Exploring the Neuroimmune Interface and Future of Pain Management with Professor Mark Hutchinson

Welcome to this week's episode of the Modern Pain Podcast. This week we're going to be having a conversation with Professor Mark Hutchinson. In this episode we discussed the concept of a neuroimmune interface and how it has come into more consideration in the research and in clinical practice. We discussed Mark's thoughts on how the model of professional lines and roles needs to be flipped, with the consumer in pain at the center. What is the role of precision medicine with a biologic focus in the context of complex pain conditions? What can we do as professionals to apply this information to help someone in pain? Is it realistic to expect a single intervention and research to make a large, lasting difference in pain? Have we been able to relate molecular patterns of cognitions to a pain experience where how we think can be tied to pain? What is neuroinflammation and how does our understanding of it help us clinically, and what developments are coming that have Mark most excited? Give the episode a listen and get the answers to these questions and more. While you're at it, please subscribe to the podcast on your podcast provider or on YouTube so we can better spread this information to clinicians and patients. Enjoy the episode. This is the Modern Pain Podcast with Mark Karjula. Welcome to the podcast, Mark.

Thank you for having me, Mark.

Always good to talk to folks across the pond Mark and I were talking about he's in the Southern Hemisphere enjoying some cool temperatures there in Australia. I'm in Phoenix and if you see me a little glistening on the video feed of this it's because of my house is hot it's 118 degrees out right now and my air conditioning is battling to keep up with it. But what we'll make do. But I'm excited to have Mark on the podcast. I've read a lot of his work. He's been working a bit and kind of collaborating with the Neu Group, lorimer Mosley and David Butler's group and have, as I said, read some of his research and was bummed when I was able to attend some of the master classes he did with Lorimer's but talked to those who did and had nothing but a complimentary things to say about it. So excited to have you here, mark, and if you don't mind, can you introduce yourself to the audience? I know you've had a unique journey with some multiple specialties and trying to really unsilo things. I've read some of the articles of your development and your training as far as seeing things siloed and trying to bring some things together. But I'd love to if you could share kind of your journey with folks.

Yeah, thank you, mark, it's really great to be able to join you here, and then also the listeners to the podcast. My dog is deciding to talk just as we start, of course. So I'm first and foremost in Australia. It's our tradition to acknowledge country and I pay my respects to those of the Ghana people on whose land I work, live and play here in South Australia, and pay my respects to elders, past and present, and acknowledge the enduring connection to country that the Australian indigenous people have for the longest living civilization continuous in the world 65,000 years here in Australia. So, yeah, thank you for having me here. Yeah, mark Hutchinson, professor of Medicine here at the University of Adelaide in sunny but wintery South Australia. I have a range of roles. I'm also the director of the ARC Centre of Excellence in Nenascale Bioprtonics and we might get to talk a little bit about bioprtonics and what on earth that has to do with pain. I'm also the president at the moment of Science and Technology Australia, so that's the peak body that represents 125,000 scientists and technologists across government and industry and academia in Australia. So it's our equivalent of the AAF in the US. And then I have a range of other roles in the pain world on the chair of the Australian Pain Solutions Research Alliance, where we're trying to get everybody to come together and do something for the good of pain consumers, rather than me sitting in my ivory tower in academia just publishing more papers and navel gazing about what is pain and using terms that perhaps are useless to the patient. And then, finally, I'm the co-chair of a National Security National Advisory role with the Safeguarding Australia through Biotechnology Response and Engagement Alliance, which again draws lots of people together to come and do bigger and better and good things for the safety of the country. So I have a diverse range of activities that tries to keep me out of trouble, but most of the time I find myself in a little bit of hot water.

So what makes things fun in life. You got to kind of test the boundaries a little bit from time to time and kind of push things. But really impressive what you're up to and we'll get into more of that detail. For sure we're going to talk a little bit. I actually reached out to Mark after we had a podcast where there were some discussions of the immune system and really focusing strictly on the biologics and to the I don't want to say the exclusion, but maybe to the deemphasis of the psychosocial and how we had kind of moved a little bit too far to that end. But we're going to get into that. But I'd love to maybe get a little bit because picking your brain and a lot of this is my nerdy selfishness, wanting to chat with you about this stuff, because things we see clinically where this whole autoimmunity and the neuroimmune interface it's been a kind of more buzz topic as of late neuroimmunology, a field I know you're very well versed in I'd love if you could kind of explain to folks maybe a little bit about this whole, how the neuroimmune interface has really come to be something more considered as we're starting to see complex pain conditions, and maybe how you've seen it develop, and you've obviously contributed to our development of that understanding. So if you could share some of that, that'd be great.

