Description of graphical content is included between Description Start and Description End. Transcript Start [Silence] Fade up from black. Animation: Text for TSBVI transform into braille cells for TSBVI. Fade to black. Fade up from black. [ Slide start: ] Description Start: Title: Looking Inside the Adaptive Brain of Individuals with Ocular Blindness and Cortical Visual Impairment Content: center graphic: profile of a large metal sculpture of a brain with a metal worker on top holding a hammer Reference: Lofti B. Merabet; The Laboratory for Visual Neuroplasticity, Massachusetts Eye and Ear Infirmary, Harvard Medical School Description End: Merabet: First and foremost, I consider myself a neuroscientist. I, I study the brain, I'm fascinated about the brain and that's what I think about basically all the time. [ Slide end: ] I hope to convince you as well, that the situation of blindness and visual impairment is an incredible model to study the brain and development. It's a really fascinating opportunity to understand how the brain develops; and that's strictly obviously from the neuroscience standpoint. I'm also an optometrist, I see a lot of patients, particularly with brain damage, visual impairments, children, as well as adults. And my thought is what I learn in the research lab can ultimately translate into, into the clinical care and education of these individuals. I'm also a big believer of assist, assistive technology, I think, I think that assistive technology -- [Laugh] How ironic, huh? [ Laughter ] Merabet: Technology is a good thing. There we go. [ Laughter ]. I'm a big believer in technology, I think technology is an enabler, and in my second lecture I'll show you a little bit of work that we have been doing about video games, and how we can use video games with blind children, as a way to help with orientation, mobility, and navigation. And the final thing I'll mention is I also have a background in public health. I, I really think that what I, what I do in the clinic, and what I try to do in the research lab ultimately should translate in the way that we, we legislate and we take care of these individuals. And in Massachusetts, much like in Texas, these are states where we have invested in education. It's in, it's in the culture of the people. And I think that's, that's really something extremely important. I think that's why things, things get done. So with that said, let me get started and let me just give you the first slide to give you a sense of how I kind of approach these ideas and think about this, this aspect about neuroscience, cognition, behavior and learning. If you're a neuroscientist you fundamentally believe this mantra: that the mind is what the brain does. That's really kind of what we think. There is an intimate relationship between cognition, behavior, how we think, how we act, how we behave and the structure and the function of the brain. How do we do this? [ Slide start: ] Description Start: Title: "the Mind Is What the Brain Does" Content: Top graphic: arcing arrow from left-side graphic to right-side photo, titled "manipulate" left-side graphic: b/w image of a brain, titled "Brain" center graphic: block arrows pointing left & right, titled "?" right-side photo: b/w medium shot of chess master Bobby Fischer leaning over a chess board, head cradled in his right hand, gazing at the chest peices. bottom graphic: arcing arrow from right-side photo to left-side graphic, titled "measure" Reference: measure - measuring brain structure or function as a subject is engaged in a particular behavior manipulate - changing the brain's structure or function to see it's impact on behavior Description End: Well, the first thing that we do is we measure. We measure the brain in terms of its structure and its function, in response of somebody doing something. The second thing we do is we manipulate. We change the brain somehow and see how it affects cognition, behavior and learning. That might be through natural causes like brain damage. [ Slide end: ] It might be through a situation like visual development in the case -- or development in the case of visual impairment. It might be through brain stimulation, for example. Exogenous stimulation of the brain, I will show you an example of that, also. So, this loop, if you will, allows us to create this understanding between how the brain acts, its structure and its function, and how we behave, how we think, how we learn, how we develop. Just out of curiosity, anybody know who this person is? The picture that I'm showing here? [ Slide start: ] Repeat slide above Participant: Bobby Fischer. Merabet: Bobby Fischer. Yeah. The first American Grandmaster Champion of chess. Uh. Very, very interesting individual. [ Slide end: ] I always show you his picture because, if some of you know his history, he kind of had two lives: He was this incredible child prodigy, the first American to win, he, he, he beat all of the world's best chess masters, and after that became extremely reclusive, had all sorts of psychiatric issues, and paranoia, and all sorts of things. And I always, I always like this sort of picture to remind me just how quickly things can change, right, in a person's life. If we understand the structure and the function dramatically, has impacts in terms of a person's life. So, again, this mantra of the mind is what the brain does is fundamentally what, what we think about. Some things I always like to talk about, when I, when I get the chance to, to lecture with these groups, as neuroscientists we're always kind of concerned about these neuromyths, these, these statements, if you will, that get propagated throughout cocktail parties and so on. I'm sure you've heard this one, [ Slide start: ] Description Start: Title: "Neuromyths" Content: do we only use about 10% of our brains? right-side graphic: movie poster for the film "Lucy" Description End: this idea that we only use 10% of our brains. Yeah? Just, just out of curiosity, who thinks, who thinks that's true? I know it's being filmed, but don't worry, it's all right. You can tell. [ Laughter ] We're friends, it's okay. [ Slide end: ] Just out of curiosity. Who think that's we only use 10% of our brain, anybody? Participant: [Indiscernible] Merabet: You believe it. Yeah? You believe-- Also the person in the sound room believes it. Yeah? I see that as well. Well, the-- the reality is, and I think what you're trying to say is that we have potential. Right? We can do much more than, than we think. And I think that's absolutely true. But I certainly don't think that it's 10%. The fact of the matter is you use all of your brain all of the time. Doesn't matter how smart you think you are or who your favorite football team is, it's true. Everybody is the same. Here's, here's the sort of the rationale. If you think you're only using 10% by definition, 10%, that means that you know what 100% is. You have to know what the baseline is, what does 100% look like? It's like saying that person is only using 40% of their faith, for example, it doesn't make any sense. You use all of your brain all of the time. What makes you different from me from the person sitting next to you is how it's wired, how it's connected. I'm going to show you examples of how blindness, in the particular case of blindness, and also in the case of C-V-I are perfect examples of that, that principle. So, that's the first thing to keep in mind. [ Slide start: ] Description Start: Title: "Neuromyths" Content: right-side graphic: movie poster for the film "Lucy" Do we only use about 10% of our brains? Is 90% of all information that comes into our brain visual? (from Brain Based Learning, Eric Jensen, 1996) Description End: The second one that I hear a lot is 90% of all information that comes into our brain is visual. Same problem, right? If you know what 90% is, that also means that you know what 100% is? What is 100% information? [ Slide end: ] As a scientist, I love to measure things. I would love to know what 100% information is. It's just-- you just can't measure such a thing. At the same time, think of the counter-argument: If 90% of our information that comes in is visual, does that mean that a blind child, or a child born blind, can only understand 10% of the world? It just doesn't make any sense, right? So, these are a lot of, what I would say, these sort of myths that sort of kind of get through, and I think they're important to kind of think about because, as I said, they tend to get sort of propagated. [ Slide start: ] Description Start: Title: "Neuromyths" Content: right-side graphic: movie poster for the film "Lucy" Do we only use about 10% of our brains? Is 90% of all information that comes into our brain visual? (from Brain Based Learning, Eric Jensen, 1996) center graphic: screen-shot of PubMed webpage citing article titled, "The Information that drivers use: Is it indeed 90% visual?" Description End: In fact, the only, the only study that I could find online from a peer review journal said that it's actually not, there's no evidence that it's 90%, to be perfectly honest with you. So, I just, I wanted to kind of share those, those points with you. [ Slide end: ] So, the main theme of my lecture, and, and sort of the theme of the lab and what we do is this concept of neuroplasticity. "Neuro" obviously referring to the brain, "plasticity" coming from the Greek word "plastikós" which means "to mold," right? Or "to shape." Just like a piece of plastic can change its shape and its form to do something else. So, too, can the brain under the right conditions. So, I, I really like this definition: [ Slide start: ] Description Start: Title: Neuroplasticity: Content: left-side photo: A young boy gazes at a model cross-seciton of a brain that he holds above his head. right-side text: The ability of the brain to change its structural and functional organization in response to development, experience, the environment, or damage... Description End: "The ability of the brain to change its structural and functional organization in response to development, experience, the environment, or damage." This, in a nutshell, is what plasticity means and you have this for life. [ Slide end: ] It's an intrinsic property of the brain that you take with you throughout your lifetime. And there's all sorts of great stories. As neuroscientists we always try to look, look at the media and so on, trying to come up with some good neuroplasticity stories, so here's one I'd like to share with you. One of my favorites. [ Slide start: ] Description Start: Title: Neuroplasticity: Content: left-side text: "Tiny brain no obstacle to French civil servant" left-side photo: MRI image with small LV section right-side text: The ability of the brain to change its structural and functional organization in response to development, experience, the environment, or damage... Reference: http://uk.reuters.com/article/idUKN1930510020070720 Description End: This is a standard M-R-I image. You're looking in sagittal cut here: this is the person's eye, this is gray matter on the top here, white matter in between, and the little L-V in the middle is the lateral ventricle, this is typically where fluid resides, cerebral spinal fluid. One day, this gentleman in France went to see his doctor. I'm showing just you that's what a standard M-R-I image looks like, of the brain. One day this gentleman in France: middle aged-- 45, 50‑year‑old, [ Slide end: ] goes to see his doctor and says, "You know what, I have, I have these headaches, um, and they just don't seem to go away." And if you've lived in France like I have, I'm sure the doctor just told him, you know, "go home, have some wine, it'll be fine, don't worry about it." He comes back two, three times and says, "You know what, I don't understand, I've taken aspirin, you know I've-- I just don't understand what, what's going on." So, finally the doctor says, "Okay, fine, we'll get an M-R-I." And here was the patient's M-R-I. [ Slide start: ] Description Start: Title: Neuroplasticity: Content: left-side text: "Tiny brain no obstacle to French civil servant" Top left-side photo: MRI image with small LV section right-side text: The ability of the brain to change its structural and functional organization in response to development, experience, the environment, or damage... Bottom left-side photo: MRI image with large LV section Reference: http://uk.reuters.com/article/idUKN1930510020070720 Description End: That's his brain. About this three, four centimeter lip around there and all that you see in black here is water. That's his cerebral spinal fluid. This guy had no idea that he was going through life like this. He got married, he got a job, he's a civil servant, he has two kids, has normal intelligence, had no idea that that -- that's what his brain was like until under this certain circumstances, quote "headaches." [ Slide end: ] So it just goes to show you that something really, really important about the brain is that when things happen early and when things happen slowly the brain is very, very good at adapting. When things happen very quickly and when we're adults, less so. Think about traumatic brain injuries and concussions, for example. Very, very different scenario and the brain is not as good at adapting under those situations. So, just to give you a dramatic example of neuroplasticity. [ Slide start: ] Description Start: Title: Neuroplasticity: Content: right-side text: The ability of the brain to change its structural and functional organization in response to development, experience, the environment, or