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THE ASPEN INSTITUTE

ASPEN IDEAS FESTIVAL 2017

ASPEN LECTURE: TRANSFORMING MENTAL ILLNESS THROUGH

TECHNOLOGY

Koch Building, Booz Allen Hamilton Room

Aspen, Colorado

Sunday, June 25, 2017

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LIST OF PARTICIPANTS

KAFUI DZIRASA

Assistant Professor of Psychiatry and Behavioral

Sciences, Duke Institute for Brain Sciences

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ASPEN LECTURE: TRANSFORMING MENTAL ILLNESS THROUGH

TECHNOLOGY

(8:00 a.m.)

SPEAKER: And a huge success. We're so excited

to have had this great festival; really excited for our

last morning. Be sure to head over a little bit early to

the opening -- to the closing session. It's going to be

really great, but there's also going to be a lot of

security differences. So we need to make sure people are

seated and ready. So when you start moving that way, be

sure to give it a little extra time and we would really

appreciate it this morning.

Excited to be here in this building. For those

of you who are not at the Aspen Institute a lot, Herbert

Bayer designed the buildings to have sort of form follows

function. So the rooms are all round because the tables

for our seminars are round. So the rooms are normally not

set in a theatre, and that idea that form really follows

function is a big thing that we think about a lot here at

the Aspen Institute, which ties really directly to that

idea of sciences and the arts combining. And I think what

we're really excited about having Kafui here today to talk

about technology and mental illness, and how we can link

some of these things and really create change is sort of an

exciting part of bringing the Aspen Institute together. So

Kafui, thank you so much for being here today.

Kafui is a professor at Duke University. In the

–- and I'm going to get this right –- the Institute for

Brain Sciences.

MR. DZIRASA: Yes.

SPEAKER: All right. I stuttered on that one.

Thank you so much for being here.

MR. DZIRASA: Thank you. So every great science

story begins with science fiction. My story is no

different. I remember when I was seven, I finally

convinced my parents to let me watch Star Wars. So I got

to the second one, Empire Strikes Back and there's this

scene where Luke Skywalker gets into this battle with the

guy who ends up being his father Darth Vader and he cuts

off his hand. And you know, this could be like really

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traumatizing for a little kid, you know, Luke Skywalker's

walking around without a hand, but next thing you know,

Luke's got a new hand, right. It's this robotic engineered

hand that's working, and as he thinks about moving his

hand, this hand is working just like his own. And I

remember being struck that that picture of technology

augmenting and improving folks who had been -- had injuries

in improving their function never left me.

I stayed with that picture until I was finishing

undergrad. I did chemical engineering and I got near the

end of undergrad, I was trying to figure out what to do

with myself, and all of a sudden I was reading all these

articles showing up in The New York Times about this field

that was being launched called brain machine interface.

And I've read about the work that was being done at Duke

University. It was a pioneering scientist. His name was

Miguel Nicolelis, and what he'd figured out how to do was

he put individual wires, each the size of a piece of hair,

into a monkey's brain. And what he was able to do with

these little metal wires was read what the monkey was

thinking. So he could get information out of a part of the

monkey's brain that dealt with movement, the motor cortex,

and so he was seeing the brain as the monkey was moving its

arm around.

And so he gave the monkey a video game, let's say

something like Pac-Man, so the monkey's playing Pac-Man and

he's watching his brain as the monkey's playing Pac-Man.

And what they were able to do is take all of these

electrical signals that were coming out of the monkey's

brain and decode them. And they could say, "okay, the

monkey is going to move Pac-Man left. I can see left in

the brain. The monkey is going to move Pac-Man right, I

can see right in the brain." And so they decoded all of

these signals and then built a robotic arm. And so instead

of sending these robotic signals, right, these signals into

another computer, they sent it into the robotic arm. And

so as the monkey was playing Pac-Man moving arm left,

moving arm right, the robotic arm started moving around.

And then what they taught the monkey how to do

was they got them -- they sent visual feedbacks to the

monkey. So the monkey now realized that he could move this

robotic arm. And then the last piece was they disconnected

the joystick. So the joystick was no longer feeding into

Pac-Man. The monkey's brain was feeding into Pac-Man and

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the robotic arm, and the monkey learned to use the robotic

arm. And there was nothing as powerful as the day when the

monkey realized that he didn't actually need to move his

own arm to move Pac-Man or the other arm. He could just

move the arm by thinking about it. So by thinking about

this movement, he could have control over this whole

different robotic arm. He'd gotten a new limb, and all of

a sudden this idea that I'd seen as a little kid when I was

watching Star Wars, science fiction had become science.

I knew I had to go to Duke. I applied and I

joined their MD Ph.D. program, and the way it works is you

spend 2 years doing all your basic science coursework and

your first set of clinical rotations and then you join the

research lab. And so my first clinical rotation I was

stationed at the state psychiatric hospital. And I

remember I walked in, I had my little white coat, you know,

my clipboard with all the questions I was supposed to ask,

and you know, we'd gone through seeing patients and

evaluating them over and over again. So I knew exactly

what I was supposed to do, I knew what the scene was going

to be like.

So I was in the state psychiatric hospital. I

walk in the room, and I was totally blown away. There's a

guy sitting in the corner and he had a blanket over him and

he was shivering because he was really cold. And I'll

paint this scene as in a graphic way as I can. So he had

on you know, the glasses that the doctors give you after

you've had your eyes checked, the really thick dark ones,

he had those on. And he was sitting there and he was

shivering and you know, we all, you know, have seen little

kids when they shiver in the winter and they sort of have a

little bit of dripping crystallize on their face. He'd

been leaning forward and shivering so long that he'd formed

a little crystal on the tip of his nose. And so I walked

in and I started to ask him, I said, "sir, so how are you

doing? What brought you into the hospital?"

