In this presentation, Jean-Philippe Langevin, MD, discusses emerging options for mood disorders and anxiety disorders, and a general framework for circuit-based neuromodulation.
and our next speaker uh This is jp jean Philippe Langevin who is a neurosurgeon. Uh J. P. Is also the director of restore restorative neurosurgery and leads the restorative neurosurgery and deep brain stimulation programs at the pacific movement disorders center. Uh He will be speaking about neuromodulation for mood and anxiety. Thank you so much. Jp Take it away. Thanks scott and thank you for the organizer to invite me and for people to be in here listening to the toxicity. So it's been a great presentation so far. Uh You know as it was mentioned of the neurosurgeon in charge of the functional neurosurgery uh in our field it's been really exciting recently with new developments both on the technology side as well as on different applications for neuromodulation. Uh And today I wanted to touch based on basically what we can offer for mood and anxiety. Uh And so here are my disclosures. I don't I don't have any uh you know director potential conflict of interest but I will discuss off label use. And so basically what I wanted to mention is I'm discussing neuromodulation for mood and anxiety disorders but it's still a lot of it is still under the research realm. So it's gonna be mostly off label use except for a few exceptions. So these are the objective of the lecturers but basically we want to cover what potential emerging neuromodulation options will be able to offer for depression and various anxiety disorders and try to put everything in the in the context of a general framework that's based on circuit based neuromodulation. So just briefly we know that depression is a major issue in the us uh and worldwide, but approximately 30% Lifetime occurrence, 9% yearly. And fortunately the majority of patients will respond to ssris various medications as well as psychotherapy as was discussed in the previous lectures. However, about 30% of the patients will go on to develop uh you know, treatment resistant depression. So these are the ones that we're going to be focused on today. Um and you know, this is a slide from the company live in Nova. But essentially, you know, once patients have failed to respond after a couple of medications, the likelihood that they will respond to the to the third or the fourth medication is very unlikely. We're less likely. So, you know, that's where we may have an opportunity to bring in new options uh and when we discuss in neuromodulation and functional neurosurgery, uh we have to keep it on the anatomy side and try to bring the network to life so that we have an actual target where we can modulate the activity and improved function. So this is an old study from May burn basically where she she took patients with depression and perform pet scans before and after recovery. And what you can notice is that essentially when the patients are sad uh you know, there's more activity in the eventual aspect of the brain. Uh so they what they call area 25, so the ventral aspect of the medial prefrontal cortex. Um and uh you know, the the activity has increased in the dorsal lateral prefrontal area. Once the patient is recovered from depression, uh the opposite of cures where the activity at the base of the brain is reduced and conversely the activity at the top of the brain is increased. And so that letter to come up with this model here where essentially it's it's viewed as a term of stack Where, you know, area 24 is sort of like allowing the activity to be regulated, shifted between ventral aspect or dorsal lateral aspect and the more activity you have in the eventual aspect than that can lead to more depression symptoms, morbid vegetative symptoms, whereas when the activity is uh more in the dorsal aspect than its more goal directed activity is more production and less depression. So it's just very over simplification of our model. But it's actually just to give an example of how we can bring uh you know, certain diseases or pathological state to life with those circuit based neuromodulation. Uh And it sort of makes sense, you know, in this research that was done on primate, that's why, you know, the circuit would be really critical for depression. And so in this study here, at the NIH, they were giving monkeys essentially different stimuli that they lie. So either like a banana versus an orange. And so when you feed a monkey, you know, several bananas in a row and then you give them the choice after that between a banana and orange. Uh The normal behavior would be to then choose the orange because they've you know, the value of the banana is reduced since they've been exposed and they've had plenty of it. And so what Murray at the NIH found out is that when uh you know you have a wild uh control animal, then obviously like the devaluation score is normal, such as they choose the appropriate stimulus when they were presented with. But when they created different lesions in those areas of the brain