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Explorers of the Brain: Research from the Frontiers of Neuroscience (transcript)

From the National Science Foundation, this is Explorers of the Brain--research from the frontiers of neuroscience. (MUSIC IN) Right now, inside your head, there's a 3-pound, non-stop, multitasking marvel.

POEPPEL: In some sense it shouldn't work. The fact that it works at all is kind of miraculous.

Your brain--literally the nerve center of your universe.

POEPPEL: Why you like something or not, why you make a decision, how you speak.
ZITO: How we think, how we perceive the environment, how we learn.
KOPELL: Looking for a car as you cross the street.
HOFMANN: Should I run or should I jump or should I just lie down?
POEPPEL: How breathing works, how your temperature is regulated, the fact that your heart is going on.
KOPELL: All of those things involve many different parts of the brain that have to work together.

But despite its centrality--or maybe because of it--much about the brain remains a black box. Van Wedeen is a professor at the Harvard School of Medicine.

WEDEEN: If you asked the first biologist you meet what the heart is for, they can tell you in one second (snaps fingers) how the structure of the heart relates to the function of the heart.

That's not the case for the brain. The complexity involved in understanding the brain is profound. David Poeppel is a Professor of Neural Science at New York University. The best analogy he has?

POEPPEL: Compare it to the structure of the universe.

We have a pretty good idea how many stars there are in the Milky Way Galaxy.

POEPPEL: It turns out to be around 80 to 100 billion. Keep that number in mind. And now compress that number into the size of two fists, which is about the size of your brain. We have about 80 to 100 billion neurons in our head.

But the complexity doesn't stop there.

POEPPEL: Each of those cells--it's connected to 1,000 neighbors. Each Lego block is connected to 1,000 other Lego blocks.

And all of it works together at speeds almost impossible to comprehend. Nancy Kopell is Professor of Mathematics at Boston University.

KOPELL: In fractions of a second, all these different parts of the brain have to coordinate their activity. We're just starting to understand how that kind of coordination can take place.

To give you a sense: Imagine this ...

NAT SOT--METRORAIL
AUTOMATED VOICE: (bell) Doors closing.
FADE AND LEAVE UNDER

You're on the subway after work. You can feel the train rocking from side to side.

NAT SOT--METRORAIL DRIVER STATION ANNOUNCEMENT
DRIVER: Welcome aboard the Red Line. Next stop Friendship Heights.
FADE AND LEAVE UNDER

The handrail's cold and you notice you're sweating. In the next seat, your friend is telling you about the latest fight at work,

NAT SOT--PERSON TALKING WHILE ON THE SUBWAY
FRIEND: And she says, "No! You can't do that. Just like that!
FADE AND LEAVE UNDER

You can smell that someone just cut into an orange and it occurs to you: "Isn't there a rule about eating on the subway?"

NAT SOT--METRORAIL DRIVER STATION ANNOUNCEMENT
DRIVER: Welcome aboard the Red Line. Next stop Tenleytown, American University
FADE AND LEAVE UNDER

And--oh--your stop is in three stations and you're answering your friend's question and the woman in the seat near you has the most gorgeous suit on and you have a dentist appointment next week and ... all of this is happening at once. Everything is parsed, synthesized and made seamless by the incalculable power of your brain. How does it do that?

MUSIC (and sound windows of the subway trip)

WEDEEN: There are certain parts of the brain that have relatively specialized and specific functions.
SEJNOWSKI: That allows us to filter out just those parts of the sensory stream that are directly relevant for the task at hand.
POEPPEL: What it does is effectively make lots and lots of little sub-problems like listening to your friend complaining about work, remembering to pick up your dry cleaning, you know, smelling the orange
SHEA-BROWN: Information about how much your arm is extended or what the light level is.
HOFMANN: Whether you're healthy or sick. And whether you're hungry or not.
KOPELL: In fractions of a second, all these different parts of the brain have to coordinate their activity.

Electrical signals are pulsing through neurons telling you to do things, or not do them.
HOFMANN: You might adjust your posture in a way that makes it more comfortable so you're less likely to fall off this chair.
ZITO: You don't want to constantly be telling your brain "I'm sitting, I'm sitting" because there's neurons down there that are sensing that you're actually sitting. But you don't want that

And while scientists know a lot about this process, at this point, David Poeppel says

POEPPEL: How that works is actually a deep, deep mystery

So much so, that according to Terry Sejnowski, Director of the Computational Neurobiology Lab at the Salk Institute

SEJNOWSKI: The brain is so complex that, in fact, every single branch of science and engineering are going to be required to really get down to basic understanding of how the brain functions.

MUSIC

KOPELL: There's chemistry. There's genetics.
ZITO: Worms and flies, mice and zebra fish. People study fish.

NAT SOT--HOFMANN IN HIS LAB
HOFMANN: We have about 5,000 gallons worth of fish water with several thousand fish in three large rooms.
FADE AND LEAVE UNDER

KOPELL: There's physics. There's mathematics.
POEPPEL: Psychology and Neural Science
HOFMANN: We need people who do various kinds of imaging to examine how neurons function, how they interact. How the interactions change, for example, as learning and memory happens.

NAT SOT--POLDRACK'S LAB
TECHNICIAN: Alright, we're going to start the resting state in 4, 3, 2, 1. (MRI noise)
FADE AND LEAVE UNDER

HOFMANN: We need people who build tools.

