The role of the basal ganglia in motor control: contributions from PET

JOURNAL OF THE

NEUROLOGICAL SCIENCES

ELSEVIER Journal of the Neurological Sciences 128 (1995) 1-13

Review article

The role of the basal ganglia in motor control: contributions from PET

David J. Brooks * MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London W12 OHS, UK

Received 30 March 1994; revised 14 July 1994; accepted 10 August 1994

Abstract

This article reviews PET activation data on basal ganglia function that have been reported in association with performance of different motor tasks by normal subjects and movement disorder patients. PET findings are contrasted with electrophysiological observations both in man and in non-human primates and with observations on clinical and cognitive function of movement disorder patients. Possible roles that the basal ganglia may play in motor control are discussed in the light of these data.

Keywords: Basal ganglia; Positron emission tomography; Cerebral blood flow; Motor control; Parkinson’s disease; Dystonia

Contents

1. Introduction . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Normal motor function ................................... ............................. 2 2.1. Non-human primate observations .......................... ............................. 2 2.2. PET observations in normal subjects. ........................ ............................. 3

3. Parkinson’s disease ..................................... 3.1. Cognitive and locomotor function .......................... 3.2. Animal models ..................................... 3.3. PET activation studies in PD .............................

4. Dystonia ........................................... 4.1. Clinicopathological correlations ........................... 4.2. Animal models ..................................... 4.3. PET studies. ......................................

5. Conclusions . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

The role that the basal ganglia play in controlling motor function remains enigmatic. Suggested roles have included: (a) determination of movement parameters (Hallett and Khoshbin 1980; Anderson and Horak

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19851, (b) preparation for movement (Kimura 1990; Alexander and Crutcher 1990; Schultz and Romo 1988), (c> enabling movements to become automatic (Brotchie et al. 1991a), (d) facilitation of sequential movement (Kimura 1990; Marsden 1987; Brotchie et al.l991a), (e> inhibition of unwanted movements (Penney and Young 1983; Mink and Thach 1991~1, (f) adaptation to novel circumstances (Schultz 1992; Rolls and Williams 1987; Brown and Marsden 19901, (g) facilitation of rewarded

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2 D.J. Brooks /Journal of the Neurological Sciences 128 (1995) l-13

actions (Ljungberg et al. 1992; Schultz 1992), and (h) promotion of motor learning and planning (Taylor et al. 1986; Gotham et al. 1988; Robbins et al. 1994; Aosaki et al. 1994).

The rich connectivity of the basal ganglia is, in part, responsible for obscuring their purpose. At least five distinct parallel loops involving the basal ganglia are now known to exist (Alexander et al. 1990). These include a “motor” loop involving supplementary motor area (SMA), primary motor cortex, putamen, pallidum, and ventrolateral thalamus; a dorsolateral prefrontal cortex (DLPFC) loop involving caudate and ventroan- terior thalamus; and anterior cingulate (ACA) and orbitofrontal cortex (OFC) loops projecting via ventral striatum. The SMA and DLPFC are believed to play a primary role in selecting self-generated movements (Thaler and Passingham 1989; Frith et al. 1991) while ACA is thought to subserve attention and OFC to direct motor responses to novel or rewarding situations (Posner and Peterson 1990; Rolls et al. 1980). As a consequence, if the basal ganglia are lesioned, so inter- rupting pathways from these cortical areas, it may erroneously appear that the basal ganglia play a primary role in directing these higher motor functions.

PET provides a means of studying regional cerebral function in man in vivo under both resting and activating conditions. Activation studies usually involve mea- suring associated regional cerebral blood flow (rCBF) changes during performance of different tasks. If a particular task is performed several times over by an individual the presence of significant regional activation can be detected by applying a t test to the 3D voxel sets of mean rCBF values obtained under resting and activating conditions. This procedure has been termed “statistical parametric mapping” (SPM). Alter- natively, a group analysis of the mean rCBF values obtained when several different individuals perform a particular task can be performed.

Motor tasks lead to alterations in both global and focal blood flow. In order to remove the global compo- nent from focal blood flow changes ANCOVA can be applied with global flow as the confounding variable (Friston et al. 1990). This approach assumes that the global and focal rCBF changes associated with performance of activation paradigms are uncorrelated. Alter- natively, levels of global blood flow under different activating situations can simply be normalised (Fox et al. 1985). The functional resolution of state of the art PET cameras is 4-8 mm but ,if activation data for groups of individuals are being compared the 3D data set needs to be transformed into standard stereotactic space (Friston et al. 1989). This requires additional smoothing and functional resolution falls to around 1.8 cm. This resolution is good enough to allow blood flow and metabolic changes in the lentiform nucleus and head of caudate to be separately monitored but, unfor-

tunately, does not allow putamen, pallidum, and subthalamic function to be individually identified. Despite these limitations, useful information about possible basal ganglia functions can be derived from PET activation studies.

