According to the World Health Organization, more than 300 million people  worldwide suffer from depression.

And an even larger number of  people struggle with anxiety. So it comes as no surprise  that a lot of scientists are trying to find treatments  for mental disorders like these.

The most well-studied methods  we have for treating them involve tweaking the level of brain  chemicals, like dopamine or serotonin. We know that this strategy often works, and that many patients do feel better  when given these kinds of medications. But, they don’t work for everyone, and they can have some side effects  that patients aren’t thrilled about.

Which is why one researcher is looking at  the issue from a totally new perspective. Instead of chemicals, Kafui Dzirasa is  interested in the brain’s electrical activity. Now, lots of neuroscientists have  studied the brain’s electrical activity.

But up until now, there have  been limited ways to do it. One is to take an image of the whole  brain at a particular moment in time, like with an MRI brain scan. Another is to measure electrical activity over a longer time using a few electrodes  poked into a tiny region of neurons.

But Dzirasa began his career as an engineer, so he wants to know how the whole  systems work, not just little pieces. He studies the patterns of electrical signalling across the entire brain  over long stretches of time. And the discoveries he and his team  are making could totally rewire mental   illness treatment as we know it.

Which sounds like the kind of story  that would be cool to tell in person. That’s why we created SciShow Field Trips … to see cutting edge research in action. We sent our friend Madelyn Leembruggen  to Dzirasa’s lab at Duke University to learn how he is trying to engineer a better  future for people with psychiatric disorders. [INTRO music] Kafui Dzirasa's title is almost as  complex as the subject he studies.

My name is Kafui Dzirasa,  and I am both an investigator with the Howard Hughes Medical Institute  and an endowed professor at Duke University. But my favorite title is  vision and value scientist. I am also in the Department of  Psychiatry and Behavioral Sciences.

I'm in the Department of Biomedical Engineering, I'm in the Department of Neurobiology,  and in the Department of Neurosurgery. You sound like you get a lot of emails, Yes, a lot of emails. Just a little busy But the story of how he got interested  in the brain is a lot simpler.

It begins at the movies. I grew up watching Star Wars,  and there's this magical scene. Luke Skywalker has gone off, and he's  fighting this super villain, Darth Vader.

For those of you who haven't  seen it, I want to give it away. Turns out he's his dad, right? Woah woah woah, spoiler alert!

Now, I’m sure that a lot of future  scientists who watched the Star Wars movies would have been inspired to  try to invent a lightsaber. But Dzirasa was more interested in something else. And there's this scene where Luke  Skywalker gets his arm cut off, and at the end he's in this medical bay, and  they've attached this robotic prosthetic arm, and Luke Skywalker is doing  this, and he's moving it again.

And I thought, wow, wouldn't it be so  cool to take engineering and science and figure out how to create body  parts for people who are suffering and then able to walk or unable to move. Dzirasa studied chemical engineering in college, and eventually got interested  in biomedical engineering, a field that combined healing and  medicine with cutting-edge tech. But for Dzirasa, becoming the  best biomedical engineer he could,   meant understanding the body inside and out.

And that meant becoming a medical doctor, too. He went into medical school with  the dream of creating robotic arms, but ended up focusing on a very  different part of the body. During one of Dzirasa’s first clinical rotations, he was introduced to a patient in the  psychiatric ward, a veteran with schizophrenia.

And I walked in, and I just asked  him, you know, how you doing? What brings you in, are you having difficulties? And he starts telling me about  how he's having this headache. and I'm filling out my form and finally I asked him when the headache started, and he tells me about how he was  in Vietnam and how he was captured, and how the people who captured  him start drilling into his head.

And ultimately, the story ends with him telling   me the people who captured him  implanted a chip in his head. And my best guess at the time was that  that is what we would call a delusion. I actually got really curious  about how his brain had generated this experience that probably  didn't match all of reality, and how were the electrical signals in  his head causing everything differently.

But while the other doctors knew which  medicines tended to work for illnesses like schizophrenia and bipolar disorder, nobody had a solid answer for what exactly  was going wrong in this patient’s brain, nor the exact solution needed to fix it. It was then that Dzirasa had a thought  that would shape the rest of his career: If we can engineer a robotic tool that  restores function to someone’s arm, why can’t we do the same with our brains? I'm still an engineer.

