Odolfo Llinás comes from a long line of physicians; there are four generations of doctors in his family. But this physician-scientist’s insights on health and sickness come from studying some of the smallest structures in the brain: tiny channels, no more than 10 nanometers across, in the walls of neurons. Llinás probes the way nerve cells use these channels to manage and transmit electric signals. Textbooks say that in a neuron, electrical or chemical inputs at one end of the cell spark an action potential (a rapid voltage change) that pulses along the cell and activates connections on the other end. That simple explanation glosses over most of what neurons really do, Llinás has found. Along with these events, neurons engage in constant low-level electrical communications, a kind of intrinsic chatter. In the 1980s Llinás also demonstrated that
Neurons don’t just respond to information but set up their own rhythmic activity. Groups of neurons oscillate together, and he argues that changes in these fluctuations underlie perception, attention, and consciousness itself.
In his lab at New York University, Llinás described to Discover his unconventional view of the brain, one that emphasizes frequency, time, and coherence as much as anatomy and neurochemistry. From his perspective, thinking and sensing begin inside the head, in electrical reverberations that are modified by outside information. Llinás’s version of the brain is not an input-output machine, reactive in nature. Internal activity is where everything begins: We all truly live inside our heads.
Discover: People often think that the brain mirrors the outside world. You counter that it functions intrinsically. What’s the difference between these views?
Odolfo Llinás: Historically, the idea has been to consider the brain as a type of computer. Take the example of vision: Light hits the retina, the signal goes to the thalamus at the center of the brain, then to the cortex, or outer layers of the brain, and so on. Somehow the transformation of this information triggers events inside that are converted into subjectivity, into the perception of vision. This is the reflexological view.
A totally different way of looking at the brain is this: It evolved to allow intelligent movement. Multicellular entities that move all have brains. For movement not to be dangerous, you must be able to predict. If you’re going to jump, you have to have some general idea of which direction is most advantageous. The brain has evolved to make images of the external world in order for the body to be able to move. This is what’s known as the intrinsic view.
How does this intrinsic view change the way we think about the workings of the brain?
OL: The difference between the reflexological view and this intrinsic view is fundamental. In the intrinsic view, what the sensory system does is modify a pre-existing functional event. Almost like the heart. You can make it pump faster or slower, but it is not the external world that allows the heart to pump. The heart pumps intrinsically. So, too, the brain functions intrinsically. That’s how you plan, you think, you write. It all comes from the inside.
Another way to put it, and this might sound strange, is that the brain is a device to dream. You dream in two different ways. When you are awake, your dreams are modulated by your senses. When you are asleep, your senses are not working, so your brain can do its own thing. Consciousness is a dreamlike state, modulated by the senses.
That’s completely different from the way we usually think of the brain, as a device whose main purpose is to respond to new information.
OL: I have a story about this. When I was in medical school, in Bogotá, I asked a question in class: Do people who are born blind dream? My professor of psychiatry gives me a letter of introduction to an asylum for the blind. There, I meet a man who is 19, exactly my age. He has no eyes. Just empty orbits. I ask him, when you fall asleep, do you dream? He says, of course. So what do you dream about? I ask. He says: I dream about my life, of course. For instance, I dream that I get up, there’s my washbasin, I wash, I dress, my clothes are on top of the chair, I have my Braille there, I go out to the right. It’s a nice day, the sun is shining, I can feel it on my face.
Then I ask him to draw what he thought his environment looks like. He draws it with all the right angles. He has an image of the external world.
I was amazed. I expected something like this, but not at this level. Then he told me something that completely changed my life. He said, the problem with you is that you have eyes, so you think you can “see” with them.
It makes sense, it’s pretty evident. The system works with what it has, because it has everything inside it already.
So what is happening when we are dreaming, almost completely cut off from the world?
OL: If you look at the activity of the brain of somebody who is dreaming, you find that the activity is not in the visual cortex. It is in the association cortex, where complex mental processing takes place. The things you hear, think, and see in your dreams do not require primary cortical input. Your frontal lobe is disconnected. Dreaming is an orgy of sensation, things coming from memory and things being invented.
