Neurobiology And Anatomy 1

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NEUROSCIENCE LECTURE SUPPLEMENT Nachum Dafny, Ph.D., Professor Department of Neurobiology and Anatomy University of Texas Medical School at Houston

C. Motor System

TABLE OF CONTENTS Page

Overview of the Motor System................................................................................1 Motor Units and Muscle Receptors .......................................................................12 Spinal Reflexes ......................................................................................................23 Cerebellum.............................................................................................................33 Basal Ganglia .........................................................................................................43 Motor Cortex..........................................................................................................53 Integrated Motor System and Disorders of the Motor System ..............................61

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OVERVIEW OF THE MOTOR SYSTEM James Knierim, Ph.D. Much of the brain and nervous system is devoted to the processing of sensory input, in order to construct detailed representations of the external environment. Through vision, audition, somatosensation, and the other senses, we perceive the world and our relationship to it. This elaborate processing would be of limited value, however, unless we had a way to act upon the environment that we are sensing, whether that action consist of running away from a predator; seeking shelter against the rain or wind; searching for food when one is hungry; moving one’s lips and vocal cords in order to communicate with others; or performing the countless other varieties of actions that make up our daily lives. In some cases the relationship between the sensory input and the motor output are simple and direct; for example, touching a hot stove elicits an immediate withdrawal of the hand (Fig. 1). Usually, however, our conscious actions require not only sensory input but a host of other cognitive processes that allow us to choose the most appropriate motor output for the given circumstances. In each case, the final output is a set of commands to certain muscles in the body to exert force against some other object or forces (e.g., gravity). This entire process falls under the category of motor control.

ENVIRONMENT

Senses

Action

Fig. 1. Sensory receptors provide information about the environment, which is then used to produce action to change the environment. Sometimes the pathway from sensation to action is direct, as in a reflex. In most cases, however, cognitive processing occurs to make actions adaptive and appropriate for the particular situation.

Cognition Some Necessary Components of Proper Motor Control (1) Volition. The motor system must generate movements that are adaptive and that accomplish the goals of the organism. These goals are evaluated and set by high-order areas of the brain, including the prefrontal cortex. The motor system must transform these goals and desired movements into the appropriate activations of muscles to perform the desired activity. (2) Coordination of signals to many muscle groups. Few movements are restricted to the activation of a single muscle. Rather, most movements result from the coordinated activity of different muscle groups. The act of moving your hand from inside your pocket to a position in front of you requires the coordinated activity of the shoulder, elbow, and wrist. Making the same movement while removing a 10-lb weight from your pocket may result in the same trajectory of your hand, but will require different sets of forces on the muscles that make the movement. The task of the motor system is to determine the necessary forces and coordination at each joint in order to produce the final, smooth motion of the arm. 1

(3) Proprioception. In order to make a desired movement (e.g., raising your hand to ask a question), it is essential for the motor system to know the starting position of the hand. Raising one’s hand from a resting position on a desk, compared to a resting position on top of the head, results in the same final position of the arm, but these two movements require a very different pattern of muscle activation. The motor system has a set of sensory inputs (called proprioceptors) that inform it of the length of muscles and the forces being applied to them; it uses this information to calculate joint position and other variables necessary to make the appropriate movement. (4) Postural adjustments. In addition to the coordination of muscles necessary to produce the desired output, the motor system must also constantly produce adjustments to the body’s posture in order to compensate for the changes in the body’s center of mass as we move our limbs, head, and torso. Without these automatic adjustments, the simple act of reaching for a cup would cause us to fall forward, as the body’s center of mass shifts to a location in front of the body axis. (5) Sensory feedback. In addition to the use of proprioception to sense the position of the body before a movement, the motor system must use other sensory information in order to perform the movement accurately. By comparing desired activity with actual activity, sensory feedback allows for corrections in movements as they take place, and it also allows modifications to motor programs so that future movements are performed more accurately. (6) Compensation for the physical characteristics of the body and muscles. To exert a defined force on an object, it is not sufficient to know only the characteristics of the object (e.g., its mass, size, etc.). The motor system must also account for the physical characteristics of the body and muscles themselves. The bones and muscles have mass that must be considered when moving a joint, and the muscles themselves have a certain degree of resistance to movement. (7) Unconscious processing. The motor system must perform many procedures in an automatic fashion, without the need for high-order control. Imagine if walking across the room required thinking about planting the foot at each step, paying attention to the movement of each muscle in the leg and making sure that the appropriate forces and contraction speeds are taking place. It would be hard to do anything else but that one task. Yet we can walk, talk, chew gum, button a shirt, and think about how fascinating neuroscience is, all at the same time. A number of motor tasks are performed in an automatic fashion that does not require effortful processing by higher brain areas. Moreover, the motor system must be able to perform a number of tasks of which the organism is completely unaware. For example, many of the postural adjustments that the body makes during movement are performed without our awareness. These unconscious processes allow higher-order brain areas to concern themselves with broad desires and goals, rather than low-level implementations of movements. (8) Adaptability. The motor system must adapt to changing circumstances. For example, as a child grows and its body changes, different constraints are placed on the motor system in terms of the size and mass of bones and muscles. The motor commands that work to

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raise the hand of an infant would fail completely to raise the hand of an adult. The system must adapt over time to change its output to accomplish the same goals. Furthermore, if the system were unable to adapt, we would never be able to acquire motor skills, such as playing a piano, hitting a baseball, or performing microsurgery. These are some of the many components of the motor system that allow us to perform complex movements in a seemingly effortless way. The brain has evolved exceedingly complex and sophisticated mechanisms to perform these tasks, and researchers have only scratched the surface in understanding the principles that underlie the brain’s control of movement. Functional Segregation and Hierarchical Organization The ease with which we make most of our movements belies the enormous sophistication and complexity of the motor system. If you want to get a cup of coffee, you simply stand up, walk to the coffee pot, and pour yourself a cup. Simple, right? Yet very smart engineers have spent decades trying to get machines to perform such simple tasks, and the most advanced robotic systems do not come close to emulating the precision and smoothness of movement, under all types of conditions, that we achieve effortlessly and automatically. How does the brain do it? Although many of the details are not understood, two broad principles appear to be key concepts toward understanding motor control: Functional Segregation. The motor system is divided into a number of different areas that control different aspects of movement. These areas are located throughout the nervous system. One of the key questions of research on motor control is to understand the functional roles played by each area. Hierarchical Organization. The different areas of the motor system are organized in a hierarchical fashion. Lower levels of the hierarchy control the “nuts and bolts” of motor processing, such as calculating the amount of force generated by a single muscle and coordinating simple reflexes. Higher levels of the hierarchy calculate the trajectories of whole limb movements and sequences of movements, and they evaluate the appropriateness of a particular action given the current environmental context. Because of the hierarchical nature of the motor system, the higher-order areas can concern themselves with more global tasks regarding action, such as deciding when to act, devising an appropriate sequence of actions, and coordinating the activity of many limbs. They do not have to program the exact force and velocity of individual muscles, or coordinate movements with changes in posture; these low-level tasks are performed by the lower levels of the hierarchy.

The motor system hierarchy consists of the following parts (Fig. 2): • • •

Spinal Cord Brainstem Motor Cortex

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• •

Association Cortex Side Loops o Basal Ganglia o Cerebellum Level 4: Association Cortex Side Loop 1: Basal Ganglia Level 3: Motor Cortex

(Caudate Nucleus, Putamen, Globus Pallidus, Substantia Nigra, Subthalamic Nucleus)

Fig. 2. Schematic representation of the different levels and interconnections of the motor system hierarchy.

Thalamus Level 2: Brain Stem (Red Nucleus, Reticular Formation, Vestibular Nuclei, Tectum, Pontine Nuclei, Inferior Olive)

(VA,VL,CM)

Side Loop 2: Cerebellum

Level 1: Spinal Cord

Spinal Cord. The spinal cord is the first (lowest) level of the motor hierarchy (Fig. 3). (1) The spinal cord is the site of motor neurons. These motor neurons reside in the anterior horn of the spinal cord and synapse directly onto muscle fibers. Motor neurons are the only way in which commands from higher areas can be transmitted to muscle. Damage to motor neurons results necessarily in paralysis of the muscles that were innervated by those neurons. (2) The spinal cord contains the circuitry for many reflexes. These spinal reflexes include the myotatic reflex (also called the stretch reflex or deep tendon reflex), the flexor reflex (limb withdrawal away from a painful stimulus), and many others discussed in the next 2 lectures. (3) The spinal cord controls many complex actions. The most obvious complex action that is controlled by circuitry entirely within the spinal cord is gait. Although higher areas can issue commands to begin walking, the circuitry that actually controls the rhythmic motion of the legs resides in the spinal cord itself. (4) The spinal cord is influenced by higher levels of the hierarchy. Although many reflexes and complex actions are controlled by neural circuits within the spinal cord, these circuits can be influenced in complex ways by higher brain centers. This top-down control is necessary for ensuring that the low-level circuits within the spinal cord are utilized in an adaptive manner.

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Fig. 3. A motor neuron in the spinal cord.

Brainstem. The brainstem is the second level of the motor hierarchy. (1) Brainstem nuclei that are important for motor control include the red nucleus, the vestibular nuclei, the pontine reticular formation, and the medullary reticular formation. (2) These nuclei process selected afferent sensory inputs that are used to program and adapt motor commands. As discussed later, the use of sensory input to guide motor output is a necessary and ubiquitous feature of motor control. (3) Brainstem nuclei modulate motor circuits that control posture, eye movements, and head movements. Motor cortex. The motor cortex is the third level of the motor hierarchy (Fig. 4). (1) The motor cortex processes numerous task-related variables to produce the desired action. Neurons in the motor cortex then give rise to descending motor commands. Information encoded in these commands includes which part of the body should move, as well as the force and direction of the movement. (2) Motor cortex can be divided broadly into 3 areas: primary motor cortex, premotor cortex, and the supplementary motor area. (3) Descending pathways from the motor cortex can be divided into two systems: a. The corticospinal system controls motor neurons and interneurons in the spinal cord. b. The corticobulbar system controls brainstem nuclei that innervate cranial muscles.

Fig. 4. The motor cortex, the third level of the motor system hierarchy, is composed of three major areas: the primary motor cortex (also called M1), the premotor cortex, and the supplementary motor area. Note that the supplementary motor area extends onto the medial wall of the cortex.

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Association Cortex. The association cortex is the fourth (highest) level of the motor hierarchy (Fig. 5). (1) High-level association cortical areas create a frame of reference for directing movements. This task is largely associated with the posterior parietal cortex. In addition to other tasks, this brain region calculates transformations of sensory inputs from bodycentered (egocentric) coordinates to world-centered (allocentric) coordinates, allowing movements to be directed to the external world regardless of the current orientation and position of the body. Lower areas of the hierarchy transform the output of these areas back to the appropriate egocentric coordinates necessary to generate the proper muscle output. The posterior parietal cortex is also involved in directing attention to salient objects in the world. (2) Association cortex integrates behavior to produce goal-directed action appropriate for the particular context. These poorly understood functions are largely associated with the prefrontal cortex. Actions that are appropriate in one behavioral context (e.g., giving a hard slap on the back to congratulate a basketball player who just made a critical 3pointer) may be completely inappropriate in another context (e.g., giving the same hard slap to one’s grandmother to celebrate her 80th birthday). This type of processing, although not traditionally motor processing per se, is important for producing movements that are behaviorally adaptive. Fig. 5. The fourth level of the motor system hierarchy is the association cortex, primarily the posterior parietal cortex and the prefrontal cortex.

Side loops. Two important brain regions are not part of the motor hierarchy, but they influence the motor cortex profoundly through their connections with the motor thalamus. (1) Basal ganglia. The basal ganglia comprise a number of distinct forebrain structures that act as an integrative center for motor output. Damage to the basal ganglia produces deficits of motor planning, speed of movement, and the ability to enable certain stereotyped motor programs. Parkinson’s disease is the most well-known of basal ganglia disorders. (2) Cerebellum. The cerebellum modulates the activity of brainstem nuclei (through direct connections) as well as motor cortex (through its thalamic connections). The cerebellum is important for fine control and timing of movements; it is thought to be necessary for motor learning (i.e., learning the precise patterns of movement necessary to achieve fine

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control of the body and limbs). Damage to the cerebellum can produce ataxia (lack of coordination in movements) and inability to maintain balance, among other deficits. Parallel and Serial Processing. Although the motor system is organized in the hierarchical fashion described here, it is important to realize that the hierarchy is not a simple chain of processing from higher to lower areas. Many routes enable the different levels of the hierarchy to influence each other through multiple pathways (Fig. 6). Thus, the flow of information through the motor system has both a serial organization (communication between levels) and a parallel organization (multiple pathways between each level). This parallel organization is critically important in understanding the various dysfunctions that can result from damage to the motor system. If the motor hierarchy had a strictly serial organization, like a series of links on a chain, then damage to any part of the system would produce severe deficits or paralysis in almost all types of movements. However, because of the parallel nature of processing, paralysis is actually a relatively rare outcome, produced by damage to the lowest level of the hierarchy. Damage to higher levels results in deficits in motor planning, initiation, coordination, and so forth, but movement is still possible. The parallel nature of organization is also important for the ability of undamaged parts of the motor system to compensate (at least partially) for injuries to other parts of the system.

Fig. 6. Parallel and serial organization of the motor system. Higher areas can direct lower areas by multiple pathways (parallel organization) and through polysynaptic processing chains (serial organization).

Motor Control Requires Sensory Input One of the major principles of the motor system is that motor control requires sensory input to accurately plan and execute movements. This principle applies to low levels of the hierarchy, such as spinal reflexes, and to higher levels. The study of motor control has utilized principles from the engineering field of control theory to characterize the interactions between sensory input and motor output. There are three types of control systems in this framework: open loop system with no sensory input, closed loop system with feedback control, and open loop system with feedforward control. 7

Open Loop System with No Sensory Input. Before describing the role of sensory input, it is useful to describe the properties of a control system without such input. A system in which there is no sensory feedback into the system is termed an open loop control system. In such a system, a desired output is fed into a controller circuit, which in turns directs the effector machinery (e.g., robotic arm, biceps muscle, etc.) to produce the output (Fig. 7). In this type of system, there is no role of sensory information to direct, guide, or modulate the output; movements are ballistic and, once initiated, cannot be modified. Such a system is rarely present in a biological motor system. A nonbiological example would be a timer-controlled heating/cooling system. In order to cool a room to a desired temperature, a control circuit with a timer would turn on the air conditioner for a preset amount of time. Once the timer was set, however, there would be no way to keep the air conditioner on longer if the desired temperature was not reached, or to turn on the heater if the air conditioner made the room too cold. Perhaps one of the few examples of a biological realistic example of such a ballistic system would be a reflexive drop to the ground to avoid an incoming object. DESIRED OUTPUT

CONTROLLER

OUTPUT

EFFECTOR

Fig. 7. An open loop control system.