And he says, "Man, I'm not doing good. I've got

a headache." I said, "Oh, this is good. Headaches I know

how to do." So "Sir, like, so tell me more like about this

headache. Is it sharp? Is it dull?" And I started

running through my medical school chart checklist. He's

like, "Oh, it's sharp." I'm like, "Okay, great I can do

sharp headaches." I said, "Sir, so when did the headache

begin?" And he said, "well, you know, I was back in

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Vietnam and the government captured me, and when they

captured me, they put my head in a vise. And when they put

my head in the vise, they opened it up and then they

inserted a chip into my brain using a drill. And just when

the pain stopped, they drilled some more and then they

finally put the chip in there. And ever since they put the

chip in my brain, they've been reading all my thoughts and

that's why I have a headache."

So all of a sudden my checklist, like, I was a

little thrown off, because I wasn't quite expecting that,

and so I'm thrown off for a minute. And then, I think,

okay, I've got to go back to this. "Sir, are you seeing

things that no one else is seeing?" He says, "no." I

said, "Sir, are you hearing things no one else is hearing?"

He says, "no." I said, "okay, great." "Sir, are you

having any thoughts of hurting yourself?" Finally, that's

the first point in the whole interview, he stops, he

paused, he takes off his glasses, he looks directly at me,

and he says, "you know what, no, I'm not having any

suicidal ideations, but I'm starting to have some homicidal

ideations." It was time to go.

(Laughter)

MR. DZIRASA: And so after I collected myself and

left the room and called my attending, I remember walking

out of that experience thinking to myself, you know, we've

gone through so much of pathophysiology, learning about the

heart, the lungs, the kidneys, and yet there was a person

sitting in front of me. He was clearly sick, and nobody

could tell me what was wrong with the organ that was

leading to this sickness, and nobody could tell me why the

medicines worked or why they didn't work, why this guy had

been in the hospital so long, what was the dysfunction that

was going on in the organ called the brain.

And from that day I came along this incredible

curiosity about wanting to understand how the brain worked

and then asking the question, "could we apply technology to

ultimately treat folks, like the patient that I had seen

that day?" And so it was fascinating, it was an amazing

time in science, it was 2003-2004 they'd just finished

sequencing the human genome and so there was this massive

hope in the field that ultimately we would find the gene

for schizophrenia and the gene for depression and the gene

for bipolar disorder, in the same way that we'd figured out

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the genes that caused Huntington's disease and the genes

that ultimately gave rise to things like cystic fibrosis.

And so it was a very exciting time for me.

And as things continued and progressed throughout

my time in graduate school, it became clearer and clearer

that our hopes of finding that single gene probably wasn't

what was ultimately going to end up happening. It turned

out there were many genes, there were many changes that

could happen that could give rise to each of these

illnesses. And as I was trying to use technology, I was

trying to use technology to understand how genes changed

brain function, it became clear that there was something

that was fundamentally missing in the approach and how I

was thinking about the problem.

So I finished up med school and grad school and I decided

that I just needed to get a better handle around some of

the illnesses and that I needed to get more hands-on

experience and understand the nuances better. And so I

decided to do clinical residency in psychiatry. And there

was a patient encounter that I had that shaped how I really

see the field evolving and how I see technology ultimately

interfacing with help.

And so that patient's name was CJ. CJ was a 19-

year-old kid and he graduated valedictorian of his class.

He went off to college. He was full of the hopes that he

could change the world, but as soon as he got to campus, he

started having all these problems concentrating and they

sort of got worse as the semester went along. He failed

his first semester of classes and his parents just had no

idea what had happened to the son. They like took him to

see a psychiatrist and a neurologist and a pediatrician,

and after all of this they had no answers whatsoever.

Nobody could tell them what was going on with their son.

And the only thing they knew was that CJ was like

in no condition to go back for a second semester of

classes. So they kept him home. And so as they were

sitting at the kitchen table one day, CJ just gets up, he

walks up to his bedroom on the second floor of their house,

he opens the window, and he jumps out. And so they're

still sitting there at the kitchen table when they heard

the crash in the bushes outside, and his parents had no

idea what to do. They never experienced anything like this

before.

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So they decided that the best thing they could do

was just take 12-hour shifts watching CJ. So they took 12-

hour shifts and this went on for like a week and a half,

and after that week and a half they were completely

exhausted, and to make matters even worse, CJ wasn't

actually getting any better, right. He was now like seeing

angels and demons. They were talking to him. They were

telling him that it was worthless, that he deserved to die,

and the pictures on his wall were screaming all day long at

him. And they were just completely exhausted and they knew

that they had to finally seek help. So they decided to

take him to hospital.

As they were driving on the way to the hospital,

CJ reaches over and opens the door in the back of the car

and tries to jump out. His mom just happened to be sitting

in the back seat with him, so she grabbed his arm and

pulled the door shut, and this was CJ's second suicide

attempt in the last 2 weeks. The drive for them it seemed

like an absolute eternity. They finally got to the

hospital, and in the hospital he was in the emergency room.

It took him about a week and a half to get admitted, and he

finally ended up on my in-patient psychiatric unit.

So when I met CJ, he was absolutely terrified.

