I don't have any personal financial relationships, but I do work with some companies listed there below. I'd like to give at least a little bit of an overview on a bit of brain stimulation. I've broadened it slightly from DBS, and I'll start by just mentioning something about bioelectronic medicine and give a little bit of a perspective on targets, and a lot of that focuses on the centromedian nucleus, and so we'll start there and talk a little bit about IgE2, and I'll finish just with a few conclusions. Bioelectronic medicine, if you haven't thought about it, it's nice to be reminded that many of us at least feel like neurons are the fundamental computational unit of the brain. They communicate with electricity, and that way electricity is in some sense a language of the brain, and bioelectronic medicine is then a way to use electricity to potentially diagnose and treat a disease with epilepsy. One of the challenges is that we don't have a way to know what we're doing right away, so I'll highlight this. Brad did a great job of highlighting some of these problems, too, and that's we really need a little bit of extra work on biomarkers because we're kind of stuck guessing a lot of the time. Those of you who practice clinical medicine know this on a day-to-day basis. As we talk about brain stimulation for epilepsy, there's three FDA-approved invasive brain stimulation approaches, or just brain stimulation approaches, non-invasive, aren't yet FDA-approved for epilepsy, and you can see the years there from 1997, most recently, to 2018 with DBS. The approximate outcomes are basically 30 to 50 percent for median seizure reduction or responder rate. Similar, they tend to improve over time. I want to note just as far as approach that these brain stimulation approaches differ in kind of two fundamental ways. One is how they deliver stimulation, and the second is where they deliver stimulation. With focal epilepsy, of course, we can try to target the seizure onset zone. With generalized seizures, we tend to focus on a node, more like VNS or DBS. Then there's this idea of whether it's responsive or continuous or duty cycle. We'll talk about that, but the landscape is more or less like this. You can see in the top left, you have DBS, RNS, and VNS. Those are the three that are FDA-approved. CSS is something that we've done a little bit more at Mayo Clinic, chronic sub-threshold stimulation. In some sense, it's a combination between DBS and RNS where it's open-loop but targets the seizure onset zone. But lest you think that invasive brain stimulation is all there is, when you look at the number of stimulation devices out there, it by far weighs over onto the non-invasive brain stimulation side. You can verify this yourself just by going on Amazon, if you like, and typing in brain stimulation. You can buy any number of brain stimulation devices to help you play a musical instrument, lift more weights, run faster, or whatever it is you would like to do. So I'll just mention that briefly, but it is an area where there is a lot of change right now. When we think about brain stimulation, it is a little bit different than medications. You choose a medication and a target dosage, and then you go from there. Brain stimulation, there's even roughly four basic parameters that we think about, amplitude, frequency, pulse width, and electrode configuration, and I'm not even really discussing where you put the electrodes themselves. And I'll just highlight electrode configuration. So you have these electrodes, and they have contacts on them. There's pluses and minuses that are cathodes and anodes. It gets confusing, even for those of us who do this all the time. Just as you'll even highlight, you ask somebody what a cathode is, and sometimes they'll say a plus. And that's true. If it's on your car battery, it is a plus. If it's on a brain stimulation device, it's a minus. We think the cathodes do the heavy lifting, so it matters where they go. And how do the pluses and minuses relate, and how do we program that? Well, as I mentioned before, we do that a lot by guesswork and maybe dogma. And if you think about stimulation strength, again, something else to think about is that invasive brain stimulation, as far as electrical fields, we're about 1,000 volts per meter. Just as a side note, interestingly, when you think about RNS versus DBS, typically, charge densities of RNS are at least 10 times less than DBS, even though efficacies tend to be similar. Transcranial magnetic stimulation, again, about a tenfold less magnetic electric field. TDCS, 10 to 100 times less. And if you want to compare this with motor voc potentials, that fits somewhere in the middle. And of course, those patients are being stimulated through their scalp while they're anesthetized. So it's a little bit of a different situation. I just want to highlight by background, we'll talk a little bit about LGS. And Brad did a great job, thank you, for introducing IGE. As far as LGS goes, just as a reminder, these are patients with multiple seizure types, including tonic seizures, cognitive impairment and some EEG characteristics, such as slow spike and wave and generalized paroxysmal fast. With IGE, I want to note that the strict definition, such as in this paper, really is those four well-defined entities, CAE, GAE, JME, and GTCA. When we say IGE or people say IGE, they don't always mean those four, though. So you have to be a little bit careful. Sometimes what they really are saying is patients who more or less have normal cognition and they have generalized onset convulsive seizures, plus or minus absence. So sometimes you'll see even patients with some EMA or some other entities, and sometimes we talk about this. So I guess you have to decide whether it's truly IGE or not, and I'll leave it up to those who classify these things carefully. I wanted to mention VNS. Even though John initially mentioned, maybe I should talk about DBS, I think it's important to mention VNS. It has at least the most evidence in terms of numbers and length of use. In 2013 there was an AAN guideline that recommended VNS may be considered not just for children, which it is now FDA-approved four years and up, but also for LGS. That came from an assessment of 113 patients with about a 50% median seizure reduction and the responder rate. And then subsequently there's been other studies. There's a registry, a VNS registry and then an evaluation of that with Dr. Englott, again showing 50-60% efficacy. 