Physiology_Levy

Physiology_Levy. The Medial System The ventral corticospinal tract and much of the corticobulbar tract can be regarded as medial system pathways. These tracts end on the medial group of interneurons in the spinal cord and on equivalent neurons in the brainstem. The axial muscles are controlled by these pathways. These muscles often contract bilaterally to provide postural support or some other bilateral function, such as swallowing or wrinkling of the brow. Other medial system pathways originate in the brainstem. These include the pontine and medullary reticulospinal tracts, the lateral and medial vestibulospinal tracts, and the tectospinal tract. The cells that give rise to the pontine reticulospinal tract are in the medial pontine reticular formation. The tract descends in the ventral funiculus, and it ends on the CHAPTER 9 Organization of Motor Function ipsilateral medial group of interneurons. Its function is to excite motor neurons to the proximal extensor muscles to support posture.


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function ipsilateral medial group of interneurons. Its function is to excite motor neurons to the proximal extensor muscles to support posture. The medullary reticulospinal tracts arise from neurons of the medial medulla, particularly those of the gigantocellularis reticular nucleus. The tracts descend bilaterally in the ventral lateral funiculus, and they end mainly on interneurons associated with cell groups of medial motor neurons. The function of the pathway is mainly inhibitory.


Physiology_Levy

Physiology_Levy. The lateral vestibulospinal tract originates in the lateral vestibular nucleus, also known as Deiter’s nucleus. This tract descends ipsilaterally through the ventral funiculus of the spinal cord and ends on interneurons associated with the medial motor neuron groups. The lateral vestibulospinal tract excites motor neurons that supply extensor muscles of the proximal part of the limb that are important for postural control. In addition, this pathway inhibits flexor motor neurons because it also excites the reciprocal group Ia interneurons that receive group Ia input from extensor muscles, which in turn inhibit flexor motor neurons. The excitatory input to the lateral vestibular nucleus is from both the semicircular canals and the otolith organs, whereas the inhibitory input is from the Purkinje cells of the anterior vermis region of the cerebellar cortex. An important function of the lateral vestibulospinal tract is to assist in postural adjustments after angular and linear


Physiology_Levy

Physiology_Levy. the Purkinje cells of the anterior vermis region of the cerebellar cortex. An important function of the lateral vestibulospinal tract is to assist in postural adjustments after angular and linear accelerations of the head.


Physiology_Levy

Physiology_Levy. The medial vestibulospinal tract originates from the medial vestibular nucleus. This tract descends in the ventral funiculus of the spinal cord to the cervical and midthoracic levels, and it ends on the medial group of interneurons. Sensory input to the medial vestibular nucleus from the labyrinth is chiefly from the semicircular canals. This pathway thus mediates adjustments in head position in response to angular acceleration of the head. The Tectospinal Tract The tectospinal tract originates in the deep layers of the superior colliculus. The axons cross to the contralateral side, just below the periaqueductal gray matter. They then descend in the ventral funiculus of the spinal cord to terminate on the medial group of interneurons in the upper cervical spinal cord. The tectospinal tract regulates head movement in response to visual, auditory, and somatic stimuli.


Physiology_Levy

Physiology_Levy. In addition to the lateral and medial systems, less specifically organized systems descend from the brainstem to the spinal cord. These include several pathways in which monoamines serve as synaptic transmitters. The locus coeruleus and the nucleus subcoeruleus are nuclei located in the rostral pons, and they are composed of norepinephrine-containing neurons. These nuclei project widely throughout the CNS, and their projection to the spinal cord travels in the lateral funiculus. Their terminals are on interneurons and motor neurons. The dominant effect of the pathway is inhibitory. The raphe nuclei of the medulla also project widely throughout the CNS and give rise to several raphe-spinal pathways. With regard to motor function, the ventral horn projection may enhance motor activity.


Physiology_Levy

Physiology_Levy. In general, the monoaminergic pathways act to alter the responsiveness of spinal cord circuits, including the reflex arcs. In this way, they induce widespread changes in excitability rather than discrete movements or specific changes in behavior. Motor Deficits Caused by Lesions of Descending Motor Pathways


Physiology_Levy

Physiology_Levy. A common cause of motor impairment in humans is interruption of the cerebral cortical efferent fibers in the internal capsule; such interruptions occur in capsular strokes. The resulting disorder is often termed a pyramidal tract syndrome, or upper motor neuron disease, although these names are misnomers. Motor changes characteristic of this disorder include (1) increased phasic and tonic stretch reflexes (spasticity); (2) weakness, usually of the distal muscles, especially the finger muscles; (3) pathological reflexes, including the sign of Babinski (dorsiflexion of the big toe and fanning of the other toes when the sole of the foot is stroked); and (4) a reduction in superficial reflexes, such as the abdominal and cremasteric reflexes. Of importance is that if only the corticospinal tract is interrupted, as can occur with a lesion of the medullary pyramid, most of these signs are much reduced or absent. In this situation, the most prominent deficits are weakness of the distal


Physiology_Levy

Physiology_Levy. tract is interrupted, as can occur with a lesion of the medullary pyramid, most of these signs are much reduced or absent. In this situation, the most prominent deficits are weakness of the distal muscles, especially those of the fingers, and a Babinski sign. Spasticity does not occur; instead, muscle tone may actually decrease. Evidently, the presence of spasticity requires the disordered function of other pathways, such as the reticulospinal tracts, as would occur after loss of the descending cortical influence to the brainstem nuclei of origin of these tracts.


Physiology_Levy

Physiology_Levy. The effects of interruption of the medial system pathways are quite different from those produced by corticospinal tract lesions. The main deficits associated with medial system interruption are an initial reduction in the tone of postural muscles and loss of righting reflexes. Long-term effects include locomotor impairment and frequent falling. However, manual manipulation of objects is perfectly normal. The Decerebrate Preparation The decerebrate preparation has been useful for experimentally investigating how various descending pathways interact with the spinal cord circuitry. Surgical decerebration is achieved either by transection of the midbrain, often at an intercollicular level, or by occlusion of the blood vessels feeding this area. In the latter case, a lesion also occurs in the anterior vermis of the cerebellum, an important distinction.


Physiology_Levy

Physiology_Levy. With the intercollicular transection, some descending pathways, such as those originating in the cerebral cortex, are interrupted, whereas others, such as those originating in the brainstem, remain intact.


Physiology_Levy

Physiology_Levy. However, remember that the corticospinal tract is only one component of the cortical descending fibers. Many other cortical fibers project to locations throughout the brainstem, including the nuclei of origin for the medial descending pathways. Loss of these cortical control systems results in altered activity in the intact descending pathways. As a result, affected animals show hypertonia and suppression of some spinal reflexes, such as the flexion reflex, and exaggeration of others, such as the stretch reflex; this condition is called decerebrate rigidity. Decerebrate animals maintain a posture that has been called exaggerated standing. Human patients with brainstem damage may also develop a decerebrate state that has many of the same reflex features as animal preparations. The prognosis in such patients is poor if signs of decerebration appear.


Physiology_Levy

Physiology_Levy. Loss of descending control on the reticular formation results in increased activity in the pontine reticulospinal pathway and decreased activity in the medullary reticulospinal pathway. Such increase and decrease in activity, respectively, produces increased excitation and decreased inhibition (disinhibition) of the motor neurons, which explains the observed rigidity. Interestingly, this hypertonia can be relieved by cutting the dorsal roots, which indicates that the reticulospinal tracts have a major effect on γ motor neurons. This is because γ motor neuron activity alters muscle stiffness by increasing muscle spindle sensitivity and thereby causes increased activity in the group Ia and group II afferent fibers, which travel through the dorsal roots into the spinal cord in order to innervate the α motor neurons.


Physiology_Levy

Physiology_Levy. When vessel occlusion is used to generate the decerebrate state, the lateral vestibulospinal tract becomes hyperactive because of damage to Purkinje cells in the anterior vermis of the cerebellum, which provide the major inhibitory projection to the lateral vestibular nucleus. This hypertonia is actually not lost after transection of the dorsal roots, which implies that the lateral vestibulospinal tract is acting to a significant extent directly on α motor neurons (either monosynaptically or via interneurons). Brainstem Control of Posture and Movement


Physiology_Levy

Physiology_Levy. Brainstem Control of Posture and Movement The importance of motor control pathways that originate in the brainstem is evident from observations of the extensor hypertonus and increased phasic stretch reflexes that occur in decerebrate animals. Particular brainstem systems have been identified as influencing posture and locomotion. Brainstem circuits are also critically involved in the control of eye movement; these circuits are discussed in a separate section at the end of the chapter. Several reflex mechanisms are evoked when the head is moved or the neck is bent. There are three types of postural reflexes: vestibular reflexes, tonic neck reflexes, and righting reflexes. The sensory receptors responsible for these reflexes include the vestibular apparatus (see ), which is stimulated by head movement, and stretch receptors in the neck.


Physiology_Levy

Physiology_Levy. The vestibular reflexes constitute one class of postural reflex. Rotation of the head activates sensory receptors of the semicircular canals (see ). In addition to generating eye movement, the sensory input to the vestibular nuclei results in postural adjustments. Such adjustments are mediated by commands transmitted to the spinal cord through the lateral and medial vestibulospinal tracts and the reticulospinal tracts. The lateral vestibulospinal tract activates extensor muscles that support posture. For instance, if the head is rotated to the left, postural support is increased on the left side. This increased support prevents the person from falling to the left as the head rotation continues. A person who has any disease that eliminates labyrinthine function in the left ear tends to fall to the left. Conversely, a person with a disease that irritates (stimulates) the left labyrinth tends to fall to the right. The medial vestibulospinal tract causes contractions of neck muscles that


Physiology_Levy

Physiology_Levy. to the left. Conversely, a person with a disease that irritates (stimulates) the left labyrinth tends to fall to the right. The medial vestibulospinal tract causes contractions of neck muscles that oppose the induced movement (vestibulocollic reflex).


Physiology_Levy

Physiology_Levy. Tilting the head also changes the linear acceleration on individual hair cells of the otolith organs of the vestibular apparatus. The resulting changes in hair cell activity can produce eye movement and postural adjustment. For example, when a quadruped, such as a cat, tilts the head and body forward (without bending the neck and consequently without evoking the tonic neck reflexes), the result is extension of the forelimbs and flexion of the hind limbs. This vestibular action tends to restore the body toward its original orientation. Conversely, if the quadruped tilts the head and body backward (without bending the neck), the forelimbs flex and the hind limbs extend. Otolithic organs also contribute to the vestibular placing reaction. If an animal, such as a cat, is dropped, stimulation of the utricles leads to extension of the forelimbs in preparation for landing.


