Adrian Miranda: So what we’ve done for years is used medications, to try and alleviate the pain. But then the idea came and I think over time it’s sort of evolved and it’s starting to catch on now that we could use other modalities outside of medications to potentially change way these signals are being processed. and this could be introduced peripherally or it could be implantable. there’s already several companies doing this, that are sort of Modulating the traffic and how these signals are being processed in the brain, and that’s one of the things we’ve studied in the lab.

Guest Introduction

Bruce Bassi: welcome to the Future of Psychiatry podcast, where we explore novel technology and new innovations in mental health. I’m your host, Dr. Bassi, an addiction physician and biomedical engineer. Today we are with Dr. Adrian Miranda, who is a pediatric gastroenterologist the chief medical officer of Neuro Axis, a medical device company developing neuromodulation therapies to address.

Chronic and debilitating abdominal conditions in children. you’re wondering why we’re gonna be talking about abdominal conditions in a psychiatry podcast, because we’re also gonna be discussing the gut-brain access and the interaction between the two. Miranda is an adjunct professor of pediatrics at the Medical College of Wisconsin, a physician scientist, and has spent the last 15 years of his career investigating the pathophysiology of visceral and somatic pain.

His focus has been on studying the effects of adverse early life events, neuroplasticity, the development of chronic pain. Neuro axis is dedicated to advancing science with its proprietary percutaneous, which means across the skin, electrical nerve, field stimulation, technology, neuro axis. . Already has market approval for the first ever therapy IB stem for functional abdominal pain associated with IBS in children ages 11 to 18.

we’ll be talking more about what that is, but it’s a non-surgical device works by sending gentle electrical impulses into cranial nerve bundles located in the ear. Therefore stimulation targets the brain areas that are involved in processing pain and aids in the reduction of functional abdominal pain.

Associated with IBS currently has one FDA indication in the market, they are undergoing clinical trials for the PNFS in multiple pediatric conditions underway for focusing on unmet healthcare needs in children. So welcome Dr. Miranda.

Adrian Miranda: Thank you. My pleasure.

Bruce Bassi: tell us a little bit about your professional background and how you got interested in this.

was there any sort of, patient interactions that made you realize there’s huge disease burden here that need to focus on? That was not being well-treated.

Adrian Miranda: Yes. Uh, I was in, fellowship, after my residency in pediatrics, we encountered many patients with chronic abdominal pain. and I would always ask my professors, what’s driving this? what is the, the pathophysiology? And nobody could tell me why these children were having these symptoms.

And they all presented differently, but were categorized the same. They would present with abdominal pain. of ’em would have nausea, others would have fatigue. And so nobody could give me an answer why these children were suffering from these sometimes debilitating conditions. And so, I decided to take it upon myself to, to study this further, only clinically but in the laboratory as well.

Shortfalls of the Traditional Approach

Bruce Bassi: What was the traditional, classic approach to addressing these types of issues, and what kind of shortfalls did you see in that?

Adrian Miranda: Well, it’s interesting because when you look at these children, half of ’em, about 50% of children who have chronic functional abdominal pain some sort of underlying either anxiety or depression. And so for many years these children were considered they used the term psychosomatic to describe them. In fact, the first book that was published in the 1950s was a British pediatrician. His name was, John Apley. And Dr. Apley, I think was the one who coined the term little belly acres because he would do million dollar workup on these children, including scans and ultrasounds and, blood work.

And nothing would ever come up positive. And so We were labeling these children as either, type A or high functioning or anxiety, but that didn’t encompass all the children. There was some children who didn’t have these comorbidities yet still suffered from pain. So started, at the time we would treat them with, medications. And to this day, not much had changed, in 60, 70 years in terms of our approach using, medications that are off-label, meaning they’re not approved for these conditions, helped with migraine headaches. So figured why not try them, in the gut, or other conditions for chronic pain.

First Physical Symptoms

Bruce Bassi: What is the beginning of the gut-brain cycle in children in particular, since that’s your area of expertise, how does it begin? Are there any hypotheses as to whether or not they’re, like, what is the physical beginnings that start to amplify the anxious thoughts, and how does that start for a child?

