Brain (2001), 124, 2131–2146

R E V I E W A R T I C L E

Pathophysiology of bradykinesia in Parkinson’sdiseaseA. Berardelli,1 J. C. Rothwell,2 P. D. Thompson3 and M. Hallett4

1Dipartimento di Scienze Neurologiche, Istituto Correspondence to: Professor Alfredo Berardelli,Neurologico Neuromed IRCCS, Universita di Roma ‘La Dipartimento di Scienze Neurologiche, Viale Universita 30,Sapienza’, Rome, Italy, 2MRC Human Movement and 00185 Roma, ItalyBalance Unit, The Institute of Neurology, London, UK, This paper is dedicated to the memory of Professor3The Royal Adelaide Hospital, The University Department C. D. Marsdenof Medicine, Adelaide, Australia and 4Human MotorControl Section, NINDS, NIH, Bethesda, Maryland, USA

SummaryBradykinesia means slowness of movement and is oneof the cardinal manifestations of Parkinson’s disease.Weakness, tremor and rigidity may contribute to but donot fully explain bradykinesia. We argue thatbradykinesia results from a failure of basal ganglia outputto reinforce the cortical mechanisms that prepare andexecute the commands to move. The cortical deficit ismost apparent in midline motor areas. This leads toparticular difficulty with self-paced movements,prolonged reaction times and abnormal pre-movementEEG activity. Movements are often performed withnormally timed EMG bursts but the amount of EMGactivity is underscaled relative to the desired movementparameters. There are also abnormalities in sensoryscaling and sensorimotor integration. The brain appears

Keywords: bradykinesia; Parkinson’s disease; movement; motor control

Abbreviations: BP � Bereitschaftspotential; CNV � contingent negative variation; fMRI � functional MRI; MEG �magnetic electroencephalography; SMA � supplementary motor area

IntroductionThe term bradykinesia was first used by James Parkinson todescribe one of the cardinal features of the disease thatnow bears his name. It is now recognized, however, thatbradykinesia may be part of the motor dysfunction in manymovement disorders.

Bradykinesia is often used synonymously with two otherterms: akinesia and hypokinesia. Strictly speaking,bradykinesia describes the slowness of a performedmovement, whereas akinesia refers to a poverty of

© Oxford University Press 2001

to be able to compensate to some degree for the basalganglia deficit. There is overactivity in the lateralpremotor areas during task performance and movementscan be speeded by giving sensory cues. Attention tomovement is also beneficial. However, we propose thatthe engagement of compensatory processes may also leadto reduced performance in other tasks. For example,patients’ problems in performing more than one task atthe same time could result from lack of sufficient resourcesboth to compensate for their basal ganglia deficit and torun two tasks simultaneously. Surgical therapies areunlikely to work solely by normalizing basal gangliaoutput to that seen in healthy individuals. It seems moreplausible that surgery removes an interfering signal thatallows more efficient compensation by other structures.

spontaneous movement (e.g. in facial expression) orassociated movement (e.g. arm swing during walking). Othermanifestations of akinesia are freezing and the prolongedtime it takes to initiate a movement. Hypokinesia refers tothe fact that, in addition to being slow, the movements arealso smaller than desired, as in the micrographia of patients’handwriting. Although these three symptoms are related, theymust also be separate to some extent, since they may not bewell correlated with each other in individual patients (Evarts

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et al., 1981). Parkinson’s disease patients often appear clumsy,and it is likely that this results from several aspects of themotor disorder.

In this review we will use the term ‘bradykinesia’ toencompass all these problems of slowness or absence ofmovement. However, where we think that separatemechanisms are involved we will always define the particularfunctional deficits that we think are relevant in each case.Before discussing the central mechanisms of bradykinesiaand how they relate to the basal ganglia dysfunction that isat the heart of Parkinson’s disease, it will be useful firstto consider other secondary factors that can contribute tobradykinesia.

Secondary causes of bradykinesiaThere are five factors that can potentially contribute tobradykinesia in Parkinson’s disease. These are muscleweakness, rigidity, tremor, movement variability and slowingof thought.

Muscle weaknessSeveral studies (Stelmach and Worringham, 1988; Stelmachet al., 1989; Jordan et al., 1992) have compared the strengthof patients with Parkinson’s disease and healthy age-matchedsubjects. All of them found a mild reduction of strength ina variety of muscle groups, even though this sometimesfailed to reach statistical significance. One probable reasonfor this lack of agreement is that it is difficult to matchpatient and control groups for the amount of daily exerciseand diet.

