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Basal ganglia: Motor influences mediated by sensory interactions
EXPERIMENTAL
NEUROLOGY
77, 534-543 (1982)
Basal Ganglia: Motor Influences Mediated Sensory Interactions J. S. SCHNEIDER,
F. J. DENARO,
by
AND T. I. LIDSKY’
Department of Psychology, State University of New York, Stony Brook, New York 11794 Received October 12. 1981; revision received March 17, 1982 Striatopallidal lesions in rats cause an increase in trigeminal motor nucleus excitability. This hyperexcitability is not due to disruption of basal ganglia-mediated inhibition of the motor nucleus. Rather, basal ganglia lesions disrupt an inhibitory influence upon either the sensory pathway or the link-up between the sensory pathway and the motor nucleus. These data suggest that one way in which the basal ganglia influence movement is by gating sensory influences into motor areas.
INTRODUCTION Although the motor functions of the basal ganglia have been extensively investigated, the mechanisms by which this neural system actually influences movements are not known. In contrast to other neural networks with motor functions (e.g., the pyramidal system) the basal ganglia possess no descending fibers with relatively direct excitatory influences upon bulbar or spinal motor nuclei (27). Low-intensity electrical stimulation of a variety of motor structures evokes contraction of either single muscles or small groups of muscles at short fixed latencies (2). In contrast, low-level stimulation of the basal ganglia produces no motor activity (20, 23, 24). With much more intense stimulation, basal ganglia activation modulates movement evoked by stimulation delivered to other motor areas (e.g., motor cortex) (28). In addition, high-intensity basal ganglia stimulation affects Abbreviations: EMG-electromyogram, MES 5--trigeminal mesencephalic nucleus, VPMnucleus ventralis posteromedialis. I We thank J. R. Morse and N. K. Squires for critical comments. This work was supported by National Institutes of Health grants NS 15328 and NS 16054. Dr. Schneider’s present address is the Department of Psychiatry, Mental Retardation Research Center, UCLA, Los Angeles, CA 90024. Please send correspondence and reprint requests to Dr. Lidsky. 534 0014-4886/82/090534-10$02.00/O Copyright 0 1982 by Academic Prom, Inc. All rights of reproduction in any form rexmcd.
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locomotion responses (1). With respect to these final two results, however, basal ganglia stimulation produces effects which are similar to those produced by structures not traditionally thought to have primary motor functions [e.g., amygdala (10, 12), hippocampus (3, 36), and lateral hypothalamus (26, 35)]. There are mechanisms for affecting movement other than via direct influences upon motoneurons. Studies of feline predation stress the role of sensory inputs in motor control. Electrical activation of hypothalamic sites which elicits predation sensitizes the perioral area so that touch around the lips causes the animal first to turn its head toward the stimulus and then to open its mouth. Such somatosensory-evoked movements are observed only during predation-evoking brain stimulation (6). Consideration of these data and more recent findings concerning the role of nucleus accumbens and the ventral tegmental area in attack led Goldstein and Siegel to “suggest that other stimulus and goal directed behaviors (e.g., feeding, mating) may also be understood in terms of response components made operative by the emergence of receptive fields. . . .” ( 13). Thus, modulation of either sensory processing or the ease with which sensory inputs gain access to motor regions can be an effective means of influencing movement. The experiments described in the present paper were designed to assess the role of the basal ganglia in such processes. METHODS Lashley rats (225 to 490 g at surgery) were used in all experiments. All procedures were chronic. Electrodes for stimulating and producing lesions were stereotaxically implanted prior to behavioral testing. When lesions were subsequently made (see below), the animals were lightly anesthetized with ether for a short period (approximately 5 min). For electrical stimulation, side-by-side bipolar electrodes were constructed from 000 stainlesssteel insect pins insulated except for 0.5 mm at the tip. Recording electrodes were similarly constructed. The same materials were used to make monopolar lesioning electrodes. Two related procedures were used in this experiment. First, the effect of striatopallidal lesions on motor nucleus excitability was tested. Subsequently, the origin of motor nucleus excitability changes were investigated. This second procedure was specifically designed to test if motoneural excitability changes caused by striatopallidal damage were due to direct effects upon the motor nucleus or influences upon sensory pathways which ultimately affect the motor nucleus. Procedure 1. Observations were made of the effects of striatopallidal lesions on the conduction of sensory information to a motor nucleus. In
536
SCHNEIDER,
DENARO,
AND
LIDSKY
nine animals, electrodes were implanted unilaterally in the trigeminal sensory ganglion (3 1) for stimulation, and ipsilaterally in the trigeminal motor nucleus or temporal muscle for recording. Lesioning electrodes were implanted bilaterally in the globus pallidus. Single-pulse electrical stimulation of the trigeminal ganglion (0.05- to 0.5-ms square wave pulses at 0.5 Hz) activates orofacial primary sensory afferent fibers. This stimulation also evokes a short-latency field potential in the trigeminal motor nucleus (whose elements control jaw movement) and jaw muscle activity (15). The thresholds of these potentials are a measure of the ease with which somatosensory information can reach the relevant motoneurons. During a 3- to 5-day period, 10 threshold measurements were taken. Striatopallidal lesions were then made and, for the next 3 to 5 days, thresholds were reassessed. Threshold was defined as that stimulation intensity at