Adrian Miranda: That’s a great question and you know, ask me this all the time in the clinic. Well, my child was fine up until six months ago, a year ago when this started, and . I don’t think we fully understand it yet, but there are some theories regarding, early life, events, child, traumas.

there’s a lot of things that can trigger these and certainly viruses. We’re hearing more and more about covid I symptoms now, or long covid. we’ve been talking about this for years, even before covid because we’ve seen viruses can definitely trigger, these events. so any infection, if you look at, any enteric infection, salmonella, anything that invades the, colon sort of unmask that underlying, whether it’s a, genetic or a epigenetic phenomenon or even you know, we see it in children who’ve had early life traumas. And this is one of the reasons I went into the laboratory to study this because what I realized from doing animal experiments is that if you look at an adult rat for example, and you inflict sort of adverse event, whether it’s maternal separation or isolating the animal or some sort of discomfort in the somatic region, in the leg, they do develop pain Or a hypersensitivity to whatever stimulus you’re doing, but that tends to go away after two, three weeks. if you do the same stimulus or the same adverse event, if you will, in the neonatal rack. That persists for a lifetime. And so the neuroplasticity that occurs at a time of, of development where the brain is plastic, meaning the brain is forming those connections, can lead to long-term, problems or long-term pain symptoms. I think it’s important to, to realize that. Adverse early life events can definitely, increase the risk for this to develop. And then you have a second hit, whether it be, like I said, a viral infection, an enteric infection, a traumatic experience, bullying at school, something that unmask that

Bruce Bassi: How do parents typically respond when they hear that hypothesis of how it could have potentially started? Is that something that they feel like it helps explain and validate it, or do they feel more shame about that?

Adrian Miranda: No, I think it, does help validate it. I don’t think they feel shame in general, and I think that parents are sometimes grasping, straws trying to figure out. What’s driving this, and for some parents it’s difficult to really accept. some parents it’s, more of, I want to do more testing.

I want to make sure we’re not missing anything. we have to explain to them that, the intestine, the enteric nervous system is made up of millions and millions of neurons. you have 30 trillion bacteria in the intestine, that are also, playing a role. And then you have the vagus nerve that Communicates from the intestine, the stomach, the pancreas, the gallbladder from all these different organs up to the brain, sending messages, and traffic going up to central pain region. So the brain and the gut are definitely connected and we’re learning more and more about this. And I think it’s explaining to the parents that, you it’s not their fault.

this is a process that occurred over time, and we just try and do our best and try to manage symptoms.

Bruce Bassi: what is the workup like to make that diagnosis? Is there clear cut standards for how to make the diagnosis or is something more along the lines of a fibromyalgia where they come up with a criteria and set that you have to meet?

Adrian Miranda: it’s more along those lines. There

is a basic workup looking for what we call alarm symptoms or the red flag. if a child for a pediatrician’s growth and development is critical. So if a child is not growing well or losing weight, if you’re having blood in the stool, any type of abnormal labs such as iron deficiency, anemia, low protein in the blood, gives you clues. But it doesn’t make a diagnosis. And unfortunately, even now, 70 years later, we’re still talking about symptom-based criteria, where you are basically giving a diagnosis based on symptoms and not underlying pathophysiology.

Bruce Bassi: So for our adult counterparts who might be listening to the episode, what kind of parallels are there? Can all of this information be applied to adults or are there any differences or subtleties that people need to know about?

Adrian Miranda: Yeah, they’re very similar actually. If you look at the criteria, call it Rome criteria, and that’s the, the criteria that has been used. they’re very similar in adults and in children. we believe that the pathophysiology is very similar, unfortunately. It may be that it starts very early on and this is why one of the things that I’ve been promoting for quite some time is let’s start treatment early so that we don’t have children right now. Some statistics and studies show that about 40% of children who have pain early in their life, whether it be adolescence or early life, will go on to have Same type of pain are slightly different in adulthood. So the children, we’ve always said, right, it’s pediatricians, children are not little adults.

We have to treat ’em differently. But what we do in the course of, treatment, it does impact their life later on. So these children do become adults eventually, and, and they do become, some of ’em become adults with irritable bowel syndrome, chronic pain. You mentioned fibromyalgia.

Neuromodulation

Bruce Bassi: it sounds like is real . pain signals being sent through the afferent receptors into the brain, and then our interpretation of that pain is just amplified and totally ramped up. how does that play into why neuromodulation started to be looked at for treating an abdominal issue?

Tell us a little bit about how that came about as a treatment option. Neuromodulation.

