Okay. Hi, everyone. Welcome, and thank you for tuning in. I'd like to thank you for tuning into this webinar, which is produced exclusively by the North American Neuromodulation Society. The topic of this webinar is Emerging Indications for Invasive Neuromodulation, and we're joined by a panel of experts. We're very excited to hear their viewpoints on selected topics and innovative therapies in the future. Please put any questions into the chat, and we will administer to those at the end of the three talks. Hopefully, we'll have about 15 minutes to answer questions, and those will be moderated by myself and Dr. Abigail Rao. I'm Jeffrey Raskin. I'm a pediatric neurosurgeon at Lurie Children's Hospital in Chicago, an assistant professor at Northwestern University Feinberg School of Medicine. Dr. Rao, would you like to introduce yourself, please, and the first speaker? Sure. Thanks, Dr. Raskin. I'm Abigail Rao. I'm a stereotactic and functional neurosurgeon at Norton Neuroscience Institute in Louisville, Kentucky, and it's my great honor to introduce Dr. Josh Rosenow, our first speaker. Dr. Rosenow is Director of Functional Neurosurgery and Epilepsy Neurosurgery at Northwestern University. He is Professor of Neurosurgery, Neurology, and Physical Medicine and Rehabilitation. He will be speaking to us about closed-loop DBS. Thanks so much, Abby, and thank you so much for inviting me to be part of this webinar. It's an exciting time in neurostimulation, and I think we're all going to present some very unique and engaging topics on this, and I'd like to start off with some aspects of closed-loop brain stimulation. Here are my disclosures. You saw some of them in the slide that was earlier presented. So, when we think about closed-loop… Dr. Rosenow, I don't see your slides. I want to make sure that everyone can see them. I'm not the only one. Let me un-share and re-share. Are they up now? Sure are. Closed-loop stimulation. Okay, super. Sorry about that. Something must have been… My slide was saying that it was sharing, but I guess there was some internet hoo-ha that was not sharing. So, when we think about closed-loop stimulation, we think about a self-contained system, the idea being is that a system that senses what's going on in the nervous system and then corrects or alters its own settings, usually with short latency, and that while there may be some initial setting up of the device, teaching it something or setting its general parameters, in general, in an ideal setting, the system should be able to sense and correct and sense and correct and sense and correct. In order to do that, you need a couple of important things. One, you need a therapeutic target, some place where you stimulate and it will cause the desired effect that you want to have. But more relevant is you need a biomarker relevant to the clinical condition that the system can detect and which it can key on to respond. Without those two things, then closed-loop stimulation doesn't work so well. So, we already have some active closed-loop neurostimulation systems. We have a responsive neurostimulation system that is FDA-approved to treat focal epilepsy, and this could either be used as a treatment or in some cases just as long-term intracranial EEG monitoring, such as somebody with bitemporal epilepsy, where you can implant the device and see over a long period of time which temporal lobe has more seizures than the other. And this is a device that has a cranial mounted pulse generator and the ability to connect two electrodes. In these x-rays, there is one depth electrode and then there is one strip electrode. And there's a lot of exploration for use in other disorders using EEG as a biomarker, and I'll talk about some of those as part of this talk. And it's in trials currently for looking at other epilepsy conditions such as Lennox-Gastaut and idiopathic generalized epilepsy. And this is a system that's been proven. So, this is a system that we can implant and that can sense EEG. We can teach it abnormal EEG, and it can respond with stimulation when it senses that abnormal EEG. And this is some data from the pivotal trial for this that showed that the stimulation on in the treatment group showed progressive improvement over nine months post-implant. The group that was then assigned to sham and then turned stimulation on had a decrease as well once that stimulation was started in delayed fashion. And over time, we actually see a true neuromodulation effect in some people, where once we activate the device, there's a lot of stimulation as there's a lot of EEG abnormalities for it to detect and respond to. But over time, the number of EEG abnormalities actually can decline in some people, and so the number of stimulations that are evoked go down. So, you can see an actual neuromodulatory effect on the nervous system, where it's not simply whacking the moles all the time, it has fewer moles to whack. And we have a closed-loop system that exists for movement disorders. And unlike EEG, the movement disorders system monitors what are called local field potentials, which are kind of aggregate neuronal impulses. It looks like a standard DBS generator, but it incorporates the ability to sense these local field potentials. And there's some research that shows that there's some local field potential patterns that correspond with better symptoms in something like Parkinson's disease. And so you can sense the local field potential energy, and specifically what we look at is what's called the beta band in these people. And we can look at the beta band, and this is the commercial generator, and you can program it and let it sense the beta band in response to your programming, and you can continually optimize how the programming is doing based on the beta band power. Now, right now, this does not sense and respond on its own, but the capability in this device is clearly there, and it's in trials to do just that. And if those trials validate the ability of this to sense and respond to this beta band power and optimize programming and optimize clinical results, that will be unlocked and free to be used by anyone who has this device implanted. So now that we have the ability to, say, sense these local field potentials and to sense EEG and possibly respond to these, what are some of the things we can do to this? Well, let's look at other syndromes. So Tourette's is a very unusual syndrome that's kind of a combination movement disorder and psychiatric syndrome put together, meaning it has some psychiatric overlay as part of it, but it also has these motor tics. And so if you implant electrodes in some of these patients with Tourette's, and especially if you put a lead in the centromedian thalamus and a four contact strip on the motor cortex, you can sense that there is a very reliable 10 hertz thalamic signal that shows up right before these people have a motor evoked tic coming from the motor cortex. So