Vagus nerve stimulation for chronic illness and better health

Elisabetta Burchi (0:00): 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 treatment approach and technology, because it is a technology that can give options to patients to people that have unmet clinical needs for syndromes and conditions that are complex and that are currently missing treatments that are inter systemic.

Emily Kate Stephens (0:38): Welcome to Make visible the podcast shining a light on complex chronic illness. I am your host, Emily Kate Stephens. Welcome to another episode. Hello, Gez. How are you?

Gez Medinger (0:57): 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's look, I say, all the old days, everybody else who doesn't have complex chronic illness probably does this already. They look forward to Friday, right? For me, I still have in my, in my head the idea that I have to be productive, but once it gets to 5o'clock or so, I let myself off the hook, so I'm looking forward to that sort of 5o'clock moments of actually releasing myself from the psychological pressure of feeling like I need to be doing useful things.

Emily Kate Stephens (1:29): 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'd 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.

Gez Medinger (2:09): So, Tuesday I had a shoot out in South Wales, which is a long way away. So, Monday I've got to get 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 over stimulates the nervous system. So, what do I notice in my body? Well, I notice that I can't fall asleep that night because my body just can't shut off. My heart rate's still going mad, my brain's still going mad.

Emily Kate Stephens (2:37): There's something about the adrenaline, isn't there, that -

Gez Medinger (2:40): Yeah, it doesn't switch off. My night sleep is then very shallow as well. I wake up a lot. I was awake for 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, I'm exhausted by a 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 what to do the next day, and then what happens after that, that's when I crash. Hey, crash. So, there is this, this weird thing of this retained nervous system going haywire, 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, a 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."

Emily Kate Stephens (3:28): Yeah, it's almost like your body set goes into some kind of overdrive that thinks, "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 it, I actually realized 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 these 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 I absolutely could not shut down, just push your nervous system to such a level of activation 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.

Gez Medinger (4:25): 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 from other long haulers about how they experience it.

Emily Kate Stephens (4:33): Yeah, so I thought that was a useful way for us to enter today's interview and discussion, which is with a psychiatrist called Elisabetta Burchi, who works with Parasym, and they are the company behind the neuromodulation device, Nurosym, 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 tragus. And just to mention, for those of you not familiar, your tragus 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 coeruleus, 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 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?

Gez Medinger (6:24): I have. Yeah, so I have an alpha stim device, which is, I guess, a competitor at some level for the neurosim 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 shoe, 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.

Emily Kate Stephens (6:52): Okay, so let us listen to Elisabetta Burchi talking about the device that they have developed for neurosim 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. So tell me, how you have ended up working in this bioelectronic 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 want to call them psychological - you have a very wide-ranging 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 medicalized things like heart failure, chronic heart heart failure. 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 kind of marrying this very physical. Talk to me about that rooting.

Elisabetta Burchi (8:25): I like that you like that. Maybe the main reason, which taps into my origins, is that I'm Florentine, so you know, Renaissance style, multifaceted. I've always had an understanding of reality and things, which is three fully 360 degrees, or the largest possible. I will always have this 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, not 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, 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 behavioral, phenomenological level of the other side.

Emily Kate Stephens (9:57): Is that really looking at it as an electrical? When you say circuits, are you looking at it as an electrical system?

Elisabetta Burchi (10:06): Yes, because we know that neurons used 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 circuit level, we talk about the electrical functioning of these systems, which is the way in which that's a very interesting question, yours, but yes, if you think about, if you think about the way we measure functioning, narrow circuits, we use multiple techniques, like techniques which uses 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 is one of the main features or way of looking at them. So, so, yes, I thought that the neural circuits 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 everything. I decided to go to get an MBA, a master in business administration, so totally unrelated to medicine,

Emily Kate Stephens (11:38): that is the thing, isn't it? The vagus nerve because I wanted to magnify the impact of my practice, the more is essentially the connection between what we perceive to be systemic level to affect the well-being, I guess, of more people, so compared to the individual level, which I the physiological and the psychological, essentially the usually operate with my patients, so I completed my MBA concept of mind body, but actually we are just one, we are and got some innovation skills, which then I wanted to just one body, we are all one. consolidate in the concrete world, so I turned myself to the biotech med tech space, and I was looking for interesting companies that connected to the neuroscience space, and then I

Elisabetta Burchi (12:10): Absolutely.

