Thank you very much, and many thanks to the organizers for including me. I'm really excited to learn from all of you about mapping in the brain, and I hope to share some of our work with you, too. As was billed, my talk's going to be about language dysfunction, but really, it's a mapping conference after all, so we really need to talk also about how we map language dysfunction in the brain, and the way I'm going to talk about it today is using lesion analysis of patients with vascular aphasias. I'm going to talk about kind of highlights of some of the last, well, 30 years of our research, in which I've been able to collaborate with many wonderful people from many different fields. I also want to thank, of course, our funding agencies, and particularly the patients who've given their permission to use their videos for this presentation. I'm going to do all of this in 20 minutes, so I'm going to talk fast and leave out the verbs. Okay, if I don't get to say anything else, I want to convey these points. Language is a very complex system that involves numerous processes. Most of these are linguistic, but as we saw from Bob's talk, some of them are non-linguistic, involving memory systems, for example, and these are all subserved by different brain regions. When we break language down into its sub-processes, that's when we really find the most effective way of trying to map language areas in the brain, so I hope I can convey that to you today. Now, even though discrete brain regions may support different components of language, they're still part of a very extensive network of areas and fiber pathways, we can't forget those, that help to support language. So, as we've already seen in the first two talks, lots of brain areas contribute in different ways. The more discrete we can narrow down the functions we're looking for, the better off we are in terms of mapping them. Well, one of the ways to understand how language can be disrupted is by working with people who have sustained a sudden brain injury. All patients teach us very important things, but the reason I'm going to talk to you today about aphasia is because these are people who had perfectly normal language. One minute, and a few minutes later, it was gone, or it was disrupted in some significant way. And those individuals can teach us a lot about how language goes wrong, and that language is, in fact, can be affected in a multitude of ways. All right, well, what we see is that most aphasic patients do, in fact, have multiple deficits. So you might ask, well, how can such cases possibly tell us anything about how language is organized in the brain? And the answer is that unless you're lucky enough to have a clinic where every unusual and interesting case in the world comes into CU, then the way you have to go about it is accumulate a lot of cases, which is luckily what we've been able to do. So briefly, at our aphasia center, what we do is conduct very extensive speech-language, neuropsychological, and thanks to Bob, neurological evaluations of aphasic stroke patients to determine the specific language, cognitive, and neurological deficits that they're experiencing. And then we also perform a lot of neuroimaging. So we do structural MRIs, diffusion imaging, for example, resting-state fMRI, perfusion, the list goes on. And we use this information to help us to define the structures of the brain that were affected by the stroke. And then we evaluate those deficits in relation to the brain areas that are affected by the injury, and this is what we mean by lesion analysis with aphasic patients. Then we can use these data to test brain-language relationships. So, for example, one way we can do this is, let's pick all the patients who have the same specific deficits. I'm using apraxia of speech as an example here. And we use the computer to overlap their lesions to determine if a common area of injury can be found. That's one way we can do it. Another way we can do it is to apply voxel-based lesion symptom mapping techniques that statistically examine brain-behavior relationships at a high resolution in large numbers of patients. So we can take all comers. Every patient who ever came into the lab, we can put all of their data into the computer and sort out, depending on the specific task we're interested in mapping. We also evaluate the role of fiber pathways in the brain that also support language functions. I hope to talk a moment about that as well. Okay, what we've learned, bottom line, again, narrowing down the deficits to more discrete functions does result in better language mapping. So when we do a clinical assessment, for example, we're interested in measuring fluency, auditory comprehension, naming, repetition. But, in fact, each one of those things has many, many different components to it. And if we try to localize fluency or auditory comprehension, we don't have very much luck. But if we break it down, we do. So, for example, let's take the production of single words. I'm using single words as an example, particularly because I know that is something that's frequently mapped in neurosurgical patients. And I want to just point out the many different stages involved that I know all of you take into consideration as well. First, you need to find the words that describe the concept you want to express. So what's the name of this thing? Okay, you know what it is and how to use it, but what's its lexical representation? What's the word that describes it? You have to suppress things that are related to it, maybe pen or pencil, but really this is a pointer. So you have to suppress the other choices and choose the one you actually want. You might need to apply grammatical markers if necessary, such as the plural. This is still very much under discussion, so I'm