Adrian Miranda: 100%. I think one of the most important things when you see a patient in clinic is to validate their pain because, it or not, there are still, physicians and providers out there that tell children or patients that it’s in their head, when in fact we know the pain is real. And so you need to validate the patient and the family by acknowledging that this is real pain. The signals are being interpreted by the brain as pain, and so, which is very different than what we see, for patients who, who don’t have pain, they, process coming from the gut.

You’re digesting your meal. There’s a lot of gases. there’s Chemical reactions. there’s distension of the bowel, there’s motility that occurs, and movement, uh, in peristalsis. But normally you don’t feel that because the body does a good job of suppressing that. So you can go about your day and you don’t have to think about those things. like you said, in these, patients, what you see is an amplification or different areas that are processing the pain. So what we’ve done for years is used medications, to try and alleviate the pain. But then the idea came and I think over time it’s sort of evolved and it’s starting to catch on now that we could use other modalities outside of medications to potentially change way these signals are being processed. and this could be introduced peripherally or it could be implantable. there’s already several companies doing this, that are sort of Modulating the traffic and how these signals are being processed in the brain, and that’s one of the things we’ve studied in the lab.

Polypharmacy Problem in Children

Bruce Bassi: It’s very interesting. So have this option. What is the lead up like in order before they are presented with this treatment option? I’m sure they need to . Some imaging lab tests, how often do you see them before recommending this option? ‘ cause you have to do a medical workup initially, right?

For a new patient who presents to you with abdominal pain, don’t immediately assume it’s IBS diagnosis, correct.

Adrian Miranda: right. So the umbrella term that is now being used to encompass these disorders that involve pain, it’s called disorders of the gut brainin interaction. used to call them functional abdominal pain disorders. And recently the, terminology has changed to include all of these, but some of them are involved pain.

So d GBIs or disorders of the gut brain interaction include irritable bowel syndrome, functional dyspepsia, abdominal migraine, and functional abdominal pain, not otherwise specified. reason to develop the symptom-based criteria was, twofold. One was to, be able to study these patients. Clinically and, say let’s put ’em in categories to see what medications and what treatment options and how we can improve their quality of life. The other reason was to be able to limit the amount of testing that you do clinically. you don’t want to spend dollars doing unnecessary testing, just from from a, fiscally responsible perspective, but also to limit testing on patients is important. So most gastroenterologists feel comfortable making this diagnosis, with limited testing. Now they usually present to the pediatrician first, and the pediatrician, in charge of making that diagnosis or referring to the gastroenterologist to say, Hmm, I don’t feel comfortable with this diagnosis. And sometimes my conversations with pediatricians about this, I’ve learned that They feel very comfortable making the diagnosis, but a lot of times it’s the parent who says, I want to see a specialist. I want to make sure that we’re not missing anything. So, I hope that majority of children who are sent for further workup aren’t getting endoscopies and ultrasounds and colonoscopies. I’m a firm believer that we need to start treating children early. if you look at The long-term effects of having pain. I’ve always said the longer you have pain, the longer you have pain. In fact, neurons that fire together, wire together. So by the time they see the pediatrician, the time get the referral, the time they make the decision to start treatment, and most, to answer your question more directly, most people will start some sort of treatment first before going to Some type of neuromodulation device only because it’s new. it’s always easier to, use a medication than to implement something new that may, may not be covered by insurance. That’s difficult to get sometimes, depending on which center you’re at. I think that we’re trying to change that, sort of practice pattern that physicians have in the west of Drug first mentality. And I think that’s gonna be important, particularly in children, there are no approved drugs in children. There are no therapies that you can say, oh, this is, approved. And again, going back to the neuroplasticity, anytime you introduce pharmacological therapy, there’s going to be a change.