2. Normal motor function

2.1. Non-human primate observations

Visually cued movements of awake monkeys cause pallidal cells to fire at about the same time as onset of electromyographic (EMG) activity (Brotchie et al. 1991b; Mink and Thach 1991a; Anderson and Horak 1985). Most pallidal neurones activated by limb movement respond selectively to direction of movement rather than the pattern of muscular contraction (Mitchell et al. 1987) and cell firing is evident in association with both active and passive joint movements (Hamada et al. 1990). Pallidal firing rates do not correlate well with strength of active muscle contrac- tions employed against loads during movement (Brotchie et al. 1991b; Mink and Thach 1991b) but there is divergence of opinion over whether they are influenced by movement amplitude and velocity (Brotchie et al. 1991b; Mink and Thach 1991b; Mitchell et al. 1987; Hamada et al. 1990). In a study where pallidal neurones specific for wrist movement were identified, their firing pattern was independent of movement amplitude (Mink and Thach 1991b). Pallidal neurones appear to be unselective over the character of the movement activating them, individual neurones firing during phasic, ramp, and sinusoidal tracking (Mink and Thach 1991b). Taken together, these observations suggest that the primary function of pallidal neurones is unlikely to involve determination of the basic parameters of movement.

Two clues about the possible role of pallidal neurones arise from the following observations: First, during sequential movements, some neurones fire biphasi- tally signalling both onset and cessation of EMG activity (Brotchie et al. 1991a). They could, therefore, be signalling the supplementary motor area to switch to the next movement in a sequence and so facilitate its performance. In support of this view, it has been noted that biphasic firing of pallidal neurones is most evident when sequential movements have become automatic. Second, inhibiting pallidal neurones by injection of the GABA agonist muscimol leads to involuntary co-contraction during movement (Mink and Thach 1991~). This suggests that the basal ganglia may act to suppress inappropriate muscular activity during running of de- sired motor programmes.

Passive and active joint movements are somatotopi- tally represented at multiple sites in the striatum and

D.J. Brooks/Journal of the Neurological Sciences 128 (1995) l-13 3

limb movements can be generated by microstimulation (Crutcher and Delong 1984a; Alexander and Delong 1985b; Alexander and Delong 1985a; Kimura 1990). Like pallidal neurones, most striatal neurones activated by motor tasks appear to be selective for direction of limb movement rather than the pattern and strength of the muscular activity employed (Alexander and Crutcher 1990; Crutcher and Delong 1984b). In visually cued movements striatal neuronal firing coin- cides with EMG activity (Crutcher and Delong 1984b). These findings, therefore, are also against striatum acting primarily to determine movement parameters or to prepare for externally cued actions. When monkeys perform learnt sequences of movements two classes of putamen neurones can be identified: one class fire at least 100 msec before the onset of the sequence and are then silent while the second class fire prior to each movement in the sequence (Kimura 1990). This observation would support striatum, along with pallidum, as having a role in facilitating learned sequences of movement (Brotchie et al. 1991a).

Striatal neuronal activity has been studied during GO-NOGO paradigms and during self-initiated movements and separate populations of preparatory and executive cells have been identified (Schultz and Romo 1992; Romo et al. 1992). Most preparatory neurones are interested only in the GO situation, but are non- selective in that they fire before both cued and self-initiated movements. The finding of preparatory cells in the striatum has led to the suggestion that it plays a role in motor planning. Neurones in the SMA, however, fire on average around 270 msec before striatal cells when self-initiated actions are performed (Rome

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and Schultz 1992). The time for neuronal impulses to travel around the “motor” basal ganglia loop has been estimated to be of the order of 35 msec and so information could be transmitted from SMA to striatum 16-25 times before onset of movement (Rome and Schultz 1992). It is more likely, therefore, that the striatum, rather than playing a primary role in initiat- ing movement, acts to optimise a selected motor programme in some fashion before it is transmitted to motor cortex and the spinal cord.

Activity of striatal neurones is modulated by dopaminergic input from the substantia nigra compacta. Electrophysiological studies suggest that dopaminergic neurones are primarily activated by movements in response to novel or rewarding situations or by stimuli predicting reward (Schultz 1992; Ljungberg et al. 1992) and do not fire in preparation for movement (Romo and Schultz 1990). Striatal neurones re- sponding specifically to rewarded movement have also been identified; particularly in ventral areas (Apicella et al. 1991). These findings are compatible with the basal ganglia playing a role in motor reaction to novel or rewarding circumstances.

2.2. PET observations in normal subjects

A number of studies have reported on the striatal blood flow changes associated with performance of motor tasks. Playford et al. (1992a) examined contralat- era1 lentiform nucleus flow increases during paced joystick movements. The joystick could be moved in four possible directions; in the first paradigm subjects

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Fig. 1. Statistical parametric maps (SPMs) showing significant rCBF increases in sagittal, coronal and transaxial projections associated with paced joystick movements using the right hand for a group of six normal subjects. The left image shows activation due to movements in freely chosen directions and the right image the areas activated by repetitive forward movements. It can be seen that the lentiform nucleus and primary sensorimotor cortex are equally activated in both types of movement but that dorsal prefrontal, rostra1 SMA, and parietal association areas are differentially activated by movements in spontaneously selected directions. (Courtesy of Dr. E.D. Playford.)

4 D.J. Brooks /Journal of the Neurological Sciences 128 (1995) 1-13

were asked to move it repetitively in a forward direction while in the second paradigm subjects were asked to freely chose the direction of movement each time the tone sounded. Both paradigms activated the lentiform nucleus but, while free selection of movement direction led to significantly greater activation of dorsolateral prefrontal and rostra1 supplementary motor area than stereotyped movements, there was no significant difference in levels of either contralateral primary motor cortex or lentiform nucleus blood flow (see Fig. 1). Deiber et al. (1991) compared the activation patterns obtained when the directions of paced joystick movements were cued by the pitch of the tone, freely selected, or always in a forward direction. No difference in basal ganglia activation was found between these various paradigms.

