Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. E.J. Chichilnisky. Dr. E.J. Chichilnisky is a professor of neurosurgery, ophthalmology, and neuroscience at Stanford University.
He is one of the world's leading researchers trying to understand how we see the world around us, that is how visual perception occurs, and then applying that information directly to the design of neural prostheses, literally robotic eyes that can allow blind people to see once again. Today's discussion is a very important one for anyone who wants to understand how their brain works.
Indeed, E.J. spells out in very clear terms exactly how the world around us is encoded by the neurons, the nerve cells within our brain, in order to create these elaborate visual images that we essentially see within our minds.
And with that understanding, he explains how that can be applied to engineer specific robotic AI and machine learning devices that can allow human brains not only to see once again in the blind, but also to perceive things that typical human brains can't, and indeed for memory to be enhanced, and for cognition to be enhanced.
This is the direction that neuroscience is going. And in the course of today's discussion, we have the opportunity to learn from the world expert in these topics where the science is now and where it is headed. During today's discussion, we also get heavily into the topic of how to select one's professional and personal path. And indeed, you'll learn from Dr. Chicholnicki that he has a somewhat unusual path, both into science and through science.
So for those of you that believe that everyone that's highly accomplished in their career always knew exactly what they wanted to do at every stage, you'll soon learn that that is absolutely not the case with E.J. So we have a lot of different types of research and research that we have in our lives, wandering through three different graduate programs, taking several years off from school in order to dance.
Yes, you heard that correctly, to dance. And how that wandering, and indeed dancing, helped him decide exactly what he wanted to do with his professional life, and exactly what specific problems to try and tackle in the realm of neuroscience and medicine. So, if you're a scientist or no, young or old can benefit from and can apply the specific tools that E.J. describes in their own life and pursuits.
Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. This is Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.
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Welcome. Good to see you. For the audience, we are friends. We go way back. E.J. has been a few years or more ahead of me in the science game. And the best way to describe you and your work, E.J. is here in astronaut. You go places. No one else has been willing to go before. He developed new technologies in order to do that. All with the bold mission of trying to understand how the nervous system, which of course includes the brain, works and how to make it better with engineering.
So today we are going to get into all of that, but just to start off and get everybody on the same page, maybe we could just take a moment and talk about the brain and nervous system. And what it consists of that allows it to do all the sorts of things that we're going to get into, like see things in our environment and respond to those things in our environment. So at risk of throwing too much at you right out the gate, what's your one to five minute version of how the brain works?
Oh, I don't have a one to five minute version of how the brain works, but I can tell you how I think vision is initiated in the brain. And you and I go back a long way. So we have a lot of common understanding about this, but I'll narrate it from scratch if that makes sense.
So vision is initiated in the retina of the eye, which is a sheet neural tissue at the rear of the eye that captures the light that is incident on the eye that comes in through the through the eye transforms that light into electrical signals processes those electrical signals in interesting ways and changes them up. And then sends that visual information to the brain where it is used to bring about our sense of vision.
And you asked me about the one to five minute version of how the brain works. I don't know, but I do know that the brain receives all these patterns of electrical activity coming out of these nerve cells in the retina and somehow assembles that into our visual experience, whether that be responding to things coming at us or our circadian rhythms. That that govern our sleep and behavior or identifying objects for prey or avoiding predators or appreciating beauty.
And what we know is that the brain receives a fantastically complex set of signals from the retina and puts that all together into our visual experience. And we are very visual creatures, obviously. So I think that's a big part of how the brain works because so much of what we do revolves around vision revolves around how the brain puts together these signals coming out of the retina. And I would love to understand how that works at the moment.
I don't. And what we're trying to do is get a really complete understanding of how that begins in the retina and then how we can restore it in those who've lost sight. Why focus on this issue in the retina? This thin set of layers of neurons that line the back of the eye. Why explore vision there? I mean, obviously there are centers within the brain that of course contain neurons, nerve cells that are involved in vision.
If one wants to understand visual perception, and I agree, by the way, that visual perception is one of the most dominant forces in the quality and experience of our life. Why focus on the retina? Why not focus on the visual cortex or the visual thalamus? I mean, what's so special about the retina? Well, we have to focus on all of it because understanding the retina won't give us a full understanding of how all this works, obviously.
And if you don't have your visual cortex and visual thalamus, you won't see. But if you don't have your retina, you also won't see. You won't even have a chance to see. So I focus on the retina because I enjoy the possibility that we can really understand a piece of the nervous system in our lifetime. We can understand it so well that we can build it, replace it, restore its function. That's farther off in the central regions of the brain. That's going to be quite a bit harder.
I find satisfaction in really understanding something so well that I can write down in a mathematical formula what it's doing that I can test my hypotheses up and down. And yes, we really get how this little machine works and that I can engineer devices to replace the function of that circuit once lost that to me is just deeply satisfying.
But there also has is a really fundamental role for people who want to go and do more exploratory work in the visual brain, as you mentioned in the visual cortex and the thalamus and other places. Because ultimately those retinal signals won't lead to anything if those areas aren't putting it all together to govern our perception and our ultimately our behavior. So let's talk about the retina in its full beauty and detail. Three layers of cells that line the back of the eye like a pie crust.
Somehow take light comes into the eye lens focuses that light if it doesn't do that well we put lenses in front of our eyes such as contact lenses or spectacles. And somehow takes that light and transforms it as you said into neural signals and processes that within the retina. Let's take a deep dive into the retina and do so with the understanding at least my understanding is that in part thanks to your work and the work of others this is perhaps the best understood piece of the brain.
Yes, I think it's a solid argument that it's the best understood piece of the brain and we'll turn back to that in a minute. So the retina begins with a sheet of cells called the photoreceptor cells that are highly specialized these are cells that essentially don't exist anywhere else in the brain.
And what they do is transform light energy into electrical signals in neurons very specialized very demanding cells they require a lot of maintenance and they die relatively easily which is what gives rise to some of the forms of blindness. Those are the you might call them pixel detectors or tiny cells called photoreceptors that each one captures light from a particular location in the world.
That sheet of cells has done that initial transduction process where light is converted into neural signals that the brain can then begin to work with.
The second layer is responsible for processing adjusting changing mixing and matching comparing signals and different neurons many complex operations that we're still trying to understand and consists of dozens of distinct cell types that extract features if you will of the visual world from the elementary pixels represented in the photoreceptor cells. The second layer is receiving the input from that sheet of photoreceptors and picking stuff out of it.
The third layer of cells is the so called retinal ganglion cells that's the only term that I'd like to probably will come up repeatedly in this conversation. So for your for your viewers and listeners these retinal ganglion cells are the ones who are responsible for taking the signals that are there in the retina and sending them to the brain so that the process of vision can begin. The messenger's if you will from the retina to the brain.
The retinal ganglion cells and there are about 20 different types in humans are again feature extractors they pick out different bits and pieces of the visual scene and send interesting stuff to the brain trying to leave out the uninteresting stuff. And the 20 or so cell types all pick out different types of information from the visual scene you can a sort of think of them as photoshop filters each cell type in the retina.
Again about 20 different ganglion cell types each type represents the full scene the entire visual world but picks out different features such as some cells pick out spatial detail tiny little points of light almost. Some cells pick out and signal information about things that are moving in the visual world some cells pick out information that's been captured about different wavelengths from the photoreceptor cells.
And they're there by giving us our sensations of color and probably more things in those 20 different ganglion cell types that we don't fully understand.
The result then is that the retina has this sort of a representation of the visual world but it has 20 different representations not one it's not one picture that comes out of the retina and gets sent to the brain no no no it's 20 different pictures and you can think of maybe as 20 different photoshopped pictures but one of them has the edges highlighted one of them has the colors highlighted one of them has movement.
Encoded in it and these somehow these filters send the information to many different targets in the brain and our brain puts it all together and then we have a cohesive sense of the visual world which is the remarkable feature that we really don't understand.
Is it fair for those that don't work with photoshopped to think about these different photoshopped filters perhaps as like different movies of the visual world one movie contains the outlines of objects and people and things another movie is showing the motion of blobs in the environment meaning whatever's moving environment is kind of just represent as blobs another movie is just the color in the environment another move and then all of those.
What I'm calling movies are sent into the brain and then the brain somehow combines those in ways that allow us to see each other and see cars and objects and recognize faces is that is that one way that's exactly how I think about it maybe it's a better way to say and no I like the photoshop filter analogy I just for those that don't work with photoshop you know I just think that the movie analogy might might be a decent alternative.
How the retina works is an example we think of how all sensory systems work there's an initial representation in a specialized cell type that is that is responsible for incapable of extracting physical features from the world.
And then neural circuits in the brain use that information in different ways to grab stuff out of the visual world in the auditory system there's the sound world is represented also in specialized cells that capture sound energy and transduce that into neural signals and then subsequent.
And then the stages of processing in the auditory system pick out different features of our auditory world like the frequency how higher how low a tone is right the direction it's coming from right the movement of that how loud it is different features are extracted so. Visual system is just an example of how the external world is represented in our brain and of course in some sense in a philosophical approach to the brain is really saying well there's the sensory world.
And then there's the actions we take and there's almost nothing else that we really know other than those two things have a sensory world comes in and then finally it results in our action that's what our brain is about.