Closed Loop System with Feedback Control. An improvement on an open loop control system is to incorporate sensory information during the execution of a task in order to improve accuracy. One method of accomplishing this is a feedback control system (Fig. 8). In such a system, a desired output is sent to a comparator, which compares the present state of the system with the desired output. If there is a mismatch between the present and desired outputs, an error signal is sent to the effector machinery that instructs it to bring the actual output closer to the desired output. In order to detect the present state of the system, a sensor must be present to measure the present state of the system. The flow of information, from the comparator to the effector, to the sensor, and back to the comparator, is called a closed loop. A common example of a feedback control system is the thermostat in your home. The thermostat is set to a desired temperature (e.g., 72°), and a thermometer measures the current temperature in the room. If the comparator detects that the room is cooler than the desired temperature, it sends an error signal that turns on the furnace. If the comparator detects that the room is warmer than the desired setting, its sends an error signal that turns on the air conditioner. COMPARATOR

DESIRED OUTPUT

+

Error signal

EFFECTOR

OUTPUT

Feedback signal

SENSOR

Fig. 8. A closed loop system with feedback control

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Feedback control systems can produce very accurate outputs; however, in general they are slow. In order to change the output, the effector must wait until information is transmitted from the sensor to the comparator and then to the effector. At this point, another comparison is made, and the process continues. Consider further the thermostat example. If the temperature reads 5° cooler than desired, the thermostat can instruct the furnace to turn on at a moderate heat. It reads the new room temperature, and, if it is still too cool, it instructs the furnace to deliver more heat, and so on. Although this will eventually produce an accurate room temperature at the desired point, it takes a number of cycles to reach that point. One possible solution for quicker results would be to turn an enormous furnace on full-blast, such that is heats the room very quickly. This solution, however, can generate another problem. It will tend to cause the system to oscillate if the feedback pathways are slow. For example, assume that the furnace can heat the room at the rate of 5° per second, but that it takes 2 seconds for the thermometer to adjust to the new temperature, and for the new error signal to turn the furnace off. In those 2 seconds, the furnace has heated the room up 10°, and now it is too warm. So the error signal turns on the air conditioner, and it cools the room at 5°/sec. Of course, it also takes 2 sec to receive the feedback, and by the time it is told to shut off, it has cooled the room by 10°. You can see what happens: the system will be sent into an endless oscillation of being 5° too hot and 5° too cold. In order for a feedback system to work well, the transmission time of sensory information through the comparator to the effector must be rapid compared to the time of the action. Thus, the advantages of a feedback control system are: (1) It can produce very accurate output. (2) It is a very efficient mechanism in that all it requires of the operator is to set the desired output level, and the system automatically adjusts itself to maintain that level. The operator does not need to manually turn the effectors on or off to constantly adjust the movement. The disadvantages are (1) It can be a slow system, often requiring many iterative cycles to produce the final desired output. (2) It is prone to oscillations. As we shall see, many simple reflexes can be understood as feedback control systems, but such systems are often too slow to control the accurate execution of many voluntary movements. Open Loop System with Feedforward Control. A second manner in which sensory information can be used to guide movements is by incorporating that information in advance of the movement, during the planning and programming stages of motor execution. Such a system is a feedforward control system (Fig. 9). In this type of system, when a desired output is sent to the controller, the controller takes readings from sensors about the state of the environment and about the current state of the effector itself. It then uses this information to program the best set of instructions to accomplish the desired output. Importantly, in a pure feedforward system, once the commands to the effector are sent, there is no feedback pathway to alter the effector during the execution of the movement. This is why it is termed an “open loop” system. Note that a feedforward system differs from the open loop system with no sensory control, as the feedforward system uses sensory information to plan the movement.

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The major advantage of the feedforward control system over the feedback system is speed of execution. Whereas the feedback system can be slow and prone to oscillations, the feedforward system (when working well) can produce the precise set of commands for the effector without needing to constantly check the output and make corrections during the movement itself. The main disadvantage, however, is that the feedforward controller requires a period of learning before it can function properly. In most biological systems, the environment and conditions under which actions are made are constantly changing, and the feedforward controller must be able to adapt its output commands to account for this variability; it is hard (perhaps impossible) to pre-program all of the possible sensory conditions that the controller may encounter during the life of the organism. DESIRED OUTPUT

SENSOR

ADVANCE INFORMATION

FEED-FORWARD CONTROLLER Feed-forward control signal

EFFECTOR

OUTPUT

Fig. 9. An open loop system with feedforward control uses sensory information in advance to output an appropriate control signal to the effector.

Let us extend the thermostat example to see how a temperature controller operating as a feedforward system would work to raise the temperature of a room from 70° to 75°. The controller would use diverse sensory information about the environment before sending its command to the furnace. For example, it would read the current temperature, the current humidity level, the size of the room, the number of people in the room, and so forth. Based on this information, it would direct the furnace to turn on for a pre-set period of time, and that’s it. There would be no need to continually compare the current temperature with the desired setting, as the system has predetermined how long the furnace needs to be working in order to achieve the desired temperature. How did the controller obtain this information? A feedforward controller requires a large amount of experience in order to learn the appropriate actions needed for each set of environmental conditions. If on one trial it turns the furnace off too soon and the room does not reach the desired temperature, it adjusts its programming such that the next time it encounters the same environmental conditions, it turns the furnace on for a longer period of time. Through many such instances of trial and error learning, the feedforward system creates a “lookup table” that tells it how long the furnace needs to be active under the current conditions. The key distinction between a feedback and feedforward system is that the feedback system uses sensory information to generate an error signal during the control of a movement, whereas a feedforward system uses sensory information in advance of a movement. Any error signal about

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the final output is used by the feedforward system only to change its programming of future movements. Thus, the advantages of a feedforward control system are (1) It is very accurate (2) It is very fast (3) It does not require constant monitoring of the output during the execution of the movement The disadvantages are (1) It requires a period of learning before it can perform accurately

Motor deficits from sensory pathology. There are specific motor deficits seen with particular sensory pathologies. The importance of feedback and feedforward control is evident in the effects of loss of sensory input. This occurs in large fiber sensory neuropathy. A patient with large fiber sensory neuropathy cannot sense their position nor detect motion of joints, since input from muscle spindles and Golgi tendon organs is not present. Tactile information is also impaired. Manual dexterity is devastated, since estimates of contact with objects cannot be made precisely. However, pain and temperature sensation is preserved. These deficits are quite severe: limb position can be maintained only if the patient can see them. In this case, patients must learn visually guided, feedback and feedforward control strategies to compensate for the loss of proprioceptive feedback and feedforward control signals. In severe cases, patients will collapse the moment the lights are turned off, as they lose the visual feedback necessary to maintain posture and are unable to make coordinated movements at all. As we will encounter repeatedly, feedback and feedforward control are distributed among the hierarchical levels of motor control. Many movements are the result of combinations of both feedback and feedforward control.

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MOTOR UNITS AND MUSCLE RECEPTORS

The Spinal Cord: The First Hierarchical Level The spinal cord is the first level of the motor hierarchy. It is the site where motor neurons are located. It is also the site of many interneurons and complex neural circuits that perform the “nuts and bolts” processing of motor control. These circuits execute the low-level commands that generate the proper forces on individual muscles and muscle groups to enable adaptive movements. Because this low level of the hierarchy takes care of these basic functions, higher levels (such as the motor cortex) can process information related to the planning of movements, the construction of adaptive sequences of movements, and the coordination of whole-body movements, without having to encode the precise details of each muscle contraction.

Figure 1. Spinal cord with motor neuron in anterior horn

Motor Neurons Alpha motor neurons (also called lower motor neurons) innervate skeletal muscle and cause the muscle contractions that generate movement. Motor neurons release the neurotransmitter acetylcholine at a synapse called the neuromuscular junction. When the acetylcholine binds to acetylcholine receptors on the muscle fiber, an action potential is propagated along the muscle fiber in both directions. The action potential triggers the contraction of the muscle. If the ends of the muscle are fixed, keeping the muscle at the same length, then the contraction results on an increased force on the supports (isometric contraction). If the muscle shortens against no resistance, the contraction results in constant force (isotonic contraction). The motor neurons that control limb and body movements are located in the anterior horn of the spinal cord, and the motor neurons that control head and facial movements are located in the motor nuclei of the brainstem. Even though the motor system is composed of many different types of neurons scattered throughout the CNS, the motor neuron is the only way in which the motor system can communicate with the muscles. Thus, all movements ultimately depend on the activity of lower motor neurons. The famous physiologist Sir Charles Sherrington referred to these motor neurons as the “final common pathway” in motor processing. Motor neurons are not merely the conduits of motor commands generated from higher levels of the hierarchy. They are themselves components of complex circuits that perform sophisticated information processing. As shown in Figure 1, motor neurons have highly branched, elaborate dendritic trees, enabling them to integrate the inputs from large numbers of other neurons and to calculate proper outputs. 12

Two terms are used to describe the anatomical relationship between motor neurons and muscles: the motor neuron pool and the motor unit. (1) Motor neurons are clustered in columnar, spinal nuclei called motor neuron pools (or motor nuclei). All of the motor neurons in a motor neuron pool innervate a single muscle (Figure 2), and all motor neurons that innervate a particular muscle are contained in the same motor neuron pool. Thus, there is a one-to-one relationship between a muscle and a motor neuron pool. (2) Each individual muscle fiber in a muscle is innervated by one, and only one, motor neuron. A single motor neuron, however, can innervate many muscle fibers. The combination of an individual motor neuron and all of the muscle fibers that it innervates is called a motor unit. The number of fibers innervated by a motor unit is called its innervation ratio.

Figure 2. Motor unit and motor neuron pool

If a muscle is required for fine control or for delicate movements (e.g., movement of the fingers or hands), its motor units will tend to have a small innervation ratio. That is, each motor neuron will innervate a small number of muscle fibers (10-100), enabling many nuances of movement of the entire muscle. If a muscle is required only for coarse movements (e.g., a thigh muscle), its motor units will tend to have a high innervation ratio (i.e., each motor neuron innervating 1000 or more muscle fibers), as there is no necessity for individual muscle fibers to undergo highly coordinated, differential contractions to produce a fine movement. Control of Muscle Force A motor neuron controls the amount of force that is exerted by muscle fibers. There are two principles that govern the relationship between motor neuron activity and muscle force: the rate code and the size principle. (1) Rate Code. Motor neurons use a rate code to signal the amount of force to be exerted by a muscle. An increase in the rate of action potentials fired by the motor neuron causes an increase in the amount of force that the motor unit generates. This code is illustrated in Figure 3. When the motor neuron fires a single action potential, the muscle twitches slightly, and then relaxes back to its resting state. If the motor neuron fires after the muscle has

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returned to baseline, then the magnitude of the next muscle twitch will be the same as the first twitch. However, if the rate of firing of the motor neuron increases, such that a second action potential occurs before the muscle has relaxed back to baseline, then the second action potential produces a greater amount of force than the first (i.e., the strength of the muscle contraction summates). With increasing firing rates, the summation grows stronger, up to a limit. When the successive action potentials no longer produce a summation of muscle contraction (because the muscle is at its maximum state of contraction), the muscle is in a state called tetanus.

tetanus

Figure 3. Rate code

(2) Size Principle. When a signal is sent to the motor neurons to execute a movement, motor neurons are not all recruited at the same time or at random. The motor neuron size principle states that, with increasing strength of input onto motor neurons, smaller motor neurons are recruited and fire action potentials before larger motor neurons are recruited. Why does this orderly recruitment occur? Recall from previous lectures the relationship between voltage, current, and resistance (Ohm’s Law): V = IR. Because smaller motor neurons have a smaller membrane surface area, they have fewer ion channels, and therefore a larger input resistance. Larger motor neurons have more membrane surface and correspondingly more ion channels; therefore, they have a smaller input resistance. Because of Ohm’s Law, a small amount of current will be sufficient to cause the membrane potential of a small motor neuron to reach firing threshold, while the large motor neuron stays below threshold. As the amount of current increases, the membrane potential of the larger motor neuron also increases, until it also reaches firing threshold.

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Figure 4. Size principle

Figure 4 demonstrates how the size principle governs the amount of force generated by a muscle. Because motor units are recruited in an orderly fashion, weak inputs onto motor neurons will cause only a few motor units to be active, resulting in a small force exerted by the muscle. With stronger inputs, more motor neurons will be recruited, resulting in more force applied to the muscle. Moreover, different types of muscle fibers are innervated by small and larger motor neurons. Small motor neurons innervate slow-twitch fibers; intermediate-sized motor neurons innervate fast-twitch, fatigue-resistant fibers; and large motor neurons innervate fast-twitch, fatigable muscle fibers. The slow-twitch fibers generate less force than the fast-twitch fibers, but they are able to maintain these levels of force for long periods. These fibers are used for maintaining posture and making other low-force movements. Fast-twitch, fatigue-resistant fibers are recruited when the input onto motor neurons is large enough to recruit intermediate-sized motor neurons. These fibers generate more force than slow-twitch fibers, but they are not able to maintain the force as long as the slow-twitch fibers. Finally, fast-twitch, fatigable fibers are recruited when the largest motor neurons are activated. These fibers produce large amounts of force, but they fatigue very quickly. They are used when the organism must generate a burst of large amounts of force, such as in an escape mechanism. Most muscles contain both fast and slow-twitch fibers, but in different proportions. Thus, the white meat of a chicken, used to control the wings, is composed primarily of fast-twitch fibers, whereas the dark meat, used to maintain balance and posture, is composed primarily of slow-twitch fibers. Figure 5 demonstrates how the rate code principle and the size principle interact to signal muscle force. In this classic experiment by Monster and Chan (1977), the firing rate of individual motor neurons was measured as a function of the amount of force being generated by a muscle. Each line on the graph corresponds to the firing rate of an individual motor neuron. With small amounts of force, only a small number of motor neurons fire; these are the small motor neurons that are recruited first. As the muscle generates increasing amounts of force, more and more motor neurons fire; these additional neurons are the larger motor neurons. This is the size principle. Notice that as each individual motor neuron fires more rapidly, it produces a greater force on the muscle. This is the rate code principle.

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Figure 5. Interaction between rate code and size principle in determining muscle force. Data from Monster AW & Chan H (1977) Journal of Neurophysiology 40:14321443.

Muscle Receptors and Proprioception As discussed in the previous lecture, the motor system requires sensory input in order to function properly. In addition to sensory information about the external environment, the motor system also requires sensory information about the current state of the muscles and limbs themselves. Proprioception is the sense of the body’s position in space based on specialized receptors that reside in the muscles and tendons. The muscle spindle signals the length of a muscle and changes in the length of a muscle. The Golgi tendon organ signals the amount of force being applied to a muscle. Muscle Spindles Muscle spindles are collections of 6-8 specialized muscle fibers that are located within the muscle mass itself (Figure 6). These fibers do not contribute significantly to the force generated by the muscle. Rather, they are specialized receptors that signal (a) the length and (b) the rate of change of length (velocity) of the muscle. Because of the fusiform shape of the muscle spindle, these fibers are referred to as intrafusal fibers. The large majority of muscle fibers that actually contract and allow the muscle to do work are termed extrafusal fibers. Each muscle contains many muscle spindles; muscles that are necessary for fine movements contain more spindles than muscles that are used for posture or coarse movements. Figure 6. Muscle spindle and Golgi tendon organ

Intrafusal fibers

Extrafusal fibers

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Types of muscle spindle fibers. There are 3 types of muscle spindle fibers, characterized by their shape and the type of information they convey (Figure 7). (1) Nuclear Chain fibers. These fibers are so-named because their nuclei are aligned in a single row (chain) in the center of the fiber. They signal information about the static length of the muscle. (2) Static Nuclear Bag fibers. These fibers are so-named because their nuclei are collected in a bundle in the middle of the fiber. Like the nuclear chain fiber, these fibers signal information about the static length of a muscle. (3) Dynamic Nuclear Bag fibers. These fibers are anatomically similar to the static nuclear bag fibers, but they signal primarily information about the rate of change (velocity) of muscle length. Figure 7. Muscle spindle detail

A typical muscle spindle is composed of 1 dynamic nuclear bag fiber, 1 static nuclear bag fiber, and ~5 nuclear chain fibers. Sensory innervation of muscle spindles. Because the muscle spindle is located in parallel with the extrafusal fibers, it will stretch along with the muscle. The muscle spindle signals muscle length and velocity to the CNS through two types of specialized sensory fibers that innervate the intrafusal fibers. These sensory fibers have stretch receptors that open and close as a function of the length of the intrafusal fiber. (1) Group Ia afferents (also called primary afferents) wrap around the central portion of all 3 types of intrafusal fibers; these specialized endings are called annulospiral endings. Because they innervate all 3 types of intrafusal fibers, Group Ia afferents provide information about both length and velocity. (2) Group II afferents (secondary afferents) innervate the ends of the nuclear chain fibers and the static nuclear bag fibers at specialized junctions termed flower spray endings. Because they do not innervate the dynamic nuclear bag fibers, Group II afferents signal information about muscle length only.