damage... ... it is not a "guaranteed fix;" it is the inevitable consequence of how the brain works throughout a lifetime. upper left-side photo: male legs pictured just above the knee, right lower leg is photo edited out with title, "Phantom limb pain." lower left-side photo: Waist-high outline of a person with their arm missing below the elbow, spine and brain sketched in gray, two, red arrow lines running both directions from the brain to the end of the arm, red dots at the end of each line with circles radiating out. Description End: I also want to remind you that it's not a guaranteed fix. We have this idea that neuroplasticity can fix all our problems and don't worry, the brain will figure it out. Well, it's not entirely true. It's not a guaranteed fix, it's the inevitable consequence of how the brain works throughout a lifetime. And to give you an example of negative plasticity, I like this one, this is phantom limb pain, for example. So, these are patients who have either a hand or an arm that was amputated, or a leg, and they feel that pain, that, that, that their hand is in a vise, it's being crushed. [ Slide end: ] Right? Even though there's absolutely no limb. And the reason why is because the brain hasn't understood or, or doesn't adapt to the fact that that limb is gone and it signals that as pain; and massive, chronic, intractable pain in some cases, as well. So, plasticity, as I said, is the way that the brain adapts, but in some cases it can be negative and sometimes it can be positive. Our goal, as neuroscientists, what we hope to do is to try to understand those cues. What makes it go one way versus another and how do we leverage that in a, in a positive way for rehabilitation and education. Another very, very important principle when it comes to brain development is the idea of the critical period. [ Slide start: ] Description Start: Title: Visual Development: Critical Period Content: top left-side photo: male toddler with glasses looks a hard-bound book held in his hands. bottom left-side photo center photo: b/w photo of a kitten look straight at camera top right-side photo: b/w photo of D. Hubel and T. Wiesel from 1981. bottom right-side graphic: table with three columns an two rows; top row shows a drawing of a kitten with no eyes covered, one eye covered, both eyes covered; bottom row shows diagram of brain tissue thickness. Reference: Description End: And a lot of the work that was done in this area were done by two of my heroes, this is David Hubel and Torsten Wiesel. They won the Nobel Prize in 1981, for their work. And what they did is they understood-- essentially discovered and understood the physiology of the visual brain, the visual cortex. So some of the work that they've done, this is just one example, is they would take kittens and they would rear them under certain situations. They would suture one eye, they would close the other eye, change the different timings of that. They would, they would put opaque lenses over the lens, over the eyes and so on. And they would get a sense of what the physiology and the anatomy of the visual cortex was. And that was really groundbreaking work because from there the way we take care of amblyopia, example, is fundamentally a result of that work. So, it's a wonderful example of how basic neuroscience research ultimately can translate into the care of individuals. [ Slide end: ] And I think that's, that's very, very much the strategy that we, we all are trying to pursue. Another thing to think about is that that critical period has a sort of sense that it's finite and it's really not true. We now know more and more that plasticity exists throughout a lifetime. It's certainly easier to learn a language when you're six compared to when you're 60, but it's not impossible. And I'll speak a little about that and how as we get older why plasticity changes and why things get harder. The fact of the matter is, plasticity is for life and it's never ever over. Okay. So, a couple, a couple of questions I'd like to talk about specifically about the case of ocular blindness. To set up the terrain and then we'll switch to the case of C-V-I. So, as I set it up this way I think it'll make sense from a neuroscience perspective why we pursued this question: first in terms of ocular blindness and how we got into the case of C-V-I. [ Slide start: ] Description Start: Title: How does the Brain change in response to Ocular Blindness? Content: - Behavioral changes: are blind individuals better at non-visual tasks? - Structural changes: use it or lose it? - Functional changes: what is the fate/role of "visual" areas of the brain? How does the brain "re-wire" itself in the context of profound visual deprivation? Description End: So, a couple of things to think about, first and foremost what are the behavioral changes in blind individuals? Are they better at non‑visual tasks? This is something I'm sure you've all, you've all heard about. And I'm going to share with you some scientific evidence that does indeed support, that in the case of ocular blindness these individuals do show superior non‑visual performance. What about structural changes? Use it or lose it. Right? How does the brain change as a function of the skills that you rely on? So, as a blind individual who is a, is a proficient braille reader, do parts of the brain change as a function of that, for example, than someone who doesn't? And I think a very, very interesting question are functional changes. So, for example, what is the fate and the role of visual areas of the brain? How does the brain rewire itself in the context of profound visual deprivation? [ Slide end: ] You all know that there's a large chunk of the brain dedicated to vision, right, so the question is what happens to that part of the brain in the case of blindness and we'll get into that as well. [ Slide start: ] Description Start: Title: Is Blindness an "Advantage?" Content: Photo: Stevie Wonder sitting at electronic keyboard Description End: So here, here's a, a picture I'm sure you all recognize. This is Stevie Wonder. Obviously who was, who lost his eyesight at a very, very young age, was born blind, became a very, very successful, artist and musician. I think there's a very interesting philosophical question you might, you might want to ask yourself is: [ Slide end: ] Would Stevie Wonder be the Stevie Wonder he is today if he wasn't born blind? In other words, did blindness somehow confer an advantage in terms of his ability to, to develop his musical skills and to be the person that he is today? [ Slide start: ] Description Start: Title: Is Blindness an "Advantage?" Content: Photos: Andrea Bocelli singing; Ray Charles singing; Stevie Wonder sitting at electronic keyboard; Mt. Everst climber, Erik Weihenmayer; track star (not identified) Description End: And of course it's not just in music. There are many, many arenas that we see very, very successful individuals who lost their sight early in life or later in life and have gone and, and had incredibly independent, [ Slide end: ] independent lives and successful lives and I think it's an interesting question to ask that what did blindness do in terms of that development? How did it actually impact them? [ Slide start: ] Description Start: Title: Is Blindness an "Advantage?" previous content with additional text below. right-side text: Evidence of Enhanced Compensatory Behaviors: Tactile Processing: e.g. van Boven et al. Neurology 2000 Auditory Localization: e.g. Gougoux el al. Nature 2005 Olfacctory Identification: e.g. Cuevas et al. Neuropsychologia 2009 Verbal Memory Recall: e.g. Amedi et al. Nat Neuroscience 2003 Description End: So, in terms of that question of enhanced compensatory behaviors there is actually quite a bit of scientific evidence along these lines. There's evidence, for example, that ocular blind individuals with ocular blindness have enhanced tactile perception. They also have enhanced auditory localization. They can identify sounds and space better than sighted individuals. Also better at identifying smell. Also better at verbal memory recall. Again, a lot of studies have, have shown this [ Slide end: ] so the evidence certainly seems to be there of these enhanced compensatory behaviors. But there are caveats and I think that's an important thing to kind of think about. [ Slide start: ] Description Start: Title: Is Blindness an "Advantage?" previous content with additional text below. Caveats: - Controlled experiments vs real-world? - Sensory thresholds vs attention? - Comparison to sighted controls? - Contributing factors? (e.g. onset, profoundness, education level, etc.) Description End: The first is what, what underlies these superior performances. First of all, it's not universal. It's not across the board. It's not every individual that shows this. The second thing to realize is that this is very much under very controlled scientific specific questions that we ask. A lot of times these enhancements that we see in the lab don't necessarily translate to the real world. So that's an important thing to realize. Secondly in terms of sensory thresholds versus attention, so what the evidence suggests is that this isn't enhanced hearing, per se, or enhanced mechanistic touch, it's enhanced attention spent or delivered to those to those senses when you take vision out of the equation and again I'll show you more, more evidence about that. The third point that's important to think about is comparison to sighted controls, right? So are the blind really better than sighted people or are sighted people just really bad when you ask them to do this without their sight? [ Slide end: ] I think it's important to look at it, both, both sides of the, of the coin, if you will. And the last thing is contributing factors: the onset, for example, born blind versus later -- later -- later in life, the profoundness of the blindness, your education level. We don't know how these covariants intimately relate to these behavioral, behavioral changes. I have a picture here on the top, and and -- your top left, I should say, of Andrea Bocelli. I'll share a quick story with him. I had the pleasure to meet him a couple of years ago doing some work for his foundation. And just to prove to you how big a nerd I am, when everybody was at the gala asking for his autograph and pictures and stuff like this, I went up to him and I said, "Mr. Bocelli, do you hear better? Do you have a keener sense of touch? What's your verbal memory recall?" and all this. And, and he said, "You know, I- I've never, I've never been tested formally. I really don't think so." And when I asked him, "Why do you think you're the person you are today?" he said, "It's really, really simple. I had an extremely dedicated family. I had resources early on. I never grew up thinking that I couldn't do the things that I wanted to do. It was all about resources. It was all about opportunities." You may know he was an individual who lost his sight in his early teens or or around, around 10 or so. He was also a -- practicing lawyer for a couple of years and one day decided, "Do you know what? I don't, I don't want to do this anymore. I want to be, you know, a singer. That was my true passion." And sure enough, he's, he's very successful today. So, just goes to show you that neuroscience can only explain so much. At the end of the day it's about resources and it's about opportunities. Okay. So here's that fundamental question that I talked about from a neuroscience perspective. [ Slide start: ] Description Start: Title: Localization of Function in the Brain Content: center graphic: drawing of the brain with different colors and labels indicating the five senses: - red, front, smell; - yellow, middle-top; touch - green, middle-bottom; taste & hearing - blue, rear; vision Large red circle circle with a line drawn through and an arrow pointing to a large red question mark over the vision section of the brain. Description End: The localization of function in the brain. And you all know this that the five senses are all processed in different parts of the brain. Parts of the brain responsible for smell, for touch, for taste, for hearing and vision. And the visual part of the brain in the back here is what's called the occipital visual cortex. And that's about 25-30% of your cortical surface, that's a lot of hardware dedicated for the purposes of seeing. So the question becomes: If you were born blind, what would all this do? Right? Does it stay silent, does it do something else? Can it do something else? If you're born blind versus losing your sight later in life, does that matter in terms of its developmental fate? [ Slide end: ] So there's an interesting neuroscience question that a lot of people were, were interested in. And the way that we answered it was using a technique called "functional magnetic resonance imaging," [ Slide start: ] Description Start: Title: Functional Magnetic Resonance Imaging (FMRI) Content: top left-side photo: FMRI machine top right-side photo; patient inside FMRI machine bottom left-side photos: silhouette of person running with label "active;" sculpture of "Thinker" by Rodin with label "rest;" center graphic: block arrow pointing to the right; right-side photo: FMRI cross-section of a brain with active areas indicated in red; colored t-value scale with color values from blue at 0.0 to red at 8.0. Description End: you are all familiar with M-R-I. F-M-R-I sees the brain in action and it works a little something like this. It turns out that when the brain works doing a particular task, the