Jenkins et al. (1994b) studied the regional cerebral blood flow changes associated with paced and self- paced index finger extension. In the first paradigm subjects spontaneously moved their index fingers at freely chosen intervals between l-7 seconds, each movement generating a tone. In the second paradigm the tones generated in the first paradigm were played back at identical time intervals and were used to pace extension of the subject’s index finger. Self-paced finger movements resulted in significantly greater rostra1 SMA and DLPFC activation than those that were cued. Activation of contralateral lentiform nucleus and sensorimotor cortex was the same, however, whether movements were volitional or paced. Taken together, the observations of these workers suggest that, while dorsolateral prefrontal and rostra1 supplementary motor areas play a primary role in making decisions over direction and timing of volitional movement, this is not true of the basal ganglia which are equally activated whether movements are self-initiated or cued.

Grafton et al. (1993) examined the functional anatomy of procedural learning. Subjects were required to keep the tip of a metal stylus against a 2-cm metal target on a rotating 20-cm disc (a pursuit rotor). Serial blood flow measurements were performed as the subject gained proficiency at the task. The contralat- era1 lentiform nucleus, primary motor cortex, and cau- da1 supplementary motor area were all activated by this motor task. As subjects acquired greater skill, as evi- denced by increased duration of time of stylus on target, blood flow significantly increased in primary motor cortex and caudal supplementary motor area but stayed constant in the lentiform nucleus. This finding suggests that, while the basal ganglia are activated during performance of skilled movements, they are not primarily involved in the process of procedural learning.

This conclusion can also be drawn from the findings of Friston et al. (1992) and Shibasaki et al. (1993). Friston and co-workers asked their subjects to perform

paced sequential thumb oppositions against each finger of the right hand for 3.5 min. Subjects underwent six measurements of rCBF, alternating the motor paradigm with rest. Contralateral sensorimotor cortex, lentiform nucleus, and caudal SMA were activated by sequential finger-thumb opposition, while the cerebellar cortex and nuclei were activated bilaterally. Repetition of the paradigm three times led to a significant fall in SMA and cerebellar activation as the finger opposition movements became familiar. There was no change, however, in levels of sensorimotor cortex or lentiform nucleus activity.

Shibasaki et al. (1993) compared the regional cerebral activation associated with performance of a repetitive opposition of all fingers simultaneously to the thumb to that associated with performance of a complex sequence of finger opposition movements. The paradigm used was somewhat complicated in that, although finger movements were self-paced, subjects were instructed to perform oppositions at a regular frequency of 2 Hz so that in practice timing of movements became automatic. Subjects were also required to count silently after finger movements. SMA and ipsilateral motor cortex were significantly more activated by complex sequential than stereotyped finger opposition movements but these two motor tasks resulted in similar increases in contralateral sensorimotor cortex and putamen rCBF. These findings argue against basal ganglia playing a significant role in either acquisition of skilled movement or facilitation of sequential movement.

Jenkins et al. (1994a) examined the role of the basal ganglia in motor sequence learning. They performed six rCBF measurements on their subjects under three experimental conditions, each one occurring twice over. The baseline condition was rest while the two active conditions required the subjects to perform on a key- pad with four keys using the fingers of the right hand for 3.5 min. Finger movements were paced by a tone which sounded every 3 sec. One active condition involved learning a new sequence of key presses, eight moves long, by trial and error. When the subject heard the pacing tone they pressed a key. If they correctly identified the first key press in the series a high-pitched tone sounded while a wrong key press resulted in a low-pitched tone. They then tried another key-press when the next pacing tone sounded. At the end of eight key presses the sequence was restarted. Over the course of the 3.5 min, while rCBF was being measured, the subject gradually built up the correct sequence of key presses. This paradigm, therefore, differed from that of Grafton et al. (1993) in that subjects were competent at performing the task, but unsure which movements to make. The second active condition con- sisted of performing a sequence of eight key presses at 3-set intervals which had been prelearnt, before scan-

D.J. Brooks /Journal of the Neurological Sciences 128 (199.5) l-13 5

ning, in the same way as new sequence acquisition until it had become automatic.

Jenkins et al. (1994a) came to the following conclusions (see Fig. 2): (1) Prefrontal cortex was only activated during new motor sequence learning suggesting a primary role in making motor decisions. (2) The cerebellum was activated by both new sequence learning and performance of automatic movements, but was significantly more activated by the former. This suggests that the cerebellum may play a role in the process by which movements become automatic. (3) The sensorimotor cortex and lentiform nucleus were equally activated whether sequences of movements were being learnt by trial and error or performed automatically.

Taken together, the above PET experiments suggest that while the lentiform nucleus is invariably activated by limb movement, it is not primarily involved in making decisions about direction or timing of actions, which appears to be the preserve of prefrontal cortex and rostra1 SMA. It also does not appear to play a role in acquiring motor skill or in learning or facilitating sequences of movement. It seems to be the cerebellum, rather than the lentiform nucleus, that is the subcortical structure most involved in the process by which movements become automatic.

