Tractography Technology in Neurosurgery

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- Colleagues and friends, thank you for joining us for another session of Atlas Innovations from the neurosurgical Atlas. We have equate presentation today, really exciting and great discussion regarding the next generation of tractography for neurosurgical planning. And we have three guests. We really go in depth regarding this very exciting technology. So we have a number of new things to share with you, and I'm hoping that we can have all of you guys be with us for the rest of the presentation. I'm going to present our speakers today. Our first speaker is Donald Trendier. He's from King's college in London, very accomplished Mr. Physicist and extensive experience in probabilistic tractography and how we can use those applications in surgery our next speaker would be Christian Dick Quintana. He is from Sant Pau Barcelona. He is the director of neurosurgical oncology there, and he will share his experience in terms of intraoperative tractography and applications in neurosurgery. And last then, for sure, not least is Jeremy. Jeremy is an neurosurgeon at university of South Florida, and he is also very much involved in epilepsy surgery and movement disorders. And we'll review his experience and exciting upcoming technologies for tractography. Medtronic has been very kind as always to support this presentation and really present their very exciting technologies in this area. So with that in mind, I wanna ask Donald to please go ahead and thank you.

- Hello, So today I'm gonna talk about higher order analysis of diffusion MRI data. I'll start off with the usual disclaimer, and also state that I do some consulting work for Medtronic. So what is diffusion? First of all, it consists of the random, so many different motion of water molecules in our face. And it so happens that in MRI, we can prove distances of the order of five to 10 microns, which are very similar to the size of the cellular structures. And so we can use diffusion MRI to probe tissue micro structure. How does it work in general with diffusion MRI, we label the molecules by applying a field gradient along a particular direction, which labels them according to that position along that gradient. we allow the molecules to diffuse, and then we reverse the labeling operation by applying the opposite gradient essentially. And in samples where we have relatively low diffusion, the effect of the two labeling among the operations essentially cancels out, and we have relative preservation of the signal. Whereas in regions where we have high diffusion, then there's a large difference in the position of the molecules and so the labeling and non labeling operations don't cancel very well and we end up with relatively low signal. And we can see this quite readily in the brain. You can see, for example, in the ventricles that the attenuation is very rapid versus it's relatively slow in the parenchyma, as we increase the, the diffusion waiting, either the B valued. But perhaps more interestingly, the orientation dependence of the tissue is what we're gonna be looking at. And you can see, for example, in the spring, in the Corpus callosum here, that the signal changes quite radically, depending on the direction of the diffusion regions that we apply. And the reason for this is related to the microstructure of the tissue and white matter, which consists of density factor Axiom of fibers. And you can imagine that in this environment, one of my rituals will diffuse much more rapidly along the fibers and they do across them. So when we do an diffusion MRI experiment, we acquire lots of diffusion imaging volumes, each sensitized, to a different direction of diffusion. And if we focus on a particular region of the brain, for example, where the white matters are aligned, fibers are aligning on that direction. We can imagine that the signal would look something like that. So low signal when you measure it along the direction of fibers, but relatively high. And when we measure it perpendicular to the fiber direction and the model that was originally proposed to model, this is a diffusion sensor model leading to DTI, Diffusion Tensor Imaging, which can actualize a diffusion by this characteristic ellipsoid. And you can see that the direction of the major axis of the diffusion flip-side is a good representation of the fiber orientations. And so arms with a fiber orientations, which we've now were submitted in every voxel in the main, we can then essentially join the dots to do fiber tracking, also known as tractography to establish how different parts of the brain are connected to each other. So that's stratigraphy in a nutshell, and we can use that to delineate very important, white matter structures, such as for example, here, the Perisylvian language network, nice study done by Margaret Brittani and Derek Jones. We can also display the anisotropy map which consists basically, of measure for non spherical and where it fits perfectly. It's focused. We get anisotropy zero where it's very long, it's high on massage therapy And we can also calculate this by direction to depict the orientation of the white matter of fibers of that location. But we can already see a little problem , in this image here. For example, if I look at certain regions of the white matter, for example, at this position here, you can see that there is a drop in anisotropy, which where the white matter signal itself is relatively uniform. There's nothing specifically worrying there. And when we look at the direction you go in map we can see that this coincides with an area where there is a difference in orientation. So an interface between two different orientations and this is what gives rise to the drop in. So if we look at the situation where we have a nice single orientation, everything works fine, but as soon as we have crossing fibers, then the ellipsoid that we get has a different shape. It's no longer nice and elongated. In that sense, it's an oblate tensor where the direction doesn't really reflect the inner of the two, five orientations present and also its shape Is on such a views obviously affected. And so for this reason, we need to start thinking about moving away from DTI, and we can see this quite readily in the brain. For example, here's a region of the brain here where there's very nice high anisotropy in directly below that is a region with very low anisotropy and another region that further down with very high anisotropy again and these are all perfectly normal, healthy, what matter regions and all that's happening is that the orientations of the white matter fibers at that location are nice and from