Decoding the Brain

A useful way to organize our understanding of reality is to think in terms of things that are very large, such as stars in black holes, very small, such as molecules, atoms, and subatomic particles, or very complex aggregates of many particles that are highly ordered or structured. Let's focus on one of these three categories: the complex human

brain

. It is not unusual to hear the

brain

described as the most complex structure in the entire universe, but because we have so little knowledge of what might be out there, one is not prepared to make that commitment and the brain does not need to be complex and its functions are not only wonderful, but are the very substrate of who we are as individuals and as a species, so the attraction to understanding the brain is strong;

This program is called Decoding the Brain because the work of all the scientists we will speak to is contributing in one way or another to a deeper understanding of the cascading electrical processes that crackle in our brains and that somehow result in our experiences. , our emotions and our behaviors, in short, We will explore several ways in which new tools that allow us to directly probe brain processes are helping to reveal that the most complex object here on Earth is the human brain. Our first guest is Michael Holasa, Class of 1958 Professor of Career Development in the Department of Brain at MIT. and cognitive sciences and is also a research associate at the mit mcgovern institute for brain research.

His goal is to understand the basic architecture and functional connections in the brain that underlie cognition and has identified basic circuit mechanisms for attention and decision making. your home on the outskirts of boston welcome michael thank you brian great to be here our next guest is edward chang who is joan and samford wild chair of the department of neurological surgery at the university of california san francisco co-directs the center for neural engineering and prosthetics which brings together engineers and neuroscientists to develop technology that can restore function to patients with neurological disabilities. He joins us from San Francisco.

Welcome Eddie Hi Brian. Our next guest is Michael Cahanna, the Edmond J and Louise W Khan Professor of Psychology at the University of Pennsylvania, where he is the principal investigator of the university's Computational Memory Laboratory, studying human episodic memory, and currently working on building a prosthetic device to improve it. He joins us from his office in Philadelphia, thanks, Brian, welcome, Michael, happy to be here. Our next guest is Helen Mayberg, Director of the Center for Advanced Circuit Therapy and Professor of Neuroscience, Neurology, Neurosurgery, and Psychiatry at the ICAN School of Medicine at Mount Sinai. She has done pioneering work to discover the neural circuits of depression and treat it through deep brain stimulation she joins us from her office in new york welcome helen it's a pleasure to be here brian finally we have yuri birjaki who is the professor of Neuroscience from New York University of Medicine.

He is the author of The Brain Inside Out in which he proposes a new paradigm for the study of the brain and is currently

decoding

the underlying patterns by which the brain operates. He joins us from his office in New York. Welcome Yuri. Thanks Brian. Thank you all for joining us and let me begin. a basic question that is really for the group. I'd love to hear all of you chime in if you have a perspective on this, what this is. Do any of you have a favorite metaphor for thinking about how the mind works and what it thinks? about the computer metaphor, is it a reasonable way to think about the brain for some purposes or is it a metaphor that should be retired, so maybe let's start with Eddie Chang, you know from my point of view, it's actually very difficult?

For me to think of the brain as a computer because when I go to the operating room and see it every week it doesn't look anything like a computer, its substrate is fundamentally different, but we use the analogy all the time and so on in our work. It is useful to ask some questions in terms of the information processing of the mind in the framework of a computer, but there is much more that is generated from the internal model that is inside the mind, in the substrate of the brain, which is much more beyond what modern computers do right now, in fact, I think the analogy with computers in the future might be more like the mind than the other way around, michael halasa, yeah, that's a great question, Brian and I We echo what Eddie already mentioned.

I should say that, you know, one of the things I think about a lot is the idea of ​​scales in the brain and this multi-scale organization and vertical integration across these scales and I think some of these scales in computer science can be extremely valuable in providing the language to describe them. I think what we're potentially missing is a vertically integrated theory to connect all of these scales in a way that would be useful to connect them to real-world applications, so that while the metaphor can work. for certain scales at certain times, I think we're simply missing a unifying theory for neuroscience to make sense of all these ideas.

I'm sure Helen thinks about that, I think it's interesting because she, as a neurologist, she studies a psychiatric disorder like depression. One wanted to start with modules and think about modular organization, but I think, as Michael says, you know thinking on different scales is really critical and I think maybe the only metaphor for depression in this conversation is the nature of what it feels like. like a black hole. kind of an attractor state and as soon as you bring that metaphor into the conversation, the idea of ​​a computer quantifying that or giving us an organizational structure becomes a little more difficult, so I'm really interested in how well Yuri answers this question . a good hint in yuri's metaports are useful and we have nothing else.

The way the brain works is that it always compares. We know the unknown with the help of the known, so we always substantiate something that we do not understand with the help. of something that we think we do, like a computer, and this is a useful metaphor, but we have a lot of other things that are blocking this and the reason we are taking this this way is because it is the computer world that took the initiative and says, oh, you know, this is like the brain and the reason why computers and computer scientists think this way about the brain is because they took the wrong model of the brain and the wrong model of the brain is that the brain is a passive device like a computer in which you enter information and the computer has no choice, the human mind has no choice, this is what is called the tabula rasa or the blank slate model and this is not by chance, you know that's one of the giants of AI and the computer scientist Alan Turing explicitly said that the brain, the newborn brain, is like a white piece of paper that we have to prescribe things on and this is where we fill it out now we just saying that the real problem here is that the If you follow this recipe of the brain and artificial intelligence, then the complexity of the human brain of any brain or artificial intelligence system depends on the amount of information you input and I can tell you later why I think it's not like this. fundamental difference: the brain is a self-organizing system, while the computer is a man-made machine, right, so we'll have time to discuss that in more detail later, but Michael Kahana reflects on the metaphors of choice for thinking about the thought.