Like engineers and computer scientists.

HOFMANN: Of course, we need molecular biologists,

SOUND--KAREN ZITO IN HER LAB
ZITO: If we throw on a drug now, we add to the bath where the brain slice is sitting, we add a pharmacological inhibitor. So this is just a drug that inhibits this protein from working.
FADE AND LEAVE UNDER

KOPELL: The direction that brain science is going in now is to attempt to make all of these different areas talk together much more to pool their expertise.

And now that they've started doing that, the pace of discovery has been astonishing. If you took all the knowledge humans have gained about the brain since the beginning of time, it wouldn't add up to what we've learned in just the past 15 years.

MUSIC UP FULL AND ENDS

That stunning pace, and all the knowledge it's yielded, have injected a new sense of excitement in the field of brain research. Now when it comes to this field, you hear stories in the news all the time about this breakthrough or that breakthrough. That's not what we'll be doing. Instead, we're going to show you the work that makes those kinds of breakthroughs possible--researchers who are trying to understand the most basic mechanisms of the brain--how it perceives the world... Work that's bringing us closer to a fundamental understanding of how and why the brain does what it does.

SOUND--KIDS PLAYING WITH RUBY THE SOCIAL ROBOT AT UCSD
ROBOT: Where is the star? Good job! (adults applaud)

These children are learning shapes from Rubi the Robot, an educational tool at the U-C San Diego Early Childhood Education Center.

SOUND--KIDS PLAYING WITH RUBY THE SOCIAL ROBOT AT UCSD
ROBOT: Where's the triangle? No. That's a diamond.
ADULT: adult: That's a diamond.

But it's not just the kids playing with Rubi who are learning. At this age, they're all learning. About sharing. Getting dressed. About what their favorite flavor is. The brain changes at a remarkable rate in children, but as Terry Sejnowski points out, it doesn't end there.

SEJNOWSKI: Your digital computer doesn't change the transistors. The numbers of transistors are exactly the same as when you bought it. But your brain, every time you use it is changing the actual hardware on which you're running your thoughts.

These changes are not metaphorical. Thanks to a phenomenon called "plasticity," the connections in your brain are constantly getting weaker, stronger, or taking new directions as you learn. What scientists are trying to figure out today is--at the cellular level--how that happens. With all we learn and the billions of connections our brains make, how we manage to keep the important ones and lose the rest. Karen Zito is a Professor of neurobiology at the University of California, Davis.

ZITO: How does one memory stick and another one get lost? Completely unknown at this point.

Which cells need to communicate with which others? How many.

ZITO: Could we learn something with only six cells? Do we need 100? Do we need 1,000? These are the types of questions that are really fascinating researchers today.

SOUND--KIDS AT UCSD CHILD DEVELOPMENT CENTER

The emerging research on Plasticity, being done here by Terry Sejnowski and his colleagues, centers on a handful of potential answers.

SEJNOWSKI: One of the things that we've learned in the last 10 years is that there's a very, very powerful neuromodulator called dopamine in your brain which has an incredibly important influence on what motivates you.

Dopamine gives you pleasure. That's a fairly well-known process. You get rewarded and you want more. What Sejnowski's learned that's new though, is that dopamine--acting in your pre-frontal cortex, where you plan and control your social interactions--also works to get you through the hard work it can take to reach your reward.

SEJNOWSKI: Every time that you encounter a reward, your brain compares that to what you expected. And if you got what you expected then, nothing happens to any of the synapses. But if you got a better reward or a reward that you weren't expecting at all, then the brain says, "Hey, something really wonderful has just happened. You really should remember this, and next time this happens, you should be prepared."

The most important of those long-term memories are permanently stored in your cerebral cortex, where you keep track of unique objects and events.

SEJNOWSKI: It turns out that the key thing there is the order. The sensory input that comes in is associated with the reward, but it has to come in before the reward within a few seconds of the reward--otherwise you won't learn it.

SOUND--KAREN ZITO IN HER LAB
ZITO: We'll bring out a culture dish where we have the cultured brain tissue. And we can cut it with a razor just to take it out of the dish. And then I will lift it, and that's what I'm doing right here, and placing it on the microscope.
FADE AND LEAVE UNDER

The process of learning starts before an animal is born. And scientists now can watch it happen. It's what Karen Zito looks at in her lab. The way it seems to work is: neurons--nerve cells--collect information from other neurons around them--information that comes in through a part of the neuron called the dendrite.

SOUND--KAREN ZITO IN HER LAB
ZITO: And so what I can see on this microscope is I can see dendrites. And I see very clearly these small protrusions. They're called dendritic spines. And they they're in the order of microns. One micron, half a micron or less in diameter.
FADE AND LEAVE UNDER

Many of these spines are constantly in motion.

ZITO: And those ones that are moving, we think are searching for partners.

When they find them, they link. And when they link, the brain is changed.

ZITO: We think these changes are important for learning.

SOUND--BIRDS CHIRPING

A professor at Duke named Richard Mooney did a study on this with baby birds, who learn songs, of course, from their parents.

ZITO: He was looking at the movement of spines in these young birds. And what he saw was that those young birds that had a higher rate of movement of spines actually learned the songs more effectively than those that didn't.

These dendritic spines searching and linking make brains absorb like sponges in childhood. But it's hard--say--to learn a language as an adult. If these dendritic spines are important to learning, Zito wondered what caused them to grow, and ...

