- Email: [email protected]
Neural systems controlling movement
T I N S - October 1986 that in non-identical twins), there is speculation that it may be due to exposure to environmental toxins similar to MPTP. The way in which MPTP destroys the substantia nigra has been worked out in experimental studies. MPTP causes parkinsonism and nigral damage in non-human primates but not in lower species. MPTP itself is not the toxic agent; once it reaches the brain it is converted into MPP + by the action of MAO B in glia; MPP + is then taken up into nigral neurones by the dopamine uptake system; MPP + then binds to neuromelanin in nigral nerve cells, where it is trapped, and kills these nerve cells by generation of free radicals and interference with energy metabolism. This remarkable series of events can be prevented at a number of
515 points. Inhibitors of MAO B, such as deprenyl, inhibitors of dopamine uptake such as mazindol, and free radical scavengers all may prevent the neurotoxicity of MPTP, and are under trial in Parkinson's disease. Apart from the specific role of MPTP in Parkinson's disease, the story carries general implications. It graphically illustrates how an environmental neurotoxin can be targeted by normal brain mechanisms to destroy a discrete area or system in the brain. Amongst the non-hereditary movement disorders, many are due to selective system degenerations, and these are candidates for environmental toxic causes. Many of these diseases are also characterized by distinctive cellular pathology, for example the Lewy body in Parkinson's disease and the straight
neurofibrillary tangles of progressive supranuclear palsy. Understanding the nature of the disruption of the neuronal cytoskeleton that leads to these inclusions may prove as revealing as it has in the study of Alzheimer's disease. In conclusion, movement disorders advance apace. It is no longer a question of 'give us the tools and we will do the job'. The scientific tools are there, but will funds and scientists be available to deploy them as rapidly as the patient's urgent needs demand.
C. D. Marsden is at the University Department of Neurology and Parkinson's Disease Society Research Centre, Institute of Psychiatry, King's College Hospital Medical School, Denmark Hill, London SES, UK.
Neural systems controlling movement Masao Ito Neural systems responsible for motor control are organized in hierarchical levels of increasing complexity, from reflex arcs in the spinal cord and brain stem to voluntary command systems in the cerebral cortex. Specification of the structure and function of motor systems at each of these levels has been, and will continue to be a major theme of neuroscience. However, such specification is not an easy task: even the most simple of motor systems, e.g. the stretch reflex, requires the elucidation of several levels of organization. First, there must be clear behavioral characterization of the system, which, in this instance, is the reactive contraction of a stretched muscle. Second, neural elements, muscle spindles, Ia afferents, motoneurons and contractile muscle involved in the system must be defined in detail. Third, the neuronal circuitry constituting the system must be elucidated to the extent that essential features of information processing actually taking place in the system can be predicted. The principal circuit of a stretch reflex is an excitatory dineuronal chain, and divergence-convergence at these synapses governs the non-linear input-output relationship of the reflex arc. Fourth, the entire system should he modelled with the function of the system clearly specified, i.e. the stretch reflex serves as a length servoassisted control system for a musclel~ Generally speaking, the first step
described above has been the main subject of study in classical neurology and neurophysiology, whereas recent advances in neuroscience have added much to our knowledge of the second. The third and fourth steps have also benefited from recent developments in biocybernetics, and have yielded a number of important new concepts in the neural mechanisms of motor control. I wish to emphasize that the synthesis of heterogeous knowledge and concepts through these four steps has been and will continue to be essential for the understanding of a motor system as a whole, and that such a synthesis should be a major theme of our future studies of motor systems.
cases for which the system specification is unsatisfactory: specific examples being the crossed extension reflex of a limb for the maintenance of the posture during avoidance of harmful stimuli to another limb; the optokinetic eye movement response that stabilizes retinal images during movement of the whole visual field; the tonic neck reflex that adjusts the position of a body during neck torsion; and lens accommodation for securing visual acuity at varied object distances. Thus, it is important to accumulate further knowledge about reflex systems as basic elements of motor systems. A reflex arc is often associated with a local circuit for integration. For example, single shock stimuli to a skin Reflex arcs and associated neural nerve induces a long-lasting impulse integrators discharge from the spinal cord, and so One hundred elementary reflexes produce enduring flexion of a limb. operate at the bottom of the pyramid- Thus an impulse input is integrated to like hierarchy of motor systems. Each provide a step output discharge within of these involves comparatively simple the spinal cord. Recently, another clear circuitry composed of a relatively small case of neural integration has been number of neuronal types, and each described in the vestibulo-ocular reserves as an elementary control system flex, where head velocity signals are regulating a single movement para- converted to eye position signals2. meter, i.e. the stretch reflex for Although the identity of this neural muscle length, the vestibulo-ocular integrator is still obscure, it appears to reflex for visual stability during head involve the nucleus prepositus hypomovement, or the pupillary light reflex glossi3. An interesting integration controlling constancy of luminous phenomenon has also been observed in intensity at the retina. A wealth of the spinal cord, where muscle afferent information about reflexes is now volleys induce a long-lasting depolaravailable, yet there are still a number of ization in motoneurons 4. Involvement 1986, Elsevier Science Publishers B.V., Amsterdam 0378 - 5912/86/$02.00