Physiology_Levy

Physiology_Levy. The tonic neck reflexes are another type of positional reflex. These reflexes are activated by the muscle spindles found in neck muscles. These muscles contain the largest concentration of muscle spindles of any muscle in the body. If the neck is bent (without tilting of the head), the neck muscle spindles evoke tonic neck reflexes without interference from the vestibular system. When the neck is extended, the forelimbs extend and the hind limbs flex. The opposite effects occur when the neck is flexed. Note that these effects are opposite those evoked by the vestibular system. Furthermore, if the neck is bent to the left, the extensor muscles in the limbs on the left contract more, and the flexor muscles in the limbs on the right side relax. CHAPTER 9 Organization of Motor Function


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function The third class of postural reflex is the righting reflexes. These reflexes tend to restore an altered position of the head and body toward normal. The receptors responsible for righting reflexes include the vestibular apparatus, the neck stretch receptors, and mechanoreceptors of the body wall. Brainstem Control of Locomotion The spinal cord contains neural circuits that serve as central pattern generators for locomotion, as discussed earlier. These CPG circuits produce very regular rhythmic output that characterizes stereotyped behavior, such as walking. The irregularities of real-world environments, however, often require modification of this stereotyped output (e.g., if you are walking and see a hole in the floor where you are about to step, you can extend the forward swing of your leg past the hole onto solid ground beyond it). Such modifications can be the result of sensory input to the spinal cord, as shown in


Physiology_Levy

Physiology_Levy. Such modifications can be the result of sensory input to the spinal cord, as shown in Fig. 9.10 , in which stimulation of FRA fibers in a peripheral nerve caused a phase shift in the locomotor pattern. They can also be the result of descending commands along the motor pathways discussed earlier. In this case, sensory data (e.g., visual) can be used by the brain to make anticipatory modifications in CPG activity so that potential obstacles can be avoided. In addition, people can voluntarily control activation, or shutdown, of the CPG (i.e., deciding consciously when to start and stop walking). Such voluntary regulation of spinal CPGs originates in the cerebral cortex; however, much of the cortical influence on locomotion appears to be mediated via projections to brainstem regions known as locomotor regions. A locomotor region can be defined as a brain area that, when stimulated, leads to sustained locomotion.


Physiology_Levy

Physiology_Levy. There are several such locomotor regions in the brain-stem, and they are located at different levels ranging from the subthalamus to the medulla and are connected with each other. The best known is the midbrain locomotor region, which is thought to organize commands to initiate locomotion. It is located in the midbrain at the level of the inferior colliculus. Voluntary activity that originates in the motor cortex can trigger locomotion by the action of corticobulbar fibers projecting to the midbrain locomotor region. The commands are relayed through the reticular formation and then to the spinal cord via the reticulospinal tracts. Motor Control by the Cerebral Cortex


Physiology_Levy

Physiology_Levy. Motor Control by the Cerebral Cortex Thus far in this chapter, emphasis has been on reflexes and relatively automatic types of movement. We now discuss the neural basis for more complex, goal-directed voluntary movement. Such movement often varies when repeated and is frequently initiated as a result of cognitive processes rather than in direct response to an external stimulus. Thus it requires the participation of motor areas of the cerebral cortex. •Fig. 9.14 Motor Areas of the Frontal Cortex. A andB, Lateralandmedialviewsofahemisphere,showingthemajorcorticalmotorareas.FEF,frontaleyefield.Theinset inB showsthewallsofthecingulatesulcus,whichcontainthecingulatemotorareas.NumbersinparenthesesareBrodmannareanumbersforthecingulatemotorareas(CMAs).C, Diagramshowinginterconnectionsofthemotorareas.PMA,premotorarea;SMA,supplementarymotorarea.


Physiology_Levy

Physiology_Levy. First, consider what is necessary to generate a voluntary movement. For example, to make a reaching movement with your arm, you must first identify the target (or goal) and locate it in external space. Next, a limb trajectory must be determined on the basis of an internal representation of your arm and, in particular, your hand in relation to the target. Finally, a set of forces necessary to generate the desired trajectory must be computed. This process is often thought of as a series of transformations between coordinate systems. For example, the location of a visually identified target is measured in a retinotopic space, but its location is perceived in an external or world space (i.e., the position of a nonmoving target is perceived as stable, even when the eye, and thus the target’s image on the retina, changes). Next, calculation of a trajectory would involve a body-or hand-centered system, and finally, forces must ultimately be computed in a muscle-based reference frame.


Physiology_Levy

Physiology_Levy. These steps form a linear sequence, and traditionally it was thought that a hierarchy of motor areas carried out the successive steps. For example, the target of the movement was thought to be identified by pooling of sensory information in the posterior parietal cerebral cortex (Fig. 9.14A ). This information would then be transmitted to the supplementary motor and premotor areas, where a motor plan would be developed and then forwarded to the primary motor cortex, whose activity would be related to the final execution stage (e.g., generation of appropriate force levels). The motor cortex would then transmit commands, via the descending pathways discussed earlier, to the spinal cord and brainstem motor nuclei.


Physiology_Levy

Physiology_Levy. Although there is significant evidence in support of this hierarchical view of the generation of voluntary movement by the cortical motor system, more recent results have suggested a different conception: namely, that the various motor areas should be thought of as forming a parallel distributed network rather than a strict hierarchy (see Fig.


Physiology_Levy

Physiology_Levy. Fig. 9.14C ). For example, each cortical motor area makes its own significant contribution to the descending motor pathways; the primary motor cortex contributes only approximately half the fibers in the corticospinal tract that arise from the frontal lobe. Moreover, the various motor areas are all bidirectionally connected to each other, and results of the single-unit recording studies described later suggest that each of the areas plays a role in several of the stages of planning and executing a movement. This debate forms one of the themes of the following discussion because in its various guises, the distributed network versus hierarchical organization debate has been ongoing for decades and will probably continue for some time.


Physiology_Levy

Physiology_Levy. The motor areas in the cerebral cortex were originally defined on the basis of experiments in which electrical stimuli applied to the cortex evoked discrete, contralateral movement. Movement, however, can also be evoked when other cortical areas are stimulated more intensely. Thus motor areas are defined as those from which movement can be evoked by the lowest stimulus intensity. On the basis of these stimulation studies, the effects produced by lesions, results of anatomical experiments, electrophysiological recordings, and modern imaging studies in humans, many “motor” areas of the cerebral cortex have been recognized (see


Physiology_Levy

Physiology_Levy. Fig. 9.14 ), including the primary motor cortex in the precentral gyrus, the premotor area just rostral to the primary motor cortex, the supplementary motor cortex on the medial aspect of the hemisphere, and three cingulate motor areas located on the walls of the cingulate sulcus in the frontal lobe. There are also cortical regions in other lobes whose activity is related specifically to eye movement (see the section Somatotopic Organization of Cortical Motor Areas The primary motor cortex (or just motor cortex) can be defined as the region of cortex from which movements are elicited with the least amount of electrical stimulation. It is essentially congruent with the Brodmann cytoarchitectonic area 4 (see


Physiology_Levy

Physiology_Levy. Fig. 10.3). In humans it is located on the parts of the precentral gyrus that form the rostral wall of the central sulcus and the caudal half of the apex of the gyrus. On the basis of initial mapping studies, which were done with surface stimulation, the motor cortex was described as having a topographic organization that parallels that of the somatosensory cortex. The face, body, and upper limb were represented on the lateral surface with the face located inferiorly, near the lateral fissure, the torso most superiorly, and the lower extremity mostly on the medial aspect of the hemisphere. This somatotopic organization is often represented as a figurine or in a graphic form called a motor homunculus (


Physiology_Levy

Physiology_Levy. Fig. 9.15B ). The distortion of the various body parts in the homunculus indicates approximately how much of the cortex is devoted to their motor control. This simple homunculus was likened to a piano keyboard and fit well with traditional conceptions of the motor cortex being the final cortical stage and acting as a relay for sending motor commands to the spinal cord. Beginning in the 1960s and 1970s, investigators in mapping studies began using microelectrodes inserted to the deep, or output, layers of the cortex to apply stimuli. With this technique, called intracortical microstimulation, much lower stimulus intensities could be used to evoke movements and thus allowed higher resolution mapping of the motor cortex, which revealed a much more complex topography than was previously imagined (see CHAPTER 9 Organization of Motor Function


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function Fig. 9.15C ). Movement about each joint was found to be evoked by many noncontiguous columns throughout wide regions of the motor cortex. Thus cell columns related to movement about a particular joint are actually interspersed among columns that control movement about many other joints. In sum, although the motor cortex may have large subdivisions corresponding to a limb or the head, within each such area there is a complex intermingling of cell columns that control the muscles within that body part.


Physiology_Levy

Physiology_Levy. Such mixing of cell columns makes functional sense because most movement requires the coordinated action of muscles throughout a limb and most connectivity in the cortex is localized (i.e., axon collaterals that connect different cell columns are primarily confined to a 1to 3-mm region surrounding the column from which they originate). Thus when multiple cell columns that control movement about a joint are present and intermixed with columns controlling movement about other joints, multijoint movement can be generated as a whole.


Physiology_Levy

Physiology_Levy. Although the topographic map of the motor cortex is in part anatomically determined by the topography of the corticospinal pathway, it is also a dynamic map. Axon collaterals link the different cell columns, so that activity in one column could potentially lead to movement about multiple joints. In fact, this can happen, but these intercolumnar connections are modulated by inhibitory interneurons that transmit or secrete gamma-aminobutyric acid (GABA). This was shown by locally blocking GABA in one region of the motor cortex and then stimulating the neighboring region. Before the block, stimuli evoked contractions of one set of muscles, but once inhibition was blocked, contractions were also evoked in muscles controlled by the region that was no longer inhibited (


Physiology_Levy

Physiology_Levy. Fig. 9.16 ). Functional connections between cell columns can be controlled on a millisecond time scale, and depending on their state, the motor cortex map can be radically changed. Longer term plastic changes are also known to occur; for example, the use (or disuse) of a body part can affect the size of its somatotopic representation. The supplementary motor area (SMA) is located mainly on the medial surface of the hemisphere, just anterior to the primary motor cortex, and corresponds to the medial portion of Brodmann area 6 (see


Physiology_Levy

Physiology_Levy. The supplementary motor area (SMA) is located mainly on the medial surface of the hemisphere, just anterior to the primary motor cortex, and corresponds to the medial portion of Brodmann area 6 (see Fig. 9.14). It is subdivided into two regions: the more posterior part is referred to as the SMA proper (or just SMA), and the anterior portion is called the pre-SMA. The SMA proper is similar to the other motor areas already listed: it contains a complete somatotopic map, it contributes to the corticospinal tract, and it is interconnected with the other motor areas. In contrast, the pre-SMA is not strongly connected with the other motor areas and spinal cord but rather is connected to the prefrontal cortex. The results of stimulation studies show that as in the motor cortex, there is a complete somatotopic map in the SMA. Stimulation of the SMA can evoke isolated movement


Physiology_Levy

Physiology_Levy. The results of stimulation studies show that as in the motor cortex, there is a complete somatotopic map in the SMA. Stimulation of the SMA can evoke isolated movement Rostral wall of central sulcus •Fig. 9.15 Traditional and Modern Views of Motor Cortex Musculotopic Organization. A, Lateralviewofthecerebrum,showingaplaneofsectionthroughtheprecentralgyrus(primarymotorcortex)thatcorrespondstothesectionshowninB. B, Classicviewofmotorcortexmusculotopy(“muscularhomunculus”).C, Modernviewofmotorcortexorganizationinwhicheachbodypartisrepresentedmultipletimesacrossseveraldiscreteregions.


