WEBVTT 00:00:02.310 --> 00:00:06.710 My guest today is Dr. Reza Shadmir. Dr. Shadmir 00:00:06.710 --> 00:00:09.929 is responsible for developing a theory and paradigm 00:00:09.929 --> 00:00:13.009 to study the question of how the brain learns 00:00:13.009 --> 00:00:16.769 to build internal models for the purpose of controlling 00:00:16.769 --> 00:00:20.890 our movements. His education journey includes 00:00:20.890 --> 00:00:25.070 a bachelor's in electrical engineering from Gonzaga 00:00:25.070 --> 00:00:29.190 University, a master's in biomedical engineering, 00:00:29.510 --> 00:00:34.520 and a PhD. in computer science, robotics, from 00:00:34.520 --> 00:00:38.600 the University of Southern California, and finally, 00:00:38.840 --> 00:00:43.320 a McDonnell -Pugh postdoctoral fellow at MIT. 00:00:44.679 --> 00:00:47.619 Currently, he is the director of the biomedical 00:00:47.619 --> 00:00:51.840 engineering PhD program and leader of the Shadmere 00:00:51.840 --> 00:00:57.320 Lab at Johns Hopkins University. His contributions 00:00:57.320 --> 00:01:01.549 to science include consolidation of motor memory, 00:01:02.310 --> 00:01:06.989 state space theory of motor adaptation, multiple 00:01:06.989 --> 00:01:11.609 time scales of motor memory, a theory of movement, 00:01:12.170 --> 00:01:15.549 vigor and a slink to trait -like features of 00:01:15.549 --> 00:01:20.629 individuality, neural encoding of action by the 00:01:20.629 --> 00:01:25.109 Purkinje cells of the cerebellum. In addition, 00:01:25.609 --> 00:01:28.650 Dr. Shadmere is the author of three books and 00:01:28.650 --> 00:01:33.230 has numerous publications in top scientific journals. 00:01:35.370 --> 00:01:37.310 Today's episode is all about motor movements 00:01:37.310 --> 00:01:41.409 and the physics of motor movement, including 00:01:41.409 --> 00:01:45.290 motor learning and memory, prediction and air 00:01:45.290 --> 00:01:50.750 correction, purgenji cells, and more. If you 00:01:50.750 --> 00:01:53.189 remember previous comments of the podcast about 00:01:53.189 --> 00:01:57.030 how The brain is a prediction machine and it 00:01:57.030 --> 00:02:00.650 uses internal calculators and how the central 00:02:00.650 --> 00:02:03.730 nervous system is designed to move the living 00:02:03.730 --> 00:02:07.629 organism. By the end of this episode, you will 00:02:07.629 --> 00:02:12.590 know more about why I say that. Today, we will 00:02:12.590 --> 00:02:15.610 explore a very underrated yet powerful area of 00:02:15.610 --> 00:02:19.990 the brain called the cerebellum. But first, a 00:02:19.990 --> 00:02:23.629 message about Daylight Computer Company. and 00:02:23.629 --> 00:02:28.509 chroma light devices. I would like to take a 00:02:28.509 --> 00:02:32.490 moment and mention a pressing issue we are seeing 00:02:32.490 --> 00:02:38.969 in our modern world. And that is tech use and 00:02:38.969 --> 00:02:44.169 tech light. The data are impressive and concerning 00:02:44.169 --> 00:02:49.229 on isolated wavelengths of light, especially 00:02:49.229 --> 00:02:55.270 shorter wavelengths. which is blue light. For 00:02:55.270 --> 00:02:58.490 those that don't know, we have chromophores, 00:02:59.210 --> 00:03:02.969 which are special proteins that absorbs specific 00:03:02.969 --> 00:03:07.889 wavelengths of light. For blue light, the light 00:03:07.889 --> 00:03:12.250 that is LED light and tech light, that protein 00:03:12.250 --> 00:03:18.090 is called melanopsin. Melanopsin is responsible 00:03:18.090 --> 00:03:23.319 for our circadian biology. physiology and cell 00:03:23.319 --> 00:03:28.460 functioning, hormone regulation, and even a connection 00:03:28.460 --> 00:03:34.840 to an area huge for mood. A consideration we 00:03:34.840 --> 00:03:39.240 should include is this protein was not even discovered 00:03:39.240 --> 00:03:45.939 until 1998. It seems important for us to understand 00:03:45.939 --> 00:03:50.580 how our biology uses the different wavelengths 00:03:50.580 --> 00:03:55.139 of light for various aspects of our biology. 00:03:56.840 --> 00:04:00.639 This blue light chromophore is our master controller, 00:04:01.699 --> 00:04:06.379 our master clock. Remember circadian rhythm is 00:04:06.379 --> 00:04:12.479 a two -part process, two independent parts, light 00:04:12.479 --> 00:04:19.180 and dark. For a quick reference, See, the 2017 00:04:19.180 --> 00:04:24.459 Nobel Prize in Physiology and Medicine. But for 00:04:24.459 --> 00:04:27.779 now, I have something exciting. I want to introduce 00:04:27.779 --> 00:04:30.639 a product unlike any other product available. 00:04:31.579 --> 00:04:36.180 A highlight is the product from Daylight Computer 00:04:36.180 --> 00:04:39.639 Company created their product based on these 00:04:39.639 --> 00:04:44.680 factors. The Daylight Computer is completely 00:04:44.680 --> 00:04:50.160 blue light free. It has no flicker. Short wavelength 00:04:50.160 --> 00:04:54.699 flicker is extremely harmful for our eyes and 00:04:54.699 --> 00:04:58.600 downstream biology. Light flicker is constantly 00:04:58.600 --> 00:05:02.180 turning our central nervous system on and off. 00:05:03.040 --> 00:05:06.540 Essentially, it is like going to a light switch 00:05:06.540 --> 00:05:10.939 and repeatedly turning it on and off. The problem 00:05:10.939 --> 00:05:16.959 is blue light and LED light does this. and it 00:05:16.959 --> 00:05:20.220 is so rapid you cannot even perceive this in 00:05:20.220 --> 00:05:25.720 real time. The daylight computer is the lowest 00:05:25.720 --> 00:05:29.660 stimulation and foremost for sensory sensitive 00:05:29.660 --> 00:05:34.920 users. It is no question that the alternative 00:05:34.920 --> 00:05:40.220 product especially when used at night do not 00:05:40.220 --> 00:05:44.660 address or consider this in their product. It 00:05:44.660 --> 00:05:49.620 is so toxic to human biology. Big tech corporations 00:05:49.620 --> 00:05:54.339 have patents on how their short wavelength implicate 00:05:54.339 --> 00:05:59.939 the human nervous system. And a bonus, despite 00:05:59.939 --> 00:06:04.079 daylight computer not having backlight, it is 00:06:04.079 --> 00:06:08.459 very functional for outdoor use. And of course, 00:06:09.220 --> 00:06:14.240 increased sunlight is always preferred. I am 00:06:14.240 --> 00:06:17.620 happy to offer a discount for the Daylight Computer. 00:06:18.680 --> 00:06:23.779 You can use the code Autism for a $25 off coupon. 00:06:25.279 --> 00:06:29.660 Again, use the code Autism and the discount code 00:06:29.660 --> 00:06:34.800 for $25 off. See the link in the show notes to 00:06:34.800 --> 00:06:38.000 Daylight Computer Company or just give it a quick 00:06:38.000 --> 00:06:42.100 search in your internet browser. Use the code 00:06:42.100 --> 00:06:48.290 Autism. for $25 off. I would like to mention 00:06:48.290 --> 00:06:54.589 Chroma. Lights designed for humans. Chroma, a 00:06:54.589 --> 00:06:59.009 Seattle -based innovator founded by ex -NASA 00:06:59.009 --> 00:07:03.449 and Air Force engineer Michael Shapiro, is on 00:07:03.449 --> 00:07:06.870 a mission to enhance physical and mental health 00:07:06.870 --> 00:07:12.110 with purpose -built devices. Unlocking peak human 00:07:12.110 --> 00:07:15.920 health. cognitive function, and performance. 00:07:17.100 --> 00:07:19.959 Shapiro launched Chroma to restore the natural 00:07:19.959 --> 00:07:24.680 light lost to screens and indoor living, and 00:07:24.680 --> 00:07:28.300 delivers faster recovery, sharper minds, and 00:07:28.300 --> 00:07:33.819 better sleep. Their products hit hard. The Ironforge 00:07:33.819 --> 00:07:37.620 speeds muscle repair with red and near -infrared 00:07:37.620 --> 00:07:41.839 light, while the Skylight mimics sunlight. to 00:07:41.839 --> 00:07:47.240 boost sleep and energy. A standout, the Forge 00:07:47.240 --> 00:07:52.500 Lamp, is a portable gem that fires 660 nanometer 00:07:52.500 --> 00:07:58.939 and 850 nanometer light to energize mitochondria 00:07:58.939 --> 00:08:03.560 and heal tissues on the go. Remember the four 00:08:03.560 --> 00:08:06.680 red light chromophores on cytochrome c -oxidase 00:08:06.680 --> 00:08:10.540 frequently talked about in the podcast. This 00:08:10.540 --> 00:08:14.800 is why. Their products are built with military 00:08:14.800 --> 00:08:20.819 -grade durability that have lasting impact. Chroma's 00:08:20.819 --> 00:08:26.600 tech fuses precision and power. Gallium titride 00:08:26.600 --> 00:08:30.779 power supplies. Smaller, cooler, and stronger 00:08:30.779 --> 00:08:35.000 than silicone. Provide flicker -free light that's 00:08:35.000 --> 00:08:39.679 easy on the eyes. High powered LEDs target key 00:08:39.679 --> 00:08:44.340 wavelengths for skin, tissue, and cellular health 00:08:44.340 --> 00:08:48.179 with smart heat management for the lasting impact. 