Chapters Transcript Video Vagus Nerve Stimulation for POTS Stavros Stavrakis, M.D., Ph.D., presents at the Johns Hopkins POTS Grand Rounds on November 18, 2021. it is my great pleasure and honor to be with you today virtually at least uh and talk to you about autonomic or vagus nerve stimulation for for parts. Um so I have no disclosures and I would like to start my talk with this statement from the french writer Moliere uh who stated that the mind has great influence over the body and melodies over often have their origin there. So this statement actually summarizes about 2/3 of my talk. One more layer. I didn't know is that we can now actually modulate these minds influence to treat these melodies. And this is what the rest of my talk is about. So, um let's talk about the neural control of the heart. It is a complex issue and every aspect of the cardiac, electrical and mechanical function is regulated by the autonomic nervous system. There are a series of interacting feedback loops from the level of the heart uh to the level of the brain. The cardiac reference shown here in blue um transmit be to beat information ah regarding the chemical and mechanical uh milieu of the of the heart to the autonomic nervous system. There is some processing here in the brain stem and uh higher centers which you know this process we don't understand much about. And then we know that there is different information transmitted back to the heart through the autonomic ganglia that regulate the heart a very fine tuned fashion. The heart has its own uh intrinsic cardiac autonomic nervous system which has been called the little brain of the heart by drew armor. It consists of cardiac neurosis on the surface of the heart that are called ganglion a duplex i this contain different, different and local circuit neurons. And these inter neurons actually consists 80 of the nerve population of this gangland complex side. And they serve as the integration centers or the communication towers of the autonomic neural network. Well, there are some populations of neurons that respond to differently to different interventions. As shown here, let's say this is elvia pick, cardio mechanical stimulus provided uh during this time and you know, this neuron did not fire prior and now it fires uh this neuron actually uh decrease the frequency of firing etcetera. And we used to believe that uh this contain only sympathetic and parasympathetic neurons. But now we know that there are multiple neurotransmitters. Uh natural oxide CTRP substance, p histamine etcetera. The brain also controls inflammation. There is accumulating evidence that's suggesting that the vagus nerve provides a two way communication between the brain and the immune system by which the brain modulates inflammation, different vagus nerve nerve signals which originate from the vagal torso, more nucleus and the nucleus ambiguous in the brain stem. I traveled to the spleen we had a silly a ganglion leading to a central calling dependent Activation of the Alpha seven academic as the economy receptor on macrophages which in turn results in attenuated production of inflammatory cytokines. Excuse me. So taking advantage of these properties vagus nerve stimulation through an implantable device has been shown to provide a strong anti inflammatory effects in multiple animal models of systemic inflammation and sepsis more recently. Ah VNS has been shown to be anti inflammatory uh in humans. In this study uh patients with who underwent VNS for VNS implantation for refractory epilepsy uh underwent 30 seconds of VNS inter operatively and four hours later uh investigators uh drew their blood and they showed that just this brief period of stimulation was enough to decrease their inflammatory cytokines, aisle six and aisle one beta significantly compared to baseline. Uh in uh In chronic human studying patients with rheumatoid arthritis. VNS was provided for um one minute 4 times a day. Ah And this resulted in um decrease in TNF alpha and improvement in the clinical score for arthritis. And these results actually raised the possibility that we can achieve a long lasting effect with just brief periods of stimulation. Now, autonomic modulation uh there are many targets um is by receptor activation therapy, gangling and a plexi ablation. Left sympathetic renovation, spinal cord stimulation, renowned renovation uh and for the purpose of this talk vagal stimulation is very important. Um Vagus nerve stimulation can also be achieved non invasively by stimulating the auricular branch of the vagus nerve at the triggers of the external ear. In fact stimulation of this area elicits evoked potentials in the brain stem in humans. Um In this experiment they stimulated different areas of the ear and only this area did illicit uh evoked potentials in the brain stem also um functional uh Using functional M. R. I. It's been shown that stimulation in this area um leads to activation of central vagal projections such such this the bilateral nucleus nucleus tractor solitary. Uh So based on these findings uh we tested the hypothesis that trigger stimulation can also be anti arrhythmic and indeed trigger stimulation. In this rapid atrial pacing model resulted in a decrease of the atria fibrillation in