Video Circuit Therapy for Neuropsychiatric Disorders Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Circuit Therapy for Neuropsychiatric Disorders Overview Martijn Figee, MD, PhD, Director of the Interventional Psychiatry Program, discusses circuit therapy for neuropsychiatric disorders. it is a great pleasure, I think we can get started to introduce dr martin. I always try and pronounce that correctly, I never do um Martin did it as a psychiatrist who is trained in the Netherlands, uh did his residency part of it in the I. O. P. In London. Um and it really is, I think a world leader in um DBS uh using neuromodulation to treat disorders like O. C. D. And Parkinson's and other things. Um and I think it's you know, this kind of whole concept of circuit based treatments is an emerging area and uh do his work and the work of others in his group and the larger group here at Sinai Ethics Sign is becoming leaders in DBS and neuromodulation and um it's it was I think a wonderful recruitment to bring you on board and I think you and your colleagues who will also be presenting here soon um really are changing the landscape for some of these very difficult to treat cases of OCD and Parkinson's and other things like that. So look forward to your talk and thank you for agreeing to be one of the early speakers in the fall series. Thank you. It's a pleasure and an honor. Mhm. So you just mentioned my colleagues and I want to start with giving a shout out to them usually do that at the end but I want to stress how important it is to be the center which we are the center for advanced circuit therapeutics which is primarily based here at Montana West, which is where I am now On the 10th floor. For those who haven't been here come and visit us. It's it's really great that Montana gave us the opportunity to be on a floor with a team of neurologists, neurosurgeons, psychiatrists, psychologists and researchers. Again this is usually the last slide but I want to show it up front also too, remind you all how important it is to have this team approach this multidisciplinary team approach with a staff that's actually on this floor as well as staff across mount china. We're collaborating with in order to be able to not only work with um Like clinically work with very treatment resistant, severely ill patients that are undergoing surgery but also of course on top of that doing research to understand their circuit abnormalities and how to manipulate them. Um And where we start and with which patients is of course an important question. If you want to do circuit therapy. So I'm I'm gonna talk mostly about deep brain stimulation. But eventually this could apply to any form of neuromodulation now or in the future. Where we start often or a system that's actually amenable a large brain system that's amenable to neuromodulation. Is the cortical basal ganglia circuit or these are actually different circuits allowing the integration of daily actions with cognition and emotions or reward based information. two motor and prefrontal cortical regions which can actually be subdivided into topographically organized levels from door to door to ventral. With the most dorsal loops or pathways between motor basal ganglia. For instance the ottoman. The septal atomic nucleus. The global spell. It is internal connecting to multiple cortical regions which is important for movement disorders which we treat as well at our center but also for psychiatric disorders such as obsessive compulsive disorder or to read which is sort of between neurology and psychiatry and then going a little bit more down. There is the more uh cognitive or associative circuits between for example the coordinates and the dorsal lateral prefrontal cortex important for cognitive control and working memory and the integration of these systems with actions and then all the way down to the more the most faithful looks are of course limbic limbic circuits, limbic or motivational circuits between for example the incumbents the amygdala and medial and orbital frontal courts. Core regions which is relevant for many of the psychiatric conditions that we treat. But of course there's interaction between these circuits. Um And there's interactions between these circuits in each patient whether it's neurological or psychiatric which is one of the big reasons why we chose to work. Multidisciplinary and work with within psychiatry and neurology um And the way to manipulate or modulate these circuits is for example with a non invasive technique called transcranial magnetic stimulation which is something we started doing at Mount Sinai around two years ago. It's a system that's housed uptown. We're looking into moving it to the west now. Um And it can be used to uh to modulate multiple cortical regions. The S. M. A. Or the primary motor cortex. Um In Parkinson's it's actually pretty effective. Um But also in to read or in obsessive compulsive disorder. It's even a recently FDA approved treatment for obsessive compulsive disorder interestingly if you if you target prefrontal cortical regions in Parkinson's you also treat their depression and and that it's not surprising therefore that the dorsal lateral prefrontal cortex is also an effective target for depression. And if you go more ventral you can modulate the medial prefrontal cortex or even the orbital frontal cortex which allows you to to change these limbic circuits which is an effective treatment for O. C. D. But also for depression. Now if you want to get at least more deeper structures and also in a more lasting