Because vision is so important for people I find it absolutely compelling and fascinating I mean as an example as you know well many people study rodents to understand how different aspects of the brain work and you know rodents are interesting animals and do all sorts of really cool things but they interact with the world differently than we do they in a lot of ways they sense by smelling they they identify objects by smelling and they navigate with their whiskers into the brain.
We don't do any of that you don't navigate with your whiskers at least I don't think you do you don't recognize me when I walk in the room by my smell no you use vision for all that. And we humans use vision so it's a really fundamental aspect of who we are as biological creatures.
And we can wonder if just for sake of entertainment we could think about how the human retina and therefore vision in our species differs a little bit from some extreme examples of vision in other species not to make this a comparative or zoological exploration but just to really illustrate the fact that the specific cell types within our retinas and visual representation of the outside world that can be and often is very different from that of other species.
For instance or at least my understanding is that the mantis shrimp sees I don't know 60 to 100 different variations of each color that we are essentially blind to because their photo receptors can detect very subtle differences in red for instance long wavelengths of light.
What most people refer to as red pip viper is consent heat emissions essentially with their eyes but also other organs and on and on you know it's I raised this because I think the human neural retina is such an incredible example of extracting features from the visual world that then we recreate but I think it's also worth reminding everyone and ourselves that it's not a complete representation of what's out there.
Like there's a lot in light that we don't see because our neural retina just can't turn it into electrical signals right do you want to give it some examples of what we can't see and if any particular examples from the animal kingdom delight you feel free to throw those out.
Well one thing you mentioned color we experience a rich sensation of color when we look at the world and say wow I see all these colors that's immediate and that's just how we talk about it but in fact we have very little information about color color is a very high dimensional complex thing or wavelength I should say wavelength information really is about how much energy there is in the light around us at the end of the day.
We have a light around us at different wavelengths we only have three sort of snapshots of that in our retinas with the three different types of photosceptor cells that are sensitive to different wavelength different bands of the wavelength spectrum.
And we are not a lot as you just said other creatures have many more ways of capturing wavelength information and one way you can verify for yourself that we just have three is to realize that if you look at your TV there are only three primaries on your TV there's a red there's a green there's a blue that's it and from those three primaries.
And the rare richness of the experience on your TV set is composed so just those three things you basically are able to create any human visual sensation well a mantis shrimp would be like that's nothing there's so much more stuff out there that's not represented on this TV if you could speak to the mantis shrimp.
We maybe don't see another example of a difference in the animal kingdom is so again taking rodents as an example one of the one of the things that rodents have to do is to not be hunted by birds that are coming down toward them.
And so it appears that there are cells in the retina that are seem to be quite sensitive to what to looming to something dark that's getting bigger like a shadow coming from a bird coming down at you we don't know for sure that this is exactly what causes animals to avoid being eaten by birds but there's interesting evidence in that direction.
That's not really a big thing for us for humans as far as I know we're not typically hunted by huge birds so that's not a thing we need and I think that's that's where comes back to where you're headed if I understand right. Which is we occupy different biological niches we and the mantis shrimp and the rodents and our visual systems reflect that we have different stuff that we're looking for in our visual environment and other creatures are.
And so our eyes are different and that's one of the reasons that we emphasize work on the human retina as opposed to other certain other animal species that would be less clearly relevant to the visual experience you and I have. So let's talk about these incredible experiments that your laboratory has been doing for several decades now. I've had the privilege of sitting in on some of these experiments and they are very involved.
To say the least if you could just walk us through one of these experiments I think the audience would appreciate understanding what goes into quote unquote trying to understand what's going on in the electrical activity of these specific retinal cell types the retinal ganglion cells in particular. You know what does this look like you know you're in your laboratory at Stanford and you get a phone call someone says I got a retina what happens next.
We scramble like crazy we drop everything we're doing cancel all our appointments and get ourselves ready for 48 hours of non stop work down the lab getting as much data as we possibly can from the red. The most exciting example of what you just said is when we get a human retina when for example there's a donor who has died and the retina is available for research we jump at that opportunity how soon after.
The person is deceased do you need to get the eye globe the eyeball in order to get the retina in a condition that will allow you to record electrical signals from it a few minutes just to just waiting in the hospital. The way we typically get these eyes is from brain dead individuals so people who are legally and medically dead but their hearts are still pumping and therefore their retinas are still alive and functioning when when those individuals.
The cells are used their bodies of those individuals are used for organ donations. We can benefit from that organ donation setup that organ distribution centers do to save many people's lives and also to promote research so we sometimes get those retinas and that begins the experiment for us.
I'm going to ask for a few more details here just to put the picture in people's minds and not to be gruesome I just really want people to understand what's involved here so you'll get a call we've got a patient who is soon to be deceased. They've consented to giving their eye globes their eyeballs for research so that you can study the human retina.
Is it you who goes over and takes the eyes out to somebody do that or hand them to you in a bucket of ice I'm sorry if I'm making people queasy at all but this is folks how one goes about trying to understand how the human brain works absolutely and this is also how you go about donating your heart so that you can save somebody else's life who needs a heart transplant.
The same incredible organizations that do the harvesting of the tissue for us their primary goal is to do that for organ donations to save lives they save lives every day these people are incredible donor network west is one of those organizations the one that we work with.
They're really amazing so their technicians or a retinal surgeon will take the eye out give it to myself or somebody from my lab will bring it back to the lab and we have a way to keep the eye alive and functioning just the eye by itself.
Is this always at Stanford or do you sometimes travel elsewhere local hospitals up to an hour away so then you drive them back we drive them back it's the retina express and when when we're bringing back the retina express it's again it's all hands on deck in our lab we are scrambling setting up all of our equipment getting everything ready you've been at these experiments their intense and they really are really are 48 hour marathons of incredible activity by really dedicated individuals so we might get those eyes sometimes again.
Two in the morning that's common and from that to in the morning time begins experiments so we bring the eyes back we open them up and we we have access to the rear of the eye which is what where the retina is it's a thin sheet of neural tissue at the back part of the eye.
We have a set the eye cut it in half so that we can see the back it's like half a blow if you will and then we put in relax and cuts and lay it out flat so we can see what we're working with and we take little segments of ratna out in the subsequent 48 hours cut them out maybe a three by three millimeter piece of the red not little chunk of rental tissue and bring it into an electrophysiology recording and stimulation apparatus that allows us to interact with it and we do two types of experiments with that so this.
Electrophysiological recording and stimulation apparatus is very custom built by our physics collaborators who have developed high end equipment it allows us to record and stimulate through 512 channels simultaneously at very high density. This is pretty high end stuff in terms of technology for interrogating and manipulating the electrical signals in the ratna that's what we specialize in in my lab.
I just asked a question about this device I've seen it before it's very small as you mentioned you're recording from a few millimeter square of the of the retina from this recently deceased patient. It looks a little bit like a bed of nails right like tiny little micro wires all arranged very closely to one another you got the retina laying down on top of it's from that bed of nails can extract meaning record the electrical signals that are coming out of the brain.
The retina is still alive so you are in a position to shine light on it and essentially make it behave in the same way it would if it were still lining the back of a healthy alive person that is the beauty of these experiments so because we can keep the retina alive and happy and because the retina ganglion cells the cells that are the ones that.
Message the visual information to the brain are on the surface we can put them right next to the electrodes and we can record their electrical activity in other words we record the signal that those cells would have sent to the brain if they were still in the living person.
And at the same time as you said we can focus an image that we create on a computer display onto the retina so we're treating the retina if you will as a little electronic circuit which it almost is honestly delivering light to the photos after cells so that they are electrically excited and then recording the electrical activity that the retina is sending out if you will that allows us to study how the retina works normally.
What we also do with that same electrical apparatus is turn around and pass current through those electrodes in order to see if we can activate those ganglion cells directly with no light just electrodes why do we do that we do that because it allows us to design future methods of restoring vision by electrical stimulation of the retina which we'll probably talk about in a few minutes.
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Let's take this moment to talk a little bit about cell types. So you mentioned there are about 20 different types of these retinal ganglion cells what we may refer to in brief as RGCs. So retinal ganglion cells are AGCs same thing. And as you mentioned these cover the entire retina so that if each cell type is extracting a different set of features from the visual or motion color specific colors etc.
That essentially no location in the world around us fails to be represented by these cells put differently these cells are looking everywhere. Each cell type is looking everywhere so that if movement occurs in any region of our visual world we are in a position to detect it.
But maybe we could talk a little bit about cell types cell types is such an important theme in the field of neuroscience and indeed in all of biology but it's actually not something we have talked about very much on this podcast before either in solo episodes or in guest episodes. I don't have any specific reason for that we've talked about brain area is prefrontal cortex, basal ganglia, anterior mentally cortex and on and on we've talked about neural circuits.
But we've never really talked about cell types so the ganglion cells rather you let me down talking about cell types well but that's why you're here that's why you're here.
Tell us about cell types how do you figure out if you have a cell type how do you know if it's a cell type or you know is it the shape is it how it responds how do you know if you have a cell type what what what's this about I want to just put in the back of this question or rather in the back of people's minds that this issue of cell types is not just an issue pertinent to the retina this is an issue that is critical to understanding how the brain works.
It's critical to understand consciousness I know a lot of people like what is consciousness we're not going there just yet but what are cell types how do you determine if you have a cell type and why is this so important understanding how the brain works.
