#35 Vagus nerve stimulation for chronic illness and better health with Dr Elisabetta Burchi

I'm particularly excited about this technology because it's a paradigmatic change. It's really a theoretical paradigm shift. One is trying to fill the gap and provide a frequent approach and technology because it is a technology that can give options to patients, to people that have a met clinical needs for syndrome, and conditions that are complex and that are currently missing, treatments that are inter-systemic. Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Kate Stevens. Welcome to another episode. Hello, Jazz, how are you? I'm suffering a little bit, but I've been mostly functional today. I think I made too much of the slight functionality I had, and now I'm hanging on a little bit. I get to that point, like in the old days, people say, "Oh, the old days, everybody else, you doesn't have complex chronic illness, probably does this already." They look forward to Friday, right? For me, I still have in my head the idea that I have to be productive, but once I get to five o'clock or so, I let myself off the hook, and so I'm looking forward to that sort of five o'clock moment of actually releasing myself and the psychological pressure of feeling like I need to be doing useful things. I do want to talk to you about how you got to this place on a Friday. We record on a Friday, and today we are doing an episode that is about a specific technique for nervous system regulation, and I wanted to talk to you about that in terms of your activity, because you left me a message earlier in the week. You had a really busy few days, and I just love for you, because I'm sure it's very similar to a lot of us. Share what happens to your body when you have that kind of intense period of activity that you had this week. So, Tuesday, I had a shoot out in South Wales, which is a long way away. So, Monday, I've put it out there. Tuesday's full-on, it's very exciting, it's wonderful, it makes me feel alive. So, that's why I do it, and that's why I subject my body to arguably the risk of doing so. But it certainly overstimulates the nervous system. So, what do I notice in my body? Well, I noticed that I can't fall asleep that night, because my body just can't shut off. My heart rate is still going mad, my brain is still going mad. There's something about the adrenaline, isn't there? Yeah, it just doesn't switch off. My night's sleep is then very shallow as well. I wake up a lot, I was awake the three hours during the night, and the sleep I do have is very shallow. I never managed to get into deep sleep, the deep restorative sleep. And then the next day, I'm also exhausted by function of having had a busy day and the lack of sleep, but I'm also still quite wired. And that wiredness just about compensates for the exhaustion to get me home, which is why I do the next day. And then what happens there after that, that's when I crash. Hey, Crash. So, there is this weird thing of this retained nervous system going, "Hey, why, whether that's doing things with cortisol and adrenaline, potentially, I don't know, I wasn't doing blood draws on myself to find out, but that's what it feels like, sensory perspective, and then there's the delayed crash after that, where the body does slow down and then goes, "Oh, you've really done it now." Yeah, so it's like your body set goes into some kind of overdrive that keeps things, "Oh, I've been operating at this level, I need to keep going, I need to do this big push." And when you were talking to me about that, she realised that. I think I had that historically before I had long COVID, when I did shoots that I would sometimes work for 36 hours without sleeping, or I would do the shoots say six days straight, and I'd maybe be sleeping three hours each night, and then you're busy for the whole of the rest of the time. And after that, I would have, or even after my wedding, I would have three or four nights where absolutely could not shut down. Just push your nervous system to such a level of activation that you, it's very hard to retract from. And I was just thinking about this with the long COVID. Do you feel like I used to feel like it was a buzzing, like my whole body was buzzing for several days when I was in that activated state? That's quite common with people long COVID. I don't personally feel like that, but that's something I've been told so many times, my long haul is about how they experience it. Yeah, so I thought that was a useful way for us to enter today's interview and discussion, which is with a psychiatrist, a co-delizabeth burky, who works with parasym, and they are the company behind the neuro-modulation device, Neurysym, what is called a transcutaneous, auricular vagus nerve stimulation device. And what they are trying to do with this technology is, is a small device that you clip on your ear, and it sends electrical pulses through your triggers. And just to mention, for those of you not familiar, your triggers is this small piece of cartilage that protrudes at the front of your ear. This interview does contain some scientific language from things like homeostasis, which is the body's ability to maintain a stable internal environment, to locus cerulius, which is a small region in the brainstem that produces noradrenaline, and it plays a key role in attention and alertness. But rather than breaking the flow of the conversation, I have included a glossary of some of the more scientific terms in the show notes. So do you have that open alongside the episode? And please let me know if that is helpful to you when we delve into these science episodes. And in that vein, please keep feeding back, engaging, and sharing your stories. They are so helpful as we try to shape this podcast to be of greatest help to you. Have you had experience with such devices or such electrical stimulation, neuromodulation? I have, yes. So I have an alpha-stimmed device, which is, I guess, a competitor at some level for the neuroseum one. And I find it's quite helpful. So let's say, for example, that I'm on my way back from having done a shoot or from having done something that's strenuous. I'm in the car. The first thing I'll do is to put it on. And for however long I've got to get home, I need to calm this body down, and it does seem to help. But yes, the answer is I do have experience of using them, and I do continue to do so. Okay. So let us