WEBVTT

00:00:00.017 --> 00:00:02.997
That's a cheeky question, and you're going to hold me to that,

00:00:03.017 --> 00:00:04.037
aren't you? Of course, what do you think?

00:00:04.957 --> 00:00:09.797
Why do you think we're recording this? Absolutely. This is the Convergent Science Network podcast.

00:00:11.917 --> 00:00:15.517
Leading researchers in the domain of neuroscience, brain theory,

00:00:15.677 --> 00:00:20.017
and technology are interviewed by Paul Vershoor and Tony Prescott.

00:00:20.877 --> 00:00:23.997
It's Paul Vershoor with the Convergent Science Network podcast,

00:00:24.097 --> 00:00:27.177
and I'm here with my colleague Tony Prescott. Scott.

00:00:27.897 --> 00:00:31.337
We're both in our BCBT summer school here in Barcelona 2015.

00:00:32.297 --> 00:00:39.577
And I'm here with Narender Ramnani, who was giving us actually a very different

00:00:39.577 --> 00:00:41.077
kind of view on cerebellum because,

00:00:41.557 --> 00:00:45.477
the standard view on cerebellum is really like, well, this is sort of this little

00:00:45.477 --> 00:00:50.877
appendix that hangs off your brainstem, and it might be involved in some form of motor control.

00:00:50.937 --> 00:00:56.777
But But when things really get interesting, cognition, decision-making, forget it.

00:00:56.817 --> 00:01:00.077
We go look at cortical areas, mainly prefrontal cortex.

00:01:00.257 --> 00:01:05.637
And you sort of turn that whole perspective upside down. So how did you come to that perspective?

00:01:06.237 --> 00:01:12.917
Well, that's an interesting question. So this goes back again to everything

00:01:12.917 --> 00:01:19.117
being the foundation for my views are really the anatomy of the system.

00:01:19.117 --> 00:01:26.277
And so one of the things that I became very curious about was the looped architecture

00:01:26.277 --> 00:01:33.017
of the corticocerebellar system and this idea that our knowledge of what the

00:01:33.017 --> 00:01:35.637
cerebellum is talking to is incomplete. complete.

00:01:36.437 --> 00:01:42.297
And then over the years, the gap started to become filled and some very nice

00:01:42.297 --> 00:01:48.657
work came out from Peter Strick's lab and from the work that Schmarman and Pandya

00:01:48.657 --> 00:01:51.477
did shortly before that.

00:01:51.937 --> 00:02:00.337
And this work really highlighted the idea that the cerebellum isn't simply talking to the motor to cortex,

00:02:00.697 --> 00:02:07.817
there are many other parts of the cerebellum that are communicating with really,

00:02:08.497 --> 00:02:15.537
quite a diverse range of different areas of the neocortex, such as the prefrontal cortex.

00:02:17.077 --> 00:02:22.717
And, in fact, many different parts of the frontal lobe and also the parietal

00:02:22.717 --> 00:02:24.897
cortex. So there's this diverse range of inputs.

00:02:26.145 --> 00:02:31.105
So the question is, if it's just a motor structure, what on earth is it doing

00:02:31.105 --> 00:02:33.885
just doing motor control?

00:02:34.985 --> 00:02:38.225
And so that's really where it all kicked off from.

00:02:38.605 --> 00:02:44.305
Right. You began also by talking about what is now quite a classical view of

00:02:44.305 --> 00:02:46.785
Sarah Ballin, sort of the Mar-Albus theory.

00:02:47.065 --> 00:02:50.405
Could you just summarize that for us again?

00:02:50.505 --> 00:02:54.365
And also, do you think that that's still a useful framework to think about Sarah

00:02:54.365 --> 00:02:55.325
Ballin? Oh, undoubtedly.

00:02:55.765 --> 00:02:58.185
I mean, it's a framework that hasn't changed very much, actually.

00:02:58.285 --> 00:03:04.605
I mean, people have tinkered around the edges with it, but the fundamental message

00:03:04.605 --> 00:03:08.665
of what Mara and Albus were talking about is still very much there.

00:03:09.965 --> 00:03:14.925
And the perspective that they offer is, the theoretical perspective that they

00:03:14.925 --> 00:03:19.925
offer is this idea that Purkinje cells are the computational unit,

00:03:20.125 --> 00:03:21.645
the principal computational unit,

00:03:22.625 --> 00:03:28.345
and that this is a system that's capable of plasticity for supporting learning.

00:03:28.925 --> 00:03:35.685
And that learning is achieved by adjusting the inputs into Purkinje cells.

00:03:36.245 --> 00:03:37.945
And these inputs are.

00:03:40.065 --> 00:03:46.385
Typically parallel fibers and those changes occur under the guidance of a teaching

00:03:46.385 --> 00:03:52.405
related error signal from the inferior olive now having said that there are

00:03:52.405 --> 00:03:54.365
new perspectives emerging um,

00:03:55.970 --> 00:04:06.110
They also talk about adjusting the synapses between cerebellar units and their inputs.

00:04:06.630 --> 00:04:11.750
And I think it's recognized now that this is not the only source of plasticity

00:04:11.750 --> 00:04:18.490
in the cerebellum, but you also have plasticity involving a lot of other cell

00:04:18.490 --> 00:04:19.590
types in the cerebellar cortex.

00:04:19.970 --> 00:04:25.030
But one of the basic messages out of that is that there's a sort of microcircuit.

00:04:25.030 --> 00:04:30.130
And that it's repeated across the cerebellum. Do we still hold with that?

00:04:31.170 --> 00:04:38.930
There's very little data to argue against that view. And so the microcircuit

00:04:38.930 --> 00:04:43.850
or the microcomplex idea is still something that's very much in play.

00:04:44.870 --> 00:04:48.470
And the anatomy and physiology work bears that out really,

00:04:48.610 --> 00:04:54.810
particularly in relation to the work that's been done using eye movements or

00:04:54.810 --> 00:05:00.230
using classical eye blink conditioning where people have identified very specific

00:05:00.230 --> 00:05:06.370
microzones that might contain the Purkinje cells that house that plasticity.

00:05:07.610 --> 00:05:11.890
But as you were saying, sort of classically, people have thought this microcircuit

00:05:11.890 --> 00:05:13.230
is doing something in the motor domain.

00:05:13.490 --> 00:05:18.470
Yeah. But you now want to generalize it. Absolutely. So the architecture of

00:05:18.470 --> 00:05:21.330
the cerebellum is considered to be quite uniform.

00:05:21.330 --> 00:05:24.530
Form, it's really very, very different from the architecture that you find in

00:05:24.530 --> 00:05:28.930
the cerebral cortex, where site architecture is quite diverse.

00:05:29.290 --> 00:05:37.210
So people will have come across the concept of Brodmann areas in the cerebral cortex, where the...

00:05:38.101 --> 00:05:46.821
Area 4 has a different profile of cells from its neighbors in Area 6 or wherever.

00:05:47.381 --> 00:05:54.041
The idea about the cerebellar cortex is that it's much, much more uniform than that.

00:05:54.961 --> 00:06:01.221
So the computations that are going on in any given location will be the same

00:06:01.221 --> 00:06:04.381
in one location as in any other.

00:06:04.501 --> 00:06:10.621
So that idea still holds up. Although people are starting to find some interesting

00:06:10.621 --> 00:06:17.761
biochemical differences that suggest that there may be some interesting but

00:06:17.761 --> 00:06:22.401
subtle differences between these areas.

00:06:22.801 --> 00:06:32.361
So one of them, for example, is the idea of, there's this substance called aldolase C,

00:06:33.041 --> 00:06:40.021
or zebrin, that's differentially expressed in different parts of the cerebellar cortex.

00:06:40.841 --> 00:06:45.401
And one of the interesting things about zebrin is that if you stain the cerebellum

00:06:45.401 --> 00:06:49.261
for zebrin, you get a stripy parasagittal organization.

00:06:49.821 --> 00:06:57.141
That in itself tells you something about the parasagittal functional organization of the cerebellum,

00:06:57.181 --> 00:07:02.261
but it also suggests that maybe there are some subtle differences in the way

00:07:02.261 --> 00:07:07.621
that these adjacent zones compute. Right.

00:07:08.201 --> 00:07:12.361
And how many zones do we think we have, say, in the primate?

00:07:12.661 --> 00:07:18.061
Oh, crikey. That's a difficult question to answer because….

00:07:19.511 --> 00:07:22.611
I think as you go out more laterally, they become more and more refined.

00:07:23.011 --> 00:07:30.111
And the other thing, of course, is there are slightly different ways of characterizing a zone.

00:07:30.411 --> 00:07:37.611
I mean, Zebrin is one way, but there are many, many subzones, I think.

00:07:37.731 --> 00:07:42.991
The system I know better, the Basal Ganglia, has a similar notion of a microcircuit,

00:07:42.991 --> 00:07:44.271
which is repeated across.

00:07:44.271 --> 00:07:47.211
Cross yeah but when you drill down and ask people to define

00:07:47.211 --> 00:07:50.511
the micro circuits it all gets very hazy

00:07:50.511 --> 00:07:53.331
yeah and you end up with some people say there's larger domains

00:07:53.331 --> 00:07:57.091
of which there might be a handful and

00:07:57.091 --> 00:08:00.571
some people say well there's very small micro domains i mean

00:08:00.571 --> 00:08:03.431
so is is there still a controversy in the cerebellum about

00:08:03.431 --> 00:08:06.431
the granularity of the domain i think there probably is

00:08:06.431 --> 00:08:10.691
i mean there's still this slightly old-fashioned controversy that

00:08:10.691 --> 00:08:16.311
continues to rumble on about whether you have patchy somatotopy that's determined

00:08:16.311 --> 00:08:24.411
by the parallel fiber inputs or whether there's this other organization that's

00:08:24.411 --> 00:08:26.751
determined by, you know, Zebrin.

00:08:26.811 --> 00:08:30.651
But the other interesting thing I should say about Zebrin is that it seems to

00:08:30.651 --> 00:08:41.031
correspond very closely with one of the important input systems from the inferior olive.

00:08:41.031 --> 00:08:47.951
So climbing fibers project to the cerebellar cortex almost on a one-to-one basis.

00:08:48.071 --> 00:08:55.691
So one climbing fiber will completely dominate the physiology of any given Purkinje cell.

00:08:55.691 --> 00:09:02.451
And it seems as though the parasagittal organization.

00:09:03.411 --> 00:09:09.111
That we find with Zebrin seems to correspond with the parasagittal organization

00:09:09.111 --> 00:09:12.711
as determined by the projections from the inferior olive.

