I tried to learn for a while but I didn't get the dopamine that I needed,
sex and drugs and rock and roll and I don't have milk, that's what you want,
I should have yeah, I used artificial dopamine I did some of that that's what
Eric said this is the Convergent Science Network podcast,
leading researchers in the domain of neuroscience, brain theory,
and technology are interviewed by Paul Vershoor and Tony Prescott.
This is Paul Vershoor with the Convergent Science Network podcast with my colleague Tony Prescott.
And we're talking with Greg Reckenzone, who was speaking today at the BCBT Summer
School 2015 here in Barcelona, on something that I was told as a student didn't
exist, which was adult cortical plasticity.
So, Greg, why did you go over that topic? What's important about that question? question.
Well, part of the reason why I did this, that I talked about this,
which I don't usually talk about when I give seminars, is that Leah specifically asked me to.
And she reasoned that back in the days when we were graduate students,
it was, as you said, impossible and it didn't occur.
And it was a real revolution in the way that we thought about how the cerebral cortex worked.
And it's been so well accepted at
this point that students today just kind of take it for granted
and don't really get ever taught kind of
the classic papers and studies that were done in order
to demonstrate it to the point where we all now you
know believe it so that was my main motivation today and plus you know it's
eight years of my life working on that thing so it's kind of nice to revisit
it and and um still see some enthusiasm about that kind of stuff right but now
how do you explain that transition historically that's a good question too it It seemed,
you know, as I was going through the beginning of my talk,
that back in the 1800s, everybody knew that it had to exist and it was trivial.
And then for some reason, since nobody had been able to really demonstrate how
the brain changed when you actually did learn something, and then Hubel and
Wiesel said, look, it stops changing after a certain period in development,
which made perfect sense, it just got kind of lost in that shuffle.
And so it took a 10-year hiatus, really, where people just kind of thought critical
period, critical period, critical period, and nothing about,
wait a minute, how did I just learn about this? I'm an adult.
My brain had to have changed somehow, right, for me to learn this.
But it couldn't have, but it just, you know.
I have no idea why people got stuck on that and coming from mercenek's lab where
he never considered that as a you know a serious proposition for learning i
would never got caught up in that mindset right so i i always uh you always
believe your mentor that's always important right i recommend exactly the opposite to my students.
But now but then i add to that disagree with them but give a better alternative Yeah, absolutely.
But for you, this history starts with Mike Mertzenich and John Kass. Right.
Very much, right? So what was the key insight, you think, that brought them
to that point of reviving these ideas about adult plasticity in the cortex?
Well, I've talked to both of them about this a number of times.
Because it was remarkable. It was a stretch. And it was a struggle.
Because many people did not want to believe those early papers.
Versus the antigen amputation paper and the median nerve section.
They wanted to think of unmasking and all these other things.
But they're both pretty passionate scientists, and they both thought that it
just made more sense that it worked that way, right?
And I think they just believed, right? And Mike would say that all the time,
that he just kind of believed that it had to be something like that,
and he just wanted to show how it was done.
And so those early studies I thought were brilliant in the sense that they weren't
supposed to work, and every time they did something, they learned something new.
And so it was a really exciting time for everybody in those labs to be doing
those kinds of experiments.
So can you describe one of these sort of early experiments that really brought the message home?
Well, for me, the one that actually solidified in my mind what happened is when
you look at the map of the hand in Area 3b in a monkey,
which is really precise and elegant, and each finger is represented very cleanly
and distinctly and from the wrist to the fingertips, it's all very topographic, right?
And then the critical period genetic model would say that if you lost a finger,
then that part of the brain just wouldn't have anything to respond to anymore, right?
And what they did is ask the question, is that really what happens?
And so what they found was that indeed the neurons that used to respond to the
missing finger now responded to the other ones. And another key insight that
I didn't talk about today that really made, um.
Made them think about it differently is that it wasn't simply the case that
the old map was there and then some new things happened also.
The whole map looked like a four-fingered monkey. So there was the same kind
of overlap and the same progression and the same topography,
but just with the missing finger.
And so that gave them the insights that what must be happening is that the receptive
field of a particular neuron has to be dynamic.
It has to be able to change over a very short time course, right?
Probably, you know, in a dramatic thing like this over the course of two months,
but probably does it over the course of several days, right?
And so there was something in there that these neurons are always actively changing
the weights of their synapses to see what parts of the skin that they should
represent relative to what all their neighboring neurons are representing, right?
And that's how you keep the topography.
Now, it was really lucky they did that in area 3B because if you look at the
visual cortex that Charlie Gilbert did, it doesn't work that way.
They all stack up, right? And so it's not this ordered topography that you see
in the somatosensory cortex.
In the auditory cortex, if you do a cochlear lesion, essentially what happens
is the cells that used to respond to the now lesion frequencies respond to the
one that was spared, the edge of the lesion.
So all three of them are very different. And so it was really fortunate that
they did the 3B study because it made the most sense, right,
at the time. But also in retrospect, it was the most effective choice.
Yeah, in retrospect, they didn't know about the other two, right?
Those came subsequently, so they lucked out, essentially.
But now, when these amputation studies were done with these results, did they...
What was the resistance that you faced in the community?
Yeah, so personally, fortunately, I didn't face any of that.
So Mike was a champion. He would accept anybody's invitation to go out and talk
to their research group and give a spiel and then spend the next half hour defending
it because people said, no, no, you can't change the brain like that.
It's just unmasking or you just, you know, it's just something that's not in
any way related to any sort of perceptual differences, right?
And I didn't see him a whole lot as a graduate student because he seemed to
be gone all the time, going and just going out there and pitching his story
and defending it the way that only he can do.
And eventually people came around, I guess.
I mean, when the accumulation of evidence, if he had stopped after the digital
amputation, it would have been all over.
That would have been the end of it, right? But we kept going and going and going.
Then other people get on board too and start doing these experiments.
And it's like, look, it always changes, right? So it must be real, right?
So what is the now consensus? Because obviously we have a revised view of plasticity.
This battle has been won, but also the notion of critical periods is still there.
You know, we've talked about it several times in the last week.
What would you see as the consensus now about the amount of adult plasticity
and how that compares to plasticity in infancy.
Well, there's absolutely no doubt that there's critical periods,
and the lid sutures do cause ocular dominance column shifts and all these kinds
of things. So that's absolutely certain, right?