listen to Elizabeth Aberke talking about the device that they have developed for neuroseum, the way in which it stimulates the vagus nerve to calm the nervous system. And we talk about some of the studies that they have done to look at the efficacy of the device that they've created. Tell me how you have ended up working in this bio-electronic space coming from the psychiatry space. Because we're going to talk today, and our audience is quite focused on complex chronic illness. But you have a history of interest in more, I don't know what to call them, psychological. You have a very wide-raging history in terms of your interest. You've done studies into alcohol, use disorder, you've looked at OCD. So you kind of look across the board at these conditions. And then Parasim has gone down roots of very, very medicalised things like heart failure, chronic heart failure. So what I really, really love about what you've done is it's so broad. You're approaching it from a psychiatrist perspective, but you're kind of marrying this very physical. Talk to me about that routine. I like that you like that. And maybe the main reason which taps into my origins is that I'm a Florentine. So you know, Renaissance style, multifaceted. I've always had an understanding of reality and things, which is that we are hopefully, three hundred and sixty degrees, or the largest possible. I've always had this also aspiration to embrace more and more. So I've always tried to acquire multiple methodologies, paradigms to look at things. And of course, as a doctor, I decided to become a doctor because I wanted to help people in the first place. But at the same time, I was enticed by the object of study, you know, the human being. And specifically, the human mind and brain, and I'm deciding to become a psychiatrist, which is one of those were already related to the neuromodulation field. Why neuromodulation? So neuromodulation techniques in general can be considered treatment approaches that directly targets neural circuits. And if we think about the brain, the brain mind object, maybe the most privileged level of analysis is the circuit level, which is in between, you know, the cellular, molecular, genetic level and the behavior of a phenomenological level on the other side. And is that really looking at as an electrical? When you say circuits, are you looking at it as an electrical system? Yes, because we know that neurons use in a certain way electrical ways of interacting between them. There are also neurotransmitters involved, so there is also a chemical level. But I guess, yes, when we talk about the secret level, we talk about the electrical functioning of these systems, which is the way in which, that's a very interesting question, yours. Yes, if you think about the way we measure functioning the neuroseirquits, we use multiple techniques like techniques, which use these different ways of measuring activities in the circuits. So, it's very complex. But if we have to name one, I would say electrical functioning is one of the main features, or way of looking at them. So, yes, I thought that the neuroseirquits was one of the privileged access way to the understanding of mental states and then also mental health disorders. Not only to understand them, an access way to understand, but also to affect their functioning and treat these conditions. So that's why I got interested in the space. And once I completed my fellowships, so I did some research in the neuroscience space, coming back to my broader aspiration of embracing a little bit of everything, I decided to get an MBA, a Master in Business Administration, so totally unrelated to medicine. Because I wanted to magnify the impact of my practice, the more system level to affect the well-being, I guess, more people. So compared to the individual level, which I usually operate with my patients. So I completed my MBA and got some innovation skills, which then I wanted to consolidate in the incoheritial world. So I turned myself to the biotech, comatect space. And I was looking for interesting companies that connected to the neuroscience space. And then I discovered Parasima, which was at the beginning, I think I joined the company where we were only in three. And so I started working with them, I was excited about what they were doing. Not only because they were dealing with neuromodulation, the specific neuromodulation technique, which is known in the easy vagus nerve stimulation. I will say also talking about the vagus nerve, which is the longest cranial nerve in humans and carries the majority of the fibers of the parasympathetic nerve system. Intrinsically, this nerve, which with this technique, we modulate, is involved in many physiological processes across the body. And so having the possibility to modulate its function allows us to really overcome the usual boundaries in medicine. So my aspiration to embrace was found a little bit around what Parasima was doing multiple levels. So with the technique, which could actually redesign the understanding of diseases and these, or that's not just diseases of a specific physiological system, but as diseases, illnesses of multi-systemic diseases, which is the, in truth, what I believe about many chronic conditions or also mental health conditions. And that is the thing, isn't it? The vagus nerve is essentially the connection between what we perceive to be the physiological and the psychological essentially, the concept of mind-body. But actually, we are just one. We are just one body. We are all one. Absolutely. So what you do at Parasim is you're taking your psychiatry background, but you are using it to treat on such a physiological level. Talk to me about, well, let's go from the beginning in terms of what Parasim does. I have previously done an episode looking at the vagus nerve and an implanted vagal nerve stimulation. So I would love you to talk to me about transcutaneous orricular vagus nerve stimulation, which is what Parasim does. There are also other transcutaneous methods, but talk to me about the method that you use and that you have developed with Parasim. The pleasure, rightfully you mentioned the invasive VNS techniques predated our approach. Initially, VNS was a very long story in more than one century. Let's say more recently in the latest 40 years, it was developed and approved this surgical invasive procedure for major depression for resistant epilepsy. In any