that I described in that network in the medial prefrontal cortex or amygdala when he realizes that the devaluation score was reduced, meaning that the monkey was unable to determine which stimulus had more value. And they were randomly selecting one versus the other. So you can imagine in your life that uh if you know everything has the same value, all the stimuli are are equivalent. Then there's no motivation and doing one activity or selecting one stimulus over another. And so that's sort of like in general terms the equity of depression. So the neuro modulating uh those circuits to get rid of uh that type of abnormal activity may restore normal function or at least reduce the symptoms of depression over the last several years. Uh You know, there's been an increase in the interest and interventional psychiatry uh depression leading the field. So historically, right? so we know about electroconvulsive therapy. Uh There is from that like direct cortical stimulation but more focal and less invasive. So there's uh TMS or transcranial magnetic stimulation on the far left here. And so that's when the patient comes in, receives multiple sessions of a few minutes each to essentially modulate those circuits. And generally the psychiatrist will apply the stimulation to the dorsal lateral prefrontal cortex to increase the activity in that network and push the activity in that sense so that the thermostat, so to speak with reduced uh the reflectively reduce the activity in the eventual aspect of the brain and basically lead to more motivational behavior, more goal directed behavior and less depressive symptoms. Uh So now, you know, TMS is an approved uh therapy and it's offered at the brain health center um as well and with with great results um and there's more invasive therapy that were offered, you know, in uh it's been trialed including dbs deep brain stimulation in which case the surgeons were placing actual electrodes in the area that we're overactive. So where my cursor is that uh basically the eventual medial Prefrontal Cortex An Area 25. And as you can see here in uh three months after dBS versus six months after dBS. Again, the general concept was to reduce the cerebral metabolism or like the activity at the base of the brain and conversely increase it at the dorsal aspect of the brain and so between transcranial magnetic stimulation or uh the brain stimulation. The idea is that um we're doing the same thing. So modulating modulating that neuro circuitry to push the activity in in a direction that's going to reduce the symptoms. So this is clearly an off label use and currently on a proof. But there was initially a very high degree of interest for this type of therapy. As you can see, the Hamiltons score decreased significantly in patients that were highly resistant to depression before she hasn't led to full of the approval because the pivotal trial did not result in clear benefits. So the jury is still out more recently. Other groups are even using so called closed loop neuromodulation. So you may have seen a study that was just recently published in Nature Medicine, but the idea is similar. So uh you know, stimulating uh the nuclear site comments in this case part of the network of depression to improve mood. But this time to do it on demand based on sensing from the amygdala. Remember from the private study, the amygdala may play a role into value based adjustment of the stimulus. So that's kind of a fancy way of doing that. Obviously this is still highly investigational. This is the first patient I was implanted in the world. But as you can see uh you know, again that had significance or encouraging improvement on the angleton score um uh the depression skills in terms of approved therapy and a real neuromodulation. So we can offer vagal nerve stimulator. And so this picture just shows the actual device implanted in a patient. Um It's a very small implant and it's extra cranial, so it's attached to the bagel nerve stimulator in the next. So this is an outpatient procedure. Uh You know we you may ask like why with stimulating the vagal nerve work. Right? So I presented this uh circuitry in charge of neuromodulation definitely inside the brain. So how stimulating an extra cranial nerve would work. And we know from medical school this is sort of the slide that we were learning how like the vagal nerve is responsible for many of the parasympathetic sympathetic function inside the body. Right? So that has nothing to do with depression. Something to keep in mind though is that 80% of the vagal nerve is actually a parent fibers that are going back into the cranial e. And uh they could be there a stimulation of the nuclear solitary track. So this is a busy slide. But essentially you know when you look at a broad spectrum activation from the nucleus of the society track into the brain then you recognize the general suspect in charge of depression. Right? So like middle uh look at syria list and if you go even further the medial prefrontal cortex all the regions that were involved in that