All right, welcome everybody to our session on Harnessing the Power of Noninvasive Brain Stimulation for Chronic Pain. I hope you're all enjoying Orlando and Disney. In honor of being here, I am wearing an Alice in Wonderland shirt. I know it's hard to see from there, so I wanted to point it out. I hope everybody is enjoying the conference and we have a really great lineup of speakers today. These are all people who are really advancing research in chronic pain and at the forefront of noninvasive brain stimulation. Dr. Leung and I are co-chairing this session. First, we'll have Dr. Leung talking about RTMS and then Dr. Martinez talking about ECT and nonconvulsive ECT for chronic pain. Then we have Dr. Fragney here who will talk about transcranial direct current stimulation and Dr. Townsend who will talk about transcranial alternating current stimulation, which is different, and cranial electrotherapy stimulation. So Dr. Leung is the director of the VA San Diego Health System Center for Pain and Headache Research and Center for Transcranial Magnetic Stimulation. He is a professor of anesthesiology and pain medicine at UCSD. He receives funding from the DOD, the VA Office of Research and Development, and the NIH for his ongoing research focusing on mechanisms and effectiveness of noninvasive brain and peripheral stimulation for nerve function restoration and headache pain relief. He also founded the first TMS clinical unit for pain and headache treatment in the VA healthcare system, so he actively uses this modality for pain treatment. He's highly active in the clinical TMS society. Dr. Martinez is a psychiatrist and professor at the New York State Psychiatric Institute and Columbia University Irving Medical Center. Her research focuses on substance use disorders and its comorbidities, including chronic pain, using a range of modalities such as ECT, TMS, ketamine, and peripheral nerve blocks. Dr. Martinez also serves as co-director of the Interventional Psychiatry Program at Columbia Psychiatry and a T32 fellowship in addiction psychiatry. And then Dr. Fragney is a professor of epidemiology at Harvard Chan School of Public Health, a professor of physical medicine and rehabilitation at Harvard Medical School, the director of the Spalding Neuromodulation Center, and his research focuses on understanding and guiding neuroplasticity in brain injury. He has an MD and PhD from the University of Sao Paulo, as well as three master's degrees from Harvard University. He's an author of over 680 peer-reviewed publications and the recipient of the United States Presidential Early Career Award for scientists and engineers. Dr. Townsend is the chief scientific officer of Electro-Medical Products International and president of Pulmonary Neuro. Her research is in cutting-edge neuromodulation, translating it into commercially viable treatments and indications such as depression, anxiety, insomnia, substance use disorder, and chronic pain. She led the technology and clinical development of closed-loop TACS and clinical trials of CES. She has secured over $4.5 million in SBIR grants to support collaborative research and development work with academic partners and numerous academic and government collaborations. So as you can see, we have a wide range of specialties and interests and diversity in our panel. And then there's me. Hello. I am Anna Woodbury, and I'm an associate professor and vice chair of research at Emory University in anesthesiology and pain medicine. My research interests include the neural underpinnings of chronic widespread pain syndromes, developing and evaluating targeted non-pharmacological treatments to improve pain and function. And I'm a PI on VA-funded awards for research in fibromyalgia in veterans. And I have a special interest in neuromodulatory and non-invasive brain stimulation techniques. So many of these individuals are my collaborators. And if you have questions for me, I'm happy to answer them as well. I also enjoy vagus nerve stimulation, which I guess is a separate but related topic. All right. So we'll have Dr. Liang present next. Good morning. Let me begin my talk by thanking Dr. Woodbury for doing all the groundwork for putting this symposium together, and also my co-speaker for making the effort for being here, and more importantly, you being here so early in the morning. So my talk here is really about one of the most versatile non-invasive brain stimulation modalities that we have currently. I'm just curious, how many of you have heard about transcranial magnetic stimulation? Very good. How many of you are actually using it in your clinical practice or your research? Not too many. Okay. So yeah. So just sort of level the playing field a little bit. Let me give you a brief summary of what TMS is all about. So the physical principle of TMS is actually quite straightforward. If you remember your high school physics, we had the right-hand and the left-hand rule interchanges. If you pass an electrical current through a coil, that coil will induce a magnetic field, and that magnetic field going through the cortex into the brain, think of a brain as a circuit, as sort of the electrical wire, it can induce electrical current in the very focal area of the brain. It depends on what setting you dial into the TMS machine, which is essentially a big capacitor that allow you to charge or discharge the currents over there. High frequency in general, anything about five hertz can induce excitatory event in the brain, versus a low frequency tend to inhibit brain functions. Before we talk about pain modulations, we need to talk a little bit about how pain actually being perceived in the brain. If you hit yourself with a hot iron, that intense heat stimulations will first excite the peripheral nociceptors. That nociceptor will then be transmitted through your spinal cord. Majority of them will go through the spinothalamic tract into the region of the brain called the thalamus, which really serve as a relay center to transmit to the other parts of the brain of that intense signal. First it will go to what is known as sensory discriminatory regions, which is primarily the primary and secondary sensory cortex. Some of these will then be transmitted into what is known as the affective region of the brain, predominantly in the anterior cingulate cortex, the ACC, which really give you the unpleasant feeling, the ouch feeling of pain, and that tells you that's not good, you need to do something about it. Later we talk about the brain actually has this intrinsic ability to modulate pain. These areas really, what I circle here, is coming from the motor cortex, the prefrontal cortex. For instance, monks meditate, their prefrontal cortex is extremely active, and they are known to, through meditation, they can enhance the function of the prefrontal cortex. They can actually modulate pain and enhance their pain tolerance. So throughout the years, various studies have been done looking at how we can harness this intrinsic ability to modulate pain perceptions. By far, with TMS, there are two