parts of the brain that are working the hardest are going to command more blood and are going to command more oxygen. And that sets up a contrast that the scanner can detect. So, what we do is we ask an individual to do something in the scanner: look at pictures, count to ten backwards, recall names. And then we scan the person doing nothing. At rest, if you will. And we subtract the two. And when we subtract the two, what's left over? These little hot spots of activity theoretically are associated with the task that person was performing. Right? Everybody understand that? [ Slide end: ] [ Slide start: ] Description Start: Title: Functional Recruitment of Occipital Visual Cortex in the Case of Ocular Blindness Content: right-side photo: profile FMRI of brain with active areas indicated in yellow and red. right-side photo: hands on a page of braille Reference: Saddo el al. Nature, 1996 Description End: Okay, so let's look at some data. Here was the very, very first one. You're looking at the side view of a brain right here, and in this blue circle you see a large spot of activity in the occipital visual cortex of this individual. But this person is congenitally blind. So the question is is why would their visual brain be active if they're congenitally blind? And the answer is this person is reading braille. And that was one of the very, very first examples of these compensatory behaviors. [ Slide end: ] That the occipital visual cortex is active for non‑visual tasks. And many people have replicated this and also found in other scenarios as well: [ Slide start: ] Description Start: Title: Functional Recruitment of Occipital Visual Cortex in the Case of Ocular Blindness previous content with additional images: top right-side photo: Sound Localiztion, profile FMRI, Geougoux et al. Nature 2004; top center photo: Olaction, top FMRI, Kupers el al Neuropsychol 2011; bottom right-side photo: Verbal Memory, profile FMRI, Amedi el al Nat Neurosci 2003; bottom center photo: Language, profile FMRI, Bedny el al PNAS 2011. Description End: localizing sound, identifying smells, verbal memory recall, also in the case of language. In all these cases the occipital visual cortex is involved in this processing. [ Slide end: ] So, the take home message here is that the seed of compensation-- or compensatory behaviors I should say-- in the case of occular blindness is the visual cortex. Turning your visual cortex into a non‑visual processor, if you will, is part and parcel part to the compensatory behaviors in this group. Now I'm going to show you some more evidence that this is indeed seems to be the case. [ Slide start: ] Description Start: Title: Occipital Visual Cortex Plasticity: Early vs. Late Blind Content: top right-side photo: hands on a page of braille left-side photo: Early Blind, profile FMRI with large active area indicated in yellow and red. right-side photo: Late Blind, profile FMRI with smaller active area indicated in yellow and red. Reference: Burton el al. J. Neurophysiol 2002 Description End: The first question you may ask is "If I'm born blind versus losing my sight later in life, how does that change?" Well, someone did, did look at that point. This is Harold Burton's work a few years ago. He found individuals who are early blind, lost their sight before the age of two or three versus individuals who we classified as late blind-- lost their sight in their teens or in their, or in their 20s-- who were matched for braille reading ability. And that's the important thing, so they had the same braille reading skill level. And what he found is that in both cases the occipital visual cortex was active. But notice in the case of early blindness there's a lot more activation than there is in the case of late blindness, so the sooner you do this, the more intensive intervention is the more you can recruit the visual brain to do that. [ Slide end: ] All right? I'm going to show you some other examples about this. Here's sort of an extreme example, you know, 'cause-- [Laugh] This is, this is an interesting experiment. When I was a fellow, when I first joined um, when I first joined the group, this was an experiment that I was involved with called the "blindfold experiment." [ Slide start: ] Description Start: Title: The Blindfold Experiment Content: left-side photo: two images of blindfolded male subject left-side graphic: table with four columns labelled left-to-right, Baseline Day 1, Day 2, Day 5, Post-blindfold Day 6. Reference: From Pascual-Leone et al. Description End: So the question was: If you weren't born blind and you weren't a proficient braille reader, could you turn your visual brain into something else? And this is, this is how it was done. So we took normally sighted adults in their 20s and their 30s, and they came and lived at the hospital for five days. And they were blindfolded throughout that period. [ Slide end: ] And every day they were professionally taught braille- by a professional braille instructor- for four to six hours. They lived at the hospital, they hung out at the hospital and all they did was learn braille, right? Paid very well. [ Laughter ] I know what you are thinking, right? [ Laughter ] New England winters, people are -- people are looking for things to do, right? [ Laughter ] So what you're looking here, what I want to show you here is the serial F-M-R-I of the back of their brain as the week proceeds, all right? [ Slide start: ] Description Start: Title: The Blindfold Experiment Content from previous slide with three rows of FMRI images in columns Day 1, Day 2 & Day 5, showing increased activity indicated in yellow. Description End: So, on day one, we put them in the scanner and look at the back of brain: very, very quiet in terms of response to tactile stimulation. Day Two: See the visual brain turning in, turning more and more tactile. Day Five it's now robustly activated in response to tactile stimulation. So, five days is enough to make these changes happen in an adult brain that already has fully normal developed vision. [ Slide end: ] Why do I think this is possible? It's the intensity of the intervention, the profound blindness, the intensity of the training, the brain likes that. That's when changes typically occur. A couple of other pieces of information I'll share with you: on the Sixth Day we take the blindfold off for 24 hours, and we put them back into the scanner, [ Slide start: ] Description Start: Title: The Blindfold Experiment Content from previous slide with FMRI images in column Day 6, showing decreased activity indicated in yellow. Description End: use the same tactile stimulation and activities we've already done. So very, very reversible as well. Other interesting piece that comes to this, we had a control group, so we had a group of individuals who were also at the hospital learning braille but they weren't blindfolded. [ Slide end: ] So they were going through the same formal instruction, right? These individuals did not learn braille as quickly and as well as the individuals who were blindfolded, right? So the blindfolding seemed to have been able to accelerate their braille learning ability. Another thing that is interesting, when we take the blindfold off, we give them 24 hours and we test them again, what do you think happened to their braille reading skill? Went down, exactly. So putting vision back into the equation threw the system out as well. So, I think it's an interesting question. If you have an individual who you know is going to go blind from R-P, for example, do you teach them braille through sight, through residual vision or do you teach them blindfolded? I think that's an interesting impact along those lines. [ Slide start: ] Description Start: Title: The Blindfold Experiment Content from previous slide with right-side photo: 2 Way Comparison: Day 5 > Day 1, Blindfold > Non Blindfold, profile FMRI image with cross-hairs indicating yellow activity in the rear of the brain. Reference: Merabete et al. PLOS One 2008 Description End: Here's the group data. Just to show you that it wasn't just one individual. We had over 36 individuals enrolled in this study, I'm showing you what's called a two‑way comp, two-way comparison. I take all of the activity on the brain on Day 5, I subtract that from Day 1, and then I take all of the individuals in the blindfold group versus all of the individuals in the control group. I subtract all that out and I show you where the activation is. And sure enough, that activity is right in primary visual cortex. [ Slide end: ] So, all this is happening across the groups in, in this particular part of the brain. Let me show you the opposite situation. [ Slide start: ] Description Start: Title: Project Prakash Content: top left-side graphic: three interconnected ovals over a circular blue background bottom left-side photo: 35 small portraits of young people with label, "28,000 children screened, and over 1,800 provided treatment including surgical cataract removal." top center photo: two men and boys observe a man in dress shirt and tie who is instructing two children looking at a laptop computer, seated with their father. right-side graphic: profile drawing of the brain with cross-hairs indicating small red area of activity in the rear portion. Reference: Slide courtesy of Pawan Sinha, http://www.projectprakash.org/ Description End: So this is something called Project Prakash, this is led by a colleague of mine and dear friend named Pawan Sinha from MIT. He's of Indian origin and one day, while visiting his, his native country of India, said, "You know, it's absolutely astonishing the number of blind children in this country," [ Slide end: ] and they largest number per capita of blind children in the world. And the other thing that's pretty astonishing is the majority of them have treatable blindness, in most cases it's, it's, it's it's cataracts. So he had a very, very interesting question, he said, "You know, what if we had the chance to learn how we see?" Right? It's very, very hard to ask a baby what they're going through, obviously, as they learn to see. But what if you had the opportunity of taking a young adult, giving them sight and asking them what it's like to learn to see? And that's exactly what his project is. Project Prakash-- "prakash" means light. So he's essentially giving light to these children. And it's a wonderful, wonderful project because not only is he trying to, to to answer a very, very important neuroscientific question, he's also trying to have this really strong humanitarian arm as well. Close to now 30,000 children screened, over close now to 2,000 who have been provided free cataract surgery. It's really quite remarkable. I'm going to show you a video from one of the children. This is Soumitra, she's 12 years old, she had dense cataracts due to rubella as a child. And I'm going to show you the baseline situation. [ Video start: ] Description Start Titles: Soumitra, Pre-surgery. Girl walking in an open air hallway with concrete floor and painted white wall. Two men and a boy observe her from behind. On her left is a potted plant and box of chocolates. She takes a few steps and stops. She squats with her hands on the floor. The boy comes up behind her and touches her on the shoulders. A man ushers the boy away. From behind, the other man speaks to her and motions to the box of chocolates. While continuing to squat, the girl moves forward a few steps and sweeps her hands on either side, then turns around and repeats sweeping. Titles: Soumitra, Post-surgery. Girl walks in to the same open-air hallway, observed by two men behind her. After a few steps she appears to notice a box of chocolates on the floor against the white wall and immediately scoops up the box, smiling. Titles: project prakash Description End And a very, very simple scenario to kind of show you what's happening here. So, here's Soumitra pre-surgery, she's walking, and again as I said she's 12 years old. And they put a box of chocolates right next to the wall there on her left. And we asked her, "Soumitra, can you find, can you find the box of chocolates?" And she looks around, has no idea, and this is a classic sort of scenario, they feel really kind of like they're on the spot, and they, they feel like they're failing, and they just sort of like hunker down like this, and they get very, very discouraged in these types of situations like this. Despite probing, despite some indications and prompting, she really has no idea where, where the chocolates are. So she's going to -- get up here. And this is about three to four days after cataract surgery. Not years, not months, three, four days. Bring her back into the corridor and without any prompting, there you go. Grabs, grabs the box of chocolates right away. So really, really dramatic. When you think in a country like India with extreme poverty, extreme issues, [ Video end: ] this is monumental and it's really, really life changing for these individuals as well. So it's an incredible opportunity, as I said, to understand visual development, but at the same time also there's this, this incredible humanitarian arm as well. So we have a study now with Pawan where they're scanning these kids, doing the M-R-Is and shipping us the M-R-Is through the internet and we're looking at their brains as well. [ Slide start: ] Description Start: Title: Cortical Thickness Changes in Visual Cortex Content: center graphic: profile drawing of the brain with cross-hairs over a red area in the rear of the brain. Colored scale, blue -5.00 to yellow 5.00. Description End: And