which a response was evoked in 50% of all trials. An example of threshold stimulation is shown in Fig. 2C. Procedure 2. Stimulating electrodes were implanted unilaterally in the trigeminal mesencephalic nucleus (MES 5) of nine rats. Electromyogram (EMG) recording electrodes, made of single-strand stainless-steel wire, were placed ipsilaterally in the jaw elevator muscles (temporalis or masseter). Electrical stimulation of MES 5 monosynaptically activates trigeminal alpha motoneurons which project to the jaw elevator muscle ( 15). The threshold of the EMG response (Fig. 2C,D) recorded after stimulation of MES 5 is a direct measure of motoneuronal excitability. Electrodes for making lesions were implanted bilaterally in the globus pallidus. As in procedure 1, threshold measurements were made before and after the lesions were made. After the excitability changes caused by lesions were documented, the perioral and facial tissues were locally anesthetized with Xylocaine. By eliminating orofacial afferent fibers, the role of disrupted sensory processing in lesion-induced motoneuronal excitability changes could be determined. Control Procedures. Interpretations of the effects of striatopallidal lesions are complicated because these structures are traversed by numerous fibers of passage. In addition, striatopallidal lesions frequently encroach upon the internal capsule (Fig. 1). Several control procedures were used to assess the contributions of damage to these fiber systems to the observed effects upon motoneuronal excitability. The major sources of these fibers are the thalamus and cortex. The thalamocortical output from nucleus ventralis posteromedialis (VPM) passes through the globus pallidus (22). The effects of VPM lesions on trigeminal excitability (assessed in procedure 1) was tested in two rats. In an additional four rats, the effects of larger thalamic lesions were also tested. Finally, the effects of lesions in portions of the frontal cortex (Fig. 3A) which are the sources of the majority of
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fibers of passage damaged by striatopallidal lesions (22) were also investigated. Histology. At the completion of testing, the animals were deeply anesthetized with barbiturate and perfused with Formalin-saline. Brains were removed and subsequently sectioned (40 pm) and stained with cresyl violet. RESULTS Histo1ogv. Striatopallidal lesions were pear shaped involving the globus pallidus (40 to 60%) ventrally and extending into the corpus striatum (Fig. 1). In four animals the damage in the globus pallidus was asymmetrical with the medial aspect damaged on one side and the lateral aspect damaged contralaterally (example in Fig. 1). Animals with asymmetrical lesions did not differ from those with symmetrical lesions with respect to threshold changes. The internal capsule was also damaged unilaterally in 7 of the 18 animals with striatopallidal damage. The former did not differ electrophysiologically from the latter. The VPM lesions destroyed the nucleus ventralis posteromedialis bilaterally and also encroached upon nucleus posterolateralis and centre medianum. The larger thalamic lesions caused bilateral damage in nucleus medialis, ventralis pars dorsomedialis, ventralis, posteromedianus, ventralis medialis pars magnocellularis, and parafascicularis [according to the terminology of K&rig and Klippel ( 16)]. Frontal cortex lesions destroyed the dorsal portion of the pole (Fig. 3A) and extended ventrally into the white matter (Fig. 3B). The anterior portion of the corpus callosum was unilaterally damaged in one rat (Fig. 3B). Procedure 1. The threshold of the trigeminal motor nucleus field potential evoked by stimulation of primary somatosensory afferent fibers was stable for each animal. Striatopallidal lesions caused a significant decrease in threshold (prelesion: mean threshold 45 +_ 35 PA; postlesion: mean threshold 20 + 20 PA; f&r = 4.46, df = 8, P < 0.01) (Fig. 2A). This increase in excitability was observed full blown immediately after dissipation of ether anesthesia. It remained unabated for at least 5 days. Striatopallidal lesions therefore facilitate conduction from the sensory to the motor components of the trigeminal system. There are at least two possible explanations for this effect. The basal ganglia could, during normal functioning, have a polysynaptic inhibitory influence upon trigeminal motoneurons. Striatopallidal lesions would then lead to disinhibition so that the now hyperexcitable motoneurons would be more easily affected by any afferent input. Alternatively, the lowered threshold of somatosensoryevoked motor potentials could be due to interference with an inhibitory influence upon either the sensory system itself or the association between
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FIG. 1. Histological reconstruction of a typical striatopallidal lesion. Successive sections are 300 pm apart. Plates are adapted from the atlas of Kanig and Klippel (16). Abbreviations: CP-caudatoputamen, GP-globus pallidus, IC-internal capsule.
the sensory pathway and the motor nucleus. In this case the disinhibition caused by brain lesions would lead to a more potent effect of stimulation of the sensory afferent fibers. To assess the relative validity of these explanations, a second experiment was performed. In this procedure, motor nucleus excitability changes caused by direct basal ganglionic influences were distinguished from excitability changes mediated by influences upon the sensory system. Procedure 2. The EMG response evoked by threshold MES 5 stimulation is illustrated in Fig. 2C. Striatopallidal lesions caused a significant decrease in threshold (prelesion: mean threshold 60 f 29 PA, postlesion: 32 f 31 PA; tdiff = 4.74, df = 8, P < 0.002 (Fig. 2B-D). Again, this increase in excitability could be due, most easily, to one of two mechanisms. First, basal ganglia damage could have eliminated a tonic inhibitory influence
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B
A
60
In PRE LESION
POST LESION
PRE LESION
POST LESION
FACE ANES.