ZITO: Could we find some kind of target that we could just activate and cause them to grow out more in the adult?

Her lab searched, and they think they may have found it.

ZITO: There's a protein that's inside the dendrite that's prohibiting the outgrowth of these spines.

When we experience something, the brain makes less of that protein. Less protein means more spines. Dr. Zito doesn't know yet what the protein is, but she's looking for it.

ZITO: You could imagine if we could find that protein, we could find a way maybe to cause it to get degraded, and that would allow more spines to grow out just routinely. And that's one of the fascinating goals that we're pursuing right now.

The work on dendrites and on dopamine evolved out of ground-breaking work in 1963 that taught us definitively how portions of the brain communicate. One of the principal means is something called "Action Potentials" or electrical "Spikes."

SEJNOWSKI: The brain has to represent everything in the world by a sequence of these spikes.

If you think about it in the way a computer works, he says, the spikes are the code. This code is transferred through the nervous system through a series of wires called "Axons." Here's Harvard's Van Wedeen.

WEDEEN: What's traveling from one area of the brain to another is coded information in the form of electrical impulses that move like sharp waves down these wires.

ZITO: That electrical information gets sent down that axon and then communicated through chemical signaling from one neuron to the next.

The fascinating thing, Karen Zito says, it that after that starts,

ZITO: It causes the neighboring part of the neuron to do the same thing. And then the neighboring part and the neighboring part and the neighboring part.

While scientists know spikes are there, Boston University's Nancy Kopell says

KOPELL: What all of those spikes mean is a huge mystery at the moment. What in fact are those signals? They're not just the spikes of individual cells because they come in patterns.

As scientists get better at understanding spikes or what Terry Sejnowski calls ...
SEJNOWSKI: The machinery that gives rise to behavior...

... It gives rise to a number of additional questions too, like: Do spikes coordinate with one another? How do spikes from hundreds or thousands of cells all manage to say something coherent when they get where they're going? Now, even though spikes appear to dominate the flow of information over a neural network, Eric Shea-Brown, a professor at the University of Washington points out,

SHEA-BROWN: They're not the only game in town.

Which gives rise, in turn, to another question:

SHEA-BROWN: What is it that really matters beyond spikes?

And even after we know that, Boston University's Nancy Kopell says we're not close to finished.

KOPELL: The actual connection is only step zero of understanding this.

You're listening to Explorers of the Brain--research from the frontiers of neuroscience. Coming up, understanding what it all means, using mice, math and machines. Stay with us.

This is Explorers of the Brain--research from the frontiers of neuroscience. We've just heard how scientists are learning how we learn things. Now let's explore how we come to understand.

MUSIC IN

POEPPEL: We're at NYU at Washington Square in the MEG Lab, the Magneto Encephalography Lab
CROSS FADE TO
POLDRACK: (over a talk-back mic.): I'm inside the bore of our Siemen's MRI scanner
CROSS FADE TO
ZITO: We're here at the Center for Neuroscience at UC-Davis, and we're in my lab.
CROSS FADE TO
GHOVANLOO: So we are at Emory University in Professor Manns' lab.

It's here, in the laboratories at some of America's premier research universities that the drive is on to gain a deeper understanding of the workings of the brain. Studying animals of all sizes. From worms to rats

GHOVANLOO (in the lab): Along with that tiny device on the rat's head we are developing a smart cage.

All the way up.

POEPPEL (in the lab): Our participant Gwyneth is lying there, and she has earbuds in.

Examining brains of the living and of the dead.

ANNESE (in the vault): This is the brain library--the vault where we keep the brains.

Trying to see things from a brain's-eye view. Where the world (narration sounds intentionally choppy) Sounds. Like? This. When. You. Hear. Exploring how the brain "breathes," and how knowledge comes in waves. (wave sound). How cutting up a brain (sound from Annese's lab) might tell us something different than scanning it from outside

LAB TECH: OK, the machine is now on.

MUSIC SHIFTS

Understanding how we learn is one thing. Understanding how we understand? That's quite another. Think about it: You hear this (Beethoven music) and you recognize it on multiple levels. You know it's music. but if you know music theory, you understand the dynamics and the interplay between the instruments. Or you hear this (sound of a professor lecturing), you know it's words. The sound passes into your ears and somehow somehow your brain breaks it down into its constituent parts and begins the process of comprehension.

FADE IN SOUND OF DAVID POEPPEL'S GIVING A TOUR OF HIS LAB
POEPPEL: The MEG system is about the size of a big refrigerator. And we're going to open the door now. (sound of the door opening)

Just how we manage to do that is one of the things being studied here by David Poeppel. We met David in our last segment. In his lab at NYU, David is trying to figure out how it is that we come to the point where we don't just absorb information, we move beyond into the realm we call "understanding."

POEPPEL: If we knew what "understanding" was, I would be very rich and very famous.

While he hasn't uncovered the key to understanding, he is part of the way there. David studies that ability of the brain to hear, process and understand language. Imagine if you could actually watch the brain doing that. David Poeppel can.

SOUND IN DAVID POEPPEL'S LAB
POEPPEL: Gwyneth is going to lie down, and then they're going to back her into the machine. (noise of the bed moving around)

David studies brains as people listen to words--trying to figure out how sounds turn into ideas and concepts.

