This is the Convergent Science Network podcast. Leading researchers in the domain
of neuroscience, brain theory and technology are interviewed by Paul Verschoor and Tony Prescott.
This is Paul Verschoor with Convergent Science Network and I'm here with my
colleague Tony Prescott and with our guest, the speaker of our summer school, John Kass,
the great anatomist with whom we already did a podcast, I think that was two
years ago, if I'm correct.
Where we focused at that time very much on the evolution of the brain.
In your talk today, I mean, two years ago, your talk was so fantastic,
we definitely wanted you to come back. you expanded much more on the work you
actually started to do about two years ago on the organization of the motor system.
So what brought you to looking at motor function in more detail?
What got you to that point?
Actually, it was on a visit to give a talk at Princeton, and an investigator
there had an electrode and motor cortex and he stimulated for a half a second.
And every time he did that, there was a macaque monkey looking around completely bored.
And whenever he did that, the monkey put its hand to its mouth.
And I thought this was the most fantastic thing ever.
And then I thought, I've got to try this when I get home.
And we simplified because it takes a long time to put a chamber on a monkey and do everything.
So we had an anesthetized prosimian primate, a Gallagher, and we put electrodes
down in the motor cortex and premotor cortex and posterior parietal cortex.
We got movements with the long-term stimulation, half-second electrical pulses in all these places.
And we can see that they were related to one another, and we started to get a plan.
So why did you pick the Gallagher for that?
The reason wasn't very deep. We had a colony of about 50 of them,
and they were right there.
And I didn't have to order any animals or do anything like that.
And actually, I thought it would never work.
I thought it was not a macaque monkey.
It's anesthetized. That's enough. And it won't work.
But when it worked, then I saw it must be what's— and they didn't know the complete
story for macaque monkeys. Yeah.
Graziano was an investigator and
he was just looking at motor cortex and a little bit in premotor cortex.
And actually, he gave up this line of research due to lack of funding.
And we had funding problems initially as well.
And then it started to emerge. We decided we can do, we did next macaque monkeys,
and we did a very limited study on macaques because it was expensive and hard to do.
And then we switched back to New World monkeys, and we did two different species
of New World monkeys, and we got such similar results from prosimia and galagos, New World monkeys,
and our limited studies in macaque that I thought, this is something that's
going to be true for all primates from this.
Because what you found seemed to, in some sense, contradict,
if you want, our standard interpretation of how brain and motor systems are organized,
in the sense that often there's a view of a very hierarchical kind of structure
where things all are converging onto, let's say,
a motor area like M1, on and then from
there action is executed right and also in the
standard interpretation well then the encoding of a motor
command at level is fairly primitive right but
you actually what you found was rather different so how would you describe the
functional consequence of these results so we would agree on one part of that
and that's the part that it is fairly hierarchical because if you You cool any
part of motor cortex that causes a movement when you stimulate.
You can't get the movement anymore from stimulating premotor or posterior parietal cortex.
So it depends on that cortex being intact for the stimulation to work.
So our view is that the posterior parietal cortex is activating at the same
time motor and premotor cortex.
And premotor cortex is activating at the same time when you're simulating posterior
parietal, for example, motor cortex.
So it's a series that jumps ahead in the sense it's not completely serial.
It also jumps ahead to motor cortex directly from posterior parietal cortex.
And that's pretty common in cystic cysts. But wait, would this mean that you
would get this result anywhere where you were stimulating cortex,
or it's more to restricted areas where you would see this effect?
So it's a small area that we would get hand coming to mouth,
but it's a small region in posterior parietal cortex. It's a small region in
premotor cortex, and it's a small region in motor cortex.
A defensive movement protecting the head from a blow would be in all three areas.
Reaching would be in all three areas. eye movements would be in all three, except.
Eye movements are hard to get actually from motor cortex to get from frontal eye field.
But you get this posterior parietal cortex going to premotor cortex to motor
cortex for all these different things.
They all involve small regions that we think are in competition with one another
locally within the overall region, posterior parietal cortex,
premotor cortex, or motor cortex.
So you found these results in monkeys.
And you said in your lecture that there was a difference here from non-primate
mammals and something that it seems to have changed in evolution,
in the evolution of primates.
Two things, yeah, you can say. One is that posterior parietal cortex in tree
shoes or mice or squirrels or rabbits,
a lot of those kind of animals, posterior parietal cortex, if we try to define
it in the same way, is a small part of the brain. It's the narrowest triple cortex.
There's not much distance between primary visual cortex and primary sensory
cortex in those animals.
Pretty close together. There's not much room there.
But in primates, it's a big expansive region, and it's even more so in the human
brain than it would be in the galagal brain. It's a large region.
We also have evidence from other
people's studies that it's the part of the human
brain that expands the most in development
so we think it expands in evolution in primate evolution and then and it's late
developing in in the formation of the brain part of this cortex is non-responsive
to electrical stimulation you stimulate there for a half a second at any level
of current you get nothing.
That's the most posterior part of posterior panthrointics. Then you get into the movement part.
The part that doesn't initiate movements actually projects to the part that does.
So it's a feed-in of higher-order visual information, basically.