h”--------
I-------I4
d
4
FIG. 2. Effects of striatopallidal lesions on trigeminal motor neuronal excitability. A-lesion effects on mean threshold for activating the trigeminal motor nucleus by stimulation of primary somatosensory afferents. B--e&&s of lesions and facial anesthetization on mean threshold for monosynaptic activation of the trigeminal motor nucleus by stimulation of 1A afferent fibers. C-masseter EMG responses evoked by threshold stimulation (24 PA) of IA afferent fibers in a normal rat. Each trace is a single trial. Note the absence of response on trials 3 and 4. D-EMG responses evoked in the same animal as in C after striatopallidal lesions. Stimulation is just suprathreshold at 7 pA. Arrows indicate time of 05ms stimulus pulse. Time calibration in D is 2 ms.
exerted directly on the motor nucleus. Alternatively, striatopallidal lesions could have facilitated the transmission of influences from ambient somatosensory stimuli to the motor nucleus thereby producing tonic excitation. If the latter mechanism was operative, however, then elimination of somatosensory influx should restore motor excitability to normal values. Therefore, to differentiate between the alternative explanations, a local anesthetic agent was injected subcutaneously into the faces of all rats with lesions. Removal of orofacial influences caused a significant elevation of threshold (postlesion: 32 + 31 PA; face anesthetized: 58 + 45 PA, tdir = 4.9, df = 8, P < 0.002) (Fig. 2B). Indeed, mean prelesion thresholds and postlesion postanesthetization thresholds did not significantly differ. Local anesthetization of the orofacial region in six intact control animals caused a slight (22%) but not significant (P > 0.10) elevation of response threshold. The effects of local anesthesia also rule out a third possible explanation for the heightened excitability of the motor nucleus after striatopallidal lesions. It is conceivable that the lowered threshold is due to increased fusimotor drive leading to tonic excitation via IA afferent fibers. If this were the case, however, elimination of cutaneous afferent input would not restore the threshold to normal. Taken together, these data
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FIG. 3. The effects of cortical lesions on trigeminal motor neuronal excitability. A-lateral and dorsal views of ablated region in one animal (CTX. 2). B-coronal sections through damaged region of CTX. 2 showing depth of damage. C-effects of cortical lesions in CTX. 2 (x) and another animal with similar damage (CTX. 1) (0) on motor neuronal excitability. For comparison, data from nine animals with striatopallidal lesions (SP) (0) are also plotted.
indicate that the changes in motoneural excitability that follow basal ganglia damage are due in large part to cutaneous somatosensory influences. Control Procedures. Neither VPM nor larger thalamic lesions caused effects similar to those of striatopallidal damage. Thalamus lesions caused slight increases in response threshold. Cortex ablation also produced effects which differed from those of striatopallidal lesions. The threshold decrease from striatopallidal damage lasted unchanged for at least 5 days. Indeed, in pilot studies, the effect was undiminished after 14 days. In contrast, cortical lesions caused a much smaller increase in excitability (10% for cortex lesions vs 47% for striatopallidal lesions) which lasted only 2 days. By the third day postlesion thresholds began to increase again and, by the fourth day, thresholds were double the prelesion baseline (Fig. 3C).
DISCUSSION The results described in this paper show that striatopallidal damage produces long-lasting changes in the excitability of trigeminal motoneurons. Inasmuch as these motor cells control the muscles of mastication, this alteration in excitability presumably underlies many of the feeding problems known to accompany basal ganglia lesions (22). Interestingly, the long duration of trigeminal hyperexcitability exceeds that of the aphagia and adipsia caused by striatopallidal lesions (22). Recent findings, however,
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show that despite the recovery of feeding and drinking after such brain damage, severe ingestional difficulties persist for many months (18, 22). The present findings show that the basal ganglia have the potential for affecting movement by gating sensory influences into neural systems which more directly control muscle contractions. Symptoms of basal ganglia pathology in humans are suggestive that the basal ganglia operate in this fashion. Patients with Parkinson’s disease, Wilson’s disease, and Huntington’s chorea fail to respond to vestibular and proprioceptive signals with appropriate postural reflexes. These problems do not stem from simple motor loss because movements similar to the postural reflexes can be made in other contexts (25). Tardive dyskinesia, a hyperkinetic syndrome attributed to sensitization of striatal dopamine receptors (33), is characterized by heightened motor reactivity to sensory stimulation. In dyskinetic adults light touch of perioral tissues evokes tongue movements similar to those which can be evoked by identical stimulation in neonates (34). In order to have a role in sensory gating, the basal ganglia must have access to sensory systems. Acute studies show that the basal ganglia have potent effects on visual, auditory, and somatosensory processing. Electrical stimulation of the basal ganglia modulates the visual system at both thalamic and also cortical levels (7, 14) and effects on the auditory system are exerted at the cortex ( 19). Influences on somatosensory processing are exerted on lemniscal and also extralemniscal components. Activation of the caudate nucleus or globus pallidus alters the sensory responsiveness of second-order neurons in the trigeminal main sensory nucleus. Similar effects were observed in reticular formation neurons that received orofacial input (17). Basal ganglia stimulation also affects somatosensory responses in the intralaminar thalamic nuclei (5). There is more direct evidence that the basal ganglia act to regulate the access of sensory influences to other brain regions. Anterior hypothalamic neurons receive convergent auditory, visual, and somatosensory inputs. Lesions in the basal ganglia result in a decrease of convergence and an overall decrease in sensory responsiveness of hypothalamic neurons (4). In the context of the suggestions made in the present paper regarding possible mechanisms of basal ganglia motor control, it is important to note the suggested role of the hypothalamus in visceromotor processes and oroingestive motor patterns (11, 30). The present findings do not suggest that the basal ganglia operate exclusively by routing sensory influences to motor regions. For example, Frigeysi presented strong evidence that basal ganglia output to nucleus ventralis anterior and nucleus ventrlis lateralis of the thalamus acts to gate information flow to motor cortex (8, 9). Recent work showed that this information is, for the most part, not sensory in nature (21, 29, 32). The
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role of the basal ganglia in sensory to motor integration described here would represent one aspect of a multifaceted involvement in motor control.