A recent study by Corcos and colleagues attempted toresolve this problem by measuring strength at the elbow inpatients when ON and OFF L-dopa following overnightwithdrawal of therapy (Corcos et al., 1996). When OFFmedication, there was a 30% reduction in the strength ofmaximum elbow extension and a 10% decrease in elbowflexion. Because intrinsic muscle properties could not havechanged in the short period between the OFF and ONconditions, the difference in strength must have been due toan inability of patients to activate the elbow musclesmaximally. In that study, the patients appeared to be highlymotivated to produce strong contractions when OFF and ONtherapy, so that lack of volitional drive was not thought tobe a factor. A later study by Brown and colleagues on thewrist extensors showed that one physiological reason for thereduction in strength is the persistence of action tremorduring maximal contraction (Brown et al., 1997). Tremor at~10 Hz in patients OFF therapy prevents maximum fusionof motor unit contraction and can contribute to weakness.However, this cannot account for the decrease in strength inall muscle groups, so that other, presumably central, factorsmust also be involved. The conclusion is that patients withParkinson’s disease can be weak in some muscle groups andthis will inevitably contribute to slowness of movement.

It is not clear whether attention might affect the results ofstrength testing. The fact that patients fail to energize theirmuscles fully, especially when OFF drug treatment, indicatesonly that they lack some part of the normal volitional inputto lower motor centres. Why this occurs is unclear. There isno obvious lack of effort by patients and there does notappear to be any lack of concentration. Patients will frequentlysay they are trying as hard as possible. Similarly, the existenceof physiological differences in the EMG activity in patientscompared with normal subjects suggests that the voluntarydrive to contract is not organized in the same way as usual.However, phenomena such as paradoxical kinesia suggestthat there are mechanisms that can overcome this apparentlack of volitional drive but this is probably not an attention-related phenomenon.

RigidityLong-latency stretch reflexes are enhanced in Parkinson’sdisease (Tatton and Lee, 1975; Berardelli et al., 1983;Rothwell et al., 1983). They could potentially contribute tobradykinesia if they were elicited in an antagonist muscleduring an active isotonic contraction of the agonist. Johnsonand colleagues tested this hypothesis by using a torque motorto stretch muscles unexpectedly during active sinusoidalmovements of the wrist (Johnson et al., 1991). They showedthat reflexes elicited in the antagonist muscle were notsuppressed as much as in normal subjects, and that thedegree of abnormality was related to the amount of clinicalbradykinesia. The one flaw in this argument was that theamount of activity in the antagonist muscle duringunperturbed flexion/extension movements was no greaterthan that seen in normal subjects. Thus, there was no evidencein the actual movements tested that antagonist co-contractioncould have been a limiting factor. Indeed, co-contraction hasnever been described as an important feature even in veryrapid movements, in which the triphasic ballistic movementEMG pattern has been analysed in some detail. The conclusionmust be that the role of rigidity in bradykinesia has yet tobe proven conclusively.

Rest and action tremorWe noted above that action tremor can contribute to weaknessin Parkinson’s disease. In addition, rest and action tremorcan also be a factor in prolonging reaction times. Hallettand colleagues and Wierzbicka and colleagues showed thatpatients with Parkinson’s disease tend to time the onset ofagonist muscle activity at the elbow or wrist with the timeof activation of the same muscle in any ongoing tremor(Hallett et al., 1977; Wierzbicka et al., 1993). This could,on average, slow the initiation of any movement.

Action tremor can also be a factor in pacing the speed ofvoluntary alternating movements. Logigian and colleaguesshowed that voluntary movements are entrained by actiontremor if patients attempt to move at frequencies close to

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that of their natural action tremor (Logigian et al., 1991).The extent of the entrainment depends on the amplitude ofthe patients’ ongoing tremor.

Movement variabilityThe movements of patients with Parkinson’s disease are lessaccurate than normal, particularly if they have to move asfast as possible (Sanes, 1985; Sheridan and Flowers, 1990;Phillips et al., 1994). In other words, the speed–accuracytrade-off is less efficient in patients than in healthy subjects.Sheridan and Flowers suggested that bradykinesia might bedue to an active strategy of patients to move more slowly inorder to improve their accuracy (Sheridan and Flowers,1990). Although this is a plausible strategy, other factorsmust also be involved since bradykinesia remains in tasksin which spatial accuracy constraints have been removed(Teasdale et al., 1990).