It's still about the brain, it's  still about electrical process, and it's still about prosthetic devices. It's just now, instead of thinking about the  parts of the brain that create motor function, you might be thinking about  other parts of the brain, things that you'd hear about, like the amygdala or other parts  of the brain that shape emotions and creating prosthetic devices for that. And because the animating force behind  both robotics and the brain is electricity, that’s where he decided to focus his efforts.

Dzirasa likes to compare the  brain to a complex highway system, with cars as the electrical signals driving  on roads crisscrossing everywhere. How does information travel in the brain? Yeah, so for humans, for example, we  have over 200 billion cells in the brain.

It's a ton, and half of those cells  actually can create and move electricity. When those cells create and move electricity, can send those electricity down highways,  right down highways and tunnels. And in neuroscience, we tend to call those axons, but they're basically highways and  tunnels for electricity to move.

The cars are individual electrical signals, and they move through our brains via neurons, the cells in our brains that transmit information. There are little gaps between  each neuron called synapses, and for the electrical signal to jump the gap, it needs a chemical called a  neurotransmitter to pass it along. Those are the things like dopamine,  serotonin, and noradrenaline.

For your brain to pass a message along, the neuron releases a bunch of the  neurotransmitter into the open space. It binds to the next neuron, which  triggers the electrical signal. Then once the message gets sent, those neurotransmitters unbind from the receptors, get released back into the open space, and then most are reabsorbed by the  original neuron to be used again.

And while this is a nice,  tidy system in lots of people, people who struggle with mental illnesses often don’t have the right amounts  of the neurotransmitters they need to keep the right parts of  the brain actively signalling. So what kind of treatments for  psychiatric disorders currently exist, and what are the benefits and downsides that  you're trying to maintain or to solve for? Brain cells release chemicals,  which we call neurotransmitters, and those neurotransmitters  convey information to other cells.

So that is what people are typically targeting  when they say, brain chemistry, right? You're targeting either the synthesis  or creation of these chemicals, the release of these chemicals, or the ability of these chemicals  to connect with the other cells. And many of our medications do that.

The greatest challenge with  this, this class of chemistries, is that the medication you take goes everywhere And so it can have effects on cells  that you don't want to be targeted And so some of these same sort  of connections or receptors, things that connect to the chemistry,  is in other parts of your body. It's why you might take a medication  for some form of psychiatric illness, which may make you nauseous, right? Because those same sort of connections, those same sort of cells that produce  electricity, are also in your gut.

Which is why Dzirasa thinks that  looking at mental illness in a new way could open up treatment opportunities  for the people that can’t be helped by what’s currently out there. And it starts by considering the entire brain. If you really want to understand the whole brain, you have to look at what’s happening with the flow of those electrical  signals across regions, and not just the chemicals in the synapses. if you want to make sense of all of  those cars and where they're going, you ultimately need something  like Google Maps or Waze, right?

Because there's constant movement that you have to understand how all  of those pieces are working together. That's exactly why we ran into a problem. Right?

As soon as you start thinking about  how many cars are on the road, you now need to make sense of the patterns. What's changing from moment  to moment and day to day? So Dzirasa started studying the patterns of  electrical activity that underlie emotions, as well as what those patterns look like  in people with psychiatric disorders, or even people who are under a lot of stress.

We have this kind of electrical map  for other body parts, by the way. When a doctor wants to check  how your heart is working, they measure the electrical activity of your  whole heart using something called an EKG. Right, so I've had like, an EKG done before, and that seems that, in itself, seems complicated, but then you talk about the size of the brain.

So it's much, much harder to map something  like the brain than it is the heart. That's right, I came to appreciate this. I'm also a physician, and so I also put  those 12 leads of EKGs onto somebody's chest to measure information, electrical  information in the heart.

And from those, what we call 12 leads, or sort  of 12, you know, stickers that you put on, you can see 12 electrical waves. So for each of those leads we put  in the brain, we also get a wave. But in this case, we're not getting  12 waves, we're getting 1000 waves.

And so you can see how quickly  this becomes a challenge, right? You're getting 1000 waves, but then you're also getting another 2000,  3000 individual brain cells, in their activity, and then you have to find patterns in all of that. We want to find the patterns  that show up over and over again in this large electrical data set that includes  brain waves like what you would get from EKG.

The data set, the scope of the  brain, it's so much more complicated. Electricity doesn't just flow in this direction. It flows in every direction.

When Dzirasa was a postdoc researcher, he decided he wanted to map how electrical  activity in a mouse brain changes across time. And he needed some very specific  tech to be able to do it. So, Dzirasa invented it himself.

