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Bogdan: Hello, everyone and welcome to a new Novalis Circle webinar. My name is Bogdan Valcu. I'm the director of the Novalis Circle. I also serve as the Director of Clinical Affairs for Brainlab. And today I have the distinct pleasure of welcoming two of our research partners, who will present novel ideas for treatment of functional disorders.

Modern imaging techniques, and especially dedicated processing tools such as those provided by Brainlab allow us today to perform safe neuroablation as an alternative or a complement to neuromodulatory treatments. Brainlab has a unique set of tools aimed at both the nurse surgeon and the radiation oncologist to enable you to not only safely identify the targets, but also provide validation with a patient's own anatomy that you are in the right location, therefore, enabling you to do a safe radiosurgical treatment.

The webinar today will provide a review of traditional stereotactic techniques for target identification, introduce the novel tools for anatomical confirmation, and address the overall radio surgical considerations in the patient selection criteria. To begin, I have the pleasure of introducing Dr. Nader Pouratian, professor of neurosurgery, bioengineering, and neurosciences at University of California in Los Angeles. Dr. Pouratian is also the Vice Chair of Academic Affairs, as well as the director of multiple departments inside the multidisciplinary UCLA neurosurgery program, inclusive of radio surgery and the functional program. We had the privilege over the last few years to work with Dr. Pouratian on validation for some of our new enrichment solutions such as fiber tracking. And in his lecture today, he will provide a recap of some of his results.

Following his talk, I'm also glad to introduce Dr. Mohamed Khattab, who is the chief resident physician in the department of radiation oncology at the Vanderbilt University Medical Center in Nashville, Tennessee. Over the last few years, we had the privilege to also work with the Vanderbilt group to provide both a retrospective review as well as a prospective validation of patient-specific targeting tools for a cohort of patients with essential tremors.vAs you may know by now, Novalis Circle is very active in dissemination of scientific knowledge. Yet, we are equally involved in generation of new concepts and new treatment ideas, and the research endeavors to validate and enrich stereotactic radiosurgical treatments are of paramount focus for us at Brainlab.

As always, we continue to provide CE credits for this webinar. Should you require CAMPEP, MOCB, ASRT credits, please email us at upon successful completion of this webinar. And don't forget to sign up for our new event coming up on September 3rd, when we will introduce a novel idea of "A Case of the Month Review." Doctors Kaprealian, Macyszyn, Agazaryan from UCLA will be the first ones to start this new series of webinars and discuss a spine patient from patient selection in tumor board discussions all the way through planning treatment, and follow up.

And lastly, as we all rely on internet connections these days, please remember to either utilize Google Chrome or Safari to view this webinar today. And should you have any connection issues, please just refresh the window. Don't forget to send us questions via the chat line. We will review and answer those questions upon completion of the two lectures. Keep track of our polling interface for questions that we may like to ask you. And should you choose to follow us on social media, please use the hashtag Novalis Circle. And now I'd like to turn it over to Dr. Pouratian for the first presentation.

Dr. Pouratian: Thank you very much for the opportunity to speak today about safe neuroablation via advanced image processing tools. I'll start with my disclosures. I do have grant support from Brainlab and speaker for Brainlab as well as my other disclosures here that are relevant to treatment of movement disorders.

So, in my talk today, I wanna discuss several important issues. And first and foremost, we are taking care of patients, so I wanna talk about the patient selection criteria. In the spirit of safety, you know making sure that we're treating the right patients is of utmost importance when we're talking about safety. And then I wanna talk to you about how radiosurgery fits in our algorithm for treating patients with essential tremor or other forms of tremor. And then get into some of the details about the stereotactic planning and how we make it safer and how we use advanced image processing to improve our treatment paradigm. And some of the data that we've used to motivate our current algorithm will also be discussed.

So, I do wanna give a little bit of a historical perspective. In our modern world, our contemporary world of neurosurgery, we often talk about neuromodulation or brain stimulation. And for many years, we moved away from this idea of ablating the brain in with a preference for stimulating, doing something that's reversible. But it's important to look back to our history to know what's important and what developed our field. This idea of ablating the brain is very much a part of who we are in our field. We have examples here of Walter Freeman doing the icepick lobotomy, Irving Cooper who did cryosurgery, but also anterior choroidal artery ligation.

And we should remember that the entire field of stereotactic radiosurgery was developed by Lars Leksell whose initial intent was not to use radiosurgery the way that we use it now, but to do ablative procedures like pallidotomies for movement disorders as well as treatment of psychiatric disorders. So, we have a deep history of ablating the brain. And we shouldn't think of it as something that is necessarily unappealing to patients. In fact, some patients like the idea of having a treatment done without having to have an implant or having to have long-term maintenance.

But we did move away from that and we moved into a field of neuromodulation, but I think we are rediscovering the importance of ablation. So, I do wanna talk about patient selection for both neuromodulation and neuroablation for tremor. In this case, making sure that you select patients correctly ensures that we maximize safety. So for essential tremor and for tremor dominant Parkinson's disease, we really have to go through three things, right? We have to confirm the diagnosis. We wanna make sure that they failed medical therapy because most patients, in fact, can be managed with medicines. And then we wanna make sure that the tremor is enough of a source of disability that we should be considering a surgical treatment.

So, for essential tremor, key factors it's usually bilateral. There's usually a strong family history of it. There's also patients often report that it's alcohol responsive. Essential tremor has a postural and kinetic component, and there should not be rigidity or bradykinesia. That's in contrast to tremor-dominant Parkinson's disease, where it's usually progressive, it's usually unilateral in nature, before it becomes bilateral. There's also a family history there. But it's also has rigidity or bradykinesia along with a rest tremor, as opposed to the postural and kinetic components.

Going back to essential tremor, really critical, there are strong studies that support first-time medications including propranolol and primidone. If patients haven't tried those, or there isn't a reason why they shouldn't try them, we need to make sure that they do. And I've had many patients who have started on those that never come back for any treatment, which is the right thing to do. Tremor-dominant Parkinson's disease, in the interest of safety, I would emphasize that really having a movement disorder specialist or neurologist is critical to their management, making sure that they've exhausted all the medication treatments before they go on to surgical treatments of any kind. And, of course, we want to make sure that what we're treating is actually a source of disability. I will highlight an important source of disability often is social discomfort. A lot of people feel like their tremor isn't that bad, but they may not be able to socialize the way that they wanted to, and so a treating tremor in that case can be critical for someone's well-being.