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of a serotonergic mechanism has been suggested. In addition to the closed loop and multiple chain circuits that have long been considered as possible prototypes of neural integrators, new models are now being proposed 5, although much remains to be learnt about the actual mechanisms involved. Local motor programs The spinal cord and brain stem contain different types of local circuitry that represent subroutines regulating particular types of motor behavior, such as rhythm generation for the scratch reflex, stepping, locomotion, mastication, nystagmus, and breathing. Rhythm generators for stepping and locomotion in hindlimbs are located in lumbar segments of the spinal cord6. The rhythm generator for mastication has recently been localized to the medial bulbar reticular formation, to which signals from the cerebral cortical masticatory area are directed after having been relayed from the dorsal part of the paragigantocellular reticular nucleus7. The neuronal mechanisms underlying rhythm generation have also been investigated in lower animals, e.g. in the leech8, mollusc9, locust 1°, and lamprey1~. A variety of neuronal circuits have been thought to be responsible for rhythm generation. These structures have some common features, such as the inclusion of reciprocal inhibitory connections in the network, but the fundamental question is whether the rhythm is generated by pacemaker cells, as in the heart, or by an oscillatory circuit consisting of multiple neurons, or both. An important example of a subroutine system underlying voluntary movements has been found in the cervical segments of the spinal cord 12. C3-C4 propriospinal neurons mediate the supraspinal motor command for forelimb target-reaching movements. These neurons receive convergent monosynaptic excitatory input from several supraspinal centers, and their axons project directly to forelimb motoneurons. They also receive inhibitory inputs from skin and joint afferents 13. Further investigations of this system should reveal some of the features of the local organization of the basic subroutine building blocks underlying voluntary movements.
c a ] a l s a r a w m g 03 c e r e o e u u m .
studies of the role of the superior colliculus in directing saccadic eye movements. A saccadic eye movement toward a visual target is driven by high frequency burst inputs to extraocular motoneurons. For a horizontal saccade TM, these bursts are generated in the so-called saccade generator located in the paramedian pontine reticular formation (PPRF), whereas vertical saccades are generated in the midbrain reticular formation15. Retinal signals monitoring errors occurring during the foveation of a visual target drive a saccade generator to produce burst impulses. The neuronal circuitry of the PPRF saccade generator has been dissected in recent years, but mechanisms for burst generation are still unknown. The superficial layer of the superior coUiculus contains orderly aligned cells with well-defined visual receptive fields, and apparently represents a map of visual space. In contrast, the deeper layers contain cells whose activity is related to the goal points of saccadic eye movements, regardless of initial eye positions16. It appears that a sensory map in the superficial layer is Tectal motor map The important concept of a neural transformed into a motor map in the space map has been derived from deep layer, on which a vector from an
initial eye position to a goal eye position is represented. This vector is then translated into command signals for saccade generators such as the PPRF. Understanding the neuronal mechanisms of these transformations and translations will be attractive subjects of motor physiology in the coming years. Postural and locomotion centers Posture is maintained by the concerted activity of numerous reflexes such as the stretch reflex, crossed extension reflex, tonic labyrinthine and tonic neck reflexes. In addition, there is a center in the midbrain for a reflex that is triggered by labyrinthine, neck and visual stimuli, which helps the animal to regain an upright position after a fall. This righting reflex is of special interest in motor physiology, for it suggests the existence of a neural device for measuring the center of gravity of the whole body - this would require the integration of afferent signals from a variety of sensors located in different parts of the body. It is pecufiar that there is almost no information about the neuronal elements or circuits in the midbrain that might be concerned with this reflex.
TINS- October 1986 By comparison, locomotion center in the midbrain is better defined since its discovery by Shik 17. It is located in the cuneiform nucleus which lies beneath the inferior colliculus, and impulses emanating from it drive segmental rhythm generators into action. Signal generation in this center is controlled by GABAergic inputsTM.
The cerebellum The cerebellum has been wellstudied at each of the four levels alluded to at the beginning of this essay19. First, it has been found to be responsible for high-order motor control of coordination, orthometria and compensation in classic lesion studies on animals and humans19. Second, neuronal elements of the cerebellum are well identified. Evidence of a special type of synaptic plasticity that would act as a memory element of the cerebellar cortex has accumulated. Third, neuronal networks composed of these elements in cerebellar cortex constitute a computer-like neuronal network for parallel, distributed information processing20-22. A small area of the cerebellar cortex termed a microzone23 is connected to a small group of cells in the vestibular or cerebellar nuclei to form a corticonuclear microcomplex. Such a nuclear cell group could serve as an interface between a microzone and an extracerebellar system. Thus a corticonuclear microcomplex could act as a 'chip' in the cerebellar 'computer'. A close analogy may be drawn between characteristic cerebellar functions (coordination, orthometria and compensation) and the high-order control performance of modern machines utilizing computers (multivariable control, predictive control and adaptivelearning control). The model system above applies best to cerebellar control of the vestibuloocular reflex. In this instance, a microzone in the fiocculus would constitute a self-tuning regulator (a type of adaptive control system) for the reflex 19. Numerous reflexes would likewise be attached to corticonuclear microcomplexes so as to acquire highorder control performance. It is tempting to assume that similar principles also apply to cerebellar control of voluntary movements. In order to comprehend diverse aspects of cerebellar roles in motor control, I wish to propose a new control theory concept'control augmentation', based on the computer action of cerebellar circuits.