disability. When uh in the three hours that trigger stimulation was applied. Um We translated these results in humans with paroxysmal atrial fibrillation who presented to the ePA lab for ablation. Before ablation was performed af was induced with rapid atrial pacing ah Before and after one hour trigger stimulation. And as you see here the af atrial fibrillation duration was significantly shortened. The cycle length was significantly prolonged, mm hmm, suggesting that trigger stimulation affected uh the substrate for atrial fibrillation. Um In addition low level traders stimulation has been shown to improve heart rate variability and muscle sympathetic nerve activity in humans. This is from our own data when we showed that heart rate variability changes favorably after one hour of stimulation. Uh This is from a group in the UK that measure sympathetic nerve activity um showing that there is a decrease significant decrease uh in the frequency and amplitude of the nerve activity. And this result suggests that trigger stimulation is actually anti Catron urging. Um as I alluded to earlier ah non invasive vagus stimulation or trigger stimulation is anti inflammatory shown here from our own data. one hour of trigger stimulation resulted in a significant decrease and zero TNF alpha. And After six hours 6 months of ah one hour daily stimulation. Uh huh. TNF Alfa was significantly decreased by 23% in this population. Um And importantly uh it was showing it was shown using functional M. R. I. That noninvasive VNS also exhibits memory like invasive VNS does with the effect lasting much longer than the stimulus application. Um Some new data that recently were published also suggests that trigger stimulation improves mood and cognitive function. Um in stimulates or as I said earlier it activates uh central vagal projection but it also activates uh thalamus, hypothalamus and amygdala. Um and uh other areas in the brain that are responsible for uh mood and cognitive function. Uh In this uh an analysis of clinical studies that examined the effect on depression showed that there was a decrease significant decrease versus uh control with um traders stimulation in the depression score. And there are some other intriguing reports showing that uh non invasive vagus stimulation uh improves learning of nobel letter sound relationships in adults. It has also been used for uh neonatal opioid withdrawal syndrome. Actually it has received FDA approval for this. Um And importantly for patients with pots it also decreases or improve uh influencers improves gastric motility in healthy individuals. So um clia tropic effects of uh non invasive vagus stimulation have been shot. So I will swift ah switch gears now and talk about something very familiar to you. Uh The postural for static tachycardia syndrome or pots. So the definition of parts ah Includes it is a clinical syndrome lasting at least six months that is characterized by an increase in heart rate by more than 30 beats a minute Within 5 to 10 minutes of quiet standing or upright tilt. The absence of Ortho static hypertension and frequent symptoms that occur with standing. And it's a syndrome. It's not just tachycardia because it includes this other symptoms like lightheadedness, palpitations, generalized weakness, blurred vision, brain fog etcetera. Um It's quite common. Um 0.2 To 1% the prevalence in the US population uh and it affects predominantly young adults With females comprising about 80% of this population. Now let's look at what happens when we start. Um So there is blood pooling in the veins which activates the battle receptor reflects to increase sympathetic outflow. Ah That increases heart rate contracting city and cardiac output. There is also a constriction of the arterials ah And constriction of the veins which ah increase or maintain the blood pressure towards normal. Now in part uh there is somehow impaired there's a constriction exaggerated by receptor activation, exaggerated sympathy neural response which causes tachycardia without a drop in blood pressure uh But parts is not it's a heterogeneous, it's it's actually a heterogeneous disease. There are different subtypes that is the neuropathic subtype uh that is auto immunity. There is the higher Opara genetic parts, mast cell activation disorder volume. This regulation et cetera. And that can account uh for are the difficulty in treating these patients because there are we're trying to apply um a single treatment for all of them but some may not respond. Um So central to the path of physiology of Parts as alluded to earlier is this uh decrease venus return and reduced stroke volume which causes um increased sympathetic activity. Tachycardia. And the rest of the manifestations of Parts. Um and this uh symptoms uh caused diminished activity which cause cardiovascular dis conditioning, worsening of symptoms. And there is a vicious cycle that aggravates the problem. I would like to draw your attention to. Uh this uh although antibodies that play a role in in parts is something that our group has shown. And by doing so, I cannot help but pay tribute to Dr David kim who recently passed away. Ah He was my first mentor, a true gentleman and scholar who conceived the idea and inspired all this work on auto