A new approach to brain health, one neuron at a time

Neuroscientist Paul Nuyujukian https://bil.stanford.edu/paul-nuyujukian likens the brain to a stadium full of people. To eavesdrop on the crowd you could put a microphone in the middle of the stadium. But to understand the conversations you need to record individual people. He thinks about the brain the same way. To understand brain disease, he studies neurons—one at a time. And his insights are shedding light on a big global issue—stroke. The World Health Organization predicts one in four adults https://www.who.int/news-room/fact-sheets/detail/stroke will have a stroke in their lifetime. Strokes can cause death, or lead to paralysis or speech problems. But there’s still a lot researchers don’t know about how the brain recovers from an event like a stroke. Nuyujukian directs a lab at Stanford University that studies how the brain controls movement, including after neurological events like stroke. We get into how he does this, and why he hopes his research could eventually help people who’ve been paralyzed. Email us your questions about the brain – or anything else to do with science at [email protected] mailto:[email protected]. We may turn it into an episode in the future! Listen to every episode of Short Wave sponsor-free and support our work at NPR by signing up for Short Wave+ at plus.npr.org/shortwave http://plus.npr.org/shortwave. See pcm.adswizz.com https://pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences. NPR Privacy Policy https://www.npr.org/about-npr/179878450/privacy-policy

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  Hey, short wavers. Producer Rachel Carlson in the host chair today with a story about brain machine interfaces, brain implants. Paul Nuyujukian studied this for a long time. He's at the Brain Interfacing Lab at Stanford University. And you guys, Paul does so many things. He's a medical doctor, an engineer, a neuroscientist.

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  I have a lot of hats.

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  Around 10 years ago, Paul was at a point in his research where people who'd been paralyzed from the neck down could get one of these devices implanted in their brain. And then they could sit next to a bunch of computers.

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  And just think about what they wanted to happen. And a little cursor on the screen of a tablet would sort of move around and let them type on the screen, send emails, text messages, play games.

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  Which was so exciting for Paul. So one day, he's at a big medical conference on brain machine interfaces.

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  I distinctly remember a conversation with a director of a very prominent medical device company.

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  Naturally, he's eager to show off all the strides he's made in his research. So he pulls out his phone and starts to show these industry guys a video of his work.

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  Oh, wow. That's, that's really cool, Paul, right? Congratulations. This is, this looks like it's clinically useful. And I jumped for joy. It's like a little victory point, right? Like, hurrah, all right.

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  And he's like, OK, let's talk about patenting and licensing.

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  And without missing a beat, they just laughed in my face.

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  Politely.

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  But we're never going to touch this.

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  They told Paul it would take hundreds of millions of dollars to create a medical device that could be sold to people who were paralyzed. And even if they sold a device to every person who needed it, they'd never make back their investment.

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  That was pretty deflating, right? Because I felt like I had been working in a space with the aim of trying to help people.

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  So after a decade of research, he had to pivot.

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  You know, if I wanted to help these individuals, if I wanted to see my, my, my work make it past the finish line, I would have to go after bigger problems in brain disease.

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  Meaning, problems affecting more people. And one problem that affects a lot of people? Stroke. One in four adults are predicted to have a stroke in their lifetime. That's according to the World Health Organization. So Paul pivoted.

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  Today on the show, how does the brain recover from stroke? We go down to the individual neuron level with Paul to see how studying single cells could be the key to getting a bigger picture of the brain. You're listening to Short Wave, the science podcast from NPR.

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  We're talking to Paul Niu-Jukian, whose lab at Stanford studies how the brain controls movement, including after neurological events like stroke. See, brain tissue needs blood flow to function. And when that blood flow is interrupted, like in a stroke, that tissue starts to die. Strokes vary from person to person. They can be so small, someone doesn't even know they had one. Or a cause of death. And in between, they can cause speech problems, numbness, paralysis. And Paul studies the brain, mostly monkey brains. But he does it in sort of an unusual way.

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  A lot of the times, neuroscientists look at groups of neurons, brain cells. But Paul's lab uses single neurons, which lets them get finer details than they could by looking at the group.

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  In our conversation together, Paul compared the brain to a stadium. And if you want to capture what's going on inside the stadium, you could just put a microphone in the middle of the field.

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  You will hear the crowd roaring, the crowd falling silent, right? The crowd just sort of, you know, being bored and not very, not very excited. But I believe that in order to advance brain disease treatment, right? To develop the most sophisticated brain-mission interfaces, we got to get into the stands with the microphone to hear those individual conversations between neurons.

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  Paul, you study individual neurons in the brains of monkeys, mostly. How do you do that?

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  Well, we do it with these tiny little wires that are implanted surgically into the brain. These little wires called electrodes measure the individual voltage changes that one neuron signals to another, the little digital event that says, ah, I've got something to say. Boop, last one millisecond.