He'd have long conversations with the walls, each one

ending the exact same way with him just begging for them to

let him live. I'd seen these symptoms before and so I

started him on an anti-psychotic agent, and over the course

of several weeks, CJ went from being what I'd say as

critically ill to being severely ill. And so I pulled his

parents aside to talk to them, and they were at a complete

loss, right. CJ has been in the hospital now for multiple

weeks, and for them this wasn't the CJ that they knew,

right. They wanted to know what happened with their son.

So I steadied myself, because I'd seen these set

of symptoms before. CJ, he had schizophrenia, and so I

braced myself because every time I'd have to deliver a

diagnosis like this, every family treats it and handles it

in a different way. For some people they're confused;

other people treat it like a death sentence. But CJ's

parents they had a reaction that I'd never quite

experienced before. As soon as the words schizophrenia

left my mouth, both his parents started trembling, and I

thought I needed to explain the disease and the prognosis

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and the course, and I only got this look of defiance from

both of his parents. And so I kept going, and finally his

dad just stops and he pauses and he looks at me and he

says, "Dr. Dzirasa, pick another diagnosis. Pick

depression, pick early-onset Alzheimer's." He said, "pick

anything but that."

And I thought it was really important to do

psychoeducation and help them to understand, and I was

absolutely getting nowhere with explaining this to them.

And finally CJ's mom looks at me and says, "Dr. Dzirasa,

you just don't understand. If you give CJ that diagnosis,

you don't understand the stigma that he'll have to face.

You don't understand the shame that he'll have to deal with

for the rest of his life." And -- but I did. My family

has struggled with mental illness for generations.

And in fact, when I was in grad school working on

this, all these questions, I had one family member that we

had to commit to an inpatient psychiatric unit. It was the

first time that my family had ever like talked about mental

illness. I discovered that one of my parents' siblings at

a three out of four of them carries a diagnosis of

schizophrenia or bipolar disorder or depression. I

remember what it was like for my family to hire a private

investigator. We found one of my family members in the

alleyway on another continent hallucinating.

So I understand every bit of the stigma and the

shame that CJ's parents were dealing with. I understand

this stigma it's so palpable that every time I give a -- go

off to give a talk, my family members say, "just don't let

them figure out who I am." Right. For me it was this

dramatic transition that happened in grad school that as I

was studying these disorders and there was this tremendous

curiosity, all of a sudden this curiosity became fear as I

started learning about psychiatric genetics in my family's

history. And it was this fear that one day I would wake up

hallucinating or one day I would be seeing demons.

And once I transitioned into my 30s and passed

that critical window, that fear became a fear that one day

my children or my nieces or my nephews would be diagnosed

or having to deal with one of these illnesses that 20% to

30% of Americans suffer from every year annually. So I

started with this dramatic –- the curiosity about the brain

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and that curiosity transitioned into fear of understanding

this organ.

So the brain is made up of over 200 billion

cells, and who we are is locked within those cells and

their interactions with each other. For centuries,

scientists and philosophers have really tried to understand

like what this organ is and how this organ works. And

we've made a lot of progress. So we now understand things

like there are differences between your left brain and

movement and things like speech and things like creativity.

And -- but what was remarkable is that as we were making

all of those progress -- all that progress. It turned out

that those early scientists and philosophers didn't

appreciate that your brain used a force that they couldn't

see or they couldn't touch, and it turns out that force is

electricity.

And so I'll frame my talk today from this

perspective and this is a perspective that we've been

wrestling with. What if psychiatric illnesses are actually

illnesses of electricity? And so this might sound far-

fetched, right. I'm a physician, so I can frame these

things for you. Imagine if one day you or your friend or

your family member was having chest pain, right, you would

go to the emergency room. They check your blood pressure

and your heart rate, and then they would do the strangest

thing. They would put, like, 12 -- that was strange. They

would put 12 leads on your chest and those 12 leads what

they would be doing is they will record or measure

electrical activity flowing through your heart. And based

on those patterns of electricity flowing through your

heart, they might make some decisions.

On the one hand they might decide that you just

need some medication. On another hand they might decide

that you need a stent or something that opens up blood flow

in your heart. But in some cases what they'll do is put

little electrical leads on your chest and deliver a little

bit of electricity that allows your heart rhythm to become

normal again. In another case they might say, wow, you

need a lot of electricity and so they'll defibrillate you,

right. They'll shock you -- your heart back into rhythm.

So electricity in this case is the medicine.

And in another cases one heart rhythm might

suggest that they actually need to put in a pacemaker,

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something that allows you to maintain normal electrical

rhythms in your heart. So it's not that farfetched when we

think about the heart that we can have diseases of

electricity in the heart that can be treated with

electricity, and so it always struck me that it might not

be that farfetched to start thinking about the brain in

that manner.

So electricity is defined as a movement of

charge. In the brain, charge is made up of chemicals.

Those chemicals are sodium, potassium, calcium, and

chlorine, and about -- just under about half of those 200

billion cells are able to move those chemicals across the

first surface to generate electrical pulses. So in the

brain, the electrical communication between cells is

directly related to chemicals. As psychiatrists for the

last few decades we've focused on these chemicals, right.

It's why we use terms like electrical or chemical

imbalances, but for neuroscientists the real Holy Grail is

understanding how those electrical pulses interact with

each other to form feelings and thoughts and emotions.

So it turns out if you think about an illness

like depression, what most people don't know is that one of

the best treatments for depression is actually putting

electricity into the brain, directly into the brain. And

what surprises many people, as I talk about this, is that

they don't realize that most major medical centers in the

country still use this therapy called shock therapy. It's

one of the most effective treatments for depression. And

so the question then is if this -- the Holy Grail for

neuroscientist and what I would frame as the future of

psychiatry is understanding electrical pulses and

electrical rhythms and electrical information in the brain,

then how come we haven't been able to figure out how this

works and come up with new treatments.