00:09:12.951 --> 00:09:18.011
So there's an interesting story there.

00:09:18.211 --> 00:09:21.111
So the microcircuit is really defined by the climbing fiber.

00:09:22.631 --> 00:09:26.631
Arguably, that's what's been claimed by some authors, yes.

00:09:27.591 --> 00:09:31.951
Absolutely. So you also made the claim that there's sort of this co-evolution

00:09:31.951 --> 00:09:33.191
of cerebellum and cortex.

00:09:33.551 --> 00:09:37.531
And that in that sense, the cerebellum performs like a universal transformation,

00:09:38.191 --> 00:09:42.631
from its inputs that it receives over the pons to its outputs that go out over

00:09:42.631 --> 00:09:43.571
the deep cerebellar nuclei.

00:09:44.171 --> 00:09:49.651
But also as Maureen Albers tells us, this is all dependent, independent how this output is shaped.

00:09:49.711 --> 00:09:52.431
It's all dependent on the error signal you get from your inferior olive.

00:09:53.191 --> 00:09:57.511
So now in the case of classic conditioning, it's fairly easy to understand where

00:09:57.511 --> 00:10:00.651
that error signal comes from because it's linked into the periphery that just

00:10:00.651 --> 00:10:04.151
says, okay, you just got shocked on your orbit or you got an air puff hit on your cornea.

00:10:04.691 --> 00:10:09.091
But if we now say, well, a huge chunk of cerebellum is actually bidirectionally

00:10:09.091 --> 00:10:10.531
interfaced to prefrontal.

00:10:11.743 --> 00:10:15.543
What's the error signal in that case? Well, that's another really fascinating question.

00:10:15.683 --> 00:10:20.443
I think one of the problems that we're confronted with is that there's so little

00:10:20.443 --> 00:10:25.023
data, so little physiological data that can answer that question.

00:10:25.163 --> 00:10:28.003
And it kind of highlights how much work there is left to do.

00:10:29.103 --> 00:10:33.283
But some of those questions could be answered in terms of the anatomy.

00:10:33.903 --> 00:10:41.183
We know, for example, that there are parts of the dopamine system that encode prediction error.

00:10:41.743 --> 00:10:49.443
We also know about the fact that elements of the dopamine system are sending

00:10:49.443 --> 00:10:52.783
their outputs to the cerebellum,

00:10:52.803 --> 00:10:57.603
and so there's a route there for this information to reach it.

00:10:57.683 --> 00:11:06.243
For example, the VTA not only sends its error signals off to quite large areas

00:11:06.243 --> 00:11:07.423
of the prefrontal cortex.

00:11:07.563 --> 00:11:13.503
But interestingly, there are collaterals that branch off from those projections

00:11:13.503 --> 00:11:20.663
that end up forming connections with Purkinje cells. And these are dopamine connections.

00:11:21.960 --> 00:11:29.240
So, it's as if the cerebellum is receiving a copy of the error signals that

00:11:29.240 --> 00:11:30.460
are reaching the neocortex.

00:11:31.840 --> 00:11:35.840
Okay. So, you're saying maybe for interaction with frontal areas,

00:11:36.080 --> 00:11:41.040
if your olive becomes less important to convey error and will be more derived

00:11:41.040 --> 00:11:46.080
from a VTA-dependent dopamine signal, which might signal something like a reward prediction error.

00:11:46.240 --> 00:11:50.920
Does that would be the idea? Well, that's one thing that one could claim.

00:11:51.020 --> 00:11:54.340
I think we shouldn't underplay the importance of the olive.

00:11:54.500 --> 00:11:59.480
There is recent data that has demonstrated there

00:11:59.480 --> 00:12:06.520
are in rats prefrontal inputs to parts of the olive that then project on to

00:12:06.520 --> 00:12:15.280
areas like cruce one and cruce two that receive input from the prefrontal cortex from the other system.

00:12:15.280 --> 00:12:19.700
So there's a lot of different anatomical routes through which that could happen.

00:12:20.420 --> 00:12:24.180
And one of these areas in the prefrontal is the anterior cingulate.

00:12:24.540 --> 00:12:30.920
And we know that the anterior cingulate does play a major role in the monitoring

00:12:30.920 --> 00:12:35.720
of errors that are cognitive in origin, you know, errors in your own cognitive

00:12:35.720 --> 00:12:36.860
processing, for example.

00:12:37.660 --> 00:12:42.720
And those areas do seem to send in rats and output to the olive.

00:12:42.720 --> 00:12:47.380
And then the olive then sends those projections back to... For you,

00:12:47.440 --> 00:12:48.640
which area would that happen?

00:12:48.780 --> 00:12:51.620
Would that then play out in red? What areas are we talking about?

00:12:52.100 --> 00:12:56.080
Which neocortical areas? So the anterior cingulate cortex.

00:12:56.520 --> 00:13:01.340
I don't remember off the top of my head which particular anterior ACC areas,

00:13:01.480 --> 00:13:06.880
but Tom Rickrock has basically characterized that system.

00:13:06.960 --> 00:13:11.720
And if we can just run over the thalamus to the inferior olive, Or is this a collateral?

00:13:11.960 --> 00:13:18.840
No, this would go directly from the neocortex to the olive.

00:13:19.827 --> 00:13:25.167
And from there on into cerebellum are direct inputs.

00:13:25.547 --> 00:13:32.447
And these are topologically mapped. That means these anterior cingulate projections

00:13:32.447 --> 00:13:35.907
that end up in the inferior olive target climbing fibers.

00:13:36.187 --> 00:13:41.847
Yes. The target regions of the cerebellum are recurrently coupled to that same bit of neocortex.

00:13:42.007 --> 00:13:47.807
That's right, because the study was conducted using transsynaptic traces.

00:13:49.307 --> 00:13:54.487
And because these traces have the ability to jump synapses, it's possible to

00:13:54.487 --> 00:13:56.127
do that point-to-point connectivity.

00:13:56.447 --> 00:13:59.267
Right. So that's cool, right? Because it means you're heuristic to say,

00:13:59.347 --> 00:14:02.027
okay, in case we don't understand, let's follow the anatomy.

00:14:02.267 --> 00:14:06.487
Yeah. It's then again paying off. At least the idea of having the finger olive

00:14:06.487 --> 00:14:12.107
as your error signal generator is still intact also for these interactions. Absolutely.

00:14:12.207 --> 00:14:19.347
And I think the other thing it does is to open up the possibility of physiological

00:14:19.347 --> 00:14:24.467
studies to try and investigate these circuits at a functional level.

00:14:24.467 --> 00:14:30.007
Right but now to finish up the inferior olive okay I just want to say that,

00:14:30.547 --> 00:14:33.407
the other thing which however I felt

00:14:33.407 --> 00:14:38.587
I didn't see back in your in your diagram in a too prominent role is a negative

00:14:38.587 --> 00:14:42.187
feedback between the deep nucleus and the inferior olive I mean it might sound

00:14:42.187 --> 00:14:47.407
like a detail but if it turns out that these Purkinje cells are actually actively

00:14:47.407 --> 00:14:52.487
controlling the errors that they receive over the inferior olive so um.

00:14:53.694 --> 00:14:58.954
Is this kind of error feedback control that occurs within the cerebellum for

00:14:58.954 --> 00:15:01.054
you computationally less relevant

00:15:01.054 --> 00:15:03.814
at this stage or just something that you ignore for other reasons?

00:15:04.034 --> 00:15:09.574
I think it's an extremely important facet of the circuit.

00:15:09.794 --> 00:15:15.534
And in fact, I think if I'm not mistaken, there was an inhibitory output coming

00:15:15.534 --> 00:15:18.914
out in those diagrams that I showed projecting back to the olive.

00:15:18.914 --> 00:15:31.714
One of the things that this seems to be involved in is the damping down of error-related activities.

00:15:31.714 --> 00:15:36.074
So, for example, in classical eibling conditioning, you'll be aware,

00:15:36.734 --> 00:15:44.754
perhaps more than I would, that this pathway is important for decreasing,

00:15:45.014 --> 00:15:48.034
in some ways, the salience of the unconditioned stimulus. this.

00:15:49.774 --> 00:15:55.654
So, you know, Jerry Hessler's work has shown that the,

00:15:55.834 --> 00:16:01.134
and Chris Yeo's work has also shown that the amplitude of the US is decreased

00:16:01.134 --> 00:16:06.354
in the presence of a conditioned response.

00:16:07.514 --> 00:16:10.054
So if there's a copy, there's an inference copy, if you like,

00:16:10.114 --> 00:16:15.434
of the CR that leaves the cerebellum and on its way,

00:16:15.454 --> 00:16:23.014
it basically goes down back to the olive and reduces the salience of the US.

00:16:23.594 --> 00:16:28.894
There are some interesting parallels that one could apply that to in the cognitive domain.

00:16:31.274 --> 00:16:37.054
If there's a system like the cerebellum that's specialized for feed-forward

00:16:37.054 --> 00:16:40.794
behavior that that doesn't really benefit from feedback,

00:16:41.674 --> 00:16:46.714
and indeed could be impaired by any sort of ongoing feedback if it causes an

00:16:46.714 --> 00:16:48.194
interruption to the processing.

00:16:48.574 --> 00:17:02.514
You do want a system that dampens down the effects of any ongoing error feedback coming into the system.

00:17:04.389 --> 00:17:08.929
I wanted to clarify about your diagram. So you have the inferior olive feeding

00:17:08.929 --> 00:17:16.029
back to three areas of cerebellum, and then you have VTA feeding into another area. Is that right?

00:17:16.289 --> 00:17:25.229
Yeah. So is VTA, is dopamine signaling something similar then to what the inferior

00:17:25.229 --> 00:17:27.589
olive is signaling in these other areas?

00:17:27.789 --> 00:17:33.669
Well, the diagram that you're talking about is simplified, And there are a few

00:17:33.669 --> 00:17:34.909
speculative things about it.

00:17:34.989 --> 00:17:42.669
But in essence, there will be some things that are similar.

00:17:43.009 --> 00:17:46.489
But there will probably be some things that are different too.

00:17:47.649 --> 00:17:51.129
So in answer to your question, what would be similar?

00:17:53.069 --> 00:18:00.449
One of the things that it could signal are the higher level cognitive errors

00:18:00.449 --> 00:18:01.509
that we spoke about earlier.

00:18:02.309 --> 00:18:10.289
Um the the what could be different um again you know this is speculative because

00:18:10.289 --> 00:18:16.849
nobody's ever sat down and recorded from both of them to see how they differ um.