here to the cases, but there was a lot of crossings in the other case, and this is actually quite a widespread problem. When we did a study a while back where we try to figure out how much of the brain was affected and the, basically the red voxels, we were pretty sure there's only one five orientation, but everywhere else, we can at least quite a lot bit detect at least two or more and take a message here is about 90% of what might've voxel seem to contain at least to find the orientations. So what can we do about this? Well, the kind of more advanced techniques now rely on high angular resolution, diffusion, imaging, or Hardy, where we just sample more directions over the sphere and typically use a slightly larger B value. And the idea is to characterize these kind of funny structures in the signal,which contained this orientation structure. Once we have this, we can then use techniques such as very cool deconvolution, which is basically saying ,if we know what the signal looks like for one fiber orientation, then we know what fiber orientations are present, then we can predict the signal, which is on the right. So what we want to do is measure the signal of what we do, and then we can perform the reverse operation, which is historical deconvolution to estimate what we want, which is a fiber orientation distribution. That'sthe information that tells us how many fibers will, how much of the voxel is aligned in one direction or another. And that's just very nice results. So here's an example in a coronal section and essential in semia alley where we can see the current critical fibers coming in from the left, joining the central semia valley, which is got a lot of crossings. And we're looking here at the division, tensor, it's quite difficult to make out what's going on, but as soon as I processed exactly the same data using deconvolution, we can now make out a lot more structure here. We can visually almost trace these fibers structures as they kind of got across. You can see the crystal fibers or fibers coming right that whole region and cutting through the Corona radiata and the SLF. And this can be used then to do tractography. So here's an example of tractography is in that kind of five orientation estimation technique. And we can see lots of structures in that, but we have another problem on top of that, which is that we have noise and other sources of certainty in the data. So that means that if I acquire data set on a particular subject, one day, I might do my streamline tractography and get this result. But on the next day, because of noise, because of other factors, it might go off slightly sideways, or it might go off the other way. And you can see that quite rapidly. We can get big divergences over the course of a few voxels. And obviously as soon as the string mind ventures a little bit sideways into a different structure altogether, then we end up identifying completely erroneous connections. So there's a lot of sources of uncertainty, not just imaging noise. The other one that we have is the fact that axons are not straight. They're not characterized by nice single orientation. There's a lot of spread and light dispersion and curvature and all sorts of other things going on, which make it very difficult to be sure as to exactly where these streamlines should be doing. So the one way to address this is to use probabilistic tractography. So deterministic tractography, we start from a given location and we just follow that best estimate that we have it's probabilistic. We do this thousands of times, but every time we try and sample from the distribution of likely orientations at every, at every point. And what we ended up with is a more distributed depiction of the areas that are likely to be connected to this original point. And this depiction of uncertainty is quite important because now we can see that there are the locations that these Eastern lands can be going, as well, as the one that was pulled out the first time. So just to look at what these looked like in a bit more detail, this is deterministic 10 searcher topography. So that's what we will currently have on the current generation of systems. And you can see there's lots of connections here that just don't make a huge amount of sense. And we certainly don't get these commissural projections of the Corpus callosum for example. If we switched to vocal the convolution, we can now see that we are able to depict a lot more of these lateral projections of the Corpus callosum. And if this is still deterministic chatter, if I now switch to probabilistic tractography, I'm getting slightly more, you know, that a depiction of the uncertainty as well as everything else. And so many of these, yes, I showed you this earlier. We can convict some the anatomy quite nicely. So here's coronal cut through a healthy brain, and you can see lots of, one of the instructors here in producing Corpus callosum for next. And what is what attracts terms of pontoon fibers. He is also a, an actual projection here through the brain. Again, lots of interesting structures, and here's a sagittal projection through the accurate, and obviously we want to use these in surgery, So here's an example that was done, a study that was done a few years ago, this is using the deterministic DTI tractography implementations that you would currently have access to on the current generation of systems. If we add a probabilistic element to the DTI, it kind of does a little bit better, but we still essentially get the same results, especially on good data. When we switch on to constraints, faculty convolution in this case and probabilistic tractography, we can now recover a lot more of these lateral projections in this example, which is the motor attracts. We expect to see a lot of the motor homonculus the recovered here. And that obviously makes quite a difference in surgery is a simple example here, but we have a lesion just below the hand motor regions. So this is a hand if MRI activation and you can see what tends to attract tography. We just about managed to get a few stream as they get close to the, to the activation region. Whereas if we use very called deconvolution, we get quite a different depiction of, of that connection and of note, that connection does go through the region that would've otherwise been a candidate for, for a section here. So just a recap, to do tractography well, we need three essential steps when it to get your data, this essential step, and then get the right fiber orientation, Mr. Motions, and then use a good string. Nice tractography algorithm is preferably probabilistic to account for all the uncertainty. So each of these steps needs to be reliable. Thank you.