Sure, yeah. So I guess the starting point probably needs to go back to Renee Descartes. And the body is a machine philosophy and the mind body dualism approach that really sets us off Brilliant Reductionist Western medicine. Don't get me wrong, we had to start somewhere. But we are not a machine. You can't take me apart and then put me all back together again and expect me to work the same way. And so I think what we have evolved to in the field now is to acknowledge that we have learned almost as much as we can out of applying a Descartes approach, of reductionist approaches. And that is my lymph node in isolation will operate as a lymph node and that's interesting. But when the lymph node is in the body, it is in the context of the body and receiving auto-crine signals and paracrine signals and neuronal signals that are changing the function of something as simple as a lymph node. Now, when you then try and scale that up to a multi-systems organism that does not operate in straight lines, we are not linear that Descartes system breaks and that is troubling for many who think of I am an immunologist and I think of the immune system or, even worse, a single immune cell operating in isolation. We don't work like that. So that is the journey that we have been all on in the past realistically two decades to then advance our understanding further of what it truly means to be human and a complex organism, where the discussion and realization that maybe we are more complicated than we thought and, critically, our brains are more than just a neuronal, electrical, ionic organism, organ only, which probably asking the simple question how do we know we are sick? Now it is probably a good time for us to ask that question. Having come out in the back of an academic, an academic pandemic, we really are at this interesting point where we have all experienced illness, we have all seen illness. Now, if we were to follow the Descartes principles of what illness could arise from, we should not feel sick Because, embodied from that understanding of the body as a machine, the brain should be immune, privileged, it should not receive or even detect immune signals. Now, clearly it does, and we know we are sick. And that is not because our bodies are somehow deprived of the energy stores, because we are fighting off a bug of some description. It is because there are indelible signals within our immunology that communicate defined signaling pathways via a variety of methods to modulate central nervous system function. Now those pathways are varied. Yes, we can have immune molecules like cytokines, chemokines, right through to prostaglandins and reactive oxygen species released by infection, released by damage and danger. That then can circulate to our brain and spinal cords. That then are detected and change. The presence is detected. That then changes and broadly black boxing at here changes neuronal function. We also know that we can have immune cells migrate up to and adjacent to the blood brain barrier to then change and release factors that then change the central nervous system function. We know that there are peripheral primary afferents that selectively respond to the release of those immune factors. That again leads to an ascending projection of neuronal activity that changes brain function. The scariest one, but probably the most exciting one for us to actually acknowledge, is that there are immune cells that go into our brain and spinal cord. That is a healthy brain and spinal cord and results in changes in central nervous system function because these otherwise classically sort of peripheral immune cells are going in there to do things. Now there's a myriad of things that they are doing and most of them we don't understand yet, but clearly their mere presence is fundamentally changing the way our brain and spinal cords work. So that then means when we start talking about how do we know we are sick? We know we are sick because our mind and body are connected and it's like, well, of course that was the case, but no, actually that is a profound statement to actually integrate into the complex siloing of our medical disciplines within Western culture. Our mind and body are connected. That means that what we think and how we behave and act changes our physiology and our periphery, and then how our peripheral physiology is adapting and changing or responding is changing then how we think. We are not straight lines, we are connected circles of very much entangled Venn diagrams of multi-circles upon multi-circles and in amongst that. I've been enjoying the last three decades of trying to tease apart little parts of that to explain tiny parts of what we understand. It means to experience pain and how our immunological status, our environmental status, our nutritional status, our genomics, our sort processes and a little bit of injury contributes to the experience of that complex pain experience.

Yeah, so I mean a lot to unpack and I you know there's a few things I'd love to. I mean you speak to some of the siloing of, you know, western medicine, which I think makes it difficult to tie these two together. And I think you rightfully identified the biomedical model. Obviously has its strengths and has done some amazing things and should be grateful for some of the developments there. But it kind of has this linear straight line to cart classic diagram of the old foot in the fire type thought process with pain. That doesn't bring in the complexity of this emergent complex system that we work with with humans. You're obviously, you know, one person who's trying to cross some of these borders where you know immunology, pharmacology and different you know these, you know things and also obviously pain and consulting with physios. I'm wondering where you see with pain. You know, obviously our professional lines have sort of been drawn and you know it's hard thing to change at this point. I think you know the sunken cost is there and you know folks feel the turf gets threatened and but there's a lot of folks that are obviously really working hand in hand. We know that pain isn't going to be one professions solution, but I wonder how you see some of these professional lines, maybe blurring, and where you think ideally, I know, minus the political and all the other challenging things that go into the these professional lines being drawn. I'm wondering where you think you know these professional lines could better serve patients, or and maybe how rigid or blurred they should be in your opinion.

