- Email: [email protected]
Adaptive Plasticity in Primate Motor Cortex as a Consequence of Behavioral Experience and Neuronal Injury
Seminars in NEUROSCIENCE 9, 13–23 (1997) Article No. SN970102
Adaptive Plasticity in Primate Motor Cortex as a Consequence of Behavioral Experience and Neuronal Injury Randolph J. Nudo,1 Erik J. Plautz, and Garrett W. Milliken2 Department of Neurobiology and Anatomy, University of Texas Houston Health Science Center, Houston, Texas 77030
It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual’s life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills. r 1997 Academic Press KEY WORDS: Motor cortex; plasticity; rehabilitation; stroke; learning.
Studies conducted in cortical sensory areas over the past several years have revealed that representational maps are alterable both as a function of the integrity of their sensory inputs, and as a function of experience (1). Since representational plasticity has now been demonstrated in somatosensory, auditory, and visual cortex of adult individuals representing a wide variety of mammalian species, it would appear that the life-long capacity for functional reorganization is a common feature of sensory neocortex. More recent studies now indicate that motor maps, like sensory maps, are alterable in adult animals. Motor maps can be differentially altered by electrical stimulation, pharmacological manipulation, behavioral training, and peripheral or central nervous system injury. These findings should be of general interest to students of brain plasticity for two reasons. First, the motor cortex has long
been implicated in motor learning. Plastic changes in cortical motor topography that are correlated with behavioral training may reveal fundamental mechanisms of the motor cortex for skill acquisition. Second, since motor cortex is frequently involved in clinical stroke and traumatic brain injury, changes in cortical motor topography that occur after injury may reveal neural mechanisms involved in recovery of function. In the first part of this article, the current understanding of the organization of motor cortex is reviewed. Next, the evidence for adaptive plasticity in motor maps resulting from artificial manipulation and from behavioral experience is examined. Then, recent data suggesting that motor maps are alterable after cortical injury are reviewed. Finally, the putative mechanisms that might account for functional alterations in motor cortex are addressed.
1To whom correspondence and reprint requests should be addressed at Center on Aging, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7117, Fax: (913) 588-1201, e-mail: [email protected]. 2Present address: Department of Psychology, Auburn University, Auburn, AL.
FUNCTIONAL TOPOGRAPHY OF PRIMATE MOTOR CORTEX
1044-5765/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.
For more than a century the motor cortex has been delineated by noting those neocortical regions that
13
14
Nudo, Plautz, and Milliken
FIG. 1. Location and somatotopic organization of primary motor cortex (M1) in a squirrel monkey. The distal forelimb, or hand area of primary motor cortex, is located rostral to the central sulcus, near its lateral edge. In addition to M1, other motor areas include dorsal premotor cortex (PMD), ventral premotor cortex (PMV), the supplementary motor area (SMA), and cingulate motor areas (cing.; hidden from view on the medial walls of the cerebral cortex). The locations of the primary somatosensory area (S1) and area 3a are also shown.
require the least electrical stimulation to evoke movements of specific body parts (2). The neuroanatomical basis for this phenomenon is the high density of corticospinal neurons that lie within layer V of this so-called ‘‘excitable cortex.’’ The axons of many of these corticospinal neurons terminate directly on spinal cord motor neurons (corticomotoneuronal cells). Within motor cortex, neurons controlling all parts of the skeletal motor apparatus are laid out in an orderly map (the motor homunculus), roughly resembling the arrangement of body parts in the periphery (Fig. 1) (3). The primate motor cortex comprises several distinct areas, each thought to play a separate role in the cortical control of movement (Fig. 1) (4, 5). M1 (primary motor cortex or area 4) is thought to mediate skilled voluntary movements, especially of the distal musculature. Because of its importance in human motor control, the hand area of M1 has been the focus of intensive study for more than a century. Most of the examples of adaptive plasticity in motor cortex have been derived from studies in the hand (or distal forelimb) area of M1. However, it should be noted that other cortical motor areas, including the premotor cortex (6), the supplementary motor area (7), and the
cingulate cortex (8) are involved in motor control. It is likely that adaptive plasticity occurs in these other areas as well. Early cortical surface stimulation studies described a single representation of the hand in M1 (9). As microelectrode stimulation techniques were developed in the late 1960s, investigators were able to derive motor maps in much greater spatial detail (10). It soon became apparent that individual muscles and movements were represented in multiple, discrete loci within the M1 hand area. As the microelectrode stimulation techniques were pushed to their spatial limits with fine-grain maps, it was found that representations of different muscles overlap extensively (11). This overlapping arrangement of muscles results in a map of hand movements that is somatotopic on a global scale (i.e., with respect to hand vs face representations), but fractionated, or mosaical, on a local scale (i.e., with respect to digit vs wrist representations; Fig. 2) (11–14). The precise number of representations of a given joint movement (e.g., finger flexion) is highly variable among individuals. Overlapping representations of hand movements have also been demonstrated in human motor cortex using functional magnetic resonance
Copyright r 1997 by Academic Press
15
Adaptive Plasticity in Motor Cortex
FIG. 2. Representations of muscles and movements in the hand area of primary motor cortex (M1) in a squirrel monkey. Muscle and movement representations were derived using microelectrode stimulation techniques in a ketamine-anesthetized monkey. Microelectrodes were sequentially introduced at a depth of 1750 µm. Interpenetration distances were 500 µm. (A) Selected muscle representations in M1. Stimulation of cortical territory contained within thin colored lines evoked significant electromyographic (EMG) activity in the indicated muscles. Stimulation of cortical territory contained within thick colored lines evoked particularly high amplitude EMG activity in the indicated muscles. Stimulation current was 30 µA at each site. FDS (red line): flexor digitorum superficialis; EDC (gray line): extensor digitorum communis; ECU (blue line): extensor carpi ulnaris; ECR (green line): extensor carpi radialis. Heavy black line indicates limits of hand movement area as defined by near-threshold current stimulation. Representations of individual muscles overlap extensively and extend beyond the borders of the hand area as defined by evoked hand movements. (B) Representation of movements evoked at threshold current levels in the same cortical territory. As a result of the overlapping representation of individual muscles, joint movement representations are fractionated or mosaical (65).
imaging (15). Thus, as techniques used to define cortical motor representations have improved, our concept of motor cortex topography has evolved from a single, undifferentiated motor homunculus to multiple, mosaical representations. There is increasing evidence that M1 (and also premotor cortex (16)) can be divided further into caudal and rostral subfields. For example, caudal and rostral M1 differ in their specific connections with other cortical areas (14). Further, neurons responsive to cutaneous stimulation are confined primarily to caudal M1, whereas neurons responsive to muscle stimulation and joint manipulation predominate in rostral M1 (Fig. 3) (17–19). Still further, recent findings in human motor cortex suggest that caudal and rostral M1 differ in soma density and neurotransmitter receptor binding (20). Despite these differences, the overlapping motor output representations of individual hand muscles can extend across both subfields (Fig. 2). The intrinsic connectivity within M1 is still under
investigation. However, it is already clear that the different hand movement representations are locally interconnected across the entire M1 hand area (21–23). The neural mechanisms by which these local connections might contribute to shaping motor outputs will be addressed in a later section.
ACTIVITY-DEPENDENT ALTERATIONS IN MOTOR MAPS Artificially Induced Alterations in Motor Maps As early as the beginning of this century, it was recognized by Graham Brown and Sherrington that electrical stimulation of the motor cortex can result in rapid changes in the movements evoked from subsequent stimulation of adjacent regions of motor cortex (24). While this study was performed using surface
Copyright r 1997 by Academic Press
16
Nudo, Plautz, and Milliken
FIG. 3. Sensory representations in sensorimotor cortex of a ketamine-anesthetized squirrel monkey. (A) Multiunit sensory responses recorded in area 3b (primary somatosensory cortex or S1), area 3a, and area 4 (primary motor cortex or M1). The thick solid line encompasses sites where electrical stimulation evoked hand movements in this same monkey at #30 µA (i.e., the M1 hand area). The thin solid lines encompass sites where neurons were responsive to cutaneous stimulation. Cutaneous responses in M1 are primarily located in the caudal aspect of the M1 hand representation. (B) Representative cutaneous receptive fields in M1 and S1. Using von Frey hairs, a criterion threshold was defined for a typical cutaneous response in S1. Then, at each site in M1, responses were designated as cutaneous (i.e., responds exclusively to skin indentation or hair deflection) or noncutaneous (i.e., responds to light taps, but probably driven by muscle or joint receptors). Using this strict criterion, many cutaneous responses were found in M1, although receptive fields were considerably larger than those found in S1. H, hand; Hyp, hypothenar; The, thenar; P, pad; t, responds to light taps; j, responds to joint manipulation; d, dorsum; D, digit; W, wrist; F, forearm; S, shoulder; E, elbow; NR, no response; f, flexion; ex, extension; ad, adduction; ab, abduction; mr, medial rotation; su, supination; pro, pronation; el, elevation; re, retraction; u, ulnar; L, lateral; R, rostral. Numbers indicate specific digits (19).
electrodes to produce evoked movements, it represents one of the earliest demonstrations of functional plasticity in the cerebral cortex. These results were replicated recently using microelectrode stimulation techniques in forelimb motor cortex of rats (25). The movement represented at a site that was repetitively stimulated for at least 30 min temporarily came to be represented over a larger cortical territory. In another artificial, but more physiologically specific, manipulation, Jacobs
and Donoghue injected bicuculline into the forelimb representations of rats before and after microelectrode stimulation mapping. Significant shifts occurred in representational borders, resulting in temporary expansion of the forelimb representation (26). It was suggested that these results occurred due to unmasking of horizontal excitatory connections within the cortex. Motor output representations can also be systematically altered by adjusting the posture of specific joints.
