0:18 My name is Grégoire Courtine, I'm a neuroscientist and I work with spinal cord injury. But today, I would not only like to tell you the scientific story, but also the human journey that led my teen to develop an intervention that restore voluntary control of locomotion after paralyzing lesions of the spinal cord. And the journey starts with a dramatic consequence of a spinal cord injury for affected individuals who life shatters in the matter of a handful of seconds. And Christopher Reeve, the man of steel, better than anyone, has incarnated the devastating consequence of such injuries. And you know, Christopher believed in research. He believed that recovery was possible. And he loved to talk with scientists. I mean, I remember sitting in a meeting
1:08 all day, and at the end of the day, he talked to us, and he said, you know, you scientists, tomorrow, when you leave the laboratory, I want you to stop by the rehab center, and to look at the people who are fighting to take a step, struggling to maintain their trunk. And when you go home, you will think of what you can change tomorrow in your laboratory to make their life better. And you know what he says, it just stuck to me, to the point that I can say that Christopher and my work with the Foundation has altered the course of my life. But let's continue the journey with the basics. Why does a severe lesion of the spinal cord lead to paralysis? In this scheme, the spinal cord is cut in two sections. This means that all the information from the
1:54 brain I interrupted, the spinal cord below the injury is in a dormant state. And both human and rat, after such lesion, remain permanently paralyzed. So should we proceed in order to restore function? Well, the more widely accepted principle consists of applying factors that will promote the growth of the severe fibres to their original target. And you know, this seems extraordinarily complicated to me. I mean, imagine, not only the fibres have to grow, but they have to communicate with some of the millions of neurons below the injury in a functional manner. So we, my colleague, we thought to shift the paradigm and to take advantage of
2:39 the neural network below the injury. We know they can coordinate locomotion, but they are dormant. And you know, at the time, I had just arrived in Los Angeles after finishing my PhD in France, where professors don't necessarily promote independent thinking. So you know, I have this idea, but I don't know, can I put it forward? But you know, I just muster up my courage, I push the door of my wonderful mentor, Reggie Edgerton, And I expose my idea, enthusiast, and he looks at me, and then he's like, why don't you try? You know, and this was a turning moment in my career, when I realized that a great leader believed in young people and their idea. And this
3:27 was the idea. I'm going to use a simple metaphor to explain to you. Imagine that the locomotive system is a car. The spinal cord is the engine, but it's turned off. How do we proceed to reactivate this system? First, you need to provide the fuel. Second, you need to press the accelerator pedal. And finally, you have to steer the car. And my idea was to mimic this input, to provide the spinal cord with the kind of information that the brain would deliver naturally in order to walk. And this is how we proceed. Ten years of research summarized rapidly To provide the fuel, we design a pharmacological cocktail that optimally prepare the neuron to fire. And to mimic the push on the pedal, we apply electrical stimulation on the
4:14 dorsal aspect of the spinal cord. And together, this stimulation is what I call an electrochemical neuroprosthesis, which can transform the dormant network in the spinal cord to a highly functional state. And this is what you are going to observe. The rat here you see is completely paralyzed. Five minutes later, with the stimulation, the animal can stand. As soon as the treadmill starts moving, the spinal cord produces coordinated locomotion. This is involontary, but not stereotypical, because if you increase the speed of the treadmill belt, immediately the spinal cord is capable of changing the gait and know The rat is actually sprinting on the treadmill belt until we stop and the animal will just stand.
5:02 And this observation really compelled me to call this neuronal network the spinal brain. We need to recognize a remarkable capacity to use the sensory information as a source of control for locomotion and to take decisions as to how to activate the muscle in order to produce a very complicated movement without any input from the brain. And you know, we play a lot with my friend in Los Angeles, understanding this locomotion, but I was very frustrated. I mean, this is completely involuntary. Clearly, the steering system was missing. And it became pretty obvious to me that we had to move away from the treadmill setting and develop a robot that would allow us to train the rat under natural conditions, you know, over ground. So we developed this robot
5:50 in a fancy technology. There is a suspension system at the extremity of which the rat is attached. And the idea of this robot is that it provides support against the direction of gravity as well as in the lateral directions, but does not facilitate locomotion in the forward direction. So let me summarize. The animal suffers a paralyzing lesion. We enable highly functional states with the electrochemical neuroprosthesis. The robot provides a safe environment for the rat to try to engage highly. And then, to motivate the animal, we use the more powerful pharmacology of Switzerland, the fine chocolate. And when the robot arrived in the laboratory, we were all so excited, you know, will the animal be capable of walking over ground? And this is what we
6:38 observed. Very, very frustrating. The animal was incapable of initiating and sustaining locomotion. Whereas the same rat, five minutes before, would walk superbly on the treadmill. You know, I'm a stubborn person. So I told Rubia, with a therapist here on this video, you have to motivate the animal. Do anything for them to activate the hyaline. Use the chocolate, but also the vocal stimulation. And actually, you can hear this on video, and Rubia thinks that the rat understands her. I don't know if it's true, but after a few additional weeks of training, the rat could stand quietly, and whenever she decided, she initiated full weight-bearing locomotion to sprint toward the reward.
