydney, has spent most of her career looking after young people with very complex mental health issues, and what she's found over the years is that there's a solid biological reason for some of these young people to have these complex mental health issues, and in fact it's the immune system causing it. This has just been published, and it's a small series, 43 young people, starting at the age of 12, who had complex mental health issues, but in fact what was going wrong with them was their immune system and they had an autoimmune disease, and when they found that out, they were able to treat it. And so this has been an obsession but also a strong research interest of Liz Scott, who works at the Brain and Mind Centre at the University of Sydney.

Elizabeth Scott: They present with very severe mood disorders, complicated sometimes by syndromes like OCD. They have psychotic type symptoms that come and go, so they don't have sustained psychosis.

Norman Swan: And just to decode some of that, when you say mood disorders, so they've got really quite profound depression.

Elizabeth Scott: Yes, they have quite severe depression or unstable mood, bipolar type syndromes where they go from having very kind of elevated, activated mood, not always very happy mood, often it can be kind of irritable or agitated with a lot of energy, changes in impulsivity, often a lot of self-destructive behaviours or suicidal ideation, or very low mood and low energy states where people can't get out of bed, they want to hibernate, they don't want to socialise with people, again can be very irritable. And these syndromes can be extremely difficult, not only for the young person but also for their families. They're very hard to understand and can be quite changeable over time, so can present initially with OCD type symptoms or anxiety, then develop more severe depression, have psychotic type episodes, and also have quite significant cognitive impairment. So one of the real characteristics of these syndromes are the deterioration in their cognitive function, capacity to think, capacity to attend to things, to sustain attention, concentration, short-term memory. So it's a deterioration in people's capacity to kind of think and engage with the world often.

Norman Swan: And dominantly women. 

Elizabeth Scott: Yeah, so interestingly in our series it's a very high proportion of females, and that relates to the health bias where young women are more likely to see care. It also reflects the fact that autoimmune and immune conditions are much commoner in young women than they are in young men.

Norman Swan: And the youngest in your series was age 12.

Elizabeth Scott: Yes, we do see quite early onset in some cases of young people who've experienced a kind of autoimmune syndrome earlier in life, or Tourette's type syndrome with OCD symptoms and tics, motor tics, that then go on to develop these atypical mood or psychotic disorders as they grow up through adolescence.

Norman Swan: These people have been around forever, you would assume, so what are the labels that they're getting and parents being told that's wrong with their child?

Elizabeth Scott: To some extent those people who are labelled as treatment resistant then become reclassified as having personality disorders, or they are told that they have a somatisation disorder, that it's really about the physical expression of psychological distress, or the increasing kind of trend to label people as having functional neurological disorders with neurological symptoms where there isn't an obvious neurological cause, so people get sent off for psychotherapy, which is not particularly helpful and often causes a lot of distress and delay in treatment.

Norman Swan: Now, you say they're rare, but there's been this whole thing which has grown through the years, that even schizophrenia and regular depression has got an immune story in the brain.

Elizabeth Scott: Correct. Increasingly people are aware of the underpinning, the immune or inflammatory processes that underpin brain development in adolescence. So you change your brain by activating your immune system and turning on your genes of the immune response.

Norman Swan: Now, you've used the word 'autoimmune', meaning the immune system's turning against the body, but I remember years ago we did a documentary on…it was predominantly women who got it, it looked like an extreme version of schizophrenia, they had cognitive decline, and they had a tumour, and when it was removed that cured them.

Elizabeth Scott: That's right. The syndrome that was originally described, thought to be extremely rare, was anti-NMDA antibody syndrome, where you make antibodies to these particular receptors in the brain, and that occurs when people have ovarian tumours, for instance, and that immune system gets activated and makes antibodies to these brain receptors, causing this very acute florid brain-on-fire type syndrome. We know that's not the only cause of anti-NMDA encephalitis, because young men can get it too.

Norman Swan: And what I remember from that one is that it had to be detected early because you could get permanent damage.