Yeah I mean as you said as far as we understand every single brain circuit is full of very distinct cell types those cell types are distinguished by their genetic expression their shapes and sizes which other cells they do contact and which cells they don't contact where they send their information to in other parts of the brain and what they represent and as far as we know this is true throughout the brain.
And it's true in the retina the different ganglion cell types retinal ganglion cell types about 20 of them each of which is looking at the whole visual scene extracts different stuff this cell type one extracts one thing cell type two extracts something else but they all represent the entire visual scene. But those cell types we know from lots of beautiful work work that you're closely connected to and some of which you've done.
Those cell types have different morphology different shapes and sizes different patterns of gene expression different targets in the brain they send their outputs to different places in the brain. So really to study the retina without understanding cell types you're kind of lost right away you have to know what's going on with the cell types otherwise you can't make sense of this retinal signal.
The way we we identify them in two ways and different for different purposes the basic way we identify the different cell types is their function because we study their function we study how they respond to light images and we can clearly separate them out and in fact it's it's a simple thing to say but it's really true.
Our 512 electrode array technology which you've seen in our lab and stuff that we developed with collaborators about 20 years ago was crucial for this because with that 512 electrode technology we could see many cells of each type and we can clearly parse them apart from one another whereas previous studies working on one cell at a time had great difficulty doing that.
So with our technology with 512 electrodes we record hundreds of cells simultaneously so there's 20 of these there 50 of those there 26 of those and here they are we can just set them in different bins and say OK this is what's present in this retina just what the information is they're extracting.
There's another purpose again referring forward to the neuroengineering aspect we need to identify the cell types not just based on what visual information they carry but based on their electrical features properties electrical properties of the cells cells as you know neurons are electrical cells they fundamentally receive and transmit electrical information and the way that they do that has a distinctive electrical signature that turns out to be super important for developing devices to restore vision.
Could you explain how you determine what a given cell type does its electrical properties. Let's just draw a mental image for people the retina is taken out of this deceased individual put down on this bed of nails of electrodes those electrodes can detect electrical signals within the ganglion cells you are able to shine light onto the retina and see how the retinal ganglion cells respond meaning what electrical signals they would transmit to the brain if they were still connected to a brain.
They're not connected to a brain in the experiment they're sitting there but they're trying. I could imagine playing those cells a movie of I don't know a checkerboard going wherever square on the checkerboard goes from white to black to gray could do that I could play a cartoon I could show it this year's Academy Award winner for best picture but how do you decide what to show the retina this is a human beings retina after all.
Presumably it looked at things that are relevant to human beings until that person died but how do you determine cell type electrical signals. If you don't know what specific things to show it I mean you're going to show it I know Disney movies like what what do you show it.
So what we show now reflects the fact that we've built up a lot of information and our work stands on the shoulders of many scientists who have studied the retina for decades to figure out what different cell types respond to. And we know that certain cell types respond primarily to increments of light when light gets brighter than it was so a change from a certain brightness to a higher brightness this particular cell type fires.
Another cell type fires are sense spikes to the brain when it gets darker. Some cell types respond primarily to large targets in the visual world other cell types respond better to small targets in the visual world. Some cell types respond to different wavelengths of light that we can identify there exists certain cell types that are still poorly understood that respond to movement so we can tailor visual stimuli to type.
So we can tailor visual stimuli to types that we kind of already know about because of much preceding research. That's not actually how we do it in our experiments for the most part instead we use a very unbiased flickering checkerboard pattern as it turns out which is a really efficient unbiased way to sample many cells simultaneously so that in a half hour of electrical recording from a red we can figure out what all the 512 or so cells are that we're recording and know all of their types.
And the way we do that is to play essentially random garbage TV snow type image to the rat not for a period of time and determine which bits of brightening or darkening or moving or whatever in that random garbage activated this particular cell by looking at average of cross the half hour recording and saying oh it looks like this cell was always firing when it became bright in this region of the screen that must be an on cell sensitive to light in this region of the screen and so on.
So we have sophisticated efficient ways of doing it but it all comes back to these basic things about what features in the visual world tend to cause a given cell to send a signal to the brain. Yeah that makes a lot of sense so you take essentially what you called random garbage snow white black and gray pixels on a screen.
The retina views that and then the cells in the red note will respond every once in a while with an electrical potential the fire as we say spike sometimes called and then you take sort of a forensic approach.
A bit later you look back in time and you say you know what was the arrangement of pixels in this random garbage right before this cell fired in electrical potential that's right spike and then from that you can reconstruct the preferred stimulus you can say oh this cell and cells around it seem to like motion of things going in a particular direction for instance.
And how do you know that the cell doesn't also like a bunch of other stuff that you didn't pick up on using this random garbage yeah two things for let me just say for the record we don't record from these cells that signal motion in particular directions they are an elusive cell type that is best understood in rodents and other creatures and not well understood in the primate as you know although some people are discovering potential cells of that type now and have.
Have have recently discovered them okay so let's say cells that respond to small like spots that are red. You know that go from dim red to bright red right yeah so we can go through that colored TV snow and pick out the cells that responded to a transition of the kind you described from darker to lighter or from greener to redder or something like that cells tend to respond to transitions in the visual scene rather than static image.
And so we can pick that stuff up but you ask the question will G is the TV snow going to capture everything about what these cells are doing that's a really important question that I want to just mention more. Quite likely not that's a scientific instrument it's an unbiased way to sample a whole bunch of cells you know first cut look at you know generally speaking what are they up to.
But that doesn't mean we've really captured their role in natural visual perception because actually you don't go through the world perceiving visuals know you go through the world perceiving objects and meals and mates and targets and all these things right so. The study of how the retina response to more naturalistic visual stimuli in my lab and many other labs around the world is really getting off the ground now and I would say we have limited understanding.
I would say we know that our simple laboratory experiments with the TV snow don't capture the whole story there's more there are about 20 different cell types in the right now we have basic characterizations of seven of them if you count a certain way.
We know that there are another 15 or so lurking right behind the curtain that we've started to sample we don't know what naturalistic targets they respond to in the visual life of the animal that's work that's underway exciting interesting work because this we know that the retina they got to be there for something.
One one way to think of it I'm pretty sure you think about this way to is that the retina is a highly evolved organ with a lot of evolutionary pressure for it to be efficient to have a small optic nerve sending to the brain.
It's probably the case that there's no accidental stuff sitting around the retina that's vestigial and sending information to the brain it's probably the case that this those signals are all doing something important for our visual behavior for our well being for our sleep all sorts of stuff.
And I think and the field is still trying to figure that out these these are the big mysteries I think that in terms of the retina what are those signals exactly in all those different cell types what different behaviors and aspects of our life do they control. What is the wildest cell type you've ever encountered.
Like what did it do like what did it respond to that's that's what I mean when I say wildest you know it sells red don't ganglion cells that respond to you know increasingly red portions of the visual scene or decreasing the green portions of the visual scene like okay cool that's seem school like get some you know around the time of Christmas that that's useful and it's useful in other days of the year as well but you know given that the retina is indeed the best understood piece of the brain.
And given that you have 20 cell types 20 is in 20 million it's you know it seems tractable you probably get to understanding it in its entirety or understanding them in their entirety excuse me.
One would like to know what what what stuff is are we paying attention to at the level of the retina I mean are there like spiral cells that like spiral stuff in the environment or there's cells that like emojis like what's going on in there you spend a lot of time doing this we do we spend a lot of time to give up to night sleep which is kind of incredible way I'll just do a little.
Take a moment here and just say you know for a guy that's been doing this for this long with the sleepless nights and you look pretty good you're pretty rested I tend to go home I go home before the graduate students to stay up they stay up I was just a
I used to step until my mid 40s I was I was in there doing the all night or type things got it and maybe you can help me figure out my sleep patterns but yeah we can talk about that this episode we talk about how to pull all nighters and still survive.
