0pEpB479

1
2    Charlie Rose: Series" underwritten by the Simons Foundation coming up. Tonight we continue journey to the most exciting frontier of science -- the brain. Last month, we examined how the brain interprets information from the five senses, focusing on the visual system. Tonight we'll show you how the brain uses that information to interact with the outside world. Our subject is the acting brain. Taken together, the parts of the central nervous system devoted to movement are known as the motor system. The motor system allows us to plan, coordinate, and execute every action that is needed to survive in the physical world. All of the movements that we make from the breathing of our heart to the hitting of a tennis ball are controlled by the brain and the nervous system. As the legendary biologist Charles Sherrington once said, "To move things is all that mankind can do, and for this task the sole executant is a muscle, whether it be a whispering of a syllable or felling of forest." The question is, then, how does the brain do it? How does the brain translate subjective intentions into basic physical actions? What happens in the brain when we learn a new skill? Why are some of us graceful and others clumsy? Why does practice make perfect? Much like the visual system, the motor system is astounding in its complexity. It controls over 650 muscles, giving rise to an immense repertoire of movement and actions. Coordinating these muscles is a tremendous challenge, which the motor system carries out mostly without conscious instruction. Reflexes, for instance, allow us to respond immediately and unconsciously to changes in our environment. Other essential functions such as breathing are also performed automatically and unconsciously. But while some motor functions are innate, most of our physical abilities must be learned through practice. During infancy and childhood, we learn to crawl, walk, and use language. By the time we reach adulthood, these difficult tasks have become effortless. In fact, most of what the motor system does is taken for granted until it is interrupted by injury or disease. Tonight, we'll examine two devastating motor illnesses: stroke and ALS, also known as Lou Gehrig's disease. Both of these diseases are tragically common. Stroke is the third-leading cause of death in the United States. But for those who survive, the brain's remarkable plasticity offers hope of recovery. ALS attacks the individual neurons responsible for controlling our muscles. Despite decades of research, the disease is 100 percent fatal. Joining me this evening a remarkable group of scientists who have devoted their careers and their lives to understanding how the brain controls movement. They are Thomas Jessell. He studies groups of nerve cells known as circuits, which form the basis for our entire motor systems. He leads the Jessell lab at Columbia University and he is a Howard Hughes medical investigator. Daniel Wolpert -- his research uses mechanical models that mimic human behavior. He heads the Wolpert lab at Cambridge University in England. John Krakauer -- he is interested in how the brain learns new skills and how it can regain function even after stroke or injury. He is an associate professor of neurology and neuroscience at Columbia University. Robert Brown -- he is a geneticist, a physician, and an all-around expert on Lou Gehrig's disease. He teaches and practices at the University of Massachusetts. And once again, my co-host is Dr. Eric Kandel. He is, as you know, a Nobel laureate, a professor at Columbia University, and also an investigator at the Howard Hughes Medical Research center. I am pleased to have one more time a chance to talk about this extraordinary thing, this brain. We've gone from the general, we've gone to visual, and now we go to movement. What are the themes that we're going to look at tonight. 
304:19
4    Eric Kandel: Charlie, you outlined them so beautifully in your introduction. Every behavior is mediated through motor systems, from the simplest to the most complex. All sensory perception, visual perception we discussed last time, reaches its completion through the actions of motor systems. In fact, we can think of the motor systems in some ways as being the mirror image of the sensory system. The sensory systems create a schema, an internal representation of our brain of the outside world. The motor system uses that internal representation in action. And, like the sensory system, the motor system is localized to particular regions, and it has three important components, a hierarchy, if you will, to decide, to make an action to pick up a glass of water, to mobilize the muscles to actually make that movement, and then to report back that that movement has been carried out successfully. Motor actions vary tremendously from the simplest kind of action to marvelous pirouettes that ballet dancers can do or high jumping pole vaulting, extremely skilled performances. Some of these are inborn and, as you indicated, many of these are learned. And the flexibility, the plasticity of the motor system is extraordinary. Throughout our lives, we can continue to modify our behavior. We play tennis next to one another, I see your tennis game getting better from month to month. 
505:47
6    Charlie Rose: You didn't think it was possible to get better at my age, did you? 
705:56
8    Eric Kandel: Even at my age it has a chance of getting better. And we only see, as you indicated, this automatic behavior that we take for granted because we do so much of it automatically. We only see that it is important to us when something goes wrong. We can see this, for example, in the sad case of Lou Gehrig. Can we have the video on Lou Gehrig, please? A spectacular baseball player who was hitting about . 350 for most of his career, an extraordinary career running over 12 years. Never missed a game, game after game throughout the season. All of a sudden he began to find a weakening in his stroke. He still saw the ball as clearly as he ever did, but he couldn't get his bat around and really meet it powerfully. And you could see the dramatic decline in his batting average, going from . 350 to . 150 in the period of a year and a half. And ultimately, for the first time in over a thousand games, he had to be benched. That was because he developed amyotrophic lateral sclerosis, a disease we're going to consider today. 
907:04
10    Charlie Rose: I just make this point about science, that science builds on what you have learned before. Here is Sir Charles Sherrington, this book, "The Integrative Action of the Nervous System" published in 1906. This is also based on some lectures he did at Yale. And it' a remarkable story of how science works. 