circuitry. Uh and if you look at the specific neurotransmitters are involved A lot of them are actually Also involved in treatment for mesotherapy treatment of depression. So it seems that at least 80% of those fibers from the big old nerve will actually eventually leading to activation of the proper neural circuitry inside the brain to treat depression. So again, just a different side showing how like, you know, a small device place here will eventually lead to broad spectrum network activation uh inside the proper area for depression. The studies have shown improvement that builds up over time. So this is uh the score of the matters At six months, 12 months, 24 months where you see the proportion of responders to VNS improve up to above 50% at the end. And so with those results and and the company was able to obtain the approval for uh for VNS and depression. uh and this is the remission scores at 24 months and we see two shy of about 40% of patients were re emitters at around that time. Uh And this slide stresses stresses out the fact that the VNS effect builds up over time. Um and so this is like several years out at five years, a cumulative effect, both for remission as well as response rates. And so you see response rate at 68% cumulative risk and remission at 43%. And so this is very similar than what we see uh in VNS for epilepsy where the results tend to build up slowly over time. So currently there's a study on going where we're recruiting patients at P. And I for this therapy. Uh And so this is sponsored by CMS. But essentially the idea is to have a cross over design where everybody gets a device implanted. But half the group has a device not activated initially up until the one year mark. And then the groups then go on to have a full open label activated of the device. I just briefly I just want to show how the surgery is performed out patient with small incisions, both the cervical area as well as under the collarbone. Um And uh the device as I mentioned is small and so uh pretty hard to see once it's implanted. So we're offering this kind of cool trust. It's a multi group effort between providence P. And I. The brain Health center and CMS is essentially sponsoring it uh by paying for the device implant The last 10 minutes. Uh wanted to discuss uh neuromodulation for anxiety disorder. So we discussed a few options for mood disorder, one of which is currently of the approved for anxiety disorder. Um 11 neuromodulation is uh partially approved. So it's obsessive compulsive disease. Um And I say partially because Medtronic, the company has received humanitarian device exemption approval for the therapy. Uh It involves a deep brain stimulation. So slightly more invasive than big owner simulations since the electrodes are placed intracranial E. Um But the HD requires the hospital system to have an I. R. B. Approval in place so that the patients are monitored. Uh And if there was a complication is reported to the FDA. So that HD has been in place now for Approximately 5-6 years. Um But essentially you just want to go over some of the rationale for using DBS in the context of O. C. D. Uh This is a study that was done years ago at U. C. L. A. In 1994. But essentially just scanning patients at rest using a pet scan, you can see the normal control with regular uh cerebral activity. And then when you see here, regular O. C. D. Patients address you can see it and increase activity in the frontal lobes. Uh Then further studies were done on the symptomatic phase, right? So like in those disease we can expose the patient. So if they have and you'll see two contamination for example you can place them in the scanner and for my or pet scan and re scan them after exposing them to the offending agent. And so then at that point you can do within patients uh symptomatic versus rest. And so again so now you can really focus on those network activity that are relevant to the symptoms. And again you can see very similar areas also involved in mood disorder. But the orbitofrontal cortex are highly activated um as well as the card, it's uh and the basal ganglia. So rationale for using dBS uh the uh eventual striatum or or nucleus accumbens area. So we just showed some functional neuroimaging showing increased activity in those regions. Uh And we know also that interior capsule economies years ago was able to reduce those symptoms. The patients that we selected, these types of therapy. I felt essentially everything. Uh So obviously they've had O. C. D. S for a number of years there the white box which is one of the main scale for the city is very high of about 30 at least three trials and medications films like oh therapies essentially patients who are end of the line completely incapacitated by their disease. So essentially unable to function normally. Uh and I failed every. The surgery involves the placement of dBS electrodes just at the juncture, at the bottom of the interior limb of the internal capsule, essentially the area of the nucleus accumbens. So this is a slide to showing roughly the region, you know