- Donald. Thank you again, this, that was very illuminating. The technology is very interesting and often very elusive to the neurosurgeons. Our next speaker is Dr. Christian de cantana, he's from Barcelona and he will discuss his personal experience with the use of tractography in neuro-oncology. Christian.

- Thank you for being with us and are very much interested in learning from you. Please go ahead.

- Okay. First of all, thank you for the opportunity to share or speak in tractography as specific in neuro-oncology first of all in disclaimer. Okay. We are going to, to answer the question. Why is important? Why is tractography so important in neuro-oncology? And here is a beautiful article about the one of the most important tumors in neuro-oncology and the association of the stairs or section we survivor. So as you can see here in the Baton, our gross total resection is better in the survivor than the resection. Even if you do a subtotal, resection is better. On the same lines. We have this another nice article about this case. Low-grade glioma another important two more in neuro-oncology and they compare biopsy gross, total resection in an indifferent items like survival, seizure-free mortality or malignant transformation. And once I in a gross total resection is better than sub total resection of an extent. And this is better than the myopsi, However, we need to keep in mind when there is a new permanent deficit in this kind of patients, there is a negative impact in this, on the survivor. So once again it's a balance between external resection with all new permanent deficit. So why is tractor official important? We already know the majority of lesions area. So the majority of new impairment and deficits is cortical areas. So when we see the different probiotic status, we can see different options in the cortical area like full Shaun MRI, TRANSCOM. I might think of stimulation or rates, but we only have one option in the area. We only have the trophy as the reason because it's so important in neuro-oncology navigate or plus a DTI is an important tool to plan this area. I always say to my residents, all patients deserve that you spend your time, the, of hazard to try to avoid surprises in surgery, especially in this kind of patients in our wake patients, eh, we factor Murphy with a good clarification. You can save time. And this is very important because in this patients more time awake means the patient is more tired. He can go back to his life along the same lines. We have this article. How about interpretive use some benefits of patients in total 66 patients 19, we had the technology, we had tractography and 17 we didn't, we always do the same technique. This is a three-step flood technique athlete, our car sleep. We calculate the awake time with tractography awake time was 93.6 minutes. And we thought that more or less 120 minutes. So with tractography shorter than they are this time by 26.1 minutes. So is another benefit of topography and these kind of patients, then that trophies as use useful technique, but it's easy to do it. The answer is absolutely yes. We only need to keep in mind two concepts, the deck, the, the exam they call it costs. And the Roy, the region of interest, the deck is a very easy step to do it. There are different programs, but not to spend more than by minutes to do it. And the other important thing is the Roy, you draw a box and the program will allow the fibers cross through the, through the box. Here, we are going to see the most important tracks in neuro-oncology classify and the level of difficulty. So engrain is a very easy tracks in, in general, it's a normal, difficult tasks. And in red is a hard, difficult tasks. The motor pathway, you can choose internal capsule or Blanca, or even both. It's very easy to recreate the Infor front of. I like to use two Royce, one in external capsule, very specific in external capsule. Another one in the occipital lobe, more or less 15 is lies. The infant reminds you that our first seekers, they have two general Roy's because it's temporal law, the anthropology and the occipital lobe. This is not difficult to recreate. You only need to keep in mind. They are very close to the iPhone. So it's very easy to contaminate fiber from each other. The frontal attack, there is a connection about supplementary mortor area and the inferior fronto fasciculus. So they're always are in these two areas. Classica. There is the Royce, they broca region and the region. We are going to see 1, 3, 2 to do this fast, easy to recreate. And the last one is the B-cell pathway. Another difficult fastball because they along, especially mayor loop and the classical Royce are in the optic track. And we are going to see two tricks to easier this process to recreate this hospital. Here's the typical limits of a, the Royce of Aquafest equals one in the broker guests, when I'm burning vision. Usually you do when you put these Roy's nothing appears because a, there are two superfoods. So here is the trick. The trick is go to a coronal plane. The Fitzroy is very specific. This typical triangle green shape, because this is, this is the area of their equate, and this is the deep part or the. We are going to see that with a video. So once I gain the Fitzroy is very specific in this area. Remember this, the triangle shape in green is game because the external, the fibers and this not necessarily a big right here, very specific, we are going to do another two in the guests are in region. As you can see here, particular, the color is in purple because the orientation of the fibers you bet, and the other Roy is here in region. Usually in, in green color, you can adapt this to Royce because you are very specific in the phase one. So you can do these two Royce vigor and we can compute is always arrived. There is here. We can see the quite fast equals the members, this fist specific Roy, because he's the key to recreate. We can go to the, to the slice. There's an example of. This is 41 years old man, with Caesars. These are low-grade gliomain the parietal lobe, this the segmentation of the lesion, the contact, but nothing feels right in that case. They're quite Fastly crews. This, I interpret this picture. As you can see in around the T is the tumor and the other parts of the tumors. Very important for language. We are very lucky here in Katherine, because almost all the patients minimum to speak two language in that case, Spanish and Catalan, and here is the post-operative MRI with a complete resection, because the two more don't infiltrate the great festivals. Here, We are going to see the same, but in the visual pathway, the Fitzroy is saying in the optic track, typical, this color is in general because the orientation of the fibers is not green is not right, is in the middle. So the color is, is in yellow, and you can put another look use. I like to put a little bit medial and posterior to see all the track here is one six, not put all the three Royce at the same time, put the first and the second one and after that the second one, I see one, and you can recreate all the pathway. As you can see here is very common. You lose the mayor loop and you lose the, a loop, and we can fix a two ways. One way is that atomic way, that that atomic way is when you recreate the iPhone. If you're a front occipital, first, the cruise, we know that the iPhone is always lateral for the optic radiation. So if you're okay, this festival is very easy to recreate. If you don't go deep of this fast, you don't touch the, the optic variation. Another way to, to fix this problem is, eh, do a probabilistic analysis because it's better with when you have a high angulation of fibers or cross fibers. So we can go back to those lines. Here's another example, this 57 year old man with headaches and Caesar, the person went to emergency with hydrocephalus. My colleagues and here is vision. We, we saw the, the resource pathway was below or the lesion. And here the was in the anthro part of the lesion. So we decided, I know there is different ways to go to the Calamos, but here we decided we suck trophy, go in passcode, pecan transplants, call our approach with our computer center, a MRI after 24 hours of operation. So we need to know the limitation of a neuro-oncologist is important on that too quickly because the virus can be deviated for the tumor can be infiltrated or destroyed or faded, eh, by edema is a rule just because you can see the fibers does not means they are not there one way to minimize or avoid this limitation is use a probalistic tractography. So in conclusion factor is an important tool in Susie. Come planning. It's a time very important now with patients and it is easy to, to perform, but we must know the limitations, especially in oncology. One of solution of that limitation is the probalistic tractography. Thank you for your attention.