A lot of these areas also get direct visual input from identified visual areas.
So you have areas, yes, I can say this is V3 or this is the amorosome identified,
and it's projecting to areas that cause movement.
But most of the original input is from a higher level that goes in there. It's indirect.
So it's already fairly analyzed visual information. There's a lot of somatosensory
information, a lot less somatosensory information for reaching,
and a lot more for grasping and manipulation.
And it makes sense what kind of information you need to initiate this behavior.
So that means what you're identifying is
let's say a subsystem that could
control if you want goal-oriented behavior and you call it that yeah it's not
reflexes really right yeah we call it some systems yes it would be a goal-oriented
behavior or is that provided would it be these are different possible goal-oriented
movements and we think that they're basic the primate behavior,
or a lot of animals behavior, you think a lot of.
Say, rodents don't need all these steps.
They do have motor cortex and premotor cortex. A lot of this behavior might
be in a modular form or a domain form in motor cortex and even in premotor cortex.
There's some evidence already for this, but they don't have the full repertoire. core.
And a lot of these behaviors would be just controlled subcortically,
and subcortical centers will contribute in primates as well.
For example, you might get protective reflexes by electrically stimulating the superior follicles,
because you have visual information coming in, and you have access to motor
movements that would not just be eyes, but moving of arms and head to avoid a blow.
So subcortical areas could be involved.
But now it looks to us like we're
getting more cortical control over basic behaviors that all animals need.
To various extents, animals might reach for food or they might use their face and reach for food.
But primates are going to reach with their hand for food a lot.
These are things to pick them up and bring to their mouth or manipulate them
or do something like that.
So that's more developed in primates. But we think that now three stages are
well-developed in all primates.
Posterior parietal stage is probably more developed and more expansive in humans
by far than it would be in prosimian primates.
And it's more in a macaque monkey by far.
And I would say it's expanded out so that it has more satellite information coming in.
The cortex right around the domain where you get the movement is also involved.
And we know it's involved for two reasons.
Say you have a grass barrier where you're stimulating and you get grasping movements
or you might say manipulation on something.
If you go just outside that region where you're getting the grass,
you won't get grasped by electrically stimulating anymore but if you record
from the neurons they're active during this.
So they might be and they are interconnected directly with the grass domain.
So they're involved in the grass behavior as well. So that extra cortex that's
involved in it, it occupies, we think, more of the brain in the macaque monkey than in the calico.
It gives more options, more ways of modifying that behavior through, we think, learning.
Mm-hmm. There are two aspects to this, I mean, there are many aspects,
but two that I would like to ask you about.
So, let's look at this region, right? So, we have, let's say,
now a subset of brain areas.
So, on the one hand, we have this posterior parietal area with M1,
and then we have a prefrontal area.
Okay, we might want to draw borders around that, but maybe we can have you on that later.
But these are sort of like now three interconnected stages of the control of behavioral patterns.
So this posterior parietal area is more, let's say, perceptual.
Would you say purely visual or multimodal? Multimodal, but depending on the behavior.
A behavior that doesn't need much somatosensory and probably doesn't need auditory
at all, which would be reaching to a target.
The target is identified by visual information.
So reaching to a target is going
to be almost mostly exclusively added vibrational information. Right.
Manipulation of something will have a lot of tactile information and proprioceptive
information added to that. Cell visual.
Okay. And then we have in the, so this is, let's say if you want the sensory
component, perception component, like you said earlier, it's fairly high level.
It's not really at the level of the signals coming from a retina.
It's really a process signal as a percept we're dealing with,
you know, like an object. And then we would have this prefrontal area,
which would supposedly be more executive, decision-oriented, I would presume.
And then you'd have the motor area, which is then more with,
let's say, fine-tuning or programming the action itself.
Would that be a decomposition you would agree with? Yes, and I would add,
besides fine-tuning to motor cortex, the connection with premotor areas that
we haven't talked about much would be the supplementary motor area,
the pre-supplementary area, and three-singular motor areas.
And some of these will have to do with reward expectancies.
Some of these will have to do with error correction, like that was a wrong movement.
And some general motivation, levels of motivation.
So that all impinges on primary motor cortex.
Okay, so that would mean there would then be a fourth zone that you haven't
really identified yet, dealing more with valuation.
That's input that comes into the motor cortex, and that's the last step at the
cortical processing that you're sending out.
We've already sent out some cortical information from premotor cortex,
even from posterior viral cortex but the critical output is from motor cortex
you take that away these other areas at least if you take it away immediately
like in cooling or immediately after a lesion the other areas now don't function
they don't give movements anymore,
We haven't looked at what the long-term consequences of a lesion might be.
Because my guess is, if you do a lesion, you don't get the movement from other areas.
I would bet in a month's time, you would, maybe less. I mean, two weeks, three weeks.
Because there's a lot of plasticity, and you can take over functions and reinforce
connections that were not strong enough before, but become strong enough to
elicit the behaviors. years.
But that'll be another whole chapter. The plasticity and the ability to take
hormone and make up for lesions will be another whole chapter in this kind of
research. Not started yet.
