The physiological basis of clinical deficits in Parkinson’s disease

Progress in Neurobiology 69 (2003) 27–48

The physiological basis of clinical deficits in Parkinson’s disease J.H. McAuley∗ Department of Neurology, Royal London Hospital, Whitechapel, London E1 1BB, UK Received 7 January 2002; accepted 12 December 2002

Abstract Despite the fact that Parkinson’s disease (PD) is a relatively common neurological condition, the physiological derangements that result in its clinical features remain unclear. On combining findings from psychophysical, clinical and electrophysiological studies, an overriding theme is proposed that PD deficits are essentially quantitative rather than qualitative in nature. This may arise because the normal function of the basal ganglia is to activate neural processes selectively, providing appropriate diversion of “attentional” resources for decision-making aspects of motor tasks and appropriate “energising” of the executive aspects of such tasks. It is suggested that these concepts of attention, an idea stemming from psychophysical studies, and of energisation, which has derived from kinematic studies, may in fact reflect the same universal process of selective facilitation of particular processes and inhibition of others. In PD, without efficient facilitation, tasks may still be performed but less well than in normal individuals. Possible underlying mechanisms of basal ganglial function are discussed in the context of new findings on direct and indirect pathway actions and the role that oscillatory modulations may play in achieving selective facilitation is explored. Further investigation of disturbances of such mechanisms in PD may prove important in understanding the underlying pathophysiology of the condition. © 2003 Elsevier Science Ltd. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Hypothesised role of the basal ganglia in motor control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. The “selective facilitation” hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Anatomical studies and various basal ganglial diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Psychophysical studies in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Decision making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Motivation and arousal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Neurophysiological and clinical studies in PD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1. Motor programs and plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2. Execution of movement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.1. Rigidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.2. Bradykinesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.3. Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.4. Postural control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.5. Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.6. Eye movements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Summary of evidence for selective facilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: CBD, corticobasal degeneration; CNS, central nervous system; CRT, choice reaction time; DOPA, dihydroxyphenylalanine; EEG, electroencephalogram; EMG, electromyogram; GPe, globus pallidus externa; GPi, globus pallidus interna; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MSA, multiple systems atrophy; PD, Parkinson’s disease; PET, positron emission tomography; PSP, progressive supranuclear palsy; SNc, substantia nigra compacta; SRT, simple reaction time; STN, subthalamic nucleus ∗ Tel.: +44-20-8970-8279; fax: +44-20-8970-8236. E-mail address: [email protected] (J.H. McAuley). 0301-0082/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0301-0082(03)00003-0

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3. Parallel pathway organisation of the basal ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Oscillatory activity and CNS processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. How oscillatory activity may mediate selective facilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The thalamus and CNS oscillations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Basal ganglial oscillations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Low-frequency widespread oscillations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. High-frequency localised oscillations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In 1817, James Parkinson first formally described the clinical features of the condition that bears his name. His account included “involuntary tremulous motion . . . in parts not in action . . . with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured.” As the disease progresses, movements “are accomplished with considerable difficulty, the hand failing to answer with exactness the dictates of the will.” Parkinson’s disease (PD) is now typically described in terms of the classic triad of bradykinesia, rigidity and rest tremor, combined with a loss of normal postural control, and is identified as a common condition affecting 1% of the population over the age of 50 (Adams and Victor, 1993). Since its identification as a degenerative disease arising from a rather specific dopaminergic deficit in the basal ganglia, this clinical syndrome can now be anatomically localised, resulting in the collection of an enormous quantity of information on anatomical connections, lesioning effects, electrophysiological recording and stimulation, neurotransmitter activity, functional imaging and psychophysical studies. A “dual pathway” model of basal ganglial action has been developed based upon the idea of parallel anatomically and pharmacologically distinct “direct” and “indirect” pathways. However, it has proved difficult to link such underlying “internal” mechanisms to the “external” manifestations of basal ganglial action and to link their dysfunction in PD with clinical rigidity, tremor and bradykinesia. Physiological and psychophysical studies on Parkinsonian behaviour tend instead to highlight a bewildering array of motor deficits and subtle perceptual and cognitive deficits. Thus, most neurophysiologists would still be hard pressed to answer the basic question, “what goes wrong with basal ganglial function to result in PD?” in the way they could explain the physiology underlying other neurological states such as sensory loss or spasticity. Recent studies have begun to throw doubt upon the established dual pathway basal ganglial model, highlighting other processes such as complex interactions between transmitter systems and neural oscillatory behaviour. It is therefore timely to review the various physiological manifestations of PD. Rather than empirically listing information on physio-

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logical deficits in PD, this review starts with a hypothesis on the fundamental function of the basal ganglia and uses this framework to relate the known manifestations of PD with new concepts on basal ganglial mechanisms.

2. Hypothesised role of the basal ganglia in motor control Clinical, physiological and pathological evidence indicates that PD is primarily a motor disorder related to basal ganglial dysfunction. Although autonomic deficits, cognitive problems and positive sensory symptoms are frequently associated with PD, the overall clinical impression still supports Parkinson’s initial comment that the brunt of involvement is borne by the motor system, with major cognitive and perceptual defects often indicating a different diagnosis, such as one of the so-called “Parkinson plus” syndromes of multiple systems atrophy (MSA), dementia with Lewy bodies, corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP) (Weinmann, 1975). Neurophysiological recording of the basal ganglia in animals shows that over half of globus pallidus (GP) neurones are found to fire in response to motor activity but virtually none are triggered by passive limb movement (Iansek and Porter, 1980). Finally, while neuronal degeneration in PD is found in the midbrain reticular formation, sympathetic ganglia and lower brainstem nuclei, these changes are much more mild than in the substantia nigra, the main source of dopaminergic inputs to the basal ganglia. (In PD, the substantia nigra actually become visibly pale to the naked eye.) To consider the actual nature of the Parkinsonian basal ganglial motor disorder, one might start by postulating where the basal ganglia are likely to fit into an overall scheme of motor organisation (Fig. 1). The purpose of such a scheme is not to purport that loosely definable terms such as “idea” and “decision” may be boxed and linked to provide an accurate model for cerebral function, but to form a rough framework for dealing with the overall processes in simple terms. It is considered that the basic motor pathway (Fig. 1, thick arrows) involves processes starting in the association cortex areas, being translated via mossy fibre inputs to the lateral cerebellum into a form suitable for simple motor

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Fig. 1. A scheme of motor organisation. The primary function of the basal ganglia may be in selective facilitation of processes required for completion of a particular task and inactivation of other processes. In psychophysical terms applied to decision-making processes and selection of movement strategies, this has been called focussed or selective attention, while in generation of the full amount of motor activity, the function may be termed “energisation”. (There may also be a voluntary process of facilitation, e.g. to heighten certain senses or “concentrate” upon certain activities, and a parallel “autonomic” facilitation that may bypass basal ganglial pathways to engage “fight or flight” responses).

cortex commands, and descending from motor cortex down the motor tracts to the muscles. As well as this direct hierarchy of motor organisation from the original idea to move to its execution, there may be a number of other systems that impact on this pathway. Motor activity directly employs sensory information in the form of feedback in the performance of the task (Fig. 1, bottom left). Such a system may be called closed loop feedback, i.e. dependent on ongoing sensory reafference, and its simplest manifestation is the sensorimotor reflex. In addition, there may exist an open-loop pathway (Fig. 1, bottom right), where movements can or must be performed by predicting their effect rather than by ongoing feedback. An “efference copy” of the output motor commands (what was intended) is passed to the intermediate cerebellum via pontine nuclei and mossy fibres (Allen and Tsukahara, 1974). This can later be compared with proprioceptive input (what actually happened) via climbing fibres to modify the subsequent execution of commands and make them more accurate. If efference copy connections are progressively modified to mimic peripheral feedback more closely (i.e. prediction), the efference copy loop could provide a more accurate “surrogate” for actual peripheral feedback. An example of an open-loop task would include one where hand motion is directed in such a way that a thrown ball hits a distant target; visual information can be used to modify the trajectory of the ball on subsequent trials to improve accuracy (Martin et al., 1996). In contrast, an equivalent

closed-loop task would include ongoing maintenance of the hand position against a continuous unpredictably varying force. In addition to cerebellar motor adaptation to improve open-loop task performance, cerebellar and cortical pathways are likely to mediate the learning of completely new tasks (labelled motor learning). 2.1. The “selective facilitation” hypothesis Where might the basal ganglia fit into this scheme of motor organisation? In this review, the hypothesis is developed that the basal ganglia are structures primarily concerned with focussing neural resources by selective facilitation rather than with actually implementing any particular activity. This concept arises as an evolution of some previous hypotheses separately generated to explain the subtle cognitive deficits and gross motor deficits of Parkinson’s disease. From early neurophysiological investigation of perceptual processes in animals, Hassler (1978) initially hypothesised that the basal ganglia focus the “attention, the emotional participation and the excitability on one single event” while suppressing all others. Denny-Brown and Yanagisawa (1976) came to similar conclusions from animal lesioning studies. More recent human studies addressing the psychophysical aspects of dysfunction in PD have led to the related hypothesis that the capacity of the brain for computation and processing has a finite capacity, which is selectively directed by the basal ganglia to those activities requiring resources

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at any given time (Brown et al., 1993). While some of this direction of activity in the human occurs at a conscious level by “concentration” upon certain percepts and motor tasks, there are likely to be lower level mechanisms mediating voluntary activity and wholly directing subconscious activity that selectively allocate resources toward motor task decision making and processing. The basal ganglia may control this selective allocation of resources to the cognitive processing of attention-demanding motor tasks. The motor deficits of PD strongly indicate a role for the basal ganglia in the execution of movement as well as in higher-level perceptual and decision-making processes. Neurophysiological studies on bradykinesia, a fundamental motor Parkinsonian deficit, have led to the hypothesis that the basal ganglia “energise” the lower-level executive aspects of motor tasks to generate EMG bursts sufficient for the desired amplitude of ballistic arm movements (Hallett and Khoshbin, 1980). Despite focussing on very disparate aspects of function, the hypotheses of selective diversion of attention to cognitive processes and energisation of muscle activity have some common ground. This review attempts to combine the two hypotheses into an overall concept of selective facilitation and thereby explain both the psychophysical and motor deficits demonstrated in PD. The rest of this review section will describe in more detail how this combined concept relates to the large body of available anatomical evidence and clinical observations on PD and other basal ganglial diseases, as well as to the various psychophysical and neurophysiological studies. It is hoped that the hypothesis will explain an overriding theme that becomes apparent on reviewing the multifarious Parkinsonian deficits, namely that they nearly all have a quantitative rather than qualitative flavour. In other words, the PD patient typically does not have a specific inability to perform a certain function, such as perceiving an object properly, deciding upon the correct movement to make or smoothly tracking a target, but instead simply performs many different functions less well than would a normal individual. 2.2. Anatomical studies and various basal ganglial diseases Classical physiological understanding of the anatomical localisation of neurological function in humans has progressed in large part through the study of the derangement of normal function that results from anatomically defined lesions. While lesioning and anatomical studies have broadly identified functions of most cortical areas, brainstem nuclei and the cerebellum, anatomical lesions of the basal ganglia result in deficits that are unpredictable and hard to define in terms of a clear motor, sensory or cognitive function. This led to the consideration that the basal ganglia have a modulatory role rather than controlling any one specific function (Denny-Brown and Yanagisawa, 1976).

Fig. 2. Schematic pseudo-axial view of the basal ganglia and some of their anatomical connections. There may be two functionally distinct pathways from the dopaminergic inputs leading from the substantia nigra compacta (SNc). The direct pathway (black arrows), perhaps mediated more by D1 dopaminergic receptors, passes from the striatum direct to the globus pallidus interna (GPi) on its way to the thalamus, while the indirect pathway (open arrows), mediated more by D2 receptors, passes from the striatum first to the globus pallidus externa (GPe) and then to the subthalamic nucleus (STN) before reaching the GPi. Excitatory and inhibitory influences are indicated. The dashed borders of the SNc and STN represent their non-anatomical locations; the STN actually lies inferior to the thalamus and the SNc just inferior to the STN within the midbrain.

