Journal of Clinical Nearophysolory TNgis20 41 Raven Press, Ld New York (© 998 Amendan Eleceoencephilopaphe Society Basal Ganglia-Thalamocortical Circuits: Their Role in Control of Movements Garrett E. Alexander Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, U.S.A. ‘Summary: The motor circuitry of the basal ganglia is organized in parallel with basal ganglia circuits involved in oculomotor, associative, and limbic functions. ‘These circuits comprise reentrant pathways that originate in various neocortical domains and pass through the basal ganglia before returning, by way of the thala- ‘mus, to select portions of the frontal lobe, Recent progress in characterizing the anatomy and physiology of these pathways has provided new insights into the pathophysiology of basal ganglia-rclated movement disorders and enhanced ‘our understanding of the normal role of the basal ganglia in movement control and adaptive motor behavior. Key Words: Basal ganglia—Thalamus—Motor behavior FUNCTIONAL ORGANIZATION OF BASAL GANGLIA The basal ganglia comprise the striatum (including, the neostriatum, composed of the putamen and cau- date nucleus, and the ventral striatum), the globus pallidus, the substantia nigra, and the subthalamic nucleus, all of which are functionally subdivided into skeletomotor, oculomotor, associative, and limbic territories based on their physiological properties and on their interconnections with cortical and thalamic territories of the same functionalities (Alexander et al., 1990). As indicated in Fig. 1, the large-scale orga- nization of the basal ganglia can be viewed asa family of reentrant loops that are organized in parallel, each taking its origin from a particular set of functionally related cortical fields (skeletomotor, oculomotor, etc.), passing through the functionally corresponding portions of the basal ganglia, and returning to parts of those same cortical fields by way of specific basal ganglia-recipient zones in the dorsal thalamus. Due to maintained segregation along each of these ‘Address corespondence and reprint requests to Dr. GE. Alex. ander at Department of Neurology, Emory University School of Medicine, WMB-6000, 1639 Pieree Dr, P.O. Drawer V, Atlanta, GA 30323, USA. 420 cortico-basal ganglia-thalamocortical circuits, there is little direct communication among the separate functional domains. While virtually the entire cortical mantle is mapped topographically onto the striatum, often considered the “input” portion of the basal gan- alia, the cortically directed signals from the basal gan- glia output nuclei (internal pallidum and substantia a pars reticulata) are returned exclusively to foci within the frontal lobe (after first passing through the corresponding portions of the thalamus.) Because of their parallel organization, it is generally suspected that the operations performed at corresponding sta- tions along each of these loops are quite similar. In this review, the focus will be on the organization and physiology of the skeletomotor loop. MOTOR CIRCUITRY OF BASAL GANGLIA ‘The skeletomotor circuitry of the basal ganglia in- cludes several noteworthy features, some of which may be important in shaping the specific contribu- tions that these structures make to the control of movement. The broad outlines of basal ganglia motor circuitry are depicted in Fig. 2. Like the cerebellum, the basal ganglia receive topo-FIG. 1. Parallel, functionally scaresated, basal ‘ganglis-thalamocortical loops Information Nov is irom narrow to wide end ofeach pathway graphic inputs from most of the sensorimotor territo- ries of the cerebral cortex, including primary and sec ondary somatosensory areas, primary motor cortex, and a variety of premotor areas including the supple- mentary motor area, the dorsal and ventral premotor areas, and the cingulate motor areas (Kiinzle, 1975, 1977, 1978; Selemon and Goldman-Rakic, 1985; Ca- vada and Goldman-Rakic, 1991; Dum and Strick, 1991; Flaherty and Graybiel, 1991, 19936; Hoover and Strick, 1993; Yeterian and Pandya, 1993). Di- rected toward the sensorimotor portion of the neostri- atum, these coordinated corticostriatal inputs impose a well defined somatotopic organization upon their target nucleus, which, in primates, coincides roughly with the putamen (Crutcher and DeLong, 1984a; Al- exander and DeLong, 1985a: Crutcher and Alexan- der, 1990). In addition to