We're gonna talk about a pivotal moment that we're at in the history of neuroscience, in the history of science really, because scientists are helping to decipher what you could arguably say is the most complex structure in the universe.

Christof Koch: When I was still a tenured professor, now I'm just a mere mortal, when I was still a tenured professor at Caltech and I could leap over tall buildings, I was, um... My main pursuit was studying consciousness the neural basis of consciousness. And in particular I felt the best way to pursue that was to work on theoretical ideas, but also to pursue experiments in humans, 'cause if there's one thing we know for certain about consciousness, is that most of us are conscious most of the time.

In order to understand anything about the brain and ultimately about psychology, we have to understand neurons. We know a lot about nerve cells in post-mortem, in dead brains and of course in animals. But there's a rare occasion when you can actually listen in to the way neurons talk to each other, and that's during neurosurgery. So in some subset of patients, that have epileptic seizures, there's an idea that if you can locate from the place in the brain from which the seizure originates, and if you can then surgically remove that, then in many cases depending on the type of epileptic seizure the seizures will go away. Now in some patients you can't locate it from the outside, so then what the neurosurgeon does, implants up to 12 microelectrodes into the patient's head. And so you can essentially triangulate. When the patient has a seizure you can triangulate, and then you can pinpoint where the seizure originates. So now in principle we can listen to individual neurons. And I say listen because the way they talk to each other is they're sending out these brief electrical pulses called action potential or spikes. You can put them on a monitor and you can actually listen to them.

So these are actually neurons, nerve cells, in a brain of a patient that are chatting to each other. We don't--we're only beginning to understand the code that they use to talk to each other. But we can pick up this signal and it's very similar in animals. So the patient is conscious, you can do all sorts of games with the patients or you can show him or her images. So what we did, we probed and we showed different things to the patients because we wanted to uncover what is the trigger, what turns these individual neurons on? See here, what you can see, we show this image of a spider, of an animal, of the Eiffel Tower, of a bunch of Kobe Bryant, of a bunch of other famous people, and here, of an actress called Jennifer Aniston. Some of you may know her, she's a famous Hollywood actress. But now, if you show images of Jennifer Aniston the neuron will respond... Very reliable, on each trial. The neuron didn't respond at the time she was married to another famous actor, and, uh... And the neuron didn't respond to that. This is now in the textbook and is called Jennifer Aniston neurons. So the idea is that things that you're very familiar with like actresses or actors, politicians, your spouse, your kids, your workers, your car, your dog, anything that you see again and again your brain abstracts and represents by a bunch of neurons. Not one, this isn't just one Jennifer Aniston neuron. There may be 10,000, or maybe even more neurons that respond relative specifically to Jennifer Aniston. And so the idea is this tells us something about the way neurons... The things that neurons care about. So in this high-level part of the brain, they care about things that we care about. It's not surprising. I mean, we care about abstract things like people and the relationship, or like idea, concept things like justice or democracy or America or Afghanistan, all those things, and there will be groups of neurons that very specifically respond to that when you think about those things. So you can do a lot of research at that level.

Um, so this is a neuron. Here you have its sort of input region. This is called the dendrite, in red. And then here at the cell body there's a lot of electric machinery that we understand quite well. It generates this action-- this pulse when it's sufficiently excited, and then it sends out that pulse onto the wire. This is the output wire, it's very complicated. And every time there's a connection this is indicated in yellow and that's a synapse. The synapse is a contact point between two neurons. And how much one neuron influences the next neuron is encoded in the strength of that synapse. And all the evidence shows that a memory, like the memory of my first kiss, or the memory that I know what Julius Caesar said when he was killed by his friend Brutus, all that sort of memory is encoded in the strength of billions of synapses that constitute memory and that also ultimately give rise to consciousness, the feeling of something. What really gives rise to thought and consciousness and memories is the cerebral cortex. The cerebral cortex is really a sheet. It's a pizza. It's pretty much... Think of a pizza that's two to three millimeters thick, pretty much like my vest here, two to three millimeter. It's this size, and we've got two of them, but they're highly folded. And this is a computational tissue that evolution invented roughly 200 million years ago. It's common to all mammals, and it gives rise to our identity, who we are, our feelings, our memory our sense of selves.