- Christian, thank you for your gait lecture. Really enjoyed it. So before we go further, I want to ask a question that's very much a burning going from me, and I'm sure the audience and Donald, if may, please, Amy, that shoe and the in terms of clinical applications and physics of it, what's the difference between what we have now. And what's the next generation of what you guys are talking about. If you could please clarify that out, be appreciative.

- Yeah. Sure. So just in simple terms, we're trying to talk with you. You, there's two bits that we need to get. One is to estimate the orientations of the white matter, where, where they are in each box. And the second one is how to propagate that information through the data to then establish how the white matter, the path of the white matter tracks basically, and the traditional system currently rely on DTI. So the diffusion tensor model to estimate the orientations and deterministic streamlines algorithm, like fact is the original one to delineate these orientations and establish the connections. Well be talking about in the next generation is to, is changing both aspects of the fiber orientations. We can use something like spoke with the convolution to estimate orientations more reliably, especially when there are crossing fibers and for the propagation a bit, when we delineate these pathways, we use probabilistic algorithms that also give you a sense of, you know, well, the whole range of latency connections, rather than just the kind of best guess that you might get with the deterministic approaches. So there's two parts and both parts of changing is that.

- Yeah, it does. And I think for all our clinicians and surgeons, the biggest question is how does all that new information relate to what we find in the operating room? And in other words, the post operative outcome of a patient. And I think that really jumps into the lecture Jeremy's planning to give us. So Jeremy, if you would like to go ahead and come in and start your lecture. I sincerely appreciate.