So do the basal ganglia have a primarily executive role in control of movement once decisions as to the timing and direction have been made by frontal association areas? There are two ways of examining this question with PET. First, the effect of changing basic parameters of movement on levels of basal ganglia activation can be studied. Structures which primarily determine these basic parameters would be predicted to increase their rCBF in proportion to frequency and force of movement. Second, one can determine which

KBF changes in the right prefrontal cortex

cerebral regions are activated when movements are imagined rather than performed. An imagination paradigm effectively renders motor executive systems redundant and so areas primarily involved in determining movement parameters would not be expected to be activated.

We have examined regional cerebral activation when paced joystick movements were performed in freely chosen directions at frequencies increasing from once every 5 set to once every second (Jenkins et al. 1994~). As frequency of movement increased there was a parallel increase in sensorimotor cortex and cerebellar blood flow. In contrast, dorsal prefrontal and lentiform nucleus blood flow remained at a constant level of activation. Regional cerebral blood flow has also been measured when a morse key was pressed with increasing force using the right index finger paced by a tone. Again, contralateral sensorimotor cortex blood flow rose with increasing level of force but lentiform nucleus flow remained constant (Dettmers et al. 1994). These findings suggest that while sensorimotor cortex and cerebellum play a primary role in determining basic movement parameters this is not true of the basal ganglia.

Ceballos-Baumann et al. (1994) compared regional cerebral activation when paced joystick movements were either imagined or performed in freely chosen directions. Imagination of movement led to significant activation of dorsolateral prefrontal cortex, SMA, and lentiform nucleus but not sensorimotor cortex or cerebellum (see Fig. 3). Performance of movement led to no significant change in the level of striatal activation but significant increases in contralateral sensorimotor cortex, caudal SMA, and cerebellar rCBF were observed. The finding of equal basal ganglia activation

rCBF changes in the left cerebellar nuclei

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Fig. 2. Scatter diagrams showing the individual rCBF levels of six normal subjects at rest, while learning a sequence of key presses, and while performing a prelearned sequence with the right hand. The left, middle, and right diagrams show flow changes in right dorsal prefrontal cortex, right cerebellar nuclei, and left lentiform nucleus. (Courtesy of Dr. I.H. Jenkins.)

D.J. Brooks /Journal of the Neurological Sciences 128 (1995) 1-13

Imagined Movements

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Fig. 3. An SPM showing significant rCBF increases associated with imagination of paced joystick movements in freely selected directions using the right hand for a group of 4 normal subjects. Significant activation of the left lentiform nucleus and thalamus, SMA, cingulate, and right dorsal prefrontal and bilateral parietal areas, but not primary sensorimotor cortex, are evident. (Courtesy of Dr. A.O. Ceballos-Baumann.)

associated with both imagination and performance of movement suggests that these nuclei play a role in movement preparation and execution.

So, to summarise these PET findings, the basal ganglia are equally activated whether movements are performed or imagined but levels of activation appear to be independent of the frequency and force of movement, of whether decisions on movement direction or timing are being made, and of whether motor skills are being acquired or sequences of movements are being learned or reproduced. It could be argued that the failure to see differential changes in levels of basal ganglia activation in these various motor paradigms reflects a limitation of PET technology rather than true physiology. This, however, is unlikely to be true. In the studies on the correlation of levels of rCBF with frequency of joystick movement graded rCBF changes were clearly evident in the cerebellar nuclei which are of a similar size to the lentiform nuclei.

What role for the basal ganglia is then compatible with these PET findings? Most cells in the basal ganglia that respond to movement are target directed. One possibility, suggested by Connolly and Burns (1993a,b), is that when a motor decision is made by higher centres the basal ganglia facilitate the required movement by continuously monitoring and optimising the pattern of muscular activity so that the goal state is reached most efficiently, whether the movement be self-initiated or cued. As a motor programme is being optimised it is

relayed to the primary motor cortex for execution at the appropriate force and velocity and to the cerebellum to promote automaticity. This suggested role for the basal ganglia would explain their activation during imaginary actions and also their lack of involvement in making motor decisions and determining the basic parameters of movement. It is also compatible with the observation that pallidotomy in Parkinson’s disease results in improvement rather than disability (Laitinen et al. 1992). If, once optimised by the basal ganglia, a programme is dumped in the cerebellum, its future automatic running would not require pallidal output. As a consequence, as long as PD patients performed previously learned as opposed to novel movements, pallidotomy could act to reduce rigidity without affect- ing the automatic running of learned motor programmes.

3. Parkinson’s disease

3.1. Cognitive and locomotor function

The observed cognitive deficits in Parkinson’s disease (PD) have been extensively used by psychologists to draw conclusions about the role of the basal ganglia despite the obvious drawbacks of using a lesion model. The pathology of PD targets the nigro-striatal dopaminergic projections and the primary clinical deficit is slowness of movement, particularly when actions are volitional (Marsden 1989). When a PD patient performs an action it comprises a series of hypo- metric moves to the target which is eventually accu- rately reached. PD patients experience greatest diffi- culty with volitional sequential and simultaneous movements, requiring both additional planning and execution time (Benecke et al. 1986, 1987). These observations led to suggestions that the basal ganglia act to define basic parameters of movement (Hallett and Khoshbin 1980) and/or to facilitate performance of complex movement patterns.