case, the potentiality of modulating the vagus nerve were already perceived, now in the field, but the fact that you could only do it, basically, reduced accessibility of the technique. So in more recent years, what we have done at Parasim and in other company, but I will I'm proud to say that we are definitely the leaders in the trans-orricular space because of the data we have gathered, not because of market share, which I don't care about. I care about the scientific backup of our claims. So we have published so far with our technique more than 50 clinical studies and we have a similar number of ongoing clinical studies. With more than 100 research collaborations worldwide. So we are really heavy on science and we've always put research at the core of our, what we do. I have a lot of heavy claims on your website about how all of what you do is backed up by scientific studies and I thought, okay, well, I'm going to dig into this and yes, Parasim. It was real. Yeah, yeah, yeah, absolutely. And it's not just that it's been you testing it for Parasim. Parasim has been used to test this technique across multiple conditions and we can go into some of that in more detail, but I just wanted to mention at this juncture that they are actually verified. Yeah, absolutely. Since the inception of the company was there, but I joined the 2021, I believe at the beginning, they have always found that they really cared about scientific record. Yeah, scientific record exactly. So we developed the system which is capable of modulating the vagus nerve through the tragus of the year. So through the surface of the skin here, at the level of the tragus where underneath lies this auricular branch of the vagus nerve, which is an afferent branch, what does it mean afferent, which brings information up to the brain, specifically the brain stem, where you find that there are no close of tracts solitalis, which is close of the brain stem. And we have developed a signal delivery system which is capable of delivering electrical stimulation. So it speaks the same language of the neurons as we mentioned before. And this capable of doing it in an unimbezifession in a safely manner. When I say safely backed up by science versus a sea mark, the medical device, deemed no silly risk by the FDA multiple clinical trials. And effectively, safely and effectively, we have this showing that we actually modulate the vagus nerve. There are multiple ways of corroborating this claim. One of the main biomarkers is this, I would say now, renown the markets, HIV, heart rate variability, which is measured by many variables, that we all have and we use for tracking our own well-being overall. That's one of the main markets, going to the parasympathetic tone. In other words, the vagus nerve is the main component of the parasympathetic nervous system, which is a branch of the autonomic nervous system. I think it's important. Let's reframe everything. We chose a central role in dynamically controlling the homeostasis of the body through action or multiple systems, from the cardiovascular system to the respiratory system to the gastrointestinal motility, metabolic balance, thermoregulation, etc. So the vagus nerve is the main component of this autonomic nervous system. And so basically our device, which is wearable, can be used at home very easy to use. It's been designed for at home, used in people can buy it without prescription. This is based on the safety, I would say mainly. And I think with the device, we have designed this very intuitive to be used. Yes. That's how it works. It works initially, so the stimulation of the auricular branch of the vagus nerve. Then the signal gets to the brainstem and then there are a series of cascade of physiological effects. across these other systems we mentioned, the cardiovascular, the immune system. If we want to categorize maybe the effects, I like to see three many areas. And is the modulation of the autonomic tone. So this balance between the sympathetic and the parasympathetic tone. Another category of effects is the anti-inflammatory action, which is implemented through specific pathway, multiple pathways. One of those is the collinegic anti-inflammatory pathway to the spin. And the third category of effects is the neuroplastic one, which is more involved in all the applications through gypsychiatry, neurology, et cetera. So these are the three main areas and we have gathered data in all of this. And if you think about these effects, you can imagine already the plethora of the professional therapeutic applications of these technologies. So when parasympathetic was first developed, because you are talking about something that is used for multiple applications and you currently have research ongoing, I believe, a lot into this sort of neuro, but you've also been using it looking at actual fibrillation and so it very much a physiological in terms of the heart. When parasympathetic was first developed, what was the idea behind it? What was the primary focus in terms of developing something of that neuromodulation? Was it for complex chronic conditions, such as we deal with at visible, or was it for a much wider purpose? That's a very good question. I don't know if initially the vision was clear, already defined for sure, currently, the vision is to. it's a broad one. It's a broad one. And it taps onto two different, I will say, broad scopes. One is for sure trying to fill the gap and provide a technology, equipment approach and technology, because it is a technology, they can give options to patients, to people that have a met-clinicalness, for syndromes and conditions that are complex and that are currently missing, treatments that are inter-systemic. So this is one of the scopes. The other one, and maybe we can see how we can pursue both goals, is to improve and boost the well-being of the majority of the people out there, even without the need of specific diagnosis. And we can actually pursue both of these goals because of the functional characteristics of the Vagus Nav. Because if we think about this capability to modulate all these internal processes, with the goal of maintaining Gomeostasis, namely the stability of the internal environment, while adapting to external challenges, we can think of how this is relevant in disorders, but also when there are no overt clinical conditions. Because we didn't mention that if we think about maintaining