2017, this is from a large Japanese registry with a combination of patients, but a number of them had generalized seizures, either primary or secondarily generalized. So it was a little bit unclear from that study. But again, 67% median seizure reduction. And then finally, Brad already mentioned this study too, but GGE or LGS with 60 and 40% responder rates respectively. So VNS is definitely something to consider for patients who have intractable seizures and are struggling with side effects. I think the other point to mention is that brain stimulation in general has a different side effect profile. You don't tend to get the cognitive fatigue and just vague impairment that we hear from the medications. But there are other side effects that you have to talk about, you know, VNS of course with hoarseness and so forth. So I'll focus just a little bit more on brain stimulation before I just try to give a broad perspective of some of the literature out there. And by starting to say that it's approved for a number of other things, but not generalized seizures. It started out being approved for tremor, Parkinson's, and then most recently in 2018, focal epilepsy for the anterior nucleus of the thalamus. So it's not approved for other nuclei in the thalamus or other targets. And you can see there where the anterior nucleus is and the centromedian nucleus. That is not to say that it has not been used for other targets, of course. Everything listed here has been a target at one time or the other for brain stimulation or deep brain stimulation, some kind of brain stimulation. Maybe with the possible exception of one or two, centromedian is really the only one for which it's been studied for generalized onset seizures. All the others are really for focal seizures. So that's why I'd like to go through a number of studies just about the centromedian nucleus because that's where much of the work has been done. So the centromedian nucleus is a part of the intralaminar thalamic nuclei. It's typically thought to be involved in attention arousal as other intralaminar nuclei are also thought to be involved. It has extensive connectivity throughout the cerebral cortex, various areas including the insula, the subcortical regions, inputs from the reticular activating system, and so forth. And some of this is relevant because generalized seizures can be elicited from the brainstem. It's thought to be involved in them. And the centromedian also is somewhat appealing because it's a little bit on the larger side and easier to target side compared to at least some of the other thalamic nuclei. What you can see in the bottom right there is a trace from background scalp EEG on the left before centromedian stimulation, and the right side is during centromedian stimulation. So what you see is a, quote, calming of the background there. And that came from the Velasco's. We'll talk about their studies, and in fact, we'll start in 1987. That's when one of their first studies was done with primary generalized or multifocal seizures, just a small group. And I would just point out, I'm going to go through a number of studies here, I just will point out a few interesting points about the studies, maybe not all the details. This was an implant of bilateral centromedian nucleus with externalized leads. So what that means is that the leads were implanted, but they were not connected to an IPG or implantable pulse generator. They were left out. And then these patients were stimulated for two hours on each side each day for three months. It's actually quite a feat. And then they were able to record EEG that way. So they could see that there was a focal seizure reduction, 60 to 80 percent, generalized GTC reduction, and a reduction in inter-ectal discharges. And what was interesting is that some of these reductions happened over time, over weeks. And if you see in the bottom right, and I'm actually going to, so you can see that this is the left LCM trace down here at the bottom, the rest is scalp, and this is the right. And so you see this trace here, and this is actually some post-stim discharges, this is what I'm mentioning down here, that they saw started days after stimulation was started, or weeks even. And this is when, so as you stop stimulation, like after a couple weeks, and then you would see this discharge start and last for some period of time. So there are certainly things that were happening over long periods of time during these three months. And what they also noticed was the stimulation, the effects of stimulation, far outlasted the stimulation itself, so for weeks to months. So we often tell our patients that changes that we make in stimulation now may not have a full effect for weeks or even months later. So again, a little bit different than medications. There was a double-blind crossover trial in 1992, Bob Fisher, seven patients with centromedian nucleus implanted. Again they're getting stimulated about two hours a day. The interesting thing here is that one of the patients did so well that they would not cross over, so that was a problem for the study. And it did not meet its primary endpoint. But the open-label extension showed about a 50% responder rate there, three of six. Again this is scalp EEG and what you can see here is some induced discharges from centromedian stimulation. So these are slow waves, spike waves that resulted bilaterally during stimulation. What they mean, a little bit unclear, but it's doing something. We'll go on here. I just mentioned a few more. Again, this is back from the group of the Velascos. And here you can see now they're down to three days of externalization. Why do you externalize