But now the consequence of this is a bit tuition. On the one hand,
we can pose the question, okay, how
does it really then sit with standard interpretations of motor control?
And on the other hand we can also ask how does,
this three layered control system of behavior relate to the subcortical control
so on the one hand if you look at more,
common ideas of motor control the granularity is already very different I'm
thinking of the standard idea of M1 being encoding action along population vectors
where every neuron would encode very very discreet movement directions and amplitudes.
And then if you would sample across large populations, then the common response
would give you a direction of movement.
But this is a much lower granularity of organization than the one you're describing.
So do you see this as a conflict, or can these two views be made compatible?
I don't see it as a conflict, and I think it will be our job to try to fit them together.
But it's not fitting together. just yet.
If you electrically stimulate and you get that particular movement by reaching
and you start stimulating around and moving the electrode, you'll eventually,
in a short few millimeters or less, move out of that territory into another
territory where you get another movement.
Or you might move out where you get no movement and then you move a little further
and you start getting another movement.
This is also the model you proposed, right? That's the model.
But the movement, as you move the electrode, isn't exactly the same.
So it may be that you're getting somewhat different sets of neurons activated.
When you look at the connection pattern, say in posterior parietal cortex,
because we have that posterior parietal cortex, one region will connect widely to all other modules or
domains that I've been talking about.
If you turn this around now and optically image while you're doing that,
you get a totally different picture.
Optical imaging is where you would activate neurons high enough to recover a
threshold. So it's not whether there's any activation.
It's whether you change the ongoing activity to a higher level.
And there you see a much different picture. You'll see around the electrode
stimulation, neurons are activated at a higher level over a very short distance.
And then you'll see patches around that domain that are activated,
and more distantly you see nothing, although the connections are there.
So our interpretation of that is that the connections are largely connecting
inhibitory neurons, and those inhibitory neurons are downregulating the activity.
If you add a negative image, like it can have an fMRI, but not so easily an
optical imaging, because you're going over a threshold new set.
If you look at functional imaging, I would predict in there that you would get
a down regulation and less activity than if you're doing an optical and nose region.
So you're saying, and this is how you showed it, right, that actually there's
a very clean organization of these behavioral zones, if you want.
And your idea would be that they are quietly excitatory coupled across these
three pages of the control system, but then they are tightly,
let's say they're competing with each other through inhibition. Yes.
But inhibition regulated through cortical-cortical connections.
Right. Okay. So you don't see a role in this kind of, let's say,
competition and action selection for subcortical structures such as basal ganglia.
When you see this play out as a pure cortical problem? We don't know the role
of subcortical structures yet, but we know that if we inject tracers in free-reach
zones, for example, one in posterior paracortex,
one in premotor cortex, and one in motor cortex,
and we have a medical student working on this project just right now,
the connections, interconnections are to the same part.
They're all overlapping completely in the basal ganglia.
If you go to a reach and a defense area in the same region of cortex or in different
regions, they'll be in different parts of the basal ganglia.
So the basal ganglia has a chance of having.
Information coming from all three areas at once and feeding back,
ultimately, to all three areas.
So what the basal ganglia might be contributing, we don't know yet.
But it's intriguing knowing that basal ganglia are essential for heaven formation.
I think that this is a place where that kind of learning can alter the functioning
of these cortical ligaments.
So our understanding is at a very primitive level you have to get how to not
only how to standard behaviors come about but how do you vary these behaviors
how do you how do you unite them how do you,
get learning sequences of behavior coming
about and we're not there yet but we want to go there eventually sure the example
you described is sort of basically guided region graph in primates and so it's
easy to imagine in the evolution of primate that uh.
We moved from being animals that essentially use their mouth as their main effector
to being animals that would use their hands as their main effector.
And our eyes start to face forward and we do stereo.
And we were able to then really precisely control the movements of the arm and
hand, which wasn't possible before.
And perhaps this posterior parietal cortex, therefore, evolved to fit this need
of visiting guidance of reach.
But would you say that it's more general than that, that it's involved in other
aspects of motor control, or is it particularly for those kind of movements?
When we go most new, we get movements, combined movements of forelimbs and hindlimbs.
We've only done this in anesthetized animals, and so we don't know what that
means, but it looks like it's running or climbing.
Okay. So… So, but it could be involved in regulating pain? There could be something
for initiating climbing or running escape behaviors or whatever. I don't know.
But it's promising to go in that direction and try to figure that out.
Have you looked in non-primate animals that maybe have good vision and grasp
to see if they have anything similar to this development?
I don't think you would get in posterior parietal cortex because the stripping cortex is so small.
And actually you get a lot of visual inputs directly to premotor cortex and
even motor cortex in rodents and free shoes and a lot of other animals.
They're not adding this extra step in there and that means you've lost the connection as well.
You're gaining a large expanse of posterior parietal cortex and you're not having
these direct visual connections to motor and sensory areas.
But now the, you could, so this is, and this is a pretty clean scheme, right?
Because you would say, look, at the level of prior motor cortex,
you would have, let's say, clusters that control different joints of the body.
This is the motor of the mind, right?
And they are again grouped together in a, if you want, a zone that controls
a specific behavioral pattern.
