#26 The truth about exercise & pacing in ME/CFS, Long Covid & POTS with Todd Davenport

One of your big points that you have to repeatedly refute is that paste-exasional malaise or you actually call it post-exasional symptom exacerbation is not deconditioning. It's different. We've done the physiological studies, we've analyzed the symptom responses and it's just different and always. It's different from the perspective of the signs and symptoms that people report following exercise and how long they report them. Our participants had not only a greater predominance of the signs and symptoms that you normally would expect in terms of fatigue and weakness and muscle burning and so forth, but they also had really unusual signs and symptoms that we would not have expected in someone who's deconditioned like cognitive dysfunction and sleep disturbance and signs and symptoms of viral reactivation in response to an exercise stressor. So just a whole-sale difference in that symptom pattern that really is the cause of so much misery and disabling. Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Cape Stevens. Welcome back to Make Visible and welcome back to Jess, who will be joining me again. Today we are bringing you an interview that I did with Todd Davenport, physiotherapist and academic who has done so much research into complex chronic illness. Before we dive into the interview, Jess, how are you doing? Today's a rough one. It happens, pushed it too hard last week, had a big day out in the cold on Sunday and now it's the sort of 36 hour later slandown. So I've spent the day in a dark bedroom with the curtains drawn, with ear plugs in, doing as little as possible and trying to stay off my phone. So hopefully I have enough spoons to make words go in the right order today. We'll find out, won't we, in due course? Well, I appreciate you being here and this is such a fine example of what we're going to be digging into today, which is post-exertional malaise or post-exertional symptom exacerbation as Todd Davenport likes to call it. But before we do that, I just want to talk a little bit about our episode last week. We've had a pretty favourable response to it. I think people are happy to have you and I back chatting. Tell me what response have you had to last week's episode? So I put out an extract of it, about 12 minutes or so, where I talked about EMDR and I put out my YouTube channel and had some very nice responses on there, but also a few people who were unhappy with the content. I don't know how many of them watched all of it, or were simply responding to the thumbnail, hard to know, but I think it's worth talking about this subject of, I almost don't want to say the two words mind-body, because that's sort of the hot potato that gets thrown around in the community a little bit. And the reason why I get thrown around as a hot potato is because of the history that ME/CFS patients have had over the last 30 years or so. So I just want to address that quickly. So some of the comments that came in on my YouTube video were saying things like, "Your patient blaming?" This is doing patients harm by talking about this subject and essentially, "You're a psychologist." And where this comes from, what they're talking about is this sort of the history that's happened with ME/CFS, where there was a cohort of scientists who were trying to argue that the condition was essentially psychologically led and that psychological conditioning, depression anxiety, lead to an activity, inactivity leads to deconditioning, and then it becomes a feedback loop where the body gets stuck in this. And all you need to do to get better is get out more. And then there were the later paste trial that subsequently got debunked. There is a huge and torrid history on all of this. And are you, and very much on the side of the ME/CFS patients who went through it? And we're very cognizant of this. You and I are talking about it and all of the research that we have done, this is so much at the forefront of our mind and we would never ever be sitting here, patient blaming, or psychologizing this illness at all that is not what we are doing. And to agree, the way that that flips back on you, I find that upsetting because you are someone who has been such an advocate for this patient community. So for you to get kicked back, for talking about things, we've had this last week, we said we want to be able to have these conversations and bring some of these things into the fore without immediate judgments or without seeing that title and deciding before you've even dug into it or listened to what you have to say on it, what the opinion is, or what we're trying to say with it, because from everything that we have done, what we are trying to do is help people understand what's going on for them and understand what options might be available to them in their specific circumstance. Very in mind, as we said last week, that everyone got into their various illnesses in different ways and everyone is going to find a different path out. Absolutely. I'll just try and sort of frame the context around where I come from when I'm talking about this stuff in terms of how I see that history, how I see this idea of psychologizing and how we can or should talk about things now when it comes to talking about long COVID, MECFS, chronic Lyme, fibromyalgia and all of these complex chronic illnesses. So I'm fully aware of the history. I've got an interview with David Tuller, who's well known within the community on the channel, had a full chapter in my long COVID handbook talking about this. And where I want to straw the line is by saying there's a huge difference between this idea of the psychologists, which is saying that it's a condition that comes out to depression, anxiety and activity, deconditioning. And what we understand with long COVID in particular, where this is a condition that is caused directly by the SARS-CoV-2 virus, that was an infection at the time, which may be persistent, either active or inactive in the terms of viral debris. So there is a very direct cause here that is not psychological. If we look at this larger picture and take step back, not everybody who catches COVID goes on to develop long COVID. So there's something different about the people who do develop long COVID. Not just that, we've had studies that have looked at biopsies from gut tissue and found that even people who did not have long COVID symptoms had viral debris in their gut tissue, the same as people who had long COVID. Although it was more represented in the people who have had long COVID, suggesting there was a relationship there, but having it in itself was not directly linked to developing symptoms. My point here being is there is something about us as individuals that has meant that we have developed long COVID from that specific event, whatever that is. And what is that? Well, the answer is it's going to be some combination of our immune system response, our nervous system response, our metabolic system response, and that will be in part genetic, and it will be in part a collection of every single life experience we've had, every other