SOUND IN DAVID POEPPEL'S LAB
LAB ASSISTANT: OK, the machine is now on.
POEPPEL: OK, so now we're ready to do the experiment.

He's gained some fascinating insights. Like this one, about what we perceive as the seamless flow of experience.

POEPPEL: It appears like this continuity of experience is kind of I guess it's an illusion. We should think of it as an illusion.

Yes, reality is an illusion. What you see as the solid, continuous world around you--is not that at all, at least according to your brain. Let's go back to the subway.

SOUND--MAN TALKING ON THE SUBWAY

Here's your friend again, talking about work. And here's how your brain sees him.
POEPPEL: Imagine that you are watching a movie, but it's really chopped up into little pieces.

SOUND--MAN TALKING WITH TINY PAUSES INSERTED, MAKING IT SOUND CHOPPY

POEPPEL: Let's say you insert a little white screen every couple of seconds. So it seemed very chopped up.

SOUND--MAN TALKING WITH TINY PAUSES, MAKING IT CHOPPY

The world is coming at you all five of your senses, plus your comprehension of what they're telling you. As it does,

POEPPEL: You go chop, chop, chop.

Each experience is processed. Broken into tiny blocks.

POEPPEL: Maybe it's only, you know, a hundredth-of-a-second long. And these different sizes of elements give you different aspects of your experience.

The longer blocks may allow you--based on your friend's vocal inflection--to figure out if he's asking a question.

SOUND-–MAN TALKING ON THE SUBWAY
MAN: You know what I mean? They are, like, such PESTS!

Shorter blocks do things like split up the syllables.

POEPPEL: Suppose you want to distinguish the word "pets" from the word "pest." The sound puh-eh-t and sss. But you have to get the order right.

It's all happening--some of it quicker, some of it slower.

POEPPEL: Your brain does different things at very different clock speeds, and it's as if you're processing movies at very different rates.

While you're comprehending each individual word, you're also recognizing all the words as part of a sentence.

SOUND OF POEPPEL'S LAB
LAB TECHNICIAN: Gwyneth, We're going to present some sentences for you to hear in English.
GWYNETH: OK.

In his lab in Manhattan, David is using ultra-fast scanning machines to test and prove that this chopping process is, in fact what your brain is doing.

POEPPEL: Techniques like EEG or electroencephalography. Or MEG, magnetoencephalography.

Fast enough to measure the electrical activity that's generated as your brain absorbs the sound of words rushing by.

SOUND OF POEPPEL'S LAB
POEPPEL: So we're now going to play and here come sentences in English.
VOICE: It makes no difference that evidence points to an opposite conclusion.
POEPPEL: We're going to look a little bit more carefully at the data on the screen here. So each of these lines is the output from one of the MEG channels.

The machine pulses every millisecond--fast enough to watch the brain as it takes in and then processes the sentences--ones that makes sense, and ones that don't.

VOICE: The triumph of warrior exhibit naive heroism.

The hypothesis he's testing is that brain waves ride on top of the speech waves--and that that's how we're able to break the sounds into syllable-size units that we can use to look up words in our mental dictionaries.

SOUND OF POEPPEL'S LAB
VOICE: He held his arms as close as he could, and made himself as small as possible.

If it works the way he says it does, your brain is taking in all the world's stimuli

POEPPEL: And you assemble them to actually give you the correct interpretation. And that interpretation connects with something you understand about how the world is organized. One of the elementary units so one of the kind of crucial Lego blocks for how language works in the brain turns out to be roughly the syllable, and that's regardless of what language you're talking about.

VOICE: It made no difference that most evidence points to an opposite conclusion.

POEPPEL: As I'm talking to you what your brain is doing is going chop, chop, chop, chop, chop. And the size of each chop--each unit--is actually about a syllable size.

And he has this crazy demonstration that shows this to be true. Listen to this sentence.

VOICE: (impossible to understand)

It's a fair guess that you didn't understand it at all. Now try this one.

VOICE: Ants carry the seeds, so better be sure there are no ant hills nearby.

A little better, but not perfect. Now this one:

VOICE: We've all been rich and spoiled long enough to hate the machine age.

You could probably make that one out just fine. Here's the thing ... all three of them, are flipped around backwards. In each case, the sentence is broken up into chunks of exactly the same length that are stacked in their proper order, but each chunk is played backwards. What's different in each case, though, is the size of those chunks. In this one:

VOICE: Ants carry the seeds, so better be sure there are no ant hills nearby.

Each chunk is 200 millisecond long. But, David has learned, if you go down to chunks that are 50 milliseconds long, even though you're hearing the chunks backwards, your brain is turning it around so it sounds correct. Listen:

VOICE: We've all been rich and spoiled long enough to hate the machine age.

Each chunk goes into your ears backwards and comes out of your brain sounding just fine. Amazing. So, how does your brain do that?

POEPPEL: It's well beyond what we can imagine.

What he does know is this: the brain has multiple layers. When brain cells communicate across these layers, the architecture of the system forces them to operate in waves or rhythms, that have particular time constants--as you just heard 50 milliseconds, 200 milliseconds-- whatever. We talked about "spiking" earlier in the program. That's one way information passes within the brain. These waves are the other.

SOUND--BRAIN RHYTHM PULSING

This is the actual sound of a brain rhythm. Inside your head, cells are joining up to make waves that pass information up through the layers.