you see this signal here, and then there's the tic movement, signal, and then tic, and it's very reliable. So that obviously begs the question, can you then sense this tic, stimulate somewhere, whether it's stimulating back in the thalamus or stimulating on the motor cortex to ablate the tic? And there are trials of this going on right now to look at this, but these are some of the things we think about as we consider these applications of closed-loop stimulation is now you have a biomarker in this case, which is this 10 hertz thalamic signal, and then can we develop the target, the therapeutic target to ablate the tics? Now, whether that's the motor strip or somewhere else in the brain, such as the thalamus, that is still being worked out. But there are some times when the therapeutic target or the biomarker need to change depending on what the patient's doing. So for Parkinson's folks, this beta band power is very good in some respects, but once the patient starts moving around, then the detection becomes a little more hairy. However, if we look at the gamma band, which is up at about 90 hertz, there's been a very reliable peak found in patients who are dyskinetic. And so here is, you know, blue is patients are dyskinetic, and the red is not dyskinetic, and there's this very reliable peak here about 90 hertz. And that peak is there whether they are at rest, whether they're moving their arm, or whether they're walking. So this is another possible target for a biomarker to use to determine your programming in DBS. If you are evoking these dyskinesias, then the device needs to adjust itself in some way or another. However, there are issues. So for instance, you need to have a biomarker that's relevant, but that biomarker always has to correspond to the clinical symptoms. And as I said, we've currently been looking mostly at this beta band power in the local field potentials in terms of closed loop DBS or movement disorders. But does it always correspond to the clinical symptoms? Yes, and maybe not always. So here's a study that took patients who had sensing DBS electrodes in and looking at the power in the globus pallidus in the STN between rest and movement, and then looking at the difference between resting and movement. And what you can see is that in the globus pallidus, there is a decrease here between rest and movement in that beta band power. This dips down. And there's a decrease here around the beta band again in STN. So there is a difference in both. But look at what happens here if you look at the correlation between the beta power and the clinical scores. In the globus pallidus, there actually is a correlation in the Brady-Kinesia score, meaning as the Brady-Kinesia score gets better, the beta band power is improved, and also in general with movement. So both with rest and movement. However, the difference, no matter what you look at here between Brady-Kinesia, rigidity, and tremor are all not significant between rest and movement. And more importantly, in the subthalamic nucleus, they were not significant here. And you'll see that if you look all the way down this, there are no significant differences here at all in the subthalamic nucleus, which is one of the other more common nuclei that we use for Parkinson's disease. So yes, the beta band can be useful, but is it infallible? Is it perfect? No, it's not fully perfect. So the beta band may correspond, it may not. And this is an ongoing discussion as we develop these closed-loop stimulation therapies for movement disorders, is do we truly have a biomarker that firmly corresponds to the clinical symptoms? We have the targets in this case, the GPI and the STN, that are very well defined. But the biomarker is good, but could there be a better biomarker or could we do better than beta band for this? So how about other disorders that we could look at? If you look at something like post-traumatic stress disorder. So there was a pilot study, two patients who had PTSD who had longitudinal mesial-temporal responsive neurostimulation electrodes implanted. And there was a separate cohort of patients with these electrodes in who did not have a diagnosis of PTSD. And what they found is that if you looked at the EEG theta power, which is again another measure of EEG power, at the theta band, the PTSD patients showed increased amygdala theta power when they were shown negative images. This was not present in the non-PTSD patients. So if you showed patients with PTSD neutral or positive images, you didn't see this increase. If you showed them negative, what are called negative valence images, disturbing images, then you saw this increase in EEG theta power. In the non-PTSD patients, it didn't matter what images you showed them, you know, negative, positive, or neutral, they did not have a change in this theta power. In addition, when you then played recordings to these patients of descriptions of their traumatic experiences, recordings that they had done prior to the study, you again saw this amygdala theta power increase as compared to playing them recordings of non-traumatic experiences. The non-PTSD patients did not have any changes. So this change in theta power was present with visual and auditory inputs. They were then programmed to get responsive stimulation in the amygdala in response to EEG theta power levels. And they ended up getting, believe it or not, 2,000 to 3,000 stimulation episodes a day. And if you looked at how they did after 11 months of this responsive stimulation that was specifically triggered by this low frequency amygdala activity in the theta band, you saw a reduction in their symptoms on the CAHPS-5 scale of, you know, it was two patients. So one patient got better by 70 percent, one patient by 40 percent. If you looked at their subjective improvements on the PCL-5 scale, one patient got better by 57 percent and one patient by 34 percent. And in addition, that change in the theta EEG power that was evoked by the negative images was eliminated after 11 months of stimulation. So now we have a target and we may have a biomarker that in a larger study may show this to be a possible therapeutic target for this. So this could be a very promising area for closed-loop neurostimulation. What about depression? We have seen studies in the past that show that there are differences in brain imaging on things such as PET and SPECT when patients are better and worse in their depression levels. So when patients are better treated, there are changes compared to when patients are not as well treated with their depression. So this is some work from Sumir Sheth showing that what they are looking at is SEG-informed DBS for depression. So you basically take two competing brain targets, in this case the subcalosal cingulate gyrus region and the ventral striatum, ventral internal capsule, and all the patients in this pilot study got four electrodes, bilateral subcalosal cingulate and