1107:23
12    Eric Kandel: You're absolutely right. There are occasional people, we call them giants, who not only make extraordinary contributions -- Sherrington worked out the simplest reflex pathways in the spinal court, stimulated the motor cortex, saw how it moved particular limbs, but also he had the insight to see how the whole brain works. The integrative action of the nervous system means sensory information has come in. It's processed to give rise to a variety of movements. This not only applies to motor systems, it applies to every aspect of nervous system function. There is a citation of appropriate movement, inhibition of inappropriate movement. This is a brilliant, prescient set of insights we owe to Sherrington. We're still living in Sherringtonian world today. 
1308:09
14    Charlie Rose: We will talk about and touch on all these things that we have been talking about. Eric and I have assembled a group of people that I think you will find extraordinary in terms of their insight and how they can demonstrate what we're talking about, because we're talking about motor functions, which you can see. You will also discover as you listen to them that there is a remarkable thing that is coming out of this -- insight into how the brain functions at its highest level. So we begin with understanding the significance of the motor system. 
1508:43
16    Daniel Wolpert: I think you have to ask a very fundamental question, perhaps the most fundamental question you can ever been asked. Why do we animals have brains? It's a pretty fundamental question, because there are many species in our planet who don't have brains. So that's the fundamental question we should be taught on our first day of school. And if you think about that question, it's obvious why we have a brain. We have a brain for one reason and one reason only, and that's to produce adaptable and complex movement. There's no other reason to have evolved a brain. So if you think about it the only way we can affect the outside world is through contractions of muscles. So if you think about communications - - speech, gestures, sign language, writing, they're all mediated by contracting muscles. So we need to remember that things like sensory processing, the perceptual system, memory, and cognitive processes are all important. But they can only be important to drive action or suppress future actions. There's no point in laying down memories of childhood or perceiving the color of a rose if it doesn't leave you to do something different with your motor system later in light. So if you think from an evolutionary point of view, there'd be no point in having the thinking processes if they can't be expressed through action. So I'm really a movement chauvinist. I think to understand the brain we have to understand movement, which is the final output. 
1709:55
18    Charlie Rose: To understand the brain, we have to understand movement? 
1909:59
20    Daniel Wolpert: We can't look at memory or perception in isolation from action. And we can say, if you don't believe in this argument there are many species who live very happy lives on our planet, do very well socially, but they don't need to move. So the tree is a very nice example. It doesn't require complex movements. It hasn't developed a brain. But the clinching evidence. For those who don't believe in this view, there is this animal here. This is the humble sea squirt. It is very rudimentary animal, and it has a brain, a spinal cord, and it swims around in its juvenile life. And at some point its life it implants itself on a rock and never leaves the rock again. And the first thing it does upon implanting on that rock is to digest its own brain and nervous system for food. So once it doesn't need to move, it doesn't need that brain anymore. So I think it's really -- the brain is there for movement. 
2110:46
22    Charlie Rose: And is this the reason we've never had a robot that can be as graceful has a six-year-old walking down a road? 
2310:53
24    Daniel Wolpert: That's a very good question. So we could ask, how well are we doing understanding how the brain controls movement? And the answer is I think we've done pretty well, but we've got a long way to go. And you can illustrate this by asking, as you do, how well can we build machine which is can do what humans can do. Take the game of chess, which is a nice example. How well can we build machines to decide which what piece to move where? If we pit Gary Kasparov, for example, against IBM's Deep Blue, occasionally IBM's Deep Blue will win. And I think if it played anyone here, it would win every time. But we think about now build a machine which has the manual dexterity of a five-year-old. Pit a five-year-old's dexterity to manipulate a chess piece against the best robots of the day, there is absolutely no competition. The five-year-old wins easily. And so you can say, why is that the first problem of deciding what to move so easy and the control problem so hard. And one reason is the five- year-old child would tell you, the computer code you need to solve what piece too move where. Of all the possible moves at the end of the cam, choose what makes you win. The algorithm is very simple. The problem is all different moves, but with fast computers and approximation we get very close to the answer. When it comes to being dexterous it's very unclear what the problem are you need to solve to be dexterous, and as we'll see later on, there're real problems of it's sensing the world and acting upon it, which had a lot of complexity. But I'd love to show you a video. 
2512:13
26    Charlie Rose: Please do. 
2712:15
28    Daniel Wolpert: I'd like to show you a video of what's cutting edge now in robotics and what's cutting edge now in human performance just to give a feel of how close we're getting. So if we could roll the video of the robot. What this video shows the en of a three-year project by my colleagues in Germany teaching a robot to pick up a jug of water and pour some water into a glass. And as you can see, it does the task, but clearly it's not doing it anywhere as fluidly or speedily as a human doing it. You would regard this as poor performance. So this is a very challenging task. And if you want to train the robot to do something different, you'd be starting another three-year project. There's no generalization from one task to another. So this is a fundamentally very difficult problem. Let's compare that now to what we regard perhaps as the cutting edge human form. So what we're going to see is a small child, I think a nine- year-old, winning the world record for cup stacking. Cup stacking is a popular sport in America. It involves taking up to 12 cups and stacking them and un-stacking them in a particular sequence as fast as you can. 