Yes, those are all great points and I love Yuri's point about a self-organizing system. The metaphor that interested me in memory was the theory of condensed matter, rotating glass systems or complex thermodynamic systems where a system could be in multiple states, I mean A simple example would be water, it could be solid, liquid or gaseous, but in nature there are even more complex systems, so I found that metaphor very attractive as a way of thinking about the brain differently than the computer analogy and in line with the idea of ​​a self. -organization system that you already mentioned with that as a preamble, let's move on to some of the amazing and truly remarkable work that you all have pioneered, Eddie, I'm going to start with you, your focus at least for some time has been on understanding the I think that one of the goals of the speech neural circuit is to be able to have some sensors that can have some understanding of the electrical and other properties that happen in the brain and, from those signals, to be able to get some understanding of what is happening in the brain. brain.

The patient is trying to say it. Can you give us an idea of ​​what his approach has been and what he has found? Our focus has been on understanding the neural code of our ability to articulate words and speak. What I mean by that is the The pattern of electrical activity that is generated by brain activity in the temporal lobe and the cortex above it is a very precise coordination of the neural activity that gives rise to words and sentences, so for the last decade we have worked with patients from ours in san francisco at the university of california san francisco who have volunteered as part of the medical treatments they have received for the treatment of their seizures when implanted electrodes were placed directly on the surface of the brain with very, very small sensors, perhaps the ones you We mean to record that electrical activity in the order of millimeters and milliseconds and with those types of recordings we have been able to decipher and correlate those brain electrical patterns with consonants and individual vowels, as well as with syllables to give rise to words.

So if I were one of those patients, you would ask me to imagine saying words and monitor what happens inside my head when I do so. Yeah, a lot of what we focused on actually wasn't so much on imagining speaking, but on actually, the actual production of words, so what I mean by that is, when I'm saying these words right now, how does the activity neural at a particular point about a millimeter wide controls the movements of my tongue in a very particular trajectory to create a Duh, the sound or sight that is right next to it controls my lips when we sun, so there is a map that basically controls all the very precise movements of the vocal tract and we study it when people speak normally but also in other conditions, for example when they are imagining or sometimes even when they speak different languages ​​and it is important that you get the If the patient actually says the words, the physical act of speech rather than the mental act of imagining a word, do those give radically different results? signals if you try to measure them, yes, great question, we have looked at it very carefully and it turns out that imagining speaking is very, very different from actually speaking, so the act of speaking is a totally intentional and volitional event, whereas when you are Simply thinking a thought or even imagining the words is a different pattern of neural activity that is much more subtle and complex and we have a lot more work to figure out how it works, but the actual production of words has become much clearer. over the last five years and is it fairly consistent across different patients if they all intend to articulate a cat or is the same signal generally generated?

Yes, that's right, so they all have a little bit of variability in the absolute position of where these locations are in the brain, but they're confined to the sensory motor cortex of the part of the brain that controls the parts of our vocal tract and when you look at the precise position of all those neurons, can be very variable from one individual to another, but when you look at the patterns at a higher order, they are actually remarkably similar and you also have a kind of dictionary or map, yes, both, basically, is a map of the different articulators of the vocal tract and the target sounds. that we try to speak when we articulate words and we call it a dictionary because, for example, in English there are only about 40 phonemes, different speech sounds that give rise to every possible syllable of a word, so a dictionary is a very useful way to think about it. that you have this elemental set of units that by themselves have no meaning but in combination can give rise to all possible meanings, so basically you just go through that exhaustive or fairly exhaustive list of elemental building blocks, map them, and then you can paste them together together, I collect them in your dictionary to generate more or less anything that someone would say yes, exactly and when, when, when, when, when you say exhaustive, something that is very important to think about, that's just in a couple of minutes . that we've already talked about, we've gone over most of thatdictionary not just once but a couple of times, so with a simple conversation, just speaking, um you know, random sentences, even you can try all this and what is really amazing. is that as people generate new sentences, we are resampling that core dictionary, that core set of units and recombining forms to give rise to completely new meanings and sentences and then I guess you can test this on new topics and determine how well it works for you. goes into your system by

decoding

signatures in the brain that are read through the implants.

Yeah, that's right, we can basically take that code and, um, in the same person or a different person with some modifications of that code, essentially translate that brain. activity for a completely new sentence and reconstruct from brain activity alone what someone meant or actually said and how well you do it. I think we're starting to get to the point where things are starting to sound intelligible, so, for example, if you wanted to translate brain activity into words and sentences that you actually hear with your ears using speech synthesis using a machine algorithm to translating brain activity into real sounds that you hear through speech synthesis we are starting to get to the point where it is intelligible, which for us is not a really important milestone, there is a lot of room for improvement, but where we are now is that You can actually make out the words even if they are a little blurry, the impression you are seeing is a sign of rolling wheels, the proof.