Now, in terms of our algorithm of how to treat or select the proper treatment modality for patients with tremor, we really want to think about many factors, and I've listed several of them right here. First and foremost, and important consideration is whether a patient is seeking bilateral treatment or not. For the most part, if someone wants both hands treated, then they should be considering deep-brain stimulation as a first line therapy. Other than that, if unilateral stream is gonna be okay, then we can think about focused ultrasound and radiosurgery. And in this case, we're talking about LINAC-based radiosurgery.

The other consideration is whether people want to have an incision or they're okay with an incision, they're okay with an implant, they're okay with infection risk, or if they're just a surgical candidate in general. If all of that is yes, then we can still continue deep brain stimulation. Some people, you know, don't need bilateral treatment, but they...and they absolutely don't want any of these other things that involve open surgery, and so you consider the non-incision based treatments like focused ultrasound or LINAC radiosurgery.

Now, here are where the other differentiators come in between focused ultrasound and LINAC radiosurgery, a head shave. So, for focused ultrasound, you do need a full head shave. And for some people, that's a game changer. Skull density ratio, you know, with radiosurgery we can treat anyone with a head and any type of skull with focused radiation, whereas focused ultrasound does require different...a specific minimum skull density. Stereotactic frame, some people don't even want to a stereotactic frame place. With our modern technologies, we can do mask-based thalamotomys with radio surgery, and so we avoid even placing a frame on patients with radio surgery.

Long-term maintenance, and this is not maintenance of therapy, but of the device, the brain [inaudible 00:11:27] requires the device to be maintained. And then the immediacy of the effect. The only treatment that really has an immediate effect is focused ultrasound. But recall that the vast majority of these patients have had tremor for many, many years are not in the acute crisis, and so the immediacy of the effect is not necessarily a big treatment decision.

Now, getting to radiosurgical thalamotomy, it's an effective treatment. I would say in many cases, it's underutilized. The average improvement in tremor, whether it's writing or drawing, or other quality of life measures, is about a 50% improvement in the tremor, and about 90% of patients are going to respond to a radiosurgical thalamotomy. This is some recent data published using Gamma Knife therapy, but really emphasizing the role of radiosurgical thalamotomy. And the dark gray bars for each of these different measures whether it's a tremor score, drawing score, drinking or writing, what you see is the dark gray bars are pretreatment with very high scores. And then after treatment, everything shifts to the right to mostly zeros and ones, which is a good therapeutic effect.

And importantly, we look at the probability of tremor relief, which as I discussed earlier, is about 90%. And you can see the timeline is about 10 months to see that effect or to get to that plateau. But importantly, the maintenance of tremor relief, about 80% of people maintain tremor relief 10 years and beyond. So, we have a very good therapy that I think overall, as I said, is probably underutilized.

Again, I wanna call some major...bring some attention to some of the major issues. One is we cannot or generally do not treat bilaterally. There is some data on bilateral treatments. And I'm actually gonna show you something contrary to that because we have treated some patients bilaterally but in a stage way. But that should be the exception, not the rule. But complications people worry about the complications. And it's probably roughly equivalent to deep brain stimulation. It's hard to know because there aren't prospective studies of radiosurgical thalamotomy in a large cohort. But the complication rate ranges somewhere between 2% and 4% of permanent neurological deficits, three-quarters of which are motor. But this could include having some gait impairment, having some mild weakness in the arm, which we also see with deep-brain stimulation as well as focused ultrasound.

So, let's get into the technique a little bit. Stereotactic radiosurgery, especially using a frameless approach or a mass-based approach, we use a dose of 140 gray. And we evolved through this because the literature supports anywhere between 120 up to 150 gray point dose. When we treated with 120 gray, we had at least one case where we could not even see a radiographic change on follow up and we increased our dose to 140 gray. And in that case, what we really saw was that imaging changes generally occur to about 120 gray isodose line.

And then targeting, and I'm gonna talk about the traditional targeting, which I've described here. And then in a little bit later, I'll talk about some of the finer details about how to do it better or we think better. The traditional targeting is 25% of the anterior and posterior commissure distance in front of the poster commissure two millimeters above that line in order to stay away from the cortical spinal tract, and then 11 millimeters lateral to the third ventricle, but maintaining the 30% isodose line medial to the internal capsule to reduce the dose to the capsule and reduce the risk of neurological deficit. If you use that formula, you'll be good in most cases and get the types of outcomes that we've seen in the literature.

But now, I wanna get into why we talk about doing patient-specific targeting using advanced imaging. The thalamus we target with indirect targeting, which means we're using those measurements based on the anterior commissure and posterior commissure. And this is just looking at the various measurements across multiple targets we use and deep brain stimulation. But you'll see patients brains are different sizes. They have different ventricular sizes. And there's actually a fair amount of variability. So if we look at the bottom group down here, the ViM thalamus, you'll see that there's actually a fair amount of variability, you know, 12 to 14 millimeters, that could be 5 to 6-millimeters anterior to posterior commissure or 25% of the length. There's the 11 millimeters [inaudible 00:16:20]. There's a lot of variability. In fact, if we take 452 subjects, and we account for differences in the anterior and posterior commissures, and we average those brains, you get a cloud of a brain. And that just highlights how much intercepting variability there is and why patients retargeting is actually valuable.

The other thing is, even when we do have great visualization, we need to think about what we're actually doing with neuroablation or with neuromodulation in that we're not actually just targeting a certain part of the brain, but we're targeting a network. And not all of these...not all targets are visible and for sure not all these white matter connections are visible. And so we turn to more improved imaging to get some more information about those targets. And I often say that stereotactic surgery, but in general stereotactic radiosurgery is a field that's enabled by technology, precision, and advanced imaging.

You know, the reason why we were able to translate from whole brain radiation and conventional radiation to more precise radiation is because we have improved imaging because we can target a small lesion in the internal acoustic natives or the trigeminal nerve or trigeminal neuralgia. Without advanced imaging, we wouldn't be able to advance our field. And now advanced imaging is moving beyond just structural imaging. So, it's not just a matter of going from 3 Tesla to 7 Tesla and seeing our structures better, which we can do, but it's looking at brain networks and looking at brain connectivity.