And they're linked together They had an executive and had perceptual systems.
And then you could argue within that behavioral zone, you might find something
like a population response, but collectively they really control the whole behavioral pattern.
This would be roughly the picture, right?
But one challenge here is, of course, that you could argue if you now want to
scale up towards, let's say, macaque performance or human performance, Mm-hmm.
One thing that characterizes us, if you want, is that we actually are less dominated
by stereotype behavioral patterns.
And in our case, we can play musical instruments, we can generate,
let's say, and control arbitrary behavioral patterns.
So, and also using the Gallagher, you could say, well, there's still a fairly primitive brain.
And maybe what you see is more the behavioral organization of a primitive brain
as opposed to one of a more advanced brain.
That is, that you look at the control of stereotype behavioral patterns that
are very much brainstem dependent, but that in the end the organization of arbitrary
behavioral patterns as we kept producing them would follow different principles.
How would you look upon that challenge? I would speculate, and we don't know
much about human brains in this, or we don't I don't know very much about macaque cranes yet.
But we would speculate that exactly the expansions in the direction you're going.
So we have a primitive system that is important for all these primates,
new world monkeys, old world monkeys, pursuing primates.
We don't know how chimpanzees might be or humans might be, but there's a lot
of reason to suspect these basic modules have been retained across all these animals.
But they would also be built upon.
And especially, say, from grasping to being able to do grasping in all sorts of different ways.
And of course, most of what we do with grasping is not in conscious awareness.
Then you reach out and you do the appropriate position of all the fingers for
whatever you're going to do.
And it's been pointed out, I don't know if this has been studied in macaques
to any extent, but in humans, you not only reach the best grass if you're just
going to pull a twidge or something,
but if you're going to do something next,
like turn it upside down, then you do a different grass for turning upside down.
So there's the potential for a lot more going on than what we're seeing.
And how does that occur and where does that occur?
We don't know. We don't know. But I suspect a lot of that is due to circuits
in posterior parietal cortex,
where instead of a small grasp area, you have a huge region involved for manipulation,
grasping and manipulation.
And maybe only part of that will give you a simple grasp.
And other things all combine in different ways to add complexities to this.
And then you think you have to know what you're going to do more than one step
in advance to do a lot of this and yeah so,
The challenges are great. But there's something interesting about scaling this.
If you scale up, because I think we're going to hit the bottleneck.
Because you could argue, okay, if we now scale up this Gallagher brain that you're investigating,
then if the same principle would hold for a human brain,
which is, let's say, much more diverse in its behavioral output,
almost arbitrary in what it can do, you would say, well, that would mean that
instead of having, let's say,
eight of these behavioral zones that you've seen to go, like defensive,
grasping.
Stereotype behaviors you identified, now I have, let's say, a large thousands
of these three-staged controllers that define very specific behavioral patterns.
Would that be the scaling up that you envision? That's one possibility.
That's one possibility. It might not be. That's the way it goes.
Maybe what happens is individually variable according to learning experience
and modifications in the circuits that come from the learning experiences and
may depend more on basal ganglia.
It might depend more on different parts of the whole complex system.
We don't know that. But if you start to think about other parts of the brain,
premotor cortex looks pretty simple in the Gallagher goal and fairly enlarged
and complex in a macaque monkey array.
And then you think of the complexities. Where did speech come from?
The motor circuits for speech and so on.
How did that get elaborated? We actually have no animal model.
It's partway there that we can look at. You have to learn from humans how this
happened and what circuits are involved in. So...
Big jumps, there may be big jumps. We're so far away from macaque monkeys,
they use them and say, this is what, we're just scaling this up for human brain.
I'm thinking that's probably not going to be the case. And so we're going to see a budding off.
Grass barrier will have functional subdivisions and there'll be some that'll be standard.
And that means a lot of different grass behaviors will be there for every human child.
And then there will be a lot of things that will be acquired and acquired on
the basis of experience.
But the cortex will be there that can be modified for other parts of the brain.
It doesn't have to be cortex.
It can be modified according to the learning experience and,
you know, sort of making stone tools or whatever.
You're not going to do that well the first day you're doing it.
But there's some things that you have to do well on the first time avoid a bullet to the head. Right.
Reaching out and a newborn human baby doesn't have to do very much to survive.
But a lot of primates are very good at grasping and holding on and reaching out.
As newborn infants, their visual system has functioned. They can do that.
So So a lot of experience is needed for some of these behaviors.
And even if they're late developing or emerging in humans postnatally,
I'm not sure that experience is an important thing.
It's just the maturation of the system.
So it's sort of like the old studies of children crawling upstairs and you don't
let them crawl upstairs.
It doesn't make any difference if they have the experience or not.
At a certain age, they do it. but now.
So if we take the scaling up question, one bottleneck I would see is how can
I build my decision-making system, my executive functions of prefrontal?
Because, for instance, in the perceptual case, you would argue,
well, this is convergent because I have a number of objects.
Objects afford certain actions. So you can already see that there's some sort
of mapping there, which is not completely arbitrary, right?