prime locations we can use for simulations. One is the motor cortex, and the other one is the dorsolateral prefrontal cortex. And as you can see, the different arrows that are being presented here represent different studies being done in the past with different mechanisms of how pain is being modulated with the simulation in these two areas. When you simulate the motor cortex, the effects are pretty direct. It affects the descending inhibitory pathway, versus if you simulate the LPFC, the effects seem to be very diffuse. It can modulate the motor cortex. It can also help to modulate the somatosensory cortex and indirectly the descending inhibitory pathway. So are there any mechanistic differences from a biochemical standpoint? And this is a study looking at the reversibility of motor cortex stimulation and the analgesic benefits by using naloxone, which will reverse the effect of endogenous opioid, essentially. And it's been shown here that if you infuse naloxone, it actually reverses the effect of motor cortex stimulation, suggesting that the motor cortex stimulation induced analgesic benefit primarily through the descending inhibitory pathway, through the endogenous pathway. This other study looking at the use of capsaicin in bilateral extremities and looking at DLPFC stimulation primarily at the left DLPFC stimulations. It's been shown that if you just stimulate the left DLPFC, the analgesic benefit is not unilateral, rather it's quite diffuse. And that effect itself is not endogenous opioid reversible, suggesting that there are perhaps a different pathway linking to the DLPFC stimulations, which now thought primarily through the dopamine as being the primary neurochemical mediator for the analgesic benefits. So with the understanding how RT-MS works, the next question is, does it really work clinically? RT-MS was really something that had been developed over a period of more than a century. It has been known a long time ago that if you pass a dynamic amniotic field through the brain, you can induce different neurological events. For instance, deltsulfon in France demonstrate that if you pass that current through the visual cortex, you can induce frostbites. That was done more than a hundred years ago. And so the question about how does it get to the pain? Well, the technology has been advanced with recent electronic advancements. Now we can rapidly stimulate the brain using repetitive stimulations. And the literature has been really grown exponentially over the past two decades. And aside from psychiatry, which is currently the FDA approved indication for TMS, pain being the second most studied indications. So around 2020, we assembled a panel of international experts looking at clinical outcome evidence for TMS for treating pain and headaches. So the tasks for the panel is really look at current evidence, the level of confidence of the evidence, the quality of the evidence, and then based on those, we ran a recommendation whether we can utilize TMS or clinically implement TMS for pain or headache treatments. The panel work really looking at several indications, acute pain, chronic pain, and traumatic headache versus non-traumatic headache. Also looking at some of the comorbid condition and cost effectiveness. What the panel have reached in this conclusion is that currently we have sufficient evidence to say that TMS works for neuropathic pain, especially those with higher neuroanatomical origins, things like post-structural pain and trigeminal neurologies. It also has good evidence to suggest the use of short-term outcome, based on short-term outcome for mild TBI headaches, which is sort of the outlier at the time of the review is we're not quite sure where to put mild TBI post-concussive headache. This is the category of patient I deal with a lot as I work at the VA. So mild TBI headache is not just restricted to military personnel. CDC estimated in the civilian population, we had about 1.7 to 1.8 cases of TBI every year essentially. So kids go to soccer game, professional athletes, they all sustain some degree of concussions throughout their activities. The more we look at TBI headache, the more we come to the realization that we're really dealing with neuropathic pain conditions. Why? Well, on the left, in your left-hand side, this sort of typical neuropathic pain condition that we deal with, they have what is known as dysesthesia, aledenia, hypogesia, all-term motor sensory functions, enhanced sympathetic activities, as well as mood changes. So dysesthesia is essentially the feel of pain sensation without any provocations. That's what most TBI patients felt. They have constant headaches and really frequent debilitating exacerbations. Aledenia, non-nauseous touching induced pain sensations. And these patients, if you just lightly sometimes tap their skull, they will tell you that's uncomfortable. Hypogesia, they're extremely sensitive to any sort of touch. So clinical hormones really point to the indication that we're dealing with neuropathic pain conditions. Earlier on, we did a study comparing these patients with healthy control, looking at resting state functional MRI studies and looking at functional connectivity from the prefrontal cortex to different areas of the brain. What we found is there's a decrease of functional connectivity for these patients to the sensory discriminatory area of the brain, primarily the secondary sensory cortex, suggesting that they have impairment with pain modulations from the prefrontal cortex. There seemed to be also an evolving maladaptive state with these patients. On the left-hand side, we have patients with mild or no headache with those patients sustained mild TBI headache. As you move through the spectrum to the right, you'll notice that their ability, activity-wise, for the prefrontal cortex significantly diminished as their headache intensity increases over time. Suggesting that as the degree of severity of headache increases, their ability to modulate the connectivity from the prefrontal cortex to the remaining, the rest of the pain perception areas have significantly diminished over time. So this is the early study we did with a left DLPFC stimulation. This is a new navigation-guided, functionally-guided targeting of left DLPFC. Very brief, it's four sessions, 10 hertz, 2,000 pulses per session. What we found is the decrease of a headache, especially in the debilitating headaches, a composite score, which will involve the duration, frequency, and intensity of the headaches, as well as the frequency of the persistent headache. One of the sort of striking hallmark feature of mild TBI headache patient is, unlike migraines, their headache is 24-7 for the majority of them. They feel this little nagging pressure sensation all around their head all day long. So this is a very promising outcome that we feel for most patients, that's the most debilitating part of the headaches. What's interesting, what we found is this sort of a, as you know, TMS is approved for depression, primary use for depression clinically. And just with this short