The striking neuroanatomical feature of the basal ganglia is their widespread connectivity (Carpenter, 1976), making them ideally placed to subserve this modulatory action. A pathway is revealed (Fig. 2) where inputs from association cortex and other cortex areas converge on the striatum (putamen and caudate nucleus) where they are modulated by dopaminergic projections ascending from the pars compacta of the substantia nigra. The striatum outputs to the globus pallidus and the substantia nigra reticulata via direct and indirect pathways, the latter involving the subthalamic nucleus. Finally, these structures give descending outputs to certain brainstem nuclei as well as outputs to the thalamus, specifically the nuclei ventralis lateralis and anterior, the centrum medianum and the lateral habenular nucleus. These thalamic nuclei have widespread ascending projections to motor and frontal cortex, completing a complex cortico–striato–thalamo–cortical loop. As a result, striatal lesions are often found to mirror the effects of lesions in specific frontal lobe areas. These effects may take the form of rather complex behavioural deficits, such as problems with choice tasks (Oberg and Divac, 1979). Certain neurological diseases other than PD affect the basal ganglia. Some have extrapyramidal features that may overlap with PD, such as MSA and PSP, while others,

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if anything, appear to represent a state opposite to that of Parkinsonism, such as choreiform Huntington’s disease and hemiballism resulting from subthalamic infarction (Weinmann, 1975). In Parkinsonism, there is diffuse rigidity that is difficult to break through, while the latter conditions are characterised by distractibility and excessive movements sometimes generated by voluntary actions that seem to spread out of control. It therefore appears that different basal ganglial diseases represent extremes along a continuum of facilitation levels. 2.3. Psychophysical studies in PD 2.3.1. Perception Psychophysics is in large part concerned with perception, so many such studies have been directed at investigating perceptual deficits in PD. Despite the fact that PD has been considered to be a disease of the motor system rather than of perceptual processes, a number of deficits have been identified in the latter domain. When subjectively adjusting a line to vertical in the face of body tilt, PD patients tend to overcompensate so that the line is in fact tilted in the opposite direction to that of body tilt (Procter et al., 1964). There also appears to be delayed tactile recognition of objects (Dinnerstein et al., 1962). In unilateral Parkinsonism, there can be a relative unilateral visual neglect in terms of exploration of the environment (Ebersbach et al., 1996). However, when there are perceptual deficits in PD, they are generally in the context of motor tasks and there are many other studies specifically arguing against such deficits. For example, in experiments where targets must be tracked with a joystick, when the task changes unexpectedly PD patients perceive this as often as normal subjects, but they are much slower to correct their false moves (Angel et al., 1970). This cannot be simple rigidity or antagonist over-activity because the crucial factor is here the delay in stopping an ongoing inappropriate movement. This was inferred as representing a problem with the motor processing step between decision making and execution, but more broadly indicates that the problem lies more with the motor aspects of tasks that their perceptual aspects. 2.3.2. Decision making If PD patients perceive tasks normally, perhaps, as suggested by the tracking experiment above, their slowness to react relates to an inability to use normally perceived information to make motor decisions. This represents the “highest level” and perhaps least-understood area of CNS function, namely the decision-making level of processing lying between sensory “input” and motor “output”. The fact that such functions are also proposed to be subserved by the pre-frontal cortex may reflect the strong reciprocal connections between such cortical areas and the basal ganglia. A number of related hypotheses have been put forward to describe a decision-making level deficit of PD. Cools et al. (1984) considered that PD patients have a loss of flexibil-

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ity in information processing which becomes manifested in specific problems with performing two tasks simultaneously and with task switching. However, in other experimental designs the specific problem did not lie in this area but in tasks demanding active “effort”, e.g. in a recall as opposed to a recognition memory task (Weingartner et al., 1984). Finally, a particular deficit with Wisconsin card sorting tasks, where a subject must sort coloured and shaped cards according to criteria he must work out for himself by trial and error, led to the hypothesis that a fundamental deficit in PD is with self-directed tasks requiring internal rather than external cues (Taylor et al., 1986). Investigation of such hypotheses has been led largely by measurement of reaction times, a way of quantifying the processing slowness of PD. One example is a version of the Stroop test (Brown and Marsden, 1988). A screen shows the words “red” or “green” written in ink of the opposite colour and the cue “ink” or “word” defines whether the subject should press a red or green button according to the colour of the ink or to the meaning of the word. The “ink” versus “word” cue alternates every 10 trials. In an externally cued task, the screen shows the cue each time, while in an internally cued task, the subject must remember the current response pattern after being told at each switch. It was found that PD patients were relatively slower and made more errors on the internally cued task. Although the PD patients may simply have had psychomotor slowing (Hart et al., 1998), as suggested by a poorer affect-arousal state and by slowness on a control task where colour and word matched, the internal cue deficiency was an additional specific deficit and there was no interaction between individual patients’ affect-arousal scores and the effect of lack of cues on performance. The lack of problem with the externally cued Stroop task clearly argued against a Stroop effect of counter-intuitive cues, and the normal pattern of reaction times within and between the switches every 10 trials showed there was no task switching problem in PD. The difficulty with internal cues does not mitigate against the hypothesis that “effort” demanding tasks are harder. Provided the resource capacity of the brain for processing is limited and that there is a performance ceiling effect, where an easy task (the externally cued task) would be performed just as well by PD patients as by normal subjects, then the observed difficulty with internal cues might simply be because it is a more difficult task requiring more resources for a certain level of performance (Fig. 3). This hypothesis predicts that control subjects would behave like PD patients if the resources available were somehow reduced. When this was done by requiring the subjects simultaneously to perform a resource-demanding secondary task (random number generation), there was the expected greater decrease in performance for the internally cued that for the externally cued task (Brown and Marsden, 1991). Both normal subjects and PD subjects showed this effect. As predicted, a non-resource-demanding secondary task (speaking nonsense syllables), did not impair performance.

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Fig. 3. Performance resource function for processing of externally and internally cued tasks. The task is here to speak a colour depending either upon the meaning of a displayed word or upon the actual ink colour of the word (“red” displayed in green ink or “green” displayed in red ink). In the externally cued task, the response criterion (semantic versus ink) is displayed on each trial while in the internally cued task the current criterion must be remembered. It is hypothesised that limited resources are available for performing these “effort” demanding tasks, that there is a ceiling effect of maximum performance (speed and accuracy) no matter how many resources are devoted to the task (Pmax ), and that there are a minimum level of resources that must be allocated to perform the task at all (Rmin ). The externally cued task (dashed line) is easier than the internally cued task so it reaches its maximum level of performance for a lower level of resources used, but for a normal subject they are both maximised given the level of resources available (R1—resource level available to control subject). However, there becomes a disparity when there are reduced resource levels such as in PD (R2—resource level available to PD patient) or when resources must be devoted to a secondary task such as random number generation (R3—resource level available to control subject who must simultaneously call random numbers). Thus, the PD patient and the subject simultaneously calling random numbers both have a relatively defective performance on the internally cued task. Produced with permission from Brown and Marsden (1991).

However, this model does not fit all observations. When the secondary task was foot tapping, this impaired the performance of PD patients but not controls, suggesting that repetitive limb movements become resource demanding in PD. Possibly related to this is the fact that only “on” PD patients can use the predictability of repetitive tasks to improve performance (Jahanshahi et al., 1992). Predictive behaviour is dependent upon attention to internal cues. Complications related to medication “on” versus “off” effects may partly be accounted for by the finding that excessive dopaminergic stimulation can improve or worsen cognitive performance (Gotham et al., 1988). This may explain why the task-switching type functions described above, which are mediated by dopaminergic pathways that tend to be affected in PD, are sometimes improved with dopaminergic replacement. On the other hand, probabilistic reversal learning, whose dopaminergic pathways may relate more to reward-based behaviour rather than to selective attention, is preserved in PD and is found to be worsened after dopaminergic medication in both PD patients (now over-stimulated for this task) and in normal subjects (Cools et al., 1984; Mehta et al., 2001). In animal behavioural experiments, the

latter pathways appear to be selective for unexpected desirable as opposed to undesirable attention-grabbing stimuli (Schultz, 1998). Perhaps excessive signalling of the occasional “wrong but scored correct” stimulus–outcome association early in a probabilistic experiment interferes with subsequent learning. Further complications arise when one looks at a different experimental paradigm (Goodrich et al., 1989; Brown et al., 1993). In a simple reaction time (SRT) task, a subject must move to press a single button according to a visual cue. Such a task utilises an automatic pre-planned strategy (moving the hand in an already known direction) requiring internal “attention”. Conversely a choice reaction time (CRT) task involves a visual cue indicating which of two buttons must be pressed and therefore requires processing of perception. Although both PD patients and controls were faster at the easier SRT task than the CRT task, the PD patients had a relatively worse SRT compared to controls. These findings are paralleled by Bereitshaftspotential and positron emission tomography (PET) data on self-paced versus cued finger movements—the greater differences between PD and control patients are found for the self-paced task (Jahanshahi et al., 1995). Such findings are at odds with the resource limitation hypothesis, where harder tasks should be performed worse, and support the hypothesis that internal cues are the specific problem. Finally, when the CRT task is made more complicated by having a counterintuitive array of four choices, the PD patients become relatively worse at the CRT than the SRT (Brown et al., 1993), now supporting the resource limitation hypothesis! Clearly, the true deficit is likely to reflect components of both processes. Perhaps one might consider that while PD patients have reduced availability of resources, internal cues are also relatively more resource demanding in PD so that they perform self-paced tasks less well unless the externally cued task is much harder. The basis for this reduction of available resources in PD could simply be a reduction in total processing capacity. However, this might be expected to be more a feature of dementia than of idiopathic PD, a condition in which clinically manifest dementia is conspicuously absent. (Dual task performance is in fact impaired in early Alzheimer’s disease (Baddeley et al., 2001).) An alternative explanation for a reduction of available resources is that PD patients have reduced ability to direct or focus a normal level of resources, an idea that parallels the selective attention deficit proposed from animal lesioning behavioural studies. Despite the finding that task-switching was normal in PD, the particular problem with self-paced and predictive tasks, where the subject must allocate resources spontaneously rather than on cue, supports the latter explanation. 2.3.3. Motivation and arousal As discussed above, specific deficits seem to occur in PD more at the decision-making level of processing than in motivation or arousal. Indeed, rather than an arousal

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deficit in PD, an anecdotal feature is that sudden visceral “autonomic” arousal can temporarily allow patients to bypass their deficits—severely bradykinetic individuals may activate a sudden “fight or flight” response to avoid being hit by a speeding car. The effect of arousal on performance appears to be selectively preserved and presumably focuses resources via an alternative pathway to that involving the basal ganglia (Fig. 1). Nevertheless, PD patients are well known to have a flat affect and abulia and this is associated with psychomotor slowing. In support of these observations in patients, studies in animals without experimental Parkinsonian lesions indicate that most phasic midbrain dopaminergic activity appears to signal reward-associated stimuli appropriate for motivation-driven learning behaviour (Schultz, 1998). It must be remembered, however, that abulia is not the main PD deficit. Degeneration in PD is not uniform among midbrain dopaminergic projections; severe damage occurs to neurones terminating in the dorsal striatum while projections most likely to have a role in motivational behaviour, such as those to the nucleus accumbens or to non-striatal areas, are only lost late in the disease (Agid et al., 1993). 2.4. Neurophysiological and clinical studies in PD While the perceptual, motivational and decision-making levels of the motor pathway are perhaps best explored by psychophysical studies, motor programs and their execution can be investigated more directly by careful clinical observations and by neurophysiological stimulation or recording of central neural and peripheral motor activity. 2.4.1. Motor programs and plans Motor programming may be considered to be the process occurring in preparation for movement where the initial command is reformulated or “translated” into signals that will direct each relevant muscle to act in the appropriate manner (Fig. 1). There is little electrophysiological evidence for a central role of the basal ganglia in this process. Although there are quantitatively reduced amplitude Bereitshaftspotentials in PD (Shibasaki et al., 1978), they are qualitatively little changed, indicating that preparation for movement is not grossly disrupted. Similarly, the firing of pallidal cells, reflecting the striatal output, does not generally occur specifically at the time of preparation for or initiation of movement but sometimes such units fire only after such movements have already started (Iansek and Porter, 1980). The units are more generally linked to specific movements of specific body parts rather than to the timing of such movements. In addition, stimulation of the striatal units generally does not actually result in movements of these body parts in the same way that is found with stimulation of the appropriate motor cortex area. Striatal stimulation instead results in stereotyped whole head and neck versive movements to the contralateral side, with a widespread inhibitory effect upon other areas of the

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CNS (Delgado, 1979). Similarly, internal caudate nucleus stimulation in the freely behaving cat results in head turning, while ventromedial caudate stimulation produces arrest and crouching reactions (Murer and Pazo, 1993). These effects are blocked by pallidal lesioning, indicating that they arise specifically from striato–pallidal pathways. Large bilateral striatal lesions cause general inattention (Denny-Brown and Yanagisawa, 1976). As described above, such findings have been interpreted as indicating that the basal ganglia are involved in complex behaviours related to directing attention and inhibiting distracting sensory input. Perhaps, therefore, the recordings related to specific body part movement reflect a “sensory” function. However, the units do not fire in response to passive movement of the body part, indicating that they are specific for motor activity, although they would appear to “signal” such activity rather than generate it. Moreover, some studies indicate that for striatal units to be involved, such specific movements must also be part of a more complex whole (Rolls et al., 1979). Since stimulation (presumably of large numbers of units) seems to relate to general or lateralised attentional activity, the role of specific striatal units might be to direct attention to movement of a specific body part that forms part of a more complex motor task without actually directly controlling the movement of that body part. Marsden (1982) interpreted these findings, particularly those where pallidal firing tends to occur after movement initiation, as suggesting a role in the “automatic execution of learnt motor plans.” Rather than the basal ganglia preparing motor programs in advance of movement, they process an efference copy of motor instructions. They are then able to sequence the relevant motor programs in a plastic manner for more facilitated execution of future movements of this type (Bernstein, 1967). Since the efference copy is not actually controlling the movement, the temporal relationship of firing may be rather loose and electrical stimulation of the basal ganglia will not necessarily result in these movements. Marsden distinguished this stored “motor plan” from a pre-execution “motor program” by using the analogy of handwriting. Different muscles are used when writing on paper from when writing on a blackboard and yet a person’s signature is still the same in character, although obviously greatly different in size; motor programs control the muscles, while the stored motor plan determines the handwriting style. Thus, one might consider that motor programs are muscle coded while motor plans are task coded. A single motor plan selects and sequences a number of lower-level motor programs. Using this hypothesis, the clinically observed inability in PD to perform two tasks that overlap in time may be interpreted as a problem with planning the sequence of programs. If the basal ganglia were indeed critical for learning and then automatically sequencing motor plans, one would expect the main deficits of PD to involve motor learning in terms of automation of tasks. However, in making specific types of ballistic movements, it is the initial slowness that