The way I think the field has come to a consensus is you have these developmental
time points where you can do largely anatomical differences,
right, but not necessarily.
And then once all those things are over with, you're left
with the adult plasticity
which is how you change the weights of your synapses and
how you mess with inhibition and things like that and that is
what's basically the difference between critical periods and adult plasticity
is an adult plasticity you don't expect much of any changes in the underlying
anatomy so this fundamentally different mechanism yeah so it's fundamentally
different and they're both working independently essentially.
So now we look really at changing the periphery.
We remove a finger or you switch your two fingers together to make a four-fingered
monkey, and then you see these changes in the somatosensory representation of
the body as you described.
But now how far do these changes percolate into the system?
Like, for instance, if I have a somatosensory change due to this change of my
hand, And is it matched also to changes in, let's say, primary motor cortex, premotor cortex?
How far do these changes really percolate down into the system?
You know, that is a question that, to my knowledge, hasn't ever been looked at strongly.
So I know that Randy Nudo did a whole series of experiments where he had the
monkeys do different sorts of motor tasks, and then he looks at motor cortex,
and there's predictable kinds of changes that would associate with that.
And so clearly, any time you're interconnected networks, like 3B and 3A and
M1, one, you're going to see these changes percolate at least to the extent
that they need to be, right?
So I imagine that if I looked in the motor cortex of those same animals that
I studied, I would see all kinds of things that were related to the reach and
to the release and all these things because they were doing that,
and that was very important to them too, right?
So is that because of the somatosensory changes? Probably not as much as it
is to the actual motor movement, but they're going to work together.
But auditory cortex didn't change, even though they heard this stuff,
right? So there's some limit to how much it goes.
And it's probably just to what's really primarily task-related.
Because that was sort of the next step in your experiments, right?
So now, first we change the periphery. You could say, okay, it's a rather strong
perturbation, so we have a reorganization of the map.
But then you start to look really at the learning component of this by engineering
the task where you provide haptic feedback back or tactile feedback to the, to the monkey.
Um, and then trying to see what kind of changes you would then get in,
in, uh, the smetacensory cortex.
So, um, what kind of changes did you get there in that experiment?
The changes in the somatosensory? Okay, so the monkeys were trained to feel
a vibration on one small part of their finger, starting at 20 hertz,
and to detect when it went faster in a subsequent presentation.
So we saw a great deal of changes, some of which were related to the behavior,
and many of which were not.
Okay, so one thing that wasn't related to the behavior, as far as we could tell,
was the size of the receptive fields got bigger.
And the thinking at the time then was that, well, that's because it's not,
It's a pretty big stimulus.
It vibrated a lot of skin, and so everything is being synchronously activated
by this 20-hertz stimulus, and that's a consequence of the mechanisms by which
you change your weights.
Another thing that happened was there was an expansion of the representation of that skin.
And that was correlated with the ability of the monkey to do the task, but not super well.
And if that had been the end of the day, I would have been perfectly happy with
it, because that's what I was looking for, a change in the map related in some
way to the change in the behavior.
The main thing that was related to the behavior was the ability of the neurons
to follow each individual cycle of that 20 hertz or 21 or 24 hertz stimulus.
And what was interesting to me, the two changes that really made the big difference
was for the brain, when the skin was stimulated on the finger that was being trained,
there was a lot more neurons that responded in that way to each cycle of the stimulus.
But every individual neuron that did respond that way responded about as well
as ones that did the untrained skin.
So if you did some sort of measurement of the fidelity of the response relative
to the stimulus itself, there was no difference between trained and untrained.
And so that would mean, well, the signal is just louder because there's more neurons doing it.
But it was more than that. What happened that really made the difference was,
for the untrained skin or normal skin, if you will, So the way that the timing
of the response to each cycle of the stimulus varied quite a bit between individual neurons.
So that would make kind of, if you did all the population, you have a broad tuning function.
And the trained monkeys, they all lined up with each other.
So the temporal fidelity across the population was enhanced.
So it was a louder signal, it was a better signal.
So it got much tighter, which allowed the monkey, I'm interpreting,
to be better able to tell the difference between 20 and 22 hertz because there
was less slop, less variability, and it was a much cleaner, tighter signal.
But you would say, is that expressing something like what fires together wires together?
Like I'm driving these neurons simultaneously, they fire simultaneously,
this drives local plasticity, they get coupled more tightly together,
and as a result, their response becomes sharper in time. Absolutely. Okay.
But then the other thing you showed is all this elongation of these receptive
fields. Right. That's the thing that didn't make any sense to me.
Why would these receptive fields get so much larger in terms of their sensitivity
along the finger? Along the finger.
Yeah, so when the monkey has his hands on the apparatus and the thing comes
up and starts to vibrate, it vibrated quite a bit, right?
And so it wasn't the same as when you're doing the mapping experiment and you're
just barely touching the skin. It's actually a pretty significant stimulus.
And I felt it. I wanted to see what it felt like.
And it felt pretty big, right? So it was as though, even though the probe was
kind of small, since it was moving so much, it was moving a lot of skin,
almost the whole phalanx.
And I think that's wires, fires together, wires together, is the same kind of
thing. You're moving all the skin together at once, right?
And there was no penalty for having a big receptive field, right?
I would guess that if I had two probes and I asked the monkey to tell me,
am I just doing one or two then they would get small but
it needs more than files together wires together because there's
an effective reinforcement here that you need the reinforcement right
right exactly they have to they have to know that they're
doing it right and it's all this making the script discrimination
gets you the peanut whatever right exactly yeah
so it's a more complicated system than simply
heavy and learning you know if you experience something a lot
then through heavy in learning you might refine your receptors
but if right if it's important for a reward then that's
going to be i think as you've shown much bigger effect much bigger
effect so if you do exactly the same stimulation but the monkey listens to the
sounds instead then you don't see the big receptor fields in the big area and
the tighter tuning so this this is this is not heavy and then or at least it's
a heavy role that's being modulated well that's the question right Is it just
driven by the statistics of the input,
or does it depend on an additional neuromodulatory signal that says,
ah, this is really great, we should get it again?
Yeah, I think it's the latter. Okay. Yeah.
But now, the other thing you saw is also in terms of the response latency,
there were changes, right?