course of a simulation, four sessions, in comparison to 20, 30 sessions of depression, this very short course will have a transient benefit on the depression severity or depressive symptom severity, even though it's transient, but I think it's something that we should look into more. So what exactly is TMS doing to the brain? In the same group of patient, we look at their pre and post functional connectivity differences. The left side is the real group, and the right side is the sham group. As you can see in the real group, there's an enhance of functional connectivity represented by this brown, reddish colors in those regions relative to pain perceptions from the prefrontal cortex. Versus during the same period of study, you actually see a negative sort of a disconjugation of, if you might, functional connectivity from the prefrontal cortex at the sham group, suggesting that over time, if you don't do something about it, this condition of diminished functional connectivity actually get worse for those patients. Shortly after we published our studies, Sterling, the group in Canada, actually published this long-term study at the LPFC without any maintenance treatment protocols, and showed that long-term, this is up to a six-month study, TMS stimulation has a benefit for the both headache and depressive symptom for this group of patients. So this is very encouraging that to show that there's a long-term benefits. More recently, we finished a VA funded study. This is a long-term study we have done. It's a three-month, up to three-month follow-up studies. As you can see, with 10 session of the treatments, which is a bit more intense than the initial four session, 10 hertz, 2,000 pulses, neuro-navigation guided. We are able to demonstrate there's a decrease of frequency of the duration of the headaches, as well as the frequency of the persistent headache. Again, that's the most debilitating conditions for these category of patients. So this is very encouraging. And clinically, we are doing more a maintenance protocol as well. As you can see, over time, the effect of this kind of a stride back a little bit without any maintenance protocol. So maintenance is the key to maintain the benefit of the analgesic benefit of TMS. Just want to touch upon some of the comorbid condition with pain. Depression share a 50% comorbid rate with pain. You can look at depression literature or pain literature. They tell you about the same thing. They share a very high comorbidity here. So it will be nice we can cure two births with one stone, right? So, and TMS does allow us, seem to allow us to do that. So, but not the two location had the same benefit. The panel actually looked at both M1 and DLPFC, and M1 doesn't appear to be any benefit for depression, whereas the DLPFC seem to have benefits for both conditions. You can look at pain literature or a study was done primarily for depression and primarily was for pain. It shows the same, similar results. For the cost-effective standpoint, this is the cost-effective analysis that we look at. It will make sense to use a treatment for both conditions as a cost savings. This is the blue column represent the cost with drugs versus the brown column represent the cost without two TMS treatments. So it is a cost-saving in the long run clinical intervention for both conditions. So in summary, we have strong outcome evidence to suggest that TMS for pain, particularly in neuropathic pain with high and low anatomical origins, and mild TBI being one of those conditions. We also have short-term evidence. Now we have more and more long-term evidence, and definitely we need more long-term evidence for that. So it will make sense moving forward for all the study looking at not just pain, but also both pain and depressions. I would like to stop my talk and end here. Thank you. Thank you. So we'll have Dr. Martinez go next. Can everybody hear me from this speaker? Okay, great. So if we could bring up Dr. Martinez's slides next, that would be great. And we'll try to budget. We've budgeted for some time for questions at the end, hopefully. So just hold on to your questions until then, please. Hello. Hi, I'm Diana Martinez. I'll be talking to you today about ECT and non-convulsive ECT for chronic pain. So I'll start with a little bit of data on ECT for chronic pain. So ECT, electroconvulsive therapy, has been around for depression for many, many decades. It's been FDA cleared since the 70s. It's incredibly efficacious. And we were interested in looking at the data specifically with ECT and chronic pain. Most of this data is when it's comorbid with major depressive disorder. And there was a systematic review done by Yoon in 2023 that went back and looked at 22 articles, 109 cases of chronic pain with comorbid major depressive disorder, and showed that there was an improvement in chronic pain in patients who had depression with chronic pain receiving ECT. There's even a couple of reports of patients who received ECT for chronic pain alone showing improvement. None of these are controlled studies, but it is interesting that these reports go back to about the 1940s of improvement in chronic pain. It's not all types of chronic pain, as you can see from this graph up here. CRPS, slow back pain, fibromyalgia, neuropathic pain, but post-stroke thalamic pain didn't show an improvement. And we were interested about ECT for chronic pain. And I won't belabor this point because my colleague reviewed it, because we were interested mostly in stimulating the prefrontal cortex, which modulates sort of the cognitive control over pain and the emotional response to pain. And these brain regions that modulate this do overlap with depression. But the issue with ECT is it's greatly underutilized. It's used about 1.5% of patients who are eligible receive ECT, so this is patients who have refractory difficult-to-treat major depressive disorder, and yet still only 1.5% get ECT. It's mostly available in more affluent communities. It's not available in most of the country. And it's largely a combination of a lot of stigma. The seizure is frightening to many patients, and also the cognitive side effects. So ECT does have an effect on cognition. Mostly the effect is on memory, mostly autobiographical memory, verbal fluency, and verbal memory. These are reversible. The memory does come back, but as you can imagine for a lot of patients, having an impairment, especially in autobiographical memory, which is remembering family events or different things about yourself, might be fairly frightening. So we wanted to look at the question is, can ECT be delivered without a seizure? ECT has always been linked with a seizure for about a century, but we also know that brain stimulation itself has therapeutic effects. So maybe we can deliver the same stimulation with ECT without the seizure and get a benefit. So we found this study that was published in 2015. It's a very interesting study. It was published by an ECT doctor named Bill Reganold, who was at the University of Maryland. And he had a number of patients who were