And not objects most objects don't afford an infinite amount of of radically different actions,
at the action side it's highly convergent you have to go to
your skeletal muscle systems it's very constraint with a
level of executive control where you have to if
you want to now these actions to the rules that you find
in your environment that's almost open-ended right environment
also for the color goal in theory environments can change
dramatically and they still have to adapt to that so wouldn't
would dare not be a bottleneck for
this idea of very strict zones because that would
also mean that the information you can now use of capturing
the rules of your environment the opponent rules your environment is
actually very limited now because i i'm tied to a certain set of connections
in a very small zone to pick up an arbitrary set of rules right So don't you
think that there we need a bit more access to memory than your model would predict?
You need access to memory, and where memory comes in isn't so clear,
but you can start to tease this apart by looking at humans with perispherian injuries,
but it also can be done more productively, I think, with primates where you
can do selective cooling or inactivation on parts of surface and see what happens.
But I would, you know, just as an example, say, well, one of the hard things
for, and I tell you, the frontal cortex develops enough is to inhibit a natural movement.
So if something moves in the visual field and you look at it,
but you can tell a person not to do that. Don't look.
And that would be a command that they understand the rule and they argue. you.
But a person with frontal lobe damage might have a hard time not looking.
And so that suggests that the interaction is in the frontal lobe.
Things that are from the frontal cortex, prefrontal cortex, are important in that decision.
Otherwise, it's more sensory crib. Right.
But anatomically, you have not found any evidence for this more,
let's say, broader other accent of memory.
Anatomically, you find very sort
of restricted, zone-like organization is called a vertical projection.
So we don't know where that happens, but we'd say in short term,
it's just that short term thing, that working memory.
Coleman and Ritchie would say prefrontal cortex. Long term memory,
which certainly if you told me not to look, I wouldn't have to keep that in,
a short-term memory because I'd remember that the next day saying,
well, I'm in this situation.
I'm not supposed to look. I'll just look straight ahead. So how does that,
Where does that access to that memory, how does that get retrieved?
And then it gets harder. Okay, but this might imply that there's a fifth zone you should consider.
Because although there's a fourth zone dealing with value and effect,
which must be still identified, but maybe there's a fifth zone that is more
a broader cognitive memory system.
That is, if you're playing this piano of these zones, these behavioral zones
you have identified, would that be reasonable as an intervention?
Yes, absolutely. So we have to think of both understanding what the rules of the game are.
And we can pick that up verbally very easily. But the problem would be for a
monkey to understand rules.
They have to understand by the training procedure that they now are getting
the idea of how to solve the problem.
But then you have to know all sorts of other things.
You have to know if there's a reward if you're doing the right thing.
What's the value of the reward? And the value of the award would not be consistent
if it's a food reward because you're hungry or less hungry.
So if it's a punishment, what's the value of that? And all that information has to be there.
So it's a huge task to try to explain these complex behaviors.
So I think we're at the very early stages of trying to do that.
And looking at basic components.
And maybe you're right. Maybe the basic components could fade into the woodwork
as you get a more complicated system.
But my analogy is one that I'll steal from John Ullman in his little book that
he wrote on the evolution of quinnets because I used to work with him.
And he said he went to the power station in Los Angeles and said,
They have some of the most ancient equipment in there and some of the most modern.
And the reason that they have both is that they never can shut down the power
system because they have to keep it running all the time. So they add to it.
And brains are like that in evolution in the sense that it has to keep working
all the time and you can start to modify it and tinker with it.
But you can't shut it down and redesign and say, I have a much better design.
That's maybe pushing it too far because maybe the new additions make some of
the older components less necessary and they might fade or disappear if it's
possible. But it might be a different system.
But my bias is that we're going to see this primitive system,
which isn't so primitive because it's new with primates as opposed to a trial
organization. and fish.
That premise is since preserved in all primates, but greatly modified in the
human brain especially.
But also we think macaques will be modified considerably from prosimian primates. Right.
So you mentioned the possibility of using neuropsychology or cooling to tease
out some of these questions.
Do we have evidence from that already maybe of the impact for instance,
of stroke on posterior to parietal cortex. What does that show us?
So when Randy Nuda made small lesions on part of the hand cortex,
he wasn't looking at specific modules or domains.
He was just doing, this is hand cortex, Randy, sum of this out.
With a little experience in three or four weeks, you couldn't tell the animal unless it's cortex.
So Leah Kruitzer has done this in posterior parietal cortex,
making a small lesion of an area involved in grass behavior.
And in three days, you can't tell.
So the reason we want to look at cooling is that we realize that the brain has
enough plasticity and is going to change the strengths of connections and modify
actually where the connections are,
even over short periods of time, that it's a moving target.
You can't figure out what the
machinery is doing if it's modifying itself while you're looking at it.
So cooling will give us a chance to look. look, we're going to change the machinery
for a short period of time and we're going to restore its original organization.
And hopefully there aren't permanent changes in the machinery by doing that.
There might be. You might not ever be able to go back.
So we're both interested in the plasticity and the ability of the machinery
to adjust and change because that's going to be important in the learning and
experience component of everything we do.