bilateral VCVS electrodes. And on top of that, they then got 10 SEG electrodes each. That's a lot of electrodes in someone's head. And the idea behind the SEG electrodes is that it allows us to look at brain recording power in response to various program settings in each of these targets to then better figure out which settings in which target reduce the best changes in EEG. And so these patients all had all these electrodes put in. They hung out. These are some sample setting parameters on the bottom right that were tried. And then they went back to the OR, the SEG electrodes are removed, and then the treatment is then performed with internalized electrodes according to these best settings. So this is very cool and very interesting. It's hard to generalize this, though, to a lot of patients. So you're going to think about taking this out and taking this to a large number of patients. It's hard to take something like this, which is a really wonderful granular scientific exploration, and generalize it to a lot of people. So in order to do that, we not only need the biomarker, which may or may not be the theta power, okay, of the EEG, but we then need to figure out whether that biomarker is the theta power that's read in which area of the brain, right? In this case, these patients had all of these stereo EEG electrodes, and which one are going to be the most useful for figuring out the settings? That's still to come. Just one last thing is looking at closed-loop DBS for eating disorders. So this is a pilot study from Casey Halpern at Penn. They took two patients with binge eating disorder who had high BMI, and knowing that in rodents, high fat food cratings are associated with an increase in low frequency oscillations in the nucleus accumbens, they gave these two patients responsive neurostimulation electrodes in the nucleus accumbens. And then they were given both standard meals and what you would call loss of control meals, meals that were associated with setting off their binge eating disorder. And then what they were able to do is look at the EEG coming from these electrodes as they looked at and ate these meals. And what they found is that before the bites of these loss of control meals, there was a significant increase in low frequency LFP signal in the left, specifically in the left nucleus accumbens. Over six months of responsive stimulation that were keyed to this low frequency LFP signal increase, what they saw was that there was significant decreases in both the severity and the number of binge eating episodes. That was six months, and there were small losses in weight in both patients. But it's just a very interesting early finding showing this nucleus accumbens signal that, again, may prove to be a biomarker that we can significantly key on later on. And this is, again, we have a target possibly, we may have a biomarker, remains to be seen, but this is interesting early results. What about in the future? Well, other disorders, can we look at disorders such as other addictive disorders, such as drugs, alcohol, and gambling? And what would the biomarkers be? Would it be activity? Could you somehow detect what someone is doing? Could you look at blood alcohol level in some way if you needed to? How about location? We have GPS trackers in all of our phones. Could you have a biomarker that involves a patient being in an area that is associated with high risk behavior, whether it be a place where drugs are obtained? Could it be in a place such as a casino where gambling is going on? Could you look at autonomic factors? Could you even look at facial recognition? You know, people are around other individuals who are associated with their high risk behavior. Someone even suggested in one speculative paper using contact lenses, something out of black mirror that could facial recognize someone in front of them. It's all very interesting and novel and where it goes, we will see. So thank you very, very much for inviting me and let's get on to everybody else. Dr. Rosenau, thank you so much. That was a very inspiring talk. I knew it would be and give us a lot of opportunity for discussion and thank you for those very specific examples. We will move on. We'll keep questions till the end. Please put them in the chat if you have any and we'll address them at the end. There is already one in by Dr. Gupta, who's our next speaker. So Dr. Gupta, if you wouldn't mind sharing your slides as I introduce you. Dr. Kunal Gupta is a friend of mine. We were residents together at OHSU. We were also colleagues together in Indiana recently, and he just moved to Medical College of Wisconsin in Milwaukee. He's an assistant professor of neurological surgery and a functional neurosurgeon and researcher. And tonight, today, he's going to discuss a very interesting topic. Kunal, please take it away. Thanks very much for the introduction. Can everyone see my slides? We do see them. Yeah, thanks. OK, so I'm excited to talk to you about a new indication for deep brain stimulation that we are studying as a joint venture between Indiana University, my former stomping ground, and the Medical College of Wisconsin. As you can see, it's sort of a large group of principal investigators and co-investigators spanning a number of subspecialties. I have a few disclosures which aren't directly relevant to the talk. One in epilepsy, and I was site PI for a couple of DBS trials at Indiana. So this is a group, and really I include the slide just to demonstrate that it's a team. So when studying a speech disorder, it's important to have high-quality speech research, neurology for DBS, and of course myself and associated folks in neurophysiology, imaging, and ENT. We're registered on clinicaltrials.gov, so you can go there to find some more information. And we are recruiting for this trial further, and we're funded through the NIH. So what is laryngeal dystonia? It is a focal dystonia of the vocal cords. I sort of described this very clearly here. However, there's a lot of controversy in the field about what the exact sort of diagnostic indicators are for this, and whether there really is a sort of an organic biosignature that can be used clinically. You may also know it as its former name is spasmodic dysphonia, but this has since been changed by the NSDA or National SD Association. It's characterized by breathiness and vocal breaks, and it improves, oddly enough, with forced voicing, and that includes whisper and shout, which I roughly equate to the sensory trick you often see in other forms of focal dystonia. The reason you'll encounter it in some functional neurosurgery practices is up to 60% of a concomitant tremor of the voice and arms, especially the arms. And as I described, there are significant challenges in diagnosis and treatment, even at the ENT and neurology level. There's been some research trying to identify a biomarker of this due to its difficulties in diagnosis and