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function •Fig. 9.16 Dynamic Nature of a Motor Cortex Musculotopic Map. InhibitoryGABAergicinterneuronsplayanimportantroleinshapingmotorresponsestostimulationofeachregionofthemotorcortex.A, Schematicviewofexcitatoryconnectionsbetweentworegionsofprimarymotorcortexandlocalinhibitoryneuronswithinasingleregion.B, Schematicviewofaratbrain,indicatingmotorcortex(MC)regionswhereelectricalstimuliwereappliedtoevokemovements(Vibregion)andbicucullinewasappliedtoblockGABAergicsynapses(intheFLregion).FL,forelimb;Vib,vibrissa.C, ForelimbEMGrecordsshowingresponsetostimulationoftheVibregionbeforeandduringtheapplicationofbicucullineandafteritwaswashedout.NotethatVibstimulationevokedvibrissaemovementinallconditionsbutevokedforelimbmovementonlywheninhibitoryinterneuronsinFLwereblocked.(DatafromJacobsK,DonoghueJ.Science. 1991;251:944.) about single joints, similar to that after stimulation of the motor cortex, but stimulation must be of higher intensity and longer duration;


Physiology_Levy

Physiology_Levy. 1991;251:944.) about single joints, similar to that after stimulation of the motor cortex, but stimulation must be of higher intensity and longer duration; moreover, the evoked movements are often more complex than those evoked by stimulation of the motor cortex. However, longer duration stimulation of the primary motor cortex can also evoke complex, apparently purposeful movement sequences, and so the distinction is not absolute. In addition, stimulation of the SMA can produce vocalization or complex postural movements, but it can also have the opposite result: namely, a temporary arrest of movement or speech. Removal of the supplementary motor cortex retards movement of the opposite extremities and may result in forced grasping movements with the contralateral hand.


Physiology_Levy

Physiology_Levy. This area lies rostral to the primary motor cortex and is contained in Brodmann area 6 on the lateral surface of the brain (see Fig. 9.14 ). It can be distinguished from the primary motor cortex by the higher stimulus intensities needed to evoke movement. The premotor area has been divided into two functionally distinct subdivisions: dorsal and ventral. Like the motor cortex, both subdivisions are somatotopically organized and both contribute to the corticospinal tract. The dorsal division (PMd) contains a relatively complete map representing the leg, trunk, arm, and face. In contrast, the somatotopic map of the ventral division (PMv) is mostly limited to the arm and face, with only a small leg representation. Thus the PMv appears to be specialized for control of upper limb and head movement. A second difference between the subdivisions is that the PMd contains a large representation of the proximal muscles, whereas the PMv has a large representation of the distal muscles.


Physiology_Levy

Physiology_Levy. These motor areas are located within the cingulate sulcus at approximately the same anterior-posterior level as the SMA. There are three cingulate motor areas (dorsal, ventral, and rostral; see Fig. 9.14B ). Each contains a somatotopic map and contributes to the corticospinal tract. Microstimulation in these areas evokes movement similar to that evoked by motor cortex stimulation, except that, again, higher stimulus intensities are needed. Single-cell recordings during movements have shown that the spontaneous activity of neurons in the cingulate motor areas is related to the preparation and execution of movements. Connections of the Cortical Motor Areas


Physiology_Levy

Physiology_Levy. Connections of the Cortical Motor Areas The motor areas of the cortex receive input from a number of sources, cortical and subcortical; however, the largest source of synapses in an area is the area itself: specifically, the local intrinsic connections. Moreover, all the motor areas described earlier are bidirectionally connected to each other with high topographic specificity (see


Physiology_Levy

Physiology_Levy. Fig. 9.14C ). For example, the arm regions of the primary motor cortex and the cingulate motor areas project to each other. Ascending pathways relay sensory information to the thalamus. This information can reach the motor cortex directly from the thalamus or indirectly by way of the somatosensory cortex. Both somatosensory information and visual information are conveyed to the motor areas from the posterior parietal cortex. The motor areas of the cortex also receive information through circuits that interconnect them with the other major brain regions involved in motor control: namely, the cerebellum and basal ganglia. These two structures project to distinct parts of the thalamus (the ventral lateral and ventral anterior nuclei), which then project to the cortical motor areas.


Physiology_Levy

Physiology_Levy. The output of the cortical motor areas to the spinal cord and brainstem is conducted through several descending pathways. These pathways include not only direct projections through the corticospinal and corticobulbar tracts (to the cranial nerve nuclei) but also indirect projections to the red nucleus and to various nuclei in the reticular formation. Descending projections from these brainstem sites were reviewed in the section .” Control of head and neck muscles is mediated by projections to the various cranial nerve nuclei. The motor regions also project to the cerebellum and basal ganglia, thus completing neuroanatomical loops with these structures. The major connection to the cerebellum is via the corticopontine projections to the basilar pontine nuclei, which in turn project to the cerebellum. In addition, the cortical motor areas project, mostly via disynaptic pathways that synapse in the midbrain, to the inferior olivary nucleus, another important precerebellar area. The


Physiology_Levy

Physiology_Levy. the cerebellum. In addition, the cortical motor areas project, mostly via disynaptic pathways that synapse in the midbrain, to the inferior olivary nucleus, another important precerebellar area. The cortical motor regions project directly to the striatum of the basal ganglia. Finally, there are major projections to the thalamus by which the cortex regulates the information that it receives.


Physiology_Levy

Physiology_Levy. Activity of Motor Cortex Cells The role of individual motor cortex neurons in the control of movement has been extensively investigated in trained monkeys. In these experiments, discharges from a neuron in the primary motor cortex are recorded during the execution of a previously learned simple movement, such as wrist flexion, made immediately in response to a sensory cue (Fig.


Physiology_Levy

Physiology_Levy. 9.17 ). Motor cortex neurons were found to change their firing rates before initiation of the movement, and the onset of this change was correlated with the reaction time (i.e., the time from the cue to onset of the movement). Moreover, in this task, the change in firing of motor cortex neurons was often correlated with the contractile force of the muscle that generates the movement and with the rate of change in force rather than with the position of the joint. These findings suggest that these cells are involved in the final stages of planning and executing movements, which is consistent with the hierarchical view of the cortical motor areas.


Physiology_Levy

Physiology_Levy. However, even in these early experiments, the firing rates of some motor cortex cells appeared to relate to earlier planning stages. Moreover, even when a monkey was trained to withhold the movement for a certain period after the cue, the firing rates of motor cortex neurons still changed despite the absence of any movement. Such “set-related” activity has been amply confirmed in a variety of other tasks and suggests that motor cortex activity may be involved in the earlier planning stages along with activity in other motor areas of the cortex. It also suggests the possibility that other, perhaps subcortical, systems may be needed to generate a trigger signal for the initiation of movement. In subsequent studies, researchers have used tasks in which animals were trained to move a manipulandum (a device with a handle to hold and a small circle on the end) to capture lighted targets on a surface in front of them (Fig.


Physiology_Levy

Physiology_Levy. 9.18A ). These experiments demonstrated that cells in the arm region of the motor cortex showed changes in their firing rates in response to movement in many different directions and thus were described as broadly tuned (see Fig. 9.18B ). That is, a cell that showed a maximal increase for movement in one particular direction, called its preferred direction, would also show somewhat smaller increases or even decreases for movement in other directions (see Fig. 9.18C ). Moreover, the preferred directions of the different cells were uniformly distributed across all 360 degrees of possible movement directions.


Physiology_Levy

Physiology_Levy. Fig. 9.18C ). Moreover, the preferred directions of the different cells were uniformly distributed across all 360 degrees of possible movement directions. These results implied that a particular cell is probably involved in most arm movements, but they also raised the issue of how precise movements could be made with such broadly tuned cells. It was suggested that although changes in the activity of individual cells could not precisely predict or specify the direction of the upcoming movement, the net activity of the population could. To test this idea, models were made in which the activity of each cell is represented as a vector (see Fig. 9.18D ). The direction of each cell vector is determined by the preferred direction of the cell, and the magnitude of the vector for a particular movement is proportional to the firing rate of the cell during the time preceding the movement. The individual cell vectors (see


Physiology_Levy

Physiology_Levy. Fig. 9.18D , black lines) from hundreds of cells can then be vectorially summed to get a resultant or population vector (see Fig. 9.18D , red lines) that accurately predicts the upcoming movement. One of the difficulties in assessing the relationship between firing of cortical cells and various movement parameters, such as force, velocity, displacement, and target location, is that these parameters are normally correlated with each other. Therefore, variations of the tasks described earlier have been used to decorrelate these various parameters (e.g., using weights to vary the force needed to make a movement without changing the displacement, as illustrated in


Physiology_Levy

Physiology_Levy. Fig. 9.17A , or rotating the starting position of the wrist so that different muscles are required to generate the same trajectory in external space). The results of these experiments showed that the activity of motor cortex cells may be related to each of the various motor planning stages. Furthermore, the activity of a single cell may be correlated with one parameter initially and then switch as the time for onset of movement approaches. Activity in the premotor and supplementary motor areas is in many ways similar to that in the primary motor cortex. Cells in these areas show activity related to upcoming