517 Control augmentation is a major component of modem vehicle control technology, and a remarkable recent development of its use is the attainment of six degrees of freedom in airplane control: there are normally four (pitch, roll, yaw and thrust), but now two more have been added (direct side and up-down translocations). It is worth noting that the degrees of freedom for a forelimb of a human, including fingers, are as many as 30, which requires an extreme degree of control augmentation.
brain stem may be better understood from this viewpoint.
The cerebral cortex There are three major cerebral cortical areas involved in motor control: the main motor area (Brodman's area 4), the premotor area (area 6) and the supplementary motor area (a part of area 6 extending to the medial surface of the cerebral hemisphere). Each site in the motor area appears to code simple patterns of movements involving a limited number of muscles. The premotor area may generate spatiotemporal patterns of voluntary Basalganglia The disorders of the basal ganglia are movements. It is supposed that these now well-known, and detailed know- patterns are transferred to the motor ledge is available about the degener- area and translated to motor command ation at the neuronal elements com- signals there. The supplementary posing this large assembly. However, motor area, on the other hand, appears little progress has been made regarding to generate signals that establish a the normal neuronal network structure preparatory status of the motor area for of the basal ganglia. Cortico-caudato- responding to signals from the prepallidal projections may look like a motor area, the somatosensory area or filter that condenses cortical inform- the thalamus. Possible differential ation to pallidal output. However, this roles of the three cortical areas have model is too simple to provide any been derived from lesion studies and useful predictions. The purpose of the are supported by recent recordings of basal ganglia as a motor system is also neuronal signals. However, our knowonly vaguely understood, despite ledge, at the level of neuronal elements, numerous suggestions. In this respect, circuits and systems, is still at a rather the classic neurological concept of primitive stage. hypokinesia in parkinsonism and Thus, identificationof cerebral cortihyperkinesia in chorea should be cal motor systems largely depends on recalled. These would suggest a role for future investigations, in which neuthe basal ganglia in the stabilization of ronal counterparts of the following motor systems: an overstabilization should be clarified. First, a motor map would lead to hypokinesia, whereas a for voluntary control should be located loss of stabilization would result in within the cerebral cortex. There is hyperkinesia. Here I wish to introduce now evidence suggesting that such a a new control theory concept, 'stabiliz- motor map represents an equilibrium ation augmentation'. In contrast to the point for a muscle-load system that 'control augmentation' hypothesis determines the postural state of the introduced for the cerebellum, the system24'25. Goal points of limb moveimportance of stabilization is obvious ments would be designated on this in a complex system, and a need for map, and displacement of a goal point stabilization augmentation would pro- from one site to another underlies gressively increase as a system becomes execution of a voluntary movement. larger. It is also important to note that Second, motor programs representing augmented stability may make a system spatiotemporal patterns of voluntary less controllable or vice versa; both movements, as in playing a piano or stabilization augmentation and control speaking, should be formulated and augmentation may not be achieved via stored somewhere in the cerebral the same strategy. There is thus a cortex. Together with concepts of demand for the CNS to develop neural maps, concepts of neural proseparate devices: the cerebellum for grams are now moving into the control augmentation and the basal limelight as major targets in neuroganglia for stabilization augmentation. science studies of not only motor This view need not be limited to motor systems but also other functional control, but might also apply to any systems of the brain. Third, the 'will to neuronal activity underlaid by a com- move' should be initiated somewhere plex, large-scale system structure. within the CNS and forwarded to Connections of the basal ganglia to premotor and supplementary motor wide areas of the cerebral cortex and areas. The question as to where
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voluntary command signals originate, however, remains the most intriguing one in motor system neuroscience.