way because TMS is a treatment that you can apply for a couple of weeks if it doesn't work after the application it's hard to continue applying it patient has to come to the office. So if you want to go at these deeper structures you can actually implant Elite or two elite usually um going to for example motor structures like the sip polemic nucleus or the G. P. For Parkinson's. Um Or the more limbic loops like the interior limp of the internal capsule the alec or the Eventful alec which connects these limbic basal ganglia with medial prefrontal cortical regions and it's actually the target of choice here in Mount Sinai for obsessive compulsive disorder. Um And the target of choice for depression in our center is the super colossal single. It which is not exactly within these loops but at least it's connected to the ventral striatum amygdala, but it's also connected to a more elaborate mood control circuit involving various cortical regions. And of course that's the target that Helen Mabruk has examined for years and now brought to Mount Sinai for depression. Um We started targeting the ventral alec um by actually targeting the incumbents which as you can see is a little below the ventral alec is actually this bundle of white matter fibers connecting um The the idea comments with the medial prefrontal regions and thalamus and rinse them. And although we started we and other groups started targeting the incumbents because we we knew it was an important structure for reward. And also we found abnormalities in obsessive compulsive disorder. We ended up going uh and and activate the context because each lead has four contacts that were always more uh in the ventral interior interior capsule. This is actually something that has happened over time in dbs in general, especially dbs in psychiatry. We used to we used to target gray matter structures but only to find out over time that actually most effectively treatment was usually in white matter fibers. Again making the argument that it's more of a of a of a network um um intervention. So this is the way we used to do it. It's actually an atlas based uh coordinate. They should then um translate onto the patient's brain scan and then you can actually place the lead specifically in this corner. But it's sort of a one size fits all because it's atlas and coordinate based nevertheless working pretty good. So this is the these are the most recent results from my previous Amsterdam group which I'm still sort of involved in. And as you can see it works these are again severely ill completely refractory patients and at least half of them response even though it's sort of a one size fits all uh intervention. Um um It also works for depression and anxiety as you can see by the drop in Hamilton's a in Hamilton's discourse which is one of the reasons we also tried this same target in a group of the press stations with also very good results. And this is these are all open results Um in 70 patients but we also have a placebo controlled or sham stimulation controlled results showing a significant difference between real and sham stimulation and this is one of the reasons why for O. C. D. Now the brain stimulation is as an FDA approved although still also experimental treatment. Um However, 50% is okay but it still leaves room for opportunity which is what I and our group wants to try and achieve here at Mount Sinai. One of the things we found in our Amsterdam patients is and these are 12 patients using individualized diffusion tensor imaging is two things. One thing you can see in these 12 patients that ah despite the fact that the atlas based with EMR based coordinate is pretty similar in each patient. If you overlay that with their track topography, it's really different in each patient. So the way it is bundles these limbic bundles that we try to target of course in each patient is highly variable. and in these these 12 patients, we actually found that that's not a trivial thing. It's it's important because we found that like the top patients that have a larger white box, decreased white boxes of course the most prominent OCD outcome, The more likely they were in one versus the other, a little track in our hands. This was a track that was seeded from the ventral segmental area vs one that was more medial coming from the interior telemachus at the same time, other european centers, we're exploring like a similar question. Um But they didn't have the luxury of using individualized track topography, which needs to be of high quality. So they used normative uh like healthy control based tractor graffiti data overlaid with the patient's implants. And this is work from Andreas Horn who is a prominent DVs neuroscientist who was trained in one of the other circuit therapeutic centers here at Harvard and now works in Berlin. And this is um results from a meta analysis in 33 ventral alec OCD patients across different centers in Madrid and Berlin grenoble. Um And as you can see um there's actually a wide variety of most of the basal ganglia cortical loops that I showed before that are actually connected to the stimulated context. From all of these patients grouped together, you can see some Mikala fibers, fibers going to the the prefrontal regions, some motor fibers and fibers going through the brain stem. However, if you if you only plots the ones that um had a good response or actually correlate them with the amount of response. You will find that these therapeutic fibers are more alike. What we showed in our Amsterdam sample, meaning fibers coming from