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function flexion movement results from relaxation of antagonist •Fig. 9.17 A, Experimentalarrangementforrecordingfromacorticospinalneuronwhileamonkeyperformstrainedwristmovements.Astimulationelectrodeisusedtoelicitantidromicspikesthatareusedtoidentifythemotorcortexneuronspecificallyasapyramidaltractneuron.Stimuliarenotappliedwhilethemonkeyisperformingmovements.B, Thepyramidaltractneuron(PTN)dischargesbeforetheonsetofmovementorEMGactivitywhenflexorsneedtogenerateforce(noloadandflexorloadconditions).Moreover,thefiringrateiscorrelatedwiththelevelofflexorforcethatisneeded.Intheextensorloadcondition,flexorsdonotneedtocontracttogeneratemovement,andthusthereisnoactivityinthisPTN.Thetoptraceshowswristmovement,whichisessentiallyidenticalforallthreeexperimentalconditions.Thusthiscell’sactivityinvolvesencodingforcemagnitudeanddirection,butnotdisplacement.(Figure basedonworkofEvartsandcolleagues.) movement, and the activity is correlated with movement parameters,


Physiology_Levy

Physiology_Levy. basedonworkofEvartsandcolleagues.) movement, and the activity is correlated with movement parameters, such as displacement, force, and target location, just as primary motor cortex activity can be, which is consistent with the distributed network view of the cortical motor areas. There do, however, appear to be some real differences between the areas as well, although these differences may be more quantitative than qualitative. For example, the percentage of cells in the premotor and supplementary motor areas that show activity related to earlier motor planning stages is higher than that of such cells in the primary motor cortex. In addition, the premotor and supplementary motor areas can be distinguished from each other by the apparently greater involvement of the premotor area in movements made to external cues (such as in the task shown in


Physiology_Levy

Physiology_Levy. Fig. 9.18 ) and the greater involvement of the supplementary motor area in movements made in response to internal cues (i.e., self-initiated). Research has also revealed that each of these areas is functionally heterogeneous and can therefore be further subdivided; however, such details are beyond the scope of this discussion. Motor Control by the Cerebellum Overview of the Role of the Cerebellum in Motor Control


Physiology_Levy

Physiology_Levy. In the early 1900s, scientists showed that damage to the cerebellum led to deficits in motor coordination. That is, damage or loss of the cerebellum does not lead to paralysis, loss of sensation, or an inability to understand the nature of a task; rather, it leads to an inability to perform movements well. Yet it has been hard to define the precise role or 45 135 225 315° Direction of movement • Fig.


Physiology_Levy

Physiology_Levy. movement • Fig. 9.18 A, Experimental setup in which a monkey holds onto the arm of the apparatus and captures light spots with the distal end of the arm. The monkey first captures the central light spot and then captures whichever of the surrounding targets that becomes illuminated. B, Raster plots showing the activity of one motor cortex cell during movement in eight different directions. T indicates the time at which the target light turns on, whereas M indicates the time at the onset of movement, which is at the center of each raster. Each mark on a raster represents a spike of a motor cortex cell, and each row of marks shows the cell’s activity during one trial. C, Cosine function was fit to the firing level as a function of the direction of movement. The horizontal bar indicates the average spontaneous firing rate in the absence of an upcoming movement. Note that for most directions, the activity in the periods just before and during movement changed significantly from baseline.


Physiology_Levy

Physiology_Levy. •Fig. 9.18, cont’d D, Vectormodelofpopulationactivityinthemotorcortex.Black lines representindividualcellvectors.Whenallofthemaresummedforaparticulardirectionofmovement,theresultingpopulationvector(red) pointsinessentiallythedirectionoftheupcomingmovement.(B andC, ModifiedfromGeorgopoulosAP,etal.J Neurosci. 1982;2:1527.D, ModifiedfromGeorgopoulosAP,etal.InMassionJ,etal[eds].Experimental Brain Research Series, vol.7:Neuronal Coding of Motor Performance. Berlin:Springer-Verlag;1983.) roles of the cerebellum in generating movement, although, paradoxically, scientists have more detailed knowledge of its deceptively simple anatomic and physiological organization than of any other CNS region. The cerebellum is proposed to play a critical role in the learning and execution of both voluntary and certain reflex movements. However, hypotheses about these roles face significant challenges that prevent their complete acceptance. In this section, the behavioral effects of damaging the cerebellum


Physiology_Levy

Physiology_Levy. certain reflex movements. However, hypotheses about these roles face significant challenges that prevent their complete acceptance. In this section, the behavioral effects of damaging the cerebellum are discussed, followed by a description of its connectivity, both intrinsic and with the rest of the CNS, and then finally a discussion of its activity.


Physiology_Levy

Physiology_Levy. Behavioral Consequences of Cerebellar Damage Damage to one side of the cerebellum impairs motor function on the ipsilateral side of the body. This reflects a double crossing of most cerebellum-related output as it travels to the motor neurons. The first crossing typically occurs in the cerebellar efferent pathway, whereas the second crossing takes place in the descending motor pathways. For example, the cerebellum projects to the contralateral motor cortex, via the thalamus, and the corticospinal pathway recrosses the midline at the lower medulla. The specific motor deficits that result from cerebellar lesions depend on which functional component of the


Physiology_Levy

Physiology_Levy. The specific motor deficits that result from cerebellar lesions depend on which functional component of the CHAPTER 9 Organization of Motor Function cerebellum is most affected. If the flocculonodular lobe is damaged, the motor disorders resemble those produced by a lesion of the vestibular apparatus; such disorders include difficulty in balance and in gait and often nystagmus. If the vermis is affected, the motor disturbance affects the trunk, and if the intermediate region or hemisphere is involved, motor disorders occur in the limbs. The part of the limbs affected depends on the site of damage; hemispheric lesions affect the distal muscles more than paravermal lesions do.


Physiology_Levy

Physiology_Levy. Types of motor dysfunction in cerebellar disease include disorders of coordination, equilibrium, and muscle tone. Incoordination is called ataxia and is often manifested as dysmetria, a condition in which errors in the direction and force of movement prevent a limb from being moved smoothly to a desired position. Ataxia may also be manifested as dysdiadochokinesia, in which rapid alternating of supination and pronation of the arm is difficult to execute. When more complicated movement is attempted, decomposition of movement occurs, in which the movement is accomplished in a series of discrete steps rather than as a smooth sequence. An intention tremor appears when the subject is asked to touch a target; the affected hand (or foot) develops a tremor that increases in magnitude as the target is approached. When equilibrium is disturbed, impaired balance may be seen, and the individual tends to fall toward the affected side and may walk with a wide-based stance (gait ataxia). Speech may


Physiology_Levy

Physiology_Levy. is approached. When equilibrium is disturbed, impaired balance may be seen, and the individual tends to fall toward the affected side and may walk with a wide-based stance (gait ataxia). Speech may be slow and slurred; such a defect is called scanning speech. Muscle tone may be diminished (hypotonia), except for lesions of the anterior vermis (see earlier section on decerebrate rigidity); the diminished tone may be associated with a pendular knee jerk. This can be demonstrated by eliciting a phasic stretch reflex of the quadriceps muscle by striking the patellar tendon. The leg continues to swing back and forth because of the hypotonia, in contrast to the highly damped oscillation in a normal person.


Physiology_Levy

Physiology_Levy. These disorders reflect, in part, abnormal timing of muscle contractions. Normally, limb movements involve precisely timed EMG bursts in both agonist and antagonist muscles. There is an initial agonist burst followed by a burst in the antagonist and, finally, a second agonist burst. With cerebellar damage, the relative timing of these bursts is abnormal ( Fig. 9.19


Physiology_Levy

Physiology_Levy. The cerebellum (“little brain”) is located in the posterior fossa of the cranium, just below the occipital lobe, and is connected to the brainstem via three cerebellar peduncles (superior, middle, and inferior). From the outer surface, only the cortex is visible. Deep to the cortex is the white matter of the cerebellum, and buried within the white matter are the four cerebellar nuclei: proceeding medially to laterally, the fastigial, globose, emboliform, and dentate nuclei. The middle two nuclei are often grouped together and referred to as the interpositus nucleus. For the most part, cerebellar afferent fibers to the cortex and nuclei enter the cerebellum •Fig. 9.19 Disruption of Cerebellar Activity Alters the Timing of EMG Responses During Movement.


Physiology_Levy

Physiology_Levy. nucleus. For the most part, cerebellar afferent fibers to the cortex and nuclei enter the cerebellum •Fig. 9.19 Disruption of Cerebellar Activity Alters the Timing of EMG Responses During Movement. Thecerebellarnucleiwerecooledtoblocktheirfunctioningtemporarilywhilemonkeysperformedmovementsabouttheirelbow.LossofcerebellaractivitydisruptstherelativetimingofagonistandantagonistEMGbursts.Thisleadstoabnormalaccelerationofthelimbandamovementtrajectorythatovershootsthetargetposition(hypermetria).(DatafromFlamentD,HoreJ.J Neurophysiol. 1986;55:1221.) via the inferior and middle peduncles, and efferent fibers from the cerebellar nuclei leave via the superior peduncle.


Physiology_Levy

Physiology_Levy. The cerebellar cortex is subdivided into three rostrocaudally arranged lobes: the anterior lobe, the posterior lobe, and the flocculonodular lobe ( Fig. 9.20A ). The cerebellar lobes are separated by two major fissures, the primary fissure and the posterolateral fissure, and each lobe is made up of one or more lobules. Each lobule of the cerebellar cortex is composed of a series of transverse folds called folia. The cerebellar cortex has also been divided into longitudinal compartments (see


Physiology_Levy

Physiology_Levy. The cerebellar cortex has also been divided into longitudinal compartments (see Fig. 9.20B and C). Initially, the cerebellar cortex was divided into three such compartments: the vermis, which lies on the midline; the paravermis, which lies adjacent to both sides of the vermis; and the lateral hemispheres. These regions have now been subdivided into many further compartments on the basis of myeloarchitectonics (patterns of axonal bundles in the white matter) and the expression patterns of specific molecules, such as aldolase C. Although the functional significance of these compartments is not fully known, the topography of cerebellar afferent fibers, particularly the olivocerebellar system, is precisely aligned with them, and the receptive field properties of cerebellar Purkinje cells also tend to follow this organizational scheme.


