 Today I have the job of explaining an entire section of Kandel, about five chapters to you on the motor system. I'll talk really fast. And clearly, well, it's mashed already. Mason has done an excellent job of putting my draft lectures up on the website. He is going to have some differences from the most recent draft. I have a special guest appearance by Jonathan demonstrating the stretch reflex. You're used to my procedure of starting with molecules and going to higher systems. But Ralph and I have been mixing it up this year, beginning with higher order events and going down to reductionist events. So we're going to try that for the motor system, too. We're going to talk about higher motor functions, then about motor cortex, about the basal ganglia, so still in the brain, then the corticospinal tract, which goes from the brain to the spinal cord, then motor neurons in the spinal cord, and then reflexes and the properties of muscles. From top to bottom, top-down approach, this keeps me interested and therefore it's a nice challenge. Now, we already have some clues to organization of the brain from lesions and from damage. But a more recent clue to the organization of the brain comes from patients with intractable epilepsy, who are not very well controlled by drugs. In this case, people implant some rather simple arrays of electrodes into the brain, in this case in the motor cortex. And this helps to localize an epileptic focus. We haven't discussed epilepsy here. You know that epilepsy is a seizure disorder characterized by more than one seizure, by recurrent seizures, and you really do want to find out where the seizure originates. And so people put electrodes into the brain for the purpose of recording those seizures. But in the process, it is legal and ethical to stimulate with those electrodes. And one sees a large range of either motor events. For instance, with 16 electrodes, you can actually 32 electrodes. I guess if you stimulate between A1 and B1, you get a motion of the right foot. And clearly there are some additional motions of the foot with nearby stimulations. Then there are motions of the trunk and of the hip. And then in some places, as we move along, there's not actually a motion, but the person reports an urge to move. And so this gives us an indication that we have in the cortex both higher order phenomena, the idea that we're going to move, and also more motor associated phenomena. And there appears to be a map of the body on the motor cortex. I think I have maintained that slide, at least I hope so, because it's really quite pretty. If not, there are elements in Candel of the map, the so-called homunculus. To give you a summary of where we are in understanding motor systems in 2015, here is work from Richard Anderson's lab right here at Caltech. You can read a little more about his and other people's attempts to interact with the brain directly in one of the boxes in Candel. As you remember from Ralph's lectures, the motor cortex is in the frontal lobe. It's everything forward of the main sulcus. And here in the parietal lobe is some more abstract ideas. So in the process of vision to motor transformations. And so if we go to work from Richard's lab from a recent paper that he published, let's go first of all to the patient who has left and right hand on top of your head. Left hand to mouth, left hand to head, right hand to mouth, right hand to head. This is an array of, signals from an array of electrodes. I don't know how many there are, probably 16 or 64. In the patient's cortex, this patient is not an epileptic. He is a quadriplegic. He cannot move any of his limbs due probably to damage in the spinal cord. So the title of the paper is Decoding Motor Imagery from the Pasteur Parietal Cortex of a Tetraplegic Human. So the idea is that you want to understand what the human wants to do by recording the volition in his Pasteur Parietal Cortex, which would get transmitted to the motor cortex, but does not get transmitted to the spinal cord, presumably because of spinal injuries. And you want to allow a robot to do that instead. So here now is the patient being instructed by one of Richard Anderson's postdocs. And one of the electrodes in the patient's cortex, the subject's cortex, is giving signals that are good enough to display on a computer. The computer is recording all the time here. And so it's taking all the data in. And when it gets a signal that exceeds threshold, it displays that signal. And so the patient is being commanded to think about doing various actions. And the array of electrodes is decoding which cells are giving that information. Left hand to belly. Left hand to head. Right hand to forehead. Right hand to head. Left hand to mouth. Left hand to head. Left hand to the back of your head. Left hand to mouth. Left hand to head. Right hand to your chest. Right hand to your eyes. Right hand to your