7:26 It was really surprising. I was absolutely not expecting such results. So I challenged Rubia. I said, what can they do? What are the limits of this animal? Train them in more complicated locomotor tasks. And Rubia, she picked up the challenge, and after a few additional weeks of training, a rat with a paralyzing lesion was capable of basically sprinting along a staircase. And this recovery is really unprecedented. This is the very first time that we observe, after a paralyzing lesion of the spinal cord, the recovery of not only voluntary but even adaptive control of the high limbs. And you know, I was very enthusiastic, I loved this result, I go to a conference, I present this data to my colleague. They did not like it. The
8:13 approach was so different. It was possible, what are the mechanisms? This walk is completely involuntary. The spinal cord controls it. And in a way, they are right, because this study really challenges the idea of voluntary and involuntary motor control. As I am walking now, the spinal cord takes care of most of the underlying operations so that my brain is free to talk to you, even the upper limb. I'm French, so I use my hand too much when I talk. That's what my mother said, at least. And, you know, this is voluntary? Involontary? I don't know. But this resistance of the establishment to accept this result really created a lot of problems, first with my institution, but even in my laboratory,
9:00 because people were afraid. You know, they said, we are taking too much risk. And I told them, do you believe in this data? And they said, yes, yes. OK, so let's take this opportunity, this critique, to investigate even deeper the underlying mechanism and prove our point. And after two additional years of very hard work, this is what we observe. We found that this active training on the highly functional state with the willpower of the rat promoted an extensive reorganization of the central nervous system by which the brain established new connections relay that bypass the injury and restore suprapinal control over the neuron below the injury. And what you see in this picture here is red fibers that are coming
9:50 from the brain. The blue neuron project below the injury. And what it essentially tells you is that the brain is reconnected with the locomotive network. And this plasticity, we not only observe it at the level of the injury, but throughout the central nervous system. including in the brainstem, where we found a 300% increase in the density of the projection from the motor cortex. This may be the more extensive reorganization of the neuronal projection observed to date after a lesion of the central nervous system. I'm going to the next conference, and I show this data to my colleague, but there was still These are blind
10:37 teeth. They were arguing, but the motor cortex of the rat is not involved in controlling locomotion. And I remember going home in the airplane, looking through the window, and I'm upset. And the next day I go to the lab and I tell my people, we have to record the neuron in the brain. And remember, this is a really complicated task. Imagine, the rats suffered a very severe lesion. We gained the capacity to walk with intense training, and then, asked to undergo an additional surgical procedure in order to position micro-wire into the cortex in the vicinity of this yellow neuron that project to the lesion area. And then,
11:26 while you stimulate the spinal cord electrically, there is a big robot hovering over the head of the animal, you have to record microvolts in order to obtain this wave. They are the signature of the neuron. And now we can translate this wave into audio, and what you will hear now is the neuron in the motor cortex of a rat that fires when the animal walks voluntarily with his own will.
12:12 I can tell you, when we obtained this data the very first time, it was a very special moment in the laboratory. I have all my wonderful team all around me, and we were all observing, listening to this brain symphony with a very large smile, because we were thinking if we validated our claims. This is not the end of the journey. You are all wondering, what is the potential therapeutic impact of this kind of intervention for humans with spinal cord injury? And the truth is that we don't know. But I would like first to let David, who is potentially our first patient and role in the plain clinical trial, to provide you with his own perspective on this research.
13:02 I had an accident. On the 8th of November, it will be one year ago. In my sports teacher education we went to a center to practice acrobatics and there I made somersaults with two or three rotations and once I landed on my head somehow and after that I came here. It's difficult to say how it will be with humans. Maybe it will be better, maybe it will be worse. But I think you've got to try to do the impossible to make the possible possible. So, yeah, I think
13:52 it's important to have a dream, but if it's realistic or not, I'm not sure. But I think if you don't try, you won't find out. So let's hope and go for it. And I really would like to emphasize that this is not a cure for spinal cord injury. But this may be an important piece of this complicated puzzle, and we may have gotten one step closer. And what I hope I've been able to convince you of during my talk is that by swimming upstream, by thinking out of the box, and pursuing your idea with perseverance, you can achieve an outcome that was thought previously to be impossible. And I hope that with this journey, we
14:42 have inspired new thinking to restore motor function after spinal cord injury. Thank you. I have a question. I mean, isn't it kind of strange to make rats walk on their two feet? Yeah, you are right to point this out, Darcy. So it's not the physiological posture, clearly, for a rat to walk on two legs. But there
15:27 is a very important scientific reason to test the animal on two legs. You know, because the four limbs are intact, the animal, if we would put him on all four, would be able to move forward with his four limbs, and basically the high limb would just follow, just like on the treadmill. and this gate can be completely involuntary. So the only possibility to test whether the brain can actually engage the endium in order to work voluntarily is to position the rat in this, okay, surprisingly bipedal posture, but very useful, heuristically. And it's also pretty nice, it makes a nice picture. Thank you, Grégoire. You're welcome.
