The Nuts and Bolts of Better Brains: Harnessing the Power of Neuroplasticity

The current abilities of our newborn human, Augie Nelson, are somewhat limited. He can cry, sleep, eat and hiccup. The turtle, also newborn, can crawl, separate from its siblings and begin a vast transatlantic migration, alone, without parents or learning. His brain has already formed all the connections he will need for the great journey that awaits him. Seven months later, Augie is learning to sit up. In about a year she will be walking. A decade from now, she'll be walking to school alone. By then, the turtle will have completed a 9,000-mile solo circumnavigation of the Sargasso Sea and will have returned to the shores where it was born to build its own nest.

The turtle brain was designed to masterfully navigate the ocean, but Augie's human brain was designed to adapt to any environment, play any instrument, calculate the existence of the space-time singularity, navigate the Atlantic alone, yes. you want it that way. Everything he needs to learn these things is already there. We are born with as many neurons and as many connections as you need. They can go from anywhere in the brain to anywhere with as many connections as possible. It is a brilliant design by Mother Nature because it gives us an incredible amount of possibilities for the future.

But there is a problem. That gift of possibility doesn't last forever. Like childhood itself, it comes to an end. For every skill, we have a golden period when learning is easy. Periods of development in which we have greater plasticity to shape neuronal circuits and which we refer to as critical periods. Learning to play the guitar as a child is like opening a door and as a child we have many doors. During this time, our neural circuits are fine-tuned. Our brain learns which connections will be important through the principle of use it or lose it. Certain connections are reinforced, sustained and improved at the expense of others.

Those connections that are not activated because it has been learned that they are not necessary are removed. In fact, they die and open doors begin to close. As an adult, if you've never played, you've missed that door. So right now, Augie can learn to speak any human language perfectly without an accent, but when he is an adult, he will have lost that ability. If he doesn't start learning to play the violin before he's seven, he'll probably never play at Carnegie Hall. If you never had the connections to begin with, you can blow dry as hard as you can.

You will never get there. But what if we could change that? What if we could modify our brain to learn as easily as a child? It's called The Holy Grail of Neuroscience and it's tantalizingly close. We can, to some extent, bend over backwards and reopen critical periods to say that we will allow changes to occur later, in ways we did not anticipate would be possible. Scientists are learning how we learn, and that will soon give us the opportunity to reopen those doors. So what really is

neuroplasticity

? Neuroplasticity is the brain's ability to adapt to changing circumstances.

In a changed environment, our brain's ability to learn, simply put. But there is another side of the coin. Just as we need to be able to learn to adapt, we also need stability. The opposite of plasticity,

neuroplasticity

, is brain stability. In fact, we're going to focus a lot on that balance tonight. Our first participant was the first woman to chair the Department of Neurobiology at Harvard Medical School. Today she is a professor of Biology and Neurobiology at Stanford University. Let's welcome one of the world's leading neuroscientists, Carla Shatz. Our next participant is an associate professor of Psychology at Columbia University, director of the Affective Developmental Neuroscience Laboratory.

Let's welcome Nim Tottenham. Our third participant this afternoon is a professor of Neurology at Harvard Medical School. As a medical doctor, he says his research focuses on the area between the brain and the mind. Let's welcome Álvaro Pascual-Leone. So welcome everyone. So Carla, let's start with the brain itself. We are going to talk about the plasticity of learning, how the brain learns, how skills become habits. But what do these things look like structurally in the brain? We already saw some nice photographs in the introduction, if you remember these black things. Structurally, the brain is made up of neurons and supporting cells.

Neurons communicate with each other using electrical signals; Chemical electrical signaling. The most important aspect of this is that these communications are transferred across structures known as synapses. That's where the learning happens. That's where memories are stored and, as we talked about in the video, that's where the pruning continues, this pruning process, this use-it-or-lose-it process continues throughout development. So, in fact, the structure of the brain is simply that the brain is packed with these neurons, packed with these synapses and also very long connections. Some of them can be seen in this beautiful graph shown now. So the brain connections link various parts of the structure together, and those are the beautiful colors that look like Us and so on, these paths.

But they are made up of hundreds and thousands of connections of individual neurons. I used to joke that there are more neurons in the brain than stars in the universe, but in fact, an astronomer corrected me and said that wasn't true. So when you look at an amazing image like that, we're really looking at the axons, the wiring... The wiring. Is the brain fundamentally disconnected from the beginning? The brain is not fundamentally disconnected at the beginning. But it's surprising, if we just take the visual system, for example, the eye is not connected to the brain to begin with.