Copyright r 1997 by Academic Press
17
Adaptive Plasticity in Motor Cortex
Simply changing the position of the forelimb from wrist extension/elbow flexion to wrist flexion/elbow extension during a microelectrode stimulation experiment results in an expansion of the forelimb representation into the former vibrissae representation of anesthetized, adult rats (27). These data suggest that motor output maps in M1 can be modified by changes in proprioceptive input. Variability in responses evoked by stimulation techniques has been a common finding for a century. Although some investigators have argued that response variability limits the usefulness of stimulation techniques in defining motor output organization, others have suggested that this variability is the result of genuine temporal variation in the physiological condition of the motor system. Since recent, highly controlled studies have shown systematic changes in motor representations due to manipulation of specific variables, it is likely that microelectrode stimulation techniques can be used effectively to reveal basic mechanisms of motor cortex plasticity.
Behaviorally Induced Alterations in Motor Maps If the functional organization of motor cortex can be altered by artificial manipulation, it is possible that these adaptive mechanisms are used normally by the motor cortex in the natural learning of motor skills. Early studies by Woody and colleagues demonstrated that large changes in movement representations occur in motor cortex of cat, and these changes are related to conditioned movements (28). Later, Fetz and colleagues showed that isolated cells in motor cortex can be operantly conditioned to increase or decrease their firing rate within minutes (29). While these experiments were not designed to examine changes in the detailed topography of motor representations, they provided early indications that certain training paradigms may significantly alter the physiology of motor cortex. The view that the functional organization of motor cortex may be alterable by behavioral experience is further supported by the observation that mosaical motor maps of distal musculature are highly idiosyncratic (12, 13). It is possible that individual map variability reflects each animal’s experiences up to the time in life that the cortical map is derived. Further support came with the demonstration that the spatial distribution of hand movement representations in M1 of primates is correlated with each animal’s hand
preference (13). Hand movement representations in the dominant motor cortex (opposite the preferred hand on a reach and grasp task) are slightly larger and more spatially complex, i.e., more mosaical. Other studies in which motor maps of primates were tracked before and after motor training examined the effects of behavioral experience directly (30). In these studies, squirrel monkeys were trained over a period of about 2 weeks to extract food pellets from a small, cylindrical well with one or two fingers. Posttraining maps revealed a large expansion of finger representations (Fig. 4). Movements used more frequently in a behavioral task are selectively magnified in their cortical representations. More recent findings suggest that motor maps are altered by motor skill acquisition, but not by repetitive use alone (31). In this study, one group of monkeys retrieved pellets from a small food well, as before. A second group of monkeys retrieved pellets from a substantially larger food well, a task requiring no training to master efficiently. Monkeys in the two groups were matched for total number of finger flexions. No systematic changes were seen in motor hand maps in the monkeys retrieving pellets from the large well (Fig. 4). These experiments suggest that adaptive plasticity in motor maps is a manifestation of basic neural processes involved in the learning of complex motor skills. As new movement patterns are acquired and used to master a motor task with increased efficiency, the representations of the newly acquired, or learned, motor patterns are reflected in altered motor maps. Most of the studies demonstrating representational plasticity in motor cortex have been performed in nonhuman primates or in rats using invasive procedures (typically microelectrode stimulation). With the widespread use of noninvasive imaging and stimulation techniques it has become possible to demonstrate that alterations also occur in the functional topography of human motor cortex as a result of motor experience. Using positron emission tomography (PET), transcranial magnetic stimulation (TMS), and functional magnetic resonance imaging (FMRI) techniques, several investigators have now shown that the area of activation for the hand representation in M1 increases as subjects practice complex finger movement tasks (32– 41). These studies indicate that the functional organization of motor cortex is dynamically maintained by skilled use in humans, as in other mammals.
Copyright r 1997 by Academic Press
18
Nudo, Plautz, and Milliken
FIG. 4. Differential effects of motor skill acquisition and motor use on functional organization in primate motor cortex. (A) Training procedures consisted of retrieving small banana-flavored pellets from a Plexiglas board containing food wells of graded diameters. Adult squirrel monkeys were trained to retrieve pellets from either the smallest well or the largest well. The monkey can easily place its entire hand into the largest well, but can only insert one or two fingers into the smallest well. For both groups, the task criterion met before the posttraining mapping procedure was approx. 12,000 total finger flexions over the course of training. Thus, both groups had an equivalent amount of motor use during the training period. (B) Small well training resulted in an improvement in motor skill (fewer flexions per retrieval) over the course of training (30). Conversely, animals trained in the large well showed near-perfect performance throughout the task, and thus no evidence of a change in motor skill (31). (C and D) Pre- and posttraining maps of distal forelimb movements were produced by microelectrode stimulation techniques. In this and the following figure, movements evoked at threshold current levels are shown. Posttraining maps showed robust changes following small well training (30), but few systematic changes following large well training (31). These results indicate that the functional topography of motor cortex is shaped by learning of new motor skills, not simply by repetitive motor use.
Peripheral Lesions
INJURY-INDUCED ALTERATIONS IN MOTOR MAPS In addition to changes that occur during motor learning, motor maps are systematically altered by various types of peripheral or central nervous system injuries. In general, these injury-induced alterations are even more widespread than those induced by behavioral experience in intact individuals.
In a series of experiments using microelectrode stimulation techniques, Donoghue and colleagues demonstrated that cortical motor representations can be altered by peripheral nerve lesions in developing and adult rats. When the forelimb was amputated in perinatal rats, the vibrissae and shoulder representations expanded, presumably into the former forelimb
Copyright r 1997 by Academic Press
19
Adaptive Plasticity in Motor Cortex
FIG. 5. Effects of injury to motor cortex with or without rehabilitative training. (A and B) Remodeling of motor hand representations in M1 following a focal vascular infarct. Infarct destroyed 21% of digit and 7% of wrist/forearm representation within M1 (dotted line). Monkeys in this group were not provided rehabilitative retraining (spontaneous recovery). Three months after the infarct, the undamaged digit area (red) adjacent to the lesion decreased by an additional 40% (50) (C and D) Remodeling of motor hand representations in M1 following an infarct and rehabilitative training. Monkeys in this group underwent daily, repetitive training on a pellet retrieval task. A jacket with a long sleeve restricted use of the unaffected limb, forcing the monkey to use the impaired limb. In this monkey, the infarct destroyed 22% of digit and 4% of wrist forearm representation. Following rehabilitative training, the spared digit representation increased by 15% and the spared wrist/forearm representation increased by 59% (51). These results suggest that after cortical injury, motor experience plays a major role in the physiological reorganization that occurs in adjacent, undamaged tissue. (C and D) Reprinted with permission from Nudo, R. J., Wise, B. M., SiFuentes, F., and Milliken, G. W. (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272, 1791–1794. Copyright 1996 American Association for the Advancement of Science.
Copyright r 1997 by Academic Press
20
Nudo, Plautz, and Milliken
territory (42). Additional experiments demonstrated that this phenomenon persists in adulthood. When the forelimb was amputated in adult rats, the shoulder representations expanded into the former forelimb territory (43); when the facial nerve was damaged, the forelimb territory rapidly expanded into the former vibrissae representation (43–45). These modified motor maps were stable for months after the facial nerve lesions. There is now evidence that a similar phenomenon occurs in humans. Using intraoperative cortical stimulation techniques in patients with arm amputations, Ojemann and Silbergeld recently found that the face and shoulder representations expanded, paralleling the earlier electrophysiological results in rats (46). Similar findings have been obtained in humans using TMS techniques (47, 48).