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is found to characterise the condition and the improvement with training is in fact normal (Platz et al., 1998). A similar study indicates that the slowness to move may be paralleled by a slowness to train, but the final amount of training improvement is still ultimately normal (Soliveri et al., 1997). To extend the handwriting analogy, the impression one has in early PD is that the plan of handwriting is preserved— the signature is smaller but still recognisable as belonging to the same individual. Only when the friction of the pen on the paper seems too great to overcome does the actual pattern deteriorate. The deficits of PD seem to relate more to quantity of movement than to quality of motor plans. Simple single-joint ballistic movements (see below) would not appear to require much of a plan, and yet they are significantly impaired in terms of slowness. Finally, the fractionation of movement observed in PD that has been attributed to defects in sequencing of motor plans (Schwab et al., 1954) could just as easily be interpreted as a specific problem with attending to multiple tasks. In this manner, the problem is rather analogous to the psychophysical deficits found in dual task paradigms. Perhaps, therefore, the abnormalities in production of sequences of complex movement can similarly be attributed to a defect in focussing attention and the resultant inability to allocate processing resources efficiently. 2.4.2. Execution of movement It appears that the motor deficits of PD, apparent during single joint as well as complex programmed and planned movements, might be more those of execution than of programming or planning. However, while the simple fact that PD is a movement disorder means that there are obviously deficits in the execution of movement, this does not prove that the deficit actually acts at the level of execution and not some higher level that secondarily becomes manifest in task performance. Nevertheless, a physiological exploration of the main movement disorder features of PD may provide insight into the underlying basal ganglial deficit. 2.4.2.1. Rigidity. The nature of PD rigidity was perhaps first addressed in detail by Walshe (1924). Although studies on PD patients with deafferentation from coincident tabes dorsalis gave conflicting results, the selective loss of rigidity without loss of voluntary strength with infusion of anaesthetic to block spindle afferents suggested that rigidity was mediated by peripheral feedback. (Interestingly, the PD tremor was not relieved.) Since rigidity represents an increase in tone in the resting state when not actively engaged in voluntary activity, it seems reasonable to pursue tonic reflex mechanisms as a cause of rigidity. This notion is supported by the fact that steady-state reflexes, polysynaptic reflexes mediated by skin afferents, long latency (possibly transcortical) reflexes to maintained stretch and the tonic vibration reflex all tend to be increased in PD but the H-reflex remains normal (Andrews et al., 1972; Delwaide et al., 1974; Tatton and Lee, 1975; McLellan, 1973).

The dependence of rigidity upon certain reflexes and increased reflex gain in PD would be consistent with the possibility that the rigidity is mediated via reflexes as well as with the notion that it actually occurs at the reflex level, and the selective effect upon certain reflexes supports the former idea. In fact, the gain of ␥-efferent activity, which specifically drives muscle spindles to set reflex sensitivity, remains normal and increases in spindle activation are simply secondary to increased ␣-activity, the main descending drive from the CNS to the muscles (Burke et al., 1977). In other words, rigidity in PD reflects the fact that patients’ muscles are never at rest but subject instead to a continuous descending activation which at the same time activates the more complex steady-state reflexes. The idea of centrally derived rigidity may be explored by cortical stimulation experiments. In PD, there is little abnormality in single-shock thresholds for limb electromyogram (EMG) activity produced by transcranial magnetic stimulation over the contralateral hemisphere, although paired magnetic shocks separated by 1–5 ms reveal decreased cortico–cortical inhibition (Ridding et al., 1995). On looking at more widely spaced paired shocks, the normal silent period following stimulation is somewhat shortened and yet the degree of EMG inhibition during this silent period is greater (Berardelli et al., 1996a). Clearly, there are complex activating and inhibiting effects on cortical activity in PD that might parallel the equally complex peripheral manifestation of increased tone combined with reduced movement. 2.4.2.2. Bradykinesia. The clinical impression of PD is that the main problem is poverty of movement. The actual composition of movement, in terms of the synergistic and antagonistic actions of individual muscles, seems preserved, both from clinical observations and from EMG recordings of reciprocal inhibition (Wilson, 1925; Day et al., 1981). When a slow movement is all that is required, PD patients have little difficulty, even if the movement requires fine control and accurate sensory feedback. Thus, there seems to be little qualitative problem with the motor programs that determine the actual structure and control of movement. The specific PD deficit of speed of movement, whether simple or complex, leads naturally to a physiological study of single-joint open-loop ballistic movements. Such movements normally consist of a triphasic pattern of agonist burst, antagonist burst and second agonist burst. The antagonist burst functions to brake the initial pulse of movement, while the second agonist burst dampens down the unstable oscillations that might otherwise result. As perhaps expected, the basic motor program of the triphasic pattern is preserved in PD. However, EMG records show that instead of a single triphasic pattern, there is a whole series of smaller triphasic bursts (Fig. 4). This was first interpreted as a failure to “energise” the appropriate muscles and a saturation of the size of the agonist burst so that multiple bursts are required to generate the required amplitude of movement (Hallett and Khoshbin,

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Fig. 4. Electromyographic (EMG) recording of a rapid elbow flexion movements of 10◦ (A), 20◦ (B) and 40◦ (C) amplitude made by a Parkinsonian patient, showing the repeated burst pattern. A normal subject would generate a single large EMG burst (consisting of a triphasic pattern of first agonist burst, antagonist burst, second agonist burst). The periodicity of the bursts is here approximately 100 ms, corresponding to a 10 Hz rhythmicity during this trial. From Hallett and Khoshbin (1980), with permission.

1980). However, subsequent experiments showed that the agonist burst could vary in size with no clear maximum level (Berardelli et al., 1986), so it seems that the motor system simply “underestimates” the effort required. Nevertheless, although PD patients can scale their agonist bursts (insufficiently), they often tend to adopt the strategy usually reserved for large movements in normal subjects (Gottlieb et al., 1989), where movement amplitude is scaled by varying movement duration rather than movement speed. Indeed, when the task is to control movement duration rather than movement amplitude, PD patients perform comparatively well, although the movement profile is abnormal, with maximum force coming relatively late in the movement (Teasdale et al., 1990). Single-joint movement deficits therefore suggest a quantitative problem, with poor scaling of agonist bursts rather than a limit on size, and a relative tardiness in development of maximal force. In fact, when the task is easy, such as when the accuracy requirement is low and the amplitude small, there is no ballistic movement bradykinesia in PD patients when compared to normal subjects of similar age (Sanes, 1985).

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Motor programming to control muscle synergies and smooth slow movements seems instead to fall within cerebellar function. The cerebellum shapes the proper triphasic organisation that is fundamental to the motor control strategy for ballistic movements, especially the braking antagonist burst (Hore et al., 1991). Thus, the deficit of cerebellar disease is a qualitative disruption of movement through damage to the basic programming strategy. One might interpret the quantitative problem in PD as there being not enough “neural energy” to drive the preserved programs properly. Speaking more physiologically, it is tempting to think in terms of neural thresholds—might the basal ganglia prime certain neural collections near threshold so that control impulses are strong enough to achieve the desired effect without spreading to activate neighbouring collections and thereby producing undesired effects? The advantages of such priming would be to reduce noise in the system and allow factors such as motivation to focus activity. Ballistic movements made by patients with Huntington’s disease, dystonia and athetosis have EMG bursts that are prolonged and variable, with co-contraction of antagonist instead of discrete agonist and antagonist bursts and a spread of activity into other muscles (Berardelli et al., 1996b) As in PD, the final result is slowness of movement, but the mechanism is clearly distinct. The abnormalities suggest that there is too much unselective and unfocussed facilitation and supports the notion that different basal ganglial diseases represent quantitative extremes along a continuum of selectivity of facilitation, with normality lying somewhere in between. 2.4.2.3. Tremor. PD tremor is sometimes considered to reflect similar mechanisms to those underlying rigidity. Its co-contracting nature has led to it being thought of in terms of intermittent “cogwheel” rigidity or, to use the early 20th century term, “rigidity spread thin” (Walshe, 1924). It might therefore be considered that the repetitive EMG agonist bursts during active ballistic movement also derive from the same tremor mechanism. However, the frequency of the agonist bursts often bears no relation to that of PD rest or postural tremor (in Fig. 3 the frequency is 10 Hz, while in other studies it may be nearly 20 Hz (Teasdale et al., 1990)) and a constancy of frequency in the face of altering movement parameters has not been adequately demonstrated. Moreover, both within individuals and across extrapyramidal diseases, Parkinsonian rest tremor is not a universal accompaniment of rigidity and bradykinesia. The anatomical and pathological lesions that tend to result in or ameliorate this tremor also seem rather distinct from those influencing rigidity and bradykinesia (Kupsch and Earl, 1999). Thus, distinct mechanisms have been proposed for generation of PD tremor, such as deafferentation of the thalamus resulting in release of widespread thalamic 4–6 Hz oscillations (for a review specifically on the pathophysiology of tremor see McAuley and Marsden (2000)).

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2.4.2.4. Postural control. Postural responses are defined as those made to maintain equilibrium against gravity and to compensate for changes to equilibrium arising from voluntary or passive movement (Martin, 1967). Clinical observations reveal major problems with postural and gait control in PD, with loss of arm swing, a forward shift in centre of gravity, reduced stride length and gait initiation abnormalities apparent early on in the disease and, later on, a more dramatic failure of righting reflexes with frequent falls. An anatomical correlate of the importance of the basal ganglia in posture and gait exists in that, as well ascending connections of the basal ganglia output nuclei to the cortex via the thalamus, there are equally strong descending connections to brainstem nuclei important in posture, such as the pedunculopontine nucleus (Pahapill and Lozano, 2000). Gait problems commonly arise from frontal cortical lesions and their presence also in PD would not be unexpected given the strong reciprocal connections between this region and the basal ganglia. Normally, posture control is derived from a combination of visual, vestibular and proprioceptive information and the relative importance of these varies according to circumstance (Bronstein, 1986). PD is characterised by an abnormal bias of these inputs and a failure to make circumstantial adjustments (Bronstein et al., 1986). There is a similar failure of modulation of the gain of ankle stretch reflexes that normally occurs during the step cycle (Dietz et al., 1988). Such findings suggest a failure of automatic or anticipatory adjustment. These adjustments may involve subconscious attention mechanisms and so the observed postural deficits are consistent with the general selective attention hypothesis. In addition, possibly because of increased attentional demands of posture control in PD, performing secondary tasks results in a differential deficit in PD patients compared to controls (Morris et al., 2000). This is analogous to the problems with decision-making dual task performance. Other postural and gait problems relate more simply to the rigidity and bradykinesia of PD. Patients have particular difficulties in gait when it is “complicated” by having to negotiate objects, but when external cues are actually used to stimulate movements, such as stripes on the floor or auditory cues directing individual foot movements, the bradykinetic steps can be much improved (Stern et al., 1980). Finally, it must be noted that postural instability in PD, especially in the later stages of the disease, is only modestly levodopa responsive, indicating that many of these aspects of PD may not directly result from the specific nigrostriatal dopaminergic deficit (Bonnet et al., 1987). Posture control involves not only gravity and gait adjustments, but also adjustments in response to body displacement caused by voluntary movements or external perturbations. The anticipatory leg EMG “tulips” first described by Marsden et al. (1981) occurring in expectation of oncoming arm displacements are particularly deficient in PD (Traub et al., 1980). The defining property of anticipatory responses is that they do not result from direct external cues but are self-generated or occur in response to indirect

cues. Analogies may thus be drawn with the psychophysical findings on reaction times already described, where there is relatively greater difficulty in reaction time tasks when the cues are internal. 2.4.2.5. Strength. Despite featuring in Parkinson’s original description, the poorly quantitative nature of bedside examination of power has meant that strength no longer features as one of the main deficits of PD. However, accurate measurement has reaffirmed this abnormality, which is levodopa reversible and found most notably in axial muscles, extensor muscles and distal hand muscles (Yanagawa et al., 1990; Corcos et al., 1996; Bridgewater and Sharpe, 1998; McAuley et al., 2001). The weakness of PD does not simply reflect antagonist co-contraction but, at least in some muscles, may reflect the loss of descending inputs normally modulated by the Piper rhythm, a fast 40 Hz oscillatory activity arising from the CNS and manifest in the EMG (McAuley et al., 2001). 2.4.2.6. Eye movements. While PD-plus syndromes have rather characteristic eye movement abnormalities, such as failure of vertical saccades in PSP, slow saccades in olivopontocerebellar atrophy and delayed saccade initiation in CBD, the deficits of idiopathic PD are more subtle. They nevertheless show striking parallels with limb studies. Although saccade reaction times are more mildly slowed than limb reaction times (Warabi et al., 1986), PD patients have hypometric saccades that are analogous to the fractionation of ballistic limb movements into numerous agonist bursts. Eye movement deficits are relatively worse for remembered and predictive saccades. In such saccades, with no direct target, the final eye position is still normal, suggesting a motor problem rather than a memory or perception problem (Kennard and Lueck, 1989). This is similar to the already-described findings for anticipatory postural movements and for internally as opposed to externally cued reaction time tasks. In PD, there is qualitatively normal smooth eye pursuit, but quantitatively there is a reduction in smooth pursuit gain at a variety of speeds (White et al., 1983). Again, this reflects limb studies where there are smaller but nevertheless scalable agonist burst sizes. Unlike the problems with planning a saccade to a target that has not yet appeared, there is a normal improved performance when smooth pursuit tracking becomes predictable, indicating a difference in organisation between anticipating visual feedback lags during target pursuit (probably cerebellar) and making predictive saccades (requiring self-generated cues) (Bronstein and Kennard, 1985). During sinusoidal tracking, while PD patients are able to compensate for the feedback phase lag, the overall pattern of tracking appears rather unique, with a series of “staggered” saccades made in place of smooth following (White et al., 1983) (Fig. 5A). However, even this apparently qualitative Parkinsonian abnormality reflects a quantitative deficit; when the tracking task is made more difficult by obscuring