The nerve cells in the eye have to develop their connections along pathways and select the correct part of the brain, that is, the visual part of the brain, not the auditory part of the brain or the motor part of the brain. So the wiring from the beginning is very organized and the formation of these long tracks or paths is dictated by very strict signals, such as roads or even paths with traffic signs, so that these growing connections or growing axons follow these roads. . But the surprising thing is that once the connections between these very distant regions of the brain are formed, there comes this period of overproduction and pruning that we're going to talk about.

A period of great plasticity where the outcome is actually predicted by the use of one's own circuitry and one's own experience. So there's a kind of hard wiring directed early, followed by this remodeling plasticity that happens later and really persists to some extent throughout life. So based on that, if you think about it, if you're building a house, you're not going to run copper wires everywhere and then take out the ones that don't seem to be working right. . But that seems to be what we're talking about. It seems quite inefficient and the brain represents 2% of the body weight, but it still receives 20% of the blood flow and 25% of the glucose.

So why does the brain do it that way? NIM Yes, at first glance, there are many things about brain development that seem inefficient, but in reality it is that seemingly inefficient path that actually gives rise to the incredible complexity of the brain, especially in the case of humans. So when we're developing, what our brain does is first go through this period of overproduction of neurons and synapses and then through experience, learning what's important in the environment, which synapses are activated, which ones remain, and everything. the rest. It is eliminated because it is inefficient to maintain all those synapses.

So why would we go through this whole process of overproduction and then withdrawal? That is really the core of the function of childhood in the human being. So if you think about humans as a species, we are amazing in many ways. We can live anywhere on the planet. We can speak any language, we can eat various foods, etc., and live very well. Some of the reasons we can do this is because of this long period of brain development that we have. So the brain overproduces, it's like throwing a big fishing net into the ocean because you're not sure which house you're going to end up in.

You're not sure what language people will speak to you. Then you are ready, you have all the bases covered. Then, depending on the signals that come to the brain, the brain learns, "Okay, I'm going to keep the synapses, but I'm going to get rid of them. So if I'm growing up in a Japanese-speaking home, I'm going to keep the synapses." synapses that help me understand Japanese, but I'll get rid of the synapses that support other languages ​​because that's really efficient." So it's really this really long period of development in humans that gives rise to our incredible adaptation to our particular environments.

So, Álvaro, is this a new concept? We all think that everything has been solved in neuroscience in the last 20 years, but this need to balance stability and plasticity, tell us a little more about that, about the history of that concept. I think there are many new developments, but many of the ideas are not fundamentally new; we have the tools to test the concepts. But the first person to talk about plasticity and stability as a term and apply it to behavior; to human behavior, it was Williams James; psychologist Williams James in the 1890s. He wrote about plasticity as the property of the substance of an organ, presumably the brain, that allowed us as humans to perform certain behaviors and become really good at it.

He was talking about behavior, a habit, not the structure of the brain. He said that the surprising thing is that it has the property of yielding to influence but not giving in completely at the same time. You want to have some plasticity but not too much. You want the right kind of plasticity, the right amount of plasticity. Presumably, it was Ramón y Cajal, not much later, who began to investigate where that actually happens in the brain and describe the synopsis and the changes in connectivity and the change of how effective those connections were in creating new ones as the substrate for that plasticity that Williams James talked about.

So ideas are 100 years old, and yet when he was studying medicine, they told me, "Things don't change in the brain and when you get older, well, it's hard." I thought, 'God, I hope we can do something about this because I hope to get there one day.' I think we started and we all know, we've always known, as an old dog, you can still learn new tricks. It was against everyone's experience. that it is possible to learn new things. So how do they combine? Great. Now we were talking about this concept of critical period. Children learn language much more easily than adults. other examples of critical periods that you see in your work with children?

So, for a while, people thought that there was a critical period in the development of the human brain and then it became clear that critical periods are in. actually a property of a developing neural circuit. So if that's true, then maybe it's appropriate to think of every neural circuit we have as going through its own critical period, the metaphor people often use for a critical period is that. it is a window of opportunity that opens when the environment can truly have its greatest impact on the nature of the future functioning of that system. If it's true that each neural circuit has its own critical period, then perhaps we can map time across the entire brain.