So I frame this and I'll frame this from a

perspective to say let's say we wanted to understand an

electrical machine like a computer, right. If you wanted

to understand a computer, the first thing you might do is

take it apart, right. When you're young, it's called

breaking things. When you're old, it's called reverse

engineering, but the principle is still the same, right.

(Laughter)

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MR. DZIRASA: You're going to take it apart piece

by piece. So I thought this slide would be a great framing

for this idea of taking computer apart. So this is the

we'll say the great Institute of higher learning, the

Academy of Athens, right and so this is Plato and

Aristotle. They would basically sit around and think about

ideas and think about the world and think about how things

work. And so the picture's sort of a joke, but you can

imagine what would happen if you plop the laptop computer

in another room one day as these philosophers were sitting

around thinking, right.

And you know, they probably spend the first,

let's say, 7 or 8 hours totally surprised that there was

light coming out of this box, right. And they would be

staring at it and then they'd say what it's like the sun in

there. Like what's going on, why is there light coming out

of this box? But at some point in time, the power would go

out, the computer would turn off, and they might take it

apart. And as they began to take it apart, they'd see all

these cool pieces, right. They'd see like chips and they'd

see hard drives and they'd see -- but they would have no

sort of framework for how these things work together.

And even if they were able to sort of piece all

the pieces back together, they'd have no concept of like

electricity, right, and the role that electricity played in

getting this machine to work. And even if they were able

to figure out electricity, like they would have no idea

like what Word was or PowerPoint was or we can get into

even more complicated concepts like Wi-Fi or -- I mean, you

could imagine like Plato or Aristotle trying to explain

this idea of like a search engine on Wi-Fi, right. You

take your best ideas, stick them in the box, the box sends

those up into the air, the air sorts all of it out, brings

the ideas back in the box, and then gives you the answer,

right.

This would sound like so incredibly farfetched,

and in a lot of ways this is where we started with the

brain, right. When -- if you look back even you know, 100-

150 years ago, the approach was to take the brain once

folks had passed away and then you do slices of the brain,

and you look at the pathophysiology or the pathology in the

brain. And what you would do is you'd look at someone's

symptoms, the problems they were having when they were

alive and then you'd look at their brain when they passed

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away, right. These are post-mortem studies. And then you

try to link the two of these together, right. And there

was a lot of progress made in this. Folks could have

strokes and you'd see like part of their motor part of

their brain was no longer there, and then you'd say, "oh

well, the left side of the brain, right side of the body."

And then in other cases you'd have diseases in

which people started shaking and you'd say, 'oh well, some

of these cells in an area of the brain called "substantia

nigra" have died and this ultimately became Parkinson's

disease, or you'd look at the cells and you look closer and

you'd see plaques and tangles and this became Alzheimer's

disease. And so there were -- we got understandings of the

brain by looking at pathology. And these are the diseases

which two things happened: one, they generally became named

after people, either the people who described the pathology

or described the behavioral changes.

And so that was the first thing that happened.

The second thing is this became an entirely new field

called "neurology." And this field was the field where

there was something wrong with the brain. And then there

was an entire different field that emerged, which is when

you took the brain and you slice it up and you did the

histology, you didn't see anything wrong, and these became

the psychiatric illnesses.

And so much of the stigma that we deal with in

the context of psychiatric illness is based on this

framework of splitting this organ into two forms of

diseases, diseases in which there's something wrong with

the brain and diseases in which there's something isn't

wrong with the brain. And this is why psychiatric diseases

have names like bipolar disorder or schizophrenia, which

means splitting of the soul. It was this inability to link

this pathology to an organ.

Now, certainly over the course of a 100 years

we've learned much more about the brain, including that

there are receptors, including what the chemicals are, and

we can see changes in those areas, but much of the stigma

still persists. But the idea now is that as people started

to study the brain, so that's the brain when the

electricity isn't running through it. As people started to

study the brain with the electricity running through it,

they noticed some really interesting phenomenon. The first

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thing that they noticed was that, and this was through

putting electrodes, like the hard electrodes they put them

on the head, they noticed these things called brain waves

where you would have electricity in the brain and it would

sort of go up and down like waves over time.

And as they studied these waves, people started

having these -- change in their conceptual framework, and

the conceptual framework said, well, what if these waves

are like almost like little conductors and they serve as

little conductors in an orchestra and they allow brain

cells to keep their tempo such that brain cells can work

together to produce music in the same way that all of the

musicians in a symphony can produce music together by being

coordinated by the conductor.

And as scientists did more and more research

around this, what they found in human beings was that many

brain cells were actually being coordinated by this brain

wave as it went up and down. And they found that as they

looked in animals as well that these same brain wave

changes they can find cells or individual electrical

neurons that were being coordinated by these brain wave

changes in the brain.

So you can see how a brain rhythm or this brain

wave or this -- we'll call it a miniature brain metronome

could work. And so I'm just showing a brain wave on the

left-hand side, which is setting the tempo, and then every

time the brain wave gets to the top, you have a certain

number of cells that fire or they activate or deliver an

electrical charge and then another couple of cells that

deliver an electrical charge at the bottom. And this brain

wave allows the red cells and the green cells to work

together to produce music.