BradyphreniaSlowness of thought, or bradyphrenia, could lead tobradykinesia by interfering with movement planning and, forexample, increasing reaction time. Whether bradyphreniaexists in Parkinson’s disease has been controversial. In part,this is due to the fact that many patients with Parkinson’sdisease do develop dementia from several aetiologies, andthere is certainly slowing of thinking in dementia (Berryet al., 1999). Additionally, there is slowing of thought inageing and depression (Cooper et al., 1994), and these factorsneed to be considered. Lastly, many ‘cognitive’ studies haveemployed procedures that have required a motor response,so that bradykinesia might cause an apparent bradyphrenia(Rafal et al., 1984). Confusion has arisen from a number ofstudies that have not taken these factors into consideration.Moreover, thinking is not just one process and whether it isslow might depend on the nature of the task. Some studieshave claimed to find bradyphrenia (Cooper et al., 1994; Pateand Margolin, 1994), but most have not (Rafal et al., 1984;Duncombe et al., 1994; Howard et al., 1994; Spicer et al.,1994). It is likely that bradyphrenia is not responsible forslowing when dementia is not present and the patient is noton drugs, such as anticholinergics, that might interfere withcognitive processes.

Primary bradykinesiaAlthough all the factors above can contribute to bradykinesia,they must be distinguished from the core disorders ofcentral movement control that are responsible for primarybradykinesia. In this section we describe those features ofbradykinesia that cannot be explained by secondary factors.

Bradykinesia could potentially be due to slowness informulating the instructions to move (programming) or toslowness in executing these instructions. Althoughprogramming and execution are usually thought of as separate

and sequential operations, they could well overlap, at leastto the extent that programming could continue duringexecution. It is possible, therefore, to study some of theprocesses involved in programming if we confine ourselvesto measurements such as reaction times or EEG/magneticencephalography (MEG) studies made before the onset ofmovements. Measurements made after movement onset mayreflect both execution as well as programming.

Preparation to move: studies of reaction timesPatients with Parkinson’s disease react more slowly thanhealthy subjects of the same age and this contributes toakinesia. The more advanced the disease, the slower thereaction times. A question is whether patients are slow instarting to move because they have a problem in preparingthe instructions to move, or whether the problem is inreleasing those instructions.

Some information about preparatory processes can beobtained by comparing reaction tasks in which the movementcomponent is constant but the amount of preparation isvariable. In a simple reaction task, the same response is madeon every occasion and healthy subjects can prepare theresponse fully in advance of the imperative signal. In achoice reaction task, the response depends on the reactionsignal. Subjects know the set of possible moves they mighthave to make but not the precise one that will be needed onany particular trial. They cannot prepare the movement fullyin advance and have to complete more of the preparationafter the imperative signal is given. The result is that choicereaction times are longer than simple reaction times.

Simple reaction times are prolonged in Parkinson’s disease(Heilman et al., 1976; Evarts et al., 1981; Rafal et al., 1984;Bloxham et al., 1987; Sheridan et al., 1987; Hallett 1990;Jahanshahi et al., 1992, 1993; Kutukcu et al., 1999; see alsoZimmerman et al., 1992; Harrison et al., 1993; Revonsuoet al., 1993). The situation with choice reaction times ismore complex. Some authors have reported that they are thesame as normal (Evarts et al., 1981; Bloxham et al., 1987;Sheridan et al., 1987) and have suggested that patients haveslow simple reaction times because they fail to take advantageof the opportunity to programme their response fully inadvance. However, other authors have reported that choicereaction times are longer than normal (Wiesendanger et al.,1969; Stelmach et al., 1986; Mayeux et al., 1987; Duboiset al., 1988; Lichter et al., 1988; Reid et al., 1989; Pullmanet al., 1988; Jahanshahi et al., 1992; Brown et al., 1993b).It is not clear why there is so much variety in the resultsreported. Some may arise because different patient groupswere studied at different stages of the disease; some may bedue to elements in the design of the task, such as stimulus–response compatibility, which may be handled differently inpatients with Parkinson’s disease (e.g. Brown et al., 1993b).Whether or not patients can take full advantage of priorprogramming, there is evidence that patients are likely to

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be slower than normal in preparing expected responses(Jahanshahi et al., 1992).

