My guest today is Dr. Reza Shadmir. Dr. Shadmir
is responsible for developing a theory and paradigm
to study the question of how the brain learns
to build internal models for the purpose of controlling
our movements. His education journey includes
a bachelor's in electrical engineering from Gonzaga
University, a master's in biomedical engineering,
and a PhD. in computer science, robotics, from
the University of Southern California, and finally,
a McDonnell -Pugh postdoctoral fellow at MIT.
Currently, he is the director of the biomedical
engineering PhD program and leader of the Shadmere
Lab at Johns Hopkins University. His contributions
to science include consolidation of motor memory,
state space theory of motor adaptation, multiple
time scales of motor memory, a theory of movement,
vigor and a slink to trait -like features of
individuality, neural encoding of action by the
Purkinje cells of the cerebellum. In addition,
Dr. Shadmere is the author of three books and
has numerous publications in top scientific journals.
Today's episode is all about motor movements
and the physics of motor movement, including
motor learning and memory, prediction and air
correction, purgenji cells, and more. If you
remember previous comments of the podcast about
how The brain is a prediction machine and it
uses internal calculators and how the central
nervous system is designed to move the living
organism. By the end of this episode, you will
know more about why I say that. Today, we will
explore a very underrated yet powerful area of
the brain called the cerebellum. But first, a
message about Daylight Computer Company. and
chroma light devices. I would like to take a
moment and mention a pressing issue we are seeing
in our modern world. And that is tech use and
tech light. The data are impressive and concerning
on isolated wavelengths of light, especially
shorter wavelengths. which is blue light. For
those that don't know, we have chromophores,
which are special proteins that absorbs specific
wavelengths of light. For blue light, the light
that is LED light and tech light, that protein
is called melanopsin. Melanopsin is responsible
for our circadian biology. physiology and cell
functioning, hormone regulation, and even a connection
to an area huge for mood. A consideration we
should include is this protein was not even discovered
until 1998. It seems important for us to understand
how our biology uses the different wavelengths
of light for various aspects of our biology.
This blue light chromophore is our master controller,
our master clock. Remember circadian rhythm is
a two -part process, two independent parts, light
and dark. For a quick reference, See, the 2017
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for a 10 % off discount. Can you share a little
bit about your path into research and specifically
the cerebellum? Sure. I was a kid raised in Tehran
in Iran and when I was a teenager I was lucky
that the U .S. Embassy on Roosevelt Street some
50 years ago, 1977. They decided that I was good
enough that I could deserve a visa to come to
the U .S., and I did. I went to Spokane, Washington,
which is a small town on the eastern part of
the state, and raised by foster parents who love
me just like their own son. And I was watching
TV one day, and I was watching public television.
And they had a show about the brain, and it really
excited me because I thought that this is the
most interesting thing in the world to study
but not just studying using biology and techniques
of biologists but techniques of engineers and
you know the idea being that in engineering one
has tools to study complicated systems and maybe
if we applied some of those tools to how the
brain worked it would you know uncover some mysteries
that would be otherwise difficult to understand
and so I remember going to my academic advisor
and telling him I wanted to study the brain.
And he said, well, you can't do that here. You
have to go to grad school. So I said, that's
what I wanted. And so I did. And then in grad
school, I became interested in thinking about
control and movements because I was taking courses
in robotics. And I realized that robotics is
sort of like asking the engineer to be the god.
you are the god of this machine, make it move
the way you want to. And I thought some of the
principles that are in engineering that describe
how machines should be controlled presumably
relate to how the brain controls our movements.
And so if we could apply some of the tools from
robotics to control of behavior, maybe it will
help us understand how the brain controls our
movements. And that was the basis of my lifelong
goal in trying to understand how the brain controls
our movements, in particular, arm movements and
eye movements. Yeah, the engineering is a fascinating
pathway into this, I think, because I was reminded
of like a computer numeric controller, which,
you know, like a CNC programming controls the
machine, the speed, where it goes, you know,
its endpoint, where it returns home and everything.
It's kind of like That pathway with the engineering
gave you this access that I think a lot of other
people were overlooking or didn't even think
about yet. Yeah, you know, if you think about,
like you said, the CNC machine, you are dictating
to the machine its actuators to move things the
way you wanted them to. And that gives you a
window to asking questions like, why do we move
the way we do? You know, what's good about the
way we move? that makes us all want to move the
same way. Meaning, like my hand, when I ask to
reach to an object, I more or less do the same
as the way you do it. And so this was actually
one of the first questions that my field became
interested in is sort of regularity in how people
move and what's the basis of this regularity?