- Yeah, sure. I think that's obviously the question that surgeons are looking for. And I'm going to talk a little bit about, you know, it's not gonna be the focus of my talk, but I'm going to talk a little bit about how other studies have compared deterministic and probabilistic cartography, and in terms of what they find relative to some of the tracks that we're interested in epilepsy and movement disorders, for instance. Okay. So again, thank you very much for giving me the opportunity to speak with you all today as the standard disclaimer, and just my disclosures. And so really what we're talking about when we apply tractography in the operating room is avoidance of the neurological and cognitive deficits by avoiding eloquent structures, including eloquent fiber tracks, and sort of as a reimagining of the idea of eloquence in the brain and optimizing surgical outcomes, potentially disconnecting, or even modulating pathological networks, I'm gonna start with epilepsy. So this is an example of an anatomic dissection in Canada, Erik specimen, within the temporal lobe, the temporal lobe is a common target for neurosurgical interventions and epilepsy because temple of epilepsy is the most common type of partial epilepsy. And it's often refractory to the anti-seizure medications. So some of the unique aspects of the temporal lobar that it has folded genetically older structures, including ARCA cortex and the hippocampus. It's a big alum as well as Petrarch is cortex and the adrenal cortex. And then there are many tracks which pass through this structure, including the superior, or at least the inferior part of the superior longitudinal fasciculus, the middle longitudinal for cyclists inferior along the tunnel to take that on Senate for cyclists in fear of enter your commissure and then several projection fibers, which pass through the thalamus into the temporal lobe and beyond this is some work that's been done by Dr. Schuh group, looking at conductivity of the different pathways that are in the temporal lobe, which can give us a sense together with stimulation studies and in studies in patients that have damage to these fibers as to what these fibers do, the projects from the anterior temporal pole and amygdala to the lateral aspect of the orbit or frontal gyrus, and then for your frontal lobe. And it's thought to be involved in socio physiological limbic and cognitive functions, including impulse decision making, emotional understanding and regulation, semantic memory retrieval and language processing. The SLF is the largest and most complex of the long range fiber rentals in the brain. And it connects the peri Sylvia and frontal pridal and posterior temporal regions, as well as the occipital lobe. And as I mentioned before, I'm a part of this passage through the temporal lobe. So it's two is in play in surgeries in the temporal lobe. The middle longitudinal fasciculus is poorly understood, but it connects the superior temporal gyrus and superior temporal sulcus with a visual cortical regions. And it's presumed to play a role in language function, particularly semantic processing. And it's thought to be a component of the ventral stream of language processing, which is the more semantic element of language processing, as opposed to the phonetic processing that occurs in the dorsal stream, the inferior frontal occipital stimulus connects regions involved in visible visual processing in the Knesset lingual gyrus with the secure private labial and the inferior frontal lobe along the upper color GRI. And it's also involved in semantic speech processing. And then there's the inferior longitudinal for which connects to the posterior fusiform gyrus and visual processing areas of the occipital lobe to the anterior temporal region, including the Paralympic temple gyrus and damage to the inferior. How long to tune off the stimulus causes deficits in odd object recognition and electrical stimulation, and probably results in impaired optic recognition and reading ability. And so, again, all of these structures are in play. When we're talking about surgery to the temporal lobe, with tractography, we're able to visualize these structures. And so that gives us the opportunity of potentially avoiding these or targeting them as the case may be. If we're trying to disconnect a particular pathway, this is a comparison of surgical implications of different types of interventions for mesial temporal of epilepsy. One of the more common surgeries in patients with temporal lobe epilepsy is a surgical resection of the mesial temporal structures, the hippocampus and the amygdala. And there's different ways of trying to get at those structures. If the secondary goal of the surgery is to preserve other pathways, there's the lateral surgical approach, typically going through the cortex, either through the superior or middle temporal gyrus to the temporal horn, and then from there to the hippocampus. And he made me love, you can also approach those structures through an inferior temporal approach, either, either under the other subtemporal or through the inferior temporal gyrus, or you can approach it via transsylvian approach as described by Dr. Gasser Gill, which is performed by splitting the Sylvian fissure followed by our record academy and the medial part of the superior temporal gyrus at the level of alumina insula, and the table here demonstrates that there are pathways that can be disrupted via each of these techniques. And so, again, depending on what the goal of surgery is, this information can be important in surgical planning, optic radiations are probably the most commonly studied fibers in the temporal lobe, as it relates to surgical outcomes in epilepsy. The reason being is that there is a very clear anatomical organization of the optic radiations. The optic regulation at Raven radiations can be divided into several components. There's fibers that convey input from the peripheral upper visual field. And these are the