The neurons also seem to be responding earlier to the stimulus than the control
condition. Mm-hmm . So how would you count real effect?
You know, that's a really good question, too. Why would you get,
I mean, it's clear to see why you would get sharper, right?
But why would you get sharper and earlier, too?
And I have no really good answer for that, right?
So it's somehow as though these early responses are the ones that the monkey
was using and pulling the other neurons towards the shorter latency. Okay.
But it was a discrimination test that the monkey had to perform.
Right. Right? So you changed the stimulation frequency and the monkey had to
say, ah, I detected that.
Right. If it was correct, it got a reward. Right. Right?
So how frequent were these changes in frequency?
So the way we decided to do it is the first one was always 20 hertz.
If I remember correctly, the second one was always 20 Hz, and then it could
change on the third, fourth, fifth, sixth, or seventh with equal probability.
So on average, there was five-ish of these 600 millisecond duration things.
So we were thinking at the time that we had to do a lot of stimulation because
the Jenkins experiment had millions of stimuli and saw big changes.
So I was afraid that if you didn't do quite so many,
if you did just one and then another
other one you know two choice right then that wouldn't
necessarily do it i think now that that would have worked and probably would
have saved me a lot of time but right so i
mean looking across these two experiments you see that differentiation
leads to changes in the map that that
probably have a lot to do just with the input
statistics to the map because this is task there's no task dependent anyway
right so well on when we started bringing a task and it's really very much also
the reward content or the task contingency the relation to reward or punishment
that would impose further changes to the map you you read that interpretation
there's no learning mechanisms.
At work okay but now how stable would
that learning be like for instance if what you
already saw what these these peripheral changes like fusing two
fingers and then disconnecting them actually the map follows that manipulation
but it might do it more slowly as it might follow let's say the task contingency
in in the the stimulation experiment you described right so what is sort of
the the characteristic time constants of these two learning processes,
yeah that's something that um i never address specifically but it's obviously a critical,
component mostly because the idea of course is that you can use this for learning
for good for rehabilitation and all these kinds of things and how long does
it take to do this and once you do change do you ever want to change back or
can you change back or do you need to change back and.
So, I think that's going to be really largely task-dependent and really largely
how much neuromodulator can you get in there based on pharmaceutical or just
the desire to do it or the importance of the stimulus to you, et cetera.
So, my guess is that it will probably take days or weeks or months depending
on all those different kinds of things, right?
Okay. But in case of the differentiation or the amputation experiment,
how much time does does it take for that map
to stabilize yeah unknown okay so
uh those early experiments they also did uh
two-digit amputations and they waited
two months or three months or whatever and what
they found there was that there would be a silent zone so the
two-digit amputation deafferent too big of a portion of the cortex for the afferents
to actually reach each other then ted jones and And Tim Pons looked at the silver
spring monkeys a decade or two later that had dorsal rhizotomies done to them
15 or 20 years beforehand,
and they saw complete recovery in the map.
And that was correlated with changes in anatomical distributions as well,
all the way from the cuneate and the thalamus up to the cortex.
So if you wait long enough, presumably, there was a huge deafferentation.
That's the whole arm, right? And they still saw centimeters of change as opposed
to... I think the early studies were something like 500 or 600 microns.
If you got beyond that, you couldn't recover or you couldn't change your map.
But you know, you only wait two months, right? If you're not going to really
wait 10 years, that's a hard grant to get in the United States.
But sort of the task-dependent change under the influence of neuromodulation
can go relatively rapid, right? Right. Months, yeah.
Days or weeks, yeah. With a task-specific change, certainly if you go to the
matter of conditioning, You might see MAP changes in dozens of trials, no? Oh, yeah, sure.
Norm Weinberger has done that for decades. Exactly. Yeah. Right.
Yeah, yeah. Well, then these amputation experiments show that the overall,
let's say, topological organization of the MAP depended on the periphery.
It might be a much slower process that might require, let's say,
throwing out new processes, building new connections, and so on.
Would you see it like this? That's it.
The amputation, the processes underlying the reorganization of amputation are
slow, and the task-specific ones, depending on neuromodulation,
are fast, or you wouldn't really see it in those simple terms?
I would say that's probably accurate, because when you think about a small deafferentation.
The consequences of that to the animal are not as dire as you have to do this
task in order to get your food.
Right so so how much neuromodulation would
there be in in a situation where you
have a digit amputation it's probably not nearly as much so in
that sense it would go much slower because the need for it
to go faster is just not there you mentioned um
in the talk you were talking about this is requiring attention
uh and uh so what's interesting
is attention doesn't necessarily imply reinforcement
it implies some maybe more intrinsic motivation
to attend i guess you're not directly getting
at it in this task but uh for instance
in the case of a person who's learning
some motor skill their reinforcement might
be you might have to wait a long time for it but uh
you're intrinsically motivated so that right so we
don't necessarily have to think about uh well maybe
we do want to think about a person you're modulated but the the uh
system that's delivering this could be some really
quite complex uh system around intrinsic
motivation signals rather than you know
absolutely rewards right so imagine learning to play a guitar right which is
difficult to do i can say from personal experience and the motivation is to
sound good yeah right and and that's very esoteric right so now your auditory.
Cortex is deciding how much attention or a modulator.
Your motor system is going to get, and your tactile system based on.
You know, your desire, whatever that is, to sound like, you know,
not a hack, right? To sound good. So, yeah.
And you don't necessarily know what the task is. I mean, it's,
you know, you don't know what you need to do to sound good. You're exploring
the space. There's a lot of trial and error.
Right. But I guess you're getting at the basis for that here.
Right. Right. But do we really need to have an attentional interpretation of this?
I mean, if you just get this, the banana chow, whatever you give these animals
as a reward, driving in neuromodulators like dopamine, which modulates plasticity in the cortex.
Leading to this reorganization do we need to say
oh and we paid attention to it do we really need that
interpret it's kind of right so task contingency it
could be task contingency it could be you know reward uh dopamine it could be
norepinephrine it could be all kinds of different things so so to use the word
attention uh as i did in my talk was a pretty loose interpretation of the people
who'd study attention right right so they they would they would shy away from that
necessarily being the key, right?
I kind of throw the word out there just because right after I left Mike's lab,
Mike Kilgard came and he essentially did the auditory version of the experiments in rats.