SOUND--BRAIN RHYTHM PULSING

These rhythms don't stick to a strict beat. As Nancy Kopell of Boston University says

KOPELL: It's more like a little jazz band, playing at roughly some frequencies but bending the beat a bit.

BRAIN RHYTHM SOUND DISSOLVES INTO JAZZ

Remember, this is hundreds-- maybe thousands of cells--all doing this at once. And they'll organize in unusual ways. You might see one rhythm in the top layers of the cortex and a completely different rhythm in the bottom --with the two not talking to each other. Then something will shift and they will be.

KOPELL: Part of what excites me about studying brain rhythms is that it seems to me that it's our best chance of building a bridge from behavior at the molecular and physiological level all the way up to high level behavior that we call cognition.

There are a number of tricks to figuring this out. One is: creating better tools--like machines that do their jobs better than what we have now.

MAN GIVING A LAB TOUR
MAN: What we have are rooms, dark rooms where rats can run around in circles.

This is a lab at Emory University, one where the study subjects are a lot less likely to be named "Gwyneth."

MAN GIVING A LAB TOUR
MAN: This is Mr. Flea-Bottom. He's one of our participants. Mr. Flea-Bottom has been trained to run around on a circular track and to get a little piece of chocolate for every lap that he completes.

In this lab, rats are monitored for many of the same reasons Gwyneth was--to explore how the brain functions in a living being. The advantage of a subject like Mr. Flea-Bottom though, is you get to see his brain function in its environment. He's not shoehorned into a scanning machine, he's running around--doing the things rats do. Well, he is today, and that's thanks to Maysam Ghovanloo, a bioengineer at Georgia Tech who freed Mr. Flea-Bottom to live his life more like he might want to.

GHOVANLOO: Every bioengineer knows that it's not all about the engineering side, in fact, it's the engineering at the service of medicine.

In the past, for scientists to get the kind of data they needed out of rats, the rats had to have giant cables attached to the electrodes in their brains. Those cables were tacked to the ceiling of the lab.

GHOVANLOO: And as the rat moves around it has to kind of pull this cable behind him wherever he goes.

The rat couldn't go anywhere that the cable didn't reach. And if they didn't use a power cable, the rat had to carry around a fairly large battery on its back. Dr. Ghovanloo is working to solve that too. So today,

GHOVANLOO: As the rat moves around, we will have a small chip on the rat's head with a tiny little antenna that wirelessly sends all of that information to the big computers on the back end that are number crunching.

This tool, like many tools, generates data. And that's the second trick to having this all make sense. As Nancy Kopell says,

KOPELL: We simply first need to understand more about how signals that come from one part of the brain are heard or not heard by other parts of the brain. We can understand at a physiological level what creates these different brain rhythms, and then we can study how those different brain rhythms are associated with high level behavior.

With so many cells, all working all at the same time, Nancy says:

KOPELL: Our poor little brains don't seem to be good at figuring out what the outcome is going to be.

But Nancy has tools she can turn to for help.

KOPELL: I say, "OK, David, so how is the brain accomplishing that?" And people say to me "It's your job to figure it out."

Nancy is a mathematician, so it's her job to reduce these billions of data points down to something you can get your arms around. She says that's what computer models are good for.

KOPELL: Trying to figure out how the brain can, using its physiology, its chemistry, its anatomy, actually produce the things that he sees. To try to say: How do changes at the level of physiology end up changing the rhythms, which then end up changing--say-- ability to pay attention?

Nancy can write out mathematical descriptions for things the brain is doing and how all those processes interact,

KOPELL: And then farm it out to a computer which will let you know how the behavior of the cells will progress in time.

It's from there that researchers can formulate new hypotheses and ideas.

KOPELL: There's immense breakthroughs now in how to look at the brain. There are breakthroughs in statistics to enable us to take this huge amount of data that's coming at us like a flood and be able to mine it for new things.

It's math that's pointing the way.

KOPELL: It's really, really hard to say how the changes at the cellular level--how do those things translate into anything that we recognize in our everyday life as what we do with our brain?

In fact the 2014 Nobel Prize for medicine went to research in this field. Scientists found that single cells in two parts of the brain give rats a 3-D spatial layout of the world. But while they know this all happens, still, no one can say why.

WEDEEN: We kind of have big chunks, but as to the basic story of how the chunks fit together or how structure and function are interrelated in the forebrain we are still missing that.

That's Van Wedeen, again from Harvard. Though we don't know, Van thinks he may be getting closer. He's doing it by exploiting the properties of a brain scanning technique called "diffusion MRI."

WEDEEN: This is revolutionary because they see the whole brain all at once. That's the key, and we can do it in live people.

He's used this approach to take pictures of the architecture of the brain cells-- how they're connected which has enabled a revolutionary way of thinking about how information flows.

(Sound of narrator crawling under her desk--grunting, "Ow!")

Go under your desk. See that rat's nest of cables? When scientists have thought about the wiring of the brain, this has been the predominant view. Pull out the wrong wire? (sound). The research they're doing at Harvard seems to be pointing to a structure that's not that way at all.

WEDEEN: The kind of structure that we've seen is like a grid like the streets of New York. The pathways of the brain apparently run in three mutually perpendicular directions. You have north/south, east/west and up/down.

A 3-dimensional grid. At least on average. Van believes it's this simple structure that helps explain how information can, so easily pass from one part of the brain to another. It may look like a jumble, because of all the brain's folds and curves, but this grid system, he says

WEDEEN: Makes describing the whole thing tremendously easier than describing the tangle.