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Because of their patterns of innervation onto the three types of intrafusal fibers, Group Ia and Group II afferents respond differently to different types of muscle movements. Figure 8 shows the responses of each type of afferent to a linear stretch of the muscle. Initially, both Group Ia and Group II fibers fire at a certain rate, encoding the current length of the muscle. During the stretch, the two types differ in their responses. The Group Ia afferent fires at a very high rate during the stretch, encoding the velocity of the muscle length; at the end of the stretch, its firing decreases, as the muscle is no longer changing length. Note, however, that its firing rate is still higher than it was before the stretch, as it is now encoding the new length of the muscle. Compare the response of the Group Ia afferent to the Group II afferent. The Group II afferent increases its firing rate steadily as the muscle is stretched. Its firing rate does not depend on the rate of change of the muscle; rather, its firing rate depends only on the immediate length of the muscle.

Figure 8. Responses of muscle spindles

Gamma motor neurons. Although intrafusal fibers do not contribute significantly to muscle contraction, they do have contractile elements at their ends that are innervated by motor neurons. Motor neurons are divided into two groups. Alpha motor neurons innervate extrafusal fibers, the contracting fibers that supply the muscle with its power. Gamma motor neurons innervate intrafusal fibers, which contract only slightly. The function of intrafusal fiber contraction is not to provide force to the muscle; rather, gamma activation of the intrafusal fiber is necessary to keep the muscle spindle taut, and therefore sensitive to stretch, over a wide range of muscle lengths. This concept is illustrated in Figure 9. If a resting muscle is stretched, the muscle spindle becomes stretched in parallel, sending signals through the primary and secondary afferents. A subsequent contraction of the muscle, however, removes the pull on the spindle, and it becomes slack, causing the spindle afferents to cease firing. If the muscle were to be stretched again, the muscle spindle would not be able to signal this stretch. Thus, the spindle is rendered temporarily insensitive to stretch after the muscle has contracted. Activation of gamma motor neurons prevents this temporary insensitivity by causing a weak contraction of the intrafusal fibers, in parallel with the contraction of the muscle. This contraction keeps the spindle taut at all times and maintains its sensitivity to changes in the length of the muscle. Thus, when the CNS instructs a muscle to contract, it not only sends the appropriate signals to the alpha motor neurons, it also instructs gamma motor neurons to contract the intrafusal fibers appropriately; this coordinated process is referred to as alpha-gamma coactivation.

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Figure 9. Gamma activation of intrafusal fibers. (A) Muscle is at a certain length, encoded by firing of Ia afferent. (B) When muscle is stretched, muscle spindle stretches and Ia afferent fires more strongly. (C) When muscle is contracted again, muscle spindle become slack, causing Ia afferent to fall silent. The muscle spindle is rendered insensitive to further stretches of muscle. (D) To restore sensitivity, firing of gamma motor neurons causes spindle to contract, thereby becoming taut and able to signal.

Golgi Tendon Organ The Golgi tendon organ is a specialized receptor that is located between the muscle and the tendon (Figure 6). Unlike the muscle spindle, which is located in parallel with extrafusal fibers, the Golgi tendon organ is located in series with the muscle and signals information about the load or force being applied to the muscle. A Golgi tendon organ is made up of a capsule containing numerous collagen fibers (Figure 10). The organ is innervated by primary afferents called Group Ib fibers, which have specialized endings that weave in between the collagen fibers. When force is applied to a muscle, the Golgi tendon organ is stretched, causing the collagen fibers to squeeze and distort the membranes of the primary afferent sensory endings. As a result, the afferent is depolarized, and it fires action potentials to signal the amount of force.

Group Ib afferent

Figure 10. Golgi tendon organ detail

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In summary, (1) Muscle spindles signal information about the length and velocity of a muscle (2) Golgi tendon organs signal information about the load or force applied to a muscle Functions of Muscle Spindles and Golgi Tendon Organs: An Introduction to Spinal Reflexes As noted in the previous lecture, a sense of body position is necessary for adaptive motor control. In order to move a limb toward a particular location, it is imperative to know the initial starting position of the limb, as well as any force applied to the limb. Muscle spindles and Golgi tendon organs provide this type of information. In addition, these receptors are components of certain spinal reflexes that are important for both clinical diagnoses as well as for a basic understanding of the principles of motor control. Myotatic reflex The myotatic reflex is illustrated in Figure 11. A waiter is holding an empty tray, when unexpectedly a pitcher of water is placed on the tray. Because the waiter’s muscles were not prepared to support the increased weight, the tray should fall. However, a spinal reflex is automatically initiated to keep the tray relatively stable. When the heavy pitcher is placed on the tray, the increased weight stretches the biceps muscle, which results in the activation of the muscle spindle’s Ia afferents. The Ia afferents have their cell bodies in the dorsal root ganglia of the spinal cord, send projections into the spinal cord, and make synapses directly on alpha motor neurons that innervate the same (homonymous) muscle. Thus, activation of the Ia afferent causes a monosynaptic activation of the alpha motor neuron that causes the muscle to contract. As a result, the stretch of the muscle is quickly counteracted, and the waiter is able to maintain the tray at the same position.

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Figure 11. Myotatic reflex

The myotatic reflex is an example of a feedback control system (discussed in the previous lecture). A comparator (the spindle) compares the desired output (hold the limb steady at a

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particular position) with the current state of the system. Initially, when the tray is steady, there is no difference between the desired output and the current state. When the pitcher is placed on the tray, however, the muscle spindle is stretched, and this causes the Ia afferent to send an error signal that the muscle is stretched more than the desired output. The alpha motor neuron then causes the effector (the muscle) to contract, thereby realigning the current state of the system with the desired output. A major role of the myotatic reflex is the maintenance of posture. Recall that feedback control mechanisms are slow, and are typically not useful for rapid, voluntary movements. For maintaining static posture, however, feedback mechanisms are very efficient and accurate. If one is standing upright and starts to sway to the left, muscles in the legs and torso are stretched, activating the myotatic reflex to counteract the sway. In this way, the higher levels of the motor system are able to send a simple command (“maintain current posture”) and then be uninvolved in its implementation. The lower levels of the hierarchy implement the command with such mechanisms as the myotatic reflex, freeing the higher levels to perform other tasks such as planning the next sequence of movements. The myotatic reflex is an important clinical reflex. It is the same circuit that produces the knee-jerk, or stretch, reflex. When the physician taps the patellar tendon with a hammer, this action causes the knee extensor muscle to stretch momentarily. This stretch activates the myotatic reflex, causing an extension of the lower leg. (Because the physician taps the tendon, this reflex is also referred to as the deep tendon reflex. Do not be confused, however, between this terminology and the Golgi tendon organ. The myotatic reflex is initiated by the muscle spindle, not the Golgi tendon organ.) As we will learn in the next lecture, spinal reflexes can be modulated by higher levels of the hierarchy, and thus a hyperactive or hypoactive stretch reflex is an important clinical sign to localize neurological damage. Autogenic inhibition The Golgi tendon organ is involved in a spinal reflex known as the autogenic inhibition reflex (Figure 12). When tension is applied to a muscle, the Group Ib fibers that innervate the Golgi tendon organ are activated. These afferents have their cell bodies in the dorsal root ganglia, and they project into the spinal cord and synapse onto an interneuron called the Ib inhibitory interneuron. This interneuron makes an inhibitory synapse onto the alpha motor neuron that innervates the same muscle that caused the Ib afferent to fire. As a result of this reflex, activation of the Ib afferent causes the muscle to cease contraction, as the alpha motor neuron becomes inhibited. Because this reflex contains an interneuron between the sensory afferent and the motor neuron, it is an example of a disynaptic reflex.

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Ib inhibitory

Figure 12. Autogenic inhibition

For many years, it was thought that the function of the autogenic inhibition circuit was to protect the muscle from excessive amounts of force that might damage it. A classic example is that of the weightlifter straining to raise a heavy load, when suddenly the autogenic inhibition reflex is activated and the muscle loses power, causing the weight to fall to the ground. This function was ascribed to the reflex because early work suggested that the Golgi tendon organ was only activated when large amounts of force were applied to it. More recent evidence indicates, however, that the Golgi tendon organ is sensitive to much lower levels of force than previously believed. This finding suggests that the autogenic inhibition reflex may be more extensively involved in motor control under normal conditions. One possibility is that this reflex helps to spread the amount of work evenly across the entire muscle, so that all motor units are working efficiently. That is, if some muscle fibers are bearing more of the load than others, their Golgi tendon organs will be more active, which will tend to inhibit the contraction of those fibers. As a result, other muscle fibers that are less active will have to contract more to pick up the slack, thereby sharing the work load more efficiently. This hypothesized function is another example of a feedback control system.

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SPINAL RELEXES AND DESCENDING MOTOR PATHWAYS Spinal reflexes The end of the last lecture introduced two simple spinal reflexes that are initiated by proprioceptors: the myotatic (stretch) reflex, which is initiated by the muscle spindle, and the autogenic inhibition reflex, which is initiated by the Golgi tendon organ. In each case, activation of a muscle receptor causes a change in the alpha motor neurons that innervate the same muscle. The production of adaptive, coordinated behaviors requires further sophistication in these simple reflexes. For example, stretching the muscle spindle not only leads to the contraction of the homonymous muscle by the myotatic reflex, but also leads to the contraction of synergist muscles by collateral pathways. The following are further examples of more sophisticated reflex pathways. Reciprocal inhibition in the stretch reflex. Joints are controlled by two opposing sets of muscles, extensors and flexors, which must work in synchrony. Thus, when a muscle spindle is stretched and activates the stretch reflex, the opposing muscle group must be inhibited to prevent it from working against the resulting contraction of the homonymous muscle (Fig. 1). This inhibition is accomplished by an inhibitory interneuron in the spinal cord. The Ia afferent of the muscle spindle bifurcates in the spinal cord. One branch innervates the alpha motor neuron that causes the homonymous muscle to contract, producing the behavioral reflex. The other branch innervates the Ia inhibitory interneuron, which in turn innervates the alpha motor neuron that synapses onto the opposing muscle. Because the interneuron is inhibitory, it prevents the opposing alpha motor neuron from firing, thereby reducing the contraction of the opposing muscle. Without this reciprocal inhibition, both groups of muscles might contract together and work against each other.

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Figure 1: Reciprocal inhibition in stretch reflex

Reciprocal excitation in the autogenic inhibition reflex. Just as in the stretch reflex, the autogenic inhibition reflex (initiated by the Golgi tendon organ) must coordinate the activity of the extensor and flexor muscle groups (Fig. 2). The Ib afferent fiber bifurcates in the spinal cord. One branch innervates the Ib inhibitory interneuron, as described in the last lecture. The other branch innervates an excitatory interneuron that, in turn, innervates the alpha motor neuron

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that controls the antagonist muscle. Thus, when the homonymous muscle is inhibited from contracting, the antagonist muscle is caused to contract, allowing the opposing muscle groups to work in synchrony.

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Figure 2: Reciprocal excitation in the autogenic inhibition reflex

Flexor reflex. Spinal reflexes can be initiated by nonproprioceptive receptors as well as by proprioceptors. An important reflex initiated by cutaneous receptors and pain receptors is the flexor reflex. We have all experienced this reflex after accidentally touching a hot stove or a sharp object, as we withdraw our hand even before we consciously experience the sensation of pain. This quick reflex removes the limb from the damaging stimulus more quickly than if the pain signal had to travel up to the brain, be brought to conscious awareness, and then trigger a decision to withdraw the limb. The reflex circuit is illustrated in Figure 3. A sharp object touching the foot causes the activation of Group III afferents of pain receptors. These afferents enter the spinal cord and then travel up the cord. A branch of the afferent innervates an excitatory interneuron in the lumbar region of the spinal cord, which then excites an alpha motor neuron that causes contraction of the thigh flexor muscle. The Group III afferent also continues upward to the L2 vertebra, where another branch innervates an excitatory interneuron at this level. This interneuron excites the alpha motor neurons that excite the hip flexor muscle, allowing the coordinated activity of two muscle groups to withdraw the whole leg away from the painful stimulus. Thus, spinal reflexes work not only at a single joint; they can also coordinate the activity of multiple joints simultaneously.

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Figure 3: Flexor reflex

Reciprocal inhibition in the flexor reflex. When the knee joints and the hip joints are flexed, the antagonist extensor muscles must be inhibited (just as in the stretch reflex). This is accomplished by the Group III afferents innervating inhibitory interneurons that in turn innervate the alpha motor neurons controlling the antagonist muscle. Crossed extension reflex. Although the flexor reflex as described works well to synchronize the activity of multiple muscle groups to allow the coordinated movement of the entire limb, further circuitry is needed to make the reflex adaptive. Because the weight of the body is supported by both legs, the flexor reflex must coordinate the activity not only of the leg being withdrawn but also of the opposite leg (Fig. 4). Imagine stepping on a tack, and having the flexor reflex withdraw your right leg immediately. The left leg must simultaneously extend in order to support the body weight that would have been supported by the left leg. Without this coordination of the two legs, the shift in body mass would cause a loss of balance. Thus, the flexor reflex incorporates a crossed extension reflex. A branch of the Group III afferent innervates an excitatory interneuron that sends its axon across the midline into the contralateral spinal cord. There it excites the alpha motor neurons that innervate the extensor muscles of the opposite leg, allowing balance and body posture to be maintained.

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Figure 4: Crossed extension reflex

Recurrent inhibition of motor neurons (Renshaw cells). Axons of alpha motor neurons bifurcate in the spinal cord and innervate a special inhibitory interneuron called the Renshaw cell (Fig. 5). This interneuron innervates and inhibits the very same motor neuron that caused it to fire. Thus, a motor neuron regulates its own activity by inhibiting itself when it fires. This negative feedback loop is thought to stabilize the firing rate of motor neurons.

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Figure 5: Renshaw cell

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Descending Motor Pathways The spinal reflex circuits described above demonstrate that quite sophisticated and precise neural processing occurs at the lowest level of the motor hierarchy. These automatic reflexes can be modulated, however, by higher levels of the hierarchy. For example, when touching an iron to see if it is still hot, your flexor reflex may be even more sensitive than normal. As a result, you pull your hand away repeatedly before even touching the iron, anticipating that it may be hot. Conversely, if you are removing a hot dish from the oven and the heat starts to go through the oven mitt, you will suppress the flexor response so that you do not drop your dinner all over the floor as you rush to put it down on a counter top. These modulations (both facilitatory and inhibitory) of the spinal reflexes arise from the descending pathways from the brainstem and cortex. Additionally, voluntary movement, as well as vestibular-, visual-, and auditory-driven reflex actions, are controlled by the descending pathways. Descending motor pathways arise from multiple regions of the brain and send axons down the spinal cord that innervate alpha motor neurons, gamma motor neurons, and interneurons. The motor neurons are topographically organized in the anterior horn of the spinal cord according to two rules: the flexor-extensor rule and the proximal-distal rule. Flexor-extensor rule: motor neurons that innervate flexor muscles are located posteriorly to motor neurons that innervate extensor muscles. Proximal-distal rule: motor neurons that innervate distal muscles (e.g., hand muscles) are located lateral to motor neurons that innervate proximal muscles (e.g., trunk muscles).