But that's going to be a harder task. You know, the robotic studies would suggest
that there needs to be, for the control of reach and grasp,
an area that analyzes the visual affordance of an object or grasp and decides
then, okay, these are the alternative graphs I might do.
And then that would go downstream towards the motor system, which would perhaps plan a specific graph.
And when we write proposals to try to get funding, I'd say one of the criticisms
we're getting is from older people saying, you're not doing the right experiments.
For example, when an animal in your setting, some part of the brain is reaching
and grasping, why don't you put weights on the hand and see what happens then?
So, but we already know that the animal will compensate for that weight and still do the test.
How does it do that? That's an interesting question that is,
in our future, not the immediate thing to understand because we don't understand
things that come before that.
I think that's an advanced question, a part of the immediate adjustments of
circuits so you can accomplish something.
But already you can do a lot in the spinal cord, as in frogs or whatever,
that beats anything that's revealed.
That wherever the limb is, it'll come to a particular position.
Those circuits are really very elegant at that level for doing something to a specific goal.
But now with respect to the plasticity effect you mentioned earlier,
Are you with that saying that these ideas of Lashley from the 30s,
of mass action, equipotentiality, actually hold?
That means function of the brain results from the collective activity of many
of its neural units, and single neurons can basically take on a plurality of
functions dependent on the context they're in.
Do you see that confirmed by your... I think that's true, but I wouldn't agree
with everything that Lashley would say.
For example, he said that you can do everything with one-sixtieth of primary visual cortex.
You could, if you imagine doing everything by looking through a peephole, then I'd say yes.
You have all the machinery for analyzing a small little bit of visual space,
because you're doing all these different bits of space somewhat in parallel,
not completely, because there are horizontal connections that are interacting
and feedback that are interacting.
The rat would lose that in its 60s, but it still could do a lot in that little people.
And you would be fooled to think that the rat is fairly normal if you didn't
pay attention to how it was using vision.
And that's where Lashley went, of course, you take any part of the brain out,
you're degrading the function of the machine.
But the ability to compensate for loss is tremendous. That's what's so...
Would be so unexpected for people 20 years ago.
Although any physician that saw somebody with a lesion would say,
of course they get better.
It's just that imagining how the brain can change to recover.
People said, well, once you develop a brain, it's fixed. That was the view I was raised on.
It's developmental capability can change. Once it's developed, it's fixed.
Now we have so much evidence that it's not there.
But now, what's so surprising about this result that we've now been discussing,
as well as we've paid so much attention to it, is that after, let's say,
what, 150 years or so of motor system neurophysiology,
why did it take us so long to stumble on to this idea about the organization,
of motor control in this sort of, let's say, multi-layered architecture.
Why did no one stumble into that earlier? I think early on, there was a lot
of evidence that you can simulate widely in the brain and get behaviors.
And then that was forgotten as soon as we said we have a motor cortex and this
is where it's really happening.
And we can focus on that. but also single-unit, single-none recordings became the focus.
And if you look at where in the macaque monkey you can evoke grasping behavior
by electrical stimulation, it's only part of a much larger area where neurons
are active, very active during grasping.
Those neurons are all contributing in some way, but we don't know how they're contributing.
So this correlation of being active during a behavior is a good start,
but it doesn't tell you their role in the behavior yet.
And of course, you could lose a lot of them and the behavior still would either
be there or would recover.
And it doesn't tell you how that happens.
Now, one contradiction that I have, or that I have to resolve for myself,
is that if I look to your work, on the one hand, you do make a point,
also supported by a lot of anatomy,
that actually we should not interpret sensory modalities as being really so
specialized as single modalities.
There's a lot of, let's say, cross-modal responses that you find in,
let's say, primaries, in the primary sensory, some of the sensory area might
find response that led to motor actions or you might find, let's say,
visual response, whatever.
So it's much more, let's say, a mixed bag.
There's specialization, but
not strict boundaries. It depends on what sensory information is needed.
Yeah. And, of course, you know, Sixty years ago, Wellesley was saying that we
shouldn't call something motor cortex.
It's motor sensory or sensory motor.
And the second word means it's the reduced part. What's the dominant part?
You put motor or sensory. But they're all sensory motor.
Right. But now in your interpretation of the functional organization,
you seem to segregate very specifically from perceptual, executive, and mode.
So should we really put strict borders around that now?
Or do we also face, let's say, a challenge that maybe, let's say,
executive is not solely executive in that way or perceptual neither?
Yeah, I see what you're getting at. Part of the problem is that you would say, let's say.
Because I have someone in my department working on frontal light field.
And he would say that frontal light field.
If you ask an animal to move to a target, and the target has to be a red square
against green ovals, or it could be shape,
it can be color, it can be anything that you can change in the visual system, The animal will move,
and the neurons in the frontal eye field will be activated by more by the red
square than the green oval or whatever dimension you want.
So you could claim now that those neurons are sensory neurons that are selective
for whatever attribute you wanted to make up.
But in another test, they can be selective for any other visual attribute. view.
So I would say they're visual, but not in the same sense that we have a visual
processing hearing that's trying to extract bits of information.
That information has already been extracted, and now there has to be some mechanism
of having frontal eye field know what the rules are.