00:08:49.200 --> 00:08:52.519 Every design decision Chroma makes serves a purpose 00:08:52.519 --> 00:08:57.000 to create devices that are precise, durable, 00:08:57.519 --> 00:09:02.840 and effective for improving human life. Remember, 00:09:03.360 --> 00:09:05.860 humans use different wavelengths of light for 00:09:05.860 --> 00:09:10.799 different functions of life. Remember when I 00:09:10.799 --> 00:09:17.860 ask, what do you think light is? Chroma designs 00:09:17.860 --> 00:09:22.779 with our biology in mind. From sleep aids and 00:09:22.779 --> 00:09:27.460 wound healing to mitochondrial energy, full body 00:09:27.460 --> 00:09:30.919 lights and blue light blocking glasses. They 00:09:30.919 --> 00:09:35.820 are US made and chroma ships globally and accepts 00:09:36.009 --> 00:09:43.830 FSA and HSA payments. Use autism at checkout 00:09:43.830 --> 00:09:50.529 for a 10 % off discount. That's autism at checkout 00:09:50.529 --> 00:09:59.629 for a 10 % off discount. Can you share a little 00:09:59.629 --> 00:10:02.470 bit about your path into research and specifically 00:10:02.470 --> 00:10:11.320 the cerebellum? Sure. I was a kid raised in Tehran 00:10:11.320 --> 00:10:18.419 in Iran and when I was a teenager I was lucky 00:10:18.419 --> 00:10:22.299 that the U .S. Embassy on Roosevelt Street some 00:10:22.299 --> 00:10:26.679 50 years ago, 1977. They decided that I was good 00:10:26.679 --> 00:10:29.259 enough that I could deserve a visa to come to 00:10:29.259 --> 00:10:33.639 the U .S., and I did. I went to Spokane, Washington, 00:10:33.820 --> 00:10:36.259 which is a small town on the eastern part of 00:10:36.259 --> 00:10:40.700 the state, and raised by foster parents who love 00:10:40.700 --> 00:10:44.059 me just like their own son. And I was watching 00:10:44.059 --> 00:10:46.779 TV one day, and I was watching public television. 00:10:47.740 --> 00:10:51.399 And they had a show about the brain, and it really 00:10:51.399 --> 00:10:53.700 excited me because I thought that this is the 00:10:53.700 --> 00:10:55.480 most interesting thing in the world to study 00:10:55.480 --> 00:11:00.320 but not just studying using biology and techniques 00:11:00.320 --> 00:11:03.840 of biologists but techniques of engineers and 00:11:03.840 --> 00:11:07.000 you know the idea being that in engineering one 00:11:07.000 --> 00:11:09.740 has tools to study complicated systems and maybe 00:11:09.740 --> 00:11:12.039 if we applied some of those tools to how the 00:11:12.039 --> 00:11:15.840 brain worked it would you know uncover some mysteries 00:11:15.840 --> 00:11:17.960 that would be otherwise difficult to understand 00:11:17.960 --> 00:11:23.899 and so I remember going to my academic advisor 00:11:23.899 --> 00:11:25.559 and telling him I wanted to study the brain. 00:11:25.759 --> 00:11:27.279 And he said, well, you can't do that here. You 00:11:27.279 --> 00:11:31.019 have to go to grad school. So I said, that's 00:11:31.019 --> 00:11:34.419 what I wanted. And so I did. And then in grad 00:11:34.419 --> 00:11:38.779 school, I became interested in thinking about 00:11:38.779 --> 00:11:41.779 control and movements because I was taking courses 00:11:41.779 --> 00:11:44.840 in robotics. And I realized that robotics is 00:11:44.840 --> 00:11:48.100 sort of like asking the engineer to be the god. 00:11:48.330 --> 00:11:51.470 you are the god of this machine, make it move 00:11:51.470 --> 00:11:53.850 the way you want to. And I thought some of the 00:11:53.850 --> 00:11:55.529 principles that are in engineering that describe 00:11:55.529 --> 00:11:58.230 how machines should be controlled presumably 00:11:58.230 --> 00:12:00.830 relate to how the brain controls our movements. 00:12:01.250 --> 00:12:03.649 And so if we could apply some of the tools from 00:12:03.649 --> 00:12:08.470 robotics to control of behavior, maybe it will 00:12:08.470 --> 00:12:11.169 help us understand how the brain controls our 00:12:11.169 --> 00:12:16.330 movements. And that was the basis of my lifelong 00:12:16.330 --> 00:12:20.259 goal in trying to understand how the brain controls 00:12:20.259 --> 00:12:24.899 our movements, in particular, arm movements and 00:12:24.899 --> 00:12:30.139 eye movements. Yeah, the engineering is a fascinating 00:12:30.139 --> 00:12:32.720 pathway into this, I think, because I was reminded 00:12:32.720 --> 00:12:36.419 of like a computer numeric controller, which, 00:12:36.740 --> 00:12:39.659 you know, like a CNC programming controls the 00:12:39.659 --> 00:12:42.519 machine, the speed, where it goes, you know, 00:12:42.580 --> 00:12:45.059 its endpoint, where it returns home and everything. 00:12:45.820 --> 00:12:49.570 It's kind of like That pathway with the engineering 00:12:49.570 --> 00:12:53.970 gave you this access that I think a lot of other 00:12:53.970 --> 00:12:56.210 people were overlooking or didn't even think 00:12:56.210 --> 00:12:59.230 about yet. Yeah, you know, if you think about, 00:12:59.529 --> 00:13:02.809 like you said, the CNC machine, you are dictating 00:13:02.809 --> 00:13:05.570 to the machine its actuators to move things the 00:13:05.570 --> 00:13:09.450 way you wanted them to. And that gives you a 00:13:09.450 --> 00:13:12.669 window to asking questions like, why do we move 00:13:12.669 --> 00:13:15.470 the way we do? You know, what's good about the 00:13:15.470 --> 00:13:18.320 way we move? that makes us all want to move the 00:13:18.320 --> 00:13:22.080 same way. Meaning, like my hand, when I ask to 00:13:22.080 --> 00:13:24.759 reach to an object, I more or less do the same 00:13:24.759 --> 00:13:28.940 as the way you do it. And so this was actually 00:13:28.940 --> 00:13:32.759 one of the first questions that my field became 00:13:32.759 --> 00:13:35.779 interested in is sort of regularity in how people 00:13:35.779 --> 00:13:41.279 move and what's the basis of this regularity? 00:13:41.440 --> 00:13:45.509 What's good about moving this way? And writing 00:13:45.509 --> 00:13:47.429 mathematical equations, I said, maybe there's 00:13:47.429 --> 00:13:51.610 something about energy that we spent. But I think 00:13:51.610 --> 00:13:54.009 one of the coolest things that came from this 00:13:54.009 --> 00:13:59.509 was the realization that the way we move is potentially 00:13:59.509 --> 00:14:03.409 a reflection of the way we feel. And why do I 00:14:03.409 --> 00:14:06.929 say that? So, you know, if you see somebody walking, 00:14:08.210 --> 00:14:11.509 you can get a sense of whether, you know, are 00:14:11.509 --> 00:14:15.269 they depressed? or are they happy? You know, 00:14:15.429 --> 00:14:19.330 when we say the phrase, they have a spring in 00:14:19.330 --> 00:14:22.610 their step, that's because they move differently. 00:14:22.830 --> 00:14:25.889 It's a reflection of both how they feel and the 00:14:25.889 --> 00:14:28.769 way they move. And that was one of the interesting 00:14:28.769 --> 00:14:32.309 observations about the way our brain controls 00:14:32.309 --> 00:14:35.370 our behaviors, that by paying attention to how 00:14:35.370 --> 00:14:39.210 somebody moves, you get an understanding about 00:14:39.210 --> 00:14:45.259 their cognitive state. It's a downstream representation 00:14:45.259 --> 00:14:51.419 of what is going on deep inside. Something that's 00:14:51.419 --> 00:14:53.519 fascinating to me is just watching people move. 00:14:53.980 --> 00:14:58.720 It's almost like mindless movement and it's constant. 00:14:59.620 --> 00:15:02.340 I was sitting here doing it as you were talking 00:15:02.340 --> 00:15:05.440 about that. It's like, what is that? I've always 00:15:05.440 --> 00:15:11.519 been fascinated with that. understood that myself 00:15:11.519 --> 00:15:15.899 because I know that some of us have, you know, 00:15:16.340 --> 00:15:21.480 like constant movements of our leg, or it's this 00:15:21.480 --> 00:15:24.559 restlessness, there's this energy that needs 00:15:24.559 --> 00:15:29.120 to be spent, and I don't know much about that, 00:15:29.120 --> 00:15:36.279 why it's there, but I can tell you that coming 00:15:36.279 --> 00:15:39.700 back to the notion of understanding the cognitive 00:15:39.700 --> 00:15:43.179 state of an individual. I love going to the airport 00:15:43.179 --> 00:15:46.279 and watching people when they meet each other 00:15:46.279 --> 00:15:50.379 outside of security because it says a lot about 00:15:50.379 --> 00:15:53.460 how you feel about somebody, how you move toward 00:15:53.460 --> 00:15:56.159 that person. It's like this involuntary thing 00:15:56.159 --> 00:15:59.039 that we have in us that we run toward people 00:15:59.039 --> 00:16:04.000 we love. You don't do that when somebody is standing 00:16:04.000 --> 00:16:05.620 there with your name that says, I'm going to 00:16:05.620 --> 00:16:08.429 pick you up in my Uber. but you will run toward 00:16:08.429 --> 00:16:11.350 the person you love because there's this involuntary 00:16:11.350 --> 00:16:14.950 relationship between how you value that person 00:16:14.950 --> 00:16:18.470 and how you move toward them. Yeah. That's a 00:16:18.470 --> 00:16:22.450 great description. Can you give me an explanation 00:16:22.450 --> 00:16:25.750 about like an overview of the cerebellum specifically? 00:16:26.309 --> 00:16:31.649 Yeah, yeah. So let me start by going back about 00:16:31.649 --> 00:16:36.720 a century to World War I. I'm going to share 00:16:36.720 --> 00:16:42.600 my screen with you so we can look at one or two 00:16:42.600 --> 00:16:48.320 slides that are worthwhile in terms of giving 00:16:48.320 --> 00:16:52.799 us a little background. Let me show you this 00:16:52.799 --> 00:16:57.059 picture here. This is a picture of a couple of 00:16:57.059 --> 00:16:59.340 soldiers during World War I. This is a German 00:16:59.340 --> 00:17:02.539 soldier. This is a British soldier. When you 00:17:02.539 --> 00:17:04.119 look at their helmets, you notice something. 