purposefully graying it out. You need to transfer information from the language temporal lobe cortex to the anterior motor speech areas. You need to make the articulatory plan, as Bob discussed earlier. You need to coordinate complex articulatory movements in words that are hard to pronounce. You need to execute the production of the word. So either at this point you're thinking, oh my God, I'm so glad I went into neurosurgery and didn't study language, or you're thinking, hey, there's a lot of really great potential here for mapping components of the language system. Of course, I hope it's the latter. Let me give you a quick example. Coordinating complex articulatory movements. So what do we mean by that? This is where we need to get all of the articulators, the lips, the tongue, the larynx, to do exactly the right thing at the right time. So let's say you want to say the word spaghetti, and you don't want it to come out guspetti or respetti. You want spaghetti. You actually have to make all of these different sounds individually coordinate their transition and produce them in order to come out the way you want. That turns out to be a tough task, and there are patients who actually have deficits just in the programming or, excuse me, the coordination of complex articulatory movements. And we say that those patients have an apraxia of speech. They can retrieve the words they want to produce. They know what the word is. They know that's a pointer, and they'll make mistakes in describing some of the sounds or retrieving the correct sounds and coordinating them to come out the way they want. So we did just briefly a lesion overlapping in 25 patients with apraxia of speech. So all of them shared this particular disorder. When we overlapped all of the lesions, we found that all of the patients, 100% of them, had a lesion in this area of the precentral gyrus of the insula, actually only the very superior tip of the precentral gyrus of the insula, as you can see here, 100% of the cases. Well, that was surprising to us, but we remembered the wonderful work performed by George Ogiman and our colleague Harry Whitaker in actually doing electrocortical stimulation in a case in which the insula was exposed. Interestingly, they also got speech arrest in this particular area of the insula. Well, one of the concerns here is when you overlap lesions, you can get, you know, this is really right in the middle of the left hemisphere there, and maybe that's just an artifact. So of course what we did was we took all of the patients who met all the same selection criteria. We overlapped their lesions, and here's what we see. Here's 25 patients with apraxia of speech. All of them have apraxia of speech. All of them have a lesion in the SPGI. Here are 19 patients without apraxia of speech. None of them have this speech disorder. None of them have lesions in that same region. So the dissociation tells us that this area is important for coordinating complex articulatory movements. You don't need it for a word like banana, but you need it for a word like spaghetti. Just try saying them each five times fast, and you'll see that the latter is definitely much harder to do. Now, this is independent of aphasia type because here we could see that here are patients with Broca's aphasia, and as Bob pointed out, when we overlap the lesions of all the patients with Broca's aphasia, much like the first case that you saw, we see that there's actually a large area of cortex involved in most of those cases, but the critical area that they all shared was this small region in the insula. Now, what's interesting about this is that these patients all have many, many deficits, as we saw earlier, but what they all share in common is apraxia of speech. Apraxia of speech is a hallmark of Broca's aphasia. We see that all the patients had apraxia of speech. They all had lesions there. We can look at other aphasia types as well, a non-fluent anomic aphasia, for example. Here again, 100% overlap in all of those cases. Why? Because they all have apraxia of speech. So regardless of where the lesion is, or how big it is, or how small it is, if you have a lesion in this very small area of the anterior insula, you're going to wind up with an apraxia of speech. It always remains. We can train it. We can teach the patient. We can give them all kinds of therapy. It improves. It gets better. But it never completely goes away. Something really hardwired in the brain. So again, you break it down into subparts. You get an interesting localization pattern. And on the side, you also see the importance of the insula, which I hope George Georgemin would also agree is a very important area of the brain to consider for language functions. All right, I have a few minutes left, and I'm going to just show you a little bit about auditory comprehension of sentences. Many steps involved here. You have to perceive what you hear. You have to match the word to the concept. Recognize markers. Bring in things like auditory short-term memory, working memory, other cognitive skills that are also very important for understanding sentences. We did a little task where we showed patients pictures, and we gave them a sentence like the girl is sitting, and they have to pick the correct one. Aphasics love this task because they don't have to say anything. They just have to point. We give numerous different levels of syntactic complexity, and we get up to sentences like this. The girl is kissing the boy that the clown is hugging. So patients have to pick out the correct one, and I'll just give you a minute to find the right one because obviously this is a lot harder to do. Hopefully you picked that one. All right, we did a voxel-based lesion symptom mapping study in a large group of patients who all received this