2913:14
30    Charlie Rose: Wow. This is great! 
3113:20
32    Daniel Wolpert: We've got a very long way to go before we get anywhere near building machines that understand even how that child learned to do that task. That's a phenomenally hard task. 
3313:31
34    Charlie Rose: Let's look further at the anatomy. Tom Jessell, talk about how it works and what stops there are. 
3513:36
36    Tom Jessell: Yes. So the sorts of mysteries that Daniel has just outlined for you have been puzzling neuroscientists for over a hundred years or so. And Charles Sherrington was really the first of the modern scientists of neuroscientists who tried to understand the mechanisms that really link the way in to the way out. So in the brain, in the nervous system, there are many ways in. The individual senses that we've talked about in previous discussions, the sense of vision, the sense of touch, the sense of smell. But Sherrington and people of his time realized despite all of the many ways in, there's only one way out, and that is the motor system. And Sherrington was the first to articulate the idea that the motor system is really the final common pathway of all of the sensory world that impinges on the brain and the way that that information is processed to produce coordinated movement. And so in the 19th century, there had been a series of experiments trying to understand and deconstruct what movement really is. And even the simplest of movements, to move one's hand or to move one's thumb, requires several components or several processing events. The first is actually to plan the movement. One has to be able to control the nature of the movement before there's any sign of muscle contractions. The second is the execution of movement, and the third is to achieve some sense of reporting of the consequences of that movement. And Sherrington and his colleagues really outlined the idea that these different functions, planning, execution, and reporting, are assigned to different regions of the brain. And the first experiments that really change the way that we think about the field were some electrical stimulation experiments. So with the crude tools available, people started to stimulate different regions of the surface of the brain and look for the consequences in terms of movement. So some areas where you're stimulated gave no overt signs of movement. But there are other areas, hot spots, if you like, which we now know as the motor cortex and the pre-motor cortex, and they're shown here in this colored region, where very low intensity stimulation would illicit movement. And more than that, that was a precise register or map between the place in which the stimulating probe was located and the type of movement. And so it turns out in the remarkable way that somehow the brain achieves a map of the body surface, and so stimulation in one place will produce the movement of the thumb. Stimulation of an adjacent region will produce the movement of the wrist and the elbow and the shoulder, and yet another region will produce movements of the leg. So in this way, people began to realize that there was this precise register between the surface of the brain and the muscle groups, the 600 or so that you mentioned that have to be activated in a precise pattern to produce a coordinated movement. 
3716:40
38    Eric Kandel: This is really a beautiful example of, perhaps the best example we have in the brain, of functional localization. The different aspects of behavior, different aspects of sensory perception, different aspects of movement, are localized, the detailed map of the movements of the body right on the surface of the brain. 
3917:01
40    Tom Jessell: Sherrington began to reason that if the cortex is the sight of initiation or of planning of movement, yet the muscles are out in the periphery, there has to be some anatomical conduit or link between the site of stimulation and the site of muscle contraction. And what Sherrington in a systematic way did is to show the information that is being initiated in these cortical regions has all of that information, regardless of the type of movement, has to be funneled down the central nervous system eventually to the spinal cord. And Sherrington began to examine the nature of an organization of circuits that existed within the spinal cord. And very soon he realized an articulated that within the spinal cord -- so this is now a cross section, a cut slab through the spinal cord -- that the key intermediary between all of this cortical information and the actual contraction of the muscle was this group of neurons, shown here, which are spinal motor neurons. So of the tens of thousands of neurons, classes of neurons that exist within the brain, only one of those classes, the motor neuron, actually sends a process out of the central nervous system, out of the brain and spinal cord, to communicate with the periphery. So all of these dexterous tasks that Daniel showed you are really dependent on the activity of motor neurons. And if we have 600 muscle groups, we now know that in order to accommodate the combination of muscle activity, we need 600 motor neurons subtypes. So in a nutshell, the problem that the brain has to solve is how to initiate movement exactly when you want to move, how to control exactly what which part of the body you want to move, and all of that information has to be funneled down into the spinal cord and activate just the right set of motor neurons in the right combination to produce coordinated movement. 
4118:57
42    Charlie Rose: Now, is there a dramatic difference between a reflex action and a conscious action? 
4319:02
44    Tom Jessell: Yes. So this is the other great insight that Sherrington had. And it comes to the third component of movement. There's no point in moving or acting if the brain and the central nervous system and the body doesn't get some reporting of the consequences of actions. So Sherrington spent much of his life not only working on the way that the cortex interacts with the spinal cord, but the way that this information is fed back through reporting of the state of muscle contraction. So any coordinated movement, the cup stacking that we saw, requires the fact that the brain receives online information about the efficacy with which those motor tasks are performed. And that feedback information comes in through sets of sensory neurons that are acting as, if you like, a strain gauge is, monitoring the intensity and the timing of muscle contraction and feeding that in the simplest reflex circuit back directly to form a single synaptic connection with the motor neuron. So this is an involuntary stretch reflex circuit, if you like. So perhaps we could first of all demonstrate this mono-synaptic reflex in action. 
