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Basal ganglia contributions to motor control: a vigorous tutor
Robert S Turner1 and Michel Desmurget2
The roles of the basal ganglia (BG) in motor control are much debated. Many influential hypotheses have grown from studies in which output signals of the BG were not blocked, but pathologically disturbed. A weakness of that approach is that the resulting behavioral impairments reflect degraded function of the BG per se mixed together with secondary dysfunctions of BG-recipient brain areas. To overcome that limitation, several studies have focused on the main skeletomotor output region of the BG, the globus pallidus internus (GPi). Using single-cell recording and inactivation protocols these studies provide consistent support for two hypotheses: the BG modulates movement performance (‘vigor’) according to motivational factors (i.e. context-specific cost/reward functions) and the BG contributes to motor learning. Results from these studies also add to the problems that confront theories positing that the BG selects movement, inhibits unwanted motor responses, corrects errors on-line, or stores and produces well-learned motor skills.
Addresses 1 Department of Neurobiology, Systems Neuroscience Institute and Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA 15261, USA 2 Centre for Cognitive Neuroscience, UMR5229 CNRS, 67 Blvd. Pinel, 69500 Bron, France Corresponding author: Turner, Robert S (rturner@pitt.edu)

nor are all of the hypotheses mutually exclusive. These hypotheses are elaborated in the references cited above. The present review summarizes recent experimental results that, in our opinion, buttress a subset of the hypotheses and add to the list of difficulties that challenge many of the others.

Function versus dysfunction
The desire to understand normal functions of the BG is driven, partly, by the many neurologic and psychiatric disorders associated with pathology or abnormality within the BG. The examples of Parkinson’s disease (PD [15]), Huntington’s Disease (HD [16]), types of dystonia [17] and Tourette’s syndrome [18] illustrate the fact that most BGassociated clinical conditions involve some form of striatal dysfunction. In other words, clinical signs occur when the principal input nucleus of the BG network is affected (Box 1). Interestingly, a very different outcome is observed following discrete lesions of the main output regions of the BG [the globus pallidus internus, GPi, or substantia nigra pars reticulata, SNr (Box 1)]. In that case, behavioral effects are typically subtle or imperceptible [4,19], consistent with the fact that surgical ablation of large portions of the GPi (‘pallidotomy’) is an effective treatment for striatal-associated disorders such as PD and dystonia [20,21,22]. Together, these observations can seem paradoxical. BGassociated disorders arise primarily from pathology in the principal input nucleus, the striatum, and can be alleviated by lesions of a BG output nucleus. The seeming contradiction can be explained by the concept that it is better to block BG output completely than allow faulty signals from the BG to pervert the normal operations of motor areas that receive BG output [15]. Abnormalities in striatal function, whether from frank lesions [23,24] or neurotransmitter imbalance [25–27], induce grossly abnormal ‘pathologic’ patterns of neuronal activity in the inhibitory output neurons of the BG. These abnormal firing patterns are thought to disrupt the normal operations of BG-recipient brain regions. Although the actual mechanisms mediating that disruption remain to be determined, one possibility supported by biologically realistic computational models [28,29] is that pathologic firing patterns in BG-thalamic afferents degrade the ability of thalamic neurons to transmit information reliably. In this way, pathologic BG output may block effective cortico-thalamo-cortical communication [30]. In agreement with this idea, therapeutic deep brain stimulation (DBS) within GPi or the subthalamic nucleus (source of excitatory input to the BG output nuclei, GPi, and SNr; Box 1) has been shown to reduce pathologic firing patterns in BG efferent neurons [31,32]. Moreover, www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:704–716 This review comes from a themed issue on Motor systems Edited by Dora Angelaki and Hagai Bergman Available online 17th September 2010 0959-4388/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2010.08.022