And why do I think connectivity is important? Well, one, we've got a huge amount of literature that supports that diseases affect networks, right? It's not, you know, when you get Parkinson's disease, it's not just a degeneration of the substantia nigra, it affects widespread brain networks. We also know that the brain has very rich connections. So we're not...You know, white matter is not just white matter. There's a lot of information in there. We know that a brain stimulation really affects network. So, when we stimulate a certain part of the brain, it changes things in other parts of the brain. The same thing happens with ablation. When we ablate deep inside the brain, it changes dynamics in other parts of the brain. And then there's some interesting ideas that show that even with brain stimulation, whether we're using noninvasive stimulation or deep brain stimulation, those are all part of a network. So, this idea of network-based disease and network-based therapy is a huge part of our field. And I think acknowledging it really moves us into the next millennium in terms of our treatments for radiosurgery.

And so the best way that we have to look at brain networks, especially structural networks, is using diffusion tensor imaging, which, as most know by now, is looking at the preferred direction of water diffusion in each voxel. And then once you know the preferred direction, you can use different algorithms to try and link up those different directions and make a tract out of it. So, down below here, you can see the cortical spinal tract projecting up to the precentral gyrus. Also, in this case, projecting down to the cerebellum, In this particular example of tractography.

Now, even before you do tractography, you can look at what we call FAA maps or fractional anisotropy maps and get some additional information. This is one of our early work saying well If you look at the preferred direction of water diffusion within the thalamus, you can start to see some internal structure. But even having published this, I find it extremely difficult except maybe if you're looking at the internal capsule, to see internal structure within the thalamus or within the subthalamic nucleus. I think we need something more than this.

And so we did our initial work in deep brain stimulation patients. But we, what we did is, we wanted to see if we can find some internal structure within the thalamus to guide our targeting of our therapies for tremor. And what we do is we look at the preferred connectivity of every single voxel in the thalamus with different cortical lesions. And so we can find the parts of the thalamus that are preferentially connected to the primary motor cortex, preferentially connect to the premotor cortex, and so on and so forth, and we could create a map of the thalamus. Whereas it's not all just one nucleus, we can now see individual connectivity maps.

And when we did this, and we looked at where our deep brain stimulation electrodes ended up, we found that the green which is the electrode almost always ended up in the part of the thalamus that have preferred connectivity to the premotor cortices. And we also showed that there's a fair amount of variability across subjects. So, it's not enough to just say, you know, "Let's get our electrodes somewhere relative to the AC and PC. We actually can benefit from patients with retargeting."

Now, it's not just deep-brain stimulation. I'm going to show you that we did the same analysis with focused ultrasound, and we were able to show that in fact, our region for focused ultrasound thalamotomy also ends up in that same area. And if we look at these ROC curves, we see that when we have a great overlap between our thalamotomy lesion, or you could say radiosurgical thalamotomy lesion and this tractography-based map, we actually have a very high probability of having a better outcome than a worse outcome.

And so this was one of our first reports and a proof of concept of how we do our thalamotomy using diffusion tractography. This is in black and white, but showing the same idea of looking at the preferred connectivity to the premotor cortices. And we're able to prescribe 140 gray point dose to that region, as defined using Brainlab's software. And as you can see, this is an image six months after the treatment, showing an enhancement in the region of the thalamotomy. And in this patient, were able to get a significant improvement in tremor, whereas scores were 2 to 3 beforehand, at 16 months, they were between 1 and 2, and a 22 months, we had almost complete control of this tremor. And you can see this imaging 12 months post treatment with a thalamotomy in this patient.

Now, that was using software outside of Brainlab. And a question comes up, you know, can we do this in the planning environment that we often are already using for radiosurgery? And the answer is, actually, yes. And we can do this by looking at, again, contouring the precentral gyrus, which is includes both motor and premotor cortices. And looking at the parts of the thalamus that are most connected to that area, and we can get these maps. In this case, these are these probability maps, and we can translate that into our planning software.

So here, you can see a rough contour from one of our patients recently, where we've cut throughout the precentral gyrus. You can see this map of the connectivity between the thalamus and the precentral gyrus. And, in fact, it's not showing here, but you can see the connectivity down to the cerebellum and the dentate nucleus. And we plan our placement of our isocenter within the posterior part of this connectivity to the precentral gyrus. So this is using Brainlab's software to do the conductivity mapping.

And we've done some further comparisons using the technique that we've used outside of the planning elements and then inside, and you can see the maps completely converge. So you can see beautiful projections from down in the cerebellum through the thalamus to the cortex. This is using our probabilistic approach. The white is using the Brainlab tractography approach, and we have excellent overlap. Here's one patient and here's yet another patient even the direction of the contours look very similar across them, of course, depending on how we thresholded it looks slightly differently, but you can see that there tremendous overlap here. And so this planning can be done easily within the elements platform.

Now, this is the way that we do it. But it's also been described using tractography to identify other areas of importance in order to avoid them. So, you can do direct targeting of the cerebellar thermo premotor track. You can also identify other pathways. So, you can identify sensory pathways, in this case, the sensory pathways shown in blue. And the idea is to stay anterior to that. You can also find the pyramidal tract and stay medial to that and place your target within that region, if you want to do an indirect targeting, avoiding those areas that we want to preserve. Again, I want to remind you that we keep a 30% isodose line along the internal capsule.

There are other examples of this. And I've just shown these here, too, in case you want to refer to other techniques. But they're all basically building on the same idea either we create a direct map of the polemic region, or an indirect map with sensory pathways and the motor pathways, and then placing the isocenter within that corner between those two lesions, avoiding those areas at risk.

This doesn't project very well, and I'm sorry about that. This is a slide from Dr. Finoe's [SP] paper. But it basically shows that this indirect targeting, although it's not very different from...Sorry, I should say this tractography based target, although it's not very different from the indirect targeting, it is different and it does make differences on the order of one or two millimeters in some patients. And that could be extremely important for enhancing both the therapeutic efficacy as well as the safety of the procedure.

Now I've been talking a lot about tremor. I do wanna highlight this tractography is very useful for identifying other critical structures that have preferential flow of water within axons, and particularly the trigeminal nerve. In most cases, we can see the trigeminal nerve, but sometimes just want to share another example where we can target the trigeminal nerve, let's say, when there's a schwannoma near it, but someone has pain related...Sorry, not schwannoma or a meningioma, but they have pain related to it. Tractography can help us identify where the nerve actually is and target our treatment for secondary meningioma to the nerve itself.