Central Lesions Neurophysiological and neuroanatomical bases have long been sought to account for functional motor recovery following cortical injury. It is commonly assumed that other parts of the motor system must ‘‘take over’’ the function of the damaged cortex, but despite over a century of study, the precise neural mechanisms by which lost functions are regained and the structures that are involved are poorly understood. Studies by Glees and Cole in the 1950s (49) using surface stimulation techniques suggested that lost cortical functions are assumed by the adjacent cortical tissue. However, these results are difficult to interpret because of the low spatial resolution inherent in surface stimulation mapping studies. Recently, we used microelectrode stimulation techniques to examine motor representations before and a few months after a small vascular (ischemic) infarct in adult monkeys. One group of monkeys underwent ‘‘spontaneous’’ recovery. That is, no specific postinjury training was provided beyond periodic, brief assessment of hand preference and dexterity. In contrast to the results reported by Glees and Cole, movements represented in the infarcted zone did not reappear in the cortical sector surrounding the infarct. Instead, hand movement representations adjacent to the infarct that were spared from direct injury underwent a further loss of cortical territory (Fig. 5) (50). In a second group of monkeys, postinjury ‘‘rehabilitative’’ training was provided in the form of forced, repetitive use of the impaired hand in a pellet retrieval task. Retraining of skilled hand use after infarcts
resulted in prevention of the loss of hand territory adjacent to the infarct (Fig. 5). Functional reorganization in the undamaged motor cortex was accompanied by behavioral recovery of skilled hand function (51). Thus, it would appear that extensive reorganization occurs in M1 following focal infarct. After injury, repetitive training can shape subsequent reorganization in the adjacent intact cortex, suggesting that the undamaged motor cortex plays an important role in motor recovery (52). It is widely held that postinjury experience (i.e., physical rehabilitation) facilitates recovery of sensorimotor skills following destruction of cortical motor areas in humans. For example, a recent study in human stroke patients demonstrated that forced use of the affected limb for 14 days (by constraint of the unaffected limb) resulted in long-term improvement of motor function in the impaired limb (53). It was suggested that nonuse of the affected limb is a learned phenomenon and that restraint and training are effective because they overcome learned nonuse. Despite the apparent benefits that may accompany forced use after cortical injury, recent studies in rats suggest that overuse after cortical injury may cause dysfunctional alterations in cortical morphology. After sensorimotor cortical lesions in rats, Schallert and colleagues placed restrictive casts on the unaffected forelimb, forcing the rats to use the impaired limb. This procedure resulted in a significant exaggeration of the cortical injury and impaired motor recovery (54). These studies raise the possibility that extreme overuse of the affected limb after injury may be detrimental to long-term neurophysiological and behavioral outcome.
MECHANISMS OF PLASTICITY IN MOTOR CORTEX The synaptic mechanisms underlying representational plasticity in motor cortex are currently under investigation in several laboratories (55). It is now clear that both long-term potentiation and long-term depression can be produced in the motor cortex of intact animals or in slice preparations and may provide a mechanism for modulating motor maps (56–60). These synaptic events are probably mediated via intrinsic intracortical connections that link cortical modules within a given motor field (e.g., across the entire hand area of M1) (61–63). Glutamate is the major neurotransmitter of these horizontal connections, and it is likely
Copyright r 1997 by Academic Press
21
Adaptive Plasticity in Motor Cortex
that synaptic modification is mediated via N-methyl-Daspartate receptors (58). Under some conditions, modulation of the effectiveness of local, horizontal connections can occur over a rapid time course, suggesting that motor map plasticity occurs due to altered membrane excitability in local cortical circuits. In addition, motor skill training appears to induce increases in early gene expression and significant synaptogenesis in the motor cortex (64). It is tempting to speculate that changes in synaptic efficacy between neurons in neighboring cortical modules may underlie short-term modifications, while local proliferation of new synaptic connections may underlie longer term modifications in neuronal excitability, and more generally in cortical motor topography.
CONCLUSIONS It is now clear that cortical motor maps in the primary motor cortex are alterable by behavioral experience and by neuronal injury. Since topographic plasticity seems to coincide with the acquisition of new motor skills in intact individuals, or the reacquisition of motor skills after injury, it would appear that motor cortex plays a significant role in motor learning and in recovery of function. Recent electrophysiological and ultrastructural studies suggest that these topographic rearrangements occur largely by modulation of horizontal connections among various functional modules and local synaptogenesis within motor cortex. The challenge for future studies in motor cortex map alterability is to determine mechanisms for specificity in local circuit modulation, in light of the overlapping representations of muscles and movements, and the apparent widespread arborization of intracortical circuitry within the primary motor cortex.
ACKNOWLEDGMENTS This research was supported by grants from the National Institute of Neurological Diseases and Stroke (NS-30853, NS-09366), the National Institute of Mental Health (MH-10963), and the American Heart Association. This work was done during the tenure of an Established Investigatorship award from the American Heart Association (R.J.N.).
REFERENCES 1. Kaas, J. H. (1991) Plasticity of sensory and motor maps in adult mammals. Annu. Rev. Neurosci. 14, 137–167.
2. Fritsch, G., and Hitzig, E. (1870) Ueber die elektrische Erregbarkeit des Grosshirns. Arch. Anat. Physiol. Wiss. Med. 37, 300–332. 3. Woolsey, C. N. (1952) Patterns of localization in sensory and motor areas of the cerebral cortex. In Milbank Symposium: The Biology of Mental Health and Disease, pp. 193–206, Hoeber, New York. 4. Donoghue, J. P., and Sanes, J. N. (1994) Motor areas of the cerebral cortex. J. Clin. Neurophysiol. 11, 382–396. 5. Tanji, J., and Kurata, K. (1989) Changing concepts of motor areas of the cerebral cortex. Brain Dev. 11, 374–377. 6. Wise, S. P., DiPellegrino, G., and Boussaoud, D. (1992) Primate premotor cortex: Dissociation of visuomotor from sensory signals. J. Neurophysiol. 68, 969–972. 7. Wise, S. (1996) Evolutionary and comparative neurobiology of the supplementary sensorimotor area. Adv. Neurol. 70, 71–83. 8. Picard, N., and Strick, P. L. (1996) Motor areas of the medial wall: A review of their location and functional activation. Cereb. Cortex 6, 342–353. 9. Welker, W. I., Benjamin, R. M., Miles, R. C., and Woolsey, C. N. (1957) Motor effects of stimulation of cerebral cortex of squirrel monkey (Saimiri sciureus). J. Neurophysiol. 20, 347–364. 10. Asanuma, H., and Rose´n, I. (1972) Topographical organization of cortical efferent zones projecting to distal forelimb muscles in the monkey. Exp. Brain Res. 14, 243–256. 11. Donoghue, J. P., Leibovic, S., and Sanes, J. N. (1992) Organization of the forelimb area in squirrel monkey motor cortex: Representation of digit, wrist, and elbow muscles. Exp. Brain Res. 89, 1–19. 12. Gould, H. J. I., Cusick, C. G., Pons, T. P., and Kaas, J. H. (1986) The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eye fields in owl monkeys. J. Comp. Neurol. 247, 297–325. 13. Nudo, R. J., Jenkins, W. M., Merzenich, M. M., Prejean, T., and Gedela, R. (1992) Neurophysiological correlates of hand preference in primary motor cortex of squirrel monkeys. J. Neurosci. 12, 2918–2947. 14. Stepniewska, I., Preuss, T. M., and Kaas, J. H. (1993) Architectonics, somatotopic organization, and ipsilateral cortical connections of the primary motor area (M1) of owl monkeys. J. Comp. Neurol. 330, 238–271. 15. Sanes, J. N., Donoghue, J. P., Thangaraj, V., Edelman, R. R., and Warach, S. (1995) Shared neural substrates controlling hand movements in human motor cortex. Science 268, 1775–1777. 16. Preuss, T. M., Stepniewska, I., and Kaas, J. H. (1996) Movement representation in the dorsal and ventral premotor areas of owl monkeys: A microstimulation study. J. Comp. Neurol. 371, 649– 676. 17. Tanji, J., and Wise, S. P. (1981) Submodality distribution in sensorimotor cortex of the unanesthetized monkey. J. Neurophysiol. 45, 467–481. 18. Strick, P. L., and Preston, J. B. (1982) Two representations of the hand in area 4 of a primate. II. Somatosensory input organization. J. Neurophysiol. 48, 150–159. 19. Humphrey, S. M., Gardner, G. A., Raiszadeh, R., and Nudo, R. J. (1994) Loss of sensory, but not motor responsiveness in intact cortex surrounding a focal ischemic infarct in area 4. Soc. Neurosci. Abstr. 20, 179. 20. Geyer, S., Ledberg, A., Schleicher, A., Kinomura, S., Schormann, T., Bu¨rgel, U., Klingberg, T., Larsson, J., Zilles, K., and Roland, P. E. (1996) Two different areas within the primary motor cortex of man. Nature 382, 805–807.