Introduction
What are the functions of the Basal Ganglia (BG)? Despite decades of intense study and mushrooming volumes of experimental results, the question is still widely debated. Indeed, there sometimes seem to be as many hypotheses as there are groups working on the subject. Among the most influential hypotheses, one may cite: selection of action and suppression of potentially competing actions and reflexes [1–3], control of the scale of movement and related cost functions [4,5,6], on-line correction of motor error [7,8], motor learning [9,10,11], and the retention and recall of well-learned or natural motor skills [10,12,13,14]. Note that this list is neither exhaustive
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Box 1 Basal Ganglia Anatomy Two organizing principles guide our understanding of the roles of the BG in the control of movement and other aspects of behaviors. Recent advances corroborate the overall validity of these classical concepts. (For detailed reviews of BG anatomy see ([1] and [104]).) First, all regions of the BG share a common basic circuit plan (Box 1, Figure a). The striatum, principal input nucleus of the BG, receives massive excitatory inputs from most cortical areas and from particular thalamic nuclei (the intralaminar nuclei, primarily). Direct and indirect pathways through the BG originate in the striatum and converge ultimately in the primary output nuclei of the BG, the globus pallidus internus (GPi) or the substantia nigra reticulata (SNr). In a major recent advance, years of debate have been resolved by confirmation that the direct and indirect pathways originate from biochemically distinct and morphologically distinct types of striatal projection neurons [97,105]. Consistent with the classical model, direct and indirect pathway neurons of the striatum express D1-type and D2-type dopamine receptors, respectively. It has also become clear, however, that neurons of the direct and indirect pathways collateralize far more than proposed in classical models [106] or summarized here. The second major source of input to the BG arises from excitatory projections from the frontal cortices to the subthalamic nucleus (STN). The principal output pathway from the BG consists of GABAergic projections from the GPi and SNr, which tonically inhibit targets in the thalamus and brainstem. Second, parallel ‘loop’ circuits from cortex, through the BG, thalamus and back to cortex mediate distinct motor, associative, and limbic Box 1 Figure functions (Box 1, Figure b). Different regions of the striatum, GPe, and STN are devoted to these different functions. The circuit that projects to the motor cortices (i.e. the ‘skeletomotor circuit’) passes through a posterior–ventral region of GPi. Circuits sending information to prefrontal ‘associative’ cortical areas occupy more anterior and dorso-medial regions of the GPi and portions of the SNr. Limbic circuits pass primarily through the SNr. Debate continues on the degree to which information is shared between functional circuits. For example, a recent study showed that subregions of the BG circuit that projects to the primary motor cortex receives inputs from limbic cortical areas [107], thereby opening the possibility for relatively direct communication of motivation-related information to motor cortex. The general concept that anatomically segregated circuits through the BG contribute to different aspects of behavior has been confirmed in recent years by a series of studies showing that pharmacologic activation of different functional circuits elicits behavioral disorders consistent with the circuit being activated [108]. The existence of multiple closed loop circuits makes it clear that the BG contributes not only to the control of movement, but also to functions such as executive control, working memory, and motivation. The parallel circuit architecture and the common basic design of each circuit has led many to propose that different circuits perform analogous operations on different types of information. For this reason, understanding the operations of one circuit (e.g. how the skeletomotor circuit transforms the information it receives) is likely to shed light on the operations performed by other BG circuits as well.

Circuit diagrams of the BG and associated input–output connections. (a) The positions of key BG structures involved in skeletomotor control and their basic input–output connectivity superimposed on a parasagittal section through the macaque brain. The basic loop circuit includes an excitatory glutamatergic (Glu) projection from the neocortex to the striatum (caudate nucleus and putamen) and then inhibitory (g-amino butyric acid-containing; GABAergic) striatal projection (the ‘direct pathway’) to the internal globus pallidum (GPi). GABAergic neurons in GPi project to targets in the thalamus and brainstem. The main thalamic target of this circuit (VA/VL, ventral anterior/ventrolateral nucleus of the thalamus) projects to the frontal cortex including parts of the premotor and primary motor cortex. (b) Internal connectivity of the BG motor circuit (front subpanel) showing principal pathways only. Direct and indirect pathways start in projection neurons of the putamen (part of the striatum) that express D1-type and D2-type dopamine receptors, respectively. D2-type neurons project to the external globus pallidus (GPe). GPe projects to the subthalamic nucleus (STN) and GPi. STN also receives monosynaptic Glu input from the motor cortices and projects to GPi and GPe. GPi sends GABAergic projections to VA/VL and the centre median–parafascicular intralaminar complex (CMPf) of the thalamus. CMPf closes another loop by projecting back to the striatum. GPi also projects to brainstem regions such as the pedunculopontine nucleus. Dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) innervate the striatum and, less densely, the GP and STN. Successive subpanels represent the parallel BG circuits that subserve oculomotor, associative, and limbic functions. Note that these circuits pass through anatomically distinct regions at each stage, including different regions of the STN and thalamus (not shown in figure).