And so this is a case right here where we have a meningioma in this region. And we can see the deflection of the trigeminal nerve medially, and we're able to target the [inaudible 00:28:03] surgery to that region. So, not quite an ablative case, but again, using tractography to increase the efficacy as well as the safety of our procedures. And there you see the plan for this patient.

And so I wanna just conclude with a couple thoughts. Again, I focused a lot on tremor, but I wanna highlight for you that tremor is extremely important. And what I've shown you here I think improves, again, the safety and efficacy, but it also opens the doors for other treatments. Now, we haven't done this, but we've done some work using tractography to identify the best spot to target within the subgenual cingulate region for deep brain stimulation for depression. And we've used tractography to look at, you know, can we find the best spot within this general area to target with deep brain stimulation?

And so if we can find the best spot with deep brain stimulation, then maybe we can use this type of approach using tractography to target our ablations with radiosurgery or with any other technique with much more precision and greater confidence in a patient-centered manner, and open up a therapeutic doorway to treating patients with radiosurgery for other disorders that we don't traditionally do right now on a more common basis. As you may know, the radiosurgery for excessive compulsive disorder, which is a capsulotomy is an anatomic driven technique with a pretty large volume. So, maybe this will open the door to doing more targeted smaller therapeutic approaches for a wider array of diagnoses.

So I wanna conclude with a couple major concepts. Both neuromodulation and neuroablation are a network phenomena. They're occurring at the level of the target and ExacTrac. Anatomy is variable across subjects. We know that, you know, when we do stereotactic radiosurgery for trigeminal neuralgia, we don't use coordinates, we actually look for the anatomy. If we can't see the anatomy, we need to use advanced imaging to improve our therapies. I strongly believe that noninvasive conductivity, like, I've shown you here should enable patients retargeting based on knowledge of the network that we're modulating or targeting.

And I think we have a big future in this area. I think we have disease because their analysis of tracks to open up treatment for other diagnoses. We need to better understand the rule of increased spatial resolution. Many people will say, "Well, tractography only has, most commonly, one-and-a-quarter or two millimeters spatial resolution." But that might be enough for the types of therapies that we're doing in this space. There's other opportunities with functional connectivity that we haven't quite tapped yet. There's a need for user friendly interface integration. And I think that is within reach now, if not currently available, and we can do the types of things I'm showing you on a regular basis.

Finally, I encourage everyone to collect diffusion tensor imaging and resting state fMRI when they can, on all their patients as part of their imaging protocol, whether it's for deep brain stimulation, or stereotactic radiosurgery so that we can really move this field into the future and all learn from one another. So I'll conclude there. Thank you very much again for the opportunity.

Bogdan: Thank you for that excellent lecture, Dr. Pouratian. And now let's turn it over to Dr. Khattab for the subsequent talk.

Dr. Khattab: Hi, good morning, everyone. My name is Mohamed Khattab. And I'm here in Nashville, Tennessee at Vanderbilt University Medical Center. It's an honor to join you today and to follow Dr. Nader Pouratian's talk. And really I want to transition this to talking about frameless radiosurgery for functional and neuropsychiatric disease. And are we there yet? And the short answer is yes. And it's a really exciting time to be part of this field as a radiation oncologist collaborating in a multidisciplinary environment to really provide less and less invasive treatment modalities for patients with functional neuropsychiatric disease.

So, these are my disclosures here. Quickly, I just want to state that I don't have a bias. I support frame based and Gamma Knife as far linac-based radiosurgery, as long as the appropriate clinical and resource situations are available for these functional indications. As long as you have the perfect clinical and physics support. That is really the most important thing. So, all modalities have a role and are useful, and we're just trying to advance the less invasive ones, which patients are demanding.

The agenda for today, I'd like to start off with a brief background on the societal and economic burden of neuropsychiatric disease, and our emerging role as so-called radiosurgeons to alleviate this need. Many radiation oncologists are entering this field noting the importance of treating patients with non-oncologic disease. And I'd like to then discuss the evolution towards really frameless radiosurgery, because it truly is an evolution and a renaissance that we're undergoing right now as it's what patients want and what current real-time imaging, for instance, through Brainlab's ExacTrac guidance allows for. Then I'd like to discuss our institutional experience, showing excellent accuracy and efficacy in both patients with trigeminal neuralgia and tremor.

We won't go into depth or really discuss much of our treatments of other neuropsychiatric disease, which we're currently doing, like OCD and major depression as well as pain syndromes that we're currently developing treatments for, as we'll try to reserve that for future webinars and talks. But really, I want to delve deep into the results of our prospective frameless research called thalamotomy trial because to our knowledge, this is the first frameless LINAC-based functional data that exists that has been acquired prospectively. And finally, we'd like to end on advanced imaging that we're using fMRI and DTI to better understand kind of just the pathology, but also refined feature targets.

So to begin, this a chart courtesy of John Adler that from one of his talks that where he compiled the prevalence of the different neuropsychiatric diseases whilst their economic burden. And it's quite impressive just the amount of people that have addiction, obesity, pain, depression, PTSD, anxiety, OCD, and Parkinson's disease, which we'll mention, but other numbers are really staggering. And the economic burden, as a result of those, is quite impressive.

So, again, it's not just the healthcare costs. Really there's the direct costs as well as the indirect costs that contribute towards the overall economic burden. There's the direct costs such as going to the hospital, the medication, the interventions. And there's the indirect costs, especially as a lot of these patients, say a patient with OCD or PTSD, would be very young and living many, many years not able to be as productive as they otherwise would be. This includes income losses, but also productivity losses not being able to contribute towards the workforce in the same way, for instance.

And this is an image that as a radiologist oncologist really impresses me. Neuropsychiatric diseases contribute to more economic burden than all cardiovascular disease and more than double the economic burden compared to all cancers combined. So, this is images that were developed by the World Economic Forum. Looking at in terms of the total cost related to functional and neuropsychiatric disease, there was almost $3 trillion that was spent in 2010 alone, and this number is expected to more than double by 2030, which is only 10 years from now.

