The FND Society Podcast
Welcome to the FND Society Podcast, a series tailored for clinicians and researchers in the field of Functional Neurologic Disorders.
The podcast covers a wide range of topics, from basic science aspects like neuroimaging and biomarkers to clinical practice issues such as diagnosis, treatments, and outcomes. It also explores how FND is understood and treated within the current medical and psychological paradigms, with a goal to enhance knowledge and awareness across the medical community.
Our goal is to make this a valuable and accessible resource for professionals, delivering the latest research in FND through engaging conversations with experts in the field. We aim for this series to be a practical and informative experience, connecting listeners directly with groundbreaking developments and insights in FND. It's our hope that each episode will contribute meaningfully to your professional knowledge and understanding.
For more information about the FND Society visit: www.fndsociety.org
The FND Society Podcast
Daniel Clauw - Nocioplastic Pain
Use Left/Right to seek, Home/End to jump to start or end. Hold shift to jump forward or backward.
In this episode Prof Clauw explores collaborative conversations about terminology with patients and across specialities. He talks about nocioplastic pain and teases out his thoughts about long covid. There is an excellent discussion about modifiable factors in ill health and the place of integrative therapies in helping patients with FND and other disorders. It's a thoughtful, hopeful podcast from a word expert in pain
Links:
- https://medicine.umich.edu/dept/cpfrc/daniel-j-clauw-md
- https://medicine.umich.edu/dept/cpfrc/about-us
Welcome to the Functional Neurologic Disorder Society podcast. I'm your host, Erica Cotton, coming to you from Chicago, Illinois, with a special thanks to Michael Romeo, our production engineer, coming to us from Australia, and our content curator, Ingrid Hertzauer, from the UK. My guest today is Dr. Daniel Claw. Dr. Claw is a professor of rheumatology and psychiatry at the University of Michigan, also his medical school alma mater. He completed his internal medicine residency and rheumatology fellowships at Georgetown, where he eventually went on to hold roles including Chief of Rheumatology and Vice Chair of Medicine. While at Georgetown, he also assembled an interdisciplinary team who began to study the central nervous system contributions to a number of chronic pain disorders, including fibromyalgia, interstitial cystitis, low back pain, and Gulf War illness. This group of investigators, the Chronic Pain and Fatigue Research Center, CPFRC, left at the University of Michigan in 2002. So now he's just on the other side of Lake Michigan to me here in Chicago, and I'm so pleased to accept our podcast invitation. Today, we talk about his serendipitis pathway and his CP and Fatigue Research, terminology for chronic pain and fatigue, multisystem mechanisms and future directions for mechanistic research, and CFS overlap with long COVID, interdisciplinary multidisciplinary treatments, particularly inclusive of more Eastern, underappreciated alternative approaches, measuring patient outcomes in the PGIC, and optimism for the future. So, with that, here's my very enjoyable conversation with Dr. Dan Claw. So I'm just so thrilled to have Dr. Claw here with us today. And I remember, Dan, I actually heard your talk at the last FNDS meeting in Boston and just thought it was excellent. So I'm really looking forward to being able to dive into some of those topics in a bit more detail and hear some any updates that you're willing to share from your more recent work. But before we dive into all that, I'm hoping you could share a bit for our listeners who aren't familiar with you about your academic background, everyone's a little different, practitioner, scientist, specialty, and how you arrived at including Emmy and CFS in your work and which kind of career path you're on.
SPEAKER_02So I'm clinically trained as a rheumatologist. I didn't really think I was going to be a researcher, but in the second year of my rheumatology fellowship at Georgetown, I was sitting up at night doing moonlighting, and I read a tiny little article in the Washington Post that said the state of Minnesota had taken the nutritional supplement tryptophan off the market because they saw that a number of people had a very high eosinophil count, white blood fill count. And I had remembered that I had seen several people as a rheumatology fellow that had a really odd connective tissue disease and they had really high eosinophil counts. So the next day I went back in and I tried to remember the names of those individuals, and I called four people that we had seen over the previous year and just asked them, did you by chance taking tryptophan? And all of them said they were. At that time, no one was telling their doctors about what nutritional supplements they were using. So you certainly weren't going to find it in the medical record. And then I uh asked the rheumatologists in the Greater Washington, D.C. area if they had seen anyone with a high eosinophil cone. And they found three other people. And I called those three, and they all were taking tryptophan. So this sort of lit a bug in me. This disease ended up called Eosinophilia myalgia syndrome. It was due to a contaminant that was um accidentally introduced into the tryptophan as part of the manufacturing process. But these individuals initially had a really nasty autoimmune disease, but after the acute inflammatory component of the disease ended, which usually was six to 12 months after stopping taking the tryptophan, these individuals really looked like they had a really bad case of fibromyalgia. And at the same time, because I was the lowest person at the totem pole at Georgetown, I was the newest rheumatologist, I was getting a lot of referrals from an orthopedic surgeon that were seeing a lot of individuals with low back pain. And he was smart enough to know they weren't going to benefit from surgery. He didn't know what they had, and almost all those individuals had fibromyalgia as well. So, really early in my career clinically, I was seeing a lot of individuals with fibromyalgia, some of whom sort of started with more of an autoimmune disease, and that was overlaid on top of it. And we certainly see this in individuals with like rheumatoid arthritis or lupus or psoriatic arthritis. Um, and then I was seeing sort of idiopathic fibromyalgia as well. So um I was really fascinated by fibromyalgia because the sum total of the research on fibromyalgia was my mentors. The good thing was they believed it was a real disease, but there was no scientific literature. So they literally gave me an article from a newspaper that said, you know, a lot of women have this and it appears to be real.