Selected references 1 Stein, R. B. (1982) Behav. Brain Sci. 5,
535-577 2 Skavenski,A. A. and Robinson,D. A. (1973) J. Neurophysiol. 36,724-738 3 Cheron, G., Godaux, E., Laune, J. M. and Vanderkelen,B. (1986)I. Physiol. (London) 372, 75-94 4 Hounsgaard,J., Hultborn, H., Jespersen, B. and Kiehn, O. (1984) Exp. Brain Res. 55, 391-394 5 Cannon, S. C. and Robinson, D. A. (1985) Biol. Cybern. 53,937-108 6 Grillner, S. (1973)in Control of Posture and Locomotion (Stein, R. B., Pearson, K. B., Smith, R. S. and Redford, J. B., eds), pp. 515-535, Plenum Press 7 Nakamura, Y., Nozaki, S., lriki, A. and Kurasawa,I. (1986)Proc. IUPS Congr. XVI, 115
The
8 Friesen, W. O., Poon, M. and Stent, G. S. (1976) Proc. Natl Acad. Sci. USA 73, 3734-3738 9 Arshavsky, Y. I., Deliagina, T . G . , Orlovsky, G. N., Panchin, Y. V., Pavlova, G. A. and Popova, L. B. (1986) Exp. Brain Res. 63, 106-112 10 Robertson, R. M. and Pearson, K. G. (1985) J. Neurophysiol. 53, 110-128 11 Grillner, S., Wallen, P., McClellan, A., Sigvardt, K., Williams, T. and Feldman, L (1983) in Neural Origin of Rhythmic Movements (Roberts, A. and Roberts, B., eds), pp. 285-303, Society for Experimental Neurology 12 Alstermark, B., Lindstr6m, S., Lundberg, A. and Sybirska, E. (1981) Exp. Brain Res. 42, 282-298 13 Alstermark, B., Johannisson, T. and Lundberg, A. (1986) Neurosci. Res. 3, 451-456 14 Henn, V. and Cohen, 13. (1976) Brain Res. 108, 307-325 15 Biitmer-Ennever, J. A. and Biittner, U.
Of
(1978) Brain Res. 171, 31-47 16 Sparks, D. L. and Mays, L. E. (1983) J. Neurophysiol. 49, 45-63 17 Shik, M. L. and Orlovsky, G. N. (1976) Physiol. Rev. 56, 465-501 18 Garcia-Rill, E., Skinner, R . D . and Fitzgerald, A. (1985) Brain Res. 330, 43-54 19 Ito, M. (1984) The Cerebellum and Neural Control, Raven Press 20 Marr, D. (1969) J. Physiol. (London) 202, 437-470 21 Albus, J. S. (1971) Math. Biosci. 10, 25-61 22 Fujita, M. (1982) Biol. Cybern. 45, 195-206 23 Oscarsson, O. (1979) Trends Neurosci. 2, 143-145 24 Berkinblit, M. B., Feldman, A . G . and Fukson, O. I. Behav. Brain Sci. (in press) 25 Bizzi, E., Aceornero, N., Chapple, W. and Hogan, N. (1982) Exp. Brain Res. 46, 139--143 Masao Ito is at the Department of Physiology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo.Ku, Tokyo 113, Japan.
genetics on cl '.cal Allen D. Roses
The application of molecular genetic strategies directed at neurological diseases has generated considerable excitement in clinical neurology t. Virtually all the progress in this area has been achieved during the first 100 issues of TINS. A certain amount of initial good luck catalyzed the field with the discovery of G8, a DNA polymorphism from chromosome 4 (CH4) that is linked to Huntington's disease (HD) 2. The project had been conceived of as a long-term endeavor in which DNA polymorphisms randomly sampled throughout the genome would be evaluated for linkage in several large HD families. The rapid initial progress was important (one of the first twelve random probes tested was linked), not only because it provided regional localization of HD on chromosome 4, but because it was an example of a strategy which could be applied to other genetic neurological diseases. There is now a perspective with which to gauge expectations and to anticipate progress. Significant developments in HD, Duchenne muscular dystrophy (DMD) 3"4 and myotonic dystrophy (DM) 5-7 have fueled enthusiasm for similar research strategies for neurofibromatosis, Tourette's syndrome, inherited neuropathies and many other genetic neurological diseases. In this essay, I will try to present the state of progress for several neurological diseases and project the scientific and clinical future for each one. I will also
examine the prospects for molecular genetic strategies in other inherited diseases, as well as 'non-inherited' neurological diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).
Linkage studies using DNA probes The combination of family studies using large well-studied multigeneration pedigrees with molecular genetic techniques provides an excellent example of interactive strategies. Although family studies using linkage analyses make certain assumptions about the genome that are not always valid, the limits of a disease-related genetic locus on a chromosome can be defined with a high probability. If wellstructured family data are available, the location of the disease locus can be delimited to relatively manageable physical lengths of DNA. Since the methods are statistical, the larger the data set, the tighter the confidence limits of the linkage. In practical application there are relatively few neurological diseases with sufficiently well-documented pedigree data available to allow linkage methods to provide tight limits with small errors at high confidence limits. This limitation is not often appreciated, and investigators of many neurological diseases are rushing to linkage studies in order to define genetic loci. However, the limitations of linkage should be clearly appreciated in the context of each
© 1986,ElsevierSciencePublishersB.V.. Amsterdam 0378- 5912186/$02.00
disease. Complications such as identical phenocopies with multiple genetic loci could make linkage analyses difficult at best. More optimistically, even with modest pedigree data for a particular disease, linkage may provide regional localization on a segment of a chromosome. The best example to date is the assignment of the HD locus to the distal tip of the short arm of chromosome 4. While G8, the linked probe, is 4 centiMorgans or (roughly estimated) four million base pairs from the locus, it has defined the relative location of a previously unknown locus in a genome billions of base pairs in length2. Linkage allows us to state that any putative gene for HD must be within the limits of the linkage data, thus excluding not only all loci on other chromosomes, but also those on chromosome 4 outside the limits of G8. Thus any candidate gene must fit these conditions. Smaller families can be used to rule out linkage of candidate genes or random D N A sequences. It is extremely important to define reasonable and specific aims in approaching certain diseases. Combining all the available meiotic events from familial Alzheimer's disease pedigrees would provide only enough data to define the regional chromosomal locus, and would not provide tight linkage with high confidence limits. On the other hand, defining the regional chromosomal location would be a major step forward with important
515 points. Inhibitors of MAO B, such as deprenyl, inhibitors of dopamine uptake such as mazindol, and free radical scavengers all may prevent the neurotoxicity of MPTP, and are under trial in Parkinson's disease. Apart from the specific role of MPTP in Parkinson's disease, the story carries general implications. It graphically illustrates how an environmental neurotoxin can be targeted by normal brain mechanisms to destroy a discrete area or system in the brain. Amongst the non-hereditary movement disorders, many are due to selective system degenerations, and these are candidates for environmental toxic causes. Many of these diseases are also characterized by distinctive cellular pathology, for example the Lewy body in Parkinson's disease and the straight
neurofibrillary tangles of progressive supranuclear palsy. Understanding the nature of the disruption of the neuronal cytoskeleton that leads to these inclusions may prove as revealing as it has in the study of Alzheimer's disease. In conclusion, movement disorders advance apace. It is no longer a question of 'give us the tools and we will do the job'. The scientific tools are there, but will funds and scientists be available to deploy them as rapidly as the patient's urgent needs demand.