This is our LINAC-based frameless radiosurgery platform that we have here at Vanderbilt. So, I know this is a review for the majority of people watching this webinar, but there's really no surgery in radiosurgery. It's noninvasive, especially with our frameless approach. There's no incisions there's no craniotomy. And if you have a frameless platform like ours, there's no penetrating pins. There's a rigid mask that keeps...that has points affixed, points of rigidity, but without fixation that keep the cranial walls for moving. And we've shown many times that we really have submillimeter accuracy without the risks of fixation with the frame, just by using this multilayered SRS thermoplastic mask. And what we do here is we have addition to the infrared motion sensing, we also have ExacTrac orthogonal imaging that we obtain at every table angle that is with each arc.

So, is rigid fixation really safer or accurate? So, paradoxically, it might really not be. So we don't really think about this too frequently, but there's a lot of MRI distortion with, for instance, if you have a like cell frame on, there can be distortions of more than half a centimeter. And we know this from actually some of the dosimetry data when they were calculating cochlea doses and seeing what the cochlea dose constraints would be. And when it was calculated using just CT, CT-based dosimetry versus MR-based dosimetry. they found there was very, very different deviations. And when you have those, the metal from the Leksell frame, it can really distort a lot of the structures within the bone as well as within the brain parenchyma itself. So, MRI distortion is a real concern.

There's also mechanical distortion from torque during fixation. Just the act of putting it on can cause distortion. And when a patient is getting treatment, for say, one-and-a-half hours or more, say, if you have a cobalt-based treatment and the activity is going down and you have to treat patients for longer, what's really happening during that whole period of time, especially if you can't even obtain onboard imaging. So, you can't obtain imaging during the treatment time. And there's been documented high rates of skull slippage despite pin placement. So Leksell frames may actually introduce error unaccounted for during treatment, especially if you don't have onboard imaging.

And the new Elekta icon is excellent, and for the treatment of tumors, unfractionated radiosurgery in that regard. But the onboard imaging or what's called onboard imaging is really not onboard, it's a CT on rails. The patient gets essentially a cone beam CT, not in the treatment position and then gets moved, so you don't even account for that movement. With ExacTrac and in our LINAC-frameless approach, we're getting treatment in the exact treatment position.

So, these are all aside from the risks of the frame placement itself, which include bleeding, infection, signs fracture, which I've personally seen, and even rare reports. And I agree it's extremely rare, but cortical penetration and intracranial hemorrhage, and it's more likely to get bleeding in the vessels on the face, for instance. But I agree that this is very catastrophic and doesn't happen commonly, but it is a theoretical possibility.

And if we dig in deeper and try to look at perspective data, we can look at the frames that have been used more recently for MRI-guided focused ultrasound, such as Jeff Elias's prospective randomized trial in "New England Journal of Medicine" in 2016. So, the stereotactic frames that were there, in the supplementary images and data, they showed that 30% to 35% of patients undergoing stereotactic framing fixation had been cited edema, pain, or bruising. So if you ask any patient, "Do you want to frame or you don't? Do you want a 35% risk of pain, edema, and bruising?" I suspect most would say no, and that's what they're telling us, and that's why patients are commonly coming to us for a frameless approach.

So is frameless radiosurgery, safe and effective? This is actually something that we've been doing here for many years now. And before proceeding with the SRS for thalamotomy, we had a lot more experience doing this for trigeminal neuralgia. So, patients with trigeminal neuralgia that is refractory to other treatments, we usually target their trigeminal nerve as it courses out through the prepontine cistern and into Meckel's caves, as what is known the dorsal root entry zone. The doses that we prescribe here is to the isocenter Dmax of 85 gray. We use a 4-millimeter cone for this. And usually we accomplish this treatment in about seven arcs. And between each arc, every time the table moves, we obtain orthogonal X-ray imaging with ExacTrac. And, of course, you know, in the treatment planning process, we make sure that the arcs avoid critical structures.

So, our experience here has been excellent. Really up to 90% of patients that get SRS have a very meaningful response. There were some patients that we noted had not as good of a response, not that they had side effects, but that they weren't responding at high rates. And we looked into this, and we questioned if their body mass index could contribute to this. So, because the 90% rate was those with we found with a normal BMI and lower responders were patients with high BMI. So this brought the question that if you're using a frameless approach and just a mask-based approach, is there any downside towards having higher BMI that may affect that may befitting of the mask or how accurate your delivery is.

So, again, we had a nearly universal response in...this is a publication looking at our data, we had a nearly universal response in normal BMI patients and lower response rates in overweight and obese patients. So, we discussed with the physicist, "Hey, could this possibly be the mask fitting?" And we actually think that this is very unlikely. It's certainly unclear, but it's very unlikely because we're obtaining the orthogonal imaging and there is very little motion even, say, if you expect the fitting to be variable with the fat content in the face.

So, the more likely explanation, when we dug deeper, is that there's actually pain sensitization that happens in overweight and obese patients. And this is likely mediated through TNF-alpha nociceptive activation of the trigeminal nucleus caudalis. And this has been shown in many animal models. And, in fact, TNF-alpha serum levels are higher in obese patients, and TNF-alpha is shown to activate the TRPV1 channels on peripheral nociceptors and the trigeminal nucleus caudalis itself.

And just as more testament to this idea is that obese patients with trigeminal neuralgia that undergo open surgery like MVD, also have higher failure rates. And presumably, this is they don't have masks on or anything like that. So, it is unlikely that the frameless approach is what's contributing towards reduced response rates among the high BMI patients.

So, in theme with the discussion today with Dr. Pouratian and what I want to discuss, is the role of radiosurgery for essential in parkinsonian tremor. We've discussed a lot of this before in the previous talk. But for individuals above the age of 65, about 5% and 1.8% are affected by essential tremor and Parkinson's disease, respectively. Tremor is quite disabling, impairs physical and psychosocial well-being. It involves the loop connections between the motor cortex thalamus, red nucleus, and the sphere of cerebellar peduncle, and then a nucleus of the cerebellum.