SPEAKER_01And so a newspaper, that's a new one.
SPEAKER_02Yeah, but against all advice that where people said it's going to be academic suicide to study fibromyalgia, I just thought it was a fascinating condition because I thought these people really had something wrong with them. I didn't think they were making this up. And um this was sort of an opportunity. And because this condition EMS, uh, the company that caused this was a Japanese company. They ended up providing a lot of funding to study EMS. I was able to parlay that funding. Um, and then we also got funding from the Department of Defense because the Gulf War, the first Gulf War, caused an epidemic of similar like illness that was called Gulf War illness. It looked a lot like MECFS fibromyalgia. Um, and so we again got a lot of funding um to study the health consequences of the Gulf War. And in those studies, we used individuals with fibromyalgia as what we called a positive control. So the first brain imaging studies, functional MRI studies of fibromyalgia were studies that the funding was for Gulf War illness, and these this was a control group, but we were able to show that the individuals with golf war illness, their functional MRIs looked very similar to individuals with fibromyalgia and both looked different than healthy individuals. So we were able to sort of see there was really something wrong with these individuals with golf war illness and fibromyalgia. And at that time, functional neuroimaging was a relatively new research technique.
SPEAKER_01Wow, that is not the introduction that I would have expected. I would have thought you're gonna set out to do this research career and you had the idea. And no, it was just, isn't it? Serendipity is funny in certain ways. But my goodness, you certainly set off on a research path after that for sure.
SPEAKER_02Right. And then the name of our group is called the Chronic Pain and Fatigue Research Center, because the first major philanthropic donation that we received at Georgetown was from a man whose daughter had chronic fatigue syndrome, not fibromyalgia. And we were really studying both of those conditions really in tandem uh in the 1990s or so. Um, until the NIH stopped really having research centers of excellence in chronic fatigue syndrome, it became very difficult to get NIH funding in chronic fatigue syndrome, where we've been able to be very successful at getting NIH funding in a whole variety of different chronic pain conditions.
SPEAKER_01Yeah, actually, while while we're on the we're introducing the subject for our listeners and myself for terminology, what terms do you prefer for each of these conditions? What's the the newest, most accurate, updated terms for fibromyalgia, chronic fatigue? You know, I've heard of myologic encephalitis or no, what's the correct ones? Can you educate us, please?
SPEAKER_02Yeah, I'd be careful about calling them correct because when I give a talk on this, I say that a lot of different medical specialties have seen the same group of symptoms, fatigue, memory problems, sleep disturbances, multifocal pain, and they've called it something different. The psychiatrist called it somatization, the you know, and you know this. And and so I don't even the the term that the currently preferred term in the pain field is nosoplastic pain, which is a mouthful. Um, but that is the pain conditions or the pain conditions where the central nervous system seems to be causing the pain rather than the periphery. And these individuals, although they have pain, the fatigue, the sleep problems, the memory problems are often at least as disabling, if not more disabling, than the fatigue. Another thing that we've really been interested in studying, because we think that this is really part of this spectrum of illness, is that we've studied the sensory sensitivity that a lot of these individuals possess, the sensitivity, the brightness of lights, the loudness of noises, odors.
SPEAKER_01Common triggers, yeah.
SPEAKER_02Right. And in fact, um, one of the hypotheses in the Gulf War, one of the one of the diagnoses that was still in vogue at that time, this term isn't used anymore, hardly, is multiple chemical sensitivity. But really picking up on the fact that these individuals, after they developed this um MECFS fibromyalgia-like illness, because they were deployed to war, that they became more sensitive to the brightness of lights, the loudness of noises, things like that. That seems to be part of what we see in the brain in these conditions.
SPEAKER_01Great. That's um bringing up so thank you for the clarification around that. Um, as well as the flexibility around the use of terms. That's very helpful.
SPEAKER_02You know, I think sometimes researchers call this, um, I forget what the term is, but they've the cancer cluster. Um, so the so a lot of groups of researchers have identified the same exact um set of symptoms. They just have called it something different from a semantic standpoint. And I'd like to, again, not say that my field is correct in the in the term that we use. It's really more we should understand historically that that's what's occurred.
