All right, thank you very much for the opportunity to present here, and this is now, I think, 25 years today that Mitch Berger was convincing me when I was still at the NIH to start mapping patients. So we are here today, 1,200 cases later, and I do owe this to you, not as elaborate as one of the previous speakers, but with the same meaning at heart. And what I've decided to talk to you about is how we do things, but for somewhat different looking at techniques and limitations of mapping cognitive functions of patients. Unlike France, where Hubert Defoe's patients wanted to continue to drive, Israeli patients want to do everything. Actually, they asked me, will they be able to play the piano after surgery, and I say sure, because they say wonderful, because they could not play the piano before. So they have a lot of expectations for these functions. Some very general concepts that I'll fly through, because they've been discussed previously. Patient selection is critical. Patients with limited cooperation cannot be operated awake. So our patients who have limited ability to speak or comprehend and patients with respiratory problems, and I'll show you later some work that we've done that shows that even suitable patients have decrement in their language functions after surgery. We do very elaborate baseline evaluations, speech evaluation, neuropsychological evaluation. It takes about two hours periods with a neuropsychologist. We do evaluation of their emotional status, and we give all our patients anticonvulsants regardless of their seizure history. Interoperatively, we use very minimal doses of midazolam and remifentanil when entering the operating room, then attach the electrodes for MEP and VEP recordings, and we do nerve blocks. During surgery, we do them awake the entire procedure, although I like the term that our Chinese colleagues had. It's sedation, awake sedation. We do not use laryngeal mask routinely. I think we've only used it once or twice in our series of over 1,000 patients. We stop all sedatives and analgesics after a while because we want to do a second neuropsychological evaluation as a baseline in the operating room just before we start the operation. 1,000 patients receive spontaneous respiration monitored by capnography and receive oxygen of three liters per minute through a nasal cannula during surgery. Light sedation is achieved interoperatively only if needed, and that's the minority of the patients. For cortical mapping and recording, we routinely use a cortical strip electrode. We did not do this several years ago, and actually Mitch was reprimanding me over time that we must do that to look at after discharge potentials. We are convinced now we need to do that after a case a few years ago that a patient became completely aphasic during surgery, probably due to seizures, and we could not detect that then. We had to abort the procedure, and the patient then went to UCSF to have surgery by Mitch Berger, and we said never again. So we're using those cortical strip electrodes in every patient looking at ECOG of these patients using Dogeman stimulation that initially we were doing up to 10 milliamps. Now we're limited to 4 milliamps in an attempt to reduce the incidence of seizures. We did have quite high incidence of seizures initially. Even when we go down to 4 milliamps for stimulation, we occasionally do get a seizure. Having the ECOG, the cortical strip electrode, is a nice thing because sometimes you can abrogate seizures before they become clinically apparent when you see spikes on your ECOG monitoring. In extremely rare cases, we need to revert the anesthesia to adrenal anesthesia from awake patients. Now let's go now to the major topic of the presentation, which is the cognitive function, and I'm not going to talk much about it, but cognitive function is a very significant predictor of survival, probably even accepted by the FDA as an endpoint in many of the studies done for various treatments of brain tumors. There are endless cognitive functions that you can talk about, and actually that's what they make us human beings, those cognitive functions that are sometimes very difficult even to define. Of course, different professions have mandatory cognitive functions, which may differ from one patient to another. So this brings about the concept of the personalized functioning mapping, where you need to look at tasks that are important to the patient and understand with them that you're going to put most of the emphasis into these tasks. And it also represents the fact that many of the cognitive functions are network-related, so we'll discuss later some of the issues related to how you map networks, especially with these cognitive functions. We'll start with the model function, of course, there's the basic model function that you've heard before, but there are also some secondary motor areas and more complex model functions that need to be monitored. Patients receive electrodes in the contralateral side of the body, cortical strip electrode routinely used in each one of the patients. And this publication that we published several years ago actually gave us a basis on how to do model function, especially in the subcortical region, because it documented this linear correlation between the threshold of stimulation and the distance to the cortical spinal tract, which was practically linear, one milliamp to one millimeter distance from the cortical spinal tract. And by doing this, we can then use subcortical mapping to assess the distance that we are from the cortical spinal tract. By being in ADHD, as some of us are, we got sort of sick of looking and monitoring and mapping every few millimeters the cavity of the patient. So we have developed this subcortical stimulation using a Dacusa tip. It's an adaptation that we have attached to the Dacusa tip, the stimulator from the electrophysiologist. And this thing allows you to use it, allows you to