And we at the Allen Institute and many, many other scientists are trying to understand what is the universal... what is the, sort of the algorithm, what is the computation that's performed within this dense forest of 100 billion neurons? It's 100 billion trees that give rise to all of this. So now what we're gonna do, we're gonna zoom in in this last movie I'll show you. We're gonna zoom in onto one piece, a sliver here that's incredible thin. It turns out for those of you who know about numbers, twelve micrometers in thickness. That's maybe a tenth of the width of a human hair. It's very, very thin but we're gonna zoom in, in great detail because the more we look, the more details we see. I show this because the one thing that you're confronted with is overwhelming complexity. Each new generation of measurement techniques, of microscopes, reveals more and more complexity. It has to be complex because ultimately it has to give rise to the subtlety of the human mind. So what we'll see here is a piece of cortex from the mouse brain. Here again is one of those neurons just like the one we showed before. You'll see a whole bunch of them, so we're gonna take a trip with cool music, that starts up here and that goes slowly down here. And it visualizes every single synapse, so what you're gonna see are three colors. You'll see in high detail, you see magenta. Each magenta pointer, each point is a synapse. As I said, they are-- In this piece there's gonna be a couple of billion synapses. Green is a subset of one particular type of neuron, and the blue color you see is tubulin. It's dendrites and axons of other neurons. This is one millimeter again, so the millimeter is half the size of the width of a grain of rice. All right, and now... So it's a mouse brain. The common laboratory mouse. The size of the brain is roughly a sugar cube. And that's where we'll zoom in. Just remember, the magenta are the synapses. The green is one set of neurons. They happen to be called Layer Five for the experts. And blue is tubulin that shows the wiring of axons. And now we'll go through this cortex.

John Donoghue: Good evening. So you might think after seeing that movie that it's hopeless, that we can never understand anything about something so complicated. Um, so what I want to do is to say that in fact we have learned enough not only to understand some fundamental things about how the brain works, but also to intervene in ways where we can restore lost functions, and I want to give you just two examples of the kinds of things that we can do because of our understanding of the brain. So the first one is one in which... where technology we have is going to allow us, allows us to write into the brain, to actually do something to transform the brain by intervening in brain circuits.

So, let me just explain. So every day when you move around, your brain is working to produce movements, and there's a very important chemical in your brain called dopamine that comes from the bottom of the brain in the brain stem, and it comes up and basically dopamine is oozed all over your brain, and in many areas it's sort of, uh... ...your brain is taking a bath in dopamine. In some cases, the dopamine neurons degenerate, they die. In fact, in all of us, we lose a little bit as we age. But if these neurons die, the circuits don't work properly and you get something that James Parkinson described in 1817 as the shaking palsy.

And what happens here is, you can see this lady who has lost many of her dopamine neurons. She has the shaking palsy. You have a tremor, you can't move, you're rigid, and you have difficulty initiating movement. It's a severely debilitating disease, and it's because of the loss of dopamine. Now we can't put dopamine back in the brain very well. There are some pills, but it doesn't work exceptionally well in all cases. But what we can do, is we can put a stimulating electrode about the size of a small soda straw that has the ability to electrically stimulate at the end, and we can, by turning on this stimulator we can tickle these brain circuits and make them act as if they had dopamine back again, so they work again. And as a consequence, we have a very remarkable result when we turn on this stimulation. So here is the same lady, after the electrical stimulation has been turned on, and you can see the shaking, the tremor, the rigidity is gone. And this is an amazing reawakening of these motor circuits. They are no longer held slave to this disruption that's there with the lack of dopamine. This kind of intervention in brain circuits to rebalance, or what we call neuromodulation, modulating these brain circuits back to normal, is now being tried in a large number of other disorders, and as far ranging as dementia, Alzheimer's disease. Imagine now we could bring that circuit back into control so that instead of having cognitive decline, you could allow a person to retain their memory throughout life instead of losing it as happens with Alzheimer's disease.