immunity in parts And how this came about back in the late 2000s. We were studying one of antibodies to autonomic receptors contributing to a tre fibrillation in patients with grave disease. And dr kem reviewed their charts and he made the astute observation that a significant portion of them had pots or pots like symptoms even if they were not officially diagnosed. So he sought to investigate this association further. Um In fact, functional g kabul receptor autoantibodies represent a new paradigm in auto immunity. Uh They have been described in various uh diseases recently from Alzheimer's schizophrenia, uh lupus Chicago's karim arba, his etcetera. Um These antibodies can um exert an Ortho starik effect at the ligand binding site or an analyst eric effect binding at a different side than the receptor ligand. And in general uh they can be activating at the prosthetic site triggering downstream signaling. They can be uh positive ballast eric modulators increasing signaling or negative ballast eric modulators by decreasing signaling or they can be they have they can have a neutral effect. So the presence of these antibodies doesn't mean necessarily that they are activating or blocking it can be either. So um a few years ago, ah our post doc doctor lee um took a few patients, 17 patients with pots and compared them with with control and found that uh these people had increased activity of this uh autoantibodies and this activity could be blocked by either uh alpha blocker or a beta blocker. And importantly in this uh those response curve um Using my g from these patients with pots, the dose response curve was shifted to the right um When we use the alpha uh stimulator Fenella free uh suggesting that this is a negative modulator. And it also uh shifted the fraternal uh those response curves to the left, suggesting that is a positive modulator for the better one receptor. So how do we put this together? So there is uh in the presence of um the alpha one receptor antibodies there is impaired as a constriction which causes uh and increase an initial increase drop in blood pressure, exaggerated, leading to exaggerated by receptor actually activation, exaggerated uh sympathy neural response, increase norepinephrine which then causes uh tachycardia. Uh and the better 100 natural receptor autoantibodies uh enhance this uh and the partially blocked vascular mm hmm, Alpha one receptor uh leads to a compensated blood pressure in pause um in a subsequent publication uh we showed that these people saying people also harbor ah receptors Activating the Angiotensin one receptor and the chief the dose response curve to the right now, interestingly uh those people that did not have the alpha one receptor uh antibodies had uh The angiotensin receptor antibodies. So these are co present and exert the same or similar activity as the Alpha one receptors. And more recently we've shown that um There are also M2 receptor activating advantage bodies. Again shifting the dose response curve to the right so the part of the physiology uh of course uh no longer includes just um impaired vessel constriction. But now we're talking about ah different factors including these activating advantage bodies to the cardiac receptors or inhibiting uh to the vascular receptors which greatly contribute to the path of physiology of pots. So why would uh Vegas stimulation work for parts well? So Vegas stimulation and auricular vagus stimulation uh would activate these uh central wiggle projections and the higher centers in the brain which are responsible for the parts related symptoms. So could ameliorate that. How as I mentioned earlier vagus stimulation is also anti drone ergic. So it can uh attenuate the Ortho static type cardia and it's also anti inflammatory which can also affect pass. So um we had this rabbit model of thoughts ah uh caused by immunization uh from this uh alpha one receptor and better one receptor. X. Second stress out of the loop. And this ah rabbits actually exhibit pots like symptoms shown here. We we have a tilt table that to mimic the um parts uh symptoms. And you can see that there is a significant increase in heart rate without a change in blood pressure. Um And during infusion studies were showing that there is increased sensitivity of these immunized rats to either friendly effort or isil fraternal. So we subjected this a group of these rats to transport a Gnaeus vagus stimulation. And using this model we showed that the change in heart rate was attenuated during the tilt test. Ah The heart rate increase with um infusion of mhm. Many Laughren was attenuated um there was a significant improvement in heart rate variability. And there was a significant uh decrease in the inflammatory cytokines. So what about humans? Um There's one case report of vagus stimulation uh improving parts uh in a patient with both epilepsy and parts. Ah This patient underwent vagus nerve stimulation implementation. And uh as shown here the response after a few months. Uh There was a significant improvement in the Ortho static tie cardia during till this is before and this is after uh um VNS implantation. Um There are a couple of small studies ah from Vanderbilt showing that um transport a Gnaeus vagus nerve stimulation improved part