Copyright r 1997 by Academic Press
22
Nudo, Plautz, and Milliken
21. Keller, A. (1993) Intrinsic synaptic organization of the motor cortex. Cereb. Cortex 3, 430–441. 22. Huntley, G. W., and Jones, E. G. (1991) Relationship of intrinsic connections to forelimb movement representations in monkey motor cortex: A correlative anatomical and physiological study. J. Neurophysiol. 66, 390–413. 23. Plautz, E. P., Milliken, G. W., and Nudo, R. J. (1996) Anatomical connectivity of electrophysiologically identified movement representations in the M1 hand area of squirrel monkeys. Soc. Neurosci. Abstr. 22, 1083. 24. Graham Brown, T., and Sherrington, C. S. (1912) On the instability of a cortical point. Proc. R. Soc. (London) 85, 250–277. 25. Nudo, R. J., Jenkins, W. M., and Merzenich, M. M. (1990) Repetitive microstimulation alters the cortical representation of movements in adult rats. Somatosens. Mot. Res. 7, 463–483. 26. Jacobs, K. M., and Donoghue, J. P. (1991) Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251, 944–947. 27. Sanes, J. N., Wang, J., and Donoghue, J. P. (1992) Immediate and delayed changes of rat motor cortical output representation with new forelimb configurations. Cereb. Cortex 2, 141–152. 28. Woody, C. D., and Engel, J. Jr. (1972) Changes in unit activity and thresholds to electrical microstimulation at coronal–pericruciate cortex of cat with classical conditioning of different facial movements. J. Neurophysiol. 35, 230–241. 29. Fetz, E. E., and Baker, M. A. (1973) Operantly conditioned patterns of precentral unit activity and correlated responses in adjacent cells and correlated muscles. J. Neurophysiol. 36, 179– 204. 30. Nudo, R. J., Milliken, G. W., Jenkins, W. M., and Merzenich, M. M. (1996) Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J. Neurosci. 16, 785–807. 31. Plautz, E. J., Milliken, G. W., and Nudo, R. J. (1995) Differential effects of skill acquisition and motor use on the reorganization of motor representations in area 4 of adult squirrel monkeys. Soc. Neurosci. Abstr. 21, 1902. 32. Elbert, T., Pantev, C., Wienbruch, C., Rockstroh, B., and Taub, E. (1995) Increased cortical representation of the fingers of the left hand in string players. Science 270, 305–307. 33. Grafton, S. T., Mazziotta, J. C., Presty, S., Friston, K. J., Frackowiak, R. S. J., and Phelps, M. E. (1992) Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET. J. Neurosci. 12, 2542–2548. 34. Pascual-Leone, A., Nguyet, D., Cohen, L. G., Brasil-Neto, J. P., Cammarota, A., and Hallett, M. (1995) Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J. Neurophysiol. 74, 1037–1045. 35. Pascual-Leone, A., and Torres, F. (1993) Plasticity of the sensorimotor cortex representation of the reading finger in Braille readers. Brain 116, 39–52. 36. Karni, A., Meyer, G., Jezzard, P., Adams, M. M., Turner, R., and Ungerleider, L. G. (1995) Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 377, 155–158. 37. Seitz, R. J., Huang, Y., Knorr, U., Tellmann, L., Herzog, H., and Freund, H. J. (1995) Large-scale plasticity of the human motor cortex. Neuroreport 6, 742–744. 38. Jenkins, I. H., Brooks, D. J., Nixon, P. D., Frackowiak, S. J., and Passingham, R. E. (1994) Motor sequence learning: A study with positron emission tomography. J. Neurosci. 14, 3775–3790.
39. Schlaug, G., Knorr, U., and Seitz, R. J. (1994) Inter-subject variability of cerebral activations in acquiring a motor skill: A study with positron emission tomography. Exp. Brain Res. 98, 523–534. 40. Pascual-Leone, A., Grafman, J., and Hallett, M. (1994) Modulation of cortical motor output maps during development of implicit and explicit knowledge. Science 263, 1287–1289. 41. Seitz, R. J., Roland, R. E., Bohm, C., Greitz, T., and Stone-Elander, S. (1990) Motor learning in man: A positron emission tomographic study. Neuroreport 1, 57–60. 42. Donoghue, J. P., and Sanes, J. N. (1988) Organization of adult motor cortex representation patterns following neonatal forelimb nerve injury in rats. J. Neurosci. 8, 3221–3232. 43. Sanes, J. N., Suner, S., and Donoghue, J. P. (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp. Brain Res. 79, 479–491. 44. Sanes, J. N., Suner, S., Lando, J. F., and Donoghue, J. P. (1988) Rapid reorganization of adult rat motor cortex somatic representation patterns after motor nerve injury. Proc. Natl. Acad. Sci. USA 85, 2003–2007. 45. Donoghue, J. P., Suner, S., and Sanes, J. N. (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. II. Rapid reorganization following motor nerve lesions. Exp. Brain Res. 79, 492–503. 46. Ojemann, J. G., and Silbergeld, D. L. (1995) Cortical stimulation mapping of phantom limb rolandic cortex. Case report. J. Neurosurg. 82, 641–644. 47. Brasil-Neto, J. P., Valls-Sole, J., Pascual-Leone, A., Cammarota, A., Amassion, V. E., Cracco, R., Maccabee, P., Cracco, L., Hallett, M., and Cohen, L. G. (1993) Rapid modulation of human cortical motor outputs following ischaemic nerve block. Brain 116, 511–525. 48. Cohen, L. G., Brasil-Neto, J. P., Pascual-Leone, A., and Hallett, M. (1993) Plasticity of cortical motor output organization following deafferentation, cerebral lesions, and skill acquisition. Adv. Neurol. 63, 187–200. 49. Glees, P., and Cole, J. (1950) Recovery of skilled motor functions after small repeated lesions in motor cortex in macaque. J. Neurophysiol. 13, 137–148. 50. Nudo, R. J., and Milliken, G. W. (1996) Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J. Neurophysiol. 75, 2144–2149. 51. Nudo, R. J., Wise, B. M., SiFuentes, F., and Milliken, G. W. (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272, 1791–1794. 52. Castro-Alamancos, M. A., Garcı´a-Segura, L. M., and Borrell, J. (1992) Transfer of function to a specific area of the cortex after induced recovery from brain damage. Eur. J. Neurosci. 4, 853–863. 53. Taub, E., Miller, N. E., Novack, T. A., Cook, E. W. I., Fleming, W. C., Nepomuceno, C. S., Connell, J. S., and Crago, J. E. (1993) Technique to improve chronic motor deficit after stroke. Arch. Phys. Med. Rehab. 74, 347–354. 54. Kozlowski, D. A., James, D. C., and Schallert, T. (1996) Usedependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J. Neurosci. 16, 4776–4786. 55. Donoghue, J. P. (1995) Plasticity of adult sensorimotor representations. Curr. Opinion Neurobiol. 5, 749–754. 56. Iriki, A., Pavlides, C., Keller, A., and Asanuma, H. (1991)
Copyright r 1997 by Academic Press
23
Adaptive Plasticity in Motor Cortex
57.
58.
59.
60.
Long-term potentiation of thalamic input to the motor cortex induced by coactivation of thalamocortical and corticocortical afferents. J. Neurophysiol. 65, 1435–1441. Aroniadou, V. A., and Keller, A. (1993) The patterns and synaptic properties of horizontal intracortical connections in the rat motor cortex. J. Neurophysiol. 70, 1553–1569. Hess, G., Jacobs, K. M., and Donoghue, J. P. (1994) N-Methyl-Daspartate receptor mediated component of field potentials evoked in horizontal pathways of rat motor cortex. Neuroscience 61, 225–235. Hess, G., and Donoghue, J. P. (1994) Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. J. Neurophysiol. 71, 2543–2547. Castro-Alamancos, M. A., Donoghue, J. P., and Connors, B. W. (1995) Different forms of plasticity in somatosensory and motor areas of the neocortex. J. Neurosci. 15, 5324–5333.
61. Jones, E. G., Coulter, J. D., and Hendry, S. H. C. (1978) Intracortical connectivity of architectonic fields in the somatic sensory, motor and parietal cortex of monkeys. J. Comp. Neurol. 181, 291–348. 62. Keller, A. (1993) Intrinsic connections between representation zones in the cat motor cortex. Neuroreport 4, 515–518. 63. Weiss, D. S., and Keller, A. (1994) Specific patterns of intrinsic connections between representation zones in the rat motor cortex. Cereb. Cortex 4, 205–214. 64. Kleim, J. A., Lussnig, E., Schwarz, E. R., Comery, T. A., and Greenough, W. T. (1996) Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning. J. Neurosci. 16, 4529–4535. 65. Bertelson, J. A., Plautz, E. J., and Nudo, R. J. (1996) Reorganization of muscle representations in motor cortex following a focal ischemic infarct. Soc. Neurosci. Abstr. 22, 2023.