The body’s going to try to find homeostasis, right? So it pushes back and it changes What you’re doing in order to, find what the body considers normal. And in children when the brain is developing, you use medications that could potentially block the transmission of, impulses between neurons block synaptic connections. an example are the anticholinergic medications. you look at all the medicines that are being used. For children, for chronic abdominal pain, they pretty much all fall into the category of an anticholinergic. You talk about the antispasmodics, you talk about amitriptyline, some of the SSRIs, cyproheptadine. So what’s interesting is in the adult. populations. There’s a, a big push to limit the amount of anticholinergic activity or what we call polypharmacy these adults can develop memory issues, increased risk for dementia. If use these anticholinergics in combination, what they call the, anticholinergic burden, but the conversation hasn’t reached children yet. We use these medications quite often. Again in the developing brain. So we have no idea what’s gonna happen long term when we treat these children for six months a year, sometimes years. this is one thing that’s really been concerning to me, I point this out to my nurse. It’s interesting ’cause my nurse and I have been working together for 20 years

we see the same population. and what we’ve seen is this increase in . medications that are being used in adolescents, pediatricians have become very comfortable using SSRIs. For example, presents with anxiety. Let’s start an SSRI. Let’s see how you’re doing and how you do. But by the time they get to us, already on multiple medications and I always worry that we really don’t know The long-term effects of these medications. And so I think there’s a role these medications for sure. And I think it’s important that we are judicious in how we use these medications and the duration of therapy needs to be discussed. I also think that sometimes it’s too easy to prescribe drugs and then you get into this polypharmacy that we see in children.

PNFS Device

Bruce Bassi: So let’s talk a little bit about the for a second, because I think it’s really fascinating. We need to have some time to discuss how it works. And from engineer in me, I just, I think it’s pretty cool. so it’s Percutaneous electrical nerve field stimulator. do you all have a nickname for this for short to

off the tongue a little

Adrian Miranda: PNFS.Yes.PNFS is what we call it.

Bruce Bassi: I’ll read what’s off your website. So it’s intended to be used in patients 11 to 18 years of age with functional abdominal pain associated with IBS. The IB STEM is intended to be used for 120 hours per week, to three consecutive weeks the application to the branches of the cranial nerves 5, 7, 9, and 10.

The vagus. And the occipital nerves as well, are identified by trans illumination, which I also want to talk you about that, how, what that is and how, that works as an aid in the reduction of pain combined with other therapies for IBS. as a mouthful, what it also, is interesting to me that it’s not just the vagus nerve, but there’s also five, seven, and nine here in other occipital nerves and

tell us a little bit about the basics for how it works, and then we’ll go into more specific detail.

Adrian Miranda: so, the idea here is that you’re stimulating the branches of these cranial nerves. In the ear, right? So that gives you access to the brain. So you have peripheral access. It’s sort of like a USB port that you can connect to the ear and it gives you access to the central nervous system. And you could actually, did this experiments in the lab, which is how this all started early on in this population where, you could do electrophysiology, recordings from animals and pick a spart in the brain where you can record. And what we found was that, particularly when we looked at the amygdala, the amygdala is part of the limbic system that’s involved in fear. The emotional response to pain also helps control the autonomic nervous system. there’s several studies already in humans using FMRI and other modalities showing that the amygdala is involved in, the pathophysiology of irritable bowel syndrome and other chronic pain conditions like fibromyalgia, pain conditions. And so we noticed that by stimulating the ear in the animals, you could reduce the firing of neurons in the amygdala by 50, 60%, 20 minutes after stimulating. So that was very interesting and it gave us an idea that. Perhaps what we really were doing is neuromodulation, because you can change how neurons are firing. But I think that was the tip of the iceberg because when you stimulate the cranial nerves, and you mentioned vagus is in there as well, cranial nerves give you access the first stop in the brain is an area called the nucleus tract de solitar or the NTS. And once you get to this area, you’re able to, go to other parts of the, brain and also decrease the periphery, send signals to the periphery, to the stomach, to the gut. And so that was the beginning. Later on, there was other studies in patients with fibromyalgia that showed that perhaps you could change, connectivity in the brain. but that’s the basic principle is that the ear has these cranial nerve branches that give you access. if you can imagine the, ear as a Brillo pad and you’re putting an electrical current and you light up the entire ear with four different electrodes part of the secret sauce is that you’re actually changing the polarity of the electrodes. You can’t Stimulate a nerve continuously because the body figures it out. It’ll stop firing. attenuates after some time. But the idea is to change the polarity of the electrode so that you can continuously stimulate for five days. so patients will keep this on for five days. get a two day break, then they put it on again in the clinic, and then they get another five days.

So every week is a five day with a two day rest, period.

Bruce Bassi: Gotcha. How is it different from other neurostimulation devices I think VNS is implantable vagal nerve stimulation, then they have transcutaneous auricular VNS device now.

Adrian Miranda: Right.