Gomeostasis in response to challenges, we think about the stress response. Maybe it's not up to me to say, but I believe that in our contemporary society, all of us is involved in this, because we are constantly under pressure, we are constantly stressed out because of demands need to perform in multiple and different ways. So what the Vagus Nav does, and the para-sinpatratin-eva system does, is working as a break on the stress response. So even if we just think about that in a healthy person, but potentially a little bit chronically stressed because of just the environment, we can imagine that we can potentiate the Vagus Nav, the para-sinpatratin response could actually boost well-being. So it's possible to pursue these two visions, providing new treatment approaches that can be combined, that's another key point, with many other approaches. Now, because neuromodulation techniques, tranzoric olivianes can be combined with pharmacotherapy, and can be combined with behavioral therapies, in a way that are differences between these approaches clearly. One of the main ones, I will say, that while with some exceptions, but probably speaking, pharmacotherapy is less precise, especially and temporarily. In our description of the neuromodulation techniques, they say, targeted stimulation specific neural circuits. So it's a complementary, directed and so complementary to the other approaches. So we are providing something that can be combined with other approaches. But at the same time, you are providing an approach that can empower people in their everyday life with a tool that can help them boost their resilience, if you think about this stress response. And we have data, and that's, there is a theoretical rationale behind what I'm saying, but there are really some pilot finding that we have that is possible. If we look at that, we are all as humans in the current society to a degree dysregulated in terms of our stress response. And look at what you've developed here in terms of neuromodulation. In your opinion, are many of the conditions that you are able to help with a result of a dysregulation of the nervous system due to life in general, rather than very specifically, I'm not saying that some of these conditions aren't directly correlated with a viral hit or that there is not a driver, but are we all more prone to these conditions because of that societal stress dysregulation? Very good question. I think you already give the answer. There are different triggers. If you think about one of the main chronic conditions that arose in the last year's low-covid, there is definitely there a trigger, a viral trigger. But in a certain way, the syndrome that arose from that low-covid, the risk from the acute infection, now it is kind of independent of the trigger. Point is, why did some people, why were some people absolutely able to recover from it? And some people have a residual impact from these things that our bodies should theoretically be able to process. Evolutionarily, we should be able to either process them and survive or. Yes, yes, we are so complex that then there is this shade of grazing between, even if evolution doesn't care about us anymore, once we are not fully functional from a reproductive perspective, but then gladly, gladly, we do not in our lives, I think. We are not subjugated to this evolutionary rules. So now we can survive chronic conditions and etc. But no, yours is a very good point. I believe that among the various factors that can trigger these conditions, there is definitely the environmental pressure, which makes us more or less vulnerable to these kind of conditions that have in the. these autonomies, in these autonomies, they are common denominates. Since you are interesting, these kind of conditions, low-covid, the fibromyalgia, they present the same phenotypic features, think about fatigue and think about cognitive dysfunctions, so-called brain fog, widespread pain, orthostatic intolerance, which is clearly a dysautonomic feature, but even the other ones, the dimensions. They present with similar features and all the possible viral syndromes, just to corroborate the fact that the syndrome is an away independent on the trigger, but then at least evaluates the hypothesis that the autonomic nervous system is pivotal in the pathogenesis, in whichever ways it becomes disrupted, but then it becomes disrupt. And I agree with you probably being constantly chronically stressed, stimulated on the stress response. It can be one of the main reasons why we have such a prevalence of these conditions. And the fact that they are metclinical need, I believe, is related to the fact that we didn't have much approaches to address specifically, and temporarily, especially the autonomic nervous system, till we develop an approach that could actually specifically target the vagus nerve. And non-invasively, it's an important feature of that. Okay, since you joined Perissom, as we mentioned, you have been involved in multiple research studies, collaborations, clinical studies and trials. And if we focus on the long-covid, you have been involved in at least two trials, one in 2021, one in 2024, that did show that your version of neuro-modulation was impactful in long-covid patients. And I think some of the things that really stood out for me, were things such as. It was actually a relatively short time over which these people were treated in these trials. And the neuromodulation did not necessarily kick in immediately, but it's sort of six to eight days into it. Things started to happen. Repacutions of the neuromodulation continued after the treatment ended, so the trajectory. This neuromodulation put patients on an upward trajectory in terms of their symptoms. Talk to me about what were the most marked improvements in that, because you've already mentioned fatigue just now. What were the most marked improvements in and how does that neuromodulation impact these patients directly? Yeah, actually, yes. You are very well prepared. Yes, these two studies that is the third one down on Monsoon in New York. And we have been pioneering the field of Transorecola, Vienna in low-covid, with these two tests, one, three studies. And we were very excited because the first study, as you mentioned, was done in 2021, and pretty early on, and raised to the researchers, and all that wanted. I was just joining the company at the time, so we was really set up the