the brain stem and the telemachus to these prefrontal regions. Um The Montana patients, I think we've done 14 so far. This is results from from 10 of them are actually along the same lines in terms of response. Again, it's a it's an average 44% decrease in white box, which is pretty good for this refractory patients. And it's also significant. And again, this is mostly based on coordinate based targeting but it's it's a very decent result. Um And if we tried to overlay and this is worked by Andrew smith who's following um physician research track working with us. Um If you overlay that to the media track from the european sample, you can see that the leads from our patients are sometimes in this track, sometimes outside of it. And in fact there's also a blue track going going to Jamaica that I depicted before, that was actually negatively correlated to to response. So it seems to matter where you are. Again, this is based on normative data. Um and if you correlate like the response, like the white box improvement in our mountains china patients again, it seems to overlap with these fibers going from the brain, salmon and the thalamus to prefrontal regions. Sure do, the more, the higher the fiber score, the more overlap with this track and the higher their response on the white box. You can also see a few places that do have a good response but are not in this track. When we modeled this. This was actually more towards the dorsal pathways. Um so there seems seems to be individual variety, which is important because that might be the key to further improving this treatment. I want to have you look at a poor responder um and this is a patient. I'm gonna show you a video by the way. I'm going to show several videos, of course uh in agreement with each individuals because I think it's important for you all to see like the effects of this method in actual patients. It's one of the reasons why it's so inspiring to to do this work and why it's um so um interesting to to look at these tracks because you can actually see the immediate effects uh of this method. So this was a patient. This was one of the poor responders of the Mount Sinai cohort. His compulsions are religious who he is literally taking him hours to to to say his prayer. And this also engaged in all sorts of hand washing rituals. And as you can see, we did actually with his stimulation as we applied it trial and error. Um we did actually engage these a Michelob fibers which might according to the media and I was actually be negatively correlated with response. But we didn't engage these brain stem prefrontal or thalamic fibers. And this is the patient being engaged in his compulsive ritual and have to make sure that I'm actually also sharing sound. Yeah, I do. Mhm. Ah Thank you. I don't know. Yeah. I thought of something in the middle. We need to start all over again. Thanks. Mm hmm. Shima. So we modeled a different setting activating one more doors will contact. And now we did actually get these fibers that are associated with therapeutic effects. And right after we we we we made this change as modeled. You can see the result now all of a sudden you can hear um him actually saying his prayer much faster. Like three times faster and also very fluent. Oh boy. I know boy. Whoa. So um you can probably understand now why it's so inspiring because because you can see these immediate effects. And this was actually one of the good responders which I depicted here and um this is one of the most recent patients where we actually applied track tomography informed targeting. So um kissing and I work with dr Copple are north surgeon to to not to actually leave the method of coordinate based or atlas based targeting but really targeting at these specific tracks which as far as I know only a few centers are starting to do but if you do so at least so far you can see very immediate effects. So this is a patient with all sorts of mental mental compels of rituals. It's very hard to engage him into uh an interview because he's constantly preoccupied with his rituals. He's also moving his body um and and he's constantly counting. Um and this was one of the patients that we actually were able to implant like right in this therapeutic track as you can see here. And when we activated his the neuro stimulator we saw an immediate response with the patient becoming more engaged. Um and actually forgetting about most of his compulsive rituals. And up up up till today this we're now one year after surgery, he's still doing very well. Um Of course I'm also hugely inspired by helm a bird's results so far which is basically this method. So in her patients in her emery cohorts um with working with her book um some of them who are now here um she was actually able to to show um in enormous improvements of outcome using these methods um Where the efficacy or the effects of sub close all dbs Improved from 40 to around 72 now over 80 using tractor graffiti based targeting and programming. And um so so this means that there's definitely room for improvement Um and that we shouldn't be happy with the 50% that we're getting. Now. Looking at the alec, it's interesting to learn from tracer studies and human tracks geography studies for example those from Susan Haber's group um depicted here to see that the ALEc is actually projecting two different cortical regions. So um so could we pretty precise are targeting by looking at these cortical projections in each patient. So you see the ALEc and you you can actually see that the lateral parts of the internal capsule