Physiology_Levy

Physiology_Levy. There are two major classes of cerebellar afferent systems: mossy fibers and olivocerebellar fibers. Mossy fibers are named for their distinctive appearance in the cerebellar cortex: as a mossy fiber courses through the granule layer, on occasion it swells and sends out a bunch of short twisted branchlets. These entities are called rosettes and are points of synaptic contact between these fibers and neurons in the granule cell layer. Mossy fibers arise from many sources, including the spinal cord (the spinocerebellar pathways), dorsal column nuclei, trigeminal nucleus, nuclei in the reticular formation, primary vestibular afferent fibers, vestibular nuclei, cerebellar nuclei, and the basilar pontine nuclei. The details of specific mossy fiber projection patterns are beyond the scope of this chapter; however, several general points are worth noting: 1. Mossy fibers are excitatory. 2.


Physiology_Levy

Physiology_Levy. Mossy fibers are excitatory. 2. They convey exteroceptive and proprioceptive information from the body and head and form at least two somatotopic maps of the body across the cerebellar cortex. However, like those of the motor cortex, these maps are fractured in the sense that contiguous body regions are not necessarily represented on contiguous areas of the cerebellar cortex; rather, the maps are complicated mosaics. 3. Mossy fibers conveying vestibular information are restricted to the flocculonodular lobe and regions of the vermis. As a result, the flocculonodular lobe and regions of the vermis are sometimes referred to as the vestibulocerebellum. However, these same regions also receive a variety of other information (e.g., visual, neck, oculomotor), and so their function is not exclusively vestibular. 4. The largest sources of mossy fibers are the basilar pontine nuclei, which serve to relay information from areas throughout much of the cerebral cortex. 5.


Physiology_Levy

Physiology_Levy. Mossy fibers enter the cerebellum via all three cerebellar peduncles and provide collateral fibers to the cerebellar nuclei before heading up to the cortex. In sum, via the mossy fiber system, the cerebellum receives a wide variety of sensory information, as well as descending motor-related and cognitive-related activity. In contrast to the diverse origins of mossy fibers, olivocerebellar fibers all originate from a single nucleus: the inferior olivary nucleus, which is located in the rostral medulla, just dorsal and lateral to the pyramids. Almost all the olivary neurons are projection cells whose axons leave the nucleus without giving off collaterals and then cross the brainstem to enter the cerebellum primarily via the inferior cerebellar peduncle. Like mossy fibers, olivocerebellar axons are excitatory and send collaterals to the cerebellar nuclei as they ascend through the cerebellar white matter to the cortex. In the cerebellar cortex, olivocerebellar axons may synapse with


Physiology_Levy

Physiology_Levy. axons are excitatory and send collaterals to the cerebellar nuclei as they ascend through the cerebellar white matter to the cortex. In the cerebellar cortex, olivocerebellar axons may synapse with basket, stellate, and Golgi cells, but they form a special synaptic arrangement with Purkinje cells. Each Purkinje cell receives input from only a single climbing fiber, which “climbs” up its proximal dendrites and makes hundreds of excitatory synapses. (The terminal portion of the olivocerebellar axon is referred to as a climbing fiber.) Conversely, each olivary axon branches to form about 10 to 15 climbing fibers.


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function •Fig. 9.20 Anatomic Divisions of the Cerebellum. A, Schematicmidsagittalviewofthefoldingofthecortexintolobe,lobules,andfolia.B, Schematicviewofanunfoldedferretcerebellarcortextoillustrateearliercompartmentationschemesforsubdividingthecerebellarcortexintothree(vermis,paravermis,andhemisphere)andthensevenlongitudinallyrunningzones(A,B,C1,C2,C3,D1,D2).Thelight yellow portionofeachhemisphereindicatesanareaforwhichnodatawereavailable.


Physiology_Levy

Physiology_Levy. C, Schematicviewofanunfoldedratcerebellum,showingitssubdivisionintomorethanI 1+2+3+3−3b−2b−*2a−5a−4−d−d−6−1−a−c−5−5−e2−e1−f−Par 4−5a−4a−4b−3−3−2−1−*3b+4+a+a+a+2+*2b+d+d+c+5+5+4+5a+6+4b+6+3+3+2+2+1+1+7+e2+*f+4+4+e1+b+2−1−b−III II IV V VII VIII IXa CP Cr IIb Cr IIa Cr Ic Cr Ib Cr Ia Sim b Sim a pf DPFL VPFL FL 5 mm 1 mm Rostral Left Right Caudal IXb IXc Xa Xb Vld Vla Vlb Vlc C •Fig. 9.20, cont’d 20compartments,accordingtostainingformolecularmarkers:inthiscase,zebrinII(aldolaseC).Letters and numbers on the right half ofthecerebellumindicatethezebrincompartmentnumber.Roman numerals down the center indicatecerebellarlobules.Names on left hemisphere indicatenamesofcerebellarlobules.CP,copulapyramis;Cr,crus;DPFL,dorsalparaflocculus;FL,flocculus;Par,paramedian;pf,primaryfissure;Sim,simplex;VPFL,ventralparaflocculus.(B, ModifiedfromVoogdJ.InLlinásRR(ed).Neurobiology of Cerebellar Evolution and Development. Chicago:AmericanMedicalAssociation;1969.C, CourtesyofDr.IzumiSugihara.)


Physiology_Levy

Physiology_Levy. The inferior olivary nucleus is a distinctive brain region for several reasons. As already noted, its neurons are virtually all projection cells, and so there is little local chemical synaptic interaction between the cells. Instead, olivary neurons are electrically coupled to each other by gap junctions. In fact, the inferior olivary nucleus has the highest density of neuronal gap junctions in the CNS. This allows olivary neurons to have synchronized activity that gets transmitted to the cerebellum. Afferent fibers to the inferior olivary nucleus may be divided into two main classes: those transmitting excitatory input, which arises from many regions throughout the CNS, and those transmitting inhibitory GABAergic input from the cerebellar nuclei and a few brainstem nuclei. Although these afferent fibers can modulate the firing rates of olivary neurons (as is typical in most brain regions), the membrane properties of olivary neurons limit this modulation to a range of a few hertz and


Physiology_Levy

Physiology_Levy. afferent fibers can modulate the firing rates of olivary neurons (as is typical in most brain regions), the membrane properties of olivary neurons limit this modulation to a range of a few hertz and endows these neurons with the potential to be intrinsic oscillators. Instead of just modulating firing rates, olivary afferent activity also acts to modify the effectiveness of the electrical coupling between olivary neurons and thus changes the patterns of synchronous activity delivered to the cerebellum. Afferent activity may also modulate expression of the oscillatory potential of olivary neurons. Thus the inferior olivary nucleus appears to be organized to generate patterns of synchronous activity across the cerebellar cortex. The functional significance of these patterns remains controversial. One hypothesis is that they provide a gating signal for synchronizing motor commands to various muscle combinations.


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function •Fig. 9.21 Three-Dimensional View of the Cerebellar Cortex, Showing Some of the Cerebellar Neurons. Thecutfaceattheleftisalongthelongaxisofthefolium;thecutfaceattherightisatrightanglestothelongaxis.BC,basketcell;BCA,basketcellaxon;CF,climbing(olivocerebellar)fiber;CN,cerebellarnuclearcell;GC,Golgicell;Glm,glomerulus;GrC,granulecell;MF,mossyfiber;PC,Purkinje cell;PF,parallelfiber;SC,stellatecell. Cellular Elements and Efferent Fibers of the Cortex


Physiology_Levy

Physiology_Levy. Cellular Elements and Efferent Fibers of the Cortex Despite its enormous expansion throughout vertebrate evolution, the basic anatomical organization of the cerebellar cortex has remained nearly invariant. The circuitry is also among the most regular and stereotyped of any brain region. The cerebellar cortex contains eight different neuronal types: Purkinje cells, Golgi cells, granule cells, Lugaro cells, basket cells, stellate cells, unipolar brush cells, and candelabrum cells. These cells are found in all regions of the cerebellar cortex, with the exception of unipolar brush cells, which are limited mainly to cerebellar areas receiving vestibular input. These eight cell types are distributed among the three layers that make up the cerebellar cortex of higher vertebrates (


Physiology_Levy

Physiology_Levy. Fig. 9.21 ). The outer or superficial layer is the molecular layer; stellate and basket cells are found there. The deepest layer is the granule cell layer; this layer has the highest cellular density in the CNS and contains granule, Golgi, and unipolar brush cells. Separating the molecular and granule cell layers is the Purkinje cell layer, formed by Purkinje cell somata, which are arranged as a one-cell-thick sheet of cells. Candelabrum cells are also located in this layer. Lugaro cells are situated slightly deeper at the upper border of the granule cell layer. The sole efferent fiber from the cortex is the Purkinje cell axon, which also has local collaterals and is GABAergic and inhibitory. Thus the remaining seven cell types are local interneurons. Of these, the stellate, basket, Golgi, Lugaro, and candelabrum cells are also inhibitory GABAergic neurons, whereas the granule and unipolar brush cells are excitatory. Microcircuitry of the Cortex


Physiology_Levy

Physiology_Levy. Microcircuitry of the Cortex The dendrites, axons, and patterns of synaptic connections of most neurons within the cerebellar cortex are organized with regard to the transverse (short) and longitudinal (long) axes of the folium (Fig. 9.21 ). In the vermis, where the folia run perpendicular to the sagittal plane, these axes lie in the sagittal and coronal planes, respectively. In the hemispheres, where the folia are oriented at various angles with regard to the sagittal plane, this correspondence is lost, and the local axes of the folia must then serve as the reference axes.


Physiology_Levy

Physiology_Levy. The Purkinje cell dendritic tree is the largest in the CNS. It extends from the Purkinje cell layer through the molecular layer to the surface of the cerebellar cortex and for several hundred microns along the transverse axis of the folium but for only 30 to 40 µm in the longitudinal direction. Thus it is like a flat pancake that lies in a plane parallel to the transverse axis of the folium. Accordingly, a set of Purkinje cell dendritic trees can be thought of as a stack of pancakes, with the stack running along the longitudinal axis of the folium.


Physiology_Levy

Physiology_Levy. •Fig. 9.22 Functional Connectivity of the Cerebellar Cortex. Becauseofthegeometricorganizationofthecerebellarcorticalcircuits,thefunctionalconnectivityofthecellularelementscanbedeterminedelectrophysiologically.Thefiguredepictsaclassicparadigminwhichstimulationofthecerebellarcortexactivatesabeamofparallelfibers(orange). Recordingsfromthestellateandbasketcells(green cells) andPurkinjecells(PCs;orange cells)inlinewiththisbeamshowthattheyareexcitedbytheparallelfibers.Incontrast,Purkinjecellsflankingthebeamreceiveonlyinhibition(purple areas) asaresultoftheperpendicularspatialrelationshipoftheparallelfibersandthestellateandbasketcellaxons.