very wary of ECT and the cognitive effects, and some of whom he couldn't get a seizure on. So he decided to use a therapy, which he called non-convulsive ECT or NET. And he ran a small proof-of-concept open-label study. He used a bifrontal electrode placement with ECT so that you're really just stimulating the frontal cortex and not other parts of the brain. And he used an age-based stimulation method to determine the dose of ECT. So sometimes when we deliver ECT, we find the seizure threshold, like we will turn the device until we get a seizure. But in this case, he used an older method where you take the patient's age, because older patients have higher seizure thresholds, and he used their age to determine the dose. So he took that age-based dose and decreased it to one-eighth of the normal ECT dose so the seizure was not elicited. And he used the same equipment, same technique as ECT, the thymotron system, and included 13 patients in this study. And the results showed an improvement in depression. He used the Hamilton Depression Rating Scale, which went from 20.3 to 8.6. The response and remission rates were pretty high. This is typical for ECT, again, this is a small study. And importantly, he looked at the change in cognition with tests or with NET and showed that there was no change in cognition. This was done using the Mini Mental Status Exam, which is sort of used frequently in ECT studies. It's not a comprehensive measure of cognition and memory. It certainly doesn't look at autobiographical memory, but it was good to see that there was no change whatsoever in MMSC, which is normally the case. And he also looked at autobiographical memory, which is the AMI, and so no change in autobiographical memory. So we decided to do a similar study in patients using NET, non-convulsive ECT, in participants with chronic pain. So we tried to do a study that was actually kind of the inverse of the normal clinical trial that we do. So we do a lot of clinical trials in my group, and usually, you know, we try to have as straightforward a population as we can. So if we're looking at, for example, substance use disorder, we try and exclude a lot of comorbidities. In this case, we took patients or participants with chronic pain, and we allowed any psychiatric comorbidity as long as it was safe. And one of the advantages of ECT is it is remarkably safe. It has efficacy across most psychiatric conditions. It actually can be given to pregnant women. It can be used in patients who have different kinds of health issues. So we were like, given the safety of it, and given the fact that we're trying to develop a treatment for people who have multiple comorbidities, this is the group we're going to recruit. So we admitted patients to an inpatient research unit. We were required to do this by our hospital, even though it's not ECT. They still required us to do an inpatient study. So they came into the inpatient unit. We did eight to nine sessions of NET. We did these three days a week, just like you would use for ECT. We used the same stimulation parameters as biliruginol, so we did 1-8th the ECT dose. We did the anesthesia a little bit differently. With ECT, it generally requires or does require general anesthesia. Because of the seizure, you do have to do neuromuscular blockade and sedation. But because we weren't generating a seizure, we figured we could get away without the succinyl choline. So we gave succinyl choline only for the first two doses. When we saw no seizure, we dropped it, and we just give patients propofol. And one of the advantages of this is when you do ECT, the patient, because of the tonic-clonic seizure, takes about 30 minutes to recover from the seizure. One advantage with NET is that we had very little—people woke up clear as could be with a low dose of propofol. Our outcomes were feasibility. Our first question was, will chronic pain patients accept something like ECT as a treatment for their condition? Tolerability. We wanted to know if there were going to be serious side effects. We wanted to make sure we could do this procedure without generating a seizure. And then our secondary outcomes were brief pain or pain with BPI, depression, and cognition. In this case, we used the R-bands, which is a very comprehensive cognitive battery of testing. And this was open-label. So our main outcomes were feasibility and tolerability. And then the other outcomes were secondary. And these are results. We had only six participants so far. Five females. They had fibromyalgia, post-surgical back pain, and chronic low back pain. All had psychiatric comorbidities, mostly major depression, sickness of affective disorder when depressed type, and dysthymia. Feasibility. Patients were remarkably accepting of NET for their chronic pain. These are patients who have been through a lot of treatments and not responded. Tolerability. We had no seizures elicited. Everybody completed all sessions. We did have two serious adverse events, which were not related to NET per se. They were during our follow-up period. One person stopped her SSRI abruptly, and the other participant worsened after being prescribed physistigmine for her chronic pain by her provider. But we had nothing related to the NET procedure per se. And we saw an improvement in depression. HRDS. Sorry. Now I can't go back. Yes, I can go back. HRDS. The depression improved from 13 to 6. We saw a decrease in pain as well. These measures, it was an open-label study. We're giving people a lot of attention. We have an inpatient unit, so I would have been surprised if we hadn't seen an improvement. I would have dropped it from there. But we did see no change in cognition with ARBANs, which I do think was important. We saw absolutely no impairment whatsoever, and in fact, every participant increased at least a little bit. So taken together, NET for chronic pain is acceptable for patients, might be most appropriate for those with co-occurring psychiatric disorders, probably most likely depression. It was very tolerable in our trial. No cognitive effects. And we saw an improvement in pain and depressive symptoms. In addition to this study, we also just did a survey study where we recruited patients online and did interviews with them, chronic pain patients, and asked them about whether or not they would use NET or be interested in NET. And certainly, we got a lot of positive reports. We did find that most patients, I think it was 80 percent, and this was just a sampling of chronic pain patients who were refractory to treatment did have psychiatric comorbidity, which is probably not a surprise, but it sort of reinforced that, what we see in the literature. And we did also see a lot of individuals were using substances to address their pain. And I mostly do substance use disorder research, so I was particularly interested in that. And then we talked to physicians who treat pain and found that they were also very accepting of this as being a potential treatment for their patients. With that, I'll turn it over to my colleague. All right. So we'll have