It is also recognised that non-demented PD patients perform poorly on tests considered sensitive to frontal lobe function. Patients have been reported to be impaired on tests of verbal fluency, card sorting, set shifting, spatial and digit working memory, and planning (Robbins et al. 1994; Brown and Marsden 1990; Cools et al. 1984; Sagar et al. 19881, the impairment taking the form of slowness rather than inaccuracy. Administration of levodopa usually, but not invariably, improves performance of these functions (Gotham et al. 1988). These observations have led to the suggestion that the basal ganglia may play a role in facilitating motor learning, planning, and attention. Loss of caudate dopamine, however, effectively results in deaf- ferentation of caudate-prefrontal projections and so is

D.J. Brooks /Journal of the Neurological Sciences 128 (I 995) l-13 7

likely to result in secondary frontal dysfunction. Addi- tionally, loss of prefrontal dopamine, serotonin, noradrenaline, and acetylcholine terminals occurs in PD and Lewy body inclusions can often be found in frontal areas of non-demented cases. It seems, therefore, more likely that impairment of planning and set shifting in PD arises directly from frontal rather than basal ganglia dysfunction. This conclusion would be supported by the observation that patients with isolated lesions involving the SMA and anterior cingulate can show similar motor deficits to PD patients (Dick et al. 1986).

3.2. Animal models

Lesioning the substantia nigra compacta in non-human primates with the toxin MPTP results in striatal dopamine depletion with associated limb rigidity and bradykinetic movements (Crossman et al. 1985). The MPTP lesioned primate, therefore, provides an animal model of Parkinson’s disease and has enabled the effects of dopamine depletion on basal ganglia function to be extensively studied. There are two main pathways from the caudate-putamen to the main basal ganglia output, the GPi (Penney and Young 1986): The first is a direct, inhibitory, monosynaptic striatal-GPi pathway comprising neurones containing GABA and substance P (SP). The second is an indirect, facilitatory pathway comprising striatal projections to GPe, then STN, and finally to GPi. The striatal-GPe projections are inhibitory and contain GABA and enkephalin. GPe-STN projections are also inhibitory and GABAergic while STN-GPi projections are excitatory and glutamatergic (Robertson et al. 1990).

Nigral cell death following MPTP exposure results in a fall in substance P mRNA expression in GPi and increased levels of glucose metabolism and enkephalin mRNA expression in GPe (Crossman et al. 1985; Au- good et al. 1989). It would appear, therefore, that loss of dopamine projections results in inhibition of the direct striatal-GPi inhibitory pathway and disinhibition of the indirect striatal-GPi facilitatory pathway. The net effect of nigral damage is, therefore, increased inhibitory output from the GPi to the ventral thalamus which in turn leads to inhibition of the SMA and prefrontal areas with consequent rigidity and bradykinesia. Single unit recordings from the GPi in MPTP treated monkeys show increased non-selective firing of neurones during both active and passive limb movements (Miller and Delong 1987). The parkinsonism resulting from MPTP lesioning can be most effectively relieved by reversing the disinhibition of the indirect striatal-GPi pathway. This can be achieved in two main ways: first, by lesioning the STN with either ibotenic acid, thermocoagulation, or high-frequency electrical stimulation (Bergman et al. 1990; Aziz et al. 1991). Second, by blocking the excess glutamatergic output

from STN to GPi with injections of an NMDA antago- nist into GPi or by internal pallidotomy (Graham et al. 1990; Laitinen et al. 1992).

3.3. PET activation studies in PD

Resting levels of lentiform nucleus glucose metabolism in PD patients with early disease are either normal or mildly elevated (Miletich et al. 1988; Wolf- son et al. 1985). If covariance analysis, however, is applied to resting regional cerebral glucose metabolism data sets it can be shown that relative lentiform and thalamic hypermetabolism and premotor hypometabolism is present (Eidelberg et al. 1994). PET is currently unable to separate putamen and pallidal signals but it is likely that the increased lentiform nuclear glucose utilisation represents increased synaptic activity of striatal-GPe projections. Patients with more established disease may show reduced levels of resting striatal metabolism and this is uninfluenced by administration of dopaminergic agents (Wolfson et al. 1985; Kuhl et al. 1984; Leenders et al. 1985). Non-demented PD patients either have normal resting levels of cortical blood flow and metabolism or show mildly depressed frontal function.

Activation studies enable one to demonstrate more fully the effects of dopamine loss on basal ganglia and cortical function. Current theories of basal ganglia connectivity suggest that the major dorsal putamen output is to caudal SMA, while dorsal caudate outputs to rostra1 SMA and dorsal prefrontal areas and ventral striatum outputs to anterior cingulate and orbitofrontal cortex (Alexander et al. 1990). As a consequence, one might predict that dopamine loss would deafferent these particular cortical areas but leave primary motor and lateral premotor cortex function relatively spared.

Playford et al. (1992a) examined the above predic- tion by studying the patterns of regional cerebral blood flow (rCBF) increases in PD patients associated with performance of paced joystick movements. Two paradigms were used: in a “fixed” paradigm the joystick was always moved in a forward direction while in a “free” paradigm the joystick was moved in spontaneously chosen directions avoiding repetition. rCBF levels associated with the motor tasks were compared with resting blood flow, which was in fact normal in these patients. The PD cases were all able to perform the motor paradigms successfully, but took 15-20% longer to respond to the buzzer and complete stereotyped and free-choice joystick movements. As predicted, they showed attenuated increases of contralat- era1 lentiform nucleus, SMA, anterior cingulate, and dorsolateral prefrontal rCBF compared to age-matched controls but there was no significant difference in levels of contralateral sensorimotor and lateral premotor activation (see Fig. 4).