I've done plenty of those but yeah like what's yeah lots at stake here there's a human retina you know meaning a human gave up their eyeballs to for this experiment after they died of course yeah you've got many people on this these are these sorts of experiments are very expensive a lot of fancy equipment a lot of salaries to try and figure this stuff out this is the chief mission of the national
institute there's a lot tax dollars like this is in my opinion as important as the space program probably more important in my opinion you restoring vision to the blind obviously so what are you finding in there yeah and we have the privilege of being on the front lines of that funded by the national institute and other institutions to be out there figuring out what's going on in this human retina I'm with you on that so I'll tell you how we go
today's there about seven cell types that we understand pretty well what they're doing there it's not they're not complicated they just have different properties color size this kind of thing temporal properties their timing of their signals and those seven cell types we understand pretty well but we're trying to really nail down the details why because of neuroengineering for vision restoration then there's another I'm going to say 15 or so and we end the
anonymous the people who study the shapes and sizes of the cells have long known that there were more cell types lurking in the retinal circuitry but their function has not been known and because we didn't have many recordings from them we didn't have electrical recordings in response to light that would tell us what they naturally do we've actually had a breakthrough in the last few years led by senior research in my in my lab named Alexandra Kling who has figured out that
there are 15 or so cell types lurking in those recordings that if we look more carefully they're there and they have crazy properties and so the crazy properties I can tell you about have to do with the spatial region of the visual world that they respond to the well known cell types that you know and I know from the textbooks
kind of respond to a circular spot in the visual world if there's light in this little circular area they'll fire a spike if there's no light there they don't care well okay some cells is not quite circular some cells respond to the light that's there and and the difference from the light that's around it so if it's brighter than the light that's nearby then you think you get a big response
the new cell types are more puzzling than that some of them respond to three or four blobs in the visual world that's kind of strange unexpected definitely I expect that based on the textbooks and the newest ones are weirder yet some of them their their visual response profiles that is the region of the visual world that they are sensitive to light in almost has a spidery shape almost like the dendrites of a cell like the processes of a cell
and some of them have blobby light sensitivity their sensitive to light increments here and decrements there and increments here and decrements there and some blue light over here and blue light over here we don't understand these cells to be clear the seven that we understand reasonably well and I'm trying to just pin down and really nail for vision restoration the sort of first cut at at cell type specific vision restoration
those ones don't have these weird properties they're a little simpler to understand so we're which but we're just working out all the details of the timing of their of the responses and all that these new ones we don't know what's going on with them so we're doing experiments those seven cell types constitute maybe 70% of all the neurons that send visual information from the eye to the brain so we think it's a really solid target for vision restoration to work with the simple ones
and so and I when I say that I think that the retina is the best understood circuit and nervous system I'm talking about those seven cell types which we know a lot about what they do we really do know a lot it's not done but we know a lot
I'm not talking about the other 15 cell types which are a minority of the population but seem to be doing very strange and surprising things that are yet to be determined so there it's a mix we know some really good stuff and then there's really some deep mysteries out there about these other cell types
so we've been talking a lot about how to understand the signals that the retina sending the brain and I know your lab has done incredible work in this arena and figured out a number of the different signals as you describe some of the features that the different cell types are extracting just a moment ago these blobs of different colors etc
what good is this to you know every day person right what what in addition to wanting to understand how we see you know what sort of sorts of medical applications can this provide in terms of potentially restoring vision to the blind
but perhaps even larger theme is this notion of neuroengineering right taking this information and creating devices that can help us help our nervous system function better maybe even function at super physiological levels I know there's a lot of interest in this these days
in part due to neural link right because elons out there front facing very vocal about his vision of the no pun intended of you know chips being implanted in people's brains that would allow them to be in conversation with you know 100 people at the same time just by hearing those voices in the head maybe filtering things out so it doesn't sound like a clamor of 100 different voices perhaps giving people super memory I mean you know sky's the limit no one really knows where this is all headed
you're working in what we call a very constrained system where it has specific properties that you're trying to understand and once you understand those you can start to think about real applications of like what's possible like could you create a visual system that can extract more color features from the world that no other human can see can you restore pattern vision to somebody who is essentially blind independent on a cane or a dog or you know God for big can even leave their house because they can't see anything at all
you know where is this headed what is the information useful for and perhaps we should frame that first within the medical rehabilitative context of repairing or restoring vision rather and then get into the more kind of sci-fi type neuroengineering stuff
absolutely yeah this this really is my passion these days turning that corner continuing to figure out the mysteries in the retina but also saying wait a second we actually know quite a lot about this shouldn't this be the first place that we can solve problems like restoring vision restoring function or augmenting our function I think it should be the concept of how to do this is straight forward and not invented by us in any way and that is the following
one of the major sources of blindness in the western world is loss of the photoreceptor cells that capture light macular degeneration and red night is pigmentosa or to well known elements that you've rise to vision loss and the vision loss is because the cells that capture light in the first place that we talked about earlier die off so you're no longer sensitive to light and then
your blind the concept is that you may be able to bypass those early sections of the retina that capture the light and process the signals and instead build an electronic implant that connects up directly to the retinal ganglion cells and this electronic implant would do the following it would capture the light using a camera which is relatively easy
it would process the visual information in a manner similar to the way that the retina normally does similar as possible and then it would electrically activate the retinal ganglion cells by passing current and causing the ganglion cells to fire spikes and send those spikes to the brain and if we do this really well
we can essentially replace those first two layers of the retina and piggy back on to the third layer and say okay we'll just jump right into that third layer we're going to force those ganglion cells to send reasonable visual signals to the brain and then the brain is going to think that got a natural visual signal and proceed accordingly that's the concept
this is not our idea people have had this concept for decades and some people have even started to make it work in in human patients and what I mean by that is implanting electrodes on the retina stimulating and causing people who have been profoundly blind for decades to see visual sensation blobs and streaks of light in their visual world that that that are reproducible
so that's happening now that's happened people who were at once blind are able to see objects are able to see crude blobs and flashes of light in ways that allow them to navigate their world a little bit a little bit avoid a coffee table maybe or at least see a bright window in a dark wall and be able to point to that bright window or the bright doorway in a dark wall something like that so it's a glass half full half empty story that I want to turn that I'd like to turn attention to
in this conversation because I think it's very exciting yes you can see stuff by artificially electrically stimulating the ganglion cells and you can see stuff that actually helps you interact with your world a tiny little bit so great that's the glass half full the glass
the glass half empty is it's nothing remotely resembling what we understand as naturalistic vision where we see spines facial detail and color and objects and can navigate complex environments and all that's not chance you can't do anything remotely like that you can see that there's a bright doorway over that way
and turn toward it which is a helpful step in your human experience but there's a long way to go so the question is why does this existing technology fail to give us high quality vision what what's needed to give us high quality vision and this is the piece I'm really passionate about
it turns out that the devices that have been implanted in human so far by pioneering bioengineers who did really hard stuff were fairly simple devices that treated the retinas if it's a camera that is just a grid of pixels and they put a grid of electrodes down there and they stimulated according to the pixels in the visual world and thought well hopefully that will cause the retina to do the right thing and send a nice visual
piece of visual information to the brain initiate vision unfortunately they left the science on the table and this is actually what I'm dedicating the next phase of my career too bringing the science that we know that we talked about to the table for vision engineering and in particular the fact that there are there really are 20 or so distinct cell types and they send different types of visual information to the different targets in the brain
I like to think of them a little bit as an orchestra playing a symphony each different cell type has its particular score the violins do one thing the elbows do something else it's a very organized signal coming out of the retina presenting to the brain this complex pattern of electrical activity at the brain assembles into our visual experience
well current retinal implants unfortunately are too crude to do anything like that the conductor has just scattered the sheet music everywhere and people are playing whatever it's cacophony okay you can maybe recognize a tune in there a little bit sometimes navigate toward a doorway
but you're not going to get the full richness of the experience by ignoring the different cell types and I'm so passionate about this in part for reasons that a little bit are similar to your reasons for doing this kind of work that you do which I think is great which is I feel we have a mission to give back as scientists to take all this stuff we've been talking about because we find it so interesting and cool
and to deliver something to the society that has allowed us to explore these fascinating areas and in our case it's in the case of my lab and what we've done it's a turn around and say wait a second we understand that there's these different cell types we understand a lot about what they do none of this information appears in current
retinal implants can't we do better by using the science to restore vision in a way that respects the circuitry of the retina that's what we're trying to do and the mismatch is intense I told you when we were chatting before that nothing that we have learned about the retina since the founding of the national high institute in 1968 is incorporated into the existing retinal implants nothing
we've learned a ton about the retina your research was funded by the national institute my research is funded by national institute a fantastic organization that allows us to learn all these things
how is this showing up in the neuroengineering to restore vision to people currently it's not and so we're trying to do that now doing that turns out to be hard and maybe we'll talk about that it's a it's a technological feat that's really challenging you have to build a device that you can implant in a human that can recognize the distinct cell types see where they are stimulate them separately from one another and conduct this orchestra
to create a musical score that reasonably closely resembles the natural one that's what we're all about doing and as it turns out and maybe we'll talk about that separately that mission of being able to restore the patterns of activity that the retina normally creates also has extremely exciting spin-offs in three directions one of them is understanding better how the brain puts the signals together that's research for the brain
the second one is augmenting vision creating novel types of visual sensations that weren't possible before and maybe doing something along the Elon Musk lines of delivering more visual information that was ever possible and third figuring out how to interface to the brain more broadly because as you and I know the structure of the retina is very much representative of the structure of many brain areas
and if we're going to figure out how to interface to the visual cortex we don't well but are fit figure out how to interface to the retina first that's what we're all about doing in my lap these days is figuring out how to do that well that's a mixed science and engineering effort we've done about 15 years of basic science on that how do we stimulate cells how do we recognize cells how are we going to build a device that does all this and talks to the cells in this way and I can go into lots of
gory detail about it but that's what we've been doing the basic research on in the last few years we've worked at Stanford with fantastic engineers from various disciplines electrical engineers material scientists others to figure out how to put together the pieces and build an implant that can do this in a living human.
So is the idea to build a robotic retina to build a essentially an artificial retina that could be put into the eye of a blind person or even put into the eye of a sighted person that would fundamentally change their ability to see or in the latter case enhance their ability to extract things from the visual world that. They would otherwise not be able to see like like seeing twice as far getting you know hawk like resolution of the visual world.
Yep which that would be cool yep could be distracting yeah I'm not sure I want to see the the fine movements of a piece of paper and somebody's notebook from across a cafe as they flutter the pages.