So the second disorder I want to tell you about is the loss of the ability to move, paralysis. And there are a large number of ways you can become paralyzed, and that basically cuts off a brain that functions from the body. So, let's just sort of see what happens when you move. So basically, when you're thinking about planning to say, pick up a pen and jot down a phone number or take some notes here, your brain, many areas of your brain collaborate together and work to produce a plan and that plan is turned into action, and it largely engages this one important area called the motor cortex. It's a strip that runs from the top of your head down to your cheekbone, about an inch wide or so. And if you're thinking about jotting down a note to control your arm, there's a region at about the middle third of this area that controls your arm. And that sends out a bundle of fibers, these axons. It's a compact bundle about the size of a pencil lead that has a million of these fibers. It runs down through the brain stem and down into your spinal cord, and it's the requisite pathway, it's the important pathway to send commands from your brain to move out to your muscles.

So, for example, if you were to have a spinal cord injury, that would interrupt this path you would be paralyzed. You couldn't move your arms and legs. If it was the whole path destroyed, you would think about moving, but nothing would happen. We call that tetraplegia. And even more devastating damage can happen with destruction in the brain stem, where it still interrupts the pathways, but because it's higher up in the brain, it not only will render a person tetraplegic, they cannot speak and sometimes they can't move at all in the worse condition. We call that a locked-in syndrome. They can only move their eyes up and down and that's it.

So, I'm gonna tell you about two people. Cathy Hutchinson, who had a brain stem stroke about 15 years before this picture was taken when she was sitting on her couch. She was completely locked-in for a while, and then was able to move her face and eyes and head, but not able to speak any longer and not able to move. And Matt Nagle had a spinal cord injury when he was involved in a fight and a knife went into his neck and severed his spinal cord. So he can talk and he can move his head but he cannot move his body at all. And what I'm going to tell you about is a project which we call Braingate, but it's a kind of brain-computer interface. Our attempt to take signals from the motor cortex, take them outside the body and allow people to run machines and control devices to free them up, to give them independence to control again. And what we do is we have created this electrode array that is implanted in the arm area of your motor cortex. Now the electrode array is a tiny, baby aspirin-sized implant, and it has a lot of these little prongs sticking out.

These are electrodes that are actually inserted into the cortex to get up close to these neurons that you just saw. And the reason we have to put this into the brain is the action potentials, the spikes, the electrical impulses that come out of individual neurons only go a very short distance. So in order for us to listen in to those impulses we have to put electrodes up very close. But those impulses are the message of movement. So what I'm gonna do is let you listen in to a recording in which a technician is telling... In this case, it's Cathy, he's telling her to imagine opening and closing your hand, and you'll hear the spikes change their firing rate. So it'll get higher and lower, and you can hear that there is, in fact, a code there. High means that the hand is open, and low means the hand is closed. So just listen in for a second.

Man: Relax. Imagine you're opening your hand. Relax. Close your hand.

Donoghue: See, it shuts off. 

Man: Relax. Open your hand.

So, this is the basis of the device that we've created. Not only recording from one cell, but taking the pattern of many, many neurons and trying to relate what the person is thinking about to what something in the real world will do. And this is the set-up that we have. The person has this electrode array implanted in their arm area of the motor cortex, We have now in this rather crude, primitive version because it's just an early stage version, they had a plug in their head. The electronics are connected by a cable that amplifies those little, tiny signals, takes them through a computer and the computer basically counts up and measures those spikes, and tries to figure out, well, that means up, or that means open or that means closed.

