Our human newborn, Augie Nelson's current
abilities are somewhat limited. He can cry, sleep, eat and hiccup. The turtle, also newly hatched, can crawl,
separate from her siblings and begin a vast trans-Atlantic migration, alone without parents
or learning. Her brain has already formed every connection
she'll need for the great journey ahead. Seven months later, Augie is learning to sit
up. In a year or so, he'll be walking. Another decade, he'll be walking to school
by himself. By that time, the turtle will have completed
a solo 9000 mile circumnavigation of the Sargasso Sea and returned to the shores where she was
born to build her own nest. The turtle's 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 by himself, if he wants. Everything he needs to learn these things
is already there. We're born with as many neurons and as many
connections as you're going to need. They can go from any spot of the brain to
every spot with as many connections as possible. That's a brilliant design by mother nature
because it gives us this incredible amount of possibilities for the future. But there's a catch. That gift of possibility doesn't last forever. Like childhood itself, it comes to an end. For each skill, we get a golden period when
learning is easy. Periods in development when we have a heightened
plasticity for shaping neural circuitry and we refer to those as critical periods. Learning to play the guitar as a child is
like opening a door and as a child, we have lots and lots of doors. During this time, our neural circuitry gets
fine tuned. Our brain learns about which connections are
going to be important through a use it or lose it principle. Certain connections become reinforced and
sustained and enhanced at the cost of others. Those connections that aren't being activated
because they're learned not to be necessary, get pruned away. They actually die off, and the open doors
begin to close. As an adult, if you've never played, you've
lost that door. So right now, Augie can learn to speak any
human language perfectly without an accent, but when he's an adult, he will have lost
that ability. If he doesn't begin learning the violin before
he's about seven years old, he'll probably never play Carnegie Hall. If you never had the connections to begin
with, you can dry as hard as you can. You're never going to get there. But what if we could change that? What if we could tweak our brains to learn
as easily as a child? It's called The Holy Grail of Neuroscience,
and it is tantalizingly close. We can, to some degree, do the impossible
and reopen critical periods to say we allow changes to happen later on, in ways that we
didn't anticipate would be possible. Scientists are learning how we learn, and
that may soon give us a chance to reopen those doors. So what actually is neuroplasticity? Neuroplasticity is the ability of the brain
to adapt to changing circumstances. To an environment changed, the ability of
our brain to in a nutshell learn. But there's 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. So in fact, that balance is what we're going
to focus on a lot tonight. Our first participant was the first woman
to chair the Department of Neurobiology at Harvard Medical School. Today, she's professor of Biology and Neurobiology
at Stanford University. Please welcome one of the world's foremost
neurosciences, Carla Shatz. Our next participant is Associate Professor
of Psychology at Columbia University, director of the Developmental Affective Neuroscience
Laboratory, Please welcome Nim Tottenham. Our third participant this evening is Professor
of Neurology at Harvard Medical School. An MD-PhD, he says his research falls in the
area between the brain and the mind. Please welcome Alvaro Pascual-Leone. So welcome everybody. So Carla, let's start with the brain itself. We're going to be talking about learning plasticity,
how the brain learns, how skills become habit. But what do these things actually look like
in the brain structurally? We saw already some nice photographs in the
introduction, if you remember of these black things. Structurally, the brain is composed of neurons
and support cells. The neurons communicate with each other through
electrical signaling; chemical electrical signaling. The most important aspect of that is that
these communications are transferred across structures known as synapses. That's where learning happens. That's where memories are stored, and as we
were talking about in the video, that's where the pruning, this pruning process goes on,
this use it or lose it process goes on during development. So, in fact, the structure of the brain is
just the brain is packed with these neurons, packed with these synapses and also with very
long connections. Some of those you can actually see in this
beautiful graphic that's being displayed now. So the brain connections link various parts
of the structure to each other, ad those are the beautiful colors that look like Us and
so on, these pathways. But those are made up of hundreds and thousands
of connections from individual neurons. I used to joke 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 picture like
that, we're looking really at the axons, the wiring-
The wiring. Is the brain fundamentally un-wired at the
start? The brain is not fundamentally un-wired at
the start. But it is amazing, if you just take the visual
system, for example, the eye is not connected to the brain to start with. The nerve cells in the eye, have to grow their
connections along pathways and select the right part of the brain, namely 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 very beginning is very
highly organized and the formation of these long tracks or pathways is dictated by very
strict cues like pathways or even like roads with street signs on them, so that these growing
connections or the growing axons follow these pathways. But then the amazing thing is once the connections
form between these long distant regions of the brain, then there's this period of overproduction