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Fig. 5. Eye movements made in tracking a horizontal sinusoid target moving at 0.5 Hz (A). Upward deflection represents rightward movement. The PD patient makes a qualitatively distinctive staggered saccade following pattern. However, the fundamental pursuit deficit in PD is a quantitative impairment of pursuit gain. The staggered pattern is a normal response produced when smooth pursuit cannot match target velocity and can be brought out in normal subjects, as shown by a more difficult task where a normal subject pursues a 0.25 or 0.5 Hz sinusoidal target that is obscured during all but the left and right extremes of its motion (B). From White et al. (1983) and McAuley et al. (1999a), with permission.

the target during parts of the waveform, normal subjects will also produce this following pattern (McAuley et al., 1999a) (Fig. 5B). Thus, in the same way that increasing task difficulty during reaction time tasks makes normal subjects behave similarly to PD patients (see Fig. 3), both groups show similar eye movement behaviour. Making staggered saccades is clearly a normal compensatory response when smooth pursuit cannot be generated at sufficient velocity to keep up with the target. In the case of PD patients, this occurs due to the above-described quantitative deficit of smooth pursuit gain. When making combined ballistic limb and saccadic eye movements to a peripheral visual target, PD patients seem unable to make a combined movement but instead wait until the eye movement is finished and the target is foveated before, then making the limb movement (Warabi et al., 1988). This is reminiscent of other simultaneous task problems. 2.5. Summary of evidence for selective facilitation Psychophysical concepts of a cognitive attentional or focusing problem in PD have arisen from findings indicating

that normal subjects have finite processing resources and that these become poorly directed in PD so that such patients have an extra deficit with tasks requiring internal direction of resources and with dual tasks when the secondary task is resource consuming. Such ideas may account for many clinically observed motor task deficits in PD, such as the difficulties with overlapping or simultaneous actions. Given the assumption that in most circumstances acting according to internal cues demands more attentional resources than reacting to external cues, one may also explain the relatively greater problem that PD patients have with self-generated movements. A problem with focusing attention upon processing resources would be expected to lead to quantitative deficits with a wide variety of processing tasks rather than a qualitative defect with any one domain, and this is what is generally observed. Patients can generally accomplish all perceptual, decision making, motor planning, motor learning and motor programming functions but, beyond a certain difficulty level, they do most of them less well. This review argues that a selective attention/facilitation role might in addition be applied to executive motor functions. Many lines of evidence point to the fact that in PD

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the executive deficits, similar to processing deficits, are also quantitative rather than qualitative in nature. Thus, there appears to be little problem with slow movements and with the actual co-ordination of agonist, synergist and antagonist actions. In contrast, there is a quantitative reduction in scaling of agonist bursts during ballistic movements without a ceiling on maximum level. Analogous abnormalities occur related to gait step size and to saccade size and there are similar quantitative reductions in strength. It therefore seems attractive to consider that the primary executive problem is an attentional/focusing defect that would normally input into motor centres to modulate their degree of activity. As a result, in PD there is a failure automatically to “energise” such activity to the required level, although this problem can be bypassed by a high degree of conscious motivation or arousal. This deficiency of “energisation” is not meant strictly in the sense originally expressed by Hallett and Khoshbin (1980), where there was considered to be a saturation of motor activation of the agonist burst, but rather a quantitative deficiency at many degrees of motor activity beyond a certain “easy” level. This is analogous to the processing deficiency in reaction time tasks being one of directing resources at different difficulty levels and not just a lowered maximum capacity. To postulate that selective facilitation may be applied to executive function, one must show that there is in fact a fixed reservoir of resources for execution as well as for psychophysical levels of processing. This does in fact seem to be the case—Fitts’ hypothesis (1954) states that the performance capacity of the human motor system is relatively constant for various task conditions and that this reflects a fixed capacity of “quality control.” In other words, there is an accuracy constraint for a certain magnitude and timing of movement. This accuracy component as well as force generation component of task difficulty might relate to demands on simultaneous processing of both agonist and antagonist activity. A limitation on meeting such demands in PD probably means that the deficit would have to occur at a relatively “high-level” stage of muscle control. On the basis of their anatomical and physiological connectivity, the basal ganglia would seem well placed to act at this level of function. Further exploration of possible Parkinsonian defects in selective “energisation” of motor activity is needed. Experiments of the effects of dual tasks, different cues and distractibility on executive defects such as slowness of movement, strength and agonist burst size might be performed along the lines of those already conducted on reaction times.

3. Parallel pathway organisation of the basal ganglia If the basal ganglia have a role in selective facilitation by enhancing certain aspects of CNS activity and suppressing others, their functional organisation may provide clues as to how this may be achieved. The classical view of basal

ganglial connections is based upon the identification of two distinct striato–pallidal pathways (Fig. 2). The direct pathway leads from the striatum straight to the globus pallidus pars interna (GPi) and other basal ganglial output nuclei while the indirect pathway first transmits to the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN) loop. Two distinct anatomical and electrophysiological subtypes of striatal neurones have been identified that may influence the two pathways. Type I neurones (direct pathway) are preferentially acted upon by D1 dopaminergic agonists, have a delayed but augmented response to paired electrical stimuli separated by a very short interval (i.e. high frequency) and mainly terminate directly within the basal ganglia output nuclei, while type II neurones (indirect pathway) are influenced by D2 agonists, have response facilitation to paired stimuli separated by a longer period of around 100 ms (10 Hz) and terminate within the GPe (Onn et al., 2000). The sequences of inhibitory and stimulatory synapses would initially suggest that the two pathways exert opposing and balancing influences upon the output nuclei and that their imbalance in PD could account for its clinical manifestations. The parallel facilitation and inhibition might therefore mediate a selective attention function. However, D1 and D2 receptors are respectively positively and negatively coupled to adenylate cyclase intracellular messenger systems so that dopamine actually has opposing effects upon direct and indirect pathway striatal neurones (Gerfen et al., 1990), thereby cancelling out the opposing directions of action upon the output nuclei. This pattern of connectivity is consistent with the finding in PD that patients in the “off” state have increased GPi and STN electrophysiological and metabolic activity compared to patients with levodopa-induced dyskinesia, a state in some ways the opposite of bradykinesia (DeLong, 1990; Obeso et al., 2000). By inference from animal model recordings, the normal activity state may lie between these extremes. However, findings on GPe activity, which is specific for the indirect pathway, are less conclusive, with some studies indicating that bradykinesia and dyskinesia are not associated with differential changes in activity (Boraud et al., 2001). Moreover, therapeutic stereotaxic blocking of GPi activity ameliorates dyskinesia more than bradykinesia, even though activity is already abnormally low in the dyskinetic GPi (Marsden and Obeso, 1994). These inconsistencies may be explained by considering that dopamine is not simply excitatory or inhibitory but has a physiologically variable modulatory action (Calabresi et al., 2000a). A more complex functional split has been proposed, where the two pathways mediate different aspects of Parkinsonism rather than having simple opposing or adjunctive actions. Some studies, such as those on DOPA responsive dystonia (Segawa, 2000), where the main deficiency is said to relate to D1 effects, suggest that the direct pathway mediates dyskinesia and dystonia. The fact that the GPe lies only on the indirect pathway explains its lack of activity change in dyskinesia. Abnormal activity in the indirect pathway

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may be responsible instead for the bradykinetic aspects of PD. Studies on the physiological effects of selective D1 and D2 agonists provide little support for this model because D1 agonists seem as good as D2 agonists in ameliorating the negative “off” symptoms of PD, while D2 as well as D1 agonists may produce dyskinesia if administered chronically (Bedard et al., 1999). However, specific agonists (and genetic receptor subtypes) may prove an unreliable means of isolating pathway actions. The direct pathway afferents and the subthalamic nucleus (indirect pathway) may each feedback upon both pathways via the substantia nigra compacta, suggesting that the two pathways are not really functionally distinct. Furthermore, the receptor types themselves may interact on the same synaptic terminal. Thus, D1 as well as D2 agonists are found to influence the GPe. A further model considers a more functional split of parallel processing on the basis of fine control of movement versus gross motor function. The apparent anatomical split has arisen simply because the direct pathway is relatively more important for fine control and the indirect pathway for gross function, an idea supported by histological findings that the direct pathway tends to have more specific dendritic connectivities. More fundamental is that some dopaminergic activity is phasic for specific behavioural control, and some tonic for gross motor control. Behaviourally relevant reward-associated activity appears to be associated with phasic intrasynaptic dopamine release from dopaminergic action potentials (Grace, 1991). At the same time, leakage of some of the dopamine outside the synapse can act tonically on presynaptic D2 receptors to inhibit this phasic response. The tonic dopamine release may also be stimulated via glutamate leaking from cortico–striatal synapses and acting on glutamate presynaptic receptors on the dopaminergic terminal or acting via nitrous oxide release. This tonic dopamine can in turn inhibit cortico–striatal activity via presynaptic D2 receptors on the glutamate terminals, creating a “double” negative feedback upon striatal inputs. It is suggested that tonic extra-synaptic activity is most relevant for type II spiny neurones since they can return to normal activity levels when agonists are administered (extrasynaptically of course) to correct for dopaminergic synapse damage (Onn et al., 2000). Type I activity, proposed to be phasic and synaptically dependent, cannot similarly be restored. Functional studies also support the notion of parallel phasic reward-associated function and tonic gross motor control function. Dopaminergic phasic bursting is selectively associated with unexpected reward signals (Schultz, 1998); this activity is actually rather widespread, but its synaptic dependence possibly generates specificity for certain responses via the requirement for concurrent cortico–striatal inputs onto the same dendritic spines. However, as previously noted (Section 2.3.3), such dopaminergic pathways may not be those that are preferentially lost in PD. Nevertheless, a better behavioural quality of finely controlled “on” activity in MPTP animal models may result from D1 agonism (Grondin et al., 1997; Pearce et al., 1999), which indirectly supports a

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role for specific and possibly reward-associated phasic stimulation in the pathogenesis of parkinsonism. Conversely, the gross effect of subthalamic electrical blocking, which acts specifically on the indirect pathway, leads to a general amelioration of PD symptoms (Benabid et al., 1998), mimicking closely the effects of levodopa in badly affected individuals who have lost most of their dopaminergic synapses and who are presumably only able to respond tonically. Although the nature of generation of bradykinesia and rigidity still remains unclear, many studies have focused specifically upon the aetiology of levodopa-induced dyskinesias because this phenomenon represents the current major challenge in clinical management. Excessive and intermittent D1 stimulation in the absence of dopaminergic synapses may result in abnormal activation of protein kinase signalling by cortico–striatal glutamate neurones (Gerfen, 2000). This leads to the induction of immediate early genes which cause D1 receptors to adopt a supersensitive state leading to dyskinesia susceptibility. Reversing this aberrant signalling could potentially correct levodopa-induced dyskinesia and may explain the beneficial action of NMDA antagonists such as amantadine and riluzole. Graybiel et al. (2000) have proposed that these D1 receptor changes are not associated with the direct pathway but with a third pathway that arises from striatal striosomes (rather than striatal matrix) and connects back to the substantia nigra compacta. Whichever pathway is important, the important factor is the chronic intermittent nature of stimulation, since D1 agonists, D2 agonists and levodopa given in this way all have the same dyskinetic effect (Calon et al., 2000). New strategies in prevention of levodopa-induced dyskinesia are therefore increasingly stressing the importance of a more even dopaminergic stimulation throughout the day (Chase et al., 1994), rather than selectively influencing any particular pathway. This shift in emphasis away from anatomical pathways and toward synaptic interactions, changes in gene expression and tonic versus phasic firing patterns has led to the suggestion that the notion of discrete pathways is an oversimplification and that there are in fact a myriad of pathways and loops that run “horizontally” between basal ganglial nuclei as well as “vertically” through the traditional “cortico–striato–pallido–thalamo–cortical” loop (Obeso et al., 2000). In this model, dopamine has a regulatory rather than simply stimulatory or inhibitory function which is realised in an unknown way by the pattern of neuronal activity and not by gross firing rates. Indeed, some studies show that changes in raw firing rates do not correspond with behavioural changes in animals with experimental Parkinsonian lesions (Ruskin et al., 1999).