most anterior fibers in Myers loop, which is demonstrated in the bottom kind of their sections. And it's the part of the optic radiations that runs anteriorly in the temporal lobe. So if you look at table number three, there's a number of studies that have been done and categoric specimens, trying to assess the distance that the anterior portion of that Mars loop is from the temporal pole and overall data from these four studies is relatively can coordinate that or about 26 millimeters with a range of approximately 15 to 37 or so. Table two is a study that was done comparing the, the anterior extend of Myers loop based on different tractography stratigraphic techniques. So with the deterministic tractography that's DTG in this table, the mean distance from the temporal pole was 44 millimeters. And then the other rows in this table are probabilistic tractography with different thresholds. And what you can see with this in this table is that probabilistic tractography at a threshold of less than or equal to 1% is most consistent with the studies that were done in categoric. C-sections, that's what this slide highlights is that you can certainly be lulled into a state of complacency. If your attract tography is demonstrating that fibers don't pass where you're going to operate. And so it's very important to validate with studies such as this, the degree to which your tracker graphic findings correlate with anatomic resections and what you find in profitably surgical implications. This is work that was done retrospectively to assess the utility of a tractography to predict and hopefully prevent visual field defects and operative patients. This is work from Dr Duncan's group. And what it demonstrates is the utility of a probabilistic tractography and predicting visual field defects in 20 patients undergoing anterior temporal lobectomy, 12 of whom suffered postoperative visual field defects. When the DTI was registered to a postoperative scans, it showed that the resection margin was, was anterior or sorry. The, the resection margin was anterior to the Myers loop and these patients, whereas it was sorry. It was enter to the Myers look, patients who did not sustain a visual field defect. Whereas the resection margin was behind the anterior extent of Myers loop. And those patients who did sustain a visual field defect and that when they modeled the, the predict damage to Myers loop, they found that it was significantly correlated to the degree of visual field defects, such that for each additional one millimeter of damage to Myers loop, a further 5% of vision in the upper quadrant was lost. So how can you integrate this in open surgery? This is again, a information study from Dr. John Duncan's group and Dr. where they looked at patients who were undergoing enter your temporal lobectomy for a musical temporal of epilepsy. And here a preoperative three Tesla DTI was overlaid on the surgical field using a microscope link to the neuro navigation system. And they found that with this technique, they were able to avoid clinically significant injury to a visual, the visual fields in all at one patient. And when they looked retrospectively at that patient, they found that the resection actually did not injure the optic radiations, but instead it was due to placement of the retractor. And so they then use this to prospectively guide, not only resection, but also placement of retractors in open surgeries. And then I also want to comment on its use in disconnection surgery, specifically Corpus callosotomy Corpus callosotomy is a procedure that's done in an effort to prevent secondary generalization of seizures, and also to prevent drop attacks in particular, by dividing the Corpus callosum. And so you can use tractography to assess the degree of disconnection that you've done in surgery, or potentially even to predict the type of surgical disconnection that you're going to get with a planned surgery, either open surgery or even laser Corpus callosotomy. I did a study with Dr. Vicario, where we compared computer assisted planning for laser Corpus callosotomy with manual planning. And we used probabilistic tractography to estimate the residual interhemispheric connectivity for a given resection. So this is a useful tool in, in planning these types of surgeries as well. Despite many years of research, the precise mechanism of deep brain stimulation has, is poorly understood, but it's increasingly understood that deep brain stimulation does not simply recapitulate a lesion in the brain. Lots of work has been done by people such as Dr. Kevin McIntyre, Chris Butson and Warren grill, who have tried to model what electrical stimulation does in the brain. And so this is an example from their work where they created a model of the film, a cortical relay neuron, and describe what would happen to this model. If you applied extracellular potentials, including high-frequency deep brain stimulation. And what they found is that extracellular high-frequency stimulation results in independent firing of the cell body and the axon of that neuron, the axon was able to respond one-to-one with the stimulation frequency while the cell body was really unable to follow with high-frequency stimulation. And so it's in terms of, of what we surmise the effects of DBS might be it's, it's going to have effects on the, on the XML elements that are around the nucleus, where the stimulator was applied, but it's also potentially going to have effects on the fibers of passage that surround those nuclei. And so that's increasingly a target of study in deep brain stimulation. There are a number of relevant tracks in and around the nuclei that are typically stimulated in DBS for patients with essential tremor or where the traditional target is the ventral intermediate nucleus of the thalamus. There's the dental entire rubric thalamic track, which links surveil reference with white matter tracts is sending from the thalamus to the motor cortex, premotor cortex and