And instead of training them, he just electrically stimulated the basal forebrain
and got all the same effects.
Right, exactly. And there was no attention there, right?
But that was auditory and auditory conditioning, right? Right,
exactly. Yeah, exactly.
Yeah. So he dumps a bunch of acetylcholine on the cortex right when the sounds
are playing and the maps change like crazy. Right. Exactly. Yeah.
So then, so after these experiments that really demonstrate,
that really contributed significantly to demonstrating that we have a dot plasticity
in the cortex and to show also some of its organizing principles,
in particular the role of neuromodulators, I think,
and let's say input statistics on on how these maps are organized um what are
the boundaries on that process though i mean would you be able if i would give
you just enough time and monkeys and training equipment could you just easily
retrain the auditory cortex into a visual cortex.
And make it as large or small as you wanted it to be. In adults.
Yeah. Take normal adults and then see how you can manipulate that.
Yeah. So we heard a couple of days ago in the seminar that you blindfold a person
and their visual cortex will start helping them learn Braille, right?
So in that sense, you know. Or to echolocate.
Or to echolocate, exactly. So in that sense, you know, all bets are off.
It sounded like from that limited amount of data right but where would you start
when we're going to make an echolocating monkey where would you start how would
you do this most efficiently.
Uh probably easier to teach him to read braille than to
echolocate at least from the training point of view and then uh if if you were
going to do that if you deprived a bunch of cortex of its normal input then
it would and and demanded that it use its hands you know efficiently well and
its visual cortex, for example, is not doing much of anything,
I think it would take days to weeks to start getting that activated without
doing the neonatal manipulations that you can do to get all this rewiring that
Magranca showed a long time ago.
So, yeah, you know, in 1992 when those publications came out,
I'd say, well, that's never going to happen because there's no substrate for
that, right? It's just not going to work.
It's all cortical and it's all done, right? Today, we know much more about it,
and so it is possible to do these kinds of things.
And exactly how that's done is still not entirely clear, but it happens,
so you can change these things.
So the second part of the talk, you focused on sound localization, right?
So we moved to different preparation, we moved also to different kinds of tasks.
Right. So why does sound localization help you to understand this issue of adult
plasticity? Great, so um.
I started doing those sound localization experiments when I became an assistant
professor at least five or more years ago.
And really my motivation at that time was to learn what is it about the brain
that allows us to perceive complicated things.
And the plasticity part of my life, it seemed to me, was pretty much over by
then. So I came, I conquered, I left, right?
And I wanted to make a name for myself independent of Mike Merzenich and Bob
Wirtz, which is no easy task because these guys are just fantastic scientists, right?
And so, like I said in the talk, there was really not much going on in the auditory cortex.
And I think it's really, really important, right?
So human beings, a lot of people will say, a human being is a visual animal, right?
So we have this huge visual cortex and we just like to look at stuff,
right? The other argument is that we're really a social animal,
and what we really want to do is talk to each other.
That's a strong motivator in the human brain.
If you can't talk to other people, usually you go crazy.
You really need that sort of social interaction. actions. So in that sense,
we have this great auditory system that lets us do things like understand speech.
And so in that sense, I thought, well, this is equally, if not more important
than visual system, right? So it should get some people studying it.
And we have the visual system to compare our studies to.
So on the one hand, if you do the same kinds of studies that have been done
decades ago in the visual system and the auditory system, it's new, right?
You already had this all sort of figured out if it works exactly the same way, right?
So my motivation was to go ahead and do something that was novel.
And what I really wanted to do was understand how complicated perceptions could
be formed in the cerebral cortex.
So people have said, oh, you were a somatosensory guy, then you were an auditory
guy, then you were a vision guy.
I've always been a cortex guy. So I'm a clinical snob, I'll admit it.
And I've always been interested in how does the cortex drive perceptions, right?
One way you can do it is you can have plasticity to get better.
Another way you can do it is you say, well, how do you do it without a whole
bunch of plasticity? How do you do this?
And the auditory system and the sound localization system is really nice in
my mind because it's not topographic and I know what it's trying to represent,
which is azimuth and elevation.
So I know exactly what the thing's trying to do and that will give me some handle
on figuring out how it does that. Yeah.
So not being topographic was a motivation you mentioned also in the talk. Right.
But doesn't that make it life harder for you if you take something which is not topographic?
Or is the goal to show that the same principles apply whether there's topography or not?
Well, it does make it a lot harder, right? So if you're nicely topographic,
you can do some really cool experiments like microstimulation or microlesions and things like this.
And you can probe the system much more easily.
I had tried for a while to do microstimulation of the auditory cortex to see
if I could change the percept.
Ken Britton is a colleague of mine at the Center for Neuroscience,
and he has a long history of microstimulating MT and showing really elegantly
that it does perturb the perceptual abilities of the animal.
And he loaned me all his stimulation stuff, and nothing ever seemed to work.
And I think it's likely because you can't just
pick one spot like he could in
MT with the best direction and set your stimulus up to
do that instead you stimulate this one
percent of the neurons that are contributing to the percept and
you can never measure that in the noisy thing so
there's a distinct disadvantage to that so the real motivation was thinking
that um a lot of the brain a lot of the interesting parts of the brain that
we do cognitive things in that we can't really study because we don't know anything
about how those cells work because they're not topographic and it's not an easy label.
If we understood how you could do it in the cortex and something that you know
is not topographic, then maybe
you'd get some insights into how to look at other places in the brain.
But now that you say you want to understand perception and complex perception,
we look at localization where in some sense you can say, well,
all I need to do is just know the interaural time difference and the attenuation
that I get through my pina and my skull, and I have a good estimate of where
things are, and I can just delegate this down to my superior colliculus. Right.
So what's the leverage looking at sound localization?
Actually, it is mostly studied looking at the superior colliculus.
So what's the leverage you get looking at that problem? at the cortical level?
Well, it's because the cortex is necessary for you to report what you,
to perceive where you've heard the sound from.
So for example, you can take a cat and you can put it and train it in a sound
booth to go into the middle of the booth. You can play a sound from one of the speakers.
It will orient towards the sound and walk towards it and get a treat.
You lesion the cerebral cortex, A1 and around it, and then the cat doesn't do that.