In contrast to the disagreement over the extent ofprogramming deficits in Parkinson’s disease, there is muchclearer evidence that slowness in executing motor commandsis an important factor in prolonging reaction times. The reasonis that motor excitability has to build up to a certain thresholdlevel before movement or even EMG activity can be detected.If this is slow, the threshold is reached later than normal. Forexample, EMG activity in patients usually rises slowly afterits onset, and this can delay the time at which movement isdetected. The same argument can be applied to the intervalbefore the onset of EMG: motor excitability has to build up tothreshold before motor neurones are discharged. Experimentswith magnetic transcranial stimulation have confirmed thatpre-movement excitability increases more slowly than normalin patients with Parkinson’s disease (Pascual-Leone et al.,1994). The conclusion is that little of the increase in simplereaction times is due to problems in starting the commandsto move. The deficit arises either because the wrong (slow)commands have been chosen or because the correct commandsare executed more slowly than normal.

Our conclusion from these reaction time studies is thatslowness in simple reaction tasks is as much due to problemsin the execution of a stored motor command as it is tomaintaining that command in store at an appropriate state ofreadiness. The situation for choice of reaction tasks requiresfurther study.

Preparation to move: activation of specific brainareasEEG, MEG, PET, functional MRI (fMRI) and magneticstimulation techniques have all been used in an attempt tounderstand which parts of the motor system are functioningabnormally in akinetic patients with Parkinson’s disease.However, because brain activity during movement reflectsboth outgoing motor commands and the sensory input thatresults from moving, studies of motor activity haveconcentrated on the period just before the onset of movementwhen changes in sensory input are minimal. In most instances,the movements are self-paced; reaction tasks involve pre-movement sensory input that can complicate the interpretationof the data obtained. A general finding from these studies isthat there is underactivity of midline [supplementary motorcortex (SMA) and nearby areas] cortical motor areas, perhapscoupled with extra activation of lateral premotor areas. Theformer may be related to difficulties in preparing instructionsto move; the latter may be an active process of compensationand may be related to the improvement in performance thatcan be observed when external cues are given to guidemovement (see below).

The pre-movement EEG potential, sometimes called theBereitschaftspotential (BP), is a slowly rising negativity thatoccurs over widespread areas of the scalp before the onset

of a self-paced voluntary movement. It has two majorcomponents. The early component (sometimes known as BPbut here referred to as BP1) begins 1–2 s before movement.It is bilaterally symmetrical and is largest at the vertex. Thesecond component (sometimes known as NS1 or NS� buthere called BP2) rises more steeply, beginning ~650 msbefore the onset of EMG activity. Recent recordings fromsubdural electrodes suggest that the BP1 predominantlyreflects bilateral activity in the motor and supplementarymotor areas, whereas the BP2 also has a contribution from thecontralateral motor and premotor cortex (Ikeda et al., 1992).

In early studies, there was some debate over whether theBP was abnormal in Parkinson’s disease. Some of thecontroversy was resolved by Dick and colleagues, whoshowed that L-dopa could affect the amplitude of the BPboth in normal subjects and in patients, and that a differencebetween patients with Parkinson’s disease and normal subjectswas crucially dependent on the level of dopaminergic function(Dick et al., 1989). They went on to show that the BP inpatients OFF therapy was reduced in the early part (BP1)but larger than normal in the later part (BP2) (Dick et al.,1989). The net effect was that the peak BP was virtually thesame in the patients as in normal subjects. They suggestedthat underactivity of a source in the SMA was responsiblefor the reduction of the early component, and that this wascompensated for by overactivity in lateral motor areas nearerthe time of onset of movement. Recent studies have tendedto confirm this idea. For example, Jahanshahi and colleaguesnoted that pre-movement EEG activity was normal in patientswith Parkinson’s disease when they performed an externallytriggered task compared with the reduction that is seen inself-paced movements (Jahanshahi et al., 1995) (Fig. 1).Cunnington and colleagues proposed that underactivation ofthe SMA in Parkinson’s disease patients made them morereliant on external cues so that they did not use predictivemodels when cues were available (Cunnington et al., 1995,1997). Pre-movement activity could, however, be induced inpatients if they were asked to attend to the time of the nextmovement, and this improved task performance (Cunningtonet al., 1999). The authors suggested that attentional processesallow lateral premotor systems, which are less impaired bybasal ganglia dysfunction, to compensate for deficiencies inmidline motor systems that are normally active in internallygenerated tasks.