Dr. Fragni present now. Thank you so much. Okay. Hello. Can you hear me? Yes. Yes. Thank you very much for this panel, Dr. Woodbury. Everyone, so we'll try to keep it short. I'll try to keep it short because we're running a little bit behind and my slides are there. Yes. Oh, I saw over here. Sorry. Okay. Perfect. So, instead of showing just the results of all the trials we are conducting, in these 10 minutes, I'll try to go and overview development of TDCS as a potential tool for chronic pain. So I'll go sort of the whole development since we started looking in TDCS in 2005 and 2006, and then what happened and how we got where we are now. And on that story, so again, you know well TDCS is different than other techniques of brain stimulation. And why is that? Because TDCS causes this, what we call polarization. That's how we knew TDCS before. It creates this difference in potential and then it creates a gradient of voltage and that creates ionic changes and causes depolarization, hyperpolarization in the areas that it's stimulating. Again, TDCS is one of the techniques, as you know well, of non-invasive brain stimulation. You can use direct electrical stimulation such as TDCS or you can use magnetic stimulation to induce electrical currents as Dr. Leung showed before. This is not a new technique and that's an interesting part. For those who are new to the field, you should know that, again, this has been used for more than 50, 60 years, but with another name. If you go and look for it, you see brain polarization and the name. And again, and why it became interesting, TDCS, back in 2005 and 2006, because there is an interest in it and it's easy to use it, it's not painful. And at the beginning, again, most of the research, at least, was a bit skeptical. And when you start looking at the modeling and you start seeing that, look, the current passes the skull and it goes to the tissue. And that's what we saw in different modeling studies. Although, you should notice as well, look, this is not focal and that's true. And I was talking to Dr. Leung before we start, focalization, you can think in different ways. We can discuss more if we have time on that. But again, the important thing when we are starting to look, starting to understand TDCS is that we knew that at least computer modeling and other studies as well, the current passes the skull and it goes to the gray matter. Several models show that. And we also start seeing a number of neurophysiological studies, the results that you can change, especially you can change the level of excitability. And you see that in animal studies. The interesting part of TDCS, remember, it is not a neurostimulation technique. It doesn't cause action potentials, it doesn't induce action potentials. It causes what? A depolarization, a hyperpolarization, in case of another cause of depolarization. It enhances spontaneous neuronal activity, that's important differentiation. And you have this dual effect, although I have to tell you, so this was, again, the initial trials, and I want to show the story of that, the history of that. You see the cathode though, theoretically it induces a hyperpolarization, but we don't see that much. We see more as a nodal causing a depolarization and the effects, they do last after the end of stimulation. And let me show a bit of our development, the history of our phantolin pain development using TDCS. The rationale was obvious, and it was interesting as well, phantolin pain. Why? Because some patients, after amputation, they have it, other patients, they don't. So meaning that something happens in their corticoplasticity that causes pain or not. And there's a number of neuroimaging studies showing the amount of reorganization is associated with that as well. And then we start back in 2007 and 2008, doing the first pilot trials. And that comes in the interesting part here, we're looking different areas of the brain using TDCS. We went to parietal cortex, we went to motor cortex, the LPFC. We also used TDCS and CMS, and the best results, primary motor cortex. Again, quite interesting. And that goes back since the initial trials from Tsubokawa from 1991. The primary motor cortex for pain is still a main area. And that actually, it's an interesting part of phantolin pain because amputation also causes this change in reorganization in corticoplasticity in the motor cortex. And then we decided we go with TDCS based on these pilot studies. That was the first R01. And we wanted to combine with a technique. We combined with mirror therapy, which was also very interesting because we saw that the mirror therapy, the mirror, the visual illusion was not what was causing pain improvement, but also the mental imagery was quite interesting additional finding on this one. But anyway, we focused on that to try to look how the brain changes with that as well. Initially also, this trial also helped us to understand which patients respond more or less to that. One thing that was important, we start seeing that phantom limb sensation was a predictor as well for patients respond better as well. So meaning, again, going back to the amount of reorganization of these patients. And we run some analysis with the TMS and also with MRI. And again, same thing as well. The interesting part of TMS is that, as you know, so you expect amount of reorganization in the primary motor cortex, which you saw, which is yes. However, the interesting part is that that's not associated with the level of pain. And that comes an important thing as well for you when you wanted to apply clinically or in research, start thinking as well. Two important circuits here should be considered differently. One is sensory motor that causes or not, that's how I see it as well. That may cause or not pain. And the other one is the emotional circuits, emotional related circuits that may be associated with the intensity of pain. You see, so then you have to think as well when you develop your treatments, how to modulate these two different circuits. We also show that using MRI with volumetric analysis and also bone analysis, same thing as well. The level of reorganization associated with important parameters as well, neuropathistic duration of disease, duration of phantom limb pain, and also with the phantom limb sensations. So we did some machine learning as well, same thing in terms of the predictors. And the final results of this trial, the initial trial with 132 subjects, we showed GDCS has independent effect. It was interesting that mirror therapy compared to covered mirror had the same effect. At the end, what we saw was that the mental imagery was what was important. But GDCS had an independent effect, which was interesting. And then after this trial, again it was a large trial, we got the renewal for this R01. And that was the current trial. It was a pragmatic trial, 290 patients, and we're using home-based GDCS, which is also quite interesting. We thought it would be easier for us, but actually it's much more difficult training the subjects, supervising the sessions, but that's