So the sound comes from the contralesional space, sometimes it will move its
pinna, sometimes it will move its head and face the speaker,
and then it will walk to a random one.
And what Hugh Hefner interpreted this to me, it happens in monkeys too,
he's done this in monkeys,
and what he said is, there is neural circuitry that tells you where the sound
came from, collicular and brainstem, etc., but you don't have the percept that
that's where the sound came.
So when you're going to do something like walk toward where the sound was,
you really have no conscious percept of where it came from.
Even if you're looking right at the speaker, because you instinctively turned your head toward it.
So that means that the target setting is missing, or the transformation of identifying
the target and location into a goal-oriented action is missing, or both?
At least the latter. Okay.
So then, wouldn't you expect the deficit to not so much be affected by areas
that are so close to auditory processing, but more those that are close to working
memory and goal setting, frontal areas, and so on?
Well, probably because we see this kind of behavior in all kinds of mammals.
You don't have to have a whole big frontal cortex for you to show this deficit, right?
So Andy King has done a bunch of really elegant studies where he's shown that
those simple interpretations from the psychophysics from the 70s and 80s doesn't
really hold in ferrets and probably in any real animal.
If you have long enough stimuli and allow the animal to move its head,
as was being discussed, then you can lesion A1 and there's not really much of a deficit.
You have to lesion more than just A1 for that to not work.
What's interesting in his studies that I find really remarkable is if you lesion
A1 in a ferret, and then he can overcome this deficit, but then if you plug one ear,
a normal ferret will adjust to that and be able to localize fine,
but not one with an A1 lesion.
Okay, so A1 is necessary for you to learn how to use these new cues,
right? And presumably a place like CL in the macaque monkey is where you're
really doing the sound localization, right?
And it's not necessarily A1 specific, but it is cortically mediated.
Because in that sense, in the macaque brain, you've compared quite a number
of areas to see where would you find the specificity to the location of the sound source.
And that's actually surprisingly specific. Only one area jumped out that really
gave you this. the strongest location-modulated response, and actually A1 wasn't
one of them. So how do you explain that?
Well, the thinking is that the stimulus comes into A1, A1 contains all of the
necessary information,
and then it projects to Cl, and the Cl neurons are specific in the way that
they interpret that information, and they get the nice small receptive fields,
which allows then some other area, not Cl,
to make some sense out of that, and give the monkey the percept of where that
sound actually came from.
So, but area CL, if that gives you the percept, is then CL talking to another
area to translate that to a goal-oriented action?
Presumably, that's how it works, yeah. Probably the caudal parabelt is going to be critical.
I imagine that if I did my experiments there, I would see very good correlations as well.
But then, what's the latency of the response in CL?
Normally, if you're not old, it's a little bit longer. and so
Joseph Rauschecker did a really nice study quite some
time ago and what he found was that if you
lesion a1 the responses in CM which is its neighbor good to tones goes away
but to noise stays so the thinking is that there's both noise and tone information
coming from the thalamus and the cortex to CL and it's getting combined and
if you take it away the tone information is lost Okay,
but now the stimuli you use were largely white noise bursts. White noise, yeah.
Okay, so I could argue then from the perspective of having an auditory percept, that's rather reduced.
Oh, absolutely. So if we now would start to use, let's say, calls of other monkeys
or sounds of predators, would you expect that the result might look different,
that you might find more specificity in other areas?
More specificity for the different call for example
no because now we have meaningful sounds actually you use a sound that is
not meaningful right well it's meaningful in the sense that you had to figure
out where it was coming from oh you got a reward to it as well you got a reward
yeah right so i made it meaningful exactly okay okay okay so that that might
have helped and that's okay you're right exactly so the other the other thing
you done um so now we have we have of localization,
we are looking at issues of adult cortical plasticity.
Now the famous experiments people would do with, let's say, the orienting system
of the superior colliculus, you put prisms on the owl monkey or,
or no, on owls, sorry, on barn owls.
And then, and then you can show that sort of the maps get dramatically reorganized
also, also in adults, so that the orienting response is aligned.
Would you expect to see something comparable in in your monkeys when we start
to sort of uh distort this mapping of sound to location would you also see similar re-mappings in cl,
oh i predict that you would right as soon as the monkey was able to to do well
at localizing it my prediction would be that cl would show changes that would
be really interesting to look at because it's not clear.
Since there's no topography, you can't really see, oh, these cells changed where
their best direction was, right?
You wouldn't be able to see that, but you would see that at the end of the day,
they all changed appropriately for that to happen.
Right. Yeah. But to trigger the goal or movement, do we see something similar as we see in vision?
Like in vision, you might go to frontal eye field and then sort of communicate
with the colliculus to then set a gaze direction,
reaction would you believe it's a similar pathway that would
trigger the orienting response to altruistic stimulus and then the the
movement to the source i would
imagine that that would be the case but it might be very much
different than that why is that well the visual system and gaze shifts are all
dependent on what you see is depending on where your gaze is right and so in
the auditory system that's not quite as much so you saw the um psychophysical
results for these pretty,
you know, fairly not-quiet sounds,
it didn't really matter where the sound was coming from, you could tell where it was, right?
So that would be gaze-independent, right?
So if you had to orient to the spirit of clickless, you know,
how exact, it wouldn't surprise me if that was a little bit or a lot different
than the visual system just for that reason, that the gaze-shifting isn't part
of the sensory input, right? True.
But the other thing is also for the auditory stimuli, you might have more ambiguity
because the visual scene is in front of you and you deal with it,
and so the information is out there.
Well, in an auditory display, the source localization might be more difficult
that you would have to make several orienting movements before you really can pinpoint the source.
Right. So the amount of error that you will make if you, I didn't show these
data, but if you're in a dark, you hear a sound, and I ask you to point your
head toward the sound, the amount of error you make is considerable.
So that means it might be more an iterative process.
You do several orienting responses before you really have targeted the source.
Would that mean that areas like CL have more of a working memory property that
you might find in more vision-oriented cortical systems?
That's a good question and the jury is out on that because the auditory stimuli
are quite a bit different than what you see with visual stimuli.
They're temporary. You don't have really a lasting auditory stimulus.
It's pretty rare in nature that something just hums for a long period of time.
Whereas if you look at the rock, the rock's there and the rock doesn't move
and you see the rock the whole time.