So generally what people find is that the brain develops in this backward C-shaped nature, where the regions of the brain that are low and backward tend to develop earlier, then the development curves in waves. So what you often see, the sensory systems develop first, they experience their critical periods, followed by the motor and language systems, and finally more of these higher cognitive functions that, particularly in humans, we spend so much time on. time thinking. Things like our emotion processing or our cognition, academic performance, etc. So that hierarchical structure really makes sense when you think about what the needs of the developing child or adolescent will be.

In the video, we saw a baby turtle that doesn't really have a childhood. She jumps into the ocean and takes off, whereas humans have this extended period of childhood where all of this has to happen. One could argue that because we have more to live experientially, we have the longest childhood. I think it's another good example of what inefficient design looks like, right? So if we are going to stay and mature for that long, then we need someone around us who is willing to invest in staying with us for that long. So if you look at this period of immaturity in the human being, it is really a long time, right?

In most species, this period of immaturityIt's on the order of weeks, maybe months. In humans, it is years. So it's a funny design by Mother Nature because it's a big energy drain for a parent, right? Raise another human being. I don't remember, I don't know what the numbers are, but someone calculated how many calories it would take to raise another human being and it's huge. So there has to be a really big reward. One of the arguments is that the payoff is that this gives us, as a species, this incredibly long period of plasticity so that we can do all the learning necessary to become a very complex adult.

So at the same time, I think what we're learning is that there's this notion of development and then you reach a certain level of maturity, which I'm still waiting for, and then you reach a plateau and at some point, at that point things go wrong. and if you're unlucky, you start to lose control. This way of thinking about it is probably the wrong way to think about it. That, instead, we should think of ourselves developing our entire lives until we die and that, therefore, plasticity, although it may be through different mechanisms and different efficiencies and working on different substrates, is still there.

It is still there throughout life. So it is not a critical period in the sense that plasticity is over and now plasticity can be reactivated. Opportunities can open up, but the ability to change, to balance stability, is there throughout life, which is, from the point of view of a neurologist or a neurosurgical perspective, a great opportunity and reason for hope and interventions. . This balance between stability and plasticity is really interesting. If you only think about some of the systems that have to form, then you don't necessarily want plasticity throughout life in a system, say, like our visual system, where we need to have a stable representation of the world inside our brain.

Then we can take advantage of that to do calculations and have insights, etc. So it's actually quite interesting. So some systems really need to go through this learning period, but then become more stable than other systems. So let's build on that a little bit, Carla, because the visual system, your mentors at Harvard, Hubel and Wiesel, won the Nobel Prize in 1981 for their seminal work on the first understanding of this whole concept and the visual system. So help us understand that a little more. Oh, of course. These are David Hubel and Torsten Wiesel. My mother... I used to call them Hubel and Wiesel and my mother thought she was one person, one person, Hubel and Wiesel, until she met them.

But yeah, these two wonderful scientists explored the visual system and started trying to understand what it's like, well, here's the question. How is it that we see with a single vision of the world, even though we have two eyes? So both eyes have a complete circuit. It's like you have two cameras. I mean, both eyes bring complete images of the world to the brain, but unless there is pathology, we only see one view of the world. The answer to this lies both in the wiring of the connections and in the fact that the brain has to learn to use both eyes at the same time.

It does so during a critical period of development. Then the connections of the two eyes begin to mix as the connections move from the periphery, from the retina itself to the central nervous system. The first binocular cells are actually integrated in the back of the brain, in the occipital cortex. That is your primary visual cortex. But although the connections know they grow to the visual part of the brain, they don't actually know how to tune themselves to form binocular neurons. One way to do this is to interdigitate the connections between the right eye and the left eye into a series of beautiful stripes of right eye, left eye, right eye, and left eye.

You'll actually see two images here. So there is an image where there are black and white stripes and those stripes are the same size, on the left. On the left. Then there is another image on the right where there are small black holes in the middle of a sea of ​​white. Now what you're seeing, let's say on the left, each little white dot is the size of about one synapse. So one of these connections and you're seeing literally millions of these connections. What you notice is that they are beautifully organized in stripes. When Hubel and Wiesel first discovered this mixture of two inputs, which are essential for forming binocular neurons, everyone thought they were hardwired.