improves parts or at least improves tachycardia. And this uh It took 14 people patients with pots and they did five minute recording blocks Using different frequencies. Uh and then they perform till tests using uh 50 hertz stimulation. And they showed that uh they were able to tolerate tilt uh much better or significantly better after. Uh huh. After stimulation, This one has an acute study. Uh Then they did same the same study. Uh But now they took nine patients uh and stimulated for one hour, four times a day for 14 days. Uh and they had uh better uh quality of life score and Better heart rate response during tilt test, 14 days after treatment. Now both these studies are published as abstracts. Ah And so we're waiting for the full manuscript. Um There are a few randomized clinical trials using transport Tania's vagus stimulation for parts, The one from Vanderbilt transdermal vagus stimulation for pots. Ah This is cute VNS stimulation when I looked in clinical trials dot gov. It's been uh closed for enrollment. Ah And there is another one again from Vanderbilt vagus stimulation impulse, the autonomic inflammatory reflex, which again, it's an acute study that applies transmute a Gnaeus VNS with placebo or combination of either Galanter mean or period of statement acutely in parts examining heart rate responses and Ortho static type Correa tilt. Yeah, this is close for enrollment. Um Then there is uh they study from italy long term effects of transportations vagal stimulation and posture, Ortho static type cardia syndrome. Um Which is a I would say sub acute study uh 14 days of stimulation four hours a day. Uh And this one examines heart rate, blood pressure and muscle sympathetic nerve activity uh tilt. And this one is active. And we have our own study uh which aims to investigate the potential therapeutic mechanisms of transport A Gnaeus vagus nerve stimulation. In patients with pots. Uh And we're about to start enrollment. So uh in our study patients will be randomized to low level traders, stimulation versus sham for one hour daily for two months. We're using the paralyzing device which is like a tense tense unit that has an ear clip attached to either the triggers uh for active stimulation. I remember this area is activated is innovated by the auricular branch of the vagus nerve And for sham stimulation. We're using the ear lobe which is devoid of vagal innovation. We're using 20 Hz Frequency 200 microseconds, posture rations. And we're uh individually tight trading the Stimulation amplitude to one million below that is comfort threshold and uh this level of stimulation we've shown in previous studies that it doesn't cause bradycardia, so it's it's safe. Um The outcomes include Ortho static type area which we're measuring, measuring using a Fitbit heart rate variability based on five minutes, CCGS, antibody activity and inflammatory cytokines. Um And uh We plan to enroll uh 40 patients. Uh and I hope I will update you with some results in the near future. Um At this point I would like to acknowledge ah our funding sources are research and postdoc fellows, collaborators, clinical coordinators without whom these studies would not be able to be performed and I will stop here and happy to answer your questions. Thank you very much. Thank you very much. It was a very fascinating talk. We have some questions in the checkbox. Do You Wanna Comment 1st? Oh I just I just had mentioned in the chat um when dr stavros was doing the vagus nerve stem research in pots. The criteria was six months. Um but it has, there's a newer consensus statement that says three months um which actually doesn't have anything to do with covid. But a lot of people think we changed it because of that. It was decided in 2019 before COVID was an issue. But anyways I just wanted to mention for those who might be newer two pots that the criteria for now is actually three months of illness. Thank you, Lauren. Well actually I have two questions first. Uh so it seems like the Vegas nervous stimulation to continuous traders, stimulation kind of activates vagus nerve at the brain steam level. So it seems like it activates pretty broadly all the bagel effect. So um I mean a couple of questions first, there's some evidence that it may reduce inflammation, but but it seems like the evidence base in that is reduced cytokine levels such as TNF alfa actual clinical evidence showing that DNS can reduce kind of course of any autoimmune diseases or anything like that. Uh Yes. Uh So there is one study uh that I showed in patients with rheumatoid arthritis. Uh There was also an abstract that I saw during the recent a cr that used these in loops and they had some uh preliminary good results. Um So there is some evidence and we also have evidence that's from a mouse model, but I'm collaborating with our rheumatology ease here. Um and we have a mouse model of osteoarthritis. We're doing trigger stimulation in mice with osteoarthritis. We've shown some good preliminary results. I see. So as soon as I posted the question Lauren uh center link, I took a look at quickly. It's a chronic disease and pilot study of nine patients without any control. But my final question is so do you think the VNS works on participation because of this anti inflammatory