#83 - The Science of Non-Invasive Vagus Nerve Stimulation with Dr. Navaz Habib, Part 1

Hi guys, welcome to another episode of The Factor Podcast. I'm your host, Jessica Riddle. Welcome and thanks for listening. Today we unpack a new training with Dr. Nawaz Habib. A Toronto-based chiropractor, acupuncturist, and functional medicine practitioner that has dedicated his career to the study of the vagus nerve. In part 1 of this 2-episode series, we'll explore how the vagus nerve's regulatory pathways impact inflammation, the role of acetylcholine in modulating immune responses, and how these mechanisms can be leveraged to improve conditions such as autoimmune disorders, neurological diseases, and more. I know you hear me say this a lot, but this episode is truly jam-packed with great insights that can help you approach your patient care a little differently. Be sure to hit that bookmark or download link so you can listen more than once. Let's dive in.

Thank you so much, Jessica. I'm excited to be here and excited to share some of the amazing research and findings that I've had in incorporating vagus nerve stimulation into my practice. I am a chiropractor. I'm based in Toronto, Canada. I graduated in 2010 from Canadian Memorial Chiropractic College. I was actually lucky enough to be the class valedictorian of my year, and that was wonderful. I have since, and I'll just give you a brief breakdown. I have been an associate. I've owned a chiropractic practice. I've sold a chiropractic practice and have shifted into working with patients via telemedicine and working more with consulting clients all around the world with regards to their vagus nerve and optimizing their overall health. It's been an interesting shift and it's been a positive one. I'm excited to tell you a little bit about the vagus nerve a little bit more because I think it's something that we tended to scoot by in understanding in our school. It's one of those things that I think if we give it a little bit more attention, we'll realize just how important it truly is to creating an optimal environment for health. The vagus nerve, what happens in vagus, not the city obviously, is we have communication, bidirectional communication between many different organs and the brain. 80% of the information on the vagus nerve is actually afferent, meaning coming from all of the organs, sharing status information from the organs back to the brain. That's huge. That's a big component. We tend to think of parasympathetic as being much more efferent in its pathway, being much more from the brain to the body. Only 15% of the information on the vagus nerve is actually parasympathetic efferent information. This is where we get this rest-digest information from the brain to the organs. A really important area here is the actual inflammatory control via the cholinergic anti-inflammatory pathway, also known as the CAIP. This is a really important thing to understand. Because when it comes to chronic health conditions that a lot of our patients are dealing with, whether they be autoimmune or inflammatory in nature, always have the lack of control of inflammation as the pathway to the disease progression. This is a really important area to fully understand. The control of inflammation is the primary job of the vagus nerve within the body. This is where we have that specific effect of being able to limit the amount of damage that inflammation can do. Inflammation is a necessary piece to the optimization of our body's puzzle, but the control of inflammation is what often needs to be talked about. That's what the job of the vagus nerve is. For the math people out there, that's only 95% of the role. 4% of the information here is motor information, and that's specifically going to the pharyngeal and laryngeal muscles. Those are the muscles of the airway, throat, and vocal cords. So maintaining the openness and patentness of an airway is the job of the motor component of the vagus nerve, and as well as having a bit of a role to play in vocal pitch and tone. So being able to go really, really low or really, really high with my voice is there because I have motor control of the laryngeal muscles that tension and pull on vocal cords themselves to create tension, allowing for pitch to change. The last area here is 1% of the information is actually sensory information from the skin of the ear, and actually in a very particular area. And this is an area that acupuncture has been utilizing for generations to help improve vagus nerve stimulation or vagus nerve function. There's actually a few points in there, particularly vagus nerve points, and another one with the name of Shen Men, which is right in that center area. That's an area that will play a really positive role in improving vagus nerve function overall. Next, we want to get into the pathway that I talked about, and that's the cholinergic anti-inflammatory pathway. It's actually multiple directions, and that's what's really exciting about it. The vagus nerve has inputs going in primarily to the nucleus tractus solitarius in the brainstem. And then coming from the dorsal motor nucleus of vagus in the brainstem and coming out. Okay, so this is where the inputs and the outputs are being relayed to within the brainstem nuclei. The vagus nerve courses down, sends a signal out to the lungs, has a direct branch that goes to this celiac ganglion or the celiac superior mesenteric plexus ganglia. Just go with the celiac ganglion to make it easy. Over here, it releases acetylcholine. This is the reason for the name cholinergic in the cholinergic