and pruning that we're going to talk about. A period of extensive plasticity where the
outcome is really predicted by the use of the circuit itself and the experience itself. So there's both directed kind of hard wiring
early, followed by this remodeling plasticity that happens later and really persists to
some extent throughout life. So then building on that, if we think about
it, if you're building a house, you're not going to lay copper wires all over the place
and then pull out the ones that don't seem like they're working well. But that seems to be what we're talking about. It seems pretty inefficient and the brain
is 2% of the body weight, but yet gets 20% of the blood flow and 25% of the glucose. So why is the brain doing it that way? NIM Yeah, so on face value, there's so much
about brain development that seems inefficient, but actually it's that seemingly inefficient
path that actually gives rise to the incredible complexity of the brain, especially in the
case of the human. So when we're developing, what our brain does
is first goes through this period of over producing our neurons and synapses and then
through experience, through learning what's important in the environment, what synapses
are getting activated, those get to stay and everything else gets snipped away because
it's inefficient to keep all of those synapses. So, why would we go through this entire process
of over producing and then pulling back? That's really at the core of what the function
of childhood is in the human. So if you think about humans as a species,
we're amazing in many ways. We can live anywhere on the planet. We can speak any language, we can eat a number
of foods and so on and live very well. Some of the reason why we can do that is because
of this long period of brain development that we have. So the brain overproduces, it's like throwing
a big fishing net out into the ocean because you're not sure which house you're going to
end up in. You're not sure what language people are going
to be speaking to you. So you're ready, you've got all your bases
covered. Then depending on what signals are coming
into the brain, the brain learns, "Okay, I'm going to keep the synapses, but I'm going
to get rid of these. So if I'm growing up in a Japanese speaking
household, I'm going to hang on to the synapses that help me understand Japanese, but get
rid of the synapses that support other languages because that's really efficient." So it really is this developmental period,
a really long one in humans, that gives rise to our incredible adaptation to our particular
environments. So, Alvaro, is this a new concept? We all think everything's been figured out
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 conceptual. I think there's lots of new developments,
but many of the ideas are not fundamentally new, we have the tools to actually test the
concepts. But the first person to speak about plasticity
and stability as a term and apply to behavior; to human behavior, was Williams James; the
psychologist Williams James in the 1890s. He wrote about plasticity as being the property
for substance of an organ, presumably of the brain, that enabled us as humans to do certain
behaviors and become really good at it. He was talking about behaviors, a habit, not
about the brain structure. He said, the amazing thing, it has a property
of giving in to influence but not giving in all at once. You want to have some plasticity but not too
much plasticity. You want the right kind of plasticity, the
right amount of plasticity. Presumably, it was Ramón y Cajal, not much
longer, who started to look into where does that actually happen in the brain and describe
the synopsis and the changes in the connectivity and the change of how efficacious those connections
were in making new ones as the substrate for that plasticity that Williams James was talking
about. So the ideas are 100 years old, and yet when
I was studying medicine, I was told, "Things don't change in the brain and when you get
old, well tough." I thought, God, I hope we can do something
about it because I hope to get there one day." I think we start and all know, we've always
known, as an old dog, you can still learn new tricks. It was against the experience of everybody
that it is possible to learn new stuff. So how does that gel together? Great. So now let's go back to this. We were talking about this concept of a critical
period. We all know the old adage that children learn
language a lot more easily than adults. But what are some of the other examples of
critical periods that you see in your work with children? So for a while, people were thinking that
there is a critical period of human brain development that was the language that people
used and then it became clear that critical periods are really a property of a developing
neural circuit. So if that's true, then maybe it's appropriate
to think of each neural circuit that we have as undergoing its own critical period. That moment, the metaphor that people often
use for a critical period is that it's a window of opportunity opening up when the environment
can really have its biggest impact on the nature of future functioning for that system. If it's true that every neural circuit has
its own critical period, then maybe we can sort of map out the timing across the brain. So in general, what people find is that the
brain develops in this backwards C-shaped nature where regions of the brain that are
low and back tend to develop earlier, then the development curls around in waves.So what
you often see, sensory systems develop earlier, experience their critical periods, followed
by motor systems and language systems, and finally more of these higher cognitive functions
that particularly in the human, we spend so much time thinking about. So, things like our emotion processing or
our cognition, academic performance and so on. So, that hierarchical structure really makes
sense when you think about what the needs of the developing infant child or adolescent