Physiology_Levy

Physiology_Levy. The dendritic trees of the molecular layer interneurons (stellate and basket cells) are oriented in a manner similar to that of the Purkinje cell dendritic tree, although they are much less extensive. The axons of stellate and basket cells run transversely across the folium and form synapses with Purkinje cells. Stellate and basket cells synapse onto Purkinje cell dendrites. In addition, basket cells make synapses on the Purkinje cell soma and form a basket-like structure around the base of the soma, which gives the basket cell its name.


Physiology_Levy

Physiology_Levy. Granule cells are small neurons with four to five short unbranched dendrites, each ending in a claw-like expansion that synapses with a mossy fiber rosette and with terminals from Golgi cell axons in a complex arrangement known as a glomerulus. The axons of granule cells ascend through the Purkinje cell layer to the molecular layer, where they bifurcate and form parallel fibers. The parallel fibers run parallel to the cerebellar surface along the longitudinal axis of the folium (perpendicular to the planes of the Purkinje, stellate, and basket cell dendritic trees) and form excitatory synapses with the dendrites of the Purkinje, Golgi, stellate, and basket cells.


Physiology_Levy

Physiology_Levy. The orthogonal relationship between the parallel fibers and the dendritic trees of the Purkinje cells and molecular layer interneurons (basket and stellate cells) has significant functional consequences. This arrangement allows maximal convergence and divergence to occur. A single parallel fiber, which can be up to 6 mm long, passes through more than 100 Purkinje cell dendritic trees (and also interneuron dendrites); however, it has the chance to make only one or two synapses with any particular cell because it crosses through the short dimension of the dendritic tree. Conversely, a given Purkinje cell receives synapses from on the order of 100,000 parallel fibers. Thus a beam of parallel fibers can be excited experimentally, which excites a row of Purkinje cells and interneurons that are in line with this beam (


Physiology_Levy

Physiology_Levy. Fig. 9.22 ). In addition, because the axons of the interneurons run perpendicular to the parallel fibers, this beam of excitation is flanked by inhibition. Although this classic electrophysiological experiment clearly demonstrates the functional connectivity of the cerebellar cortex, whether such beams of excitation occur normally remains a controversial question.


Physiology_Levy

Physiology_Levy. The Golgi cells are inhibitory interneurons in the granule cell layer. The geometric organization of their axonal and dendritic arbors is an exception to the orthogonal and planar organization of the cortex in that their dendrites and axons carve out approximately conical territories: like two cones, tip to tip, in which the soma is at the point where the two cone tips meet. The dendritic tree forms the upper cone, which often extends into the molecular layer, and the axon forms the lower one. Golgi cells are excited by mossy and olivocerebellar fibers and by granule cell axons (parallel fibers) and inhibited by basket, stellate, and Purkinje cell axon collaterals. They in turn inhibit granule cells. Thus they participate both in feedback (when excited by parallel fibers) and in feedforward (when excited by mossy fibers) inhibitory loops that control activity in the mossy fiber–parallel fiber pathway to the Purkinje cell.


Physiology_Levy

Physiology_Levy. Lugaro cells have fusiform somata from which emerge two relatively unbranched dendrites, one from each side, that run along the transverse axis of the folium for several hundred microns, usually just under the Purkinje cell layer. Purkinje cell axon collaterals provide the main input to these neurons, and granule cell axons add minor input. The axon terminates mainly in the molecular layer on basket, stellate, and possibly Purkinje cells. Thus these cells appear to sample the activity of Purkinje cells and provide both positive-feedback signals (they inhibit the interneurons that inhibit Purkinje cells) and negative-feedback signals (they directly inhibit the Purkinje cell).


Physiology_Levy

Physiology_Levy. Unipolar brush cells have only a single dendrite that ends as a tight bunch of branchlets that resemble a brush. These cells receive excitatory input from mossy fibers and inhibitory input from Golgi cells. It is thought that they synapse with granule and Golgi cells, which would make these cells an excitatory feedforward link in the mossy fiber–parallel fiber pathway. Candelabrum cells are GABAergic cells located in the Purkinje layer. Their dendrites and axons terminate in the molecular layer, where the axonal arborization pattern resembles a candelabrum. The cerebellar nuclei are the main targets of the cerebellar cortex. This projection is topographically organized in such a way that each longitudinal strip of cortex targets a specific region of the cerebellar nuclei. The gross pattern is that the vermis projects to the fastigial and vestibular nuclei, the paravermal region projects to the interpositus, and the lateral hemisphere projects to the dentate nucleus.


Physiology_Levy

Physiology_Levy. The cerebellar nuclear neurons in turn provide the output from the cerebellum to the rest of the brain (with the primary exception of Purkinje cells that project to the


Physiology_Levy

Physiology_Levy. CHAPTER 9 Organization of Motor Function vestibular nuclei). In discussing the output of the cerebellar nuclei, it is useful to group the nuclear cells according to whether they are GABAergic because the GABAergic cells project back to the inferior olivary nucleus and form a negative-feedback loop to one of the cerebellum’s principal afferent sources. Of importance is that GABAergic cells project to the specific part of the inferior olivary nucleus from which they receive input and from which their overlying longitudinal strip of cortex receives climbing fibers. Thus the cerebellar cortex, cerebellar nuclei, and inferior olivary nucleus are functionally organized as a series of closed loops. The non-GABAergic, excitatory nuclear cells project to a variety of targets from the spinal cord to the thalamus. In general, each nucleus gives rise to crossed ascending and descending projections that leave the cerebellum via the superior cerebellar peduncle. The fastigial nucleus also gives


Physiology_Levy

Physiology_Levy. to the thalamus. In general, each nucleus gives rise to crossed ascending and descending projections that leave the cerebellum via the superior cerebellar peduncle. The fastigial nucleus also gives rise to significant uncrossed fibers, as well as a second crossed projection called the uncinate gyrus, or hook bundle, that leaves via the inferior cerebellar peduncle.


Physiology_Levy

Physiology_Levy. Although there are differences in the specific targets of each nucleus, in general, the ascending cerebellar projections target midbrain structures, such as the red nucleus and superior colliculus, and the ventral lateral nucleus of the thalamus, which connects to the primary motor cortex and thereby links the cerebellum to motor areas of the cerebrum. (The cerebral motor areas are likewise linked to the cerebellum by multiple pathways, including ones that relay in the basilar pons and inferior olivary nucleus.) It should also be mentioned that ascending cerebellar projections, particularly from the dentate nucleus, also target nonmotor regions of the cerebrum, particularly in the frontal lobe. The descending fibers target mainly the basilar pontine nuclei, inferior olivary nucleus, and several reticular nuclei. Lastly, a small cerebellospinal pathway arises principally from the fastigial nucleus. In addition, the fastigial nucleus has significant projections to the vestibular nuclei.


Physiology_Levy

Physiology_Levy. Activity of Purkinje Cells in the Cerebellar Cortex in the Context of Motor Coordination Mossy fiber input to the cerebellar cortex, via their excitation of granule cells, causes a Purkinje cell to discharge single action potentials, referred to as simple spikes (


Physiology_Levy

Physiology_Levy. Fig. 9.23 ). The spontaneous simple spike firing rate of a Purkinje cell typically is between 20 and 100 Hz but can be modulated over a much wider range (from 0 to >200 Hz), depending on the relative balance of excitation from parallel fiber input and inhibition from cerebellar cortex interneurons. Thus this activity reflects the state of the cerebellar cortex. Interestingly, evidence from studies performed in the early 2000s indicates that the spontaneous levels of simple spike activity vary systematically across the cerebellar cortex: Firing rates in zebrin-negative regions average twice those of the zebrin-positive regions. The full significance of this discovery is not known, but it suggests that despite the anatomical uniformity of the cerebellar cortical circuits, they might be functionally quite distinct.


Physiology_Levy

Physiology_Levy. •Fig. 9.23 Responses of a Purkinje Cell to Excitatory Input, Recorded Extracellularly. A, Granulecells,viatheirascendingaxonsandparallelfibers,excitePurkinjecellsandtriggersimplespikes.B, Climbingfiberactivityleadstohigh-frequency(≈500-Hz)burstsofspikesknownascomplex spikes inPurkinjecells.Notethatthespikesfollowingtheinitialonearesmallerandreferredtoasspikelets. In contrast, a climbing fiber discharge causes a high-frequency burst of action potentials, called a complex spike (see Fig. 9.23 ), in an all-or-none manner because of the massive excitation that is provided by the single climbing fiber that a Purkinje cell receives. This excitation is so powerful that there is essentially a one-to-one relationship between climbing fiber discharge and a complex spike. Thus complex spikes essentially override what is happening at the cortex level and reflect the state of the inferior olivary nucleus. The average firing rate of a spontaneous complex spike is only about 1 Hz.


Physiology_Levy

Physiology_Levy. Because the climbing fibers generate complex spikes at such a low frequency, they do not substantially change the average firing rates of Purkinje cells, and as a consequence, it is commonly argued that they have no direct role in shaping the output of the cerebellar cortex and are therefore not involved in ongoing motor control. Instead, it is commonly thought that their function is to alter the responsiveness of Purkinje cells to parallel fiber input. In particular, under certain circumstances, complex spike activity produces a prolonged depression in synaptic efficacy of parallel fibers, termed long-term depression (LTD). This phenomenon is the proposed mechanism by which climbing fibers act in motor-learning hypotheses. According to typical hypotheses about it, the parallel fiber system and hence simple spikes are involved in generating ongoing movement, and when there is a mismatch between the intended and actual movement, this error activates the inferior olivary nucleus and


Physiology_Levy

Physiology_Levy. and hence simple spikes are involved in generating ongoing movement, and when there is a mismatch between the intended and actual movement, this error activates the inferior olivary nucleus and complex spikes result, which then lead to LTD of the active parallel fiber synapses. This adjustment in synaptic weight changes the motor output in the future. If this change results in a properly executed movement, activation of the inferior olivary nucleus does not occur, and the motor program is unchanged, but if there is still an error, the olivocerebellar system triggers additional complex spikes that cause further changes in synaptic efficacy, and so on. Major challenges to this view are that motor learning can occur when LTD is chemically blocked and that learned behavior can remain after removal of portions of the cerebellum in which the memory is supposedly stored.