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the therapeutic efficacies of different forms of DBS (stimulation at different frequencies and degrees of regularity) correlate well with their ability to restore the fidelity of cortico-thalamic communication in computational models [29]. Results from functional imaging studies are also consistent with this idea. Pallidotomy and DBS normalize patterns of brain activity in non-BG brain regions [33,34]. Abnormalities in GPi activity also change toward normal firing patterns during effective pharmacotherapy [35]. In summary, growing evidence suggests that the therapeutic efficacy of pallidotomy, and of DBS as well most probably, comes from its ability to block the spread of pathologic activity from the BG to other brain regions. A corollary of this insight is that many of the symptoms of BG disorders, and the behavioral sequelae of experimental manipulations of the striatum, represent dysfunctions of BG-recipient brain regions rather than ‘negative images’ of normal BG functions. This view runs contrary to a frequent assumption that the primary problem in these disorders is loss of normal BG functions (i.e. loss or corruption of the normal task-related information transmitted through the BG). As a consequence, it is difficult to infer normal functions of the BG accurately from the behavioral impairments that accompany clinical disorders or experimental manipulations of the striatum. The possibility that a subset of clinical signs may reflect normal BG functions is considered below.

directly in movement execution, but rather that it brings cognitive and motivation-related signals together with signals related to movement kinematics [37]. Second, during the performance of a choice reaction time task, peri-movement changes in neuronal activity begin later in the striatum and globus pallidus than in connected regions of cortex. In GPi, for example, onset latencies of peri-movement changes in neural firing are typically clustered around the time of earliest agonist muscle activity (‘EMG’; 50–80 ms before movement onset; see [36] for references) and after the activation of primary motor cortex ($120 ms before movement). Interestingly, peri-movement increases in GPi firing have later onset times than peri-movement decreases [36], a point that will be revisited later. The timing of movement-related activity in GPi makes it impossible for GPi output to contribute to processes that are completed before the initial activation of a movement’s prime moving muscles (e.g. selecting which agonist muscles to activate or triggering their activation). Based on timing, GPi activity may modulate the ongoing commands issued by BG-recipient motor control centers. Third, movement-related changes in discharge consist of an increase in firing in 60–80% of GPi neurons (the exact percentage varying between behavioral tasks) [36,41]. Given that increases in GPi firing inhibit activity in recipient motor control circuits, this observation has been cited as evidence that an important function of output from the BG motor circuit is to suppress or inhibit patterns of motor activity and reflexes that would be inappropriate or in conflict with the movement being performed [1–3]. The late timing of peri-movement GPi activity, particularly that of increases in firing [36], appears to conflict with that concept. To be more specific, the rest activity of antagonist muscles [42,43] and the gain of reflexes that might interfere with a desired movement [44,45] are suppressed tens of millisecond before activation of a movement’s prime moving muscle. At the cortical level, suppression of potentially competing activity patterns also begins before the initial activation of agonist muscles [46,47]. Thus, the known inhibitory processes that contribute to movement selection begin too early to be mediated by output from the BG. Cortical mechanisms may mediate most aspect of movement selection [6,48]. A potential role for GPi movement-related activity in the control of movement vigor is discussed below.

Timing and characteristics of BG output signals
The loop organization of BG-thalamocortical circuits makes it difficult to disentangle the relative roles of different stages of the circuit. One productive approach to this problem has been to investigate how the BG circuit ‘transforms’ the information it receives from cortical and thalamic inputs. Ultimately, this amounts to determining the nature and timing of information encoded in the activity of BG output neurons. Current understanding regarding this point can be summarized as three key facts about the BG circuit devoted to skeletomotor function. First, movement-related changes in firing in GPi are almost always influenced by specific characteristics of a movement such as its direction, amplitude, and speed (i.e. movement kinematics) ([36], and references therein). However, motor activity in GPi neurons is also often influenced by the context of the behavioral task being performed. Single-cell responses in GPi can differ depending on the memory requirements of a task [37], whether the movement is discrete or part of a movement sequence [38], the reward contingencies of the task (i.e. whether or not a primary reward is expected to follow the movement [39]), and the learning context [40]. Similar influences of behavioral context have been observed in the oculomotor circuit in animals performing eye movement tasks [3]. These observations suggest that the BG motor circuit is not involved
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Interrupting BG output
A complementary approach to disentangling BG functions is to determine what aspects of motor behavior are impaired and, just as importantly, spared following transient inactivation or permanent lesion of the GPi. Because the GPi is the principal output nucleus for the BG skeletomotor circuit, inactivation of the skeletomotor region of the GPi essentially disconnects the BG from www.sciencedirect.com Basal ganglia contributions to motor control: a vigorous tutor Turner and Desmurget 707