REFERENCES 1. ARBUTHNOIT, G. W., ANDU. UNGERSTEDT. 1975. Turning behavior induced by electrical and chemical stimulation of nigro-neostriatal system of the rat. Exp. Neural. 47: 162172. 2. ASANUMA, H. 1981. Functional role of sensory inputs to the motor cortex. Prog. Neurobiof. 16: 241-262. 3. BLAND, B. H., AND C. H. VANDERWOLF. 1972. Electrical stimulation of the hippocampal formation: behavioral and bioelectric effects. Brain Res. 43: 89-106. 4. DAFNY, N., AND S. FELDMAN. 1970. Unit responses and convergence of sensory stimuli in the hypothalamus. Exp. Neural. 17: 243-257. 5. DALSASS, M., AND G. M. KRAUTHAMER. 1981. Behavioral alterations and loss of caudate modulation in the centrum medianum complex of the cat following electrolytic lesions of the substantia nigra. Bruin Res. 20% 67-79. 6. FLYNN, J. P., S. B. EDWARDS, AND R. J. BANDLER, JR. 1971. Changes in sensory and motor system during centrally elicited attack. Behav. Sci. 16: l-19. 7. FOSSEL, M., M. PRITO, M. C. LASSONDE, AND K. H. PRIBRAM. 1975. Modification of single unit responses in the cat’s visual cortex by electrical stimulation of the basal ganglia. Neurosci. Sot. Abstr. 1: 191. 8. FRIGYESI, T. L. 1971. Organization of synaptic pathways linking the head of the caudate nucleus to the dorsal thalamus. Inf. J. Neural. 8: 11 I-138. 9. FRIGYESI, T. L. 1975. Structure-function relationships of the interconnections between the caudate nucleus, globus pallidus, substantia nigra and thalamus. Pages 13-46 in T. L. FRIGYESI, Ed., Subcortical Mechanisms and Sensorimotor Activities. Huber, Bern. 10. GARY-B• BO, E., AND M. BONVALLET. 1975. Amygdala and masseteric reflex. I. Facilitation, inhibition and diphasic modifications of the reflex induced by localized amygdaloid stimulation. Electroencephalogr. Clin. Neurophysiol. 39: 329-339. 11. GLICKMAN, S. E., AND B. B. SCHIFF. 1967. A biological theory of reinforcement. Psychol. Rev. 74: 81-109. 12. GODDARD, G. V. 1964. Amygdaloid stimulation and learning in the rat. J. Comp. Physiof. Psychol. 5s: 23-30. 13. GOLDSTEIN, J. M., AND J. SIEGEL. 1981. Stimulation of ventral tegmental area and nucleus accumbens reduce receptive fields for hypothalamic biting reflex in cats. Exp. Neural. 72: 239-246. 14. KADOBAYASHI, I. 1972. Effects of caudate stimulation on unitary responses of the lateral geniculate body to light. Exp. Neural. 37: 462-468. 15. KIDOKORO, Y., K. KUBOTA, S. SHUTO, AND R. SUMINO. 1968. Reflex organization of cat masticatory muscles. J. Neurophysiol. 31: 695-708. 16. KOENIG, J. F. R., AND R. A. KLIPPEL. 1967. The Rat Brain. A Stereotaxic Atlas of the Forebrain and Lower Parts of the Brain Stem. Kreiger, New York. 17. LABUSZEWSKI, T., AND T. I. LIDSKY. 1979. Basal ganglia influences on brain stem trigeminal neurons. Exp. Neural. 65: 471-477. 18. LABUSZEWSKI, T., R. LOCKWOOD, F. E. MCMANUS, L. R. EDELSTEIN, ANDT. I. LIDSKY. 1981. Role of postural deficits in oro-ingestive problems caused by globus pallidus lesions. Exp. Neural. 74: 93- 1 IO.