As opposed to, there's debate what's an auditory object, does it even exist or is it an event?
And maybe an event is a better way to think about it. So the way I think about
it, what's the auditory system in a primate really supposed to do.
You're minding your own business. You hear a twig snap behind you.
You can't see what made the twig snap, right? But you hear it and it's a discrete event.
And so what do you do? You orient and you have to get within plus or minus 15 degrees of it.
And then you use your visual system to see what snapped the twig.
Is it something I can eat? Something that's going to eat me or something doesn't matter, right?
So it's really not that common in
a primate like a macaque who's diurnal and
can use its visual system a lot to really worry that much
about what it's listening to and now
a monkey might be very different because it's nocturnal right so
it doesn't see that well and maybe in that species these kinds of things would
be quite a bit different right right so then as an um application domain uh
of your understanding of adult plasticity in in auditory auditory processing
you also start to look at the aging brain yes right and and how
the aging brain actually started to change its responses to auditory stimuli.
So what are the most remarkable differences you found there?
Well, I was really surprised when I did those studies that the activity of the
brain is so much greater than it is in younger animals.
Because I came in with the completely false assumption that the older animals
would have slower brains that would be less active.
I thought they would probably be more like an anesthetized rat brain as opposed
to a weight-behaving monkey brain, which is very active.
Everything makes sense when you're recording from MT in a macaque because the
motion goes in a certain direction, the cell screams like crazy,
and you don't have to be a neuroscientist to go, I bet it's doing something
with the direction of motion, right?
It's pretty clean. But the old monkeys, they were more active,
and they were much more sloppy.
Right and the older monkeys that we
were studying at the time acted very old they
would sleep a lot they didn't seem that astute they didn't
seem like they were really perceiving things very well and i naturally
equated that with not much brain activity right as opposed to
the opposite so it was really surprising to see that and
when we were doing the studies we were uh double
checking and triple checking and trying to make sure that we're doing everything right
that we're not messing up with our window discriminators and we're not
recording a bunch of noise and we're always is looking for
60 cycle and all these kinds of things to convince ourselves that no
the neurons are really firing more they're just not firing
well right so you get this loud sloppy ugly signal
which i guess the monkeys themselves
means they have you know weaker percepts
right and then that's kind of how it all
ends up to work but is it
more is it more like say a noisy brain is there
there's more noise in the brain or is it is more dynamically modulated that
also if you present a stimulus the response is still specifically tuned in time
but it's just much much amplified it's more amplified and it's not as specifically tuned in time.
So i think one of the things you you mentioned there was the possibility that
that there was perhaps selective loss of inhibitory systems,
which we know are important for tuning up the dynamics of perceptual systems
so that you get a clean percept.
So I think thinking, for instance, of work in RAT-S1,
Dan Simons, for instance, has talked about the role of interneurons and shutting
down some of the activity that you will get through the excitatory networks in cortex.
And then you have a wave of inhibition coming in to make sure that doesn't get it out of control.
So that it sounds quite consistent with a network which has got some damage,
but it's not less activity, as you say.
It's just a lack of appropriate tuning of the inhibition systems.
Exactly. So I think what's happening in these older animals is their inhibitory network has, um.
Crashed, essentially, right? It's not doing as well as it. And it's not just in the cortex.
It's in the cochlear nucleus and the superior olive and inferior colliculus and the geniculate.
So it's all along the ascending auditory system that there are these problems.
And by the time it gets to cortex, it hasn't been very well refined, right?
And so it's a louder, sloppier system, and it just doesn't get any better at the cortical level.
And has anybody looked for sort of selected loss of inhibitory?
Not in the cortex. It's been seen in the brainstem and the midbrain.
Donald Casper's group has shown these kinds of things.
And there's all kinds of neurochemical changes that happen down there.
And it hasn't been studied, certainly not in the macaque auditory cortex.
And the inferior colliculus is the place most people stop on the way up.
So the cortex is very complicated and it's got layers and all these kinds of things.
So it hasn't been studied to my knowledge. And I think, as you also said,
there's an implication of this, which is that if someone's suffering hearing loss,
the last thing you want to do is actually shout at them, because they're overstimulated anyway.
Anyway, so slower and lower is the way to go, right?
And the other key is if you have a hard time temporally processing.
Speech sounds are temporally very complex and words don't, the way we talk,
we don't pause between words. We pause at the stop consonants, right?
So if you're stopping at only the stop consonants and you're running words together,
right, which we always do, and we can interpret that easily enough,
it's hard if you can't hear the modulation right yeah
so the key to talking to an older person is not necessarily talking
louder that's not going to really work but to pause between
words right and that way they can get
each one easily it's the same thing as when you learn
a language and you're not very good at it and then you go to
the country and everybody talks really fast right because you're
you're doing word word word word word right and
they're pausing at stop consonants so all these words run
together right right so it's
it's same things happening in older people but now
if you look at that these uh the data you present on um the response to these
older monkey brains versus the younger monkey brains it's actually the latency
the response latency in the older
brains seem shorter as well very much correct yes absolutely so so So,
but also the gain is just up in the system.
Right. So how about an alternative could be that you say, okay,
the cochlea, given also this partly mechanical sensor with the hair cells moving,
that sort of loses sensitivity.
And what the brain now must do in response is just crank up the gain and everything that follows. Yes.
So then it's not so much that we lose inhibition due to aging,
but we're cranking up the gain because the periphery is less sensitive. Would you buy that?
That certainly would be a reasonable possibility, but I think the evidence certainly
from the rodent suggests that what's happening is you have less input coming out of the cochlea.
And so you adapt to that by doing things that effectively decrease inhibition
as opposed to increase the signal specifically. I think that's where the evidence
is headed towards at this point.
And that's based a lot on neurochemical evidence and the changes in the GABA, GABAergic neurons.
There are two ways to think about this, right? Because you can think about inhibition as gain control.
Sure. Right? Or you can think about it as sort of sharpening a response that
you say, look, I have a bunch of frequencies coming in.
I set up some sort of wind attack all among them. So I sharpen the most salient
aspect of my input signal.
Right. I see the two different views on how you can think about the inhibition.
So do you see it as a sort of a non-specific regulatory adjustment or loss or a more specific one?
If I had to guess, which you're making me guess. Yeah, of course.