What you are looking for is not available in books. She believes video should ruin any process. Shipbuilding is a fascinating process, so we are very excited in terms of achieving that milestone, but there is still much more to do to improve it. That's fascinating. work eddie michael gahanna let's turn to you there isn't a person among us who wouldn't love the perspective we hear in science fiction scenarios that one day we will be able to enhance our memories through some kind of medical intervention and I know that you We have started working in that direction, so, for us to move forward, how well do we understand the biological process by which memories are formed in the brain?

Well, I would say that we are still at a very early primitive stage in our understanding of the biological processes of memory formation, but we have a very good ability to decode neural signals that predict whether or not memories will be stored and whether they will be accurately retrieved. or not, so we're treating the memory imprinting process as a kind of I guess it's a black box and it says we don't really understand how it happens in the brain, but we're just going to look at it and find the patterns. Do you feel like you'll ultimately need to understand the actual process that's happening? inside our brains or we can just treat it as that black box, well, I think you need to proceed on multiple tracks, if you want to address the one in 12 Americans, for example, who has significant memory loss, then you want to move forward.

Before waiting to have a complete understanding or even a good rough understanding of the underlying processes that govern the storage and retrieval of memories, I believe that the most interesting process in the brain is the process by which we retrieve memories rather than the process by which which we store memories because for memory retrieval you may have a memory that is very well stored, I mean you have experienced this many times and clearly this memory comes to mind frequently and then you find yourself in a situation where that you need that information. I just can't find it right, then something is happening, the memory is there and if you just think about the fact that we walk around with vast stores of knowledge of memory experience in our minds and yet at any given moment our ability to Access to that information is actually quite limited.

It really makes you wonder about the memory search process. How do we search our memories? How do we recover them? And we can't just look at each one of them. We can't go through the library and look. Every token we need a mechanism by which to find those memories, so tell us about the work you've done in that regard to try to understand it in more detail and I also meet to try to develop approaches that can improve the ability. of an individual to recover those memories well, so I think most of us wonder why one person's memory is good and another's is bad, why I can't remember things like I used to when I was much younger, but there is a fascinating paradox. or mystery about memory, which is that within a given person at a given time, let's say today my memory is going to fluctuate between periods of better and worse functioning, there will be a dynamic process by which my memory varies in my ability to access to those memories that I know from my ability to create new memories and we can demonstrate with detailed experimental studies that that variability is not due to inexplicable external experimental factors, but is something in the brain, something in my head that makes the memory good. sometimes and not good. at other times now, if you can decode that physiologically, if you can use electrodes to measure electrical signals, the brain is, after all, an electrical network, if you can measure those electrical signals and predict when you're going to have a memory lapse using the electric system. signals recorded from the brain, then the idea would be that maybe you could make the brain look better when it's at its worst, so the idea is that if you can first decode or predict this complex system that is varying and then you can identify the moments of a memory lapse and somehow persuade or nudge the system from this worst state to this best state, the best state is a state that we know the brain can express, then perhaps memory could be significantly improved and that's the kind of therapeutic approach that my team is taking and is also working with human subjects and putting them through various memory tests and seeing when they do well and when they don't and recording what happens inside their head and building the correlation of that. manner.

That is, the approach that is exactly correct is that we have a patient who undergoes the same type of neurosurgical evaluation that dr. eddie chang, he will play instead of playing games where he talks or listens to speech, he will play memory games. at my job and we'll track moments of good memory and moments of bad memory and then try to see if we can build a mathematical model so that tomorrow when we go back to the patient's bedside and they play the game, they can predict when their memory is going to be good and when it isn't, moment by moment and now, if that mathematical model provides a reasonably accurate prognostic prediction, we can now use very mild electrical stimulation of the brain to try to coax it to function better. memory state and what we do is we track those fluctuations in memory in real time to determine at any moment if you're about to forget something, if you're going to have trouble remembering something and then we apply electrical stimulation at that moment.

When memory failure is predicted to align with the type of stimulation that would generally push it in the direction of a better prediction of good memory and thus memory can be significantly improved in many patients, how significant it is varies from person to person. person If you were to ask how significant in terms of percentage of memory improvement is about 19 improvement in different studies between 15 and 20 percent in our last work 19.2 percent um if you ask what does it mean if your memory is 19.2 better, what does it mean? that number means 19.2 percent, which is about half, a little more than half of the deficit that would be incurred in a patient who had a moderate to severe traumatic brain injury, so in other words, on average half of the memory loss would be restored. in a patient like this and really what that means is that, let's say, for a third of the patients it would almost completely restore that loss, for a third it does nothing and for a third it is approximately half of the restoration of that loss by memory. fascinating, let me move from that to uh michael halassa, who you've been focusing on, you've been focusing on trying to understand what it is to have attention and if, for example, there's another metaphor that certainly we've all used that goes something like this, This spotlight, you know, that's what the brain is shining on, you know, that's what we're focused on, what you've learned, is a good metaphor for thinking about the things that catch our attention.