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19. LAGRUTTA, V., G. AMATO, AND L. MILITELLO. 1970. The responsiveness of acoustic area after stimulation of the caudate nucleus. Experienriu 26: 259-260. 20. LAURSEN, A. M. 1963. Corpus striatum. Acra Physiof. &and. (Suppl.) 59: 211. 21. LEMON, R. N., AND J. VAN DER BERG. 1979. Short-latency peripheral inputs to thalamic neurons projecting to motor cortex in the monkey. Exp. Brain Res. 36: 445-462. 22. LEVINE, M. S., N. FERGUSON,C. J. KREINICK, J. W. GUSTAFSON, ANDJ. S. SCHWARTZBAUM. 1971. Sensorimotor dysfunctions and aphagia and adipsia following pallidal lesions in rats. J. Camp. Physiol. Psychol. 77: 282-293. 23. LIDSKY, T. I., J. S. SCHNEIDER, AND J. A. HARPER. 1980. Jaw movements evoked by substantia nigra stimulation: role of extranigral current spread. Brain Res. Bull. 5: 487-489. 24. MAGOUN, H. W., S. W. RANSON, AND C. FISHER. 1933. Corticofugal pathways for mastication, lapping and other motor functions in the cat. Arch. Neural. Psychiotr. 30: 292-308. 25. MARTIN, J. P. 1967. The Basal Ganglia and Posture. Lippincott, Philadelphia. 26. MILES, P. R., AND W. E. GLADFELTER. 1969. Lateral hypothalamus and reflex discharges over ventral roots of rat spinal nerves. Physiol. Behav. 4: 671-675. 27. NAUTA, W. J. H., AND W. R. MEHLER. 1966. Projections of the lentiform nucleus in the monkey. Brain Res. 1: 3-42. 28. NEWTON, R. A., AND D. D. PRICE. 1975. Modulation of cortical and pyramidal tractinduced motor responses by electrical stimulation of the basal ganglia. Brain Res. 85: 403-422. 29. NYQUIST, J. K. 1975. Somatosensory properties of neurons of thalamic nucleus ventralis lateralis. Exp. Neural. 48: 123-135. 30. ROBERTS, W. W. 1969. Are hypothalamic motivational mechanisms functionally and anatomically specific? Bruin Behov. Evol. 2: 317-342. 31. SCHNEIDER, J. S., F. J. DENARO, U. E. OLAZABAL, AND H. 0. LEARD. 1981. Stereotaxic atlas of the trigeminal ganglion in rat, cat, and monkey. Brain Res, Bull. 7: 93-95. 32. STRICK, P. L. 1976. Activity of ventrolateral thalamic neurons during arm movement. J. Neurophysiol. 39: 1032- 1044. 33. TARSY, D., AND R. J. BALDESSARINI. 1976. The tardive dyskinesia syndrome. Pages 2961 in H. L. KLAWANS, Ed., Clinical Neuropharmacology, Vol. 1. Raven Press, New York. 34. THACH, B. T., AND J. M. WEIFFENBACH. 1973. The influence of controlled oral stimulation on tongue movements in patients with oral facial dyskinesia: elicitation of lateral tongue movements. Pages 370-383 in J. F. BOSMA, Ed., Fourth Symposium of Oral Sensation and Perception. U.S. Govt. Printing Office, Washington, D.C. 35. VALENSTEIN, E. S., V. C. Cox, AND J. W. KAKOLEWSKI. 1968. The motivation underlying eating elicited by lateral hypothalamic stimulation. Physiol. Behav. 3: 969-97 1. 36. VANEGAS, H., AND J. P. FLYNN. 1968. Inhibition of cortically elicited movement by electrical stimulation of the hippocampus. Bruin Res. 11: 489-506.
NEUROLOGY
77, 534-543 (1982)
Basal Ganglia: Motor Influences Mediated Sensory Interactions J. S. SCHNEIDER,
F. J. DENARO,
by
AND T. I. LIDSKY’
Department of Psychology, State University of New York, Stony Brook, New York 11794 Received October 12. 1981; revision received March 17, 1982 Striatopallidal lesions in rats cause an increase in trigeminal motor nucleus excitability. This hyperexcitability is not due to disruption of basal ganglia-mediated inhibition of the motor nucleus. Rather, basal ganglia lesions disrupt an inhibitory influence upon either the sensory pathway or the link-up between the sensory pathway and the motor nucleus. These data suggest that one way in which the basal ganglia influence movement is by gating sensory influences into motor areas.