Elizabeth Scott: That is correct. So in all autoimmune conditions, whether they affect your joints or they affect your thyroid or they affect your brain like MS, detection and early intervention are key to prevent the damage associated with these immune processes, and that is absolutely true in these types of conditions in young people; if we don't detect them early, if we don't treat them early, then people are likely to go on to have long-term damage and the disability associated with that.

Norman Swan: Okay, so you've got these unusual symptoms which go together, which should now trigger a warning sign that the immune system might be majorly involved. But are there tests that are going to reveal this?

Elizabeth Scott: We used a set of clinical criteria based around what we've discussed, this kind of very severe atypical mood disorders or psychotic symptoms, or OCD type symptoms that don't respond to conventional treatments, or conventional treatments actually make you worse, that have this kind of deteriorating cause, deteriorating cognitive function, and associated with particular sets of family history and laboratory markers to define who we thought was at risk and then who needed to go on to further, more detailed assessment, and then planning for more specialised immunotherapy treatment.

Norman Swan: Just give us a sense of how you decided what you were going to use. And this is not the immunotherapy used in cancer, this is immunotherapy used largely in autoimmune disease.

Elizabeth Scott: That's correct. So the decision for treatment was based on a panel decision with an immunologist, a neurologist and a psychiatrist. We involved the young people and their families. So these were really collaborative decisions, and they were brought about by consensus. 

Norman Swan: This wasn't a randomised trial, you were just observing what happened to these people. In a sense they were their own controls, because they had a pattern up to that point. You then instituted immunotherapy, and you got a result. What were the results?

Elizabeth Scott: We found that there was a significant response rate to people having immunotherapy, and these were young people who were really not doing well. They'd had repeated periods of hospitalisation, very aggressive psychiatric treatment, including things like ECT, a high proportion of them were not in education or employment, and their level of functioning was poor. So, comparatively, after treatment they were all doing very well. So we got about an 88% response rate in terms of improvement in symptoms and improvement in function, which is pretty remarkable. 

Norman Swan: So their cognitive capacity came back.

Elizabeth Scott: Their cognitive capacity improved, it did not come back to pre-disease levels in all people, but it certainly improved significantly, enough for a very high proportion of young people to get back into education, training and employment and to have a substantial improvement in their level of function. 

Norman Swan: What about side effects? Because these are not harmless drugs.

Elizabeth Scott: About 20% of people, a bit over 20% had moderate to severe side effects associated with therapies, including things like recurrent skin cancers in some cases. So they're certainly significant, and they certainly need to be monitored.

Norman Swan: So somebody who's listening to this conversation and they realise that they themselves or they have a child with this pattern, what is a person to do in the current health system to get this sort of care? 

Elizabeth Scott: Really it's about raising awareness. The people that have gotten to care often have parents that have advocated for their treatment and assessment, have really not accepted poor treatment or deteriorating function or disability. We're trying to raise awareness in the medical profession, we would like to establish specialised clinics in all states where people could be properly evaluated and assessed, and more importantly we can collect the data that is required to both make sure that these treatments are safe and that they're effective, but also to drive research. We screen all of our patients presenting to our psychiatric services early, so we look at their immune, inflammatory and metabolic markers, and we've published the data on this. So I think as we get better at understanding some of the early changes that you see around these kind of immune inflammatory processes, we'll be able to pick people up earlier, make sure that we put them into the appropriate treatment streams where these things are monitored, so that we can pick up changes quickly.

Norman Swan: Associate Professor Elizabeth Scott, who's principal research lead in Youth Mental Health at the Brain and Mind Centre in Sydney. So there may well be people listening whose child or the young adult in their family has exactly these symptoms, and it can unlock diagnosis and treatment. Important story.

Preeya Alexander: You're with the Health Report on ABC Radio National.

Norman Swan: This next story has similarities to the previous one with Liz Scott. A form of dementia called frontotemporal dementia, you may have heard about it in relation to Bruce Willis, the actor who was diagnosed with frontotemporal dementia about a year after being diagnosed with the inability to speak, aphasia, and so he has got it very severely. You know, communication challenges are just one of Bruce Willis's challenges with frontotemporal dementia, but even he who could hire the best medical minds in the United States took a year to be diagnosed. 