4520:13
46    Charlie Rose: All right. 
4720:17
48    Robert Brown: I'm now going to try to fool Tom's nervous system, in particular his lower spinal cord, into thinking that this knee has been flexed. And what you will see is that independently of any of tom's efforts to the contrary, the nervous system will respond by attempting to extend the knee back out. And I will fool it by using a reflex hammer and essentially using a very standard reflex. Tom, you just want to relax. What you can see is that -- short percussion here, he kicks the leg back out. And this involves three elements. It involves the spinal cord perceiving the fact that there's been a stretch. This has a sensory feedback into the spinal cord. There's an integration of that sensory information to the spinal cord to the motor output, which allow essentially a motor signal saying "Let's correct the problem, let's extend the knee." 
4921:04
50    Tom Jessell: Basic reflex alert. 
5121:09
52    Robert Brown: This would work in his sleep. 
5321:12
54    Tom Jessell: So here is the circuit. Here is the spine cord, here are the muscles, the knee, this pathway, we've activated the sensory input into the spinal cord. Then through one synapse we've transformed sensory input to motor output. Normally sensory input comes in from vision, and it's transformed through a series of pathways eventually to a motor action. Here is the simplest version of this sensory motor transformation that exists in the central nervous system. And Sherrington, again, through these very simple devices, worked out many of the ideas about the way that circuits in the spinal cord integrate this information. 
5521:53
56    Eric Kandel: This is a very beautiful example, because one of the great challenges of brain science is to understand the logic of neural circuitry. Here in 1900 he worked out the logic for the simplest neural circuit that we know. 
5722:07
58    Tom Jessell: If one looks through the history of neural science, many of the core principles that we now accept as part of the canon of the field first came through studying this sensory and motor circuit. First of all, the existence of reflex circuits, second the nature of synaptic communication between one cell and another -- these were all worked out essentially by studying the simple circuit. 
5922:29
60    John Krakauer: From a general viewpoint that you can great this two things. One is in terms of the architecture of the circuit, it's recapitulated all the up the hierarchy. But it just gets a little more complicated. So you have sensory input, some processing that goes out, and then an output. And as you get more complex -- so when you ask the difference between a reflex and a voluntary movement, you can say that voluntary movements have to require circuits that are based on this architecture but are more complicated. And two, another interesting thing is that this circuit isn't just there for that reflex that you saw. The brain has been clever enough to use that building block for voluntary behavior. So the same spinal circuits that you can actually isolate with a reflex hammer are also incorporated into useful behaviors. 
6123:15
62    Charlie Rose: Let's talk a bit about disease and what happens to a sensory neuron when we have an awful thing happen to a person, whether it's a stroke or ALS. 
6323:23
64    Robert Brown: I think one of the questions is, in fact, if we could start with this very figure, what happens if one interrupts various components of the circuitry. If, for example, there is a viral infection that eliminates the function of the sensory feedback, what are the consequences for movement? I think we have a very good video which will illustrate some of these features. So here is a gentleman who has, in fact, had such a viral infection whose motor strength, whose motor power is perfectly normal, but whose ability to know where his limbs and joints are in space is severely impaired. Thus when he wishes to take a sip from a cup of coffee, it's a herculean labor to get the fingers to grip the handle and it still requires both hands to get the cup to his lips. And that's without any loss of power whatsoever. And I think this illustrates very dramatically how critical it is to have that sensory input guide, modulate, serve as mechanism the control of final motor output. 
6524:15
66    Tom Jessell: In this case the motor neurons are still present, still connected with muscle. The only thing that is missing is the ability of that motor system to receive sensory feedback. 
6724:26
68    Robert Brown: So this will show the same gentleman being asked simply to stand on a chair, something any one of us can do. And what one can see, and this is a real-time photo, this is a laborious, slow act, which essentially he cannot fully carry out despite having full power in his legs. So as you can see he falls forward, then rolls until he achieves an upright position. He's now out of the chair but of course a long way from standing. And this in itself is an achievement, hence the thumbs up, but severely disabled because of loss of sensory function. 
6924:57
70    Daniel Wolpert: John has talked about a thing where you have a desired behavior and you have to generate the behavior, but there's a flipside which is very important in learning, and that's prediction. So control is about what I want to do and how do I generate the commands. But the other side you have to learn is how to predict. That is to say, given the commands I sent out, can I predict what's going to happen. 
7125:14
72    Eric Kandel: How do you do that? 
7325:16
74    Daniel Wolpert: We know now a lot of the brain actually has internal stimulators. When I send a command out I get feedback from my arm, from vision. That's done by the physics, the physics of my body and my sensory receptors. But we now know within the brain this is a neural simulator which says, I can see the command going out. Let me try to anticipate or predict what's going to happen. And so as I'm moving around the world doing things, my brain is simulating what's happens and trying to anticipate it. Why would you want something giving it's already going to happen? And there's several reasons to have that. One is you can just sit here and simulate movements to decide what the best one is. But a really important one is one of the problems with movement is when I send a command out and I get the feedback, there's about a quarter of a second delay between sending it out and getting the feedback due to delays in the system. That's a very long time if you want to play a fast tennis stroke. So one idea is rather than working on reality, you can work on internal stimulation, which is faster. And we'll give you a little demo that we can show you to prove to you that prediction. And what we brought along one of the heaviest books you can find in the library. 