their respective corticostria- tal neurons, most of the putamen-projecting sensori- motor areas also contain separate populations of neurons that project directly to the spinal cord (Hum- ‘melsheim et al., 1986; Hutchins et al., 1988; Dum and Strick, 1991). Some evidence suggests that the cortical message conveyed to the striatum may differ from that projected directly to the spinal cord (Bauswein et al., 1989). If'so, the prevailing view that the basal gan- lia receive cortical signals that are faithful replicas of corticospinal commands, i.e., simple corollary dis- charges, may need to be revised. The majority of the putamen-projecting sensorimo- tor areas also send topographic projections to the sub- thalamic nucleus (Hartmann-von Monakow et al GLIA-THALAMOCORTICAL CIRCUITS IN MOVE: 1978). Both the corticostriatal and the corticosubtha- lamic projections are excitatory and probably gluta- matergic (Wilson, 1986; Cherubini et al., 1988; Na- kanishi et al., 1988; Kawaguchi et al., 1989) [as are most of the corticospinal projections (Valtschanoff et al, 1993)], but the conduction velocities of these two pathways may differ significantly. Direct comparisons in the rat suggest that the corticostriatal projection ‘may be substantially slower than the corticosubtha- lamic (Kitai and Deniau, 1981), which could have a significant influence on the way information is pro- cessed within the basal ganglia. Thus far, direct com- parisons of these two pathways have not been made in the monkey, but it does seem clear from primate stud- ies that conduction along the corticostriatal pathway is substantially slower than conduction along the pathways leading from cortex to brainstem and spinal levels (Bauswein et al., 1989) Nevertheless, there are significant species differ- ences in basal ganglia connectivity, so extrapolations must be made with caution. In rats, for example, the ‘earliest cortically induced EPSPS in striatum appear to come from axon collaterals of large-diameter, brainstem-projecting fibers (Donoghue and Kitai, 1981), but in primates this collateral projection seems to be lacking, with the massive corticostriatal pro- jection arising almost exclusively from a separate pop- ulation of small-axoned, direct-projecting corticostri- atal neurons (Jones et al., 1977). In the putamen, as in the rest of the striatum, the large majority of neurons (>75% in primates, up to J.Clin Neurophysiol, Vol 1, No.4, 1998422 G, E, ALEXANDER 95% in rodents) are of the medium spiny type (MSN) (Wilson and Groves, 1980). MSNs are y-aminobut- yrate-(GABA)-ergic projection neurons (Kita and Ki- tai, 1988), and in primates they comprise two distinet populations, one projecting to the external segment of the globus pallidus (GPe) and the other projecting cither to the internal segment of the globus pallidus (GPi) or to the substantia nigra pars reticulata (SNr) (Selemon and Goldman-Rakic, 1990; Flaherty and Graybiel, 1993a), At rest, putamen projection neu- rons are nearly silent (Alexander and DeLong, 19855; Kimura ct al., 1990), but most have well defined sen~ sorimotor fields and discharge selectively in relation to specific parameters of movement or specific aspects of the preparation for movement (Liles, 1985; Alex- ander and Crutcher, 1990a,b; Crutcher and Alexan- der, 1990; Kimura et al., 1992). ‘The other type of putamen neuron that has been well studied is the large, aspiny interneuron (Wilson et al., 1990; Kawaguchi, 1992). Converging evidence from anatomical studies as well as from extracellular and intracellular recording studies indicates that these neurons have the following properties. Unlike MSNs, the large interneurons are spontaneously active (with discharge rates of 3~7 Hz), and they do not discharge in relation to specific parameters of movement prepa- ration or execution. Rather, they discharge briefly (only one or two spikes) and synchronously following the presentation of a conditioned sensory stimulus 1.Clin, Neurophysiol, Vol 1, No.4, 1994 FIG. 2. Basal ganglia skeletomotor circ ‘Major motor pathways involving the basal sla, Excitatory pathways are indicated by light Shading. inhibitory by dark shading. Pathway Srigins and terminations are indicated by nar- ow and wide ends, respectively. Connections tetween thalamus and cortex are reciprocal [Not shown are connections to and from SNr, ‘which parallel those of GPi. GPe, extemal