viral infection we've had, every other bacterial infection we've had. All of these things will shape our immune system, every life experience we've been through will have shaped our nervous system and our metabolic system. All of these things are linked. And when it comes to looking at researching the condition or treating the condition, this is a very complex multi-system condition. And we have to look to be addressing each one of these systems and not all of those interventions are necessarily going to be pharmacological. Some of them are going to be behavioral. Some of them may be psychological that can help your nervous system get into a more evenly balanced state with less sympathetic activation, which isn't a controversial thing to say when we see how widespread disovenerior is in the condition. So where I'm coming from in this and when we talk about this is almost become toxic to expression mind body to some in the community, I think, is more about looking at this whole picture and saying, yes, this is caused by a viral insult that may or may not still be present and there are very complex reactions from that. But how we deal with this, we have to look at dozens of different ways of trying to deal with this. Not all of those are going to involve a pill. So that's where I think we talk about on this podcast is a very open-minded response to looking at all of these systems of the body in a sense which have been affected and seeing what we might be able to do at this point in time that might be able to improve our symptoms. And that involves all kinds of different therapeutic parts. Because we are also talking about if people take supplements or if people go out and get sunshine, if people layer on these different things, it's about improving a base level of health that has then the potential to allow your body to do what it is designed to do. But there is something, as you say, there is a breakdown of barriers, there's a breakdown of cells, there's a breakdown of communications within our neurons, whatever it be in those people that are affected with these persistent conditions. There are things that you can try. It's what we're saying. There are things that are outside the pharmacological box that we could explore. The body is normally very good at trying to find itself back to homeostasis, right? By that term, homeostasis, we're talking about that baseline, that equilibrium when you are balanced and your body is actually able to manage itself. It's able to perform the processes that the human body is designed to do. Something has happened here that is not the body out of homeostasis. And what we're sort of talking about is this idea that is it possible to layer enough interventions on top of each other, even if none of them is a magic bullet by themselves, but the but you might be able to get the body to a tipping point where it can find its way back to the whole of your stasis. And we hear these stories of spontaneous recovery. And probably what's happening in those cases is the body has got to a place where it can actually just overwhelm the forces against homeostasis and find its way back to equilibrium and health. Yeah, yeah, absolutely. The other thing that I just wanted to mention from hearings and reaction, look, we are completely open to feedback from all opinions. We're open to feedback from people with many different conditions, but I do just ask that we try to do it with openness and inclusivity and understanding that people like you are suffering from long-cavid and approaching it from that position of not full wellness. I had people when I was at my worst, levying criticisms at me about me not being ill enough to represent the community. And I just like to point out that the only way that I am able to represent the community is because I am so lucky to not be as bad as other people. So we are all trying. We're all here for the same aim of trying together. Yeah, genuinely are. Yeah. And when you and I talk, what we're trying to do now with this podcast is take these heavily scientific ideas and themes and relate it to our personal experience. We are only ever giving our personal experience. We are not doctors. We are never giving medical advice. We are simply giving you anecdotally how these things impacted us and how the things that our experts talk about have related to our experience. Absolutely. So this and your condition today actually leads us nicely into our major subject matter for today's interview, which is that of exercise, which similar to mind body, it is such a divisive word in the community. In this episode, there are going to be some theories and phrases, most of which Todd Davenport explains, but I just wanted to point out that we will include in the show notes some information about the terms such as cardiopulmonary exercise testing, mitochondrial dysfunction, oxidative phosphorylation. If I said that right, just you have submaximal exercise testing, ventilatory anaerobic thresholds. Some of these might seem a little bit scientific. We are going to include information or in the show notes. So as you are listening, do check out the show notes for a little bit more background on some of these terms. So let's dive in. Your role is to improve the quality of life of people. And we are primarily talking about complex chronic illnesses here. You have a long history working in ME/CFS prior to long COVID coming on the scene. Now, I recently did an interview with Amy Muni, who is an occupational therapist, and she said the same thing that high primary function was to improve people's quality of life. Do you just be kind enough before we start to for our patients living with complex chronic illness, explain what your role as a physiotherapist brings to people and how you enable people to improve their quality of life that is different to what people will have heard on the episode with the occupational therapist. Absolutely. Amy is a close colleague and friend and really does some remarkable work in this space and have really appreciated the things that she has brought for a long time, especially related to children with ME/CFS and her most recent endeavors with the Bateman Horn Center in terms of the education that she's been able to provide, just has been crucial. So, as how physios address complex chronic conditions, probably the easiest way to remember that it's physio is synonymous with physiology. That is our bread and butter. It's how we were trained is very much along the lines of the basic sciences. And so the way we approach the world is through that lens of what happens in the body, in health and disease, and how in particular we can use exercise to ameliorate or improve either those underlying pathophysiologies or to improve quality of life despite them. Now, obviously that's fraught into space. The whole question of exercise and activity is fraught. So often when I introduce myself as a physio, that sort of strike one. Then when I introduce myself further as an exercise scientist, that strike two. What I think we should all be cognizant of is if you understand the influence of exercise and activity on the body, then you can