Bruce Bassi: similar in theory? you know how it, differs from these other types of stimulators cause those are more geared towards psychiatric, symptoms in adult patients.

you talk to us a little bit about that?

Adrian Miranda: of the things that’s very different is again, what I talked about, the changing the polarity. The other is you really have to in in my opinion, penetrating the skin offers a whole new level of stimulation because you’re dispersing the signal throughout the skin. The skin is a great barrier. So although there are some data looking at transcutaneous cervical stimulation, just in psychiatric conditions, there’s example, cluster headaches, migraines, and other conditions. There are some studies showing that perhaps it could be beneficial. companies have taken advantage of the cervical vagus nerve to implant, vagal nerve stimulators. There’s one that’s very interesting that’s actually doing, a cervical implantable, stimulator to modulate the immune system. what they’re doing is they feel like they found the perfect parameters of stimulation to modulate the immune system because There’s hundreds of papers that show that the immune system can be modulated by vagus nerve. and so by doing this, they’ve shown data on rheumatoid arthritis data on Crohn’s disease. it’s very interesting, the implantable. Now that’s a surgical procedure, that requires implantation of this small microchip looking device. and again, you know, people have tried to stimulate the vagus nerve from many different directions,

but I think what’s unique about this is, the titanium needles that disperse the signals, and really, encompass the entire, structure of the ear and the cranial nerve branches that are there.

Bruce Bassi: Is there any adjustment of the frequency or um, amplitude of the signal the IB STEM is using, over time or is it just a one, setting for all patients?

Adrian Miranda: that’s a great question. Right now, it’s one setting. there are changes for some, in terms of the duty cycle when it turns on, when it turns off, But in terms of the voltage and the frequencies, the reason to change that is not so much because we feel that we can improve the technology as far as improving symptoms, but there are patients who have allodynia, for example, that’s an exaggerated response to a normally non-painful stimulus. And, a small number of, Children or adolescents do have a hypersensitivity. And so we have to turn down the voltage. Eventually we’re working on version two, that’s gonna allow us to tailor stimulation parameters, those patients who, who feel, who have this hypersensitivity.

But right now, it’s one size fits all if you will.

Research and Outcome Data

Bruce Bassi: what is the research saying about this device? How, convincing or impressive is the outcome data from this?

Adrian Miranda: that’s one of the most exciting, that we have. I’m a data-driven person. I’ve done research my entire life in, the basic science lab and also clinically, that’s one of the things that we set out to do is say, let’s make sure that we have the data to back this up and The first study that was published in The Lancet, 2017 was a, sham controlled randomized control trial that, compared, active device versus a sham device that looked exactly the same. and this device, didn’t have this electrical stimulation. It only had, the needles that were inserted in the ear and the data, for pain, the data on functional disability. ‘ cause I think that’s one of the most important things that we see consistently. And mostly all the papers that have been published. I think we have now 14 publications in the same area of study. We’re not trying to look at other areas. We’re really laser focused on these disorders of the gut brainin interaction.

And eventually we’re expanding. We already have some trials in other but we wanted to make sure that we, really, up good data. And there’s, multiple, uh, sites, and institutions doing the studies showing improvements in, functional disability, and pain, and also Interestingly enough, this is off label, but we’ve seen improvements in, every measure of anxiety. and again, this may go back to what we were talking about earlier in the amygdala, the anxiety could be related to that. This is the studies using validated questionnaires and measures to say, look, we’re improving these symptoms, but what we’re focused on is really improving the quality of life of these children. to me, and the psychologists have talked about this for years, improvements in functional disability are key. ’cause if you start functioning You will eventually get better. And that means for our patients, means getting back to school. It means going to soccer practice, going to dance, going to, all your activities. If you wait for the pain to get better, usually it takes longer or, or you’re not gonna get better. And so think that’s really important. And I think the other thing, you know, speaking of data and studies that have been published, I think it’s also important that in this day and age, if you really look at some of the studies that have been done, it’s hard not to find conflicts of interest with people doing the data and doing your studies.

And one of the things that we’re very proud of, and this may resonate with some people, is that study that we have ever done is an investigator initiated study. People come to us to do the studies and we don’t put limitations. We just say, go do it. Here are some devices and we’ll help you with whatever we can. so these are top institutions around the country that are doing studies, because they, they believe in it. they wanna see if it works, and they’re, they’re about it.