es. tent of globus pallidus; GPi, internal segment fof globus pallidus, NRT, reticular nucleus ofthe thalamus. PPN, pedunculopontine nucleus: ‘SNe, substantia nigra pars compacta; STN, sub- thalamic nucleus; V-thalamus, basal ganeli e- ‘Gpient zone in ventrolateral thalamus. To sim- Diy the illustration, the thalamostriate proj- ction from the centromedian nucleus is shown arising from VLthalamus. ‘that signifies the imminent delivery of a reward (Ki- mura, 1986). These spontancously active interneu- rons appear to be cholinergic (Bolam et al., 1984), but their synaptic influence on neighboring MSN has not een directly determined. Electron microscopic stud- jes have shown that cholinergic synapses on the So- mata and dendritic shafts and spines of MSNs are of the symmetrical type (Phelpset al., 1985), which sug gests that the aspiny interneurons may have an inhib- itory effect on MSNs. “Those portions of GPi and SNr that receive input from the putamen constitute the sensorimotor output nuclei of the basal ganglia, sending GABAergic pro- jections to their respective targets in both the ventro- Jateral thalamus (n, ventralis lateralis and n. ventralis anterior) and the centromedian nucleus of the thala~ ‘mus (Carpenter et al,, 1976; Kim et al., 1976; Ueki et al., 1977; Uno et al., 1978; Penney and Young, 1981; De Vito and Anderson, 1982; Yamamoto et al., 1985). Anatomically GPi and SNr share many com- ‘mon features, and from a functional standpoint they ‘can be viewed as two subdivisions of a single basal ganglia output nucleus (Nauta, 1979; Parent, 1986). In GPi/SNr, large projection neurons are by far the ‘most abundant cell type, but a minute population of ‘small cells that may represent interneurons has also been described (Fox and Rafols, 1976; Difiglia and Rafols, 1988). Neurons in the sensorimotor territories of GPi/SNr have movement-related receptive fieldsBASAL GANGLIA-THALAMOCORTICAL CIRCUITS IN MOVEMENT 423 FIG.3, Direct and indirect pathways through basal ganglia. Conventions same asin Fig. 2. that are similar to those of the putamen’s MSNs, but GPi/SNr neurons differ from MSNs in having rela- tively high spontaneous discharge rates (60-80 Hz) that are modulated both upward and downward de- pending on their particular sensorimotor response fields (DeLong et al., 1983; Mitchell et al., 1987; Ha- mada et al., 1990), Neurons in the sensorimotor terri- tory of GPe have discharge properties and sensorimo- tor fields that are comparable with those in GPi/SNr (Mitchell et al., 1987). The basal ganglia output nuclei (GPi/SNr) receive not only direct inputs from the striatum via the GPi- and SNr-projecting MSN, but also an important con- verging source of information via what has come to be termed the “indirect” pathway through the basal ganglia (Alexander and Crutcher, 1990c). The direct and indirect pathways are illustrated in Fig. 3. The in- direct pathway takes its origin from the GPe-project- ing MSNs. In turn, the GABAergic neurons of GPe project mainly to the subthalamic nucleus (Carpenter and Jayaraman, 1990), whose excitatory, gluta- matergic neurons send feed-forward connections to GPi/SNr, completing one arm of the indirect pathway (Kita and Kitai, 1987; Smith and Parent, 1988; Ro- bledo and Feger, 1990). Subthalamic neurons also send glutamatergic feedback connections to GPe and to the putamen (Nakano et al., 1990; Parent, 1990; Robledo and Feger, 1990). Recently a second arm of the indirect pathway has been revealed: GPe projects not only to the subtha- lamic nucleus, but also to the output nuclei, GPi/SNr (Hazrati et al., 1990; Bolam and Smith, 1992). A re- markable consequence of this is that activation of MSN associated with either arm of the indirect path- way should increase basal ganglia output by increas- ing neuronal activity at the level of GPi/SNr: in one case, by disinhibiting the subthalamic nucleus with its excitatory projections to GPi/SNr: in the other, by di- rectly disinhibiting GPi/SNr. In contrast, activation ‘of MSNs associated with the direct pathway should decrease basal ganglia output by directly suppressing activity at the level of GPi/SNr. It has long been recognized that the large-scale or- ganization of the basal ganglia constitutes a reentrant system, with cortical influences passing through the basal ganglia and being returned to cortical levels through specific portions of