SPEAKER_01Yeah, great. Oh, that's wonderful and very flexible. And I think is definitely more open for collaborative and shared understanding and um cohesive conversations about this constellation of symptoms. On that note, I'm wondering if you could share your views about overlaps with your work and long COVID in terms of mechanisms, that constellation of symptoms, what is distinct versus what is different, and how you how you think about all that, which I know it's we don't have those answers yet, but we all have thoughts or hypotheses, and you probably the most educated among many. So we'd be very, very grateful to hear that.
SPEAKER_02Well, I wrote an article with some co-authors about four months into the pandemic, predicting that we would see long COVID because we'd seen this with other post-infectious syndromes, the the earlier cases of SARS, um, Epstein-Barr virus. There's a lot of different infections that trigger the exact same symptom complex. So we wrote about this, and I think that is largely what happened. We've we published an article recently showing that someone that has one of these chronic overlapping pain conditions, like fibromyalgia, chronic fatigue syndrome, headache, irritable bowel, was much more likely to get long COVID if they got a COVID infection than someone that didn't have one of those chronic overlapping pain conditions. But we also showed that the same thing happened after an influenza infection, is that this is not at all specific to COVID. I think because of the intensity of the, especially some of the earlier strains of COVID, I think the post-infectious syndrome was probably more common than it is in other infections. But again, we've seen this over and over again with other types of infections. This isn't new.
SPEAKER_01That yeah. So I remember reading even in the earlier studies of fibromyalgia, that it often onset after a viral illness, right? Whether the trigger trigger of viral illness then sparking um fibromyalgia or chronic fatigue. And then yeah, it it that there's something about I think maybe the density of people exposed to COVID, like you said, the the severity of the initial virus. So in summary, you would disagree that COVID represents some new distinct illness, or long COVID at least represents a new distinct illness in terms of symptom presentation and mechanisms. It's likely shared in terms of things that have been around for a long time in in response to other illnesses and triggers.
SPEAKER_02Yeah, there's certainly some individuals with long COVID that have some organ damage from the acute infection, either lung damage or things like that.
SPEAKER_01But I think the overwhelming majority of non-hospitalized kind of mild severe symptoms after mild infection.
SPEAKER_02I think it's the same thing. And again, it's this is not to minimize it. It's that it's the this I devoted my life to studying these conditions. They're very serious conditions, but it's not an active um infection. That's one of the things that you have to over and over sort of dissuade people of. Again, I'm old enough to remember that that MECFS was called chronic um EBV syndrome for about 10 years.
SPEAKER_00Wow.
SPEAKER_02You know, the because yeah, because if you do the one of the problems is that um in conditions like CFS or fibromyalgia, the immune system is altered. It's not an autoimmune disease, but it's altered.
SPEAKER_00Right.
SPEAKER_02Individuals have higher levels of antibodies to anything they've been exposed to earlier in life. So if you check titers to something like the Epstein bar virus, you will find them to be higher in people with conditions like CFS or fibromyalgia. It doesn't mean that the infection is causing their illness. And again, we see the same thing with post-Lyme disease, the individuals that have been successfully treated with antibiotics for the Lyme, but they have this post-infectious um syndrome. And I get that the patients that have these would rather have post-Lyme disease than MECFS fibromyalgia, but I think that the scientific evidence um really suggests that this is a stereotypical response that occurs not just after infections, after being deployed to war, after being exposed to different types of stressors. Um, and it could just happen idiopathically.
SPEAKER_01Right. And that brings up two of my next thoughts. I just could pick your brain all day about this. Picking's probably the wrong word. Gratefully absorb any information you will willingly give. Um, but mechanisms and treatment, right? So you touched on and shared an overlapped, you know, awareness and learning from each. So you're touching on mechanisms about the role of immune and immune system modulating symptoms, not necessarily autoimmune, but immune dysfunction, um, and how that relates. How do you can you explain or more expand on the overlap between immune regulation and brain function or the role of the nocioceptic process with the immune system for readers who might be less familiar?
SPEAKER_02I don't think we know that yet. I think we um you know, we know that, for example, that you know, you can identify things like glial cell activation and these conditions, but I don't I think glial cells are activated in any disease involving the nervous system. So I I actually push back a little bit when people use terms like neuroinflammation, because I'm not sure that we really know that the you know the brain is inflamed. In fact, I don't think it is like cerebritis, like we see in people with autoimmune diseases or things like that. Could the activation of the inflammatory system, both in the periphery and in the central nervous system, be responsible for some of the symptoms? Absolutely. But I but as a rheumatologist, the one of the lessons that I learned is when we see these individuals with whatever you want to call this, fibromyalgia, chronic fatigue, um, nosoplastic pain superimposed upon rheumatoid arthritis lupus, when we use these really powerful biologics to treat the inflammatory conditions, the fibromyalgia chronic fatigue doesn't get better. That's like 40% of patients with autoimmune diseases still are very symptomatic after you treat their autoimmunity because they have these things in the background, these problems in the background. So, one of the reasons I'm skeptical that these conditions are really innately inflammatory conditions that are going to need, we're gonna be using anti-inflammatory treatments as the fundamental treatments, is that at least in rheumatology, that hasn't been the experience where we're, you know, unless it's a different set of biologics that we need, but we throw around a lot of really powerful immunosuppressive drugs.