effects? Because it's autoimmune condition or it's just offset sympathetic tone. It is the technical area. I think it's multifactorial. I don't think it's one mechanism. Um ah It is anti inflammatory. It is anti the energetic. Um we believe. Mhm. It it will decrease the antibodies as well. So, I don't think it's one mechanism. And I think that's why that's why it would be a better treatment than just say, targeting one mechanism with medical therapy. Because it's it has this plea a tropic effects. Mhm. I see. Um Okay. The next David um doing that. Yeah. Pretty, pretty simple question. Uh The idea that the autonomic nervous system consists of sympathetic, parasympathetic and interest is a century old and that is mm hmm. It doesn't take into account the neuro endocrine aspects, especially adrenaline. So, very simple question. What does vagal stimulation due to plasma adrenaline levels? Does anybody know? Um I'm trying to I have I'm not I'm not sure. That's it's a simple question in mm hmm. I have not seen any studies. We have not measured cara column in levels in these patients. All right, thanks. Um And your point is well taken that, you know, it's not sympathetic parasympathetic. This is obsolete anymore. Okay. Thanks. Um can I ask a question. Yeah. You mentioned that uh systemic or vessel constriction is effective in parts a systemic vascular resistance been measured and has it been shown to be reduced? Uh Not in this patient, not in our patient population. We did not measure of vascular resistance. I'm sorry. What what kind of vascular, I didn't hear you. You said peripheral vascular disease, we have not measured has has anyone because we made statements about peripheral vascular resistance or at least that's how I interpreted that. Yeah. I think that's that's the presumed mechanism. Okay. Yeah. There's there's a lot of Presumptions here and I think Julian is on target. Uh you have to be careful even if you have a really rational, compelling explanation, you have to have the data to support it. And I don't think there's any literature documenting that there is a an abnormality of either skeletal muscle renal or total peripheral resistance. Yeah. Well, you know, we we and and and others including the Levin group generally find increased upright, systemic vascular resistance as as might be analogous lee scene in the first stage of hemorrhage. You know, it's compensatory for volumetric shifts. Let's say. I'm not going to say that's the only way it works. But so far I haven't really found any evidence locally. Yes, locally there can be differences in vascular resistance but one would presume that this mechanism is not so local. I mean, I don't know. Maybe the the investigators can can comment on whether the effects of the immune mediated shifts or vagal shifts are localized in some fish. No. Okay, it's all right. It's a complicated question. I want to I want to caution people that using beats, scope or model flow in order to go from finger cuff, blood pressure to two stroke by him and then from there to cardiac output. In total peripheral resistance is a risky business. And uh I would not depend on those those calculated algorithm based changes or inactions exchanges the absolute levels at all. It's true. Mhm. Can I ask a question real quick. Go ahead. Okay, well, first of all, I think these are very important studies from clinical standpoint because, you know, we can argue a lot about mechanisms and what's true and what's not. But at the end of the day, if they are shown to be beneficial for reduction and symptoms in pots or gastric paralysis or pain, I think that's very, very important. And so those are great studies and great presentation. I I liked it a lot. And my question is um so do you recommend today with all the evidence we've gathered, Do you recommend that patients use one hour of noninvasive vagal nerve stimulator at you said 56 you know, herds of intensity four times a day because you feel that in two weeks or a month they'll have a they'll have a meaningful kind of improvement that they can object subjectively themselves confirm. Well, uh right now, I think we have a good we have good preliminary evidence but I wouldn't say we have good evidence to suggest that. So that's why we're doing this uh as a randomized clinical trial. Um uh Now if this proves beneficial in a randomized clinical trial over time then yes I would I would recommend uh that. But um at this point um I when I see patients with parts, I I don't recommend I you know I prefer to enroll them in in these clinical trials. I think there is still a quick close but here's what happens. You know they paid a lot of patients are very much self starters. They don't want to wait for us. Quite a few of my patients have purchased these devices. They're doing it themselves. And then they're asking me, well do you have the parameters, what regimen do you recommend? Of course I only have your papers to go by and so I am just wondering, its either like we join on their bandwagon or we are behind and we appear these ignorant doctors because patients know and that they're doing it themselves. So I think that's where the question is. Quite a few of my patients, they're doing it. Um so far I haven't heard anyone reporting any