Then what could be the purpose of dreaming?
OL: I’ll explain it as follows. One of my students comes in and asks me something. I give a quick answer and proceed. Then, later in the afternoon, I suddenly say to myself, oh, my God. I was wrong, I told this person the wrong thing. I find the student, who asks me, had you been thinking about this all that time? No, I had not. I was minding my own business, when suddenly I realized I was wrong. At any particular time there is more than one thought process going on, and some of them get to solutions faster than others. At the end of the day, you have a lot that you have not finished computing. You have to zero it out, to get rid of all this stuff. It is very important to fall asleep and very important to dream. If people are allowed to sleep but not allowed to dream, they hallucinate. The system gets overwhelmed with partly solved problems. Terminating thoughts—coming to an end—is what this is about.
One of your most important findings was that the electric charge of neurons changes in cycles, going up and down in specific rhythms. What’s happening here, and why is it important?
We discovered many years ago that neurons have intrinsic oscillation. The cell is almost a perfect oscillator: The electric potential of a cell membrane goes up and down in a smooth rhythm. If they’re electrically coupled, groups of cells oscillate at the same rhythm. In the inferior olive and the cerebellum, two brain regions that are involved in movement coordination, the system oscillates at 10 Hz [cycles per second]. Those particular cells trigger timing throughout the nervous system. The intriguing thing is that this type of oscillation is present in all vertebrates and is very similar in invertebrates as well. It is fundamental. In general terms, we all move at 10 Hz.
The other big part of the picture is the perception of reality, which occurs at a higher frequency: 40 Hz, something called gamma band.
That’s weird: Why do we perceive the world at a faster rate than we could possibly move?
OL: The trick is to make an image of the external world fast enough to be able to predict the next step. The measurement of what’s happening must be faster than what I’m going to do about it. If I am boxing, for example, I have to move aside when the punch comes and counterpunch. In order to do that, I have to find out how fast the fist is moving and when to strike back.
The beauty is that vision, audition, smell and taste and all other perceptions operate at gamma band, so our senses stay ahead of our movements.
You look at the tiny channels that move ions, and therefore electric charge, in and out of neurons. Why take such a microscopic view?
OL: I’m fundamentally a cellular physiologist. The question I ask myself very seriously is, what levels of knowledge must I have in order to understand neurons? It became clear to me that I would have to understand channels, because the activity of neurons is produced by the activation of channels that allow ions through. If you want to know something, you have to understand it at least two orders of magnitude up and down the size scale.
Much of your research has focused on the thalamus, which is supposedly just the brain’s sensory relay station. Why do you think it is important?
OL: The basic idea had been that information comes, for example, from the eye to the thalamus, and then to the cortex, and that you actually see with the cortex. I think it’s really not like that at all. Cognition is not a cortical event. It’s at a more fundamental level. The connections between the thalamus and the cortex are always active—the thalamocortical system is continuously talking. When you see, all you’re doing is modifying the recurrent activity of that system.
According to standard models, the cortex is where all the sophisticated thinking happens. What does the thalamus do during all this back and forth?
OL: The thalamus has an outer part, which is mostly sensory, and an inner part, which is mostly about arousal and attention. At any particular time, only the systems that are oscillating together in time generate cognition. If you are walking down the street and you drop something and bend to retrieve it, somebody can take your wallet from your pocket, and you won’t feel it. The sensory system felt it, of course, but you didn’t. You were not paying attention. The nervous system filters. It allows information in that is in agreement with the context of what you’re thinking.
Sensory information—the input that tells you what’s happening—goes to the dorsal thalamus. The central thalamus is what pays attention. Only when the two oscillate together are you aware of what’s going on around you. You need both of them simultaneously. That’s how it works.
Is this what happens when we’re lost in thought, and then suddenly snap back to the real world?