Copyright r 1997 by Academic Press
Adaptive Plasticity in Primate Motor Cortex as a Consequence of Behavioral Experience and Neuronal Injury Randolph J. Nudo,1 Erik J. Plautz, and Garrett W. Milliken2 Department of Neurobiology and Anatomy, University of Texas Houston Health Science Center, Houston, Texas 77030
It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual’s life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills. r 1997 Academic Press KEY WORDS: Motor cortex; plasticity; rehabilitation; stroke; learning.
Studies conducted in cortical sensory areas over the past several years have revealed that representational maps are alterable both as a function of the integrity of their sensory inputs, and as a function of experience (1). Since representational plasticity has now been demonstrated in somatosensory, auditory, and visual cortex of adult individuals representing a wide variety of mammalian species, it would appear that the life-long capacity for functional reorganization is a common feature of sensory neocortex. More recent studies now indicate that motor maps, like sensory maps, are alterable in adult animals. Motor maps can be differentially altered by electrical stimulation, pharmacological manipulation, behavioral training, and peripheral or central nervous system injury. These findings should be of general interest to students of brain plasticity for two reasons. First, the motor cortex has long
been implicated in motor learning. Plastic changes in cortical motor topography that are correlated with behavioral training may reveal fundamental mechanisms of the motor cortex for skill acquisition. Second, since motor cortex is frequently involved in clinical stroke and traumatic brain injury, changes in cortical motor topography that occur after injury may reveal neural mechanisms involved in recovery of function. In the first part of this article, the current understanding of the organization of motor cortex is reviewed. Next, the evidence for adaptive plasticity in motor maps resulting from artificial manipulation and from behavioral experience is examined. Then, recent data suggesting that motor maps are alterable after cortical injury are reviewed. Finally, the putative mechanisms that might account for functional alterations in motor cortex are addressed.
1To whom correspondence and reprint requests should be addressed at Center on Aging, The University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7117, Fax: (913) 588-1201, e-mail: [email protected]. 2Present address: Department of Psychology, Auburn University, Auburn, AL.
FUNCTIONAL TOPOGRAPHY OF PRIMATE MOTOR CORTEX
1044-5765/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.
For more than a century the motor cortex has been delineated by noting those neocortical regions that
13
14
Nudo, Plautz, and Milliken
FIG. 1. Location and somatotopic organization of primary motor cortex (M1) in a squirrel monkey. The distal forelimb, or hand area of primary motor cortex, is located rostral to the central sulcus, near its lateral edge. In addition to M1, other motor areas include dorsal premotor cortex (PMD), ventral premotor cortex (PMV), the supplementary motor area (SMA), and cingulate motor areas (cing.; hidden from view on the medial walls of the cerebral cortex). The locations of the primary somatosensory area (S1) and area 3a are also shown.
require the least electrical stimulation to evoke movements of specific body parts (2). The neuroanatomical basis for this phenomenon is the high density of corticospinal neurons that lie within layer V of this so-called ‘‘excitable cortex.’’ The axons of many of these corticospinal neurons terminate directly on spinal cord motor neurons (corticomotoneuronal cells). Within motor cortex, neurons controlling all parts of the skeletal motor apparatus are laid out in an orderly map (the motor homunculus), roughly resembling the arrangement of body parts in the periphery (Fig. 1) (3). The primate motor cortex comprises several distinct areas, each thought to play a separate role in the cortical control of movement (Fig. 1) (4, 5). M1 (primary motor cortex or area 4) is thought to mediate skilled voluntary movements, especially of the distal musculature. Because of its importance in human motor control, the hand area of M1 has been the focus of intensive study for more than a century. Most of the examples of adaptive plasticity in motor cortex have been derived from studies in the hand (or distal forelimb) area of M1. However, it should be noted that other cortical motor areas, including the premotor cortex (6), the supplementary motor area (7), and the
cingulate cortex (8) are involved in motor control. It is likely that adaptive plasticity occurs in these other areas as well. Early cortical surface stimulation studies described a single representation of the hand in M1 (9). As microelectrode stimulation techniques were developed in the late 1960s, investigators were able to derive motor maps in much greater spatial detail (10). It soon became apparent that individual muscles and movements were represented in multiple, discrete loci within the M1 hand area. As the microelectrode stimulation techniques were pushed to their spatial limits with fine-grain maps, it was found that representations of different muscles overlap extensively (11). This overlapping arrangement of muscles results in a map of hand movements that is somatotopic on a global scale (i.e., with respect to hand vs face representations), but fractionated, or mosaical, on a local scale (i.e., with respect to digit vs wrist representations; Fig. 2) (11–14). The precise number of representations of a given joint movement (e.g., finger flexion) is highly variable among individuals. Overlapping representations of hand movements have also been demonstrated in human motor cortex using functional magnetic resonance
Copyright r 1997 by Academic Press
15
Adaptive Plasticity in Motor Cortex
FIG. 2. Representations of muscles and movements in the hand area of primary motor cortex (M1) in a squirrel monkey. Muscle and movement representations were derived using microelectrode stimulation techniques in a ketamine-anesthetized monkey. Microelectrodes were sequentially introduced at a depth of 1750 µm. Interpenetration distances were 500 µm. (A) Selected muscle representations in M1. Stimulation of cortical territory contained within thin colored lines evoked significant electromyographic (EMG) activity in the indicated muscles. Stimulation of cortical territory contained within thick colored lines evoked particularly high amplitude EMG activity in the indicated muscles. Stimulation current was 30 µA at each site. FDS (red line): flexor digitorum superficialis; EDC (gray line): extensor digitorum communis; ECU (blue line): extensor carpi ulnaris; ECR (green line): extensor carpi radialis. Heavy black line indicates limits of hand movement area as defined by near-threshold current stimulation. Representations of individual muscles overlap extensively and extend beyond the borders of the hand area as defined by evoked hand movements. (B) Representation of movements evoked at threshold current levels in the same cortical territory. As a result of the overlapping representation of individual muscles, joint movement representations are fractionated or mosaical (65).
imaging (15). Thus, as techniques used to define cortical motor representations have improved, our concept of motor cortex topography has evolved from a single, undifferentiated motor homunculus to multiple, mosaical representations. There is increasing evidence that M1 (and also premotor cortex (16)) can be divided further into caudal and rostral subfields. For example, caudal and rostral M1 differ in their specific connections with other cortical areas (14). Further, neurons responsive to cutaneous stimulation are confined primarily to caudal M1, whereas neurons responsive to muscle stimulation and joint manipulation predominate in rostral M1 (Fig. 3) (17–19). Still further, recent findings in human motor cortex suggest that caudal and rostral M1 differ in soma density and neurotransmitter receptor binding (20). Despite these differences, the overlapping motor output representations of individual hand muscles can extend across both subfields (Fig. 2). The intrinsic connectivity within M1 is still under
investigation. However, it is already clear that the different hand movement representations are locally interconnected across the entire M1 hand area (21–23). The neural mechanisms by which these local connections might contribute to shaping motor outputs will be addressed in a later section.
ACTIVITY-DEPENDENT ALTERATIONS IN MOTOR MAPS Artificially Induced Alterations in Motor Maps As early as the beginning of this century, it was recognized by Graham Brown and Sherrington that electrical stimulation of the motor cortex can result in rapid changes in the movements evoked from subsequent stimulation of adjacent regions of motor cortex (24). While this study was performed using surface
Copyright r 1997 by Academic Press
16
Nudo, Plautz, and Milliken
FIG. 3. Sensory representations in sensorimotor cortex of a ketamine-anesthetized squirrel monkey. (A) Multiunit sensory responses recorded in area 3b (primary somatosensory cortex or S1), area 3a, and area 4 (primary motor cortex or M1). The thick solid line encompasses sites where electrical stimulation evoked hand movements in this same monkey at #30 µA (i.e., the M1 hand area). The thin solid lines encompass sites where neurons were responsive to cutaneous stimulation. Cutaneous responses in M1 are primarily located in the caudal aspect of the M1 hand representation. (B) Representative cutaneous receptive fields in M1 and S1. Using von Frey hairs, a criterion threshold was defined for a typical cutaneous response in S1. Then, at each site in M1, responses were designated as cutaneous (i.e., responds exclusively to skin indentation or hair deflection) or noncutaneous (i.e., responds to light taps, but probably driven by muscle or joint receptors). Using this strict criterion, many cutaneous responses were found in M1, although receptive fields were considerably larger than those found in S1. H, hand; Hyp, hypothenar; The, thenar; P, pad; t, responds to light taps; j, responds to joint manipulation; d, dorsum; D, digit; W, wrist; F, forearm; S, shoulder; E, elbow; NR, no response; f, flexion; ex, extension; ad, adduction; ab, abduction; mr, medial rotation; su, supination; pro, pronation; el, elevation; re, retraction; u, ulnar; L, lateral; R, rostral. Numbers indicate specific digits (19).
electrodes to produce evoked movements, it represents one of the earliest demonstrations of functional plasticity in the cerebral cortex. These results were replicated recently using microelectrode stimulation techniques in forelimb motor cortex of rats (25). The movement represented at a site that was repetitively stimulated for at least 30 min temporarily came to be represented over a larger cortical territory. In another artificial, but more physiologically specific, manipulation, Jacobs
and Donoghue injected bicuculline into the forelimb representations of rats before and after microelectrode stimulation mapping. Significant shifts occurred in representational borders, resulting in temporary expansion of the forelimb representation (26). It was suggested that these results occurred due to unmasking of horizontal excitatory connections within the cortex. Motor output representations can also be systematically altered by adjusting the posture of specific joints.