what we are doing now. And they also do what you call a somatosensory training. And we also measure here heart rate variability as some sort of a marker as well, as we're doing at their home. But that's the current trial. And one thing that's interesting as well, when you think on development, again, we went through all the phases of development, and you can ask, so what is next? Again, the next is none of these trials, and that's one thing that's interesting as well. So we could have, especially with the second trial, the large trial, we could have applied as well for the FDA as well. So having them reviewed, we did not, but that's something for you to consider. But at least now, we wanted to see in real life the effects of GDCS. And just to finalize here, again, and there is a number of evidence-based reviews. One of ours showing the effects of GDCS. And if you want me to, again, summarize in a few seconds, what do I think in terms of the field? GDCS still has moderate effects. We still need to learn more patients who are responsive, and also improving the technique. One of the new things, and I'll leave it for the questions, is combining with ultrasound. With that, and thank you very much, and then we can talk more on the questions. Thank you. All right, thank you. And now we have Dr. Townsend. Good morning, everyone. I have the dubious honor of being the last speaker, so bear with me. I'll try to be concise, so we can have a really robust discussion about neuromodulation approaches for chronic pain. So I'll be discussing TACS and CES for chronic pain. All right. So first, I want to orient you to these two types of stimulation as you may not be familiar with them. TACS applies a periodic alternating stimulation waveform, typically a sine wave. It doesn't have to be. And there's different electrode montages available. And accordingly, in terms of the anode and cathode that Dr. Fragmi mentioned, it's really not used because both electrodes alternately are conveying both inward and outward currents. As I mentioned, there's different types of electrode configurations and montages because today, this is primarily a really exciting research tool that has a lot of promise. There's no FDA-cleared approach for TACS in chronic pain. It's an area of investigation. CES, on the other hand, is FDA-cleared for the treatment of anxiety and insomnia. That applies a bilateral phasic patterned waveform to the ears and is thought to modulate various deeper brain cortical circuits. Now, what I want to draw your attention to, however, is that both of these techniques are an active area of investigation in terms of chronic pain. And so today, we're going to be having more of a theoretical discussion about how could you adapt these two techniques to investigate chronic pain and develop an intervention. And so I'm excited for the Q&A session because I think this is an area of really exciting, promising research. I also want to call your attention to the fact that because these are patterned, rhythmic, low-amplitude electrical waveforms, there's a lot of parameters we have to consider that my colleagues on the panel don't have to consider with their techniques. So in addition to things like amplitude, you also have the specifics of the waveform you're applying in terms of frequency and waveform structure. You also have electrode montage. There's a lot of flexibility there. And so the parameter space is quite large. So I want to first just kind of go over things to consider when adapting these types of techniques for different indications and specifically chronic pain. So as my colleagues already alluded to, disease state is really critical. And I'm going to argue that underlying circuit distortion is really critical because we really need to start taking into account these things when we design and identify our patient populations. Bergman summarizes really nicely in a 2018 review. So this is an ongoing topic of interest in the field. I've heard multiple talks at this conference talking about controlling for brain state and thinking about patient populations. But I think this is nicely summarized in a paper from Riddle et al. This is in depression. But it showed that healthy controls have an actually different EEG response to something as simply as a positive valence stimuli that you don't see in patients with major depressive disorders. So something as simple as that. You're really already seeing significant differences in the underlying neurobiology. So it's kind of naive to think that a healthy control with an experimentally induced pain paradigm is going to be a solution for every study design, right? So we need to think about, you know, when is a healthy control appropriate? Absolutely they are. But we also need to think about, okay, is a chronic pain population maybe more appropriate for this particular project? I also want to talk about how you're controlling brain state, right? You know, there's a growing literature looking at how, you know, the stimulation, the effect of stimulation can actually vary depending on what tasks the patient's engaged in, right? So we need to be thinking about, okay, are we, you know, having our patients watch, you know, a passive nature scene and maybe, you know, we're able to control that brain state and reduce some of the heterogeneity in the clinical trial results we're seeing. So in summary, I think choosing the right patient population and stimuli to control brain state is really going to be critical for successfully investigating TACS and CES for the indication of any indication of interest, especially chronic pain. And then, as I mentioned, because we have patterned low amplitude electrical stimulation, right? And we were talking milliamps and microamps here, right? You really need to dial in, you know, how you're delivering that stimulation, you know, both in terms of amplitude, in terms of frequency, right? Because like Dr. Fregni, we're not overriding endogenous oscillations. We have to work with endogenous oscillations to strengthen or weaken them potentially. And so it really matters, both electrode placement, amplitude, et cetera. So I want to call your attention to some promising early research using TACS in chronic pain. Some collaborators of ours and on it all applied two milliamps with a three electrode montage. So bilateral and two frontal, and then one return. They saw a positive results compared to a sham in chronic low back pain, really exciting finding. And then May et al decided to try to replicate that finding and then extend it. So in on, they were doing alpha oscillation. So a 10 Hertz frequency applied with TACS. In May, they investigated both alpha and gamma. And what I thought was interesting was this was in healthy controls with a tonic painful heat stimulation paradigm. They only used two electrodes and they used about quarter of the amplitude. And so, you know, again, we need to think very critically, you know, this is already such low amplitude stimulation, you know, is it justified scientifically in going that low in this case to half