the thalamus (DeLong, and Georgopoulos, 1981). Of some interest recently has been the question of how the direct and indirect pathways may differentially influence thalamocorti- cal operations. Current evidence indicates that these ‘two pathways have opposing effects on the output nu- clei. Activation of the direct pathway should result in a corresponding suppression of GABAergic GPi/SNr output, thereby disinhibiting the basal ganglia-receiv- ing portions of the thalamus, while activation of either arm of the indirect pathway should lead to an en- hancement of GPi/SNr-mediated thalamic inhibition J.Clin Neurophysiol. Vol. 1. No.4, 1904424 G. E. ALEXANDER (Alexander and Crutcher, 1990¢). Given the reentrant nature of basal ganglia-thalamocortical connections, cortically initiated activation of the direct pathway might therefore be expected to result in positive feed~ back at cortical levels, with corresponding activation of the indirect pathway giving rise, conversely, to neg- ative feedback. A detailed understanding of how the basal ganglia’s motor circuitry operates is complicated by a variety of pathways that feed backward or forward across multiple nuclei. Two of the feedback pathways in- clude excitatory projections returned to the putamen: Already mentioned was the projection from the sub- thalamic nucleus (Parent, 1990); also noteworthy are the thalamostriatal projections that originate in the centromedian nucleus (Parent, 1983; Francois et al., 1991), Both of these pathways appear to provide pos- itive feedback to the putamen. GPe sends an inhibitory, feed-forward projection to the nucleus reticularis of the thalamus (NRT) (Haz- rati and Parent, 19915), which in turn imposes a ro- bust, GABAergic modulation upon the basal ganglia recipient nuclei of the ventrolateral thalamus (as well as upon other thalamic nuclei) (Jones, 1985). There appears to be a functional consistency among the var- ious GPe projections, in that cortically induced acti- vations of GPe-projecting MSNs should have the net effect of producing negative feedback at cortical lev- els, based on the functional effects of each of the known GPe projections—including both arms of the indirect pathway and the GPe projections to the NRT. On the other hand, the role of the NRT in basal ganglia operations may be much more complicated. It isgenerally accepted that the NRT plays an important role in gating thalamocortical transmission from the dorsal thalamus and that it does so in a roughly topo- graphic manner that links specific portions of the NRT with specific thalamic nuclei and their cortical target zones (Jones, 1985). The NRT receives collat- eral, excitatory inputs from corticothalamic as well as thalamocortical fibers that must pass through this nu- cleus en route to their respective termination zones in thalamus and cortex. In addition, the NRT may also receive collateral inputs (Jones, 1975) from both the inhibitory pallidothalamic pathway (Uno and Yos- hida, 1975; Uno et al., 1978) and the excitatory tha- lamostriate projections (Wilson et al., 1983) While the pedunculopontine nucleus (PPN) is not generally considered to be part of the basal ganglia, this structure has strong reciprocal connections with the basal ganglia output nuclei and with the subtha- J.Clin Newophysol, Vol. 11. No.4, 1994 lamic nucleus, and it also sends unreciprocated pro- Jjections to the dopaminergic neurons of the substantia nigra pars compacta (SNe; see later) as well as to the putamen and caudate nucleus (Kim et al., 1976; De- Vito et al., 1980; DeVito and Anderson, 1982; Har- nois and Filion, 1982; Carpenter and Jayaraman, 1990; Nakano et al., 1990; Smith et al., 1990; Hazrati and Parent, 199 1a). In primates the majority of palli al inputs to the PPN are apparently collaterals of pal- lidothalamic projections (Hamois and Filion, 1982; Parent, 1990; Hazrati and Parent, 19914). The PPN contains two populations of neurons, one cholinergic and the other noncholinergic (Lee et al., 1988). Itis mainly the noncholinergic neurons that project back to GPi/SNr and the subthalamic nucleus (Rye et al., 1987; Lee et al., 1988), while the cholinergic neurons project primarily to the thalamus (Hallanger et al., 1987; Hallanger and Wainer, 1988). The noncholin- ergic neurons have excitatory effects on their basal ganglia targets (Gonya-Magee and Anderson, 1983; Hammond et al., 