OL: While you are awake, the system is continuously either observing or thinking. So one can be looking at a crowded harbor, allowing the information to come in, or one can be thinking about some unrelated problem. It is very difficult to do both simultaneously, but you can go back and forth very quickly. If you are thinking about something and suddenly an explosion occurs, you have to be able to stop thinking and start running.
I’ll give you a lovely example, from [the writer] Gabriel García Márquez, who is a dear friend. He writes in a double room, a room inside another room. He goes into the room, and things begin to happen in his mind, and he writes them down. The people that will be in his novels appear in his mind. The double room is because he doesn’t want to be distracted. If somebody knocks, everybody in his head, all the people, disappear. So here, if someone knocks, he hears it only faintly. He has time to fold everything back up. It takes some minutes.
So the thalamus is the part of the brain that decides whether we’re conscious and paying attention or far away, lost in thought?
OL: What you think of as your self—the conscious “I”—is just one functional state of the brain. The functional state of the brain that “we are” is what happens if you depolarize cells in the thalamus, and the membrane potential becomes less negative. Under those circumstances, the thalamus tends to fire at a particular frequency, at gamma-band frequency. As soon as you fall asleep, that system disappears, and then you disappear—your hopes, your fears, your very existence. The system is not there anymore.
So the thalamus holds both the ability to feel and the ability not to feel. As a scientist, I don’t believe that the “mind” is a separate entity. It’s just the workings of the brain.
What about the cortex, the alleged seat of consciousness—are you saying it doesn’t matter?
OL: No, it’s very important. It gives you the granularity in perception. It is the CPU for the thalamus. But without the thalamus, all of this is meaningless.
You think that many neurological diseases are the result of these rhythms between the thalamus and cortex being out of step. How does that work?
OL: In order to be conscious, your thalamic neurons must be in a depolarized condition, producing high-frequency gamma-band oscillations that drive the recurrent thalamocortical activity and result in the generation of an image of the external world. When thalamic neurons are hyperpolarized, meaning that their electric potential becomes more negative than usual, the system goes into a low-frequency oscillation. You are not conscious anymore. The system is cleaning up house.
In Parkinson’s disease patients, it had been observed that the thalamus has a low-frequency oscillation, as though it were asleep. We thought that maybe a lot of the brain pathology in Parkinson’s and other disorders has to do with part of the thalamus falling asleep, while the rest is still awake. This is the idea of thalamocortical dysrhythmia. It simply says there are conditions where the thalamocortical system is awake, but a particular part is firing at low frequencies. If part of the thalamus is oscillating at low frequency, the cortical system is basically not present. It is asleep.
What kinds of problems could such a broken brain rhythm cause?
OL: Each dysrhythmia gives you different neurological conditions. In Parkinson’s disease, you have problems initiating movement. In other parts of the cortex, it gives you a tremor. In the auditory system, you’re going to be deaf, and have tinnitus.
If you happen to have thalamocortical dysrhythmia in the frontal cortex, you’re going to have schizophrenia. In another part you’ll have depression, in other parts, obsessive-compulsive disorder. We’ve actually measured this, with MEG (magnetoencephalography, which measures brain activity via the magnetic fields generated by electrical activity). We can see low-frequency activity in parts of the brain that correspond to so-called negative symptoms, such as difficulty initiating movement in Parkinson’s.
That’s a pretty shocking claim: that tinnitus, Parkinson’s, and schizophrenia all derive from the same basic type of brain dysfunction.
OL: The question really is, how could it be otherwise? If there were different mechanisms for different parts of the brain, how could the brain be a unity? What is wrong is the way you’re thinking about the brain. The fact is, psychiatry and neurology are the same thing.
A few years ago, I gave a lecture here at NYU on thalamocortical dysrhythmia. The head of neurosurgery is in the audience. He’s very straightforward. He says: ok, then. I have a neurological problem, and I’m not going to tell you what it is. You tell me what I have. In two weeks, we’ll have another grand rounds, where you come tell everybody what it is. So we did MEG on him. We saw the most spectacular low frequencies in the auditory cortex. The number of neurons firing simultaneously was huge: He has tinnitus. Two weeks later, the whole medical school was there. I showed him the picture from the MEG. I said, you have low-frequency tinnitus, mostly on your right side. He was amazed.