are projecting to the doors of lateral prefrontal cortex. In the ventral lateral prefrontal cortex the most ventral part is going to the ventral medial N. O. C. And then the more medial parts of the Alex are projecting to the dorsal A. Cc. And the dorsal medial prefrontal cortex. And ki sung choi Our neural imager was actually able to show in our patients in the mount sina patients if you average average their track topography maps to the stimulated regions. The same regions came up in our patients meaning that that the way we use dBS. Now in these patients. We're also modulating these various cortical projections of the alien. Um And in fact we could see that it's important for the response you can see here plotted the number of of streamlines from the region where we end up stimulating in these in each patient to these cortical projections. And you see that responders sort of share projections to all of these cortical regions. However, the non responders seem to have overlapped to some of these cortical projections for for example those most ventral but not so much to dorsal lateral or ventral lateral. They seem to lack um those streamlines at least less than the responders. Um And it might even be like was also showed in this meta analysis um that there are negative tracks which may delay or even negatively influence the outcome in our hands. This ventral medial prefrontal um track which was actually correlated with a negative response. So is there a way to selectively stimulate each of these pathway in each patient? And yes there is there are now available commercially available directional leads with which you can actually selectively and directionally stimulate in the lateral and medial directions at least for the middle two contexts. Um And was able to to show with these electric field models that they are actually the applicable two modulating these different cortical regions. So we found when we model it that the lateral segments are actually able to connect to dorsal lateral prefrontal cortex and ventral lateral prefrontal cortex as predicted. And then the media wants would take you to dorsal, medial and dorsal whereas whereas the lowest contact will go to ventral, medial prefrontal cortex and orbital frontal cortex so that's all fine. But which are the ones that are optimal for OCD. And how can we use these for individual patients? This is a patient with like really outspoken motor compulsions. It can take him hours to walk through the door because it doesn't feel right. It needs to go back and forth as you can see here on the day of his surgery. And we imagined that ventral lateral prefrontal cortical stimulation might really help this patient because my previous work showed that elite DBS is actually able to normalize VL PFC activation associated to multiple inhibitory control in patients with O. C. D. So we modeled um these fibers going to the ventral lateral prefrontal cortex which again would be one of the segmental um context. And we were able to to show with this very selective segmented setting um that he was able to to walk fluently again. Um This is a patient where we apply this method to selective stimulation. Inter operatively dolo is one of our researchers that greatly helped me set up video and sound and also like sliders with which we can selectively measure different symptomatic outcomes to intra operative stimulation. You can see the patient here with the stereotype stick frame that the surgeon needs to to steer the implantation to the right target. This is the patient before we activate the system and you can see right after activating the system he starts to smile. Especially with this first ventral medial orbitofrontal connection. It's actually also sort of a unilateral smile which is interesting. This is right sided stimulation. It's actually prescribed in the literature before. Probably connected to like in the middle of motor uh fiber. And you can also see like when we plotted his symptom responses like a huge increase in specifically motivation. Not so much mood which aligns to like the the function of these motivational limbic fibers as well as a selective improvement with this lateral presumably ventral lateral prefrontal cortex target contact. So this is very promising that you can already see intra operatively the reviews case of very selective steam. So now we have to find out what is actually the right sort of stimulation map for all of our patients as well as individual patients. So this is a study that we're about to run here at Mount Sinai where we are individualized individual individually targeting 20 patients using cryptography as showed before. And then every two months we're measuring their outcomes as well as behavioral tasks that map on two different circuits which I will show you in a minute and then after one year. Well pick apart responders from non responders and try to differentiate the they're stimulated targets or tracks. Um And working with XiaO SI and Vincenzo from the computational lab we've designed a battery of tasks that actually tap into these different circuits for motor control for reward, positive and negative reward prediction and for reversal learning and flexible control. And so each two months we're trying to map outcomes with these tasks onto selective steam. Which is great for exploring like individual targets for each patient but it also gives you a nice almost production map of tasks, outcomes associated to stimulation in in these different circuits. Allison Wallace has a great E. G tool which we also use