INTRODUCTION Although the motor functions of the basal ganglia have been extensively investigated, the mechanisms by which this neural system actually influences movements are not known. In contrast to other neural networks with motor functions (e.g., the pyramidal system) the basal ganglia possess no descending fibers with relatively direct excitatory influences upon bulbar or spinal motor nuclei (27). Low-intensity electrical stimulation of a variety of motor structures evokes contraction of either single muscles or small groups of muscles at short fixed latencies (2). In contrast, low-level stimulation of the basal ganglia produces no motor activity (20, 23, 24). With much more intense stimulation, basal ganglia activation modulates movement evoked by stimulation delivered to other motor areas (e.g., motor cortex) (28). In addition, high-intensity basal ganglia stimulation affects Abbreviations: EMG-electromyogram, MES 5--trigeminal mesencephalic nucleus, VPMnucleus ventralis posteromedialis. I We thank J. R. Morse and N. K. Squires for critical comments. This work was supported by National Institutes of Health grants NS 15328 and NS 16054. Dr. Schneider’s present address is the Department of Psychiatry, Mental Retardation Research Center, UCLA, Los Angeles, CA 90024. Please send correspondence and reprint requests to Dr. Lidsky. 534 0014-4886/82/090534-10$02.00/O Copyright 0 1982 by Academic Prom, Inc. All rights of reproduction in any form rexmcd.
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locomotion responses (1). With respect to these final two results, however, basal ganglia stimulation produces effects which are similar to those produced by structures not traditionally thought to have primary motor functions [e.g., amygdala (10, 12), hippocampus (3, 36), and lateral hypothalamus (26, 35)]. There are mechanisms for affecting movement other than via direct influences upon motoneurons. Studies of feline predation stress the role of sensory inputs in motor control. Electrical activation of hypothalamic sites which elicits predation sensitizes the perioral area so that touch around the lips causes the animal first to turn its head toward the stimulus and then to open its mouth. Such somatosensory-evoked movements are observed only during predation-evoking brain stimulation (6). Consideration of these data and more recent findings concerning the role of nucleus accumbens and the ventral tegmental area in attack led Goldstein and Siegel to “suggest that other stimulus and goal directed behaviors (e.g., feeding, mating) may also be understood in terms of response components made operative by the emergence of receptive fields. . . .” ( 13). Thus, modulation of either sensory processing or the ease with which sensory inputs gain access to motor regions can be an effective means of influencing movement. The experiments described in the present paper were designed to assess the role of the basal ganglia in such processes. METHODS Lashley rats (225 to 490 g at surgery) were used in all experiments. All procedures were chronic. Electrodes for stimulating and producing lesions were stereotaxically implanted prior to behavioral testing. When lesions were subsequently made (see below), the animals were lightly anesthetized with ether for a short period (approximately 5 min). For electrical stimulation, side-by-side bipolar electrodes were constructed from 000 stainlesssteel insect pins insulated except for 0.5 mm at the tip. Recording electrodes were similarly constructed. The same materials were used to make monopolar lesioning electrodes. Two related procedures were used in this experiment. First, the effect of striatopallidal lesions on motor nucleus excitability was tested. Subsequently, the origin of motor nucleus excitability changes were investigated. This second procedure was specifically designed to test if motoneural excitability changes caused by striatopallidal damage were due to direct effects upon the motor nucleus or influences upon sensory pathways which ultimately affect the motor nucleus. Procedure 1. Observations were made of the effects of striatopallidal lesions on the conduction of sensory information to a motor nucleus. In
536
SCHNEIDER,
DENARO,
AND
LIDSKY
nine animals, electrodes were implanted unilaterally in the trigeminal sensory ganglion (3 1) for stimulation, and ipsilaterally in the trigeminal motor nucleus or temporal muscle for recording. Lesioning electrodes were implanted bilaterally in the globus pallidus. Single-pulse electrical stimulation of the trigeminal ganglion (0.05- to 0.5-ms square wave pulses at 0.5 Hz) activates orofacial primary sensory afferent fibers. This stimulation also evokes a short-latency field potential in the trigeminal motor nucleus (whose elements control jaw movement) and jaw muscle activity (15). The thresholds of these potentials are a measure of the ease with which somatosensory information can reach the relevant motoneurons. During a 3- to 5-day period, 10 threshold measurements were taken. Striatopallidal lesions were then made and, for the next 3 to 5 days, thresholds were reassessed. Threshold was defined as that stimulation intensity at which a response was evoked in 50% of all trials. An example of threshold stimulation is shown in Fig. 2C. Procedure 2. Stimulating electrodes were implanted unilaterally in the trigeminal mesencephalic nucleus (MES 5) of nine rats. Electromyogram (EMG) recording electrodes, made of single-strand stainless-steel wire, were placed ipsilaterally in the jaw elevator muscles (temporalis or masseter). Electrical stimulation of MES 5 monosynaptically activates trigeminal alpha motoneurons which project to the jaw elevator muscle ( 15). The threshold of the EMG response (Fig. 2C,D) recorded after stimulation of MES 5 is a direct measure of motoneuronal excitability. Electrodes for making lesions were implanted bilaterally in the globus pallidus. As in procedure 1, threshold measurements were made before and after the lesions were made. After the excitability changes caused by lesions were