using sound discrimination tasks. There have been fMRI activation identified in sensory motor cortices with modal or standard voicing compared to forced voicing, which abates symptoms sort of an internal control that can be used. However, current assessment is really based on audio perceptual judgment, which really just means professional opinion. And that's been shown to have low inter-tester reliability. And if you try to validate this with stroboscopic examination, there's a number of problems with tracking error, which I'll come to with some videos later on. So independently of the diagnostic difficulties, treatment of current standard of care is very limited. It's speech therapy and Botox injections to the laryngeal intrinsic muscles. And those that receive Botox, only 30% improve to transient function. This is transient. So upon injection, patients can experience softness of the voice, head drop even from spread to the extrinsic muscles of the neck. Then sort of a transient phase where some of the motor activity recovers, voicing becomes normal, and then it continues again. So an injection should be repeated every three months. And as you can imagine, having needles put in your laryngeal apparatus probably isn't the most pleasant thing to undergo. So that led us to deep brain stimulation due to the comorbidity with arm tremor. We had we implanted a patient with a VIMDBS targeting the arm tremor. However, this person had laryngeal dystonia. So we had a natural candidate for testing VIMDBS in a patient with laryngeal dystonia. However, we wish to try this against DBS of the GPI or the globus pallidus internus. And that's an established treatment for focal dystonia. And so we were fortunate enough to have two patients who had differing symptoms and were able to sort of systematically try this in a head to head trial. So given that laryngeal dystonia is a focal dystonia, we hypothesize that GPI-DBS may be more effective than VIMDBS. However, this has not been systematically filed previously. In a fairly large case report of about 35 patients for focal dystonia, they had one patient that also had comorbid spasmodic dysphonia. And the investigators in the study described doing intelligibility scores and found that they were within normal range. However, things that they didn't test such or they didn't test in a quantifiable way, perceived naturalness of speaking, phonation, prosodic parameters, they benefited considerably from stimulation. And they said that if they only looked at intelligibility alone, they wouldn't have noticed the benefit from GPI-DBS. And this really gave us impetus for testing this. So our group, we completed a head to head trial of GPI-DBS versus VIMDBS as a preliminary study with comprehensive acoustic analysis and interoperative neurophysiology. So what we found as a summary, and I'll go through the data, is that DBS of the globus pallidus improved voicing and speech intelligibility as the previous study predicted it would. Whereas DBS of the VIM thalamus resulted in a greater improvement of tremor rate. So while this may seem sort of like an expected result, this was not known in literature prior to our investigation. So as you can see in this study, in this table, we examined tremor rates, extensive frequency and extensive intensity modulation, which are measures of tremor, vowel voicing, which is a greater measure of intelligibility as well as septal peak prominence or CPP, which is a sort of a global measure of speech dysfunction. And then another measure of speech intelligibility. And what we found is that while tremor improved more significantly with VIM, you found greater improvements in vowel voicing, CPP and speech intelligibility with GPI, which was a sort of fascinating separation of speech physiology with two different targets. So in terms of what this looks like. So if you take a normal voice and then you analyze the waveforms and you take a look at the blue line, which demonstrates voicing. So under control, you can see the sort of continuous line with sort of this natural cadence, whereas when you look at a person with spasmodic dysphonia, you'll see these disruptions to the blue line, which represent vocal breaks, which are more prominent with voice sentence and sustained vowels. And we were able to use these acoustic data for those for those analyses. So what we found is that whereas if you look on the left side, you see these breaks in voicing in the blue line after DBS, you see that the breaks are restored by stimulation therapy. But of note, you do see sustained tremor. And indeed, this was both for the sustained vowel, which I showed you previously, as well with the voice sentence, so it likely results in a functional improvement. And you can see a small break here that was that was retained. We also performed interoperative electrophysiology. This was specifically for the VIM thalamus. And what we found actually was fairly similar data to data you'd find in central tremor. So elevated spectral power in the four to eight hertz range, as might be expected, as well as the 10 to 25 hertz. There's some discussion in literature about laterality being important for therapeutic effect in laryngeal dystonia. And what we found was a similar electrophysiological data signal for both sides. So so at the moment, what we've done is we've expanded our prelim study to a clinical research trial. The goal is to identify novel vocal fold vibratory clinical biomarkers. And that's something that can be used pre-op in an ENT clinic or neurology to try and improve diagnosis. So we're trying to improve the diagnostics and that will also help stratify patients to enter our trial. We then have the operative arm where we're testing GPI-DBS for improving tremor. And we have interoperative electrophysiology as well to identify a biomarker, a biosignature interop as well, and correlate this with interoperative acoustic recording as well as interoperative vocal fold movement, which I'll show you a video. And so the third aim is then to identify a non-invasive biomarker through resting state functional MRI for both disease, disease severity, as well as therapeutic effect from DBS. Now we're specifically looking at doctoral laryngeal dystonia. So this is how our trial is designed. So they get evaluated for inclusion criteria. The standard range is sort of what would be considered the conventional age range for DBS. Due to differences in sort of voice lateralization, we're specifically looking at English speaking, primary language, right-handed patients without a psychiatric or structural CNS disorder. And of course, patients have to be at least three months past botox treatment to enter the DBS trial. We're performing neuropsychological testing to exclude any side effects from DBS. They undergo preoperative high speed video endoscopy as well as voice recording, voice handicap index, as well as resting state functional MRI. They