4. Oscillatory activity and CNS processing Certain aspects of basal ganglial neuroarchitecture have the effect of promoting rhythmic or oscillatory neural firing patterns, both through the properties of the numerous

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feedback loops and through the synaptic property of “non-renewal”, which tends to average out instantaneous firing rates into a more regular pattern (Eggermont, 1990). It is therefore possible that oscillatory behaviour is an important pattern of neuronal activity in the basal ganglia. 4.1. How oscillatory activity may mediate selective facilitation There have been many recent hypotheses that common oscillatory firing patterns may link functionally distributed areas of the brain which process different aspects of the same task (Eckhorn et al., 1988; Farmer, 1998; McAuley and Marsden, 2000) and it has already been suggested that such oscillatory binding may be important in the basal ganglia (Marsden, personal communication). Ideas concerning oscillatory binding are most well developed in regard to sensory information processing, where it is considered that a common 40 Hz range oscillation “binds” the various neural activities occurring in different cortical regions that all relate to a single percept. In this way, the brain can recognise that different aspects of a percept, such as the colour, shape and movement of a visual image, all relate to a single point in space and time, even though parallel processing of these aspects may take different lengths of time (Eckhorn et al., 1988). Such oscillatory binding could also mediate selective facilitation. In auditory perception, 40 Hz transient responses are found to become enhanced during selective attention (Tiitinen et al., 1993), indicating that the focusing of attention, a proposed basal ganglial function, could be mediated by oscillatory binding. Clues as to how this occurs are offered by the finding that synchronised signals are not only able to link the different aspects of processing together but are intrinsically more effective in activating units than equivalent unmodulated signals (Gray et al., 1989). Thus, the synchronised oscillatory modulation of signals has a selective activating effect upon their neural targets, which is precisely what it is proposed the basal ganglia achieve. Further oscillatory strengthening of signals may occur at the anatomical level by strengthening the neuronal pathways along which they are transmitted (a “learning” effect), since nitrous oxide-mediated mechanisms which result in coupling of neurones to modulate synchronisation also have a role in mediating synaptic plasticity (Calabresi et al., 2000b). While the above sensory and proposed basal ganglial oscillations have a binding and activating role, other CNS oscillations are clearly associated with low arousal or alertness states, such as the well-known attenuation of 10 Hz range EEG alpha rhythms with eye opening and alertness (Stam et al., 1993). The brainstem reticular activating system appears to desynchronise (suppress) generalised EEG rhythms in modulating intracortical synchronisation in sensory areas (Munk et al., 1996). This oscillatory suppression effect, in apparent contradiction with the oscillatory strengthening effect described

above, may lie in the fact that facilitatory oscillations important in binding are likely to be specific and will not cause large generalised scalp EEG deflections. The latter would indicate that massive areas of the brain are bound together and so would defeat the purpose of the selectivity of binding. An extreme example of widespread synchronised activity is that which occurs during a generalised seizure—the large amplitude waves are clearly not associated with useful CNS processing. When studies refer to a spread of synchronised rhythmic activity over the cortex in association with complex tasks, they have in fact recorded over a few millimetres of the cortex surface (Murthy and Fetz, 1996), not gross oscillations detected over the scalp. Thus, even when binding occurs between widely different motor structures, such as between eye and limb movements during visuomotor tracking (McAuley et al., 1999b), the impression on attempting to look at cortical correlates on scalp recording is that the bound oscillation would be lost among the huge number of different oscillatory activities at that frequency (personal observation). While coherence analysis (a statistical measure of the similarity of two oscillatory signals in terms of frequency and phase relationship (Jenkins and Watts, 1968)) is designed to be uninfluenced by absolute signal strength relative to noise, a very large number of oscillations all of similar frequency are likely to exceed the capacity of coherence to differentiate. In relating oscillatory activity to the proposed selective facilitation role of the basal ganglia, this review proposes that widespread synchronisation could determine the general level of neural activity. At the same time, specific localised synchronised activity (too small to be detected on scalp EEG) could have the effect of linking or “binding” together related signals to aid in signal processing, while its oscillatory nature would have both the already-demonstrated direct activating effect and a “learnt” activating effect mediated through synaptic plasticity. In combination, the two oscillations could provide a continuously controlled means of background suppression and specific facilitation of activity, thereby constituting the basis of selective facilitation. Indirect evidence already exists that the basal ganglia influence widespread and localised oscillatory activity in a manner consistent with the proposed dual suppression/facilitation role. In PD, there is indeed found to be excessive widespread EEG synchronisation. Even in PD patients without dementia, it is found that there is a shift in EEG spectrum towards higher amplitude slow 5–10 Hz rhythms (Calabresi et al., 1988; Neufeld et al., 1988). The corresponding failure of attenuation of slow EEG rhythms that normally occurs in relation to voluntary movement correlates with the general degree of bradykinesia and is reversible with levodopa (Yaar, 1977; Magnani et al., 1998). The increased levels of widespread synchronisation could lead to bradykinesia as a result of difficulty in conveying specific motor signals through the increased “noise” of the abnormally strong diffuse slow synchronised discharges. In addition, the increased diffuse activation of descending

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pathways mediating background levels of tone might lead to general rigidity (c.f. tonic phase of a generalised convulsion). The reverse may apply in Huntington’s disease where the observed general attenuation of EEG might result from a lack of widespread synchronisation. Abnormally weak dampening of specific cortical activity could explain the clinical manifestations of chorea, occasional cortical myoclonus or even hypomania (Thompson et al., 1994). Conversely, while there appears to be excessive widespread oscillatory activity in PD, there is indirect evidence for a deficiency of potentially energising localised activity. The Piper rhythm is a 40–50 Hz range EMG oscillation that is thought to derive from a CNS oscillation transmitted to the muscle via descending motor pathways (McAuley et al., 1997). This oscillation is not coherent between different muscles (McAuley and Brown, 1995), indicating its localised nature. It is found to be lost in the EMG of PD patients in a levodopa-reversible manner that parallels these patients’ inability to achieve full-strength voluntary small hand muscle contractions (McAuley et al., 2001). These studies on the manifestation of oscillations in scalp EEG or in EMG activity are necessarily indirect, merely indicating the pattern of spread rather than the origin of CNS oscillations. Further exploration of the origin, nature and function of oscillations having a potential role in selective facilitation is likely to proceed through more invasive studies on candidate structures within the brain. 4.2. The thalamus and CNS oscillations A good candidate for the generation of oscillations mediating selective facilitation is the thalamus. This structure is known to display its own oscillatory activity (Steriade et al., 1991) and, because of its strong inputs to most cortical areas, could easily spread to and thereby link intracortical oscillations, providing a means of control. It has already been suggested that the thalamus is important in generation of the oscillations that result in various forms of tremor and epilepsy (Buzsáki et al., 1990; Jeanmonod et al., 1996). Finally, since the basal ganglia output to the thalamus, they could direct these thalamo–cortical oscillations and thereby fulfil their role in directing selective attention. It could be this direction of thalamo–cortical oscillation that fails in PD. Sleep spindle activity at 7–14 Hz arising from the thalamus indicates that thalamo–cortical oscillations are involved in perceptual awareness during light sleep (Steriade et al., 1993) and it appears that both this and similar visual stimulus dependent synchronisation may be controlled by thalamo–cortical oscillatory loops (Contreras et al., 1996). While this suggests a role in selective attention related to sensory information, there is also some evidence for a role in the motor system. In animal studies, thalamo–cortical coherent oscillations are found at high frequencies (30–100 Hz) within the cerebellar thalamus, implying a possible motor, if not basal ganglial, influence (Timofeev and Steriade, 1997).

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They are also found at low 7–12 Hz frequencies related to active whisker movements made in exploring the environment (Nicolelis et al., 1995). Finally, coherent oscillatory activity may be found between the cortex, the Vim thalamic nucleus and EMG in variable frequency ranges (not just at tremor frequency) in patients who have had thalamic electrode implantation for treatment of different movement disorders (Lenz et al., 1988; Hua et al., 1998; Marsden et al., 2000). 4.3. Basal ganglial oscillations While it is possible that the basal ganglia may control thalamo–cortical oscillations, the various basal ganglial nuclei are found to display their own oscillatory activity and so it is equally likely that oscillations important in selective facilitation could actually arise here and then pass downstream to the thalamus before reaching the cortex. 4.3.1. Low-frequency widespread oscillations Animal studies have revealed oscillatory activity in different basal ganglial nuclei and at different frequencies. Normally, the firing of many globus pallidus units (reflecting the striatal output) is unmodulated, with a minority firing in a rapid bursting pattern of greater than 20 Hz frequency. In MPTP-treated monkeys (a PD model), while the overall level of neuronal activity is increased, there is an underlying specific increase in regular bursting at a slower frequency of 4–10 Hz (Nini et al., 1995). This oscillatory tendency is levodopa reversible and is synchronised in a widespread manner between many pallidal units (Bergman et al., 1998). Subthalamic nucleus inactivation, known to improve bradykinesia in PD humans, also decreases this slow pathological oscillatory activity, in addition to decreasing overall GPi activity (Wichmann et al., 1994). Finally, electrical stimulation at the slow frequency results in gradual cessation of the animal’s spontaneous movements (Hassler and Dieckmann, 1967). Thus, it appears that this slow pathological activity may have a direct role in producing Parkinsonian rigidity or general bradykinesia. The fact that idiopathic dystonia is associated with an abnormally strong low frequency correlation between muscles (Tijssen et al., 2000) suggests that fixed dystonia may arise by a similar mechanism. Perhaps the abnormally widespread slow oscillation of pallidal cells could have a descending influence on brainstem nuclei to result in the stiffness of both Parkinsonism and dystonia. However, in the case of some dystonic disorders, factors at a lower level in the motor pathway may also contribute, such as a higher frequency, possibly motor cortical or corticospinal, 20 Hz synchronisation (Farmer et al., 1998) and abnormalities in spinal reciprocal inhibition (Nakashima et al., 1989). New developments in GPi stimulation as treatment for different dystonic disorders may in future enable direct experimental recording of CNS oscillations in such patients. It is possible that slow striato–pallidal oscillatory activity may not arise de novo but by dopamine-regulated

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Fig. 6. Speculative scheme showing how dual frequency bands of oscillation could influence normal and disturbed basal ganglial activity. In a normal subject (A), the dopaminergic stimulation from the basal ganglia may allow selective facilitation of appropriate striatal units by cortical inputs important for task processing, possibly via relatively specific phasic intrasynaptic modulation. This in turn sets up localised 30–40 Hz range oscillatory behaviour in a few selected GPi units. The thalamus has resonator properties and so will propagate these localised high-frequency oscillations back to the cortex, “binding” signals relating to the task and completing a resonance loop helping selectively to activate the task-related pathways. (Oscillatory signals are shown to be more effective in activating units than equivalent unmodulated signals.) The majority of striatal units will not be activated by the cortex because they do not relate to the task, leaving most of the GPi units to fire non-rhythmically. Uninvolved cortical areas will therefore not receive any resonant enhancement of activity. In dyskinesia and chorea, however, striatal dysfunction could result in excessive GPi high-frequency oscillatory activity, leading to too many localised cortical resonances and excessive activation of undesired movement-related units, or a subnormal level of regulating general slow activity. In a PD (B), the lack of dopaminergic input may mean that the cortex fails to activate any striatal units, even those that are desired for the motor task. There is therefore no 40 Hz localised resonance and a resultant failure in selective facilitation leading to Parkinsonian bradykinesia for specific tasks. In addition, the failure of normal dopaminergic drive, perhaps especially that responsible for tonic extrasynaptic modulation, results in