first study. So, in the research community, there was already interested for this technology, and they close about it, even so early on, they thought that could have been beneficial in this syndrome. And so, they set up the study. Of course, these are two pilot studies that they already showed. In a very short period of treatment, 10 days of simulation if I'm not wrong, talking about one hour, 35 minutes of simulation day, which is not much. If you think that you can have this simulation while you are doing other things, that's part of the accessibility and the low barrier for patients, for people to use the device. So, it was really not a demanding treatment. So, in a short time, days of simulation in this way, they could measure significant improvement in male fatigue, but many other symptoms as well. And I would say the second study, the later one, and the one Dana, Casa Colina, in California, which studied female cohort. So, they were all female patients. We know that long COVID is more frequent in females, in any case. And that second study focused on cognitive improvements instead. And I think that was, of course, the improvement in fatigue central, because it's central core of the syndrome and affects many other overall functionality, I would say. But the cognitive, the brain fog 2 is the other key symptom. And we passed out, we, the research has passed out, the cognitive impairment into the multiple cognitive dimensions. And they saw improvement across all of them, which in a way, because our studies are mainly clinical, namely, we generally are interested in providing clinical improvement, because we want to improve the well-being of the patients. But at the same time, we try to elucidate the pastofiziology and the pinning these improvements, right? So, the idea is that in order to get these results, we leverage those two pathways dimension before all of these, but mainly I will focus on the anti-inflammatory effect, because we know that, we know. These are hypothesis, because we are still early on in the, in the research around long COVID for instance. But we think that long COVID is definitely also associated to nerve inflammation, right? And then we think we also leverage the neuroplastic pathway. So, if you think about the nucleus of tractorstoritalis, which is the nucleus we mentioned before, the brain, the brain, the brain, the brain, the brain, the brain. It is connected to many other areas in the brain. So, it's sub-carticle area, which though is connected to many cortical areas, which also explains the effect on multiple cognitive dimensions. Not only cognitive, there is also the emotional side, which is more limb because of sub-carticle, but specifically thinking about the effect on brain fog, what we think happens actually is stimulation of the locus chirule, which is an other nucleus in the brain stem, which produces no radrenaline, and we know that no radrenaline is connected to a passion. And so, improvement of attention might have boosted improvement in many other cognitive dimensions that we measure clinically in this study. Yeah, and you actually relied on the NIH cognitive toolbox to do the assessment of the cognitive improvements. Yeah, yeah. It's quite rigorous the things you're here to. Yes, assessment, yeah, yeah, yeah, no, absolutely. And I always like to highlight that all this study is that we mention also in our website, all done with our technologies. So, we do not translate results obtained with other devices. That's important because neuro-modulation space field is a scuthing edge. There is still a lot of confusion. Often, we see people mentioning studies done with other devices, but you cannot really do that because each and every device has a different signal, the delivery system, now different simulation parameters. So, we need to be careful when we translate results. So, everything we mention, everything we cite is achieved with our own technology, but at the same time, my studies are all independent. We have not funded the study. So, the researchers publish whatever they want, and we do not emendate anything. So, that's another important facet, the transparency and the independency of the research. So, now, I hear about saying that to be collaborative in the protocol design, we give, of course, advice, a suggestion of we know the technology, but the implementation of the trials is fully on the shoulders of the researchers, so it's fully independent. So, that's another relevant facet. Talk to me about, I've spoken to someone before who said that one of the main problems with transcutaneous, whether or regular, or otherwise, vagal nerve stimulation is the adherence. It's reliant on the patient fitting it properly, wearing it for the correct amount of time, and that is something that will have impact on its efficacy and impact on some of these studies. How are you able to ensure the best results, the best adherence for your patients? Is it very simple to use? Is it that you have very clear instruction for how people are able to get the best results? It's different from just taking a pill, a drug once a day, and that allowing your body, it is reliant on humans. And that's true. Yes, adherence, compliance. We actually have a very high compliance in our studies, we have reported very high compliance. So, I think the relative difficulty in using it is compensated, but this is my psychathetic side, by the fact that people are engaged in the treatment, which I think it's important for care in general, in engagement of the. Kind of willingness of the person. So, I think these two aspects are compensated, and then explain the compliance. The compliance is also explained by the fact that the treatment, that despite everything is pretty easy to use it. We do have clear instructions, we have crafted them, but it's actually very easy. The stimulation parameters are already set there. The patients are teaching every session, just have to place the electrode, the earpiece, the troubles, and regarding the precision of that, it's not like since we mentioned other trans-cutaneous approaches, the other one is the cervical one, I can delve into why, according to us, the auricular approaches superior to the cervical one, but for sure, on the precision side, that's pretty clear, because the tragus is pretty small, despite anatomical differences between people, the tragus is the tragus, the cervical area is wider, so we have