D.J. Brooks /Journal of the Neurological Sciences 128 (1995) l-13

FREE SELECTION CONTROLS P.D.

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Fig. 4. An SPM showing significant rCBF increases associated with performance of paced joystick movements in freely selected directions using the right hand for 6 PD patients. Significant activation of the left motor and lateral premotor cortex, but not the lentiform nucleus, SMA, or dorsal prefrontal areas, are evident. (Courtesy of Dr. E.D. Playford.)

The above study investigated activation deficits in PD associated with paced movements in stereotyped and freely selected directions. Subsequently, Jenkins et al. (1994b) investigated the activation deficits in PD associated with self-paced movements. PD patients and controls were asked to extend their right index finger from a key pad at self determined times, intervals spontaneously varying from l- to 5-set intervals. Self- paced index finger extension activated contralateral motor cortex, lateral premotor cortex, SMA, anterior cingulate, dorsolateral prefrontal cortex and the lentiform nucleus in controls. The PD patients successfully performed the paradigm but, while contralateral motor and lateral premotor cortex activated normally, significant impairment of contralateral striatal, SMA, anterior cingulate, and DLPFC activation was seen.

Striato-frontal projections can be functionally reaf- ferented in PD by administering the dopaminergic agent, apomorphine. Jenkins et al. (1992) performed rCBF measurements in a group of eight patients when at rest and then again when performing paced joystick movements in freely selected directions. Patients were studied off medication for 12 h, then after a subcuta- neous injection of apomorphine but before they had “switched on”, and then once more after improvement of their akinesia. These PD patients were all chronic apomorphine users and administration of this agent per se had no significant effect on rCBF levels. Rever- sal of akinesia was associated with a significant increase in SMA and dorsolateral prefrontal cortex blood flow implicating these areas in selection of volitional movements. In a separate study with ‘33Xe SPECT, Rascal et al. (1992) have also demonstrated improvement in SMA flow when PD patients are treated with apomorphine.

The above PET findings in Parkinson’s disease support modern ideas of basal ganglia connectivity. Loss of

striatal dopamine is associated with functional deaf- ferentation of SMA, anterior cingulate, and dorsal prefrontal areas but appears to spare primary motor and lateral premotor cortex activity. It is, therefore, hardly surprising that PD patients show impairment when performing cognitive tests thought to reflect frontal function (card sorting, set shifting, verbal fluency, planning) and that these frontal deficits should in part reverse after dopaminergic agents are adminis- tered. As a consequence, it cannot be assumed that the cognitive problems exhibited by PD patients are giving us insight into the primary role of the basal ganglia. It is likely that they are telling us as much about frontal as basal ganglia function.

4. Dystonia

4.1. Clinicopathological correlations

Dystonia is a syndrome characterised by abnormal posturing, muscle spasms, and tremor due to involuntary co-contraction of muscle agonists and antagonists. This abnormal posturing is often action induced and the co-contraction leads to slowness, but not inaccuracy of movement (Van der Kamp et al. 1989). Dysto- nia can be task specific, patients only developing co- contraction when performing skilled movements such as writing. These observations suggest that the disorder is likely to be central in origin. The majority of idiopathic cases are now thought to be dominantly inher- ited with around a 40% penetrance and very variable manifestations (Fletcher et al. 1990; Bressman et al. 1989; Korczyn et al. 1981). In some families a locus has been identified on chromosome 9q (Ozelius et al. 1989; Kramer et al. 1990). The dystonia gene/genes and the biochemical nature of the disorder has still, however, to be identified. There have been few pathological studies on cases of idiopathic torsion dystonia (ITD) and these have shown no specific abnormalities. In two cases, alterations of noradrenaline and dopamine levels in brainstem structures have been reported (Horny- kiewicz et al. 1986) but other workers have found no such abnormalities (Jankovic and Svendsen 1987).

The suggestion that dystonia may primarily arise from a disorder of basal ganglia function has in part arisen from observations on acquired cases. Disorders that target the basal ganglia, such as Wilson’s, Hunt- ington’s, Parkinson’s, Hallervorden-Spatz, and Leigh’s diseases, can all be associated with dystonia (Caine and Lang 1988). Additionally, acquired hemi- and focal dystonia cases may show structural lesions in the caudate, lentiform nucleus, or ventral thalamus while associated cortical lesions are rare (Marsden et al. 1985; Pettigrew and Jankovic 198.5).

D.J. Brooks /Journal of the Neurological Sciences 128 (1995) 1-13 9

4.2. Animal models

There are no satisfactory animal models of ITD though dystonic posturing can be induced in non-human primates. Injection of the GABA agonist, muscimol, into the globus pallidus, blocking normal inhibitory output to ventral thalamus, or destruction of GPi with kainic acid, results in involuntary co-contraction when monkeys reach for food (pinch grip is associated with abnormal finger extension). This observation prompted Mink and Thach (1991~) to suggest that a role of the basal ganglia is to inhibit unwanted movements during performance of motor programmes. Lenz et al. (1992) noted that, during interoperative recordings, dystonic patients showed abnormal overactivity of posterior thalamic neurones during active and passive limb movement. This finding confirms that thalamic hyperexcitability is a feature of dystonia and would be compatible with reduced pallidal inhibitory output being present in these patients.