What's good about moving this way? And writing
mathematical equations, I said, maybe there's
something about energy that we spent. But I think
one of the coolest things that came from this
was the realization that the way we move is potentially
a reflection of the way we feel. And why do I
say that? So, you know, if you see somebody walking,
you can get a sense of whether, you know, are
they depressed? or are they happy? You know,
when we say the phrase, they have a spring in
their step, that's because they move differently.
It's a reflection of both how they feel and the
way they move. And that was one of the interesting
observations about the way our brain controls
our behaviors, that by paying attention to how
somebody moves, you get an understanding about
their cognitive state. It's a downstream representation
of what is going on deep inside. Something that's
fascinating to me is just watching people move.
It's almost like mindless movement and it's constant.
I was sitting here doing it as you were talking
about that. It's like, what is that? I've always
been fascinated with that. understood that myself
because I know that some of us have, you know,
like constant movements of our leg, or it's this
restlessness, there's this energy that needs
to be spent, and I don't know much about that,
why it's there, but I can tell you that coming
back to the notion of understanding the cognitive
state of an individual. I love going to the airport
and watching people when they meet each other
outside of security because it says a lot about
how you feel about somebody, how you move toward
that person. It's like this involuntary thing
that we have in us that we run toward people
we love. You don't do that when somebody is standing
there with your name that says, I'm going to
pick you up in my Uber. but you will run toward
the person you love because there's this involuntary
relationship between how you value that person
and how you move toward them. Yeah. That's a
great description. Can you give me an explanation
about like an overview of the cerebellum specifically?
Yeah, yeah. So let me start by going back about
a century to World War I. I'm going to share
my screen with you so we can look at one or two
slides that are worthwhile in terms of giving
us a little background. Let me show you this
picture here. This is a picture of a couple of
soldiers during World War I. This is a German
soldier. This is a British soldier. When you
look at their helmets, you notice something.
fundamentally different, right? So the back of
the German head soldier, you have this cover,
whereas in the British soldier you don't. And
what this meant is that during World War I, the
British soldiers suffered from certain kinds
of damage from shrapnel or other things that
affected the back of the head. And that's where
the cerebellum is. And Gordon Holmes was this,
he was a British neurologist that was stationed
in France. And he examined these patients and
he noticed that These soldiers, when they had
damaged the cerebellum, there was a specific
part of their movement that was affected, which
was near the end of their movement. So they could
make the movement well to start with, but then
they couldn't end it well as the, for example,
the arm came to the target. And he called this
dysmetria, which means that the metric of the
movement is something wrong with it. So the basic
idea about what the cerebellum did came from
these observations in patients that damaged their
cerebellum. And it said that it looked like it
was important for control of movements, particularly
the end of the movement. And this went along
with certain other aspects of cerebellar function.
I'll just describe some of the other ones. So
it's not just the movement itself, but probably
also has something to do with sensory processing.
And this came with experiments that looked at
a simple animal called an electric fish. Electric
fish is this interesting animal that puts out
a motor discharge, an electric field to sense
the world around. So electric fish lives in a
muddy water. And for it to detect prey around
it, what it does is that it puts out this electric
field and then measures the electric field around
itself and the distortions in it, it picks out
and says, well, there must be something there.
I'm going to pay attention to it. Maybe it's
something... that I can eat. So what was discovered
is that there's a structure in this electric
fish which is called the cerebellolike structure.
And what that structure did is that it said,
you just generated an electric field, that's
going to overwhelm your sensors. I'm going to
cancel the sensory, expected sensory consequences
of this field so that I can detect the small
item that exists out there in this field. And
that's the second idea about this. It's called
forward models, which means that the cerebellum
is attempting to predict something about the
sensory world around us. And when under normal
conditions, probably this sensory prediction
allows us to cancel out a lot of things that
would have been easily predicted because of...
the actions that we perform. So in this case,
if it's an electric fish, if it generated this
electric field, its sensors don't want to pick
out its own field. They want to pick out the
difference between what the field produced and
the distortion caused by this prey. And so that's
the notion of forward models, having something
to do with predicting sensory things. That's
one of the functions of the cerebellum. The third
function has to do with learning. And the idea
behind learning is that there is a relationship
between a teacher and a student. The teacher
is this input that comes from the cerebellum.