mouth. Right hand to your ear. Right hand to your nose. Right hand to your mouth. Right hand to your head. Left hand to your eyes. Left hand to your mouth. Left hand to your head. So remember that there's an array of electrodes doing this recording. And after the software has learned the patterns, it is possible... Here's the patient who's got an array of electrodes on his head. It's following the target on the screen, and his assignment is... It has actually been possible for patients like this to show data like this. Thank you, Matthew. Thank you, Jonathan. That was about two orders of magnitude better than I have ever done this. This is great. This is terrific. And what causes that? This is hyperthyroid or too much thyroid hormone? Thank you, sir. This was wonderful. Just wonderful. Thanks. Barred this from my wife, the FNP. Okay. Good. So Jonathan has a key element, actually, in the patellar reflex. Is that these rinshaw neurons here are inhibitory neurons. So in order to extend the leg, the body relaxes the flexors. So flexing means toward the body. Extending means away from the body. So in order to get good extension, you relax the flexors. And vice versa, in order to get good flexion, you relax the extensors. Now, when you're in the gym, you always exercise both extensors and flexors, not at the same time, but on different machines or different weights so that they are equally strong and one can nicely oppose the other. So what is actually going on when Jonathan tapped Matthew's tendon? We'll explain that in a minute. But the key element in order to explain what has gone on is that, as Jonathan explained, there are the alpha motor neurons, the final common pathway, are commanded by descending facilitation and inhibition from the corticospinal tract, and also, as Jonathan explained, you can inhibit those motor neurons from above. And so there's a feedback loop synthesized by the alpha motor neuron. For instance, the force required to hold an object is specified crudely, and then the length change in the muscle fiber is fed back and modulates the motor neuron to get exactly the correct amount of force and displacement. And in fact, when Jonathan was hitting Matthew's patella, he was actually stretching the muscle, and the receptors in the muscle were perceiving a stretch. And you could think then that they were sending their response back to the alpha motor neurons, which were readjusting, but in an open loop fashion. So some of the stretch receptors in the muscle are the spindles. Just bulge out a little bit. Very small fibers. Spindles are actually neat because they detect stretch. They are both sensory and motor organisms. So they get commanded by motor neurons to contract. That allows them to set the desired length that the spindles should be at. But the spindles also include sensory fibers, which detect the deformation of the spindle itself. So these spindles are marvelously complicated. They have both motor innovation. They don't get their motor innovation from the alpha motor neurons from the final common pathway. They get their information from smaller motor neurons called the gamma motor neurons. And so the gamma motor neurons set the length of the spindle, which is then sensed by a couple of fiber types. Now back in the old days, when all you had was a stimulating electrode and an oscilloscope, you could stimulate the nerve to a muscle and record the groups of fibers on an oscilloscope near the brain. Some of them were very fast. They would be called group one. And then in group one, and they had the highest, the lowest threshold, so you could stimulate them very nicely. And so the ones that stimulated very nicely and were the fastest were called the 1A and then the 1B, etc. And then there were group two. And people spent lots of time categorizing the velocity and the threshold of these fibers. That's nice, but we have other ways of doing it these days. So there we have the spindle. And you can then excite the spindle fibers in one of two ways. You can excite them by stimulating the gamma motor neurons, which contract the spindle. Or you can excite them by stretching the muscle, as Jonathan did to Matthew. And so this diagram shows that if you supply external strength, you can measure signals, external stretch, you can measure signals from the afferent axons, that is the ones leading to the central nervous system. You can also stimulate the static, the gamma motor neurons. And again, there are a couple of types of gamma motor neurons. And these themselves will stimulate the fibers in the spindle. And so you can basically what the body does is to set the desired length and to use the gamma motor neurons and the spindle afferents as sensors to feed back onto the alpha motor neurons. There's another type of sensory organ in the muscle, the so-called Golgi tendon organs. And even though Jonathan was hitting the Golgi tendon, it