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  Got it. So you do neurosurgery, you implant these wires, electrodes, and then they're measuring the little blips in the brain of the monkeys. What kinds of studies do you do after you've implanted these electrodes?

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  So we can now study how our animals perform reaching tasks simultaneously with measuring their brain activity. So we can see both the way their arm moves as well as what is happening in their brain when their arm moves. And so we give them these little tasks to perform where they got to like move their hand to chase a little green dot on the screen and they get it and they get a little drop of juice. That's like video games for monkeys.

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  So these are monkeys playing video games and you're watching what's going on in their brain, is that right?

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  That's right.

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  That's amazing.

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  It's really fun.

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  And part of what you're doing is seeing how stroke impacts this area of the brain, right? So how do you do that with the monkeys?

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  So we make very small, nearly invisible injuries into the brain, right where the electrodes are, which had previously never been possible. That lets us study the immediate impact of a very small number of neurons being lost, which is invisible from a behavioral standpoint to the monkeys. They don't feel this, they don't see any deficits, they go about, you know, moving just fine. But because they're performing these very practiced, careful behaviors on these reaching tasks that we give them in our, in our lab environments.

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  We can see very small changes in their reaching behaviors. And with this model, we're now able to ask the question, how does the brain change? And how does it recover when something like a stroke occurs?

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  And after some of the neurons in that system have been lost, how does the system behave differently?

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  Right, so there are, what we see are immediate changes to the activity of the remaining neurons. That change in activity lasts for about a few days to a week-ish. And then what we see is that the behavior of the neurons returns back to what it was before the injury. And the behavior also is restored. And so the degree of neural loss that we are generating, the brain can recover from. And that's very important to help us understand how humans might be recovering from their strokes as well. Even though we don't, in many cases,

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  as people recover completely because the degree of injury is so vast, it's very likely that the mechanisms are likely conserved.

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  Got it. What does this research mean for humans?

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  So what we have found are signatures of brain activity that are conserved after recovery and altered during injury. If that's true in people as well, then we could use these signatures to track and monitor and help treat the recovery from injuries like stroke.

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  Very cool. And so that being said, what do you think the big picture implications are of studying single neurons in this context?

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  The promise for studying single neurons, if we can measure enough of them simultaneously, is to carefully estimate and understand what the brain itself is doing.

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  In the setting of these diseases and injuries as well as in the normal setting. Because if we can track how injured or damaged the person's, a patient's brain is, then we can develop therapies using that measurement to sort of nudge us closer to where the normal state of the brain should be.

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  Yeah, and I kind of want to back up a little bit even more to where your research started. You started your work studying people who have tetraplegia. So I'm curious if what you're learning right now could benefit people outside of those impacted by stroke.

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  Yes, the way medical devices work is that you just need one device to get across the finish line, to be approved and to have a market, right, where it's economically viable. Once that's in place, researchers have access to what's called off-label use.

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  Ah.

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  And from there, we can very easily take these approved devices, explore other applications and other diseases at fractions of the cost.

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  Wow, okay. So the hope would be, you know, you get a device approved to treat stroke, but then maybe it can be used off-label?

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  That's exactly right. And we can just use the same device for different brain diseases. The problem right now is that there's not a single device currently medically approved used for any routine clinical purpose that measures individual neurons. We don't record the brain to treat brain disease. Instead, what we've been doing up until this point is studying proxies, right, downstream effects of that brain injury. I liken it to treating diabetes. Imagine we were trying to treat diabetes. We know that there's a disease. We know it has something to do with insulin. But the way which we're dosing insulin is by looking at the person and saying, oh, do you feel really tired? Or are you sweating?

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  Or are you about to faint? And we're not measuring a blood sugar. And that's sort of where we are right now in brain disease. We don't record from the brain. We look at downstream proxies of it. And there's reasons for this, right? I understand why it's in it's a surgery involved. It's it's challenging. There's risks involved. But some of these diseases are so debilitating. And our devices are getting to the point where the safety and risk arguments are not as dangerous as they were 20 years ago.

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  Yeah.

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  And so it's it's quite possible to start thinking about a new category of medical device, looking at treating some of these bigger brain diseases. And if we do that, we'll get a better view into exactly what is damaged, how much it is damaged, and how far away from normal it is.

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  Paul Niu-Jukian is a neuroscientist at Stanford's Brain Interfacing Lab. Paul, thank you so much. This was fascinating.

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  Thank you very much for the time.

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  Short Wavers, we're trying to grow our show, and you can help. I know you have a nerdy friend who might not know about us. Maybe you can send them this episode. It's the kind of thing that makes a big impact on our show. I produced this episode, and it was edited by Burley McCoy. Tyler Jones checked the facts. The audio engineer was Ko Takasugi Chernovin. I'm Rachel Carlson. Thanks for listening to Short Wave from NPR.

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