are going to be. So the video, we saw a baby turtle that really
doesn't have a childhood. It jumps in the ocean and takes off whereas
humans, we have this extended childhood period where all of this has to happen. You could argue that because we have the most
to go through experientially, that we have the longest childhood. I think it's another good example of what
seems like an inefficient design, right? So if we're going to stay and mature for that
long, then we need somebody around us who's willing to put in the investment to stick
around with us that long. So if you look at this immature period in
the human, it's really a long time, right? In most species, this period of immaturity
is on the order of weeks, maybe months. In humans, it's years. So that's a curious design from mother nature
to come up with because it's a huge energy suck for a parent, right? To raise another human being. I don't remember, I don't know what the numbers
are, but someone computed how many calories it would take to raise another human being
and it's enormous. So there's gotta be a really big payoff. One of the arguments is that the payoff is
that this affords us as a species, this incredibly long period of plasticity so that we can do
all the learning that's 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 get to some level of maturity,
which I'm still hoping for, and then you have a plateau and at some point things go wrong
and if you are unlucky, you start losing it. This way of thinking about it is probably
the wrong way to think about it. That, instead, we should think of us developing
our entire lifespan until we sort of die and that therefore plasticity, even though it
may be through different mechanisms and different efficacies and working on different substrates,
but it's still there. It's still there throughout the lifespan. So it's not a critical period in the sense
that plasticity is done and now you can reactivate plasticity. You can open opportunities, but the capacity
of change, balancing the stability is there for the entire lifespan, which is from a neurologist's
point of view or neurosurgical perspective, a huge opportunity and reason for hope and
of interventions. This balance between stability and plasticity
is really interesting. If you just think about some of the systems
that have to form, then you don't want necessarily plasticity throughout life in a system, let's
say, like our visual system where we need to have a stable representation of the world
inside our brain. Then we can draw upon that to make computations
to put together and to have perceptions and so on.So it's really quite interesting. So some systems really need to go through
this learning period, but then to become more stable than other systems. So let's let build on that a little Carla,
because the visual system, your mentors at Harvard, Hubel and Wiesel won the Nobel prize
in 1981 for their fundamental work on really the first insights into all this concept and
the visual system. So help us understand that a little more. Oh, sure. So, this is David Hubel and Torsten Wiesel. My mother ... I used to call them Hubel and
Wiesel and my mother thought it was a person, one person Hubel and Wiesel, till she met
them. But yeah, so these two wonderful scientists
explored the visual system and began to try to understand how it is, well, here's the
question. How come we see with one view of the world,
even though we have two eyes? So both eyes have complete circuit. It's like you have two cameras. I mean, both eyes bring complete images of
the world to the brain, yet unless there's pathology, we only see one view of the world. The answer to this as both in the wiring of
the connections and also the fact that the brain has to learn how to use both eyes together. It does that during a developmental critical
period. So the connections from the two eyes begin
to be mixed together as the connections move from the periphery, from the retina itself
into the central nervous system. The first binocular cells are actually built
in at the back of your brain in your occipital cortex. That's your primary visual cortex. But even though the connections know to grow
to the visual part of the brain, they actually don't know how to tune up to make binocular
neurons. One way they do that is to interdigitate the
connections between the right eye and the left eye into a series of beautiful right
eye, left eye, right eye, left eye stripes. You'll see two images here actually. So there's an image where there are white
and black stripes and those stripes are equal in size-
On the left. On the left. Then there's another image on the right where
there are little teeny black holes in the middle of a sea of white. Now what you're looking at, let's just say
on the left, every little white dot is the size of about a synapse. So one of these connections and you're looking
then at literally millions of these connections. What you notice is that they're beautifully
organized in the stripes. When Hubel and Wiesel first discovered this
intermixing of the two inputs, which are essential for making the binocular neurons, everybody
thought they were hardwired. But they did a very important experiment. The experimental result is on the right. Let me tell you about it in just one other
context, which is really to talk about the mystery of the cataract. So you know perfectly well if as an adult
you have normal vision your whole life and you get a cataract as an adult, you lose the
vision in your eye because there's a clouding of the lens. Then a miracle can happen. That you go to the surgeon and he replaces
the lens with a clear lens and you see beautifully again, immediately. This replacement could happen after maybe
10 years of not being able to see well through your eye. Now, in contrast, a little child who might
be born with a congenital cataract or have some other problem with vision in one eye,
if that cataract is not a corrected immediately, then that child will be permanently blind