task. We get lovely maps like that. We can translate them into regions that emerge as important areas for the comprehension of sentences. Essentially what we found was five different brain regions that were important for sentence comprehension, and each one of them contributed to a different type of comprehension deficit. I don't have a lot of time to go over all of them, but let me give you the highlights. For the comprehension of simple sentences, sentences like the girl is sitting, you really need your middle temporal gyrus for that. So this yellow area that you see here, when that area was infarcted, that caused the most severe comprehension problems. So not only do these patients not understand complex sentences, they don't even understand simple sentences, and in some cases even single words. So this area of the temporal cortex, very important for lexical semantic storage of words and their concepts. Now, when we get to more complex sentences, such as the one that took us all a little bit longer to figure out, we see that there's actually many other processes in supporting brain regions that become involved. Yes, there are big globs of cortex. We haven't been able, with lesion analysis of aphasic patients, to narrow it down to such nice local levels such as we heard in the previous two talks, but that's why working with neurosurgical patients with stimulation mapping and ECOG mapping is so exciting to have that opportunity to break language down into smaller and smaller pieces, functionally and neuroanatomically. We see regions here for helping to recognize that there's grammatical structure in the sentence. We have areas for working memory, for example, that also play a very, very important role. All right, I just want to give a shout-out to the white matter pathways, which are also extremely important, if maybe not even more important sometimes, for processing language. So in our VLSM map, what we saw were these red regions, important for understanding sentences, but you can see also these are lesions that extend quite deep up to the posterior horn of the lateral ventricles that really incorporate white matter that underlies the middle temporal gyrus as well. My colleague Ann Turkan and I isolated the fiber pathways that go underneath the middle temporal gyrus, and this is what we find, a very extensive network of fiber pathways, including all of these, the arcuate, the IOFF, the ILF, middle longitudinal fasciculus, which hasn't been looked at very much in language yet, and of course the tapetum of the corpus callosum, which is going to connect the two temporal lobes to each other. And so we see five major fiber pathways passing underneath this critical brain region. So it's not just about the cortex, it's important, we need it, but it's also about the connections between temporal lobe regions and other areas of the brain that help us to do this magnificent thing we're doing right now called language. We can do hardy tractography, for example, in different patients. Here's an example of a patient with a persistent comprehension deficit. Here's hardy tractography of his middle temporal gyrus fibers that run in the right hemisphere. You see a very lovely network, a blossoming, really, of fibers that are involved or that pass through that region. Here in the left hemisphere, these are injured fibers. All of these fibers, if you just compare the sheer volume, you see a big difference in the available white matter pathways that these patients have at their disposal. You can also see really interesting patterns of recovery. Here's a patient who has very poor recovery of his comprehension skills, and here's one who's continuing to recover. So again, we're looking at the involvement of white matter pathways, and it must be said that, of course, white matter matters as well. All right, I hope that I've shown you that there are numerous ways to explore language processing in the brain, that many different areas are involved. We haven't talked about resting state, but that will have to be for another day. We've seen that lesion analysis can reveal very specific brain behavior relationships if we narrow the behavior down, and I'm confident that the more we narrow the behavior down, the better localization we see. Again, I think that neurosurgical patients are a remarkable opportunity to be able to explore this further, and we're lucky that they are so cooperative in helping us do that. This does not mean that every part of the language system can be localized to discrete areas of the brain. We can see that nice localization in something as hardwired as apraxia of speech or coordinating complex motor movements, but it's not true for something like where the lexical semantic system is, right? Where are words stored? Where do we put our vocabulary in the brain? That's a big region. That's the temporal lobe and underlying white matter that help to associate all of those different concepts and words together. We also need to remember that it's a complex system that requires an extensive group of brain areas and their connecting fibers, and these together form very interesting complex networks that support language. We're talking about mini-networks. We're talking about a larger network of language. Each of these sort of functions has its own little mini-network of areas that help to support what they're doing, and when we understand these networks, they give us not only the tools for understanding how language is mapped in the normal brain, but, of course, most important of all, to help guide ourselves in how we can best assist our patients. I'm going to stop there, and I want to just thank you very much for your time. Thank you.

language dysfunction

brain mapping

lesion analysis

vascular aphasias

neuroimaging techniques