miraculous improvements. But of course they're doing 20 minutes. You know they're doing half an hour, there is no standardized way uh and I think that's very interesting because while we're awaiting these trials and um on the vagus nerve stimulator and I. V. I. G. And everything else. You know people don't want to wait because they've been sick for decades and they just wanted asap. Yeah. Yeah. Your point is well taken. So if somebody's already using them I will join their wagon and uh you know help them do it as um you know effectively as as soon and safely as possible. Um So based on our experience uh and extrapolating from other diseases um I think one hour daily using 20 hertz 20 micro segments is reasonable. I'm not saying it's the perfect but I think it's reasonable for how long two weeks, four weeks man lately um I would do it for for a month. Okay thank you. Yeah that's very helpful. Or even two months there is a memory effect again. Knowing from traveling from what we know from other diseases. There is it builds up, there is a memory effect. Uh And the more you do it there is um ah more more beneficial effect. What is the danger or the potential side effects can just like diarrhea or something like that because it stimulates Vegas there. Or we haven't seen any device related side effects in our studies and we probably done it in about More than 100 patients. Ah so far. Um And before we started our study in atrial fibrillation we had to go to the FDA and we submit an I. D. For that. And I. D. I mean the FDA came back and said this is a non significant risk device and no idea is needed. So um I would say it's it's it's a we haven't seen any side effects and certainly no like vagal activation like diarrhea and stuff. And as I mentioned there is no bradycardia either. So we're not seeing um that you know that the traditional vagal effects. So. Okay but the vacant activity based on the functional MRI studies right with the same dose of operation. Okay uh Question. Our results measured when with the patient subject attached to the device or with the device removed. In other words they have chronic therapy with this when they come back. So the results are with their device removed. So we are measuring the chronic effects not the acute effects. And are the um investigators blinded? Yes. Yes. Very good investigators are blinded. Um And uh patients are blinded as well. We don't tell them which one is the active and which one is the Shan? Um We've done this successfully in patients with atrial fibrillation. We hope to do the same with these patients. Now these are a little bit more uh involved patients. So we'll see how it goes. Yeah for sure Jeff do you Nicole, yeah so obviously a lot of the older research was done in implantable VNS stimulators. So are are those felt or the external triangle VNS stimulators felt to be equivalent to the implanted ones? Or is there some somewhere to achieve equivalency with those? Mhm. So that's a good question. So um as you know the implantable VNS have been approved for epilepsy and depression in 20 years or more um for so um for epilepsy there is uh there was there is comparison, I'm not aware of any other studies uh comparing the two in in other other diseases. Um Obviously you can stimulate the vagus nerve much more effectively with cervical VNS. Um The issue with with triggers VNS is that that's what we showed in uh in patients with atrial fibrillation. There is there is variability in the response and this variability. It could be from, you know, from a variety of sources. First of all, you're stimulating the triggers area if there is ah and and and you're measuring, we're measuring activation of the of the brain or the heart effects. So we don't know what's what's in between. You know. So I think there are two things that could be happening. Either we are not ah delivering the correct parameters of stimulation or we are not selecting the correct population. Ah Perhaps not everyone with, with parts would uh benefit from this and maybe there are some patients may be the those that have hyper energetic pots uh may benefit more? Or there may be some other characteristics that would select patients that are more likely to benefit from this? So is there a difference between also between the implanted versus external VNS with regard to frequency amplitude and duration of the stimulation pulses. Yes. Clearly. So with we have to increase the amplitude a lot to achieve vagus stimulation from ah from from the triggers um amplitude or mean frequency is the same pass with uh is the same but we need way more amplitude. So for cervical VNS it's in the point It's less than 1.1.2 million amps. And we're using, you know 15 2 20 wow. Mhm. Another quick question. So in your primary data you show that with the vagus stimulation their heart rate responses can improve. But did you what other clinical improvement did they um In terms of their symptoms, did they get better with the fatigue or, I mean you didn't see any diarrhea or anything like that. But did they improve? A lot of people have um So what we've measured so far is is the In our study its its heart rate response. Uh Vanderbilt group showed improvement in in quality of life in those nine patients after 14 days