therapeutically dial up exercise or activity or you could therapeutically dial it down. And the way of deloting or offloading the body in stress. And I think that's where physical therapists at least initially make their chief contributions to people with complex chronic conditions. I think that word exercise is hugely divisive and it can be quite contentious within this space. So, would you be able to dial a little deep, but because you have a huge history of research, you've previously worked with the NIH, you've got so many academic papers, you're obviously a professor at the university, but you still also have a clinical presence and a hands-on experience with the patient. So when you're dealing with this patient group, what does that time exercise actually mean? You're not talking about necessarily going for a run. Yeah, absolutely. That's actually the easiest way to find these conditions in a common hallmark of these conditions, which is post-exertional malaise, is to go for a run. So I'll start with a patient's story that I hear very frequently, which is I got sick. Didn't get better for a while, took me a while to improve, and then when I approved, it was only to maybe 80%. It wasn't quite all the way back. So I decided I can't really live with that last 20% I've got to do something. And since I'm tired, I'll do what seems to make sense, which is I'll go out to the gym or I'll go out for a run or a walk or a solid session in the garage there, put in my favorite exercise video and just give it a go. And frequently people in response to that will say that made me sick all over again. I felt worse than I did when I was sick. For example, people with long COVID would say I swear I had COVID again in response to that. That's exactly my experience. Yeah. So as you mentioned, exercise is very fraught. There's a whole science behind this, probably one of the few areas of science that's been replicated pretty repeatedly in MECFS and in beginning to see the same types of studies in long COVID and crediting my colleagues at the Workwall Foundation, Stacey Stevens, Jared Stevens, Mark Van S and Chris Snell. We've been working on a paradigm that called the two-day Cardi Opelman exercise tests for a number of years in order to really understand the effective exercise on the body. And what we're seeing are some characteristic reductions in the body's ability to use oxygen to burn fats and sugars as part of complex chronic conditions. And we think that has to do with the activity limitations that we observe and also the corresponding inability to exercise and also the science and symptoms that we see after people exert. This is obviously works that you've been focusing on for a long time, but actually you started this with the Workwall Foundation in about 2022, that this specific piece looking at the abnormal response in post-exertional malaise. And was it then that you tried to give it a clear definition of that post-exertional malaise, or was that even prior to that? This methodology actually dates back to the 90s, you know, when music was better and my kids were born away that they were just playing cool music on the radio for a free instead of Spotify. It was at that time that Stacey was a master student here at Pacific and she is a person who lives with ME trying to understand her condition through the lens of what she was learning as an exercise scientist, being a person with ME and an exercise scientist has to be a pretty interesting position in life. She was the first person to put herself through a 2-day CPET and identified that sub-maximal exercise decline that the some, you know, not universal, but fairly characteristic in people with post-exertional malaise. So this is work that's been going on for a gosh what year is it, almost 30 years. Right. And of course I came later to this part of my origin story is that Stacey showed me two two CPET reports and then she insisted they were the same person separated by 24 hours and they just didn't look like they say look like two completely different people. And so that was that was my whole. Because of what happened as a result of the exercise. Exactly. Just to look like two different people you do not expect people to look totally different 24 hours apart. And what are the differences that you observe in that what does the exercise actually physiologically do to these patients? So what we notice is a decline in the ability for a person to consume oxygen at what we call the ventilatory anaerobic threshold, which is the transition point between the body using oxygen and the body no longer able to use oxygen efficiently. On the second test we notice that the utilization of oxygen tends to drop and tends to drop more precipitously and earlier at a lower workload on the second test suggesting that people are less efficient with using oxygen. And the other thing that we notice is that people don't exert as much torque against the pedals, which we refer to as work rate or work. workload, then those things happen together. And the thing is notable about ventilatory anaerobic threshold is that you can't fake it. Peak values, they're a little harder. You've got standard criteria to ensure someone achieves a max test. But the ventilatory anaerobic threshold, you go back and literally plot breath by breath and you identify it based on a breath by breath plot after the fact. So, a person doesn't know that they're going through that point when they're going through it. And do you have any theory as to why that oxygen efficiency changes? So, most of our observations are done at the systems level. And as such, we've got a grosser idea of what's happening. But there's only so many things that it could be subsequent studies by their groups have sort of drilled in on various aspects that are really interesting. Maybe this has to do with impaired circulation. Maybe this has to do with a breathing abnormalities. Maybe this has to do with mitochondrial impairment. The mitochondria aren't functioning properly. So, they're not taking in as much oxygen and they're not using as much substrate. And I think when we look at muscle biopsies, even if we start looking at immune cells, that this pattern of inappropriate mitochondrial respiration just keeps coming back again and again and again as a replicable pattern across body cells and body tissues. And so, if I had to have a favorite hypothesis, that would be the one. Okay. And is that to do with the ATP production or uptake of the ATP in the cells? It is. So, mitochondria, everyone to recognize is the powerhouse of the cell. And probably the best way to think of a mitochondria, mitochondria singular is like a little battery. They're like little capacitor. And they essentially, there's this conversion of fats and sugars that we consume to chemical energy through releasing bonds and those bonds release electrons and the electrons to infwanda the basis of the battery. And so, there's a whole cycle called oxidative phosphorylation, citric acid cycle, old people like me know it as the creb cycle. And it's the first thing you learn as a clinical student in biochemistry. And it's the first thing you want to