what I'm showing you in this particular photo down here is we're comparing all the kids who got cataract surgery versus the kids who didn't. And the biggest changes in terms of cortical thickness- and thickness is an indicator of brain development- is right again in the primary visual cortex. All right, so again this is where things are happening. Notice the location here how similar it is in this particular location here. [ Slide end: ] So, the biggest changes seem to happen in the primary visual cortex in this particular case. Now I know what you're thinking. "Okay, you're coming in with all your fancy brain scans and how do I know this isn't Photoshopped?" And, you know, that sort of thing. I'm going to give you some experimental evidence that indeed what's happening in the visual cortex actually matters in this particular case. So, this is a clinical case that I- a patient, I should say, I had a chance to work with, but this story happened before I came to the hospital. So I'm telling you the story the way that I was told the story. [ Slide start: ] Description Start: Content: Case Report - 63 y.o. right-handed female - blind at birth (retinopathy of pre-maturity) - normal milestones, Braille at 6 y.o. - proficient reader: 120-150 symbols/min Compalint: light-headedness, diffculty swallowing, loss of consciousness - admitted to emergency - falls into coma - withing 24 hrs; alert and interactive - "normal physical and neurological exam" Reference: From Hailton et al. 2000; Neuroreport and Merabet el al. 2004, Neuron Description End: In the particular case, at the time of the study this was a 63‑year‑old right‑handed female. She was blind at birth, she had retinopathy of prematurity. Profound because her visual, her reported visual acuity was "no light perception" in either eye. She hits normal milestones. She learns to read braille at the age of six and she's a highly, highly proficient braille reader. I don't need to convince you that 120, 150 symbols per minute is a very, very fast braille reading speed. This is someone who is very, very good at this skill. In fact, she was an editor for a braille journal back in in Spain for ONCE, which is the Spanish organization for the blind. Very, very proficient braille reader. One day she's not feeling well. She wakes up, she has a really, really bad headache, has difficulty swallowing, tingling sensation. She doesn't really know what's going on, but she decides to go to work nonetheless. A few hours later symptoms get worse, she passes out, she loses consciousness. She's rushed to the hospital and she falls into a coma for 24 hours. She wakes up, the doctors come in and say, "You're fine, you're safe. You had an, an event. Everything's okay. Everything, everything's going to be all right." And she said, "Great. Thank you so much. Would you mind giving me my, my phone book? My, my personal effects because I'd like to contact some family members and so on." They said, "Of course." They hand her her phone book, which is written in braille, and she starts reading it like this. And she says, "You know, this is really, really strange. I- I- I can feel the dots. [ Slide end: ] But I have no idea what this says." Anybody know what happened? I'll give you a hint. She had a stroke, the question is where? In her visual cortex. Right? [ Slide start: ] Description Start: Title: Braille Alexia Following an Occipital Stroke Content from previous slide with right-side photo: two top view MRIs of white areas in the occipital lobes. Description End: So, it was an embolism at the tip of the basilar artery -- it knocked out both banks of occipital circulation, and to this day she is alexic, the acquired inability to read braille, [ Slide end: ] because of the damage to her visual brain. Not the part of the brain responsible for for language, not the part of the brain responsible for touch. The part of the brain that theoretically she wouldn't have use for. Right? So, pretty pervasive, pretty tragic uh- evidence that indeed what's happening in the visual cortex is intimately related to these compensatory behaviors. Let me give you a more experimental evidence for this. And this was also part of the work I did as a, as a fellow. [ Slide start: ] Description Start: Title: Modulating Braille Reading Performance by Modulating Brain Activity Content: left-side graphic: 3-D drawing of a head with the brain revealed; two circles connected to a shaft, like an old key labeled, "TMS coil;" white lines radiating from the coil labeled, "Generated Magnetic Field;" red arrow labeled "induced current" pointing through coil to a flash point in the brain. Blue label: Low frequency (e.g. 1 Hz) = lowered excitability Red label: high frequency (e.g. 10-20 Hz) = increased excitability right-side photos: profile of the skull revealing the brain with a drawing of a TMS coil, photo of hand on a page of braille. right-side graphic: Graph with y-axis label Braille reading speed (words per min), 50 to 110; x-axis label rTMS condition, Sham, 1 Hz and 10 Hz; graph label: "Fig. 3 The effects of rTMS on Braille reading speed. Experimental conditions were either 1 Hz or 10 Hz rTMS stimulation, or 'sham' (a non-stimulating control condition). Open symbols refer to performance prior to rTMS and filled symbols refers to performance immediately following rTMS to the occipital cortex. Symbols display the mean values and error bars the standard deviation values for five early-blind subjects." Sham position, standard deviation approx. 62 to 87 wpm, filled symbol at 72 wpm. Low frequency, 1 Hz position, standard deviation 53 to 87 wpm, open symbol 74 wpm and filled symbol at 63 wpm; High frequency, 10 Hz position, standard deviation 60 to 105 wpm, open symbol at 72 wpm, filled symbol at 90 wpm. Reference: Roy H. Hamilton and Alvaro Pascual-Leone TICS 1998 Description End: It turns out there's a way to stimulate the brain using a technique called Transcranial Magnetic Stimulation non-invasively, and I'll explain to you very quickly how this works. So, T-M-S is essentially a big battery, it's a machine that stores an enormous amount of charge. And when you hold this coil over a person's skull you can actually send a magnetic pulse, an electromagnetic pulse through the brain that can stimulate or inhibit the brain below it depending on the frequency that you use. So, if I use a low frequency, so sending one pulse about every second, I can silence the brain. I can deactivate the brain. If I stimulate at high frequency, around 10 to 20 hertz, 10 to 20 pulses per second, I can actually excite the brain. So, this is what we did working with, with proficient braille readers. So, what you see here, what's called the sham condition, in other words we just hold the coil, there's no stimulation, they're reading at about 70 symbols, 70 words per minute. When we use low frequency simulation we can decrease their braille reading speed. Right? So, we're silencing the visual brain. When we use high frequency stimulation we increase their braille reading speed. [ Slide end: ] And we do this in a -- in a randomized fashion so they don't really know what's coming and, and the results really seem to hold true. So this is active manipulation of their visual cortex that is impacting their ability for braille reading. So, again, showing you causal evidence that what's happening at the level of the visual brain is intimately related to their compensatory behaviors. So, here's my summary slide in terms of ocular blindness. [ Slide start: ] Description Start: Content read by speaker; center photo: close-up of white cane and users shoes walking toward camera In the setting of Description End: "In the setting of ocular blindness, compensatory skills and behaviors are intimately linked to how the brain rewires itself and in particular the developmental fate of the occipital visual cortex." [ Slide end: ] [ Slide start: ] Description Start: Title: Ocular vs. Cortical/Cerebral Blindness? Content: center graphic: profile drawing a transparent skull with the jaw bone, brain and spine visible, circle with line drawn through it over the eyes, rear of the brain colored yellow; four small photos, hands on page of braille, hand with a bow tied on a finger, close-up profile of a nose, and man standing in a room of acoustic tiles. Description End: So, here's a summary visual of those same principles. In the case of ocular blindness, the visual brain becomes non‑visual. It is responsive and is responsible for the processing of touch, for memory, for smell, all sorts of language skills and this again as I said is the compensatory seat of behaviors or, or, or the seat of compensatory behaviors, I should say, in the case of ocular blindness. So now I think this begs the question: What happens if you're born with your eyes and they're fine but your occipital cortex is damaged? Where does all this compensation happen or does it even happen at all? And sure enough there's a population that exactly fits that -- very much that, that, that profile. [ Slide end: ] And that's C-V-I, of course, or the case of cortical or cerebral visual impairment. You're all very, very familiar with this so let me just give you some, some background about this so we're all on the same page. [ Slide start: ] Description Start: Title: The case of Cortical/Cerebral Visual Impairment (CVI) Content: ... a public health crisis? CVI affects nearly 2 out of every 1,000 live births, and accounts for nearly 20-25% of visually impaired children in developed countries. Description End: So, C-V-I affects nearly two out of uh um- excuse me- two out of every thousand live births and accounts for nearly 20 to 25 percent of visually impaired children in developed countries. Not developing. Developed countries. [ Slide end: ] And I was really, really struck. When I was going through school I had never heard of C-V-I. I had no idea what C-V-I was. And now all of a sudden it's this public health crisis. [ Slide start: ] Description Start: Title: The case of Cortical/Cerebral Visual Impairment (CVI) Content from previous slide with right-side grahic, table labeled, "Causes of vision loss in students from school for hte blind in the United States (n=3070)" Reference: Kong et al. Journal of AAPOS 2012 (USA) Description End: So this is some epidemiology data that comes from the United States that rank orders all the causes, in -- the rank order of causes of visual impairment in children in schools for the blind throughout the country. And number one is cortical visual impairment. And it's really striking. When I talk to ophthalmologists and optometrists back in Boston and ask them this question: Where do you think CVI ranks? They have no idea that it's a top cause, in fact, the top cause. Look at the other things just out of curiosity. You have things, for example, like syphilis and herpes, right? These are all things that are infectious, right? Theoretically, we'll get better and better at taking care of this. Retinopathy of prematurity has always been a big one, but we figured that out, we figured out that we were the ones doing that and we're much better at taking care of these children. Right? And then you also have to think that as we get better with things like retinitis pigmentosa and Lebers, genetic gene therapy, gene studies, and so on that's also going to decrease as well. [ Slide end: ] So I submit to you that over 20, 30, 40, 50 years the profile of what it means to be visually impaired is going to change dramatically as we get better and better dealing with these causes, but not so good in terms of C-V-I. So I think we're, we're heading to a very, very dramatic situation. The question is why are they so prevalent? Why are all these kids out there? And, of course, the reason is we're getting very, very good at taking care of premature babies. [ Slide start: ] Description Start: Title: The case of Cortical/Cerebral Visual Impairment (CVI) Content from previous slide with lower-left-side graphic: cover of Time magazine, headline Saving Preemies. Description End: We weren't so good before, right? 