Elisabetta Burchi (12:11): reduced have published so far with our discovered Parasym which was at the beginning, I think I joined the company where we were only three, so I started working with them. I was excited about what they were doing, not only because they were dealing with neuromodulation, a specific neuromodulation technique, which is on invasive vagus nerve stimulation, but 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 nervous system. Intrinsically, this nerve, which with this technique we modulate, is involved in many physiological processes across

Emily Kate Stephens (12:57): and an implanted vagal nerve stimulation. So I would love you to talk to me about the body, and so having the possibility to modulate its function allow us to really overcome the usual boundaries in transcutaneous auricular vagus nerve stimulation, which is what medicine. So my aspiration to embrace was found a little bit parasim does. There are also other transcutaneous methods, but talk to me about the method that you about what parasin was doing multiple levels, so with the technique which could actually redesign the understanding of technique more than 50 clinical studies, and we have a similar diseases and disorders, not just diseases of a specific physiological system, but as diseases, illnesses of number of ongoing clinical studies with more than 100 multi-systemic disease, which is the in truth what I believe about many chronic conditions, or also mental health research collaborations worldwide, so we are really conditions, heavy on science, and we've always put research at the core of our what we do.

Emily Kate Stephens (16:13): Do you 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 gonna dig into this, and yes, Parasym, it..

Elisabetta Burchi (16:27): was real, yeah, absolutely,

Emily Kate Stephens (16:31): and it's not just that it's been you testing it for Parasym. Parasym as 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

Elisabetta Burchi (16:48): verified.

Emily Kate Stephens (16:50): Yeah,

Elisabetta Burchi (16:50): Absolutely. Since the inception of the company, I was not there, but I joined the 2021 I believe, at the beginning. They've always, you know, the founders, they've really cared about

Emily Kate Stephens (17:02): Scientific rigour?

Elisabetta Burchi (17:04): Yeah, scientific rigour, exactly. So we developed the system, which is capable of modulating the vagus nerve through the traverse of the ear, so through the surface of the 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 the nucleus of tract solitaris, which is close of the of the brainstem, and we have developed signal delivery system, which is capable of delivering electrical stimulation, so it speaks the same language of the of the neurons as we mentioned before, and is capable of doing it in a non-invasive fashion, in a safely manner. When I say safely backed up by science versus a C marked medical device deemed not deemed no significant risk by the FDA multiple clinical trials, and effectively simply and effectively we have data 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 renowned markets, HRV, heart rate variability, which is measured by many wearables, and all that we all have, and we use for tracking our well-being overall. That's one of the main markers, gauging the parasympathetic tone, and as we mentioned, the vagus nerve is the main component of the parasympathetic nervous system, which is a branch of the autonomic nervous system. I think, although let's reframe everything, which has a central role in dynamically controlling the homeostasis of the body through action on multiple systems, from the cardiovascular system to the respiratory system, to the gastrointestinal motility, metabolic balance, regulation, 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, has been designed for at home use. Indeed, people can buy it without prescription. This is based on the safety, I would say, mainly, and I think the device we have designed this very, very intuitive to be used. Yes, so that's that's how it works. It works initially, so the stimulation of the duocular branch of the vagus nerve, then the signal, yes, the brainstem. And and then there are a series, a 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. One 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 pathways, multiple pathways. One of those is the cholinergic anti-inflammatory pathway to the spin, and the third category of effects is the neuroplastic one, which is more involved in all the applications regarding psychiatry, neurology, etc. 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 of the potential applications of this technology.

Emily Kate Stephens (21:00): So when Parasym 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 atrial fibrillation, and so it very much a physiological in terms of the heart. When Parasym 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?