7526:17
76    Charlie Rose: Written by? 
7726:18
78    Daniel Wolpert: This is written by Tom and Eric. It's the standard textbook in the field. This is called the waiter task. The waiter brings you something on a tray, and you life the thing off the tray. But we'll do the weight task. So John, I want you to support this book. He's supporting the book. To do that he has to contract his muscles. He might get tired if I wait too long. Normally we wait. We like to have naive subjects. But John's naive enough for our -- what I'm going to do is remove the book and ask him to keep his hand still. Watch what happens to his hand as I remove the book. It's impossible to keep his hand still, to anticipate the timing and to therefore relax the muscles. But if I ask John to remove the back himself with his other hand, his brain will be predicting the consequences and he can do it without any motion at all. This is something you can try at home. It's impossible to learn to keep your hand still when someone else removes it, but because the brain is anticipating the actions of one part of its body and the other can do it perfectly. And this predictor mechanism even explains why we can't tickle ourselves. So we know that our actions affect the way we perceive sensory feedback. And the reason I can't tickle myself is because of this predictive mechanism. I predict what's going to happen in terms of sensory feedback and I'm not surprised by it. 
7927:38
80    Eric Kandel: You're trying to get a demonstration? 
8127:42
82    Charlie Rose: So two questions I have about that. One, the import of all this or in terms of what insight it's giving us in terms of understanding function. 
8327:47
84    Daniel Wolpert: One insight it gives us is now we know about how we predict what we do. We're beginning to learn what other people do. And that's a very exciting arena now not that not only do I have to predict what my actions are about but what your actions are about. And John has nice data on this. 
8527:58
86    John Krakauer: Right. So in other words to become skilled, it's not enough to know how your body's going to respond to commands, but you need to be able to predict what the player or your opponent is going to do ahead of time. 
8728:09
88    Charlie Rose: Exactly! This is now to our favorite sport, tennis. 
8928:14
90    John Krakauer: Basketball. Which I didn't know a lot about, but I'll manage. So this is a very interesting study that came out of Italy where they were interested in seeing whether it would be possible for an observer to know whether a basketball player at the free throw line will hit or miss the basket. 
9128:32
92    Charlie Rose: Right. 
9328:34
94    John Krakauer: And they looked at professional basketball players watching this, coaches, and regular spectators. And what they found was that professional basketball players to a high degree of accuracy can actually tell you whether the ball will go in or not before it ever leaves the shooter's hands. 
9528:46
96    Eric Kandel: This is the observer. The observer can predict. 
9728:50
98    John Krakauer: So they are able -- basically, running, as Daniel said, a sort of simulation of what you can imagine is themselves doing it, and therefore -- and the way they do it and what was done in this study is that it looks as though before the ball ever leaves the hand here, there is differing degrees of activations in the observer's motor cortex that go to the very same muscles they themselves would use to perform this task. And that seems to be a readout or simulation of what's happening when they're watching the player, and that's why they can predict if the ball will go in or not, because in a sense they've simulated doing it themselves. 
9929:18
100    Charlie Rose: Here is what I need to know -- what can people can do that? 
10129:23
102    John Krakauer: The basketball players themselves. Even coaches and observers can't do it. 
10329:29
104    Charlie Rose: A highly skilled basketball player can watch another one and predict before the ball leaves his hands if it's going go in the basket. 
10529:37
106    John Krakauer: And you question is crucial, which is in order to get these predictive circuits working, you have to have done motor practice yourself. 
10729:45
108    Tom Jessell: I want to take you back to the case that Bob described of motor performance under conditions in which sensory feedback is lost, the two videos that we saw. What we saw is the normal response to the loss of sensory information. But there are a few remarkable individuals who, faced with the same viral loss of sensory input, have somehow found ways of co-opting other sensory systems to compensate for the loss of the sense of touch and the sense of limb position. And so the general idea that we'll be talking about is that normally the loss of proprioception, the loss of limb position and muscle contraction, leads to this dramatic mis-coordination, that there's an individual in England, Ian Waterman who was incapacitated for the first two or three years, but by a supreme act of will somehow learned to use his visual input to compensate for the loss of sensory input and recovered over the course of these two or three years through intense effort to the point that he can now move, walk down the street. And this is a remarkable recovery for someone who was essentially bedridden for the first two or three years following this viral infection. So if we look at the video here then you can see that his walking. His step is somewhat abnormal. But if you look, he's looking at his feet the entire time. Now, he's going to collide with another, and despite that, he waves him on but keeps his eyes on his feet. And if you deprive Waterman of vision, then his motor performance reduces and is degraded to something that we saw earlier. So this is a remarkable case of plasticity in a sense, to take the five or six senses that come in and then in an alternating way to change the sense that is being used to feed into the motor system. 