00:17:04.190 --> 00:17:06.230 fundamentally different, right? So the back of 00:17:06.230 --> 00:17:09.230 the German head soldier, you have this cover, 00:17:09.349 --> 00:17:11.650 whereas in the British soldier you don't. And 00:17:11.650 --> 00:17:15.569 what this meant is that during World War I, the 00:17:15.569 --> 00:17:18.049 British soldiers suffered from certain kinds 00:17:18.049 --> 00:17:21.390 of damage from shrapnel or other things that 00:17:21.390 --> 00:17:22.990 affected the back of the head. And that's where 00:17:22.990 --> 00:17:25.609 the cerebellum is. And Gordon Holmes was this, 00:17:26.690 --> 00:17:28.730 he was a British neurologist that was stationed 00:17:28.730 --> 00:17:31.150 in France. And he examined these patients and 00:17:31.150 --> 00:17:34.670 he noticed that These soldiers, when they had 00:17:34.670 --> 00:17:36.849 damaged the cerebellum, there was a specific 00:17:36.849 --> 00:17:39.450 part of their movement that was affected, which 00:17:39.450 --> 00:17:41.170 was near the end of their movement. So they could 00:17:41.170 --> 00:17:44.250 make the movement well to start with, but then 00:17:44.250 --> 00:17:49.269 they couldn't end it well as the, for example, 00:17:49.390 --> 00:17:52.430 the arm came to the target. And he called this 00:17:52.430 --> 00:17:55.569 dysmetria, which means that the metric of the 00:17:55.569 --> 00:17:57.549 movement is something wrong with it. So the basic 00:17:57.549 --> 00:18:00.450 idea about what the cerebellum did came from 00:18:00.450 --> 00:18:03.849 these observations in patients that damaged their 00:18:03.849 --> 00:18:05.970 cerebellum. And it said that it looked like it 00:18:05.970 --> 00:18:08.569 was important for control of movements, particularly 00:18:08.569 --> 00:18:14.230 the end of the movement. And this went along 00:18:14.230 --> 00:18:16.630 with certain other aspects of cerebellar function. 00:18:16.650 --> 00:18:18.730 I'll just describe some of the other ones. So 00:18:18.730 --> 00:18:21.450 it's not just the movement itself, but probably 00:18:21.450 --> 00:18:23.710 also has something to do with sensory processing. 00:18:24.390 --> 00:18:28.849 And this came with experiments that looked at 00:18:29.039 --> 00:18:32.779 a simple animal called an electric fish. Electric 00:18:32.779 --> 00:18:35.819 fish is this interesting animal that puts out 00:18:35.819 --> 00:18:39.579 a motor discharge, an electric field to sense 00:18:39.579 --> 00:18:42.339 the world around. So electric fish lives in a 00:18:42.339 --> 00:18:46.000 muddy water. And for it to detect prey around 00:18:46.000 --> 00:18:48.339 it, what it does is that it puts out this electric 00:18:48.339 --> 00:18:51.819 field and then measures the electric field around 00:18:51.819 --> 00:18:54.460 itself and the distortions in it, it picks out 00:18:54.460 --> 00:18:55.960 and says, well, there must be something there. 00:18:56.160 --> 00:18:58.039 I'm going to pay attention to it. Maybe it's 00:18:58.039 --> 00:19:02.309 something... that I can eat. So what was discovered 00:19:02.309 --> 00:19:04.109 is that there's a structure in this electric 00:19:04.109 --> 00:19:06.589 fish which is called the cerebellolike structure. 00:19:07.049 --> 00:19:09.890 And what that structure did is that it said, 00:19:10.329 --> 00:19:12.869 you just generated an electric field, that's 00:19:12.869 --> 00:19:16.029 going to overwhelm your sensors. I'm going to 00:19:16.029 --> 00:19:21.349 cancel the sensory, expected sensory consequences 00:19:21.349 --> 00:19:24.509 of this field so that I can detect the small 00:19:24.509 --> 00:19:28.319 item that exists out there in this field. And 00:19:28.319 --> 00:19:30.759 that's the second idea about this. It's called 00:19:30.759 --> 00:19:34.019 forward models, which means that the cerebellum 00:19:34.019 --> 00:19:37.720 is attempting to predict something about the 00:19:37.720 --> 00:19:43.200 sensory world around us. And when under normal 00:19:43.200 --> 00:19:47.400 conditions, probably this sensory prediction 00:19:47.400 --> 00:19:51.680 allows us to cancel out a lot of things that 00:19:51.680 --> 00:19:54.859 would have been easily predicted because of... 00:19:54.519 --> 00:19:56.880 the actions that we perform. So in this case, 00:19:56.900 --> 00:20:00.740 if it's an electric fish, if it generated this 00:20:00.740 --> 00:20:04.359 electric field, its sensors don't want to pick 00:20:04.359 --> 00:20:06.640 out its own field. They want to pick out the 00:20:06.640 --> 00:20:09.299 difference between what the field produced and 00:20:09.299 --> 00:20:12.619 the distortion caused by this prey. And so that's 00:20:12.619 --> 00:20:15.640 the notion of forward models, having something 00:20:15.640 --> 00:20:18.799 to do with predicting sensory things. That's 00:20:18.799 --> 00:20:21.259 one of the functions of the cerebellum. The third 00:20:21.259 --> 00:20:25.470 function has to do with learning. And the idea 00:20:25.470 --> 00:20:29.569 behind learning is that there is a relationship 00:20:29.569 --> 00:20:33.390 between a teacher and a student. The teacher 00:20:33.390 --> 00:20:35.930 is this input that comes from the cerebellum. 00:20:36.109 --> 00:20:38.390 It's called the climbing fiber. It comes from 00:20:38.390 --> 00:20:40.230 a region of the brainstem called the inferior 00:20:40.230 --> 00:20:44.289 olive. The students are the Purkinje cells, which 00:20:44.289 --> 00:20:48.890 are these principal cells in the cerebellum that 00:20:48.890 --> 00:20:52.690 basically provide the output from the cerebellar 00:20:52.690 --> 00:20:56.849 cortex. So these were the three main ideas that 00:20:56.849 --> 00:20:58.769 describe the function of the cerebellum. One 00:20:58.769 --> 00:21:00.529 is it has something to do with control of movements, 00:21:00.630 --> 00:21:02.950 particularly the end point of the movement. Second, 00:21:03.029 --> 00:21:06.049 it has something to do with predicting sensory 00:21:06.049 --> 00:21:09.470 events, consequences of things that you should 00:21:09.470 --> 00:21:12.890 be able to predict. And third thing is that it's 00:21:12.890 --> 00:21:15.910 a place where learning takes place. And that 00:21:15.910 --> 00:21:18.690 learning has a teacher, in this case the inferior 00:21:18.690 --> 00:21:21.730 olive, that provides climbing fibers and students, 00:21:21.789 --> 00:21:30.119 which are the Purkinje cells Yeah, okay, so I'll 00:21:30.119 --> 00:21:32.380 I'll go ahead and then and I'll and I'll stop 00:21:32.380 --> 00:21:35.940 there see what you think Where is the inferior 00:21:35.940 --> 00:21:39.720 olive right? Yeah, it's part of the brain. It's 00:21:39.720 --> 00:21:42.079 part of them It's in the medulla and so it's 00:21:42.079 --> 00:21:45.200 actually like behind behind that if you if you 00:21:45.200 --> 00:21:47.500 could get it's one of those places that's incredibly 00:21:47.500 --> 00:21:50.839 hard to reach because It's it's almost behind 00:21:50.839 --> 00:21:54.130 the throat in the brain stem So it's really hard 00:21:54.130 --> 00:21:55.930 to record from it. It's really hard to do anything 00:21:55.930 --> 00:21:59.170 about it. But it is... I think of the inferior 00:21:59.170 --> 00:22:03.609 olive as the god of the cerebellum. It tells 00:22:03.609 --> 00:22:08.490 the cerebellum how to organize itself. Okay. 00:22:09.170 --> 00:22:12.450 So that's fascinating because they're both subdivided 00:22:12.450 --> 00:22:16.630 from the rhombencephalon. So that makes the cerebellum 00:22:16.630 --> 00:22:22.609 and the pons and the medulla. Are they? sensory, 00:22:22.650 --> 00:22:26.750 motor, and interneurons going into the cerebellum 00:22:26.750 --> 00:22:30.309 and does the cerebellum have each of those three 00:22:30.309 --> 00:22:33.369 types of neurons? So no. So there are no motor 00:22:33.369 --> 00:22:36.750 neurons in that sense in the cerebellum. The 00:22:36.750 --> 00:22:42.069 cerebellum by far most of the newer part of the 00:22:42.069 --> 00:22:46.009 cerebellum is far away from motor neurons. It 00:22:46.009 --> 00:22:48.369 projects onto things that eventually reach the 00:22:48.369 --> 00:22:51.660 motor neurons but itself is still rather many 00:22:51.660 --> 00:22:55.799 synapses away. However, there are these large 00:22:55.799 --> 00:22:58.779 inputs to the cerebellum, which are called mossy 00:22:58.779 --> 00:23:02.180 fibers. Basically, whatever the brain is doing, 00:23:02.339 --> 00:23:05.700 whatever the rest of the brain is doing, a copy 00:23:05.700 --> 00:23:08.259 of it is sent to the cerebellum. The cerebellum 00:23:08.259 --> 00:23:10.640 computes something based on that information 00:23:10.640 --> 00:23:14.240 and sends it back to whatever region was performing 00:23:14.240 --> 00:23:23.500 that computation. Can you can you explain a little 00:23:23.500 --> 00:23:26.660 bit about how it's sensory predicting especially 00:23:26.660 --> 00:23:31.240 I know you use the example of the fish but Humans 00:23:31.240 --> 00:23:33.779 and the monkeys that you study obviously use 00:23:33.779 --> 00:23:36.039 something different besides that. Can you say 00:23:36.039 --> 00:23:41.180 more about that? Yeah. Yeah. Okay, so the gating 00:23:41.180 --> 00:23:44.299 of sensory information I know that this is a 00:23:44.299 --> 00:23:47.259 particular interest because you know people with 00:23:47.259 --> 00:23:52.259 autistic on the spectrum they they report having 00:23:52.259 --> 00:23:57.059 abnormally sensitive or less than normal sensitivity 00:23:57.059 --> 00:24:00.680 to sensory feedback. And we can talk about the 00:24:00.680 --> 00:24:02.920 relationship between the cerebellum and autism, 00:24:03.420 --> 00:24:05.200 but I can tell you that there is a relationship 00:24:05.200 --> 00:24:09.039 between cerebellum and control of sensory input. 00:24:09.640 --> 00:24:13.220 So let's call this the gating of sensory information. 