forget because it's really complicated. It feels like carmic justice that this is my life understanding this. But there are specific steps within that creb cycle that they get followed. And those steps are mediated by specific chemicals. And some of those chemicals are demonstrably decreased in people living with post-agertional malaise, whether this is with me initially or now with some of the data coming out with on COVID. And so, some of the studies identify slightly different steps. But there is something about this process that gets disrupted in across body cells, which is notable because it's easy to kind of think, well, this exercise specific, this must be a muscle thing, use a physio. But we see this also in immune cells and so forth. So this inappropriate metabolism just sort of seems to be a key theme in post-agertional light. Okay. I guess one of the things that our audience would really like to know is if that is what has happened to the cells, what are the strategies that you have been working on to try and enable people to rehabilitate? For example, you've recently been looking at the feasibility of using heart rate monitors. And I'd raise that right now because that is looking at, it's not actually looking at your VO2 max exactly, is it? But it correlates with that with the CPET testing that you were doing. So, have you found methods like that that might actually enable patients to move forwards or have strategies that enable them to prevent this big post-exessional malaise crash? Yeah, it's a good question. As for what do you do, that is the, well, if it's the NIH recover study, it's a $1.15 billion question. It's not even a million dollar question anymore. It's a big ticket item. And there are a lot of smart people working on lots of different hypotheses related to this. One of the things that I work well colleagues and I have worked on for a number of years is really working off of this simple idea that if you have a dysfunctional energy system, but you have other energy systems you can use to try to stop relying so much on the one that doesn't work and use the ones that do. And so, that's the fundamental idea here. And the thinking is if you can keep yourself out of, for example, aerobic metabolism because we know the aerobic energy system is not working properly, it's unreliable, it seems damaged, but you have short term energy systems that you can use. Then the idea is to try and monitor your activity intensities to keep yourself out of aerobic metabolism. What do you mean by short term energies? Yeah, so you've got three main energy systems. The first one really is it predominates within two minutes. Your muscles are using substrate that it has on hand to create ATP, which is the power molecule. And then after two minutes is when your body really starts using oxygen to create ATP using this oxidative phosphorylation or a creb cycle. And it's a very efficient process that creates lots of ATP, but over time and with increased intensities, the cycle defeats itself. It creates waste products, lactate, reactive oxygen species that end up gumming up that nice cycle. And so, it no longer is something that's efficient, it's efficiency. So then you start to generate so much lactate that your body at the very end starts to try to metabolize that lactate to create ATP, but it actually occurs at a debt at a cost. And so this is, people don't tend to want to do that for very long because it's very uncomfortable muscles burn and so forth. And then that's when you just sort of need a rest. So you do have a variety of oxygen system, rather energy systems that are active when you were, when you're up and moving around and they're all on together, but they have some that tend to predominate at different intensities and different durations of activity. So the idea is to try and keep yourself out of aerobic metabolism so much because that's not working as well. And you end up at this end of trying to metabolize your lactate, which occurs at a deficit. And so trying to keep yourself within that short term energy system as much as you can and keep yourself so much reduced your time spent in a row of metabolism is the name of the game. And it would be nice to measure VO2, but you'd need to carry around a computer and a mask and a big tank. And so it becomes very unwieldy to try to do that. And so as a result, we use heart rates in order to serve as a proxy for activity intensity. And so we generally can estimate where you are with regard to the energy system you're using based on your heart rate. You know, people, a lot people who are subdued into exercise kind of know this already, they know that they have a threshold within which maybe they used to exercise a certain heart rate range. And that heart rate range was to optimize your use of aerobic metabolism. And we're just thinking about it the opposite that we need to stay under that so that you don't use your aerobic metabolism. And for patients with these conditions, you use the resting heart rate and then the ventilatory anaerobic threshold, you actually calculate via a sort of mathematical equation rather than pushing people into that. Is that fair to say or do you do a sort of testing with people to push them? So of people who have tests, we will use that the the ventilatory anaerobic threshold heart rate on the second test because they're in post-exertional malaise. And so we have a sense of what their bad day heart rate at that transition zone is. And so we'll use that. And in people who don't have tests for a variety of different reasons, tests aren't for, aren't for everybody. It doesn't mean they're for no one, but they're not for everyone that there may not be available. There may not be skilled folks to conduct and interpret them where you live. Then we can estimate using some, some pretty simple arithmetic. And maybe we can post some guidance there in the show notes. But okay, great. Yeah. But this is, this is, think if I'm not mistaken, some of the backbone actually of the visible app is in with this. Yeah. It's idea. Absolutely. And you did this feasibility study into interfacing using the heart rate monitor and actually proved that it was feasible. So your suggestion there is that this kind of tools using your heart rate is actually productive, not just to help people pace, but actually is it, is it enabled to start alleviating a symptom burden? Yeah. We think it can help improve people's baseline from what we've observed. And by baseline, I mean capacity for functional activities at at a low symptom burden. We're all to sort of show this case study that we did in 2010, essentially where we re asked a person to to maintain her activity heart rates below that heart rate at the ventilatory and a recreational, despite she could. And then we retested, actually retested her in about, I want to say a year. And her cardiopulmonary exercise test measurements actually improved, which is weird because she was actively not exercise. So, so that kind of broke people's brains a little bit when we started sharing that in response to pacing and no exercise people with this particular health condition actually can