00:18:18.609 --> 00:18:25.709
But the dopamine system signals reward related error and so that's why you know

00:18:25.709 --> 00:18:29.949
i've included it in that uh in that pathway and that diagram yeah i mean so

00:18:29.949 --> 00:18:32.409
you have these overall domains of cortex,

00:18:32.589 --> 00:18:37.249
which I guess they're defined in part by where they get their input from in cortex,

00:18:37.869 --> 00:18:41.429
but then also they're defined in part by where they get their feedback from.

00:18:43.129 --> 00:18:48.149
Yes, although I'm not ruling out the possibility that the olive could also be

00:18:48.149 --> 00:18:55.249
feeding into the high-level circuits that I was mentioning. I'm not ruling that out.

00:18:55.989 --> 00:19:02.229
It's just that we need to see some sort of concrete evidence for their existence

00:19:02.229 --> 00:19:04.549
before we could do that. Sure.

00:19:06.009 --> 00:19:12.529
So then, you presented us with a really fascinating diagram,

00:19:12.729 --> 00:19:15.789
which I liked a lot, and there's a lot to discuss about it.

00:19:16.909 --> 00:19:22.369
But, of course, there's also data behind it. And I think what's really impressive

00:19:22.369 --> 00:19:27.149
is that you've been able actually to replicate a lot of the phenomena that we

00:19:27.149 --> 00:19:29.109
know about cerebellar learning in humans.

00:19:29.609 --> 00:19:35.389
So could you, to what extent is, let's say, at least in your mind,

00:19:35.469 --> 00:19:41.169
is the response of the human cerebellum actually identical or similar to what

00:19:41.169 --> 00:19:44.049
you might expect in a rodent or a macaque,

00:19:45.269 --> 00:19:48.389
under classical conditioning conditions or VOR?

00:19:49.149 --> 00:19:54.769
Yeah, so one of the things that I alluded to in my talk was this idea.

00:19:57.925 --> 00:20:06.105
Of a conditioned stimulus being processed similarly, regardless of whether it's

00:20:06.105 --> 00:20:10.085
involved in the process of classical conditioning or whether it's involved in

00:20:10.085 --> 00:20:11.265
the process of instrumental learning.

00:20:11.725 --> 00:20:16.905
And so one of the things that I found very interesting was to basically draw

00:20:16.905 --> 00:20:21.665
from the classical conditioning literature because things are so very well known in that area.

00:20:21.665 --> 00:20:32.005
And one of the things that I mentioned was the idea that when you record from

00:20:32.005 --> 00:20:35.005
the eye blink microzones in the cerebellar cortex,

00:20:35.265 --> 00:20:41.985
you find a decrease in the activity of the Purkinje cell in response to a conditioned

00:20:41.985 --> 00:20:44.705
stimulus during classical conditioning.

00:20:45.325 --> 00:20:52.005
So the issue is that if If there is such a thing as a universal cerebellar transform,

00:20:52.345 --> 00:21:01.445
where a similar form of information processing is applied to, let's say, inputs...

00:21:02.751 --> 00:21:06.131
Going into a part of the cerebellar cortex that's receiving from prefrontal

00:21:06.131 --> 00:21:11.631
cortex, if you take a higher level form of learning, for example,

00:21:11.631 --> 00:21:17.531
like instrumental learning of rules, the question would be, do you see something similar?

00:21:17.651 --> 00:21:28.131
Do you see a decrease in the activity of a patch of cerebellar cortex when a

00:21:28.131 --> 00:21:30.391
CS is presented at the same time?

00:21:30.391 --> 00:21:35.071
And the work that I mentioned seems to bear this out. There seems to be a decrease in activity.

00:21:35.811 --> 00:21:40.371
Which is important, right? Because on the one hand, you replicate what we would

00:21:40.371 --> 00:21:46.151
expect from physiology, which is we obtain a pause in pericardial cell firing,

00:21:46.211 --> 00:21:50.211
which means less oxygen consumption and reduced blood flow.

00:21:50.311 --> 00:21:55.551
But it also means the pause is not dependent on another, let's say,

00:21:55.591 --> 00:21:59.051
population of interneurons And so now inhibits the perky cells because then

00:21:59.051 --> 00:22:01.731
your blood flow pattern might not have changed so much.

00:22:01.851 --> 00:22:04.911
Would you agree with that? Absolutely. And I think one of the things we have

00:22:04.911 --> 00:22:09.471
to be very careful about when we interpret imaging is, you know,

00:22:09.471 --> 00:22:11.731
what does an increase mean?

00:22:11.871 --> 00:22:16.311
You know, because this could mean an increase in inhibitory activity which could

00:22:16.311 --> 00:22:19.151
be manifest in a different way if you're using electrophysiology.

00:22:19.151 --> 00:22:26.651
One of the things that was very interesting about the work that I've just mentioned

00:22:26.651 --> 00:22:30.971
that uses electrophysiology is the use of gabazine.

00:22:31.191 --> 00:22:38.411
And so gabazine inhibits the action of neurotransmitter, inhibitory neurotransmitter,

00:22:38.411 --> 00:22:41.811
inhibitory inputs onto Purkinje cells. else.

00:22:43.831 --> 00:22:49.731
But the CS-related decrease that you observe is still there,

00:22:49.851 --> 00:22:53.951
despite the fact that the gabazine has acted on the system.

00:22:54.091 --> 00:22:58.811
And what that suggests is that the input of the,

00:22:59.951 --> 00:23:06.811
that's driving this inhibition are probably the excitatory inputs coming in via parallel fibers.

00:23:07.471 --> 00:23:16.271
And the value of understanding that for imaging is that if you have a decrease

00:23:16.271 --> 00:23:21.811
in activity during imaging, it's probably the case that there are,

00:23:22.131 --> 00:23:28.271
you know, there's a similar explanation involved that doesn't involve the ramping

00:23:28.271 --> 00:23:33.751
up of activity by increased metabolic demand, for example, from inhibitory endurance. Yes.

00:23:34.811 --> 00:23:40.451
Is there a sort of subtleties about how you interpret the fMRI data with cerebellum?

00:23:40.491 --> 00:23:44.211
Because when you have learning, you actually have decreased activity.

00:23:44.891 --> 00:23:51.211
Is that right, generally? So as you see learning proceed, you don't necessarily

00:23:51.211 --> 00:23:55.271
expect once the system is tuned up Do you see a lot of activity there?

00:23:55.331 --> 00:23:59.911
I think sometimes it's very difficult to interpret this sort of data.

00:23:59.971 --> 00:24:03.331
We know what we can say is that it's consistent with the electrophysiology.

00:24:04.651 --> 00:24:10.691
But there are studies that show learning-related increases in cerebellum too.

00:24:10.911 --> 00:24:15.271
And of course, we will never know why because we don't know what cell types

00:24:15.271 --> 00:24:16.731
are generating that information.

00:24:19.811 --> 00:24:23.571
We basically don't know what is driving that activity.

00:24:23.771 --> 00:24:30.871
So, for example, in a study of learning where you see an increase,

00:24:31.151 --> 00:24:34.451
that could be that you're,

00:24:36.050 --> 00:24:38.650
you're ramping up activity in the cerebellum for other reasons.

00:24:38.790 --> 00:24:47.910
It may not be that you see this sort of Mar and Albus type change that I spoke of before,

00:24:47.990 --> 00:24:53.550
or this Albus type decrease that we were comparing with.

00:24:55.250 --> 00:25:00.670
It's possible that you're getting inputs in that are ramping up the signal from

00:25:00.670 --> 00:25:03.470
other areas of cortex for other reasons.

00:25:03.470 --> 00:25:06.910
Um learning related activity

00:25:06.910 --> 00:25:09.930
is not always going to be manifested as

00:25:09.930 --> 00:25:12.990
a decrease in the cerebellum so what's the

00:25:12.990 --> 00:25:20.150
strategy then what do you have that's a hard one um imaging is is is a great

00:25:20.150 --> 00:25:25.730
tool to use for many reasons i mean not least because you can image the entire

00:25:25.730 --> 00:25:31.390
brain in one go and plus the fact um uh.

00:25:33.950 --> 00:25:37.730
You could look at anatomically very specific areas and so on.

00:25:39.390 --> 00:25:43.730
There are lots of benefits to imaging, including the fact that you could do

00:25:43.730 --> 00:25:48.910
it in humans, you can examine tasks in humans that you wouldn't otherwise be able to do in animals.

00:25:49.190 --> 00:25:56.790
But the key thing to remember is that fMRI is otherwise a very imperfect tool.

00:25:57.230 --> 00:26:01.350
Every tool has its drawbacks. And with fMRI,

00:26:01.530 --> 00:26:06.150
you're not going to be able to tease apart things like which cell type is contributing

00:26:06.150 --> 00:26:10.830
to my signal and the indirect nature of it,

00:26:10.890 --> 00:26:16.670
the fact that you're depending on a secondary measure of electrical activity

00:26:16.670 --> 00:26:18.490
rather than the electrical activity itself.

00:26:19.495 --> 00:26:23.335
So there are lots of things that get in the way of the interpretation,

00:26:23.715 --> 00:26:26.135
but it's still an excellent tool to use. Right.

00:26:26.895 --> 00:26:32.815
But now, so the paradigm you've used on humans, which is really interesting,

00:26:33.035 --> 00:26:38.075
sort of moves away a bit from the traditional division we have between operant

00:26:38.075 --> 00:26:42.135
learning going back to Thorndike and what's called classical conditioning going

00:26:42.135 --> 00:26:46.875
back to Pavlov, where in the first case, we are learning about the effect of

00:26:46.875 --> 00:26:47.975
our own actions on the world.

00:26:47.975 --> 00:26:52.835
And in the second case, the world exposes itself to us and we have to pick up

00:26:52.835 --> 00:26:54.415
whatever correlations are in that data.

00:26:54.915 --> 00:27:00.375
So you have tried to find a paradigm where you really merge instrumental aspects

00:27:00.375 --> 00:27:04.675
of learning with classical aspects of it. So how do you exactly balance that?

00:27:04.755 --> 00:27:07.635
How do you make sure that you can really still call it instrumental?

00:27:08.935 --> 00:27:15.675
Well, we can call it instrumental because of the nature of the contingencies in the trial design.

00:27:16.675 --> 00:27:21.455
So with instrumental learning, well, let me start with classical conditioning,

00:27:21.695 --> 00:27:25.115
where classical conditioning, you have a conditioned stimulus,

00:27:25.115 --> 00:27:31.035
and that will always be followed, regardless of what the subject does,

00:27:31.235 --> 00:27:35.435
by an unconditioned stimulus, which will cause an unconditioned response.