But you might want to for a moment there might be a moment when you want to and if you have an electronic device that you can control that you can dial in to sense different aspects of the visual world under you know by by your choice you might be like yeah it's pretty cool I want to be able to do that right now there's an example I like to give which I think maybe is helpful for interpreting what we're talking about when we say.
Being able to do more things with the optic nerve you gave the example of many voices and stuff here's an example that I like we know that we can drive down the road and have a phone call. Hands free and do that quite safely pretty safely right and you're big why because you're tapping in there you've got two types of signals coming into your brain your visual signal of the cars on the freeway anyone which could kill you in an instant.
So it's important and the sound coming into your ears which carries the voice of your girlfriend that's telling who's telling you something that you're interested in hearing and these are different parts of the brain processing this information and so you can do both of these things at the same time because there's no interference one part of the brains work in doing one thing in other parts doing something else you're good.
What you can't do is to read your texts and drive down the freeway at the same time that's not good because now that visual system of yours that needs to be detecting these fast moving dangerous objects is being distracted by looking at the text and you might die and some other people might die with you. So a lot of people texting and driving yeah that's why I like to point out this example to remind people you can't do it well it's like it's like you can't do well you probably talk about it.
Yeah it used to be you know I will just take a brief tangent here into this topic a few years back there were a lot of news articles a lot of discussion about texting and driving a lot of attention to getting people to stop texting and driving. I've seen a few people pulled over for texting and driving before but I would say texting and driving is rampant reading what's on one's phone while driving is rampant.
All you have to do is be on the freeway here in Los Angeles look in the car next to you look what I'm looking and be really reading and texting while driving presumably when they're doing that they're just using their peripheral vision to detect any kind of motion and no doubt this is caused the deaths of many people.
Yeah change lanes get away from them that's you know just just like that other driver so so here's the thing and this is this is I say there's a bit tongue in cheek but it's sort of a real example. It may be that if we harness the different cell types in the ratna to deliver different visual information to different cell types.
Like the image of the text on your screen to a certain cell type that you know the so-called midget cells or the motion of the objects in the visual scene the cars to a different cell type that you know. And so that's just because they're very small. Yes and by named by an atomist decades ago so we carry that nomenclature forward.
And the parasol cells which are different cells that you can potentially encode the movement of the cars in the parasol cells and if those two systems are operating independently which we sort of think they may be from research that you know very well from your extensive studies in vision.
We can do those two things safely at the same time not by the way that's not my research goal to text and drive at the same time just to be clear but it's a very tangible real world example of if we do really have parallel pathways that can be modulated and controlled independently of one another.
This opens the door to streaming all kinds of visual information in parallel into our very high bandwidth visual systems that wasn't possible during evolution because we didn't have control over the cell types. So I think of that as the world of visual augmentation and it starts to get interesting if the different cell types are behaving in an independent way in when they transmit visual information to the brain.
Now how are you going to figure that out? Well we need a device that can stimulate the different cells independently and then study that to see whether people can and can do this kind of thing right.
What's that device the artificial right now the same in plan I'm telling you about that can restore vision to people because electronic device that can dial up and the activity in different cell types that same device is what we can use as a research instrument to understand if the different pathways are parallel.
If the signals interact with one another and explore how the brain receives that information and then we can use that to explore can we augment vision and allow allow ourselves to have new visual sensations that we don't even know what that would look like. We don't even understand what it would look like to us to see those sensations but it might be able to deliver lots of information to our brain and if we can do all those things.
Then we can take that same set of tools and engineering technologies into the brain to access different cell types as well. I'd like to just take a quick break and acknowledge one of our sponsors inside tracker inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you.
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If you'd like to try inside tracker you can go to inside tracker dot com slash huberman and you get 20% off any of inside trackers plans again that's inside tracker dot com slash huberman. So to just summarize a little bit of the linear flow here of what you've done.
You started off with the understanding that the neural retina is perhaps the best place to try and understand how the brain works because of its arrangement the cell types etc. You spend a number of decades doing these wild experiments on human retinas and other retinas recording the different cell types with these high density what I call bed of nails to an hour decades not bad. Two and a half decades. It's your robustness that matters you and you have plenty of it.
You figure out what the cell types are so then you gained an understanding of how light is transformed into different types of electrical signals that encode different features in the visual scene. Then comes the challenge of developing neuroengineering tools to try and stimulate the specific cell types in a way that more or less mimics their normal patterns of activation like not.
Activating a huge piece of retina so that you know the cells that like increases in redness are also being stimulated with the cells that like you know edges in a way that creates some shmooey like crazy representation of the outside world. No, you want the same precision that light stimulation of these cells in the intact human eye provides in this.
This is a planted retina this retina on this bed of nails but then a device that essentially can mimic what the retina does and you needed to do all that earlier work. Understanding like what is the normal retina do what is the healthy retina do in order to try and develop this prosthetic device to either restore vision or. Because it puts you in the position of being able to stimulate cells however you want in theory you could create a situation in a human where the cells that respond to.
You know outlines of objects are hyper active so that you know the person could effectively see objects in one's environment better than anyone else could perceive I know motion is a tricky one but motion better than anyone else could see detail in the visual world that no one else could detect we're not talking about turning people into mantis shrimp.
But the analogy works because mantis shrimp can see things that we can't and vice versa and so we're talking about here is neural augmentation through the use of engineering.
And we often do talk about it as sci fi because the sci fi writers have been talking to have been you know writing about this for decades it's not sci fi anymore it's sci it's straight up sci right now it's really we just need to build the instrumentation and start working with those experiments to figure out how to make it work.
I think we have a responsibility to do this because this is the way we take this kind of information all that's been learned about the visual system by the national institute since 1968 and all the people that it's funded to do this research and turn the corner and make a difference for humanity with it. And I assume and think that humanity will be leverage nervous system knowledge to build all sorts of devices that we can interface to the world with.
I think you know I don't know Elon Musk but I think he's right about that that that's where we're headed. It should be done well it's important to do it well. We will hopefully be more connected to truth in the world if we're able to build devices that give us better sensations more acute understanding of what's going on out there better abilities to make decisions and all that let alone just see stuff.
So that frontier of developing technologies to allow our brains and our visual systems initially and then other parts of our brains to do things better is unbelievably exciting it is sci fi but I just want to emphasize I think it's the responsible way to go to think about how to do that well.
All technologies that we develop can be used for good or for real and I'm sure some of your listeners who are a lot of very passionate thinking people out there thinking about neuroscience and the implications worry what does mean we're going to be introducing electronic circuits and our brains to do stuff yeah well we will. We pretty much clear the humanity will do that.
And so in any technology development you have to think about well how do you do it well how do you do it for good or there are popular movies right now about technology development such as understanding the structure of the atom. And that technology development can be used for good or for ill to blow up cities or to save civilizations. How's it going to go well I think I think as scientists were responsible for advancing that in a thoughtful and meaningful way.
I think we can do this in the retina it is the place to start it's the and you know you I'm curious what you think actually as a scientist your background is in this field or very close field to mine. I know you speak with all sorts of scientists on this podcast but this is pretty much your field or very close not the neural engineering part but understanding the retina I'm curious if you agree that this is the place to start doing this stuff.
The first guest ever asked me a question on this podcast during a guest interview I think this would be a fun place to both answer and riff on this a little bit because first of all I think the retina is absolutely the place to start because we understand so much of.
What it does what the cell types are but maybe by comparison a different brain region the hippocampus which is involved in the formation of memories and other stuff but formation of memories about what one did the previous day what one did many years ago et cetera is an area that I think any time the conversation about neural prosthetics or neuroengineering or neural augmentation comes up people think when to be cool that like a little stimulating device in the campus.
And then if I want to remember a bunch of information from a page or from a lecture I just stimulate and then voila all the information is batched in there. While that's an attractive idea I think it's worth pointing out right now that sure there is a pretty decent understanding of the different cell types in terms of their shapes some of their electrical properties of the hippocampus but there is in no way shape or form.
The depth of understanding about the hippocampus and what the individual cell types do and what the different layers of it do that one has for the neural retina so what we're really saying is if you stimulate the hippocampus you'll likely get an effect but it's unclear what the effect is and it's not clear how to stimulate that's to me the best reason to focus on the retina because you know what the cell types are thanks to the work of your laboratory many other laboratories you know what sorts of stimulation matter.
And it provides the perfect test bed for this whole business of neural augmentation or neuroengineering I think there's also a bigger discussion to just frame this in which is so much of what we discuss on this podcast with guests and in solo episodes relates to things like dopamine neuromodulator serotonin everyone is interested in these things because they can profoundly change the way that we perceive and interact with the world.
But one only has to look to the various pharmaceuticals that increase or decrease these neuromodulators and know that indeed those pharmaceuticals can be immensely beneficial to certain individuals I want to be clear about that but that whatever quote unquote side effects one sees or lack of effect over time is because those receptors are like everywhere over the around the brain so you can't just increase dopamine in the brain and expect to only get one specific desire to fact so the reason you're here today.
It's not because we both worked on the retina it's not because we happen to also be friends it's because to my mind your laboratory represents the apex of precision in terms of trying to figure out what a given piece of the brain in your case the neural retina does parse all its different components and then use that knowledge to create a real world technology that can actually tickle and probe and stimulate that piece of the brain.
And that's the way that's being made that piece of the brain in a way that's meaningful right not just like sending electrical activity and and that to me is so important I think we were going to think about levels of specificity from manipulating the human brain to get it and effect you would say OK.