So my guess is that it's a little bit of both, but it's probably 70-30 and 70%
is the sharpening part and the 30% is just kind of a global background at the
single mantra. And that means, in your opinion, this would not be happening at the cortex.
This would be all subcortical. I think that's what's happening subcortical,
and I'm really keen to look in the cortex and see what… The cortex is much more
well-behaved as far as things like palvarbumin being in GABAergic neurons and things like that,
and the brainstem, it doesn't really do that, right?
So I would be keen to look in the cortex and see, is there in fact losses of
GABAergic neurons and which kinds and how would that, how would that work out?
Because there is a general loss of neurons in the cortex of these animals.
And another piece of evidence, I think, that speaks to the inhibitory story
rather than this amplification story is the sort of oscillation that you see.
Where the firing is high and then it drops and then it comes back high and then drops again.
And that suggests some alteration in the cortical dynamics dynamics,
rather than just a raising of the gain generally.
And that could easily be consistent with loss of inhibitory neurons.
So for instance, you've got fast-spiking inhibitory neurons,
which are coming into the cortex quite soon after the initial excitatory burst.
And people are suggesting that these are there to damp down the response and
make sure that the neurons that are corresponding are the ones which are most
finely tuned, which should be very consistent with what you're saying.
And if that's lost or that's delayed, then you'd imagine dynamics could be upset
so that you get these oscillations. Do you mind that, Greg?
No, that works for me. Because then I think you're both wrong.
Because I think if Tony's interpretation is correct,
that would also imply a loss of specificity at the cortical level,
because I'm tuning down my inhibition at the cortical level,
which means if I have overlaps in my receptive field responses,
I lose my ability to filter those out.
And if I look at your data, you don't necessarily look to specificity.
The specificity isn't necessarily lost in the response.
It's just really the amplitude that is strongly affected.
So I think you're both wrong if you agree with Tony. Well, I would say if you
look in CL, it's pretty clear that the specificity is lost because the spatial
tuning is about to sink. So I'm sunk now, you're saying.
I'm sure we're both right. But there's something else that now worries me because,
okay, here we go. We're getting older, true for all of us.
Things getting messed up from my cochlea all the way up to my cortex.
The responses get strongly amplified to get much stronger.
But in the meantime, you're telling me we have this sort of continuously plastic cortex.
So if I'm pumping in higher amplitude signals, why is the cortex not adjusting
to this? It's almost like sewing together two fingers, right?
I get a stronger drive onto a certain cluster. I have to reorganize my map.
So are these maps reorganizing and are they reorganizing them in a functionally related way?
Right. So how do you put these two things together? How come the old monkey
doesn't have a plastic brain to adapt to all this?
I don't know the answer to that, but I can guess again.
And the way I see what happens is you're in your 40s.
And your hair cells and your spiral ganglion cells, et cetera,
are starting not to work as well as they used to.
And so your brainstem and auditory midbrain is beginning to try to adjust to this.
And it's adjusting this by messing around with the inhibitory system.
And your cortex is getting a weird signal, and it's being plastic,
and it's changing. And you have no symptoms.
Okay, so it works. It's been working for a while, right?
By the time you're 78, 79 years old,
for whatever reason, either loss of neurons or loss of the ability to quickly
adapt or the fact that you are slowing down quite a bit and you're not re-updating
your maps as often as you are,
makes it so that that process breaks down.
And then you start to do plasticity that's hurting you, right?
So what happens when you're a little bit older and you're having a conversation
and you keep making up parts of the words that you're missing and then your
model of the conversation goes south and you ask a really stupid question and
you get laughed at, right?
And how is it as you're older and it's a little bit harder to hear,
so you have to do this, you start to not go into those situations.
So all of these things that you're normally doing to make sure that your maps
are okay and you're doing all right, you start to self-deprive these things.
And what's that going to do? That's going to drive your maps in a bad direction. Right?
So use it or lose it, you know, is what's been said.
So if you start to avoid social situations because you can't hear very well,
you're not going to get better at hearing.
Sure. Well, that's why I'm training myself to not be bothered with posing a stupid question.
It's inoculation against my future hearing loss.
This does also suggest a potential way of developing a program to reduce hearing loss.
Hearing training that might help us preserve our hearing as we get older.
Well, that's in some sense what Mike is also doing with his company, Puzzle Science, right?
Right, so he's doing that. Nina Dronkers in Chicago is doing this with music.
So if you use motor input and she's looking at the inferior colliculus,
but there's no reason it's not being translated throughout the system,
and that will give you the benefit of keeping your maps up to date and maintaining that standard.
So if I listen to music, that's going to help me maintain a good map.
It's better than not listening to music, but not as good as playing music.
It depends on the amplitude.
The amplitude? At which you play the music.
If you play it too loud, that's detrimental. You're right. Yeah.
Well, we can listen to Tony playing this evening. He knows the whole Beatles
songbook by heart. It won't be too loud. Okay.
So, but now, so, so this is really great that, that you also start to touch
upon these more applied to issues and try to get insight in how we actually
can deal with hearing loss.
But on the other hand,
You could also argue that the disinhibition we might see with aging might actually
also have a positive effect in cognition.
We could call it wisdom in some sense, right? Because if people get more disinhibited
or more disconnected from, let's say, their immediate emotional responses to things,
they can exist in a state of pure cognition or not. Or fantasy.
Or pure delusion. Yeah, delusion. yeah
yeah um so now
you finished up by your speculations about
the homunculus right and we'd also sort of
to think a bit about this question okay if we have this adult plasticity we
have some handle on these mechanisms how would you actually be able to grow
a new module into a cortex or remove one right so how can we do that how can
we add let's say a radar map to our own cortex right so um what got me thinking about that
was the difference in the somatosensory cortex between old world and new world monkeys.
Where old world monkeys have a clear area 2, which is non-cutaneous,
and it's between area 1, which is cutaneous, and area 5, which is visual and non-cutaneous as well.
And new world monkeys don't have that so much, right? So the experiments by
Jeff Padberg, it really opened my eyes that there was a big difference,
and it always was curious to me, how would you actually make a new field?
Because that's what evolution does, we make new fields and humans have
more than macaques and the common ancestor had some number less
than both of us right and so um the fact that when you train a monkey to to
pay attention or to discriminate a tactile stimulus on their finger and you
essentially change the morphology and the functional functionality of an entire
cortical area over that representation area 3a.