24 weeks, 26 weeks is not unheard of now to, to survive and the problem is that they're surviving with complications, right, and C-V-I is, is a big one. [ Slide end: ] [ Slide start: ] Description Start: Title: The case of Cortical/Cerebral Visual Impairment (CVI) Content: left-side text: Major causes of CVI: - Perinatal hypoxia/ischemia - head injury/trauma - Infection (e.g. encephalitis, meningitis) CVI is suspected by: - a "normal" eye examination (ocular findings do not correspond to visual impairment) - visual acuity ranging from near normal to profound blindness and visual field deficits (usually inferior). = characteristic neuroradiological findings (Periventricular leukomalacia: PVL) - a medical history which includes neurological impairment (e.g. cerebral palsy) - the presence of unique visual/behavioral dysfuntions (e.g. visuo-spatial and motion processing, complexity/crowding, and attention) right-side graphic: drawing of front of infant skull revealing the brain, labels pointing to Ventriculomegaly and Hypomyelination; inset grahic of smaller skull with indiscernible labels. Reference: http://pediatrics.ucsf.edu/node/58 Description End: Little bit more information about this: the major causes of C-V-I again, as you know: perinatal hypoxia, ischemia is the biggest, biggest driver. There is a bleed that happens in utero. There's blood that rushes into the ventricles of the brain. And as the baby develops, this blood is resorbed, but you see now this enlargement of the ventricle, and there's what's called focal necrosis of all the white matter pathways that surround the the ventricles and I'll get back to that in just a second. Head injury trauma also possibilities. Infections like encephalitis is another one. But the big one is certainly some sort of a hypoxic or ischemic event. Other things to think about in the case of C-V-I: Typically we, we say that these kids with C-V-I have a normal eye examination, that's not entirely true. I think a better way to think about it is that they have visual disturbances or visual dysfunction that can't be explained by their eyes. Right? It's not a refractive error, it's not strabismus, it's not an infection or anything along those lines. There are higher order complex visual processing problems that can't be explained by the eyes, and that's what makes it very, very challenging. They go and see their eye doctor. Said, "Looks okay to me, your kid must be faking this, your kid must have some sort of learning disability, your kid must be lazy." I'm sure you've all heard similar stories as well. This is what concerns me tremendously, not just on the clinical side by also on the, on the care side as well. Visual acuity can range from anywhere from near normal to profound blindness. Visual field deficits are also very, very common and typically they're in the inferior visual field. I'll give you some, some some neuroimaging evidence as to why that's the case. And the characteristic finding in a lot of these kids is what's called P-V-L, Periventricular Leukomalacia. Right? So, "periventricular" meaning "surrounding the ventricles," "leuko" meaning "white," and "malacia" meaning "soft." Right? And it's not because somebody took their brain stuck their finger in and said, "Oh, that's soft." No. It's, it's actually because it looks soft on an M-R-I. That area has sort of a fluffy appearance and that's where P-V-L comes from. Typically they have a medical history with that includes some sort of neurological impairment, typically it's cerebral palsy when it's affecting motor pathways as well, cortical spinal tracks. So, often you see the two together. And then the presence also of unique visual behavioral dysfunctions, as I said, including visuo‑spatial and motion processing, complexity, crowding, and attention deficits. These aren't things to fix with glasses. Right? These are things that are higher order, definitely somehow involved with how the brain processes information. [ Slide end: ] [ Slide start: ] Description Start: Title: The Visual System: A division of Labor; "Dorsal Stream Dysfunction" Content: center graphic: profile drawing of infant skull with brain functions labeled and color coded; large blue arc from rear of the brain to the front labeled "dorsal stream;" large red arc from rear to the front labeled "ventral stream;" large yellow arc from rear to front labeled "Frontal stream." Dorsal = Where?/Spatial Ventral = What?/Object Occipital-Frontal = Attention/Eye Movements Description End: Some background as well that you might be familiar with. A lot of individuals in this field have called this what what what I refer to this as a dorsal stream dysfunction. So, just to remind you, that the visual system is parsed into three, three major streams. There is what's called the dorsal pathway. This is the "where" pathway, this connects the occipital cortex to the parietal cortex into the front of the brain. This is responsible for identifying where things are in space, right? There is also the ventral stream or the ventral pathway. This connects the occipital cortex to the temporal cortex. This is involved with identifying an object, the actual identity of an object, and these two things- there's a division of labor between these two, these two aspects. And the third pathway, which represents direct connections from the occipital cortex to the frontal cortex. This is responsible for attention and eye movements and this, this, the division of labor exists in the visual system. [ Slide end: ] And we also know that clinically this is true because damage to one stream spares the others. And the idea now is: is C-V-I a dorsal stream dysfunction? Right? That's a big sort of theory. And we wanted to get into this idea in terms of neuroimaging to try to give a, a neurophysiological basis for it. [ Slide start: ] Description Start: Title: The Visual System: A division of Labor; "Dorsal Stream Dysfunction" Content from previous slide with top-right-side graphic of tree-like structure, two roots merge into broad trunk which splits into three sections with many smaller branches. Description End: Just some other pieces of information: Gordon Dutton- you might know this individual- did a lot of work as well, has an interesting perspective called the Tree of Visual Per-- of Visual Perception. He talks about how eyes are kind of like the roots and then there's one big branch, which is the ventral stream, the other big branch is the dorsal stream. I think it's kind of an interesting way to think about it. [ Slide end: ] I'll be honest with you, I'm not a big, big fan of this particular view because I think it, there's a misconception that vision is just a bottom-up phenomenon: it comes into the eyes and somehow magically is all figured out in the brain. [ Slide start: ] Description Start: Title: The Visual System: A division of Labor; "Dorsal Stream Dysfunction" Content from previous slide with bottom-right-side graphic of flow chart or organizational chart of brain functions all interconnected with hundreds of fine lines. Reference: http://mikeclaffey.com/psyc170/notes/notes-vision.html Description End: The fact of the matter is that the brain is really a look, looks more like this in terms of information is being constantly cycled all the time. What's coming in versus what you think you see is constantly being compared. And I think in the case of C-V-I there's disruption. And in particular I think there's a problem of, of connectivity in the brain as well. And we'll get deeper and deeper into this, this issue as well. [ Slide end: ] [ Slide start: ] Description Start: Content: Two overhead MRI cross sections of the brain labelled, "A. Sighted control" and "B. Ocular blind" Description End: So, let's start looking at some data. I'm showing you here standard M-R-I images, right, if you were to go and ask for an M-R-I of, of one of your patients this is what it would look like. This is an actual scan, slicing through the brain. Here is a sighted control individual, in their, in their late teens. Here is an ocular blind individual. Looks awfully similar, doesn't it? Right? [ Slide end: ] [ Slide start: ] Description Start: Content from previous slide with Two overhead MRI cross sections of the brain labelled, "C. CVI 1 (16 year old female)" and "D. CVI 2 (22 year old male)" Here are two individuals with C-V-I that we've been working with. This one- C-V-I 1- is a 16‑year‑old female, C-V-I 2 is a 22‑year‑old male, and the first thing you see is this enlarged ventricle form here, right, these enlarged ventricles, again what we call P-V-L, periventricular malacia. The problem is that we can't really tell more than that, apart from the fact that they have P-V-L. In other words standard imaging doesn't tell us anything about their underlying deficits. Right? I'm going to try to demonstrate that for you in this particular game. We're going to play a game here, right? You guys ready? [ Slide end: ] [ Slide start: ] Description Start: Title: The Neuroradiology Paradox: Content: Four overhead MRI cross sections of the brain labelled 1 through 4. left-to-right. Each MRI shows ventricles of different shapes and sizes. Labels revealed later: Lesion load (extent of apparent damage) does not always correlate with clinical symptoms; labels under each MRI, left-to-right, 20/40, 20/80, 20/20, ?. Description End: You guys remember Sesame Street? Right? [sings] "One of these brains is not like the other." Right? [ Laughter ] We're going to do that right now. So, I have four brains here that I'm going to show you. And you can all see they have different levels in terms of their, their ventricular, their ventricular structure. Right? So pretty extreme here, pretty extreme here, a little bit intermediate, and looking pretty normal there. So my question to you now is: Who has the best acuity and who has the worst visual acuity? Just based on what you see. And just- uh for the interest of time: your, your rationale probably is something like this. You said, "This is probably the most normal looking brain there, so that's probably going to be the best acuity. This one's probably intermediate, Number 2. And probably a toss-up between Number 3 and Number 1. Maybe Number 1 because it seems a little bit more symmetrical. Does that kind of make sense? You think? Well, here are the answers. It turns out that the worst visual acuity was Number 2. Number 3 actually has normal visual acuity. The intermediate one was Number 1. And Number 4 was actually in a coma, I just threw that in, we had no idea what-- [ Laughter ] [Laughs] Just to show you. Or to make my point, I should say. What we call a neuroradiology paradox. The fact is that lesion load-- the extent of apparent damage-- does not always correlate with clinical symptoms. And that's the problem. [ Slide end: ] I see this in my clinical practice as well. Sometimes I'll look at an M-R-I, there's extensive damage. And I say, "Wow. This, this guy's really, really in bad shape." I go into the room and he's standing up talking to me. Right? There's other ones I've seen where I'm like "Yeah, that looks really- that looks fine, I don't see anything." And sure enough, you know, they, they can't speak or they have all sorts of motor issues as well. And that is the big, big challenge particularly in the case of C-V-I, is that even with M-R-I imaging it doesn't really tell us what's going on with these kids and with these individuals. So we need another way to scan them. And let's get into that right now. So here's my hypothesis that I, I hope to, to kind of convince you. [ Slide start: ] Description Start: Contents read by speaker. Description End: C-V-I is a disorder of brain connectivity ...underlying connectivity is associated with observed visual dysfunction. So, this how we're going to try to figure this out. [ Slide end: ] [ Slide start: ] Description Start: Title: How are Brains Wired?: Diffusion Based Imaging Content: left-side graphic: embedded video of water molecules, random movement, constrained movement; upper right-side graphic: "Virtual Dissection," graphic showing yellow, red, and green neuropathways; lower right-side graphic: top MRI scan of brain with left-side, blue and right-side, red Occipito-temporal connections in the human brain. Reference: Modified from video by the Laboratory of Neuro Imaging, University of Southern California Description End: So, we use a technique called "diffusion based imaging." All right? This is not standard M-R-I. This is a different way of looking at the brain. And it allows us to figure out the brain connectivity, the white matter projections to the brain. And this is how it works. So, it turns out that your brain is essentially anywhere between 70 to 90 percent water. Right? So what the scanner is doing is tracking the motion of water in your brain. And if it was following one water molecule and it was moving equally in every direction in three dimensional space we would call that isotropic diffusion. So, in other words, no matter where it was it could move freely, we call that "isotropic diffusion." If, however-- I'm talking a little, talking a little bit quicker than the video-- If, however, that motion was somehow constrained, in other words, it was moving along one axis more than it was along the other axes, we call this "anisotropic diffusion." And why would that water movement be constrained? Well, if it was associated with a brain cell. Right? So. that axon constrains the motion of that water molecule and what the scanner is doing is figuring out- voxel-by-voxel, pixel-by-pixel- what those water molecules are doing and from there inferring the orientation of white matter tracks. The nice thing about this is that you can do something that's called "virtual dissection." You can pull tracks out in terms of looking at specific areas and connectivity and, and, and parts of the brain to see how they're wired together. Here's a nice example of looking just at the optic tracks, for example, from the thalamus in the middle here all the way to the back of the brain. These are the optic radiations. It allows you to reconstruct specific tracks of interest. [ Slide end: ] [ Slide start: ] Description Start: Title: White Matter Tractography and Reconstruction Using High Angular Resolution Diffusion Imaging (HARDI) Content: embedded video described by speaker. Description End: So, here in this video is an example of what this technique looks like and I'm going to rotate this in three dimensions. This is a three dimensional reconstruction of a 15‑year‑old normal sighted control of their brain and here is the dissection that I talked to you about. So what we did here is we asked the software, "Tell us how the visual brain in the back here is connected to the rest of the brain." All right? So we can look specifically at the information superhighway, if you will, of your brain. This is the connectivity of your brain. Couple things to keep in mind. First of all the brain is not pretty colors like this, obviously. That's just a nomenclature system. Blue means its axons are traveling up and down. Green meaning to the front and to the back of the brain. And red means moving side to side, right? So it's just an orientation. The second thing is it doesn't look like spaghetti like this either. That's just the resolution of the software. Each one of those thin threads is thousands and thousands and thousands of axons, or brain cells. And it just has to do with the resolution ability of that. [ Slide end: ] So just because you don't see the axon doesn't mean there's nothing, it just means that there's a really, really small number. All right? So let's take a look in the case of C-V-I what happens, right? [ Slide start: ] Description Start: Title: Recostruction of Cortical-Cortical Visual Pathways Content: left-side graphic: label, "Sighted Control" Profile MRI of brain, colored pathways, red, green and blue; blue label, "SLF = Dorsal = Where?