10931:43
110    Eric Kandel: To what degree can one use that plasticity in overcoming the consequent of stroke? 
11131:47
112    John Krakauer: So in stroke, and I'll just give you an example. This is a brain image. And this white area shows you where a stroke has happened. This is tissue that has died because of loss of oxygen and blood. And this person, if this is on the left side of their body, they'll have a right-sided paralysis. So the big challenge for people after stroke is, everybody gets better to some degree. The brain seems to have an intrinsic plasticity that allows it to get better. And what we want to know what is that plasticity, how can we enhance it, and how can we predict how good a job it's going to do? And interestingly enough, we've been able to show that early after stroke we can identify brain networks that somehow are going to tell you what the potential for the brain is to recover in the future, and somehow what we think is happening that -- I'll walk you through this. This is the side view of the brain. This is motor cortex in red, and this is the pathway down to the spinal cord that Tom told us about. And a stroke like the one I showed you in that image is basically where you interrupt that descending pathway where that crosses. OK, so now there's no longer a pathway to the spinal cord and a person losing their ability to move. But you'll see in this lighter color other descending pathways coming from other areas of the brain. So what we think is happening is over time that brain network I showed you that seems to predict people's recovery is somehow training people to unmask and strengthen these weaker connections down to spinal cord that over time can substitute for this one we've lost, and now they're just as intense as the original pathway was at the beginning, and through this learning process you've now found a new route down to the spinal cord to get function back 
11333:29
114    Eric Kandel: This is the sort of the parallel in the motor system which you for visual compensation. You're using another pathway to take over for damage to the initial pathway. And one of the wonderful things that John and other people of his generation have shown is that unlike the early teaching in which physical therapy is introduced rather late after stroke, these people now initiate treatment very early. You may want to elaborate on that. 
11533:54
116    John Krakauer: Yes, so I think going back to your question about children being better learned than adults, what's really interesting is those heightened plastic conditions that you see in childhood seem to be recapitulated briefly after injury to the brain. 
11734:07
118    Charlie Rose: Now, why briefly? 
11934:10
120    John Krakauer: Well, we don't really know. What seems to happen is that genes that promote growth factors get turned on, and then a little later genes that inhibit those growth factors get turned on. I think the idea would be that you don't want this plasticity to go on forever. So you have this brief window that it a little bit like plasticity that you see in childhood, in early development. And the key thing is to intervene, as Eric said, in this window of heightened plasticity with stimulation and with behavior to get more recovery than we used to. 
12134:39
122    Charlie Rose: The critical question about the critical time is how long is the time and -- 
12334:45
124    John Krakauer: All right. So in animal models it looks like two to three weeks. We think based on our work in humans that window may be as long as three months, although my feeling is we should really be getting in the first month. 
12535:00
126    Charlie Rose: And that's -- 
12735:03
128    Eric Kandel: What is really remarkable about this is a complete reversal of what we were taught in medical school in which one did not intervene with physical rehabilitation until much later in the disease. Now these people are intervening very early, taking advantage of this critical period which is therapeutically so beneficial. 
12935:21
130    Charlie Rose: Let me go to ALS and talk about ALS and what we're learning there and where we are and what we know. 
13135:26
132    Robert Brown: The best way to introduce that is to turn again to the figure that we've seen previously from Tom Jessell, making the point that the final common output for all movement and, indeed, any form of human expression, is this spinal motor neuron which goes from the spinal cord down to the muscle. I want to digress for just a moment to comment a bit on this particular cell. This is an extraordinary entity. It is among the largest of cells in the body. It is so large you that can almost see it with a naked eye. It's a tenth of a millimeter. But what's extraordinary is despite the enormous size of the cell body, the process that goes down to the muscle itself is truly extraordinary, so that, for example, if this room were a motor neuron, say in your low back, sending a process to a muscle down here, that muscle would be about 150 miles away. 
13336:16
134    Charlie Rose: Wow! 
13536:19
136    Robert Brown: And that's valid. And so the point is that somehow this cell has to sustain this process, keep it alive basically to function normally. But here's the extraordinary point. That is cell that essentially has almost no capacity to repair. It has a limited capacity to sprout, it has no capacity to divide and replace itself, and so the extraordinary question is really why it survives as long as it does. So in motor neuron disease th fundamental problem is that this cell dies. Now, you've heard in stroke and spinal cord injury and in other diseases one can recruit other parts of the nervous system to supplement or make up for dysfunction and produce pseudo-motor output, which is almost normal. And we've seen examples of that here. But the problem is when this spinal common pathway is shot, there is no compensation, there's nothing else. And so sadly when people have motor neuron disease and this cell type dies, typically they in turn die in three to five years. 
13737:14
138    Charlie Rose: It goes to their lungs and they can't breathe. 
13937:17
140    Robert Brown: Exactly. So all muscle then becomes de-nervated unplugged from motor nerves, breathing fails, and they die. 
14137:24
142    Charlie Rose: Do we know what causes that neuron to die? 
14337:26
144    Robert Brown: So we don't. And in fact, I'll comment on that, because that's a burning question in terms of the way we understand this problem clinically. We suspect that there are many factors that contribute. Certainly in about 10 percent of cases we know there are mutant genes that make sick or toxic proteins that actively kill a neuron. But we also know that behavior probably plays a role. There's some data that that soccer players in Italy, for example, have a higher-than- expected incidence of ALS. We know head trauma may be a factor. We know the environment also influences the disease. And there may be some role fo what we call stochastic events -- bad luck. 
14538:04
146    Charlie Rose: Right. 
14738:07
148    Eric Kandel: This is such an important principle, because what Bob is showing here for amyotrophic lateral sclerosis, if almost a general principle in the nervous system. Most diseases, Parkinson's disease, they have multiple causes, so one doesn't think of simply a single factor like genes. That's one way of producing the genes but there are other ways of producing it also. 