It's called the climbing fiber. It comes from
a region of the brainstem called the inferior
olive. The students are the Purkinje cells, which
are these principal cells in the cerebellum that
basically provide the output from the cerebellar
cortex. So these were the three main ideas that
describe the function of the cerebellum. One
is it has something to do with control of movements,
particularly the end point of the movement. Second,
it has something to do with predicting sensory
events, consequences of things that you should
be able to predict. And third thing is that it's
a place where learning takes place. And that
learning has a teacher, in this case the inferior
olive, that provides climbing fibers and students,
which are the Purkinje cells Yeah, okay, so I'll
I'll go ahead and then and I'll and I'll stop
there see what you think Where is the inferior
olive right? Yeah, it's part of the brain. It's
part of them It's in the medulla and so it's
actually like behind behind that if you if you
could get it's one of those places that's incredibly
hard to reach because It's it's almost behind
the throat in the brain stem So it's really hard
to record from it. It's really hard to do anything
about it. But it is... I think of the inferior
olive as the god of the cerebellum. It tells
the cerebellum how to organize itself. Okay.
So that's fascinating because they're both subdivided
from the rhombencephalon. So that makes the cerebellum
and the pons and the medulla. Are they? sensory,
motor, and interneurons going into the cerebellum
and does the cerebellum have each of those three
types of neurons? So no. So there are no motor
neurons in that sense in the cerebellum. The
cerebellum by far most of the newer part of the
cerebellum is far away from motor neurons. It
projects onto things that eventually reach the
motor neurons but itself is still rather many
synapses away. However, there are these large
inputs to the cerebellum, which are called mossy
fibers. Basically, whatever the brain is doing,
whatever the rest of the brain is doing, a copy
of it is sent to the cerebellum. The cerebellum
computes something based on that information
and sends it back to whatever region was performing
that computation. Can you can you explain a little
bit about how it's sensory predicting especially
I know you use the example of the fish but Humans
and the monkeys that you study obviously use
something different besides that. Can you say
more about that? Yeah. Yeah. Okay, so the gating
of sensory information I know that this is a
particular interest because you know people with
autistic on the spectrum they they report having
abnormally sensitive or less than normal sensitivity
to sensory feedback. And we can talk about the
relationship between the cerebellum and autism,
but I can tell you that there is a relationship
between cerebellum and control of sensory input.
So let's call this the gating of sensory information.
So as I mentioned, the work in the electric fish,
the scientist who did the work was called Curtis
Bell. Curtis Bell demonstrated that the electric
fish could survive only because it has this structure
that could predict and cancel the sensory feedback
that it would get. Otherwise it would just be
overwhelmed by its own sensory, by its own feel
that it would generate. Then my colleague Cathy
Cullen here at Johns Hopkins, studied the vestibular
system. So that's the system that you use to
move your head, that head causes motion, that
your eyes respond to it. And so what they showed
is that during voluntary head rotations, when
you move your head, the Purkinje cells, that's
the principal cells of the cerebellar cortex,
seem to predict and then cancel the vestibular
input that's coming to the to the cerebellum,
and also the proprioceptive input. So from the
neck muscles and the vestibular organs in your
head, the Purkinje cells in that case seem to
basically remove the component of the sensory
feedback that's due to the motion of the animal's
own head. So when the animal themselves moves
their head, they cancel this sensory feedback.
Perhaps it has something to do with what Curtis
Bell had seen in the electric fish. Okay, so
that kind of makes sense with autistic phenotype,
I think. Because maybe they're not canceling,
because they're not moving their head to bias
themselves to the environment. Because in large
part, our eyes are doing that. Are there any
inputs or communication with the superior or
inferior colliculus? Yeah, yeah, so superior
colliculus. Let me tell you about that So superior
colliculus as you know you guys have described
it in you guys have had a podcast about it It's
an area that's important particularly in mammals
in primate specially for moving the eyes so making
saccades and the superior colliculus has a map
of space and it basically, you know the fact
that I when I'm reading the fact that I can move
my eyes from word -to -word is because of this
input that comes from the colliculus, that comes
to the colliculus from the retina, from the basal
ganglia, from the cortex, cerebral cortex, that
describe what I think of it as like a value function.
Where is important stuff on this visual field?
Where should I move my eyes? Okay, so then you
are able to control your gaze The basal ganglia
is inhibiting it, saying, don't look over there.