That's certainly true. Problem is, there's also evidence the wires may not form a grid.

Jacopo Annese is someone well-placed to know how the wires of the brain are laid out. He's a researcher in San Diego with an unusual collection. Dr. Annese collects brains. Human brains. Now there are lots of brain banks in the world, but Jacopo Annese's brain library is different; it is a digital kind of brain bank, where brains are processed and distributed as images and data.

ANNESE: Instead of creating chunks of tissue to distribute, we process the brain as a whole and we slice it into thousands of sections.

Then they scan those slices with a large format microscope scanner. The result:

ANNESE: A whole 3-D model of the brain that is comparable to the MRI, but you can keep zooming in further and further.

Once his collection is mature, any scientist around the world can compare thousands of different brains and see them at the level of individual cells. Here is the source of the disagreement between these two researchers: Dr. Wedeen looks at diffusion MRI scans; Dr. Annese looks at physical tissue. When it comes to brains being laid out as a grid, Annese's not convinced.

ANNESE: We see a lot of places where we study these fibers in the real brains that really look very, very intricate.

He's seen plenty of connections that look like spaghetti. He's seen grids too. But here's the thing. Both these researchers' techniques have limitations. Looking at tissue slices lets you see microscopic details of brain cells, but the slices have to be stained and reconstructed into a 3-D image on a computer. That can cause distortions. Diffusion MRI reveals neural connections over the entire brain, but it detects some connections better than others, depending on the path they follow. Both methods are open to different interpretations of the data. So the issue isn't settled. At least not yet. But that's life on the frontier of neuroscience.

Coming up: Your brain's Blue Light Special. And a fish that could win Father of the Year. This is Explorers of the Brain. Stay with us.

This is Explorers of the Brain, from the National Science Foundation.

SOUND--DAD GETTING KIDS READY TO GO OUT
DAD: Should we get your jacket on now? You still wanna go to the playground?
3YEAR-OLD BOY: Yeah.
DAD: OK, let's get your jacket on.

Another amazing thing happening in your head is the way your brain makes what it does seem so easy. Millions of interactions happen every given second, but it's all seamless. So seamless, that sometimes it lets us convince ourselves it's not even there.

SOUND--DAD GETTING KIDS READY TO GO OUT
DAD: Alright ramblers. Let's get ramblin'.
3YEAR-OLD BOY: OK, boys, let's get rambin'!
DAD: (chuckles)

HOFMANN: There is this odd dichotomy--which turns out to be a big mistake--about the distinction between the mind and the body.

Hans Hofmann is a professor of Biology at U-T in Austin, and he suggests, there is, in fact no distinction between mind and body. The two things are one in the same.

HOFMANN: You might have a dream. It doesn't come just from somewhere. It comes and originates in your brain, and your brain is organic matter.

Biology--chemicals passing--spiking-- across distinct channels. That's what's behind every thought we have.

SEJNOWSKI: You may think that you've made a conscious decision to go to that movie. But it may well be that there are subtle biological reasons that are driving you that you're not even aware of.

That's Terry Sejnowski again, from the Salk Institute. And that's not just the case for the big decisions in life, involving things like food and reproduction.

SEJNOWSKI: Even aesthetic feelings that, you know, we associate with music and other emotional states.
HOFMANN: From a scientific point of view any thought process that might go through your head originates in this material basis of the brain.
SEJNOWSKI: Our conscious experiences are just the tip of the iceberg. And the real complexity is all down beneath the surface.

SOUND--DAD AND KIDS IN THE PARK
3 YEAR-OLD BOY: (yelling) Meerstars and sorgons!
DAD: Zorgons are coming?
3 YEAR-OLD BOY: Yeah! And meedors.
DAD: And meteors?
3 YEAR-OLD BOY: Yeah!
DAD: Well what'll we do captain?
3 YEAR-OLD BOY: Hard to port!

This family at the park is a great way to see that. Let's take a look, for example, at their social interactions. in action starting first with how they got here.

SOUND--DAD AND KIDS IN THE CAR
DAD: Which way should we go to get there?
5 YEAR-OLD GIRL: The regular way.
DAD: The regular way. So this way?
3 YEAR-OLD BOY: That way!

On the drive over, there's a lot you take for granted.

POLDRACK: You don't want to think about whether to turn right at a particular intersection if that's the same thing you're going to do every day.

Russ Poldrack is a Psychology professor at Stanford who studies things like how we develop habits. Why do you always get to the park by turning right at the same street?

POLDRACK: There's a system called the basil ganglia that is involved in choosing actions.

In most situations, there are a number of different ways you can go. Every time a choice presents itself, the basil ganglia computes the value of your options.

POLDRACK: Do I eat a candy bar or a piece of fruit?

And then neurons in the basil ganglia fire, once you decide. When they do …

POLDRACK: There's a signal that basically tells the brain whether that action ended up being better than you expected it to be in terms of the outcome. And that signal is dopamine.

Dopamine, you remember, is a chemical that helps you learn. It's also constantly telling you whether or not the world is better than you expected it to be.

POLDRACK: Your brain is always predicting what's going to happen out in the world. And if the world behaves exactly as you expected it to, there's not really anything to learn because your model of the world is perfect, right? If the world is better than you expected it to be, then dopamine fires. And what that does is it strengthens the connections within the basil ganglia for the particular neurons that fired for you to make that choice.