C. D. Marsden is at the University Department of Neurology and Parkinson's Disease Society Research Centre, Institute of Psychiatry, King's College Hospital Medical School, Denmark Hill, London SES, UK.
Neural systems controlling movement Masao Ito Neural systems responsible for motor control are organized in hierarchical levels of increasing complexity, from reflex arcs in the spinal cord and brain stem to voluntary command systems in the cerebral cortex. Specification of the structure and function of motor systems at each of these levels has been, and will continue to be a major theme of neuroscience. However, such specification is not an easy task: even the most simple of motor systems, e.g. the stretch reflex, requires the elucidation of several levels of organization. First, there must be clear behavioral characterization of the system, which, in this instance, is the reactive contraction of a stretched muscle. Second, neural elements, muscle spindles, Ia afferents, motoneurons and contractile muscle involved in the system must be defined in detail. Third, the neuronal circuitry constituting the system must be elucidated to the extent that essential features of information processing actually taking place in the system can be predicted. The principal circuit of a stretch reflex is an excitatory dineuronal chain, and divergence-convergence at these synapses governs the non-linear input-output relationship of the reflex arc. Fourth, the entire system should he modelled with the function of the system clearly specified, i.e. the stretch reflex serves as a length servoassisted control system for a musclel~ Generally speaking, the first step
described above has been the main subject of study in classical neurology and neurophysiology, whereas recent advances in neuroscience have added much to our knowledge of the second. The third and fourth steps have also benefited from recent developments in biocybernetics, and have yielded a number of important new concepts in the neural mechanisms of motor control. I wish to emphasize that the synthesis of heterogeous knowledge and concepts through these four steps has been and will continue to be essential for the understanding of a motor system as a whole, and that such a synthesis should be a major theme of our future studies of motor systems.
cases for which the system specification is unsatisfactory: specific examples being the crossed extension reflex of a limb for the maintenance of the posture during avoidance of harmful stimuli to another limb; the optokinetic eye movement response that stabilizes retinal images during movement of the whole visual field; the tonic neck reflex that adjusts the position of a body during neck torsion; and lens accommodation for securing visual acuity at varied object distances. Thus, it is important to accumulate further knowledge about reflex systems as basic elements of motor systems. A reflex arc is often associated with a local circuit for integration. For example, single shock stimuli to a skin Reflex arcs and associated neural nerve induces a long-lasting impulse integrators discharge from the spinal cord, and so One hundred elementary reflexes produce enduring flexion of a limb. operate at the bottom of the pyramid- Thus an impulse input is integrated to like hierarchy of motor systems. Each provide a step output discharge within of these involves comparatively simple the spinal cord. Recently, another clear circuitry composed of a relatively small case of neural integration has been number of neuronal types, and each described in the vestibulo-ocular reserves as an elementary control system flex, where head velocity signals are regulating a single movement para- converted to eye position signals2. meter, i.e. the stretch reflex for Although the identity of this neural muscle length, the vestibulo-ocular integrator is still obscure, it appears to reflex for visual stability during head involve the nucleus prepositus hypomovement, or the pupillary light reflex glossi3. An interesting integration controlling constancy of luminous phenomenon has also been observed in intensity at the retina. A wealth of the spinal cord, where muscle afferent information about reflexes is now volleys induce a long-lasting depolaravailable, yet there are still a number of ization in motoneurons 4. Involvement 1986, Elsevier Science Publishers B.V., Amsterdam 0378 - 5912/86/$02.00
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of a serotonergic mechanism has been suggested. In addition to the closed loop and multiple chain circuits that have long been considered as possible prototypes of neural integrators, new models are now being proposed 5, although much remains to be learnt about the actual mechanisms involved. Local motor programs The spinal cord and brain stem contain different types of local circuitry that represent subroutines regulating particular types of motor behavior, such as rhythm generation for the scratch reflex, stepping, locomotion, mastication, nystagmus, and breathing. Rhythm generators for stepping and locomotion in hindlimbs are located in lumbar segments of the spinal cord6. The rhythm generator for mastication has recently been localized to the medial bulbar reticular formation, to which signals from the cerebral cortical masticatory area are directed after having been relayed from the dorsal part of the paragigantocellular reticular nucleus7. The neuronal mechanisms underlying rhythm generation have also been investigated in lower animals, e.g. in the leech8, mollusc9, locust 1°, and lamprey1~. A variety of neuronal circuits have been thought to be responsible for rhythm generation. These structures have some common features, such as the inclusion of reciprocal inhibitory connections in the network, but the fundamental question is whether the rhythm is generated by pacemaker cells, as in the heart, or by an oscillatory circuit consisting of multiple neurons, or both. An important example of a subroutine system underlying voluntary movements has been found in the cervical segments of the spinal cord 12. C3-C4 propriospinal neurons mediate the supraspinal motor command for forelimb target-reaching movements. These neurons receive convergent monosynaptic excitatory input from several supraspinal centers, and their axons project directly to forelimb motoneurons. They also receive inhibitory inputs from skin and joint afferents 13. Further investigations of this system should reveal some of the features of the local organization of the basic subroutine building blocks underlying voluntary movements.