So, in all honesty, I think we need to flip the whole model to be actually appreciating the pain consumer at the centre. Let's not make a pain consumer find us in our stupid you know in Australia wonderful Medicare supported system. Let's actually try and help this, orient our care to the needs of that individual who is experiencing and trying to live life with acute through to persistence of pain. And so I think what that means is we need to actually acknowledge the complexity of it. Sometimes the discussions that we have within the academic ivory towers about terminology and naming, whilst they may appear to be important to us, the pain consumer is still experiencing a hell of a lot of stuff that they call pain. So, unless that discussion is going to lead to a profound adaptation or change in access of a potential pain treatment or some tool that allows for that pain patient, pain consumer to live their life in less pain or live their life with pain to a better degree, why, why are we wasting our breath on it to some extent? Now, that's, that's all nice and well and good to say, but you know, I know we need to start talking about terminology and be careful with our use of language, because it does often close doors rather than open doors. So where I see us needing to evolve our practice, our approach to complex things of broadly, issues that are of central nervous system and body connectivity and this is the same discussion we could be having around depression, anxiety, other mental health disorders, right through to pain we need to acknowledge that when we see an expression of someone's pain, that is, their individual experience of their health status and their expression of pain when they have come to to experience that pain at that point in time is the sum indelibly the sum of who they are, who they have been, what they've experienced and their current physiological status. And that status can be drilled down, at the end of the day, to cells and molecules all operating in a very, very complex soup that happens to be contained in most cases in a skin layer that we know as the human body Also happens in animals, but maybe we can talk about our animal work at some later point. But that means that then, when we start identifying that this person does have this complexity, how do we bring the skills and tools that we have as professionals to help that individual? The worst thing that we can do for that patient who may have waited in Australia up to three years to see a specialist to say, ah, sorry, you don't fit into my toolbox kit, I can't help you, see you later. And yes, I come. Those individuals come to that day at their work with their set of tool kits and that's all that they have to offer for that individual. And surely, if that's the best we've got in the evolved, complex system that we have today in human society, that's wrong. We shouldn't have to one wait for that amount of time, but two to be told now, sorry, I can't do anything for you. So where we're starting to see an opportunity in Australia especially, are these multi-disciplinary teams of health professionals broadly coming together to work with patients. That means that it is absolutely appropriate that the patient is seeing a psychologist, a physiotherapist, an occupational therapist, a general practitioner, some nurses, a surgeon, a pain specialist, perhaps even a specialist pharmacologist, to understand how they are responding to and adapting to the treatment and their current underlying causes, whatever those might be, of their current pain experience. And as that pain experience is unwrapped for that individual, it may identify in the future perhaps some cellular molecular signals within the brain and spinal cord that are of a neuro-immune origin, perhaps that are then leading to this exacerbated response to danger and the experience of pain. It may unearth that there's some ways that the individual's been thinking and thought processes that can be trained and exposed to other ways of thinking. That allows for the same no-susceptic experience to be dealt with in a different way, meaning that the person can still experience the pain but it's less debilitating for them to then move on. Or maybe in the future there may be disease modifying cellular therapies, biologics, antibodies, small molecules insert here some magic box that goes bing with a fancy light on it. We don't know what those are yet. That may be disease modifying and the person over a course of a treatment can have molecular neurosurgery done on the various bits and pieces of their somatosensory system that allows for their body to move beyond that danger response that they have. But at the moment we have very delineated systems set up and I think the best thing we could do is not have a patient leave a clinic having heard I can't do anything for you, the end for that person. But rather I don't have the skills for what you are experiencing today. But here are a list of people you can talk to and engage with and here are a list of life skills that can be attempted or practiced or refined, that may take this to the next level for your experience of pain, yeah, yeah, well said.

You definitely touch upon the complexity and some of the challenges we deal with systemically and we had had some discussions with some past guests about the possible future of biologics really targeting and being able to modulate this nociceptive apparatus. My question and some of the discussions that resulted on social media humans don't live in this vacuum. They have to navigate back into an environment and a social world and a culture and a workplace and a home life and things that we know modifies neuro immunologically, if I can say the word right. It impacts the experience. I'm just wondering where you think. I mean, obviously, I think there's definitely a place for biologics and that the ability to maybe target something specific to somebody's pain phenotype and doing those type of things. But then how do we? I mean, I think, do you think we need to be careful, just getting too focused on the biologics and forgetting that this person then needs to be able to navigate a world? Or if you send somebody out, you pull them out of the haunted house and you treat them with a nice biologic and then the biologic does its thing, but then they go back to the haunted house. That's their life. Things seem like they would just dysregulate all over again and we'd be back to square one. I'm just curious your thoughts on that.