Elisabetta Burchi (21:42): It's a very good question. I don't know if initially the no.. 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 treatment approach, and technology, because it is a technology that can give options to patients to people that have unmet clinical needs 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 value snack, because if we think about this capability to modulate all these internal processes with the goal of maintaining homeostasis, namely the stability of the internal environment while adapting to external challenges, we can think 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 homeostasis in response to challenges, we think about the stress spots. Maybe it's not up to me to say, but I believe that in our contemporary society, all of us is involved, engaged, interested 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 nerve does, and the parasympathetic nervous system does is working as a break on the stress response. So even if we just think about that in a healthy person, the healthy potential potentially a little bit chronically stressed, because of just the environment. You can imagine that we can potentiate the vagues nerve, the parasympatheric 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, I'm sorry, call a VNS can be combined with pharmacotherapy and can be combined with behavioral therapies. In a way, there are differences between these approaches, clearly one of the main one I will say that, while with some exceptions, but broadly speaking, pharmacotherapy is less precise, especially and temporarily. In our description of the modulation techniques, we were saying all the targeted stimulations, specific neural circuits, so it's 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're providing approach that can empower people in their everyday life with a tool that can help them boost their resilience, if you think about the stress response, and we have data, and that there is a theoretical rationale behind what I'm saying, but there are already some pilot findings that we have that this is possible.

Emily Kate Stephens (25:35): 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?

Elisabetta Burchi (26:23): 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 long COVID, is definitely there a trigger, viral trigger, but in a certain way the syndrome that arose from that Long Covid arose from the acute infection, in a way, is kind of independent of the trigger, no.

Emily Kate Stephens (26:46): The 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 body should theoretically be able to process evolutionarily, we should be able to either process them and survive, or or not.

Emily Kate Stephens (27:08): research over

Elisabetta Burchi (27:08): Yes, yes, we are so complex that then there is this shade of graze in between, even if evolution doesn't care about us anymore, once we are not really functional from a reproductive perspective. No, but then gladly, gladly, we do not in our lives, I think, we are not subjugated to these evolutionary rules. So now we can survive such conditions, and etc, etc. But no, yours is a very good point. I believe that among the various factors that can trigger these conditions is definitely the environmental pressure, which makes us more vulnerable to this kind of conditions that have in the dysautonomic... the dysautonomias, as the common but is it sort of six six to eight days into it, things denominator, since you are interested in this kind of started to happen, repercussions of the neuromodulation continued conditions, Long Covid, fibromyalgia, they present the same phenotypic features. Think about fatigue and think about after the treatment ended, so the trajectory this cognitive dysfunction, so-called brain fog, widespread pain, neuromodulation put patients on a an upward trajectory in terms orthostatic intolerance, which is clearly a dysautonomic feature, but even the other ones, that I mentioned, and they present with similar features, and all the post-variant syndromes, they are just to corroborate the fact that then the syndrome is in a way 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 disrupted. 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 prevalence of these conditions, and the fact that the unmet clinical 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, that's an important feature of that. 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, and how does that neuromodition impact these patients directly?

Elisabetta Burchi (30:53): Yeah, actually, yes, you are very well prepared. Yes, these two studies, there is a third one down in Mount Sinai in New York, and we have been pioneering the field of transit recollection of VNS in Long Covid with these two tasks, one, three studies, and and we were very excited, because the first study, as you mentioned, that was done in 2021 pretty early on, and is that to the researchers and all that wanted, I was just joining the company at the time, so it was really set up the first study, so in the research community there was really interested for this technology, and they thought about it, even so early on, they thought that they could have been beneficial in the syndrome, and so they set up the study. Of course, these are two pile of studies that they already showed in as it's very short period of treatment, 10 days of simulation. I'm not wrong, talking about one hour 35 minutes of simulation day, which is not much if you think that you can have the stimulation while you are doing other things, that's part of the accessibility and low barrier for patients, for people to use the device, you know, so it was really not a demanding treatment, so in a short as 10 days of simulation in this way, they could have significant improvement in mainly fatigue, but many other symptoms as well. And I would, I will say the second study, the one did a later one, the one done at Casa Colina in California, which studied a female cohort, they were female patients, we know that Long Covid is more frequent in females. In any case, and that second study focused on cognitive improvement, 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 will see, but the cognitive, the brain fog, too, is the other key symptom, and we passed out, we, the researchers, 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 pathophysiology underpinning these improvements, right? So the idea is that in order to get these results, leverage those two pathways I mentioned before, all of these, but mainly I will focus on the anti-inflammatory effect, because know that we know these are hypotheses, because we are still early on the research around long COVID, for instance, but we think that long COVID is definitely also associated to neuroinflammation, right? Then we think we also average the neuroplastic pathway, so if you think about the nucleus of tract storytaris, which is the nucleus we mentioned before the brains, and it is connected to any area, any other areas in the brain, so it's a particle 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 in, because of subcortical, but specifically thinking about the effect on brain form. What we think happens actually is stimulation of the locus cheruleus, which is another nucleus in the brainstem now, which produces no adrenaline, and we know that no adrenaline is connected to attention, and so improvement of attention might have boosted improvement in many other cognitive dimensions that we measure clinically in this study.