Figure 6: Flexor-extensor/proximal-distal rules

Descending motor pathways are organized into two major groups: (1) Lateral pathways control both proximal and distal muscles and are responsible for most voluntary movements of arms and legs. They include the (a) lateral corticospinal tract (b) rubrospinal tract

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(2) Medial pathways control axial muscles and are responsible for posture, balance, and coarse control of axial and proximal muscles. They include the (a) vestibulospinal tracts (both lateral and medial) (b) reticulospinal tracts (both pontine and medullary) (c) tectospinal tract (d) anterior corticospinal tract Corticospinal tracts. The corticospinal tract originates in the motor cortex (Fig. 7). The axons of motor projection neurons collect in the internal capsule, and then course through the crus cerebri (cerebral peduncle) in the midbrain. At the level of the medulla, these axons form the medullary pyramids on the ventral surface of the brainstem (hence, this tract is also called the pyramidal tract). At the level of the caudal medulla, the corticospinal tract splits into two tracts. Approximately 90% of the axons cross over to the contralateral side at the pyramidal decussation, forming the lateral corticospinal tract. These axons continue to course through the lateral funiculus of the spinal cord, before synapsing either directly onto alpha motor neurons or onto interneurons in the ventral horn. The remaining 10% of the axons that do not cross at the caudal medulla constitute the anterior corticospinal tract, as they continue down the spinal cord in the anterior funiculus. When they reach the spinal segment at which they terminate, they cross over to the contralateral side through the anterior white commissure and innervate alpha motor neurons or interneurons in the anterior horn. Thus, both the lateral and anterior corticospinal tracts are crossed pathways; they cross the midline at different locations, however. Function. The corticospinal tract (along with the corticobulbar tract) is the primary pathway that carries the motor commands that underlie voluntary movement. The lateral corticospinal tract is responsible for the control of the distal musculature and the anterior corticospinal tract is responsible for the control of the proximal musculature. A particularly important function of the lateral corticospinal tract is the fine control of the digits of the hand. The corticospinal tract is the only descending pathway in which some axons make synaptic contacts directly onto alpha motor neurons. This direct cortical innervation presumably is necessary to allow the powerful processing networks of the cortex to control the activity of the spinal circuits that direct the exquisite movements of the fingers and hands. The percentage of axons in the corticospinal tract that innervate alpha motor neurons directly is greater in humans and nonhuman Figure 7: Corticospinal tracts 28

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primates than in other mammals, presumably reflecting the increased manual dexterity of primates. Damage to the corticospinal tract results in a permanent loss of the fine control of the extremities. Although parallel descending pathways can often recover the function of more coarse movements, these pathways are not capable of generating fine, skilled movements. In addition to the fine control of distal muscles, the corticospinal tract also plays a role in the voluntary control of axial muscles. Rubrospinal tract. The rubrospinal tract originates in the red nucleus of the midbrain (Fig. 8). The axons immediately cross to the contralateral side of the brain, and they course through the brainstem and the lateral funiculus of the spinal cord. The axons innervate spinal neurons at all levels of the spinal cord.

Figure 8: Rubrospinal tract

Function. The rubrospinal tract is an alternative by which voluntary motor commands can be sent to the spinal cord. Although it is a major pathway in many animals, it is relatively minor in humans. Activation of this tract causes excitation of flexor muscles and inhibition of extensor muscles. The rubrospinal tract is thought to play a role in movement velocity, as rubrospinal lesions cause a temporary slowness in movement. In addition, because the red nucleus receives most of its input from the cerebellum, the rubrospinal tract probably plays a role in transmitting learned motor commands from the cerebellum to the musculature. The red nucleus also receives some input from the motor cortex, and it is therefore probably an important pathway for the recovery of some voluntary motor function after damage to the corticospinal tract.

Vestibulospinal tracts. The two vestibulospinal tracts originate in 2 of the 4 vestibular nuclei (Fig. 9). The lateral vestibulospinal tract originates in the lateral vestibular nucleus. It courses through the brainstem and through the anterior funiculus of the spinal cord on the ipsilateral side, before exiting ipsilaterally at all levels of the spinal cord. The medial vestibulospinal tract originates in the medial vestibular nucleus, splits immediately and courses bilaterally through the brainstem via the medial longitudinal fasciculus and through the anterior funiculus of the spinal cord, before exiting at or above the T6 vertebra. Function. The vestibulospinal tracts mediate postural adjustments and head movements. They also help the body to maintain balance. Small movements of the body are detected by the vestibular sensory neurons, and motor commands to counteract these movements are sent

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through the vestibulospinal tracts to appropriate muscle groups throughout the body. The lateral vestibulospinal tract excites antigravity muscles in order to exert control over postural changes necessary to compensate for tilts and movements of the body. The medial vestibulospinal tract innervates neck muscles in order to stabilize head position as one moves around the world. It is also important for the coordination of head and eye movements.

Figure 9: Vestibulospinal tracts

Reticulospinal tracts. The two reticulospinal tracts originate in the brainstem reticular formation, a large, diffusely organized collection of neurons in the pons and medulla (Fig. 10). The pontine reticulospinal tract originates in the pontine reticular formation, courses ipsilaterally through the medial longitudinal fasciculus and through the anterior funiculus of the spinal cord, and exits ipsilaterally at all spinal levels. The medullary reticulospinal tract originates in the medullary reticular formation, courses mainly ipsilaterally (although some fibers cross the midline) through the anterior funiculus of the spinal cord, and exits at all spinal levels.

Figure 10: Reticulospinal tracts

Function. The reticulospinal tracts are a major alternative to the corticospinal tract, by which cortical neurons can control motor function by their inputs onto reticular neurons. These tracts regulate the sensitivity of

flexor responses to ensure that only noxious stimuli elicit the responses. Damage to the reticulospinal tract can thus cause harmless stimuli, such as gentle touches, to elicit a flexor

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reflex. The reticular formation also contains circuitry for many complex actions, such as orienting, stretching, and maintaining a complex posture. Commands that initiate locomotor circuits in the spinal cord are also thought to be transmitted through the medullary reticulospinal tract. Thus, the reticulospinal tracts are involved in many aspects of motor control, including the integration of sensory input to guide motor output. Tectospinal tract. The tectospinal tract originates in the deep layers of the superior colliculus and crosses the midline immediately. It then courses through the pons and medulla, just anterior to the medial longitudinal fasciculus. It courses through the anterior funiculus of the spinal cord, where the majority of the fibers terminate in the upper cervical levels. Function. Little is known about the function of the tectospinal tract, but because of the nature of the visual response properties of neurons in the superior colliculus (the optic tectum), it is presumably involved in the reflexive turning of the head to orient to visual stimuli.

Figure 11: Tectospinal tract

Influences of descending pathways on spinal circuits Voluntary movement. The most distinctive function of the descending motor pathways is the control of voluntary movement. These movements are initiated in the cerebral cortex, and the motor commands are transmitted to the musculature through a variety of descending pathways, including the corticospinal tract, the rubrospinal tract, and reticulospinal tracts. How voluntary movements are initiated and coordinated by the motor cortex is the subject of the next lecture. Reflex modulation. Another critical function of the descending motor pathways is to modulate the reflex circuits in the spinal cord. The adaptiveness of spinal reflexes can change depending on the behavioral context; sometimes the gain (strength) or even the sign (extension vs. flexion) of a reflex must be changed in order to make the resulting movement adaptive. The descending pathways are responsible for controlling these variables. For example, consider the flexor reflex under two conditions.

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(a) Imagine a situation in which you want to pick up a dish from the stove top, but you are uncertain whether it is hot or cold. You may attempt to lightly touch the surface, and this will often lower the threshold of the flexor reflex, making you more likely to pull your hand away even if the dish is not particularly hot. (You may even withdraw your hand numerous times before even touching the dish!) Descending pathways have lowered the threshold for producing the reflex in this case, making it easier for a weaker nociceptive input to trigger the reflex; these pathways can also change the gain of the reflex, making the withdrawal response greater than usual. (b) Imagine now picking up the dish in order to move it to the table. As you hold the dish, more of its heat begins to transfer to your hand, and it starts to get quite hot. Rather than dropping the dish and spilling your dinner all over the floor, you rush to the table to put it down, before withdrawing your hand and wishing you had used an oven mitt. In this case, the descending pathways inhibited the flexor response. Gamma bias. Recall from the previous lecture that there are two types of spinal motor neurons. Alpha motor neurons innervate extrafusal muscle fibers, which provide the force for a muscle contraction. Gamma motor neurons innervate the ends of intrafusal fibers and help to maintain the tautness of muscle spindles, such that they are sensitive to changes of muscle length over a wide range. In order to work adaptively, the activity of alpha and gamma motor neurons must be coordinated. Thus, whenever motor commands are sent by descending pathways to alpha motor neurons, the appropriate compensating commands are sent to gamma motor neurons. This coordination of alpha-gamma motor commands is called alpha-gamma coactivation, and the adjustment of spindle sensitivity by gamma activation is called gamma bias. Consider the following two examples: (a) When a command is given to a muscle to contract, the muscle spindles become slack, thereby making them insensitive to further changes in muscle length. To compensate for this, the gamma motor neurons that innervate these intrafusal muscle fibers are activated in concert with the alpha motor neurons, allowing the intrafusal fibers to contract with the muscle. This preserves the sensitivity of the muscle to unexpected stretches of the muscle. (b) When a muscle contracts, the antagonist muscle is stretched during the movement. An obvious problem arises when one considers the stretch reflex of the antagonist muscle. If contraction of a muscle causes the activation of the stretch reflex of the antagonist muscle, the antagonist muscle will contract to resist the movement of the limb. How is it possible to ever flex a joint when the stretch reflex of the extensor muscle causes it to extend the joint instead? Alpha-gamma coactivation solves this problem by relaxing the contraction of the intrafusal fibers of the antagonist muscle, allowing the muscle to be stretched without triggering the stretch reflex during a voluntary movement.

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CEREBELLUM Overview: Functions of the cerebellum The cerebellum (“little brain”) is a structure that is located at the back of the brain, underlying the occipital and temporal lobes of the cerebral cortex (Fig. 1). Although the cerebellum accounts for approximately 10% of the brain’s volume, it contains over 50% of the total number of neurons in the brain. Historically, the cerebellum has been considered a motor structure, because cerebellar damage leads to impairments in motor control and posture and because the majority of the cerebellum’s outputs are to parts of the motor system. Motor commands are not initiated in the cerebellum; rather, the cerebellum modifies the motor commands of the descending pathways to make movements more adaptive and accurate. The cerebellum is involved in the following functions:

Figure 1. Cerebellum

Maintenance of balance and posture. The cerebellum is important for making postural adjustments in order to maintain balance. Through its input from vestibular receptors and proprioceptors, it modulates commands to motor neurons to compensate for shifts in body position or changes in load upon muscles. Patients with cerebellar damage suffer from balance disorders, and they often develop stereotyped postural strategies to compensate for this problem (e.g., a wide-based stance). Coordination of voluntary movements. Most movements are composed of a number of different muscle groups acting together in a temporally coordinated fashion. One major function of the cerebellum is to coordinate the timing and force of these different muscle groups to produce fluid limb or body movements. Motor learning. The cerebellum is important for motor learning. The cerebellum plays a major role in adapting and fine-tuning motor programs to make accurate movements through a trial-and-error process (e.g., learning to hit a baseball). Cognitive functions. Although the cerebellum is most understood in terms of its contributions to motor control, recent studies have revealed that it is also involved in certain cognitive functions, such as language. Thus, like the basal ganglia, the cerebellum is historically

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considered as part of the motor system, but its functions extend beyond motor control in ways that are not well understood. Cerebellar gross anatomy The cerebellum consists of two major parts (Fig. 2A). The cerebellar deep nuclei (or cerebellar nuclei) are the sole output structures of the cerebellum. These nuclei are encased by a highly convoluted sheet of tissue called the cerebellar cortex, which contains almost all of the neurons in the cerebellum. A cross-section through the cerebellum reveals the intricate pattern of folds and fissures that characterize the cerebellar cortex. Like the cerebral cortex, cerebellar gyri are reproducible across individuals and have been identified and named. We will only be concerned with some of the larger divisions of the cerebellar cortex.

Figure 2. (A) Cerebellar deep nuclei and cerebellar cortex in an idealized brain section. (B) External morphology of the cerebellum

Divisions of the cerebellum. Two major fissures running mediolaterally divide the cerebellar cortex into 3 primary subdivisions (Fig. 2B, Fig. 3). The posterolateral fissure separates the flocculonodular lobe from the corpus cerebelli, and the primary fissure separates the corpus cerebelli into a posterior lobe and an anterior lobe. The cerebellum is also divided sagittally into 3 zones that run from medial to lateral (Figure 3). The vermis (from the Latin word for worm) is located along the midsagittal plane of the cerebellum. Directly lateral to the vermis is the intermediate zone. Finally, the lateral hemispheres are located lateral to the intermediate zone (there are no clear morphological borders between the intermediate zone and the lateral hemisphere that are visible from a gross specimen). Cerebellar nuclei. All output from the cerebellum originates from the cerebellar deep nuclei. Thus, a lesion to the cerebellar nuclei has the same effect as a complete lesion of the entire cerebellum. It is important to know the inputs, outputs, and anatomical relationships between the different cerebellar nuclei and the subdivisions of the cerebellum (Fig. 4).

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Figure 3. Divisions of cerebellum

(1) The fastigial nucleus is the most medially located of the cerebellar nuclei. It receives input from the vermis and from cerebellar afferents that carry vestibular, proximal somatosensory, auditory, and visual information. It projects to the vestibular nuclei and the reticular formation. (2) The interposed nuclei comprise the emboliform nucleus and the globose nucleus. They are situated lateral to the fastigial nucleus. They receive input from the intermediate zone and from cerebellar afferents that carry spinal, proximal somatosensory, auditory, and visual information. They project to the contralateral red nucleus (the origin of the rubrospinal tract). (3) The dentate nucleus is the largest of the cerebellar nuclei, located lateral to the interposed nuclei. It receives input from the lateral hemisphere and from cerebellar afferents that carry information from the cerebral cortex (via the pontine nuclei). It projects to the contralateral red nucleus and the ventrolateral (VL) thalamic nucleus. (4) The vestibular nuclei are located outside the cerebellum, in the medulla. Hence, they are not strictly cerebellar nuclei, but they are considered to be functionally equivalent to the cerebellar nuclei because their connectivity patterns are identical to the cerebellar nuclei. The vestibular nuclei receive input from the flocculonodular lobe and from the vestibular labyrinth. They project to various motor nuclei and originate the vestibulospinal tracts. In addition to these inputs, all cerebellar nuclei and all regions of cerebellum get special inputs from the inferior olive of the medulla (discussed below).

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It is convenient to remember that the anatomical locations of the cerebellar nuclei correspond to the cerebellar cortex regions from which they receive input. Thus, the medially located fastigial nucleus receives input from the medially located vermis; the slightly lateral interposed nuclei receive input from the slightly lateral intermediate zone; and the most lateral dentate nucleus receives input from the lateral hemispheres.

Figure 4. Inputs/outputs of cerebellum

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Cerebellar peduncles. Three major bundles of fibers carry the input and output of the cerebellum. (1) The inferior cerebellar peduncle (also called the restiform body) primarily contains afferent fibers from the medulla, as well as efferents to the vestibular nuclei. (2) The middle cerebellar peduncle (also called the brachium pontis) primarily contains afferents from the pontine nuclei. (3) The superior cerebellar peduncle (also called the brachium conjunctivum) primarily contains efferent fibers from the cerebellar nuclei, as well as some afferents from the spinocerebellar tract. Thus, the inputs to the cerebellum are conveyed primarily through the inferior and middle cerebellar peduncles whereas the outputs are conveyed primarily through the superior cerebellar peduncle. The inputs arise from the ipsilateral side of the body, and the outputs also go to the ipsilateral side of the body. Note that this is true even for the outputs to the contralateral red nucleus. Recall from the lecture on descending motor pathways that the rubrospinal tract immediately crosses the midline after the fibers leave the red nucleus. Thus, cerebellar output to the red nucleus affects the ipsilateral side of the body by a double-crossed pathway. Unlike the cerebral cortex, the cerebellum receives input from, and controls output to, the ipsilateral side of the body, and damage to the cerebellum therefore results in deficits to the ipsilateral side of the body. Functional subdivisions of the cerebellum The anatomical subdivisions described above correspond to three major functional subdivisions of the cerebellum. (1) The vestibulocerebellum comprises the flocculonodular lobe and its connections with the lateral vestibular nuclei. Phylogenetically, the vestibulocerebellum is the oldest part of the cerebellum. As its name implies, it is involved in vestibular reflexes (such as the vestibuloocular reflex; see below) and in postural maintenance. (2) The spinocerebellum comprises the vermis and the intermediate zones of the cerebellar cortex, as well as the fastigial and interposed nuclei. As its name implies, it receives major inputs from the spinocerebellar tract. Its output projects to rubrospinal, vestibulospinal, and reticulospinal tracts. It is involved in the integration of sensory input with motor commands to produce adaptive motor coordination. (3) The cerebrocerebellum is the largest functional subdivision of the human cerebellum, comprising the lateral hemispheres and the dentate nuclei. Its name derives from its extensive connections with the cerebral cortex, via the pontine nuclei (afferents) and the VL thalamus (efferents). It is involved in the planning and timing of movements. In addition, the cerebrocerebellum is involved in the recently discovered, yet poorly understood, cognitive functions of the cerebellum.