improve their ability to metabolize. And if you think of these aerobic substrates as being used up too early, or you're allowing, you're allowing people to sort of replenish and function within a replenished sort of state. Maybe that doesn't, that's not altogether nonsensical after all. There's a lot that's reversed, isn't there? So for example, one of your big points that you have to repeatedly refute to people is that paste-exasional malaise, or you actually call it post-exasional symptom exacerbation. Is that right? Is not deconditioning. So there, that's what that's almost a flip as well. It doesn't have the same impact as when someone exercises with deconditioning because if someone is deconditioned, they exercise and then they're getting incrementally better. And the trajectory is actually exactly the opposite way around with paste-exasional symptom exacerbation. I've seen you write and tell people repeatedly, it's clearly not deconditioning. It's different. We've done the physiological studies, we've analyzed the symptom responses, and it's just different in all ways. It's different from the perspective of submaximal aerobic dysfunction that we've talked about. It's also different from the perspective of the signs and symptoms that people report following exercise and how long they report them. So an early study that we did comparing people with ME/CFS compared to sedentary controls suggested that within about 24 to 48 hours are sedentary controls. After a two-day CPET, we're basically down to normal, maybe they're a little sore, but that wasn't a very common finding. Our participants with ME had not only a greater predominance of the signs and symptoms that you normally would expect when someone first gets off that cycle orometer in terms of fatigue and weakness and muscle burning and so forth, but they also had really unusual signs and symptoms that we would not have expected in someone who's deconditioned, like cognitive dysfunction and sleep disturbance and signs and symptoms of viral reactivation in response to an exercise stressor. Yeah, because that deconditioning tends to just be a physical response. I read that the post-exertinal malays in neuroimmune exhaustion is one of your areas of great interest. I think we have a big disconnect a lot of the time in the medical professional and in the real world between the body and the mind. So can you talk to me, you've just mentioned there about the neurological impact in post-exertinal symptom exacerbation? Can you talk to me there about that neuroimmune exhaustion that you see in this and the way that that is marked in these conditions? Yeah, there's a huge issue of definitions and terminology and I'm afraid that your viewers and listeners are going to tune me out because this sounds very academic, but I promise it has a point. I mean frequently you'll hear post-exertinal symptom exacerbation, post-exertinal malays and post-exertinal neuroimmune exhaustion being used all synonymously and interchangeably and you'll hear them used with more colloquial terms that are derived from lived experience, so things like exacerbations and crashes and so forth and so trying to sort of pick through these terms and what they mean and what they mean to whom can be really complicated. So my preferred way to think about this problem that we're talking about is post-exertinal neuroimmune exhaustion or P-E-N-E and it's really defined nicely and the international consensus criteria for myologic and cephalomyelitis, it's a complex structure case definition that I won't go into in great detail, but just to say that the central feature is what's called post-exertinal neuroimmune exhaustion and it has various different characteristics to it. Post-exertinal malays is what everybody calls it. It is kind of like the nickname, it has a more prolonged use maybe dating back to the early 90s, starting to be integrated into myologic, cephalomyelitis, chronic fatigue syndrome case definitions as early as 1994, as a non-compulsory criterion kind of vaguely defined and PEM is just what everybody calls it. There are some problems with PEM because it's vaguely defined, people don't like the malays portion. The malays? Yeah, the malays. Just makes you sound like you're a little bit. Yeah, I just feel feeling wrongly. People get people get this mental image of fainting ladies on couches in Victorian times and that's not fair. This is a very old fashioned word, isn't it? Very old fashioned and it's really under cells, the severity of what we're talking about. What I enjoyed about the definition of with the neuroimmune exhaustion is it suggests this idea that it's a depletion in your nervous system, in your neurology that is then driving the physical exacerbation. It's almost like there's a kind of flow it feels like to me rather than you've just got tired muscles. Yes. I think the key here is validation. I think that case definition, set of case definition criteria does the best to link back to a specific disease state, specific pathobiology, whereas as we look at post-absorptional layers and post-absorptional symptom exacerbation, which finds common usage in the long-covid community, but it's actually part of the international consensus criteria and what it means is that symptoms are exacerbated after an exertion and that that could include a whole host of different things. So maybe not as specific for the for the phenomena of interest, which is where we get into to issue that issue of terminology becoming important. It gives people, I think, as we get into malaise and as we get into symptom exacerbation, it gives people a little bit more daylight to begin to question the underlying path of biological validity. On that subject, you have been quite clear to say that ME CFS is not long-covid. Some people with long-covid fulfill the diagnostic criteria now for ME CFS, but they are not the same thing. Could you touch on what you observe as the primary differences in your patients between the two and how we need to keep clear in our classifications or whether we can put people in together? I mean, we can't deny that all of the research that's gone into ME CFS has been absolutely instrumental in asking this far in long-covid, but I'd just like to hear your take on the differences there. Yeah, thank you for that. So absolutely, in the great Venn diagram of everything long-covid can be. One of the things it can be is ME CFS. And the confounding thing is that as we start thinking about this, is we tend to kind of think of of these conditions as being mutually exclusive. So we get reductionists in a hurry. It can only be one thing at a time, but really, I think talking about complex chronic diseases challenges is thus there. So people can have more than one thing. They can meet case definition criteria from more than one thing. And so ultimately, within the great circle that is long-covid, there are portion of people who do need case definition criteria for ME CFS. Like who cares? I mean, that sounds like an academic point made by an academic and maybe not immediate to lived experience. But when we think that people who meet these case definition criteria