Or is there another view of consciousness and attention that has emerged from your research, so Brian, I'm going to take a detour to answer your question after having followed Eddie and Michael Kahana in what they talked about, so, uh Did they, they, speak? about action, you know, from Eddie's perspective, you know, articulation, movement, um and and and memory and and and I think you can argue that one of the main purposes of having a brain is to plan our next action without without without the ability to move and act in the world, it doesn't make sense to have a brain in the first place, that's why plants don't have brains and, you know, as you go through evolution, organisms appear that are more capable of planning the sequences of their actions have bigger brains, they have bigger internal models of how they control those actions over long periods of time and there's a temporal hierarchy there and ultimately they have a pretty good way of using these stored patterns of past inputs. what we call memory. and my work has been at this sort of intermediate level of organization between, temporally speaking, between immediate action and long-term memory, which is this idea of ​​cognitive control, one of the aspects by which we control our cognition. through attention, how we prioritize incoming sensory information, how we filter it and then how we format it in a way that is appropriate for both short-term and long-term action planning, then we talk about making models of the world, which It's vital, right, because look, we're inundated with information all the time, I mean, right now I'm sitting here in this theater and the electromagnetic waves hitting my eye have these oscillating electric fields and magnetic fields. billions of times per second, if I were sensitive to even that information at that level of description, my brain would be overwhelmed trying to cope with that data, so what does the brain do to cope with this influx of information?

So I think it's a fascinating question and I think it's useful, you know, coming from mit, I think it's useful to invoke David Marr Mar stipulated that we can think of the brain like we can think of a computer like uh and I'm not saying that the brain be a computer I'm just saying that this is a useful metaphor for approaching the types of things we do as neuroscientists to understand the brain. There is a computational level that is the high-level goal that we are trying to achieve for any particular neural process. The algorithmic level that What is the series of steps that the brain could take to perform this calculation and then the implementation level?

How is this actually implemented in neural hardware to activate neurons correctly and for any particular neural operation? I think I think about things. in this particular way and this type of division is useful and ultimately one understanding may be how we link these different levels of description together, where it becomes natural to talk about the algorithms of the mind implemented in the neural hardware of the spikes . neurons, the work we've done in my lab has focused on implementation at the algorithmic level, so we record individual neurons in the brain in areas like the prefrontal cortex, this front part of the brain and that's where I think a lot of cognitive control operations and the way we imagine they control things like what memory we should retrieve or what things we should pay attention to is by sending what we call these top-down instructions to downstream neural circuits to change their functioning in such a way that we damp out the noise. of the things we don't care about, we amplify the signals from the things we care about and you know, we retrieve the memories we're currently looking for, we turn up the memories we care about, etc., is it accurate to say that the brain, from a perspective hardware and maybe also from an algorithmic perspective, you have sort of gatekeepers that information is trying to get to the place of attention and consciousness, but those gatekeepers are just letting some things through is that a reasonable way to think about it is great analogy and I would say it's not just in the domain of sensory systems, I would say this is also in the domain of cognition, I think even andI'm going to make, you know, kind of a guess here that, even when we're trying to recover, you know, generative hypotheses about what's happening in the world, I would say that most people would be going through this filtering process.

In To maximize the probability that what's out there is correct, I mean this is statistical inference machinery that we have in our brain to infer what's happening in the outside world and we have these things running automatically in the background everything time to get to the world as we see it, I think that in certain disorders, for example, like psychosis, schizophrenia, etc., these types of inferential filtering mechanisms at the level of cognition are impaired and that is why we end up seeing, I guess I mean again, this is my kind of main hypothesis for what's happening in some of these diseases is that these filtering operations in that domain are broken and you end up with people that you know and you conclude that the FBI is after them. , aliens are landing in your backyard, etc., fascinating, like that, like that. helen, we have seen a lot of discussion up to this point about patterns in the brain that give us insight into words and speech in the work of eddie chang understanding memory retrieval the work of michael kahana issues of attention and consciousness gatekeeping aspects of the brain and the work of michael halas As I understand it, your work also focuses on patterns in the brain, but your focus has been on patterns that correspond to depression, so can you give us an idea of ​​what that work Has revealed?

Is there a kind of uniform mental brain? pattern that one can associate with that type of affective disorder, so I think it's important to define the term first. I mean, depression is actually a very common and serious medical illness. I will argue that it is a brain disease. We can put people in scanners and we can get maps of what the topography is. functional topography of areas of the brain that are abnormal and it turns out that there is not just one place, any of these complex systems, but even in these syndromes, if you have problems with mood, impulse, thoughts and actions, it is not a big surprise that you see multiple areas of the brain acting. together or not acting together that are abnormal and can be mapped and subsequently can be mapped how the brain dynamics changes with the treatments and our decoding work, so to speak, or actually our use of causal manipulations in the brain, not only with medications. or therapy, but in real time with electrodes it helps us see that you can go from having no capacity at all to, in a matter of seconds, having a total change in how you can see the outside world when you are stuck internalized, can you tell us a little?