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Histology and connectivity of cerebellar cortex The cerebellar cortex is divided into 3 layers (Fig. 5). The innermost layer, the granule cell layer, is made of 5 x 1010 small, tightly packed granule cells. The middle layer, the Purkinje cell layer, is only 1-cell thick. The outer layer, the molecular layer, is made of the axons of granule cells and the dendrites of Purkinje cells, as well as a few other cell types. The Purkinje cell layer forms the border between the granule and molecular layers.

Figure 5. Cerebellar circuitry. This basic pattern is repeated throughout all regions of the cerebellum.

Granule cells. Granule cells are very small, densely packed neurons that account for the huge majority of neurons in the cerebellum. Indeed, cerebellar granule cells account for more than half of the neurons in the entire brain. These cells receive input from mossy fibers and project to the Purkinje cells. Purkinje cells. The Purkinje cell is one of the most striking cell types in the mammalian brain. Its apical dendrites form a large fan of finely branched processes. Remarkably, this dendritic tree is almost two-dimensional; looked at from the side, the dendritic tree is flat and almost dimensionless. Moreover, all Purkinje cells are oriented in parallel. This arrangement has important functional considerations, as we shall see below. Other cell types. In addition to the major cell types (granule cells and Purkinje cells), the cerebellar cortex also contains various interneuron types, including the Golgi cell, the basket cell, and the stellate cell. Connectivity. The cerebellar cortex has a relatively simple, stereotyped connectivity pattern that is identical throughout the whole structure. Figure 5 illustrates a simplified diagram of the connectivity of the cerebellum. Cerebellar input can be divided into two distinct classes.

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(1) Mossy fibers originate in the pontine nuclei, the spinal cord, the brainstem reticular formation, and the vestibular nuclei, and they make excitatory projections onto the cerebellar nuclei and onto granule cells in the cerebellar cortex. They are called mossy fibers because of the tufted appearance of their synaptic contacts with granule cells. There is a large degree of divergence in the mossy fiber-granule cell connection, as each mossy fiber innervates hundreds of granule cells. The granule cells send axons up toward the cortical surface. Each axon bifurcates in the molecular layer, sending a collateral in opposite directions. These fibers, called parallel fibers, run parallel to the folds of the cerebellar cortex, where they make excitatory synapses with Purkinje cells along the way. The two-dimensional arbors of the Purkinje cell dendrites are oriented perpendicular to the parallel fibers. Thus, the arrangement of Purkinje cells and parallel fibers resembles telephone lines running between telephone poles. Each parallel fiber makes contact with hundreds of Purkinje cells; because of the high degree of divergence of the mossy fiber-granule cell synapses, the firing of each Purkinje cell can be influenced (disynaptically) by thousands of mossy fibers. (2) Climbing fibers originate exclusively in the inferior olive and make excitatory projections onto the cerebellar nuclei and onto the Purkinje cells of the cerebellar cortex. They are called climbing fibers because their axons climb and wrap around the dendrites of the Purkinje cell like a climbing vine. Each Purkinje cell receives a single, extremely powerful input from a single climbing fiber. In contrast to mossy fibers and parallel fibers, each climbing fiber contacts only 10 Purkinje cells on average, making ~300 synapses with each Purkinje cell. Thus, the climbing fiber is a restricted, but extremely powerful, excitatory input onto Purkinje cells. The Purkinje cell is the sole source of output from the cerebellar cortex. It is important to note that Purkinje cells make inhibitory connections onto the cerebellar nuclei. (Note the distinction between the Purkinje cells, which constitute the sole output of the cerebellar cortex, and the cerebellar nuclei, which constitute the sole output of the entire cerebellum.) Almost all of the spikes generated by the Purkinje cell are caused by its parallel-fiber inputs. These inputs cause the Purkinje cell to fire at a high resting rate (~70 spikes/sec), tonically inhibiting its cerebellar nucleus targets. The powerful inputs from climbing fibers occur less frequently (~1 spike/sec); thus, they have a minor influence on the overall firing rate of the Purkinje cell. The Purkinje cell spikes that are generated by climbing fibers are calcium-spikes, however, which allow the climbing fibers to initiate a number of calcium-dependent changes in the Purkinje cell. As described below, one important change appears to be a long-lasting change in the strength of the parallel-fiber inputs to the Purkinje cell. Damage to cerebellum produces movement disorders Much of what is known about cerebellar function comes from studies of patients with cerebellar damage. In general, such patients display uncoordinated voluntary movements and problems maintaining balance and posture. The following are some symptoms of cerebellar damage: (1) Decomposition of movement. Most of our movements involve the coordinated activity of many muscle groups and different joints to produce a smooth trajectory of the body part through space. Patients with cerebellar dysfunction are unable to produce these coordinated,

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smooth movements. Instead, they often break the movements down into their component parts in order to execute the desired trajectory. For example, touching one’s finger to one’s nose requires the coordinated activity of shoulder, elbow, and wrist joints. Cerebellar patients must first perform the shoulder movement, then the elbow movement, and finally the wrist movement in sequence, rather than as one, uniform motion. (2) Intention tremor. When making a movement to a target, cerebellar patients often produce an involuntary tremor that increases as they approach closer to the target. For example, if reaching for a cup, the hand starts out in a direct line toward the cup; as it gets closer, however, the hand begins to move back and forth as it attempts to make contact with the cup. (3) Dysdiadochokinesia. Patients have difficulty performing rapidly alternating movements, such as hitting a surface rapidly and repeatedly with the palm and back of the hand. (4) Deficits in motor learning. Experimental studies have demonstrated that cerebellar damage causes deficits in motor learning in both human patients and experimental animals. One prominent experimental model is the vestibuloocular reflex (VOR). This reflex allows us to maintain gaze on an object when the head is rotated. Vestibular signals detect the head movement, and send signals through the cerebellum to the eye muscles to precisely counter the head rotation and maintain a stable center of gaze. The motor commands to the eyes must be calibrated precisely with experience, and this calibration appears to be the job of the cerebellum. Experiments have been performed in which subjects wore prisms that reversed the visual field. When the subjects’ heads were moved, the VOR actually caused the visual image to rotate on the retina rather than remaining stable. Over days, however, the VOR slowly adjusted, such that the proper compensatory eye movements were made to keep the retinal image stable when the head was rotated. In experimental animals, lesions to the cerebellum prevent this adjustment of the VOR. A second example of cerebellum-dependent motor learning involves the execution of accurate, coordinated movements. Subjects wore prism goggles that shifted the visual image to the right, and they were asked to then throw darts at a target. Because of the prisms, the accuracy of the subjects was initially quite low, as the darts consistently hit to the left of the target. With repeated practice, however, the subjects became more and more accurate at hitting the target. When the goggles were removed, the subject now began to throw the darts to the right of the target, because their motor programs had been recalibrated to use the shifted visual input. Over time, once again, they gradually increased their accuracy. Patients with cerebellar damage never learned to compensate for the prism, as their darts always landed to the left of the target when the goggles were worn. When the goggles were removed, they were immediately accurate at hitting the target, because they never made compensations for the earlier prism trials. A third example involves the Pavlovian classical conditioning of the eye blink reflex. In this task, a neutral stimulus (such as a tone) is paired with a noxious stimulus (such as a puff of air to the eye) that causes a reflexive eye blink. Over time, experimental animals will learn to close their eye when the tone occurs, in anticipation of the air puff. This learned eyelid closure is remarkably well-timed to peak at the expected time of the puff. Animals with cerebellar damage do not learn to produce the eyelid closure in response to the tone.

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Cerebellum as feedforward and feedback controller What do the various symptoms of cerebellar damage have in common that reveal the function of the cerebellum? A number of different theories have been proposed. Recall the discussion in Chapter 1 of feedback and feedforward controllers, and the ubiquitous use of sensory information in motor control. The cerebellum appears to be acting as a feedback and feedforward control system for motor control. In some circumstances, the cerebellum appears to integrate ongoing sensory information in order to correct for errors in movements during the movement (feedback control). In other situations, the cerebellum appears to act as a feedforward controller. Recall that feedforward control mechanisms can act very fast, but that they require learning. This requirement may explain the role of the cerebellum in motor learning. For example, the cerebellar involvement in the VOR may be explained in terms of the learning requirements of a feedforward controller. When the head moves, a compensatory eye movement must be made to maintain a stable gaze. The cerebellum receives sensory input from the vestibular system informing it that the head is moving. It also receives input from eye muscle proprioceptors and other relevant sources of information about current conditions in order to make an accurate compensatory eye movement. It evaluates all of this advance sensory information and calculates the proper eye movement to exactly counterbalance the head movement. What if the eye movement does not match the head movement, however, and the visual image moves across the retina (such as in the experimental condition in which a prism was worn, or in a real-life situation in which an individual wears new prescription eyeglasses)? The retinal slip constitutes an error signal to tell the cerebellum that next time these conditions are met, adjust the eye movement to decrease the retinal slip. This trial and error sequence will be repeated until the movement is properly calibrated; moreover, these mechanisms will ensure that the movements stay calibrated. As another example, the coordination of movements requires that muscle groups be activated in precise temporal sequence. Not only do the different joints need to be coordinated temporally, but even antagonist muscles that control the same joint need precise temporal coordination. For example, an extensor muscle needs to be activated to start a reaching movement, and the corresponding flexor muscle needs to be activated at the end of the movement to stop the movement appropriately. The precise timing of muscle contractions and the force necessary for each contraction varies with the amount of load placed on a muscle, as well as on the inherent properties of the muscle itself (e.g., elasticity). These variables are constantly changing throughout life, as one grows, gains/loses weight, and ages. Moreover, a similar movement will require different patterns of motor activity depending on the weight being born by the muscle (for example, if an extended hand is empty or holding a heavy weight). The cerebellum appears necessary for the proper timing and coordination of muscle groups, very likely through a trial-and-error learning mechanism discussed previously. Such a role helps explain the deficits seen in dysdiadochokinesia, in which patients cannot perform rapidly alternating sequences of movements. It is believed that the mossy fiber inputs to the cerebellum convey the sensory information used to evaluate the overall “context” of the movement. Mossy fibers are known to

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respond to sensory stimuli; they are also correlated with different movements (Fig. 6). These fibers convey such information as: Where are the appropriate body parts (proprioceptors), what is the current load on the muscle (proprioceptors, somatosensory receptors, etc.), what other sensory information can predict a useful response (e.g., the tone in the eye blink conditioning), what are the desired movements (motor cortex). The error signal is believed to be conveyed by the climbing fiber inputs. Climbing fibers are known to be especially active when an unexpected event occurs, such as when a greater load than expected is placed on a muscle or when a toe is stubbed. Thus, the large divergence of input from the mossy fibers to the granule cells to the parallel fibers is believed to create complex representations of the entire sensory context at present and the desired motor output. When the desired output is not achieved, the climbing fibers signal this error and trigger a calcium spike in the Purkinje cell. The influx of calcium changes the connection strengths between parallel fibers and Purkinje cells, such that the next time the same behavioral context occurs, the motor output will be modified to more closely approximate the desired output. (As an exercise, review the example of feedforward control of temperature in Chapter 1 and compare the components of that circuit with the feedforward control of movement by the cerebellum.)

Figure 6. Cerebellum as a feedforward controller

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BASAL GANGLIA The previous 4 lectures have described the anatomy and function of the 4 levels of the motor system hierarchy: the spinal cord, the brainstem, the motor cortex, and the association cortex. Two other brain structures can be considered as “side loops” in the motor hierarchy. They influence the processing of motor control and modulate the output of the descending pathways without directly causing motor output. Both of these structures—the basal ganglia and the cerebellum—are now known to have other functions in addition to modulating motor control. Because the most obvious clinical signs of damage to these areas are a wide variety of motor impairments, they are still generally considered to be motor structures. Basal ganglia dysfunction causes a set of symptoms that are quite different from damage to descending motor pathways, and thus the basal ganglia were at one time considered to form an “extrapyramidal motor system” that was distinct from the pyramidal tract pathways. It is now known that the basal ganglia do not originate a separate motor pathway. Instead, they influence and modulate the activity of motor cortex and the descending motor pathways in ways that cause distinct symptoms when different basal ganglia structures are damaged. Gross anatomy of the basal ganglia The basal ganglia comprise a distributed set of brain structures in the telencephalon, diencephalon, and mesencephalon (Fig. 1 and 2). The forebrain structures include the caudate nucleus, the putamen, the nucleus accumbens (or ventral striatum) and the globus pallidus. Together, these structures are named the corpus striatum. The caudate nucleus is a C-shaped structure that is closely associated with the lateral wall of the lateral ventricle. It is largest at its anterior pole (the head), and its size diminishes posteriorly as it follows the course of the lateral ventricle (the body) all the way to the temporal lobe (the tail), where it terminates at the amygdaloid nuclei. The putamen is also a large structure that is separated from the caudate nucleus by the anterior limb of the internal capsule. The putamen is connected to the caudate head by bridges of cells that cut across the internal capsule. Because of the striated appearance of these cell bridges (Fig. 1b), the caudate and putamen are collectively referred to as the striatum or neostriatum, and the nucleus accumbens is often called the ventral striatum. Functionally, the caudate nucleus and the putamen are considered equivalent to each other; indeed, most mammals have only a single nucleus called the striatum. It is unclear whether there is any functional significance of the separation of the striatum into the caudate and putamen in primates. The putamen and the globus pallidus are collectively called the lenticular nucleus, or lentiform nucleus. The globus pallidus is divided into two segments: the internal (or medial) segment and the external (or lateral) segment.

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Figure 1. Basal ganglia nuclei. (A) Location of basal ganglia components in idealized brain section. (B) Cell bridges between the caudate and putamen give a striated appearance.

Basal Ganglia Corpus striatum

Lenticular nucleus

Nucleus accumbens Caudate Putamen Globus pallidus Subthalamic nucleus Substantia nigra

Striatum or Neostriatum

Figure 2. Basal ganglia nomenclature

The subthalamic nucleus is part of the diencephalon; as its name implies, it is located just below the thalamus. The substantia nigra is a midbrain structure, composed of two distinct parts: the pars compacta and the pars reticulata. The substantia nigra is located between the red nucleus and the crus cerebri (cerebral peduncle) on the ventral part of the midbrain. The pars compacta is the source of a clinically important dopaminergic pathway to the striatum; loss of neurons in this area is the cause of Parkinson’s disease (see below). An area that is functionally analogous to the substantia nigra pars compacta is the ventral tegmental area, which is located nearby and makes a dopaminergic projection to the nucleus accumbens. Basal ganglia afferents The striatum is the main recipient of afferents to the basal ganglia (Fig. 3). These excitatory afferents arise from the entire cerebral cortex and from the intralaminar nuclei of the thalamus (primarily the centromedian nucleus and parafascicularis nucleus). The projections from different cortical areas are segregated, such that the frontal lobe projects predominantly to the caudate head and the putamen; the parietal and occipital lobes project to the caudate body; and the temporal lobe projects to the caudate tail. The primary motor cortex and the primary

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somatosensory cortex project mainly to the putamen, while the premotor cortex and supplementary motor areas project to the caudate head. Other cortical areas project primarily to the caudate. Thus, along the C-shaped extent of the caudate nucleus, the caudate cells receive their input from the cortical regions that are close by. The enlarged head of the caudate reflects the large projection from the frontal cortex to the caudate. In addition, the nucleus accumbens (ventral striatum) receives a large input from limbic cortex.