So, the treatment options for ATRP were previously discussed, but they include medical management. However, even with frontline agents, like, propranolol and primidone, over 60% of essential tremor patients respond while 40% don't. And those that respond often have to deal with the side effects. Notoriously, Parkinson's patients are also frequently medically refractory. So, the other options include surgical thalamotomy. Again, those have the surgical and anesthesia risks, which are the bleeding infection, intracranial hemorrhage, because you're creating a tract through the brain, so risk of injury to a vessel and whatnot. DBS has those surgical and anesthesia risks. There's also the risk of hardware malfunction in up to 25% of cases and, of course, planned battery replacements. So, that's an inconvenience for patients and something that many patients would rather not do.

Also, during the tunneling of the of the wires as they go from the leads all the way to the pulse generator, there's actually a risk of pneumothorax, if there's penetration of the apical lung. So there's another emerging modality MRI-guided focused ultrasound, with data most recently presented in the New England Journal in 2016 in that prospective randomized trial by Jeff Elias. So, the downsides of MRI-guided focused ultrasound are really that it can be limited by skull thickness, because there's this concept of bone heating that limits the focusing of the ultrasound beams. And in their study, even though they had great results, there were actually more toxicities than anything that we see with radiosurgery 36% rate of paraesthesias or numbness and this really persisted even at 12 months to 9% and 14%, respectively. There was 20% that had ataxia, 4% persisted with ataxia at 12 months, and 60% had developed unsteadiness and 5% had persistent symptoms of such.

So, the tremor reduction also appeared potentially less than with SRS. It is unclear from review of the New England Journal paper because they looked specifically at just hand tremor and they had a reduction of about 8.3 points at six months, I believe, which is, I'm not sure, it it's if they were only looking at FTM Part A overall tremor, but it's unclear. But it appears to be somewhat less than what we achieve with SRS, at least in the data that I'm about to present.

So SRS itself. So traditionally it's been done with Gamma Knife stereotactic radiosurgery with frame fixation. And our question is, can it be possible now with our technology to do it without rigid fixation? I just wanted to bring this up because we think of interventions as carrying more risks. But even medications for essential tremor and parkinsonian tremor are aren't without side effects. So, if we go down this list here of side effects and look at the two frontline agents primidone and propranolol, we see that they have significant toxicities that many patients would not want to take on.

So we know that Gamma Knife radiosurgery is quite effective for treatment of Parkinson's and essential tremor. In this data from 2008 from Dr. Kondziolka's group, we see that a lot of patients that were involved that were in this study that started out with Mark and severe amplitude tremor had significant reduction in their FTM tremor score. But the question remains, can we achieve similar results with a less invasive and frameless radiosurgery now with real time imaging, as something that can aid us in accomplishing that.

So, we started out with the first few patients in a pilot study assessing for accuracy. So by accuracy, we looked at the planned isocenter we wanted to treat in the ViM, and the actual lesioning that was produced about three months later, which shows very well on T1 post contrast MRI. So these are the screen here in a is the pretreatment axial view and then B, C, and D are just different planes showing that necrotic lesion that's been produced. So, we aim to measure the distance between the isocenter and the necrotic center that was actually developed to determine the accuracy of our target positioning and actually the realized lesioning.

So, and what we showed here is that we were able, at least in the first six patients, and our technique has only improved since then, is that we were able to achieve submillimeter accuracy in all planes. So, with this knowledge, we then proceeded with a clinical trial to look at famous SRS style thalamotomy. And these are patients that had thorough evaluation by radiation oncology, neurosurgery, and neurology, and were found to be medically refractory previously to medical management and other interventions, and they chose to enroll.

And we follow these patients with objective tremor evaluations looking at their FTM score. And then also quality of life evaluations, looking at their quest scores for quality of life and essential tremor patients, or PDQ 39 to look at quality of life in Parkinson's patients. And we planned the treatment and then we followed them at 3 months, 6 months, 9 months, and 12 months. This shows the target that we used, although Nader Pouratian went into more depth in the previous talk.

So, this is just some of the sample questions that are included in the QUEST questionnaire. But really, a lot of these you can see would affect quality of life. So being able to partake in hobbies, work, if any financial issues come up as a result of the patient's tremor, and how the tremor may interfere with the job or profession, as well as some psychosocial things such as maintaining conversations with others, things that make sense for why they would affect a person's quality of life.

So, our frameless LINAC-based SRS planning, so we obtained CT with thin slices as well as T1 MRI with thin slices. We also obtained DTI on all patients. We used iPlan Brainlab for treatment planning, the treatment on the Novalis Tx, 6 MV energy, we used a 4 millimeter cone, standard QA using Winston-Lutz. And then with our ExacTrac tolerance, we accepted a translational, a deviation of no more than 0.5 millimeters and no more than 0.7 degrees rotational shift. Again, this is all set up here. And we prescribed to Dmax of 160 gray. Most of our treatments, and I checked with our therapist recently, actually do not go over 1.5 hours. And we're really excited for the dynamic ExacTrac to come out as well to see if this treatment time can be reduced furthermore.

So this is just a representative post-treatment MRI and you see in this patient's left ViM the necrotic center that is produced here on the T1 post-contrast axial as well as the T1 post-contrast coronal. So, this is just a depiction of our study participants and their demographics. Again, this was 160. The majority of patients had right upper extremity tremor, therefore, we targeted their left ViM. Most patients had essential tremor, and about a third of patients or less than a third had parkinsonian tremor.

This is patients level numerical changes just to depict in this waterfall chart the individual patient improvement in FTM. But if we really dig deeper, and this is FTM at three, six, nine, and one year. But if we dig deeper, we can actually break down the FTM score in two parts A, Part B, and Part C. Part A being tremor severity during rest posture, action positions. Part B, handwriting and pouring. And Part C, functional disability. Functional disability being things, like personal hygiene, buttoning one's shirt, you know, being able to take care and self-care for oneself.

And we, at all time points at 3, 6, 9, and 12 months, there was a statistically significant improvement in the patient's tremor in all of these domains. And if we...This kind of really peaked at six months. But importantly, a lot of patients, we didn't collect data before three months, but a lot of patients had a notable improvement. They would tell us at four weeks to six weeks, which is actually consistent with what we see in the literature that patients have early response. However, the necrotic lesion develops commonly at three months, which is why we had our first follow-up start at three months. At 6 months, there was a median 20-point reduction in FTM. And this represented...this was found in about 83% of patients that responded.