documented, the perioral and facial tissues were locally anesthetized with Xylocaine. By eliminating orofacial afferent fibers, the role of disrupted sensory processing in lesion-induced motoneuronal excitability changes could be determined. Control Procedures. Interpretations of the effects of striatopallidal lesions are complicated because these structures are traversed by numerous fibers of passage. In addition, striatopallidal lesions frequently encroach upon the internal capsule (Fig. 1). Several control procedures were used to assess the contributions of damage to these fiber systems to the observed effects upon motoneuronal excitability. The major sources of these fibers are the thalamus and cortex. The thalamocortical output from nucleus ventralis posteromedialis (VPM) passes through the globus pallidus (22). The effects of VPM lesions on trigeminal excitability (assessed in procedure 1) was tested in two rats. In an additional four rats, the effects of larger thalamic lesions were also tested. Finally, the effects of lesions in portions of the frontal cortex (Fig. 3A) which are the sources of the majority of
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fibers of passage damaged by striatopallidal lesions (22) were also investigated. Histology. At the completion of testing, the animals were deeply anesthetized with barbiturate and perfused with Formalin-saline. Brains were removed and subsequently sectioned (40 pm) and stained with cresyl violet. RESULTS Histo1ogv. Striatopallidal lesions were pear shaped involving the globus pallidus (40 to 60%) ventrally and extending into the corpus striatum (Fig. 1). In four animals the damage in the globus pallidus was asymmetrical with the medial aspect damaged on one side and the lateral aspect damaged contralaterally (example in Fig. 1). Animals with asymmetrical lesions did not differ from those with symmetrical lesions with respect to threshold changes. The internal capsule was also damaged unilaterally in 7 of the 18 animals with striatopallidal damage. The former did not differ electrophysiologically from the latter. The VPM lesions destroyed the nucleus ventralis posteromedialis bilaterally and also encroached upon nucleus posterolateralis and centre medianum. The larger thalamic lesions caused bilateral damage in nucleus medialis, ventralis pars dorsomedialis, ventralis, posteromedianus, ventralis medialis pars magnocellularis, and parafascicularis [according to the terminology of K&rig and Klippel ( 16)]. Frontal cortex lesions destroyed the dorsal portion of the pole (Fig. 3A) and extended ventrally into the white matter (Fig. 3B). The anterior portion of the corpus callosum was unilaterally damaged in one rat (Fig. 3B). Procedure 1. The threshold of the trigeminal motor nucleus field potential evoked by stimulation of primary somatosensory afferent fibers was stable for each animal. Striatopallidal lesions caused a significant decrease in threshold (prelesion: mean threshold 45 +_ 35 PA; postlesion: mean threshold 20 + 20 PA; f&r = 4.46, df = 8, P < 0.01) (Fig. 2A). This increase in excitability was observed full blown immediately after dissipation of ether anesthesia. It remained unabated for at least 5 days. Striatopallidal lesions therefore facilitate conduction from the sensory to the motor components of the trigeminal system. There are at least two possible explanations for this effect. The basal ganglia could, during normal functioning, have a polysynaptic inhibitory influence upon trigeminal motoneurons. Striatopallidal lesions would then lead to disinhibition so that the now hyperexcitable motoneurons would be more easily affected by any afferent input. Alternatively, the lowered threshold of somatosensoryevoked motor potentials could be due to interference with an inhibitory influence upon either the sensory system itself or the association between
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FIG. 1. Histological reconstruction of a typical striatopallidal lesion. Successive sections are 300 pm apart. Plates are adapted from the atlas of Kanig and Klippel (16). Abbreviations: CP-caudatoputamen, GP-globus pallidus, IC-internal capsule.
the sensory pathway and the motor nucleus. In this case the disinhibition caused by brain lesions would lead to a more potent effect of stimulation of the sensory afferent fibers. To assess the relative validity of these explanations, a second experiment was performed. In this procedure, motor nucleus excitability changes caused by direct basal ganglionic influences were distinguished from excitability changes mediated by influences upon the sensory system. Procedure 2. The EMG response evoked by threshold MES 5 stimulation is illustrated in Fig. 2C. Striatopallidal lesions caused a significant decrease in threshold (prelesion: mean threshold 60 f 29 PA, postlesion: 32 f 31 PA; tdiff = 4.74, df = 8, P < 0.002 (Fig. 2B-D). Again, this increase in excitability could be due, most easily, to one of two mechanisms. First, basal ganglia damage could have eliminated a tonic inhibitory influence
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B
A
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In PRE LESION
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FACE ANES.
h”--------
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FIG. 2. Effects of striatopallidal lesions on trigeminal motor neuronal excitability. A-lesion effects on mean threshold for activating the trigeminal motor nucleus by stimulation of primary somatosensory afferents. B--e&&s of lesions and facial anesthetization on mean threshold for monosynaptic activation of the trigeminal motor nucleus by stimulation of 1A afferent fibers. C-masseter EMG responses evoked by threshold stimulation (24 PA) of IA afferent fibers in a normal rat. Each trace is a single trial. Note the absence of response on trials 3 and 4. D-EMG responses evoked in the same animal as in C after striatopallidal lesions. Stimulation is just suprathreshold at 7 pA. Arrows indicate time of 05ms stimulus pulse. Time calibration in D is 2 ms.