It was the first example of Dzirasa using an  engineering approach on a biological question. We talked to lab manager Stephen Mague, who walked us through some of the details. So yeah.

So this is how we  build our electrodes in house, based on an approach that Kaf  developed when he was in grad school. So we start off with a single wire. As you can see, I can barely see it!

That makes sense. It's only  50 microns in diameter. And so this is tungsten wire that is insulated  throughout so that only the exposed tip, which will be implanted into the brain, can record electricity and  pass it along to the other end, which will be attached to the  other parts of the electrode.

And so we sort of gently put it into this grid, and this allows us to tailor each  electrode to the specifics or confirmation, of the brain region that we want to target. And so we can send those electrical pulses  from one brain area down to the other. If you look here on the screen, you can  actually see those electrical pulses.

You can see them, and you can hear them, and they sound like tiny crackles  and pops in the background. This is four different brain cells out of  that 100 billion that can create electricity. BRAIN AUDIO CRACKLE That is the talking of brain cells  sending that electrical information down the highways and  tunnels to other brain areas.

His ultimate goal is to create an electome, which is like a genome, but for the human brain. Can you tell me about the electome? Yeah.

So we came up with an idea. It was, you know, 2015 or 2016 and the idea was having gone into the  clinic and seeing what an EKG can do, you could see the brain in action. And from these patterns of these 12 leads, you can determine what was  going on with the heart.

We wondered if you could do the  same type of thing with the brain. So our idea was, well, maybe the brain  generates emotions in the same way by coordinating large parts of  electrical activity together. And could we find patterns,   which will say patterns of functional  activity, or electrical activity, and we ultimately call that the electome,  electrical functional connectome.

And so you might have a pattern  that shows up when you're happy, or a pattern that shows up when you're sad, or a pattern that shows up where you  really want to hang out with your friends, or a pattern that shows up when you  might be a little bit anxious or scared. And so that was the idea. Could we discover these  patterns in preclinical models, and then see if these ultimately showed up  in patients down the line as a diagnostic?

We as neuroscientists, have been  pursuing this challenge for some time, and we got really excited as a  nation on this effort in around 2013. There's a huge initiative launched  called the BRAIN Initiative. It's a great name for  understanding the brain, right?

And the goal was to create a new class of  technologies to make sense of the brain. We realized at the time we were recording 20 or  30 brain cells at a time in preclinical models, and we needed to get up into the  10s of 1000s or hundreds of 1000s. Well, the brain is electricity,  but it's also chemistry.

And so we also needed to create new sensors   for brain chemistry and brain  electricity at the same time. And then you needed machine learning or AI based  tools to integrate all that information together, and then that tells you sort of about physiology. It's a massive undertaking,   but we're really optimistic about what  this will tell us about the brain, and ultimately, how changes  in the brain produce illness so that we can come up with treatments and cures.

Step one, build the map. Step two, identify the road blocks. Step three, figure out the detours!

It’s an exciting trajectory  with a lot of potential, even while we’re still at step one. And one of their first big successes in  building up these neurological highway maps came when they identified the electrical signal  network underlying stress resilience in mice. Stress can work as a kind  of switch that might turn on any number of psychiatric  disorders in certain people..

When I was training as a psychiatrist, I would go in the hospital, and  I would see different patients. I kept seeing the same thing over and over, and that was when they would end up  in the inpatient psychiatric unit, many of them had a major stressful event a little bit before, right? In some cases, somebody was having  problems with a family member.

In some cases, the major stressor  was just like a student going off   to college for the first time and  missing home, the stress of exams. So I what I ultimately came to  realize was that if I understood how stress triggered all of these things, maybe I could come up with a brain  pacemaker that helped with stress. And if you do something like that, maybe you can help everybody who  might have problems down the line before the problems start.

And they’re not just focused on the downers. Long-term, they also want to understand  other feelings or experiences like love, pleasure, and even hunger. He also wants to use those  findings to correct the patterns when they’re causing the symptoms of mental  illnesses or neuropsychological disorders.   Dzirasa’s team is investigating a group  of proteins called connexin proteins, which sit on the ends of neurons.

Sticking with the whole roads analogy, you could think of these proteins  as two halves of a drawbridge. The cars only get through when  both halves are connected. Not enough connections, and you get  those neurological traffic jams, or parts of the brain that  should communicate, but don’t.

So if you need more cars to get through faster, one way to do that might be building more bridges. And in this case, they want  to add more connexin proteins to see if that makes signals  travel better across neurons. But not in humans, or even in mice.