then undergo DBS with me, including high speed video endoscopy during surgery, interoperative recording, microelectrode recording, which is my standard. And then we have the same battery of tests to evaluate a six month response after DBS. And again, you can find our clinical trials identified just below for recruitment details. So this is a video obtained from our first handful of cases. You can see this image on the left is a standard trial. So normal video endoscopy that you see in a normal ENT clinic. And due to our research involvement from Dr. Patel, we have high speed video endoscopy and you'll see a marked difference. So you can really follow the edges of the vocal folds and identify breaks and identify vibratory abnormalities using this high speed video endoscopy. So we're doing this as standard during intra-op, during stimulation recording. So this is what our setup looks like. We have a patient, myself will be off screen, the OR for imaging. This is Dr. Patel with a research setup. We have the microelectrode recording machine synchronized with a microphone. So we've got synchronized microelectrode recording as well as acoustic recording. And this also pairs with the high speed endoscope, which you can see just to Dr. Patel's left side. So, again, awake DBS with microelectrode recording, synchronized interoperative research data. And we've recruited three patients so far and we're analyzing that data right now. So take home points is that we do hear a lot about new indications for DBS and some of them can be feel like a stretch or the data doesn't seem particularly good. However, I'm particularly excited about this one. It seems to be on the fringes of focal dystonia. And this does seem to be amenable to DBS, at least in our early analysis of our first four patients. Target selection may be guided by disease markers and physiology. So this segues back into the debate of STN versus GPI and how we've sort of narrowed on how they're probably at the end of the day, essentially the same in Parkinson's disease. Whereas in, at least in laryngeal dystonia, we're seeing separation of target effect by associated physiology. So we hope to demonstrate in the study or determine in the study whether evaluating and understanding disease mechanism can help guide therapeutic strategy and influence therapeutic success. So acknowledgments, of course, the research group, various funding bodies, my email and scheduling telephone number and the clinical trials number on this. If anyone has any questions or looking to identify patients. So glad to talk to you and hope you're excited about this. Thank you, Dr. Gupta. That was a fascinating look at really groundbreaking research you're doing. So thank you for the insights. So we're going to move on to our final speaker. And then after our final speaker, we will review any questions and the moderators will also stimulate some discussion, hopefully. So our final speaker this evening is Dr. Allison Engel. Dr. Engel is assistant professor of anesthesiology at Northwestern University. She has a particular interest in emerging indications for invasive neuromodulation. She's going to speak with us on the pain side. Thank you. And thank you for inviting me. It's hard to follow such great talks. It's wonderful to hear everyone's research. I love it. So next slide, please. We'll talk about the pain pathway neuromodulation therapy devices. We'll focus on spinal cord stem indications, their mechanisms of action and emerging clinical indications for neuromodulation. Next slide, please. So our pain pathway is broken down for a recap to our first order, second order and third order neurons. In your first order, nociceptive neurons, you have your A, delta and C fibers. Go back. Second order, you have your wide dynamic range neurons and your nociceptive specific neurons that are your A, delta and C fibers. And then your third order neurons are your thalamocortical projections, which include your relay and reticular cells. Next slide. So in the pain pathway, you first have transduction, transmission, modulation and perception. Here we will focus on neuromodulation. Next slide, please. Our neuromodulation therapy is defined as targeted delivery of an electrical or chemical stimuli to nerves in the body. The devices typically that provide this stimulate the targeted nerves that modulate abnormal neural pathways through either pharmaceutical agents, ultrasound, electrical or magnetic stimulation. Next slide, please. So there's many devices that are emerging, lots of exciting stuff in the field right now from noninvasive to invasive neuromodulation devices. Here we're going to talk, have a focus on invasive. Next slide, please. As Dr. Rosenow touched on, deep brain stimulation and Dr. Gupta, the essential tremor, Parkinson's disease, dystonia, epilepsy, depression, OCD, Tourette's syndrome. There are so many applications for that. Carotid artery stimulation for hypertension. You have vagal nerve stimulation, also has a lot of emerging indications and investigation, which migraines, epilepsy, depression, obesity and many more. You all have gastrointestinal stimulation for functional disorders and colon stimulation, which is quite exciting for people with IBS and eating disorders as we have looked at. Sacral nerve stimulation for incontinence and pelvic pain and intrathecal drug delivery systems. And then spinal cord stimulation is for chronic intractable pain and ischemic disease at present. And we are going to focus on this area as it is the most common treatment for neuromodulation. And next slide, please. So our typical indications for neurostimulation in pain management is chronic neuropathic pain. We see some ischemic disease, mononeuropathies. Migraines are more related to vagal nerve stimulation, but do have a pain application. And chronic intractable unilateral or bilateral pain of the trunk or limbs associated with post-laminectomy syndrome, CRPS, diabetic peripheral neuropathy, pelvic pain, foot pain. Next slide, please. So the mechanisms of spinal cord stimulation are not completely understood. We do think that the stimuli modulate the pain pathways to the spinothalamic tract and the thalamocortical projections to the cortex. And most of the mechanisms depend on the type of device, the program and the patient characteristics. So we'll go through tonic, high frequency, burst, just to name a few, and then touch on some of the newer therapies that are being investigated. And then closed loop and DRG stimulation, among others. Next slide, please. So our traditional tonic stimulation, you have dorsal column axonal fibers are the target. And paresthesia coverage of pain is considered a necessary but not a sufficient requirement for efficacy. So this is where we have mapping as our critical factor to achieve pain relief. Then you have activation of the dorsal column fibers, which releases glutamate. Glutamate binds to