But they did a very important experiment. The experimental result is on the right. Let me tell you this in another context, which is actually to talk about the mystery of the waterfall. So you know perfectly well that if as an adult you have normal vision all your life and you get a cataract as an adult, you lose the vision in your eye because there is an opacity of the lens. Then a miracle can happen. That you go to the surgeon and he will replace your lens with a transparent one and that you will see wonderfully again, immediately.

This replacement could occur after perhaps 10 years of not being able to see well through the eye. Now, on the other hand, a young child who may be born with a congenital cataract or have some other vision problem in one eye, if that cataract is not corrected immediately, then that child will be permanently blind or have severe vision loss at that time. eye. eye. So what is the difference? My grandmother had a cataract, 10 years old, corrected, good vision, and then the child maybe only has cataracts for a year, maybe even half a year, and it is corrected, the optics of the eye are corrected, the camera works, but the brain cannot see.

So what is the difference? Hubel and Wiesel did an experiment in which they tested the connections between the eye and the brain shown on the right side. Open-eye and white-eye connections take over much more than their fair share of cortical circuits for vision. The closed eye has those small, insignificant black holes. This was an amazing demonstration, a very important demonstration, in fact, the first of the use it or lose it concept in the brain. That brain connections require use to maintain and, in fact, even require use to form. So can you tell us a little bit about how you've been building on that work?

I think you have a video for us on how the brain does this in real time. This really illustrates a critical period of development that occurs after birth. But we were actually quite interested in whether there are earlier critical periods of development in the visual system. What we discovered is that even before babies are born, the eye sends signals to the brain to start shaping these beautiful stripes and these connections in the central pathways. The signals are electrical signals that are sent from neurons in the retina to the central part of the brain. They are actually like test patterns, they test the connections, the ones that are appropriate are kept and the rest are removed.

So this is the same topic. The video you see now is an image of that signaling process in the eye. So you can imagine that it's like phone calls are made to the brain at a very early stage of development and that each little black dot here in this video is again about the size of a nerve cell, not a synapse. So it's a larger scale, but you can see that when... when the cells turn black, it means they're making phone calls and sending their signals to the brain. So what you're seeing here are neighborhoods of nerve cells, all making phone calls together.

This is actually part of another principle of development: cells that fire together wire together. This is one way the eye can test to make sure the connections are arranged in the target structure. This is happening. So the brain is actually initiating vision before vision is even possible because it's in the womb, and it's before the rods and cones have appeared. Now that we know this happens in the visual system, this type of starting and testing has been found to occur throughout the brain during development, in the early stages of development. You've been studying ways to potentially reopen the visual system.

So tell us a little bit about that. Yes. Well, the question is really if these windows close, can you open them at any time? And really, to try to understand how to do it, it's important to know something about the molecular mechanism. So what are the molecules that open and close these critical periods of development? And really in particular, what are the molecular mechanisms that control the pruning process itself, this selection process, which synapses should we maintain? How does the brain know that certain synapses have been used and need to be strengthened and that other synapses have not been used as much so we don't need them and can in fact eliminate them?

We can then use animal models to begin to discover those molecules for pruning. In fact, in doing so, we found a number of candidate molecules that we wanted to test to see if they were important for this pruning process. We genetically engineered mice that lack these molecules to see what would happen to their critical periods and pruning. To our great surprise and delight, what we discovered is that if some of these molecules, when they are not there, allow the persistence of the critical period of development in the visual system, pruning does not occur. This illustrates two points.

One is that it is possible to continue extending a critical period for a longer period of time. It also points to the idea that brain plasticity itself can be regulated in a very deliberate way, and if we knew the whole story about the molecular mechanisms, we could actually make pills and I could take a pill as an adult and learn French without needing to. aid. accent. That brings up an interesting point because Álvaro is there smiling and shaking his head. So, as a clinical neurologist, I took the pill exactly. No, but would you like to take it right now?

As a clinical neurologist, you think about that and we talk about the balance between stability and plasticity and as you care for patients with strokes and things like that, what do you think about children like... Well, because Obviously everyone will say, "Well, we have to introduce them into humans. We have to find ways to expand these windows for children and for diseases in adults." So let's talk a little bit about the pros and cons of that. Yes, I think it's a really important issue and it's a double-edged sword. So having a very efficient plastic brain that is capable of making us learn French or English without an accent can be very attractive.

But at the same time, having too much plasticity can come at a cost. If so, not in a genetically modified mouse, but in a disease in which, by design, because of its pathology, the brain is too plastic, learns too quickly, and that seems, at first glance, a great thing. You can acquire skills beyond the average of us. You can open a box of matches, drop them on the floor and say 27 and be right or 225. You can learn a whole book of names and phone numbers and we call those wise skills. It's kind of cool and certainly partly a joke.