c a ] a l s a r a w m g 03 c e r e o e u u m .
studies of the role of the superior colliculus in directing saccadic eye movements. A saccadic eye movement toward a visual target is driven by high frequency burst inputs to extraocular motoneurons. For a horizontal saccade TM, these bursts are generated in the so-called saccade generator located in the paramedian pontine reticular formation (PPRF), whereas vertical saccades are generated in the midbrain reticular formation15. Retinal signals monitoring errors occurring during the foveation of a visual target drive a saccade generator to produce burst impulses. The neuronal circuitry of the PPRF saccade generator has been dissected in recent years, but mechanisms for burst generation are still unknown. The superficial layer of the superior coUiculus contains orderly aligned cells with well-defined visual receptive fields, and apparently represents a map of visual space. In contrast, the deeper layers contain cells whose activity is related to the goal points of saccadic eye movements, regardless of initial eye positions16. It appears that a sensory map in the superficial layer is Tectal motor map The important concept of a neural transformed into a motor map in the space map has been derived from deep layer, on which a vector from an
initial eye position to a goal eye position is represented. This vector is then translated into command signals for saccade generators such as the PPRF. Understanding the neuronal mechanisms of these transformations and translations will be attractive subjects of motor physiology in the coming years. Postural and locomotion centers Posture is maintained by the concerted activity of numerous reflexes such as the stretch reflex, crossed extension reflex, tonic labyrinthine and tonic neck reflexes. In addition, there is a center in the midbrain for a reflex that is triggered by labyrinthine, neck and visual stimuli, which helps the animal to regain an upright position after a fall. This righting reflex is of special interest in motor physiology, for it suggests the existence of a neural device for measuring the center of gravity of the whole body - this would require the integration of afferent signals from a variety of sensors located in different parts of the body. It is pecufiar that there is almost no information about the neuronal elements or circuits in the midbrain that might be concerned with this reflex.
TINS- October 1986 By comparison, locomotion center in the midbrain is better defined since its discovery by Shik 17. It is located in the cuneiform nucleus which lies beneath the inferior colliculus, and impulses emanating from it drive segmental rhythm generators into action. Signal generation in this center is controlled by GABAergic inputsTM.
The cerebellum The cerebellum has been wellstudied at each of the four levels alluded to at the beginning of this essay19. First, it has been found to be responsible for high-order motor control of coordination, orthometria and compensation in classic lesion studies on animals and humans19. Second, neuronal elements of the cerebellum are well identified. Evidence of a special type of synaptic plasticity that would act as a memory element of the cerebellar cortex has accumulated. Third, neuronal networks composed of these elements in cerebellar cortex constitute a computer-like neuronal network for parallel, distributed information processing20-22. A small area of the cerebellar cortex termed a microzone23 is connected to a small group of cells in the vestibular or cerebellar nuclei to form a corticonuclear microcomplex. Such a nuclear cell group could serve as an interface between a microzone and an extracerebellar system. Thus a corticonuclear microcomplex could act as a 'chip' in the cerebellar 'computer'. A close analogy may be drawn between characteristic cerebellar functions (coordination, orthometria and compensation) and the high-order control performance of modern machines utilizing computers (multivariable control, predictive control and adaptivelearning control). The model system above applies best to cerebellar control of the vestibuloocular reflex. In this instance, a microzone in the fiocculus would constitute a self-tuning regulator (a type of adaptive control system) for the reflex 19. Numerous reflexes would likewise be attached to corticonuclear microcomplexes so as to acquire highorder control performance. It is tempting to assume that similar principles also apply to cerebellar control of voluntary movements. In order to comprehend diverse aspects of cerebellar roles in motor control, I wish to propose a new control theory concept'control augmentation', based on the computer action of cerebellar circuits.