In these early studies the subjects repeated the samemovement over many trials. Later studies have required thesubjects to choose to make different movements (e.g. movinga joystick up, down, left or right) on each trial. In healthysubjects, the BP is much larger than when subjects make thesame movement on each occasion, perhaps reflecting theadditional processing necessary to choose betweenmovements on each trial (Touge et al., 1995; Praamstra et al.,1996a, b, 1998; Dirnberger et al., 2000). Praamstra andcolleagues used dipole modelling to show that the most likelysource for the extra activation was the SMA (Praamstra et al.,

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Fig. 1 (A) Premotor potentials preceding self-initiated movements for normal subjects (continuous line) and patients with Parkinson’sdisease (broken line). (B) Premotor potentials preceding externally triggered movements for normal subjects (continuous line) andpatients with Parkinson’s disease (broken line). The mean time of stimulus presentation is 253 ms prior to EMG onset for patients withParkinson’s disease and 212 ms for normal subjects. Pre-movement EEG activity was normal in patients with Parkinson’s disease whenthey performed an externally triggered task compared with the reduction that is seen in self-paced movements. From Jahanshahi et al.,1995.

1996b). This extra activation is lacking in patients withParkinson’s disease, consistent with the model outlined above.

Abnormalities in cortical activation prior to and duringmovement have been also found with the technique of event-related desynchronization (Defebre et al., 1996; Magnaniet al., 1998). The amount of power in the alpha (10 Hz) andbeta (20 Hz) ranges of EEG activity decreases ~1 s beforethe onset of movement and remains lower than at rest whilemovement occurs. It has been suggested that the 10–20 Hzrhythm occurs because the activity of cortical neurones tendsto become synchronized during periods of relative inactivity.If so, event-related desynchronization is a measure of corticalactivation that reflects uncoupling of the population activityinto more discrete temporal and spatial patterns. In patientswith Parkinson’s disease the duration of the event-relateddesynchronization prior to voluntary movements is shorterand the pattern of movement-related attenuation of the alphaand beta rhythms during various types of motor tasks isabnormal. Brown and Marsden found that dopaminergicstimulation in Parkinson’s disease restores the movement-related attenuation of the alpha and beta rhythms (Brown

and Marsden, 1999). This effect was specific for the motorareas involved in the motor task and correlated with theimprovement of bradykinesia. Wang and colleagues reportedsimilar findings in their study of simple and complexmovements (Wang et al., 1999). The above studies suggestthat the basal ganglia have a role in releasing cortical elementsfrom idling rhythms during voluntary movement. In a recentreport, Brown carried this idea one stage further by examiningthe effect of dopaminergic stimulation on the coupling ofactivity between different nuclei of the basal ganglia (Brownet al., 2001). They recorded local potentials from patientswith implanted electrodes in the subthalamic nucleus andinternal pallidum, and found that they were coupled byactivity at 20–30 Hz when the patients were OFF medication,whereas ON medication this changed to 60–70 Hz.

Motor executionSingle ballistic movements at a single jointSingle movements made as fast as possible about a singlejoint are slower than normal in patients with Parkinson’s

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Fig. 2 Rapid movements performed at a single joint in a normalsubject (15° and 60° of movement amplitude) and in a patientwith Parkinson’s disease (OFF and ON therapy, 15° of movementamplitude). The normal subject performed the movement with asingle triphasic EMG pattern in the agonist and antagonistmuscles, whereas the patient performed the movement withmultiple EMG bursts. EMG activity was recorded from theforearm flexor (FF) and extensor (FE) muscles.

disease (for a review, see Berardelli et al., 1996a) (Fig. 2).Part of this slowing may be due to weakness of the agonistmuscle discussed above, but much must be due to otherfactors. For example, even though maximum contractionstrength of the biceps decreases by 10% in the OFF condition,the speed of elbow flexion may halve. Similarly, EMGrecords show that there is no excessive co-contraction of theantagonist that might slow the movement down more thanexpected from the decline in strength. It seems instead thatslowness of movement is caused by problems in recruitingthe appropriate level of muscle force sufficiently fast.