This time, they wanted to look at worms. I am Julia Derk, and I'm a senior scientist  for Howard Hughes Medical Institute, and I study Worms. So why are C. elegans the right  worm to use for this kind of study?

Yeah, so any invertebrate would be a clean system because they express innexins, not connexins. So as opposed to … We put the connexins into the mouse brain, we have to worry about them potentially  binding to something else in another connexin, like their Connexin 36 is  all over lots of neurons. But the worms don't have that, and so it's a really great way of  understanding that the manipulation is only really happening in that particular  neuron subset and with those particular proteins.

So they’re basically adding in synthetic bridges to see if the electrical  signals would use them too. It’s a specially engineered form  of a connexin protein called LinCx. LinCx stands for Long-term  integration of circuits using connexin Which is a mouthful.

So, LinCx for short. But what's really wild is that we've now, through mutagenesis of changing  one amino acid at a time, changed these Connexin proteins that  are usually found in a white perch fish, and so they should only bind to each other. And that's really a huge component  of what makes LinCx special is that it's not any of the connexins  that were found out in the wild.

It's slightly modified Connexin proteins  that should only specifically dock to and work with and bind to each other. But then, they tried the DIY  connexin proteins on mice, which was trickier because they’re mammals, and  mammals do have their own connexin proteins. That means there’s the potential for the proteins  to link up with ones that are already there, and totally mess up the signalling.

One errant protein might result in your  fancy bridge getting built to nowhere. To overcome that problem, more engineering! So we use viruses that target specific  brain regions and or different cell types.

And so, for instance, a virus essentially  is just a replication machine, but we can sort of remove the  parts of a virus that we don't, you know, don't want, and don't want replicated, but use the inherent machinery that  basically replicates its own, own genome, and then we can put in, put a splice  in the parts that we want to have, sort of made for us. So you kind of scoop out the  virus, stuff inside the virus, and use it as a little delivery vehicle? Exactly.

So what part of the brain  are we looking at right now, and what is it responsible for? This part of the brain is called  the striatum, or nucleus accumbens, and it plays a really big role in  how the brain experiences reward. So in the case of illness like depression, the activity in this part of the brain  might be altered or changed or decreased.

So is the red that's showing  up there, the Connexin protein. That's exactly right. What we're trying to do is see how well the  Connexin proteins are expressing in these brains.

The idea is, in the future, we will use this Connexin  proteins as a potential treatment. So we want to make sure that  we can get them in the brain and that they change the way  the brain is functioning. So the goal with all this is to find  treatments for mental health disorders that work for the people that  can’t take traditional medications, and to have another tool in the tool belt when it comes to treatment-resistant disorders.

What would a treatment based on Connexin  protein look like in a human eventually? Maybe? If you want to get certain proteins  in the body, it's pretty easy, right?

You can either ingest it, or if you go  to the doctor and you have a syringe, you can get an injection Now, getting into the brain  is a little more complicated, because your brain has a lining that  prevents things from getting in. And as part of the BRAIN initiative, they were creating tools to overcome that  challenge of getting things in the brain. One used this type of technology  where they created nanoparticles, these really small particles in  which you can put things inside.

And you could use a device to open up this barrier just slightly  so the nanoparticles could go through. This device uses sound energy, and so you  basically put sound waves in the brain. They gently shake the blood brain barrier, it opens up and the nanoparticles go through.

It's called focused ultrasound. If we get our connexin proteins  inside these nanoparticles, we could open up the blood brain barrier  and it'll carry them into the brain. The second type of tool that the field was  creating was called adeno associated viruses, or AAV viruses.

So the virus is sort of the delivery mechanism. So down the line, that's sort of the treatment that we could anticipate someone would go into  the doctor's office, and in the doctor's office, they might, one time in life,  open up the blood brain barrier or give them this essentially vaccine, which carries the connection proteins  to the right location in the brain, forms these connections and then makes individuals  more resilient to the impacts of stress. Dzirasa’s work is pushing the boundaries of how we  think about mental illness and psychiatric care.

These innovations could be the start  of some truly phenomenal breakthroughs, and help a lot of people who need it. The road may be long, but at least we  have people like Dzirasa building bridges. SciShow Field Trips are made with our friends at  HHMI Tangled Bank Studios.

We’ve come together to bring you face to face with researchers at the cutting  edge of scientific discovery. You can watch more of Tangled  Bank’s science content at tangledbankstudios.org. [ OUTRO MUSIC ]