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transmission of slow cortical oscillations in a widespread manner through the striatum and thence to the pallidum. Dopaminergic depletion in rats with chronic experimental nigrostriatal lesions may stimulate striatal neurones to a depolarisation plateau state, allowing this transmission to occur (Tseng et al., 2001). Similarly, depth recordings in the mouse striatum reveal that synchronisation of oscillations is increased by dopamine antagonists and such oscillations can be desynchronised again by application of apomorphine, a dopamine agonist (Yurek and Randall, 1991). However, these cortically transmitted oscillations in rats are of an even slower frequency (<2 Hz) and it is therefore not certain they can be linked to the striatal output oscillations. A neural substrate for the development of the observed Parkinsonian increase in widespread slow frequency synchronisation could be the opening of gap junctions between striatal cells, perhaps triggered by behaviourally relevant afferents from the cortex via nitrous oxide signalling (Onn and Grace, 1999). Lesions of the dopaminergic system seem to increase this cellular coupling. Gap junction synchronisation is not frequency-specific and this could explain the wide frequency range of these oscillations. In fact, dopamine receptor-modulated widespread slow pallidal oscillations as low as 0.1 Hz have been recorded (Walters et al., 2000). The re-emergence of deep brain stimulation or lesioning procedures as treatment for PD fortuitously allows direct human recording of the basal ganglia. Slow single unit oscillatory activity at around 5 Hz has been recorded in the Parkinsonian GPi. Sometimes this oscillation is phase locked to tremor (Hurtado et al., 1999; Magnin et al., 2000). This could mean that the oscillation simply on occasion becomes entrained with a thalamic tremor pacemaker, or could mean that in circumstances when the pallidal rigidity- and bradykinesia-related oscillation is strongest, such as during widespread background activity while the patient is at rest, it can be amplified downstream by the thalamus so much that it becomes manifest in peripheral EMG. 4.3.2. High-frequency localised oscillations The Parkinsonian increase in widespread oscillations may represent only one aspect of basal ganglial function. In addition to the widespread suppression of activity that such oscillations might achieve, more localised oscillatory activity could mediate selective increase in activity through specific binding of functionally linked groups of neurones. Interestingly, experimental subthalamic inactiva-

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tion in animals, which decreases slow pallidal oscillations, is also associated with an increase in the high frequency 40 Hz bursting displayed normally by a minority of pallidal units (Wichmann et al., 1994). Thus, the low-frequency activity found in the GPi in PD reflects the Parkinsonian state while the high-frequency activity found on returning to normal reflects the physiological state. High-frequency localised oscillations have also been found in the cortex of normal (non-MPTP treated) animals. For example, the supragranular layer of the rat cerebral cortex displays an intrinsic local 40 Hz oscillatory tendency (Plenz and Kitai, 1996). The primate motor cortex reveals similar local field oscillations in relation to preparation for voluntary movement (Sanes and Donoghue, 1993). These pallidal and cortical findings, combined with the fact that the thalamus also has an oscillatory tendency in the >30 Hz range (Jeanmonod et al., 1996), suggests that a proportion of pallidal units could form part of a high frequency range cortico–striato–pallido–thalamo–cortical resonance. If the basal ganglia do in fact suppress most activity and selectively facilitate the particular activity that is desired, one would only expect a small proportion of units to be in this activating state at any one time. The topographical organisation of firing behaviour of pallidal units, where specific neurones appear to “label” specific joint movements (see above), seems consistent with this attention focusing role. The general suggestion that co-existing multiple frequency bands may represent different aspects of normal motor control has already been considered. Cortical frequencies around 20 and 40 Hz may be involved with control of distal motor tasks and sensorimotor integration, while slower 10 Hz range frequencies appear to be more related to cerebellar and brainstem activity (McAuley and Marsden, 2000). It is therefore tempting to link the loss in PD of the 40 Hz range Piper frequency distal muscle EMG oscillation directly with the loss of those pallidal units that have a similar frequency of rhythmic firing. Due possibly to their localised nature and because such activity is in any case deficient in PD, human GPi recordings through therapeutically inserted electrodes have so far revealed little on high-frequency oscillations. A better disease model for detecting selective high-frequency oscillations in the basal ganglia might be disorders characterised by too much discrete motor activity rather than too little activity, such as the hyperkinetic states of chorea and levodopa-induced dyskinesia. Recordings of GPi and GPe

excessive release of widespread slow 5–10 Hz range pathological oscillations downstream through the basal ganglia. This spreads via the thalamus into an excessive widespread slow cortical oscillation which could result in rigidity and “off” dystonia. Alternatively, these phenomena might result from the GPi slow oscillation influencing descending basal ganglial connections. The slow oscillation arising from the basal ganglia in PD and linked here with rigidity does not seem to spread down to descending tracts strongly enough to be manifest in EMG or as tremor (although there is a possible increase in 10 Hz peak EMG power in PD and in idiopathic dystonia). However, the thalamus has its own rhythmic 4–6 Hz tendency that appears to be released when it is deafferented. The abnormal input resulting from the dopaminergic deficit, especially at rest when there may be a general lack of input even in normal circumstances, might result in the typical Parkinsonian 4–6 Hz rest tremor that tends to subside during concentration and activity. The paradoxical effect of therapeutic GPi electrical stimulation is explained here on the basis that it would suppress both the excessive localised high-frequency oscillation responsible for dyskinesia in abnormal PD “on” states and the excessive widespread low-frequency oscillation responsible for “off” state dystonia or idiopathic dystonia.

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in MPTP-treated animals who have been given chronic levodopa to render them dyskinetic do reveal complex effects on unit firing patterns and mean frequencies (Obeso et al., 2000) but the data were not analysed for specific oscillatory frequencies. There were differential effects of selective dopamine agonists on such firing patterns, suggesting the intriguing possibility that the direct and indirect pathways might have distinct and parallel roles in modulation of the proposed dual oscillation frequencies. The direct pathway, proposed to mediate specific movement activity with phasic intrasynaptic modulation, might be more associated with the specific high-frequency oscillations, while the indirect pathway could tend to be associated with more tonic dopamine release and so be more important in down-regulating widespread low-frequency oscillations. Indeed, the finding described above that paired electrical stimuli distinguish types I and II striatal cells suggests a selective responsiveness to high- and low-frequency resonances, respectively. It would be interesting to extend the animal studies by making similar human single unit recordings through therapeutically inserted GPi electrodes to explore localised high-frequency oscillations in the GPi of dyskinetic patients and the effects of various agonists upon such oscillations. In addition, one might be able to record how small populations of units with fast oscillatory activity (perhaps coherent with similar cortical oscillations) change with the task being performed, while at the same time obtaining a topographic map of the single-joint movement responsiveness of various units. The STN is also a therapeutic site for lesioning in PD. Local field potential (not single unit) recordings through such electrodes do in fact reveal high-frequency activity at around 30 Hz in PD patients. However, such activity tends to be widespread and broadly tuned. Correlations have been found with EEG and EMG (Marsden et al., 2001) and with the GPi (Brown et al., 2001) but it is difficult to interpret their relevance since the coherence and power spectral peaks are at non-matching frequencies (e.g. STN:EEG in a broad 30 Hz range and STN:EMG at 18 Hz in the same patient). In general, when spectral peaks are “broad band”, this might simply reflect the modal frequency of the inputting or outputting neurone population rather than a “tuned” oscillation. When one area has strong anatomical connections with another having broadly similar modal firing rates, the probability of firing of units of one area may be modulated by those of the other, resulting in a statistical correlation of oscillatory activity without any real tuned linking oscillation. The widespread nature of such oscillations means they are unlikely to have a role in selective facilitation, while the fact they are broad-band argues against a useful “binding” function. If oscillation resonances had a specific function in selectively facilitating a specific task, one might indeed be surprised that a specific sharply defined coherence would be detected among the large number of units contributing to an STN local field potential and the EEG.

The widespread nature of the STN oscillation in PD may mean it is more akin to the lower frequency widespread oscillation of the Parkinsonian pallidum or it may simply be a property of the STN not relevant to oscillations elsewhere in the basal ganglia. Of note in this context is the fact that therapeutic stereotaxic blocking of the STN behaves rather like levodopa in helping bradykinesia without protecting against dyskinesia. The STN may have a widespread tonic and non-oscillatory excitatory influence and electrical stimulation simply blocks this excessive activity. In contrast, GPi lesioning (and electrical 100 Hz “blocking”) appears to ameliorate bradykinesia and dystonia, but unlike levodopa it helps rather than worsens drug induced “on” dyskinesias (Benabid et al., 1998). Perhaps the GPi lesioning has a dual action to block both the slow widespread oscillation that results in negative Parkinsonian symptoms or idiopathic dystonia and the excessive high-frequency localised activity that results in “on” dyskinesia. This proposal would account for the heretofore unexplained paradox of the effects of lesioning this nucleus. (See Fig. 6 for a speculative scheme summarising the hypothesised dual frequency band control of selective facilitation.) An attraction of considering loss of high-frequency oscillations in PD, rather than just the development of pathologically strong slow oscillations, is that the emphasis of the disease is shifted from a pathological gain of function to a loss of physiological function. If the widespread slow oscillation is considered simply a pathological entity that can be conveniently blocked by therapeutic lesioning of the GPi, one would otherwise be left to ponder the actual function of the nucleus (although perhaps it is likely that a modest degree of widespread oscillation is functional and desirable). In fact, GPi electrical stimulatory “blocking” in PD leads to reversible subtle deficits in tasks such as Wisconsin card sorting and conditional learning (Jahanshahi et al., 2000), affirming that the nucleus does have an underlying function whose “selective attention” flavour corresponds precisely with the proposed role of the localised high-frequency oscillations. Thus, the procedure blocks the deleterious effects of the excessive slow oscillations, which presumably relate particularly to problems with tone and inactivity, and blocks the beneficial effect of high-frequency oscillations in directing attention. Finding such discrete selective attention abnormalities is all the more remarkable given the fact that the high-frequency oscillations would presumably already have been greatly disrupted by the disease itself and its pharmacological treatment.

5. Conclusions Many different aspects of PD impairment, ranging from abnormalities of reaction time to a paucity of ballistic movements, eye movements and walking step size, all appear to suggest a common theme, namely that such deficits are characterised by their quantitative nature. It has therefore been

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argued that selective attention, a term originally applied in a psychophysical context, may be generalised to embrace the concept of energisation. In this way, the process of facilitation of neural activity corresponding to specific tasks, whether they be cognitive or motor, may represent the fundamental function of the basal ganglia. Some evidence exists to suggest that selective facilitation (here defined as constituting both attention and energisation) may be mediated by the binding of synchronised oscillatory activity, an idea previously applied to sensory information processing. While classical views of basal ganglial function relate to dual direct and indirect anatomical pathways, it is postulated that an important aspect of functional organisation may in fact be dual frequency bands of activity, a high frequency reflecting a binding function that allows selective facilitation of cortical and basal ganglial neural ensembles involved in specific tasks, and a lower frequency responsible for regulating background activity levels. In PD, a lack of the former may lead to the observed specific deficits in selective attention and in generating quantitatively adequate specific movements, while an excess of the latter may account for the failure of general tone and movement control. Such ideas are highly speculative, but they nevertheless provide a framework for a hypothesis-driven investigation of the relevance of rhythmic activity in the basal ganglia and may open up new avenues of exploration of symptom-specific pharmacological and stereotaxic treatments for PD.

Acknowledgements I would gratefully like to thank Prof. Michael Swash for helpful comments on the manuscript and the late Dr. Tom Koeze (deceased 15 November 2002), who was a great personal source of encouragement and who in running the London Hospital Neurostimulation Clinic dedicated many years providing invaluable care for his patients and support for his staff. References Adams, R.D., Victor, M., 1993. Principles of Neurology, fifth ed. McGrawHill, New York, p. 976. Agid, Y., Ruberg, M., Javoy-Agid, F., Hirsch, E., Raisman-Vozari, R., Vyas, S., Faucheux, B., Michel, P., Kastner, A., Blanchard, V., Damier, P., Villares, J., Zhang, P., 1993. Are dopaminergic neurons selectively vulnerable to Parkinson’s disease? Adv. Neurol. 60, 148–164. Allen, G.I., Tsukahara, N., 1974. Cerebrocerebellar communication systems. Physiol. Rev. 54, 957–1006. Andrews, C.J., Burke, D., Lancet, J.W., 1972. The response to muscle stretch and shortening in Parkinsonian rigidity. Brain 95, 795–812. Angel, R.W., Alston, W., Higgins, J.R., 1970. Control of movement in Parkinson’s disease. Brain 93, 1–14. Baddeley, A.D., Baddeley, H.A., Bucks, R.S., Wilcock, G.K., 2001. Attentional control in Alzheimer’s disease. Brain 124, 1492–1508. Bedard, P.J., Blanchet, P.J., Levesque, D., Soghomonian, J.J., Grondin, R., Morissette, M., Goulet, M., Calon, F., Falardeau, P., Gomez-Mancilla, B., Doucet, J.P., Robertson, G.S., DiPaolo, T., 1999. Pathophysiology of l-dopa-induced dyskinesias. Mov. Disord. 14, 4–8.