I'm going to release the inhibition so you can
look over there. The frontal eye field, the cerebral
cortex, lateral interprithal areas provide information,
excitatory information, saying that, oh, there
is something useful over there. Move your eyes
over there. So the balance of inhibition and
excitation moves your attention to some part
of the visual space. The colliculus in that part
generates neural activity. you generate a saccade,
the eye moves to that location, you look over
there. You don't need the cerebellum for this.
However, as that movement is generated, the cerebellum
gets a copy and during that movement, it adds
information. And that information that's added
makes it so that the saccade ends on the target.
Without a functioning cerebellum, the patient
will show dysmetria in their eye movements, overshoot
or undershoot the target, having to repeatedly
correct for it. Can you show the video? Yeah,
yeah. And while you're pulling that up, are there
any excitation inhibition, like glutamate GABA,
running through the cerebellar? Yeah, absolutely.
I can tell you about that as well. So let me
share my screen. I will, let me show you a couple
of examples of patients and their deficit. So
here's a reaching deficit. Okay, so that's a
reaching deficit. Here's a saccade deficit. Yeah.
Okay. So, you know, we study the cerebellum,
and here's an MRI of the cerebellum of the monkeys
that we study. These are called marmosets. And
marmosets are these beautiful monkeys that live
in the Brazilian jungle in the Amazon. They're
a wonderful model to study because, first, they
are highly social animals. They live in families
of 10 or 20 marmosets. They are They have an
alpha female, so they're, as far as I know, one
of the few primates that are ruled by females.
And they are really smart. They vocalize. The
recent reports suggest that they not only communicate
through vocalization, but they even potentially
name each other. They have this high cognitive
ability to recognize each other, use sounds that
are specific to a given marmoset, and they have
this fabulous cerebellum, as you can see here.
Just this amazing structure that dominates, dominates
the brain. So here's the brainstem here, and
if we look at the cerebellum, you get a sense
of its organization. You can see the folding.
So you can see how here's a Here's this group
of neurons that live in a sheet, and that sheet
has been folded over and over, you know, to fit
a small volume on the back of the head. And if
you look closer, you see that there's these three
layers in this structure. This top layer is called
the molecular layer. That's where you have the
inner neurons that are all inhibitory. They all
rely on GABA to interact with the Purkinje layer.
So the Purkinje cell is this line here that you
can see. This line has a single sheet of Purkinje
cells. And the Purkinje cells are these large
principal neurons of the cerebellum. And then
below it, this white layer is called the granule
layer. You have these tiny neurons called granule
cells. It makes it so that there are more neurons
here than all of the rest of the brain combined.
So more than something like 70 % of all the neurons
in your brain are here in the cerebellum. And
the reason for having so many neurons is here
because in this white region here, the granule
layer, you just have an incredibly dense collection
of what's called granule cells. And their job
is to convey information that they get from the
rest of the brain via what's called mossy fibers
to the molecular layer and then eventually the
Purkinje layer of the cerebral. The Purkinje
cells. In autistics, the data show that there's
a loss of, there's not as many Purkinje cells.
And this is starting to make sense to me now.
Yeah, so why is that? It's not just an autism.
I think many cerebellar diseases, the sacrificial
lamb is the Purkinje cell. Why? And I can tell
you that in my experience Purkinje cells, they
sort of live at the edge of a cliff. They are
these large cells that They're active all the
time. They're getting, they're producing spikes
when you're sleeping, when you're awake, when
you're taking a nap, when you're moving, when
you're not moving. They're just always are producing
spikes. They increase their activity or decrease
their activity when you're doing something, but
otherwise they're just producing 50 spikes a
second or so. And so it's really incredible to
have a neurons in the brain that are producing
all these spikes, even when you're not doing
anything. And it's really interesting to ask,
why are we spending all this energy? What's the
purpose of this? And I don't know the answer,
but it's one of the puzzles. Nevertheless, damage
to the cerebellum often involves the Purkinje
cells, which are the output neurons of the cerebellar
cortex. So without those neurons, whatever computation
is taking place in the cerebellum, it is defective.
It is not able to produce what it would otherwise
do if the majority of the Purkinje cells were
there. I think two questions that came to mind
is, Purkinje cells are only in the cerebellar,
correct? And the amount of GABA that I'm learning
about now is... Because with autism, there's
an imbalance. Too much excitation, I think, and
or too few GABA. So that might have some problems
with this computational model. So Ryan, the excitation
inhibition balance is a common, when there's
something wrong with that, you see there's disorders.