Dystonia can be induced in MPTP-lesioned monkeys by chronically treating them with dopaminergic agents (Boyce et al. 1990). This dystonia model is really more akin to dopa-induced dystonia in Parkinson’s disease than ITD but is of interest. Using 2- deoxy[ “C]glucose autoradiography, Mitchell et al. (1990) have reported increased striatal, pallidal, and subthalamic, but reduced ventral thalamic glucose metabolism associated with apomorphine-induced dystonia in MPTP-lesioned monkeys. As 2-DG uptake in the basal ganglia primarily reflects afferent synaptic activity, these authors concluded that dystonia results from decreased pallidal inhibition of thalamus resulting in an inappropriately excessive input into SMA.

4.3. PET studies

Studies on resting blood flow and metabolism in dystonia have tended to yield conflicting results. This, in part, may reflect the heterogeneity of the cohorts of patients examined. Familial, sporadic, dopa responsive, and secondary dystonia cases have all been grouped together at times and early studies concentrated on hemi- and focal dystonics in order to perform side-to- side comparisons of basal ganglia function. As a consequence, the relevance of some of these PET findings to familial ITD remains unclear.

Chase et al. (1988) studied six sporadic cases of idiopathic dystonia with 2-[‘8F]fluoro-2-deoxyglucose (‘sFDG) under resting conditions. Three of the six dystonics had increased lenticular, and two of these three increased caudate, glucose utilisation contralat- era1 to the more affected limbs. Eidelberg et al. (1990) also reported increased resting lentiform nucleus glucose metabolism contralateral to the affected limbs in two cases of idiopathic hemidystonia, one familial and

the other sporadic. In contrast, Gilman et al. (1988) were unable to find any consistent pattern of abnormal “FDG uptake in their 5 patients with sporadic asym- metrical ITD; four had normal striatal glucose metabolism while one showed contralateral caudate hypermetabolism. Stoessl et al. (1986) were also unable to demonstrate any consistent changes in rCMRGlc in 16 patients with torticollis, four of whom had additional focal limb dystonia. These authors, however, noted a reduced covariance between striatal and thalamic glucose metabolism in their torticollis patients and postulated that striatal-thalamic connectivity was dis- turbed. Recently, Karbe et al. (1992) have reported reduced mean resting lentiform nucleus and frontal glucose metabolism in a mixed group of dystonia cases compared with normal controls. In summary, normal, increased, and decreased resting striatal metabolism have all been reported in dystonia cases.

Activation studies on ITD cases appear to show more consistent findings. Tempel and Perlmutter (1990) examined the integrity of central sensory connections in a group of 11 subjects with idiopathic hemi- or focal dystonia, 6 of whom had writer’s cramp. They used vibrotactile stimulation to activate the sensorimotor cortex (SMC), and measured the resultant increase in blood flow. The dystonic subjects had a normal pattern of resting regional cerebral blood flow (rCBF) but showed a significant attenuation of the contralateral SMC blood flow response to tactile stimulation (80% of normal). This was true whether the affected or “normal” hand was stimulated. The authors did not report on basal ganglia function.

There were, however, difficulties with the above study: he first t was that some subjects developed dystonic spasms in response to the vibrotactile stimulus which could possibly have influenced the rCBF response. The authors controlled for this by having some controls imitate dystonic spasms during stimulation and showed that their SMC activation was increased rather than diminished by voluntary posturing. It is not entirely clear, however, that this was a valid control for the effects of involuntary muscle spasms on cerebral activation. A second problem was that their dystonic patients were on average 25 years older than their controls. More recently the same group compared the cerebral activation associated with vibrotactile stimulation in 6 unilateral writer’s cramp cases and 8 age- matched normal controls (Tempel and Perlmutter 1993). In this study attenuated activation of caudal SMA as well as sensorimotor cortex was noted in the dystonic patients.

Playford et al. (1992b) performed PET activation studies on 6 familial ITD patients off medication, mea- suring rCBF changes while they performed paced joystick movements with their right hands. Two motor paradigms were used: in a “fixed” paradigm the joy-

10 D.J. Brooks /Journal of the Neurological Sciences 128 (1995) I-13

stick was always moved in a forward direction while in a “free” paradigm the joystick was moved in freely selected directions avoiding repetition. rCBF levels associated with the motor tasks were compared with resting blood flow, which was normal for these patients when compared with age-matched controls.

The ITD patients were able to perform the motor paradigms, but took about 20% longer to respond to the buzzer and complete joystick movements in both stereotyped and freely chosen directions. Although bradykinetic compared to age-matched controls, the ITD patients showed significantly increased contralat- era1 putamen, supplementary motor, premotor, and dorsolateral prefrontal area activation. This was, therefore, the opposite of the pattern associated with Parkinson’s disease where these areas were found to be underfunctioning (Playford et al. 1992a). Activation of contralateral sensorimotor cortex was reduced to 40Y0 of normal in spite of the presence of co-contraction during right arm movements. This rCBF reduction did not, however, reach statistical significance. The authors concluded that dystonic limb movements are associated with inappropriate overactivity of the lentiform nucleus and frontal association area projections.