More on exactly that, so if you have a patient who is clinically depressed diagnosed as depressed, presumably the brain patterns are recognizable enough that simply by looking at that data you would recognize that that would be the appropriate diagnosis. Can you go that far? aligning them well I think you know we like to think that we work in groups of patients. You know that our team has taken the approach of diagnosing depression according to the standard of practice. Put people in a scanner. Take an image of the resting state of the brain. Treat. people with different types of treatments, you know in three months it's okay or it's not, go back to the beginning and see if you can tell the difference in how people responded.

It's working now that you can start looking at an individual. The patient has to make a decision about which way to treat and we and others are trying to look at that type of treatment-specific biomarker, but it's the same network in the brain but in different states, so the question is whether each patient is different or there is one. pattern there is no single pattern because we don't know what the instigator of depression is and when a patient is sick there are many maladaptive patterns that you are seeing and so you are really trying to cut through all this noise to get to the core that could be useful and in that point you'll know, like Yuri said, that the self-organizing system is totally self-organizing to try to adapt and now you really have to figure out what state you're in.

Now you're lost, so how do you take someone lost and figure out what you can do to move him back to a place where he can retrain and be found? And that's really, in our work with implants it's become much clearer what that really means. It was harder to see when people were less sick, so with implants and you mentioned this, this really amazing result in minutes that you mentioned, sometimes you can see a change in a person, just tell us a little bit about how it's stimulating that person. Was it through some type of electrode in the brain and what was the response in some of these notable cases?

There have been many now, so I started this 15 years ago in Toronto with a team and a neurosurgery team, Andrés Lozano, Sid Kennedy. As a psychiatrist, we basically took the hypothesis based on these images on this map that we had that actually told us that there were areas of the brain that were working together but their synchrony was dysregulated and we basically had reason to believe that an area deep in the brain seemed to being the ringleader, it really focused on the subclosal cingulate connections with the midline thalamus, as Michael talks about its connections with the hippocampus, as my kahana talks about its connections with the frontal cortex, the hypothalamus, and other parts of the brainstem. , seemed to be focused. in a place that if it didn't change wreaked havoc on everything else we don't accept epilepsy patients we accept depressed people who had failed multiple medications psychotherapy electroconvulsive shock therapy they are practically at the end of the line they were on that attractor state is trapped and can't come out and we basically said, can we leverage the technology that's used in the parkinson's implant with anatomical precision in this area and in the white matter that connects it to these other areas in this putative circuit and In fact, when we stimulate at high Often it's like we release the blockage of this region and people come out of it, so as we get better and better with our imaging, we can plan the surgery precisely within millimeters, place it in this convergence of these multiple pathways that we know They interact with each other and we know that from animal studies we know that from epilepsy studies and when we apply high frequency stimulation we can predict that someone will emerge and what they describe is that the negative turns off and it is as if they reconnect, they can pay attention , they feel connected, they feel like they can move, so the paralysis goes away and that happens very quickly and if you give the stimulation even in the operating room, 10 to 15 minutes so that we can record and really see what happens, we come out of the operating room and they will remain fine, you know, several weeks without further stimulation and then we turn it on and give stimulation and we have patients who have these chronic implants have this pacemaker in all Time and people are better and mind their business, so we have restarted something very quickly and then allowed the brain again.

I will use this principle of self-organization to relearn who you are with a brain that doesn't get stuck, yes, that's remarkable, Helen, that a small electrical nudge in the right place in the brain can have such a dramatic long-term effect. Now, Michael Kahana, you have also discovered that the right electrical push can have a big impact on raising capacity. of patients to recover memories, so Michael, when you add these little electrical impulses to the brain, my guess is that the patient doesn't feel it, they just feel the repercussions of that stimulation, so you're really manipulating the brain.

The patient does not know when he is doing it, but they will still show a difference in these memory tests that shows a marked difference between before and after. What we do is we apply stimulation, these stimulation protocols randomly on certain lists of certain memory games. The game can be like 30 seconds or a one minute test with or without the patient doesn't know, the experimenter doesn't know and that's how we measure the beneficial effects and also do you think the ability to read these signals and even manipulate them? signals, which is what you are doing now, this will ultimately lead to a complete understanding of the memory retrieval process and I would also love memory formation.

Is this the root towards that goal? Yeah, I mean, I think that's a really critical question. that we want to know the answer to meaning if you have people, suppose we can create a therapy whose benefit is significant enough that many people who need the therapy receive it and the risk is low and the benefit is high and now you have people walking around with devices that decode variable memory states in the brain and transmit those encrypted signals to a cloud that is capable of analyzing those signals and building a massive database of information about how the brain works when you are studying and remembering. information or even just acting by going about your usual activities of daily living once you have that massive database you could imagine you could start testing theories and improving and refining them much like you know, maybe the Hubble telescope or some other devices give you information about in the cosmos, this type of technology could give us tremendous insights into understanding memory encoding and retrieval, Eddie, the technology you have developed synthesizes speech based on the intention to form words, Have you applied this in situations where the individual has had speech problems for a long time?