SPEAKER_01Yeah, with non-minimal side effects and non-minimal risks, especially for a lot of the women, a lot of the population that experiences this of young women who are of like childbearing age or reproductive, you know, age. And those are not necessarily minor, minor medications.
unknownYeah.
SPEAKER_02So anyway, I put I push back on this a lot. And you know, that when people say, you know, there's an animal study that suggests that fibromyalgia is an autoimmune disease, or that this it's like, no, I don't think there's evidence of that at all, really. I think that there is a there is an inflammatory component to this. I think it's neurogenic inflammation. I think it's the kind of inflammation that again, we know often occurs when there's immune activation, release of things like substance P, CGRP, that again, things that have been that we know are associated with when the nervous system is activated, that there's a component of the immune system that's activated as well. And I suspect that's the kind of inflammation we're largely seeing in these conditions. And I'm not positive it's a target for treatment or whether or it's an epiphenomenon.
SPEAKER_01Right. And I'm torn between asking one more mechanistic question versus moving on to treatment, but I think I'm going to do mechanism first, which is, you know, you mentioned, and and we see it, you know, in across multiple conditions, not just a viral illness or um like another medical illness. But like you mentioned, stress or trauma, certain events can be the precipitating factor for the development of ME or CFS and FND. But I'm wondering if you would then view or share a similar mechanism that it would be that particular stressor and a normative immune response to stress, to prolong stress, to extreme stress, in addition to various environmental environmental factors that might start that cascade of process? Or do you think that would be a leap taking it too far to understand some of the potential contributory factors?
SPEAKER_02I don't think that's a leap. I think there's a lot of evidence that that individuals with this problem sort of as an underlying predisposition or diathesis are going to be just more vulnerable to different types of things that happen in day-to-day life. Um and I think that uh there again, there seems to be sort of a stereotypical response. There's an increased responsiveness to different types of sensory stimuli. The autonomic nervous system is involved in this as well, and things again in ways that we don't entirely um understand. But it it I liken it sometimes to what used to be called essential hypertension is now primary hypertension. It's sort of a coordinated set of things that that look the same at the with respect to the N phenotype, but you know, it's partly a kidney problem, partly a brain problem, partly a uh vessel problem. And there's a lot of different things that are wrong. And then I think what we're doing now, and as we're trying to apply precision medicine approaches to these conditions, is to say which of these things are really targets for treatment.
SPEAKER_01Which are modifiable. So a multi-systems-based issue that leads to a core set of similar constellation of symptoms, but ultimately, what does that mean as far as what can be modified?
unknownYeah.
SPEAKER_02Exactly. And and certainly we've been doing a lot of studies um using the um ABCD study. It's a really large NIH-funded study that looks at children that start in the study as healthy children at age nine, and it follows them all the way until they're 18, and it asks them a lot of questions, and it does brain imaging every couple years. But in we've had some really interesting studies out of ABCD that have shown that now focusing on the pain outcomes, but again, I think it's all the same, is that that. Of these kids that develop this constellation of symptoms, the sleep problems, the fatigue, the multifocal pain, the memory problems, the temporally, the sleep problems almost always come first. When we look back in ABCD, and then the fatigue and the memory problems come, and then the pain problems come, and then the mood problems come. In two different studies, we've shown that mood problems in in like a nine or a 10-year-old do not make them more likely to have pain, which is sort of counterintuitive, because I think most of I think most a lot of people think that you know that that a lot of pain, like fibromyalgia pain, starts out as, you know, sort of psychological pain. But I as we see this start to happen in children and adolescents, and we can study like symptoms as they occur temporally, that's made me and our group really focus a lot on the sleep, the inactivity that occurs really early in these conditions with respect to treatment. Of course, there's a lot of different things you can target. Um, but but certainly in the pain side, the pendulum is swinging back now towards sleep really being uh an important sort of factor and even I think driver of a lot of these symptoms in a lot of individuals.