Figure 1

Disconnection of the BG skeletomotor circuit does not impair movement initiation or performance of an overlearned motor sequence, but selectively affects movement speed and extent. Animals moved a joystick (a, top) through a series of four out-and-back component movements ((b–d) red, blue, green, and cyan traces, respectively) before and after an injection of muscimol (a long-acting GABAergic inhibitory agent) into the GPi. (a, bottom) illustrates sites of injections (letters) in a typical coronal plane through GPe and GPi. Performance is illustrated for single trials under the Random preinjection (b), OverLearned pre-injection (c) and OverLearned post-injection (d) conditions. The left and right panel show position and velocity data, respectively. Black sections of the velocity curves indicate periods of immobility (velocity < 25-mm/s). Left: Continuous arcs in corners indicate positions of the instruction cues. Dotted arcs indicate the peripheral target zones for cursor movements. Right: Dots on the velocity curves indicate the instant of presentation of the instruction cue. Under the OverLearned condition (c), outward movements to capture a peripheral target were often anticipatory, beginning before the instruction cue was presented, and this anticipatory performance persisted post-injection (d). Numbers define targets (left) and which target was indicated by each instruction cue (right). The figures are scaled to show the central region of the workspace. (e) Inactivations had a negligible effect on reaction times [RTs; left, compare pre-injection (open symbols) versus post-injection means (filled symbols)]. This was true irrespective of whether animals performed OverLearned sequences or Random sequences, or whether the target to capture was indicated by a cue’s spatial location (circles) or its color (triangles). By contrast, muscimol injections consistently reduced movement velocity (middle) and extent (right) under all conditions. Symbols indicate means Æ SEM from 19 separate injections of muscimol into the contralateral GPi of two animals. (b–d) is from [55] used with permission from the Society for Neuroscience. (e) is adapted from [109].

the rest of the motor control apparatus (Box 1). Several studies over the past three decades have investigated the effects of GPi inactivation on motor performance in neurologically normal animals [4,49–54,55]. Although very different motor tasks were used and minor disparities were sometimes noted [4], results from these studies are surprisingly consistent. Overall, they reveal a relatively discrete group of deficits and a wide range of preserved functions. Five points are particularly noteworthy. www.sciencedirect.com First, GPi inactivation does not lengthen reaction times (RTs; Figure 1e [4,50–52]), consistent with the frequent clinical observation that pallidotomy, if anything, speeds movement initiation [21,22]. These observations are not consistent with the idea that the BG contributes to the selection or initiation of movement. Second, GPi inactivation does not perturb on-line error correction processes [4] or the generation of discrete
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corrective submovements in a single-joint movement task [52]. These findings are consistent with the observation that rapid hand-path corrections are preserved in PD patients [56], but present challenges for the idea that the BG mediates the on-line correction of motor error [7,8]. Third, GPi inactivation does not affect the execution of overlearned or externally cued sequences of movements. This was shown in two recent studies in monkeys [4,55] (Figure 1b–e). The animals were trained to perform four out-and-back reaching movements in quick succession toward four possible target locations. The targets were either chosen at random with replacement (Random) or presented in an immutable, completely predictable order (OverLearned). Before GPi inactivation, the animals practiced both tasks for 6 months and more than 50,000 trials. At the end of this intensive training, task performance was very different for the two experimental conditions. Under the Random condition, the animals stopped after each movement and a standard RT ($190-ms) was observed following presentation of each target. Under the OverLearned condition, there was little or no pause between component movements of the sequence and, in a majority of trials, RTs were clearly predictive (