use it both for, there's no sound, okay, both for model monitoring but also for language functions continuously. And you can modify the threshold of stimulation as you're getting closer to the functional area. So we usually start at 15 milliamps and then bring it down to today as low as two or three milliamps when we want to get really close to the functional site. Very convenient, very, saves you a lot of time and a lot of confidence of doing that. Now for advanced motor mapping, when you need to go in areas such as premotor or SMA regions, you must have a patient awake. When you just go for the M1 or subcortical spinal tract, you can have patients anesthetized. But doing this advanced motor mapping gives you a lot of information. We've done and published a lot about the SMA. But if you do a simple finger tapping test in patients when you operate in the SMA region, this gives you information about comprehension of the patient, gives you about initiation of movement, the motor functionality, and rhythmicity, which is a very important cognitive function for a musician. So this is what it looks like. The monitor tells the patient who is pre-trained on how to do this. I think we need the sound on. Anyway, so we can do that and it gives us a lot of information in those advanced motor mapping. Language function, it's again very standard. We do all those things that are listed here. Questions that represent object naming, verb generation, simple instructions, semantic retrieval, and so forth. One word of caution is that sometimes you do get vocalization or effects on language and speech that are not related to language, such as dissonance or vocalization when you monitor. Oh, that explains it. Okay. When you stimulate the motor cortex, for example, and this has nothing to do with language sites. And you get images that you've seen before. This is a routine. A routine. All right, so that was an example of a patient that had a problem of comprehension. And this is the way that you go about these procedures. What about vision? We use the same electrodes that we use for subcortical stimulation of the motor pathway. But in this case, we do recording from these electrodes. We do not stimulate routinely. And we have found specific fingerprints that tells you when you're getting very close to the optic radiation. So we put cortical strip electrodes on the visual cortex that you see here on the right. And then we do the recordings from the electrode in the subcortical areas. And as you're getting closer and closer to the optic radiation, you're seeing this specific pattern that comes before the occipital or the visual cortex VEP and tells you that you're getting very close to the optic radiation. Now, there is no robust correlation, as we see, with the motor stimulation. There is no one-to-one correlation between the threshold of stimulation. So it is not as safe as with the motor mapping. But it does tell you when you're getting close. You can do this in anesthetized patients. You can do this in awake patients. When you do this in awake patients, you can stimulate and get an output, a visual output from the patient that would tell you in the corresponding visual field that he's seeing or she's seeing a visual input, usually unformed visual hallucinations. And this is by using this LED goggles that you can put on anesthetized or awake patients and getting to try and preserve the optic radiation. Then a few years ago, we got very interested in mapping emotions. Emotion, it's a very difficult phenomenon to explain. We know that there is no one site related to emotion. But there's no argument that this is a high cognitive function. And we have ways to induce emotional responses in patients. One of the very effective ones is to show them a high-intensity emotional stimulus. And you can use any one of those movies that are tear-squeezing, you know, love stories, office choice, whatever you want. And this is an example of a movie called Stepmom with Susan Sarandon. She's the grandmother. She's going to die. She has a grandchild. The grandson loves her. And watch on the right side when we use the graph theory mechanism of taking the input, the single input from the fMRI, and we plot it as a graph. And look what happens when the movie evolves. Watch the changes here. Now this is going to be hard. Look at this emotional outburst that you can see in the brain. This is finished. Everything is going to light down, turn down. All right. So taking and using the graph theory, we can then plot this graph on the surface, superimposed on the surface of the brain of the patient that we're going to operate. Obviously, there are many nodes here. Many of them are sub-cortical. We don't know where they are. We don't know what their connection. But we do know that we can identify nodes that contribute to this specific network. And we can actually measure the amount of input of these nodes into this network. And we ask ourselves, how can we map these nodes on the surface of the brain? How can we do that? How can we map these nodes on the surface of the brain? How can we interpret what we're saying in relation to the network that activates those cognitive functions? And to do that, we had to develop some new methodology. And instead of doing network mapping sub-cortically, we decided that we're going to try a new approach, which is completely experimental at this stage, with the assumption that if you disrupt the function of U-fibers by multi-site stimulation of the cortex, you may affect the input of those U-fibers into larger networks that are adjacent to the area that you stimulate. So, this is some example of those multi-site stimulation. We use two, three, even four sites in areas that single-site direct cortical stimulation caused no deficit. So, we're sure that what we're getting is something related to the multi-site stimulation. And now we're getting many responses, many effects. This summarizes a group