or have severe vision loss in that eye. So what's the difference? My grandma had a cataract, 10 years worth,
corrected, good vision, and then the child maybe has a cataract just for a year, maybe
even half a year, and it's corrected, the optics of the eye are corrected, the camera
works, but the brain can't see. So what's the difference? Hubel and Wiesel did an experiment where they
actually checked the connections between the eye and the brain that was shown in the right
hand side. The open eye, the white eyes connections take
over way more than their fair share of cortical circuitry for vision. The closed eye has those little piddly 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 the brain connections require use in
order to be maintained and in fact even require use in order to be formed. So can you go into a little bit how you've
been building on that work? I think you've got a video for us of how the
brain does this in real time? This really illustrates a developmental critical
period that happens after birth. But actually, we were quite interested in
knowing whether there are earlier developmental critical periods in the visual system. What we discovered is that even before babies
are born, the eye is sending signals to the brain to start to really shape up these beautiful
stripes and these connections in the central pathways. The signals are the electrical signals that
are being sent from the neurons in the retina into the central part of the brain. They're actually like test patterns, they're
at testing the connections, and the ones that are appropriate are being maintained and the
other ones are being pruned away. So this is the same theme. The video that you see now is a picture of
that signaling process in the eye. So you can just imagine it's like phone calls
being placed to the brain really early in development and every little black dot here
in this video is again about the size now of a nerve cell, not a synapse. So it's a bigger scale, but you can see that
whenever ... when the cells become black, it means they're placing the phone calls and
they're sending their signals to the brain. So, what you're seeing here is neighborhoods
of nerve cells, all placing phone calls together. This is actually part of another principle
of development, cells that fire together wire together. So this is a way that the eye can test to
make sure the connections are orderly in the target structure. This is happening. So the brain is really jump starting vision
even before vision is possible because it's in utero, and it's before the rods and the
cones have appeared. Now that we know that this happens in the
visual system, it's been found that this kind of jump starting and testing is happening
all over the brain during development, very early development. You've been studying ways to potentially reopen
the visual system. So tell us about that a little bit. Yeah. Well, the question is really if these windows
close, can you open them up at any time? And really to try to understand how to do
that, it's important to know something about the molecular mechanism. So what are the molecules that are opening
and closing these developmental critical periods? And really in particular, what are the molecular
mechanisms that control the pruning process itself, this selection process, which synapsis
should we keep? How does the brain know that certain synapses
have been used and they should be strengthened and other synapses have not been used so much,
so we don't need them, so we can actually prune them away? So we can use animal models to begin to discover
those molecules for pruning. In doing that, in fact, we found a number
of candidate molecules that we wanted to test to see if they were important for this pruning
process. We engineered genetically mice that lack these
molecules to see what would happen to their critical periods and to pruning. To our great surprise and delight, what we
discovered is that if certain of these molecules, when they're not there, permit the persistence
of the developmental critical period in the visual system and in fact pruning fails to
happen. So this is illustrating two points. One is that it is possible to continue to
extend a critical period for a longer period of time. It also indicates the idea that brain plasticity
itself can be regulated in a very deliberate way, and if we only knew the whole story about
the molecular mechanisms, we really could make pills and I could take a pill as an adult
and learn French without an accent. So that brings up an interesting point because
Alvaro is over there smiling and shaking his head. So as a clinical neurologist-
I've taken the pill, exactly. No, but would you want to take it right away? As a clinical neurologist and you think about
that and we talk about the balance between stability and plasticity and as you're taking
care of patients with strokes and things like that, what do you think about in kids as ... Well,
'cause everybody's obviously going to, "Well, we got to get these into humans. We've got to figure out ways to extend these
windows for kids and for disease to adults." So let's talk a little bit about the pros
and cons of that. Yes, I think it's a really important topic
and it is a double edged sword. So to have a great efficient plastic brain
that is able to get us to learn French or English without an accent, it may be very
appealing. But at the same time to have too much plasticity
can come with a cost. If you have, not in a genetically engineered
mouse, but a disease where by design, because of their pathology, the brain is too plastic,
is learning too fast, and that seems at face value a great thing. You're able to acquire skills that go above
the average one of us. You can open up a box of matches, have them
fall on the ground and say 27 and be right or 225. You can learn a whole book of names and phone
numbers and we call those savant abilities. It's sort of cool and it's certainly partly
a joke. But it comes to the course because what happens