Yeah, so I think what you're touching on. There's a few key points here that I think that are worthwhile unpacking. First and foremost, in Australia we have interesting current affairs programs that go on the TV every night and they speak to roughly every fortnight. There's some miracle cure for your pain and everybody should stop everything else they're doing and just take this one thing because it worked for me, and there's wonderful consumer stories of I was in the abilitating pain. I took this magic solution and it worked for me and therefore it must work for you. Now that does not work. It is not the case. If it were the case, we would not be hearing about it from the current affairs programs. It would be in an esteemed medical journal and there would be some science backing it up. The key part to that is in the pain field we do not yet have precision medicine tools. What I mean by that? In cancer, for example. 20 years ago you had cancer full stop. That was it. You might have a particular cell type of cancer where that that cancer arose from. Now we have genotyping and molecular phenotyping tools for individual cancers. That allows for a targeted precision treatment of that specific type of cancer at where it is in its treatment response, with the acknowledgement that a cancer will evolve and become resilient to one treatment and then you go to the next one, because it's the next logical thing to do, because we know so much about that cancer biology. We do not have those tools in the pain fields today. We can't get the full color of the rainbow of all the types of pain and delineate you have blue pain, you have red pain and you have green pain. But those tools are coming and when they do come, what it will demonstrate to us is that somebody who Joe and Josephine, who present with exactly the same type and experience of pain, actually at the molecular and cellular basis their response may be the same but the etiology underpinning that are profoundly different and therefore shouldn't be treated the same and there are different mechanisms are best for that individual. Like we've got precision cancer care, we will have precision pain care. That then means that we do have the opportunity for a biologic at one particular point in time for an individual to be the best treatment for that individual in time. But in two weeks, in four weeks, it may be a foundationally different cellular molecular mechanism that is responsive to a profoundly different treatment. That needs to be engaged and used appropriately to intervene in that person's pain management or, hopefully, journey to disease modification and therefore out of the hyponose accepted experience they have. All of that is on the background of we live in a complex world with a lot of family pressures, ex-society pressures, monetary pressures and ongoing injury and health and illness. So therefore, we are changing as our pain experience changes and that means that we need to then be looking at resilience, enhancing behaviors, eating well, sleeping well, getting some exercise. That changes the, the, the tide level of our resilience to experience hyponose reception, exaggerated pain and danger responses if we live a little bit better and do the things that we all know we should be doing increasing our alcohol intake, getting better sleep, eating healthier, going for those lovely walks, either in the crazy hot summer like you have, or, you know, pretty generous winter we have here that changes our physiological set points across multiple systems, and those all are things that need to happen alongside the best precision medicine that we have and will have into the future. So, yes, biologics have a place, but there is never going to be one single drug, small molecule that targets one single receptor system that is going to fix everybody's pain and anybody who claims that, or any, any, any sales rep that tries to argue that, shut the door.

Tell them to go home and do a little bit of homework, because that's just not how we work yeah, yeah, it's the, the complexity, and we've had a few clinicians kind of weighing in because I had kind of said what should I ask Mark about when I taught him in the podcast and they were you've you've touched upon a lot of the like biologics and our ability to, and also talking about what we do as physios where the push for like lifestyle medicine has been pretty large within physiotherapy, recognizing that we need to push people to better, you know, exercise habits, better movement habits, better stress management, you know diet, all the good things. I'm wondering what you think if we kind of take this to, to this whole thoughts of neuromunology with a clinician on the front lines, because I think sometimes too I know I see this clinically I'll see patients where they may be getting this like little bucketed, siloed view of their condition. Yet you see them and they're sensitive to everything. They're allergic food, allergies, to everything. They have sight, you know, smell, sound, I mean some of it being a company of migraines sometimes, did not they're? They're getting widespread pain there and all these different things going on. Obviously we work to communicate maybe with our, our physician colleagues and other folks to maybe look at, you know, some of these more complex, you know diagnoses and systemic dysregulation, things. But I'm just wondering, like as maybe a physio, because I'm selfish and I want to talk about my profession, I guess but what do you think we can do as as physios, and maybe not even just because we got OT colleagues and a lot of other folks who are in that rehab front line, to maybe use this information to better, you know, help people? I mean? What would you think on that?

yeah. So my the reason to keep I am still passionate about the work that I do is that I see it as a glass half full, and that glass half full is going to be filled further with some hope. Because, at the end of the day, if we knew everything there was to know about pain now and we still had the rates of pain that we got. There's an Australian saying for that which I won't share with you, with your listeners, but it involves some expletives and and we are not there, right. So we do not know everything and that is a great thing. So let's acknowledge that. And if our patients can actually ignore, hear that from us, that's gold because we're human too, right. So letting them know that we don't know everything, but we're going to have a really good crack at what we do know. And what we do know is that these things that they see as being potentially connected to their current experience may have some cellular, molecular origins to the basis. So the classic one that I hear a lot about is I was doing so well and then I had a car accident and I really stressed that day and all of this stuff just happened and my pain came back, or I was doing really well and everything was fantastic and now I got an upset stomach and again I just everything just came back and my big left toast started hurting again. Why? Why would I be getting a big left toe pain after having an upset stomach if you take the day car approach where you go down to the big left toe again and look for the problem in the big left toe? That's not where this is arising from. We know that now we're connected. So all of these life experiences in the logical experiences, work, stresses actually all get integrated into the complex things that we are. Our immune system adapts, our central nervous system adapts to then identify a change in that tide level of resilience and either all the boats have risen and we're doing a little bit better or the time's gone out a long way and all those boats are now sitting on their side, not looking so fancy as they once were. If we can help patients identify the, the relevant points around that not to not to inflame it, but to identify those relevant points it starts opening up opportunities for them to say well, the days when I did actually feel better in this part of my symptom milieu were the days when I did XY and Z, and XY and Z probably were I got a better night's sleep and I got a. I ate better and I had a de-stressed morning, for example. And those may lead to acute connectable benefits for these other things, whilst maybe not touching the reason why they're with you for their fundamental pain presentation. But if we can start shipping away at those other things that then lead to beneficial behavioural changes that we all know we need to be doing, then those lead to a connection between beneficial behaviour and, at the end of the day, a rewarding stimulus for the individual to say I've improved my behaviour and I can see a change. And that change, whilst it may not be directly linked to the pain state, it's all part of that likely connected up system of the rising tide of our neuroimmune adaptations that are occurring. So my military colleagues often talk about crawl, walk, run. If we start trying to expect to run straight away, we're going to be very disappointed. So let's start with that crawling, and that crawling often is it's get up, let's get a good amount of sleep. Let's look at your, your sleep hygiene. Let's look at simple things like the approach that you have to your daily practice. How do you actually go about this. Let's create some sort of safety signals in those days so we can then start looking at that rising tide on. By the way, here's some helpful physical exercise activities that might actually help you gain confidence in your movement, because if you're exhausted and you haven't eaten well and you're already grumpy probably not the best day to be doing the exercises which you know in danger in me thinking I'm going to be somehow not safe to do these moves. So I mean, sometimes it's. It's actually then about having that conversation with the person to work out where they're at and and, of course, within a normal consult time frame, unpacking all of that and then spending five minutes at the end on what you think is actually the targeted things you can actually do for this person, for their pain. Maybe it's actually all the conversation altogether.