517 Control augmentation is a major component of modem vehicle control technology, and a remarkable recent development of its use is the attainment of six degrees of freedom in airplane control: there are normally four (pitch, roll, yaw and thrust), but now two more have been added (direct side and up-down translocations). It is worth noting that the degrees of freedom for a forelimb of a human, including fingers, are as many as 30, which requires an extreme degree of control augmentation.
brain stem may be better understood from this viewpoint.
The cerebral cortex There are three major cerebral cortical areas involved in motor control: the main motor area (Brodman's area 4), the premotor area (area 6) and the supplementary motor area (a part of area 6 extending to the medial surface of the cerebral hemisphere). Each site in the motor area appears to code simple patterns of movements involving a limited number of muscles. The premotor area may generate spatiotemporal patterns of voluntary Basalganglia The disorders of the basal ganglia are movements. It is supposed that these now well-known, and detailed know- patterns are transferred to the motor ledge is available about the degener- area and translated to motor command ation at the neuronal elements com- signals there. The supplementary posing this large assembly. However, motor area, on the other hand, appears little progress has been made regarding to generate signals that establish a the normal neuronal network structure preparatory status of the motor area for of the basal ganglia. Cortico-caudato- responding to signals from the prepallidal projections may look like a motor area, the somatosensory area or filter that condenses cortical inform- the thalamus. Possible differential ation to pallidal output. However, this roles of the three cortical areas have model is too simple to provide any been derived from lesion studies and useful predictions. The purpose of the are supported by recent recordings of basal ganglia as a motor system is also neuronal signals. However, our knowonly vaguely understood, despite ledge, at the level of neuronal elements, numerous suggestions. In this respect, circuits and systems, is still at a rather the classic neurological concept of primitive stage. hypokinesia in parkinsonism and Thus, identificationof cerebral cortihyperkinesia in chorea should be cal motor systems largely depends on recalled. These would suggest a role for future investigations, in which neuthe basal ganglia in the stabilization of ronal counterparts of the following motor systems: an overstabilization should be clarified. First, a motor map would lead to hypokinesia, whereas a for voluntary control should be located loss of stabilization would result in within the cerebral cortex. There is hyperkinesia. Here I wish to introduce now evidence suggesting that such a a new control theory concept, 'stabiliz- motor map represents an equilibrium ation augmentation'. In contrast to the point for a muscle-load system that 'control augmentation' hypothesis determines the postural state of the introduced for the cerebellum, the system24'25. Goal points of limb moveimportance of stabilization is obvious ments would be designated on this in a complex system, and a need for map, and displacement of a goal point stabilization augmentation would pro- from one site to another underlies gressively increase as a system becomes execution of a voluntary movement. larger. It is also important to note that Second, motor programs representing augmented stability may make a system spatiotemporal patterns of voluntary less controllable or vice versa; both movements, as in playing a piano or stabilization augmentation and control speaking, should be formulated and augmentation may not be achieved via stored somewhere in the cerebral the same strategy. There is thus a cortex. Together with concepts of demand for the CNS to develop neural maps, concepts of neural proseparate devices: the cerebellum for grams are now moving into the control augmentation and the basal limelight as major targets in neuroganglia for stabilization augmentation. science studies of not only motor This view need not be limited to motor systems but also other functional control, but might also apply to any systems of the brain. Third, the 'will to neuronal activity underlaid by a com- move' should be initiated somewhere plex, large-scale system structure. within the CNS and forwarded to Connections of the basal ganglia to premotor and supplementary motor wide areas of the cerebral cortex and areas. The question as to where
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voluntary command signals originate, however, remains the most intriguing one in motor system neuroscience.
Selected references 1 Stein, R. B. (1982) Behav. Brain Sci. 5,
535-577 2 Skavenski,A. A. and Robinson,D. A. (1973) J. Neurophysiol. 36,724-738 3 Cheron, G., Godaux, E., Laune, J. M. and Vanderkelen,B. (1986)I. Physiol. (London) 372, 75-94 4 Hounsgaard,J., Hultborn, H., Jespersen, B. and Kiehn, O. (1984) Exp. Brain Res. 55, 391-394 5 Cannon, S. C. and Robinson, D. A. (1985) Biol. Cybern. 53,937-108 6 Grillner, S. (1973)in Control of Posture and Locomotion (Stein, R. B., Pearson, K. B., Smith, R. S. and Redford, J. B., eds), pp. 515-535, Plenum Press 7 Nakamura, Y., Nozaki, S., lriki, A. and Kurasawa,I. (1986)Proc. IUPS Congr. XVI, 115
The
8 Friesen, W. O., Poon, M. and Stent, G. S. (1976) Proc. Natl Acad. Sci. USA 73, 3734-3738 9 Arshavsky, Y. I., Deliagina, T . G . , Orlovsky, G. N., Panchin, Y. V., Pavlova, G. A. and Popova, L. B. (1986) Exp. Brain Res. 63, 106-112 10 Robertson, R. M. and Pearson, K. G. (1985) J. Neurophysiol. 53, 110-128 11 Grillner, S., Wallen, P., McClellan, A., Sigvardt, K., Williams, T. and Feldman, L (1983) in Neural Origin of Rhythmic Movements (Roberts, A. and Roberts, B., eds), pp. 285-303, Society for Experimental Neurology 12 Alstermark, B., Lindstr6m, S., Lundberg, A. and Sybirska, E. (1981) Exp. Brain Res. 42, 282-298 13 Alstermark, B., Johannisson, T. and Lundberg, A. (1986) Neurosci. Res. 3, 451-456 14 Henn, V. and Cohen, 13. (1976) Brain Res. 108, 307-325 15 Biitmer-Ennever, J. A. and Biittner, U.