to the brain is that normally it yields to influence to the environmental change. Then we stop and then we experience a new
thing and that new thing falls on to fertile grounds, ready to learn the new thing. But it doesn't get colored, but what we just
learned. The risk of having too much plasticity is
that the brain is change and then the change falls on to the change and the change into
the change and the change ... it is often a messy, noisy system. We think that for example, diseases like autism
are characterized by excessive, too good at plasticity, that leads to a failure of pruning
and to a developmental disorder because of the number of plasticity. So to have too much may be a bad thing. So you've been studying that in autism specifically
to try to look at plasticity in the autistic brain versus in the neurotypical non autistic
brain. So what do you find, how do you go about teasing
that apart and what do you find? You have to come up with experiments is it
worthy to show that people with autism can be better at learning for example than the
individuals that are not autistic? And things like learning a sequence of finger
movements that repeat themselves by doing it to figure out the pattern underneath the
finger movements. Individuals with autism learn to do that faster
than those without autism. But if you have one pattern followed by another,
then they break down because they run into interactions between the two things that they
are learning. At the same time, we want to look in the brain
and see what is changing in the brain to allow them to learn these skills faster. We do that in a similar way, that we've learned
to do it in animal models or in slices of the brain using electric stimuli to evoke
a response and then using trains of little stimuli to modify those connections and see
for how long they remained modified. We use that using a technique called transcranial
magnetic stimulation. So tell us a little more about that technique
and how you're able to use it noninvasively to test something like this. To perturb the brain transiently. It's a bit like science fiction. It's still to me. You basically put a coil of copper wire over
the subjects head then as the current passes through the copper wire coil, it induces a
current that goes through the skin and the skull and induces a current in the brain. Maybe we can show it and it has a little explanation
that goes with it. TMS stands for transcranial magnetic stimulation. It is a way of inducing current in the brain. You need specific controlled part of the brain
without having to open up the skin and the skull. It turns out that when you apply repetitive
stimuli, then you're activating a zero grid over and over in your control pattern, and
that changes that zero grid. So that allows us to activate, probe, disrupt
or suppress activity in different parts of the brain depending on where we target and
what parameters of stimulation we applied. So you can probe the brain with this technique,
see the response, apply a little train to modify it. Then what you find in people with autism is
that the effect of that modification lasts literally longer than it does in neuro-typical
subjects in those without autism. So Nim, we've talked mostly and now we've
talked about vision and we've talked about motor system. You study a lot more aspects of emotional
phases of development. So let's talk about how you've been studying
that in these exact same context of plasticity and stability. A lot of our questions are related to the
point I made earlier that we have this design of spending a lot of time with our parents
while we're growing up. So we have been very interested in the role
of the parents during this putative sensitive period for emotional behaviors. So, we know since the time of Freud, that
there is this very strong association between early caregiving experiences and emotional
behavior later on in adulthood. But we don't really know at the level of human
brain development why that enduring link exists. Part of the answer may have to do with some
of these critical period timing and the influence of the parents. So we've been asking questions about, actually,
what good is a parent? We know that parents are important, but what
are they actually doing on a moment to moment basis? As I'm rushing my kids out the door to school,
shoving breakfast into their mouths to get them out the door, 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 that we've been very interested
in this group of children is because this early adversity exposure is one of the number
one preventable risk factors for emotional difficulties later on in life. We're just at the beginning stages of understanding
why early adversity in particular is so important, maybe more important than later adversity. Part of the answer is related to the concept
of critical periods that we're talking about. So you brought up the idea of a double edge
sword before. I think that there are many double-edged swords
when it comes to brain plasticity. Another one of those is that brain plasticity
is not really good or bad. It just is. It just opens you up to the environment. So when considering or evaluating brain plasticity,
it's also important to look at what's the nature of the environment that the individual
is experiencing when the brain ... when that window of opportunity is really open. So for children that have experienced significant
adversity, like caregiving adversity or what we often call psychosocial trauma, what we
have seen, well, two main things. One is that there's incredible individual
differences in outcomes. So some children show some really significant
challenges and others are thriving. So this is an individual differences story
that we really aren't very good at explaining right now. But the other piece that we've been seeing,
and this is true not only in humans but across a number of species, is that early adversity
may actually be affecting brain development on average by affecting the timing of these