There are two parts to this problem. First, patients mayfind it difficult to activate a muscle rapidly. This is certainlytrue in more advanced disease: it can take several secondsfor some patients to produce a maximum voluntarycontraction (e.g. Corcos et al., 1996). However, the rate ofcontraction is not the only cause of bradykinesia in simplemovements. The fastest movements are accompanied by a

triphasic EMG pattern in which the time and duration of thebursts varies in a highly predictable way depending on theamplitude and other parameters of movement. This patternis present in patients with Parkinson’s disease, but the firstagonist burst is small. As Hallett and Khoshbin pointed out,the result is that patients often add further bursts of EMG tothe pattern in order to achieve enough force to move thelimb to the required end position (Hallett and Khoshbin,1980). Despite this, if patients aim for a movement of largeramplitude, the size of the agonist burst can increase. Ineffect, this means that the size of the agonist burst is notalways a limiting factor in slowing movement: if the burstfor the large movement had been used for the smallermovement the speed would have been normal. The conclusionis that there is a second cause of bradykinesia in simplemovement: inappropriate scaling of the dynamic muscle forceto the movement parameters (Berardelli et al., 1986b).

Simultaneous, sequential or repetitive movementsIf any additional complexity is added to a simple movement,either by repeating the movement or by combining it withother tasks, bradykinesia becomes more prominent. Clinicaltests of bradykinesia often make use of this phenomenon.Repetitive sequential movement involving isolated fingermovements, hand opening/closing or wrist pronation/supination become smaller (hypokinesia) and slower withrepetition of the movement (‘fatigue’) (Agostino et al.,1998). Schwab and colleagues asked patients to squeeze asphygmomanometer bulb in one hand and outline a drawingwith the other (Schwab et al., 1954). They had much moredifficulty if they had to do both tasks together than if eachone was performed alone. Indeed, in most cases, patientstended to alternate between the tasks rather than performthem at the same time.

Experimental studies have analysed these features ofbradykinesia in some detail. In essence, they show thatbradykinesia is more than the slowness seen in simple singlemovements. There are additional problems in combining orsustaining complex movements. Benecke and colleaguesexamined rapid elbow flexion movements combined with asimultaneous or sequential hand movement performed witheither the same or the opposite arm (Benecke et al., 1986,1987). In contrast to normal subjects, in whom there was nodecrement of performance when two tasks were combined,patients with Parkinson’s disease showed (i) a marked slowingof movement over and above that seen in each task alonewhen both had to be performed together, and (ii) a longerpause between each element of a sequential task. Indeed, thesetwo extra deficits correlated better with clinical measures ofbradykinesia than the slowness in each simple movement.

Similar problems in performing simultaneous movementshave been described in bilateral reaching (Stelmach andWorringham, 1988; Castiello and Bennett, 1997) and crankingtasks (Johnson et al., 1998). In sequential movements,prolonged pauses between each element have been observed

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in everyday movements, such as rising from a chair to pickup an object or drinking from a cup (Bennett et al., 1995).Elements of fatigue have also been reported in longer-lastingsequences of movements (Berardelli et al., 1986a; Agostinoet al., 1992, 1994).

What is the nature of the extra deficits inperformance of complex movements?The problem of combining tasks or switching from one taskto another is not confined to movement. It can be observedin cognitive tasks or combined cognitive and motor tasks(Brown and Marsden, 1991; Oliveira et al., 1998). Suchobservations are important since they indicate that the extradeficit seen in complex movements is not necessarily apurely motor problem. They raise the possibility that globalprocessing mechanisms, perhaps involving attention, are alsoa factor. Brown and Marsden suggested that patients eitherhave a limited processing resource that interferes with theirability to run more than one task at the same time, or thatthey have difficulty in switching this resource between tasks(Brown and Marsden, 1991). An alternative is that the globalresource is the same in patients, but that tasks are performedless automatically than in normal subjects. In this case, eachtask would consume more of the processing resource, andlead to difficulties in performing several tasks at once, or inswitching between tasks. Effectively, patients may be tryingto compensate for lack of basal ganglia input by devotingmore resources to each single task they perform. Whenrequired to perform more than one task at once, this becomesa limiting factor.

Sensorimotor processingSome authors have reported abnormalities in sensorimotorprocessing in Parkinson’s disease. Schneider and colleaguesreported a decrease of precision in two-point discriminationand proprioceptive position sense (Schneider et al., 1986)and Klockgether and colleagues, in a study of arm movementstesting the effects of both visual and kinaesthetic information,suggested that peripheral afferent feedback is impaired inpatients with Parkinson’s disease (Klockgether et al., 1995).A problem in matching somatosensory and visual inputs wasdemonstrated by Demirci and colleagues (Demirci et al.,1997). The authors postulated that this was due to anabnormality of sensory scaling and drew parallels with theabnormal scaling of motor output reported by Berardelli andcolleagues (Berardelli et al., 1986b).