SPEAKER_01Yeah, wonderful. And I'm personally pleased to hear you say that. I was just at um AMPA and the American Neuropsychiatric Association's annual meeting in Houston this year. And I was attending the the sleep six. I thought, oh, sleep and FND, you know, a lot of people with F and D have really impaired sleep. And I've had a similar experience where most of the time people prior to F and D report either right at the start or before disrupted sleep and the role of sleep and maintaining symptoms, et cetera. So I'm pleased to hear that your pediatric studies are also seeming to confirm the importance. And I've always spoken of sleep as very foundational, right? Just like a foundational body process to keep everything regulated. And it's really hard to regulate anything, mood, pain, thinking abilities, otherwise, if sleep is dysregulated. Um and I think it's probably been an under, I definitely would think and spoke with colleagues about potentially expanding the investigations of sleep in FND, but I'm I'm really pleased to hear that it's also being considered in, you know, ME and CFS as well, and that it's seeming to have really strong predictive, um predictive value for development of these conditions, even in pediatrics. I'm so surprised that I again I I I just have this adult model of these conditions, you know, not pediatric model. So that's that's an even more powerful indicator, I think. Um along those lines, and I wonder if there's a difference between kids and adults for treatment. So what would you say in a reader's digest version? I'm sure we could spend a whole other podcast just talking about treatments or more readers' digest version of recommended treatments. Um and I know that might differ also by country or location, um, differences between the US and UK about treatments and first line treatment, second line treatments.
SPEAKER_02I think that the first thing to do is explain the condition to the patient or the person, you know, that it that this isn't life-threatening. Because I think there's a lot of anxiety uh about these, as there should be, when you feel terrible and you've gone to a lot of different providers. So I think first you have to establish a therapeutic rapport with the the patient. And I really strongly recommend that people start out like at the core and start with sleep and activity. Try to really slowly get the person more active, try really work aggressively on sleep. CBT for insomnia can be really helpful for these uh individuals. Uh sometimes you you might need to give them a you know a drug that might help with sleep. I'd prefer, you know, something that isn't. I think tricyclic, low doses of tricyclic drugs, one that we use a lot in the fibromyalgia space that that I love, but it's not widely used outside of fibromyalgia is cyclobenzoprene. Um it it is structurally very similar to ametryptaline, but but I think most of us haven't historically thought of it as a tricyclic. But a really low dose of cyclobenzoprene, like five milligrams a couple hours before bedtime, can be really helpful as a hypnotic five to ten milligrams. Uh but then adding the either drug or non-drug therapies based on the preference of the patient. A lot of US patients want to try to treat their symptoms with medications. And I think there are some medications that can be helpful, like um serotonin, norepinephrine, re-uptake inhibitors and tricyclics and gabapentenoids, perhaps a little bit in some individuals. Um, but I think that the mainstay of treatment of these conditions is what I now try to refer to as sort of integrative therapies, non-pharmacologic therapies, including a lot of therapies that we've historically been dismissive of in Western medicine, but that the evidence base just keeps getting better and better for mindfulness. Um now there's five flavors of cognitive behavioral therapy you can use for these individuals: pain reprocessing therapy, emotional awareness therapy.
SPEAKER_00We keep growing in our alphabet soup.
SPEAKER_02Yeah, no, but I but I think that the but getting more sub-specialized in the different, because again, until five or so years ago, it was just try plain old CBT for, and it's like that doesn't help very many people very much.
SPEAKER_01Being tired all the time is is hard.
SPEAKER_02But mindfulness and yoga and tai chi and acupressure and acupuncture and just all sorts of different therapies that again I now prefer to use a term integrative and not act like they're they should either be viewed as alternative or complementary when in fact they should be more first-line um therapies. It's all it's a challenge.
SPEAKER_01Excellent point, actually.
SPEAKER_02Figure out yeah, how to do that. But I think just using the term, continuing to use the term alternative or complementary just almost like stigmatizes those treatments rather than putting them where the evidence base is right now.
SPEAKER_01That's excellent. And um you're absolutely right. I I've can even think of instances where I've done that, like, oh, this first line treatment is this, and then the second line treatment is this, and then like the alternatives ones come later if none of those work versus yeah, why why differentiate those in that way? Well, I'm pleased to hear the foundational recommendation for sleep. And I'm a big proponent also if CBTI hasn't been tried yet, just start, you know, start there, and sleep's just so foundational. Um, but a lot of these mindfulness approaches that you're describing in like Tai Chi, et cetera, are are mind-body, right? Mind-body integration, calming a lot of the central nervous system and um more parasympathetic activation and creating a different set of experiences, which I think have probably been understudied or under underappreciated for fortunately. I think a lot of behavioral psychology and behavioral medicine is moving towards integrating these pieces, which is excellent. Um I'm curious, what do you see for the role of like physical therapy or occupational therapy in these conditions? Useful, not useful, useful in certain cases?