where we replace uh the electrode and the dBS on the schematic. So this is the electrode in place again. So just uh where the cardiac nucleus meets the entertainment. So they call it eventually try to but in this sense it's the nucleus that comments uh So medtronic gain approval through a series of trials. So this is uh one of those one of those trials that showed uh outcome at three years. Uh those highly refractory patients. And they were looking at that white box scale. They had a small sample size. But in those patients you can see how in general most patients, most of those patients reduce their white boxers symptomatic scales by about 30%. And uh the global assessment of functioning was improved as you can see her up to like mid-50s after the therapy. So a 30% improvement may seem to be pretty modest or moderate. But remember that those patients were highly Refractory with very high white box scale score. So if you have a 30% relative reduction in that score in absolute term, it's a significant reduction in that score. And so we've seen for those patients who respond to especially those patients, let's say we have contamination type of city uh really be transformative. So we've had patients who essentially resume social activity are finally going out, you know, with friends. Um whereas before they were confined to their house. Uh However, patients who intend to have a hoarding subtype of Old City tend to be uh non responder to this therapy. So there's still a lot to learn. But certainly a lot of uh promising findings. Another condition that we have been looking into is PTSD um you know, has, you know, PTSD is a condition that's highly relevant to the US given our large population and combat veterans that cost to the U. S. Government is an excessive $6 billion uh in about a third of our combat vets, you know will return with PTSD similarly to other psychiatric conditions. The current treatment are excellent. Um and with between psychotherapy uh and psycho pharmacology. So about 70% of the patients will remit. However, it is still at 30% of patients who are essentially non responder in looking again at the circuitry. What we learn uh in PTSD is that when we have symptomatic phase versus resting face or meaning, you know, you're exposing a patient too uh the index trauma that caused the PTSD like a war imagery for example, you see increased activity especially in the amygdala and a reduction in the medial prefrontal cortex. And so that's actually similar to many other anxiety disorders. Uh The NIH also look at uh their pool of data from patients went uh yet to the Vietnam War to look at different areas of the brain trauma. And what they noticed is those patients who unfortunately had a traumatic brain injury in the single area were completely actually protected against having PTSD against adding to the fact that the legalized, critical into encoding fear as well as the expression of it. Uh just just a slide essentially showing uh within the amygdala there uh some cells are mainly active when you're presenting uh in this case an animal to a fear uh condition uh and other cells that are actually only active when you're presenting the patients to an extinction paradigm. Uh So in that sense, you know, those two neurons are sitting right next to each other and in their contrasting each other, right? So you can imagine that war veterans suffering from PTSD will have a tendency to have more fierce l active and ready to be triggered when a stimulus is presented. And somebody normal have more extension sells, you know, so there's a bias towards extinction. So when we're presenting a stimulus that is not threatening like an image of a spider, for example, then the extinction is being active. Um and so our goal in this trial was to look at €2 modulating the amygdala, thinking that in those patients with PTSD, they're essentially stuck in a state of fear where the fear cells are too active. Um and so I'll uh roughly go into a few sides here since we're running out of time. But essentially, you know, we we did this study into rodents were replaced dbs inside the amygdala presented to a queue object while the Wrath was getting um shock. And uh What we do is uh seven days after uh this paradigm the Wrath is presented with the same queue object inside their house in cage. Um and you know, the uh one of the rodents uh in this case the rat has received DBS during that week. And so you can see that he's displaying a normal behavior. So he's exploring the ball uh sniffing it and playing with it, which is what, you know, rodents usually do with novel objects. Whereas Rocky is highly fearful of the objects displaying essentially absurd those symptoms of PTSD because you remembers the shock related to it. And so essentially doesn't want to have anything to do with the ball. And eventually we'll uh speed up the video here, but eventually uh buries the ball completely uh under the cover. And essentially our results show that when we did DBS, there was a return towards wild behavior and this allowed us to obtain