00:24:13.720 --> 00:24:16.559 So as I mentioned, the work in the electric fish, 00:24:17.119 --> 00:24:18.920 the scientist who did the work was called Curtis 00:24:18.920 --> 00:24:24.079 Bell. Curtis Bell demonstrated that the electric 00:24:24.079 --> 00:24:26.900 fish could survive only because it has this structure 00:24:26.900 --> 00:24:30.440 that could predict and cancel the sensory feedback 00:24:30.440 --> 00:24:32.359 that it would get. Otherwise it would just be 00:24:32.359 --> 00:24:36.400 overwhelmed by its own sensory, by its own feel 00:24:36.400 --> 00:24:39.700 that it would generate. Then my colleague Cathy 00:24:39.700 --> 00:24:44.569 Cullen here at Johns Hopkins, studied the vestibular 00:24:44.569 --> 00:24:47.309 system. So that's the system that you use to 00:24:47.309 --> 00:24:50.910 move your head, that head causes motion, that 00:24:50.910 --> 00:24:54.869 your eyes respond to it. And so what they showed 00:24:54.869 --> 00:24:57.910 is that during voluntary head rotations, when 00:24:57.910 --> 00:25:00.809 you move your head, the Purkinje cells, that's 00:25:00.809 --> 00:25:03.490 the principal cells of the cerebellar cortex, 00:25:03.509 --> 00:25:08.049 seem to predict and then cancel the vestibular 00:25:08.049 --> 00:25:11.730 input that's coming to the to the cerebellum, 00:25:11.910 --> 00:25:15.609 and also the proprioceptive input. So from the 00:25:15.609 --> 00:25:20.049 neck muscles and the vestibular organs in your 00:25:20.049 --> 00:25:23.549 head, the Purkinje cells in that case seem to 00:25:23.549 --> 00:25:26.210 basically remove the component of the sensory 00:25:26.210 --> 00:25:29.150 feedback that's due to the motion of the animal's 00:25:29.150 --> 00:25:31.670 own head. So when the animal themselves moves 00:25:31.670 --> 00:25:35.029 their head, they cancel this sensory feedback. 00:25:35.250 --> 00:25:37.650 Perhaps it has something to do with what Curtis 00:25:37.650 --> 00:25:42.740 Bell had seen in the electric fish. Okay, so 00:25:42.740 --> 00:25:47.059 that kind of makes sense with autistic phenotype, 00:25:47.660 --> 00:25:51.920 I think. Because maybe they're not canceling, 00:25:52.140 --> 00:25:54.279 because they're not moving their head to bias 00:25:54.279 --> 00:25:57.680 themselves to the environment. Because in large 00:25:57.680 --> 00:26:03.720 part, our eyes are doing that. Are there any 00:26:03.720 --> 00:26:08.019 inputs or communication with the superior or 00:26:08.019 --> 00:26:11.640 inferior colliculus? Yeah, yeah, so superior 00:26:11.640 --> 00:26:13.619 colliculus. Let me tell you about that So superior 00:26:13.619 --> 00:26:15.880 colliculus as you know you guys have described 00:26:15.880 --> 00:26:18.839 it in you guys have had a podcast about it It's 00:26:18.839 --> 00:26:21.799 an area that's important particularly in mammals 00:26:21.799 --> 00:26:25.299 in primate specially for moving the eyes so making 00:26:25.299 --> 00:26:30.339 saccades and the superior colliculus has a map 00:26:30.339 --> 00:26:34.519 of space and it basically, you know the fact 00:26:34.519 --> 00:26:36.720 that I when I'm reading the fact that I can move 00:26:36.720 --> 00:26:40.859 my eyes from word -to -word is because of this 00:26:40.859 --> 00:26:43.980 input that comes from the colliculus, that comes 00:26:43.980 --> 00:26:46.779 to the colliculus from the retina, from the basal 00:26:46.779 --> 00:26:50.180 ganglia, from the cortex, cerebral cortex, that 00:26:50.180 --> 00:26:53.480 describe what I think of it as like a value function. 00:26:53.900 --> 00:26:56.579 Where is important stuff on this visual field? 00:26:56.640 --> 00:27:00.599 Where should I move my eyes? Okay, so then you 00:27:00.599 --> 00:27:06.160 are able to control your gaze The basal ganglia 00:27:06.160 --> 00:27:09.039 is inhibiting it, saying, don't look over there. 00:27:09.460 --> 00:27:11.559 I'm going to release the inhibition so you can 00:27:11.559 --> 00:27:14.839 look over there. The frontal eye field, the cerebral 00:27:14.839 --> 00:27:19.779 cortex, lateral interprithal areas provide information, 00:27:20.059 --> 00:27:21.619 excitatory information, saying that, oh, there 00:27:21.619 --> 00:27:23.400 is something useful over there. Move your eyes 00:27:23.400 --> 00:27:25.920 over there. So the balance of inhibition and 00:27:25.920 --> 00:27:29.059 excitation moves your attention to some part 00:27:29.059 --> 00:27:32.259 of the visual space. The colliculus in that part 00:27:32.259 --> 00:27:35.259 generates neural activity. you generate a saccade, 00:27:35.380 --> 00:27:37.579 the eye moves to that location, you look over 00:27:37.579 --> 00:27:40.859 there. You don't need the cerebellum for this. 00:27:41.500 --> 00:27:45.839 However, as that movement is generated, the cerebellum 00:27:45.839 --> 00:27:52.059 gets a copy and during that movement, it adds 00:27:52.059 --> 00:27:55.180 information. And that information that's added 00:27:55.180 --> 00:27:59.940 makes it so that the saccade ends on the target. 00:28:00.940 --> 00:28:04.450 Without a functioning cerebellum, the patient 00:28:04.450 --> 00:28:09.009 will show dysmetria in their eye movements, overshoot 00:28:09.009 --> 00:28:11.650 or undershoot the target, having to repeatedly 00:28:11.650 --> 00:28:15.410 correct for it. Can you show the video? Yeah, 00:28:15.450 --> 00:28:19.529 yeah. And while you're pulling that up, are there 00:28:19.529 --> 00:28:23.289 any excitation inhibition, like glutamate GABA, 00:28:23.650 --> 00:28:27.950 running through the cerebellar? Yeah, absolutely. 00:28:27.950 --> 00:28:30.170 I can tell you about that as well. So let me 00:28:30.170 --> 00:28:36.079 share my screen. I will, let me show you a couple 00:28:36.079 --> 00:28:42.619 of examples of patients and their deficit. So 00:28:42.619 --> 00:28:54.359 here's a reaching deficit. Okay, so that's a 00:28:54.359 --> 00:29:07.309 reaching deficit. Here's a saccade deficit. Yeah. 00:29:07.890 --> 00:29:11.730 Okay. So, you know, we study the cerebellum, 00:29:11.750 --> 00:29:15.789 and here's an MRI of the cerebellum of the monkeys 00:29:15.789 --> 00:29:18.769 that we study. These are called marmosets. And 00:29:18.769 --> 00:29:21.670 marmosets are these beautiful monkeys that live 00:29:21.670 --> 00:29:25.890 in the Brazilian jungle in the Amazon. They're 00:29:25.890 --> 00:29:29.210 a wonderful model to study because, first, they 00:29:29.210 --> 00:29:32.430 are highly social animals. They live in families 00:29:32.430 --> 00:29:37.420 of 10 or 20 marmosets. They are They have an 00:29:37.420 --> 00:29:40.619 alpha female, so they're, as far as I know, one 00:29:40.619 --> 00:29:45.500 of the few primates that are ruled by females. 00:29:46.059 --> 00:29:53.339 And they are really smart. They vocalize. The 00:29:53.339 --> 00:29:56.559 recent reports suggest that they not only communicate 00:29:56.559 --> 00:30:00.880 through vocalization, but they even potentially 00:30:00.880 --> 00:30:04.819 name each other. They have this high cognitive 00:30:04.819 --> 00:30:08.519 ability to recognize each other, use sounds that 00:30:08.519 --> 00:30:13.000 are specific to a given marmoset, and they have 00:30:13.000 --> 00:30:15.380 this fabulous cerebellum, as you can see here. 00:30:15.980 --> 00:30:21.359 Just this amazing structure that dominates, dominates 00:30:21.359 --> 00:30:24.839 the brain. So here's the brainstem here, and 00:30:24.839 --> 00:30:27.819 if we look at the cerebellum, you get a sense 00:30:27.819 --> 00:30:30.200 of its organization. You can see the folding. 00:30:30.500 --> 00:30:33.809 So you can see how here's a Here's this group 00:30:33.809 --> 00:30:36.910 of neurons that live in a sheet, and that sheet 00:30:36.910 --> 00:30:40.309 has been folded over and over, you know, to fit 00:30:40.309 --> 00:30:44.369 a small volume on the back of the head. And if 00:30:44.369 --> 00:30:46.829 you look closer, you see that there's these three 00:30:46.829 --> 00:30:51.430 layers in this structure. This top layer is called 00:30:51.430 --> 00:30:53.990 the molecular layer. That's where you have the 00:30:53.990 --> 00:30:57.089 inner neurons that are all inhibitory. They all 00:30:57.089 --> 00:31:03.240 rely on GABA to interact with the Purkinje layer. 00:31:03.440 --> 00:31:05.519 So the Purkinje cell is this line here that you 00:31:05.519 --> 00:31:10.680 can see. This line has a single sheet of Purkinje 00:31:10.680 --> 00:31:17.480 cells. And the Purkinje cells are these large 00:31:17.480 --> 00:31:21.200 principal neurons of the cerebellum. And then 00:31:21.200 --> 00:31:25.019 below it, this white layer is called the granule 00:31:25.019 --> 00:31:28.000 layer. You have these tiny neurons called granule 00:31:28.000 --> 00:31:31.970 cells. It makes it so that there are more neurons 00:31:31.970 --> 00:31:35.990 here than all of the rest of the brain combined. 00:31:37.390 --> 00:31:40.809 So more than something like 70 % of all the neurons 00:31:40.809 --> 00:31:44.150 in your brain are here in the cerebellum. And 00:31:44.150 --> 00:31:46.369 the reason for having so many neurons is here 00:31:46.369 --> 00:31:49.009 because in this white region here, the granule 00:31:49.009 --> 00:31:53.150 layer, you just have an incredibly dense collection 00:31:53.150 --> 00:31:56.269 of what's called granule cells. And their job 00:31:56.269 --> 00:32:00.720 is to convey information that they get from the 00:32:00.720 --> 00:32:03.220 rest of the brain via what's called mossy fibers 00:32:03.220 --> 00:32:09.440 to the molecular layer and then eventually the 00:32:09.440 --> 00:32:15.559 Purkinje layer of the cerebral. The Purkinje 00:32:15.559 --> 00:32:22.539 cells. In autistics, the data show that there's 00:32:22.539 --> 00:32:25.980 a loss of, there's not as many Purkinje cells. 00:32:26.640 --> 00:32:29.480 And this is starting to make sense to me now. 00:32:30.599 --> 00:32:34.980 Yeah, so why is that? It's not just an autism. 