That's actually part of that whole journey that you're on with the patient over time yeah, no, that that goes to kind of what we see often clinically is just kind of I like the rising tide and that analogy is I'm gonna steal it and use it with with some patients. But it does make sense where you're not trying to like think there's just one unidimensional, you know linear factor that we're gonna find. But if we can start taking these big picture sleep, diet, exercise, stress management, find enjoying your day, what are the things that you know, helping people kind of unpack, the fact that, hey, when you're in a context where you're distracted, you're enjoying, you're engaged, your pain is significantly less and you can start plugging these people. And I know it's been termed in the past you know some of these things immune, buffering behaviors.

But I think we're seeing it's just good pain buffering behaviors, which obviously has a good immune component to it yeah, and I think that you know we think of the power of the scalpel in the hand of a skilled surgeon. The other part to these scalpels that we actually have that are associated with these immune, buffering, life buffering behaviors, these are actually molecular neurosurgical tools that we are applying to change and rebuild our own physiology. So when we sleep well, our brain clears out at the molecular level a bunch of rubbish. Every night it gets pumped out and our microglia do a great job at chewing up those bits of the brain that we don't need anymore and gets rid of that rubbish. Now, if you think about that, that's entirely within our realm of when we decide to go to sleep and when we decide to hopefully wake up with, you know, in a mingle, dogs barking, children coming in and nighttime pain waking. But all of that collectively those are within, at the realm of our control, to be able to give our brains time to undergo molecular neurosurgery to do what they need to do. And one nights of good sleep does not undo a hundred nights of poor sleep or, dare I say, 40 years of poor sleep. So those behaviors take time to build up those molecular neurosurgical changes and adaptations but they can then compound together, when we start doing little bits and pieces together, and so when you start looking for statistical significance in single studies with single interventions, many times we will see small changes that aren't statistically significant. Now my argument is we need to identify evidence-based practice, but evidence-based practice in pain is never going to be one single intervention that cures everybody's pain. If these are things that we know are beneficial to us anyway, let's do them. And then if we look at the cumulative benefit across multiple interventions, which no one runs a clinical trial, which is let's apply 20 things and look at how those 20 things work in concert, because it's not the way that Descartes would have had us through the trial. It's a noisy signal, but maybe those are the types of clinical trials we need to actually run in the future to look at complex, non-surgical, non-soul pharmacological interventions to intervene in painstaking.

Yeah, that sure would make sense because it's definitely what we see clinically rarely. Is there ever going to be that one intervention we might have the unique miracle story like you said. I chuckled inside when you were talking about the, the TV testimonial, miracle pain cures I always talk about. Turn the TV on 2-3 in the morning when all our chronic pain patients aren't sleeping and that's where you see all of these like miracle, like it's a miracle, orthotic that and folks proclaiming it was the life-changing thing for them. But yeah, it's definitely. I'd love to see research like that. I'm selfish, I don't do research. I know it's a massive undertaking and there's a lot that goes into that. But it would be lovely to see that more wide and we're seeing some of it with the Restore trial. Peter O'Sullivan's group did some good things that really looked at more of a multimodal from a psychologically informed but also movement and CBT-type approaches with it. But I wanted to kind of circle back a little bit. One of our audience members had asked and I thought this was a good question too because I read this in Explain Pain Supercharged and I'm like, oh man, if they can really start drawing some like concrete, like relations of. I think it was turned damps and camps in the Supercharged book. I know you had a big influence on that book, but you know danger associated molecular patterns and you know. And then the cognition associated molecular patterns. You talk about some of the molecular neurosurgery that we do, but we know and we don't have to get into the toll-like receptors in the history of that, although I enjoy nerding out on that stuff from time to time. But I'm wondering where we sit, or where you think we sit at being able to, because that obviously ties, like our thoughts and our cognitions to, like you know, true inflammatory experiences. You know, and I'm wondering where we are in that I may have not read things Well, I know I haven't read things because there's so much out there but I'm wondering where you think we are as far as like how cognitions can have this molecular. Obviously thoughts are molecular patterns in our bodies, of course, of neurons firing and different things. I'm wondering where you feel like we are with that tying to a pain experience.