Figure 3. Basal ganglia afferents. For diagram simplicity, in this and subsequent figures, the caudate and putamen are represented by the putamen only, as the two regions have similar connections.

Basal ganglia efferents The major output structures of the basal ganglia are the globus pallidus internal segment (GPint) and the substantia nigra pars reticulata (SNr) (Fig. 4). Both of these structures make GABAergic, inhibitory connections on their targets. The GPint projects to a number of thalamic structures by way of two fiber tracts: the ansa lenticularis and the lenticular fasciculus. The loop that processes sensorimotor information from the motor cortex and the somatosensory cortex projects to the ventral anterior (VA) and ventral lateral (VL) nuclei. The loop that processes other neocortical information projects to the dorsomedial nucleus (DM), intralaminar nuclei, and parts of the VA nucleus. The SNr projects to the superior colliculus, which is involved in eye movements, as well as to the VA/VL thalamic nuclei.

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Figure 4. Basal ganglia efferents

Basal ganglia intrinsic connections A number of intrinsic pathways interconnect various basal ganglia structures (Fig. 5). (1) the striatopallidal pathway is a GABAergic, inhibitory connection between the striatum and both segments of the globus pallidus. (2) the striatonigral pathway is a GABAergic, inhibitory connection between the striatum and the SNr. (3) the globus pallidus external segment makes a GABAergic, inhibitory connection to the subthalamic nucleus. (4) the subthalamic nucleus makes glutamatergic, excitatory connections onto both segments of the globus pallidus and the SNr. This pathway is the only purely excitatory pathway among the intrinsic pathways of the basal ganglia. (5) The nigrostriatal pathway makes a dopaminergic synapse onto striatal neurons. As we will see below, this is a mixed pathway, with excitatory effects on some striatal neurons and inhibitory effects on others.

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Fig. 5. Basal ganglia intrinsic connections

Two pathways process signals in the basal ganglia There are two distinct pathways that process signals through the basal ganglia: the direct pathway and the indirect pathway. These two pathways have opposite net effects on thalamic target structures. Excitation of the direct pathway has the net effect of exciting thalamic neurons (which in turn make excitatory connections onto cortical neurons). Excitation of the indirect pathway has the net effect of inhibiting thalamic neurons (rendering them unable to excite motor cortex neurons). The normal functioning of the basal ganglia apparently involves a proper balance between the activity of these two pathways. One hypothesis is that the direct pathway selectively facilitates certain motor (or cognitive) programs in the cerebral cortex that are adaptive for the present task, while the indirect pathway simultaneously inhibits the execution of competing motor programs. An upset of the balance between the direct and indirect pathways results in the motor dysfunctions that characterize the extrapyramidal syndrome (see below). Although the connectivity patterns of the direct and indirect pathways are relatively straightforward, the predominance of inhibitory connections in the system can make an understanding of the functional circuitry complicated and nonintuitive (Fig. 6). The direct pathway starts with cells in the striatum that make inhibitory connections with cells in the GPint. The GPint cells in turn make inhibitory connections on cells in the thalamus. Thus, the firing of GPint neurons inhibits the thalamus, making the thalamus less likely to excite the neocortex. When the direct pathway striatal neurons fire, however, they inhibit the activity of the GPint neurons. This inhibition releases the thalamic neurons from inhibition (i.e., it disinhibits the thalamic neurons), allowing them to fire to excite the cortex. Thus, because of the “double negative” in the pathway between the striatum and GPint and the GPint and thalamus, the net result of exciting the direct pathway striatal neurons is to excite motor cortex.

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Think of it as a multiplication equation, with an excitatory connection (E) equal to +1 and an inhibitory connection (I) equal to –1: E I I Cortex Æ striatum Æ GPint Æ thalamus +1 x –1 x –1 = +1 because the two negative numbers cancel each other out.

Fig. 6. Direct/indirect pathways. Thick (green) lines represent excitatory connections and thin (red) lines represent inhibitory connections.

The indirect pathway starts with a different set of cells in the striatum. These neurons make inhibitory connections to the external segment of the globus pallidus (GPext). The GPext neurons make inhibitory connections to cells in the subthalamic nucleus, which in turn make excitatory connections to cells in the GPint. (Remember that the subthalamic-GPint pathway is the only purely excitatory pathway within the intrinsic basal ganglia circuitry.) As we saw before, the GPint neurons make inhibitory connections on the thalamic neurons. To see the net effects of activation of the indirect pathway, let us work backwards from the GPint. When the GPint cells are active, they inhibit thalamic neurons, thus making cortex less active. When the subthalamic neurons are firing, they increase the firing rate of GPint neurons, thus increasing the net inhibition on cortex. Firing of the GPext neurons inhibits the subthalamic neurons, thus making the GPint neurons less active and disinhibiting the thalamus. However, when the indirect pathway striatal neurons are active, they inhibit the GPext neurons, thus disinhibiting the subthalamic neurons. With the subthalamic neurons free to fire, the GPint neurons inhibit the thalamus, thereby producing a net inhibition on the motor cortex.

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Again, think of a multiplication analogy: E I I E I Cortex Æ striatum Æ GPext Æ Subthalamic Nucleus Æ GPint Æ thalamus +1 x –1 x –1 x +1 x –1 = –1 Because there are 3 negative numbers in the equation, the net effect is negative. Thus, as a result of the complex sequences of excitation, inhibition, and disinhibition, the net effect of the cortex exciting the direct pathway is to further excite the cortex (positive feedback loop), whereas the net effect of cortex exciting the indirect pathway is to inhibit the cortex (negative feedback loop). Presumably, the function of the basal ganglia is related to a proper balance between these two pathways. Motor cortex neurons have to excite the proper direct pathway neurons to further increase their own firing, and they have to excite the proper indirect pathways neurons that will inhibit other motor cortex neurons that are not adaptive for the task at hand. The nigrostriatal projection An important pathway in the modulation of the direct and indirect pathways is the dopaminergic, nigrostriatal projection from the substantia nigra pars compacta to the striatum. Direct pathways striatal neurons have D1 dopamine receptors, which depolarize the cell in response to dopamine. In contrast, indirect pathway striatal neurons have D2 dopamine receptors, which hyperpolarize the cell in response to dopamine. The nigrostriatal pathway thus has the dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway. Because of this dual effect, excitation of the nigrostriatal pathway has the net effect of exciting cortex by two routes, by exciting the direct pathway (which itself has a net excitatory effect on cortex ) and inhibiting the indirect pathway (thereby disinhibiting the net inhibitory effect of the indirect pathway on cortex). The loss of these dopamine neurons in Parkinson’s disease causes the poverty of movement that characterizes this disease, as the balance between direct pathway excitation of cortex and indirect pathway inhibition of cortex is tipped in favor of the indirect pathway, with a subsequent pathological global inhibition of motor cortex areas. Functions of the basal ganglia Motor functions The function of the basal ganglia in motor control is not understood in detail. It appears that the basal ganglia is involved in the enabling of practiced motor acts and in gating the initiation of voluntary movements by modulating motor programs stored in the motor cortex and elsewhere in the motor hierarchy. Thus, voluntary movements are not initiated in the basal ganglia (they are initiated in the cortex); however, proper functioning of the basal ganglia

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appears to be necessary in order for the motor cortex to relay the appropriate motor commands to the lower levels of the hierarchy.

What is the function of the tonic inhibitory output of the basal ganglia? Recall from the “Motor Cortex” lecture that stimulating the motor cortex of monkeys at various locations results in stereotyped sequences of movements, such as bringing the hand to the mouth or adopting a defensive posture. It appears that a number of “primitive” motor programs are stored in the cortex, and motor control may require the activation of these elemental motor programs in the precise temporal order to accomplish a sophisticated motor plan. It is important that only one motor program be active at a given time, however, such that one motor act (e.g., use hand to bring food to the mouth) is not competing with a conflicting motor act (e.g., use hand to shield face from dangerous object). It is thought that the basal ganglia is normally active in suppressing inappropriate motor programs, and that activation of the direct pathway temporarily releases one motor program from inhibition, enabling it to be executed by the organism. Thus, the basal ganglia act as a gate that enables the execution of automatic programs in the hierarchy. Which motor programs should be released from inhibition at a given moment? The basal ganglia may have a major role in learning what motor acts result in rewards for the organism. This information is provided by the dopaminergic neurons of the SNc and ventral tegmental nucleus. Recordings from these neurons in monkeys have shown that they tend to respond when the monkey receives an unexpected reward, and they tend to be inhibited when the monkey fails to receive an expected reward (Fig. 7). Because the net effect of activation of the nigrostriatal pathway is to excite the direct pathway and inhibit the indirect pathway, this pattern of dopaminergic firing may be involved in tuning the relative balance of direct/indirect pathway activity to enhance the firing of cortical motor programs that produce rewarding outcomes and to suppress the activity of motor programs that do not result in reward. In this way, motor habits can be constructed that tend to reward the animal. Figure 7. Dopaminergic neurons signal unexpected reward or unexpected absence of reward. (A) If a reward occurs unexpectedly, the dopaminergic neuron fires briskly. This may strengthen the cortical motor programs that led up to the reward. (B) If a reward occurs that the monkey previously learned was predicted by stimulus, the neuronal firing is not altered. This may signal that all is proceeding normally. (C) If the reward-predicting stimulus does not produce a reward, the neuronal firing is inhibited. This may weaken the cortical motor programs that did not produce the expected reward.

Cognitive functions As mentioned earlier, there are a number of cortical loops through the basal ganglia that involve prefrontal association cortex and limbic cortex. Through these loops, the basal ganglia 50

are thought to play a role in cognitive function that is similar to their role in motor control. That is, the basal ganglia are involved in selecting and enabling various cognitive, executive, or emotional programs that are stored in these other cortical areas. Moreover, the basal ganglia appear to be involved in certain types of learning. For example, in rodents the striatum is necessary for the animal to learn certain stimulus-response tasks (e.g., make a right turn if stimulus A is present and make a left turn if stimulus B is present). Recordings from rat striatal neurons show that early in training, striatal neurons fire at many locations while a rat learns such a task on a T-shaped maze (Fig. 8). This suggests that initially the striatum is involved throughout the execution of the task. As the animal learns the task and becomes exceedingly good at its performance, the striatal neurons change their activity patterns, firing only at the beginning of the trial and at the end. It appears that the learned programs to solve this task are now stored elsewhere; the firing of the striatal neurons at the beginning of the maze is presumed to reflect its enabling of the appropriate motor/cognitive plan in the cortex, and the firing at the end of the maze is involved in evaluating the reward outcome of the trial.

Figure 8. Habit learning in striatum. (A) A rat is trained to run down a T-shaped maze and make a left turn for food reward if it hears a high-pitch tone or make a right turn for food reward if it hears a low-pitch tone. (B) Early in training, as the rat is beginning to learn the task, striatal neurons fire at locations all over the maze, especially at the choice point. (C) Late in training, when the rat has mastered the task and performs very quickly and accurately, the striatal neurons now fire only at the start and ends of the maze.

In humans, the basal ganglia appear to be necessary for certain forms of implicit memory tasks. Like motor habit learning discussed above, many types of cognitive learning require repeated trials and are often unconscious. An example is probabilistic classification. In this type of task, people have to learn to classify objects based on the probability of belonging to a class, rather than on any explicit rule. In one experiment, subjects were shown a deck of cards with different symbols. Each symbol was associated with a certain probability (60-85%) of predicting rain or sunshine, and the subjects had to say on each trial whether the symbol was a predictor of rain or sunshine. Because the same symbol sometimes predicted sunshine and other times predicted rain, the subjects could not devise a simple rule, and they made many errors at first. Over time, however, they began to get better at classifying the symbols appropriately, although they still often claimed to be guessing. Patients with basal ganglia disorders were impaired at this task, suggesting that the processing of the cognitive loops of the basal ganglia are somehow involved in our ability to subconsciously learn the probabilities of predicted outcomes associated with particular stimuli.

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Disorders of the basal ganglia A number of neurological disorders result from damage to the basal ganglia. Two of these disorders (Parkinson’s disease and Huntington’s disease) will be briefly discussed here to relate the concepts learned in this chapter to the symptoms of the disorders. More thorough treatment of these disorders will be given in Chapter 7. Nigrostriatal pathway and Parkinson’s disease Parkinson’s disease is characterized by slowness or absence of movement (bradykinesia or akinesia), rigidity, and a resting tremor (especially in the hands and fingers). Patients have difficulty initiating movements, and once initiated the movements are abnormally slow. The cause of Parkinson’s disease is the loss of the dopaminergic neurons in the substantia nigra pars compacta. From one’s knowledge of the effects of the nigrostriatal pathway on the direct and indirect pathways, it becomes straightforward to see why the loss of this pathway results in the poverty of movement symptomatic of Parkinson’s disease. Because the nigrostriatal pathway excites the direct pathway and inhibits the indirect pathway, the loss of this input tips the balance in favor of activity in the indirect pathway. Thus, the GPint neurons are abnormally active, keeping the thalamic neurons inhibited. Without the thalamic input, the motor cortex neurons are not as excited, and therefore the motor system is less able to execute the motor plans in response to the patient’s volition. Indirect pathway and Huntington’s disease The symptoms of Huntington’s disease are in many respects the opposite of the symptoms of Parkinson’s disease. Huntington’s disease is characterized by choreiform movements: involuntary, continuous movement of the body, especially of the extremities and face. Often these movements resemble pieces of adaptive movements, but they occur involuntarily and without behavioral significance. Huntington’s disease results from the selective loss of striatal neurons in the indirect pathway. Thus, the balance between the direct and indirect pathways becomes tipped in favor of the direct pathway. Without the normal inhibitory influence on the thalamus that is provided by the indirect pathway, thalamic neurons can fire randomly and inappropriately, causing the motor cortex to execute motor programs with no control by the patient.

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MOTOR CORTEX The previous chapters discussed the lower levels of the motor hierarchy (the spinal cord and brainstem), which are involved in the low-level, “nuts and bolts” processing that controls the activity of individual muscles. Individual alpha motor neurons control the force exerted by a particular muscle, and spinal circuits can control sophisticated and complex behaviors such as walking and reflex actions. The types of movements controlled by these circuits are not initiated consciously, however. Voluntary movements require the participation of the third and fourth levels of the hierarchy: the motor cortex and the association cortex. These areas of the cerebral cortex plan voluntary actions, coordinate sequences of movements, make decisions about proper behavioral strategies and choices, evaluate the appropriateness of a particular action given the current behavioral or environmental context, and relay commands to the appropriate sets of lower motor neurons to execute the desired actions. Motor cortex comprises the primary motor cortex, premotor cortex, and supplementary motor area The motor cortex comprises three different areas of the frontal lobe, immediately anterior to the central sulcus. These areas are the primary motor cortex (Brodmann’s area 4), the premotor cortex, and the supplementary motor area (Fig. 1). Electrical stimulation of these areas elicits movements of particular body parts. The primary motor cortex, or M1, is located on the precentral gyrus and on the anterior paracentral lobule on the medial surface of the brain. Of the three motor cortex areas, stimulation of the primary motor cortex requires the least amount of electrical current to elicit a movement. Low levels of brief stimulation typically elicit simple movements of individual body parts. Stimulation of premotor cortex or the supplementary motor area requires higher levels of current to elicit movements, and often results in more complex movements than stimulation of primary motor cortex. Stimulation for longer time periods (500 msec) in monkeys results in the movement of a particular body part to a stereotyped posture or position, regardless

Figure 1. Motor cortex areas. Note that the supplementary motor area continues onto the medial wall of the cortex.

of the initial starting point of the body part. Thus, the premotor cortex and supplementary motor areas appear to be higher level areas that encode complex patterns of motor output and that select appropriate motor plans to achieve desired end results.