And so the question is then fairly simple. If

there is a brain sort of metronomic system and if there is

-- it's important for coordinating the activity of many

cells, perhaps psychiatric illness might be due to

dysfunction in a brain metronomic system. And this is the

framework of the questions that we ask in my lab.

Now, what we try to tackle in this case is we use

animal models. And the way we frame these animal models is

we take animal models and then we expose them to things

that give rise to mental illness in humans. And so some of

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those manipulations might be genes, and so these genes

while not 100% penetrant, can give rise to symptoms that

look like things that we see in humans and I'll talk about

that in a second, or we can expose them to a lot of stress.

This stress can be things like separating them from their

moms when they're young as a model of childhood trauma. We

could expose them to things like bullying and adolescence,

or we can expose them to drugs of abuse, whether it is

things like opiates or cocaine or alcohol, and we can see

how that changes their brain metronomic systems.

And so to get after this, we're basically using

that same sort of technology that was originally used in

monkeys to help their brain move. We're now applying that

in mice. And so here's what it looks like. We're able to

take individual wires and these individual wires, each the

size of a piece of hair, we're able to implant it directly

into multiple brain areas simultaneously in a mouse. And

that on the bottom you can see in blue there is a CT image.

The blue basically probes are wires going into the animal's

head. Each one is tinier than a piece of hair, so the

mouse can tolerate it exceptionally well and we can target

many brain areas all throughout the depth of the animal's

brain. So we're recording many, many, many metronomes and

many, many, many cells simultaneously. The animal wakes up

from surgery. It's totally fine about 4 or 5 days later.

And so as the animal is awake and behaving and moving

around and experiencing the world, we're able to measure

its brain electrical activity. We're able to get

individual cells -- individual neurons firing or activating

or delivering these electrical pulses. We could measure

them in the animal's brain, and we're able to measure all

of these brain waves or the metronomes simultaneously as

the animals are moving around.

Now, this is a massive amount of data and I want

to frame this for you, because I've talked to other

collaborators who are doing this type of work around the

challenges posed by this. So the amount of data that we're

collecting is sometimes on the order of many, many

gigabytes almost terabytes per animal over multiple days.

And so the reason why work like this was just not

feasible before I sort of start dating myself. When I was

in high school I remember getting my first computer and it

had like a 100 megabyte hard drive, right. And I was so

excited about it. So 100 million bite hard drive, right.

And so now we're collecting a thousand like billion

terabytes per day, right.

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So like there was just no way of like gathering

all of that data into one place, right, you just -- the

average investigator in the lab couldn't do it. And then

the second problem is once we gather all of this data it's

really hard to like make all of this data make sense as in

animals like running around the cage and interacting with

other animals.

And so we had to bring in an entirely new field

which is called "machine learning." And the idea behind

machine learning is it can look through these large

complicated data sets right and find patterns. And so we

can make these patterns relate to what is going on in the

animals behavior and then figure out how these patterns are

different between the animals that are models of mental

illness and then the animals that are normal so they

haven't had the manipulations.

Once we're able to do that then we can figure out

where the metronomes are basically dysfunctional in the

animals head and we -- then we apply stimulation tools to

fix that. And so the stimulation tools we have to have

ways of reading information or reading what the metronomes

are supposed to be in the animal's head.

We have to pull that information out in real time

that means we've got to be able to do it in about 20

milliseconds. So twenty 1-1000th of a second we've got to

be able to get the information out of the animal's head,

process what the metronome is supposed to look like and

then send the information back in the animal's head in the

right way. And we're able to send that information back in

-- sending energy back in using either -- direct electrical

stimulation or we can use light and it is a technology

which, if anyone has questions I can tell you about, which

uses -- you can transform light into energy inside of the

brain.

So we're either putting electricity back in or

we're putting light back in. And what our early

experiments have found is that in these models of mental

illness we can actually normalize their behavior by

targeting these individual metronomes. Okay. So I could

imagine what everyone is thinking at this point in time,

and if you're not thinking it, it is probably what you

should be thinking, right.

So a mouse doesn't like get guilty, right, a

17

mouse doesn't get sad, a mouse doesn't hallucinate and a

mouse certainly doesn't get suicidal. A mouse isn't CJ, a

mouse isn't my family member, right. And so I think it's

important to say that that isn't exactly the reason why we

use mice, right. And I think in the same way that you can

study a mouse's electrical rhythms in its heart and figure

out things that are principles that are conserved across

species, it's the same way that we can use these -- these

animal models to figure out how ultimately to target brain

pacemakers in humans.

So about, wow, time flies this is about 7 months

ago, and I got invited to an event it was a closing event

that was organized by the White House called "The Frontiers

Conference." And they were -- wanted to talk about the

future of brain science and the future of precision

medicine. And so I spent about an hour on the stage with

the 44th President talking about where we thought

technology can go.

And he asked a question. There's a question

posed to the panel and the question was, well what sort of

-- like, why haven't we -- we've got all this stuff, right,

we've got all these tools the White House had just launched

an initiative 3 years before to create all these tools and

technologies to get this type of information out of human

beings' head. And the question was well, like, why haven't

we figured this out yet. And so I thought the best way to

do this was to pose a question to the audience and I asked

the question how many people in the audience were excited

about voting, raise their hand, right.