not seen a lot of variability to regenerate based on the different ways people plug the earpieces on the tragus. Okay, great. Yeah, and so, yes, the only thing that patients have to do, plug the pieces and set up the current intensity. We have a clear guidance on that, you need to find the sensitivity threshold, because we have seen that around that threshold, which can change at each and every session, because of the environmental conditions, the humidity in the air, your baseline, passing pathological activation, multiple factors led us to decide that at each and every session, patients should set up the current intensity, and the guidance given is to look for a present, sensation of this stimulation, which doesn't have to be. So that was going to be my question, is it painful? What is the sensation of it? Because I'm someone who's used a tens machine on pain, is it that similar electrical pulsing? It's an electrical tingling sensation. that you should look for. So it doesn't have to be painful otherwise you trigger the sympathetic nervous system, right? Which we don't want. So I will say it's in between the sensitivity threshold and the pain threshold, much below the pain threshold. No, you want to feel it, but it has to be pleasant. And it's like the t-t-t-t-thing link sensation, but yes, it's pretty simple to use it, pretty simple, but in the patient is to be engaged, yes, and I think it's a plus. In different studies, there have been different methods used sometimes using it 10 times a day for a short period, sometimes just using it twice a day for, I think it's for 30 minutes. Is there a different application that you have developed for different conditions or is there just a sun-sized fits or this is targeting your vagus? So do this. Another very good question. I have to praise you for the level of the questions you I can tell you're very much prepared in this place. Even here, it's a little bit in between. Plug and play. To be honest, we are far vending the research to optimize protocols for the different clinical applications. In a way, the technology is the same and we know we aim to stimulate the vagus nerve and the seat, but depending on which kind of pathways we want to leverage, we have to optimize and change the protocol of stimulation. So yes, we have done studies in which we have very intense treatments, short in time, cumulatively intense in a short period of time. I can think about studies done in acute settings, in the hospital for instance. It's also related to the physicality, but it's also related to the clinical conditions. If we want to achieve a change in HRV, let's suppose. We can achieve this in a short, that's five minutes of stimulation we have seen there. If we want to achieve anti-inflammatory effect, we might probably need a longer period of stimulation. So now there. How do you measure the anti-inflammatory effect? Because I know that in the 20-21 study, which was very early on, it was inconclusive in terms of its anti-inflammatory effect. But it said it is definitely something that we need to research and we need to look into. And it definitely has a positive effect. We just can't say that it's necessarily working on the anti-inflammatory. How do you measure that anti-inflammatory effect? Because it's not as easy as it's wearable. Exactly. So you need to have a blood draw as a minimum. So you're talking about CRP? Right. Or many other cytokines, the NFV, until at the 1/6. These are the measures in other trials in the cardiovascular space, where we had much longer period of stimulation, three or six months. And we have to have a really major significant improvement, so reduction of anti-inflammatory system cytokines in the blood. In relation to that, this study was not actually necessarily relating to the conditions that our patients will necessarily have. But you did do a study into. It was 2024 into Cardiobarriob reflex, which was in chronic heart failure patients. Something really interesting I noticed from that is that most of these techniques are reliant on using the left tragus. Am I right in saying this story revealed that the left tragus was ineffective in this, but the right tragus was effective in helping in chronic heart failure. Talk to me about that difference there. The laterality. So it's true that the majority of our studies have been done on the left side. But the majority of our cardiac studies have been on the right side. The reason is a little bit historical and a little bit functional. And there are some differences, anatomical differences, between the left and the right side. But we are still far-dening the results there, because that study gave these results, other studies, gave slightly different results saying that both sides were equivalent. So the left for the majority of your studies and for the majority of the recommendation to the patients seems effective, but it's not necessarily that the right is always ineffective. No, no, no, no. Actually both sides should be pretty effective. And then of course there is some variation in the inter-individual variation through originality. But anatomically speaking both sides should be equivalent in terms of the effects we are talking about. Yes. Sorry, I think I interrupted you there, but I wanted to know about that bilateral effect a bit. Yes, but yes, in any case, it's really natural. So in each and every study, we had never stimulated both sides at the same time, just one side. We talked about the effectiveness of our approaches, for instance, in improving resilience to stressful events, the stress response, etc. There is another way just came into my mind this time. So we didn't talk about it. It's not related to chronic conditions, but I think it can be interesting in any case to everyone, because we are who's not interested in the cognitive announcement side, no maintaining our cognitive reserve, and cognitive capabilities, no talking about other psychiatrists, yes, and bias, but I think the core of our identity lies here, no, in a certain way. And there is no match to protect our cognitive reserve, if we think about it in general, in our performance and announcement techniques, there is no match. And so I'm particularly excited about some of our pilot results in healthy people at infoculation using our device while performing certain activities, such as reading a text or doing a cognitive task. So we have seen that we could improve