14938:28
150    Robert Brown: That's exactly right. So one of the ways that scholars over the last several years have tried to understand this is to look at that 10 percent of cases where we know a miscreant gene and a sick protein have caused the disease. And so basically one can take, for example, a family, and here we have a pedigree with individuals in light and dark coloring, those with light coloring have the disease, those with dark don't. And one can essentially profile DNA and use profiles of DNA to screen the families and essentially in that manner find the disease-causing genes. I'll just tell you that it's -- 
15139:04
152    Charlie Rose: And once you do that? 
15339:07
154    Robert Brown: Well, the question is once one has the disease-causing gene, can one use that both to understand the disease and ultimately, of course, to find therapy. And the answer is thus far there have been huge insights, enormous insights into the complexity of how a motor neuron dies when there is a mutant gene. But the ability to use that information therapeutically is still not yet realized. 
15539:30
156    Eric Kandel: This has been true time and time again that even when we know the gene, even when we know what is called the mechanism of pathogenesis, how that gene does its damage, that mutant gene, we're still a long way from treatment. It takes a long time, and they will discuss various therapeutic processes in order to ameliorate the disease. It's a very difficult challenge. 
15739:49
158    Charlie Rose: Any therapies in terms of stem cell or any other area of -- 
15939:53
160    Robert Brown: We think that there are a variety of therapies that are very promising. I'll give you one two examples. So typically in most of the ALS genes that have been found so far, the concept is the mutant gene makes a toxic protein and that that wreaks havoc in many ways up and down the motor nerve. So clearly one what one would like that do is turn off the expression of the toxic protein, turning off the poison at the tap. That's essentially stopping the dominos from falling before the first domino goes over. So that's one approach. It's called silencing of the gene or using a technique called RNA silencing. But the question of whether or not one can use stem cells, as you have asked, to think about the biologist disease, is of enormous urgency and importance. Let me give you one example. It was reported approximately one year ago by colleagues here in New York and Boston that one could take a skin biopsy from an ALS patient, from that prepare skin sell, which is could be transformed though a variety of electro interventions into stem cells from which one could differentiate both motor neurons and some of the supporting cells for motor neurons. So that for the first time one had in a Petri dish a representative motor neuron from a living ALS patient in a genetic context that reproduced the patient itself. 
16141:12
162    Eric Kandel: One of the fascinating things about that area is that Tom Jessell here has been a pioneer in studying how motor neurons develop, in fact, how the nerves in the spinal cord develops. So he has figured out all the reagents, all the chemicals that are necessary and are used normally in order to get a motor neuron to grow. And that has been tremendously helpful in allowing you to do that with stem cells. 
16341:35
164    Tom Jessell: Yes, to come back to this example that bob pointed out. This arrow from stem cell to motor neuron is easy to draw on paper. 
16541:52
166    Charlie Rose: It's not a slam dunk. 
16741:58
168    Tom Jessell: But in a sense, a stem cell that has capacity by definition to give rise to every cell in the body -- to a heart cell, to a liver cell, to a kidney cell, to a hair cell. So the trick in a culture dish is how to coax those stem cells not to undergo and embark on these thousands of different pathways, but to find a recipe in which you can convert a significant number of these cells to one class of cell, a neuron. And then not just to a neuron to a motor neuron. And so remarkably it's now possible to do that. By adding just a couple of small molecule chemicals to this starting stem cell mix, you can get 50 percent of those cells to become motor neurons. And the other cells become the cells that are sitting in the environment of the motor neuron. And in the context of ALS, I think that's had a dramatic impact because it means now for the first time we can -- the field can essentially grow billions of motor neurons derived from an individual patient, and then apply the strength of modern molecular biology and cell biology to understand the causal pathogenesis. Is there a single common link? What we know from the genetics is that there are a dozen different genes that when perturbed or mutated willed give rise to what we call ALS. Are these really the same disease or are they diseases that simply affect the same cell type, the motor neuron? And so now I think the field can began to study in a rational way the origins of the disease, and in principle to think about replacing dying or dead motor neurons with other motor neurons. Now, while that may be a promising approach, for example, in diabetes or in Parkinson's disease, if we come back to the circuit issues of 600 muscle groups, each have to be enervated by their own set of muscle neuron which is has the same input from cortex, then it begins to illustrate the daunting challenges that face a cell replacement strategy. But perhaps through having patient-specific disease motor neurons growing in a tissue culture dish, you can then begin to combine this with chemical biology with the pharmaceutical industry to screen for compounds that slow the degeneration of these motor neurons in a dish and ask which of those compounds which actually be effective in animal models. 
16944:25
170    Eric Kandel: So you've pointed out two uses for stem cells. One is to study the mechanism of the disease and therefore to develop drugs that inhibit that mechanism. The other which you said is actually replacement. And your argument is this is unlikely to be very successful. Could you give examples in which it might be successful? 
17144:43
172    Tom Jessell: I'll mention them briefly. So a disease like type one diabetes, which is in very large part of the loss of insulin production, is a much more attractive candidate for stem cell therapy, for turning stem cells into the insulin-producing cells, and then reintroducing them back into the body. For a disease like ALS where the organization of the circuit is so important, it's not impossible, but it's difficult to think of how in an adult animal or an adult individual patient who's lost 50 percent of their motor neurons, how you reintroduce those motor neurons. 