1983; Scarnati et al., 1987), and there is some evidence that they may use glutamate as their transmitter (Scarnati etal, 1986). As with GPi/SNr, there is a convergence of inputs from both the direct and the indirect pathways at the level of the PPN. In this case, however, activation of either pathway at the level of the MSNs leads to the same polarity of response within the PPN (that is, ac- tivation of PPN by disinhibited subthalamic inputs or direct disinhibition of PPN by inputs from GPe or from GPi/SNr). Until recently, descending projections of the basal ganglia output nuclei have received relatively litte at- tention, it having been generally assumed that directly descending basal ganglia influences on the skeletomo- tor system extended no further caudally than the PPN. Recent studies in rats, however, have also re- vealed substantial PPN outflow to the reticulospinal system (Nakamura et al., 1989, 1990). These findings have not yet been extended to primates. One of the remarkable features of basal ganglia cir- cuitry is that functionally discrete channels of infor- mation processing are maintained throughout the various cortico-basal ganglia-thalamocortical path~ ways (Nambu et al, 1988, 1990, 1991) in the face of layer-to-layer connectivity that is highly convergent (Wilson and Groves, 1980; Yelnick et al., 1984). In the case of the skeletomotor pathways, for example, basal ganglia neurons have been shown to have highly refined sensorimotor fields that are comparable in their somatotopic and behavioral specificity to the sensorimotor fields of neurons at cortical levels (Geor-BASAL GANGLIA-THALAMOCORTICAL CIRCUITS IN MOVEMENT 425 gopoulos et al., 1983; Crutcher and DeLong, 1984b; DeLonget al., 1985; Alexander and Crutcher, 1990). Recent anatomical studies using transneuronal tracers have revealed at least three separate channels of arm representation that extend continuously throughout the basal ganglia-thalamocortical path- ways (Hoover and Strick, 1993). Each channel origi- nates in a separate cortical motor area (motor cortex, ventral premotor area, or supplementary motor area) and remains segregated from the others throughout the entire cortico-basal ganglia-thalamocortical loop. On the other hand, at the cellular level there is con- siderable convergence of inputs along these same pathways, Based on electron microscopic analyses, it has been estimated that the convergence ratio along the corticostriatal pathways, which provide approxi- mately half of the excitatory input to the neostriatum, ‘may be on the order of $,000:1. Cell counts in the hu- ‘man striatum and globus pallidus (Schroder et al. 1975; Thorner et al., 1975) suggest minimum con- vergence ratios on the order of 300:1 and 100:1, re- spectively, for the striatal projections to GPe and GP ‘The mechanisms that underlie the development and maintenance of functional specificity in basal ganglia networks (despite the abundant anatomical convergence) have yet to be identified. Much of this organization may be genetically determined, but ex- perience-dependent synaptic modification may also play a role. If synaptic plasticity in basal ganglia net- works operates according to Hebb-like principles (Brown et al., 1990), and there is some evidence that this may be the case (see following), the correlative nature of Hebbian learning might well be expected to strengthen preferentially those connections that link neurons with similar functional properties (Linsker, 1990). ROLE OF DOPAMINE Another important feature of basal ganglia organi- zation is the pervasive role of dopamine. The func- tionality of dopamine in basal ganglia operations ap- pears to be very complex. Dopaminergic input to the putamen consists of nigrostriatal projections that originate in the SNc (Parent, 1990), and the cortical motor and premotor areas receive separate dopamin- ergic projections from the ventral tegmental area (Gaspar et al., 1989; DeKeyser et al., 1990; Smiley et al., 1992), At the network level, dopamine appears to have differential effects on the direct and indirect pathways, tending to activate striatal MSNs that pro- ject directly to GPi while suppressing those that pro- ject to GPe (Alexander and Crutcher, 1990¢). Given the fact that there appear to be reciprocal reentrant effects associated with differential activation of the di- rect versus indirect pathways (i.e., positive feedback to cortex via the direct pathway and negative feedback via the indirect; see previously), the differential effects of dopamine on these two pathways suggest that its overall impact on basal ganglia operations may in- clude the enhancement of positive feedback and sup- pression of negative feedback, returned to the various cortical areas that receive basal ganglia influences. Dopamine has also been shown to have a role in synaptic plasticity within the striatum, being impli- cated in both long-term potentiation (LTP) and long- term depression (LTD) (Calabresi et al., 199246; Walsh, 1993). The nigrostriatal pathway provides an extraordinarily dense dopaminergic input to each MSN, which is comparable in magnitude to the 5,000 oso corticostriatal synapses that individual MSNs re- ceive (Doucet et al., 1986). The behavioral correlates of dopamine neurons have been studied in depth by Schultz. and colleagues (Romo and Schultz, 1990; Schultz and Romo, 1990). Unlike nearly all the other basal ganglia motor circuit neurons, except perhaps the large, aspiny interneurons of the striatum (Ki- mura, 1986; Kimura et al., 1990), dopamine neurons do not show activity changes in relation to movement. per se, but discharge instead in relation to conditions involving the probability and imminence of behav- ioral reinforcement (Romo and Schultz, 1990; Schultz and Romo, 1990). ‘The newly discovered facts that dopamine may play a crucial role in the cellular mechanisms of LTD and LTP within the striatum and that dopamine neurons discharge sclectively in relation to specific reward con- tingencies combine to suggest the intriguing hypothe- sis that dopamine neurons may play an important role in determining when striatal synapses should be strengthened or weakened. In this respect, dopamine neurons might be seen as playing a role in striatal in- formation processing analogous to that of an “adap- tive critic” in connectionist networks. It is noteworthy, however, that the striatum is not the only basal ganglia structure for which there is evi- dence of adaptive synapses. With their combined volt- age dependency and ligand specificity, N-methyl-D- aspartate (NMDA) receptors are widely assumed to play a role in at least one form of activity-dependent synaptic plasticity, viz., LTP (Rauschecker, 1991). Evidence for the existence of NMDA receptors has been found in a number of basal ganglia nuclei that are believed to receive significant glutamatergic input, J.Clin, Newophysiol, Vol 1. No.4, 198426 G. E, ALEXANDER including the striatum (putamen and caudate nu- cleus) (Cherubini et al., 1988; Young et al., 1990; Ka- ‘waguchi, 1992), the subthalamic nucleus (Nakanishi etal., 1988; Young etal., 1990), and the SNe (Mercuri etal., 1992). NMDA receptors have also been demon- strated at cortical levels (Young et al., 1990; Arm- strong et al., 1993; Kobayashi et al., 1993), where the phenomenon of LTP has been documented in many regions including some of the sensorimotor fields (Baranyi and Szente, 1987; Bindman et al., 1988; Iriki et al., 1989, 1991), Taken together, these findings in- dicate that adaptive synapses may be distributed at multiple junctures along the basal ganglia-thalamo- cortical pathways. LIMITS OF OUR CURRENT UNDERSTANDING OF BASAL GANGLIA FUNCTION Disinhibition plays an important role in many cur- rent models of basal ganglia operation (Chevalier and Deniau, 1990). In the case of the basal ganglia’s ocu- lomotor pathways, for example, there is compelling evidence that striatally induced, phasic inhibition of SNr neurons leads to the generation of saccadic eye movements through the release of command neurons in the superior colliculus from the tonic, GABAergic inhibition they receive via the nigrotectal pathway (Hikosaka and Wurtz, 1983, 1985; Hikosaka et al., 1989). The elegant simplicity of this model has helped to motivate similar models of how the basal ganglia's skeletomotor circuitry may contribute to movement control, the chief difference being the emphasis in most skeletomotor models on disinhibition at the level of the thalamus rather than brainstem (Alexan- der and Crutcher, 19900). These models of the basal ganglia’s skeletomotor circuitry assume that voluntary movements are facili- tated in the context of focused disinhibition of the basal ganglia-recipient portions of the ventrolateral thalamus. This focused