/Spatial Processing;" red label, "ILF = Ventral = What?/Object Processing;" yellow label, "IFOF - Occiipital-Frontal = Attention Processing" Description End: So here's again a normally sighted control. We've asked the software to just show us the brain connectivity of the visual cortex to the rest of the brain and there's three main pathways that show up. And the names aren't, aren't really important. The S-L-F, the I-F-O-F, and the I-L-F. So you should remember back a couple of slides I told you about the three pathways of the visual brain. This is the neuroanotomical correlate of those three pathways. The S-L-F is the dorsal stream, the I-L-F is the ventral stream, and the I-F-O-F is the direct connection between the occipital cortex and the frontal cortex. So we now have the neuroanatomy of the three visual pathways. Right? Anybody want to know what a C-V-I individual looks like? [ Slide end: ] [ Slide start: ] Description Start: Title: Recostruction of Cortical-Cortical Visual Pathways Content from previous slide and right-side graphic: label, "CVI 1" Profile MRI of brain, fewer colored pathways, red, green and blue; "Clinical Functional Assessment:" blue label, "Spatial awareness deficits;" red label, "No object identification deficits;" yellow label, "Strong attention deficits" Description End: Here it is. Yeah. A lot missing. Yeah. It's pretty, pretty dramatic. Age matched, okay? And some of the things to think about in this particular individual, we notice that in this particular individual she was quite good at identifying objects. In other words, her ventricle stream seemed to be largely intact. She also had a lot of deficits in terms of her spatial processing. And, sure enough, her S-L-F seems quite thin, but her biggest deficit was attention and sure enough we can't even reconstruct her I-F-O-F pathways, as well. So, this gets back to this idea that the connectivity should somehow reflect the deficits of these individuals are showing. Okay? Let's get a little bit deeper into this point here. [ Slide end: ] [ Slide start: ] Description Start: Title: White Matter Tractography Reconstruction of Major Visual Pathways Content: Four left hemisphere MRIs with colored pathways or SLF, ILF, and IFOF. A. Sighted Control, B. Ocular Blind, C. CVI 1 and D. CVI 2 Reference: Bauer el al JAAPOS 2014 Description End: You're looking at the left hemisphere here. Again those three same pathways, right? The I-L-F, the I-F-O-F, the S-L-F, as I showed you. This is a normally sighted control. Here's an ocular blind individual of the same age. What do you notice? It's all there. Right? In other words, all the machinery is there. Right? Very, very similar to what it looks like in a normal sighted control. And here are those two C-V-I individuals I mentioned. Again, a lot of thinning, a lot of pathways seem to be very, very thin, right? In some cases the I-L-F seems to be quite nice, the ventral stream. But the dorsal stream seems to be showing the most deficit. So kind of fitting with this idea of spatial deficits and whether or not they can make sense by underlying connectivity. So we want to pursue that a little bit more. [ Slide end: ] [ Slide start: ] Description Start: Content: Table with three columns labeled, left-to-right, "Sighted control," "Ocular blind," and "CVI." First row labeled, "A. Whole Brain Network Analysis," with diagrams representing the networks in the brain. An outline of the brain contains points and lines connecting each of the points. Diagram described by speaker. Second row labeled, "Connectivity Matrix Analysis" with scatter graphs of points representing brain connections in left and right hemispheres, colored blue, low density, and red, high density. Graphs described by speaker. Description End: Another thing just to give you some, some fancy math we can also do what's called network analysis. We can look at the brain and figure out and count the number of connections between various areas. All right? So we use what's called network-based statistics. Here it is in the case of a sighted control. These are all the connections between the brain, you're looking at the brain from the top. Here it is in an ocular blind individual. It is hyper-connected. Right? That seems to make sense given all these compensatory behaviors. By enhancing connections between non‑visual areas and eventually the visual cortex, this supports these compensatory behaviors. We're not the first ones to show this. There are many groups who have shown this in the past as well. But the dramatic thing is the case of C-V-I. It's an under-connected brain, right, compared to the case of ocular blindness and the case of sighted controls as well. Just more math behind this. This is called the Connectivity Matrix. This allows you to quantify the number of connections between various areas by hemisphere, by by brain type and so on. The more red you have, the more connectivity you have. Notice that there's a lot more red in the case of ocular blindness and a lot less red in the case of C-V-I as well. So ocular blindness hyper-connected. C-V-I under-connected. All right? [ Slide end: ] [ Slide start: ] Description Start: Title: Cortical Thickness (Surface Based Morphometry) Content: Three images of the brain colored to represent thickness, from lowest, blue, to gray, to red, to thickest, yellow. A. Sighted control - cortical area is mostly red. B. Ocular Blind - cortical area is mostly red. C. CVI 1 - cortical area has large areas of grey and some red. Description End: Other things to think about. I mentioned this idea about cortical thickness, how we look at primary visual cortex as a site of brain development giving us a sense of what's going on, right? I gave you that example of blindfold subjects and also in the case of the Project Prakash. Here it is in the case of ocular blind- sorry- sighted controls. Red means lots of thickness. That's good. The brighter it is the more, the thicker it is. Case of, of, of sighted controls: very, very thick. Case of ocular blindness: also very, very thick. Here it is in the case of C-V-I: very, very thin. Moral of the story is that this is a very underdeveloped visual brain, right, and it goes throughout life this way. That's the problem. So the question is how do you kick start this? How do you get this to start growing, if you will, so that the rest of the brain grows as well? That's a really big important question. [ Slide end: ] [ Slide start: ] Description Start: Title: Correlating Clinical, Structural and Functional Finding in CVI Content: center graphic: arcing arrows and labels show a 3-part cycle circling around an image of an MRI scanner. Labels are "Clinical," "Structural," and "Functional." Description End: Our approach is the following, I'm now going to give you a little more evidence behind this. I spent some time charging-- You all know the clinical deficits. I gave you some evidence from the structural standpoint, the brain wiring. Now we're going to talk a little bit more about the functional components of this. How does this relate to the actual behavioral deficits that we see in these individuals? And this is how we started doing it. [ Slide end: ] So as you know, it's, it's it's a challenge working with these individuals. Attention isn't always there, fixation is also kind of tough to do. They are always, you know, kind of not that interested in what you're doing, the last thing they want to do is to have their-- go through an eye exam. [ Slide start: ] Description Start: Title: Characterizing Visual Function in CVI:Tablet-based Testing Content: left-side photo: woman looks at screen of a hand-held computer tablet. top right-side graphic: label, "Contrast Sensitivity," graph representing contrast sensitivity. bottom right-side graphic: 3 smaller graphics labeled, "Biological Motion;" a group of random dots in a square, labeled, "2. Detection test" with a stick figure of a person visible from lines connecting some of dots. Another stick figure created by a series of dots and lines, labeled, "4. Distortion test." Another stick figure created by a series of dots and lines that appears to be doing a standing kick, labeled, "5. Action test." Description End: So, we spent a lot of time developing tablet-based and tactile-based eye examinations and visual assessments where the kids are very, very engaged, they hold the tablet themselves. If they're non‑verbal, they can touch, tell us what they see, what they don't see. [ Slide end: ] And we also use a lot of artificial intelligence behind this, what's called "Bayesian approaches," where your first answer ultimately affects the next question you get asked. And this allows you to get to the answer much quicker that way. So the tests are much shorter in this particular approach. [ Slide start: ] Repeat previous slide Some people have demonstrated, changes in contrast sensitivity, for example, in these kids. That I, I think is, is an interesting phenomenon. We haven't seen huge, huge deficits with this. The problem also with contrast is that it's hard to test, it takes a long time to do it. Some interesting, also, data in terms of biological motion, right? One of the biggest things that you hear in these kids is they say, "I can't recognize my parents in a crowd. I can't walk and understand what's, what's around me." Right? Or "I really don't like watching TV programs where there's a lot of action. I prefer things that are, that are much calmer, much stiller." [ Slide end: ] And there's some thought they're really not able to integrate biological motion or understand complex motion as well, and we, and we saw a little bit of evidence of that. So we wanted to go a little bit deeper into this, this motion integration question and this is how we did it. [ Slide start: ] Description Start: Title: Characterizing Visual Function in CVI: Optic Flow Motion Content: left-side text: - Importance in locomotion - Global motion integration left-side graphic: perspective drawing of approach to an airport runway; a green dot located in the middle of a line that represents the distant horizon; red arrow lines stream from the green dot to the four corners of the graphic; broad, intersecting black lines represent the runway. right-side graphic: embedded animation labeled, "Are the Dots Expanding or Contracting? > Motion Coherence Threshold;" a green dot in the center of a grey square with randomly placed black and white dots constrained in a circle within the square. When animated, the black and white dots appear to be moving toward or away from the viewer. Description End: So there's a lot of work in the psycho-physical world about trying to understand motion integration. J.J. Gibson was a, was a famous psycho-physicist and he studied how pilots would land their planes, and their understanding of what's called "optic flow." How you move through the environment and how information moves around you. [ Slide end: ] It's a really part-and-parcel property of the visual brain. Its ability to integrate all that motion around you. In terms of your heading, either moving forward or backwards. And we tried to replicate that using a very, very simple visual stimulus, which I'll show you here. This is called "optic flow." So, I'll ask you to look at this visual stimulus here. [ Slide start: ] Repeat previous slide And you'll notice these dots are going to start moving, right, kind of randomly. And at one point you'll see they're expanding. And then they're going to start going inwards. And then they're going to come out again and go inwards. And they're going to come out again. And they're going to go inwards. Everybody see that, yeah? All right. The interesting thing about this is that this is a replication of optic flow. As you move in and out of an environment, this is how information moves around you. The other thing about this is that the number of dots that have to move together is a measure of your sensitivity. In other words, how much information do you need in order to know that you're moving forward versus backwards. Right? And that's called "motion coherence." The more dots that have to move together, the more impaired you are in this ability. If you only need a small percentage of the dots, that means that you are able to move through the environment and make sense of what's happening around you. All right? There are other advantages by using this stimulus as well. So as I said there's the ecological relevance of moving through an environment. Notice also that it's very, very easily quantifiable. We can, we can measure the coherence threshold, as I mentioned, by the number of dots that move. Notice also that you're not looking at the center you can still tell me what direction it's moving in. So even