And only get excited when the cue is coming that means that you'll get water
or juice or some reward if you move your eye to there, then those neurons won't be activated.
So is that a sensory input or not?
It's probably an executive input that also has the sensory information and so on.
And when the red color in the square is there, go for it.
But that's hard, I think, to start to specify exactly how that's accomplished
in a mile. Mm-hmm, right.
So the theme of this week is about the evolution and development,
the evo-gevo of behavior.
And I wonder what ideas you might have about how this relatively reorganized
system emerges with early primates.
Sort of what are the combination of different things which are giving rise to
this, a lot of developmental mechanisms that are perhaps allowing the brain
to reorganize of this important esthetic parietal cortex area that can,
give you much more control over visually guided vision of rats.
So I think in early mammals the behaviors that were species specific and necessary
are largely subcortical under control. That's somewhat limiting.
In mammals without a motor or primal cortex which we would judge to be marsupials,
Most of them or all of them.
Somatosensory cortex is heavily involved in providing sensory information about
where touch is, where proprioceptive, and so on, to a largely subcortical motor system.
So a lot of behaviors can be evoked by stimulating subcortical stations or visual
avoidance. A lot of this can be done by deep layers of the spirit colliculus, for example.
We don't know how that's involved in this behavior that I'm talking about,
but it's certainly part of the possibility.
How this is done by extra-parietal system, for example, not so clear.
But with the advent of a separate motor cortex and what I would call the fracture
or modular organization of motor cortex, That seems to be, when you have a primary motor cortex,
it has these jumps.
It's not completely cemented topi. It's jumbled.
And the cerebellum, where you're dealing with a jazzing, using sensory information
to correct errors in motor behavior, is jumbled as well.
Why is it fractured in this way?
You have different body parts next to one another. probably for the same reason.
You have to have different combinations locally, so you have to repeat the same
inputs several times in different ways so that you can have a modular kind of organization.
So we think this already happens in motor cortex.
So one way of looking at motor cortex is to say motor cortex is just the general
purpose motor region, and its organizing feature is somatotopy,
goes from foot down to tongue. Tale to Pond.
That's the crude organization within those big blocks.
You'll see all kinds of mixtures, and this will be true of any motor cortex, rat, whatever.
So already, I think there's a sign that it's modulately organized in terms of
certain specific behaviors.
Once you set up that organization that would match with the information that's
coming from the cerebellum,
then that means that premotor cortex should follow that suit or posterior parietal
cortex should follow that suit if it's going to interact with it in a meaningful
manner and so these are steps added on older cortex first,
posterior parietal is more on the perceptual side of the beginning of this motor hierarchy in a way,
I wouldn't necessarily say so much on the perceptual side because what if the
sensory information is used in a non-conscious way where you're not aware of
how the sensory information is being used?
Right, it would still be perceptual, no? It would be sensory,
but perceptual implies an awareness.
I mean, you are aware of the visual scene, but you might not be aware of how you crawl motor behave,
well I'm not sure if we really have to bring in awareness for to talk about
perception perception maybe.
Perception essentially means that you rely on categories right that knowledge
is imposed in defining what a visual scene or what a sensory scene comprises of,
So, I'm not sure whether we have to…,
So, I'll try to make the distinction in how I think about it and see if we have some agreement.
But I would say that if an area of the brain is involved in perception,
when you electrically stimulate, you should have a perception.
And if you electrically simulate a motor cortex you might not have any perception
you might I move but I don't know why okay yeah I would I would I would disentangle
these two because I think a percept as such can be,
a representation you use to classify states,
but these states don't you don't need to enter awareness we don't need to couple
this automatically to awareness but of course we can make on definitions right but
But to bring it to the finish line, so here you are with this enormous experience
in brain research and evolution of the brain.
So how many more years do we need to really understand the brain?
I hope five more years. Because I have five years of funding.
Well, here you are. But I think it's
an endless task in the sense that our understanding is very crude now.
I feel, but much better than it was at the time I showed you the Thompson textbook pictures of cortex.
And now people are labeling functions or areas all over the place and saying,
well, this area is involved in eye movements. Well, that's pretty good.
But why would you have an area that people call LIP, which we see in all these
primates now that we can get the eye movements from posterior parietal cortex
in the region that I think is LIP that you define in humans or mechanics.
Why would you have an eye movement in there? Also another eye movement in the
frontal lobe. And then a supplementary eye.
Why all these steps? Unless each step has a different role.
And that's the heart of what I'm thinking about. And so the role of posterior
paracortex is sensory-dominated. to make the best of what the sensory information is.
And that's perception. It's perception. But I don't necessarily think that the
person, the observer, has to be aware of the perceptual decisions or the sensory decisions.
They could be or they might not be. I'm not sure.
But really, if you were designing a robot, it wouldn't make any difference, right?
What's the function of consciousness?
That's to add the executive decisions to the whole thing.
But a lot could be totally automated where consciousness is not an important component.
Right. I think, I mean, a perhaps interesting analogy,
that we might consider in robotics, you know, until maybe 10 years ago,
we were really struggling with vision for robots to do even elementary scene analysis.