Bruce Bassi: Do you think the study outcomes could generalize to the adult population too? Say if individuals wanted to use the device off label, if they are really struggling and feel like it could be helpful for them, are they allowed to, purchase this and, and for it? And though there’s not the actual evidence there to back it, there’s not the FDA approval there.

Can adults use it?

Adrian Miranda: I think they definitely can. there’s an investigator at Emory University that has done some really fascinating studies with patients, with suffering from fibromyalgia. this was at the, Veterans’ Hospital. And, she showed that, pain did improve, in patients as a small study, but she also looked at FMRI changes, and she looked at what parts of the brain were being affected by P-E-N-F-S and she compared it to standard medical therapy found very significant differences terms of the. Parts of the brain that were being stimulated standard medications, you see a decrease in the connectivity between the insula in areas of the default moat network. PNFS, you see increased connectivity in the insula to the cerebellum the executive function of patients as being modulated.

So there’s already evidence to show that it does work in certain conditions in adults. the only problem is, I, don’t want to mislead patients, is, finding a provider that will place the device. that’s the challenging part for adults who want to use it off label. know, as physicians we all have that, right?

To use something off label and say, yeah, I think it’s gonna help my patient, but finding somebody that, is a trained adult provider to place it is gonna be challenging, to answer your question can it be used in adults? my feeling is that it can based on the mechanism, and I hope that eventually the FDA agrees. it’s interesting because few devices are investigated and approved or cleared by the FDA for children first. we took the opposite route of most, medications or drug companies do. Where device companies is that we studied it in children first and got it approved, and now we trying to extrapolate to adults it’s usually the other way around.

And the FDA has guidance on what they call reverse extrapolation there’s so very few devices that approved for children. saying if you can show us that based on the mechanism and that it is safe, and that there’s data we may consider extrapolating the device from adults. Two children and a lot of things have to align. But in this case, if you really think about it, they’re adolescents. Is there really that big a difference between a 17-year-old and a 25-year-old or a 30-year-old? Probably not.

so I think that that is our goal, is to be able to get it to the adult population as well.

Transillumination

Bruce Bassi: That’s a good segue. When you mentioned trying to identify how to place the device for, talking a little bit about what trans illumination is, my guess is a lot of to the podcast probably don’t know what that is or have heard of it, including myself. Can you talk a little bit about that and how it works and how long it takes, what’s the process there?

Adrian Miranda: Yeah, the term sounds fancier than what it really is. it’s basically shining a pen light through the ear, from one side to the other. shine up a, on the ear that allows you to identify what we call the neurovascular bundles, right? So the vessels in the ear, are usually attached to the nerves. So they run together. That’s why they’re called neurovascular bundles. So by doing that, you are able to identify those larger vessels and you just wanna avoid placing the needle or the electrode directly on that neurovascular bundle. you want it in close proximity to the nerve, you don’t want it poking through or on top of it. And so that’s the only reason to transilluminate.

Bruce Bassi: Is there a lot of variability there? Is that why anatomic landmarks are not used and used the trans elimination because it could be variable.

Adrian Miranda: It does, it is variable. and when you place the electrodes, it’s in the general vicinity. You trans illuminate, you find the area you find the four segments, four areas of the, ear and anterior to the ear. and then, you place the, device. once you do one, it’ll take you 10 minutes to place the next.

And it’s really, not a surgical procedure. It’s very simple. know this is old school, I trained it was, C one, do one, teach one.

I think in this case it still applies to that. you could very easily see one, do one, teach one within a half an hour. An hour.

Bruce Bassi: So they have the device, are they able to shower with it and go about their day regularly or

Adrian Miranda: able to shower as long as they don’t get it wet.

I think that the biggest issue is, you know, getting, not because it, shock them or it’ll stop working. But mainly you don’t want to get the adhesives wet. It becomes very uncomfortable, because you do have an adhesive that goes over it. Uh, think that’s the biggest reason. But you can still shower and, wash your hair as long as you don’t get the device wet.

Patient Story

Bruce Bassi: Can you talk a little bit about a patient story, ? Who, of an individual who maybe struggled to find treatment for functional abdominal pain or, DGBI

type of issue that, had and how this neuromodulation impacted their lives?

Adrian Miranda: Yeah. Well, there’s several patient stories. There’s many, in fact, there’s several institutions now coming out with, Stories because they’re children, you know? And, and that’s one of the reasons, of us in pediatrics, that’s what we do. We try to help children and get their lives back.