have an abnormal response to exertion and seem to have an underlying abnormality in metabolism that drives that abnormal response to exertion, both physiologically at the systems level and symptomatically, then we really need to think carefully about including everyone into the same bucket when we're doing research. Because I'll just give an example of an exercise study. If I do a study of exercise in long-covid, and I'm not really paying attention to post-exertional neuroimmune exhaustion, then I'll have a portion of people with post-exertional neuroimmune exhaustion, and I'll have a portion of people without, and those people without may respond favorably to the exercise, whereas the folks with post-exertional neuroimmune exhaustion do not. And so my overall finding might be that the exercise is helpful. If I look carefully at the subgroups, I might find actually people who are harmed. And I will say that that's not a new lesson. We've learned that already when we lumped together people with idiopathic chronic fatigue with people who have, again, post-exertional neuroimmune exhaustion. And we've come to some pretty erroneous and harmful conclusions about the effect and of sub-exercise in ME. They kind of fear that we're making the same mistakes in long-covid, and not just specific to exercise, but throughout the studies that we're conducting now. And it's an interesting point, this idea of when you have more than one thing, because there are so many comorbidities in these conditions. And it's actually, again, earlier this year, just to give people an idea of the scope of your work that you were involved in something looking up exercise in pots. Yeah, a couple of different works. We did systematic review and then also a case study. Yeah, you did a systematic review of the impact of exercise to treat pots. And what's really, really interesting about that is that exercise is actually one of the first line treatments for pots. Your review showed that I think the main thing that come out of it, there's so much variability in the approaches that different people are using and in the outcomes. But one of the big things here is that pots exists within several of these complex chronic diseases, many of which do not respond well to exercise. So when you have these overlapping things, one that is traditionally helped or traditionally treated with exercise, but you have another that it's going to be detrimental. How do we start to correlate or to look at clinical guidelines for how we treat these things? Yeah, wow. So as a follow on, or kind of in parallel to developing that systematic review, where we studied the studies, we also tried to carefully document the care of one individual with pots, who also met case definition criteria for ME. So she had signs and symptoms of post-exertional waves. Because at the end of the day, the study of studies gives you a very good sense of in general on average, what will this intervention do or what effect does this risk factor have or so forth? But where systematic review is much weaker is in the descriptive power of grappling with this question that you've identified. And I think the answer to make a long story short for your audience is carefully. So this co-wrote this case study with Clayton Powers and with Nicole Miranda. And the key finding was you could use pacing in some with pots, which is sort of heretical, actually, because exercise is a frontline intervention as you noted. But in people who don't have a favorable post-exertional response that you can chalk up to post-exertional waves, you actually can get some symptom benefit from other types of interventions, stockings, salt loading, IVs is needed. So forth, treating some of the other comorbidities that surround and building some now in that case, the patient got to be feeling better enough that there was this shared informed consent that she wanted to try some exercise. And things got a little bumpy in terms of introducing the exercise and triggering post-exertional her own immune exhaustion. And so then it was the an issue of backing off instead of continuing to progress. And so it's this nonlinear use of activity that I think it kind of flies in the face of how we normally think about the body adapting, because we know that the body does not adapt normally. And starting to think maybe a little bit differently in the case of people who have abnormal exertional signs and symptoms regardless of what the literature has to say about on average, how you might be going to take care of folks. It's such a challenge, though, isn't it clinically, because actually every person that I speak to and many of the examples that you've given today, it just shows how individualized and approached we need to every single person, particularly when you're dealing with those comorbidities. But also because so many of these conditions have such variable symptom sets that there's not one size fits all, at all, in terms of how you respond to it. Yeah, there is no cookbook. I think you can just nail that. Yeah, no one size fits all approach. Your work is just prolific, but one thing I'd wanted to put out there to our audience, what you would like to do with these energy systems is for us to apply our knowledge of first aid to look after ourselves in these situations, the way that you would and the analogy used was the way that you would with a broken bone. So if you've got a broken bone, you have your first aid treatment, you have the way that you deal with it. And actually, instead of pushing people to try and just get well in a vague way, you would like to try and implement a system where we apply that same idea to these conditions. Can you tell me about that? Yeah, absolutely. And thanks for the chance to talk about it. The energy system first aid concept is really just taking these principles of first aid and looking at them through the lens of the body's metabolism. You wouldn't push a person with a broken bone because that will make it worse. Ask me how I know. So what you do is you essentially immobilize. There are secondary consequences to the immobilization. Things get tight, things get weak, but the focus is trying to restore the capacity of that bone to take on load. And once that bone can take on load and you don't have to immobilize the bone anymore, then you undergo a period of more restorative and more traditional rehabilitative interventions. Now that period of immobilization can depend on a lot of things. It depends on how long the fracture heals. And if it doesn't heal, guess what? You stay immobilized in some way, shape, or form. So really, whether and when you pass into this more restorative phase, rehabilitative phase really depends on the body's initial response to the fracture. And so if you have a situation where your body is not responding in the manner of improving baseline and response to pacing, obviously we're not pushing you to exercise. But it does leave room for the people in whom eventually they feel like a little exercise could be helpful and restorative. That that underlying metabolic issue has begun to resolve sufficiently that they would like to get in a walk