So, another great way to look at this data is over time and to see how persistent the improvement in tremor was. So, tremor was reduced significantly following thalamotomy at all time points. And if we break it down by Part A, Part B and Part C, we see that it's statistically significant in all components, and that it is very durable. You know, the confidence...This is, what we're looking at here is a smooth conditional mean and then a 95% confidence band. And the confidence band is wider once you get out to 12 months, but that's just because patient follow-up is less, so there is less certainty. But it's clearly when compared to baseline is very significant. So, if in the previous slide, we didn't distinguish between essential tremor and parkinsonian tremor and the response. But when we do, when we delineate the two, we can still see that it's significant in both cohorts at all time points and in all FTM categories Part A, Part B, and Part C.

We aim to look at quality of life. And as mentioned, we did the QUEST questionnaire for patients with central tremor and we did the PDQ-39 questionnaire for patients with parkinsonian tremor. We were able to see that quality of life actually improved in essential tremor and this was significantly...this was statistically significant. And the domains, if you look at the breakdown here, and the improvement, if you look at hobbies and leisure. So a reduction in the QUEST score is an improvement. And patients at 12 months, for instance, had a significant improvement in hobbies and leisure in their physical score as well as in their psychosocial quality of life aspects and overall as well was statistically significant.

So, in terms of looking at PDQ-39 as a surrogate for quality of life in parkinsonian tremor, we were not able to see a statistically significant improvement or decline in parkinsonian tremor quality of life. And again, at last follow up there was less...there was a small end, so it contributes to the very wide confidence interval seen here. The improvements that we saw are truly life changing. So this is a sample of a patient's drawing exercise pretreatment and three months post-treatment. So this is one of the most satisfying treatments that we do here in terms of within the functional radiosurgery domain.

As far as their adverse events, at 12 months, we actually had very low incidence of any recorded toxicity. So this is quite in contrast to the data that we reviewed earlier, looking at MRI-guided focused ultrasound, for instance. So, we actually had only two patients that developed a headache. And otherwise, our patients did quite well at this 12 months interval and we continue to follow these patients as there is possibility for longer term toxicity that we'll continue to follow.

So, overall treatments response was 83%, at six months, the FTM reduction at six months was 41%, or about 20 points. And notably, our functional decline, which is FTM Part C, regressed by 54%. Quality of life improved by 57%, according to QUEST in patients with essential tremor. I wanted to mention as I didn't before that the one issue that we had with the PDQ-39 for parkinsonian tremor is that it wasn't actually validated for patients with interventions for parkinsonian tremor. It was meant more so for patients with Parkinson's and looking at systemic treatments. So, that may be an issue for not... That may be part of the reason that we weren't able to detect any quality of life benefit. However, it is reassuring that we didn't find any quality of life detriment.

In addition to that, patients with parkinsonian tremor, their quality of life is impacted by a lot more than their tremor. They also have cognitive and other neurologic disabilities that may develop with time that may affect their quality of life outside of the tremor. So it quite reassuringly, our adverse events here, also completely resolved with supportive measures. One patient just had NSAIDs Advil and improved. And another one required short course of steroids.

So, in terms of our work in progress and really applying the advanced imaging that is available to us now, we're really interested in looking at the power of not just tractography, but also fMRI. We know that patients that undergo for instance, a left MCA stroke and functional disability as a result of that, as their symptoms improve, there's an entire functional remapping of both the circuitry and the areas in the brain, for instance, that light up now when they start to walk again, or start to speak more appropriately once again.

And with that thought we wanted to obtain fMRI and tractography on our functional patients, and perhaps fuse them as illustrated here to really tried to elucidate the neural substrate mediating the different neuropsychiatric pathologies and functional disease. And this can also be used to predict responders and non-responders in the future. So if we get a baseline, we can try to determine what kind of fMRI and fMRI areas that light up on imaging may predict those that will respond to an intervention like thalamotomy, or capsulotomy, or whatever kind of ablation, depending on the treatment being studied.

We also want to look at the tractography and fMRI after intervention. Something that is really neat about doing this kind of imaging with radiosurgery as opposed to with DBS is that we don't suffer from the artifact that is produced by having electrodes or burr hole covers or other things that can create artifact in the brain. So, uniquely, we can really find how the circuitry as well as the functioning and active areas in the brain, how they are altered by our interventions.

So we are now using Brainlab Elements. This is actually depicted here in Eclipse. But in Brainlab Elements, we're able to look at the tractography and the DTI-based fiber tracking of the DRTT, which is implicated in tremor. And to do this, we were able to identify areas in the brain like the contralateral dentate nucleus, its lateral thalamus, its lateral red nucleus, and the precentral gyrus and exclude areas, like, the postcentral gyrus. And we set particular parameters to really distinguish the white matter tracks like these things like a depression and isotropy, the length of the fibers and the angle of the fibers to really try to pull out those fibers and pick them.

So this is just a fiber overlay on T1 MRI. And looking at Brainlab Elements, we can get really great pictures and imaging that we can then study better to elucidate the targets for not using the state and now to help predict future targets for patients. So, and just as a testament of the kind of things that we plan to do is looking at the necrotic lesions that we produce and also try to see if the tracks change and what happens to those tracks after lesioning within the draft tract itself. As final "Future Directions" slide here. So we're actually doing this not just for camera, this is a patient with OCD that we're treating with bilateral capsulotomy.

So in summary, frameless radiosurgery is an effective and safe treatment modality, aided by modern image guidance. In our experience, Brainlab's ExacTrac has been instrumental in being able to do this. It does not carry the risks of frame placement, surgery, or anesthesia, and is not limited by skull thickness like an MRI-guided focused ultrasound. May also have way less toxicity compared to MRI-focused ultrasound. And our current work applies DTI and fMRI, and will only further refine our ability to select the best responders and to enhance future target selection for tremor and other neuropsychiatric disease.

So I'd like to thank Vanderbilt's departments of radiation oncology neurology, and neurology, neurosurgery and neurology, psychiatry and the Imaging Institute. And special thanks to my mentors.

Bogdan: Thank you to our both presenters today, and perhaps we can answer some questions. If you have new questions, please send them to us via the chat line. But maybe Dr. Pouratian, let's address a little bit some of the related to the comments in the chat line regarding surgical interventions versus MRI [inaudible 01:04:04].

Dr. Pouratian: Yeah, so there was a comment about the role...Is the sound okay?

Bogdan: Yeah.