45

Benabid, A.L., Benazzouz, A., Hoffman, D., Limousin, P., Krack, P., Pollak, P., 1998. Long-term electrical inhibition of deep brain targets in movement disorders. Mov. Disord. 13, 119–125. Berardelli, A., Dick, J.P.R., Rothwell, J.C., Day, B.L., Marsden, C.D., 1986. Scaling of the first agonist EMG burst during rapid wrist movements in patients with Parkinson’s disease. J. Neurol. Neurosurg. Psychol. 49, 1129–1135. Berardelli, A., Rona, S., Inghilleri, M., Manfredi, M., 1996a. Cortical inhibition in Parkinson’s disease. A study with paired magnetic stimulation. Brain 119, 71–77. Berardelli, A., Hallett, M., Rothwell, J.C., Agostino, R., Manfredi, M., Thompson, P.D., Marsden, C.D., 1996b. Single-joint rapid arm movements in normal subjects and in patients with motor disorders (review). Brain 119, 661–674. Bergman, H., Feingold, A., Nini, A., Raz, A., Slovin, H., Abeles, M., Vaadia, E., 1998. Physiological aspects of information processing in the basal ganglia of normal and Parkinsonian primates. Trends Neurosci. 21, 32–38. Bernstein, N., 1967. The Co-ordination and Regulation of Movements. Pergammon Press, Oxford. Bonnet, A., Loria, Y., Saint-Hilaire, M., 1987. Does long-term aggravation of Parkinson’s disease result from non-dopaminergic lesions? Neurology 37, 1539–1542. Boraud, T., Bezard, E., Bioulac, B., Gross, C.E., 2001. Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey. Brain 124, 546–557. Bridgewater, K.J., Sharpe, M., 1998. Trunk muscle performance in early Parkinson’s disease. Phys. Ther. 78, 566–576. Bronstein, A.M., 1986. Suppression of visually evoked postural responses. Exp. Brain Res. 63, 655–658. Bronstein, A.M., Kennard, C., 1985. Predictive ocular motor control in Parkinson’s disease. Brain 108, 925–940. Bronstein, A.M., Hood, J.D., Gresty, M.A., Panagi, C., 1986. Visual control of balance in cerebellar and Parkinsonian patients. J. Neurol. Neurosurg. Psychol. 49, 1378–1385. Brown, R.G., Marsden, C.D., 1988. Internal versus external cues and the control of attention in Parkinson’s disease. Brain 111, 323–345. Brown, R.G., Marsden, C.D., 1991. Dual task performance and processing resources in normal subjects and patients with Parkinson’s disease. Brain 114, 215–231. Brown, R.G., Jahanshahi, M., Marsden, C.D., 1993. Response choice in Parkinson’s disease. The effects of uncertainty and stimulus-response compatibility. Brain 116, 869–885. Brown, P., Oliviero, A., Mazzone, P., Insola, A., Tonali, P., Di Lazzaro, V., 2001. Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson’s disease. J. Neurosci. 21, 1033– 1038. Burke, D., Hagbarth, K.-E., Wallin, B.G., 1977. Reflex mechanisms in Parkinsonian rigidity. Scand. J. Rehabil. Med. 9, 15–23. Buzsáki, G., Smith, A., Berger, S., Fisher, L.J., Gage, F.H., 1990. Petit mal epilepsy and Parkinsonian tremor: hypothesis of a common pacemaker. Neuroscience 36, 1–14. Calabresi, P., Centonze, D., Gubellini, P., Marfia, G.A., Pisani, A., Sancesario, G., Neufeld, M.Y., Inzelberg, R., Korczyn, A.D., 1988. EEG frequency analysis in demented and non-demented Parkinsonian patients. Acta Neurol. Scand. 78, 1–5. Calabresi, P., Centonze, D., Bernardi, G., 2000a. Electrophysiology of dopamine in normal and denervated striatal neurones. Trends Neurosci. 23, S57–S63. Calabresi, P., Centonze, D., Gubelli, P., Marfia, G.A., Pisani, A., Sancesario, G., Bernardi, G., 2000b. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog. Neurobiol. 61, 231–265. Calon, F., Tahar, A.H., Blanchet, P.J., Morisette, M., Grondin, R., Goulet, M., Doucet, J.-P., Robertson, G.S., Nestler, E., Di Paolo, T., Beard, P.J., 2000. Dopamine-receptor stimulation: biobehavioral and biochemical consequences. Trends Neurosci. 23, S92–S100.

46

J.H. McAuley / Progress in Neurobiology 69 (2003) 27–48

Carpenter, M.B., 1976. Anatomical organisation of the corpus striatum and related nuclei. In: Yahr, M.D. (Ed.), The Basal Ganglia. Raven Press, New York, pp. 1–35. Chase, T.N., Engber, T.M., Mouradian, M.M., 1994. Palliative and prophylactic benefits of continuously administered dopaminomimetics in Parkinson’s disease. Neurology 44, S15–S18. Contreras, D., Destexhe, A., Sejnowski, T.J., Steriade, M., 1996. Control of a spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback. Science 271, 771–774. Cools, A.R., van den Bercken, J.H.L., Hoestink, M.W.I., van Spaendonck, K.P.M., Bergern, H.J.C., 1984. Cognitive and motor shifting aptitude disorder in Parkinson’s disease. J. Neurol. Neurosurg. Psychol. 47, 443–453. Corcos, D.M., Chen, C.-M., Quinn, N.P., McAuley, J.H., Rothwell, J.C., 1996. Strength in Parkinson’s disease: relationship to rate of force generation and clinical status. Ann. Neurol. 39, 79–88. Day, B.L., Marsden, C.D., Obeso, J.A., Rothwell, J.C., 1981. Peripheral and central mechanisms of reciprocal inhibition in the human forearm. J. Physiol. 317, 59–60. Delgado, J.M.R., 1979. Inhibitory junctions in the neostriatum. In: Divac, I., Öberg, R.G.E. (Eds.), The Neostriatum. Pergammon Press, Oxford, pp. 241–261. DeLong, M.R., 1990. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 13, 281–285. Delwaide, P.J., Schwab, R.S., Young, R.R., 1974. Polysynaptic spinal reflexes in Parkinson’s disease. Neurology 24, 820–827. Denny-Brown, D., Yanagisawa, N., 1976. The role of the basal ganglia in the initiation of movement. In: Yahr, M.D. (Ed.), The Basal Ganglia. Raven Press, New York, pp. 115–148. Dietz, V., Berger, W., Horstmann, G., 1988. Corrective responses to disturbances of stance and gait in Parkinson’s disease: impaired function of spinal reflexes. In: Amblard, B., Berthoz, A., Clarac, F. (Eds.), Posture and Gait Development, Adaptation and Modulation. Elsevier, Amsterdam, pp. 259–271. Dinnerstein, A.J., Frigyes, T., Lowenthal, M., 1962. Delayed feedback as a possible mechanism in Parkinsonism. Percept. Motor Skills 15, 667–680. Ebersbach, G., Trottenberg, T., Hattig, H., Schelosky, L., Schrag, A., Poewe, W., 1996. Directional bias of initial visual exploration. A symptom of neglect in Parkinson’s disease. Brain 119, 79–87. Eckhorn, R., Bauer, R., Jordan, W., Brosch, M., Kruse, W., Munk, M., Reitboeck, H.J., 1988. Coherent oscillations: a mechanism of feature linking in the visual cortex? Multiple electrode and correlation analyses in the cat. Biol. Cybern. 60, 121–130. Eggermont, J.J., 1990. The Correlative Brain. Springer-Verlag, Berlin, pp. 60–62. Farmer, S.F., 1998. Rhythmicity, synchronisation and binding in human and primate motor systems (review). J. Physiol. 509, 3–14. Farmer, S.F., Sheean, G.L., Mayston, M.L., Rothwell, J.C., Marsden, C.D., Conway, B.A., Halliday, D.M., Rosenberg, J.R., Stephens, J.A., 1998. Abnormal motor unit synchronisation of antagonist muscles underlies pathological co-contraction in upper limb dystonia. Brain 121, 801– 814. Fitts, P.M., 1954. The information capacity of the human motor system in controlling the amplitude of movement. J. Exp. Psych. 47, 381–391. Gerfen, C.R., 2000. Dopamine-mediated gene regulation in models of Parkinson’s disease. Ann. Neurol. 47, S42–S52. Gerfen, C.R., Engber, T.M., Mahan, L.C., Susel, Z., Chase, T.N., Monsma Jr., F.J., Sibley, D.R., 1990. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250, 1429–1432. Goodrich, S., Henderson, L., Kennard, C., 1989. On the existence of an attention-demanding process peculiar to simple reaction time: converging evidence from Parkinson’s disease. Cogn. Neuropsychol. 6, 309–331. Gotham, A.M., Brown, R.G., Marsden, C.D., 1988. “Frontal” cognitive function in patients with Parkinson’s disease “on” and “off” levodopa. Brain 111, 299–321.

Gottlieb, G.L., Corcos, D.M., Agarwal, G.C., 1989. Organizing principles for single-joint movements. I. A speed-insensitive strategy. J. Neurophysiol. 62, 342–357. Grace, A.A., 1991. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the aetiology of schizophrenia. Neuroscience 41, 1–24. Gray, C.M., Konig, P., Engel, A.K., Singer, W., 1989. Oscillatory responses in cat visual cortex exhibit inter-columnar synchronisation which reflects global stimulus properties. Nature 338, 334–337. Graybiel, A.M., Canales, J.J., Capper-Loup, C., 2000. Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis. Trends Neurosci. 23, S71–S77. Grondin, R., Bédard, P.J., Britton, D.R., Shiosaki, K., 1997. Potential therapeutic use of the selective dopamine D1 receptor agonist A-86929: an acute study in Parkinsonian levodopa-primed monkeys. Neurology 49, 421–426. Hallett, M., Khoshbin, S., 1980. A physiological mechanism of bradykinesia. Brain 115, 465–480. Hart, R.P., Wade, J.B., Calabrese, V.P., Colenda, C.C., 1998. Vigilance performance in Parkinson’s disease and depression. J. Clin. Exp. Neuropsychol. 20, 111–117. Hassler, R., 1978. Striatal control of locomotion, intention actions and of integrating and perceptive activity. J. Neurol. Sci. 36, 187–224. Hassler, R., Dieckmann, G., 1967. Arrest reaction, delayed inhibition and unusual gaze behaviour resulting from stimulation of the putamen in awake unrestrained cats. Brain Res. 5, 504–508. Hore, J., Wild, B., Diener, H.C., 1991. Cerebellar dysmetria at the elbow, wrist, and fingers. J. Neurophysiol. 65, 563–571. Hua, S., Reich, S.G., Zirh, A.T., Perry, V., Dougherty, P.M., Lenz, F.A., 1998. The role of the thalamus and the basal ganglia in Parkinsonian tremor. Mov. Disord. 13, 40–42. Hurtado, J.M., Gray, C.M., Tamas, L.B., Sigvardt, K.A., 1999. Dynamics of tremor-related oscillations in the human globus pallidus: a single case study. Proc. Natl. Acad. Sci. U.S.A. 96, 1674–1679. Iansek, R., Porter, R., 1980. The monkey globus pallidus: neuronal discharge properties in relation to movement. J. Physiol. 301, 439–455. Jahanshahi, M., Brown, R.G., Marsden, C.D., 1992. Simple and choice reaction time and the use of advance information for motor preparation in Parkinson’s disease. Brain 115, 539–564. Jahanshahi, M., Jenkins, I.H., Brown, R.G., Marsden, C.D., Passingham, R.E., Brooks, D.J., 1995. Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson’s disease subjects. Brain 118, 913–933. Jahanshahi, M., Ardouin, C.M., Brown, R.G., Rothwell, J.C., Obeso, J., Albanese, A., Rodriguez-Oroz, M.C., Moro, E., Benabid, A.L., Pollak, P., Limousin-Dowsey, P., 2000. The impact of deep brain stimulation on executive function in Parkinson’s disease. Brain 123, 1142–1154. Jeanmonod, D., Magnin, M., Morel, A., 1996. Low threshold calcium spike bursts in the human thalamus: common physiopathology for sensory, motor and limbic positive symptoms. Brain 119, 363–375. Jenkins, G.M., Watts, D.G., 1968. Spectral Analysis and its Applications. Holden-Day, San Francisco, CA. Kennard, C., Lueck, C.J., 1989. Oculomotor abnormalities in the diseases of the basal ganglia. Rev. Neurol. 145, 587–595. Kupsch, A., Earl, C., 1999. Neurosurgical interventions in the treatment of idiopathic Parkinson disease: neurostimulation and neural implantation. J. Mol. Med. 77, 178–184. Lenz, F.A., Tasker, R.R., Kwan, H.C., Schnider, S., Kwong, R., Murayama, Y., Dostrovsky, J.O., Murphy, J.T., 1988. Single unit analysis of the human ventral thalamic nuclear group: correlation of thalamic “tremor cells” with the 3–6 Hz component of Parkinsonian tremor. J. Neurosci. 8, 754–764. Magnani, G., Cursi, M., Leocani, L., Volonté, M.A., Locatelli, T., Elia, A., Comi, G., 1998. Event-related desynchronization to contingent negative variation and self-paced movement paradigms in Parkinson’s disease. Mov. Disord. 13, 653–660.