00:32:35.500 --> 00:32:39.460 I think many cerebellar diseases, the sacrificial 00:32:39.460 --> 00:32:45.440 lamb is the Purkinje cell. Why? And I can tell 00:32:45.440 --> 00:32:48.000 you that in my experience Purkinje cells, they 00:32:48.000 --> 00:32:52.119 sort of live at the edge of a cliff. They are 00:32:52.119 --> 00:32:56.509 these large cells that They're active all the 00:32:56.509 --> 00:33:02.089 time. They're getting, they're producing spikes 00:33:02.089 --> 00:33:04.970 when you're sleeping, when you're awake, when 00:33:04.970 --> 00:33:07.529 you're taking a nap, when you're moving, when 00:33:07.529 --> 00:33:09.950 you're not moving. They're just always are producing 00:33:09.950 --> 00:33:13.529 spikes. They increase their activity or decrease 00:33:13.529 --> 00:33:16.130 their activity when you're doing something, but 00:33:16.130 --> 00:33:19.589 otherwise they're just producing 50 spikes a 00:33:19.589 --> 00:33:23.210 second or so. And so it's really incredible to 00:33:23.210 --> 00:33:26.539 have a neurons in the brain that are producing 00:33:26.539 --> 00:33:28.099 all these spikes, even when you're not doing 00:33:28.099 --> 00:33:29.400 anything. And it's really interesting to ask, 00:33:29.559 --> 00:33:33.839 why are we spending all this energy? What's the 00:33:33.839 --> 00:33:37.400 purpose of this? And I don't know the answer, 00:33:38.119 --> 00:33:41.619 but it's one of the puzzles. Nevertheless, damage 00:33:41.619 --> 00:33:44.740 to the cerebellum often involves the Purkinje 00:33:44.740 --> 00:33:48.880 cells, which are the output neurons of the cerebellar 00:33:48.880 --> 00:33:53.299 cortex. So without those neurons, whatever computation 00:33:53.299 --> 00:33:56.720 is taking place in the cerebellum, it is defective. 00:33:57.259 --> 00:34:00.779 It is not able to produce what it would otherwise 00:34:00.779 --> 00:34:05.599 do if the majority of the Purkinje cells were 00:34:05.599 --> 00:34:10.380 there. I think two questions that came to mind 00:34:10.380 --> 00:34:14.000 is, Purkinje cells are only in the cerebellar, 00:34:14.000 --> 00:34:18.780 correct? And the amount of GABA that I'm learning 00:34:18.780 --> 00:34:22.769 about now is... Because with autism, there's 00:34:22.769 --> 00:34:27.650 an imbalance. Too much excitation, I think, and 00:34:27.650 --> 00:34:32.250 or too few GABA. So that might have some problems 00:34:32.250 --> 00:34:38.650 with this computational model. So Ryan, the excitation 00:34:38.650 --> 00:34:43.969 inhibition balance is a common, when there's 00:34:43.969 --> 00:34:47.670 something wrong with that, you see there's disorders. 00:34:48.190 --> 00:34:51.929 Whether it be cognitive disorders, or things 00:34:51.929 --> 00:34:56.610 that are associated with autism, it's really 00:34:56.610 --> 00:34:59.269 important for a neuron, it appears now, it is 00:34:59.269 --> 00:35:01.630 really important for it to get as much excitation 00:35:01.630 --> 00:35:05.730 as inhibition on average. So you can't just have 00:35:05.730 --> 00:35:09.090 one kind. That tends to make the neuron die. 00:35:10.610 --> 00:35:15.309 And this EI balance, as it's called, seems to 00:35:15.309 --> 00:35:21.579 be critical for survival of neurons. I want to 00:35:21.579 --> 00:35:25.199 describe to you the anatomy a little bit. So 00:35:25.199 --> 00:35:29.000 I said that the cerebellum receives a copy of 00:35:29.000 --> 00:35:31.539 everything that else is going on in your brain. 00:35:31.699 --> 00:35:35.260 It comes to it via these mossy fibers and then 00:35:35.260 --> 00:35:39.380 it analyzes that and sends something back out 00:35:39.380 --> 00:35:42.019 specific to the region that is performing that 00:35:42.019 --> 00:35:44.559 computation. And the main puzzle is to try to 00:35:44.559 --> 00:35:48.480 understand how does it do it. And what is it 00:35:48.480 --> 00:35:52.940 that is adding to that? Because look, the eventual 00:35:52.940 --> 00:35:57.519 goal is to build a machine that when something 00:35:57.519 --> 00:35:59.820 has died, let's say your Purkinje cells have 00:35:59.820 --> 00:36:02.800 died. Well, we can't bring back the Purkinje 00:36:02.800 --> 00:36:07.500 cells. But what we can do is to record what is 00:36:07.500 --> 00:36:10.719 the input that's coming, what's the normal output 00:36:10.719 --> 00:36:13.980 that should have been produced. I mean, that's 00:36:13.980 --> 00:36:15.860 what the research is about, right? Understand 00:36:15.860 --> 00:36:19.320 how it works in a healthy cerebellum and then 00:36:19.320 --> 00:36:21.960 build a machine that eventually will try to do 00:36:21.960 --> 00:36:30.460 something like that when there is damage. Is 00:36:30.460 --> 00:36:34.380 this why whenever I see like your research and 00:36:34.380 --> 00:36:38.219 things, there's learning and memory. Can you 00:36:38.219 --> 00:36:40.980 say a little bit about the memory part? Right, 00:36:41.239 --> 00:36:46.780 so As I mentioned, we think we understand the 00:36:46.780 --> 00:36:49.300 role of who's the teacher and who's the student. 00:36:49.340 --> 00:36:53.519 So we've learned that the inferior olive provides 00:36:53.519 --> 00:36:57.079 the information that is the teacher. And the 00:36:57.079 --> 00:36:59.340 Purkinje cells are the principal cells that are 00:36:59.340 --> 00:37:06.699 the students. And the learning is via this input. 00:37:07.619 --> 00:37:12.079 The memory is partly the synapses that form from 00:37:12.170 --> 00:37:15.230 was called the parallel fibers from those granule 00:37:15.230 --> 00:37:19.809 cells, those incredibly prolific and large number 00:37:19.809 --> 00:37:23.010 of cells in the cerebellum. So the parallel fibers 00:37:23.010 --> 00:37:25.090 that come from the granule cells make synapses 00:37:25.090 --> 00:37:29.289 on the Purkinje cells. And it looks like the 00:37:29.289 --> 00:37:32.150 teacher, the inferior olive, when you make movements, 00:37:32.909 --> 00:37:36.090 potentially any actions that you make, any guess 00:37:36.090 --> 00:37:38.590 that you have about something, when there's an 00:37:38.590 --> 00:37:41.340 error in it, that air is sent back to the Purkinje 00:37:41.340 --> 00:37:45.500 cells, it causes plasticity in the synapses between 00:37:45.500 --> 00:37:48.460 the peril fibers and the Purkinje cells, and 00:37:48.460 --> 00:37:54.219 that becomes the memory that you rely on to perform 00:37:54.219 --> 00:37:59.119 the task better the next time. Okay, this is 00:37:59.119 --> 00:38:01.400 making sense, too, because if you think about 00:38:01.400 --> 00:38:05.920 a little autistic child or any child, they're 00:38:05.920 --> 00:38:08.400 going through this process in learning something. 00:38:09.179 --> 00:38:13.099 maybe they catch it they catch on and then they 00:38:13.099 --> 00:38:17.039 can build repetitions and really store that ability 00:38:17.039 --> 00:38:23.260 or maybe they don't so like with those eye tracking 00:38:23.260 --> 00:38:27.099 videos that you show or the hand movement can 00:38:27.099 --> 00:38:29.860 you say a little bit about um how the living 00:38:29.860 --> 00:38:33.420 organism learns to correct that the air correction 00:38:33.420 --> 00:38:38.039 yeah yeah so one of the So actually, this is 00:38:38.039 --> 00:38:40.559 one of the main problems with treating cerebellar 00:38:40.559 --> 00:38:46.039 disease. Look, if you have a stroke, rehab helps. 00:38:47.099 --> 00:38:50.860 Because why? Rehabilitation is a process by which 00:38:50.860 --> 00:38:54.599 one is trying to teach the remaining parts of 00:38:54.599 --> 00:38:58.780 the brain how to do the task. But in cerebellar 00:38:58.780 --> 00:39:01.980 disease, the thing that's going to learn itself 00:39:01.980 --> 00:39:06.550 has been damaged. And so one of the really hard 00:39:06.550 --> 00:39:08.849 things about cerebellar disease is that there 00:39:08.849 --> 00:39:14.829 not only are no effective, really pharmaceutical 00:39:14.829 --> 00:39:18.250 ways to affect cerebellar disease, even rehab 00:39:18.250 --> 00:39:21.889 is difficult to use because the students, which 00:39:21.889 --> 00:39:24.550 are the Purkinje cells, if they have been damaged, 00:39:24.809 --> 00:39:30.150 well who's going to learn? And some of the new 00:39:30.150 --> 00:39:32.840 research would... What one is trying to do is 00:39:32.840 --> 00:39:34.860 to try to figure out how to how does one get 00:39:34.860 --> 00:39:37.679 the rest of the brain? That's healthy Like the 00:39:37.679 --> 00:39:40.059 basal ganglia. How does one get that part of 00:39:40.059 --> 00:39:42.519 the brain to try to compensate for you know, 00:39:42.519 --> 00:39:48.280 the part that has been damaged Okay kind of kind 00:39:48.280 --> 00:39:52.800 of rescue or The basal ganglia will maybe act 00:39:52.800 --> 00:39:57.280 as a supplementing that yeah. Yeah. Yeah exactly. 00:39:57.320 --> 00:40:00.440 So, you know The rules of learning for basal 00:40:00.440 --> 00:40:03.760 ganglia are different than the cerebellum, and 00:40:03.760 --> 00:40:07.579 so some of the ideas are to make the errors in 00:40:07.579 --> 00:40:10.599 such a way, it's called reinforcement learning, 00:40:11.860 --> 00:40:15.260 that engages the remaining neural structures 00:40:15.260 --> 00:40:20.039 and tries to take out the part that isn't working, 00:40:20.119 --> 00:40:22.260 the cerebellum, and try to focus the learning 00:40:22.260 --> 00:40:24.619 on the part that is working, in this case the 00:40:24.619 --> 00:40:29.809 basal ganglia. And this is a little bit different 00:40:29.809 --> 00:40:32.349 role for the basal ganglia, or is it something 00:40:32.349 --> 00:40:36.809 that's normal? No, this is normal. But for some 00:40:36.809 --> 00:40:41.289 reason, that normal function isn't good enough 00:40:41.289 --> 00:40:45.070 to help recover some of the functions that are 00:40:45.070 --> 00:40:48.070 lost from the cerebellum. And the idea is, and 00:40:48.070 --> 00:40:50.610 this is theory with just a few experiments that 00:40:50.610 --> 00:40:54.440 have... gone after it. This is Amanda Theron's 00:40:54.440 --> 00:40:57.679 work and my colleague Amy Bastian have worked 00:40:57.679 --> 00:41:01.260 in this area to try to say can we skew the error 00:41:01.260 --> 00:41:04.659 so that it becomes more the morsel of food for 00:41:04.659 --> 00:41:07.260 the basal ganglia rather than for the cerebellum 00:41:07.260 --> 00:41:10.480 so that you rely on the structures that are working 00:41:10.480 --> 00:41:13.239 well to try to compensate. This is what rehab 00:41:13.239 --> 00:41:18.639 is trying to do. Is there any consideration that 00:41:18.639 --> 00:41:23.679 there are many more Nuclei going on within the 00:41:23.679 --> 00:41:28.340 basal ganglia with those five cortical regions? 