Of
(1978) Brain Res. 171, 31-47 16 Sparks, D. L. and Mays, L. E. (1983) J. Neurophysiol. 49, 45-63 17 Shik, M. L. and Orlovsky, G. N. (1976) Physiol. Rev. 56, 465-501 18 Garcia-Rill, E., Skinner, R . D . and Fitzgerald, A. (1985) Brain Res. 330, 43-54 19 Ito, M. (1984) The Cerebellum and Neural Control, Raven Press 20 Marr, D. (1969) J. Physiol. (London) 202, 437-470 21 Albus, J. S. (1971) Math. Biosci. 10, 25-61 22 Fujita, M. (1982) Biol. Cybern. 45, 195-206 23 Oscarsson, O. (1979) Trends Neurosci. 2, 143-145 24 Berkinblit, M. B., Feldman, A . G . and Fukson, O. I. Behav. Brain Sci. (in press) 25 Bizzi, E., Aceornero, N., Chapple, W. and Hogan, N. (1982) Exp. Brain Res. 46, 139--143 Masao Ito is at the Department of Physiology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo.Ku, Tokyo 113, Japan.
genetics on cl '.cal Allen D. Roses
The application of molecular genetic strategies directed at neurological diseases has generated considerable excitement in clinical neurology t. Virtually all the progress in this area has been achieved during the first 100 issues of TINS. A certain amount of initial good luck catalyzed the field with the discovery of G8, a DNA polymorphism from chromosome 4 (CH4) that is linked to Huntington's disease (HD) 2. The project had been conceived of as a long-term endeavor in which DNA polymorphisms randomly sampled throughout the genome would be evaluated for linkage in several large HD families. The rapid initial progress was important (one of the first twelve random probes tested was linked), not only because it provided regional localization of HD on chromosome 4, but because it was an example of a strategy which could be applied to other genetic neurological diseases. There is now a perspective with which to gauge expectations and to anticipate progress. Significant developments in HD, Duchenne muscular dystrophy (DMD) 3"4 and myotonic dystrophy (DM) 5-7 have fueled enthusiasm for similar research strategies for neurofibromatosis, Tourette's syndrome, inherited neuropathies and many other genetic neurological diseases. In this essay, I will try to present the state of progress for several neurological diseases and project the scientific and clinical future for each one. I will also
examine the prospects for molecular genetic strategies in other inherited diseases, as well as 'non-inherited' neurological diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).
Linkage studies using DNA probes The combination of family studies using large well-studied multigeneration pedigrees with molecular genetic techniques provides an excellent example of interactive strategies. Although family studies using linkage analyses make certain assumptions about the genome that are not always valid, the limits of a disease-related genetic locus on a chromosome can be defined with a high probability. If wellstructured family data are available, the location of the disease locus can be delimited to relatively manageable physical lengths of DNA. Since the methods are statistical, the larger the data set, the tighter the confidence limits of the linkage. In practical application there are relatively few neurological diseases with sufficiently well-documented pedigree data available to allow linkage methods to provide tight limits with small errors at high confidence limits. This limitation is not often appreciated, and investigators of many neurological diseases are rushing to linkage studies in order to define genetic loci. However, the limitations of linkage should be clearly appreciated in the context of each
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disease. Complications such as identical phenocopies with multiple genetic loci could make linkage analyses difficult at best. More optimistically, even with modest pedigree data for a particular disease, linkage may provide regional localization on a segment of a chromosome. The best example to date is the assignment of the HD locus to the distal tip of the short arm of chromosome 4. While G8, the linked probe, is 4 centiMorgans or (roughly estimated) four million base pairs from the locus, it has defined the relative location of a previously unknown locus in a genome billions of base pairs in length2. Linkage allows us to state that any putative gene for HD must be within the limits of the linkage data, thus excluding not only all loci on other chromosomes, but also those on chromosome 4 outside the limits of G8. Thus any candidate gene must fit these conditions. Smaller families can be used to rule out linkage of candidate genes or random D N A sequences. It is extremely important to define reasonable and specific aims in approaching certain diseases. Combining all the available meiotic events from familial Alzheimer's disease pedigrees would provide only enough data to define the regional chromosomal locus, and would not provide tight linkage with high confidence limits. On the other hand, defining the regional chromosomal location would be a major step forward with important