But the course comes because what happens to the brain is that it normally gives in to the influence of environmental change. Then we stop and then experience something new and that new lands on fertile ground, ready to learn the new. But it is not colored, but rather what we have just learned. The risk of having too much plasticity is that the brain changes and then change falls on change and change falls on change and change... it's often a messy, noisy system. We think that, for example, diseases like autism are characterized by excessive, too good plasticity, which leads to a failure in pruning and a developmental disorder due to the amount of plasticity.

So having too much can be a bad thing. So you've been studying that in autism specifically to try to look at plasticity in the autistic brain versus the non-autistic neurotypical brain. So what do you find, how do you go about separating that and what do you find? You have to carry out experiments. Is it worth proving that people with autism can learn

better

, for example, than people who are not autistic? And things like learning a sequence of repeating finger movements by doing it to discover the pattern beneath the finger movements. People with autism learn to do it faster than those without autism.

But if you have one pattern followed by another, then they break because they run into interactions between the two things they're learning. At the same time, we want to look at the brain and see what's changing in it to allow them to learn these skills faster. We do it in a similar way, we've learned to do it in animal models or in brain slices by using electrical stimuli to evoke a response and then using trains of small stimuli to modify those connections and see how long they stayed. modified. We do it using a technique called transcranial magnetic stimulation.

Tell us a little more about that technique andhow you can use it non-invasively to test something like this. Disturb the brain temporarily. It's a bit like science fiction. It still is for me. Basically, a coil of copper wire is placed over the subject's head and then when current passes through the coil of copper wire, it induces a current that passes through the skin and skull and induces a current in the brain. Maybe we can show it and have a little explanation to go with it. TMS stands for transcranial magnetic stimulation. It is a way of inducing current in the brain.

It needs a specifically controlled part of the brain without having to open the skin and skull. It turns out that when you apply repetitive stimuli, you are activating a zero grid over and over again in your control pattern, and that changes that zero grid. That allows us to activate, probe, interrupt or suppress activity in different parts of the brain depending on where we aim and what stimulation parameters we apply. Then you can probe the brain with this technique, see the response, apply a little train to modify it. So what we found in people with autism is that the effect of that modification literally lasts longer than in neurotypical subjects without autism.

Nim, we have mainly talked and now we have talked about vision and the motor system. You study many more aspects of the emotional phases of development. So let's talk about how you've been studying that in exactly the same context of plasticity and stability. Many of our questions are related to the point I made before that we have this design of spending a lot of time with our parents as we grow up. That is why we have been very interested in the role of parents during this supposedly sensitive period of emotional behaviors. We have known since the time of Freud that there is a very strong association between early caregiving experiences and later emotional behavior in adulthood.

But we don't really know at the level of human brain development why that lasting link exists. Part of the answer may have to do with some of these critical periods and the influence of parents. So we've been asking questions about, really, what good is a father? We know that parents are important, but what do they really do at all times? As I rush my kids off to school, shovel breakfast into their mouths to get them out, what are those momentary episodes important for? But we also have the opportunity to ask questions about children who experience more forms of adversity early in life.

The reason we have been very interested in this group of children is because this early exposure to adversity is one of the main preventable risk factors for emotional difficulties later in life. We're just in the early stages of understanding why early adversity in particular is so important, perhaps more important than late adversity. Part of the answer is related to the concept of critical periods we are talking about. So you mentioned the idea of ​​a double-edged sword earlier. I think there are a lot of double-edged swords when it comes to brain plasticity. Another one is that brain plasticity is neither really good nor bad.

It simply is. It just opens you up to the environment. So when considering or evaluating brain plasticity, it's also important to look at what is the nature of the environment that the individual experiences when the brain... when that window of opportunity is actually open. So for children who have experienced significant adversity, such as caregiving adversity or what we often call psychosocial trauma, what we've seen, well, are two main things. One is that there are incredible individual differences in results. So some kids are showing some really big challenges and some are thriving. This is a story of individual differences that we're really not very good at explaining right now.