Whether it be cognitive disorders, or things
that are associated with autism, it's really
important for a neuron, it appears now, it is
really important for it to get as much excitation
as inhibition on average. So you can't just have
one kind. That tends to make the neuron die.
And this EI balance, as it's called, seems to
be critical for survival of neurons. I want to
describe to you the anatomy a little bit. So
I said that the cerebellum receives a copy of
everything that else is going on in your brain.
It comes to it via these mossy fibers and then
it analyzes that and sends something back out
specific to the region that is performing that
computation. And the main puzzle is to try to
understand how does it do it. And what is it
that is adding to that? Because look, the eventual
goal is to build a machine that when something
has died, let's say your Purkinje cells have
died. Well, we can't bring back the Purkinje
cells. But what we can do is to record what is
the input that's coming, what's the normal output
that should have been produced. I mean, that's
what the research is about, right? Understand
how it works in a healthy cerebellum and then
build a machine that eventually will try to do
something like that when there is damage. Is
this why whenever I see like your research and
things, there's learning and memory. Can you
say a little bit about the memory part? Right,
so As I mentioned, we think we understand the
role of who's the teacher and who's the student.
So we've learned that the inferior olive provides
the information that is the teacher. And the
Purkinje cells are the principal cells that are
the students. And the learning is via this input.
The memory is partly the synapses that form from
was called the parallel fibers from those granule
cells, those incredibly prolific and large number
of cells in the cerebellum. So the parallel fibers
that come from the granule cells make synapses
on the Purkinje cells. And it looks like the
teacher, the inferior olive, when you make movements,
potentially any actions that you make, any guess
that you have about something, when there's an
error in it, that air is sent back to the Purkinje
cells, it causes plasticity in the synapses between
the peril fibers and the Purkinje cells, and
that becomes the memory that you rely on to perform
the task better the next time. Okay, this is
making sense, too, because if you think about
a little autistic child or any child, they're
going through this process in learning something.
maybe they catch it they catch on and then they
can build repetitions and really store that ability
or maybe they don't so like with those eye tracking
videos that you show or the hand movement can
you say a little bit about um how the living
organism learns to correct that the air correction
yeah yeah so one of the So actually, this is
one of the main problems with treating cerebellar
disease. Look, if you have a stroke, rehab helps.
Because why? Rehabilitation is a process by which
one is trying to teach the remaining parts of
the brain how to do the task. But in cerebellar
disease, the thing that's going to learn itself
has been damaged. And so one of the really hard
things about cerebellar disease is that there
not only are no effective, really pharmaceutical
ways to affect cerebellar disease, even rehab
is difficult to use because the students, which
are the Purkinje cells, if they have been damaged,
well who's going to learn? And some of the new
research would... What one is trying to do is
to try to figure out how to how does one get
the rest of the brain? That's healthy Like the
basal ganglia. How does one get that part of
the brain to try to compensate for you know,
the part that has been damaged Okay kind of kind
of rescue or The basal ganglia will maybe act
as a supplementing that yeah. Yeah. Yeah exactly.
So, you know The rules of learning for basal
ganglia are different than the cerebellum, and
so some of the ideas are to make the errors in
such a way, it's called reinforcement learning,
that engages the remaining neural structures
and tries to take out the part that isn't working,
the cerebellum, and try to focus the learning
on the part that is working, in this case the
basal ganglia. And this is a little bit different
role for the basal ganglia, or is it something
that's normal? No, this is normal. But for some
reason, that normal function isn't good enough
to help recover some of the functions that are
lost from the cerebellum. And the idea is, and
this is theory with just a few experiments that
have... gone after it. This is Amanda Theron's
work and my colleague Amy Bastian have worked
in this area to try to say can we skew the error
so that it becomes more the morsel of food for
the basal ganglia rather than for the cerebellum
so that you rely on the structures that are working
well to try to compensate. This is what rehab
is trying to do. Is there any consideration that
there are many more Nuclei going on within the
basal ganglia with those five cortical regions?
Or is that not right? Is the cerebellum that
complex as well? Oh, yeah. In some ways, the
basal ganglia complexity is interesting. In some
ways, they're similar. So both basal ganglia
and the cerebellum have neurons that largely
rely on GABA, inhibitory neurons. And both of
the structures have neurons that tend to be active
no matter what. They're spending their energy.