a milliamp? And, you know, I think kind of maybe unsurprisingly, they didn't actually see an effect in 10 Hertz. So, you know, again, choosing the right dosage and waveform is really going to be critical for successfully investigating, you know, TACS and CES for any indication, but especially I'm going to argue chronic pain. And so I'm going to present a case study from depression because this is how I would love for the field to start thinking about using TACS and CES. And I want to challenge you to, you know, think about this as you're, you know, writing grants and, you know, eventually collaborating with other folks. So this is a case study from our work in depression where we've attempted to partner with academia to identify a rational target, design an intervention around it and then, you know, show that that target engagement then correlates with symptom outcomes. So Alexander et al. in 2019. So let me back up. So there's been this growing literature implicating this asymmetry and frontal alpha oscillations as a potential biomarker for major depressive disorder. That's not just our collaborators. It's kind of a growing area in the fields. It's really exciting. And so Alexander et al. were actually able to show target engagements when you apply 10 Hertz. So alpha TACS, you know, again, with that three by one montage that I already showed, they're able to show that they get target engagements in the area of interest with 10 Hertz and you don't see that in the sham control, right? So then that kind of brings it out of, hey, this is an interesting EEG finding to, hey, when we apply this type of stimulation, we actually see a decrease in activation or a modulation in that target of interest, which is very exciting. So then we decided, okay, well, let's design an intervention. So our device we designed has a closed loop EEG. So it actually monitors EEG in real time, makes stimulation decisions. So we have EEG data from the session, which is very helpful. So it's five days of stimulation. So Monday through Friday, an hour a day, and it's triggered by the patient's brain activity. So when they have alpha power over a certain threshold, they get stimulated. So again, these are patients with major depressive disorder and what you see is, you know, a really nice decrease from day one to day five. So this is a Monday and they come in depressed. By Friday, they're already feeling better. And then we have an 80% remission rate 19 days after they first walk into our clinic. This is an open label study. We're working on a RCT follow-up, very exciting work. But what is relevant for this conversation is what is going on with this target while we're doing this trial? So, you know, on a Monday when we're able to capture their alpha power and I see this really exciting decrease in alpha power by day four, which you would have predicted from the target engagement study, right? And then what's really exciting is that you then can plot the change in alpha power versus how they will eventually respond in terms of their depression symptoms. And it's a beautiful correlation. So I can almost predict on day four, how much better they're going to be 19 days after they first walk into our clinic, which is really exciting. So this is the type of approach that I would love to see, you know, taken with chronic pain and there's data that we can build on as a field, right? So Zeb Hauser did a beautiful review relatively recently looking at what do we know about potential targets for chronic pain and in what patient populations? As I mentioned, healthy controls, you know, there's a time and a place for that, but probably different underlying neurobiology than someone who suffers from chronic low back pain or with, you know, really intense fibromyalgia, for example. Oops, sorry, back. So in this review, you know, he's looking at, or they are looking at multiple, multiple studies. So each of these is a different study. It is organized by power, EEG power and connectivity in different bands. And they've organized these trials again, based on the underlying patient population. And so high-level takeaways initially are that theta power, theta connectivity and beta power are potentially really areas of interest. And so I'm really excited that we could eventually use an approach like this to then design a new intervention. So in summary, this approach could be applied to chronic pain using preliminary evidence as guideposts. You know, as I've discussed, amplitude and electrode placement is really going to be critical. Type of patient population is really going to be critical. And, you know, dosing is really going to be critical. Again, you know, I know there's, you know, seemingly this, this aversion to going higher in amplitude, but we're already talking about such low amplitudes. I think we need to, as a field, start increasing amplitude and dosing. You know, I've touched mostly on TACS. CES is developed for at-home use. You could argue TACS and CES are just different flavors of the same approach. They both apply patterned electrical stimulation. And so, you know, there's different ideas about how we could potentially put this together. And I know there's a growing area of interest in at-home stimulation. So potentially we could already leverage the at-home designed FDA-cleared product for the treatment of anxiety insomnia as a starting point to maybe design some of these at-home trials. And interesting enough, CES, there is data available showing that it's successful at modulating some of the catastrophization and psychological distortions associated with chronic pain. So thank you. And I welcome any questions. All right. Thank you. I know we've run over time a little bit. And so if you have to go to another session, we're not offended, but we will try to take a few questions if you have any. You're also welcome to email me. It's myfirstname.mylastname at emory.edu. And I can connect you to any of our speakers if you have remaining questions. Anybody have any questions? Yes, go ahead. There's a lot of good questions. I'll take them in practice. I'd like to build on what you said, Dr. Townsend. How did you decide? You talked about a lot of different modalities. In your practice, how would you select which one would be a better fitting for which patient? That's a great question. And I don't think this is working. It is. It is working? Okay, fantastic. Okay, perfect. So I think there's going to be a role for all of our approaches, and I think it'll come down to the research that we're going to engage in, right? I mean, I think the work with TDCS, increasing plasticity and those mechanisms, there's going to be a patient population where that's the most appropriate type of modulation. I think also there's going to be a type of patient population where a TACS, that sort of patterned, rhythmic, maybe you don't need so much neuroplasticity. Maybe you need to nudge the underlying circuits slightly a different way. That's the TACS is going to come into play. So I think it's an exciting area of research, but stay tuned, I