Physiology_Levy

Physiology_Levy. An alternative view is that the olivocerebellar system is directly involved in motor control (note that this does not preclude a role in motor learning as well) and, in particular, helps in the timing of motor commands. This view follows from the types of motor deficits observed in cerebellar damage and accounts for the special properties of the inferior olivary nucleus mentioned earlier: namely, that it can generate rhythmic, synchronous complex spike discharges across populations of Purkinje cells. These complex spikes would then produce synchronized inhibitory postsynaptic currents (IPSPs) on cerebellar nuclear neurons as a result of the convergence present in the Purkinje cell axon to the cerebellar nuclear projection. Because of the membrane properties of cerebellar nuclear neurons, these synchronized IPSPs could have a qualitatively different effect on nuclear cell firing than would the IPSPs caused by simple spikes, which are more numerous but largely asynchronous.


Physiology_Levy

Physiology_Levy. neurons, these synchronized IPSPs could have a qualitatively different effect on nuclear cell firing than would the IPSPs caused by simple spikes, which are more numerous but largely asynchronous. Specifically, they could trigger large precisely timed changes in the nuclear cell activity that would then be transmitted to other motor systems as a gating signal. In fact, voluntary movements appear to be composed of a series of periodic accelerations that reflect a central oscillatory process. However, determining whether the olivocerebellar system helps time motor commands requires further evidence.


Physiology_Levy

Physiology_Levy. Motor Control by the Basal Ganglia The basal ganglia are deep nuclei in the cerebrum. Like the cerebellum, a major function of the basal ganglia is to regulate motor activity and we will focus on that role in this section. However, it is worth noting that they, like the cerebellum, also contribute to affective and cognitive functions. To understand basal ganglia function in motor control, the following discussion is organized around two major themes: (1) the connections between basal ganglia and cortex form loops through which activity flows and (2) there are two functionally distinct pathways through the basal ganglia, the direct and indirect pathways. Organization of the Basal Ganglia and Related Nuclei The basal ganglia include the caudate nucleus, the putamen, and the globus pallidus ( Fig. 9.24 ). The term striatum, derived from the striated appearance of these


Physiology_Levy

Physiology_Levy. The basal ganglia include the caudate nucleus, the putamen, and the globus pallidus ( Fig. 9.24 ). The term striatum, derived from the striated appearance of these CHAPTER 9 Organization of Motor Function •Fig. 9.24 Components of Basal Ganglia and Other Closely Associated Brain Regions. Themaincomponentsofthebasalgangliaarethecaudatenucleus,putamen,globuspallidus,andsubstantianigraparsreticulata.Majorportionsofthebasalgangliaconnectwithmotorareasinthefrontalcortex,viatheventralanteriorandventrallateralthalamicnuclei,andwiththesuperiorcolliculus.Inputfromthesubstantianigraparscompactaiscriticalfornormalbasalgangliafunction.GPe,externalsegmentofglobuspallidus;GPi,internalsegmentofglobuspallidus.


Physiology_Levy

Physiology_Levy. nuclei, refers only to the caudate nucleus and putamen. The striations are produced by the fiber bundles formed by the anterior limb of the internal capsule as it separates the caudate nucleus and putamen. The globus pallidus typically has two parts: an external segment and an internal segment. The combination of putamen and globus pallidus is often referred to as the lentiform nucleus. Associated with the basal ganglia are several thalamic nuclei. These include the ventral anterior (VA) and ventral lateral (VL) nuclei and several components of the intralaminar complex. Other associated nuclei are the subthalamic nucleus of the diencephalon and the substantia nigra of the midbrain (see


Physiology_Levy

Physiology_Levy. Fig. 9.24 ). The substantia nigra (“black substance”) derives its name from its content of melanin pigment. Many of the neurons in the pars compacta of this nucleus contain melanin, a byproduct of dopamine synthesis. The other subdivision of the substantia nigra is the pars reticulata. This structure can be regarded as an extension of the internal segment of the globus pallidus because these nuclei have an identical origin and analogous connections. Connections and Operation of the Basal Ganglia With the exception of the primary visual and auditory cortices, most regions of the cerebral cortex project topographically to the striatum. The corticostriatal projection arises from neurons in layer V of the cortex. Glutamate appears to be the excitatory neurotransmitter of these neurons. The striatum then influences neurons in the nuclei of the thalamus by two pathways: direct and indirect ( Fig.


Physiology_Levy

Physiology_Levy. Fig. 9.25A ). The thalamic neurons in turn excite neurons of the cerebral cortex thereby forming closed loops with most of the cortex. Several distinct loops have been identified on the basis of cortical regions and function; however, here we will focus on the motor-related loops as a model for basal ganglia operation ( Fig. 9.25A


Physiology_Levy

Physiology_Levy. The overall action of the direct pathway through the basal ganglia to motor areas of the cortex is to enhance motor activity. In the direct pathway, the striatum projects to •Fig. 9.25 Functional Connectivity of the Basal Ganglia for Motor Control. A, Connectionsbetweenvariousbasalgangliacomponentsandotherassociatedmotorareas.TheexcitatorycorticalinputtothecaudateandputameninfluencesoutputfromtheGPiandthesubstantianigraparsreticulata(SNpr)viaadirectandanindirectpathway.Thetwoinhibitorystepsintheindirectpathwaymeanthatactivitythroughthispathwayhasaneffectonbasalgangliaoutputtothethalamusandsuperiorcolliculusoppositethatofthedirectpathway.Dopamine(DA)isaneuromodulatorthatactsonD1andD2receptorsonstriatalneuronsthatparticipateinthedirectandindirectpathways,respectively.B, ChangesinactivityflowthatoccurinParkinson’sdisease,inwhichthesubstantianigraparscompacta(SNpc)degenerates.C, ChangesinactivityflowinHuntington’sdisease,inwhichinhibitorycontroloftheGPeislost.Plus symbols (+)andminus


Physiology_Levy


Physiology_Levy

Physiology_Levy. the internal segment of the globus pallidus (GPi). This projection is inhibitory, and the main transmitter is GABA. The GPi projects to the VA and VL nuclei of the thalamus. These connections also function with GABA and are inhibitory. The VA and VL nuclei send excitatory connections to the prefrontal, premotor, and supplementary motor cortex. This input to the cortex influences motor planning, and it also affects the discharge of corticospinal and corticobulbar neurons.


Physiology_Levy

Physiology_Levy. The direct pathway appears to function as follows: Neurons in the striatum have little background activity, but during movement they are activated by their input from the cortex. In contrast, neurons in the GPi have a high level of background activity. When the striatum is activated, its inhibitory projections to the globus pallidus slow the activity of pallidal neurons. However, the pallidal neurons themselves are inhibitory, and they normally provide tonic inhibition of neurons in the VA and VL nuclei of the thalamus. Therefore, activation of the striatum causes disinhibition of neurons of the VA and VL nuclei. When disinhibited, the VA/VL neurons increase their firing rates, exciting their target neurons in the motor areas of the cerebral cortex. Because the motor areas evoke movement by activating α and γ motor neurons in the spinal cord and brainstem, the basal ganglia can regulate movement by enhancing the activity of neurons in the motor cortex.


Physiology_Levy

Physiology_Levy. The overall effect of the indirect pathway is to reduce the activity of neurons in motor areas of the cerebral cortex. The indirect pathway involves inhibitory connections from the striatum to the external segment of the globus pallidus (GPe), which in turn sends an inhibitory projection to the subthalamic nucleus and to the GPi. The subthalamic nucleus then sends an excitatory projection back to the GPi (see Fig. 9.25A


Physiology_Levy

Physiology_Levy. Fig. 9.25A In this pathway, pallidal neurons in the external segment are inhibited by the GABA released from striatal terminals in the globus pallidus. The GPe normally releases GABA in the subthalamic nucleus and thereby inhibits the subthalamic neurons. Therefore, striatal inhibition of the GPe results in the disinhibition of neurons of the subthalamic nucleus. The subthalamic neurons are normally active, and they excite neurons in the GPi by releasing glutamate. When the neurons of the subthalamic nucleus become more active because of disinhibition, they release more glutamate in the GPi. This transmitter excites neurons in the GPi and consequently activates inhibitory projections that affect the VA and VL thalamic nuclei. The activity of the thalamic neurons consequently decreases, as does the activity of the cortical neurons that they influence.


Physiology_Levy

Physiology_Levy. The direct and indirect pathways thus have opposing actions; an increase in the activity of either one of these pathways might lead to an imbalance in motor control. Such imbalances, which are typical of basal ganglion diseases, may alter the motor output of the cortex. CHAPTER 9 Organization of Motor Function Actions of Neurons in the Pars Compacta of the Substantia Nigra on the Striatum


Physiology_Levy

Physiology_Levy. Dopamine is the neurotransmitter used by neurons of the substantia nigra pars compacta. In the nigrostriatal pathway, release of dopamine has an overall excitatory action on the direct pathway and an inhibitory action on the indirect pathway. This is, however, a modulatory type of effect; that is, dopamine is apparently causing its action not by triggering spikes directly but rather by altering the striatal cells’ response to other transmitters. The different actions on the direct and indirect pathways result from the expression of different types of dopamine receptors (D1 and D2) by the spiny projection cells of the striatum that contribute to the direct and indirect pathways. D1 receptors are found on striatal cells that form the direct pathway by projecting to the GPi, whereas D2 receptors are found on striatal cells that participate in the indirect pathway and project to the GPe. The overall consequence of dopamine release in both cases is facilitation of activity in the motor


Physiology_Levy

Physiology_Levy. are found on striatal cells that participate in the indirect pathway and project to the GPe. The overall consequence of dopamine release in both cases is facilitation of activity in the motor areas of the cerebral cortex.


Physiology_Levy

Physiology_Levy. Subdivision of the Striatum Into Striosomes and Matrix On the basis of the associated neurotransmitters, the stria-tum has been subdivided into zones called striosomes and matrix. The cortical projections related to motor control end in the matrix area. The limbic system projects to the striosomes. Striosomes are thought to synapse in the pars compacta of the substantia nigra and to influence the dopaminergic nigrostriatal pathway. Role of the Basal Ganglia in Motor Control The basal ganglia influence the cortical motor areas. Therefore, the basal ganglia have an important influence on the lateral system of motor pathways. Such an influence is consistent with some of the movement disorders observed in diseases of the basal ganglia. However, the basal ganglia must additionally regulate the medial motor pathways because diseases of the basal ganglia can also affect the posture and tone of proximal muscles.


Physiology_Levy

Physiology_Levy. The deficits seen in the various basal ganglia diseases include abnormal movement (dyskinesia), increased muscle tone (cogwheel rigidity), and slowness in initiating movement (bradykinesia). Abnormal movement includes tremor, athetosis, chorea, ballism, and dystonia. The tremor of basal ganglion disease is a 3-Hz “pill-rolling” tremor that occurs when the limb is at rest. Athetosis consists of slow, writhing movement of the distal parts of the limbs, whereas chorea is characterized by rapid, flicking movement of the extremities and facial muscles. Ballism is associated with violent, flailing movement of the limbs (ballistic movement). Finally, dystonic movements are slow involuntary movements that may cause distorted body postures.