the performance, such as reading comprehension or memory retention. So another interesting use case is exactly that. We mentioned a little bit how we use the device so many times a day for how long. Looking at the studies, we have different very wide range of possibilities there. One of these use cases is using the device while performing some tasks where you want to boost learning. That's, I think, it's a very exciting use case. And next to the many other use cases, such as improving sleep quality and quantity session before going to bed, the various networks involved in switching from awake states to sleep states. So now we boost that switch. So that's another one talking about healthy, healthy people, no? Or not only healthy about in general, we can definitely apply to healthy as well. Another use case is to use it after stressful situation to help restore rebalance or for instance, even before stressful situation. Think about performance anxiety, there are people that suffer out of it, me included. So before performing physically or mentally, a performance can affect both when we talk about performance, we can think about athletes, but we can think about speakers, we can think about other kind of mental performances. Before such an activity to rebalance there for people that have a high stress reactivity, I would say. There is this personalization piece, of course, that we always need to take into account. From those various different applications that you've mentioned, is there the suggestion there form that this would have application in, after the fact anxiety, would it also have application in preventing cognitive decline? Do you've done studies in two things like Parkinson's and that physical thing, but what about Alzheimer's and going into, does it have the idea of application for those kind of things in the future? There is the hypothesis there, we have not published yet anything in the order of the generative disorder, but as you mentioned, we have said is ongoing Parkinson disease. And we have something going on in my cognitive impairment. So there is the mechanism rational, so there is the hypothesis that our technology could in a way have an effect on preventing impairment through the neuroplastic effects to the anti-inflammatory effect. So that's a super interesting field and think about a method click, a needs there is a really huge right. So we are working on that. So what is hugely exciting for me, hopefully for our audience is the way in which this sort of technology has such a wide ranging potential application that indicates that really starts to draw together how we need to stop treating so many of these conditions as being completely disparate and being completely separate because actually it's bringing them all back into potentially being activated. Or able to be helped by one point of the body, which is the vagal nerve and that idea that if we really really consider this to be an integral part of our body rather than just something that we didn't even know about, that we have the potential to actually harness some power over our bodies. That's exactly right, that's exactly right. No, besides the technological part in itself, it's really a theoretical paradigm shift because in the way we understand that, illnesses and in the way we understand treatments. So yes, and it all makes sense, say, if we think about the functional physiological role of the autonomic nervous system, which is so transsystemic. But even if we think about, we mentioned that VNS was initially approved in depression, right? Depression is not just a mental disorder. The mental features are made like features of the disease, but it's a systemic condition in a relevance group of patients with major depression. We find inflammatory biomarkers, systemic biomarkers. So it is considered a systemic condition. Similarly, so-called somatic conditions, they have mental features. Now you mentioned about the body and mind divide, which now we go back to the cartesio in Italy, which now we have always had this hard problem in science, where do the mind and the body connect? For sure, in order to have the mind, you need an organic substrate, but it is necessary. So we are talking about the same matter. Then of course, there are emergent properties, like the mind, the consciousness. They can be understood as emergent properties, but we are still talking about the same somatic, same body. So it doesn't make any sense to think about health and diseases in a scotomized, fresh, this way of understanding the nervous nervous function in the autonomic nervous system as a whole and as a central player in the maintenance of Omeostasis, allow us to really redefine treatments. And I think it's really exciting and we want to go deeper into this, even putting more effort in acquiring more data, strengthening all the data we already have gathered. We didn't mention all our cardiovascular studies, just to mention one, which can be interesting to many people. In one study we have done in hypertension, in young people with the essential hypertension, first grade, it's at the very beginning of the disease, we have showed reduction in both histolic and diastolic pressure. And this also now taps into all the cardiovascular conditions, which at the main cause nowadays of death worldwide. But there's also ties into the people who have ended up with infection associated chronic conditions end up with hypertension. So the way that these all tie together, it's mind-blowing, it is complex, it is complex and we are trying to put it out, but most of all we are interested in the clinical impact. And we are seeing clinical impact and we are trying to elucidate why we do have a clinical impact, but we do have a clinical impact. So it is exciting and I'm happy that you also contribute to this adventure spreading the world and educating people and distillating the knowledge behind this complex studies and research. I think it's very very important. I'm glad you invited me to your podcast. Well it has been such a pleasure talking to you today. Jess, what did the conversation with Elizabetha reveal to you that perhaps was not something that you already knew about the nervous system or vagal nerve stimulation? Well I didn't know that they've worked so hard on looking at how it could help other conditions and it makes perfect sense that it could help other conditions because the autonomic nervous