00:41:28.940 --> 00:41:31.380 Or is that not right? Is the cerebellum that 00:41:31.380 --> 00:41:35.739 complex as well? Oh, yeah. In some ways, the 00:41:35.739 --> 00:41:40.400 basal ganglia complexity is interesting. In some 00:41:40.400 --> 00:41:42.300 ways, they're similar. So both basal ganglia 00:41:42.300 --> 00:41:44.380 and the cerebellum have neurons that largely 00:41:44.380 --> 00:41:48.619 rely on GABA, inhibitory neurons. And both of 00:41:48.619 --> 00:41:51.400 the structures have neurons that tend to be active 00:41:51.480 --> 00:41:54.039 no matter what. They're spending their energy. 00:41:55.559 --> 00:42:00.579 But they seem to compute different kinds of things, 00:42:00.599 --> 00:42:03.659 I would say. I mean, we talked a little bit about 00:42:03.659 --> 00:42:07.920 how you direct your gaze to areas that you find 00:42:07.920 --> 00:42:12.019 rewarding. So when you open a web page, if there's 00:42:12.019 --> 00:42:14.360 a picture of a face, you're more than likely 00:42:14.360 --> 00:42:16.679 going to look at it, rather than something else, 00:42:16.739 --> 00:42:20.000 a mountain or something. that probably has something 00:42:20.000 --> 00:42:24.980 to do with this value function that your basal 00:42:24.980 --> 00:42:28.179 ganglia and maybe the frontal eye field impose 00:42:28.179 --> 00:42:30.860 on you. The faces are special, they're particularly 00:42:30.860 --> 00:42:33.579 rewarding. You should look at it. It probably 00:42:33.579 --> 00:42:37.260 has something to do with the basal ganglia. The 00:42:37.260 --> 00:42:39.679 cerebellum is more important in helping you make 00:42:39.679 --> 00:42:42.739 that movement correctly, predicting what would 00:42:42.739 --> 00:42:46.599 happen when you get there. And one of the big 00:42:46.599 --> 00:42:51.829 puzzles is Because cerebellar patients, it isn't 00:42:51.829 --> 00:42:53.289 just that they have movement disorders. They 00:42:53.289 --> 00:42:58.010 also have impulse control effects. They have 00:42:58.010 --> 00:43:01.090 this thing called dysmetria of thought. So the 00:43:01.090 --> 00:43:03.469 planning seems to be something wrong with what's 00:43:03.469 --> 00:43:07.010 happening. And I think that we just happen to 00:43:07.010 --> 00:43:09.050 see the movement disorder because it's sort of 00:43:09.050 --> 00:43:11.789 like the obvious thing that a neurologist would 00:43:11.789 --> 00:43:15.309 examine. It's much harder to examine planning. 00:43:16.460 --> 00:43:19.519 But they do have these disorders as well. So 00:43:19.519 --> 00:43:23.139 the cerebellum is involved in so much of our 00:43:23.139 --> 00:43:27.219 normal behavior far outside of just making movements. 00:43:29.179 --> 00:43:32.000 I love the idea of we use internal calculators. 00:43:32.159 --> 00:43:35.159 I call them internal calculators. Biological 00:43:35.159 --> 00:43:39.320 calculators could work as well. But whenever 00:43:39.320 --> 00:43:42.460 you're talking about that value is, I think, 00:43:43.099 --> 00:43:46.530 reminded me of that. You know, I can show you 00:43:46.530 --> 00:43:49.369 an example of an internal calculator. Yeah, I 00:43:49.369 --> 00:43:51.050 would love that. I love internal calculators. 00:43:51.170 --> 00:43:53.170 I don't know if you can see this. Let me show 00:43:53.170 --> 00:43:54.530 you a video. Let me show you a video so you don't 00:43:54.530 --> 00:43:56.730 have to look at me. So I think a video would 00:43:56.730 --> 00:44:01.190 be even better. All right. So let me share my 00:44:01.190 --> 00:44:06.130 screen again. I love the idea of these internal 00:44:06.130 --> 00:44:08.389 calculators because our brain is a prediction 00:44:08.389 --> 00:44:12.539 machine. It's the number one thing. Exactly, 00:44:12.760 --> 00:44:14.559 exactly as you said. Okay, so here's an internal 00:44:14.559 --> 00:44:17.500 calculator. Alright, so here's a simple experiment. 00:44:18.119 --> 00:44:20.659 So here's this young man, he's holding a book 00:44:20.659 --> 00:44:31.260 in his hand, and look what happens here. Okay, 00:44:31.619 --> 00:44:36.019 so the idea is, if somebody picks the book off 00:44:36.019 --> 00:44:38.840 my hand, I can't help but my arm is going to 00:44:38.840 --> 00:44:41.320 move up. And why is that? Well, because there's 00:44:41.320 --> 00:44:44.639 delay in the sensory system. I can't react fast 00:44:44.639 --> 00:44:48.079 enough to what's happening. But if me myself 00:44:48.079 --> 00:44:53.159 goes to pick up that book, my hand stays perfectly 00:44:53.159 --> 00:44:58.960 flat. This is because I'm able to predict precisely 00:44:58.960 --> 00:45:03.360 when this is going to happen. And I know by how 00:45:03.360 --> 00:45:05.739 much I should turn off the muscles, in this case 00:45:05.739 --> 00:45:08.300 the biceps, so the arm doesn't just, you know, 00:45:08.420 --> 00:45:13.380 lift up. as the book is moved up. Okay, so you 00:45:13.380 --> 00:45:17.460 see that's the basic idea of this internal calculator 00:45:17.460 --> 00:45:20.420 that is working all the time and we don't even 00:45:20.420 --> 00:45:22.679 think about it, right? We have many of them. 00:45:22.940 --> 00:45:26.300 So, the reason why the hand moves up though is 00:45:26.300 --> 00:45:30.000 because there's no way to predict accurately 00:45:30.000 --> 00:45:34.440 how fast and how much effort the other person 00:45:34.440 --> 00:45:39.539 is going to need and the time. to remove that. 00:45:40.119 --> 00:45:43.340 Yeah, exactly. So I make the joke to my students 00:45:43.340 --> 00:45:46.260 that if there's one lesson that I have is that 00:45:46.260 --> 00:45:49.679 when you go to a fancy party and you know that 00:45:49.679 --> 00:45:52.980 the waiter comes with the drinks, you let the 00:45:52.980 --> 00:45:54.980 waiter pick up the glass and give it to you. 00:45:55.179 --> 00:46:03.260 Yeah, because there's accidents. That's so fascinating. 00:46:04.849 --> 00:46:08.030 We have so many internal calculators. It's just 00:46:08.030 --> 00:46:11.230 constantly going yeah, you know and these are 00:46:11.230 --> 00:46:14.570 these internal calculators are underneath our 00:46:14.570 --> 00:46:19.650 consciousness and when they stop working they 00:46:19.650 --> 00:46:22.650 really become a Difficult thing to live with 00:46:22.650 --> 00:46:25.389 right because it they really change the way we 00:46:25.389 --> 00:46:27.409 are because we now have to pay attention to so 00:46:27.409 --> 00:46:29.010 much that we didn't used to have to pay attention 00:46:29.010 --> 00:46:34.619 Yeah, okay One of the more significant internal 00:46:34.619 --> 00:46:37.380 calculators, I think, comes from the dorsal anterior 00:46:37.380 --> 00:46:40.519 c -like cortex, which sends a signal down to 00:46:40.519 --> 00:46:44.860 the dorsal striatum. And I think that helps orchestrate 00:46:44.860 --> 00:46:49.000 motor movements and activity of the living organism 00:46:49.000 --> 00:46:54.219 quite well. And that reminds me, I want to ask, 00:46:54.239 --> 00:46:57.099 because that's more of a go -directed type of 00:46:57.099 --> 00:46:59.179 movement. And I know you've done research on 00:46:59.179 --> 00:47:02.440 go -directed. Are the inputs and the signals 00:47:02.440 --> 00:47:05.940 going through the cerebellum for a goal -directed 00:47:05.940 --> 00:47:09.340 activity different than a habit? Yeah, that's 00:47:09.340 --> 00:47:14.139 such a good question. Let me describe it to you 00:47:14.139 --> 00:47:20.539 in this way. We work with monkeys. Like any animal 00:47:20.539 --> 00:47:22.980 trainer, you train them to work for food. So 00:47:22.980 --> 00:47:25.480 you get them to do your task and then you give 00:47:25.480 --> 00:47:28.659 them food. And that's the business component 00:47:28.659 --> 00:47:31.769 of this relationship. But they make movements 00:47:31.769 --> 00:47:33.989 otherwise as well. So it's not like they only 00:47:33.989 --> 00:47:36.150 make movements because there's food. They also 00:47:36.150 --> 00:47:39.030 make movements because they want to. And it's 00:47:39.030 --> 00:47:41.869 interesting to compare when they're making a 00:47:41.869 --> 00:47:44.309 movement for us, for the purpose of getting food, 00:47:44.630 --> 00:47:46.110 versus when they're making just movement because 00:47:46.110 --> 00:47:48.489 they're interested in exploring their environment. 