thalamic disinhibition is thought to be generated either by phasic enhancement of transmission through the direct pathway, by phasic suppression of transmission through the indirect pathway, or by a combination of these two processes. Conversely, according to this same scheme, decreased transmission through the direct pathway, or increased transmission through the indirect, would have the effect of suppressing voluntary movements. This relatively simplistic model raises questions of its own, however. It is not known, for example, whether a given corticostriatal neuron (or functional J.Clin.Newrophysol. Vo. 11. No.4, 1994 group of such neurons) engages both the direct and the indirect pathways in a balanced manner. Nor is it known whether the convergence of inputs from the direct and indirect pathways onto individual GPi/SNr neurons (Bolam and Smith, 1992) results in a func tional interaction between the two pathways that is antagonistic or complementary. A possibility at one extreme would be a functionally antagonistic, push/ pull system that could be used to scale and/or brake the intended movement (e.g., with flexion-activated inputs from the two pathways being superimposed and thereby tending to cancel one another out). At the other extreme would be a functionally complemen- tary, center-surround system that might serve to facil- itate the intended movement pattern while suppress- ing potentially conflicting ones. Whether cither of these alternative schemes applies, or whether instead there may be a purely random convergence of direct and indirect projections onto GPi/SNr neurons, has important implications for any functional model of basal ganglia organization Studies of various primate models of basal ganglia— induced movement disorders have tended to confirm many of the predictions of the thalamic disinhibition models (DeLong, 1990). These models predict that excessive basal ganglia outflow should be associated with hypokinetic states such as are seen in the various akinetic/rigid disorders of movement control. Be- cause of dopamine’s reciprocal effects on the direct and indirect pathways, experimental striatal dopa- mine deficiency should and does result in excessive discharge of neurons in the subthalamic nucleus as well as in GPi/SNr. In primates with parkinsonian akinesia induced experimentally by treatment with MPTP, the discharge rates of GPi neurons as well as of neurons in the subthalamic nucleus have been found to be abnormally high, consistent with predic- tions of the thalamic disinhibition models (Filion et al., 1988; Miller and DeLong, 1988). Voluntary movements can be restored in these akinetic animals by selective lesion of the subthalamic nucleus, which results in the return of GPi neurons to more normal rates of discharge (Bergman et al., 1990). Also consis- tent with thalamic disinhibition modelsis the fact that akinesia in humans with idiopathic Parkinson's dis- ease can be relieved by selective stereotaxic lesions of GPi (especially when the lesions are centered in that nucleus’ sensorimotor territory) (Laitinen et al., 1992) Such models are also able to account for hyperki- netic disorders (e.g., involuntary ballistic or chorei- form movements) on the basis of reduced basal gan-BASAL GANGLIA-THALAMOCORTICAL CIRC! glia outflow (DeLong, 1990). Such reduced outflow is ‘thought to result in excessive disinhibition of the basal ganglia-receiving territories within the thalamus, with consequent release of involuntary movements, This explanation is consistent with various clinical and experimental data, including the fact that lesions of the subthalamic nucleus result in dyskinesias (Car- penteretal., 1950) and that such lesionsare associated with reduced levels of spontaneous discharge in GPi (Bergman et al., 1990), ‘There are, however, a number of observations that are difficult to reconcile with simple models of basal ganglia function based primarily on the concept of thalamic disinhibition. One of the most serious such conflicts involves the fact that lesions of the basal gan- alia output nuclei do not result in dyskinesias (Horak and Anderson, 1984; Mink and Thach, 1991) as the models predict they should, although dyskinesias have been reported in association with muscimol duced suppression of GPi output (Kato and Kimura, 1992). A possible explanation for this discrepancy may be that the