of 13 patients. What you see in black areas that were elicited only with multi-site stimulation, and in white areas that direct cortical stimulation did cause disturbances. And if you plot them, this was done for language. You plot them, you see that they correspond on the archaic fasciculus. And then you can go back to anatomical substrates to see if these areas with the multi-site stimulation were related to networks based on DTI data. You can see that in cases where you did elicit some disturbances, it was associated. And this, we tried to report this thing. We submitted it for publication recently. It was rejected. It needs some proof. So, we took this now into another system that's probably an extremely important cognitive function, which is creativity mapping. And I don't know if you know that, or if you read The Outliers. They wrote and they told that all those major companies, Facebook, Google, Oracle, IBM, they use creativity testing as the most important cognitive test based on which they are hiring employees. So, the way that we do this is taking advantage of resting state fMRI. Without going into details, there are seven networks that are present with the resting state fMRI, two of them intimately related to creativity. One is the default mode network, the DMN, and the other one is the frontoparietal control network, the FPC. The DMN enhances creativity. The frontoparietal control reduces creativity because it has to do with focusing on a mission. So, what we do, we parcellate those two networks from resting state fMRI of the patient. Then, we superimpose them, infuse them in the intraoperative navigation MRI scan. We identify the nodes that we want to stimulate. And then, during surgery, we go and stimulate with the multi-site stimulation, these areas, to see whether or not we are seeing some effect on creativity. Creativity is using the alternate task queues, a very validated test that's being used. This is a patient. We're asking about a tire, and she gives many alternative uses for this particular object. We can score those. The scores are validated, and we have 100 different tasks that we know that take place. But now, see what happens. She was doing great on this first thing. This is the second one with a pencil. And because we are disrupting now the DMN node, the default mode network node, she cannot come with any alternative use for a pencil, except for drawing. Actually, she was very frustrated during surgery, and she asked me, what would you do with a pencil? And it's quite stressing, if you think about it. We don't have some good answers for that. And she came to see me a week after surgery, and she brought me this present, this very large person, a pencil with an inscription that, in 10 seconds, please list what can be done with the pencil besides writing. So other cognitive functions, we can also map non-linguistic auditory functions. This is an example of a musician. She's a harp player for the Israeli Philharmonic Orchestra, who came with this lesion here. And we wanted to look at harmonic syntax in this patient. This is one example. Same thing goes for conflict monitoring. You've got indentary colossal areas that correspond to decision-making on the conflict. We have emotional areas. We have the basic stimuli of what's known as the Stroop test. And this is, again, what it looks like during surgery in a patient who has a lesion in the cingulate gyrus. He's doing the routine Stroop test, trained for it before doing it during surgery. Okay, again, this can be given values and looked at. Briefly, I'll just mention, we do calculation tasks. We do spatial perception tasks. It can be easy as this one, difficult as this one. Actually, I vetoed this one because I couldn't tell what's going to be there on the Rubik area. Free recall fluency in patients. And just, I think, a couple of slides on complications and points to consider. We never put indwelling urinary catheters in men. This is killing them. At least in Israel, it does. So we use them with women, and we use Penrose or these kind of condoms in men. Now, we have patients who tell us that they have a sensation of blinding light. We don't know exactly what that means, especially with large frontal lobectomies. You're getting transillumination. And the patients receive the light from the microscope through the globe and complain of this thing. Pain from venous and arterial retraction. Everybody knows about it. Over sedation with CO2, with brain bulging, extremely rare. But this is usually what happens when the senior anesthesiologist goes out of the room and the resident comes in. Not very well trained. Critical thing. This is a paper we published a few years ago that showed that we had 6% or so of failed procedures. And the causes of failure were mostly of poor patient selection. And this is just another work that's been submitted now that showed that patients, when they go down to the OR, they have a decline in their language function even before you start the operation. So this 15% or 17% reduction in function may make the difference between cooperative and non-cooperative patients. We also stopped the use of overdose of sedatives and anticonvulsants during surgery. Now we give none during surgery of anticonvulsants. Seizures were due to overstimulation. We limit it now to 4 milliamps. And 2% converted to general anesthesia in the initial series. Now with the new series since 2012 of almost 500 additional patients, it's less than 0.2%. And the failed mapping dropped now from 6.6% to 1.9%. And failed mapping carries a risk because patients who fail mapping have more major complications, have more mortality, and the extent of resection is lower in these patients as we demonstrated in our patient cohort. And with that, I'll finish and thank you for your attention.

mapping cognitive functions

patient selection

awake sedation

cortical strip electrodes

multi-site stimulation

patient outcomes