Now the issue which is being uncovered by Australian research is that the criteria used to diagnose frontotemporal dementia misses one important element; memory loss. So in the past, if you've got memory loss you could not be diagnosed with frontotemporal dementia. And this group in the University of Sydney believe that is wrong, and they're not the only ones in the world who believe that is wrong, and, as a result, people have been misdiagnosed. Here's an example of one personal story of this from Julane Bowen, who's a dementia law advocate whose husband Jeff has frontotemporal dementia, and what Julane found was differences in Jeff's behaviour as he approached retirement.

Julane Bowen: But when he retired, things really escalated. He'd gone from being very active, very social, involved with some volunteer things, going out on our boat, to sitting in a chair and never getting up in just the space of two months. So I was telling the doctor I was getting concerned, and he was kind of monitoring things, but not really doing anything. Then at the not quite two-year mark he was getting kind of like psychotic. He had stopped sleeping. He was getting increasingly paranoid if I would leave the house, and that all escalated one day to where he wouldn't let me leave the house. They told me he had depression, he had bipolar, he had developed late onset schizophrenia. When they finally decided to do some brain scans that confirmed FTD, his atrophy on the frontal lobe was dramatic. And his GP rang me early one morning to say that he was sorry, he had just written it off to me not coping with the fact that my husband had retired.

Norman Swan: So a really troubling story there from Julane about delay in diagnosis, and that's what Olivier Piguet has been trying to speed up, in a sense, and make much more accurate so people can get the help they need. Olivier Piguet is Professor of Clinical Neuropsychology at the University of Sydney.

Olivier Piguet: So frontotemporal dementia is rarer than Alzheimer's disease. These people will have changes in behaviour and personality in many instances, and other people will start experiencing some difficulties with language, either failing to understand the meaning of words or sentences, or difficulty expressing themselves.

Norman Swan: And does it come on earlier in life than Alzheimer's? 

Olivier Piguet: It does generally. There is a peak of disease onset in the late 50s or early 60s. In these frontotemporal dementia syndromes what we see is that we have people who are still in the workforce, potentially with kids growing up. So there are some financial implications, relationship implications that you tend not to see in the older segment of the population.

Norman Swan: So give me the typical picture before you added in this extra element of memory loss.

Olivier Piguet: What you would see is there's generally a partner who raises concern with a GP saying, 'Well, I think my husband is behaving a bit oddly. He's not as warm and empathetic as he used to be. He doesn't relate to other people, doesn't like being around, has difficulty engaging in activities.' And often at the beginning the label is more around…maybe it's a psychiatric disorder; is there depression or late onset psychosis or bipolar disorder? And often people presenting with these symptoms get the runaround and get to see a number of GPs and often refer to psychiatrists and get on some medications that don't seem to make much of a difference. And then finally they might end up with a geriatrician or neurologist who puts two and two together. In general, it takes about four years to get an accurate diagnosis for frontotemporal dementia, which is a long time, as opposed to Alzheimer's disease which usually takes about 18 months, two years. So we're talking a doubling of time that it takes to get an accurate diagnosis of frontotemporal dementia.

Norman Swan: Now, the thing that I found gobsmacking was that memory loss excludes you from the diagnosis, and yet it's a dementia.

Olivier Piguet: Yes, it is, but that's exactly the point; people tend to equate memory loss with dementia, which is not always the case, and using memory loss as an exclusion criterion, the basis for that was to exclude people who would have potentially Alzheimer's disease. But the research, not just from our group, but other researchers around the world, realised that memory problems is actually present in frontotemporal dementia as well. So what happened is that we would get referrals from various practitioners saying 'there are changes in behaviour and personality, but there's also memory problems, so I don't think it is frontotemporal dementia'.

Norman Swan: So you've reviewed this, looked at the evidence, and said memory loss should be part of this, you shouldn't be excluded from the diagnosis of frontotemporal dementia if you've got memory loss. What are the practical implications of that? I mean, there isn't a drug for frontotemporal dementia, is there? 