in this study where she was actually able to show that with selective steam you can actually you can see she was able to demonstrate also selective E. G signatures in response to the stimulation measured on the on the scope. So you can see here these different signatures which is something that we're going to use also In these 20 OCD patients. So what about motor dbs, is that really motorists? DBS for Parkinson's of course is targeted at these typical motor circuits. For example the septal atomic nucleus or the globe as palliatives internists connecting to motor cortical regions but we know that these circuits of course are interconnected with the more associative and also limbic circuits. Um And we also know this is these are results from Montana Parkinson's patients um that we measured during their deep brain stimulation screening. So these are regular medication treated Parkinson's patients. Um So we know from these patients that their motor symptoms are dope and independent. Of course Parkinson's is um in part document depletion. So if you take these patients off their dopamine substitution therapy, you'll see an enormous increase in their motor symptoms. For example, tremor and rigidity. That's something we knew. What we didn't know was whether they're non motor symptoms like their mood or symptoms that are prevalent in Parkinson's like compulsive itty anxiety or apathy are also dope and independent and indeed some of them are apathy most prominently, which is lack of motivation. Um If you take patients off of the document urging medication, you see there a motivational apathy scores increased. This was measured with the Starks teen apathy skilled assess um We also saw significant differences, but now the other way around for compulsive itty and impulsivity. So things like hypersexuality, compulsive eating, gambling spending. These are measured with a skill called the quip and and their uses reverse patterns or more complexity and more impulsivity with patients on document urging medication, there was not a significant difference between these two states for depression and anxiety. So so far it seems that mostly epithelium compulsive itty. Our document energy independent behaviors which are not traditionally addressed with dBS because it's mostly focused at these motor parts of the simple atomic nucleus. However, that might be very important. That might be actually um important to to target these non motor circuits. Because what we see and this is actually also something that's seen immediate analysis across the world that many patients with sipped, Islamic DBS and Parkinson's despite having a very good motor outcome, still suffer from apathy or lack of motivation in our on china cohort. Actually half of the patients score above the cut off of apathy. So those patients typically tell the neurologists that they don't feel that much improved, even though their motor scores show that they have beautifully improved, but they don't seem to be able to motivate themselves to get up from their chairs and move. Despite the fact that they're uh motor symptoms have greatly improved. And this is a patient with apathy and a high score on the apathy scale that actually reversed after stimulating a different context, you can see that also his motorsports improved a little bit, at least he's less dis kinetic, but definitely he looks much more alive and less empathetic. And this is also something he reported again immediately after we adjusted the stimulation Sevens. So this shows that contrary to like what is currently believed mostly in the field of neurology, this sort of motor dbs can actually also be used to address these non motor symptoms and that makes sense because if you look at um at the projections off the the soup polemic target models in our Parkinson's patients. You can actually see that where we stimulate again, this is usually targeted at the dorsal STN for motor circuits and motor symptoms. There's also definitely connections to these associative and limbic regions. And actually when we compare patients with apathy to those with no empathy after D. B. S. This is work with Lucia Bennison who was a medical student doing research with us. We can show that the apathetic patients had actually missing engagement of mostly these limbic projections. Which is an interesting finding. I mean most in the field I tend to believe again that like apathy is not something that is amenable to dbs and if so it's often believed that it's a side effect. But here we show that it's actually something that's um that's being missed in current stimulation methods. Alison again was able to find also uh effective like sort of functional readout uh of this limit stimulation. So here this is one patient using the same method that we also use for O. C. D. And also for depression when we stimulate the ventral contact. We can see um engagement of these prefrontal limbic pathways. So this is useful for studying how to best actually target these limbic prefrontal regions if we want to reverse apathy which is something that we're about to do in a study where in existing Mount sina patients we are first further mapping these apathy maps by comparing patients with uh and without apathy. After motor dbs and then we use a second cohort of prospective patients wait and see if they do or don't develop apathy if they do. We're trying to adjust their stimulation setting towards getting the non empathy map of our first cohort and then of course see if they improve in terms of motivation and empathy scores and not at