of stimulation. Actually they're graph I think showed um a dichotomy of response. Some people seem to get worse and some people got better. So that's interesting and that gives me more hope actually. Yeah. And I think that that's uh what I alluded to earlier. I think there is variability in the response mm hmm. Um Mhm. That's what we saw with extra fibrillation patients, some responded greatly and some did not respond. You would expect this because this is there are multiple and mechanisms or potential mechanisms at work here. Um This this uh actually is a reality check, which I think is very heartening. And how true then, how long would you expect those benefits stay after? Um Again, that's something we don't know. Uh I think as long as they're using it, they're gonna stay, there is a memory effect. So after stopping it, there's probably, you know, a week, two weeks, something like that um of effect. But if they stop it, I think at some point uh there will be a rebound of the symptoms. Mhm. So if and when it becomes commercially available, you expectations to do this too much every day maybe like in the morning a few times a day. Yeah, it can be part of their routine. And you know, there is uh innovation technology here in technology where you know, you don't have to put a wire, you can put something in your ear like uh you know, an ear buds or something uh and stimulate without even knowing it. Um Yeah. Don't you guys ever look for, did you ever look for gamma core or successfully? We have them FDA approved for migraine. And I'm just wondering are these devices also beneficial? We looked at, we looked at gamma core and uh we actually, I decided against it because gamma core can cause bradycardia and we felt that uh and and that you know, we felt that there may be this may be aggravating some of their uh symptoms, especially the gi symptoms. It's it's a more more intense vagus stimulation that you achieved with with gamma core. The gamma core guys told me that their device reached like if you do a regular branch, you're reaching like 10% of the vagal fibers. And if you do conceptually, you know what they claim that they're doing is direct kevin Tracy disagrees with them and says you're not just stimulating the vagus nerve, you're stimulating a whole bunch of stuff going on in that area. But that that maybe that's why there's is having sort of a a more severe effect of causing more G. I. Stuff and and causing more bradycardia because it's actually just hitting the fibers. And so maybe what they need to do is just lower their dose, you know, or something like that. But I tried to introduce them to David in the very beginning when they came and lectured at our conference several years ago. Um and they were all excited about pots and then they just weren't out of the blue. So um but there's tae you had asked a question about if it's commercially available, like depending on what device you want to use, it is commercial, you could just use a tens unit. It's already there. I brought my, I ran in my bedroom and got my two biggest nerve stem devices to show you guys I've been doing this for years. One is with a tens unit and I actually just throughout the clip because it broke, It was like a $7 ear clip off of Amazon that goes on the tree. Guess I have tried it on the concha separately and I tried to figure out if one works better than the other but the trick is just more comfortable. So I was using it there and I mean I don't have any data on myself, I just feel better when I use it and I my um tens unit stays on for 45 minutes and then automatically turns off. So I do it before I go to bed. I turn it on, I wish I could tell you the dozing I was using but the battery studs so I can't, I don't, I don't remember but I basically turned it up as much right under my pain threshold to get the biggest dose, whatever that means. And um, I also noticed as which would not be surprising that you know when you first turn it on the stem that you can tolerate below your pain threshold, it goes up, I can tolerate more over time. I also figured out completely unscientifically that an on and off stem seems to work better for me than a continuous stem. So like rather than the continuous. I have no idea if there's a rationale for that. Just what makes me feel more comfortable. But it would um, I talked to Kevin Tracey about that and he actually said that his data showed that the non continuous tim maybe actually has a more impactful immune Manjula torrey effect. Mm hmm. So have you seen anything like that in your pots or or other studies? Um no, because we haven't used pulse uh stimulation. We don't have that capability with with the device we're using. So, but that's interesting data. I mean, what you said is that there are scientific explanations for what you said. Like, you know, you said the, the amplitude, you can tolerate more after a while. Yes, that's that's, that's shown before. Um, and uh, you know, Kevin Tracey agreed with, you know, he he has the best data on the immune Immel module, a Torrey effects. So Perhaps it works better. And you did an n of one trial on yourself. I've been doing it for a while. This other devices compass 31 on yourself. I didn't, I should have, you know, this is improved uh