was probably the spindles that were being excited. And the tendon organs detect stretch only. They have no motor innervation. They are embedded in collagen fibers, which move ever so slightly when stretched. And there are, again, sensory cells, which detect very small stretches. And these fibers also send their messages back to the spinal cord. So this feedback is quite important, and it allows us to do very fine movements, including under a microscope. So there are some generalizations that we can make about damage to parts of the motor system. And the results of that damage in terms of what the subject sees. We can have damage to the lower motor neuron, the so-called alpha motor neuron. The upper motor neuron, the Betz cell in layer 5 of the motor cortex, or damage to the basal ganglia. Lower motor neuron damage obviously causes paralysis. Upper motor neuron may still allow the lower motor neuron to function, so it causes weakness, or so-called peresis. The basal ganglia do not damage to the basal ganglia, do not themselves cause what you would call paralysis. A good example of the basal ganglion disease is Parkinson's, and we'll show you Parkinson's patient who can move, but has trouble initiating movement. Again, the lower motor neuron causes muscle atrophy, even though damage to lower motor neurons is called amyotrophic lateral sclerosis. There is some atrophy simply because the muscles are not contracting. The upper motor neuron causes diseases do not cause atrophy typically, and basal ganglion diseases do not. Lower motor neuron diseases, based on what you've seen here, you can understand how reflexes would be disturbed, and because the lower motor neuron is in charge of setting the length of the muscle, you can see that the muscle tone would also be disturbed. The causes of hyperreflexia, as Jonathan explained it, too much reflex, hypertonia, too much tone, and spasticity generally arise further up in the upper motor neuron, and we've talked about the two diseases of the basal ganglia that are most common Parkinson's and Huntington's. Huntington's, as you probably know, is hereditary. Where was I that I had heard a very nice lecture on Huntington's? It was in the last week. You know from your molecular biology that Huntington's is a triplet repeat disease. The Huntington gene gets expanded in some patients. We don't understand the pathophysiology, but it selectively destroys cells in the striatum, the so-called medium spiny neurons. Chorea means writhing movements. It comes from the same route as choreography, meaning a little bit of dancing, and also patients move less. Typically motor, and now we talk about where the spinal cord decasates or crosses. Typically in the lower motor neuron, which projects right out to the muscle, there's only ipsilateral damage. Depending on whether the neurons have yet crossed, the upper motor neuron can cause a contralateral deficit if it occurs above the decastation or an ipsilateral deficit if it occurs below the decastation. That is if the axon of the upper motor neuron is damaged. In basal ganglia, the projections all cross, so they are contralateral. Going back to very high level phenomena, here in frontal cortex is a remarkable region of the brain called the anterior cingulate cortex. It is a favorite of both Ralph Adolfs and of John Allman on the faculty here, and lesions cause impairment in the will to act, which is one of the hierarchically highest levels. These patients have what you might call akinetic non-movement mutants. They're not paralyzed and they're conscious, but they respond very poorly to their surroundings. Sort of like a teenager, I guess. But they sometimes respond to very autonomic things, like picking up a phone that rings at their bedside. Again, like a teenager. But then they say nothing. Then after a bout of akinetic autism, they recover and then they explain they were fully conscious, but just lack motivation to do anything and didn't act, respond or act. The other fascinating topic has to do with links between perception and action. We've talked about those links a great deal today. The question is, why can't you tickle yourself? Why does somebody else need to tickle you? The favorite explanation these days is that when a person commands a movement, there are neurons that make predictions and make a so-called efference copy that pretend to be the movements themselves and that it is in ticklishness is in fact a discordance between the predicted sensory feedback, so-called corollary discharge, and the actual sensory feedback. And if there's no discordance between those, then one functions normally. But if there is discordance, because you got a sensation without commanding that sensation, then that's tickling. So that's what people now think about ticklishness or tickliness. And if you want to talk about this more, I'll have office hours on Friday. See you then.