00:27:35.835 --> 00:27:40.035
And so there's no contingency between the

00:27:40.035 --> 00:27:43.715
way that the subject behaves and the

00:27:43.715 --> 00:27:48.875
outcome the outcome will always be delivered so that's that's fine you know

00:27:48.875 --> 00:27:53.475
that's that's the classical that that's the classical scenario the pump the

00:27:53.475 --> 00:27:59.895
instrumental scenario of course is very different we make sure that the outcomes

00:27:59.895 --> 00:28:01.655
are dependent on the subjects behavior.

00:28:02.805 --> 00:28:09.045
So there's a very clear contingency there. So the trial design really takes care of that, I think.

00:28:10.065 --> 00:28:16.405
But now, in the operant case, you would also believe that, let's say,

00:28:16.425 --> 00:28:20.945
it's something like there's a larger time interval we're talking about.

00:28:21.285 --> 00:28:25.125
And also the feedback the subject gets has a different kind of quality.

00:28:25.785 --> 00:28:29.245
So in this case, your human subject, I guess, is not being shocked anywhere.

00:28:29.565 --> 00:28:32.465
So we're not talking about an aversive stimulus that's being applied.

00:28:33.345 --> 00:28:37.625
So do you think that is a qualitatively change for the cerebellar learning system

00:28:37.625 --> 00:28:42.785
or actually it turns out to be still operating in an identical way, in your mind at least?

00:28:44.905 --> 00:28:49.305
Well, that's an interesting question. I think that the best way to answer that

00:28:49.305 --> 00:28:59.325
is just to make clear that the inputs that come into the cerebellum come in through,

00:28:59.525 --> 00:29:05.765
you know, so it's basically in the trials that I'm using, in the methods that

00:29:05.765 --> 00:29:07.025
I'm using, I use a visual feedback.

00:29:07.865 --> 00:29:15.465
There are reports, lots of reports showing that the cerebellum has access to

00:29:15.465 --> 00:29:18.265
that information, at least at a sensory level.

00:29:20.805 --> 00:29:24.825
So whether, you know,

00:29:24.945 --> 00:29:27.785
in classical learning theory will tell

00:29:27.785 --> 00:29:30.945
you that the more intense

00:29:30.945 --> 00:29:34.085
a stimulus the faster you learn and that sort of thing those

00:29:34.085 --> 00:29:41.745
same kinds of manipulations can be applied to instrumental learning and so you

00:29:41.745 --> 00:29:46.485
can you can have a partial reinforcement schedule and so on the kinds of signal

00:29:46.485 --> 00:29:53.845
that we see coming from from the cerebellum seem to mimic the amplitude.

00:29:57.719 --> 00:30:01.699
Well, the rate of learning, I would say. And so they all seem to follow these

00:30:01.699 --> 00:30:06.439
sort of Rescorla-Wagner type rules in that sense.

00:30:06.819 --> 00:30:12.619
But now, when a task becomes instrumental, we also have to start to think about

00:30:12.619 --> 00:30:16.519
how do we represent a rule that's hidden in this task, right?

00:30:16.559 --> 00:30:20.379
And how do we then pick up the relationship between that rule and my own actions?

00:30:20.379 --> 00:30:27.099
So in your mind it is that rule representation that would be the frontal neocortical

00:30:27.099 --> 00:30:31.499
contribution and the action generation would then be the cerebellar contribution

00:30:31.499 --> 00:30:34.299
that's how you think about it yeah so the,

00:30:35.359 --> 00:30:45.559
not really I mean I tend to think so what you're suggesting is that the rule representation is is,

00:30:46.939 --> 00:30:53.279
neocortical and that the the action-related representation is coming from the cerebellum.

00:30:53.299 --> 00:30:55.259
I don't follow that path at all

00:30:55.259 --> 00:30:59.359
because if you, again, look at the wiring diagram, it doesn't support it.

00:31:01.999 --> 00:31:06.999
I find it surprising because I thought we just had agreed that all the wires

00:31:06.999 --> 00:31:09.559
are there to link these two systems together.

00:31:11.199 --> 00:31:15.319
They are. But if you look carefully at the system,

00:31:16.659 --> 00:31:20.119
the cerebellar modules are all separate

00:31:20.119 --> 00:31:22.939
from each other they don't talk to each other the only

00:31:22.939 --> 00:31:25.879
way the only scope for us

00:31:25.879 --> 00:31:28.679
for the cerebellar signal

00:31:28.679 --> 00:31:31.659
to influence the

00:31:31.659 --> 00:31:34.879
neocortical system or rather the

00:31:34.879 --> 00:31:40.059
only way in which these modules can communicate with each other is through their

00:31:40.059 --> 00:31:46.099
links via the neocortical areas that do wire up to each other so you've got

00:31:46.099 --> 00:31:53.119
prefrontal premotor primary motor cortex um all talking to each other a lot um.

00:31:54.659 --> 00:32:00.739
The cerebellum modules that are independently wired up to these areas are operating

00:32:00.739 --> 00:32:02.919
independently of each other.

00:32:03.459 --> 00:32:07.679
There is no wiring within the cerebellum that can allow them to talk to each other.

00:32:08.219 --> 00:32:12.259
So you're saying they have to operate through the neocortex?

00:32:13.219 --> 00:32:19.199
Yeah, basically that's right. Right, yeah. But in theory, they could also, let's say,

00:32:19.939 --> 00:32:24.219
via brainstem motor nuclei like the red nucleus, the peduncle pontine nucleus,

00:32:24.359 --> 00:32:29.279
you might loop back to the pons and then generate as an inference copy an input

00:32:29.279 --> 00:32:34.199
to a cerebellar, a next cerebellar circuit and loop it straight through the cerebellum.

00:32:34.299 --> 00:32:36.199
Would that be anatomically defendable?

00:32:36.899 --> 00:32:41.999
Don't run that one past me again. I missed that. So an alternative is that I

00:32:41.999 --> 00:32:46.019
send my motor command from the deep nucleus of the cerebellum down to the red

00:32:46.019 --> 00:32:51.679
nucleus and or to any other brainstem motor nucleus, peduncle pontine nucleus,

00:32:52.639 --> 00:32:56.559
from which I get an afferent copy back into my pontine nucleus,

00:32:56.839 --> 00:32:58.579
input station to the cerebellum.

00:32:58.619 --> 00:33:01.239
And now I can loop it over a next cerebellar circuit.

00:33:01.839 --> 00:33:07.559
So I think in theory and atomically, you could devise a scheme that they can

00:33:07.559 --> 00:33:12.419
loop multiple cerebellar circuits without ever talking to the neocortex. Would you buy that?

00:33:13.479 --> 00:33:17.259
Uh, I would probably find that, um...

00:33:20.027 --> 00:33:24.527
I think if if the pathways existed then i would you know i think that that may

00:33:24.527 --> 00:33:30.947
be supportable but what is the evidence uh that those those did the anatomy

00:33:30.947 --> 00:33:32.227
exist that could support those,

00:33:33.267 --> 00:33:37.147
uh that could support that uh well red

00:33:37.147 --> 00:33:40.147
nucleus for sure projects back to inferior olive for instance yes it

00:33:40.147 --> 00:33:44.127
does but but i think i think the the

00:33:44.127 --> 00:33:48.007
olive is is a very modular structure and

00:33:48.007 --> 00:33:50.787
so the red nucleus is not going to project to

00:33:50.787 --> 00:33:55.647
every part of the olive um similarly does

00:33:55.647 --> 00:33:59.727
the red nucleus you know to what extent do different elements of the red nucleus

00:33:59.727 --> 00:34:05.867
communicate with you know eventually with with areas like prefrontal and premotor

00:34:05.867 --> 00:34:11.787
cortex um well i think i can play it another way to to see if i since you like

00:34:11.787 --> 00:34:14.647
the wires i could also say okay we got an reference copy,

00:34:14.807 --> 00:34:17.747
execute the motion, comes back to somatosensory cortex,

00:34:18.687 --> 00:34:20.027
and from there straight into your pons.

00:34:20.867 --> 00:34:26.147
Right? So still, I would be able to loop multiple cerebellar circuits without

00:34:26.147 --> 00:34:27.567
ever talking to my motor cortex.

00:34:30.407 --> 00:34:36.107
I think the cerebellum is a very, very modular structure, not just intrinsically,

00:34:36.307 --> 00:34:41.927
but also the way that it is wired up with lots of other areas.

00:34:43.427 --> 00:34:49.427
I think all of the evidence to date suggests that these loops don't communicate with each other and,

00:34:51.447 --> 00:34:55.847
that's a it's a generalization in some ways but I think you know you we have

00:34:55.847 --> 00:34:58.907
to we have to go with that because that's the evidence that we have available.

00:34:59.087 --> 00:35:03.607
But is it important to your model at least how you think about the circuit functionally

00:35:03.607 --> 00:35:08.247
is this an important axiom of your of your model like it that if it would be

00:35:08.247 --> 00:35:12.487
violated the whole model collapses well that's an interesting question um.

00:35:14.914 --> 00:35:18.634
There's no computational instantiation of my model yet.

00:35:20.254 --> 00:35:25.754
So there hasn't been an opportunity to sit down and write this into a piece of software and test it.

00:35:25.894 --> 00:35:29.154
It makes it much easier to speculate about it. That's a good thing. Yes, yes.

00:35:30.134 --> 00:35:36.314
I agree. Your model sort of claims the system one, system two distinction.

00:35:36.714 --> 00:35:42.274
Yeah. And the system one, which is where you say the cerebellum has the lead

00:35:42.274 --> 00:35:44.554
role, is a sort of habit learning system.

00:35:44.914 --> 00:35:50.394
But what you've described about the anatomy would seem to suggest that the habits

00:35:50.394 --> 00:35:54.114
have to be enacted via the cortex, even if they're learned in the Sarabala.

00:35:54.254 --> 00:36:00.254
Yeah, because I think the apparatus for delivering the habit-based behavior

00:36:00.254 --> 00:36:02.214
is housed in the neocortex.

00:36:02.454 --> 00:36:05.814
Well, it could also be housed in the brainstem, you know, elsewhere.

00:36:05.934 --> 00:36:09.414
There's a lot of machinery there for controlling the motor system,

00:36:09.594 --> 00:36:12.474
where you would not need motor cortical input.