critical periods. So there may actually be an acceleration of
the timing or the opening of these critical periods. So if we know that, that's really important
to know in terms of intervention and prevention, because if the timing of these critical periods
are shifting as a function of early experience, then that informs how we want to treat individuals
and what new experiences we want to give to individuals as a function of these early experiences. And that's why you like to refer to these,
as you said before, as sensitive periods, more than critical periods. For the processes that we're interested in,
these emotional behaviors and cognitive behaviors, that seems to make more sense to me because
they do seem to be more malleable. In fact, that's why talk therapy is supposed
to work. Is that talk therapy is about teaching the
brain something new about interpersonal relationships. The reason, the only way that talk therapy
can work is if there's continued plasticity in some of these systems. So we talked a little bit about autism. Let's talk a little bit about schizophrenia
because they're another very complex condition and there are questions about whether or not
schizophrenia may have aspects of a disorder of stability and plasticity. So, Carla, maybe you could enlighten us on
that a little. Well, I mean, one main point to make about
schizophrenia is that it's not really commonly considered to be a developmental disorder. Even though often symptoms appear late in
late adolescence or even beyond, the current idea is that there's this extended developmental
critical period 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 cognition and frontal lobe behavior, all mature later. So then the question is what are the changes
that have happened in the brain? Again, it's commonly now thought that this
relationship really between plasticity and stability must be perturbed in some way. When people look into the brain of a ... not
a huge amount has been done, but there is consensus that there are changes in pruning
in the brains of schizophrenic patients who have donated their brains for studies so that
we can actually look at those brains. In human genetic studies we're looking for
susceptibility genes that might produce schizophrenia in children, some of the new gene candidates
that have been identified are known in animal models where we study how those genes actually
work, are known to regulate pruning in the animal, like the mouse developmental critical
periods. So, now you're beginning to hear a kind of
common theme that's emerging as we talk, that there are these critical periods that involve
a beautiful balance between plasticity and stability, involve pruning and may have different
outcomes, not only through our own experiences, but also when the balance somehow is disrupted
by some kind of pathological condition. let's talk a little bit about how do we harness
recovery of damage after injury. You talked a little bit, Nim, about a traumatic
situation, but what about critical periods in childhood, when we get to adulthood, how
do we attack that problem? Well, I think the way we're talking about
plasticity really say it's a huge 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 do we need to do to suppress changes
that are these double edge sword that good cause problems and to enhance others that
can benefit the subject? We have lots of interesting indications that
that is possible to do. Ultimately, that's what physical therapy,
what occupational therapy, what speech therapy promotes. Is the talk therapies guide the changes for
the benefit of the subject. But I think we have now as we understand more
of the molecular basis and the physiologic basis of these mechanisms, we have ways to
target these mechanisms with medications or with devices, with brain simulation that more
directly to the brain promote the changes. That's happening and it's happening guided
by basic research and translating that basic research to humans. So ... sorry. One of the things that I'm really excited
about in terms of intervention is thinking about how can we boost the power of current
interventions by knowledge about critical periods in plasticity? So if we can increase plasticity prior to
some known effective intervention, that's really powerful. So, as you mentioned, there are many examples
in basic neuroscience where pharmacologic or genetic administration or modification
can actually increase plasticity, and in many ways, bring the brain back to that childlike
state to allow for some environments to have a really big effect on the brain. That's really powerful and there's a demonstration
in humans too that has actually used one of these pharmacological manipulations with people
who don't have perfect pitch and perfect pitch depends on critical period learning early
in development. So perfect pitch was able to be developed
in adults who had taken this pharmacologic drug. So then the question is, well, why don't we
all do that? Right? The authors of the study make a really ... they're
very careful to say that, "Hey, remember the brain actually spends 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 remove all of the lessons that
we've learned throughout our entire developmental history? Do we want to remove aspects of our personality
and so on? So it becomes a very tricky question even
though there's a lot of promise for recovery following any type of trauma. But in that perfect pitch study, they didn't
... the people didn't lose ... I mean, they learned something new. So there's hope really. There's hope for having a selective intervention. I think that's exciting. I mean, from the animal studies. So, from looking again at the mice ... and
actually one of the authors of that study also has done work looking at the mouse critical
periods for vision as has my own lab. What we find is that you can actually go into
the adult mouse brain and really restore juvenile plasticity in the adult brain. The mechanism of doing that seems to be, again,