And so people raised their hands, right -- you

guys are raising your hands. This was obviously much more

amusing at the time it was --

(Laughter)

MR. DZIRASA: -- it's October 13th. In

hindsight, it might not have been that funny. And I

described to the President what happened. I explained to

him that my mouth generated these pressure waves, the

pressure waves traveled through the air struck the tympanic

membrane or the eardrum, that created mechanical force and

mechanical force opened up the hair cells in the ear

through the tip links and the kinocilium. It changed that

mechanical energy into chemical energy. The chemical

energy changed to electrical energy traveled down the

cochlear nuclear -- nucleus into your superior olivary

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nucleus into your auditory thalamus independent our

auditory cortex which then became pitch.

That pitch for most people in the room became

words on the left side of their brain. The words became

representations. I said if you were young in the room you

probably got excited about voting and released some

dopamine from your ventro tegmental area into nucleus

accumbens. If you were a little bit more seasoned you

probably remember the first time you voted and your

hippocampus became activated.

And I said if you're a politician your medulla

probably lit up as you are counting the number of hands in

the room. And then your hand went up and that entire

process happened in half a second, right. And so when

we're talking about the brain we're dealing with this

incredibly complex engineered system, right. We've both

got to understand the language of psychiatric illness.

We've got to understand how that interacts with electricity

and then we're dealing with all of these parts of the brain

that are working together very fast to ultimately produce

these changes that we're talking about.

But from my perspective I think the future is

bright, right. I'm hopeful, I'm hopeful for my family

members. I think ultimately the treatments that we're

working on will allow people who have been suffering from

illness to come out of the shadows to play prominent roles

in contributing to society and ultimately live their

healthiest lives. So we've got about 15 minutes, I'm happy

to take any questions if there's anybody in the audience

that has any. Thank you.

(Applause)

SPEAKER: (inaudible)?

MR. DZIRASA: Yeah, no we haven't, right. So

there are -- and there are a lot of things that are going

to be important for this, right. So there are -- and I'll

say that -- it -- the answer would've sounded more like

science fiction about 3 months ago right but even that's

changing. So the first round of technologies that worked

through this BRAIN Initiative which is the White House's

goal of creating new technologies to read information out

of human brains, implanted -- like are now implanting

electrodes in humans.

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But the idea of getting this much information

simultaneously through all depths of the human brain seemed

really far fetched 7 or 8 years ago. I think we're on the

horizon of that. It has not been applied in children. The

second challenge is even if we can get the information out

you've got to figure out how to basically stimulate the

brain, right.

And there are some tools that are being developed

that would allow some to do this. Ultimately if you can

figure out how to do this non-invasively you'd want to

start there especially with children the ways of

manipulating magnetic fields outside of the brain to change

electrical fields inside of the brain this is called

"transcranial magnetic stimulation."

And so the idea is to take all of these

individual sort of pieces and technologies that we're

creating and combine them together in systems that work and

then ultimately, we would miniaturize them. The thing that

made this seem a lot more like -- so when I gave this talk

8 months ago, it sounded like science fiction. In the last

3 months even Elon Musk has announced launching a company

to basically create what is ultimately augmented human

intelligence where there is brain and machine interface,

where human brains are interacting with computers in real

time.

SPEAKER: (inaudible)?

MR. DZIRASA: So some of the things we do can

produce what we call long-lasting plastic changes, right.

So they can tune the brain to work in a different way --

others in what we think. So we think different diseases

will require different things, right. There are diseases

which you get sick and then you get better and they sort of

have this intermittent course things like bipolar disorder.

We think in that case a reset might be okay.

There are other diseases in which the neuro systems sort of

degrade over time things like autism and Alzheimer's and

schizophrenia in which the solution will ultimately

probably be an implantable pacemaker chip that augments

neural systems and allows them to work normally. Sorry,

I'm supposed to wait for the mike to come around.

SPEAKER: (inaudible) I think I have a quick

question. Obviously the mouse your intervention is very

complex, very elegant, very (inaudible) and the

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transcranial stuff (inaudible) talking, but it isn't

working. Any rate --

MR. DZIRASA: Well, I heard you.

SPEAKER: Yeah, okay. At any rate,, the

transcranial approach is still a little primitive, obtuse,

whatever word you want to use. Can you speak to that --

MR. DZIRASA: Yeah.

SPEAKER: -- large gap?

MR. DZIRASA: Yeah. So I think there -- that the

technologies are getting better very quickly and are moving

together, right. So transcranial magnetic stimulation has

been shown to be a fairly effective treatment for

depression in some people, right. The idea is can you get

better targeting and can you get deeper. So the problem

with transcranial magnetic stimulation is you can't

stimulate the deep parts of your brain, right, you can

stimulate the shallow parts of your brain.

People are trying to learn if there's a language

they can use whether it's stimulating two sides

simultaneously to cause a certain convergence, stimulation

deep. It's just an unknown at this point in time, all of

that's work that's in progress and the BRAIN Initiative has

really put a lot of. It was -- the 21st Century Cures Act

has funded to the tune of a couple billion dollars put a

billion over the next 10 years into neuroscience research

to do exactly this. So there's a lot of energy around

this.

SPEAKER: Thank you.

MR. DZIRASA: I'll go back and forth to these

sides of the room.

SPEAKER: Thank you so much. This has been such

an interesting presentation. Do you mind if I ask a

philosophical question?

MR. DZIRASA: Sure.

SPEAKER: You did mention Aristotle. I've read

that a EEG test can show in humans that there's activity in

the brain's motor cortex fractions of a second before a

person consciously decides to act. If that's true with or

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without such interventions that you are suggesting are on

the horizon, are humans conscious authors of our own

decisions?

(Laughter)

MR. DZIRASA: That's a good -- that's a good one.

Yeah, I probably should've paid more attention in that part

of psychiatry residency.