SPEAKER_02Extremely useful if the therapist is really trying to teach people techniques that they can integrate into their day-to-day life. I don't like the passive kinds of physical therapy, you know, where someone goes and they get massaged and someone does something to them. But I love if someone goes to a physical therapist to get a home exercise program to work on the different types of things that they can do. Um so no, I I think physical therapists are are extremely helpful, but I think you want to make sure that the therapist is sort of on the same page as you. You don't want to send these people to someone that does mainly sports medicine because they work them too hard and they the people will be in bed for a week. Yeah, no, but they you again, a therapist that works that that has some experience in working with these individuals. The other thing, whether it's the therapist or the other providers, I I another thing that I've become increasingly cognizant of is just taking people where they are and understanding what would motivate them with respect to a treatment standpoint. So I don't do active patient care anymore, but when I was still doing it, I one of the first questions I would ask is what are a couple things that you can't do now that you'd really like to be able to do? It's you know, play nine holes of golf or hug your grandchild or whatever, but then set up a treatment program that is totally focused on attaining those functional goals, not like making your pain score go from a seven to a three. You know, they people don't care about their pain score, they don't care about their, they want to be able to do things that they're not able to do. And so I think all of us as healthcare providers have to get better at figuring out how we can motivate our um patients to engage in some of these integrative therapies, non-pharmacologic therapies take time, they take effort on the part of the participants. So I think it's our responsibility to sort of help teach people that if they integrate these things into their day-to-day lives, they'll feel a lot better, they'll become more functional. Maybe it'll save time because they won't have to be laying in bed feeling terrible all the time. Um, but to help get them started and motivated by figuring out what kinds of things they really want to do and targeting those kinds of activities.
SPEAKER_01Yeah, that's great. That I imagine that might pose a challenge for clinical trials and measuring clinical outcomes where those individualized goals might be harder to standardized and then measure versus a pain score that's more readily measured or a pain questionnaire that's again more readily or easily measured, um, but might not be, as you said, the target of all of those. You know, how does one compare the outcome of being able to hug your grandchild versus play nine holes of golf? I think they're extremely clinically relevant, but I think this is at least for me, while I've struggled, I've become back involved in research. I kind of got got tired of shocking people in undergrad, like literally, you know, like P300 potentials with the with the electric shocks. Like, I don't want to do this. This isn't this isn't gonna be my career. Um, but I've kind of slowly gotten back into it. And as a clinician who also kind of dips into the research, especially for clinical outcomes, I'm going, oh, some of the things that are easiest to measure are not the things that we actually care as much about for research outcomes, and trying to bridge that gap of finding meaning meaningful clinical outcomes for patients that still can be scientifically valid and standardized. You know, kind of bridging that gap. But I'm sure you've had put some time and thought into this. And I'm I'm curious how how you're currently tackling that that problem or disconnect.
SPEAKER_02Yeah, it it is a challenge methodologically, but in a lot of our studies now, the primary outcome is the patient global impression of change.
SPEAKER_01Brilliant.
SPEAKER_02You're basically just asking compared to before you started this treatment. You know, do you feel very much better?
SPEAKER_01And the nice thing seven-point scale, it's brilliant.
SPEAKER_02Yeah, the nice thing about it is it it there's a couple of nice things about it. One is it doesn't really matter how someone got there. It just you're just asking overall, how do you feel? The other thing that I really like about it is it integrates both sort of the difficulty with the treatment, either side effects or hassles involved with the the effectiveness of the treatment. But when you're saying like overall, how do you feel? It's you're really getting almost a summary of both beneficial effects and side effects.
SPEAKER_00Weight against, yeah, weight against the weight against.
SPEAKER_02It's like, well, how much how do you feel overall? So in a lot of our the big NIH funded studies now, the PGIC is actually the the main uh outcome for saying either someone is a responder or non-responder. Right. Because a lot of these trials have like both pharmacologic and non-pharmacologic therapies that people can get. Like one of the big trials we're doing in low back pain has duloxetine, uh acceptance commitment therapy, uh a website, and physical therapy. And and so the PGIC almost equalizes uh across those treatments and says, you know, if we if we uh used functional status, PT might look the best. And if we used a pain score, duloxetine might you look the best. But um if we use PGIC, it's almost agnostic and it's just asking the person, you know, how much better do you feel overall than when you started this treatment?
SPEAKER_01Yeah, like is this working for you? Are we are we removing that? Yep.
SPEAKER_02It's also a good guide to whether you you retain that treatment or discard it. If someone doesn't have a very much better or much better response to that treatment, then it's like, well, you know, maybe that's the let's get rid of that one, let's try another one.
SPEAKER_01Oh, great. I'm so pleased to hear that it within within that community and then that research sector, that that's considered a valuable outcome. I'm so pleased to hear that. I know it hasn't been as much and um that leads to my next sort of question now that we have at least an introductory level conversation and understanding of terminologies and mechanisms. Um, but I'd like to spend maybe the last 10 minutes or so um talking about FND and overlaps between chronic pain and fatigue and FND and some of the debates around similarities versus differences in those etiologies and treatments. And I think there's you know lots of evidence to suggest very similar approaches, you know, multidisciplinary, multi, you know, um pronged interventions and looking at outcomes rather than specific metrics are helpful, but I'd love to hear your views about similarities and differences. Where does one start? Where does one end? Are they the same or different?