But they seem to compute different kinds of things,
I would say. I mean, we talked a little bit about
how you direct your gaze to areas that you find
rewarding. So when you open a web page, if there's
a picture of a face, you're more than likely
going to look at it, rather than something else,
a mountain or something. that probably has something
to do with this value function that your basal
ganglia and maybe the frontal eye field impose
on you. The faces are special, they're particularly
rewarding. You should look at it. It probably
has something to do with the basal ganglia. The
cerebellum is more important in helping you make
that movement correctly, predicting what would
happen when you get there. And one of the big
puzzles is Because cerebellar patients, it isn't
just that they have movement disorders. They
also have impulse control effects. They have
this thing called dysmetria of thought. So the
planning seems to be something wrong with what's
happening. And I think that we just happen to
see the movement disorder because it's sort of
like the obvious thing that a neurologist would
examine. It's much harder to examine planning.
But they do have these disorders as well. So
the cerebellum is involved in so much of our
normal behavior far outside of just making movements.
I love the idea of we use internal calculators.
I call them internal calculators. Biological
calculators could work as well. But whenever
you're talking about that value is, I think,
reminded me of that. You know, I can show you
an example of an internal calculator. Yeah, I
would love that. I love internal calculators.
I don't know if you can see this. Let me show
you a video. Let me show you a video so you don't
have to look at me. So I think a video would
be even better. All right. So let me share my
screen again. I love the idea of these internal
calculators because our brain is a prediction
machine. It's the number one thing. Exactly,
exactly as you said. Okay, so here's an internal
calculator. Alright, so here's a simple experiment.
So here's this young man, he's holding a book
in his hand, and look what happens here. Okay,
so the idea is, if somebody picks the book off
my hand, I can't help but my arm is going to
move up. And why is that? Well, because there's
delay in the sensory system. I can't react fast
enough to what's happening. But if me myself
goes to pick up that book, my hand stays perfectly
flat. This is because I'm able to predict precisely
when this is going to happen. And I know by how
much I should turn off the muscles, in this case
the biceps, so the arm doesn't just, you know,
lift up. as the book is moved up. Okay, so you
see that's the basic idea of this internal calculator
that is working all the time and we don't even
think about it, right? We have many of them.
So, the reason why the hand moves up though is
because there's no way to predict accurately
how fast and how much effort the other person
is going to need and the time. to remove that.
Yeah, exactly. So I make the joke to my students
that if there's one lesson that I have is that
when you go to a fancy party and you know that
the waiter comes with the drinks, you let the
waiter pick up the glass and give it to you.
Yeah, because there's accidents. That's so fascinating.
We have so many internal calculators. It's just
constantly going yeah, you know and these are
these internal calculators are underneath our
consciousness and when they stop working they
really become a Difficult thing to live with
right because it they really change the way we
are because we now have to pay attention to so
much that we didn't used to have to pay attention
Yeah, okay One of the more significant internal
calculators, I think, comes from the dorsal anterior
c -like cortex, which sends a signal down to
the dorsal striatum. And I think that helps orchestrate
motor movements and activity of the living organism
quite well. And that reminds me, I want to ask,
because that's more of a go -directed type of
movement. And I know you've done research on
go -directed. Are the inputs and the signals
going through the cerebellum for a goal -directed
activity different than a habit? Yeah, that's
such a good question. Let me describe it to you
in this way. We work with monkeys. Like any animal
trainer, you train them to work for food. So
you get them to do your task and then you give
them food. And that's the business component
of this relationship. But they make movements
otherwise as well. So it's not like they only
make movements because there's food. They also
make movements because they want to. And it's
interesting to compare when they're making a
movement for us, for the purpose of getting food,
versus when they're making just movement because
they're interested in exploring their environment.
And what you see is that the cerebellum is much
more involved when the movement is made... because
there is something rewarding, something, you
know, there's a purpose for the, in this case,
to get food. It's similar movement when they
make, and it's just because they do it because
they want to explore their environment, that
the things that we see in the cerebellum are
not the same. They're much less involved in control
of that movement. So it's as if if you need to
make something, do something well, you engage
the cerebellum much more than just any movement
that doesn't matter that much. that probably
has some evolutionary considerations there about
movement for reward and how we work so hard to
sustain our species and we seek out and we navigate
for like those primitive aspects like food, shelter,
water, security, mating, all of these underlying
reward things that humans and other species have
kind of built this reward pathway from. Now,
today, we have a lot more access to so -called
rewards. And a bad part about that is, as we
were talking about, the rewards have more value
if you put effort in first, effort then reward.