or they would like to get in some exercise with stretch band or something like this. And so this construct leaves room for for that transition as well. It's such a brilliant construct there because that idea that also, when you have that plastic host taken off the broken bone, you don't immediately go on a 20 mile run. Please don't go on a 20 mile run. It's that idea of incremental rehabilitation in exactly the same way that I think that we just so many of us did not have that idea, did not have that idea of really shutting down with the view that once we had done that and done that initial phase of rest and recuperation that then you would start to rehabilitate. But I absolutely loved that concept. Fabulous. You've given us an overview of everything in here. So it's very, very much appreciated. Well, the pleasure has been mine and hopefully it hasn't been too much of a ride for your listeners. No, I think it's been absolutely fascinating for them. So I appreciate your time. Thank you so much. I really appreciate it. I absolutely love that idea. It's so simple. It seems so simple to treat these conditions with the first aid that you might offer any other condition. He specifically talks about a broken limb. But imagine a cart. You don't just leave that open, bleeding, ready to get infected. You treat it, you allow it to heal. Jess, tell me what you thought of what Professor Devon Portshed with us. Fascinating, validating. That's probably my key word if I had one pull out to some my experience of that interview up. It would be validating because what he's talking about is stuff that feels intuitively right as a patient to how it feels. A couple of thoughts just on a few bits of it. So just regarding that first aid, I think what an important intervention immediately after the viral infection. And I wish so many of us could go back in time and stick a big plaster on our foreheads and say, stop because I was continuing to try and run for two months afterwards. And I got worse and worse and worse. And I'm pretty sure that had I not tried to do that. If I had immobilized, I don't think this condition would have kicked on anything like it did. I always cried when he gave that description in the interview of someone going for that run, thinking they're better going for that run and then saying they think they had COVID again, because that's the exact email I sent to work three weeks after I had COVID. I said, I think I've got COVID again, having been for a run. And interestingly, I don't know what virus my daughter had over Christmas or two viruses she had. We tested for COVID. It doesn't say that it was COVID. I have been so specific with her school about her not having to do sport, not being pushed, being allowed to rest when she needs. I don't want to be overbearing with my child, with the idea that she's going to get sick because I got sick. But if I have learned anything about how we should behave immediately post-virus, it's that we should listen to our bodies. The slight thing about the first aid is that I don't know how useful it is once you're five years in. At about three years in, I tried going for sort of two months of radical rest or as radical rest I could get. I think it might have been too late at that point. I didn't necessarily feel any better for it. So I think obviously what do we do if that mobilisation doesn't help and obviously that's where the research has to kick in. But certainly as an intervention in the immediate aftermath of an infection for those who may be at higher risk. And when I say higher risk, it's all the same demographics and pre-existing conditions that we've seen as risk factors for long COVID. An intervention there could be absolutely critical. On that point that you just made about three years in, going for radical rest, I was listening to something the other day talking about in these conditions. When you are stuck and again, this is this whole nervous system thing, but when you are stuck in fight flight or freeze mode, when your nervous system is already that razzed up, which is a consequence of all of the symptoms and the lack of sleep and everything that you've been going through. Your body perceives rest because your system is so revved up the entire time. So it's thanks that it's actually sheltering from a predator the whole time, which is why rest is not restful when you're in this situation. Completely agree. Yeah. The other things I thought were particularly interesting is when he introduced this idea of the CPET testing and how the two sets of results one day apart for the same person could be so wildly different. Because their right in front of you is the cold hard scientific evidence of what we've been saying for years about how exercise knocks you out if you do too much. And even cognitive exertion can knock you out. That's the thing. And so there's been a lot of research that's looked at how it's all about skeletal muscles of the ones that suffer when you do too much. But what I found really encouraged to hear from Todd was it's not just the skeletal muscle cells that are damaged. It's the immune cells and by implication, all sorts of other cells too. And that certainly reflects the feeling of being struck down with the term that he used, which I quite like, a post-exertional, - Yeah. - Nourimune exhaustion. - Because that, that is a much better descriptor that seems to capture the severity and the complexity and the all-consuming nature of what it is when you crash after having those. - Yeah, and it removes that malaise phrase from it, which is so reductive in terms of what people go through. And he spelled that out also super clearly with the primary differences between deconditioning and this post-exertional neuroimmune exhaustion. It's not only physiological. We have all of these, or it's not just muscular. We have so many symptoms as a result of that exertion. And the other thing being that the trajectory is completely opposing. The other part of it, which I was very encouraged by, was how he was talking about the different theories for what could be causing this. It feels fundamental to me and every instinct in my body intuitively tells me that this is a mitochondrial problem. And obviously I'll defer to the science on this, but I'm very pleased to see the science is reflecting intuitively what it feels like. - Because it's so system-wide and you can almost feel it in every cell of your body. Going back to your point about the cognitive exertion, which we have known for quite some time. And I think you and I are specifically people who have been caught up more quickly with how we had to alter our physical exertion. And it took me so long to understand that still trying to exercise with the same cognitive capacity was not a possibility. And I live in relative wellness because of strategies that I have put in place. I live a completely different life. And my pacing is, my version of pacing is the thing that enables me to live in relative equilibrium. However, last week when we put out the first podcast of "You and I Together" of this sort of relaunch into the new year, immediately post holiday after everything that