Dr. Pouratian: Okay. There's a question about the role of surgical thalamotomy. And I didn't include it in my original presentation. I think it is important to note that it is a great therapy. I think the choice of treatment really depends on multiple factors, as I included in my slide. I think surgical thalamotomy and MRI-guided focused ultrasound actually fall in very similar categories. They both are thalamotomy different ways of delivering them. They both have immediate responses. But there are patients who simply do not want to have an open procedure. And there is really no way to change these people's minds.

As someone who offers deep brain stimulation, surgical thalamotomy, focused ultrasound, and radiosurgery, we offer everything. There are a solid number of patients who will not have an open procedure, no matter what. They will say that their tremor is a chronic issue, and they don't need to have an open procedure. So, I think having these noninvasive procedures, I should say incisionless procedures rather than non-invasive because they are invasive in that we're targeting radiation deep inside the brain at a high dose. But having these incisionless procedures opens up the therapeutic options for a great number of patients. I can't tell you the number of people who come to us and only want the incisionless options.

So, to talk about the role of radiosurgical thalamotomy is not to discount, or to say that the other treatments are not valuable, and they're not effective. To talk about radiosurgical thalamotomy is to talk about the full armamentarium and treatment options that we have to offer our patients, and to really say that it is a safe treatment option and an effective treatment option. And if we wanna compare them, we really have to do head-to-head comparisons. And that's why I backed off on trying to compare complication rates between focused ultrasound or between radiosurgery or indeed we don't have head-to-head comparison, so to really compare them is not fair. I don't think.

Dr. Khattab: Yeah, I just wanted to add...Thank you Dr. Pouratian for those comments. And you know, certainly, I think it's very important for all patients to not just see a movement specialist, for instance, if they have tremor, but they have full consultations with the neurosurgeon with the radiation oncologist to discuss all the options that exists at the institution and in their area. And depending on who does MRI guided focused ultrasound that they should be able to look in as well, depending on the practice pattern in that area. But these are, as Dr. Pouratian mentioned, these are all treatment options. You know, patients come in with variable age, variable operative candidacy, and having this as a modality that is also evolving and becoming more and more accurate is just an additional tool that patients can count on.

I think there was a question about the edema that can develop after radiosurgery. And, certainly, this is a true concern. We had very few patients that developed any significant side effects. But yes, in our case where we are creating an ablative necrotic center there is surrounding edema that is produced. It is very rarely that patients are symptomatic from this. Any kind of intervention at all it will affect kind of nearby tissues. But as are the symmetry and whether it's you're using Gamma Knife, CyberKnife, or an arc-based radiosurgery ZAP-X is all of these things really develop and minimize the dose that gets that far to even cause inflammation or outside of the necrotic center. These are things that are happening. Our edema rates now are much lower than they used to be as radiosurgery itself evolves.

So, it's just something to keep in mind is that some of the quoted edema rates are not...are based on older techniques and much less steep isodose lines than what we have now. And so I think it's an important consideration, but not something that should preclude radiosurgery as a modality to be considered.

Bogdan: So, I have a question for both of you. It seems as we have polled the audience today that a good number of our customers would be interested in starting a radiosurgery program for more functional indications. What would be your advice, words of wisdom, to those that are considering expanding their radiosurgery program into functional space beyond traditional things, like essential, like, trigeminal neuralgia?

Dr. Khattab: I can try it first. So, I think there's multiple considerations. The first one we've already spoken about, but I think it's really important, which is that this can't be a program unto itself. You can't decide that you're gonna do radiosurgical thalamotomy as an independent department of radiation oncology. It needs to be part of a comprehensive program, because I think we owe it to our patients to discuss all the treatment options that are available to them. And so you need to, just as when I do psychiatric neurosurgery, I heavily depend on my psychiatrists. I think if you develop a radiosurgical thalamotomy program, you need to have neurology involved and neurosurgery involved to make sure that all aspects are evenly considered and you end up doing the right thing for patients.

The other component is I do think imaging is having outstanding imaging and reliability for imaging. Consistency of imaging is extremely important because the safety comes from that and knowing where your targeting is based on that. So, there needs to be a fair investment in optimizing the imaging protocols to ensure that the therapy is delivered in the right space. In our field of stereotactic and functional neurosurgery, location is everything, so it can't be done with...I don't think it can be done with standard imaging. And we heard Dr. Khattab also talked about using advanced imaging.

The last thing and I'm not as involved on it. Maybe Dr. Khattab can comment on a little bit more. But all the quality control that go on the radiation oncology side and ensuring the integrity of the system and making sure that the radiation is being delivered where it's intended to be delivered with all the monitoring of patient movement between arcs and everything else related to that. I'll turn it over to Dr. Khattab at this point.

Dr. Khattab: Yeah, thank you, Dr. Pouratian. Yeah, I completely agree with Dr. Pouratian, and I would add that, so, to begin having an amazing physics team is probably the most important thing. Because as clinicians, we, you know, I may work with Dr. Pouratian and Dr. Pouratian picks a target, I design the dose and we work very closely. But if we're not delivering the treatment that we intend to treat, it's none of that means anything for the patient and can cause harm. So we absolutely need to have the appropriate physics support, the appropriate maintenance of the machines, understanding of the technology that is being used. And just quality assurance is everything in radiation oncology, as it is in most medical specialties that are image guided especially.

I want to bring up an interesting point. Our, because we're talking about all the armamentarium. And I completely agree with Dr. Pouratian that you shouldn't just have a dedicated radiation oncologist that is prescribing this, everything has to be done in a multidisciplinary approach. And we found here in our own Vanderbilt experience, actually, that once we started doing radiosurgical thalamotomy, the referrals for DBS and for surgical thalamotomy, actually, referrals for that increased.

And we see this. This is not something unique to thalamotomy, or functional disorders at all and the treatment of functional disorders. We see that across all aspects of medicine. If you're an institution that offers multiple competing modalities and provide the best care and options for your patient, the referral pattern for all of the interventions will increase. So, it's very important to offer all these modalities. And I suspect that having SRS is one component will increase the referral for open procedures as well for the [inaudible 01:13:50] candidates and while maintaining, for instance, the less invasive procedures for the perfect candidates as well.

Bogdan: Maybe I'll ask you, your opinion as well about a more technical question as it relates to planning. Obviously, we focused today more on contouring a