Physiology_Levy

Physiology_Levy. Parkinson’s disease is a common disorder characterized by tremor, rigidity, and bradykinesia. This disease is caused by loss of neurons in the pars compacta of the substantia nigra. Consequently, the striatum suffers a severe loss of dopamine. Neurons of the locus coeruleus and the raphe nuclei, as well as other monoaminergic nuclei, are also lost. The loss of dopamine diminishes the activity of the direct pathway and increases the activity of the indirect pathway (see Fig. 9.25B ). The net effect is an increase in the activity of neurons in the internal segment of the globus pallidus. This results in greater inhibition of neurons in the VA and VL nuclei and less pronounced activation of the motor cortical areas. The consequence is slowed movement (bradykinesia).


Physiology_Levy

Physiology_Levy. Before the dopaminergic neurons are completely lost, administration of levodopa can relieve some of the motor deficits in Parkinson’s disease. Levodopa is a precursor of dopamine, and it can cross the blood-brain barrier. Currently, the possibility of transplanting dopamine-synthesizing neurons into the striatum is being explored. Future research will no doubt focus on the potential for human embryonic stem cells to play such a therapeutic role. Another basal ganglia disturbance is Huntington’s disease, which results from a genetic defect that involves an autosomal dominant gene. This defect leads to the preferential loss of striatal GABAergic and cholinergic neurons that project to the GPe as part of the indirect pathway (and also degeneration of the cerebral cortex, with resultant dementia). Loss of inhibition of the GPe presumably leads to diminished activity of neurons in the subthalamic nucleus (see


Physiology_Levy

Physiology_Levy. Fig. 9.25C ). Hence, the excitation of neurons of the GPi would be reduced. This would disinhibit neurons in the VA and VL nuclei. The resulting enhancement of activity in neurons in the motor areas of the cerebral cortex may help explain the choreiform movements of Huntington’s disease. The rigidity in Parkinson’s disease may in a sense be the opposite of chorea because overtreatment of patients with Parkinson’s disease with levodopa can result in chorea. Hemiballism is caused by a lesion of the subthalamic nucleus on one side of the brain. In this disorder, involuntary, violent flailing movements of the limbs may occur on the side of the body contralateral to the lesion. Because the subthalamic nucleus excites neurons of the GPi, a lesion of the subthalamic nucleus would reduce the activity of these pallidal neurons. Therefore, neurons in the VA and VL nuclei of the thalamus would be less inhibited, and the activity of neurons in the motor cortex would be increased.


Physiology_Levy

Physiology_Levy. In all these basal ganglia disorders, the motor dysfunction is contralateral to the diseased component. This is understandable because the main final output of the basal ganglia to the body is mediated by the corticospinal tract.


Physiology_Levy

Physiology_Levy. Eye movement has a number of features that distinguish it from other motor behavior. In comparison with the movement that limbs, with their multiple joints and muscles, can perform, eye movement is relatively simple. For example, each eye is controlled by only three agonistantagonist muscle pairs: the medial and lateral recti, the superior and inferior recti, and the superior and inferior oblique muscles. These muscles allow the eye to rotate about three axes. Assuming that the head is in an upright position, the axes are the vertical axis, a horizontal axis that runs left to right, and the torsional axis (which is directed along the axis of sight). The medial and lateral recti control movement about the vertical axis; the other four muscles generate movement about the horizontal and torsional axes. Another simplifying feature is that there are no external loads for which to be compensated. Furthermore, eye movement appears to be separable into a few distinct types, with each type


Physiology_Levy

Physiology_Levy. axes. Another simplifying feature is that there are no external loads for which to be compensated. Furthermore, eye movement appears to be separable into a few distinct types, with each type being controlled by its own specialized circuitry. Thus eye movement offers a number of advantages as a model system for studying motor control. Moreover, deficits in eye movement provide important clinical clues to the diagnosis of neurological problems. We first review the different eye movement types and then discuss the neural circuitry underlying their generation.


Physiology_Levy

Physiology_Levy. Types of Eye Movement Eye movement probably first evolved to hold the image of the external world still. (In contrast, limb movements evolved to generate changes in the position of the limb with regard to the external world.) The reason is that visual acuity degrades rapidly when there is eye movement in relation to the external world (i.e., the visual scene slips across the retina). A major cause of such slippage is movement of the head. The vestibuloocular reflex (VOR) is one of the main mechanisms by which head movement is compensated in order to maintain stability of the visual scene on the retina.


Physiology_Levy

Physiology_Levy. To maintain a stable visual scene on the retina, the VOR produces movements of the eyes that are equal and opposite the movement of the head. This reflex is initiated by stimulation of the receptors (hair cells) in the vestibular system (see ). Recall that the vestibular organs are sensitive to head acceleration, not visual cues, and thus the VOR occurs in both the light and dark. Functionally, it is what is called an open-loop system in that it generates an output (eye movement) in response to a stimulus (head acceleration), but its immediate behavior is not regulated by feedback about the success or failure of its output. It is worth noting, however, that in the light at least, any failure by the VOR to match eye and head rotation results in what is called retinal slip (i.e., slip of the visual image across the retina), and this error signal can be fed back to the VOR circuits by other neuronal pathways and over time can lead to adjustments in the strength of the VOR to eliminate


Physiology_Levy

Physiology_Levy. the visual image across the retina), and this error signal can be fed back to the VOR circuits by other neuronal pathways and over time can lead to adjustments in the strength of the VOR to eliminate the error. This adaptation of the VOR is a major model for studying plasticity in the brain.


Physiology_Levy

Physiology_Levy. As stated, acceleration signals initiate the VOR. The output of the VOR, however, must be a change in eye position in the orbit. Thus the problem to be solved by the nervous system is to translate the acceleration signals sensed by the vestibular organs into correct positional signals for the eyes. Mathematically, this can be thought of as a double integration. The first integration occurs in the vestibular receptor apparatus because although the hair cells respond to head acceleration, the signals in the vestibular afferent fibers are proportional to head velocity (at least for most stimuli that are encountered physiologically). The second integration, from velocity to position, occurs in the CNS in circuits described later.


Physiology_Levy

Physiology_Levy. The head can move in six different ways, often referred to as six degrees of freedom: three translational and three rotational. To compensate for these different types of movement, there are both translational and angular VORs, as well as separate subsystems for handling movement about different directions (e.g., rotation about a vertical or a horizontal axis).


Physiology_Levy

Physiology_Levy. The optokinetic reflex (OKR) is a second mechanism by which the CNS stabilizes the visual scene on the retina, and it often works in conjunction with the VOR. Whereas the VOR is activated only by head motion, the OKR is activated by movement of the visual scene, whether caused by motion of the scene itself or by head motion. Specifically, the sensory stimulus for this reflex is slip of the visual scene on the retina as detected by motion-sensitive retinal ganglion cells. An example of the former occurs when you are sitting in a train and a train on the adjacent track begins moving: Your eyes rotate to keep the image of the neighboring car stable. This often leads to a sensation that you are moving (this is not entirely surprising because OKR circuits feed into the same circuits as used by the vestibular system).


Physiology_Levy

Physiology_Levy. The OKR can work in conjunction with the VOR to stabilize the visual image and is particularly important for maintaining a stable image when head movements are slow because the VOR works poorly in these conditions. In animals whose eyes have a fovea, it becomes particularly advantageous to be able to move the eye in relation to the world (i.e., the main visual scene) so that objects of importance can be focused onto the fovea and scrutinized with this high-resolution part of the retina. Two classes of eye movement underlie this ability: saccadic and smooth pursuit. Very rapid discrete movements that bring a particular region of the visual world onto the fovea are called saccades. For example, to read this sentence, you are making a series of saccades to bring successive words onto your fovea to be read. However, even in animals that lack a fovea, the eyes make saccades, and thus saccades may also be used to rapidly scan the visual environment.


Physiology_Levy

Physiology_Levy. Saccades are extremely rapid eye movements. In humans, eye velocity during a saccade can reach 800 degrees/second, in comparison with movement velocity of less than 10 degrees/second generated in response to typical VOR and CHAPTER 9 Organization of Motor Function OKR stimuli (velocities of up to ≈120 degrees/second can be produced by OKR stimuli in humans; however, they are still much slower than the maximal saccade velocities). Saccades can be made voluntarily or reflexively. Moreover, although they are usually made in response to visual targets, they can also be made toward auditory or other sensory cues, in the dark, or toward memorized targets.


Physiology_Levy

Physiology_Levy. Interestingly, visual processing appears to be suppressed just before and during saccades, particularly in the magnocellular visual pathway that is concerned with visual motion. This phenomenon is known as saccadic suppression and may function to prevent sensations of sudden, rapid movement of the visual world that would result during a saccade in the absence of such suppression. The mechanisms underlying saccadic suppression are not fully known, but in areas of the cortex related to visual processing, the responsiveness of the cells to visual stimuli is reduced and altered during saccades.


Physiology_Levy

Physiology_Levy. Once a saccade has brought a moving object of interest onto the fovea, the smooth pursuit system allows the person to keep it stable on the fovea despite its continued motion. This ability appears to be limited to primates and allows prolonged continuous observation of a moving object. Note that in some respects, smooth pursuit might seem similar to the OKR; in fact, there may not be an absolute difference because as the target size grows, the distinction between target and background is lost; however, for small moving targets, smooth pursuit requires suppression of the OKR. You can see the effect of this suppression by moving your finger back and forth in front of this text while tracking it with your eyes. Your finger will be in focus, but the words on this page will be part of the background scene and will become illegible as they slip along your retina.


Physiology_Levy

Physiology_Levy. When there is a prolonged OKR or VOR stimulus (e.g., if you keep turning in one direction), these reflexes will initially counterrotate the eyes in an attempt to maintain a stable image on the retina, as described earlier. However, with a prolonged stimulus, the eyes will reach their mechanical limit, no further compensation will be possible, and the image will begin to slip on the retina. To avoid this situation, a fast saccade-like movement of the eyes occurs in the opposite direction, essentially resetting the eyes to begin viewing the visual scene again. Then the slow OKR-or VOR-induced counterrotation will start anew. This alternation of slow and fast movement in opposite directions is nystagmus and can be recorded on a nystagmogram ( Fig.