Yeah, sure. So I think the part that is helpful to conceptualize here is when we have a thought. These can be drilled down to complex networks of neuronal activity which alters how our consciousness perceives things, and then we have whatever that is as that thought. Now it's critical to for a gliologist, glial-centric geek like I am to acknowledge hey, neurons are important for that process, right? So absolutely, we need an action potential, we need these networks of neurons to work together. The part where the damp camps, damp damp, all those associated molecular patterns come in is starting to look at the housing of how the neurons, what the conditions are that the neurons are actually working within, and that's all of this neuron-immune domain. Some say you're up to 20 times as many immune cells to neurons, depending on different parts of the brain, but let's say somewhere between five and ten times as many cells. The part that those neurons are operating, the function of those neurons and the way that they are operating within a complex milieu of the central nervous system, is that they are operating in a soup of factors that are released from immune cells and other neurons and other central derived or peripheral derived immune cells. That changes the immune cell function Specifically. Let's put it down to it some microglia, some astrocytes, some oligodendrocytes, which then are perfectly connected and adjacent to critical neuronal structures like synapses, to then modulate what capacity those neurons have to actually fire or to fire at all. And we're now in a situation where the molecular tools that we have to understand this, who's in control of what system? Is it that the neuron fires first and then the immune cells adapt and then change how subsequent neuronal firing is occurring? Or is it that in some cases, there's an immune cell that does something that then causes, directly linked to a neuronal response that then triggers a response? Well, yes, to both and and more. And so that's okay and we need to be comfortable with the commander, the servant, the servant-commander relationship. It's one big connected circle and we don't have the tools yet to be able to work out who came first and at the end of the day, who came first? That's just a blame exercise. Let's work out what the person has right now. So are they experiencing an immune-driven event or a neuronal-driven event? Where those associated molecular patterns come in is around immune-derived factors that are changing the tide. Set point of that immune resilience, pain-resilient state and how full a signature there is across a range of molecular signatures. Now I feel a little bit bad about using the BAMP-Camp-Zamp terminology, because what we've taken is a very large black box of stuff and now we've just created these little black, smaller boxes that sit within a large box, because we still don't fully understand the true complexity of why some of these signatures arise and it's never going to be one single molecular pattern that's responsible for it. So let me give you an example. A stress factor, a cellular stress factor which is released by cellularly stressed cells, is a factor called HMGB1. Now HMGB1 comes in various varieties. It's got different disulfide bonds and all sorts of stuff happening at the atomic level, but it is released by cells and it has then been able to cause other cells to respond because it's acting at the toluic receptor 4. Now it turns out that cellular response that can drive the increase in HMGB1, if we are psychologically and physically stressed, we also get an HMGB1 elevation by a purely cognitively driven psychological response. So now I'm saying we've got a cellular response, something that's driven by reaction, oxygen species or lack of nutrients driving HMGB1, and now psychological stress and thriving. The same release factor Enter in my new black box of an associated molecular pattern. Danger and cognitive and behavioral may actually be the same HMGB1, but its origin is slightly different. I'm using these terms to help other people understand that it's not all about an iron channel on a neuron lead to an action potential that leads to a network of neurons to fire and we are just an ionic thing that's happening in our brain around the wiring. There are these factors that are released by a variety of stimuli to our physiology. That causes a change in the set point of the ability of our neuronal system to respond and changes the network patterns that are engaged. And these are factors that we have currently no targeted pharmaceutical or molecular tool to be able to intervene and modify. We don't really know how talk-based, cognitive-based therapies change that. We don't know how diet, etc. So this is a brand new way we can change the volume knob on the whole no-susceptive sort system of our central nervous system. That's why I guess I'm excited about these kinds of concepts coming through now and being explored. The field is absolutely blowing up in terms of the discovery of these patterns because what it's acknowledged, that there are multitude of these things now being released and that the list of them is quite profound. I started out in the early days in the toll like receptor pattern recognition game because that's where the field was up to. We got a bunch of new ones out there now that are really fascinating and new targets to understand. And what's cool is we're now cycling back to the early days of even pre immunology understanding with some of these pattern nuclear receptors that are there to detect who knew danger of chemical origin. They don't just detect danger of the chemical origin, they detect a bunch of other stuff that then leads to profound transcriptomics etc. And then off you run to the races. So there's an awakening to realise we're complex and we need to acknowledge that complexity and if we did that a little while ago we wouldn't be telling the simple stories of A gets connected to B, gets connected to C and if we give you D, you're cured and you're fine. No, a is connected to A1 through a billion, and then there's yeah, it's complicated, but that's what makes it fun. We don't have all the answers. There is hope that we are getting there and we now have the opportunity to start targeting some of these important ones. That then may lead to some patients getting a better understanding of where they're at in their pain today, which may give them the idea that actually, these small changes I'm making to my behaviour and using some of the tools that my clinical team are giving me will help them move forward.