Emily Kate Stephens (35:07): Yeah, and you actually relied on the NIH cognitive toolbox to do the assessment of the cognitive improvements.

Elisabetta Burchi (35:14): Yeah,

Emily Kate Stephens (35:15): it's quite rigorous for things.

Elisabetta Burchi (35:18): Yeah, no, absolutely. And I always like to highlight that all these studies that we mentioned also in our website, all done with our technology, so we do not translate results obtained with other devices. That's important, because neuromodulation space field is cutting 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 delivery system, now different stimulation parameters. So we need to be careful when we translate results. Everything we mention, everything we cite is achieved with our own technology, but at the same time, the studies are all independent. We have not funded the study, so the researchers publish whatever they want, and we do not emanate anything. So that's another important facet, the transparency and the independency of the research. So I heard about saying that we collaborate on the protocol design, we give, of course, advice they suggest that 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 process. Talk to

Emily Kate Stephens (36:36): me about speaking to someone before who said that one of the main problems with transcutaneous, whether auricular or otherwise, vagal nerve stimulation is the adherence. It's reliant on 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

Elisabetta Burchi (37:20): pill

Emily Kate Stephens (37:20): drug once a day, and that allowing your body, it is reliant on humans,

Elisabetta Burchi (37:26): so yes, adherence compliance. We actually have a very high compliance in our studies, it reported the very, very high compliance. So I think the relative difficulty in using it is compensated, but this is my psychiatric side, by the fact that people are engaged in the treatment, which you know, I think it's important for care, for care in general, in engagement of the

Emily Kate Stephens (37:54): kind of willingness

Elisabetta Burchi (37:55): of the person, you know, so I think these two aspects are complicit, and then explain the compliance. 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, each and every session, just have to place the electrode, the earpiece at the trabus, and regarding the precision of that, it's not like since we mentioned other Chinese approaches, no, the other one is the cervical one, I can delve into why, according to us, the auricular approach is superior to the cervical one, but for sure, on the precision side, that's pretty clear, because the tragus is spread smaller, despite anatomical differences between people, but tragus is the tragus, the cervical area is wider, so we had not seen a lot of variability, heterogeneity based on the different ways people plug the ear pieces on the tragic,

Emily Kate Stephens (39:05): great,

Elisabetta Burchi (39:05): yeah, and so, yes, the only thing that patients have to do, plug the ear 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 parasympathetic 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 the stimulus, which doesn't have so

Emily Kate Stephens (39:48): That was going to be my question. Is it painful? What is that? What is the sensation of it? Because I'm someone who's used a 10s machine on pain, is it that similar electrical pulsing?

Elisabetta Burchi (39:59): It's an electrical tingling session 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 would say it's in between the sensitivity threshold, the pain threshold, much below the pain threshold. Now you want to feel it, but it has to be pleasant, and it's like the tingling 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.

Emily Kate Stephens (40:28): In different studies, there have been different methods used, sometimes using it 10 times a day for a shorter 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 size fits, or or this is targeting your Vegas? So do this.