system is tied into so much of your bodily functions whether immune or metabolic or cardiological. So it stands to reason that you should test it against some of these other conditions to see if actually you can help the symptoms of them or help those conditions resolve depending on what they are. My contact with this line of science has only ever been from the perspective of complex chronic illness so I haven't had that wider perspective on it but it makes perfect sense to me. It does correlate with the research that's done into the subcutaneous vagal nerve stimulation which is licensed in depression and epilepsy. So I feel that this space is something that is ripe for us to be only learning more and more because as I mentioned in that the hypertension that people are having from these complex chronic illnesses there is this big crossover isn't there in so many of these conditions and it's interesting to consider what the driver is of some of the symptoms and if something like this nervous system regulation in various forms can alleviate some of those symptoms then I think we're making strides forwards. One thing that I would say on this is that it is prohibitively expensive. Yeah these devices are expensive yeah and there's a there's a larger question here about what's the difference in efficacy between one of these expensive devices like an alpha stem or like a neuroseum and a simple vatal tens device that you can maybe pick up for tens of pounds or tens of dollars on eBay as opposed to hundreds. Yeah and we don't know what the differences in terms of efficacy ultimately stimulating the vagus nerve is stimulating the vagus nerve and do you have to play a certain tune on it to have the effect you want or will any tune do so that's a big question we didn't have the answer to that. However I do love when I see that a device or a methodology genuinely does have the research behind it and I really did go into that interview so I prepared so hard for that to go in and try and refute their claims. I genuinely did I went through all of their studies and I was pleasantly surprised to see they really do have the results that they say which is something that some of the others just do not have behind them however that doesn't necessarily mean that they don't work it also means that they don't have the huge marketing and power behind them to go out and get that kind of attention within the research market. Exactly and I think one of the most interesting things that came out the research was the potential anti-inflammatory effect that that wasn't something I was aware that this could do before but again it makes sense. I think part of the challenge when it comes to using these devices is around habit forming so how do you make sure that you use it for X amount of time a day every day when the effects are sometimes very subtle and also cumulative. Is that cumulative thing that is incredibly interesting? The other thing about the cumulative thing is it makes it harder to measure in a research setting because there's so many other factors that can feed into any cognitive or fatigue improvements or. Or worsening. Or worsening, hope for that period. So it's very hard to control for everything else in a condition. Any of these complex chronic conditions but certainly I think the thing that are to struggle with the most is that I feel like my alpha stem does help but am I disciplined enough about using it probably not? I probably ought to use it more but when I don't immediately see the benefits of it it's something that you have to be encouraged to do or to try and persuade yourself to do it or put it into your life in a way where you always do it at X time for X long otherwise it just doesn't happen. But Jess you have built into your life taking 72 different supplements or going downstairs and stepping outside on your grass first thing in the morning. So it is one of those things that theoretically we simply need to build that discipline into our lives. I think one of the things for me I actually really enjoy wearing it and I do think I feel some benefits but like you I am erratic in it because there are certain for example breathwork practices or there's certain yoga practices that I do that I will have an immediate shift in my nervous system. A marked immediate shift following that practice and I don't get that with the neurosim so I guess we're all slightly seeking that confirmation as soon as possible. And that's the hard thing with just about any intervention you can ever try with complex conic illness. You want to have something that tells you this work this helps and so much of the time it's very difficult to put your finger on it and it sends you crazy trying to look for signs of whether something helps or not. That's actually one of the reasons regarding you mentioned supplements I'd pretty much been all of mine I don't take any now because I just came to conclusion I had all of them and were they actually doing anything. I've got rid of them all and I don't think there's many difference. It's so it's so hard we do we do so much we try so many things just based on hopes. I guess the positive thing about a solution or intervention like this is there is clinical evidence to show that it does have an impact even if that impact is slight. I think any of us will take a percentage improvement in our symptoms. The question is just whether that percentages worth X £100 or not at the end of the day. Yeah and I think particularly when that is helping with the fatigue helping with the cognitive problems and potentially helping with what you and I have described in slightly different ways but this really really overwhelmed nervous system. Our conversation makes me want to do better with it and actually try to be more strict about it and monitor the progress I make or lack of progress. Yeah same with me. Okay so what we've done today is we're just now going to hold each other accountable for trying to build that into our routine. Let's say over the next two weeks and see if it makes any difference. for us. Yeah, I'm up for that. Yeah. Be fair. To be fair, straight after listening to that interview, I went and got on my AlphaStim for 45 minutes. So it encouraged me to do that. Amazing. Brilliant. Thank you so much for joining me, Jez. Pleasure as always. 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. 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