Yeah, yeah. And again it kind of seems to me like we're seeing how, you know, not just the biologics, but looking at how psychology and changing cognitions and some of our cognitive behaviour, if there are all these things are making molecular changes within and if we can all work together as a symphony of like-minded individuals, which obviously you're leading the charge on that, I think that is exciting stuff. You have me excited for the future of pain research and some of these things as far as we're just scraping the surface from talking with you about this. So exciting stuff for sure. One topic that commonly comes up and I had posed to me as I was soliciting some questions from our audience, is this concept of neuroinflammation. And you know I'm not well studied deeply into it but it's more of a laboratory identified thing. You know, pet scans and CSF draws and things aren't going to be your everyday thing that a physio is going to obviously be able to do and different things, and I honestly I'm not sure how much with that, you know, does that influence what I'm going to do on a clinical. I mean, I still think I'm going to be doing the things that we already talked about. But where do you see inflammation, neuroinflammation helping us maybe better. I don't get a handle on some of the things we're seeing in pain presentations and where do you see, you know, maybe treatments directed specifically at that, or where do you see neuroinflammation as a whole, that kind of are better understanding and maybe treatment that helping us in the pain front?

Yeah, sure. So this is where my language and my communication with my immunology colleagues has taught me that inflammation is, for pain, important in the periphery, but not what we're actually talking about in the central nervous system. So there are cardinal signs of inflammation. That means heat swelling, immune cell infiltration, etc. In the pain state of even persistent pain we don't see neuroinflammation. Neurodegenerative diseases are associated with neuroinflammation Gross blood, brain barrier breakdown, immune cell infiltration, cellular debris clearance, cellular loss. Absolutely Talk about neuroinflammation. Or you like, to the Calc, come Home. For Parkinson's, alzheimer's, traumatic brain injury, stroke Pain, acute pain, persistence of pain is not neuroinflammation, which opens up this fascinating opportunity to understand that we are dealing with normal communication of immune factors associated with normal functioning of the central nervous system. That then has gone beyond normal into pathological form no-ceception, but is not neuroinflammation. Now that then makes it really really hard for pain, because if we're dealing with neuroinflammation, then the biomarkers that would be available for Parkinson's, alzheimer's, stroke, tbi, those would all be available to pain. Because they're so far down the bloody obvious scale, because they're so large in magnitude, we're dealing with a little bit more than normal in the hypnosis accepted space, and that means that our measurement technologies are really going to today are really going to struggle to be able to detect most of signalling that we're actually talking about at play in pain. So PET scans, css pool you know complex imaging techniques for diagnosis In Western. We've done the numbers for Australia. We would bankrupt Australia fully if we deployed that as the frontline treatment for pain, because it's the main reason people go to the GP in Australia is because of a pain presentation. So our approach has been to say experiment all you like with the super cool far out with bang imaging technology to understand the fundamental reductionist approach of what's actually happening in pain states, in refined pain patients. But don't ever dream that you're going to suddenly have every single person in pain getting a brain scan because you're going to break the system Well, and also we won't have enough helium to then keep our MRIs there from a rise cold right. So let's look at this reality. We need to create technologies that allow for and augment the consumer's description of pain to their clinician with some objective measures that point us in the direction of precision pain management. Now, some of that may be a blood test or maybe some other kind of wearable measure of brain activity, for example, that only takes a few minutes, that only takes a few dollars to measure. But our assessment is we need to have a sub $5 pain test that takes sub five minutes, that can be done in the waiting room. So then the patient knows where they're at on their journey. The clinician knows where the person's at on their journey and, even better, gives some kind of color to the rainbow of pain experience that that person they're about to see is experiencing. That suddenly rules out almost 95% of all of the stuff that people like me are doing research on, which goes to the point. We need to start working better across disciplines to start talking to our crazy quantum physics colleagues, through to our computer engineering, through to our artificial intelligence machine learning experts, through to our engineers, to work out what actually is going to scale to deal with the pain epidemic that we have. So we've been playing around with some of that kind of tech and we're working with teams like PainQX trying to look at brain EEG levels and linking that to what's happening in the blood. We've got some measures that we think are relevant to pain states in individuals and, critically, also in animals in pain, that are delineating pain from no pain If a patient says I'm in pain. We've got to listen to them. An animal in pain doesn't have the ability yet to tell us in words I'm in pain. So we have an ethical, societal responsibility to care for our animals. So we're actually applying a lot of our learnings from humans to animals at the moment to try and understand have you got pain, can we intervene better? And then we're learning so much from our animals to then flip into our human clinical work. All of this to say the only thing that we will be measuring in the future will be the assumed connected mind and body. We won't just be looking at only a bit of the brain or at a tiny bit of the spinal cord. We will be listening to the person. We'll be hearing the asset in the way they're speaking. We'll be looking at a brain measurement. We'll be looking at their wearable technology that they've captured over the last 14 days. We'll be also looking at potentially, a collection of super fast, super cheap to measure biomarkers in their blood and together then that will be a tool Mark that you will have, hopefully sometime in the next three to five years that says you know what over the last two weeks we've done these exercises. Your measures are saying, actually we might try this today and that then sets a course for precision interventions for the person where they are at now, and by a feedback, to say all of the work that I've been doing by myself at home for the last two weeks has done something and I've actually changed the molecular surgical state of my body. It's great, let's go, and that's again a work in progress, but a lot of people are working on that at the moment.