to allow for new synaptic connections to form. If we study the story of the childhood cataract,
but now in the mouse, then remember I told you that if children have a cataract and it's
not immediately operated and, and clear optics restored, then they become either permanently
blind or that vision is seriously diminished in that eye. And really there isn't a good way of treating
that blindness, is called Amblyopia, in adulthood. But in these mice, one can actually make the
cataract model and then go in the adult mouse, and engaging these childhood mechanisms of
plasticity a effect recovery of vision in the eye that was blind, which is amazing. It's really ... demonstrates, I think, that
by understanding the underlying mechanisms that regulate these developmental critical
periods, it's possible to go in and then to manipulate them again. To me, it demonstrates another thing, which
is that there must be in the adult brain and presumably in our brains too, 'cause we have
the many of the same molecules that are being studied in the animal models, there must be
brakes on plasticity because these manipulations essentially take the brakes off and then of
course you can worry about stability. So then we come back to that, this whole theme. Again, but the idea that there's actually
more plasticity in our adult brain that we can tap into, to me is really exciting because
you could say that even if there are some downsides, that after a stroke or damage to
the brain, wouldn't it be wonderful if it were possible then to tap into that latent
extra plasticity even briefly and combine it with training and physical therapy. So somehow a pill that would let me speak
French without an accent could actually have a really important therapeutic value, which
would be to really help people recovery from brain damage. Well, what we have here is a video of a modern
rehabilitation technique with a split treadmill. Maybe, Alvaro, you can tell us about the concept
behind this. Yes. So part of what physical therapy interventions
like this or like something called constraint therapy that some of you may have heard about
it in individuals that have stroke, that cannot use both legs in walking correctly or cannot
use one hand correctly, we've come to learn that if you force the use of the other hand,
of the impaired hand by limiting the default of just using the unimpaired hand or by in
this case of the video, if you force the walking correctly by aligning the paretic leg because
it cannot cross over, so, therefore limit the pattern of abnormality that normally would
happen, that because of this repeated training doing the right thing, that promotes the rewiring
that promotes the plastic change and speeds up the recovery. So you can, by guiding, by constraining the
behavior, use that as a way to improve the recovery process. So the opportunity of opening up the mechanisms
of plasticity in such a way that they become more active and therefore benefit from the
intervention more, becomes really appealing. Examples of that do exist even in humans,
not only with medications. One of the things that we know about Alzheimer's
dementia, Alzheimer's disease is that before the clumps of this abnormal protein come together
and deposit the plaques in the brain, they are floating around. In that stage already they alter and damage
synapses. So they become damaging substances for the
mechanisms of plasticity as it were. If you take patients with Alzheimer's disease
and you try to get them to learn from video games or computer games and get better at
cognitive tasks, they derive very little benefit. It would take too long to get a benefit that
is sort of meaningful. But if you activate that zero grid with brain
simulation, for example, just before they actually engage in the cognitive training,
now you get more benefit from the cognitive training. So combining interventions, device base pharmacologic
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 benefit for patients. So we've talked a lot about aspects of disease
and repair. What about this Holy Grail idea? What about the idea of actually enhancing
the brain? Whether one day I was thinking, "Today, I
had a long day," and I was thinking, "Oh my gosh, I got to focus on what we're doing tonight,"
and I jumped in a car and when is the helmet going to come out through the ceiling or already
being built into the roof where I can say, "If I can just get my temporal lobes going
and my memory working a little better, how great that would be." How far off are we? How far off are we from everyday enhancement
of function? It didn't work this morning exactly. You were in the wrong car. I was in the wrong car. I mean, what gave me pulse is that of course
there is a lot of industry investment and really direct to consumer devices already
claiming that that's possible, that we don't need to wait at all. That you can just do it today and you can
build your own brain stimulator devices and then build it into your car if you want to. People will claim and try to convince us that
it is possible to enhance capacities. The problem with a lot of those data is that
what they show is that it's possible to get better at performing a given task, not to
actually get better at the fundamental skill that underlies the task. So, I think that the attempt to get us there
is already here, but we need greater understanding including greater understanding of that double
edge aspect that Nim was mentioning.If we get better at one thing, will it be without
a cost? Will the brain allow you to improve something
at the cost of something else. So, for example, you can ask a question and
say, "What if we were able to get better at paying attention to this part of the world? We know a lot of what the circuitry is, that
allows us to pay attention to this particular spot." So you can actually identify those brain areas
in humans, apply simulation that increases activity in those brain areas, and you can