00:36:12.794 --> 00:36:16.714
That's right. And you could imagine that with the cerebellum,

00:36:16.714 --> 00:36:21.694
you could wire up all sorts of interesting responses in the brainstem without

00:36:21.694 --> 00:36:23.414
having to bother with motor cortex.

00:36:24.414 --> 00:36:35.774
I think that's a possibility. But the neocortical architecture that supports very complex behaviors.

00:36:37.054 --> 00:36:44.574
Is better placed, I think, to execute those kinds of behaviors than the circuits in the brainstem.

00:36:44.994 --> 00:36:51.134
So in that case, system one would be about wiring up circuits in motor cortex

00:36:51.134 --> 00:36:53.914
to perform the habit behaviors.

00:36:54.534 --> 00:36:59.394
So is it more of a... I'm still not sure how this can work if the loops don't interact.

00:36:59.694 --> 00:37:03.614
I guess you've got your loops in motor cortex. But what's my prefrontal cortex

00:37:03.614 --> 00:37:07.334
loop? How is that able to help me learn a motor habit?

00:37:08.434 --> 00:37:12.554
Or am I learning something from the habit? No, you're learning these modules

00:37:12.554 --> 00:37:13.754
are learning independently.

00:37:14.474 --> 00:37:18.074
So what's habit learning in the context of prefrontal cortex?

00:37:18.114 --> 00:37:21.074
Okay, so what habit learning in the context of prefrontal cortex is,

00:37:21.174 --> 00:37:25.014
for example, the execution of a rule.

00:37:25.534 --> 00:37:29.494
The execution of, for example, the kind of experiments that I talked about earlier

00:37:29.494 --> 00:37:32.274
where you're arbitrarily pairing.

00:37:32.274 --> 00:37:43.254
Pairing, you're pairing a stimulus and a response in a completely arbitrary manner.

00:37:43.754 --> 00:37:47.354
Now, you can think of that as having motor control demands.

00:37:47.734 --> 00:37:50.914
You can think of that as having sensory demands, but you can also think of that

00:37:50.914 --> 00:37:52.054
as having cognitive demands.

00:37:52.454 --> 00:37:58.834
It's the cognitive element of that that is being basically.

00:38:00.914 --> 00:38:06.274
Being run by the prefrontal cerebellar loop. Yeah, but,

00:38:07.524 --> 00:38:11.524
To me, this doesn't make any sense, really. I'm sorry to say,

00:38:11.604 --> 00:38:15.044
but look, the point is, so let's start with Schiffer and Schneider, right?

00:38:15.104 --> 00:38:17.884
So we talk about controlled versus automatic processing.

00:38:18.164 --> 00:38:22.804
Yeah. And it also means the controlled deliberate system figures out the rules.

00:38:22.904 --> 00:38:26.424
It figures out how to map sensory states, action states, given goals.

00:38:27.084 --> 00:38:30.484
With that, you train your habits that now can be executed by your automatic

00:38:30.484 --> 00:38:32.044
system. And why do you want to do this?

00:38:32.184 --> 00:38:34.944
Because you want to be fast. You want to optimize your response latency.

00:38:34.944 --> 00:38:37.824
Or you want to free up resource and frontal contact.

00:38:37.844 --> 00:38:44.804
Yes, absolutely. Well, I would think a real fitness requirement is latency more

00:38:44.804 --> 00:38:47.864
than working memory space, but we can debate that, okay?

00:38:48.024 --> 00:38:50.304
So here I am, now I have my automatic process.

00:38:51.064 --> 00:38:54.344
What am I automizing? Time, okay, latency.

00:38:54.544 --> 00:38:59.424
So now, also in the perspective of Kahneman, you would have system one, system two.

00:38:59.484 --> 00:39:02.484
System two is the slow system, it's a controlled system, deliberate.

00:39:02.484 --> 00:39:06.484
And the system one is a fast automatic system. Great. Okay.

00:39:07.124 --> 00:39:11.864
But now you're proposing that this fast system that puts in this huge amount

00:39:11.864 --> 00:39:14.964
of metabolic resource into getting fast.

00:39:15.664 --> 00:39:18.804
And the Purkinje cells and the Cibrella circuit is fast.

00:39:18.984 --> 00:39:24.244
Right. And it really controls latency very precisely by disinhibiting the deep nuclear cells.

00:39:24.404 --> 00:39:28.764
So you rely on the rebound, which is controlled in latency to trigger an output.

00:39:29.144 --> 00:39:31.744
But that's not what you're building on. You say, no, no. no,

00:39:31.804 --> 00:39:34.224
these guys are really, maybe very precise.

00:39:34.364 --> 00:39:37.404
But again, that's the thing that goes back to motor cortex, which sits there,

00:39:37.464 --> 00:39:41.124
a piece of cortex, it's integrating, it's sloppy, it's jittery, whatever.

00:39:41.404 --> 00:39:45.464
And then that piece of cortex is going to issue this final motor command that

00:39:45.464 --> 00:39:51.784
cruises down my corticospinal tract to control the skeletal muscle system.

00:39:52.464 --> 00:39:57.444
But I'm adding latency now. Why would I do that?

00:39:58.264 --> 00:40:03.064
Because you have to parcellate up different elements of the task.

00:40:03.384 --> 00:40:08.664
So, I mean, what you're suggesting, what you're suggesting is that somehow this

00:40:08.664 --> 00:40:13.904
very high level thing that you've learned finds its way into the motor system,

00:40:14.904 --> 00:40:16.664
without going through the motor cortex.

00:40:18.124 --> 00:40:21.544
But there's no route. I mean, how would it do it?

00:40:21.664 --> 00:40:25.304
I mean, if you think about the connections of cruise one and cruise two,

00:40:25.404 --> 00:40:28.424
which are the parts of the cerebellum that are supposed to be learning these

00:40:28.424 --> 00:40:31.404
things, they have no output to the motor system.

00:40:32.964 --> 00:40:38.244
So there is no other route. But maybe they're doing something else and controlling action.

00:40:38.804 --> 00:40:43.864
Maybe they're part of the slow system and it helps the slow system to figure

00:40:43.864 --> 00:40:46.764
out, let's say, interval information, timing between events.

00:40:48.835 --> 00:40:51.615
And it is not involved at all in generating actions. For that,

00:40:51.675 --> 00:40:55.915
you train up other parts of the cerebellum. Yes. Well, that's basically what I'm suggesting.

00:40:56.255 --> 00:41:02.215
So you have modular parts of the cerebellum.

00:41:02.255 --> 00:41:07.495
So you have some parts that are specialized for dealing with prefrontal problems,

00:41:07.855 --> 00:41:10.835
some parts dealing with the primary motor cortex.

00:41:13.135 --> 00:41:20.695
And that it's basically speeding up elements of the information processing that

00:41:20.695 --> 00:41:23.155
would otherwise go on in each of these neocortical areas.

00:41:24.175 --> 00:41:28.015
But you need the neocortical areas to actually deliver the response.

00:41:28.415 --> 00:41:35.555
There is no output from CRUS-1 and CRUS-2 that can access this corticospinal

00:41:35.555 --> 00:41:42.515
tract Except through going back to places like prefrontal cortex and then,

00:41:42.535 --> 00:41:47.555
you know, sending the signal down through premotor cortex and primary motor cortex.

00:41:47.895 --> 00:41:52.715
You also exclude that there's any kind of divergence in, let's say,

00:41:52.735 --> 00:42:00.255
the deep cerebellar nuclei that might allow them to indirectly target brainstem motor nuclei.

00:42:00.555 --> 00:42:05.615
Well, that's an interesting question. So.

00:42:07.740 --> 00:42:13.480
The perspective that Peter Strick has offered us is that these are highly modular systems.

00:42:14.920 --> 00:42:20.100
Now, the missing information in all of this anatomical work that we've talked

00:42:20.100 --> 00:42:27.420
about before is the absence of any point-to-point connectivity that's been shown.

00:42:27.580 --> 00:42:32.380
So it's never been shown, for example, that there's

00:42:32.380 --> 00:42:35.500
a particular neuron in the primary motor cortex

00:42:35.500 --> 00:42:38.560
that sends its outputs to

00:42:38.560 --> 00:42:41.300
specific Purkinje cells and that

00:42:41.300 --> 00:42:45.080
those specific Purkinje cells send outputs back to

00:42:45.080 --> 00:42:49.800
thalamus and back to that particular neuron in the primary motor cortex so that

00:42:49.800 --> 00:42:54.740
point-to-point connectivity has been missing from the single cell level at the

00:42:54.740 --> 00:43:02.180
single cell but it does reach that volume of cells yeah so so that the broad areas are you know Um,

00:43:02.420 --> 00:43:07.400
so it's been shown, for example, that if you put antragrade and retrograde tracer

00:43:07.400 --> 00:43:11.160
into M1, you'll end up with, um,

00:43:11.420 --> 00:43:15.120
label in the same kinds of, the same cerebellar lobules.

00:43:16.640 --> 00:43:23.420
Um, and, uh, and that suggests quite broadly, but it suggests that there are

00:43:23.420 --> 00:43:26.460
these independent loops and that they don't communicate with each other.

00:43:26.460 --> 00:43:34.000
However, I think to be conclusive about it and to be sensible about developing

00:43:34.000 --> 00:43:39.160
computational models, you have to demonstrate that this point-to-point connectivity exists.

00:43:39.720 --> 00:43:43.580
Well, I'm not sure that's a fair constraint, really, because certainly,

00:43:43.740 --> 00:43:49.020
so what is the shortest distance at which people have found these recurrent

00:43:49.020 --> 00:43:50.300
projections to terminate?

00:43:50.440 --> 00:43:55.580
I mean, we're talking about, what, hundreds of microns? This will be the scale.

00:43:56.893 --> 00:44:03.233
So, as soon as you hit cortex, you have a highly excitable substrate with dense

00:44:03.233 --> 00:44:05.213
local coupling, with lateral coupling.

00:44:05.513 --> 00:44:09.853
So, as long as you target, let's say, an area that is, let's say,

00:44:09.953 --> 00:44:16.213
100 micron away, you can be quite sure that activity will percolate down to that neuron.

00:44:16.213 --> 00:44:21.853
Well, that's right, except that the things that we were talking about earlier

00:44:21.853 --> 00:44:28.213
were about ways in which inputs from prefrontal cortex can start to influence

00:44:28.213 --> 00:44:32.333
the motor output and so on.

00:44:32.353 --> 00:44:36.373
These are in different lobules altogether. Sure, but I wasn't,

00:44:36.373 --> 00:44:38.993
indeed, we weren't finished with that, and I have a solution.