Olivier Piguet: No, there isn't. There are two things. One is to be more flexible in the diagnostic approach, which then allows us to inform, educate families, help them to address these behavioural symptoms and behavioural changes. But you're right in that there's no drug at the moment for frontotemporal dementia, but there are clinical trials currently underway that are looking at a very specific subset of people with frontotemporal dementia who have genetic mutations.

Norman Swan: Now, what families and indeed people with frontotemporal dementia or the right diagnosis want to know is where do I go from here? How long have I got? Am I going to end up in a nursing home? What's the track of people with frontotemporal dementia?

Olivier Piguet: It's extremely tricky to determine on a case-by-case basis and that's exactly the questions that we get all the time. And I'm always put in a very difficult position because I can talk to them about population studies, so I can tell them that on average we know that from a diagnosis of frontotemporal dementia, life expectation is about five to seven years. But in our clinic we see people who will die within two years, and others will still be around 10, 12 years later. And this is another thing that we try to identify in this study, is are there features or a cluster of features that will tell us something about how quickly you will go downhill or not? And we couldn't find anything. The only important variable that comes into play is sex. Female participants tended to have a slightly shorter disease duration compared to males.

Norman Swan: Olivier Piguet, Professor of Clinical Neuropsychology at the University of Sydney. Here's Julane Bowen again on what having an accurate diagnosis has meant for her and her husband, Jeff.

Julane Bowen: We had the psychiatrist then who knew that he had a terminal illness, but for Jeff, even though he spent four more months in hospital, that doctor said, 'We'll get him stable and get him home, if that's what you want.' Prior to that, I got all kinds of answers, and every answer was then followed with, 'You will have to find him a placement at a residential facility. You can't take him home.' So getting the diagnosis met we were able to start putting in place a program, and he's still home, and that was eight years ago last month.

Norman Swan: So these things are not for pointy heads, they're really important. And if you want to read more about this, Olivia Willis, who's sometimes heard on the Health Report, has written a piece on frontotemporal dementia and its diagnosis on ABC Health online, so go there, and we'll have a link to that as well in our show notes. 

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

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.

What's in the mailbag? 

Preeya Alexander: Naomi's written in, she listened to our cognitive functional therapy episode on lower back pain. A couple of weeks ago we talked about this kind of physiotherapy that can really improve outcomes in chronic back pain. 

Norman Swan: A lot of it's about reducing fear of the pain. 

Preeya Alexander: Yeah, pain education, reducing fear, increasing activity. And Naomi says that ironically the physio used cognitive functional therapy that very day that she was listening to us, and it had a significant benefit. She says it was genuinely life changing. 'I went in on crutches and a knee brace and walked out without both.'

Norman Swan: And she went on a deep dive into CFT after that.

Preeya Alexander: She's done our job for us. Thank you very much, Naomi. And she says that the professor who pioneered the research and development of the approach is Professor Peter O'Sullivan at Curtin University here in Perth. So Naomi's in Perth, obviously. Because last week we said we didn't know where people could access cognitive functional therapy, and people had written in saying we want to know how to access this amazingness. Professor O'Sullivan and his team, Naomi writes, have the Evolve Academy, which is the training for cognitive functional therapy at a national and international level, so we could get in touch with them and find out more.

Norman Swan: And in fact (and I should have remembered it at the time) we've had Peter O'Sullivan on the Health Report (what a surprise) talking about his research, and we'll have the link to that interview, which is called 'a radical new way to treat low back pain', in our show notes.

Preeya Alexander: But please do write in, because we do enjoy it, and particularly if you're helpful like this and help us find things that we're looking for, and if you want to write in to us about GLP-1s and what you might be noticing, the address is the same, healthreport@abc.net.au.

Norman Swan: And don't forget our sister podcast, What's That Rash?, and this week we're looking at whether there's a cure for jetlag.

Preeya Alexander: And is there?

Norman Swan: You're gonna have to listen to find out.

Preeya Alexander: Usual response, Norman.

Norman Swan: It is. But anyway, stay on tenterhooks. See you next week.

Preeya Alexander: See you then.