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Like the somatosensory cortex of the postcentral gyrus, the primary motor cortex is somatotopically organized (Figure 2). Stimulation of the anterior paracentral lobule elicits movements of the contralateral legs. As the stimulating electrode is moved across the precentral gyrus from dorsomedial to ventrolateral, movements are elicited progressively from the torso, arms, hands and face (most laterally). The representation of body parts that perform precise, delicate movements, such as the hands and face, is disproportionately large compared to the representation of body parts that perform only coarse, unrefined movements, such as the trunk or legs. The premotor cortex and supplementary motor area also contain somatotopic maps of body parts.

Figure 2. Somatotopic representation of motor outputs in motor cortex.

One might predict that the motor cortex “homunculus” arises because neurons that control individual muscles are clustered together in the cortex. That is, all of the neurons that control the biceps muscle may be located together, and all of the neurons that control the triceps may be clustered nearby, and the neurons that control the soleus muscle may be clustered in a region further removed. Electrophysiological recordings have shown that this is not the case, however. Movements of individual muscles are correlated with activity from widespread parts of the primary motor cortex. Similarly, stimulation of small regions of primary motor cortex elicits movements that require the activity of numerous muscles. Thus, the primary motor cortex homunculus does not represent the activity of individual muscles. Rather, it apparently represents the movements of individual body parts, which often require the coordinated activity of large groups of muscles throughout the body. Cortical afferents and efferents The motor cortex exerts its influence over muscles by a variety of descending routes (Figure 3). Some of the descending pathways reviewed in the last chapter can be influenced by motor cortex output. Thus, in addition to the direct cortical innervation of alpha motor neurons via the corticospinal tract, the following cortical efferent pathways influence the remaining descending tracts:

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1) the corticorubral tract allows cortex to modulate the rubrospinal tract 2) the corticotectal tract allows cortex to modulate the tectospinal tract 3) the corticoreticular tract allows cortex to modulate the reticulospinal tracts

Figure 3. Parallel pathways from the motor cortex allow the cortical motor areas to influence the processing of all descending motor tracts and side loops of the m otor system.

Figure 4. Major afferents of motor cortex.

Motor cortex cytoarchitecture Like all parts of the neocortex, the primary motor cortex is made of six layers (Fig. 5). Unlike primary sensory areas, primary motor cortex is agranular cortex; that is, it does not have a cell-packed granular layer (layer IV). Instead, the most distinctive layer of primary motor cortex is its descending output layer (Layer V), which contains the giant Betz cells. These pyramidal cells and other projection neurons of the primary motor cortex make up ~30% of the fibers in the corticospinal tract. The rest of the fibers come

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from the premotor cortex and the supplementary motor area (~30%), the somatosensory cortex (~30%), and the posterior parietal cortex (~10%). Fig. 5. Pyramidal and non-pyramidal neurons in motor cortex. The cerebral cortex is organized into six layers. These layers contain different proportions of the two main classes of cortical neurons, pyramidal and nonpyramidal cells. Pyramidal cells send long axons down the spinal cord and are the major output neurons. They are abundant in layer V. Non-pyramidal cells have axons which terminate locally.

Encoding of movement by motor cortex Primary motor cortex Alpha motor neurons in the spinal cord encode the force of contraction of groups of muscle fibers using the rate code and the size principle. As discussed above, the primary motor cortex does not generally control individual muscles directly, but rather appears to control individual movements or sequences of movements that require the activity of multiple muscle groups. Thus, in accordance with the concept of hierarchical organization of the motor system, the information represented by motor cortex is a higher level of abstraction than the information represented by spinal motor neurons. What is encoded by the neurons in primary motor cortex? Clues have come from recording the activity of these neurons as experimental animals perform different motor tasks. In general, primary motor cortex encodes the parameters that define individual movements or simple movement sequences. (1) Primary motor cortex neurons fire 5-100 msec before the onset of a movement. Thus, rather than firing as the result of muscle activity, these neurons are involved in relaying motor commands to the alpha motor neurons that eventually cause the appropriate muscles to contract. (2) Primary motor cortex encodes the force of a movement. The amount of force required to raise the arm from one location to another is much greater if one is holding a bowling ball than if one is holding a balloon. Many neurons in primary motor cortex encode the amount of force that is necessary to make such a movement. Note the distinction between movement force and muscle force. Primary motor cortex neurons encode the amount of force necessary for a particular movement, regardless of which individual muscles are used. Alpha motor neurons, in turn, translate the commands of the motor cortex neurons and control the amount of force generated by individual muscles to accomplish that movement, under the principles of the rate code and the size principle.

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(3) Primary motor cortex encodes the direction of movement. Many neurons in the primary motor cortex are selective for a particular direction of movement. For example, one cell may fire strongly when the hand is moved to the left, whereas it will be inhibited when the hand is moved to the right. (4) Primary motor cortex encodes the extent of movement. The firing of some neurons is correlated with the distance of a movement. A monkey was trained to move its arm to different target locations that varied in direction and distance from the center. The firing of many neurons was correlated with the direction of movement (as in Point 3), whereas the firing of other neurons was correlated with the distance of the movement. Interestingly, some neurons were correlated with the interaction of a particular distance and direction; that is, they were correlated with a particular target position. (5) Primary motor cortex neurons encode the speed of movement. Almost all targeted movements follow a typical bell-shaped curve of velocity as a function of distance (Fig. 6). For example, when the hand reaches out to an object, the hand accelerates during the first half of the movement, reaches a peak velocity approximately halfway to the target, and then decelerates until it reaches the target object. The firing rate of some primary motor cortex neurons in monkeys correlates with this bell-shaped speed profile, demonstrating that information about movement speed is contained in the spike trains of these neurons. Figure 6. Voluntary movements typically follow a bell-shape speed profile. The firing of some neurons in primary motor cortex is correlated with this speed profile.

Premotor Cortex The premotor cortex sends axons to the primary motor cortex as well as to the spinal cord directly. It performs more complex, task-related processing than primary motor cortex. Stimulation of premotor areas in the monkey at a high level of current produces more complex postures than stimulation of the primary motor cortex. The premotor cortex appears to be involved in the selection of appropriate motor plans for voluntary movements, whereas the primary motor cortex is involved in the execution of these voluntary movements. (1) Premotor cortex neurons signal the preparation for movement (Fig. 7). Monkeys were trained to make a particular movement in response to a visual signal, with a variable delay between the onset of the signal and the onset of the movement. Recordings from premotor cortex have shown that many neurons fire selectively in the delay interval, for many seconds before the onset of the movement. A particular neuron will fire when the 57

monkey is preparing to make a movement to the left, for example, but will be silent when the monkey is preparing to make a movement to the right. Thus, the firing of this type of neuron does not cause the movement itself, but appears to be involved in preparing the monkey to make the correct movement when the “Go” signal is given.

Figure 7. Some premotor cortex neurons fire for many seconds in anticipation of a planned movement.

(2) Premotor cortex neurons signal various sensory aspects associated with particular motor acts. Some premotor neurons fire when the animal is performing a particular action, such as breaking a peanut. Interestingly, the same neuron fires selectively when the animal sees another monkey or person breaking the peanut. It also fires selectively to the sound of a peanut shell being broke, even without any visual or motor activity. These neurons are called “mirror” neurons, because they respond not only to a particular action of the monkey but also to the sight (or sound) of another individual performing the same action. Supplementary Motor Area The supplementary motor area (SMA) is involved in programming complex sequences of movements and coordinating bilateral movements. Whereas the premotor cortex appears to be involved in selecting motor programs based on visual stimuli or on abstract associations, the supplementary motor area appears to be involved in selecting movements based on remembered sequences of movements. (1) SMA responds to sequences of movements and to mental rehearsal of sequences of movements (Fig. 8). Brain activity was measured in a PET scanner while subjects made simple and complex sequences of movement. When the movements were simple, such as a repetitive movement of a single digit, the primary motor cortex and the primary somatosensory cortex were activated on the contralateral hemisphere. When the subject was asked to perform a complex sequence of finger movements, the SMA was activated bilaterally, in addition to the contralateral primary motor and somatosensory cortex activation. Finally, when the subject was asked to remain still but to mentally rehearse the complex sequence of activity, the SMA was still active, even though the primary 58

motor and somatosensory cortex areas were silent. Thus, the SMA appears to be involved in bilateral movements and in the mental rehearsal of these movements.

Fig. 8. Positron emission tomography (PET) study of simple vs. complex finger movements. Ovals indicate regions of increased blood flow. Data from Roland PE, et al. (1980) J. Neurophysiol. 43: 118136.

(2) SMA is involved in the transformation of kinematic to dynamic information. Movements can be defined in terms of dynamics (the amount of force necessary to make a movement) and kinematics (the distance and angles that define a particular movement in space). Many movement plans are represented in kinematic terms (e.g., Move the hand to the left). However, the motor system must eventually translate this to a representation based on dynamics, in order to instruct the appropriate muscles to contract with the appropriate force. Recordings from monkeys have shown that during the preparatory delay before a monkey makes an instructed movement, some SMA neurons change their firing correlates from a kinematic-based representation to a dynamics-based representation, suggesting that SMA plays a vital role in this transformation.

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Association Cortex The fourth level of the motor hierarchy is the association cortex, in particular the prefrontal cortex and the posterior parietal cortex. These brain areas are not motor areas in the strict sense. Their activity does not correlate precisely with individual motor acts, and stimulation of these areas does not result in motor output. However, these areas are necessary to ensure that movements are adaptive to the needs of the organism and appropriate to the behavioral context. (1) Posterior parietal cortex is involved in ensuring that movements are targeted accurately to objects in external space. This area is involved in processing spatial relationships of objects in the world and in constructing a representation of external space that is independent of the observer’s eye position or body position. Such representations allow a stable percept of the world that is independent of viewer orientation, as well as the representation of desired trajectories in space that are independent of body position. Damage to the posterior parietal cortex can result in a number of apraxias, that is, the inability to make complex, coordinated movements. For example, a patient with constructional apraxia is unable to replicate the configuration of a set of blocks in the proper sequence, even though the patient is able to maneuver each block individually with dexterity. (2) Prefrontal cortex is involved in the selection of appropriate actions for a particular behavioral context. It is also involved in the evaluation of the consequences of a particular course of action. Patients with damage to the prefrontal cortex have problems in executive processing. They make inappropriate behavioral decisions, and often cannot anticipate the likely consequences of their actions. They display impulsive behavior, often showing an inability to delay instant gratification for a long-term larger reward.

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THE INTEGRATED MOTOR SYSTEM AND DISORDERS OF THE MOTOR SYSTEM

The previous motor system lectures have deconstructed the motor system into its component parts, in an effort to portray how the brain’s “divide and conquer” strategy assigns different motor control tasks to different brain regions. This chapter describes the types of disorders that result from damage or disease to different parts of the motor system. In the process, the different components of the motor system are reviewed to see how they work together to produce the fluid, effortless body movements that we take for granted. An emphasis will be placed on trying to explain the causes and symptoms of motor system disorders in terms of the basic principles of neuroanatomy and neuronal function that you learned in the earlier lectures. Lower Motor Neuron Syndrome The first level of the motor system hierarchy is the spinal cord, the location of the alpha motor neurons that constitute the “final common pathway” of all motor commands. Alpha motor neurons are the neurons that directly innervate skeletal muscle, causing the contractions that produce all movements. Reflex circuits and other neural circuitry within the spinal cord underlie the automatic processing of many of the direct commands to the muscles (the “nuts and bolts” processing), thereby freeing higher-order areas to concentrate on more global, task-related processing. Motor system dysfunction can result from damage or disease at any level of the motor system hierarchy and side-loops. Differences in the symptoms that result from damage at different levels allow the clinician to localize where in the hierarchy the damage is likely to be. Damage to alpha motor neurons results in a characteristic set of symptoms called the lower motor neuron syndrome (lower motor neurons refer to alpha motor neurons in the spinal cord and brain stem; all motor system neurons higher in the hierarchy are referred to as upper motor neurons). This damage usually arises from certain diseases that selectively affect alpha motor neurons (such as polio) or from localized lesions near the spinal cord. Lower motor neuron syndrome is characterized by the following symptoms: (1) The effects can be limited to small groups of muscles. Recall that a motor neuron pool is a nucleus of alpha motor neurons that innervate a single muscle. Furthermore, nearby motor neuron pools control nearby muscles. Thus, restricted damage to lower motor neurons, either within the spinal cord or at the ventral roots, will affect only a restricted group of muscles. (2) Muscle atrophy. When alpha motor neurons die, the muscle fibers that they innervate become deprived of trophic factors necessary for their survival. Eventually, the muscle itself atrophies. (3) Weakness. Because of the damage to alpha motor neurons and the atrophy of muscles, weakness is profound in lower motor neuron disorders.

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(4) Fasciculation. When alpha motor neurons degenerate, they can produce spontaneous action potentials. These spikes cause the muscle fibers that are part of that neuron’s motor unit to fire, resulting in a visible twitch of the affected muscle. This twitch is called a fasciculation. (5) Fibrillation. With further degeneration of the alpha motor neuron, only remnants of the axons near the muscle fibers remain. These individual axon fibers can also generate spontaneous action potentials; however, these action potentials will only cause individual muscle fibers to contract. This spontaneous twitching of individual muscle fibers is called a fibrillation. Fibrillations are too small to be seen as a visible muscle contraction. They can only be detected with electrophysiological recordings of the muscle activity (an electromyogram). (6) Hypotonia. Because alpha motor neurons are the only way to stimulate extrafusal muscle fibers, the loss of these neurons causes a decrease in muscle tone. (7) Hyporeflexia. The myotatic (stretch) reflex is weak or completely absent with lower motor neuron disorders, because the alpha motor neurons that cause the muscle to contract are damaged. Upper motor neuron syndrome Damage to any part of the motor system hierarchy above the level of alpha motor neurons (not including the side loops) results in a set of symptoms termed the upper motor neuron syndrome. Some of these symptoms are opposite of those experienced with lower motor neuron disorders. Thus, one of the critical determinations a clinician must make is whether a patient presenting with motor problems has an upper motor neuron disorder or a lower motor neuron disorder. Upper motor neuron disorders typically arise from such causes as stroke, tumors, and blunt trauma. For example, strokes to the middle cerebral artery, lateral striate artery, or the medial striate artery can cause damage to the lateral surface of cortex or to the internal capsule, where the descending axons of the corticospinal tract collect. The symptoms of upper motor neuron syndrome are: (1) The effects extend to large groups of muscles. Recall from the “Motor Cortex” lecture that muscles from different body parts are activated by stimulation of parts of motor cortex, consistent with the notion that motor cortex represents movements that are controlled by many joints, rather than individual muscles. Thus, a stroke in a particular part of motor cortex will affect the activation of many muscles in the body. Likewise, a stroke that affects the internal capsule or crus cerebri could affect muscles on the entire contralateral side of the body. (2) Atrophy is rare. Because alpha motor neurons are present, muscles will continue to receive trophic agents necessary for their survival. A mild amount of atrophy may result from disuse, but it will not be as pronounced as that resulting from a lower motor neuron disorder.