Now there are many labs studying thalamocortical dysrhythmia. It is so simple. It flows so very nicely from the intrinsic properties of neurons.
Are you saying, then, that it’s wrong to think of depression as a chemical imbalance or Parkinson’s as a lack of dopamine?
OL: In medicine we say, what is the etiology? The etiology is like the trigger firing a gun. It triggers the event, but it is just the trigger. It started a process, but if there is no bullet, there’s no firing. It’s exactly the same with these explanations. Parkinson’s disease happens because cells in a part of the brain called the substantia nigra die, and dopamine decreases. So people say, “Parkinson’s disease is a dopamine deficiency.” Wait a second. Parkinson’s is what happens when you remove dopamine, and then the rest of the nervous system responds. It is the abnormal response of the nervous system due to the lack of the dopamine-producing cell. The issue of what triggers the event must be separated from what the event really is.
The way you describe the brain makes it sound more like a symphony than a hunk of flesh.
OL: I suppose one simple explanation is that brain function is a little bit like music. Music has time, pitch, and so on. If I look inside your head, I find very much the same properties. As a child, I was completely in love with Stravinsky and Bach. I was amazed when my family told me these composers were Russian or German. I wouldn’t be able to understand what they spoke, but I could immediately understand their music. Music also tells you how to move, with dance. Maybe music is a built-in language—a type of machine language for the brain.
Could we treat these dysrhythmias?
OL: We’re now studying pain, tinnitus, psychiatric diseases, and abnormal motor control such as tremor, looking at thalamocortical dysrhythmia. We’re doing clinical trials, giving people drugs that block certain ion channels, to see if we can help these disorders.
Besides looking at brain disease, what other kinds of research are you doing?
OL: Another idea we’re working on is for a type of computer that is not digital but analog. The Navy wanted an underwater device that could move fast and be intelligent, so we proposed an analog system. We found some properties of neurons that allow our system to operate very quickly, much faster than if it were digital. Also, our system is overcomplete, meaning that you can damage part of it and it will still work—again, like a real brain. Our analog computer is made out of artificial oscillatory neurons, made of silicon. They change capacitance. They oscillate and can be reset very quickly. Each one calculates probabilities, so if you get rid of some, the system will not be as accurate, but it will continue. It is more like biology.
The engineers said it has to be digital, but ultimately we beat the hell out of them with an analog system. When we tested it, it was faster and more maneuverable than the digitally based system.
You have a giant, 41-inch telescope at your house, and you’ve coauthored a paper on quantum mechanics in ion channels. As a biologist, why are you so interested in astronomy and physics?
OL: It’s all a story of synthesis, going from very fundamental things to more specific things. It’s not unlike development in biology, as you go from one cell to an entity that thinks. It is this direction toward complexity that is so beautiful and so important.
You still work in the lab, doing experiments, but you are also drawn to big ideas across the board, both within neuroscience and beyond. Why is it that so few scientists think that way?
OL: Understanding the nature of what we are should be a general theme, but many people in science are mostly interested in very tiny questions that they feel they can address comfortably. Any particular bits of knowledge may be important, but if you don’t put it in context, you’re just collecting stamps.
The ability to generate hypotheses and test them was for a long time looked down on. Give me facts, was the thinking. But facts are only valuable if they can be put in some kind of context. And sometimes facts are not facts anyway. The measurement was not well done, or the basic hypothesis is false. The only way to progress is to falsify, making hypotheses that can be proven false.
The fear that I have is that the knowledge one can gather is probably infinite and doesn’t necessarily lead to understanding. To me, the aim should be simplicity after complexity. No knowledge without context.
[This article originally appeared in print as "Brainsong."]