and activates your inhibitory interneurons. And then activation of your inhibitory interneurons causes release of your GABA neurotransmitter. GABA binds your y-dynamic range neurons, causing hyperpolarization with a net effect of reduced pain signaling to the brain. Next slide, please. High frequency then came along. And that target was thought to be the superficial dorsal horn, not the dorsal column. And it was a paresthesia independent where paresthesia coverage is not required for therapeutic efficacy. The theory is that the 10 kilohertz stimulates activation of the inhibitory interneurons located in the superficial dorsal horn in a different way than tonic. And no stimulation of the dorsal column and no release of glutamate occurs. However, you still get the activation of the inhibitory interneuron causing release of GABA neurotransmitter, which then binds your y-dynamic range neurons, causing hyperpolarization with a net effect of reduced pain signaling to the brain, again, achieving a similar desired outcome. Next slide, please. Then BIRST came along, which was considered a type of mechanism which targeted the superficial dorsal horn and not the dorsal column with a very low current of about 0.1 to 1.5 milliamps, allowing for a paresthesia-free therapy similar to tonic stimulation. It modulates the lateral pathway and the thalamocortical projections to the somatosensory cortex and additionally modulates the medial pathway responsible for more affective and attentive components of pain. And this was thought to be related to patterns of thalamic BIRST firing that are natural and naturally found in the human brain. Next slide, please. So the DRG is one of the first locations where the pathophysiology of pain is seen, resulting in allodynia and hyperalgesia. DRG transmits our sensory information from the periphery to the central nervous system, and the targets are well mapped and anatomically organized, allowing for highly focused treatment of pain. This theory is that modulation of pain transmission occurring at the DRG soma connection to the axon works at the T-junction, and this T-junction is what's filtering some of the action potentials, allowing their propagation or blocking their transmission. Again, the end result looks at specific stimulation of pathological DRG to achieve focal pain relief. Next slide, please. The DRG stimulation or DRG electrodes are placed near the nuclei in the afferent neurons compared to the dorsal column and traditional, and the most typical indications are your CRPS1 and 2 and mononeuropathies. The painful diabetic neuropathy, the mononeuropathy, post-surgical pain, not as much evidence for it, but still people can do it and do apply it for these areas. Most of the evidence supports lower extremity CRPS or mononeuropathies like foot, groin pain, and lower extremity pain. Next, we'll talk about closed-loop. Next slide, please. So closed-loop spinal cord stimulation has most likely target is the superficial dorsal horn. It's also considered paresthesia independent, where coverage of pain is not required for therapeutic efficacy, and the sensory stimuli that reach the supra-threshold elicit an evoked compound action potential. Touching on what Dr. Rose now mentioned before, these evoked compound action potentials creating the closed-loop, picking up a stimuli, and then the device senses what stimulation is induced, this ECAP, and adjust the electrical output based on the ECAP according to maintain their desired stimulation, regardless of changes in posture and position. So we still have the closed-loop neuromodulation feedback to maintain our ECAP amplitude near target amplitude. So you don't have as much variation and can achieve better outcomes with position changes, such as if a patient coughs or sneezes or does something that might modify it. Next slide, please. All right. Closed-loop indications are similar to other SES systems, your chronic intractable pain states. They advance the current technology to address some of the challenges that we have seen in typical spinal cord stimulation with changes in position, migration, and this ECAP technology really has broad applications that are being applied in research to shape the space that were presented here earlier tonight, such as in deep brain stimulation. We're also seeing some applications in vagal nerve stimulation and sacral nerve stimulation. And with the development of AI, we're also seeing close AI and closed-loop spinal cord stimulation and other areas. Next slide, please. So it's really exciting to see some of the clinical trials going on. We have DRG stimulation being looked at for arthritic knee pain. We have closed-loop deep brain stimulation to treat refractory neuropathic pain. We're looking at restoring upright mobility after spinal cord injuries and closed-loop functional spinal cord stems on walking rehab after spinal cord injuries. A lot of these functional and movement type of disorders are being looked at with closed-loop and AI for improving patient outcomes. We also have closed-loop spinal stimulation for restoring upper extremity function. So a lot of stuff in the spinal cord injury space and looking at improving locomotion and bladder function. And then you have your ambulatory closed-loop stimulation for bladder control. Most of these are spinal stimulation and not the deep brain stimulation that was mentioned earlier, but probably have similar applications, different mechanisms. Next slide, please. So in conclusion, we know our A-delta and C-fibers are our primary nerve fibers responsible for our pain perception, where our A-beta fibers are responsible for the sensation of touch and pressure, and GABA is a key neurotransmitter responsible for pain relief taking place. Our traditional high frequency and burst, we have theories on their mechanisms. They're not completely understood, but we've been able to build a lot of fundamental knowledge off of spinal cord stimulation in order to advance the field and really help patients restore some function, pain relief. And next slide, please. And novel developments. We have DRG stimulation aligned for highly focused treatment of pain where the T-junction is thought to play a role in spinal cord stim. Closed-loop, we're looking at ECAPs, getting closer to biomarker identification and creating just enough output to have more energy efficiency and clinical efficacy, adjusting our stimulation output to maintain appropriate parameters with positional changes. And I mean, it's really exciting to see some of this closed-loop neuromodulation and AI that is not quite published yet or hearing some of the research. So I thank everyone for sharing their research interests and some of what they're seeing in the lab or in the clinic and where they're applying it to. Thank you very much for the invitation, and I look forward to seeing some of the research and reading the outcomes. Yeah, thank