if they have poor fixation we still can get the data. Notice that those of you sitting in the front versus those sitting in the back also see it moving back and forth, it turns out that it's also invariant by moving distances as well. So even if the child is "[moaning]" we still can get the data pretty reliable, so that's what makes this quite robust in terms of our ability to measure it. [ Slide end: ] [ Slide start: ] Description Start: Title: Characterizing Visual Function in CVI: Motion Perception Content: left-side graphic: Label, "Motion Coherence Threshold (typical values 5-25%);" bar graph of motion coherence threshold; scale 0-50, bars labeled, red bar labeled, "Controls; 16.10 (n=18); blue bar labeled, "CVI; 43.57 (n=3);" bottom graph label, "(a higher threshold is indicative of poorer performance)" Description End: So, let's take a look at some of that data. So, here it is. This is motion coherence threshold. Remember the worse your threshold is, the more impaired you are in being able to do this task, all right? So a normal threshold are somewhere between five and 25 percent, in other words, 5 to 25 percent of the dots have to move together in order for you to be a able to tell me what direction you are moving in, forwards or backwards. And here's our group of age-matched controls: about 18 kids, and the threshold was about 16. So, right in the middle of what, what the group population data is in the literature. And here are C-V-I kids. About three times worse. In other words, they need three times the information in order to be able to tell you what direction things are moving in. This is, again, behaviorally is an indication of an impaired processing system. Right? [ Slide end: ] [ Slide start: ] Description Start: Title: Characterizing Visual Function in CVI: Motion Perception Content from previous slide and right-side graphic labeled, "Motion Processing: Area MT (V5);" profile drawing of the brain with blue block arrow labled, "MT" pointing to area in the rear of the brain; bottom label "Surrogate for Dorsal Stream Dysfunction?" Description End: Let's go back to the neuroscience question. Reminding you again that the two streams- the dorsal stream and the ventral stream- the "where" and "what" pathway, [ Slide end: ] all have different modules responsible for different things: color, faces, things like that. [ Slide start: ] Repeat previous slide And it turns out that there's a part of the brain- sorry it's a little bit covered here- called area M-T. It stands for "middle temporal." This is the part of the brain responsible for motion integration, that's all it does. It's only interested in moving objects. And notice that it's sitting in the dorsal stream. So now we have a surrogate, a functional surrogate for dorsal stream processing, right? [ Slide end: ] [ Slide start: ] Description Start: Title: Title: Characterizing Visual Function in CVI: Motion Perception; Functional Activation Content: Table with two columns labeled, "Control" and "CVI," and two rows labeled "L" and "R." Grey, profile drawings of the left and right hemispheres of the brain; yellow and red color representing brain activity; blue block arrow labeled "MT" pointing to location in the rear of the brain. Description End: So let's take a look. Let's put these kids in the F-M-R-I scanner and see what happens. Here's normally-sighted, normally-developed age-matched control. This hot spot of yellow that you see here is Area M-T. The yellow circle around there is just the probability map showing you where M-T should be. And sure enough, it's very, very strongly active. Again using that, that motion stimulus that I showed you. Here's our C-V-I subject. Basically nothing, right? Really, really a smattering. To get anywhere close to this level of activation, they need basically 100 percent coherence. In other words, all of the dots have to move together one way to the other to get M-T to even respond. So again, a really underperforming and underdeveloped visual system in this part, in this particular area. [ Slide end: ] [ Slide start: ] Description Start: Title: Title: Characterizing Visual Function in CVI: Motion Perception; Structural Connectivity Content: Two profile MRIs with colored pathways labeled, "Control" and "CVI;" each with blue block arrows labeled, "VI/V2" and "MT" pointing to corresponding parts of the brain. Description End: The connectivity also doesn't seem to be right as well. If we look at the connectivity between primary visual cortex and Area M-T, here's our normally sighted control, lots of arborization, pathways going all over the place. A lot shorter, a lot more compact in the case of C-V-I as well. [ Slide end: ] And we can, we can quantify this. So, the moral of the story is we can try to put this all together. We have the visual deficit, we have the structural anatomy, and we also have the functional anatomy and we think we can piece all this together. So that was the motion perception story. Let me give you another piece of evidence in terms of visual field, which is also a very, very common deficit or common complaint in these children as well. So you're all familiar with perimetry? Right? Like the Humphrey Visual Field Perimetry and so on? It allows you, you to look at the dots and it gives you the visual field representation. This is exactly the same thing except we're going to do it on the surface of the visual brain. All right. So we can map the visual, the visual world- excuse me- on the surface of the visual cortex. And this is how we do it. A technique called "retinotopy." [ Slide start: ] Description Start: Title: Functional Activation (Visual Retinotopy) Content: left-side graphic: label, "Eccentricity Mapping;" embedded animation; black & while ring on a square, grey background repeatedly expands until it reaches the edge of the square; at the same time red and yellow colors expand across the surface of the rear of a profile drawing of the brain. right-side graphic: lable, "Visual Field/Area Mapping;" 3 MRIs of the brain colored to show brain activity matching lower and upper visual fields. Description End: Notice for example as this this ring expands, notice how the signal propagates over the surface of the visual cortex. Notice in the figure on the right when I stimulate the left side of the visual field I get activation in the right hemisphere. All the warm colors, which is the upper visual field, show up in the lower bank. All the cold colors, the lower visual field, end up in the upper bank. So that's how we know the visual brain is organized, left is right, right is left. Up is down, down is up. And this is just a recreation, a remapping of that on the visual, on the visual surface, the visual surface of the visual brain. So let's take a look. Again, here's our normal sighted control. [ Slide end: ] [ Slide start: ] Description Start: Title: Visual Retinotopy: Upper and Lower Visual Fields Content: left-side graphic: legend identifying visual field; yellow = upper; cyan = lower center graphic: 2 drawings; grey, right-side profiles of the brain; cyan and yellow coloring of the rear area; labeled, "Control" and "CVI" right-side graphic: 2 drawings; grey, left-side profiles of the brain; cyan and yellow coloring of the rear area; labeled, "Control" and "CVI"; labels and arrows pointing to colored areas, "lower field" and "upper field" Description End: We did a very, very simple experiment. We drove the upper visual field in yellow, the lower visual field in blue and notice in our normal sighted control lots of blue up top here, lots of yellow down here for the upper and lower visual field. In our C-V-I subject we start seeing these gaps. Right? There. And this large one there and particularly corresponding to the lower visual field, right? So what would you guess her visual field would look like? Where would the deficit be? [ Slide start: ] Description Start: Title: Visual Retinotopy: Upper and Lower Visual Fields Content from previous slide with additional graphics: Humphrey visual field test results. Description End: Yeah, here's her Humphrey. Yeah. That's exactly right. So there's immediate correspondence of where the brain is activated in these early visual areas in terms of where the visual field deficit is. And this is just a mathematical active- or a computation, I should say, of the strength of activation. The lowest activation is in this, in this lower visual field. [ Slide end: ] [ Slide start: ] Description Start: Title: Optic Tract Radiations (While Matter) Reconstruction Content: top left-side graphic: 3-d drawing of the brain with lines representing optic tract radiations. lower left-side graphic: Humphrey visual field test results. upper right-side graphic: label, "Control;" left and right profile MRIs with colored pathways and arrows pointing to lower and upper field. lower right-side graphic: label, "CVI" left and right profile MRIs with colored pathways and arrows pointing to lower and upper field. Description End: We can also look at the connectivity of this as well, the optic radiations, as you all know. The upper bank is responsible for the lower visual field. The lower bank responsible‑‑ excuse me-- the lower bank, I should say, for the upper visual field, the upper bank responsible for the lower visual field. Nice, nice thick arborization in the case of this this normal sighted control. Here is our C-V-I subject. Essentially the lower field is missing. Right? [ Slide end: ] [ Slide start: ] Description Start: Title: Correlating Clinical, Structural and Functional Finding in CVI Content: center graphic: Label, "Clinical," with photo of eye chart and child waking with white cane; label, "Structural," with image of colored brain pathways; label "Functional" with top view of the brain with active areas in colored red; arcing arrows show this is a 3-part cycle. Description End: So again, the function, the structure, and the visual deficits all fit together. That's kind of the idea. And that's very, very much the goal. So our thought is that we should be able to look at any measurement of visual function. Give you why the structural connectivity isn't there, related to the structural connectivity. And at the same time with functional imaging tell you why the brain doesn't activate correctly. And no matter what way you enter the system-- if I know one piece I should be able to predict the other two. [ Slide end: ] And that's kind of the idea of how the wheel turns and as we go through more and more types of visual assessments we'll get a bigger and better picture of what's going on in terms of the underlying physiology of this condition. [ Slide start: ] Description Start: Content: read by speaker center photo: toddler Reference: www.littlebearsees.org Description End: So my summary slide for this particular case is that in the setting of C-V-I, there appears to be significant reorganization of the brain, however how this rewiring relates to visual development, compensatory strategies and the recovery of function remains largely unknown. Very, very different than the situation I presented in the case of ocular blindness, right? Does this at all surprise you that strategies that you develop for ocular blind don't work in C-V-I and vice versa? Their brains are fundamentally different, right? [ Slide end: ] But how do they come to you? Visual acuity. Right? That's, that's the problem, right? We, we classify them using the same sort of criteria, but fundamentally these are two very, very different scenarios and I hope I've, I've convinced you of that. A couple of other comments I want to share with you. A lot of people ask us how are we able to scan these kids? Right? Because we don't anesthetized them. A lot of past studies, for example, have anesthetized these children. The problem is that you can't do functional imaging when a child is asleep, right? They have to be awake. That's how we get the data. Just a couple of things that I, I want to share with you. First and foremost we spend a lot of time working with these kids, getting to know them, building their trust; not only with the kids and also the family. [ Slide start: ] Description Start: Title: Working in the MRI Scanner Environment Content: left-side photo: mother stands next to MRI scanner bed holding her child's hand. right-side photo: brightly colored MRI scanner decorated to look like a yellow submarine. Reference: Description End: We have a mock scanner where we do the work so it looks exactly the same as the real scanner but there's no active magnet. So they can go in, they can climb around, they can touch anything they want, it's not a problem. There's no security concern or safety concern for them. [ Slide end: ] We also tell them to bring their favorite stuffed animals and we scan them too and then we subtract them out in terms of the signal, as well. So that they're comfortable. We ask the mom, for example in this particular case, to be involved and she's very, very close and reassuring so that the parents are always, you know, big team members in this work as well. And, as I said, we really try to get to know a work-- what works and what doesn't work. We have MP3 files of the scanner noises which we send to the family and the kid listens to it in their iPod before they come so they get a sense of what the sounds are like also. A lot of prep time to try to understand what these kids are going through. Last thing I'll mention, we try to figure out, as I said, what works and what doesn't-- this particular child, interestingly enough, for whatever reason loves Egyptology. She watches all