anti-inflammatory pathway. It uses acetylcholine. The vagus nerve only uses acetylcholine as its neurotransmitter of choice. It also then has a direct branch to the entirety of the gut. This is very important. The gut-brain connection is physically made up by the vagus nerve. We know that 70% of our immune cells by volume are located in the gut and the gut lining. This is an important area for controlling signals to be sent via acetylcholine. This is an important area to look at from a physical standpoint. The fun relay here is, as the vagus nerve sends acetylcholine, if we look back at the celiac ganglion, we then see that the acetylcholine is released to attach to the splenic nerve. The splenic nerve is actually a sympathetic nerve, not parasympathetic, it's a sympathetic nerve. What's really exciting here is when the acetylcholine is released into this area, it actually hijacks that splenic nerve and turns it into a parasympathetic functional nerve, which is really cool. The splenic nerve will then release norepinephrine at the spleen level, activating a set of T cells called CHAT cells. They have a beta-2 adrenergic receptor on them that the norepinephrine attaches to. Then these T cells, these CHAT cells, become hyperactivated. They become activated to release acetylcholine. You can see with those red dots coming down the pathway from the T cells. These acetylcholine will make its way to splenic and other local tissue macrophages. Any organs that don't have direct innervation from the vagus nerve. We know a lot of the visceral organs do. Almost every single one has a direct innervation. But the bone, the muscle, directly to areas within other organs and tissues that are not directly innervated by the vagus nerve, including the skin, will get this signal of acetylcholine through the bloodstream via these chat cells being released in the spleen. Then these local tissue macrophages all of them have this alpha-7 nicotinic acetylcholine receptor. You can see within that red box, each of these splenic and local tissue macrophages contains that particular receptor. That receptor is the target of the acetylcholine that's being released, both directly from the vagus nerve in particular organs, and then without it being in the vagus nerve directly, where it goes out through splenic amplification the other tissues will receive this acetylcholine signal. That acetylcholine signal goes to those macrophages to tell them, we need to shut down or decrease the amount of inflammation that's happening. Then, as you can see also within that red box, we're able to decrease the release of TNF-alpha, IL-1, and IL-6. These are very, very well-known inflammatory cytokines. These are inflammatory signaling molecules that we don't want to have going off and becoming rampant drivers of an inflammatory response. That's really important. If we go back towards the brain here, you'll notice that at the NTS, we have the input coming in from the vagus nerve. Then we have a relay pathway with a green arrow that goes up to the hypothalamus. This is really, really important because not only do we have an acetylcholine release going down from the brain to the rest of the body, We actually have a signal coming up to the brain as well. And if we remember, the name of these macrophages that are within the brain and the central nervous system are the microglia. And acetylcholine is released from certain areas called particularly the nucleus basalis of Meynert within the brain. There's not going to be a test on this later, don't worry. But that area is necessary for releasing acetylcholine locally within the brain. within the central nervous system. That acetylcholine helps to manage the inflammation within the brain. This is huge because this is an area that needs to be addressed in many, many health conditions, whether they be neurodegenerative in nature, like Alzheimer's or Parkinson's or dementia, or TBI, concussion, stroke, whiplash. Those types of injuries can also severely increase the inflammatory response within the brain. The vagus nerve is heavily, heavily involved in the release of that acetylcholine in the brain as well. We also get direct signals up to the hypothalamus, which actually activates corticotropin-releasing hormone, CRH, which then sends a signal to the pituitary gland to release adrenocorticotropic hormone, ACTH, which is the yellow dots and the green arrow that goes down to the adrenals. This actually activates glucocorticoid release to help to shut down that inflammatory response as well. The glucocorticoids help in a secondary manner in affecting those local tissue macrophages and helping to downregulate the inflammatory response. This is a really, really awesome picture of what the cholinergic anti-inflammatory pathway looks like. It can get deep, and I realize this is not an easy thing to fully understand, but I'm going to do my best to help you see this. If earning a certification is on your CE plan this year, then you're in luck! Southeast Professional Education Group just launched 4 new certifications on our online learning platform. You can complete your certification in Dry Needling, Functional Nutrition, Chiropractic Acupuncture, or Clinical Human Performance with immediate access to get started learning right away. To learn more and get started, click the new certifications link in our show notes or visit online.sports-seminars.com today. Now back to the show. The target of the cholinergic anti-inflammatory system or the pathway is the marvelous macrophage. The macrophage is the organ that is necessary to be