And the drug is a drug that we know that can lead to increased connectivity between different brain regions at rest there's probably there is some demonstrate clinical benefit there's also some potential hazards but it's very broad scale we don't know what's happening when the person is thinking about a you know a piece of moss expanding into an image in a memory of their childhood
it's like a million different things are happening there and then at the other far extreme is the kind of experiment that you're talking about stimulating one known type of retinal cell seeing what that means for visual processing or modeling what that means for visual processing and then building a device that can do exactly that and then maybe you ramp it up 20% 50% because I think that represents the first step into OK how would you stimulate the campus to create a super memory
and you stimulate a particular cell type in a particular way and to my knowledge there's you know despite the immense excitement about the hippocampus and understandably so there just isn't that precision and of understanding yet so forgive the long answer but you know you ask me a question on this podcast
yeah and specificity is what you're talking about and we need technology to do that to to modulate neural circuits in a highly specific way we've got to start with the piece of the neural circuit we understand best we have best access to that's the right night sitting right there on the surface we can get right into it and in installed devices we know so much about it that's the place to start the place that we understand build electronics that is that is adaptive
but senses what circuit it's embedded in and responds appropriately it's not just electronics you stick in there and it does something and that's it no it it first figures out who it's talking to and then learns to speak the language of the binary circuitry so smart device let's push on that a little bit so put a little chip under the retina that can stimulate specific cell types is there a way that it can use AI machine learning that it can learn something about the tissue it happens to be in
the simplest possible way the device works in three simple steps step number one record electrical activity which is what we do in our lab in a room full of equipment but this is a two millimeter size chip and planted in your I record the electrical activity just recognize what cells are there when they're firing what electrical properties they have to identify the cells and cell types in this specific circuit in this human that step one step two stimulate
and record so you figure out oh this electrode activates cell number 14 with 50% probability this electrode activates cell number 12 with you pass micro app of current with this probability and so on you make a big table it tells you how these electrodes talk to these cells in your circuit that's up to calibrate the stimulation by stimulation and recording then finally when you have a visual image and you want to represent it in the pattern of activity of these cells
you say okay I know from decades of basic science what these cells ought to be doing with this image that's coming in I know exactly what they ought to be doing that's what the science has been telling us we've been studying the neural code for decades to understand this I know what they should do
use my device with my calibration where I know where the cells are I know how the electrodes talk to them and Bing Bing Bing Bing activate them in the correct sequence that's what I think of as a smart device a device that records stimulates and records and then finally stimulates
yes AI is part of that of course it is because this is a very complex transformation if you will from the external visual world to the patterns of activity of these cells not easy to write down just a few lines of code or a few equations it's complicated and AI is really helpful for that and learning by stimulating and recording and aggregating information quickly so that you can then use the device that's
absolutely a part of the engineering it let me be clear the AI doesn't help us to understand is just an engineering tool that helps us to capture what this thing normally does and then go ahead and execute and make it do thing it should normally do I hope people will appreciate this example perhaps not you know not but goodness I don't know 40, 50 years ago but still today one treatment for depression is electric shock therapy
very you know on the face of a barbaric treatment but effective in certain conditions it's still used for a reason but it can appear barbaric right you know people are like a bite you know bite device you know so they don't bite through their tongue or their lips they're you know they're strapped down and they stimulate the
whole branch of just like stimulate all neurons in the brain essentially there's a huge dump of neurotransmitters in their homogeneity drugs it's completely non-specific stimulation effectively probably even less specific than drugs and yet the clinical outcomes from electric shock therapy in some cases are pretty impressive like people the brain is quote unquote reset they still remember who they are
but presumably through the the release of the modulators like dopamine serotonin acetylcholine in a very non-specific way there has been some symptom relief in some cases what you're talking about is really the opposite extreme you know before I said pharmaceuticals that tickle a particular nodulator pathway would be the opposite extreme I think electric shock therapy is probably the most extreme where is this whole
business of neural press these these going outside of the visual system like right now I can imagine that there are little stimulators in the spinal cord for sake of restoring movement to paralyzed people I realize this is not your field but is it are you seeing impressive stuff there or is it still really really early days there's
there's absolutely impressive stuff particularly for example people reading out signals from the motor cortex or language cortex in order to help people to communicate or to move cursors on screens in order to interact with devices these are paralyzed people yes excuse me paralyzed people who can't interact with technology the way that we do
and but with their thoughts can send signals through an electronic device that can be used to control a mouse on a screen and have them connect to the Internet that's a huge deal to be able to have people do that imagine how life changing would be to be able to communicate if you couldn't before so there are wonderful examples of that you know of them so do I work of christian oi and jamehenderson at Stanford is one beautiful example of
the engineers eddy jang doing stuff now you know nor like doing doing this kind of stuff the built on the work of chinoin and henderson and stuff so that's great you know stimulating in spinal circuits as you said for creating rhythmic movements that's that's happening so this is an enormous space and in each case what you said I think is really highly relevant that
electrophotic shock therapy you can think of that is look let's say your computer is not behaving right you can reboot it might work then it'll start not working again then you have to reboot it again well how often do you want to reboot your computer it gets a little inconvenient to be rebooting computer every five minutes maybe you want to go in and actually diagnose this thing and put in a piece of software that fixes the thing that was going wrong
instead of rebooting our computer every five minutes right and I think of electric shock therapy a little bit as a reboot it's at that level so we want to intervene more specifically how do you do that what you have to understand this off where in order to do that you have to have specificity controlling this thing in your computer not this this this this this this this this particular thing that's going wrong you got to interfere with that
and change it and modulate it well that's what understanding the real circuit is about that's what building specific hardware that activates specific cells is about that's in in the case of the retina again it's just so obvious that it's right in front of us to do this stuff and it's right in front of us to take us into
augmentation to giving us better senses a fun example I like this is it's an interesting topic because the national institutes of health that funds a lot of research that goes in this direction tends to not be interested in augmenting our senses they kind of wanted there they draw a line more or less it's saying look which I'm a restore what we were as humans not create a new kind of human
and that's an interesting question because I don't think there is a fine there's an actual line a bright line between those things I don't think there's a bright line between those two things the the finest example I know is that even in the very crudest visual restoration devices you have to actively suppress the infrared sensitivity of your camera to not have infrared vision
why because many cameras are sensitive to infrared light in other words if you don't put an infrared filter in front of your camera you're going to have some infrared vision maybe won't help you very much whatever and just trying to say as soon as you start building devices to restore sensations building electronic devices augmentation is right around the corner it'll creep up on your real fast so I think you can't even really draw a line
throughout today's discussion we've been thinking of the brain is kind of a the rest of the brain I should say because the neural retinas two pieces of the brain extruded out into the eye gloves during development I like to remind people that over and over when you're looking at somebody's eyes you are looking at two pieces of their brain
snow debate about that but most people don't realize that you'll never look at anyone the same way again but this is the reason why you can tell so much about people's interstate from their from their eyes
somebody who sleep deprived it's not just about the droopingness of their eyelids or the circles under their eyes there's a there's an aliveness to the eyes that the yogis talk about people that sort of show up at the level of their eyes as opposed to sunk back into their brain you know these are very kind of abstract concepts but they
are very non abstract stuff these days looking at looking through the eye at the retina the way up the ophthalmologist to there's a lot of diagnostic capability just in those images of the retina
oh right this is glad you brought this up there's some interesting and increasing evidence that looking at the neural retina because it is a piece of the brain with neurons that have the potential to both thrive or degenerate that looking at the neural retina which one can do with these new technologies can provide a window into
the brain they're not there are forms of degeneration just such as Alzheimer's and other forms of neuro degeneration a deeper within the brain that one can't image directly because of the thick opacity of the skull right so in other words imaging the eye in order to determine if someone is developing Alzheimer's because you have a direct view into a little piece of the brain it's a it's a good signal can help you figure stuff out about what's going on in your brain even beyond the sun can eyes
really amazing so I think the rest of the brain pieces is also really interesting and maybe here we can go like semi neuro full philosophical you know that there are clearly parts of the brain that are involved in essential what I call housekeeping functions regulating respiration you know keeping us breathing keeping our heart beating digestion
threats in some sort of basic way like through the secretion of adrenaline and giving us the potential to move but a lot of the brain is is capable of plasticity and one wonders if you were to for instance develop a retinal prosthesis that would allow me to see with twice the level of detail that I currently can
would my adult brain be capable of dealing with that information we're talking about twice as much information coming in same brain tissue on the receiving end can it make sense of it do we have any idea if it can make sense of it are there are experiments that speak to that that's a fantastic and interesting question makes you think about neural development all over again right and I take some inspiration on that from the work of someone you know Eric Newtson
who discovered that there is plasticity beyond the periods of time he discovered many wonderful things but there's plasticity well beyond the period of time that we thought that there was plasticity in certain animals and in particular that if you make gradual adjustments to the sensory world
you can exhibit plasticity that you can't see if you make an abrupt adjustment so plasticity is there it just has to be brought on by more subtle manipulations that take you from A to B and little incremental steps and if you take those incremental steps you can see the adult plasticity
so coming to your question is the brain capable of receiving the kind of extra information we provided could be that if we just show up on day one bam try to deliver twice the visual resolution or whatever your visual your visual system it could be that if we try to deliver twice the visual resolution on day one it won't work you'll see it'll you know they won't look sensible to you