00:44:39.553 --> 00:44:43.653
Because maybe the thing to consider is that even though there's a universal

00:44:43.653 --> 00:44:44.593
cerebellum transformation,

00:44:45.313 --> 00:44:50.333
the cerebellar areas that are interfaced to prefrontal don't care about action

00:44:50.333 --> 00:44:53.913
generation in terms of the motor plant itself,

00:44:54.193 --> 00:44:58.373
but they assist prefrontal areas to figure out, let's say, interval information

00:44:58.373 --> 00:45:01.793
about task relevant or decision variables.

00:45:01.793 --> 00:45:05.453
Because that's the unique contribution they can give you. They can tell you

00:45:05.453 --> 00:45:06.813
something about interval timing.

00:45:07.033 --> 00:45:12.393
And this is as much necessary by acquiring the habit as it is for executing

00:45:12.393 --> 00:45:14.473
the habit. So how about that?

00:45:15.793 --> 00:45:17.333
That's plausible, I guess.

00:45:19.473 --> 00:45:22.533
So not all is lost for my canoe right now.

00:45:24.033 --> 00:45:30.513
That's like a compromise to me. Oh, really? I'm already, okay, watering it down. Okay.

00:45:31.793 --> 00:45:32.773
So, okay, good.

00:45:35.813 --> 00:45:40.153
So, now, okay, so we have different interpretations of how, let's say,

00:45:40.173 --> 00:45:44.773
the dense interaction of cerebellum and prefrontal.

00:45:44.853 --> 00:45:49.973
Would you say, I mean, how much of the hardware, the cerebellar hardware is

00:45:49.973 --> 00:45:52.933
committed to interacting with these premotor areas, you would say?

00:45:53.193 --> 00:45:55.453
The premotor areas? Well, or prefrontal,

00:45:55.453 --> 00:45:57.593
just decision-making areas in the brain, let's say. Right, okay.

00:45:58.593 --> 00:46:04.553
Okay. Estimates have varied, but a very, very significant chunk of it.

00:46:04.653 --> 00:46:09.273
I mean, I think Peter Strick, in one of his papers, if memory serves me correctly,

00:46:09.433 --> 00:46:11.193
said there was something like,

00:46:12.701 --> 00:46:19.961
40% of the territory of the cerebellum in primates was accounted for by the motor system.

00:46:21.561 --> 00:46:25.841
Then including the decision-making parts of what we now call motor system.

00:46:26.041 --> 00:46:29.961
No, no. So the issue is what is the rest of it doing?

00:46:31.041 --> 00:46:38.461
In theory, very significant chunks of it are going to be devoted to communication

00:46:38.461 --> 00:46:40.661
with prefrontal cortex.

00:46:40.661 --> 00:46:46.661
And it sort of makes sense that that's the case, because prefrontal cortexes

00:46:46.661 --> 00:46:51.701
in the human brain has expanded enormously during the course of human evolution.

00:46:53.481 --> 00:47:00.061
And if you take on board the fact that connected systems tend to evolve together

00:47:00.061 --> 00:47:05.961
because of the selection pressures being applied on systems as a whole,

00:47:06.181 --> 00:47:08.861
then yes, that sort of makes sense.

00:47:09.001 --> 00:47:14.041
It makes sense. But I find that such a strange heuristic because I might also

00:47:14.041 --> 00:47:15.601
imagine I'm an engineer, right?

00:47:15.601 --> 00:47:18.501
We're the God engineer. We're building brains. We have these modules.

00:47:18.901 --> 00:47:22.241
As you say, right? It has a very modular structure, the cerebellum.

00:47:22.281 --> 00:47:24.441
So I think also Tony mentioned it in the talk.

00:47:24.541 --> 00:47:29.541
You could imagine I engineer some animal who has to do lots of really fast movements

00:47:29.541 --> 00:47:31.301
in a complicated dynamical world.

00:47:31.381 --> 00:47:35.001
I give it a huge cerebellum and it doesn't need to solve any problems.

00:47:35.101 --> 00:47:39.121
It doesn't solve crossword puzzles and Wisconsin card sorting.

00:47:39.121 --> 00:47:41.121
Sorting is also not available in the jungle.

00:47:41.241 --> 00:47:46.481
So it just reduces its neocortex. So why do these things by necessity have to co-evolve?

00:47:48.121 --> 00:47:48.601
Well.

00:47:50.268 --> 00:47:53.248
By necessity? I mean… That's what you seem to say, no?

00:47:53.328 --> 00:48:02.328
I'm suggesting that if selection pressures apply to systems that operate functionally

00:48:02.328 --> 00:48:08.168
as a unit, then you're going to find an expansion on the whole.

00:48:08.348 --> 00:48:13.268
You know, you're going to find an expansion of the parts of the cerebellum that

00:48:13.268 --> 00:48:15.328
are communicating with the prefrontal cortex.

00:48:15.748 --> 00:48:19.548
And that's indeed what we've found. And it's expansion of the prokenia cell

00:48:19.548 --> 00:48:22.468
level, the granule cell, all of them together?

00:48:22.708 --> 00:48:25.408
Those are empirical questions. We have no idea.

00:48:25.868 --> 00:48:30.568
But one thing you did say was that there's a kind of dorsal ventral,

00:48:30.588 --> 00:48:35.988
I think, distinction in the amount that PFC talks to cerebellum,

00:48:36.028 --> 00:48:38.828
so there's much more connectivity with the dorsal area.

00:48:38.988 --> 00:48:43.688
Well, there's a dorsal ventral split in the dentate.

00:48:43.688 --> 00:48:48.148
So that the dentate nucleus is is

00:48:48.148 --> 00:48:51.028
you can you can split it up in terms of

00:48:51.028 --> 00:48:53.868
the dorsal part which is wired up

00:48:53.868 --> 00:48:58.208
with the motor system and the ventral part which is wired up with a prefrontal

00:48:58.208 --> 00:49:04.988
system right and um it's been shown that previous studies have shown when you

00:49:04.988 --> 00:49:10.108
compare across primates that there has been a selective expansion of the ventral

00:49:10.108 --> 00:49:11.868
part of the dentate nucleus nucleus.

00:49:12.508 --> 00:49:15.868
And we're now starting to explore those sorts of issues.

00:49:16.088 --> 00:49:20.008
I think I was referring to, I was hearing in your talk, you were saying that

00:49:20.008 --> 00:49:23.668
there were parts of prefrontal cortex which have a strong projection and other

00:49:23.668 --> 00:49:25.048
parts which have a weak projection. Yes, exactly.

00:49:25.288 --> 00:49:30.768
So one of the interesting things that was found by Jeremy Schmarman and Deepak

00:49:30.768 --> 00:49:35.708
Pandya was that the dorsal parts of prefrontal cortex,

00:49:36.108 --> 00:49:40.428
so areas that are dorsal to sulcus his prince upon us.

00:49:41.590 --> 00:49:45.330
Have a greater tendency to project to cerebellum than ventral parts.

00:49:45.610 --> 00:49:49.850
Right. And so you could speculate about why that might be.

00:49:49.950 --> 00:49:55.290
And, you know, that might tell us something about the kinds of information that

00:49:55.290 --> 00:50:00.290
the cerebellum wants to process, as it were.

00:50:02.530 --> 00:50:07.690
But now the other, so let's say, okay, let's say we agree, okay?

00:50:07.790 --> 00:50:10.010
So they all evolve together.

00:50:10.590 --> 00:50:13.450
Very pleased to hear that. Then we can talk about basal ganglia hippocampus

00:50:13.450 --> 00:50:14.570
and spirochaliculitis if they

00:50:14.570 --> 00:50:17.710
also co-evolved the same way and they might have done that or not, okay?

00:50:18.790 --> 00:50:24.810
But, so now we have a control system which definitely will depend on neocortex,

00:50:25.170 --> 00:50:26.630
frontal areas, and basal ganglia.

00:50:27.010 --> 00:50:29.250
I don't know, maybe you want to leave that out, I don't know.

00:50:29.850 --> 00:50:35.690
But now I have to compile my habit into my cerebrally circuit,

00:50:35.990 --> 00:50:40.470
right? So, how do I first segment a habit?

00:50:41.230 --> 00:50:45.730
And then secondly, how do I get those segments into my cerebellum that I can

00:50:45.730 --> 00:50:47.970
call them up on future occasions?

00:50:49.610 --> 00:50:53.370
That's a really interesting question and a tough one to answer. We need answers.

00:50:53.710 --> 00:50:58.390
Yeah, absolutely. Absolutely. So, the issue of how do you segment a habit,

00:50:58.510 --> 00:51:00.770
I think that's a tough one. Yeah.

00:51:02.934 --> 00:51:09.634
I think all you can say is that if there are associations being formed,

00:51:09.734 --> 00:51:17.374
if there are CSs being processed in areas of the prefrontal cortex.

00:51:18.234 --> 00:51:23.694
Then there'll be a spike train corresponding to that going down to the cerebellum by the pons.

00:51:23.694 --> 00:51:33.194
Um how you can sort of break that very high level uh representation down and

00:51:33.194 --> 00:51:37.894
and talk about it in terms of what will the spike train look like and how how

00:51:37.894 --> 00:51:42.694
will that be represented in uh uh uh in.

00:51:43.454 --> 00:51:47.714
Terms of purkinje cell activity or whatever i think i think it's it's not possible

00:51:47.714 --> 00:51:52.654
to answer that it's a tough one do you think it will exploit the segmentation

00:51:52.654 --> 00:51:57.634
do you think it will exploit already the structuring of action primitives or

00:51:57.634 --> 00:51:59.314
behavioral primitives at the brainstem level?

00:51:59.834 --> 00:52:02.674
Because as a cerebellum, if you take the eye blink conditioning analog,

00:52:02.974 --> 00:52:09.054
I am talking to my red nucleus, I'm triggering discrete behavioral primitives.

00:52:09.314 --> 00:52:14.374
I don't think so. And the reason for that is, let's think, for example,

00:52:14.374 --> 00:52:24.274
about the kinds of information that gets processed in the hierarchically organized neocortical system.

00:52:24.934 --> 00:52:30.194
So if you take, for example, cells in the prefrontal cortex,

00:52:30.414 --> 00:52:36.934
and you try to figure out what they're most interested in, the work of Earl

00:52:36.934 --> 00:52:39.494
Miller shows that they're interested in rules.

00:52:40.114 --> 00:52:44.834
They're not interested in the fundamentals of motor control.

00:52:45.034 --> 00:52:53.814
You won't find motor unit activity being represented in the cells of the prefrontal. Um...