make people get better attending to this part of the world. But when you do that, it comes at the cost
of attending to this part of the world. In fact, it does so because these two areas
sort of ... I almost say it is a yin yang kind of a relationship.So there are interactions
between the two hemispheres. So if you improve one, you worsen the other. That's easy to test in something as concrete
as spatial attention for a visual task and something that's complex as overall behavior
or more higher order cognitive functions. What exactly the cost might be, is much, much
harder to test. I think it raises not just methodological
and biological questions, but real ethical questions. If you want to improve certain skills, what
would potentially be the downside of it? What about memory? I mean, memory is something ... to varying
degrees, we're all here, slowly moving along chronologically and everybody worries about
what's going to happen to your memory. In my world, people have the ability to sometimes
put electrodes into the brain. That allows us to stimulate the brain and
there's a number of reports of different parts of the brain, if you stimulate at just the
right way, you can make somebody's memory performance better. How do you think of that, as not a way to
combat aging per se, but to help people adjust as they get older and keeping memory intact? Forget about super memory, even just trying
to keep memory intact as we go along. How do you guys see us approaching that? I mean, correct me if I'm wrong, but aren't
there less sexy, innovative ways that people think about or have studied to enhance some
of these processes? So, for example, the things that we know we
should do, like getting good sleep, exercising. Engaging in cognitive stimulation throughout
a lifetime have been associated with better cognitive aging in the long run. So those are hard things that we all know
we should do, but routine things that we should be doing that may actually be improving some
of this retention over the long term. So lifestyle modifications do work and do
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 which we just did, just published in ... there
is a ... I don't know why this is the number, but there is about 52 hours a day, 52 hours
... Talking about enhancing
It's really hard work. It's really hard work. 52 hours in six months actually. So it's not a lot and it doesn't matter how
many hours per day you do it, it's sort of a total amount of dose almost. But you need to put in some hours but it's
not a ton of hours- Of exercise? Of physical exercise that improves cognitive
function in the elderly. So I think that there is an effect of physical
exercise onto the brain and it appears to be linked to mechanisms of plasticity, at
least as one can probe them in humans with brain imaging and brain stimulation techniques. But I think rather than getting at the level
of suggestions, you should sleep better, avoid medications that are bad for you, eat the
right thing and the right amount and exercise and challenge your brain with new things and
have social relationships. All those things are true, but we should be
able to get to enough understanding that we can prescribe it, that we can tell men, "This
is the number of hours of this exercise that you need to do and here's how we're going
to help you actually convert this hopes into realities." Because it's hard to stick with a program
like that. So I think that's the step that we still don't
have, is the understanding of how to actually make this a prescribable intervention, like
we do with medications. We don't tell patients, "Take something for
that." We tell them what to take and how much and
so forth. So I think we need that level of understanding. But what about, Nim, happiness set points? Everybody wants wellness. Is it possible that we're going to someday
understand the brain well enough to say, "Okay, you've been through a really terrible life
trauma, but we can actually help your set point." Well, I would think about sort of maybe not
happiness, but that feeling of being able to regulate your emotions, to be able to feel
less sad when you want, to be able to feel more sad when you want. To have that emotion regulation ability. So there are studies, for example, with people
who meditate, which we generally think of as a healthy lifestyle practice. But there are different levels of expertise
in meditation. So there are Buddhist monks who do this for,
say 40,000 hours in total versus really, really dedicated meditators who might've done this
for 20,000 hours, and then novices. This research has shown that the amount of
meditation practice, practice being the keyword, that the behavior has to be routinely engaged
with, is associated with brain changes in the regions of the brain, like the prefrontal
cortex that we know are associated with emotion regulation. What's interesting in that finding, and it
relates back to the original walking example and the quote about habit, is that there was
this inverted U-shaped dose response function such that the individuals who were meditating
a lot but not to the degree of the Buddhist monks actually had the most different prefrontal
cortex activity and then it came back down again for the Buddhist monks, suggesting that
there is this element of plasticity in the brain regions that we know are associated
with emotion regulation, but an element of habit can come into play as well, so that
it starts to become more of a naturally occurring state of the brain that can be, as you were
referring to before, the core process that's being affected rather than the more superficial. So I would have to say in summary, that obviously
we have a really, really tight balance between plasticity stability. But as we've all learned, they're incredibly
exciting things, not just normal behavior, attacking diseases going down the road. But in the meantime, eat well, sleep well,
meditate once in a while, exercise a whole lot, and surround yourself with really smart
people who make you happy. For that, I thank all of you.