And then suddenly, people did have stereo algorithms, but it was difficult to piece it all together.
And then Microsoft came out with the Kinect and it delivered to you a 3D analysis
of the scene, which is really quite detailed.
And suddenly we can do all sorts of new things really quite easily and quickly
that were very difficult before.
So perhaps in primate vision, we have something similar is that the visual system reorganized itself
to give us good stereo because i think in a lot
of these other animals it's really a defense system and it's
not fusing it's not giving you depth it's certainly not
as you were saying in your talk giving you a high detail
so once you have this nice depth analysis of the visual world the brain can
maybe reorganize itself to make use of that in some way and that would be interesting
to try and understand whether that was one of the things that is giving rise
to this new capacity They probably have.
And what's surprising to me, even though I've studied plasticity for a long
time, is how quickly a new feature can be useful.
And the best example is adding a third cone to a squirrel monkey's eye.
Officially, everybody knows about that research, where you add a new gene to
something to coincide in the retina so that you have a third pigment.
And their color vision immediately changes.
The whole system adjusts to something new.
Would anybody ever have guessed that in advance?
I mean, I'm stunned by that, but it shows us that at least the developmental
plasticity is fantastic in adjusting to change.
And so a little change anywhere can be built. will affect the brain widely. Right.
Although I want to be careful with Tony's suggestion that the primate brain
might have been based on Microsoft architecture.
So the other thing is, so now.
What's the kind of prediction you would like to make today about the work that you're pushing now?
So you have five more years, you were telling us, funding.
What are we going to see at the end of these five years? What's the prediction
that you're really testing there?
Well, we hope to do several things. I want to demonstrate that it can be put
into a model of how posterior parietal cortex,
seven or eight functional zones interact and
how they interact and do
the same for motor cortex and premotor cortex if anything
more than that comes out of it I'll be delighted and the one way to do this
is I want to know what are the inhibitory connections and what are the excitatory
connections we have a prediction and the prediction is that there will be,
excitatory connections to excitatory neurons in a very specific local pattern.
And then the other ones will be excitatory to inhibitory neurons,
but in posterior parietal cortex, there will be mutual conflict between the
areas, and they'll be fighting on the basis of inputs to win out.
Those connections can be demonstrated now by selectively labeling connections
to inhibitory neurons and seeing which neurons go to inhibitory neurons and
which ones go to excitatory neurons.
That's possible through genetic manipulation techniques.
We haven't done that. The things that have been done in that area are not very
far along yet, but we can do it.
If I have the right collaborators, we can do it. Right.
And then, so how long have you been active in neuroscience now?
How many years are we talking about here?
Well, I started graduate school in late, I finished in early 60s.
Undergraduate, and then I was in graduate school, and so I would say I was involved
in it from the 60s, and late 60s, pretty well involved in it,
and so it's really a long career, longer than most people ever get to enjoy,
and so I'm delighted to be still here doing this thing, having this fun,
because it's really fun.
But now, based on this experience, in the study of the brain,
what is the John Kass law that we should all follow?
I'm not sure I understand your question. Well, there's like a norm that you
would like to sort of, if you want, impose upon all of us interested in the brain, a heuristic,
a rule that we should adhere to in order to make progress, to really gain understanding in the brain.
Everybody gets it understanding and in their own ways and so i wouldn't hesitate
to say this is the way i don't know the way i'm i'm learning new ways all the
all of the time and and uh i would,
after working on plasticity for a long time i
didn't intend to work on plasticity and developing think they're
dull brains but there it was and you couldn't avoid it so i guess all of us
should be open to different ways of thinking about surprises that we didn't
anticipate and then incorporating them into our thinking and um,
I think it's very hard to ever change your mind on something when you get committed
emotionally to a line of thinking.
But if we could do that more easily, it would be helpful.
One example is I was on sabbatical on the way, and my graduate student was working
on something that would provide really compelling evidence for a view I had
about the visual system.
And he said, the evidence is just the opposite. and argues that you were wrong
about how you thought the visual system.
He thought he was first hesitant to tell me about this because I was on sabbatical.
I wasn't seeing how things were happening at home.
And I thought, this is great. It's much better to announce the mistake ourselves
than have somebody tell us we were wrong.
But the evidence was so convincing that I flipped over right away.
And now I have a person that's now working with me, a crew that's there,
And she's telling me, you're wrong in another way. You have to incorporate that in your thing.
And I teased her and I said, no, that can't be right. She went away in a postdoc,
still thinking I disagree with her completely.
But I'm going to send her a paper that I want her to be a co-author on,
which I agree with her completely. It'll be a surprise to her.
But maybe it's because I've had now a couple of years to think it over.
But she didn't have a strong bias in going in. And she just looked at the data
and she came to a different view.
My other graduate student didn't have a strong bias. I had the strong biases.
It's my view that had to be changed. Theirs was easy to change because they
didn't have a strong one. So, John's law, we keep an open mind.
Keep new investigators around you. Right, exactly.
A lot of surprise. That's fantastic. So, they'll tell you where you're going.
Exactly. Well, John, thank you very much for this conversation.
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