00:52:55.453 --> 00:53:03.053
Equally, if you look at cells in the motor cortex, you won't find them being interested,

00:53:03.673 --> 00:53:08.013
and having their response properties tuned to particular rules,

00:53:08.173 --> 00:53:11.633
as you would find in the cells of prefrontal cortex.

00:53:15.413 --> 00:53:21.633
So I don't think that you're going to be, I don't think it's a useful exercise

00:53:21.633 --> 00:53:24.993
really to try and look in places like the brainstem.

00:53:26.473 --> 00:53:30.233
For things that are, you know, rule-related, as it were.

00:53:30.673 --> 00:53:36.813
If we think about the simple rule, which is like later on you might want to

00:53:36.813 --> 00:53:41.373
escape from the studio and go to the lounge, something like this, right?

00:53:41.633 --> 00:53:45.853
And if we do sufficient or enough interviews with you, then you would be having

00:53:45.853 --> 00:53:49.533
this habit of running to the lounge and breaking all the furniture,

00:53:49.693 --> 00:53:51.213
okay? So that's a habit now.

00:53:51.513 --> 00:53:55.333
But this habit will have primitive elements, which might also be getting up

00:53:55.333 --> 00:54:00.133
out of your chair, controlling posture, going to the door, you know, moving through a door.

00:54:00.193 --> 00:54:03.833
So they're very simple elements in the end that get stringed together.

00:54:03.973 --> 00:54:09.893
So what is special about the habit is its macroscopic structure that even brings

00:54:09.893 --> 00:54:12.373
you from here to the lounge where you smash up all the furniture.

00:54:12.593 --> 00:54:18.113
So the point is that with these primitive elements, we can easily account for

00:54:18.113 --> 00:54:22.173
at a brainstem level, you know, like just to get up, maintain your posture, locomote, and do that.

00:54:23.784 --> 00:54:27.884
Can you? I'm not so sure. Okay. So, give me an example.

00:54:28.064 --> 00:54:34.624
I mean, the kinds of representations that you have at the very lowest end of

00:54:34.624 --> 00:54:41.504
the motor system would be things like the control of individual muscle units and so on.

00:54:42.144 --> 00:54:44.924
No, look, if you go to the midline structures in your brainstem,

00:54:45.104 --> 00:54:48.904
where you have the central gray, for instance, we have whole behavioral patterns

00:54:48.904 --> 00:54:54.964
that are species-specific encoded in a local way. There'd be sort of hardwired things down there.

00:54:54.984 --> 00:54:58.624
Sure. There might be gaze, gaze controls, completely predefined particular formation.

00:54:58.844 --> 00:55:03.724
Yeah. So there'll be sort of aggressive aggression and all of that sort of.

00:55:04.464 --> 00:55:08.044
Sure, but they're behaviors, right? They're behavioral programs that relate

00:55:08.044 --> 00:55:09.624
to certain motivational systems.

00:55:09.844 --> 00:55:14.464
Yeah. So you don't see them as part of then the habit.

00:55:14.544 --> 00:55:21.664
You really see the habit as targeting, let's say, higher level behavioral elements

00:55:21.664 --> 00:55:22.724
that you might have learned?

00:55:23.564 --> 00:55:31.144
I think it's possible. It's perfectly possible for those lower-level behaviors.

00:55:32.684 --> 00:55:37.704
So if you think about Ma's idea, I'm building everything on Ma,

00:55:37.824 --> 00:55:39.704
as it were, and what he claimed was,

00:55:40.704 --> 00:55:51.184
that these higher-level representations can trigger the pre-learned representations in cerebellum.

00:55:51.184 --> 00:55:54.184
And cause them to execute a particular kind of behavior.

00:55:56.524 --> 00:55:58.684
There's no reason, I think, why...

00:56:00.819 --> 00:56:04.019
Maybe the brainstem could participate in that.

00:56:04.579 --> 00:56:13.159
So many years ago, the work of Leapin and Supple showed that there were cerebellar inputs.

00:56:14.359 --> 00:56:17.999
If you lesion the cerebellar vermis, you get sham rage.

00:56:19.659 --> 00:56:26.839
It's possible that that's happening because of the impact that cerebellum has

00:56:26.839 --> 00:56:29.279
on those lower-level brainstem centers.

00:56:29.279 --> 00:56:33.199
Centers right okay so you're saying it's

00:56:33.199 --> 00:56:36.179
not necessarily in the in the focus of your idea about

00:56:36.179 --> 00:56:39.419
how habits are learned or expressed but you

00:56:39.419 --> 00:56:42.419
might you cannot exclude it no that's right right okay

00:56:42.419 --> 00:56:45.659
absolutely i mean there's lots of evidence showing that there's interactions

00:56:45.659 --> 00:56:50.139
right exactly brainstem centers and the cerebellum of course so the other thing

00:56:50.139 --> 00:56:54.679
that you mention or that also becomes apparent as you said earlier and sometimes

00:56:54.679 --> 00:56:56.739
you're saying look all this the

00:56:56.739 --> 00:57:00.379
The modeling of the cerebellum is like a footnote to Marin Albus. Yeah.

00:57:00.599 --> 00:57:05.119
Right? So you really think that there has been not that much progress in our

00:57:05.119 --> 00:57:09.419
theoretical understanding or computational understanding of the cerebellum beyond

00:57:09.419 --> 00:57:14.279
what Marin Albus have identified? I think there's certainly been some progress, of course.

00:57:15.539 --> 00:57:21.139
You can't deny that we've come on leaps and bounds since 1969.

00:57:21.139 --> 00:57:29.899
What I would say is that the fundamental ideas about cerebellar plasticity and the way that they work.

00:57:31.508 --> 00:57:38.768
Have not changed all that much. The idea that the cerebellum has as its most

00:57:38.768 --> 00:57:44.608
fundamental unit the Purkinje cell and that the inputs into the Purkinje cell,

00:57:45.768 --> 00:57:52.868
the parallel fiber and the climbing fiber inputs being the principal inputs

00:57:52.868 --> 00:57:55.308
into the Purkinje cell, is still a dominant idea.

00:57:55.308 --> 00:57:58.088
Dear um that's not to say

00:57:58.088 --> 00:58:00.848
of course that we shouldn't be

00:58:00.848 --> 00:58:03.748
exploring other forms of plasticity in the cerebellar cortex

00:58:03.748 --> 00:58:08.248
there are lots of other cell types um and

00:58:08.248 --> 00:58:12.868
it's it's very clear that that you know there's been there's experimental evidence

00:58:12.868 --> 00:58:20.808
to support to support their involvement as well so um so here we are right so

00:58:20.808 --> 00:58:25.668
so you have this really very if you want ambitious and also So,

00:58:25.668 --> 00:58:28.628
an advanced scheme where you

00:58:28.628 --> 00:58:33.768
see how prefrontal cortex works together with cerebellum to realize both,

00:58:33.948 --> 00:58:37.488
let's say, controlled processing and automated processing, right?

00:58:37.568 --> 00:58:41.708
So, in that sense, I guess you also have had to sort of fight your battles and,

00:58:41.728 --> 00:58:46.988
you know, accumulate your scars to get that point across.

00:58:47.808 --> 00:58:52.748
So given your experience now in trying to understand the brain at the system

00:58:52.748 --> 00:58:58.768
level, what is Narendra's law that we should follow to understand the brain at this level?

00:59:01.068 --> 00:59:08.528
There's no law as such. Of course. Come on. I think we just have to be faithful to the data.

00:59:09.308 --> 00:59:13.708
I think the starting point, if the starting point is the anatomy,

00:59:13.888 --> 00:59:17.568
then I think you're on very sound footing. Um...

00:59:18.824 --> 00:59:24.104
It needs to be based on that sort of evidence. And the other thing is to build

00:59:24.104 --> 00:59:26.804
from what we have learned in the motor system.

00:59:28.044 --> 00:59:33.684
The motor system is what we understand best. So if we can take a set of principles

00:59:33.684 --> 00:59:35.444
that we can apply in the motor system,

00:59:37.004 --> 00:59:40.624
and find a way of extending those into the cognitive domain,

00:59:40.744 --> 00:59:43.784
I think that would be a good way forward.

00:59:44.504 --> 00:59:50.504
So look, Tony likes traveling, and then he always has me pay it,

00:59:50.544 --> 00:59:51.704
so I don't like to spend money.

00:59:52.404 --> 00:59:57.324
So we only have trips within England in the coming five years.

00:59:57.564 --> 01:00:05.344
So five years from now, he's going to come to your lab to check whether a prediction

01:00:05.344 --> 01:00:07.884
you're going to make today was actually confirmed or rejected.

01:00:08.564 --> 01:00:13.744
So what's the most important hypothesis that you want to see tested,

01:00:13.784 --> 01:00:17.604
validated in this five-year framework perspective?

01:00:18.764 --> 01:00:21.824
That's a cheeky question. And you're going to hold me to that,

01:00:21.824 --> 01:00:26.184
aren't you? Of course. What do you think? Why do you think we're recording this? Absolutely.

01:00:27.224 --> 01:00:32.284
There are so many interesting questions. I suppose

01:00:32.284 --> 01:00:36.984
one of them would be to

01:00:36.984 --> 01:00:46.864
go on testing the idea that a conditioned stimulus is processed in the same

01:00:46.864 --> 01:00:54.024
way in conditions of instrumental learning and classical conditioning.

01:00:54.704 --> 01:00:59.744
We've often talked about the possibility that there is this universal cerebellar

01:00:59.744 --> 01:01:07.524
transform, and it's an idea that people have been on about for a long time and for a good reason.

01:01:07.524 --> 01:01:10.844
Reason, I think this is a good way of doing that.

01:01:10.964 --> 01:01:16.264
I think it's a good way of pinning down that problem and saying,

01:01:16.284 --> 01:01:18.064
well, look, you've got a conditioned stimulus.

01:01:19.324 --> 01:01:25.104
Is it being processed in the same way, regardless of whether it's higher level or lower level?

01:01:26.704 --> 01:01:32.724
Are the areas that are activated when you process that instrumental CS,

01:01:32.724 --> 01:01:36.424
how are they talking to the cerebellar cortex?

01:01:37.824 --> 01:01:42.624
Or indeed, are they speaking, sorry, to the prefrontal cortex?

01:01:42.964 --> 01:01:45.724
Which parts of the prefrontal cortex are they talking to?

01:01:46.784 --> 01:01:49.664
We still don't have a handle on...

01:01:51.259 --> 01:01:56.359
Exactly what areas of prefrontal cortex are saying to the cerebellum.