this other device, your karate arteries have done that too. I actually can get myself out of some crappy tachycardia by doing that. But this device is from Europe. So I'm impressed. We had a large donor who had gone to europe to try weird treatments there and she got this. Um this is the nemo's device and I'm pretty sure this is what the humanities group is using, which decided on international funded their study, at least one of their studies on Vegas and urban pots and this device goes, you know, on your ear and it's approved for seizures. So it's already available in europe. It's kind of expensive to buy it without insurance. But um, this larger donor, she had to, so she sent one to me and she sent one to Vanderbilt actually to dr Dietrich to see if, um, you know, because we want to find a device that has government of people in different parts of the world, like not just in the US. So I think it's important, just uh dishonorably international had funded some of dr stavros research as well as a study that wasn't listed on your trials list at Children's Wisconsin. Katia Kovacic was looking at the piece stem device which has already FDA approved for pediatric I. B. S. Or sorry, I be stem is the newer name of it. Um, and she was doing that in pots with and without E. Ds looking at pain and just functioning and Gi stuff. Um, but we're looking at three different devices with what we funded and I think that the concept is more important than the individual device. And then once we know the concept works then figuring out like which is the most cost effective device to do this. You know, which device works. The best stuff like that will come next. But anyways, thank you for this talk I'm talking to. Absolutely, I completely agree with you. It's, I don't think that the results are device specific. It's it's the concept that we, that we want to prove. Ah and I'm impressed you got the nemo's, we were trying to get them two. Do you have some devices that they said they're not interested. I can, I can send you, I don't really, it's a little worn. I don't know if you want to use this on a patient. It's kind of getting funky but um I don't use this one. I like the tens device better because I have more control the knee. Most device has like pre programmed settings meant for seizure patients and I like the tens because I can set the timer and the amplitude differently and um you know, a bunch of settings on, on the tents. I think the nemo's has better um connectivity on our contact with the ear. And it has the both the inner part of the triggers and the contract. So, You know, the, the auricular branch innovates the contessa in about 90% of patients. Uh the traders in about 70, And and so there is the variable some of the variability that we're seeing with traders stimulation. Maybe just based on innovation because we're gonna miss one on one out of four just because they are a regular branch doesn't innovate the traders. So um the ideal device would stimulate both the inner part of the triggers and the contract. Are these acupoints? Um Yes, there is an acupoints that is very close two. It's not exactly on the triggers but it's very close. Yeah, because there's been some really reasonably controlled studies of acupuncture and I don't know about the ear. Uh I know that in in California they were doing some work on rats, even anesthetized rats and measuring effects in different areas in the brain. And it really seemed to uh to bear out. So there's an interesting concept in in migraine patients. There's this like kind of patient folklore that if you get a date piercing that this kind of helps like relieve your migraines and this is like a whole literally a hole through the cartilage of your trade and a little piercing and so conceptually it's you know, you have a little earring there now that kind of dangles around and kind of tickles the area all the time. So now I'm well I thought it was nonsense when I first heard about it. I'm like why why did you poke holes in yourself to like get rid of migraines? But maybe they were stimulated their vagus nerve. Yeah. You know the chinese medicine knew all along how important these points are because there were studies on fibromyalgia out of mayo clinic years ago that showed that acupuncture. Like the real kind versus sham procedures reduces pain in patients with fibromyalgia. So it's all good. We're now verifying thousands of years of would they claim? Mhm. Okay. I think you're about 10 minutes past. Is there any other kind of burning question I wanna be respectful for? It's time. Okay. Alright. Great. Well thank you very much again. That is very fascinating. I actually got to ask in the beginning. I kind of recorded it but if you can give me permission, we usually have a media team that reviews and everything and then upload it later on. Is it okay? Or if not we just delete it? Sure you cannot block it. Yeah. Thank you very much. All right. So we have thanksgiving next week. So happy thanksgiving for everybody. And thank you dr give us a talk about mitochondrial disease and parts as well. So, looking forward to it. And thank you very much. Thank you very much. Bye everyone. Bye bye. Thank you. Bye. Created by
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