Elisabetta Burchi (40:53): 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 furthering 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 that's it, but depending on which kind of pathways we want to leverage, we have to optimize and change the protocol of stimulation. So, yeah, we have done studies in which we have very intense treatments, short in time cumulatively intense, but in a short period of time, I can think about studies done in acute settings. Now, in the hospital, for instance, it's also related to the feasibility, but it's also related to the clinical conditions. If we want to achieve a change in HIV, let's suppose now we can achieve this in as short as five minutes of stimulation. We seen that if we want to achieve anti-inflammatory effect, we might probably need a longer period of stimulation. So now, do you measure

Emily Kate Stephens (42:11): the anti-inflammatory effect? Because I know that in the 2021 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 a wearable,

Elisabetta Burchi (42:34): exactly. So, you need to have a blood draw as a minimum. So, you're

Emily Kate Stephens (42:39): talking about CRP,

Elisabetta Burchi (42:40): right, or many other cytokines, the NFL, fatality one six. These have been measured in other trials in the cardiovascular space, where we had much longer period of stimulation, three six months, and we actually measured significant improvements, so reduction of these anti-inflammatory systemic cytokines in the blood.

Emily Kate Stephens (42:59): In relation to that, this study was not actually necessarily relating to the that our patients will necessarily have, but you did do a study into it, was 2024 into cardiovasal baroreflex, which was in chronic heart failure patients, and 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 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, that difference there, the

Elisabetta Burchi (43:40): 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 are done 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 right side, but we are still furthering the results there, because that study gave good results, other studies give slightly different results, saying that both sides were equivalent types of effects,

Emily Kate Stephens (44:13): 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,

Elisabetta Burchi (44:23): no, no, no, no. Actually, both sides should be pretty effective, and then, of course, there is some variation, inter-individual variation, heterogeneity, but anatomically speaking, both sides should be equivalent in terms of the effects we are talking about. Yes.

Emily Kate Stephens (44:39): Okay. Sorry, I think I interrupted you there, but I wanted to know about that bilateral effect of it.

Elisabetta Burchi (44:46): Yeah, but yes, in any case, it's really lateral. So, in each level, start, we had never stimulated both sides at the same time, just one side. We had 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, we didn't talk about, yes, it's not related to chronic conditions, but I think it can be interesting in any case to everyone. No, because we are who's not interested in the cognitive enhancement side, no, maintaining our cognitive reserve and cognitive capabilities. No, talking about as a psychiatrist. Yes, I'm biased, but I think the core of our identity lies here. No, in a certain way. So, there is not much to protect our cognitive reserve. If we think about in general, in our performance enhancement techniques, there is not much, and so I'm particularly excited about some of our pilot results in healthy people at the population using the 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 the reading comprehension or memory prevention. So, another interesting use case is exactly that we mentioned a little bit, not how we use the device so many times a day, for how long. Looking at the studies, we have a 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 nerve is involved in switching from awake stays to sleep states, so now we boost depth switch. So that's another one talking about healthy, healthy people, no, or or not, not only healthy, but in general, we can definitely apply to healthy as well, another use case is to use it after stressful situation to help store rebalance, or for instance, before stressful situation, thinking about performance anxiety, and there are people that suffer out of it, me included, so before performing physically or mentally, you know, a performance can affect both when we talk about performance, we can think about athletes, but we can think about, you know, 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. There is this personalization piece, of course, that we always need to take into account

Emily Kate Stephens (47:44): from those various different applications that you've mentioned. Is there the suggestion, therefore, that this would have application in after-the-fact anxiety? Would it also have application in preventing cognitive decline? You've done studies into 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 kinds of things in the future?

Elisabetta Burchi (48:12): There is the hypothesis there. We have not published yet anything in neurodegenerative disorders, but as you mentioned, we have studies ongoing Parkinson disease, and we have something going on in my cognitive impairment, so there is the is the mechanistic rationale, 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 thinking about unmet clinical needs, there is really huge, right? So we are working on that. I

Emily Kate Stephens (48:55): think 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 start 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 in to 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 considered 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 add some power over our bodies.