controlled in this Pathway. It is the main cell of the innate immune system. It is the main one that goes and identifies the sources of threat to our bodies. When it senses threat, it is activated into a state called M1. We'll talk about that in a moment. What it does is it sends signals of inflammatory cytokines out to bring other immune cells locally to the area, adaptive immune cells and other innate immune cells as well. This is the target. When we can control this cell through vagus nerve activation, vagus nerve stimulation, and the release of acetylcholine, we can have a phenomenal response on controlling the severity of inflammatory response that our body creates. There are tissue-resident macrophages everywhere. They all have very similar jobs and similar roles, but they're called different things in different tissue. In the skin, they're called dermal macrophages. or Langerhans cells. In the lung, they're alveolar, interstitial, and pulmonary intravascular macrophages. In the liver, they're Kupffer cells. In the heart, there are multiple different types. In the brain, they're microglia. In the kidney, they're kidney macrophages. In the muscle, there's 3 different types: CD11c+, CD11b+, F480. We've got in the bone stromal macrophages, and then One that's missing from this list is actually osteoclasts, are macrophages within the bone. Osteoclasts that we know are necessary to create osteoporosis or to maintain the shape of bone by breaking it down slightly. In the lymph nodes, we've got subscapular macrophages. In the spleen, we've got the red pulp, the white pulp, and the marginal zone macrophages. In the intestine, we've got lamina propria macrophages and submucosal. This is where 70% of our immune cells by volume are located within the body, is in the intestinal walls. And then within the pancreas, there are pancreatic macrophages as well. These tissues are everywhere. These cells are necessary as not only the detectors of threat, but they really do help to focus on identifying and maintaining the function of the organ that they're located in. And this is a necessary piece to understand because this is the target of control from the vagus nerve. This is the names of all of the target cells of the vagus nerve cholinergic anti-inflammatory pathway. The directly innervated tissues are CNS, the blood vessels, lungs, liver, gut, and then the spleen via the splenic ganglion are the directly innervated. But then via splenic amplification, we send signals out to the skin. The serosa, the muscle, adipose tissue, and bone. And this is important to understand. So these are the target cells of that entire cholinergic anti-inflammatory pathway. It can be dysfunctional in many different conditions, whether autoimmune in RA, SLE, MS, asthma, type 1 diabetes, vascular conditions like atherosclerosis, digestive conditions— very, very important here— irritable bowel, Crohn's, colitis. Metabolic conditions, obesity, type 2 diabetes, NAFLD, NASH. Neurological conditions, Alzheimer's, autism, schizophrenia, dementia, Parkinson's. And then even hormonal effects as well, endometriosis being an inflammatory condition as well. These are all conditions that may have some specific piece to the dysfunction going on and a lack of control of the inflammatory process locally within a particular organ or within a particular area. Macrophages have different states that they will work on. An M0 macrophage, the blue guy that you see at the top of the screen here, that one has not been differentiated yet into a state of being fight or fix state. But there are certain signals that will drive an M0 or an M0 macrophage into a different state. Lipopolysaccharide, LPS, and IFN gamma, which take the M0 macrophage to the left side of the screen here, will turn on what's called M1 state or M1 macrophage state. These are very high expression pro-inflammatory cell functions. These guys are meant to fight. They're meant to send a signal of inflammatory cytokines out into the bloodstream, into every area, to have them bring in more inflammatory and immune cells locally to the area where they've discovered said threat. The M2 macrophages, we can shift to using IL-4 and IL-10, which we know are anti-inflammatory cytokines. These guys helped differentiate the M0 macrophages into M2. M2 are known as the fix macrophages, not the fight guys, they're the fix guys. And then these will further differentiate depending on other signals that are there present locally. They can go into M2a, M2b, M2c, and M2d. And a lot of these are regulatory or focused on debris removal. They use the same tools as during inflammation, but they do it in a very controlled manner. And what their job is to help regulate and control and optimize the function of particular organs. And so the regulatory effect of these will come from whichever signals are being sent, whether IL-13, IL-4, IRF-4, TLR, globulin complexes, glucocorticoids, IL-10, TGF-beta, or A2AR as well. So these will differentiate the function of these to do very specific tasks using the same tools that any macrophage would. Okay, so we often think of the macrophages as being these magical engulfers of threats to us, but that's only one job. The regulatory job, the fixed job, is the one that we've often overlooked. It's the role of acetylcholine to help to actually shift from M1 state macrophages, which are the pro-inflammatories, into the M2 state macrophages. You'll see that with the green line going across. Vagus nerve stimulation is one of the best ways to do this. This has been proven. I've got a great research