17345:21
174    Charlie Rose: What I'd like that do is go to something Daniel may have touched on, but I want to make sure I understand it -- this idea that if we understand how the acting brain works and how motor functions, it will be the key to unlocking other higher forms of brain function? 
17545:40
176    Daniel Wolpert: I think in the end, it will, and people may disagree with me around the table, but I think if we can't study things like perception and the absence of how it affects movement, because effectively the way we use information is very important. And we don't do perception in isolation from action. So I think we can probably study perception and we'll know about perception, but unless we can link that to the action we won't have the whole picture. So in the end we have to understand how information is used. And therefore once we solved motor control we will have by definition have to solve all the other things. 
17746:17
178    Eric Kandel: What has also emerged, and we referred to this earlier in looking at the hand of a basketball player shooting a basket, is that even when we don't engage in movements, our motor systems are simulating the movement. So there's a lot more movement going on in our brain that is visible to the outside world. 
17946:36
180    John Krakauer: The point is that some people even said that thought is basically movement, planning without the movement. And so from an evolutionary standpoint, you can imagine that if we understood motor planning and simulation without the movement, very likely those planning processes were co-opted for higher level thought. 
18146:52
182    Charlie Rose: The hierarchy idea -- explain that to me one more time. 
18346:58
184    Eric Kandel: Well, in order carry out a movement, if I want to shake Dan's hand, I have to decide I want to do that. 
18547:04
186    Charlie Rose: Plan you want to do it. 
18747:07
188    Eric Kandel: Then I have to plan which muscles are involved, and then I need to recruit the motor system and the spinal cord in order to carry out that movement. So there's a hierarchy very much like we what we saw in the visual system. There are all complex processes, steps. But we also saw each of these steps can be selectively interfered with by different diseases. 
18947:23
190    Charlie Rose: All right. 
19147:24
192    Eric Kandel: And each of these can be strengthened by learning. 
19347:28
194    Charlie Rose: I've go thousands of questions but I have a limited amount of time. What's the one question you most want to answer? 
19547:35
196    Daniel Wolpert: For me, I would love to know what the algorithm or computer code the brain used to generate skilled movement. So if we can write down the equations that really explain how we learn and how we control the movements of our bodies, that would be wonderful for three reasons. One, it would give intellectual curiosity. Just to know that would be wonderful. But that's not the only reason. The other reason is it has two benefits. One benefit is a minor one. If we could build machine which is could do human-like tasks, that would be wonderful to be able to put that in the technology domain. But also I think understanding basic function we understand disease. There's lots of examples where if we understand the basic mechanisms, we can apply both to understand what's going wrong with disease but also for rehabilitation. So if we look at how normal people learn, it would inform us of the sorts of ways we could improve learning and the sorts of patients which John has talked about already. 
19748:26
198    John Krakauer: I would really like to know a very practical thing, which is if we were to come up with really good drugs, brain stimulation techniques, and training protocols, could we make people after brain injury and spinal cord injury really much, much better than we can now? Is that window that I talked about exploitable to the extent that we can get huge beneficial effects of rehabilitation? I really don't know how far we can go. 
19948:52
200    Tom Jessell: Now, 500 million years of evolution have been devoted to building a wiring diagram that produces action with a sophistication that we've begun to discuss. I'd be interested in understanding the way in which the assembly of motor circuits really explains the biomechanical demands that those circuits need to engage in in everyday life, to what extent all of our motor functions really are prewired through genetic programs, to what extent does experience and environment build on that pre-wiring. And if we understand that in the context of the motor system, I think we'd have a new insight into the way that wiring diagram controls all aspects of brain function. And I think that's a goal that probably is attainable in the next two or three decades, really to have this molecular, this combination of behavior and molecular programming of circuits and wiring diagrams. 
20149:52
202    Robert Brown: So Tom has taught us over the years how a stem cell assumes an identity, and with that identity establishes a biochemical and a morphological identity that says "I am a motor neuron," extends a process, and functions to go through an activate contraction of muscle. What I would like to know how those developmental phenomena are recapitulated in an adult so that as we age and as the motor neuron is exposed to a variety of kind of age dependent stressor, the system nonetheless is able to reactivate some of the early developmental processes that establish the identity of the first place to sustain normal function. Because I think it's through understanding these age dependent responses to injured motor neuron that we will finally come up with therapies for disorders like ALS. 
20350:43
204    Charlie Rose: Sum up what we just saw, but also tell us what we have to look forward to in our next episode. 
20550:49
206    Eric Kandel: Well, so far we've spoken about individual perception, individual actions. In the next episode we're going to speak about group interaction, social behavior. We're immensely social beings. We bond with one another, we like certain people, I enjoy being Charlie Rose. These are very important aspects of human interaction, but we not only bond together, but we also form groups that are aggressive to anyone from the outside. What is the nature of bonding? What is the nature of aggression? Can we understand how that's represented in the brain? Can we see examples of social behavior of bonding and aggression in simple animals, or is this something that is exclusive to higher primates, to human beings? To what degree is social behavior determined by genes? To what degree is determined by learning and later experience? Are the diseases that selectively affect the social action of human beings? These all topics we're going to consider in the next program.