J.H. McAuley / Progress in Neurobiology 69 (2003) 27–48 Magnin, M., Morel, A., Jeanmonod, D., 2000. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in Parkinsonian patients. Neuroscience 96, 549–564. Marsden, C.D., 1982. The mysterious motor function of the basal ganglia. Neurology 32, 514–539. Marsden, C.D., Obeso, J.A., 1994. The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 117, 877–897. Marsden, C.D., Merton, P.A., Morton, H.B., 1981. Human postural responses. Brain 104, 513–534. Marsden, J.F., Ashby, P., Limousin-Dowsey, P., Rothwell, J.C., Brown, P., 2000. Coherence between cerebellar thalamus, cortex and muscle in man. Brain 123, 1459–1470. Marsden, J.F., Limousin-Dowsey, P., Ashby, P., Pollak, P., Brown, P., 2001. Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson’s disease. Brain 124, 378–388. Martin, J.P., 1967. The Basal Ganglia and Posture. Pitman, Medical, London, pp. 1–152. Martin, T.A., Keating, J.G., Goodkin, H.P., Bastian, A.J., Thach, W.T., 1996. Throwing while looking through prisms. I. Focal olivocerebellar lesions impair adaptation. Brain 119, 1183–1198. McAuley, J.H., Brown, P., 1995. Frequency peaks of surface electromyogram are not coherent between different muscles of the same hand contracting simultaneously. J. Physiol. 487, 70P. McAuley, J.H., Marsden, C.D., 2000. Physiological and pathological tremors and rhythmic central motor control (review). Brain 123, 1545– 1567. McAuley, J.H., Rothwell, J.C., Marsden, C.D., 1997. Frequency peaks of tremor, muscle vibration and electromyogram during human finger muscle contraction may reflect a rhythmicity of central neural firing. Exp. Brain Res. 114, 525–541. McAuley, J.H., Rothwell, J.C., Marsden, C.D., 1999a. Human anticipatory eye movements may reflect rhythmic central nervous activity. Neuroscience 94, 339–350. McAuley, J.H., Farmer, S.F., Rothwell, J.C., Marsden, C.D., 1999b. Common 3- and 10-Hz oscillations modulate eye and finger movements while they simultaneously track a visual target. J. Physiol. 515, 905– 917. McAuley, J.H., Rothwell, J.C., Corcos, D.M., Quinn, N.P., 2001. Levodopa reversible loss of Piper rhythm in Parkinson’ disease. J. Neurol. Neurosurg. Psychol. 70, 471–476. McLellan, D.L., 1973. Dynamic spindle reflexes and the rigidity of Parkinsonism. J. Neurol. Neurosurg. Psychol. 36, 342–345. Mehta, M.A., Swainson, R., Ogilvie, A.D., Sahakian, B.J., Robbins, T.W., 2001. Improved short-term spatial memory but impaired reversal learning following the dopamine D2 agonist bromocriptine in human volunteers. Psychopharmacology 159, 10–20. Morris, M., Iansek, R., Smithson, F., Huxham, F., 2000. Postural instability in Parkinson’s disease: a comparison with and without a concurrent task. Gait Posture 12, 205–216. Munk, M.H.J., Roelfsema, P.R., Konig, P., Engel, A.K., Singer, W., 1996. Role of reticular activation in the modulation of intracortical synchronisation. Science 272, 271–274. Murer, M.G., Pazo, J.H., 1993. Behavioural responses induced by electrical stimulation of the caudate nucleus in freely moving cats. Behav. Brain Res. 57, 9–19. Murthy, V.N., Fetz, E.E., 1996. Synchronisation of neurones during local field potential oscillations in sensorimotor cortex of awake monkeys. J. Neurophysiol. 76, 3968–3982. Nakashima, K., Rothwell, J.C., Day, B.L., Thompson, P.D., Shannon, K., Marsden, C.D., 1989. Reciprocal inhibition between forearm muscles in patients with writer’s cramp and other occupational cramps, symptomatic hemidystonia and hemiparesis due to stroke. Brain 112, 681–697. Neufeld, M.Y., Inzelberg, R., Korczyn, A.D., 1988. EEG frequency analysis in demented and non-demented Parkinsonian patients. Acta Neurol. Scand. 78, 1–5.

47

Nicolelis, M.A., Baccala, L.A., Lin, R.C., Chapin, J.K., 1995. Sensorimotor encoding by synchronous neural ensemble activity at multiple levels of the somatosensory system. Science 268, 1353–1358. Nini, A., Feingold, A., Slovin, H., Bergman, H., 1995. Neurones in the globus pallidus do not show correlated activity in the normal monkey, but phase locked oscillations appear in the MPTP model of Parkinsonism. J. Neurophysiol. 74, 1800–1805. Obeso, J.A., Rodriguez-Oroz, M.C., Rodriguez, M., Lanciego, J.L., Artieda, J., Olanow, C.W., 2000. Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci. 23, S8–S19. Oberg, R.G.E., Divac, I., 1979. Cognitive functions of the neostriatum. In: Divac, I., Oberg, R.G.E. (Eds.), The Neostriatum. Pergamon Press, Oxford, pp. 291–313. Onn, S.-P., Grace, A.A., 1999. Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurones in dopamine denervated rat striatum recorded in vivo. Synapse 33, 1–15. Onn, S.-P., West, A.R., Grace, A.A., 2000. Dopamine-mediated regulation of striatal neuronal and network interactions. Trends Neurosci. 23, S48–S56. Pahapill, P.A., Lozano, A.M., 2000. The pedunculopontine nucleus and Parkinson’s disease. Brain 123, 1767–1783. Pearce, R.K.B., Jackson, M., Britton, D.R., Shiosaki, K., Jenner, P., Marsden, C.D., 1999. Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated l-DOPA-primed common marmosets. Psychopharmacology 142, 51–60. Platz, T., Brown, R.G., Marsden, C.D., 1998. Training improves the speed of aimed movements in Parkinson’s disease. Brain 121, 505–514. Plenz, D., Kitai, S.T., 1996. Generation of high-frequency oscillations in local circuits of rat somatosensory cortex cultures. J. Neurophysiol. 76, 4180–4184. Procter, F., Riklan, M., Cooper, I.S., Teuber, H.-L., 1964. Judgement of visual and postural vertical by Parkinsonian patients. Neurology 14, 287–293. Ridding, M.C., Inzelberg, R., Rothwell, J.C., 1995. Changes in excitability of motor cortical circuitry in patients with Parkinson’s disease. Ann. Neurol. 37, 181–188. Rolls, E.T., Thorpe, S.J., Maddison, S., Roper-Hall, A., Puerto, A., Perret, D., 1979. Activity of neurones in the neostriatum and related structures in the alert animal. In: Divac, I. Öberg. R.G.E. (Eds.), The Neostriatum. Pergamon Press, Oxford, pp. 163–182. Ruskin, D.N., Bergstrom, D.A., Mastropietro, C.W., Twery, M.J., Walters, J.R., 1999. Dopamine agonist-mediated rotation in rats with unilateral nigrostriatal lesions is not dependent on net inhibitions of rate in basal ganglia output nuclei. Neuroscience 91, 935–946. Sanes, J.N., 1985. Information processing deficits in Parkinson’s disease during movement. Neuropsychologica 23, 381–392. Sanes, J.N., Donoghue, J.P., 1993. Oscillations in local field potentials of the primate motor cortex during voluntary movement. Proc. Natl. Acad. Sci. U.S.A. 90, 4470–4474. Schultz, W., 1998. Predictive reward signal of dopamine neurones. J. Neurophysiol. 80, 1–27. Schwab, R.S., Chafetz, M.E., Walker, S., 1954. Control of two simultaneous motor acts in normals and Parkinsonism. Arch. Neurol. 72, 591–598. Segawa, M., 2000. Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev. 22, S65–S80. Shibasaki, H., Shima, F., Kuroiwa, Y., 1978. Clinical studies of movementrelated cortical potential (MP) and the relationship between the dentatorubrothalamic pathway and readiness potential (RP). J. Neurol. 219, 15–25. Soliveri, P., Brown, R.G., Jahanshahi, M., Caraceni, T., Marsden, C.D., 1997. Learning manual pursuit tracking skills in patients with Parkinson’s disease. Brain 120, 1325–1337. Stam, C.J., Tavy, D.L., Keunen, R.W., 1993. Quantification of alpha rhythm desynchronization using the acceleration spectrum entropy of the EEG. Clin. Electroenceph. 3, 104–109.

48

J.H. McAuley / Progress in Neurobiology 69 (2003) 27–48

Steriade, M., Dossi, R., Paré, D., Oakson, G., 1991. Fast oscillations (20–40 Hz) in thalamocortical systems and their potentiation by mesopontine cholinergic nuclei in the cat. Proc. Natl. Acad. Sci. U.S.A. 88, 4396– 4400. Steriade, M., McCormick, D.A., Sejnowski, T.J., 1993. Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679–685. Stern, G.M., Lander, C.M., Lees, A.J., 1980. Akinetic freezing and trick movements in Parkinson’s disease. J. Neurol. Transm. 16, 137–141. Tatton, W.G., Lee, R.G., 1975. Evidence for abnormal long-loop reflexes in rigid Parkinsonian patients. Brain Res. 100, 671–676. Taylor, A.E., Saint-Cyr, J.A., Lang, A.E., 1986. Frontal lobe dysfunction in Parkinson’s disease: the cortical focus of neostriatal outflow. Brain 109, 845–883. Teasdale, N., Phillips, J., Stelmach, G.E., 1990. Temporal movement control in patients with Parkinson’s disease. J. Neurol. Neurosurg. Psychol. 53, 862–868. Thompson, P.D., Bhatia, K.P., Brown, P., Davis, M.B., Pires, M., Quinn, N.P., Luthert, P., Honovar, M., O’Brien, M.D., Marsden, C.D., 1994. Cortical myoclonus in Huntington’s disease. Mov. Disord. 9, 633–641. Tiitinen, H., Sinkkonen, J., Reinikainen, K., Alho, K., Lavikainen, J., Naatanen, R., 1993. Selective attention enhances the auditory 40 Hz transient response in humans. Nature 364, 59–60. Tijssen, M.A., Marsden, J.F., Brown, P., 2000. Frequency analysis of EMG activity in patients with idiopathic torticollis. Brain 123, 677–686. Timofeev, I., Steriade, M., 1997. Fast (mainly 30–100 Hz) oscillations in the cat cerebellothalamic pathway and their synchronisation with cortical potentials. J. Physiol. 504, 153–168. Traub, M.M., Rothwell, J.C., Marsden, C.D., 1980. Anticipatory postural reflexes in Parkinson’s disease and other akinetic-rigid syndromes and in cerebellar ataxia. Brain 103, 393–412. Tseng, K.Y., Kasanetz, F., Kargieman, L., Riquelme, L.A., Murer, M.G., 2001. Cortical slow oscillatory activity is reflected in the membrane potential and spike trains of striatal neurons in rats with chronic nigrostriatal lesions. J. Neurosci. 21, 6430–6439.

Walshe, F.M.R., 1924. Observations on the nature of the muscular rigidity of paralysis agitans, and on its relationship to tremor. Brain 47, 159– 177. Walters, J.R., Rushkin, D.N., Allers, K.A., Bergstrom, D.A., 2000. Preand post-synaptic aspects of dopamine-mediated transmission. Trends Neurosci. 23, S41–S47. Warabi, T., Noda, H., Yanagisawa, N., Tashiro, K., Shindo, R., 1986. Changes in sensorimotor function associated with the degree of bradykinesia of Parkinson’s disease. Brain 109, 1209–1224. Warabi, T., Yanagisawa, N., Shindo, R., 1988. Changes in strategy of aiming tasks in Parkinson’s disease. Brain 111, 497–505. Weingartner, H., Burns, S., Diebel, R., LeWitt, P.A., 1984. Cognitive impairments in Parkinson’s disease: distinguishing between effort-demanding and automatic cognitive processes. Psychol. Res. 11, 223–235. Weinmann, R.L., 1975. Disorders of movement: a mercifully short primer. Dis. Nerv. Syst. 36, 284–286. White, O.B., Saint-Cyr, J.A., Tomlinson, R.D., Sharpe, J.A., 1983. Ocular motor deficits in Parkinson’s disease. II. Control of the saccadic and smooth pursuit systems. Brain 106, 571–587. Wichmann, T., Bergman, H., Delong, M.R., 1994. The primate subthalamic nucleus. III. Changes in motor behaviour and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of Parkinsonism. J. Neurophysiol. 72, 521–530. Wilson, S.A.K., 1925. Disorders of motility and muscle tone, with special reference to the striatum. Lancet 2, 1–53. Yaar, I., 1977. EEG power spectral changes secondary to l-DOPA treatment in Parkinsonian patients: a pilot study. Electroencephalogr. Clin. Neurophysiol. 43, 111–118. Yanagawa, S., Shindo, M., Yanagisawa, N., 1990. Muscular weakness in Parkinson’s disease. Adv. Neurol. 53, 259–269. Yurek, D.M., Randall, P.K., 1991. Striatal depth EEG reveals postsynaptic activity of striatal neurons following dopamine receptor stimulation and blockade. J. Neurosci. Methods 37, 81–91.