Playford et al.5 (1992b) study has been recently repeated using a fresh group of 8 familial ITD cases and a higher resolution PET camera (Ceballos-Bau- mann et al. 1994). These workers confirmed the observation of increased contralateral lentiform nucleus, premotor cortex, and dorsolateral prefrontal cortex activation when dystonics move their arm in freely chosen directions (see Fig. 5). Additionally, they were able to show that it is specifically the rostra1 lateral and mesial premotor areas that are over-active in dystonia

Additional activation in dystonics versus controls

motor execution versus rest

P.aO?bm- meal

Fig. 5. An SPM showing relative rCBF increases compared to controls when ITD patients perform paced joystick movements in freely selected directions with the right hand. Striatal, premotor, and prefrontal areas are relatively overactive in ITD (by courtesy of Dr. A.O. Ceballos-Baumann).

while the caudal lateral premotor and supplementary motor areas and the primary sensorimotor cortex all had significantly attenuated activation. This finding, therefore, lends support to the observations of Tempel and Perlmutter (1990, 1993) and suggests that sensorimotor cortex and caudal SMA activation is impaired in ITD.

The cortical regions with attenuated activation in ITD (primary sensorimotor and caudal premotor) are executive areas that send direct pyramidal tract projections to the spinal cord (Hutchins et al. 1988); rostra1 premotor and dorsal prefrontal areas send no such projections. A picture is, therefore, emerging where dystonic limb movements appear to be associated with inappropriate overactivity of basal ganglia-frontal association area projections but underfunctioning of the primary executive cortical areas. Such a phenomenon could be explained if the pathology of ITD were to directly affect both the basal ganglia and the executive motor areas, disinhibiting the former but inhibiting the latter.

If this hypothesis is correct, one might predict that patients with acquired dystonia due to focal basal ganglia or thalamic lesions would show normal activation of executive cortical areas as these should be free of pathology. Inappropriate overactivity of basal ganglia projections to rostra1 premotor and dorsal prefrontal cortex, however, would persist. Ceballos-Baumann et al. (1994) have scanned five such patients with acquired hemi- or focal dystonia while performing paced joystick movements in freely chosen directions. In contrast to the ITD patients, the secondary dystonia group showed reduced rather than raised contralateral lentiform nucleus activation in association with joystick movements reflecting the presence of their structural lesions. In common with ITD, premotor and dorsolateral prefrontal cortex activation was increased but, in contrast, primary motor cortex activation was increased rather than decreased. These findings, therefore, support overactivity of basal ganglia projection areas (rostra1 premotor and dorsal prefrontal cortex) on limb movement as being the unifying mechanism of dystonia and lend credence to the idea that the pathology of ITD has a direct inhibitory effect on sensorimotor cortex function.

The question then arises, what is the significance of the frontal association area overactivity that is evident in both idiopathic and acquired dystonia? Three possi- bilities can be envisaged: first, the overactivity represents a primary dysfunction of motor planning cir- cuitry. Second, the functional deficit in dystonia is at an executive level and the prefrontal cortex becomes overactive in a conscious attempt to try and suppress the unwanted movements. Third, the frontal overactivity simply represents a secondary phenomenon reflecting primary basal ganglia overactivity.

D.J. Brooks /Journal of the Neurological Sciences 128 (1995) l-13 11

In order to examine the function of planning cir- cuitry in ITD, Ceballos-Baumann et al. (1994) studied the cerebral activation associated with imagination of joystick movements in freely chosen directions. Rate of imagined movement was paced at 3-set intervals by a tone. In both ITD patients and age-matched controls imagination of movement led to significant activation of dorsolateral prefrontal and rostra1 supplementary motor areas, lentiform nucleus, but not sensorimotor cortex. No significant differences in levels of activated rCBF changes were found between the normal and dystonic cohorts. The authors concluded that the primary deficit in idiopathic dystonia must lie at an executive rather than planning level.

So, in summary, PET activation findings in idiopathic and acquired dystonia are compatible with inappropriate overactivity of the basal ganglia and their frontal projections on limb movement underlying this condition. Whether the frontal association area overactivity is simply secondary to primary basal ganglia overactivity or represents an adaptive phenomenon in a conscious attempt to suppress the syndrome is unclear. In idiopathic dystonia significant underfunctioning of primary sensorimotor and caudal premotor executive areas is also evident suggesting that the pathology of ITD may also directly affect these executive circuits.

5. Conclusions

On the basis of PET activation data currently avail- able it is possible to come to the following tentative conclusions about the role of the basal ganglia: (a) It seems unlikely that the basal ganglia play a primary role in determining basic parameters of movement. (b) The basal ganglia are not directly involved in motor skill acquisition or in promoting automaticity of movement. The cerebellum is the subcortical structure most likely to be involved in these processes. (c) As the basal ganglia are not differentially activated by performance of complex sequences of movements compared with stereotyped actions, facilitation of sequential movement is unlikely to be their primary purpose. (d) The basal ganglia do not appear to be directly involved in decisions regarding direction or timing of movement. They are, however, equivalently activated during imagination and performance of actions which suggests that they play a role in movement preparation and execution. This role could conceivably be to moni- tor and optimise the pattern of muscular activity employed by a limb to reach its target most efficiently once a motor decision is taken. (e) The finding of inappropriate basal ganglia overactivity in idiopathic torsion dystonia during limb move-

ment is compatible with the view that they also play a role in suppressing unwanted movements during motor tasks. (f> It is possible that the basal ganglia play a role in adapting to novel circumstances or facilitating rewarded actions; to date, no PET studies have ad- dressed these questions.

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The role of the basal ganglia in motor control: contributions from PET

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