For whatever reason, has it been able to function well under those circumstances? That's a great question, so for the last five years, five ten years, we've really focused on the basic science, the basic neuroscience of this code for all the different consonants and vowels. and movements of the vocal tract to give rise to speech and about two years ago, because of the results of that fundamental work, we began a clinical trial called the bravo trial in which we enrolled the first participant. a young gentleman who at the time he enrolled in the study was 35 years old and the reason he participated in this study was because 15 years ago he was in a car accident which caused complications of a brain stem stroke with disability to move their arms and legs, as well as speak, and for us it was a very important advance in the last two years to move a lot of what we had studied in the context of people who normally speak in a clinical context to the situation of someone who is completely paralyzed and who has full ability and intention to speak in the brain in the cerebral cortex but could not due to a disconnection in the brain stem and we were able to translate that brain activity into four words: The proof of principle is there and it is possible to really take advantage that rich information from those patterns of neural activity to give rise to things that are as human and as intimate as words and speech.

Yes, it is a fascinating job. Michael Halasa unlike Eddie and Helen. Mike Kahana, I understand you work primarily with animals rather than humans, so how do you do that? We train them in decision-making tasks in which they need to retrieve a reward. This is what we call alternative choice tasks. on each and we do it trial by trial, so on each trial we give the animal the option to choose between two options and the animal is required to do this based on the appropriate deployment of attention, so on each trial, for example, obtain visual or auditory vision. target and it has to choose the appropriate one, we train it to be sensitive to a cue beforehand, so we give it cues on each trial and we can make that cue somewhat ambiguous, so we can basically make this attention process a take of decisions. process decides what to pay attention to based on ambiguous inputs and that allows us to study how the brain decides what to pay attention to and both filtering at the level of cognitive operation and filtering at the level of sensory operation and those The animals are typically mice , dogs or cats, yes, a lot of the work we have published so far is on mice and the reason we choose mice is because they are mechanically tractable, we can go in and turn on the circuits. and out, using a technology called optogenetics and we can talk about that later and then in more recent studies, we have been using this organism called tepaya tree fungus and that is an organism that is a kind of intermediary between rodents and primates and that It allows us the same kind of mechanistic accessibility, but we can achieve a high level of cognition and study things like causal inference in these animals if schizophrenia, for example, lines up with the theoretical description that you're imagining that somehowway the guardian doesn't do his job.

Does that suggest a particular treatment or course of action or is it too early for that type of diagnosis? I can tell you where my intuition comes from, so my intuition comes from the study of a particular circuit of the frontal cortex, the prefrontal cortex, which is particularly developed in humans and its connection with a structure called the meteorothalamus, the part of the thalamus or essential structure in the brain in patients with schizophrenia, those connections, you know, the structural integrity of these connections is altered and that has been known for a long time in In my laboratory and others in the community we have been studying this particular network in animals and what we have found is that many of these cognitive filtering operations decide what evidence you should use to deploy your attention goes through those circuits, almost the algorithm is going through different update cycles between these two structures and in that you know that in that process, the thalamus it really acts as a filter of how reliable the information that you're getting is, so kind of the idea that patients and animals, when we, um uh, impair those struggles, when we inhibit those connections, they end up jumping to conclusions. unlikely, basically leads us to conclude that you know this is a reasonable hypothesis about these impaired inferential mechanisms in zuri schizophrenia, so we've heard a lot of researchers, the four researchers in the discussion here tonight, Eddie, talking about looking at the brain, finding the patterns that language decodes, Michaels, about memory and attention, hell, and about other patterns that allow us to understand. aspects of depression and have even suggested ways to address that situation that have been remarkably effective.

All of that I think you would describe as the outside-in approach to understanding the brain. You know, we, as outside observers, we, the objective scientists, are studying some aspect. of patterns within the brain and with that perspective of a third party trying to do something to the brain to get the pattern to change or read the pattern or do something with a pattern. I guess your opinion is that yes, this is deep work. but I think you're suggesting that there's another way of thinking about it that ultimately you think is the way to go, give us a sense of what that is and you know, historically, brain research has made its way from the world The outside expects that this systematic approach will take us to the middle and through the middle to the exit, which is action.

Now, of course, people didn't start out as neuroscientists. Early thinkers thought about the importance of the psyche, soul, mind, etc., and speculated. and that speculation was codified by the Christian philosophers and then by the British empiricist. The conclusion of all this is that human brains are there to learn the truth of the world that is outside in its entity and its beauty and in the process that we realize that we need to explain various things and that is why we invent terms like attention, memory, decision making, creativity, imagination, notepad, memory, work area that can go on and on, and on, and on, there are many, many, many words, so when neuroscience came into the picture, it seems that We already have a task.

We are on the right path. We have a roadmap. What we need to do is find homes for all of these terms and see how they work. I think you agree with me that this is a naive approach because those limits that we set in our minds and those limits that smart people a thousand years ago, hundreds of years ago, invented as a term, you really can't have a mechanism with which same boundaries within the brain, now just to give you an example, this is uh, this internal and external front which is also called tabula rasa or black slate model, etc., with the understanding that you just have to introduce knowledge into the brain because the brain is a receptor that is there ready to absorb everything. the information that comes from outside, for example, when we inspect an elephant that has a shape, a smell, etc., the goal is to discover how the brain combines or unites those attributes into a representation or a symbol and it becomes a symbol . of the elephant there is a fundamental problem with this approach, which is the attributes of the elephant or any object for the sake of are not in the object, those attributes are created by the brain, so that is where we are now, that is what I'm.