A deficit in sensorimotor integration may also be observedin precision grip/lift tasks. These are complex acts that areperformed by gripping an object with the correct amount offorce so that it does not fall between the fingers when it islifted off a supporting surface. Parkinsonian patients takelonger to develop peak grip force and show a pronouncedslowing in the rate at which grip force is generated. They

also squeeze the object more than normal when lifting it inthe air (Fellows et al., 1998). The authors thought that thelatter effect was due to problems in sensorimotor processing.We conclude that kinaesthesia may have a role in thepathophysiology of Parkinson’s disease, but that itsimportance still needs to be clarified.

Abnormalities in the contingent negative variation (CNV)can also be explained in terms of abnormal sensorimotorprocessing. The CNV is a slow negative potential that occursbetween a warning (S1) and an imperative (S2) stimulus. Itis best recorded at frontal and central electrodes and reflectsprocesses related to planning a forthcoming movement andanticipation of the imperative stimulus. Activity of theprefrontal cortex contributes to the amplitude of the CNV.In Parkinson’s disease, the amplitude of the CNV is reducedby an amount related to the severity of disease and levodopatreatment (Amabile et al., 1986; Ikeda et al., 1997;Gerschlager et al., 1999). In general, the CNV is more clearlyaffected in Parkinson’s disease than the (single movement)BP. The reason for this may be as follows. In a CNV task,S2 acts as a trigger for the final movement, whereas in aself-paced task there is no trigger. Thus, if patients OFFtherapy fail to prepare for the forthcoming movement in theS1–S2 interval, they can still rely on S2 as an external triggerto retrieve the instructions to move. In such conditions, theCNV would be substantially reduced because there wouldeffectively be no contribution at all from processes involvedin movement preparation. In contrast, in a self-paced task,preparation of some kind must have been complete beforethe movement; hence the effect on the BP will always beless pronounced than on the CNV.

Transcranial stimulationStudies using electrical and magnetic stimulation techniqueshave shown that the corticomotoneurone connection is normalin Parkinson’s disease (Dick et al., 1984). Indeed, movementsthat are elicited by direct stimulation of the motor cortex arethe same whether the stimulus is given when patients areimmobile and OFF therapy or dyskinetic and ON therapy.As noted above, this means that bradykinesia is not primarilythe result of any deficit in the final output pathways of themotor areas of the cortex. Despite this, cortical stimulationhas revealed subtle changes in cortical circuits. Some ofthese may contribute to bradykinesia whilst others may becompensatory.

Most authors report that the motor cortex of patients withParkinson’s disease has the same threshold for stimulationas in healthy subjects (Priori et al., 1994; Valls-Sole et al.,1994; Ridding et al., 1995). However, when patients aretested at rest, the slope of the input–output relationshipbetween stimulus intensity and response size is steeper thannormal. Perhaps as a result of this, voluntary contractionfacilitates responses less than in normal subjects (Valls-Soleet al., 1994) (Fig. 3). The implication is that the distributionof cortical excitability at rest is skewed towards higher values

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Fig. 3 Mean motor-evoked potential (MEP) area in normal subjects and in patients with Parkinson’sdisease at various stimulus intensities and degrees of muscle activation. In Parkinson’s disease, the slopeof the input–output relationship between stimulus intensity and response size was steeper than normal.From Valls-Sole et al., 1994.

than normal. Although this could be the result of a primarybasal ganglia deficit, it seems likely that it could also be anattempt to compensate for the slow recruitment of commandsto move by making it easier to recruit activity from aresting state.

There are also changes in the excitability of corticalinhibitory circuits. A suprathreshold stimulus given whilstthe subject makes a tonic voluntary contraction evokes amuscle twitch that is followed by a postexcitatory silentperiod. The disappearance of voluntary activity during theperiod of silence is thought to be due to the activation ofcortical GABAergic inhibitory systems that suppress motorcortical output for 100–200 ms (Fuhr et al., 1991). The silentperiod is shorter in bradykinetic patients (Cantello et al.,1991; Priori et al., 1994) and is normalized by treatmentwith L-dopa (Priori et al., 1994). Cortical inhibition can alsobe tested in subjects at rest using the double-pulse paradigmof Kujirai and colleagues (Kujirai et al., 1993). Again, inpatients the amount of inhibition is smaller than normal(Ridding et al., 1995). With long interstimulus intervalsand larger (suprathreshold) conditioning and test stimuli, adifferent type of abnormality is found. The test response issignificantly inhibited at 100 and 150 ms (Berardelli et al.,1996b); this suggests that patients with Parkinson’s diseasehave reduced facilitation during voluntary muscle activation.It may be that these effects on inhibition and excitationreflect reduced facilitatory input to the cortical excitatoryand inhibitory circuits from basal ganglia. Both could affect

the speed of recruitment of cortical motor output inbradykinesia.