you, Dr. Engel. Thank you to all the panelists. Really appreciate your perspectives and formal messages. I think this is, and we're almost right on time with 12 minutes left to ask questions and discuss amongst ourselves in a pretty organic way. I see one question from Dr. Gupta, but before we get to that, I do want to pose a question to the group just because I think this is, you know, neuromodulation is such a broad field with so many indications. I mean, laryngeal dystonia, not a common thing, right? I mean, sacral nerve stimulation that Dr. Engel touched on, DBS for obesity, Dr. Rosenhout talked about. These are sort of fringe applications, and it's so interesting. And I guess my question is, they're all something to do with electricity, right? And Dr. Engel talked a little bit about the different forms of neuromodulation. And I just wonder, what does everyone think will be the next sort of different form of neuromodulation, not electrically based, but maybe, you know, sonication or what have you? That's interesting, but it goes back to what do we consider the definition of neuromodulation, right? I mean, we often have the discussion about whether or not we consider destructive procedures to be neuromodulation, right? Is a percutaneous C1C2 chordotomy considered neuromodulation? Is a thalamic thalamotomy, whether you do it by RF or ultrasound, is that neuromodulation? If you do low-frequency ultrasound and vibrate open the blood-brain barrier to get something in there, is that neuromodulation? I don't know. That's a fun discussion that we always like to have over drinks, right? You know, I think that there's obviously a lot of interest in what we can do with opening the blood-brain barrier right now with ultrasound. And I think that's a very fruitful area for exploration. Sorry, go ahead. There's an interesting comment that's been made today on the radio of Ozempic, actually related to possible neuromodulation of addictive brain pathways. So I think that might be- So pharmacological neuromodulation. There's a lot of money interest. It might be an interest. Yeah, I'll echo those points in that we're obviously biased towards surgical forms of neuromodulation. However, there are non-invasive forms of neuromodulation, whether it be pharmacotherapy, there's also transcranial magnetic stimulation, low-frequency focused ultrasound. So I think that we're- one aspect of it, and we need to be cognizant of the sort of broader aspect of neuromodulation, that again comes into Dr. Rosenau's point of what is neuromodulation. I don't think we're quite done with electrical stimulation though, because we still- there's still so much to be done in waveforms, parameters, stimulation settings. I think we're still at the tip of the iceberg. Absolutely. Yeah, when you talk about neuromodulation, the very first separation in the algorithmic tree is invasive versus non-invasive, at least the way I look at it. And then we are all on the invasive, right? And so that's why the title of this actually is Invasive New Emerging Indications, because there's a whole field that honestly, I don't really even interact with. I don't think I fully understand it. I want to get to your question, Kunal, because, well, you put it in the chat, and I think it's very interesting. Do we believe that the amygdala signal and PTSD-RNS is specific to PTSD versus a fear response that may be associated with flashbacks or also ADHD, different forms of trauma? Of course, that would fall into PTSD, but maybe yes. Maybe if Dr. Gupta wants to comment on that. That is a super question and something that we really don't know. I think the deeper question that Dr. Gupta asked, which is also good, is could you use this as like a surrogate marker, right? I mean, do you have to have a direct marker? And the answer is maybe, maybe not. If it produces the desired clinical effect, does that matter as much? But it's all very interesting because we don't know if this is simply a specific marker to PTSD or more generalized to other fear and anxiety disorders. And is there something more specific that sets these different disorders apart? I think that's one of the nice things about we have a lot of patients who have medial hippocampal and amygdala electrodes routinely for stereo EEG. And we really have a unique opportunity in these patients to investigate these sorts of things where we have these coexisting diseases with their epilepsy. And when we have clinical reasons to have electrodes there, I know that we certainly take advantage of all these folks and have looked at a lot of other things in that area of the brain. And this is something else certainly that needs exploration. So that's a good segue into one question that I had for you, Dr. Rosnau. But I'm interested to hear everyone's thoughts on this. So, you know, you highlighted in your talk the importance of the biomarker and the hunt for the biomarker. But also you presented us some research, for instance, with the PTSD study that suggested that maybe the biomarker or as the biomarker is treated, it makes me wonder, can it be treated too well, so to say? So in the PTSD study, you know, you told us that after 11 months, the two patients had some improvement in symptoms, you know, not complete resolution, which we would all expect. You know, we don't, none of us in the field expect complete resolution, but that the biomarker improved. So it makes me wonder, is it possible to treat the biomarker too much, so to say, such that then it's no longer a reliable representation of the symptoms? And how will we work around that? Yeah, I think that's a great question. You know, what if you get rid of the biomarker and you only have partial resolution of symptoms? Does that show that you've maxed out your clinical benefit, right? And does that mean that there's something else going on in another location or another frequency band, if you're looking at EEG power or something that we're not keying on? Obviously, these disorders are complicated, right? I don't think any of us thinks that you can reduce something as complicated as PTSD to a simple, you know, LFP change or EEG change in one area of the brain. I think our lessons with DBS for depression and OCD over the last 20 years have certainly taught us that it's not as simple to treat these things as it is to treat something like tremor or Parkinson's or even dystonia. So I don't know, but, you know, we certainly see on the epilepsy side, you know, when you look at responsive neurostimulation for epilepsy, that we can see in some people this decline in stimulation amenable events over time, right? This true neuromodulation where you don't have as many stims over time, which is one of the reasons why sometimes the company keeps extending what they think the battery life is because they're seeing as it needs to do less work over time, they can stretch out the estimates of battery life. But these people aren't necessarily