I think that one of the stories that, always think about is, is child that was an adolescent who was very disabled. And so this is a child that didn’t want to come out, didn’t wanna leave his house. because he was in pain and he had chronic nausea, pain, discomfort. And so with these, conditions, they tried many different, medications.

they tried, I think tried at least seven or eight medications. And, by the way, if you look at the data, on some of studies that have been done with PE NFS, the majority of children have failed medications. they’ve gone through three, four different drugs and nothing has worked. This particular child was just disabled. but I think it’s also important to point out that not every child is like this, right? children who have abdominal pain, they have, minimal pain. They have 10 minutes of pain. That’s a, two outta 10. And mom or dad, my tummy hurts. they distract them and they go about their business and they’re fine. Those kids don’t require medications. Those kids don’t need to be treated with neuromodulation devices. Those kids need reassurance. they need maybe a diet change, potentially a lifestyle modification. but then there are those, like this particular child who was very disabled, could not go to school, had to stop, track.

He was a very, good, athlete, and had to stop doing, track. And so, it was incredible because sometimes it takes, four devices, to really see the full benefit. After the first device, this kid started Going outside, started riding his bike. three weeks later he was back in school. back in, doing the things that he loved most. and we just keep hearing stories like this all the time about how it’s changed, uh, lives. not every child’s gonna be like that. You know, it’s it’s medicine. it’s not, this is going to cure everybody and this is gonna turn your life around, but. the number of cases that we’ve seen that it does happen, it’s very rewarding and very exciting. So, yeah, going from not being able to function, being at home, not wanting to leave the house because of, these debilitating symptoms to your life back in the family, giving you hugs in the clinic, and thanking you for, getting their life back, I think is, very rewarding and why we do what we do.

Bruce Bassi: Are you starting to understand what types of individuals would benefit the most from this device or characteristics of the illness that, show that this is going to be better for them?

Adrian Miranda: Yes. And this is one of the things that we’ve set out to do, is to try to figure out who are those children that are going to respond the best. there’s one study that’s published outta Milwaukee that reanalyzed the randomized control trial data, and they went to some of the experts in vagal nerve, the polyvagal theory and in vagus nerves and what they consider vagal insufficiency. That means that the vagus nerve cannot do its job. It can’t bring up that parasympathetic rest and digest stimulation that normally is involved. So these kids could have, you know, high sympathetic tone and have lower parasympathetic tone. So they call them vagal insufficiency and they have a very sophisticated software to, to this. when they looked at the patients that responded in the clinical trial, those were the patients that had vagal insufficiency. And so that gave us an indication that perhaps it may be vly driven. and maybe it could be that it’s just a signal, but it’s certainly something to build on and to do more studies on. that was the first clue that, we’ve had, that the vagus nerve or vagal insufficiency post viral potentially, you know, like I said, Post long covid has been associated with vagal insufficiency, and other viruses. So, are the kids that have fatigue, that have chronic pain, chronic nausea, those types of symptoms as well.

Considering the Device as a Possible Treatment

Bruce Bassi: That’s so interesting. Where do you think that the device should fall in one’s treatment algorithm for these of illnesses, say from a ? Child psychiatrist perspective, an individual who has high anxiety and abdominal pain associated with their anxiety, maybe it’s not always linked temporally to their anxiety.

Would you recommend they send them to a pediatrician evaluate ? the GI pain, can you give us some characteristics that might be red flags for a child psychiatrist where they would send them directly to pediatric gastroenterologist?

Adrian Miranda: well, we have to consider that, You have to stay on label, right? So it’s approved for chronic abdominal pain. I think that where it falls in the algorithm and, the National Society guidelines are coming out soon, and see where they put it in the algorithm of treatment.

but certainly in my opinion, as a physician, If you’re considering using a medication to treat abdominal pain, then this should definitely be on your radar. I mean, it’s that simple. because if you’re using a, drug saying the symptoms are severe enough that the benefits outweigh the risk. and we talked about this earlier, the risk could be high, for some kids we just don’t know. So if you’re considering a medication, a prescription drug to treat a child with chronic functional abdominal pain or DGBI, then this should be up there in your, treatment algorithm. The other is have plenty of families now.