the approval to perform a clinical trial. Uh, U. S. Veterans to using DBS. You can see the electrodes in place the amygdala. And the general concept here is that, you know, a veteran is seeing a firework. Um and in this case they're not having a good time on the 4th of July because that triggers a reminder, traumatic memory of it provided improvised explosive device. Whereas once the basement is implanted with D. B. D. B. S. And there is no modulation at the level of the amygdala. We can temper down uh that reaction and the veteran can then enjoy the fireworks in a normal situation. So we did that so far in two veterans and you can see over time the score in the PTSD, which is called clinician administered PTS PTSD scale dropping Uh roughly about 50% thus far. Uh And the thing that was probably one of the most sensitive was nightmares. And so you can see her overall after 10 months where the patients are displaying essentially no further nightmares uh following the treatment. Um it's so just gonna skip on a few slides since uh we're out of time but essentially the, just wanted to show briefly how like, you know, we were able to perform a similar surgery in a patient who is suffering from intractable, teaching us in the context of severe anxiety disorder. Uh And today our devices are even able to tell us, you know, the activity inside the amygdala in terms of at which frequency it is the more active. So this is the patient recording uh itchiness uh events, you know over time. And the device is playing a seven hertz peak of activity during all those events. And once we bring the patient to our lab and exposing them to various imagery that are, you know, pleasant versus traumatic versus neutral. Um we tend to obtain the exact same peak of frequency at seven Earths uh meaning that uh perhaps, you know today with the newer technologies that are able to read the activity inside the brain at the level where we place the electrodes. Uh we're able to make a relationship between even in this case anxiety and pain. So meaning that perhaps anxiety in this case might be driving pain syndromes and so we can treat um anxiety and pain intended. And so on that note, just in conclusion, before I take any questions, um you know, to summarize neuromodulation may play a role in the treatment of refractory psychological conditions in the future. Uh in particular mood and anxiety disorders are active areas of research. Some of those are in a proof state, you know, from the FDA, others are still in a partial state or highly investigational at this point. Uh New techniques such as functional error imaging uh in tandem with newer devices that allow us to chronically record the brain activity may help us out to personalize uh targeting as as well as the programming of those device to improve function as well as track the illness over time. So, not only are we able to look at where we need to place the devices that we can track, you know, if the symptoms are getting better by looking at brain activity. And finally, more research is obviously needed before clinical applications. All right. Some data. Thank you very much for your attention. Thank you so much. Jp that was great. Uh Some great questions coming in here. We're going to keep the Q. And a brief just to keep things on schedule. Uh interesting question here. Uh any animal or clinical trials, any studies looking at right versus left vagus nerve stem on effectiveness of depression or other endpoints? Uh That's a great question. I haven't come across any right versus left questions for depression. I know that it was an active uh area of research for epilepsy or even actual bilateral Vienna stimulation but I don't think it's come across yet. Um you know for a depression. But it's certainly an interesting question down the line in the future. You know, the idea was that historically we were concerned by stimulating bilateral VNS. We can cause bradycardia or even cardiac arrest. So that's why uh that was never done. But more and more, you know, the studies have shown that perhaps you are able to stimulate bilaterally without problems. How about another quick one here? Uh the evidence for transcranial direct current stimulation for mood symptoms. Yeah. So I think you know, similar to TMS. Uh it's an application that's uh that's been investigational uh growing I think that you know perhaps like the entry, the cost entry is uh is lower and it can be like deployed um uh you know more at east than TMS. Um personally, you know what I like about TMS is the newer applications that use uh navigation. So nowadays, you know, some of the device allows you to not only target based on location on the skull but actually like you know, position, that magnet based on the M. R. I. Of the patient. And so you can imagine that if you have a functional M. R. I. For that patient you can more precisely stimulate. So I think there's probably more more interest you know in that in that area. Excellent. Well, thank you so much, we're gonna move on here, appreciate this excellent presentation.