seizure-free. So, right, as you said, you can tamp down the biomarker but not eliminate the clinical conditions. So we're seeing that all over the place in epilepsy. So where it comes for this, man, we're smarter than we used to be, but we're just not brilliant yet in some of these things. We got a long way to go. Yeah, we're still trying to figure out how to communicate with the central nervous system. There is a question from a particularly brave anonymous attendee. I'll read it to you. Can people weigh in on their approach to dialing in the therapeutic dose for DBS and other electrical current injection methods, particularly for non-movement disorders where symptoms are not obvious like depression, PTSD, I assume, laryngeal dystonia? Nall or Dr. Rosenau, what are your thoughts on that? Oh, I'd like Dr. Goop to take this one. Well, that's a fabulous question. I mean, right now standard of care is looking at treatment response. So that's why it's delayed. And that's why the majority of Parkinson's centers are implanting STN because they get immediate response and they don't have to wait for GPI. We've got anecdotal evidence that if you're using, so for example, the Medtronic PERCEP system and you're doing unary bands to that area, that certainly we've seen in our patients when we've implanted GPI, you can actually see a change in response when you hit a certain current level and over time. So there are sort of clinical methods now with responsive systems in DBS that might be providing us a biomarker just from our target. Then the question then becomes is, can you then identify a biomarker outside of your target? So do we need to then go to responsive stimulation where you have like a target and a sensor where they're separated rather than together? So we've now gone from patient response to intracranial biomarker to target and sensing at the same location to target and sensing at different locations. So, and then can you use the response to then adjust your waveform, your therapeutic dose? Again, you see these videos of people doing interoperative testing and awake DBS for OCD and for depression. And the question does become is, is interoperative treatment response going to be as quick? So yeah, that's a great question. I don't think we know the answer. I think we're still learning. I think it takes being really cognizant about asking the appropriate question when you sort of enter these trials. Dr. Rosen, I'd love to know your insights. I think part of the problem that we see, I mean, I can't add too much to that really thorough answer, but are, you know, one of the things we always worry about are short versus long-term effects, right? What we see in the clinic versus what happens once the patient's out of the clinic and, you know, roaming around the real world. I mean, those two things, especially if you look at, you know, behavioral disorders and mood disorders are very different. When patients are sitting in the clinic, you do one thing, and then when they're out of the clinic, it's completely different. And who knows what the stimuli are out there and what they're keying on and what the social setting is. It's very complicated to know how this works. So again, if you could find the reliable biomarker for the closed loop stimulator, it could do that all its own outside of the clinic. Yeah. And I want to highlight to the, especially for the learners in the audience that, you know, coordination of care in neuromodulation patients, especially movement disorders, the neuropsychiatric population, epilepsy, I mean, really anything that we've discussed here, also pain as well as is really benefited by the multidisciplinary setting. So, you know, I hope the learners take away that all this research we've discussed today and all these even standard clinical care is not done in isolation. I don't think any neurosurgeon is independently and in a closet programming and optimizing any of these patients. Yeah, that's correct. I think there's one more question from the attendees, and then we'll probably close it out. This one's from Christian Lopez Ramos. And I think this is a good one because it highlights the transition from stereo EEG to some sort of permanent intracranial neuromodulation. So his question is how feasible is it to adopt a stereo EEG framework to identify optimal targets, biomarkers to improve efficacy of RNS-DBS in patients with complex psychiatric or pain disorders? Is this the ideal approach to personalized treatment and is it scalable? So I just based on my own experience using stereo EEG to optimize placement of intracranial electrodes for permanent neuromodulation, I think that it is feasible. You use different EEG electrodes, particularly if you're targeting subcortical nuclei, you would make the density of the electrodes along the depth electrode higher. So not like a five millimeter spacing in a CM, you want like a one millimeter spacing. But I'll let Kunal, who's done this before and has an R01 out on it, I guess, and Dr. Rosenau as well to comment. Submitted R01. Submitted, yeah. Mostly on my animal work. So I think Dr. Rosenau sort of answered the last question, is that, is the scalable? Probably not. Is this the ideal approach? Well, scientifically, probably. But how feasible is it? So when you chat to the folks doing it, there's a very extensive bioethics components to approaching this. And I think you do have to be mindful in every sense of the term, no puns intended, to really sort of, if you're going to go down this route, it has to be done in a very methodical, mindful way. Dr. Rosenau. Yeah, I agree. I agree with that. Just to add something. So it is actually being done for pain. So one of our other colleagues actually has a grant to use stereo EEG to inform intracranial targets for simulation for chronic pain. But again, I think the hope is to find something that's consistent across all these people in these trials so that you don't have to do this for everybody. Because it's going to be very hard if everybody you want to treat for one of these disorders has to come in and get this kind of big approach to get this done. It just won't be something that we can do with any volume. You want to be able to use this to nail it down to one place or find that single biomarker and that single target. All right. So I think with that, we'll close out the session for this evening. I want to thank all the participants for joining us. Thank our three speakers, Dr. Engel, Dr. Gupta, and Dr. Rosenau. Thank you, Dr. Raskin, for moderating. And thank you to NANS for sponsoring this. It's been a great session. We hope you all enjoyed it. Thank you, everybody. Please complete the brief webinar evaluation on the link in the chat. Have a great day.

neuromodulation

invasive

indications

deep brain stimulation

closed-loop

transcranial direct current stimulation

pain management

stereo EEG

biomarkers

personalized treatment plans