But the other thing we've been seeing, and this is true not just in humans but across several species, is that early adversity may actually be affecting brain development on average by affecting the timing of these critical periods. Therefore, there may be an acceleration of momentum or opening of these critical periods. So if we know that, it's really important to know that in terms of intervention and prevention, because if the timing of these critical periods is changing based on early experience, then that informs how we want to treat individuals and what new experiences we want. give to individuals based on these first experiences.

And that's why you like to refer to these, as you said before, as sensitive periods, rather than critical periods. For the processes that we're interested in, these emotional and cognitive behaviors, that seems to make more sense to me because they seem to be more malleable. In fact, that's why psychotherapy is supposed to work. Psychotherapy consists of teaching the brain something new about interpersonal relationships. The only way psychotherapy can work is if there is continued plasticity in some of these systems. So we talked a little bit about autism. Let's talk a little about schizophrenia because it is another very complex condition and there are questions about whether or not schizophrenia may have aspects of a stability and plasticity disorder.

So, Carla, maybe you can enlighten us a little bit on that. Well, I mean, an important point to make about schizophrenia is that it's not really considered a developmental disorder. Although symptoms often appear late in adolescence or even beyond, the current thinking is that there is this critical period of extended development and this period exists beyond the visual system, as Nim has mentioned. Therefore, these systems that are maturing much later, including those that have to do with interactions and with frontal lobe cognition and behavior, all mature later. So the question is what are the changes that have occurred in the brain?

Again, it is now commonly thought that this relationship between plasticity and stability must be altered in some way. When people look inside the brain of a... not much has been done, but there is a consensus that there are pruning changes in the

brains

of schizophrenic patients who have donated their

brains

for studies, so that we can actually observe them. brains. In human genetics studies we look for susceptibility genes that can cause schizophrenia in children. Some of the new candidate genes that have been identified are known in animal models where we study how these genes really work.

It is known that they regulate pruning in the animal. , such as the critical periods of mouse development. So now you're starting to hear a kind of common theme that's emerging as we speak, that there are these critical periods that involve a beautiful balance between plasticity and stability, they involve pruning, and they can have different outcomes, not just through our own experiences. , but also when the balance is somehow altered by some type of pathological condition. Let's talk a little about how we take advantage of damage recovery after an injury. You talked a little bit, Nim, about a traumatic situation, but what about critical periods in childhood, when we reach adulthood, how do we attack that problem?

Well, I think the way we talk about plasticity really says that it's a great reason for hope, right? It suggests the fact that our brain can be guided and the challenge is to learn exactly how to guide it. What should we do to suppress the changes that are those double-edged swords that cause problems and enhance others that can benefit the subject? We have many interesting indications that this is possible. Ultimately, that is what physical therapy, occupational therapy and speech therapy promote. It is conversation therapies that guide changes for the benefit of the subject. But I think now, as we

better

understand the molecular and physiological basis of these mechanisms, we have ways to target these mechanisms with drugs or with devices, with brain simulation that promote changes more directly to the brain.

That is happening and it is happening guided by basic research and translating that basic research to humans. Very sorry. One of the things that really excites me in terms of intervention is thinking about how we can increase the

power

of current interventions by knowing about the critical periods of plasticity. So if we can increase plasticity before some known effective intervention, that's really

power

ful. So, as you mentioned, there are many examples in basic neuroscience where pharmacological or genetic administration or modification can actually increase plasticity and, in many ways, return the brain to that infantile state to allow some environments to have a really big effect on health. brain.

That's really powerful and there's also a demonstration in humans that has used one of these pharmacological manipulations with people who don't have perfect pitch and perfect pitch depends on the critical early learning period in development. Thus, the perfect tone could be developed in adults who had taken this pharmacological drug. So the question is, why don't we all do it? Good? The authors of the study are really... they're very careful to say, "Hey, remember that the brain actually expends a lot of energy to prevent these critical periods from opening up again." The brain wants efficiency, the brain wants reliability.

Do we want to eliminate all the lessons we have learned throughout our entire development history? Do we want to eliminate aspects of our personality and so on? Therefore, it becomes a very complicated question even though there are many promises of recovery after any type of trauma. But in that pitch-perfect study, no... people didn't lose... I mean, they learned something new. So there really is hope. There is hope for selective intervention. I think that's exciting. I mean, from animal studies. So, looking again at the mice... and in fact, one of the authors of that study has also done work looking at the critical periods for vision in mice, as has my own lab.