but if we gradually introduce it by the way that we're dialing up the resolution we may be able to get there and there are fascinating studies to be done you think about spike timing dependent plasticity a term that your viewers may not all know but is related to how neurons adjust their strength of connectivity to one another according to the timing of the signals in those cells
mechanisms like that tell us wow the brain really cares about the very precise timing of stuff and to the degree that that influences the way that neurons do or don't strengthen their connections to one another so fundamental and everything from memory to visual function would have you this relates to fire together wire together although it highlights the together part how closely in time do two neurons need to be active in order for them to subsequently increase their connectivity
and indeed one of them needs to be active a little bit before the other one in order for it to work optimally right so if what I what I envision is that when we have full control of the neural code with an electronic implant that can talk to the cells and do all the things that I said and we can really control the
neural code coming out of the ratna we can then start to play games and dial up that neural code very slowly and teach the remaining brain how to understand these signals not introduce some crazy thing from day one no just gradually teach is not how we do everything well is not how plasticity works
I love the subtlety and the rationality of your example because you know so much of what we see in the internet and on the news is like you know chips inserted into the brain to create super memory or you know conversations between
you know 50 people at the same time without anyone speaking you know just hearing other people's thoughts by way of you know neural signals being passed from one to the next but yet another reason why you're here today is because you represent the the realistic grounded incremental approach to really parsing this whole thing of how the brain works and how one then goes about engineering devices to augment the human brain and as you just point out it's not can be done by just stick
in the electrodes in and stimulating and seeing what happens in fact those experiments were done in the 1960s people like Robert Heath would put electrodes into the brain during the surgery stimulate and just see what the patient would do or what they reported thinking nowadays that's done still but with a lot more precision and intention and we move we move far beyond that by the way I just want to say those were important first experiments
yeah the first thing you got to do was it was it was a rather let's be honest not not the most savory character he embarked on some experiments that had a social agenda to them and was a pretty at least by my read was was not the kind of person I'd want to spend time with to say the least but but you're right those experiments were critical
because like electric shock therapy like the formulation of drugs that can massively increase certain or modulators or decrease them they led to some level crude but some level of understanding about how the brain works which is what we're really talking about today but you represent the as I said the astronauts of this astronauts don't go into space and just kind of blast off and see where they end up there's there's there's math
physics there's computer science sensors cameras that's right looking where are we about to land here on the moon is there a crater here or not what what's around us we we should sense what's there and then make our decisions accordingly and our electronic implants in the brain really we should make them smart why make them dumb we're smarter than that we can build implants that can sense what's around them and change their patterns of activity accordingly
I use a metaphor sometimes you go to if you go as an American who doesn't speak in Chinese to China and you start yelling in English maybe somebody will to learn which way to go on the street somebody might understand you at some point and help you out but it's going to be a it's going to be a you know not very effective way to get around way better if you speak the language you talk to people and ask ask them where to go
so that's what we need to know we need to say look we have the science we have incredible devices we can engineer we have a I now that even helps us to do this query of the outside world and turn it into a smarter instrument make our instruments smart make them so they know how to talk to the brain don't expect that the brain is just going to wrap itself around your your simple electronic device no make a smart device that's what we want to make smart rental implant
maybe we could just take a couple of minutes and talk a little bit about you and some of the things that have led to your choice to go in this direction so did you always know you want to be a neuroscientist from the time you started college what was your trajectory I should know this but I you were an undergraduate at Princeton at Princeton that right studying math math
so you could have just done all your work with a piece of paper in a pen but you had to try and engineer all these electrodes that's a pen and paper pen I took a very random route I studied math as an undergrad I spent a few years running around playing music and traveling and living a bohemian life tell me we're about that oh it was I basically just told you all I'm going to tell following the grateful dead no not quite following them but it was that was an important part of the story was that
an important part of your personal development yes yeah very much so free expression dance music creative exploratory music all that kind of stuff such a contrast to the the EJ that comes forward when we're talking about the precision of neural stimulation in the in specific retinal cell types but I think it's useful to hear both young and old like that one's nervous system can be partitioned into these different abilities you like go and dance and travel and you
weren't doing anything academic at that no for a few years when doing that programming computers to make a to make a living and then I started I started three different PhD programs at Stanford before I simultaneously no no no
in sequence I started in the math PhD program I learned that was not really for me and I started in the in economics PhD program in the business school there and I realized after a little after less than a year that was not for me I work in a startup company for a while there a lot of stuff for a few years and took some settling but then I decided to go into neuroscience and there were a couple formative things one is that I had gotten a really
formative experience as an undergraduate from a wonderful guy called dawn ready who taught of introductory neuroscience course who is really inspiring mentor and then when I when I was at Stanford I met Brian Wandel my PhD advisor and I was inspired by him I thought I didn't know why he was studying what he was studying but I just knew I wanted to learn from this man and I wanted to study with him I just knew this was this was the person who should be my master based on something about him yes
can I ask you about these three PhD programs because I think people here you know or or see what you're doing and and probably imagine a very linear trajectory but now I'm hearing you like tour around playing music then you start a PhD program nope then another one nope then another one without getting into all the details I mean where they're
not spent lying away thinking like what am I going to do with my life or did you have the sense that you knew you wanted to do something important you just hadn't found the right fit for you like how much anxiety on a scale of one to 10 10 being total panic did you experience at the apex of your anxiety in that kind of wondering am I allowed to go above 10 like turning up the app to 11 sure I just think it's really important for people to hear whether
they want to be scientists or not this idea that people that are doing important things in the world in my view rarely if ever understood that that's the thing that they were going to be doing there was some wandering about that sure seems like it doesn't it yeah I I experienced the same when I talked to other people and it seems like that for sure for me it just took a while of trying different things to see number one what I was
really good at and where I felt I could make a difference and it and I realized I studied math and I was okay at math but I know I have known mathematicians who are really talented gifted math mathematicians the one who really make a difference I wasn't going to be one of those people likewise playing music I don't have that intrinsic talent it's fun I can play songs in front of people
and do stuff I like it stuff like that but I don't have that kind of talent in fact I'll say something that that I say to friends sometimes and you're a good friend of mine if I had the talent to get a few thousand people on their feet dancing by playing music I'd probably just do that really as long as we've been friends I knew none of this like none of this most because I think we always end up talking about neuroscience or other
aspects of our life but I didn't know I know I know a great many things about you and I had no idea it's so interesting do you still do dance we had air Jarvis on the podcast by the way professor Rockefeller who studies at one point was studying speech in so in birds as a song in birds and then he's done a great many other things now in genetics of a vocalization and you know he actually
danced with or was about to dance with the album a Lee dance company so he really really talented dancer and so you know dance seems to be like a theme that comes up on the neuroscience guests on the podcast you still dance yeah I love to dance I'm a free
form dancer I don't I'm not a skilled dancer I love I love music I love dancing I think it's part of the human spirit I someday will understand the neuroscience by dancing right dancing is a universal human thing in all cultures what is this dancing thing why do we do this and other
cultures don't well Jarvis thinks that perhaps it's one of the more early forms of language and that song came before spoken language it's sort of interesting that birds that can actually recreate human speech oftentimes have the ability to dance as well oh wow and so there's some that can treat their they will provide a link to that episode Jarvis I would love to hear that I mean I do but if I may I just I'd like to rip on a different in a different way I did spend some time
wandering around as many people do and I think particularly for your young listeners and viewers who don't know wow you know could I ever be a scientist and develop new things like that yes you can and if you're messing around your life trying this trying that trying the other thing definitely stick with it keep looking for the thing that works for you I really
deeply believe that you got to play around you got to find what it is that works for you interestingly enough at least it's interesting for me I I spend a lot of years studying the retina in a pure basic science just curiosity driven research way as you and I have both done in the past and as it turned out I learned all the stuff I
needed to know about the retina to do to develop a high fidelity adaptive retinal implant of the type that I'm talking about in that process the technology the stimulation recording finger cell types how do you estimate all stuff I learned all that stuff and I have come to a point in my
life where I realize wow if somebody's going to do what I think needs to be done which is to take everything we've learned about the retina and instantiate that in smart technology that can restore vision and do all the things we've been talking about who are the people in the world who have the right training and background and not know how to do that stuff I'm one of them I know that and it's totally by chance that I
picked up and learned it seems by chance that I picked up and learned the things that I need to know for this so but but I'm I definitely have the right know how to do this based on all my training and the research that I've done and it feels accidental sometimes I look back on my own history I'm like how did I get here where this is obviously the thing I need to do was this on purpose you didn't seem like it was on purpose but now I got to do this because I know what needs to be
done and it's something that needs to be done so that's that's my mission for the you know coming decade or so I mean I knew you had this engineer Matthew geeky neuroscience I don't want to say geeky because I'm well because it may sound like I'm not right there in the same same raft with you but but I didn't know about this more free spirited move in all directions depending on what one feels in the moment dancing EJ it's very cool are you still a absolute level 11 coffee
snack yes okay yeah I used to go to meetings and EJ would bring his own coffee maker and coffee to meetings we're not talking about an espresso machine we're talking about like extreme levels of coffee snobbery press pot the correct ground coffee the correct kind of press