00:47:49.190 --> 00:47:55.610 And what you see is that the cerebellum is much 00:47:55.610 --> 00:47:59.269 more involved when the movement is made... because 00:47:59.269 --> 00:48:02.010 there is something rewarding, something, you 00:48:02.010 --> 00:48:04.409 know, there's a purpose for the, in this case, 00:48:04.750 --> 00:48:07.150 to get food. It's similar movement when they 00:48:07.150 --> 00:48:08.750 make, and it's just because they do it because 00:48:08.750 --> 00:48:11.469 they want to explore their environment, that 00:48:11.469 --> 00:48:13.210 the things that we see in the cerebellum are 00:48:13.210 --> 00:48:16.869 not the same. They're much less involved in control 00:48:16.869 --> 00:48:19.449 of that movement. So it's as if if you need to 00:48:19.449 --> 00:48:23.469 make something, do something well, you engage 00:48:23.469 --> 00:48:26.789 the cerebellum much more than just any movement 00:48:26.789 --> 00:48:32.440 that doesn't matter that much. that probably 00:48:32.440 --> 00:48:37.880 has some evolutionary considerations there about 00:48:37.880 --> 00:48:42.340 movement for reward and how we work so hard to 00:48:42.340 --> 00:48:46.679 sustain our species and we seek out and we navigate 00:48:46.679 --> 00:48:51.739 for like those primitive aspects like food, shelter, 00:48:51.960 --> 00:48:55.199 water, security, mating, all of these underlying 00:48:55.199 --> 00:49:02.440 reward things that humans and other species have 00:49:02.440 --> 00:49:07.840 kind of built this reward pathway from. Now, 00:49:07.840 --> 00:49:11.960 today, we have a lot more access to so -called 00:49:11.960 --> 00:49:17.679 rewards. And a bad part about that is, as we 00:49:17.679 --> 00:49:22.019 were talking about, the rewards have more value 00:49:22.019 --> 00:49:25.340 if you put effort in first, effort then reward. 00:49:25.659 --> 00:49:30.159 And that's how these circuits were made. But 00:49:30.159 --> 00:49:33.119 now we don't have to do the effort for the reward. 00:49:33.400 --> 00:49:36.260 It's like with the technology and all of these 00:49:36.260 --> 00:49:39.000 other things that are just probably not well 00:49:39.000 --> 00:49:46.260 for us. Yeah, so the relationship between reward 00:49:46.260 --> 00:49:50.280 and effort is really fascinating. As I mentioned 00:49:50.280 --> 00:49:53.340 to you, you can think about certain movements. 00:49:53.559 --> 00:49:56.989 I mean, you can think about a frog that needs 00:49:56.989 --> 00:49:59.989 to stick its tongue out in order to catch a fly, 00:50:01.469 --> 00:50:06.090 you've got to get one try and it better be on 00:50:06.090 --> 00:50:13.110 target. I think that a structure like the cerebellum 00:50:13.110 --> 00:50:17.730 is particularly well suited for those attempts 00:50:17.730 --> 00:50:23.280 that matter because we see that those movements 00:50:23.280 --> 00:50:25.619 that are associated with reward, where the goal 00:50:25.619 --> 00:50:27.920 means something important, where you have to 00:50:27.920 --> 00:50:33.519 be accurate, that's when the Cerebellum is really 00:50:33.519 --> 00:50:37.280 active. I wanted to tell you, Ryan, about one 00:50:37.280 --> 00:50:39.860 of the most surprising things that we've learned 00:50:39.860 --> 00:50:43.960 about the Cerebellum. And it goes something like 00:50:43.960 --> 00:50:46.960 this. So, you know, you think that neurons in 00:50:46.960 --> 00:50:49.800 your brain are active, because you're doing something. 00:50:50.099 --> 00:50:52.139 So say that I'm moving my arm and I see these 00:50:52.139 --> 00:50:54.719 neurons active, and I think that, oh, these neurons 00:50:54.719 --> 00:50:57.199 must have something to do with moving the arm. 00:50:57.960 --> 00:51:00.820 That seems natural. This has been like the basic 00:51:00.820 --> 00:51:04.000 foundation of so much of neuroscience to relate 00:51:04.000 --> 00:51:06.940 how neurons relate to behavior. But one of the 00:51:06.940 --> 00:51:08.860 things we found in the cerebellum that was really 00:51:08.860 --> 00:51:12.579 surprising is that, first of all, the neurons 00:51:12.579 --> 00:51:16.250 are active not just all the time, but It doesn't 00:51:16.250 --> 00:51:19.170 matter whether you move your arm up, down, left, 00:51:19.210 --> 00:51:22.190 right. As long as you're moving your arm, these 00:51:22.190 --> 00:51:24.630 neurons are active. So that was really puzzling. 00:51:25.409 --> 00:51:28.409 And then what we found was that much of this 00:51:28.409 --> 00:51:34.010 activity wasn't because to move the limb in the 00:51:34.010 --> 00:51:37.670 way you were moving it, but to cancel the activity 00:51:37.670 --> 00:51:40.809 that other neurons were producing that would 00:51:40.809 --> 00:51:43.570 otherwise harm the movement that you were making. 00:51:44.250 --> 00:51:49.699 So it's as if you have a population that's active, 00:51:50.280 --> 00:51:54.699 half of them are active to cancel the effects 00:51:54.699 --> 00:51:58.219 of each other so that they don't inject noise 00:51:58.219 --> 00:52:01.300 in the behavior that you're trying to produce. 00:52:02.099 --> 00:52:05.699 So if that's true, even if that theory is right, 00:52:06.659 --> 00:52:09.400 that says that, you know, when damage occurs 00:52:09.400 --> 00:52:13.679 and some of these cells die, part of the deficit 00:52:13.679 --> 00:52:17.780 is because the parts that are active and should 00:52:17.780 --> 00:52:21.239 in fact be suppressed are not being suppressed. 00:52:21.860 --> 00:52:24.159 Because the ones that would have suppressed them 00:52:24.159 --> 00:52:33.260 aren't there. So, head -eye coordination, or 00:52:33.260 --> 00:52:35.840 yeah, hand -eye coordination I'm in, it seems 00:52:35.840 --> 00:52:38.340 like this is involved, and precise fine motor 00:52:38.340 --> 00:52:43.139 movements. I can't get my head around How much 00:52:43.139 --> 00:52:47.360 the cerebellum is involved here and then things 00:52:47.360 --> 00:52:50.059 like the substantia nigra and the red nucleus? 00:52:52.519 --> 00:52:57.820 Okay, so let me describe the relationship. Substantia 00:52:57.820 --> 00:53:01.920 nigra has two parts, the reticulata and the compacta. 00:53:02.139 --> 00:53:05.380 Compacta has the dopamine cells. The reticulata 00:53:05.380 --> 00:53:08.019 is the output structure in the substantia. These 00:53:08.019 --> 00:53:11.480 are basal ganglia structures. I can tell you 00:53:11.480 --> 00:53:14.739 about both of these. So, Substantial Niagara 00:53:14.739 --> 00:53:17.480 reticulata is an output structure of the basal 00:53:17.480 --> 00:53:20.199 ganglia. And let's say we want to make an eye 00:53:20.199 --> 00:53:23.119 movement. It projects onto the superior colliculus. 00:53:23.199 --> 00:53:25.400 It inhibits the superior colliculus. Basically, 00:53:25.699 --> 00:53:29.860 it says, don't move. And when it releases this 00:53:29.860 --> 00:53:35.300 inhibition, then you are biased toward moving 00:53:35.300 --> 00:53:39.780 toward certain region. And that release of inhibition 00:53:39.900 --> 00:53:43.679 coincides with excitatory input that comes from 00:53:43.679 --> 00:53:47.360 the cerebral cortex. Release of inhibition coupled 00:53:47.360 --> 00:53:49.960 with excitation makes it so that you decide to 00:53:49.960 --> 00:53:52.699 make this movement. You have to release inhibition 00:53:52.699 --> 00:53:55.440 and you have to produce excitation so that now 00:53:55.440 --> 00:53:58.800 you make a movement. So you can now see that 00:53:58.800 --> 00:54:00.639 the basal ganglia would have something to do 00:54:00.639 --> 00:54:04.119 with reward because it describes how you would 00:54:04.119 --> 00:54:06.380 make movements toward things that you value. 00:54:06.670 --> 00:54:08.909 You would move toward things that you value and 00:54:08.909 --> 00:54:13.829 not care about the ones that you don't. The relationship 00:54:13.829 --> 00:54:17.710 between this and the cerebellum is that the basal 00:54:17.710 --> 00:54:21.789 ganglia has this value information. And if you 00:54:21.789 --> 00:54:25.090 now look at the cerebellum, you find that that 00:54:25.090 --> 00:54:28.690 value information makes the cerebellum work better. 00:54:29.010 --> 00:54:32.010 Meaning that, remember that cancellation I was 00:54:32.010 --> 00:54:36.510 telling you about. The cerebellum is made aware 00:54:36.510 --> 00:54:40.670 of the value of this action that you're about 00:54:40.670 --> 00:54:45.150 to make and that coordination of the neurons 00:54:45.150 --> 00:54:47.329 in the cerebellum to produce the output that 00:54:47.329 --> 00:54:51.809 they do is much better balanced so that it produces 00:54:51.809 --> 00:54:55.309 an output associated with just the action you're 00:54:55.309 --> 00:54:57.530 making and cancel the things that would have 00:54:57.530 --> 00:55:01.389 diverted that action away from it. So that's 00:55:01.389 --> 00:55:05.750 relating reward. Substantia nigra reticulata 00:55:05.750 --> 00:55:08.730 of the basal ganglia and control movements in 00:55:08.730 --> 00:55:11.110 cerebellum. Okay, now there's dopamine. Dopamine 00:55:11.110 --> 00:55:15.829 comes from SNC, Substantia nigra compacta. Dopamine 00:55:15.829 --> 00:55:18.130 is a neurotransmitter that affects so much of 00:55:18.130 --> 00:55:23.929 our behavior. And it turns out that an output 00:55:23.929 --> 00:55:29.889 from the cerebellum projects directly to SNC 00:55:29.889 --> 00:55:34.070 dopamine neurons. So the cerebellum is providing 00:55:34.070 --> 00:55:38.409 an input that's relevant to control of dopamine 00:55:38.409 --> 00:55:45.070 in SNC. This was a new discovery. Cameron Kodachow, 00:55:45.190 --> 00:55:48.829 he's a professor at Albert Einstein University 00:55:48.829 --> 00:55:52.570 in New York, he discovered this pathway and demonstrated 00:55:52.570 --> 00:55:55.269 that it's important for control of behavior in 00:55:55.269 --> 00:56:01.610 mice. cerebellar to the compacta probably up 00:56:01.610 --> 00:56:05.929 to the dorsal striatum and then it's orchestrating 00:56:05.929 --> 00:56:09.449 next movements subsequent movements yeah i i 00:56:09.449 --> 00:56:12.929 really think that you know if there is a structure 00:56:12.929 --> 00:56:15.829 in the brain that's doing something important 00:56:15.829 --> 00:56:18.789 the cerebellum more than likely is contributing 00:56:18.789 --> 00:56:27.800 to it okay recently Then the reason why I contacted 00:56:27.800 --> 00:56:31.559 you was the Purkinje cells with the tongue movements. 