(Laughter)

MR. DZIRASA: It's a great question right. So,

it depends on how you frame "decides to act," right. So if

there is a process which initiates a thought of movement

and another process that allows you to become aware of the

initiation of the process movement and another process that

moves and the timing of those don't line up perfectly which

they don't, right, you might come to the conclusion that

our conscious processes don't have anything to do with what

we do. I don't think that's the case. That seems easy.

There we go.

SPEAKER: Hi, thank you so much. I'm sure you

have maybe thought about, you know, the uses of this

technology going forward; you're talking about brain

disease and you mentioned AI. What else do you think this

might be used for in the future?

MR. DZIRASA: Yeah. So this is complicated and I

think there are a lot of ethical questions that are going

to be raised by technology like this, right. And so I

basically have been buried in the lab and in the clinic for

many years trying to cure my patients and cure my family,

right. A lot of the conversations that happened in the

last year and there's sort of two camps which are pushing

this. One camp is it's about augmented intelligence and

actually just making human beings smarter for the sake of

improving brain function, right.

In the same way that we have shoes that allow us

to run faster and jump higher, right. So it's this idea of

making our function better. There's another arena which is

-- this is an interesting one. It's worried about

computers becoming smarter than humans and taking over the

world and the solution to this, well -- right, the

singularity, and the solution to this will be humans

integrating with computers because a human computer is

better than a computer computer.

22

SPEAKER: (inaudible).

MR. DZIRASA: Yeah, yeah. And so you can read

about some of the work being done by Bryan Johnson around

this. We as a society have to wrestle with -- like every

two new technology that comes online we have to wrestle

with like how this impacts who we are and it's everything

from like Facebook or not, right, technology has a profound

impact to change us.

SPEAKER: I know is -- the electric shock therapy

does it cause memory loss?

MR. DZIRASA: Yes. Yeah. So one of the problems

with electric shock therapy, right is you're essentially

delivering shock and you're causing the whole brain to

seize, right. And so what you're doing is you're actually

causing the whole brain to sort of fire together and

synchronize itself. So it's almost like this massive

reset. So the problem with everything in medicine is the

less targeted it is the more side effects you get.

And so the side effect of the electroconvulsive

therapy is that some people can have really problematic

memory loss. It's while -- even though it is the most

effective treatment it has side effects which is why it's

not the most widely utilized treatment.

SPEAKER: I was intrigued by your comments early

on about your theory that mental illness may be electrical

disturbance in the brain. My field is endocrinology and I

have always thought that mental illness especially

depression, bipolar disease is an endocrine disorder of the

brain. Are these two concepts mutually exclusive?

MR. DZIRASA: Yeah. No. No, I don't think it is

at all, right. So the -- and it's always challenging for

some of my neuroscientist colleagues to appreciate that the

brain exists within the body and that it comes to

homeostasis with the body. In other words, it balanced

itself with the rest of the body as well, right.

So the brain doesn't like make its own oxygen,

like doesn't make its own -- right, it's getting all of

these things from the rest of the body. The brain is

interacting not only with the endocrine system, it's

interacting with the gut, it's in interacting with the

inflammatory system in a bidirectional away, right. So in

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other words the other parts of the body impact the brain

and the brain impacts the other parts of the body, right.

So I don't think that that idea is incompatible.

It might be a part of what's going on. Now, I want to be

gentle in how I say this. It could be that there are cases

in which the endocrine system interacts with the brain in

such a way that it doesn't process electricity correctly.

And it's certainly in -- because you're a doctor I love

answering the questions all the way, right.

It is certainly the case that if you have like

thyroid dysfunction, you can look like you have depression,

right. So -- or you can look like you have bipolar

disorder. So there are certain things that could happen

externally. And the way psychiatrists have dealt with this

is if your depressive symptoms are explained by the fact

that your thyroid function is low it is not depression,

right.

So this is -- it's sort of these ways of thinking

the way through the brain that are built into our ways we

practice medicine that can be really problematic for

allowing the whole system -- understanding how the whole

system works together.

SPEAKER: (inaudible).

MR. DZIRASA: Yeah. Yeah. Well, one of the

patients I had had developed auto antibodies against a

receptor type in the brain. And so they were basically --

their inflammatory system was attacking the cells in the

brain that process information, right. So in that case the

fix is not to put pacemakers in the brain it is to target

the immune system, right. But it's the same idea that it's

probably breaking the brain's ability to process

electricity normally.

SPEAKER: Where does schizophrenia and the

increased incidence or its -- it appears first during

teenage years. Have you looked at brain electrical

activity in advance of actually young people being

symptomatic? And to be able to -- whether it's a -- either

a genetic predisposition or a familial issue some of the

examples you talked about to assess the likelihood that a

particular young person would become more likely to exhibit

symptoms and then to think about what interventions are

possible in advance of the person being symptomatic.

24

MR. DZIRASA: Yeah. So I think that is the

strategy that we as neuroscientists and psychiatrists

should be taking, right. So -- because I think the heart

is such a great framework for this, right. There are

certainly interventions that we use for folks after they

have had heart attacks, right. We would prefer to give

them antihypertensive and anti-cholesterol agents before

right because it is a much more effective way. And there's

-- we can only get the heart function so optimal after the

heart attack has occurred, right.

So I would think about schizophrenia in the same

way. Now, it's not a universal disease everybody isn't

exactly the same. But there's certainly a decrease in

function that can happen with each major psychotic episode.

So schizophrenia used to be called "dementia praecox or

dementia of the young," right.