it? Because if you externalize it, you can actually sense from them. You can hook them up to an EEG amplifier. You can record. Certainly at this time, there was no ability to record EEG from these leads. We would like to be able to see what's going on, of course. And here you can see a reduction in seizures that, again, happens over months. This is for total seizures, GTCs, atypical absences, and what they're recording is a seizure decrement over months. They had a group, again, in a double-blind protocol here that also did not meet its end point, however. Again, so you can see immediately just from the plot here, again, results that improve over months. So this is from Dr. Cukert more recently, bilateral CM with generalized epilepsy, 20 patients. These all were LGS or LGS-like patients. And if you've been paying attention to the stimulation frequency, we've sort of been going back and forth between 60 and 130 hertz. Well, you say, well, why are we using 130 hertz or 60 hertz? Well, there were some initial thoughts that lower frequency caused more of those slow waves and maybe were not great. And so people moved a little bit higher in the frequency range. Also, it's influenced by the fact that for movement, for tremor, it's clear that higher frequencies typically work, whereas lower frequencies don't work as well. Ninety percent here were responders, and what we see is improvement for various seizure types. This next study was one that comes from Mayo Clinic. I worked with Luis Alcala, who's now a fellow at Jefferson, but was a resident at Mayo Clinic. And this study is interesting insofar as it talks, as we had a number of patients who actually had four leads implanted. Typically, you're only implanting two leads for DBS. This is off-label use, but we had 16 children and adults. So these were patients with bad epilepsy, up to 100 seizures per day, generalized, multifocal, poorly localized. And 11 of these 16 patients also had leads implanted in the anterior nucleus, so four leads implanted total, four leads being stimulated at the time. They were stimulated with IPGs that had that capability. At this time, they were spinal pain batteries. They work essentially the same, but have the ability to stimulate four leads. And you can see just a diagram here, where this is the CM and the ANT here. And interestingly, 14 of these 16 were admitted to the EMU for stimulation optimization. So we struggle with this. It's a big problem in stimulation. You have all these parameters you can change. Well, how do you know what to do? Well, you listen to somebody come up and talk like me, and you do what they say. Or maybe you try to get some data. Either way, there's not a lot of guidance in any real sort of way at the moment. And you can see these patients did relatively well, considering the bad epilepsy that they have. I'm waiting for the computer to recover here. We have a momentary pause. There we go. Just one or two more that I want to highlight. This is a comparison from the group out of Emory, a heterogeneous group with LGS, IGE. And again, relatively good responses. What you see here is that they started out with the first half at 60 hertz. And after the first six, they went to 130 hertz. And that was due to that previous study that they found. So there's some uncertainty as to what may be the best. But what we're seeing is relatively similar results across these groups, 90% median seizure reduction, so promising. And then maybe one of the most well-done studies, most recently published, double-blind RCT for LGS patients with CM implanted electrodes. And these patients were stimulated using typical stimulation parameters used for focal epilepsy, 145 hertz, but not that dissimilar from what other studies had done. And the initial goal was to try to go up to 5 volts, but the patients couldn't tolerate it. With CM, you kind of run into this difficulty that patients get paresthesia sensory phenomenon when you go up. We don't really run into that so much with ANT. But with CM, you get a few more side effects that you have to worry about. However, they did not meet the clinical endpoint of diary-recorded seizures because they were not different, 35% versus 17%. But there was a significant reduction in electrographic seizures as recorded by 24-hour ambulatory EEG. And at the open-label extension it was about a 50% seizure reduction. And a subsequent follow-up study suggested maybe the anterior inferior lateral portion. So the location can matter. In case you think that just DBS works, and we struggle a little bit with the terminology here. What does DBS mean? Does it mean the hardware or does it mean where you're stimulating? Here we're talking about the RNS device, but implanted for two kids, for example, here with LGS. And where do you put them? Well, in this case, they actually implanted four leads, two into the CM and two in the frontal polar, but you can only connect two. So they chose one CM and one frontal polar and then eventually connected them both to the CM and the patient did better, marked improvement with the bilateral CM. And here we're using about 5 seconds burst duration. Typically in RNS people will tend to use more like 100 to 200 milliseconds. So this is a much longer burst duration than typically used for focal seizures and still a higher frequency. There is a study that has just opened with the RNS device for LGS. It'll have either 10 or 20 participants looking at high or low frequency. It'll have two devices is the idea because you get two leads for each device. So you get one device for one side, one device for the other side with one prefrontal lead and one central median lead. And I just want to highlight that in case you think you have to do invasive brain stimulation, you can also do transcranial direct current stimulation. This is essentially sponges with the weak currents. And this is from 2016, double blind RCT, five days. And what you can see again is a difference between the active and the sham that sort of maximized around five days and slowly then got worse, but an improvement with