And that's how these circuits were made. But
now we don't have to do the effort for the reward.
It's like with the technology and all of these
other things that are just probably not well
for us. Yeah, so the relationship between reward
and effort is really fascinating. As I mentioned
to you, you can think about certain movements.
I mean, you can think about a frog that needs
to stick its tongue out in order to catch a fly,
you've got to get one try and it better be on
target. I think that a structure like the cerebellum
is particularly well suited for those attempts
that matter because we see that those movements
that are associated with reward, where the goal
means something important, where you have to
be accurate, that's when the Cerebellum is really
active. I wanted to tell you, Ryan, about one
of the most surprising things that we've learned
about the Cerebellum. And it goes something like
this. So, you know, you think that neurons in
your brain are active, because you're doing something.
So say that I'm moving my arm and I see these
neurons active, and I think that, oh, these neurons
must have something to do with moving the arm.
That seems natural. This has been like the basic
foundation of so much of neuroscience to relate
how neurons relate to behavior. But one of the
things we found in the cerebellum that was really
surprising is that, first of all, the neurons
are active not just all the time, but It doesn't
matter whether you move your arm up, down, left,
right. As long as you're moving your arm, these
neurons are active. So that was really puzzling.
And then what we found was that much of this
activity wasn't because to move the limb in the
way you were moving it, but to cancel the activity
that other neurons were producing that would
otherwise harm the movement that you were making.
So it's as if you have a population that's active,
half of them are active to cancel the effects
of each other so that they don't inject noise
in the behavior that you're trying to produce.
So if that's true, even if that theory is right,
that says that, you know, when damage occurs
and some of these cells die, part of the deficit
is because the parts that are active and should
in fact be suppressed are not being suppressed.
Because the ones that would have suppressed them
aren't there. So, head -eye coordination, or
yeah, hand -eye coordination I'm in, it seems
like this is involved, and precise fine motor
movements. I can't get my head around How much
the cerebellum is involved here and then things
like the substantia nigra and the red nucleus?
Okay, so let me describe the relationship. Substantia
nigra has two parts, the reticulata and the compacta.
Compacta has the dopamine cells. The reticulata
is the output structure in the substantia. These
are basal ganglia structures. I can tell you
about both of these. So, Substantial Niagara
reticulata is an output structure of the basal
ganglia. And let's say we want to make an eye
movement. It projects onto the superior colliculus.
It inhibits the superior colliculus. Basically,
it says, don't move. And when it releases this
inhibition, then you are biased toward moving
toward certain region. And that release of inhibition
coincides with excitatory input that comes from
the cerebral cortex. Release of inhibition coupled
with excitation makes it so that you decide to
make this movement. You have to release inhibition
and you have to produce excitation so that now
you make a movement. So you can now see that
the basal ganglia would have something to do
with reward because it describes how you would
make movements toward things that you value.
You would move toward things that you value and
not care about the ones that you don't. The relationship
between this and the cerebellum is that the basal
ganglia has this value information. And if you
now look at the cerebellum, you find that that
value information makes the cerebellum work better.
Meaning that, remember that cancellation I was
telling you about. The cerebellum is made aware
of the value of this action that you're about
to make and that coordination of the neurons
in the cerebellum to produce the output that
they do is much better balanced so that it produces
an output associated with just the action you're
making and cancel the things that would have
diverted that action away from it. So that's
relating reward. Substantia nigra reticulata
of the basal ganglia and control movements in
cerebellum. Okay, now there's dopamine. Dopamine
comes from SNC, Substantia nigra compacta. Dopamine
is a neurotransmitter that affects so much of
our behavior. And it turns out that an output
from the cerebellum projects directly to SNC
dopamine neurons. So the cerebellum is providing
an input that's relevant to control of dopamine
in SNC. This was a new discovery. Cameron Kodachow,
he's a professor at Albert Einstein University
in New York, he discovered this pathway and demonstrated
that it's important for control of behavior in
mice. cerebellar to the compacta probably up
to the dorsal striatum and then it's orchestrating
next movements subsequent movements yeah i i
really think that you know if there is a structure
in the brain that's doing something important
the cerebellum more than likely is contributing
to it okay recently Then the reason why I contacted
you was the Purkinje cells with the tongue movements.
Can you say a little bit about that? Yeah, sure
sure. So, you know control of speech and vocalization
is so hard to study because the tongue is inside
a mouth that you can't measure it so easily,
right? How do you do that? But yet if you see
a cerebellar patient, one of the first things
you notice is that it's hard for them to talk.