And so you can think about what dementia is it's

a deterioration, a stable lasting deterioration in

function. And so the idea is if we can get on the front

side of that preventing from that happening, it's a much,

much better strategy. And so there's certainly work that's

been done on the parts of the National Institutes of Mental

Health; they funded this to try to look for signatures of

high risk. Some of this includes genetics some of this

includes behavioral changes and family history as well.

I think a lot of the work looking at direct brain

activity and the processing of brain information is

something that there are increasing efforts towards now.

So this is where the field is and where we think things are

going to evolve, but I think your question is exactly

right.

SPEAKER: Hi, it was rally a fantastic talk and

can I just ask do you know what happened to CJ?

MR. DZIRASA: Yes. Yeah. Yeah. So CJ actually

ended up doing much better, right. So, CJ was ultimately

able to go back to college. And CJ in some ways -- there

were some things that worked in CJ's favor that don't

always work in everybody's favor. CJ responded well to the

medications.

So after about 2 months CJ had finally stabilized

and stopped hallucinating. CJ had a super supportive

family which turns out is an incredibly therapeutic part of

the process as well. One of the major challenges with

25

mental illness is it can -- it attacks your ability to

advocate for yourself, right.

So I always describe these as illnesses that

affect families and CJ had great care very early on in the

diagnosis, right. So if you think about a disorder that

creates dementia the longer you wait and the longer you go

the harder it is to sort of recover normal function. And

so CJ was ultimately able to go back to school and get a

job.

SPEAKER: Very interesting talk. My question to

you is what is the status of developing signatures for

schizophrenia whether it's electronic or FMRI, and do they

correspond with the psychiatric definitions that are out

there?

MR. DZIRASA: Ha! This is a fantastic question.

So the status is this is literally the cutting edge, right.

So the BRAIN Initiative launched in 2013 the DARPA -- this

is the defense agency that ultimately gave us the Internet

put about their initial 80 million dollars into this. And

so the studies have been funded and were initiated in the

last 3 years trying to look for these exact same

signatures. One of the approaches in the frameworks that

the last director of National Institutes in Mental Health

take -- took, and the new one took is part of the reason we

haven't done a great job of linking like psychiatric

diseases to biology is because our diagnosis might be

wrong, right.

And so the way we define disease categories might

be so all over the place they don't actually mirror

biology. And so the -- and this is the history of

psychiatry, right. Our disease categories are used so that

when I see something and I explain it to the next

psychiatrist we sort of understand that it's a common thing

that we're seeing but it doesn't mean it matches biology.

And the way I would explain that is if you think

of -- if you called the illness fever, right. So let's say

we have an illness called fever and a patient comes in they

have fever I see a fever you see a fever we measure if the

temperature is high. And I want to do a study of the

biology of fever and I want to test a group and I give them

antibiotics and some people get better off their fever and

some people don't, right.

And so it means the biology doesn't match to the

26

disease in most cases it's because it doesn't, right.

Antibiotics don't make you better unless you have a

bacterial wellness and it depends on what bacteria you

have. And if you have -- if you have a fever antibiotics

aren't going to make you better, if you have a heat stroke

the antibiotics aren't going to make you better.

So I think in a lot of ways the challenge that we

have in this field is we have these disease categories that

are big and the biology is very distinct within these large

disease categories. Last question, I got the last question

slide.

SPEAKER: Thanks. So I remember in the early

1980s as a pre-med student plastering electrodes on

schizophrenics brains to measure -- I think it was the P50

wave?

MR. DZIRASA: Yeah, yeah, yeah.

SPEAKER: Yeah. So this idea of the brain waves

and schizophrenia and how that connects has been going on

for a long time. But so I'm particularly interested, one,

in what mouse model you use for schizophrenia, because it's

so hard to reproduce.

MR. DZIRASA: Yep.

SPEAKER: And then I'm also thinking about if we

-- if you make advances and you're actually trying to use

some kind of therapy affecting the brain waves for

schizophrenics about how you talk -- well talk to people

about that who so often have the paranoia that you describe

that someone's putting a chip in their brain and --

(Laughter)

MR. DZIRASA: Yeah, yeah. Yeah..

SPEAKER: -- it sounds really challenging.

MR. DZIRASA: Yeah. It's why I actually started

with my first story of my encounter with someone -- a

patient with schizophrenia talking about them having a chip

in their brain, right. Yeah. So there are -- and so what

she was asking about is this idea that people would do

studies; they put electrodes or EEGs on the brain and then

they measure how the brain filters out information, right.

And the premise here is that in individuals that have

27

schizophrenia their brains do not filter out background

noise as well as other individuals do.

And so that sort of framework, the challenge with

that is we're not sure if EEG is sensitive enough, right.

So it's like measuring the surface of a ball without

actually seeing what's going on inside. And so that's one

of the first round of evolutions that are changing. In

terms of our mouse models we use a lot, right. And our

premise there is if we can find common biology that

converges across a lot of models then that is our best

approach to it.

So genetic models including disruptive in

schizophrenia one and 22q11 which give risk for these

things in humans. We can give things like PCP. which make

human beings hallucinate and ketamine. And so we're simply

looking at convergence points behind that, right. But our

premise and our framing and this is to go back to your

question is that we think the pacemakers are ultimately

going to target things like attention and social systems

and information storage, right rather than schizophrenia.

And so if we can frame these models and see how

these genes or these manipulations alter a working memory

system then we are generating a working memory pacemaker

that's useful for schizophrenia and Alzheimer's. So that's

the framework. Thank you all.

(Applause)

* * * * *