And what I'm gonna do is show you some videos that show what the patients have been able to do. Of course, we were very excited, and we asked Matt to do a whole bunch of things Here, he is gonna draw a circle, then he's gonna tell us what it's like to be able to control something. So he's controlling that cursor with his thoughts. And this is actually the world's first art, I think. Neurally drawn circle. Oh, man, I can't put it into words. It just... I used my brain... I just thought it. I said, Cursor, go up to the top right and it did. And now I got control of it all over the screen. -It's wild. He was using his consciousness to manipulate his neurons, but he actually didn't really understand what was going on. Something happens when you think, and it manifests as those spike changes, but what's really going on is the mystery. So, he hadn't moved anything in a long time, so we were able to get this prosthetic hand. And it doesn't really do anything, it's just a motorized hand that can open and close, so we ran a brain command into it, and told him tell us what you're doing, and imagine opening and closing that hand. And you're gonna hear his reaction to the first time he's moved something in a couple of years because remember, he's completely paralyzed. And you'll listen to his strong reaction.

“Whoa, holy shit.” So, just if you missed that. “Whoa, holy shit. Close. Nice. Open. Close. Not bad, man. Not bad at all.”

He really became a star by doing these things. Now, of course those aren't very practical actions, and what we really want to do is enable people to do things that are meaningful, and for people like Cathy, who can't speak, communication is extremely important. So, my colleague Leigh Hochberg and others in our group have created... If you can move a cursor, you can choose words on a screen. Instead of using a keyboard in which you have to move a cursor all over the screen, we made a radial keyboard with word prediction, and this is actually Cathy spelling out a sentence. So just to show that she can use this spelling interface to convey messages.

But we'd really like to see something even more sophisticated to do things that you can't-- she can't do. She can't do things with her arms. So here, Cathy is controlling a robot arm and we're doing something simple. We just elevated these little foam balls and told her to reach out and grab them. And because of our ability to make some sense of the way the arm is coded and reaching space, she was able to do that. So what we did is we said, Let's do something practical and meaningful for you. And so we gave her her morning coffee, and we said, Okay, Cathy, for the first time in 15 years you're gonna feed yourself your morning coffee and not have to rely on another person to come in and do that. So, here she is with the control of the robotic arm, on her own taking her first drink of coffee. We found out in the afternoon she actually sometimes had Kahlua in the coffee as well. Of course, they only use it in a research setting so far. What we want to do is make it available all the time. And in fact, what we really want to do and really strive to do over the coming decades is to be able to take a person who can't move and reanimate their own muscles. To basically create a physical nervous system where their biological one is irreparable.

So here's an example of what we're aiming to do. The idea here is that there's an implanted array. It generates signals, it comes down to something like a smartpack on your belt like a cell phone, that then communicates to an electric nervous system and it activates a stimulator which then stimulates the nerves and causes the muscles to activate. So it's what your nervous system normally does, but it's all done with physical components. And one of the next important steps is to create something that is basically a smartphone inside the head, and my colleague Arto Nurmikko has created this device, which is something that will allow us to wirelessly transmit all of those complex brain signals outside. And here in now nice, bloodless surgery done in a kitchen no less, there's the implant. The transmitter sits underneath the skin and it transmits all that information out. And this is not in humans yet, but it will be in the next coming years, but has been tested in animals. And this is feasible now. It has more sophistication than what you have in your cell phone to be able to communicate, be able to tell us what's going on, and to get that information to the outside.

So, this is coming, the ability to rewire the nervous system. And I asked Cathy to send me a note about what does it mean... What would she like to do again. And so she sent me this note, she typed it out:

I would love to garden again. I really miss gardening, canning and cooking. I also wanted to be able to hold a book with both hands, or even a robot arm. I really hope someday I'll be able to use my voice. I can handle paralysis, but lack of communication is torture.

Thank you. So, I would say thanks to them, these brave patients and thank you. I think I'll conclude with that.