supplementary motor area where they regulate find movement that track passes through these on Serta and the posterior subthalamic area, which are also targets for patients with tremor. The STN is a complex structure, and there is the hyper direct pathway, which is comprised of motor and premotor cortical fibers that travel through the internal capsule and directly enervate the STN. And then there is the secularists siblings subthalamic us and the ANSYS applying with us, which are bi-directional pathways from the STN to the pallet on, in terms of the GPI. There is the outflow pathway of the GPI, the particulars Len take Alaris and the and, and these basically are palatal thalamic projection fibers. And then of course, there's the enter limb of the internal capsule, which carries slamming and bring some fibers from prefrontal cortical regions that are associated with different aspects of emotion, motivation, cognitive processing. Decision-making. This is a study that was done by Dr. Conan at the university of Freiburg and others, where they perform DBS, specifically targeting the dentata Roberta thalamic tract, and a prospective trial of 11 patients with tremors of varying ideologies. And they found that nine months postoperatively at a mean of nine months, postoperatively tremor was reduced in all patients by approximately 70% with effective contact slows that catered insight, or in close proximity to the entire root prophylactic tract and less effective contacts being outside and more anterior to that track. And they actually have an ongoing trial comparing in a randomized fashion, more traditional microelectrode based as surgical targeting of the VIM as compared to a DTI based targeting and asleep patients of the fentanyl Rupert thalamic tract, Dr. Ellis island colleagues did a different technique of localizing the VAM, where they used tractography to identify the pyramidal tract and the medial Lummis, and then identified an imaging based or direct target using those pathways as a guide. And then in a subsequent study, they can, they compare their findings on microelectrode recordings, target versus those which might be identified in the standard VAM. And they found that there was a strong correlation. Essentially those trajectories were very similar in terms of the types of neurons they identified. And they, and it has been shown that from a reduction is indeed observed within the, the RTT when they applied stimulation in profitably with respect to the some Flon of a nucleus. This is an interesting study where Dr. working out of the grid and then subsequently out of Vancouver with Dr. Chris honey modeled the, or used tractography to segment the subthalamic nucleus into four regions based on its connectivity with, with different structures in correlated, the volume of tissue activation of DBS electrodes located in the subthalamic nucleus with improvement in different aspects of, of Parkinson's disease, be it radically easier virginity, tremor and reduction in dopaminergic medications. And then what they found is that stimulation of the, of the motor component of the STN. So the segments of the STN projecting to the supplementary primary motor areas was significantly correlated with improvement in bradykinesia. Whereas stimulation of that portion of the STN projecting to the supplementary motor area was more correlated and sorry. And that was more correlated with leads that were located or volume of tissue activation that was located in that portion of the STN projecting to the supplementary motor area stimulation of the non-motor STN was negatively correlated with improvement in rigidity, in a subsequent study, they then looked at using tractography to model the Negro fugal and palak fugal pathways. And then the overlap volume of tissue activation of VBS leads with those structures to, again, correlate improvement in specific symptoms. And they found that rigidity and tremor improvement was correlated with volume of tissue activation dorsal, and actually outside of the STN preferentially involving the palliate of fugal pathways. There was another cluster predictive of Braddock naseum improvement that was located in the central part of the STN. And then the, there was a cluster that was separately predictive of dopaminergic medication reduction, which was ventrolateral and cartel to the STN preferentially involving the Negro fecal pathways. Again, suggesting that it's not just within the nucleus, that these leads are having their effect, but also in that they're modulating the fiber pathways that are around those structures. This is an assessment of using deterministic tractography through stealth is in 11 patients to model the hyper direct pathway. And in this study, the authors divided patients into two groups, one of one group of which demonstrated a greater than 50% improvement in symptoms and the other group, which manifested less than 50% improvement in symptoms. And they found that the shortest distance correlated with greater improvement or the shortest distance from the leads to the hyper direct pathway correlated with greater improvement. And then this slide is a comparison of probabilistic and deterministic tractography to localize the sensory motor component of GPI. And why I wanted to point out here is that there's a difference in where the sensorimotor portion of the GPI is located. And depending on which of these techniques that you use with probabilistic, tractography preferentially, being locating that region in the posterolateral aspect of the STL of the GPI, whereas deterministic tractography tended to position this much more anteriorly. So in summary, the use of tractography in surgical interventions for epilepsy and movement disorders is a rapidly developing field, which will benefit from some of these more advanced techniques in photography, but as always, it's important to validate these techniques and our patients for subjecting them to, to their use in routine clinical practice.