Next time you have to make that same decision, because the connections are stronger, in a competition to decide what you're going to do, they're more likely to win.

POLDRACK: The more they win, the stronger they get. And that's how we think habits develop.

Now your brain's not just helping you make the easy decision. There's a whole range of social behaviors we take for granted that our brains are hard-wired to carry out.

HOFMANN: Social behavior seems like something that is very complex. A lot of people are surprised when they hear that other animals actually show complex social behavior.

And when Hans Hofmann says "animals," he means all kinds animals, not just mammals.

SOUND OF HOFMANN WITH THE FISH IN HIS LAB
HOFMANN: So the first thing we notice as we walk into the room is that all the fish come to the front of the tank.

From studying these fish--they're called cichlids--he's learned some fascinating things that relate to human interactions.

HOFMANN: One that I'm interested in is this phenomenon where a male and a female, after they reproduce, also raise the offspring together.

Sharing parental responsibility is not that common in mammals. But it is common in a remarkable number of other species--including cichlid fish, which have allowed researchers to ask--and maybe answer--an important question: When it comes to childrearing ...

HOFMANN: How can we actually manipulate the behavior of the father?

SOUND OF HOFMANN IN HIS LAB
HOFMANN: Every dominant male can become subordinate, and every subordinate male can become dominant. And that happens fairly frequently.

After baby fish were born, he watched the adult male who had fathered them.

HOFMANN: We measured the amount of paternal behavior that he showed over a number of days.

They also examined the brains of the fish, to see if a particular set of genes were active in
a way that's known to relate to being an attentive father. There were some existing studies in
mammals, where they'd looked at voles to see the neural basis of their paternal behavior.

HOFMANN: And it appeared that many of the same brain regions were involved.

The vole studies showed that a couple of neurochemicals were important when it comes to driving mammals to find sexual partners.

HOFMANN: Vasopressin or oxytocin that you may have heard of

And it turns out, those chemicals are also involved in making male fish care for babies. Hans treated some fish with a drug that blocks one of those chemicals from doing what it normally does in the brain. The idea was to see: If you do that, can you make the fathers stop caring for the babies?

HOFMANN: And that's in fact what happened.

The scientists who'd worked with the voles? They'd found the exact same thing.

HOFMANN: We took that as evidence that a similar neuromolecular code, if you will, might exist for the control of paternal behavior in these fish and in these voles--in these little mammals.

Keep in mind what Hans said earlier: There's no separation between the mind and the body. So as our bodies evolved, our behavior did too. Those chemicals pass back and forth--making us choose a mate, and sometimes, making males who are more caring fathers.

SOUND--FATHER WITH CHILDREN IN THE PARK
3 YEAR-OLD BOY: (crying)
DAD: Let me see your other hand. Lemme see your other hand.
3 YEAR-OLD BOY: (crying) No!
DAD: Is there a boo-boo? No, look.
3 YEAR-OLD BOY: (crying)
DAD: There's no boo-boo.

As we mentioned, the brain is constantly changing. And not just when we learn.

POLDRACK: I've been interested for a long time in how people's brains change due to experience.

That's Russ Poldrack again. Honestly, saying that he's "interested" in that subject is putting it lightly. The truth is: This became such an obsession for him, that in 2013 he took it to an extreme.

SOUND--POLDRACK IN THE MRI
MAN: You're not claustrophobic are you?
POLDRACK: (laughs) I used to be.
MAN: (laughs) Not anymore?
WOMAN: Close your eyes please. (MRI noise)

We're just outside the bore of the Siemen's MRI scanner at the University of Texas, where Russ worked until just recently. And who's that on the gurney, sliding into the machine for the 58th time? It's ... Russ Poldrack. Lots of people get an MRI once in a while. Russ got
three a week!

SOUND --POLDRACK IN THE MRI
POLDRACK (over an intercom): This is actually a pretty spacious MRI scanner, compared to some.

And that was only part of it. Every morning, he took his blood pressure. He'd weigh himself, then take an on-line survey on how he slept and how he's feeling. He'd track what he ate, how much alcohol he had, his supplements and medicines. And then …

SOUND --POLDRACK AT THE HEALTH CENTER
POLDRACK: Now we're at the student health center. We're going over to the laboratory where every week I come and they take 20 mils of blood from me.

The idea of all this was to find out

POLDRACK: How much variability there is in a relatively healthy person's brain function.

That's actually something that's never been studied in healthy people. We know that people with bipolar disorder or schizophrenia have wild fluctuations in psychological function, but we can't compare that to anything. That's what Russ wanted to find out.

POLDRACK: We see some relationships across days between my general positive mood and brain function. We also see some relationships between my blood pressure on those days and brain function.

Was this the brain controlling the body, or the body controlling the brain? Russ says, at this point we can't really say which direction the causal arrow is pointing.

POLDRACK: There's a strong hypothesis that the immune system would be related to brain function. But this hasn't really been shown.

And, in fact, in his case,

POLDRACK: We didn't see relationships in general between my overall mood and the function of my immune system. So there's still a lot to be asked here.

But answers to that kind of question are actually right within our reach today.

SOUND--ANIKEEVA IN HER LAB
ANIKEEVA: So we're walking into our lab (sound changes) and you can hear our freezers. You can hear our chemical shakers are all going. (FADE)

This is Polina Anikeeva.