study below that I'm going to share. This is a really amazing tool. Then when we have the presence of lots of M2 macrophages, that's actually inhibitory to the production of M1 high-inflammatory macrophages as well. That's indicated by the red line below there. These are important pieces to understand. It's the job of the vagus nerve when working to help to shift these cells from M1 state to M2 state and from fight to fix. The cellular effects— this is how it actually works. Remember we mentioned that alpha-7 nicotinic acetylcholine receptor on the pathway? What it's doing when acetylcholine hits that particular receptor, it has 2 very particular things that it can change. Number one, it can go down the cAMP-cFos pathway, which is the first pathway on the left here. You'll see that it activates cAMP, which goes into the nucleus and activates CFOS, CFOS, and that will lead to a decrease in the transcription of a factor known as NF-kappa-B. NF-kappa-B, when activated, sends out cytokines that are inflammatory, the IL-1, IL-6, or excuse me, IL— yeah, IL-1, IL-6, okay, and TGF or TNF-alpha as well. The second pathway is acetylcholine will hit that same receptor and activate the JAK2 STAT3 pathway, and that will actually result in the decreased gene transcription of inflammatory cytokines as well. We're actually regulating and decreasing the amount of inflammatory cytokines that will be released. There is one more scenario, and this is an interesting one that most people don't understand as yet, but that alpha-7 nicotinic acetylcholine receptor is also present not only on the cell surface, but it's also present on the surface of mitochondria. How many of us have heard about mitochondrial health and the importance of maintaining good mitochondrial health for longevity, for energy, for overall optimal function and metabolic ideals? Well, when there's a lot of ATP that's present around the cell surface, ATP will activate a channel here that allows acetylcholine to enter the cell directly, and that will activate the alpha-7 nicotinic acetylcholine receptor on the mitochondria. When that receptor is activated, it actually decreases and shuts down the release of mitochondrial DNA. This is a very common pathway by which we trigger an inflammasome or trigger this NF-kappaB gene transcription occurrence that takes place. If mitochondrial DNA is released, it will lead to the inflammasome and the release of inflammatory cytokines into surrounding areas. But when we activate the acetylcholine receptor on the mitochondria, that shuts down the mitochondrial DNA release. That allows for the DNA to remain within the mitochondria. It allows for optimal function to be restored, and we don't trigger an inflammasome. We actually don't allow this pathway to begin. And one of the best ways that I've found to help do this is through cervical transcutaneous vagus nerve stimulation. The vagus nerve is sending these acetylcholine signals out to all of these tissues, particularly those macrophages, to help with regulation and control of inflammation. When we don't have an optimally working vagus nerve, the control of inflammation is going to be reduced. Use of electrical currents to help to stimulate nerves is something that we've all seen many times. How many practices use a TENS unit or interferential current or other electrical stimulation tools like a Pointer Plus on acupuncture or something along those lines. This is a tool that directly targets the vagus nerve. So it's electrical stimulation of vagal fibers along the anterolateral cervical spine. To find where your vagus nerve is, literally find your pulse and it's right beside there. I'm going to show you a really cool image. So this is a great area to access the vagus nerve. And what you'll find is about 90 to 95% of the fibers on vagus nerve are found within the neck and not anywhere else. It's easily accessible within the carotid sheath. You'll see on the next slide that we've got the carotid artery, the jugular vein, and the vagus nerve that are nice and wound tight together. We're going to be able to activate both afferent and efferent axonal fibers. Interestingly, there are only 100,000 fibers on the left side vagus nerve and 200,000 on the right side vagus nerve— 200,000 plus. They're realizing there's more on the right for whatever reason. I wasn't there for the design process, and it's something that we're still trying to figure out why. Where is the vagus nerve? I just mentioned this. It's within the carotid sheath, just behind our sternocleidomastoid muscle, the SCM muscle. If you ever push against your head, you can push your head against your hand, excuse me, you'll notice that your SCM muscle pops up. If you just pop in front of that SCM muscle, you're You'll be able to find your pulse. Your pulse you're feeling is the common carotid artery, the CCA, that's present on this ultrasound image. You'll see the IJV there as well. That's the internal jugular vein. And then right behind it, that thick tissue that's outlined in yellow, that is the vagus nerve. So if you feel your pulse, you're very, very close to your vagus nerve as well. The thing that really introduced me to the importance of the vagus nerve was that it was the only nerve Coursing down through the neck, present within this carotid sheath. It's the only tissue there. We know how important the common carotid and internal jugular vein are, but how many of us have forgotten that the vagus nerve is part of that sheath and so, so important to our overall health and survival? So just great to see there. It's literally