Copyright r 1997 by Academic Press
17
Adaptive Plasticity in Motor Cortex
Simply changing the position of the forelimb from wrist extension/elbow flexion to wrist flexion/elbow extension during a microelectrode stimulation experiment results in an expansion of the forelimb representation into the former vibrissae representation of anesthetized, adult rats (27). These data suggest that motor output maps in M1 can be modified by changes in proprioceptive input. Variability in responses evoked by stimulation techniques has been a common finding for a century. Although some investigators have argued that response variability limits the usefulness of stimulation techniques in defining motor output organization, others have suggested that this variability is the result of genuine temporal variation in the physiological condition of the motor system. Since recent, highly controlled studies have shown systematic changes in motor representations due to manipulation of specific variables, it is likely that microelectrode stimulation techniques can be used effectively to reveal basic mechanisms of motor cortex plasticity.
Behaviorally Induced Alterations in Motor Maps If the functional organization of motor cortex can be altered by artificial manipulation, it is possible that these adaptive mechanisms are used normally by the motor cortex in the natural learning of motor skills. Early studies by Woody and colleagues demonstrated that large changes in movement representations occur in motor cortex of cat, and these changes are related to conditioned movements (28). Later, Fetz and colleagues showed that isolated cells in motor cortex can be operantly conditioned to increase or decrease their firing rate within minutes (29). While these experiments were not designed to examine changes in the detailed topography of motor representations, they provided early indications that certain training paradigms may significantly alter the physiology of motor cortex. The view that the functional organization of motor cortex may be alterable by behavioral experience is further supported by the observation that mosaical motor maps of distal musculature are highly idiosyncratic (12, 13). It is possible that individual map variability reflects each animal’s experiences up to the time in life that the cortical map is derived. Further support came with the demonstration that the spatial distribution of hand movement representations in M1 of primates is correlated with each animal’s hand
preference (13). Hand movement representations in the dominant motor cortex (opposite the preferred hand on a reach and grasp task) are slightly larger and more spatially complex, i.e., more mosaical. Other studies in which motor maps of primates were tracked before and after motor training examined the effects of behavioral experience directly (30). In these studies, squirrel monkeys were trained over a period of about 2 weeks to extract food pellets from a small, cylindrical well with one or two fingers. Posttraining maps revealed a large expansion of finger representations (Fig. 4). Movements used more frequently in a behavioral task are selectively magnified in their cortical representations. More recent findings suggest that motor maps are altered by motor skill acquisition, but not by repetitive use alone (31). In this study, one group of monkeys retrieved pellets from a small food well, as before. A second group of monkeys retrieved pellets from a substantially larger food well, a task requiring no training to master efficiently. Monkeys in the two groups were matched for total number of finger flexions. No systematic changes were seen in motor hand maps in the monkeys retrieving pellets from the large well (Fig. 4). These experiments suggest that adaptive plasticity in motor maps is a manifestation of basic neural processes involved in the learning of complex motor skills. As new movement patterns are acquired and used to master a motor task with increased efficiency, the representations of the newly acquired, or learned, motor patterns are reflected in altered motor maps. Most of the studies demonstrating representational plasticity in motor cortex have been performed in nonhuman primates or in rats using invasive procedures (typically microelectrode stimulation). With the widespread use of noninvasive imaging and stimulation techniques it has become possible to demonstrate that alterations also occur in the functional topography of human motor cortex as a result of motor experience. Using positron emission tomography (PET), transcranial magnetic stimulation (TMS), and functional magnetic resonance imaging (FMRI) techniques, several investigators have now shown that the area of activation for the hand representation in M1 increases as subjects practice complex finger movement tasks (32– 41). These studies indicate that the functional organization of motor cortex is dynamically maintained by skilled use in humans, as in other mammals.
Copyright r 1997 by Academic Press
18
Nudo, Plautz, and Milliken
FIG. 4. Differential effects of motor skill acquisition and motor use on functional organization in primate motor cortex. (A) Training procedures consisted of retrieving small banana-flavored pellets from a Plexiglas board containing food wells of graded diameters. Adult squirrel monkeys were trained to retrieve pellets from either the smallest well or the largest well. The monkey can easily place its entire hand into the largest well, but can only insert one or two fingers into the smallest well. For both groups, the task criterion met before the posttraining mapping procedure was approx. 12,000 total finger flexions over the course of training. Thus, both groups had an equivalent amount of motor use during the training period. (B) Small well training resulted in an improvement in motor skill (fewer flexions per retrieval) over the course of training (30). Conversely, animals trained in the large well showed near-perfect performance throughout the task, and thus no evidence of a change in motor skill (31). (C and D) Pre- and posttraining maps of distal forelimb movements were produced by microelectrode stimulation techniques. In this and the following figure, movements evoked at threshold current levels are shown. Posttraining maps showed robust changes following small well training (30), but few systematic changes following large well training (31). These results indicate that the functional topography of motor cortex is shaped by learning of new motor skills, not simply by repetitive motor use.
Peripheral Lesions
INJURY-INDUCED ALTERATIONS IN MOTOR MAPS In addition to changes that occur during motor learning, motor maps are systematically altered by various types of peripheral or central nervous system injuries. In general, these injury-induced alterations are even more widespread than those induced by behavioral experience in intact individuals.
In a series of experiments using microelectrode stimulation techniques, Donoghue and colleagues demonstrated that cortical motor representations can be altered by peripheral nerve lesions in developing and adult rats. When the forelimb was amputated in perinatal rats, the vibrissae and shoulder representations expanded, presumably into the former forelimb
Copyright r 1997 by Academic Press
19
Adaptive Plasticity in Motor Cortex
FIG. 5. Effects of injury to motor cortex with or without rehabilitative training. (A and B) Remodeling of motor hand representations in M1 following a focal vascular infarct. Infarct destroyed 21% of digit and 7% of wrist/forearm representation within M1 (dotted line). Monkeys in this group were not provided rehabilitative retraining (spontaneous recovery). Three months after the infarct, the undamaged digit area (red) adjacent to the lesion decreased by an additional 40% (50) (C and D) Remodeling of motor hand representations in M1 following an infarct and rehabilitative training. Monkeys in this group underwent daily, repetitive training on a pellet retrieval task. A jacket with a long sleeve restricted use of the unaffected limb, forcing the monkey to use the impaired limb. In this monkey, the infarct destroyed 22% of digit and 4% of wrist forearm representation. Following rehabilitative training, the spared digit representation increased by 15% and the spared wrist/forearm representation increased by 59% (51). These results suggest that after cortical injury, motor experience plays a major role in the physiological reorganization that occurs in adjacent, undamaged tissue. (C and D) Reprinted with permission from Nudo, R. J., Wise, B. M., SiFuentes, F., and Milliken, G. W. (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272, 1791–1794. Copyright 1996 American Association for the Advancement of Science.
Copyright r 1997 by Academic Press
20
Nudo, Plautz, and Milliken
territory (42). Additional experiments demonstrated that this phenomenon persists in adulthood. When the forelimb was amputated in adult rats, the shoulder representations expanded into the former forelimb territory (43); when the facial nerve was damaged, the forelimb territory rapidly expanded into the former vibrissae representation (43–45). These modified motor maps were stable for months after the facial nerve lesions. There is now evidence that a similar phenomenon occurs in humans. Using intraoperative cortical stimulation techniques in patients with arm amputations, Ojemann and Silbergeld recently found that the face and shoulder representations expanded, paralleling the earlier electrophysiological results in rats (46). Similar findings have been obtained in humans using TMS techniques (47, 48).