They sound like as if they have marbles in their
mouth. It's really hard to move the tongue properly.
And it's really been hard to study the control
of the tongue. How does that happen? And so marmosets
are like next to giraffes, they are the tongue
animals, in my opinion. They have a fabulous
tongue. They have this long tongue that they
use in the wild to... insert inside the tree
little holes and get sap out. And they're really
dexterous with their tongue, and they control
it in this beautiful way. And as I mentioned
to you, they're also very vocal animals, so they
can make sounds, and they use it for communication
between them. So, okay, they make a good model
to study control of the tongue. All right, so
we wanted to know, all right, how do they do
it? And what does the cerebellum have to do with
it? So we set up this task that made the marmosets
use their tongue to go laterally to food tubes
that were sitting 90 degrees with their mouth.
So they had to stretch their tongue out, put
it inside the tubes to get this slurry of food
out. And okay, so they learned to do it, and
it was no problem. It was like, okay, we know
how to do this. The animals were so good at it.
And while they were doing that, we were trying
to understand what the cerebellum is doing to
control these movements. And what we found was
that those Purkinje cells, they had a lot to
do with stopping the tongue at the right place
when the tongue went out so that it wouldn't
miss the tube, so that it would stop where the
tube was located. So just like what we had seen
with control of the eye. We saw that for control
of the tongue, there was something similar taking
place in learning to predict, you know, when
you're about to reach your target, stop the movement
now. That's good. That's a fascinating finding.
The deceleration of the tongue. Yeah, the deceleration
of the movement and stopping it on target. And,
you know, this is related to sensory feedback.
Let me tell you why. Because, you know, the movement
is taking place quickly. The sensory feedback
is slow. You know, basically, our sensors are
slow things. They detect things and transmit
their information more or less at the speed of
sound. So, so much of our accuracy depends on
not the feedback that we get, but predicting
what the feedback should be. And the Cerebellum
seems to have a lot to do with that, predicting
it. and helping you generate commands that make
your movements accurate. Makes sense. Yeah, this
is also good. Is there anything else about the
cerebellum that you find important that I haven't
asked you about? Yeah, you asked such wonderful
questions. I'm so grateful that we had a chance
to talk. I think that... There just isn't that
much interest in the cerebellum, because I think
that it's like a hard puzzle to figure out, and
that the mechanisms of how it functions and so
forth, we haven't made that much progress. But
yet, there are people that have suffered from
cerebellar disease, and maybe it has a lot to
do with autism as well, because as you know,
Anatomical studies show that people, when they
die, they've had autism during their life. The
cerebellum is probably the most important structure
that looks different than normal. There's a reduced
size and the Purkinje cells die. But it's like
this whole other brain and it has its own language.
And, you know, being a neuroscientist is like...
getting signals from a foreign, you know, from
a different planet. And you're trying to understand,
what are they trying to tell me? You know, I'm
trying to decipher this language that I don't
understand. And so much of our work and the people
in my community is about trying to understand
the language of the cerebellum, which is different
than the language of the cerebral cortex. And
yeah, and I hope that we'll get better at decoding
you know, what is the cerebellum trying to tell
us? And once we understand it, you know, building
therapies and machines that can replace the things
that have been lost. Yeah, that's well said,
because the cerebellum is definitely underrated.
It's super valuable. But last question, what
is something recently that you're most excited
about? Yeah, you know, I think that Down the
road, the goal is to build a machine that, when
there is damage to the cerebellum, it can do
something about it. You know, that you can implant
a chip that would say, I'm gonna listen to the
inputs that are coming, and I'm gonna tell you
what the output should be, even though you don't
have the Purkinje cells to produce it. And I
mean, that's the billion -dollar dream of not
just understand how something works, but replace
it. with some devices that will repair the transformations
that would have taken place and provide the signals
that would have been there if the thing was working
well. And I genuinely think that, perhaps not
in my lifetime, but in my students' lifetime,
in your lifetime, Brian, these things are coming
as we better understand how the system works,
we'll be able to someday build these circuits
that can, you know, be implanted and make it
so that the damaged system can be partially repaired.
Yeah, and your works you want to provide the
instruction manual. I hope so. Yeah, I think
so. Yeah, I can't thank you enough. This is one
of the most fascinating conversations I've ever
had in my life. You're very kind of you, Ryan.
Thanks for the invitation. Yeah, thank you for
joining.