SPEAKER_02I think they're a lot more similar than they are different. I I actually wasn't even aware of the term FND until I got asked to speak at the conference a couple of years ago. I and I didn't know there were so many FNDs. I didn't know there were so many the seizures, the movements, the dizziness, the cognition.
SPEAKER_00Yeah.
SPEAKER_02So I don't I I I would probably start by saying I don't know enough about FNDs to say that they all are the same as what I've historically studied, but I think there's a lot of overlap.
SPEAKER_01Yeah, agreed. Um I I I struggle with that as well when especially when patients present and they say, so I have, you know, I have this chronic pain condition, or you know, I've I've always had this, you know, this amount of fatigue. And is is this FND? Is it not? You know, and I I share similar responses in terms of likely shared mechanisms, shared risk factors. I don't necessarily equate them as the same illness, right? Chronic fatigue, I wouldn't say is a functional neurologic disorder necessarily. Um, but I would say that there's shared mechanisms around risk factors, genetics, immune regulation, no susceptible processes that are happening that are creating poor quality of life, the role of sleep, et cetera, the impact on mood, um, and and likely a multi-pronged treatment approach is likely going to be best. But I'm wondering if you would share similar, similar recommendations if a patient came to you for ME or CFS and also had FND, and they said, what's the overlap here?
SPEAKER_02Yeah, well, if you think of, you know, the treatments we've been talking about, they've been shown to be effective for hundreds of conditions from hypertension to diabetes to uh mood disorders to FNDs and pain disorders. And so I think what we're saying is, you know, let's not get too wrapped up in the semantic terms that are used because certainly patients get really, you know, bothered by some of the semantic terms. And I've been able to stay out of trouble largely with advocacy groups by just, you know, it's like you you can call this what you want.
SPEAKER_00Yes.
SPEAKER_02I get why you don't like some terms as a patient, and um, but I'm probably gonna be blunt with you about like what you need to do to get better.
unknownRight.
SPEAKER_02Yeah, let's let's treat the symptoms.
SPEAKER_00Let's let's let's move forward with with what to do about it. Yeah.
SPEAKER_02Yeah, what I know for sure is that if you just sit there and complain and you don't try anything, you won't get better. I that I know for sure. Um, and so look, yeah, let's let's move forward and you know, and and try some things. And uh I'll give you here's a couple drugs you could try, here's some non-drug therapies. I want to give you a lot of choices and alternatives here, but it it's not really an alternative to not try new things or or I'm the wrong provider, because I'm not gonna sit and just listen to you complain every time you come in when you don't actually try to get better. I but I think sometimes that is part of what we have to do as providers as well, is that I is really motivate patients because they get sick and tired of being sick and tired and they've tried a lot of things. And we're we're the next one. And it's like, please, Mrs. Jones, try a couple of new things because you won't get better if you don't.
SPEAKER_01Right. And and I think that's really, I imagine, a challenge or a common experience in the ME CFS world as it is in FND, which is the practice of clinically treating a condition and making evidence-based recommendations about what will be helpful while simultaneously admitting lack of full mechanistic understanding, right? And needing to continue to work towards greater research of what is actually happening at a cellular level, at a systems level, and uncovering mechanisms while moving forward with treatment, regardless, right? And I've and addressing, you know, some patients and say, well, how can how can you trust the treatment if you don't even know exactly how this is happening? It's like, well, you have to start somewhere, right? Both can happen at the same time. We can progress in treatments and we can progress with mechanistic understanding. But I think people get really stuck if they expect, well, I'll I'll try the treatment once you can tell me for sure what this mechanism is, or isolate it, you know, like, well, tell me how much of this is due to the concussion that I had or the fact that I had COVID or and then how much of this is now the FND versus, you know, the parsing it out and trying to really say exactly what percentage accounts for what percentage of symptoms versus, oi, that's way too complicated, at least for our current levels, at least I think of current levels of technology, medical awareness versus we generally know these things will work. Um how much of, and I'm looking forward to greater technological advances or medical advances for understanding these systems level, brain connection level pieces. Um, it sounds like you've early on were able to establish that there were some brain differences. Um, but where do you think technology or medical abilities to detect some of these changes needs to go in order for us to really be able to actually capture and answer some of those well-posed patient questions around what the heck is happening and how is this happening beyond how do I get better?