01:01:58.259 --> 01:02:03.659
And so I think it would be good to try and work out methods for sorting out

01:02:03.659 --> 01:02:06.179
communication between the two. Great.

01:02:07.819 --> 01:02:11.959
Rolando Romani, thank you very much for this conversation. Thank you. Thank you.

01:02:13.799 --> 01:02:19.439
That was fun. You gave me certainly a good grilling there. The CSN podcast was

01:02:19.439 --> 01:02:24.059
produced by the Convergent Science Network of Biometrics and Biohybrid Systems.

01:02:24.319 --> 01:02:29.379
A project funded by the European 7th Research Framework Program.

01:02:29.639 --> 01:02:37.179
For interviews, recorded lectures or upcoming conferences in the field of biometrics

01:02:37.179 --> 01:02:42.539
and biohybrid systems, go to csnnetwork.eu.

01:02:43.359 --> 01:02:44.699
And thank you for listening.

01:02:45.859 --> 01:02:49.119
I think this is the idea of the podcast that we

01:02:49.119 --> 01:02:51.759
can go a bit behind what you would put on

01:02:51.759 --> 01:02:55.059
the slides right and and also i think it's important

01:02:55.059 --> 01:02:57.959
for people to listen to this to understand look there's uncertainty what we

01:02:57.959 --> 01:03:00.999
do yeah right there's absolutely we make assumptions and to get

01:03:00.999 --> 01:03:03.819
that a little bit more to the foreground is really i

01:03:03.819 --> 01:03:06.799
think what we want to to achieve here and if

01:03:06.799 --> 01:03:09.439
you want to also show a bit more the more

01:03:09.439 --> 01:03:12.379
human level decision making that we have to do yeah

01:03:12.379 --> 01:03:15.379
we do these things that's often missing from talks isn't it yeah

01:03:15.379 --> 01:03:18.299
exactly but no it's really good fun i enjoyed that

01:03:18.299 --> 01:03:21.159
terrific i enjoyed it actually we were

01:03:21.159 --> 01:03:26.339
really um i'm also very much trying to figure out this whole idea of how do

01:03:26.339 --> 01:03:30.679
we compile habits you know so uh indeed how can the cerebellum contribute to

01:03:30.679 --> 01:03:35.939
that this is quite relevant for what we are doing so that's why i please yeah

01:03:35.939 --> 01:03:40.139
it's a question of getting is trying to trying to understand what is a motor habit and what is

01:03:40.219 --> 01:03:42.779
a cognitive habit, really. Right, exactly.

01:03:43.119 --> 01:03:48.339
And that's something that, yeah, I think I could have answered that a little

01:03:48.339 --> 01:03:50.979
more effectively. But, yeah, it's a tough one.

01:03:51.519 --> 01:03:56.419
But you have to admit, right, it seems really odd to claim it loops back over M1.

01:03:56.679 --> 01:04:01.099
Yeah. You're screwed. You add lots of uncontrollable latency to this whole thing.

01:04:03.099 --> 01:04:14.879
Yeah. Yeah, a big chunk of the timing is taken up with the decision-related aspects,

01:04:15.059 --> 01:04:18.399
and that's what you speed up with that prefrontal component.

01:04:20.539 --> 01:04:25.259
Yeah, but maybe we give too much importance to M1. I think M1 is pretty stupid.

01:04:26.828 --> 01:04:29.668
But there's no way out of the system without going through M1.

01:04:30.788 --> 01:04:34.448
Yeah, but I see M1 really just… How can you reach the corticospinal tract without

01:04:34.448 --> 01:04:37.588
getting M1? Exactly, but you just dump your motor program in M1.

01:04:38.228 --> 01:04:42.488
You give it a very short time window to play it down into the corticospinal

01:04:42.488 --> 01:04:44.828
tract. Yeah. You close it up again. That's it. Finish.

01:04:45.648 --> 01:04:49.608
It's just the output station, you know. Yes, but how do you get it in?

01:04:50.928 --> 01:04:52.508
Via your premotor network.

01:04:55.308 --> 01:04:59.308
Uh, premotor network being through red nucleus and so on. No, wait, wait, wait.

01:04:59.728 --> 01:05:04.768
In my model, my cerebellum does not need to talk to M1. It doesn't give a damn about M1.

01:05:04.848 --> 01:05:08.008
It just plays it out downstream immediately because it wants to be quick.

01:05:08.288 --> 01:05:12.208
Yeah, yeah. I think also from an evolutionary perspective, that's the one thing

01:05:12.208 --> 01:05:13.828
that matters. This is what makes you survive.

01:05:14.448 --> 01:05:17.248
Be quick. Yes, yes. That's why you want to do this at all. Yes,

01:05:17.248 --> 01:05:18.268
I understand. Right? Yeah, yeah.

01:05:18.488 --> 01:05:21.648
So for that, this is why you just want to play it straight down.

01:05:21.648 --> 01:05:27.608
I suppose the crux of the issue is how do you get information out of...

01:05:30.140 --> 01:05:34.960
CRUISE 1 and CRUISE 2, and into your premotor network.

01:05:36.200 --> 01:05:41.120
And I don't think there is a route except through, I mean, what would it be?

01:05:41.780 --> 01:05:45.380
Well, look, CRUISE 1 and CRUISE 2, they are talking to deep nucleus.

01:05:45.820 --> 01:05:49.680
You might have divergence. Yeah. We cannot exclude that. This is the thing with

01:05:49.680 --> 01:05:50.540
the jet. Actually, right.

01:05:51.020 --> 01:05:57.000
Okay. I would bet, certainly since it's a brainstem, damn sure you have divergence. Yes. Right?

01:05:57.580 --> 01:06:02.260
Then you throw away modularity, right?

01:06:02.780 --> 01:06:09.000
Yeah, but I wasn't committed to modularity. That was your problem. Right, yes.

01:06:09.440 --> 01:06:12.380
But we still have conserved it at the cerebellar level.

01:06:13.240 --> 01:06:18.500
But outside of the cerebellum, I just allow things to diverge or to be linked together.

01:06:18.820 --> 01:06:24.200
You still, for me, just the key is, why don't you allow lateral interaction cerebellum?

01:06:24.260 --> 01:06:28.920
You should get latency. you just you say if I go through that loop I want to

01:06:28.920 --> 01:06:35.060
get out in a predictable way can be no screwing around this is why it's important to figure out,

01:06:37.060 --> 01:06:43.240
the intrinsic connectivities within the cerebellar nuclei then absolutely and

01:06:43.240 --> 01:06:47.120
the data is not there are you sure in primates it's not there,

01:06:48.020 --> 01:06:54.020
I should ask Bjorn Merker he might know he's a good friend great expert on brainstem them.

01:06:54.780 --> 01:06:56.840
We should look at red nucleus, for instance.

01:06:58.920 --> 01:07:05.000
I remember discussing this with him a few weeks ago, but not so specifically for the red nucleus.

01:07:05.360 --> 01:07:09.340
He didn't reject the idea completely, but I didn't ask for the references. No.

01:07:10.300 --> 01:07:18.160
Yeah, a few years ago, I think this issue did bother me, and I looked and I looked.

01:07:18.540 --> 01:07:26.540
I couldn't find the anatomical evidence. And the simplest route out was through M1.

01:07:27.944 --> 01:07:32.084
Possibly because we know about the connections. Sure. And we don't know about

01:07:32.084 --> 01:07:37.144
the connections, the intrinsic connectivity within the deep-coated-tel-all-out-convections.

01:07:37.984 --> 01:07:40.764
I think I did well because I have two options now.

01:07:41.664 --> 01:07:51.344
I have plan B. Plan B is the prefrontal-oriented cerebellar regions don't care

01:07:51.344 --> 01:07:52.844
about linking to the motor output.

01:07:53.004 --> 01:07:57.744
They just care about setting the right interval information for even the amplitude

01:07:57.744 --> 01:08:01.264
time course of, let's say, a memory response prefrontal cortex. Yes, yes.

01:08:01.524 --> 01:08:04.324
They don't give a damn about motor. No.

01:08:04.404 --> 01:08:09.784
I think that's more likely, actually, because the language is different.

01:08:10.564 --> 01:08:14.744
The language that the prefrontal cortex speaks, when I say language,

01:08:14.824 --> 01:08:23.744
I mean the neural activity and what it's time-locked to and so on.

01:08:23.744 --> 01:08:27.684
It doesn't give a damn about motor

01:08:27.684 --> 01:08:31.264
it just doesn't exactly right and

01:08:31.264 --> 01:08:34.024
so maybe it isn't bothered

01:08:34.024 --> 01:08:37.044
I would buy that because then what it could

01:08:37.044 --> 01:08:40.904
look like is that you just have this prefrontal cerebellar interaction cerebellum

01:08:40.904 --> 01:08:46.084
helps keep time in that system you get your deliberate action plans you play

01:08:46.084 --> 01:08:51.484
out over M1 goes down over the cortical spinal tract but you have your collaterals

01:08:51.484 --> 01:08:54.404
into a range of brainstem areas.

01:08:54.744 --> 01:08:57.624
You have your afferents copied back to the pons. You have a lot of source information

01:08:57.624 --> 01:09:00.744
for the cerebellum now to suck in these regularities.

01:09:01.344 --> 01:09:07.044
And then from then on, I would speculate, right? It would just play this out automatically.

01:09:09.264 --> 01:09:13.944
Exploiting recurrent projections into the pons that just allow to loop multiple circuits.

01:09:14.204 --> 01:09:17.584
The function of this will make sense to me. Then I really have optimized my

01:09:17.584 --> 01:09:19.004
latency. This is what I want.

01:09:19.624 --> 01:09:23.964
Yeah. I think there's a lot of merit to that actually yeah I agree just the

01:09:23.964 --> 01:09:25.844
anatomy is missing but that's a detail.

01:09:28.504 --> 01:09:34.964
A forgettable detail exactly but I'm sure I'm sure given that people haven't

01:09:34.964 --> 01:09:43.104
looked we it's a reasonable hypothesis to go to check so I should convince some some red runner to,

01:09:43.984 --> 01:09:48.004
do some traces yeah or even even somebody who works on monkeys yeah even better

01:09:48.004 --> 01:09:52.644
or humans why can't we do this Isn't there a way to do this?

01:09:52.724 --> 01:09:54.044
Can't you look at brainstem areas?

01:09:55.044 --> 01:09:58.084
Paul, I'm going to have to go and move to a hotel. All right.

01:09:58.144 --> 01:10:02.064
So then we see you at 8.30 at the Silicon for dinner? Yeah. Possibly?