exerted directly on the motor nucleus. Alternatively, striatopallidal lesions could have facilitated the transmission of influences from ambient somatosensory stimuli to the motor nucleus thereby producing tonic excitation. If the latter mechanism was operative, however, then elimination of somatosensory influx should restore motor excitability to normal values. Therefore, to differentiate between the alternative explanations, a local anesthetic agent was injected subcutaneously into the faces of all rats with lesions. Removal of orofacial influences caused a significant elevation of threshold (postlesion: 32 + 31 PA; face anesthetized: 58 + 45 PA, tdir = 4.9, df = 8, P < 0.002) (Fig. 2B). Indeed, mean prelesion thresholds and postlesion postanesthetization thresholds did not significantly differ. Local anesthetization of the orofacial region in six intact control animals caused a slight (22%) but not significant (P > 0.10) elevation of response threshold. The effects of local anesthesia also rule out a third possible explanation for the heightened excitability of the motor nucleus after striatopallidal lesions. It is conceivable that the lowered threshold is due to increased fusimotor drive leading to tonic excitation via IA afferent fibers. If this were the case, however, elimination of cutaneous afferent input would not restore the threshold to normal. Taken together, these data
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FIG. 3. The effects of cortical lesions on trigeminal motor neuronal excitability. A-lateral and dorsal views of ablated region in one animal (CTX. 2). B-coronal sections through damaged region of CTX. 2 showing depth of damage. C-effects of cortical lesions in CTX. 2 (x) and another animal with similar damage (CTX. 1) (0) on motor neuronal excitability. For comparison, data from nine animals with striatopallidal lesions (SP) (0) are also plotted.
indicate that the changes in motoneural excitability that follow basal ganglia damage are due in large part to cutaneous somatosensory influences. Control Procedures. Neither VPM nor larger thalamic lesions caused effects similar to those of striatopallidal damage. Thalamus lesions caused slight increases in response threshold. Cortex ablation also produced effects which differed from those of striatopallidal lesions. The threshold decrease from striatopallidal damage lasted unchanged for at least 5 days. Indeed, in pilot studies, the effect was undiminished after 14 days. In contrast, cortical lesions caused a much smaller increase in excitability (10% for cortex lesions vs 47% for striatopallidal lesions) which lasted only 2 days. By the third day postlesion thresholds began to increase again and, by the fourth day, thresholds were double the prelesion baseline (Fig. 3C).
DISCUSSION The results described in this paper show that striatopallidal damage produces long-lasting changes in the excitability of trigeminal motoneurons. Inasmuch as these motor cells control the muscles of mastication, this alteration in excitability presumably underlies many of the feeding problems known to accompany basal ganglia lesions (22). Interestingly, the long duration of trigeminal hyperexcitability exceeds that of the aphagia and adipsia caused by striatopallidal lesions (22). Recent findings, however,
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show that despite the recovery of feeding and drinking after such brain damage, severe ingestional difficulties persist for many months (18, 22). The present findings show that the basal ganglia have the potential for affecting movement by gating sensory influences into neural systems which more directly control muscle contractions. Symptoms of basal ganglia pathology in humans are suggestive that the basal ganglia operate in this fashion. Patients with Parkinson’s disease, Wilson’s disease, and Huntington’s chorea fail to respond to vestibular and proprioceptive signals with appropriate postural reflexes. These problems do not stem from simple motor loss because movements similar to the postural reflexes can be made in other contexts (25). Tardive dyskinesia, a hyperkinetic syndrome attributed to sensitization of striatal dopamine receptors (33), is characterized by heightened motor reactivity to sensory stimulation. In dyskinetic adults light touch of perioral tissues evokes tongue movements similar to those which can be evoked by identical stimulation in neonates (34). In order to have a role in sensory gating, the basal ganglia must have access to sensory systems. Acute studies show that the basal ganglia have potent effects on visual, auditory, and somatosensory processing. Electrical stimulation of the basal ganglia modulates the visual system at both thalamic and also cortical levels (7, 14) and effects on the auditory system are exerted at the cortex ( 19). Influences on somatosensory processing are exerted on lemniscal and also extralemniscal components. Activation of the caudate nucleus or globus pallidus alters the sensory responsiveness of second-order neurons in the trigeminal main sensory nucleus. Similar effects were observed in reticular formation neurons that received orofacial input (17). Basal ganglia stimulation also affects somatosensory responses in the intralaminar thalamic nuclei (5). There is more direct evidence that the basal ganglia act to regulate the access of sensory influences to other brain regions. Anterior hypothalamic neurons receive convergent auditory, visual, and somatosensory inputs. Lesions in the basal ganglia result in a decrease of convergence and an overall decrease in sensory responsiveness of hypothalamic neurons (4). In the context of the suggestions made in the present paper regarding possible mechanisms of basal ganglia motor control, it is important to note the suggested role of the hypothalamus in visceromotor processes and oroingestive motor patterns (11, 30). The present findings do not suggest that the basal ganglia operate exclusively by routing sensory influences to motor regions. For example, Frigeysi presented strong evidence that basal ganglia output to nucleus ventralis anterior and nucleus ventrlis lateralis of the thalamus acts to gate information flow to motor cortex (8, 9). Recent work showed that this information is, for the most part, not sensory in nature (21, 29, 32). The
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role of the basal ganglia in sensory to motor integration described here would represent one aspect of a multifaceted involvement in motor control.
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