00:56:31.559 --> 00:56:34.280 Can you say a little bit about that? Yeah, sure 00:56:34.280 --> 00:56:38.219 sure. So, you know control of speech and vocalization 00:56:38.219 --> 00:56:41.699 is so hard to study because the tongue is inside 00:56:41.699 --> 00:56:44.159 a mouth that you can't measure it so easily, 00:56:44.300 --> 00:56:48.079 right? How do you do that? But yet if you see 00:56:48.079 --> 00:56:49.940 a cerebellar patient, one of the first things 00:56:49.940 --> 00:56:52.619 you notice is that it's hard for them to talk. 00:56:53.159 --> 00:56:55.380 They sound like as if they have marbles in their 00:56:55.380 --> 00:57:00.079 mouth. It's really hard to move the tongue properly. 00:57:01.000 --> 00:57:03.159 And it's really been hard to study the control 00:57:03.159 --> 00:57:08.659 of the tongue. How does that happen? And so marmosets 00:57:08.659 --> 00:57:12.860 are like next to giraffes, they are the tongue 00:57:12.860 --> 00:57:17.519 animals, in my opinion. They have a fabulous 00:57:17.519 --> 00:57:20.679 tongue. They have this long tongue that they 00:57:20.679 --> 00:57:24.760 use in the wild to... insert inside the tree 00:57:24.760 --> 00:57:29.219 little holes and get sap out. And they're really 00:57:29.219 --> 00:57:31.539 dexterous with their tongue, and they control 00:57:31.539 --> 00:57:33.099 it in this beautiful way. And as I mentioned 00:57:33.099 --> 00:57:35.599 to you, they're also very vocal animals, so they 00:57:35.599 --> 00:57:38.440 can make sounds, and they use it for communication 00:57:38.440 --> 00:57:40.880 between them. So, okay, they make a good model 00:57:40.880 --> 00:57:45.139 to study control of the tongue. All right, so 00:57:45.139 --> 00:57:48.860 we wanted to know, all right, how do they do 00:57:48.860 --> 00:57:51.119 it? And what does the cerebellum have to do with 00:57:51.119 --> 00:57:57.219 it? So we set up this task that made the marmosets 00:57:57.219 --> 00:58:01.480 use their tongue to go laterally to food tubes 00:58:01.480 --> 00:58:04.579 that were sitting 90 degrees with their mouth. 00:58:04.760 --> 00:58:07.880 So they had to stretch their tongue out, put 00:58:07.880 --> 00:58:10.980 it inside the tubes to get this slurry of food 00:58:10.980 --> 00:58:13.960 out. And okay, so they learned to do it, and 00:58:13.960 --> 00:58:15.860 it was no problem. It was like, okay, we know 00:58:15.860 --> 00:58:18.440 how to do this. The animals were so good at it. 00:58:18.650 --> 00:58:21.550 And while they were doing that, we were trying 00:58:21.550 --> 00:58:23.110 to understand what the cerebellum is doing to 00:58:23.110 --> 00:58:28.250 control these movements. And what we found was 00:58:28.250 --> 00:58:31.889 that those Purkinje cells, they had a lot to 00:58:31.889 --> 00:58:36.269 do with stopping the tongue at the right place 00:58:36.269 --> 00:58:39.469 when the tongue went out so that it wouldn't 00:58:39.469 --> 00:58:43.230 miss the tube, so that it would stop where the 00:58:43.230 --> 00:58:45.429 tube was located. So just like what we had seen 00:58:45.429 --> 00:58:48.179 with control of the eye. We saw that for control 00:58:48.179 --> 00:58:50.780 of the tongue, there was something similar taking 00:58:50.780 --> 00:58:54.900 place in learning to predict, you know, when 00:58:54.900 --> 00:58:58.099 you're about to reach your target, stop the movement 00:58:58.099 --> 00:59:04.460 now. That's good. That's a fascinating finding. 00:59:05.739 --> 00:59:09.300 The deceleration of the tongue. Yeah, the deceleration 00:59:09.300 --> 00:59:12.360 of the movement and stopping it on target. And, 00:59:12.519 --> 00:59:14.199 you know, this is related to sensory feedback. 00:59:14.260 --> 00:59:16.219 Let me tell you why. Because, you know, the movement 00:59:16.219 --> 00:59:20.000 is taking place quickly. The sensory feedback 00:59:20.000 --> 00:59:22.940 is slow. You know, basically, our sensors are 00:59:22.940 --> 00:59:26.039 slow things. They detect things and transmit 00:59:26.039 --> 00:59:28.300 their information more or less at the speed of 00:59:28.300 --> 00:59:31.619 sound. So, so much of our accuracy depends on 00:59:31.619 --> 00:59:34.559 not the feedback that we get, but predicting 00:59:34.559 --> 00:59:39.059 what the feedback should be. And the Cerebellum 00:59:39.059 --> 00:59:41.119 seems to have a lot to do with that, predicting 00:59:41.119 --> 00:59:45.219 it. and helping you generate commands that make 00:59:45.219 --> 00:59:49.420 your movements accurate. Makes sense. Yeah, this 00:59:49.420 --> 00:59:53.880 is also good. Is there anything else about the 00:59:53.880 --> 00:59:56.639 cerebellum that you find important that I haven't 00:59:56.639 --> 01:00:03.679 asked you about? Yeah, you asked such wonderful 01:00:03.679 --> 01:00:06.000 questions. I'm so grateful that we had a chance 01:00:06.000 --> 01:00:11.250 to talk. I think that... There just isn't that 01:00:11.250 --> 01:00:15.369 much interest in the cerebellum, because I think 01:00:15.369 --> 01:00:21.750 that it's like a hard puzzle to figure out, and 01:00:21.750 --> 01:00:25.789 that the mechanisms of how it functions and so 01:00:25.789 --> 01:00:29.710 forth, we haven't made that much progress. But 01:00:29.710 --> 01:00:34.610 yet, there are people that have suffered from 01:00:34.610 --> 01:00:36.789 cerebellar disease, and maybe it has a lot to 01:00:36.789 --> 01:00:39.230 do with autism as well, because as you know, 01:00:40.580 --> 01:00:43.039 Anatomical studies show that people, when they 01:00:43.039 --> 01:00:46.679 die, they've had autism during their life. The 01:00:46.679 --> 01:00:49.119 cerebellum is probably the most important structure 01:00:49.119 --> 01:00:52.219 that looks different than normal. There's a reduced 01:00:52.219 --> 01:00:58.739 size and the Purkinje cells die. But it's like 01:00:58.739 --> 01:01:02.559 this whole other brain and it has its own language. 01:01:04.159 --> 01:01:07.728 And, you know, being a neuroscientist is like... 01:01:07.719 --> 01:01:11.880 getting signals from a foreign, you know, from 01:01:11.880 --> 01:01:13.340 a different planet. And you're trying to understand, 01:01:13.440 --> 01:01:16.420 what are they trying to tell me? You know, I'm 01:01:16.420 --> 01:01:18.280 trying to decipher this language that I don't 01:01:18.280 --> 01:01:22.280 understand. And so much of our work and the people 01:01:22.280 --> 01:01:24.119 in my community is about trying to understand 01:01:24.119 --> 01:01:26.539 the language of the cerebellum, which is different 01:01:26.539 --> 01:01:30.739 than the language of the cerebral cortex. And 01:01:30.739 --> 01:01:36.440 yeah, and I hope that we'll get better at decoding 01:01:36.909 --> 01:01:39.369 you know, what is the cerebellum trying to tell 01:01:39.369 --> 01:01:43.409 us? And once we understand it, you know, building 01:01:43.409 --> 01:01:47.010 therapies and machines that can replace the things 01:01:47.010 --> 01:01:50.210 that have been lost. Yeah, that's well said, 01:01:50.389 --> 01:01:52.750 because the cerebellum is definitely underrated. 01:01:53.789 --> 01:01:59.909 It's super valuable. But last question, what 01:01:59.909 --> 01:02:01.929 is something recently that you're most excited 01:02:01.929 --> 01:02:07.119 about? Yeah, you know, I think that Down the 01:02:07.119 --> 01:02:11.199 road, the goal is to build a machine that, when 01:02:11.199 --> 01:02:13.480 there is damage to the cerebellum, it can do 01:02:13.480 --> 01:02:15.639 something about it. You know, that you can implant 01:02:15.639 --> 01:02:19.360 a chip that would say, I'm gonna listen to the 01:02:19.360 --> 01:02:22.280 inputs that are coming, and I'm gonna tell you 01:02:22.280 --> 01:02:25.139 what the output should be, even though you don't 01:02:25.139 --> 01:02:27.320 have the Purkinje cells to produce it. And I 01:02:27.320 --> 01:02:31.179 mean, that's the billion -dollar dream of not 01:02:31.179 --> 01:02:35.099 just understand how something works, but replace 01:02:35.099 --> 01:02:45.579 it. with some devices that will repair the transformations 01:02:45.579 --> 01:02:49.260 that would have taken place and provide the signals 01:02:49.260 --> 01:02:52.300 that would have been there if the thing was working 01:02:52.300 --> 01:02:57.719 well. And I genuinely think that, perhaps not 01:02:57.719 --> 01:02:59.960 in my lifetime, but in my students' lifetime, 01:02:59.960 --> 01:03:03.019 in your lifetime, Brian, these things are coming 01:03:03.019 --> 01:03:06.679 as we better understand how the system works, 01:03:08.059 --> 01:03:10.480 we'll be able to someday build these circuits 01:03:10.480 --> 01:03:14.739 that can, you know, be implanted and make it 01:03:14.739 --> 01:03:19.480 so that the damaged system can be partially repaired. 01:03:20.579 --> 01:03:22.940 Yeah, and your works you want to provide the 01:03:22.940 --> 01:03:26.219 instruction manual. I hope so. Yeah, I think 01:03:26.219 --> 01:03:30.739 so. Yeah, I can't thank you enough. This is one 01:03:30.739 --> 01:03:32.980 of the most fascinating conversations I've ever 01:03:32.980 --> 01:03:36.599 had in my life. You're very kind of you, Ryan. 01:03:37.559 --> 01:03:39.800 Thanks for the invitation. Yeah, thank you for 01:03:39.800 --> 01:03:40.119 joining.