Okay, so next, I guess we'll have Alessandro Gorgolo, who will be presenting a double-blind, randomized trial of V1 trigeminal stimulation for fractory major depression. Hi, good afternoon. Thank you for the opportunity to present here our double-blind controlled trial of V1 stimulation for resistant major depression. So that research was funded by the Brazilian Ministry of Health, and those are my personal disclosures. We know that up to a third of the depressive patients are refractory to standard treatments, and depression is a very complex disease involving many networks and areas of the brain, and it's now considered to be a system-level disorder, and it's so much so that we are still struggling to try to find a intracranial target for neuromodulation. On the other hand, peripheral nerve stimulation has been broadly accepted to different conditions, including depression for the vagal nerve, and that kind of makes sense, because we are using a target that has diffused connectivity throughout the central nervous system, and that will be helpful in modulating mood and mimicking what we can see when we do, for instance, electroconvulsive therapy. So the way we started this story was actually an observational finding on external stimulation for patients with epilepsy. So they got eight hours a day of external Trigem stimulation for epilepsy, and they did report an improvement in mood. So since they also improved epilepsy, it could be just a secondary effect, and then it was run a very short eight-weeks trial with very few patients at UCLA. Now these patients had actually the diagnosis of depression, and as you can see here, they did improve. Unfortunately, we have few papers in the literature discussing how the Trigeminal Peripheral Stimulation actually acts inside the brain, but we can extrapolate and see from this study that there is activation of the medial prefrontal cortex. Since we are neurosurgeons and we know that compliance is a very big issue on depressive patients, we wanted to make sure that the stimulation was continuously delivered under a very good controlled situation. So we implanted them, and as you can see here, there is a broad range of the literature on Trigeminal Subcutaneous Stimulation, but for other indications. So we know that the Trigem is the largest cranial nerve with all these connections to the tractus solitarius, locus coeruleus, thalamus, and all the frontal structures. Like here, we can see the activation of the dorsolateral prefrontal cortex, which would justify this action on depression. So we offered this surgery, and we elected 20 candidates that were refractory resistance to the conventional treatment, and as you can see here, they were about 50 years old, and they had a 20 to 25 years history of depression. So the design we used was a one-way crossover, so all the patients got implanted, and two weeks later, they were randomized to sham stimulation or active stimulation. So we had 10 patients in each arm, and the first half of the randomized period lasted about three months, so 12 weeks, which it's longer than what is usually reported in the literature for medication. And then at the time of the crossover of the randomized period that lasted for six months, we continued to deliver active stimulation for the group that was receiving active stimulation, and we crossed those who had the Hamiltonian scores at the level of baseline or worse than baseline, because one of our goals was also to see how long the placebo effect would last. And then we would rescue all the other patients as we went along the additional 12 weeks of the randomized period. And finally, the last six months of the study, they were open-label, and all of the patients knew, and they were under active stimulation. So our primary goal was to evaluate the trigeminal stimulation as adjuvant therapy at 12 weeks using the Hamilton 17 items score. Then secondary aims were to see this kind of efficacy using the depression inventory and inventory of depressive symptoms scores that the items self-rated. Also, we were interested on seeing the tolerability, relapse, and the duration of placebo effect. So inclusion criteria, they were not as we didn't enroll as deep, as severe depressive patients as the DBS trials, but they were all moderate and severe Hamiltonian scores, and they must be able to comply with the trial protocol that included visits every two weeks for the first six months. A lot of exclusion criteria, I don't have time to go over that. We confirmed the position of the electrodes through fluoroscopy intraoperatively. So all the patients came back two weeks later, and all of them were turned on while at the office. So all of them felt prestigious on the forehead. But then the group that had the sham stimulation was turned off after a minute, and the group who remained under active stimulation would leave the office with sub-threshold prestigious cessation. So nobody would feel any prestigious by the time they were released, and these are the parameters. So how about the results? When we look at the Hamiltonian score, the main outcome measure at 12 weeks, we see that the group that was under active stimulation actually did better in terms of improvement of depression in comparison to the group under placebo stimulation. Obviously, all of them responded initially, but then at about 10 weeks, this difference became statistically significant. When we look at the, this is another way to show this, but we can see almost a seven-point difference in the Hamilton scale showing the size of the clinical effect. And very nicely here, we got 60 patients responders in the active group, while we had 60% non-responders in the sham stimulation. Now, when we look for the other two scales, the back inventory of, sorry, the back depression inventory and the self-rated depression symptomatology, we see that, again, all of them improved. But at the end of the three months, we don't see a statistical difference between the groups. And we have a lot of explanation for that. If we have time, we can discuss. But one of the points is when we drop here, we already got to a level that we have moderate or light depression. So how much better than moderate or not severe we can get? So only remission. So that's probably we were underpowered to see this difference. Besides that, these patients are chronic patients. We are talking about three months. So how much can they self-evaluate themselves to have the perception that they did much better in both groups? And here, it just shows that, really, the curves, they follow the same trend. So it is coherent, even though it didn't reach statistical significance