but good good I expect nothing less proof that I'm not all circuits in the brain are neuroplastic nor should they be that's not but to bridge off of that in a more serious way despite the the free you know free exploration aspect to yourself and that hopefully other people don't suppress and it seems like you you really are good at develop like knowing your taste like it seems like the the I think
great Marcus Maister a colleague of ours who you know is also worked on the neural retina extensively of course one said you know that there's a coding system in the brain that leads to either the perception the the feeling of um yum yuck or and that so much of life is being able to register that in terms of who you interact with and how and the choices are problems to work on it seems like you have a very keen sense of like yes that and you move toward that you've always been very goal directed
since the time I've known you so and and you've picked such a huge problem but going about it in such a precise way hence the the analogy to the space space mission so like when you experience that man ask is it does it come about as like a thought like yeah that has to be the thing or is it like a whole body sensation what a great question I love that question I have two things to say that the first is that for me it's all it's all feeling
I don't make hardly any decisions out of thoughts I think I process put it all into the hopper and the hopper comes out and spits out of feeling and feelings like yeah that's the thing to do 100% and I know not everybody's like me lots of people aren't like me and particularly lots of scientists aren't like me the you know so but I definitely roll that way that is
absolutely how I work there's there's something that's related to that that I think is you know philosophically in terms of personal development and spiritual development stuff I think is quite relevant that I think you'll you'll relate to my favorite aphorism is know that self the oracle and I think because if you don't know yourself you can't do anything you you don't even know where to go you can't even orient yourself at the next thing in your life
and I think it deserves to have two carolaries that go with it or addenda know that self be that self which is not easy it's not easy to really be yourself in this world there are all sorts of things telling us to be something other than what we are and the third one is love
myself and it's you know having gone through much exploration of yourself and your life and your values and my in me too and all the things we've talked about over time that's not easy some of us are not necessarily programmed to love ourselves and it's a skill
I and I really I try my best to be with those three things all the time know that self be that self love myself Could you elaborate a little bit more on your process for the third at this is a concept that has been very challenging for for me and I think for many other people and it gets kind of opaque when it starts getting complete with like self respect and etc like loving myself do do you have practices do you meditate do you journal do you spend time trying to cultivate a love for self
Yeah, yeah, I meditate in an informal way in the morning with my coffee every morning I make a fantastic cup of coffee and I sit with it I believe you for five or 10 minutes and take in my world as it's coming toward me and start to be as I as I come into the day and come into consciousness I I
meditate like that and I have a stanga related yoga practice many of many of your viewers listeners will know about ashtanga yoga it's a very physical spiritual traditional yoga practice that has a deep meditative and breath focused component I know you've had lots of episodes in discussion about the breath and the importance of that for awareness you know at the end of a of many western yoga practices you end with namaste which is expressing your respect and for
the connectedness of what is in front of you to the whole universe and what's common to all of us and everything and I usually practice yoga by myself when I say namaste at the end of my yoga practice a part of that is to myself earlier when I asked you about how you guide your decisions you said it's all feel and you provide a beautiful description as to how and why that occurs for you and you're trusting that I don't recall you saying whether or
not the feeling is in your head or it's a whole body feeling does it have a particular signature to it that you be willing to share is it excitement that makes you want to get up and move or is it a stillness I think I ask because we've been talking throughout today's episode about you know the precision of neural coding and the signals that are at the level of individual cells and yet when it comes to feeling we actually have a pretty crude map and certainly a deficit in language to explain
what this feeling thing is and I know that people experience life and feelings differently but I think it's often insightful when somebody with your understanding of the nervous system in yourself I can share a bit like what does it feel like? I love that question and it relates to something you said to me years ago what it feels like is ease and I remember years ago when we were talking about challenging things that each of us was facing in our lives
you said to me something like I wish for you some ease with all of this it was very moving touching as that's what a good friend does is to give that to somebody to they love and it sticks with me probably ten years later so the feeling I feel when I'm on the path that makes sense for me is ease it's just nothing it's just okay this is it I love that I don't actually recall that specific conversation because we had many many conversations sitting in your yard in
San Diego on those plastic chairs with you with my bulldog Costello hanging out by the way folks EJ new Costello my bulldog massive very well and he was not a huge fan of dogs prior to meeting Costello but Costello flipped him he became a at least a Costello lover I love Costello I'll never forget him he embodied ease he did nothing but sleep and eat he embodied energetic efficiency
and everybody loves him everybody who gets to be in the same room with him loves him yeah the people I spoke to in your setup here your colleagues you know yeah yeah I could see why and you a beautiful photo of him hanging there yeah yeah he's what a great great great memory definitely embedded in my nurses I often choke up when I think about it but I want to be clear because I've already cried once about him on a different podcast I don't want to say they're not tears of sadness
it's this crazy thing like I love him so much I just kind of want to explode yeah so damn it Costello got me again and publicly again so I love that and I think if if I made you know do you think it's worth kids and adults learning to recognize those those kind of states those signals that tell them they're on the right path by paying attention to I don't know this like like we said there's sort of a deficit of language like eases in the body eases in the mind it's the release of I mean you know
it's not even worth exploring verbally because it's a it's such a whole body whole nervous system thing yeah I I feel like I actually was thinking about I was giving advice to a young fellow who is applying to graduate school recently and had a Zoom call with him
about stuff and he had received some good advice from some other people and then I gave him some advice and I saw him and speak and emote and with body language drop into like oh yeah that makes sense yeah that that feeling of course kind of the of course and I think if you can teach people to do that I don't know if the verbal communication of that is going to like you said is that going to do anything but can you at least observe it in them as a teacher as a mentor and do things
and when you know when you've done it because you see them drop into ease do you think you can detect ease in people by looking at them and seeing their body language and everything it's it's got to be an amalgam of different things that the cadence of their breathing their people size it's not worth dissecting this is an experiment I would not want to run yes but I wouldn't want to bring people into a laboratory and figure out you know what people of the eye dynamics
combine with certain rhythms of breathing relaxation of the shoulders because it's too beautiful for that it's beautiful and it's it's too nuanced and it's different when we're in motion versus when we're lying down it's like I mean science is capable of a great many things but I don't think needs to be pointed at every aspect of human experience I think that some of these things are simply worth allowing to just be
do you feel the same way about when you have a feeling about a person you meet somebody and their energy just captures you it's like wow what a cool person what what amazing energy do you want to know the science behind that I don't no I don't I think that the word that comes to mind when I experience somebody like that or something like a beautiful animal or I see something the movement of something or a beautiful piece of music or something is the word just behold
I just want to stop and and take in as much of it as possible and here's something I know you've done but I'm checking to make sure I really got this right because I've done it too because we sometimes get human retinas for doing our experiments the first thing that happens when we get the human retina we bring it back to our lab it's a big production everybody's getting ready to go a whole bunch of moving parts going on
and we have to open up the eye and look into it to see what condition that's in and it's typically on with a dissecting scope on a chair it's open sitting on a chair dissecting scope looking down look into the eye it is so beautiful it's breathtaking each time I've looked at the right now I don't know how many times each time wow this is what's initiating all the visual experiences I've ever had in my life or that person I've ever had in their life right and the beauty just keeps coming
I love it and I love it because you're talking about a behold moment that isn't just to entertain your curiosity sure it's that you want to understand how the brain works but also a behold moment that leads from that desire to understand to a deep level of understanding now
after you know more than two decades of exploration to a mission in service to humanity restore vision to the blind develop neuro prostheses and other types of neuroengineering technologies that will allow the human brain to function better than it would otherwise
so there's real purpose there too it represents kind of a perfect ecosystem of it's not just about delighting and something and spending one's time there there's a real there's a real mission there I love it well EJ Doctor Chicholnowski Doctor Huberman I rarely get called that these days
when I invited you here today I was absolutely sure that our listeners and viewers were going to get a absolutely world-class explanation of how the nervous system works and the retina and the visual system in particular and that it would be delivered with the utmost clarity which it was so thank you I know there's been so much learning in and around that and you beautifully framed for us what that means in terms of the larger understanding of how the nervous system works
and what you and other laboratories are now in a position to really do with that information and the technologies that are being built and that will be built and the purpose in bringing here today was just that but not that alone you know I think we hear so much about the brain and how it works and everyone wants to have tools and protocols to function better but it's clear that the work that you're doing is headed in an direction that's going to vastly expand the possibilities
for sake of treating human disease and for expanding human experience I'm certain of that what I did not expect however was that when I wrote down one bullet point well actually two I wrote still a coffee snob question mark the answer is yes and yoga you know that we would end up in territory where you would share some of your experience that I myself was not aware of about this
a bit of a wandering of three different PhD programs and of this cultivation of an intuitive sense of beauty and taste and preference that the way you described it takes you out of your rational mind and into the aspects of your nervous system that just really act as a compass toward what is absolutely right for you and we're also lucky that what's absolutely right for you turns out to also be what's absolutely right and beneficial for the world
so thank you for coming here today thank you for sharing your knowledge and your heart and for doing it with such an incredible degree of openness and respect so thank you so much thank you Andrew it's a great pleasure really appreciate it thank you for joining me for today's discussion with Dr. E.J. Chicholmaski to learn more about the work in the Chicholmaski lab and to find links to E.J. social media handles please see the links in the show note captions
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