sorts of movies and cartoons and reads books and so on and we said, "Oh that's, that's great. So we're, we're going to wrap you up in a blanket now, right, nice and tight, just like the mummy. Here's the mummy going into the sarcophagus." [ Laughter ] She didn't budge. Not even a millimeter. Absolutely incredible. We have stable data on these individuals because we work very, very closely with them. Really don't have this idea -- and I think in the past people have said, "Oh, let's just put them in and, and see what happens." No. You have to build a rapport with these individuals and I think that's what allows us to get higher quality data than past studies. [ Slide start: ] repeat previous slide Another one here: this isn't our scanning bay, but just to show you the creativity that a lot of people are developing. This is one site, um, I think in Milwaukee, if I'm not mistaken. And, you know, they've had this whole yellow submarine and we're watching and you're a scuba driver, you're going through, and all this sort of thing. [ Slide end: ] And when the kids are engaged-- I don't- I, I know I'm preaching to the choir-- when the kids are engaged, when there's fun and when they're safe, when they feel confident, that's when good things happen. And I think that's a very, very important piece to the study, um, as well. Some, some final thoughts as I wrap up here. Some of you might remember when Kevin Costner made good movies, a long, long time ago. [ Laughter ] Yeah. [Laugh] And, and there was one in particular called, called Field of Dreams where he was this, he played this Iowa farmer who hears these voices in his head, you know, "build it and they will come, build it and they will come." And he gets the bright idea to just mow down half of his cornfield and build a, a baseball stadium and I think at some point his dad shows up and I fell asleep, but that was-- [ Laughter ] But that was the point of the story. And I'll, I'll be very honest with you, when I started this project that's very, very much what it was like. I was going to conferences like A-E-R and so on, talking about oc- ocular blindness and there would be voices in the crowd: "What about C-V-I? C-V-I? C-V-I?" And the more I thought about it, the more I thought that, "Yeah, there was a really incredible opportunity here" and that's how the project started. [ Slide start: ] Description Start: Title: If we build it, will they come? Content: aerial photo of the field of dreams baseball diamond next to corn fields, inset photo of movie poster with Kevin Costner. Description End: The concern that I have is that will this be a field of dreams? I can tell you that there are some parents, for example, who just simply don't want to know. "Thanks, but no thanks. You're not treating my kid. I've gone through, you know, 15, 20 years of this. You're not going to add anything to, to their life." So I, I really hope it doesn't turn into a field of dreams type situation. [ Slide end: ] We really hope that this can indeed make an impact and, and, and offer some, some neurophysiological basis to something that obviously is very, very important to all of us. Let me give you sort of a scenario that, that challenges us. Let's say we pull this study off. We're able to demonstrate, for example, that it is indeed dorsal stream dysfunction and demonstrate the neurophysiology of this condition. [ Slide start: ] Description Start: Title: How does the Brain Re-wire itself in Cortical/Cerebral Blindness? ...what do we do now? Content: 3-D profile drawing of the brain with arcing arrows labeled, "Dorsal/spatial" and "Ventral/object" connected to the rear of the brain labeled, "Primary Visual Cortex." Description End: So, if it is indeed a dorsal stream dysfunction, now what? Now what do you do? Does that mean that you need to train more spatial tasks on these kids to get that up to speed or do you use more visual identification tasks to try to bootstrap the spatial components? Right? I don't think anybody knows. [ Slide end: ] But I think that we do have the opportunity to try to look at this systematically. And I think that's, that's really, I think, what the field needs and what it hasn't had in the past. I always use the analogy of autism, for example. It wasn't that long ago that we thought autism was caused by mothers who neglected their children, what we used to call the, "the refrigerator mother, principle." This was in medical records, right? Mothers who were abandoning their children. Those of you who have any experience in this area, know could anything be farther from the truth, right? We were dead wrong about this. And it took a mass effort of concerned parents, educators, uh celebrities in some cases, politicians, scientists, all coming together and applying enough pressure from enough directions to create an upswell movement to finally change the way that these kids were, were-- were taught and, and taken care of. And I think C-V-I deserves exactly, exactly the same thing. [ Slide start: ] Description Start: Title: Potential Study Impact Content: 1. Evidence-based approach and dispelling "Neuromyths." 2. Identification of neural correlates (structural and functional) associated with visual dysfunction. 3. Tragets for deficit-based training. 4. Longitudinal tracking of development. 5. Community empowerment. right-side graphic: cover of JAAPOS publication and image of Facebook page. Description End: Some, some final thoughts and some, some potential study impact. And this leads to my, to my final slide here. Evidence-based approaches. Dispelling neuromyths. I think that's one thing that in neuroscience can bring to this area: what works, what doesn't, and why?" Right? Identification of neurocorrelates-- structural and functional-- associated with visual dysfunction. For example, is it indeed dorsal dysfunction? In my, in my experience it's not that simple. Some kids have both. They're not mutually exclusive, for example. But does the physiology fit the visual deficits? Targets for deficit-based training. As we get better and better assessing these kids- beyond visual fields, beyond visual acuity- we have strategies and targets that we should work on to try to enhance their vision, and wake up these visual cortexes as I said. Longitudinal tracking of development. That is the ultimate goal. You can imagine these kids getting scanned at baseline and five, six, seven years throughout school, scanning them afterwards and trying to parse those kids who do well versus those kids that don't, and trying to understand why from a brain anatomy standpoint. And I think the last piece, which is the most important, is the community empowerment aspect as well, which is what I think C-V-I really, really deserves. We have a FaceBook page. [ Slide end: ] I promise you I get more traffic on this than I do my emails. It's really incredible. We post stories, kids that are participants and parents who are involved post as well. Relevant stories. I, I invite you to come and, and like us if if you, if you are interested. We're the CVI Neuroplasticity Research Group. This has been a big, big piece in trying to get the community engaged and involved with this. Last story-- or second, second to the last story I'll share with you. I'll, I'll give you an example of what I think is immediate impact. When we first published our, our initial findings about this tractography and visual deficits, [ Slide start: ] repeat previous slide as luck would have it, it ended up being the cover figure of this journal. Right? We had nothing to do with that. They just, the editor ended up choosing the pretty pictures, if you will. [ Slide end: ] So we thought that was kind of interesting. We, we asked for, for reprints and we started sending it to the kids who were involved in the study and said, "Hey, isn't this, isn't this kind of cool? Your, your brain is on the cover of this scientific magazine." One of the kids woke up the next morning, took the magazine, walked into her teacher's office and said, "You see? I told you there was something wrong." And she started calling the principal, her doctors, everybody saying, "I told you there was something fundamentally wrong. I'm not faking it. I don't have, you know, some sort of emotional problems or something like that." So there is a sense of empowerment, I think, getting involved with this and saying, "Maybe not so much ownership or maybe not so much that there's something wrong in my brain, per se." But they, they feel a little bit more reassured that there's something indeed that can be explained from a rational standpoint as opposed to just being dismissed very, very quickly. So I think there's, there's something to be said, um, about that. I want to just identify, say thank you in the last minutes that I have, the individuals involved. It's a massive team effort, as you might imagine, to take on a project like this. [ Slide start: ] Description Start: Content: Names and duties read by speaker; photos of project coworkers under the labels, "Clinical Evaluations," "Structural Neuroimaging," and "Functional Neuroimaging." Description End: On the clinical side we have Dr. Jenna Heidary, she's a neuropediatric opthamologist from Children's Hospital in Boston. I think in this particular case you have to align yourself with clinicians who even know what C-V-I is. First of all, for starters. That's a big, big piece, and fortunately we have someone who, who can do that. Peter Bex is a psychophysicist, he develops all the, the visual tablet-based taste-- based testing for us. And what I call The Three Musketeers, this is the group at the Perkins School for the Blind: Derek Wright- an O-T-M specialist, Dr. Barry Cran- an optometrist and head of the clinic, and Louisa Meyer- who is involved also for the evaluations for perimetry. These people tell us the reality. They work with the Perkins kids, they tell us every day what they're struggling with, what's a concern, what their parents are concerned about. So this is where we get our real world information. On the structural side I have Corrina Bauer, who is a post-doctoral fellow, in the lab. She brought a lot of that expertise in terms of the brain reconstruction. The handsome gentlemen next to her is is Andy Ellison. He runs the scanners, so that worked out really, really well. [ Slide end: ] [ Laughter ] They actually got married last month. So I-- I keep telling them "Please, please, please don't get in a fight, this is a really important study. [Laughs] [ Slide start: ] repeat previous slide And on the functional-- know what I mean?-- imaging side: David Somers, a professor at B-U, Boston University. When I did my fellow- or one of, one my fellowships I did with this individual. Everything I learned from brain imaging I learned from him, so it's great to bring him back on board. Gabriella Hirsch is a research assistant in the lab and, and really took on the F-M-R-I work and I really challenged her a year ago if she could come up with the analysis methodology and so on. So a really, really wonderful team that's a privilege to, to work with these individuals. [ Slide end: ] [ Slide start: ] Description Start: Title: ...Thank you Content: read by speaker Description End: And like, like all of you know, good team, good people, makes life a lot easier. Thank you again. Just identifying the Perkins School for the Blind. Carroll Center for the Blind as well, which I have a close relationship with. Boston University. The N-I-H, the Mass Lions Research Fund. Deborah Munroe, also a research fund. Also our patients and our families. And I want to give a shout-out to all of you. [ Slide end: ] You guys are my heroes. Don't, don't ever forget that. Don't ever think that what you do isn't important or doesn't make a difference. My mother is a teacher of, of preschool children, kids with, with developmental issues. And I learned very, very early on the challenges and I know that she did this because she believed it was the right thing to do and I 'm sure all of you feel exactly the same way, so don't ever forget how important your contribution is to this whole, this whole big picture. And the last- I promise- final story I want to share with you is this one here, um, a great picture. This picture actually is in my office. This is an interesting story. There was a photographer named David Seymour who went around Europe after World War II to try to capture the plight of children after the Second World War. What they were going through. And this particular child was in Italy, he was born blind. Learned to read braille at a very, very young age. And one day this child went out and started playing with something he shouldn't have. It ended up being a land mine. The land mine exploded, destroyed both of his hands, became a double amputee. [ Slide start: ] Description Start: Content: b/w photo; close-up, profile of teenage boy with his lips and nose on a page of braille. Reference: David Seymour. "Blind Boy Reading with His LIps." 1948. Corcoran Gallery of Art, Washington, D.C. Description End: But he still reads braille. Not because he sees the dots, because he's using the tip of his nose and the surface of his lips to feel the dots. This, ladies and gentlemen, is neuroplasticity at its best. Right? [ Slide end: ] This is what we're trying to understand. When motivation, opportunity, resources, drive are all there, good things happen. And I think you all know that and I think that's what we really need to be working together with to help these individuals. And with that I promise I'm, I'm done. Thank you. [Applause]