Elisabetta Burchi (49:44): That's exactly right. That's exactly right. I'm particularly excited about this technology, because it's a paradigmatic change. Now, beside the technological part in itself, it's really a theoretical paradigm shift, because in the way we understand illnesses and in the way we understand treatment, so yes, and it all made sense if we think about the functional physiological role of the economic nervous system, which is so trans systemic, 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 relevant 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 Descartes or Cartesio in Italian, 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 soma, the same body, so doesn't make any sense to think about health and diseases in scotomized fashion. This way of understanding the vagus nerve, its function in the phenomenal system as a whole and as a central player in the maintenance of metastasis allow us to really to 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, just to mention one, which can be interesting to many people, is one study we have done in hypertension in young people with the essential hypertension first grade, is at the very beginning of the disease, we have shown reduction in both systolic and diastolic pressure, and this also now taps into all the cardiovascular conditions, which are the main cause nowadays of death worldwide.

Emily Kate Stephens (52:34): 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,

Elisabetta Burchi (52:46): It's mind blowing.

Emily Kate Stephens (52:48): It is.

Elisabetta Burchi (52:49): it is complex. It is complex, and we are trying to pass it out, but most of all, we are interested in the clinical impact, and we are seeing clinical impact. We are trying to elucidate why we do have a clinical impact, or we do have a clinical impact. So it is exciting, and I'm happy that now you also contribute to this adventure, spreading the word 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.

Emily Kate Stephens (53:26): Well, it has been such a pleasure talking to you. Gez, what did the conversation with Elisabetta reveal to you that perhaps was not something that you already knew about the nervous system or vagal nerve stimulation.

Gez Medinger (53:47): Well, I didn't know that they worked so hard on looking at how it could help other conditions, and it makes perfect sense, right, 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.

Emily Kate Stephens (54:07): Yeah,

Gez Medinger (54:07): so, 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 resolved, 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.

Emily Kate Stephens (54:28): 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, 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 forward. One thing that I would say on this is that it is effectively expensive.

Gez Medinger (55:18): These devices are expensive, yeah, and there's, and there's, 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 Nurosym, and a simple vagal 10s device that you can maybe pick up for 10s of pounds or 10s of dollars on eBay, as opposed to hundreds.

Emily Kate Stephens (55:37): Yeah,

Gez Medinger (55:37): and we don't know what the difference is 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 font, or will any tune do? So that's a big question. We don't have the answer to that.

Emily Kate Stephens (55:50): 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, 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 somebody else 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.

Gez Medinger (56:32): Exactly, I think one of the most interesting things that came out the research was the potential anti-inflammatory effects. Now 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?

Emily Kate Stephens (56:55): Yeah, it's that cumulative thing that is incredibly interesting.

Gez Medinger (56:58): 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

Emily Kate Stephens (57:09): - or worsening -

Gez Medinger (57:10): or worsening over 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 I'm 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.

Emily Kate Stephens (57:39): But Gez, 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, breath work 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.

Gez Medinger (58:32): And that's the hard thing with just about any intervention you can ever try with complex chronic illness. You want to have something that tells you this works, 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 are pretty big, all of mine. I don't take any now, because I just came to a conclusion I had all of them, and were they actually doing anything? Got rid of them all, and I don't think it's made any difference. It's so, it's so hard, we do. We do so much, we try so many things just based on hope. I guess the positive thing about a solution or an intervention like this is there is technical 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 percentage is worth x high pounds or not at the end of the day.

Emily Kate Stephens (59:21): 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 overwhelms 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.

Gez Medinger (59:47): Yeah, same with me.

Emily Kate Stephens (59:48): Okay, so what we've done today is we're just now gonna hold each other accountable for trying to build that into our routine, let's say over the next two weeks, yeah, and see if it, if it makes any difference for us.

Gez Medinger (1:00:01): Yeah, I'm up for that. Yeah, fair. To be fair, straight after listening to that interview, I went and got on my Alpha stim for 45 minutes, so it encouraged me to do that.

Emily Kate Stephens (1:00:09): Amazing, brilliant. Thank you so much for joining me, Gez. Pleasure,

Gez Medinger (1:00:13): As always. Bye.

Emily Kate Stephens (1:00:23): Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out about what we're working on and how Visible could help you, visit our website at makevisible.com