Central Lesions Neurophysiological and neuroanatomical bases have long been sought to account for functional motor recovery following cortical injury. It is commonly assumed that other parts of the motor system must ‘‘take over’’ the function of the damaged cortex, but despite over a century of study, the precise neural mechanisms by which lost functions are regained and the structures that are involved are poorly understood. Studies by Glees and Cole in the 1950s (49) using surface stimulation techniques suggested that lost cortical functions are assumed by the adjacent cortical tissue. However, these results are difficult to interpret because of the low spatial resolution inherent in surface stimulation mapping studies. Recently, we used microelectrode stimulation techniques to examine motor representations before and a few months after a small vascular (ischemic) infarct in adult monkeys. One group of monkeys underwent ‘‘spontaneous’’ recovery. That is, no specific postinjury training was provided beyond periodic, brief assessment of hand preference and dexterity. In contrast to the results reported by Glees and Cole, movements represented in the infarcted zone did not reappear in the cortical sector surrounding the infarct. Instead, hand movement representations adjacent to the infarct that were spared from direct injury underwent a further loss of cortical territory (Fig. 5) (50). In a second group of monkeys, postinjury ‘‘rehabilitative’’ training was provided in the form of forced, repetitive use of the impaired hand in a pellet retrieval task. Retraining of skilled hand use after infarcts
resulted in prevention of the loss of hand territory adjacent to the infarct (Fig. 5). Functional reorganization in the undamaged motor cortex was accompanied by behavioral recovery of skilled hand function (51). Thus, it would appear that extensive reorganization occurs in M1 following focal infarct. After injury, repetitive training can shape subsequent reorganization in the adjacent intact cortex, suggesting that the undamaged motor cortex plays an important role in motor recovery (52). It is widely held that postinjury experience (i.e., physical rehabilitation) facilitates recovery of sensorimotor skills following destruction of cortical motor areas in humans. For example, a recent study in human stroke patients demonstrated that forced use of the affected limb for 14 days (by constraint of the unaffected limb) resulted in long-term improvement of motor function in the impaired limb (53). It was suggested that nonuse of the affected limb is a learned phenomenon and that restraint and training are effective because they overcome learned nonuse. Despite the apparent benefits that may accompany forced use after cortical injury, recent studies in rats suggest that overuse after cortical injury may cause dysfunctional alterations in cortical morphology. After sensorimotor cortical lesions in rats, Schallert and colleagues placed restrictive casts on the unaffected forelimb, forcing the rats to use the impaired limb. This procedure resulted in a significant exaggeration of the cortical injury and impaired motor recovery (54). These studies raise the possibility that extreme overuse of the affected limb after injury may be detrimental to long-term neurophysiological and behavioral outcome.
MECHANISMS OF PLASTICITY IN MOTOR CORTEX The synaptic mechanisms underlying representational plasticity in motor cortex are currently under investigation in several laboratories (55). It is now clear that both long-term potentiation and long-term depression can be produced in the motor cortex of intact animals or in slice preparations and may provide a mechanism for modulating motor maps (56–60). These synaptic events are probably mediated via intrinsic intracortical connections that link cortical modules within a given motor field (e.g., across the entire hand area of M1) (61–63). Glutamate is the major neurotransmitter of these horizontal connections, and it is likely
Copyright r 1997 by Academic Press
21
Adaptive Plasticity in Motor Cortex
that synaptic modification is mediated via N-methyl-Daspartate receptors (58). Under some conditions, modulation of the effectiveness of local, horizontal connections can occur over a rapid time course, suggesting that motor map plasticity occurs due to altered membrane excitability in local cortical circuits. In addition, motor skill training appears to induce increases in early gene expression and significant synaptogenesis in the motor cortex (64). It is tempting to speculate that changes in synaptic efficacy between neurons in neighboring cortical modules may underlie short-term modifications, while local proliferation of new synaptic connections may underlie longer term modifications in neuronal excitability, and more generally in cortical motor topography.
CONCLUSIONS It is now clear that cortical motor maps in the primary motor cortex are alterable by behavioral experience and by neuronal injury. Since topographic plasticity seems to coincide with the acquisition of new motor skills in intact individuals, or the reacquisition of motor skills after injury, it would appear that motor cortex plays a significant role in motor learning and in recovery of function. Recent electrophysiological and ultrastructural studies suggest that these topographic rearrangements occur largely by modulation of horizontal connections among various functional modules and local synaptogenesis within motor cortex. The challenge for future studies in motor cortex map alterability is to determine mechanisms for specificity in local circuit modulation, in light of the overlapping representations of muscles and movements, and the apparent widespread arborization of intracortical circuitry within the primary motor cortex.
ACKNOWLEDGMENTS This research was supported by grants from the National Institute of Neurological Diseases and Stroke (NS-30853, NS-09366), the National Institute of Mental Health (MH-10963), and the American Heart Association. This work was done during the tenure of an Established Investigatorship award from the American Heart Association (R.J.N.).
REFERENCES 1. Kaas, J. H. (1991) Plasticity of sensory and motor maps in adult mammals. Annu. Rev. Neurosci. 14, 137–167.
2. Fritsch, G., and Hitzig, E. (1870) Ueber die elektrische Erregbarkeit des Grosshirns. Arch. Anat. Physiol. Wiss. Med. 37, 300–332. 3. Woolsey, C. N. (1952) Patterns of localization in sensory and motor areas of the cerebral cortex. In Milbank Symposium: The Biology of Mental Health and Disease, pp. 193–206, Hoeber, New York. 4. Donoghue, J. P., and Sanes, J. N. (1994) Motor areas of the cerebral cortex. J. Clin. Neurophysiol. 11, 382–396. 5. Tanji, J., and Kurata, K. (1989) Changing concepts of motor areas of the cerebral cortex. Brain Dev. 11, 374–377. 6. Wise, S. P., DiPellegrino, G., and Boussaoud, D. (1992) Primate premotor cortex: Dissociation of visuomotor from sensory signals. J. Neurophysiol. 68, 969–972. 7. Wise, S. (1996) Evolutionary and comparative neurobiology of the supplementary sensorimotor area. Adv. Neurol. 70, 71–83. 8. Picard, N., and Strick, P. L. (1996) Motor areas of the medial wall: A review of their location and functional activation. Cereb. Cortex 6, 342–353. 9. Welker, W. I., Benjamin, R. M., Miles, R. C., and Woolsey, C. N. (1957) Motor effects of stimulation of cerebral cortex of squirrel monkey (Saimiri sciureus). J. Neurophysiol. 20, 347–364. 10. Asanuma, H., and Rose´n, I. (1972) Topographical organization of cortical efferent zones projecting to distal forelimb muscles in the monkey. Exp. Brain Res. 14, 243–256. 11. Donoghue, J. P., Leibovic, S., and Sanes, J. N. (1992) Organization of the forelimb area in squirrel monkey motor cortex: Representation of digit, wrist, and elbow muscles. Exp. Brain Res. 89, 1–19. 12. Gould, H. J. I., Cusick, C. G., Pons, T. P., and Kaas, J. H. (1986) The relationship of corpus callosum connections to electrical stimulation maps of motor, supplementary motor, and the frontal eye fields in owl monkeys. J. Comp. Neurol. 247, 297–325. 13. Nudo, R. J., Jenkins, W. M., Merzenich, M. M., Prejean, T., and Gedela, R. (1992) Neurophysiological correlates of hand preference in primary motor cortex of squirrel monkeys. J. Neurosci. 12, 2918–2947. 14. Stepniewska, I., Preuss, T. M., and Kaas, J. H. (1993) Architectonics, somatotopic organization, and ipsilateral cortical connections of the primary motor area (M1) of owl monkeys. J. Comp. Neurol. 330, 238–271. 15. Sanes, J. N., Donoghue, J. P., Thangaraj, V., Edelman, R. R., and Warach, S. (1995) Shared neural substrates controlling hand movements in human motor cortex. Science 268, 1775–1777. 16. Preuss, T. M., Stepniewska, I., and Kaas, J. H. (1996) Movement representation in the dorsal and ventral premotor areas of owl monkeys: A microstimulation study. J. Comp. Neurol. 371, 649– 676. 17. Tanji, J., and Wise, S. P. (1981) Submodality distribution in sensorimotor cortex of the unanesthetized monkey. J. Neurophysiol. 45, 467–481. 18. Strick, P. L., and Preston, J. B. (1982) Two representations of the hand in area 4 of a primate. II. Somatosensory input organization. J. Neurophysiol. 48, 150–159. 19. Humphrey, S. M., Gardner, G. A., Raiszadeh, R., and Nudo, R. J. (1994) Loss of sensory, but not motor responsiveness in intact cortex surrounding a focal ischemic infarct in area 4. Soc. Neurosci. Abstr. 20, 179. 20. Geyer, S., Ledberg, A., Schleicher, A., Kinomura, S., Schormann, T., Bu¨rgel, U., Klingberg, T., Larsson, J., Zilles, K., and Roland, P. E. (1996) Two different areas within the primary motor cortex of man. Nature 382, 805–807.