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(3) Weakness. Upper motor neuron disorders produce a graded weakness of movement called paresis, which is different from the complete loss of muscle activity caused by paralysis (plegia). (4) Absence of fasciculations. Because alpha motor neurons themselves are spared, fasciculations do not occur. (5) Absence of fibrillations. Likewise, fibrillations do not occur, as the alpha motor neurons are not damaged. (6) Hypertonia. Upper motor neuron disorders result in an increase in muscle tone. Recall that descending motor pathways can modulate the intrinsic circuitry that is present in the spinal cord. This modulatory input can be either inhibitory or excitatory. Through mechanisms that are not well understood, the loss of descending inputs tends to result in an increased firing rate of alpha and/or gamma motor neurons. The higher firing rate causes an increase in the resting level of muscle activity, resulting in hypertonia. (7) Hyperreflexia. Because of the loss of inhibitory modulation from descending pathways, the myotatic (stretch) reflex is exaggerated in upper motor neuron disorders. The stretch reflex is a major clinical diagnostic test of whether a motor disorder is caused by damage to upper or lower motor neurons. (8) Clonus. Sometimes the stretch reflex is so strong that the muscle contracts a number of times in a 5-7 Hz oscillation when the muscle is rapidly stretched and then held at a constant length. This abnormal oscillation, called clonus, can be felt by the clinician. (9) Initial contralateral flaccid paralysis. In the initial stages after damage to motor cortex, the contralateral side of the body shows a flaccid paralysis. Gradually, over the course of a few weeks, motor function returns to the contralateral side of the body. This gradual recovery of function results from the ability of other motor pathways to take over some of the lost functions. Recall that there are multiple descending motor pathways by which high-order information can reach the spinal cord. Thus, descending pathways such as the rubrospinal and the reticulospinal tracts, which receive direct or indirect cortical input, can begin to take over the function lost by the damage to the corticospinal tract. Moreover, primary motor cortex itself is known to be capable of reorganizing itself to recover some lost function. Thus, if the part of motor cortex that controls a certain body movement is damaged, neighboring parts of the motor cortex that are undamaged can, to some extent, alter their function to help compensate for the damaged areas. The one major exception to the recovery of function is that fine control of the distal musculature will not be regained after a lesion to the corticospinal tract. Recall that there are direct connections from primary motor cortex neurons to alpha motor neurons controlling the fingers. These connections presumably underlie our abilities to manipulate objects with great precision and to do such tasks as playing a piano and performing microsurgery. None of the other descending pathways have direct connections onto spinal motor neurons, and none of them can compensate for the loss of fine motor control of the hands and fingers after damage to the corticospinal tract.

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(10) Spasticity. A clinical sign of upper motor neuron disorder is a velocity dependent resistance to passive movement of the limb. If the clinician moves a patient’s limb slowly, there may be little resistance to the movement. As the passive movement becomes quicker, however, at a certain point the muscle will sharply resist the movement. This is referred to as a “spastic catch.” The mechanism for this spasticity is not entirely known, but altered firing rate of gamma motor neurons and their regulating interneurons may be involved, as well as an increase in alpha motor neuron activity, causing an inappropriately powerful stretch reflex to a fast stretch of the muscle. Sometimes, the resistance becomes so great that the autogenic inhibition reflex is initiated, causing a sudden drop in the resistance; this is referred to as the clasp-knife reflex. (11) Babinski sign. A classic neurological test for corticospinal tract damage is the Babinski test. In this test, the clinician strokes the sole of the foot firmly with an instrument. This elicits a normal plantar response in normal individuals, as the toes curl inward. In patients with an upper motor neuron disorder, however, an abnormal extensor plantar response is elicited, as the big toe extends upward and the remaining toes fan out. This is called a positive Babinski sign. Interestingly, the positive Babinski sign is normal in infants for the first 2 years of life. During development, however, the reflex changes to the normal adult pattern, presumably as corticospinal circuits mature. In addition to the above symptoms, damage to the motor cortex and association cortex can result in impairments in motor planning and strategies and in an inability to perform complex motor tasks. Performance of simple tasks is intact, but patients are unable to perform complex, practiced tasks. This symptom is known as apraxia. For example, patients may be unable to arrange a set of blocks to match an example block-structure in front of them. They can move the blocks individually, but cannot come up with a motor plan to arrange them properly. This disorder is known as constructional apraxia. Other apraxias include dressing apraxia (inability to dress oneself) and verbal apraxia (inability to coordinate mouth movements to produce speech). Paralysis A section or crush of the spinal cord will result in paralysis of all parts of the body below the damaged region. Even though such an injury occurs in the spinal cord, it is not considered a lower motor neuron disorder, as the alpha motor neurons themselves are not directly damaged. If the damage occurs at the cervical level, then all four limbs will be paralyzed (quadriplegia). If the damage occurs below the cervical enlargement, then only the legs are paralyzed (paraplegia). Other terms used to describe patterns of paralysis are hemiplegia (paralysis to one side of the body) and monoplegia (paralysis of a single limb). Disorders of the basal ganglia The basal ganglia have historically been considered part of the motor system because of the variety of motor deficits that arise when they are damaged. The types of symptoms that result from basal ganglia disorders can be divided into two classes: dyskinesias, which are abnormal, involuntary movements, and akinesias, which are abnormal, involuntary postures. Because the basal ganglia were once considered to form a separate, “extrapyramidal” motor system, these symptoms are called extrapyramidal disorders.

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Dyskinesia The dyskinesias that result from basal ganglia disorders are described below: (1) Resting tremors are most often associated with Parkinson’s disease. When the patient is at rest, certain body parts will display a 4-7 Hz tremor. For example, the thumb and forefingers will move back-and-forth against each other in a characteristic tremor called “pillrolling tremor.” The tremor stops when the body part engages in active movement. (2) Athetosis is characterized by involuntary, writhing movements, especially of the hands and face. (3) Chorea, which derives from the Greek word for “dance,” is characterized by continuous, writhing movements of the entire body. It is viewed by some as an extreme form of athetosis. Chorea is most closely identified with Huntington’s disease. (4) Ballismus is characterized by sudden, involuntary, ballistic movements of the extremities. Akinesia The following describes the akinesias that result from basal ganglia disorders: (1) Rigidity is a resistance to passive movement of the limb. Unlike spasticity, rigidity does not depend on the speed of the passive movement. In some patients, this resistance is so great that it is referred to as lead-pipe rigidity, because moving the patient’s limb feels like bending a lead pipe. In some patients, this rigidity is coupled with tremors and is called cogwheel rigidity, as moving the limb feels to the clinician like the catching and release of gears. As with spasticity, the mechanism is not entirely understood, but may result from continuous firing of alpha motor neurons causing a continual contraction of the muscle. (2) Dystonia is the involuntary adoption of abnormal postures, as agonist and antagonist muscles both contract and become so rigid that the patient cannot maintain normal posture. (3) Bradykinesia refers to a slowness, or poverty, of movement. A number of well-known movement disorders are associated with basal ganglia dysfunction. We shall concentrate on 3 of the most well-understood: Parkinson’s disease, Huntington’s disease, and hemiballismus. To understand how these disorders result in the specific symptoms, it is necessary to review the circuit anatomy of the basal ganglia that was presented in the “Basal Ganglia” lecture.

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Parkinson’s disease Parkinson’s disease results from the death of dopaminergic neurons in the substantia nigra pars compacta. It is characterized by a resting tremor, but the most debilitating symptom is severe bradykinesia or akinesia. In advanced cases, patients have difficulty in initiating movements, although involuntary, reflexive movements can be normal. It is as if the loss of the substantia nigra neurons has put a brake on the output of motor cortex, inhibiting voluntary motor commands from descending to the brain stem and spinal cord and activating alpha motor neurons. Although the cause of Parkinson’s disease is still not known, much has been learned in the past 15 years from the development of an animal model of Parkinson’s disease. This model was discovered by accident when a number of young patients presented with symptoms remarkably similar to Parkinson’s disease. These patients were all drug addicts who had been taking an artificially manufactured drug called MPTP (1-methyl-4-phenyl-1, 2, 3 ,6tetrahydropyradine). This drug destroyed the dopaminergic neurons in the substantia nigra, leading to a Parkinsonian disorder. Laboratory animals injected with MPTP have since become a leading model for understanding the disease and developing treatments. How does the loss of the dopaminergic neurons cause the poverty of movements associated with Parkinson’s disease (Fig. 1)? Recall from the “Basal Ganglia” lecture that the substantia nigra pars compacta projects to both direct pathway and indirect pathways neurons in the striatum. Because there are two different types of dopamine receptors, substantia nigra activity excites the direct pathway and inhibits the indirect pathway. The net effect of the direct pathway is to excite motor cortex, and the net effect of the indirect pathway is to inhibit motor cortex. Thus, the loss of the nigrostriatal dopaminergic pathway upsets the fine balance of excitation and inhibition in the basal ganglia and reduces the excitation of motor cortex. In ways that are not understood, this reduction of thalamic excitation interferes with the ability of the motor cortex to generate commands for voluntary movement, resulting in the poverty of movement of Parkinsonian patients. It is as if all of the motor programs stored in cortex are constantly inhibited by the indirect pathway, with not enough excitation of the direct pathway for the desired motor program to become activated. There is no cure for Parkinson’s disease, but a number of effective treatments exist. The earliest effective treatment was developed when it was first discovered that Parkinson’s disease was caused by a loss of dopaminergic neurons. It was reasoned that replacement of the dopamine might alleviate these symptoms. Because dopamine itself does not cross the bloodbrain barrier, L-Dopa, a chemical precursor to dopamine, was used instead. Amazingly, flooding the system with L-Dopa resulted in profound improvements in the symptoms of patients. Unfortunately, this improvement is temporary, and typically symptoms return after a number of years. Surgical intervention, such as making lesions to the globus pallidus internal segment (pallidotomy), has shown effectiveness in some patients. In recent years, a new therapy, deep brain stimulation of the subthalamic nucleus, has been gaining in popularity. In this treatment,

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Figure 1. Loss of dopaminergic neurons in the substantia nigra pars compacta causes Parkinson’s disease.

an electrical stimulator is implanted in the subthalamic nucleus. When the electrical current is turned on to stimulate the nucleus, the patient’s symptoms disappear immediately. It is not known why this procedure works, or what its long-term efficacy is. Because the projection from the subthalamic nucleus is excitatory onto globus pallidus neurons, which inhibit the thalamus, it is paradoxical that such stimulation should increase motor cortex activity. One thought is that the stimulation might actually overload the subthalamic nucleus, thereby inhibiting it and disinhibiting the thalamus. Huntington’s disease Huntington’s disease (also known as Woody Guthrie Disease) is a genetic disorder that is caused by an abnormally large number of repeats of the nucleotide sequence CAG on chromosome 4. Normal individuals have 9-35 repeats of this sequence; mutations that cause larger repeats give rise to Huntington’s disease. It is an autosomal dominant mutation, such that the offspring of a patient with Huntington’s disease has a 50% chance of inheriting the mutation. Individuals with the mutated gene will invariably develop Huntington’s disease, usually near middle age. The affected gene codes for a protein known as huntingtin, the function of which is not known. The effect of the mutated version of the gene, however, is to kill the indirect pathway neurons in the striatum, particularly those of the caudate nucleus. Huntington’s disease is also known as Huntington’s chorea because it is characterized by a continuous, choreiform movements of the body (especially the limbs and face). In addition, the disease in advanced stages is associated with dementia. There is at present no cure or effective treatment for Huntington’s disease. Why does the loss of indirect pathway neurons in the striatum cause the dyskinesias of Huntington’s disease (Fig. 2)? Recall that the net effect of the indirect pathway is to inhibit

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motor cortex. With the loss of these neurons, the excitatory effect of the direct pathway is no longer kept in check by the inhibition of the indirect pathway. Thus, the motor cortex gets too much excitatory input from the thalamus, disrupting its normal functioning and sending involuntary movement commands to the brain stem and spinal cord. Because inappropriate motor programs are not inhibited normally, the cortex continuously sends involuntary commands for movements and movement sequences to the muscles.

Figure 2. An autosomal dominant mutation causes Huntington’s disease, in which the indirect pathway cells of the striatum are selectively destroyed.

Hemiballismus Hemiballismus results from a unilateral lesion to the subthalamic nucleus, usually caused by a stroke. This lesion results in ballismus on the contralateral side of the body, while the ipsilateral side is normal (hence the term hemiballismus). The involuntary, ballistic movements result from the loss of the excitatory subthalamic nucleus projection to the globus pallidus (Fig. 3). Because the globus pallidus internal segment normally inhibits the thalamus when excited, the loss of the subthalamic component lessens the inhibition of the thalamus, making it more likely to send spurious excitation to the motor cortex. Some surgical operations have been performed to relieve the symptoms of hemiballismus, and new pharmacological treatments are in use to relieve the disorder.

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Figure 3. Hemiballismus is caused by a unilateral stroke to the subthalamic nucleus.

Disorders of the cerebellum Like the basal ganglia, the cerebellum has historically been considered part of the motor system because damage to it produces motor disturbances. Some of these symptoms were discussed in Chapter 6. Unlike the basal ganglia, damage to the cerebellum does not result in lack of movement or poverty of movement. Instead, cerebellar dysfunction is characterized by a lack of coordination of movement. Also unlike basal ganglia (and motor cortex), damage to the cerebellum causes impairments on the ipsilateral side of the body. (1) Ataxia is a general term used to describe the general impairments in movement coordination and accuracy that accompany cerebellar damage. There are two major forms of cerebellar ataxia. A. Disturbances of posture or gait result from lesions to the vestibulocerebellum. Patients have difficulties in maintaining posture because of the loss of the fine-control mechanisms programmed by cerebellar circuits that translate vestibular signals into precise, well-timed muscle contractions to counter small sways in the body. As a result, patients often develop abnormal gait and stances to compensate. For example, the feet are often spaced widely apart when the patient stands still, as this provides a more stable base to maintain balance. In addition, patients display a staggering gait, with a tendency to fall toward the side of the lesion. This gait resembles that of a drunken individual; indeed, alcohol is known to affect the firing of Purkinje cells, which may explain the loss of coordination that accompanies inebriation. B. Decomposition of movement results from the loss of the cerebellum’s ability to coordinate the activity and timing of many muscle groups to produce smooth, fluid movements. Instead, cerebellar patient must decompose each movement into its component parts, performing them in serial, rather than all at once in a coordinated fashion.

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(2) Dysmetria refers to the inappropriate force and distance that characterizes targetdirected movements of cerebellar patients. For example, in attempting to grab a cup, they may move their hand outward with too much force or may move it too far, with the result of knocking over the cup instead of grabbing it. (3) Dysdiadochokinesia refers to the inability of cerebellar patients to perform rapidly alternating movements, such as hitting a surface alternately with the palm and back of the hand. This diagnostic sign results from the lack of the cerebellum’s ability to coordinate the timing of muscle groups, alternately contracting and inhibiting antagonistic muscles, to produce the rhythmic movements. (4) Scanning speech refers to the often staccato nature of speech of cerebellar patients. The production of speech is a motor act, as muscles of the jaw, tongue, and larynx need to work in unison to produce words and sounds. Cerebellar patients have difficulty in coordinating these muscle groups appropriately, and therefore their speech tends to be slow and disjointed. (5) Hypotonia is another symptom of cerebellar damage. There is a decreased, pendulous myotatic reflex, as the decreased muscle resistance tends to cause the limb to swing back and forth after the initial reflex contraction. (6) Intention tremor refers to the increasingly oscillatory trajectory of a cerebellar patient’s limb in a target-directed movement. For example, the hand will start out on a straight path toward the target, but as it gets closer, the hand begins to move back and forth, and the patient must slow down the movement and very carefully approach the target. Note that this tremor contrasts with the resting tremor of Parkinson’s disease, which disappears when the movement is made. Intention tremor is absent when the hand is still, but appears toward the end of a target-directed movement. (7) Nystagmus is an oscillatory movement of the eyes, resulting from damage to the vestibulocerebellum. Recall that one function of the cerebellum is to fine-tune the gain of the vestibuloocular response. Damage to the cerebellum can disrupt this circuitry, resulting in a continuing oscillation of the eyes. (8) Delay in initiating movements. Cerebellar patients take longer to initiate movements, often because they must actively plan sequences of movements that are performed effortlessly by normal individuals. (9) In addition to movement disorders, cerebellar patients also demonstrate subtle cognitive deficits, such as an impaired ability to estimate time intervals.

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