tonic, atonic and absence seizures. When we get to IgE, there's actually not that much in the literature about IgE. This is what I could find. I'm sure I missed a few, but there's about seven patients using on the left. This is a DBS device and six patients more or less on the left using an RNS device. They're all stimulating in the central median nucleus. They all report good results and they're all using relatively high frequencies. So there's promising, something of promise. And with the RNS device, there's again another trial that's just opened up for IgE patients 12 years and older, where they will look at this. This is, by the way, if you didn't know, an actual nautilus, which means sailor and it has actually the rare ability to go from the bottom of the ocean, 1,200 PSI up to the top. I didn't realize that most fish can't do that. If you take them up, they die, but not these guys. One of the questions is, well, how does this compare to focal brain stimulation? We have a lot more experience with focal brain stimulation than generalized. We looked at this again. This was with Luis, who I worked with a fair bit, and we looked at all of our brain stimulation patients. This is 159, and you can see them split out here between DBS ANT, CM, RNS, chronic subthreshold stimulation, and then we just picked a subset of VNS. Our total results are here. They're actually fairly similar across the spectrum and the approaches. When we compared subcortical to cortical, we did see a little bit of a difference preferring cortical. There may be a number of reasons for that. We compared generalized onset versus focal onset. Now, of course, we had a lot more focal than generalized, but we didn't see any clear difference. That may be somewhat in line with what we see. So I'll just finish in the last two slides here with a few thoughts. One is the centromedian thalamus does appear to be an appealing target for generalized onset seizures, and we already know generalized onset seizures are in a lot of ways underserved. The retrospective studies show optimistic results. It maybe goes without saying that we should maybe be a little bit more cautious when we interpret retrospective results. I've had the opportunity to work with a couple of groups analyzing the same data set, and I can tell you that depending on who's doing it and how they're doing it, plus or minus 10-20% responder rates, not outside the realm of possibility. You just have to interpret them with a little bit of care. But it is nonetheless appealing. It's interesting that many of these stimulation approaches tend to show similar results, and I think there's a lot of room for improvement. Another interesting point is that for all these papers, there's extremely little devoted in the paper to the primary outcome measure that we look at for every single study, and that is how many seizures do patients have. You might get half a sentence sometimes. Patients reported via diary, period. That's it. I think it just highlights that we know diaries are inaccurate. We have difficulty with this, and there's a lot of biases that can go into how you ask the question, who asked the question, is it asked differently between patients? Any of you who do this clinically, how many seizures did you have in the last month? Well, I had two to eight seizures in the last month. Oh, so you had two, did you, last month? Okay, if it's baseline, oh, okay, so it was eight seizures, was it? All right, gotcha. Well, you know, there you go, 75% seizure reduction. So these are difficult issues. Ideal stimulation parameters, you know, the paper, there's a paper, the Valentin paper from 2013, they started at 60 hertz and then didn't see the results they wanted. Sorry, they started with 130 hertz, so they switched to 60. The group from Emory did exactly the opposite. They started at 60 and then they decided 130 was better. So this just highlights, we just don't know a lot of what's going on. There's a lot more, you know, well, as people often say, the strength of their feelings often are inversely correlated with the amount of data to govern that. And I'll just say that nine of 16 patients that we program, for example, under 60 hertz, although you often hear that you should never do that because you might make seizures worse. So we looked at that with RNS patients and found that, in fact, when we programmed at low frequency, we had an additional 67% seizure reduction for a subset of patients. So it is possible. And finally, I'll just mention that improved biomarkers is what we need. Dr. Nick Gregg will talk a little bit about this today at 5 p.m. And my last slide, an excitatory biomarker wish list. You know, I wonder whether stimulation-related biomarkers are going to be better than passive for a number of reasons, but we need a quick readout, ideally in seconds to minutes, that could help guide us in what we're doing. Hopefully it would be invasive and non-invasive, but it should ideally be related to neurophysiology so that we can have some better understanding about what we're doing from both ends of the spectrum, clinically as well as from a preclinical standpoint, and guide us as we make medication changes and other changes. As far as resources, these two books are great if you want to learn more about deep brain stimulation. They come at it from a little different level. This book by Dr. Marks is a little more practical. This one has a little bit more theory, but they're both excellent. Handling devices in the perioperative period for other reasons and for imaging is very complicated. We put together this review. It was a lot of work. I hope somebody finds it useful because I'm not sure if I want to do something like it again, but it's out there. And then finally, if you want hands-on experience with brain stimulation, we're putting on our second course this year, and you can have the opportunity to play around with things and ask questions and so forth. Thank you very much.

brain stimulation

bioelectronic medicine

epilepsy treatment

Deep Brain Stimulation

Vagus Nerve Stimulation

biomarkers