We can call it a dead end and we are trying to find the way out of this blind zone, so what do you think is the way out? I mean, I'm not sure everyone agrees, so I don't want to put words to anyone's opinion. mouth, but if one agrees that this is a dead end, what do you think is the way forward? what are we missing? Is it a radical change of perspective? You just need to add something to the mix to have a more complete framework. Well, an alternative to what I call the brain-centered view that I'm promoting is that we learn from our actions the task of the brain, if there is a task, you know , the evolutionary tasks are to serve the body and the consequences are to predict the consequences of our actions now let me explain the difference between the two frameworks in practical terms of neuroscience, so what we have been doing for decades is presenting something to the brain, whether it is a experimental animal or a human brain, and record it from within. brain and it could be an electrical pulse that we are capturing in michael kahana's lab or it could be a simple signal that those images receive and then we correlate the two and then we say oh wow, there is a good correlation between a moving pattern and the neurons that they activate in a particular way in the visual cortex, for example, we can go further and the whirlpool showed a very good example that we can train a computational algorithm, we say we make these systems intelligent, it is so intelligent that now we can reverse the process.

We are recording from brain activity and from previous learning we can reconstruct what, for example, music would be, what language would be from brain patterns. There is a problem here. The problem is that the experimenter is in a privileged situation that only the experimenter has. access to the outside world there and the activity of the brain in here the neurons in the brain have no idea what is happening in the outside world the neurons will simply get action potentials from their partners and they have no idea if those action potentials mean something out there in In other words, this approach is groundless, as I mentioned, you know, grounding is a process where the unknown is based on the known and there is only one source of knowledge that neurons can have other than what It comes from the outside world and this is the action on output now the action of course is a typical way where you think you are moving your arms or moving your eyes or doing something like that, but the action is also the action in your heart , action in your endocrine system and thinking is also an action now the good news is that each action system in the brain reports that it sends an output not only to the body but it also informs the rest of the brain that I have sent an output that now the neurons in visual codecs, for example, can handle it. with two types of information, what comes from outside, what comes from here, so this is the way and the only way to say that I am the actor, I am the agent of my own actions, so this is a fundamental difference. between the two approaches and I would say: let me give you an example, there is no amount of looking at a stick in the water or arguing between you and me, we would agree that the stick is broken or not, but a little movement, a little action immediately. will reveal to the brain that the stick is not broken the source of knowledge in the traditional outside model is the supposed wealth of the world waiting to be observed by a camera-like brain, in contrast in the inside out framework knowledge comes from the action. exploration and everything is compared and valued from the point of view of the organism without exploration without knowledge so I understand and I apologize if this is a summary of the course but you want to close the circle where the brain receives stimuli from the outside. but it also acts on the external world, which then affects the stimuli that we receive from the external world and that is this loop of information that is required for the brain to have a basis to know that there is an external world to know what these nerves are. dismissals actually correspond in the external sense, but what is the definition of action and I ask for the following reason, as you noted, the simplest action is to simply move your arms and legs and the salsa horse, but you also mentioned that you can Being the action of a neuron sends a signal outwards within the brain itself, so can the action be a completely internal process or does it need to access the external world?

You don't have to do this to access the external world. I give you an example when you are born before you are born we all kick you know baby kicks are very very important and baby kicks correlate with Apgar score and IQ 20 years later so they are very Importantly, what they do is help the brain build a body map and it is a very fascinating mechanism, namely that every time there is a silly teacher who says that there is some muscular activity, it sends a signal to the future somatosensory sensory representation. Now, of course, this is not a random process because the skeletal system limits how those muscles can move, so now the agonists and antagonists are represented together in time when I move my left arm or I move my finger when I'm a baby or a fetus and those synchronization effects because their proximity in time allows the neurons, when they grow, to make the appropriate connections, that's how we make a map of the body and we build it and update it every day because every week the Distance between your finger and your nose varies so it needs to be updated, so this is an example of how a real system can teach and make sensations meaningful, no matter the amount of sensation, you can have your camera, your eyes , everything and you can provide any amount of information through sensors to a robot, that robot just remains dumb without testing the distance between the tree and me and the distance between the mountain and me.

I have no idea that the mountain is bigger or smaller than a tree, so only through this action-based calibration can it feel like it makes sense, so I just want to comment on that because again it's about the observation of patients, but even though I describe this shift from a total internal focus on these depressed patients to the ability to interact outside of themselves and get feedback and what to do with time is exactly what yuri is talking about it takes time to recalibrate one's internal body and its relationship with the outside world and you are observing for months, in fact we saw a patient for a 10 year follow-up last week who when he tried to retrospectively describe each stage of recovery.

She was realizing that updating her own internal external map had been an ongoing process and that when she tried to identify it, yes, she remembered it in the operating room, but that was minor compared to what actually took a year or more. . two, really trusting her representation of her internal state in the outside world and feeling like there were dynamic predictions she could make and learn, so I'm a fan of how Yuri conceptualizes it even if on a neuron-to-neuron level, we have no idea, but the metaphors that patients use about the experience they have are that there is no depression per se, it's just the absence of the ability to make those continuous updates, so that's probably how we should look at what's really going on.