What we found is that you can actually go into the brain of an adult mouse and really restore juvenile plasticity in the adult brain. The mechanism for doing this appears to be, again, allowing new synaptic connections to form. If we study the history of childhood cataracts, but now in the mouse, then remember that I told you that if children have cataracts and they are not operated on immediately and their clear optics are not restored, then they become permanently blind or their vision is impaired. is seriously affected. diminished in that eye. And there really isn't a good way to treat this blindness, which is called amblyopia, in adulthood.

But in these mice, you can actually do the cataract model and then do it in the adult mouse, and by activating these infantile mechanisms of plasticity you achieve a vision recovery effect in the eye that was blind, which is surprising. I really... I think it shows that by understanding the underlying mechanisms that regulate these critical periods of development, it's possible to go in and then manipulate them again. To me, this demonstrates something else, and that is that there must be in the adult brain and presumably in our brain as well, because we have many of the same molecules that are being studied in animal models, there must be brakes on plasticity. because these manipulations essentially remove the brakes and then of course you can worry about stability.

So we come back to that, to this whole topic. Again, but the idea that there is actually more plasticity in our adult brain that we can take advantage of, to me is really exciting because you could say that even if there are some disadvantages, that after a stroke or brain damage, there is no It would be wonderful if it were possible to take advantage of that extra latent plasticity, even briefly, and combine it with training and physiotherapy. So in some ways, a pill that would allow me to speak French without an accent could have a really important therapeutic value, which would be helping people recover from brain damage.

Well, what we have here is a video of a modern split treadmill rehabilitation technique. Maybe, Álvaro, you can tell us about the concept behind this. Yes. So, part of the physical therapy interventions like this or something called restraint therapy that some of you may have heard about in people who have a stroke, who can't use both legs to walk properly, or who can't use one hand correctly, we have come to learn that if you force the use of the other hand, the damaged hand by limiting the default use of only using the healthy hand or, in this case from the video, if you force walking correctly by aligning the paretic leg because you cannot cross Therefore, we limit the pattern of abnormality that would normally occur, which because of this repeated training doing the right thing, that promotes rewiring that promotes plastic change and accelerates recovery.

So by guiding and restricting behavior, it can be used as a way toimprove the recovery process. So the opportunity to open up the plasticity mechanisms in such a way that they become more active, and therefore benefit more from intervention, becomes really attractive. There are examples of this even in humans, not just with medications. One of the things we know about Alzheimer's dementia, Alzheimer's disease, is that before clumps of this abnormal protein come together and deposit plaques in the brain, they're floating around. At this stage they already alter and damage the synapses. They thus become substances that are harmful to plasticity mechanisms.

If you take patients with Alzheimer's disease and try to get them to learn with video or computer games and improve on cognitive tasks, they will get very little benefit. It would take too long to make a significant profit. But if you activate that zero grid with brain simulation, for example, right before they actually engage in cognitive training, now you'll get more benefits from cognitive training. So combining interventions, device-based pharmacological interventions with behavioral interventions, I think is really a way to leverage what we know about the mechanisms of plasticity in a way that translates into benefits for patients.

That's why we've talked a lot about aspects of illness and repair. What's up with this idea of ​​the Holy Grail? What about the idea of ​​actually improving the brain? Whether one day I was thinking, "I had a long day today," and I thought, "Oh my God, I have to focus on what we're going to do tonight," and I got in a car and when is the A helmet going to come out through the ceiling or it's already built into the ceiling, where I can say, "If I could just get my temporal lobes working and my memory would work a little better, how wonderful that would be." How far are we?

How far are we from daily improvement in function? It didn't exactly work this morning. You were in the wrong car. I was in the wrong car. I mean, what gave me the push is that of course there's a lot of industry and really direct investment in consumer devices that are already saying that that's possible, that we don't need to wait at all. That you can do it today and you can build your own brain stimulation devices and then integrate them into your car if you want. People will claim and try to convince us that it is possible to enhance capabilities.

The problem with a lot of that data is that what it shows is that it is possible to improve performance on a given task, not actually improve the fundamental skill underlying the task. So I think the attempt to get us there is already here, but we need more understanding, including more understanding of that double-edged aspect that Nim was mentioning. If we improve something, will it be free of charge? Will the brain allow you to improve something at the expense of something else? So, for example, you can ask a question and say, "What if we could improve our ability to pay attention to this part of the world?