had been going on, I decided to add some heavy weights into a little gym session that I did. I have always been really, really careful since I had long COVID that I basically do yoga because I still can't push my heart rate too high. There are still certain things I can't do. But as a woman of a certain age, everyone says, you have to lift heavy weights. So I lifted heavy weights and had a massive cognitively overloaded week. And I had a little crash. So it was a really interesting point at which to notice. Yeah, one year of relatively feeling OK. And I still-- There is class ceiling is still there. And I still have to manage it. I still have to put all of those things in place. So it's not that it's all gone away. It's just that you can build those strategies in. What strategies do you have? Do you use some of those that Todd spoke about? Or what strategies do you have? And that's not necessarily today, but have you built over the last five years to try and balance things for you? So one of the things I found particularly interesting about what Todd was saying was how there are essentially three different energy creation systems. One of these appears to be knackered, which is some form of that electron transport chain slash creb cycle, the aerobic respiration, which is exactly what you do if you go for a run. That's working out your aerobic. Get to your zone too. That's how you build your maximal fitness, blah, blah, blah. So I have a long history of marathon running. I know all about training and how best to do that in the aerobic zone, where it's effective. But that's the one thing that is kryptonite for us. And that certainly reflects my experience of any time I do anything that gets aerobic. I start to feel unwell pretty quick. So he says up to two minutes, you're just about OK. Because you've got certain energy that can enable activity for the last that long. And this reflects my experiences, which is that I can help someone move so far, but I can't help the move house. That's the difference. If it takes two minutes or less, I'm OK. I've still probably got 90% to 95% of my muscle strength. But if it's anything aerobic, or if I've got to pump up a bike tire after two minutes, I'm starting to get palpitations. And that's pumping up a bike tire. That's not like running. So for me-- It's interesting. For me, it's a really effective reminder of why pacing is so key. You just have to stay below that point of aerobic exertion. So anything you do that is exertive, you just have to really listen to-- it may not be exactly two minutes in your individual case. But you just have to be very sensitive to when your body starts to tell you that something is not quite right. And that's when you stop. And you just never go into that aerobic zone. I was trying to run last summer. And I was fine running without a crash if I only ran to the point at which I could stay breathing through my nose without gasping for air. Initially on my run, I was running to a maximum of around one minute, 45, two minutes, and then I slowed down to a walk. And I could do 30, 45 minute runs like that without a crash. So that is fascinating, because that plays into that whole theory that you push it. And once you're about to go over that threshold, you pull it back. Rather than what you and I used to do when we were running, which is in those first two minutes, you reach that point, and then you push it at that point for the next 45 minutes, or in your case, for the next three hours. Oh, that's probably offensive, isn't it? You probably did marathons and less than three hours. A little bit less. But you trained for longer. So one of the big things that I'd love to know what the answer is to this. There's two parts of this I'd really love to know the answer to. Why does physical exertion lead to this horrific brain fog and cognitive crash along with everything else? What is the physiological mechanism that connects those two? And why is it, well, 24 to 48 hours later that it happens? Both of these two things, as there's sort of theories around why this might be, but doesn't quite feel like we've got the dart in the bull's eye on understanding what's going on with either of those yet. No, but this does link back to where we started this episode today, which is mind body, this intrinsic link between what is happening in our body and the impact it has on our mind and vice versa. We cannot still be separating the two. We just can't. There is way too much scientific evidence that, well, I mean, with one system, you can't live without, you can't live without your brain. You can't. True. True. So the other point that the professor, that I've said that I was pumping my fists in agreement with, was about how trials are being slightly undone at the moment by not understanding the phenotypes of the people who are going into them. So he used the example of people with pots. And in principle, exercise is good for people with pots. It helps train that autonomic nervous system and improve symptoms. But not if they are essentially energy limited and they have some form of ME/CFS. Yeah, and the primary treatment for pots is exercise-based. And I've actually got some interviews coming up on this. But there are multiple conditions, long-covid ME/CFS, EDS, where pots is a really predominant symptom and they are all worsened by exercise. So it's flipping the playbook for a lot of symptom treatment. On that subject, I think what's so key is that with a condition that's as heterogeneous as long-covid and even within ME/CFS, there are subtypes. How do we make sure that the right people of the right subtype go into the right trials? And this is undoing trials already, famously BC007, potentially undone by poor participant selection for the trial and Todd's reference without naming any that this has been a problem in the research the last few years. And I really hope that almost the most pressing thing for us to do on the research front is just work out what those subtypes are and what are the biomarkers for those subtypes so we can actually categorize people and put them in the right trials. It's a long-old process this. And Todd, it's not the only one who has said that there are multiple people that we have spoken to who have said we need to identify these subtypes and separate people out. And even then, you then need to give personalized treatment, a personalized approach. And that goes back to how we started today. Every single person is different. Let's see if we can get some buckets of subtypes in these various conditions. But every single person is going to require a personalized strategy to enable incremental improvement. Thank you so much for joining me again today, Jess. We would love to hear what you thought of this conversation, what you thought of the subject matters that we have raised. And we look forward to being back here with you. again soon. Thank you. - Thank you and look forward to chatting again in a couple of weeks. (upbeat music) - Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible. A group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you, visit our website at makevisible.com. [BLANK_AUDIO]