We see, so let me move from that to one last question, since we're running out of time. I want to go back to Eddie Chang and a question that I will ask Eddie, but I would like all of you to ask it. Weigh in if you have perspective on this, Eddie, you noticed that you walk into the operating room and you look at the brain itself and you know it's more than a computer, right? You're not looking at a motherboard with chips, it's something. beyond a computer, but from your years of staring at the brain and manipulating it and trying to decode it, where do you get to the question that, of course, has been kicking around for hundreds, if not thousands, of years is it consciousness?

True, we haven't really talked about consciousness here and some of you may roll your eyes at the idea of ​​consciousness and if that's your answer I'd love to hear it, but when it comes to consciousness, is it within this? physic structure? everything there is or do you think is even inadequate for that purpose and do you think that there has to be something beyond the physical so that we can have the kind of internal worlds that happen inside our heads yeah, Brian, thanks for um, thanks for In asking that question and from a doctor's perspective, we think about consciousness in quite concrete terms in terms of whether someone is awake or not, there issome very important medical definitions that we use to define and there are specific parts of the brain, for example, the brainstem and thalamus, Michael Halassis areas, are studied very intensively and how they interact with the cortex which needs to be intact for consciousness. .

There are many other aspects of conscious awareness and subjective perception and our appreciation of the environment. and that kind of consciousness, but in terms of the fundamental basic idea of ​​being awake versus asleep, as I understand it, the way I see it is that it is an emergent property that results from the interactions of some very central structures in the brain, including the thalamus and other subcortical areas it can be seen that when people have brain injuries in some of these areas, they may never fully wake up from those strokes or traumatic brain injuries, while in other parts of the brain there is no effect, not even the one that can be detected in many cases. the location the substrate the hardware is very fundamental to this the implementation of the operation of how neurons in these particular locations of the brain give rise to consciousness is a fascinating question that many people are working on now and is very related to all of our work michael halasa how about your opinion on purely physical consciousness?

Can any other computer ever have the kind of internal worlds that we have? I mean, I think it's a great question, Brian. I think you mean consciousness, you mean phenomenal consciousness. the experience of I mean what's happening right between my ears right now what it is to be me what it is to have a perspective what it is to have you know the redness of red the qualitative experience of the outside world I mean, I think We're really missing something fundamental in our description of science in order to arrive at an answer to the question: does a computer have consciousness or not?

Does an aunt have a conscience? Does anyone else besides me have a conscience? I think you know, we just don't know, I mean, we don't really have the theoretical framework to be able to answer a question of this nature, I mean, I'd like to think you know other people besides me. I have an internal experience and I see green and red similarly to me and by extension I can imagine dogs and cats doing the same thing and I do fundamentally believe that the brain is generating processes that can be approximated in artificial machines, uh uh , and so I don't see a reason why machines couldn't experience things similar to that, but again, I can't tell you how, yeah, Helen, any thoughts on the physical basis of consciousness versus something else um the short answer it's no and I think you know these are surrogate discussions and when we have a reading um I'm not even sure we would know that we know that that's what we are talking about it, but I'll leave that to the philosophers and neuroscientists who think they're studying it. yuri, the dream we dreamed together is reality, so it's a nice metaphor and we can go down this path, but you ask concrete questions about whether my consciousness is Brian's consciousness has something to do with your brain and only the brain.

My answer is definitely no and this is a connection between the computer and your brain and your eyes are rolling. Now I can see that your brain is not calibrated by the physical world alone. but also by my brain and the brain of many, many, many others, so this reflection of your actions towards you or towards the brain is what gives rise to something that you know we are talking about and, of course, you know that can. Also ask if computers can have it. Well, right now what we do is all that information that we give to computers.

There's usually one that computers don't have or robots don't communicate with each other, so it's an unfair comparison between you know. The knowledge of a few billion people compared to one of the few machines where thousands and thousands of people gather competition or the real thing would be that we have at least a million robots running around the world and they would team up against us and then they collaborate and stuff like that, that's where we would talk about the fun part, you know if we can be made fun of or not, right, Michael Khan, I'm giving you the last word, awareness, anything you want to share, I think the most The interesting things that the brain does are the things that it is not aware of, they are all those things behind the veil of consciousness that are working in the background and that can be the basis, for example, of why someone might eventually become depressed or why. what your memories of events that happened long ago.

They do things that affect their future behavior, they are not even aware of it. I think we want to understand all those things, the internal things that sometimes don't come to light right away, but can come out at an inopportune time. I would really like to understand those processes well. I would just like to reiterate what Michael Kahana and several of you said: Which one am I? They are my memories. If my memories are taken away, am I aware of my surroundings? God knows it's kind of you know. You are a zombie, you can react and it is difficult to know if you are the same Brian as five minutes ago, but without your past you cannot have that kind of consciousness that philosophy does not talk about, yes, no, I mean the fact that the Collections of the particles can retain a lifetime of memories as we spoke before giving us a consistent identity over time, it is of course the essence of what it means to be human, so from this human being to you, five human beings from these brain patterns to yours.

Thank you very much for this conversation about the brain. It was deeply fascinating and enlightening. Thanks for joining us. Thank you. Thank you.