Copyright r 1997 by Academic Press
22
Nudo, Plautz, and Milliken
21. Keller, A. (1993) Intrinsic synaptic organization of the motor cortex. Cereb. Cortex 3, 430–441. 22. Huntley, G. W., and Jones, E. G. (1991) Relationship of intrinsic connections to forelimb movement representations in monkey motor cortex: A correlative anatomical and physiological study. J. Neurophysiol. 66, 390–413. 23. Plautz, E. P., Milliken, G. W., and Nudo, R. J. (1996) Anatomical connectivity of electrophysiologically identified movement representations in the M1 hand area of squirrel monkeys. Soc. Neurosci. Abstr. 22, 1083. 24. Graham Brown, T., and Sherrington, C. S. (1912) On the instability of a cortical point. Proc. R. Soc. (London) 85, 250–277. 25. Nudo, R. J., Jenkins, W. M., and Merzenich, M. M. (1990) Repetitive microstimulation alters the cortical representation of movements in adult rats. Somatosens. Mot. Res. 7, 463–483. 26. Jacobs, K. M., and Donoghue, J. P. (1991) Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251, 944–947. 27. Sanes, J. N., Wang, J., and Donoghue, J. P. (1992) Immediate and delayed changes of rat motor cortical output representation with new forelimb configurations. Cereb. Cortex 2, 141–152. 28. Woody, C. D., and Engel, J. Jr. (1972) Changes in unit activity and thresholds to electrical microstimulation at coronal–pericruciate cortex of cat with classical conditioning of different facial movements. J. Neurophysiol. 35, 230–241. 29. Fetz, E. E., and Baker, M. A. (1973) Operantly conditioned patterns of precentral unit activity and correlated responses in adjacent cells and correlated muscles. J. Neurophysiol. 36, 179– 204. 30. Nudo, R. J., Milliken, G. W., Jenkins, W. M., and Merzenich, M. M. (1996) Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J. Neurosci. 16, 785–807. 31. Plautz, E. J., Milliken, G. W., and Nudo, R. J. (1995) Differential effects of skill acquisition and motor use on the reorganization of motor representations in area 4 of adult squirrel monkeys. Soc. Neurosci. Abstr. 21, 1902. 32. Elbert, T., Pantev, C., Wienbruch, C., Rockstroh, B., and Taub, E. (1995) Increased cortical representation of the fingers of the left hand in string players. Science 270, 305–307. 33. Grafton, S. T., Mazziotta, J. C., Presty, S., Friston, K. J., Frackowiak, R. S. J., and Phelps, M. E. (1992) Functional anatomy of human procedural learning determined with regional cerebral blood flow and PET. J. Neurosci. 12, 2542–2548. 34. Pascual-Leone, A., Nguyet, D., Cohen, L. G., Brasil-Neto, J. P., Cammarota, A., and Hallett, M. (1995) Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J. Neurophysiol. 74, 1037–1045. 35. Pascual-Leone, A., and Torres, F. (1993) Plasticity of the sensorimotor cortex representation of the reading finger in Braille readers. Brain 116, 39–52. 36. Karni, A., Meyer, G., Jezzard, P., Adams, M. M., Turner, R., and Ungerleider, L. G. (1995) Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 377, 155–158. 37. Seitz, R. J., Huang, Y., Knorr, U., Tellmann, L., Herzog, H., and Freund, H. J. (1995) Large-scale plasticity of the human motor cortex. Neuroreport 6, 742–744. 38. Jenkins, I. H., Brooks, D. J., Nixon, P. D., Frackowiak, S. J., and Passingham, R. E. (1994) Motor sequence learning: A study with positron emission tomography. J. Neurosci. 14, 3775–3790.
39. Schlaug, G., Knorr, U., and Seitz, R. J. (1994) Inter-subject variability of cerebral activations in acquiring a motor skill: A study with positron emission tomography. Exp. Brain Res. 98, 523–534. 40. Pascual-Leone, A., Grafman, J., and Hallett, M. (1994) Modulation of cortical motor output maps during development of implicit and explicit knowledge. Science 263, 1287–1289. 41. Seitz, R. J., Roland, R. E., Bohm, C., Greitz, T., and Stone-Elander, S. (1990) Motor learning in man: A positron emission tomographic study. Neuroreport 1, 57–60. 42. Donoghue, J. P., and Sanes, J. N. (1988) Organization of adult motor cortex representation patterns following neonatal forelimb nerve injury in rats. J. Neurosci. 8, 3221–3232. 43. Sanes, J. N., Suner, S., and Donoghue, J. P. (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp. Brain Res. 79, 479–491. 44. Sanes, J. N., Suner, S., Lando, J. F., and Donoghue, J. P. (1988) Rapid reorganization of adult rat motor cortex somatic representation patterns after motor nerve injury. Proc. Natl. Acad. Sci. USA 85, 2003–2007. 45. Donoghue, J. P., Suner, S., and Sanes, J. N. (1990) Dynamic organization of primary motor cortex output to target muscles in adult rats. II. Rapid reorganization following motor nerve lesions. Exp. Brain Res. 79, 492–503. 46. Ojemann, J. G., and Silbergeld, D. L. (1995) Cortical stimulation mapping of phantom limb rolandic cortex. Case report. J. Neurosurg. 82, 641–644. 47. Brasil-Neto, J. P., Valls-Sole, J., Pascual-Leone, A., Cammarota, A., Amassion, V. E., Cracco, R., Maccabee, P., Cracco, L., Hallett, M., and Cohen, L. G. (1993) Rapid modulation of human cortical motor outputs following ischaemic nerve block. Brain 116, 511–525. 48. Cohen, L. G., Brasil-Neto, J. P., Pascual-Leone, A., and Hallett, M. (1993) Plasticity of cortical motor output organization following deafferentation, cerebral lesions, and skill acquisition. Adv. Neurol. 63, 187–200. 49. Glees, P., and Cole, J. (1950) Recovery of skilled motor functions after small repeated lesions in motor cortex in macaque. J. Neurophysiol. 13, 137–148. 50. Nudo, R. J., and Milliken, G. W. (1996) Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J. Neurophysiol. 75, 2144–2149. 51. Nudo, R. J., Wise, B. M., SiFuentes, F., and Milliken, G. W. (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272, 1791–1794. 52. Castro-Alamancos, M. A., Garcı´a-Segura, L. M., and Borrell, J. (1992) Transfer of function to a specific area of the cortex after induced recovery from brain damage. Eur. J. Neurosci. 4, 853–863. 53. Taub, E., Miller, N. E., Novack, T. A., Cook, E. W. I., Fleming, W. C., Nepomuceno, C. S., Connell, J. S., and Crago, J. E. (1993) Technique to improve chronic motor deficit after stroke. Arch. Phys. Med. Rehab. 74, 347–354. 54. Kozlowski, D. A., James, D. C., and Schallert, T. (1996) Usedependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J. Neurosci. 16, 4776–4786. 55. Donoghue, J. P. (1995) Plasticity of adult sensorimotor representations. Curr. Opinion Neurobiol. 5, 749–754. 56. Iriki, A., Pavlides, C., Keller, A., and Asanuma, H. (1991)
Copyright r 1997 by Academic Press
23
Adaptive Plasticity in Motor Cortex
57.
58.
59.
60.
Long-term potentiation of thalamic input to the motor cortex induced by coactivation of thalamocortical and corticocortical afferents. J. Neurophysiol. 65, 1435–1441. Aroniadou, V. A., and Keller, A. (1993) The patterns and synaptic properties of horizontal intracortical connections in the rat motor cortex. J. Neurophysiol. 70, 1553–1569. Hess, G., Jacobs, K. M., and Donoghue, J. P. (1994) N-Methyl-Daspartate receptor mediated component of field potentials evoked in horizontal pathways of rat motor cortex. Neuroscience 61, 225–235. Hess, G., and Donoghue, J. P. (1994) Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical motor maps. J. Neurophysiol. 71, 2543–2547. Castro-Alamancos, M. A., Donoghue, J. P., and Connors, B. W. (1995) Different forms of plasticity in somatosensory and motor areas of the neocortex. J. Neurosci. 15, 5324–5333.
61. Jones, E. G., Coulter, J. D., and Hendry, S. H. C. (1978) Intracortical connectivity of architectonic fields in the somatic sensory, motor and parietal cortex of monkeys. J. Comp. Neurol. 181, 291–348. 62. Keller, A. (1993) Intrinsic connections between representation zones in the cat motor cortex. Neuroreport 4, 515–518. 63. Weiss, D. S., and Keller, A. (1994) Specific patterns of intrinsic connections between representation zones in the rat motor cortex. Cereb. Cortex 4, 205–214. 64. Kleim, J. A., Lussnig, E., Schwarz, E. R., Comery, T. A., and Greenough, W. T. (1996) Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning. J. Neurosci. 16, 4529–4535. 65. Bertelson, J. A., Plautz, E. J., and Nudo, R. J. (1996) Reorganization of muscle representations in motor cortex following a focal ischemic infarct. Soc. Neurosci. Abstr. 22, 2023.
Copyright r 1997 by Academic Press