- Christian. One of the questions I've always had is does tractography improve the extent of resection that's number one? I don't think we have prospective data. Number two, does it correlate with outcome or length of survival? If you could answer that? I will be very appreciative.

- This is a very good question, because there are different articles to try to compare the cell section or atrophy or experiences the type of it can, can you predict if you are going to do our complete or not complete resection, this is not different between the Excel resection because the server section the most important is the intraoperative neurophysiology, then supply field mapping. So these are the gold standard. So it's a trophy, it's a orientation, but it's not allow the Lao is the interpretive neurophysiology.

- And if I may ask Christian, have you found anything different based on track Trello attract photography gives you pre-operatively and interoperative mapping. Are there any cases that specifically the surgeon has to be careful and feel that maybe the tractography is not accurate as it always is?

- That is a really important, important point because the interpretation of your neurophysiologist is not only the gold standard permit to us to, to calculate your accuracy with tractography because it's true. Sometimes it's not a competer proxy between both and the most important track or easier track to study as the motor pathway, because you can calculate the distance with monopolar motor mapping. And there is quite a strong correlation. If you do a good factor Raphy between the brain mapping and the, and the third sort of you.

- Okay. So in other words, you don't find any cases, particularly where the concordance between the preoperative tractography and intraoperative neurophysiological findings is in any way affected.

- Yeah, so sometimes you can have doubts because like I said, there's some things there, two more, this edema around the tumor or the filtration on the two more effective tractography. So sometimes that is a reason because the most important is the remapping now, because sometimes they accuracy go down, especially when, when we have these kinds of effects.

- If I may ask from Jeremy and Christian and Donald, any of you guys, the really the most important question is how does tractography change operative planning the approach to dissection? Obviously you want to protect these tracks for sure. So how are the strategies where we can use tractography effectively to improve the outcome of the patient? Please go ahead, Christian.

- I think the trough is a very important tool for planning because you can plan the approach. You can anticipate what full circle binders are around of the tumor. Like I said, after that, the most important is the interpretive neurophysiology part is very important for planning the approach. And in, in, especially in, for example, in our week patients, you shorten the time of the surgery. That is a good point is useful, the tractography and in the preoperative planning.

- Okay. Jeremy, do you have any other thoughts about the importance of tractography for pre-surgical planning?

- Yeah. Yeah. I showed a couple of publications where cryptography has already been used to help guide surgery in the temporal lobe, both in terms of choosing how to get to the musical temporal structures and also in terms of how to use it in profitably to avoid visual field defects. And then there is emerging evidence that we can use it to help further guide our replacement of our DBS electrodes in functional neurosurgery, both in established indications and also a newer indications. The key though is having tractography that's reliable and validated. And that's where this newer approach where these newer approaches I think are going to be incredibly helpful.

- Donald, any thoughts from you?

- Well, I not being a neurosurgeon, I don't really feel qualified to answer this question, but all I can say is I've certainly seen examples where, where the tractography, the direction of the presurgical approach just by, especially in, in, when you have a massive fact, and it's not quite clear, which way the track that you're trying to preserve is going around that tumor. It's quite important to have a good idea of if there's going posterior, you go interior basically. And I've seen other examples where it's changed the strategy altogether from a surgical approach to one of, of much more aggressive chemotherapy first before, before doing for surgical resection, because you know that the track was infiltrating the tumor. So I think there's a lot of scope for tractography in these cases. And I completely want to echo Jeremy's point here. These techniques need to be reliable. They need to be validated. And I would also echo Christian's point here that, you know, the gold standard remains the interim operative and mapping. Absolutely not panacea. Yup.

- Yeah. Very well said. I think that the greatest things tried offering this for me, which you summarized Donald, is that number one are the tracks infiltrated. In that case, it becomes a biopsy procedure or soft total resection thing. That's really important for gliomas into per central and areas the per annum and corner radiata. So that's the part that's important. Number two was low grade gliomas where you want to be as aggressive. You want to know, where are the tracks? Are they anterior? Are they medial? Are you slightly posterior? How are they dispersed? I think that's a valuable data from tractography. And if anybody wants to do gross trove, section of low grade gliomas in these areas really attract tractography is indispensable. You really need to have it. It's a critical tool. So I'm excited to see the new technology that with, with a tractography you guys are talking about. I'm sure it will be a nice addition and for the intra-operative armamentarium of the neurosurgeon. So thanks to all of you guys for your excellent presentation. Thank you for being with us.

- Thank you.

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