I think people are getting smarter in saying, well, I’ve kind of read about this, and there’s no good data to show that these medications help. are there other options? If the family’s telling you, I don’t wanna put any drugs in my child’s system, that’s something that you need to consider. I think it depends on the symptom severity how disabled the child is. it’s a clinical diagnosis that I think that most people feel comfortable. Now, my, vision for the future is that I hope that something that is so safe. And has the benefits that, that have been proven, not just clinically, but also in, studies that pediatricians eventually feel comfortable treating children.

that to me would be the best approach because now you’re, waiting, entire time you’re treating with something that’s safe that could potentially be beneficial. You just have to feel comfortable with the diagnosis. and I think that, this is a topic, for another conversation, but this is where artificial intelligence in the future may help drive that. pediatricians now feel comfortable with a diagnosis of A-D-G-B-I using AI tools that could say, you know, with, with degree of confidence, child has this condition. Feel free to treat that.

Safety

Bruce Bassi: I think that’s a good opportunity to talk about the safety profile of this since we didn’t talk about it directly, more indirectly compared to medication options. I am on your website and it seems like no-brainer. The, numbers are extremely low one study, is from 2017, there was 2.8% of dermatitis at the lead implantation site generator placement site.

I mean, And another study. This is from 2016 by Roberts, these numbers are like It’s even a hundredth of a percent of either dermatitis or fainting infection or bleeding, extremely low for over 1200 patients. so basically no serious adverse effects and extremely minimal side effects.

Is that what you’re seeing?

Adrian Miranda: Yeah. And as we treat more and more patients, we’re gonna see more obviously, potentially, adverse events. But so far, it’s been very, very reassuring. Uh, fact, that’s one of the reasons the FDA liked it so much as well. and why, a lot of pediatricians and gastroenterologists are liking the idea of using this instead of medications, because the downside is, okay, so what if that number was a little bit higher in terms of dermatitis or children having a skin reaction, to the adhesive  maybe just the allodynia that we talked about. It could be as high as 10% where patients have some discomfort. and so that to me, seems Like you said, a no brainer in terms of comparing the medication. so far there have not been any serious, or significant adverse events. it’s mainly been localized to the ear or to discomfort or skin irritation.

Bruce Bassi: Dr. Miranda, this is incredible. You know, I’m really glad that I had the opportunity to talk to you about this. I’m just kind of, overwhelmed with how, safe and effective this is compared to other options The potential impact that it can have on the pediatric population as well. Not only pediatric, but when they grow up to be adults too.

Like you said, these are, lifelong issues that maybe evolve into other mental health issues as well. so you give, audience a little, summary of, how they might be able to find you or learn more about ? The device itself or any other information that you think would be helpful for them to know?

Adrian Miranda: Yes, I mean, we’re excited. wanted to learn more, you could always go to our, website called kids stomach pain.com. That, not only talks about this technology, but also, I think it’s important to talk about other treatment options and the risks and benefits and, what’s out there and, how to approach this.

I think we need more education, just for families, but a lot of, Providers, we need to change practice patterns. We need to talk to, providers and say, listen, there are other ways of doing it. it’s 2024 and unfortunately that’s

what we learn in medical school, right? We take a year of pharmacology. I remember the flashcards, and that’s what you do for a whole year. You learn, mechanisms. You learn side effects, And then that’s what you’re thinking about as you’re seeing a patient is, okay, can I use to combat this symptom? I think things are changing slowly. And, if I could, you know, give one message is let’s start thinking about what we’re doing when we do prescribe medications for children, there’s definitely a role for medications, not just in mental health, but in pain as well. But we have to think, twice, we do it. And we to have an endpoint. and we have to think about other options that are available that could perhaps be safer, and even more efficacious.

Bruce Bassi: Dr. Miranda, I appreciate you so much for coming on and talking to us more about the device and functional disorders in general. you so much.

Adrian Miranda: My pleasure. Thank you for having me.

That’s it for this episode. I’d appreciate it if you please like and share this podcast with your colleagues. It’d be especially helpful for us. And if you’d like, please leave us a rating on your favorite pod catcher. If you’re a clinician, I developed a course on how to start a private practice and for patients, I’ve also developed a course on acceptance and commitment therapy and cognitive behavioral based therapy lessons for treating and helping anxiety.

Adrian Miranda: You can find all these on our website as well, as well as the show notes and resources for each episode. Thank you so much, and I’ll see you in the next episode.