We know a lot about what the circuits are that allow us to pay attention to this part of the world." specific place." So, you can identify those areas of the brain in humans, apply a simulation that increases activity in those areas of the brain, and you can make people pay better attention to this part of the world. But when you do that, the cost It's paying attention to this part of the world. In fact, it does because these two areas in a way... I almost said it's a kind of yin yang relationship. So, there are interactions between the two hemispheres.

So if you improve one, you get worse. the other. This is easy to test in something as concrete as spatial attention for a visual task and in something as complex as general behavior or higher-order cognitive functions. What exactly the cost might be is much, much harder to test. I think it raises not only methodological and biological questions, but also real ethical questions. If you want to improve certain skills, what would potentially be the downside? I mean, memory is something... to varying degrees? , we're all here, slowly moving forward chronologically and everyone's worrying about what's going to happen to their memory.

In my world, people sometimes have the ability to place electrodes in the brain. That allows us to stimulate the brain and there are several reports of different parts of the brain. If stimulated in the right way, someone's memory performance can be improved. How do you think that's not a way to combat aging per se, but to help people adapt as they age and keep their memory intact? Forget about super memory, even trying to keep it intact as we move forward. How do you see us getting closer to that? I mean, correct me if I'm wrong, but aren't there less attractive and innovative ways that people think of or have studied to improve some of these processes?

So, for example, the things that we know we should do, like sleep well, exercise. Engaging in cognitive stimulation throughout life has been associated with better long-term cognitive aging. So those are hard things that we all know we should do, but they're routine things that we should do that can actually improve some of this long-term retention. So lifestyle modifications work and work through plasticity. So physical exercise promotes cognitive function. In fact, if you do an analysis of all the studies that have been done in the literature that we just did, that we just published in... there is a...

I don't know why this is the number, but there are about 52 hours a day, 52 hours... Talking about improving is really hard work. It's really hard work. Actually, 52 hours in six months. So it's not a lot and no matter how many hours a day you do it, it's almost a full amount of doses. But you need to put in some hours, but it's not a lot of hours. Of exercise? Physical exercise that improves cognitive function in older people. So I think that physical exercise has an effect on the brain and seems to be related to mechanisms of plasticity, at least as can be tested in humans with brain imaging and brain stimulation techniques.

But I think instead of reaching the level of suggestions, you should sleep better, avoid medications that are bad for you, eat the right things and in the right amount, exercise and challenge your brain with new things and be social. All of those things are true, but we should be able to come to enough of an understanding that we can prescribe it, that we can say to men, "This is how many hours of this exercise you should do, and this is how we're going to do it." to help you turn these hopes into realities." Because it's hard to stick with a program like that.

So I think that's the step that we haven't taken yet, is understanding how to make this a prescribable intervention, like we do with We don't tell patients, "Take something for that." We tell them what to take and how much, etc. So I think we need that level of understanding. But what about happiness set points? ?Everyone wants wellness. Is it possible that we will one day understand the brain well enough to say, "Okay, you've been through some really terrible life trauma, but we can actually help you with your baseline." I would think of something like maybe not happiness, but that feeling of being able to regulate your emotions, of being able to feel less sad when you want, of being able to feel sadder when you want.

Having that ability to regulate emotions. That's why there are studies, for example, with people who meditate, which we generally consider a healthy lifestyle practice. But there are different levels of experience in meditation. So there are Buddhist monks who do this for, say, 40,000 hours in total, versus very, very dedicated meditators who might have done this for 20,000 hours, and then novices. This research has shown that the amount of meditation practice, practice being the key word, with which the behavior should be performed routinely, is associated with brain changes in brain regions, such as the prefrontal cortex, that we know are associated with with the regulation of emotions. .

The interesting thing about that finding, and what is related to the original example of walking and the quote about habit, is that there was this dose-response function in the shape of an inverted U, so that individuals who meditated a lot but not to the degree of The Buddhist monks actually had the most different prefrontal cortex activity and then it went back down for the Buddhist monks, suggesting that there is this element of plasticity in brain regions that we know are associated with emotion regulation. , but an element of habit may come into play. Play too, so that it starts to become more of a natural state of the brain that can be, as you were referring to before, the core process that is affected rather than the more superficial process.

So I would have to say, in summary, that we obviously have a very, very tight balance between stability and plasticity. But as we've all learned, they are incredibly exciting things, not just normal behavior, that attack diseases coming down the road. But in the meantime, eat well, sleep well, meditate from time to time, exercise a lot, and surround yourself with really smart people who make you happy. For that I thank you all.