guess. I don't know if anyone else has anything. I can respond. So I like the home-based therapies, generally speaking. So like CES and TDCS, because then my patients can use them pretty much as often as they want to. TDCS, you can frankly buy off of amazon.com, though it's not recommended and that's not something I recommend, but it is easily accessible. And then for the non-convulsive ECT and RTMS, right now, that delivery model is more like in a clinic setting. And so people have to come and travel to you to get the therapy. And so for me, it's a little bit more difficult if a patient is living further away, but if they are closer and they can regularly come and for, I think, very severe refractory cases, I think that that is maybe a little bit more powerful. So that's what I've got. So, yes, due to limitation of the presentation, the time presentation, we do have some long-term data. Some of these are sort of unexpectedly came out. We have a clinic treating these patients. Currently, we have a protocol treating veterans with mild TBI headache, a lot of neuropathic pain conditions at the VA there. So our maintenance protocol after the initial 5 to 10 induction session is initially every two weeks for a couple of months, then we spread out to about a month. We have about 80% of retention rates and efficacy with those patients. So they continue to demonstrate good benefits. And what's interesting, when COVID hits, we were asked to shut down our clinic, essentially. So all these patients, they were getting maintenance protocol, cannot get the maintenance protocol. So it was about three months, those patients that were doing very well, that without any treatments. So when we reopened the clinics, we put them back on maintenance protocol. And to our surprise, the majority of them did very well, continue to do well. However, without treatment, we do see an upspike of the pain scale and functional impairments associated with that. And we actually published articles in Pain Physicians about that, and if you want, I can send you the article. So that's very encouraging, suggesting that we do have long-term efficacy, but some degree of maintenance protocol is required to keep the analgesic benefits for those patients. And then on CES, TACS, and TDCS, it's an emerging area of research, but it appears to be that in some of the studies that are coming out, you can expect six to 12 weeks of maintenance, depending on the indication and the treatment paradigm and how it's been set up. But again, an emerging area of research. Is there just, is there anybody who is speaking here or are we like holding the room up for anyone? Nope. Okay, great. Yes, sir. Let's start out. So can you share with me why VCT, yes, versus RTNF? But the question remains, if you need any indication, can you share that? You would be the right person to do this. Certainly with respect to non-convulsive VCT or NET, what we were looking at is patients who have chronic pain with significant psychiatric comorbidities. So our patients not only had refractory chronic pain, but they had ongoing depression as well. And that's why we chose a form of neuromodulation that was broad and reached most of the prefrontal cortex, well, practically all of the prefrontal cortex. We tried to avoid other brain regions so that we didn't have cognitive effects, namely the temporal cortex. So I think our treatment is really being developed for people who have significant comorbidity. And as I mentioned, like ECT can be safely delivered to people who have significant medical comorbidities, not that these other treatments can, but it's just one more thing that we're taking the model of ECT and trying to expand it while reducing the cognitive side effects. So we know RTNF won't do the same, right? I don't think that we do know. Our rationale for non-convulsive VCT was let's take patients for whom nothing has worked and stimulate as much brain as possible and see if we get an effect. So it was more of the sort of like wide net approach as opposed to trying to be more specific and selective. And also to see if I meant, we don't have a comparative study, one versus the other yet, but I think in general, it depends on what you try to accomplish. TMS, just based on a mechanistic standpoint, is a bit more focal versus thyrocrine stimulation. I think the rest of the panel will agree that you involve more neurostructures in the process. So it depends on what you try to target, that what you try to accomplish, essentially. I mean, we know with every disorder that there's no magic bullet, right? There's going to be different treatments that are going to work for different populations within a specific disorder. With respect to chronic pain, I don't think we really have a good sense yet of what the different subgroups are and how they may respond. But at least we're trying to do the research further. And one quick comment, and I think for you to think it may be helpful. The way I like to see it is, remember, TDCS or TCS, they are working with circuits that are active. Because at the end of the day, you need those circuits. You're just changing the level of acceptability of those circuits. TMS forces activity. So there's an interesting study in patients in coma on disorders of consciousness. So if you compare vegetative state to minimally conscious state, vegetative state, TDCS, zero effect, nothing. But in TMS, we start seeing some effects. You see, if you think on depression, and Dr. Martino has mentioned as well, so again, the TMS, you are driving activity on those circuits that are off. So if you have patients that are that severe, likely have very little activity there. So you need to force activity there. Electrical stimulation there with these small currents will not have an effect. What are your thoughts about multi-modal approaches? Yeah, so multi-modal, yeah, that's an interesting thing. So I remember there was the beginning, a number of groups are combining TDCS and TMS. To be honest, I never seen better results with that. And it may cause noise and actually may cause even detrimental effects when you combine the two techniques. Yeah, so that would be mine. One thing we do know with ECT, if you have a patient with refractory depression, they haven't responded to anything, and you give them ECT, you definitely improve the depressive symptoms. But ECT is not long lasting. However, once you give a course of ECT, patients are much more likely to respond to antidepressants. So that's one reason why some of these modalities, especially NET, might be the way to get somebody out of a hole, and then they can respond to other treatments that aren't quite so labor intensive. Okay, any other questions? Well, thank you so much for your attention and enjoy the rest of your conference. Thank you. Thank you.

noninvasive brain stimulation

chronic pain

transcranial magnetic stimulation

neuropathic pain

electroconvulsive therapy

transcranial direct current stimulation

phantom limb pain

cranial electrotherapy stimulation

pain management

brain stimulation techniques