right behind the anterior fibers of the sternocleidomastoid. And so if you just kind of give it a little push out of the way, you'll be able to find the pulse and you're right there. on your vagus nerve. How does non-invasive vagus nerve stimulation work? Well, this was a sham study that was done where they actually stimulated over the sternocleidomastoid versus over the carotid artery area where they found the pulse. What was found was when— obviously not within the sham activation, but within the actual activation of the nerve— when they stimulated using the electrical device, the handheld electrical device, They had an activation of particular brainstem nuclei. This will go back to which ones we saw. This is the nucleus of the solitary tract, the NTS, nucleus tractus solitarius. We had activation of the dorsal motor nucleus of vagus. This is cool because we know that we're getting activation of the 2 nuclei, the primary 2 nuclei by which vagus nerve connects. This is really important. We also got a little bit of activation in vestibular nuclei. And the medial longitudinal fasciculus as well. And as well, a little bit in the spinal trigeminal, which is linked as well. And that's actually the spinal trigeminal was not activation, excuse me, it was inhibition that occurred in the spinal trigeminal nerve. This is great for things like Bell's palsy or great for kind of the trigeminal headaches that can occur as well. And this is a reason for why this particular tool is used heavily in headache cases, migraine in particular. This was a great study, and it continued on to show that not only is the effect local within the brainstem, but it actually creates a biphasic response above in different areas of the brain. This was a 3-phase response. They did fMRIs between 3 and 5 minutes, 7 to 9 minutes, and 13 to 15 minutes later. What they found was activation of the raphe nuclei and substantia nigra in the brainstem, In the early phase, as well as the medial frontal cortex and paracingulate cortex, early phase. Then we had inhibition initially and then activation in the mid-post-VNS phase, which is a 7 to 9 minute phase. And we got activation of the raphe nuclei, the VTA, ventral tegmental area. And then we had it in the hypothalamus and the ACC as well above. This was an activation that occurred. Then we had a calming effect almost throughout the entire cortex, particularly the precuneus and paracingulate cortex had an inhibitory response. Then we had activation in the brainstem at the VTA, the PAG, the substantia nigra, and the raphe nuclei. This helps to tell us exactly how this system works. This is a neuromodulatory activation that's occurring. We're getting activation of dopamine response, of norepinephrine response, and of serotonin response within the brain. Once we go and see as well, you'll notice that the nucleus basalis of Meynerts becomes activated in particular, and that's where we get the acetylcholine release within the CNS. When we do this, what we're essentially getting is an activation of acetylcholine, norepinephrine, and serotonin within the brain. They're going to have effects on the cortex, the cingulate gyrus, the amygdala, and the hippocampus. The hippocampus being heavily involved in that pituitary response and in the production of memory as well. The cortices are going to be affected with positive income from norepinephrine and 5-HT serotonin. We're going to become activated because of the norepinephrine. Mood and affect would generally be improved with the introduction of the 5-HT, which is the precursor to serotonin. Then it also will go and affect the thalamus, which is going to allow for improvements in sleep, emotion, arousal, plasticity, and memory. This is a great area to look at. The brainstem is where the effect primarily will occur. You'll notice that transcutaneous vagus nerve stim will have this particular effect both afferently And have effects peripherally through the efferent pathway that's getting signaled as well.

That's it for today's episode. Be sure to tune in for part 2, where Dr. Habib will share compelling case studies and practical tips, including therapies like diaphragmatic breathing, dietary changes, and vagal nerve exercises. Plus, we'll discuss the promising effects of music on vagus nerve activation and dive into detailed mechanisms involving macrophages, cholinergic pathways, and neurotransmitters. You won't want to miss it. Episode 84 launches in 2 weeks. If you enjoy our content, please be sure to rate or review The Factor Podcast in your favorite podcast player, like Apple or Spotify. Or stop by our website at factorpodcast.com and leave us a review or audio recording. You can actually use your voice and tell us what you think. Be sure to check out our show notes for any special offers or links from our sponsors. We'll see you next time. Hey guys, if you like what you heard today, I encourage you to visit our website at factor-store.com. That's spelled F. Faktr-store.com to find out more information about all that we have to offer. We have a variety of online offerings as well as our hands-on Factor Rehab System course scheduled in cities around the globe. Be sure to also check out our event calendar and bookmark any of these upcoming live webinar dates coming up in the near future so you can join us live. And of course, the biggest compliment we can receive is for you to help us spread the word to your Friends, colleagues, and classmates. You'll find all the important links as well as info about our sponsors in the show notes, so be sure to check those out.