voltage-ependent, bistable properties of thalamic neurons (Steriade and Linas, 1988) may ‘cause them to respond to downward modulations of inhibitory basal ganglia input in a nonmonotonic manner. On the one hand, moderate reductions of GABAergic input from the basal ganglia, as would be expected with subthalamic lesions, may partially, but inappropriately, depolarize some thalamic relay neu- rons to the point that they enter a nonrelay burst ‘mode when they are supposed to be maximally hyper- polarized, leading to bursts of inappropriate thalamo- cortical activity and resultant dyskinesias. On the other, severe reductions in GABAergic input, as would be expected with GPi lesions, may actually re- store some stability by increasing the level of depolar- ization of all basal ganglia-recipient thalamic relay cells to the point where they enter into a more or less permanent, nonbursting, relay mode. Or perhaps the reason that complete removal of inhibitory basal gan- glia input to the thalamus is not associated with dys- kinesias is that the emergence of dyskinesias may re- quire that reduced tonic levels of thalamic inhibition be combined with the preservation of at least some degree of phasic modulation of these same inhibitory inputs (see Steriade and Llinas, 1988). A related difficulty for thalamic disinhibition theo- riesis that lesions of the ventrolateral thalamus do not result in akinesia, and yet according to such theories parkinsonian akinesia is generally attributed to in- creased basal ganglia outflow that results in excessive inhibition at the level of the ventrolateral thalamus 5 IN MOVEMENT 47 (DeLong, 1990). One possible explanation for this ap- parent discrepancy is that we may have underesti- ‘mated the functional significance of descending basal ganglia outflow to the PPN (and from there to the re- ticulospinal system), in which case lesions of the thal- amus that block only the reentrant (cortically pro- jected) influences of the basal ganglia may leave intact those descending influences that are conveyed more directly to the segmental motor apparatus. Further inconsistencies and unanswered questions continue to surface, making it difficult to accept any of the current theories of basal ganglia function as de- finitive. For example, why should striatal dopamine deficiency lead to severe akinesia whereas structural lesions of the striatum fail to do so? And if basal gan- glia dysfunction can lead to akinesia at one extreme and involuntary movements at the other, which sug- gests that the basal ganglia may play some role in the generation of movement, why is it that movement related neuronal activity in the basal ganglia begins relatively late with respect to movement onset, well after the beginnings of movement-related activity in cortical motor areas or in the cerebellum (Thach, 1978; Anderson and Horak, 1985; Crutcher and Al- exander, 1990)? And, perhaps most disconcerting of all, what sort of role can the basal ganglia be playing, in normal motor control, and how significant might that role be, if lesions of the output nuclei result only in minor disturbances of motor output (Horak and Anderson, 1984; Mink and Thach, 1991)? SUMMARY AND CONCLUSIONS Enormous progress has been made recently in char- acterizing the structure and the functional organiza- tion of the basal ganglia. We now know which parts of the basal ganglia are involved in movement control, how movement parameters are encoded in the dis- charge patterns of basal ganglia neurons, how the basal ganglia communicate with cortical and other subcortical structures involved in movement control, how abnormal activity within the basal ganglia can lead to a variety of movement disorders, and how therapeutic manipulations of these nuclei can restore motor function in certain types of basal ganglia disor- ders. ‘At the same time, much has yet to be learned. Al- though the anatomy and physiology—and to some extent even the pathophysiology—of these structures are now understood in some detail, we still do not un- derstand precisely what functions the basal ganglia subserve in the course of their normal operations. In J.C, Newophysial, Vol. 11. No.4 1994428 G. particular, we have yet to learn what specific contri- butions the basal ganglia may make to the generation and coordination of voluntary movements. 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