for these two self-rated questionnaires. In terms of placebo effect, by the time of the crossover, only three out of the 10 patients were ready to crossover. So that shows how long placebo effect in depressive patients, mainly when you offer surgery for them, can last. So as you can see here, if we wait four months, then basically, majority of them had already came back to baseline. But we did have one patient that, out of 21 weeks of stimulation, so almost five months and a half, 23 weeks post-implantation, this patient still showed placebo response for depression. When we look at the whole year, we can see here, and it makes sense to look at both curves only up to 12 weeks. Because after this, we start to have the one-way crossover. So the green line here, actually, is the truth. It reflects the entire cohort. And we can see that they do better than baseline in all time points, three months, six months, and 12 months. The same is true for the other two outcome measures. And what about relapsing? So we did have three patients that became from partial responders at six months, they became complete responders at one year. And we did have one patient that was a complete responder at six months that actually became a partial responder at 12 months. So basically, in summary, we did have about 55% of complete responders, which means an improvement of more than 50% of the Hamilton initial score at six months. And that number went up to 70% at one year. And we did have 15% of patients who were known responders at both time points. But these three patients are not exactly the same ones. So in summary, we did have 50% complete responders at six months and 70% at 12 months. Now, if you want to bump together partial responders, who are those who improved 20% to 50% in the group of known responders, then we would have only one patient that actually recurred. In terms of side effects, these patients, they have a very exacerbated corporal perception. So in the post-op day one, they had a lot of pain, a lot of this. But it didn't last too much, as it was expected while treating depressive patients. The most important side effect was that we needed to pull back three leads, because they were a little bit too pointy in the skin, and we didn't want to have any kind of erosion. But besides that, it was very well tolerated and safe. We were very successful on keeping the very same antidepressant medication throughout the whole year. So minor changes in the sleep medication used. And I just want to run this video for you so you can have a flavor of how it was the experience, if I might have the sound, even though it's Portuguese. Yeah. So you can read the legend below, but apparently it won't work. So she's just saying that she used to be absent from the work, because she really couldn't go and attend work. And now after the treatment, she's feeling much better. And now she feels she is better. She's performing better at her work. And also she feels she wants to go out and do some pleasure activities. And this is something she didn't experience for many long years. So for the past 20 years, she didn't know what that was. So in conclusion, then, the bilateral stimulation was effective. We did have 55% and 70% complete responders at 6 and 12 months. The effect is long-lasting. Placebo effect, we need to think seriously about when we elaborate the functional clinical trials design, because it may last very long. Hardware complications were very few. And the future studies should be to enroll more people, because we are talking about a small sample of 20 people, and also address the mechanism by which the trigeminoid stimulation would work in this particular population. So thank you. Any questions? So the great presentation and very interesting study, if you would stack your outcomes against the clinical trials of deep brain stimulation with something that is far less invasive brain, how do you think this works? If you would do a comparison. Well, I think that the trend about the DBS trials has been to try to find a spot in the brain where you have all this confluence of networks, right? That has been the rivipossi DTI studies. And in a way, and then you are dealing with an intracranial target. We know it's safe to perform DBS. We know about all this. But I think this is way simpler, way faster. The surgery doesn't last more than an hour and a half. So I think it does make sense. We already have the vagal nerve approval. So it's a very complex. As we move away from tremor, and even tremor, we need to improve. We just had this talk before. But it's simple. It's relatively simple. Now, we are going to way more complex. We need to think broadly. And most likely, we'll have to interfere in a lot of system pathways involving a lot of different neurotransmitters. So I doubt, maybe I'm wrong, but I doubt that we'll be able to accomplish that with one DBS lead, even if we choose that target very carefully. Yeah. What percentage of the paresthesia level did you use for the simulation? It's very low. Actually, every visit that we had, we would try it again. But usually, it was around 0.3 to 0.8 volts. And along in the open-label period, did anybody want to increase the paresthesia simulation? No, but some of them we raised later on, because they kind of adjust to the level and they tolerate more. And some, we keep on following them. They say they like to feel that, because they have the perception they're being treated. So I think it's really like a positive, supportive effect from the simulation. But if you go high, then you can have even contraction and pain. Yeah, we did that too, but later. Yeah, it's really good. So did you say that the ones who were in the sham group, the off group, on the first visit, you still turn it on to get the threshold? Every visit, because they would come every two weeks. So every time they came, and they were being the awaiting area. So, oh, yeah, I felt this, I felt that. I couldn't run the risk of masking. So all of them got one minute. But then we just leave for one minute and turn it off. Do you think this long-term placebo effect is maybe not placebo, maybe it's a very brief something, but could that be doing something to the network, whatever the network is? Almost like a TMS, I mean, it's even shorter than TMS, of course, but could it be? It was one minute for every two weeks. I mean, I can't refute that, but since they were all refractory patients, they failed three medications. And I don't know, but it could be, yeah. Any other questions? OK. Thank you.

double-blind controlled trial

V1 stimulation

resistant major depression

neuromodulation

trigeminal stimulation