ANIKEEVA: I am a materials scientist and an engineer and I consider myself a device designer.

The devices she's designing-- she's at M. I. T.--are part of a revolutionary development
that's sweeping brain science today, a technology called "Optogenetics." Pioneered by scientists
in Germany and the US, it's a way to make neurons become sensitive to light. Shine a blue light
(music shifts) you can make neurons spike. Shine a yellow light (music shifts) you can keep them from spiking.

ANIKEEVA: We can use these genetic/synthetic biology tools to manipulate neural activity on demand.

On demand. Shine a light and make a brain do what is does. This has allowed researchers some amazing insights.

ANIKEEVA: For example, you would like to find out what a certain group of neurons is doing during a specific behavior.

Like, maybe when the subject is fearful, or addicted. You can trigger spikes with blue light or inhibit them with yellow in the appropriate cells and then look at whether that changes the behavior. Or: shine a light, watch which cells spike, and then watch those same cells when the subject is doing or feeling certain things. The problem Polina's working on specifically is how to deliver light to specific neurons more easily and effectively. And also, how to record the signals coming out of the brain. The way you'd normally think to do this is with semiconductors--computer chips.

ANIKEEVA: If you take the iPhone apart and we take those chips that are inside it, we realize that they're all based on silicon which is really hard and very brittle and quite sharp.

The brain and spinal cord, meanwhile

ANIKEEVA: They have a consistency that is similar to yogurt or pudding. And now--imagine--you're introducing a device that is as sharp as a knife into the structure that is as soft as a pudding.

The result is just what you'd expect. Lots of cuts and scarring-- scars in the brain that
block the light and electrical signals from going in and out.

ANIKEEVA: We have a couple of devices here.

Polina's devices are beating this problem with softer, more flexible materials that can be
implanted with fewer complications.

ANIKEEVA: What I'm holding is a cylinder which is about an inch in diameter.

Inside, they put all the necessary features for a neural probe.

ANIKEEVA: But, then we take this template, we heat it, and we stretch it and it becomes this really long--almost kilometer long--fiber and inside that fiber, all the same features remain.

It's soft and bendable. It's incredibly strong. And they can cut it into tiny pieces and
implant it in their subjects with as little disruption as possible.

ANIKEEVA: We have this essentially fishing line-looking devices which essentially touch individual neurons inside the brain.

So they can be turned on and off, with light. As you might imagine, tools like the ones Polina is fabricating generate reams of data.

POLDRACK: Some of these imaging techniques are generating terabytes of data per day.

And while we tend to see more information as a blessing, Russ Poldrack says, it can also become a curse. In fact today, he says

POLDRACK: We're drowning in information but we're starving for knowledge. And so what we want to do is try to use tools to help us really extract knowledge some sort of understanding from the data.

To achieve this brain researchers have turned to one particular branch of their community computer scientists. Data-analysis, and statistical algorithms--now more than ever before--are helping us make sense of the information we have.

POLDRACK: A lot of tools have been developed just recently in order to help us understand what's going on in these monster data sets.

One of those tools was developed by Russ and his team--a [standardized] framework that lets scientists around the world upload and share their test results.

POLDRACK: The main thing that we do is to organize the data in a way that anybody can take it and know what to do with it.

The framework lets researchers compare their results with others' and gain confidence in
their findings. It's a way to bring together the huge amounts of brain-imaging data needed to
ask questions that could never before be addressed.

MUSIC UP AND ENDS

You'll notice that throughout this program, as amazing as the work has been, no one has been talking about new cures. The reason is: That's not the kind of work these scientists do. Theirs is "discovery research," which David Poeppel explains this way:

POEPPEL: You're not trying to do it because around the corner there's an application for a new device or a cure. It's to understand fundamental regularities about nature. In this case, the nature of the human brain.

Others will find the cures down the road--and when they do, it will be a trail blazed by the work these researchers are doing to increase our level of knowledge today. Meanwhile, brain research is inspiring new computer chips, so that driverless cars can identify obstacles and navigate. And new research on artificial intelligence is leading to new theories of brain activity.

HOFMANN: There will always be things that are fundamentally unknowable, but those gaps can be made smaller.

Smaller because researchers from so many disciplines are working together, and because new tools are making new insights possible.

POLDRACK: And so it really frees us up to be able to ask questions that we never could have asked before.

They've picked a good time be here, on the front lines of discovery. As N-Y-U's David Poeppel says,

POEPPEL: The rate of change in neuroscience is unbelievable right now.

And momentum is building. What's next? Here's Karen Zito from U-C Davis.

ZITO: I think we'll have a lot information on what specific circuits inside the brain support specific types of behaviors. And we'll understand a lot more about how sensory input in causing changes in neurons.

Harvard's Van Wedeen says that will give us a better grasp on ailments--like schizophrenia--that just don't make sense from the standpoint of human evolution.

WEDEEN: We'll be able to read the evolutionary clock and see what the pitfalls were in designing the brain that we have, and therefore why are we vulnerable to these recurring issues. These are questions that will have answers.

HOFMANN: I'm just fascinated by it. But I'm also fascinated by the fact to a good extent we can actually understand a lot of these things.

We've cracked open the lid on this black box we call our brain. There's so much we're learning now, and so much more that our brains will bring us in the future.

MUSIC UP AND ENDS

 

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