SPEAKER_02We and others are trying to integrate a lot of different types of sensors into mechanistic research. I think there's some really good sensors now that can look at autonomic nervous system, both sympathetic and parasympathetic tone. Um, I think again, some of the sensors, actographs and things like that that can measure sleep and activity more objectively. We integrate those into almost all of our ongoing studies. So I think that over time we'll be able to identify components of the in the person's phenotype with different types of sensors that say, here's someone with low parasympathetic tone. Um, you could, you know, you can either give them a vagal nerve stimulator, a transcutaneous vagal nerve stimulator, or you or by sleeping better or exercising more, they could raise their vagal tone, but at least there's a target. There's a right, it's a um, so I think that that a lot of the studies that are ongoing now have a lot of these different types of sensors, and I think we will get better and better at sort of endophenotypes, identifying endophenotypes that respond to specific types of therapies. But I'm I'm with you. I think that you know, a lot of our biggest challenge is to um is just get people started with treatments and start trying some of the simple things. One of the tricks that I used, because we sort of learn this in rheumatology, is we learn to say to someone, because everyone that comes into a rheumatologist is, oh, do I have like the lupus or rheumatoid arthritis or whatever? And we would often say, Well, Mrs. Jones, the good news for is that I can tell you for certain you don't have lupus. Um, and if I if I could tell you for sure what you did have, that would be bad. Yeah, like like like yes, yeah, yeah. That's like you don't want lupus.
SPEAKER_00You don't want, and I don't want the things we already can detect. That those are forces.
SPEAKER_02No, but I can do a you know, and I can see this antibody or this antibody, I know that's associated with a really bad prognosis. So, and you don't have any of that. Um, you you have fibromyalgia M E C F S, and we have a pretty good idea of what to do about it. And we even have a pretty good idea of what causes it, but it's not um again. The the good news is that if I could tell you more explicitly what this is, it that would be bad.
SPEAKER_00Yes, at this stage of our scientific awareness, B is generally bad. If we can, if we know about It's probably big enough that it's really bad at this point.
SPEAKER_02Right. As a neurologist, it's like uh stroke bad. Like you know, FND uh leading to stroke-like symptoms, not so bad. Better, treatable, reversible. Yeah, but yeah, exactly. Um, so I so I think, yeah, like almost like trying to turn things around for patients and get them to embrace the fact that they they have a condition that again, they don't at its face, they don't, they'd rather have lupus or rheumatoid arthritis. But please, as a physician, you don't, you wouldn't really rather have that.
SPEAKER_01Right. Yeah. Um it's validating my scope and scale conversation I have with my patients all the time. We're like, I saw a neurologist and they sent me to you. You know, I'm a neuropsychologist, psychologist, and I have to explain that. Neurologists historically have dealt with the large scale things we can see on imaging, things we could identify. Psychologists and psychiatrists have historically dealt with brain dysfunction, but at a level we can't see on imaging. Like you don't take a brain scan and see anxiety light up on, you know, unless it at an individual level, group level research, of course, you know, then you can start to see differences. But anxiety is not diagnosed by a you know brain scan in the ED that says, oh, look, there's your anxiety, right? Um, so so scope and scale and is is a huge relevance. And I'm looking forward, I don't know, I guess looking forward is the wrong term, but perhaps, you know, looking curious about the impact of if if and when we do develop those technological advances with that level of specificity and and endotype specificity of teasing apart, you know, what's the varying contributors of all of these systems? If that will help tailor treatment, um, that would be the ideal is tailoring treatment or providing peace of mind, or if you know, almost sometimes too much data creates and looking too far down rabbit holes can can create a um oh more nervousness or anxiety, you know, sort of like over-monitoring, you know, over-monitoring each little variation or levels, which would be a different problem to have, I suppose. Wonderful. Well, I want to be mindful of our time. Um, and I just really, really appreciate we could easily have you on again and continue this conversation, but it's just such a wealth of information and such a career's worth of work that I think is not just impactful for ME and CFS, but you know, just translates to so many other conditions and disciplines and especially FND is so much to learn and so many good models set by all the work that you've been doing for the past few decades. So I'm really appreciative. Are there any um final topics or thoughts that you think our listeners should really be aware of or particular paper or upcoming aspect you'd like to highlight that we could get the word out for you?
SPEAKER_02No, I'm optimistic. I, you know, I mean, uh there's other therapeutic areas that I'm up to like psychedelics. We're working in psychedelics now. I think there's a subset of people that would benefit from psychedelics, uh, perhaps some cannabinoids, a little bit. I'm not not a big fan of THC, but uh, but I get but again, I think there's just a lot of really interesting work being done now, and I and I think the future is a lot brighter for patients with these conditions because of just all the research that's been done and being done.
SPEAKER_01That's great. I will always end on optimism. Well, thank you so very much. Appreciate it.
SPEAKER_02Well, thanks for having me.
SPEAKER_01Listening to this podcast gets you access to a 50% discount for new FNDS membership. Use code FNDS006.