the cost hopefully of their motor outcomes. This is one patients where we where we tried this successfully. So the patient had apathy and as expected was relatively lacking limbic connections. Did they have did have good motor and some associative connections but not so much those limbic prefrontal connections. And when we modeled um a setting which would give us the limbic connections modeled onto our a group match. And I just showed you and adjusted the stimulation accordingly. We were able to decrease this patient's Apathy score from 22 to 12 without actually adverse events, showing that it's actually a very promising technique that of course we have to further back up with uh with with a larger number of patients to base our maps on. Um That brings me to the end of what I wanted to share with you today, ending again with this group of great people to work with. We have different other projects in the pipeline. Um Alison Waters, for example, is um is trying to decipher the brain circuits underlying urges to take and compulsions which just may also be relevant for neuromodulation of addiction. Um of course um where we're having a very promising ongoing work with Helen sub colossal patients? I'm very impressed so far with the first two patients that we implanted here at Mount Sinai. It seems to be very precise and very immediate also in terms of their outcomes which is again very inspirational for me to try to achieve. Also in the oecd in Parkinson's patients. We have very interesting work with Xiao Xi's lab and Alex um using the ultimate story where we're able to inter operatively measure dopamine and serotonin and or adrenaline which will be hugely interesting also for like a biomarker of selective stem in R. O. C. D. Patients. We're working with steve and high who is an expert in uh facial expression and speech analysis which we can actually apply to these videos that I showed you to maybe pick up more subtle changes. Then we're able to to catch with our traditional skills And then I have a very interesting project with people from Hopkins where we try to targets um substantial Niagara sensory cortex circuit for patients with schizophrenia with very promising results in in the first patient. Um so that I would like to really end and um welcome questions and discussions. Thank you. Thank you martin. So uh as a reminder used the Q. And a uh function to ask questions that was to everybody but you martin but if you want to read them or I can read them to you. Do you see them? Shari is the first question. It's a question about a patient recently mentioned transcranial direct current stimulation. T. V. C. S. I wasn't able to find much info about it. Would you commend on it? It was endorsed by a member of our Sinai faculty. We do use I mean I know the addiction group uses transcranial direct current stimulation which is uh it's a little different but but comparable to transcranial magnetic stimulation it has the advantage of being more flexible. You can also apply it even in the home setting which is one of the reasons it's being used for addiction research. It's not something we're using so far in our neuromodulation center. Um Yeah for for various reasons. But we use transcranial magnetic stimulation which seems to be a little bit more precise in terms of targeting than Tcs but it has shown some promising results also. You know C. D. And depression. Thank you. Then there's another question. You mentioned the possibility of hitting negative tracks that negatively correlated with positive outcomes. Did any of these patients actually develop worse O. C. D. Symptoms after the because that's an interesting question So far. We either seen no or little response like below the 35% responder. Um The threshold um Not particularly aversive or negative outcomes. So I think I should I should reframe that um Like the one patient that I show you with the compulsive prayer we did hit the so called negative track which was supposedly this feudal tracked. Uh And I must say that he did report some actual logic effects with this kind of stimulation. It just it didn't affect his O. C. D. So I'm not sure even if these are really negative tracks but maybe they just target other symptom constellation which may or may not be relevant for this particular patient. I must say that side side effects are actually pretty rare with the brain stimulation and if we see them it's actually very easy to to refer to them by changing or lowering the stimulation. In fact many patients are able to to stop their medication. One successfully successfully treated with the brain simulation which greatly contributes to like the experience of less side effects also in the in the Parkinson's patients. That was a fantastic talk and really exciting. I wish I was working in that space but it's too late. Um Yeah I think it's really elegant work. It's nice to see the integration of uh M. R. I. Information and track biography. That's really an amazing step forward. Um I if anybody has any last question, I'm sure martina will be happy to take it. Otherwise we'll see you in a couple of weeks again. Well we'll see you actually in november. We're gonna pause this seminar series um for october right. Yeah. Okay. Mhm. Thank you all. Thank you martin. You're welcome. That's great talk and we really appreciate it and thank you all the participants. Okay Thank you. Bye bye. Published November 30, 2021 Created by Featured Faculty Martijn Figee, MD, PhD Director of the Interventional Psychiatry ProgramMount Sinai Health System View full profile