No, that is exciting research. I'm definitely looking forward to seeing that develop. This kind of goes off of that, and maybe you feel like you've touched upon it already and we'll make this our last question because I want to respect your time. You've been generous to spend it with us for this long. What is the thing that's got you most excited as far as the future of pain research? You've touched upon some things that got me excited, as far as if I could have folks who have wearables cheap, like you said, things that can get biomarkers in their blood and almost stage them with where they're at and also be able to measure them from the changes that they're making, like you said, molecular neurosurgery within their own central nervous system, and things I'd be curious. What else do you see out there? Is there anything else that you feel like man? This is some exciting things we have coming down the pipe.

Yeah, I think, if I look at the change of what was presented in Toronto at the most recent World Pain Congress last year, compared to even just 10 years ago, there wasn't a single presentation that didn't acknowledge that it's not all about neurons and that it's such an evolution for us as a field to have taken that we are actually acknowledging it's not all pain, it's not all neuroscience, it's not all inflammation. It's actually about a connected mind and body. The fact that we're now able to have that as an evolved conversation, rather than you know the leaders of the field 20 years ago. Linda Watkins talks about speaking at clinical meetings and getting yelled off the stage because people are saying that is heretical. The brain is not immune, competent, get off the stage, you're stupid. That was what was happening 20 years ago. Now we're like oh yeah, yeah, that's sure, sure, so that's exciting. I think the part where and in addition to what we've already talked about today being excited about is this actual convergence of scientific and research technology fields together to start exploring brand new understanding of what it means for our brain to function and our spinal cords to be connected in and all indelibly working together as a connected body. That means that I think when perhaps we're talking again in a couple of years time, mark, we'll be talking about the latest developments in quantum biology and how, hey, you know those red photons that we've always been talking about in red light therapy. Here are the molecular signatures that they've changed the electron transport change in the mitochondria and done X, y and Z, and that's how it works. So let's go red light or blue light or you know whatever those new pieces are, because I've got sitting beside me a quantum physicist going yes, so it's the spin state of this particular molecular antenna that's doing X, y and Z. So we'll be, way beyond that, right, but those are the conversations that I'm having now with a range of people who are going wow, this pain problem, it's big. Maybe I should become interested as a quantum physicist in exploring this. So that gets me excited. The other thing that I'm really passionate about and working pretty hard on here in Australia is establishing the Australian Pain Solutions Research Alliance. So this is an alliance that has the consumer at the centre. This allows for that pain consumer to influence the fundamental questions that I am asking, as a reductionist researcher in pain today, to advance their work to our work forward in asking the questions that the pain consumer considers as important. That also means that we've then got the clinical community at the same table saying, well, have you thought about it this way? Oh yeah, it's great. Then industries at the table saying how are we going to scale this solution to a global market? Because at the end of the day, someone's got to put this into a capable delivery tool or scaled in a training program. Somehow. That is suddenly this convergence of ideas and culture and we're having the hard conversations at the beginning. So it's not some academic coming out and publishing a paper in nature saying look at my magic green bean. It's the best thing ever. And then the pain consumer going I didn't want a freaking green bean, I wanted a blue one, right? So why do the green bean research if it could have been blue and if we had those conversations at the beginning? So that's something that we're really quite excited about here in Australia taking a lead out of what's happening around the world together as well in the US and Europe. But as we start to draw this together, we're now identifying really important things that we thought were less important to the patients. That actually know they want simple things delivered, and that makes our jobs as the researchers easier. Government gets happy because they're not spending money on stuff that didn't need to be done. Let's look at the things that are most important. So, yeah, we're launching the Australian Pain Solutions Research Alliance soon. We'll be welcoming multiple communities of practice together for that here in Australia and connecting to like-minded communities out there globally and always love talking about pain to give people that glass half full view that there is hope. Innovations are here, there are things we do have in our control here today that can help, and there's more great stuff coming.

Yeah, no, I think anybody that's listening to this podcast. I can definitely sense the passion you have for it and the excitement you have for it and I definitely am leaving excited for the future of pain treatments and pain research going forward. So I want to thank you for all your contributions to that research and the excitement that we have around some of the future of pain, and thank you again for your time today.

Thank you, mark. Thanks to the listeners and, yeah, if any of these get others excited, you can always find me on Twitter or on the emails as well.

Yeah, we will link some of Mark's work on the show notes and we'll also link his Twitter profile and then those things as well, so you can contact Mark if you have any other questions or you want to chat with him online. So, yeah, really appreciate your time today, mark. Thank you again for everything you're doing. For those of you who are listening, we'd love if you could subscribe to the podcast on whatever podcast listening service you're having, if you're listening to the audio, if you're watching on video on YouTube. If you could give us a subscription, that would be greatly appreciated so we can get information. I want to get other people excited, like Mark's got me excited on the on the pain, the future of pain treatment. So, thank you all for listening and until next time. We'll talk to you next episode.

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