Leads me to think that well that can happen pretty quickly right and so what
would it take to get a new cortical field.
If you wanted a new cortical field, you can either change it in a lifetime,
in weeks, but you lose whatever it used to do because your brain doesn't get
bigger because it's stuck in the skull, right?
So one way that you could do this is you could alter your functional cortical
topography by changing your niche, right?
And then when you get the opportunity to get a bigger brain,
you know, you have that and then that same kind of process can fill in that space, right?
So it just seems to me that you don't have to wait 30 million years to hope
that your progenitor cells last a little bit longer so that you get a bigger
sheet. Then you decide, what am I going to do with it, right?
You can jumpstart that and already have in place something that's new, right?
And then when you do get more tissue, you're ready to fill it in with that.
So that just made sense to me. Okay. But now, isn't the notion of homunculus
not overrated to start with?
Like, for instance, it's very literal, almost like a copy of the body in the cortex.
Also, you already showed this incredible individual variability,
right, in how you organize the somatotopic maps.
Moreover, also within the somatotopic region, you might have,
let's say, duplications of such a map. You might have sub-maps within maps.
How should we think really about this? How accurate is something like a homunculus?
Well, it depends on how you measure it. So if you're Penfield and Rasmussen
and you put your stimulator every 7 to 10 or 12 millimeters across,
you get a homunculus. Okay.
Yeah. If you take a microelectrode and you penetrate every 50 to 75 microns,
it's not super duper clean, right?
The map of the hand in the owl monkey is, except that the hairy skin is in all
kinds of different weird places and there's overlap and it looks pretty good.
Um, other parts of the body are not so much, right? So when the receptive fields
start to get big, like on the rump or the leg, it starts to get a little bit sloppy too. Right.
So, um, now to, to finish, finish up the, our, our debate here or, uh, our conversation,
um, so, so you started out to look at this issue of adult plasticity where at
the beginning, so actually getting this back on the map again, right, which is great.
And to travel all the way through, let's say, some of the sensory systems,
motor systems, auditory systems.
So now if I really want to follow in a tradition in which you have me working,
what is Greg's law that we should adhere to understand the brain?
Greg's law to understand the brain.
It's harder than it looks.
Harder than it seems?
Yeah, well, I think if you want to understand the cerebral cortex,
and this is what I've done, so that's why I think it, you should not get stuck in a cortical area.
You should not say, I want to understand how the cerebral cortex operates to
provide perceptions, and to do that, I'm going to spend 30 years studying MT.
Okay so i think you're not going to gain the insights that
you need unless you look across a bunch of different
cortical areas and you know a bunch
of different species would probably be pretty smart too but i'm i'm not only
a cortical snob i'm a primate snob too so i've been i've been sticking to the
primate but um one nice thing about being a close colleague of leah kribitzer's
is that she studies all kinds of different animals and so i i know all about these things,
and it's something that you can really use to gain your insight.
So if you're not going to study them yourself, you should at least bone up on
the literature and talk to somebody who does so they can keep you grounded.
So embrace variability would be it. That would be a good one, yeah.
Okay, so five years from now, Tony likes traveling. He comes visit you in Davis.
And he's going to test, check whether you verify the hypothesis that you're
going to share with us now.
So what's the most important hypothesis
you want to see verified in the time frame of five years in
a time frame of five years so that's uh in in
the monkey world that's not very much time whatsoever right so um what i would
like to see is um how is it that this proposed parallel pathway with the rostral
and the the caudal what uh where in the rostral what pathway what is that really like?
I mean, how is it really doing? My money is that it's not going to be quite
as clean as it is in the visual system, but it's going to probably provide us
a lot more insights, I hope anyway.
Into how not just the visual system, but also the mass sensory system and others,
how you actually do the binding of these objects into, you know, a single kind of thing.
So I'm hopeful that five years from now when Tony comes by, I'll be able to
tell him almost how it works.
Great. Rick and Zoan, thank you very much for this conversation. Thank you. Thank you.
For more interviews, recorded lectures, or upcoming conferences in the field
of biometrics and biohybrid systems, go to csnnetwork.eu.
And thank you for listening.
You're off to? All right. Well, thank you, guys. That was, never done that before.
I thought it was cool. Yeah, it's good. I like it. Yeah. Nice.
Thank you. You're welcome.
It's great. I didn't know you were instructed by Leia to talk about this.
Yeah. If Leia wouldn't have given you any instruction, what would you have talked about?
Probably I would have talked all about the auditory cortex. Okay.
That's all I would have talked about. Right. And I would have done the,
we also looked at a whole bunch of different things in the temporal domain.
Uh-huh. Right? So I would have talked about that. Ah, cool. Okay.
I didn't know that. Yeah. Yeah. But all cortical. All cortical. Okay.
What's the time window which cortex can reliably represent interval? information on its own.
Like how fast can it? No, no. If I give you a beep, let's say,
or you have to hold a stimulus in memory for a certain amount of time,
what's the time window which Cortex can do this reliably in a task?
Uh, the time window in which a monkey can reliably do a, say,
a delayed match to non-sample or something like that? Seconds. Seconds.
And where is this information stored? Is it refrigerating in the cortical circuit?
Yeah, that's a question you'd have to ask one of five or six of Morton,
Michigan's postdocs. They couldn't figure it out.
But do you have any idea? Is it the cerebellum or the cortex?
It would probably have to be, I think it would probably be in the cerebellum.
So it gets to the, the auditory system gets to the thing that I said before.
I can hold this in my visual working memory really well, right?
But the auditory system doesn't have objects like this that you have to do.
And so it's been a real difficult thing for the field to figure out what you
can reliably remember in memory.
So you can train a monkey to listen to a bunch of sounds, and what it hears
is boop, boop, beep, to let go. And it can remember that all day,
and that'll be held in there forever.
But to do the classic, beep, beep, boop.
Okay, now is it beep, boop, beep, or beep, beep, boop? And it's like,
I can't remember, you know?
Right. And so all of those, Mort tried for years to do those ablation behavior
experiments that made him famous in the auditory domain and just couldn't get the stupid monkeys to,
I mean, he started those when I was in Mort's lab. Right. Simply Guitar?