Recent transcranial magnetic stimulation studies haveshown that it is sometimes easier to disrupt activity in motorareas of the cortex in patients than in healthy subjects. Forexample, Cunnington and colleagues showed that single-pulse stimulation over the SMA early before the onset ofmovement could disrupt task performance in patients, whereasit may have no noticeable effect in healthy subjects(Cunnington et al., 1996). Presumably, the compromisedactivity in midline cortical areas in patients is more readilydisrupted than usual.

Metabolic imaging (PET and fMRI studies)Data from metabolic studies are consistent with the electricaldata above, and reveal a relative underactivation of midlinemotor areas in many tasks that is sometimes accompaniedby an increase in activation of the lateral premotor areas.The studies give more information than EEG or MEG aboutthe precise cortical areas involved, but a special paradigmhas to be used to distinguish preparation and execution.

Many studies have used a self-paced joystick movementtask in which subjects choose on each trial which directionto move (up, down, left or right). There is less activationcompared with that at rest in the anterior SMA, anteriorcingulate cortex, dorsolateral prefrontal cortex, basal gangliaand thalamus in patients than in healthy subjects (Jenkins

Pathophysiology of bradykinesia in Parkinson’s disease 2139

Fig. 4 Comparison of the adjusted mean regional cerebral bloodflow between normal subjects and patients with Parkinson’sdisease for self-initiated movements relative to the rest condition.The areas showing differentially greater activation during the self-initiated movements for normal subjects than for parkinsonianpatients were the anterior cingulate, the supplementary motorareas bilaterally, the left putamen, the left insular cortex, the leftlateral premotor cortex, the right parietal area 40 and the rightdorsolateral prefrontal cortex. From Jahanshahi et al., 1995.

et al., 1992; Playford et al., 1992; Rascol et al., 1992;Jahanshahi et al., 1995) (Fig. 4). Experiments on normalsubjects suggest that activity in the anterior SMA and thedorsolateral prefrontal cortex is related to the selection orprogramming of a new movement on each trial (Deiber et al.,1991, 1996). Thus, the underactivation of these areas inpatients is consistent with the idea that producing or selectingthe appropriate commands for a forthcoming movement is afundamental component of bradykinesia. Indeed, injection ofapomorphine reduces the underactivation of these areas atthe same time as it improves measures of bradykinesia(Jenkins et al., 1992; Rascol et al., 1992). There is frankoveractivity of the SMA (and of the ipsilateral andcontralateral primary motor areas) in dyskinetic patients(Rascol et al., 1998).

Interestingly, there is evidence that some other areas ofcortex are activated more than normal during sequential fingermovements in bradykinetic patients. Samuel and colleaguesdescribed extra activation in the lateral premotor and parietalcortices (Samuel et al., 1997a). Sabatini and colleagues,using fMRI rather than PET, reported similar results but withadditional activation also in the caudal SMA, the anteriorcingulate and even the primary sensorimotor cortex (Sabatiniet al., 2000). Catalan and colleagues examined theperformance of long sequences of finger movements withsimilar results (Catalan et al., 1999). In healthy individuals,they found that activity in the primary sensorimotor, premotor

and supplementary motor cortex, as well as in the ipsilateralcerebellum, increased as the movement sequences becamelonger or more complex. In patients, there was overactivitycompared with normal subjects in the premotor and parietalcortices. The conclusion is that the parkinsonian brain mayrecruit additional circuits during movement that compensatefor the primary basal ganglia deficit.

Bradykinesia and other basal ganglia diseasesIn Parkinson’s disease, slowness of movement (bradykinesia)occurs in conjunction with a reduction in the amount ofspontaneous movement (hypokinesia or akinesia). However,in two other basal ganglia diseases, Huntington’s diseaseand dystonia, bradykinesia co-exists with hyperkinesia. Oneconclusion from this is that bradykinesia has a differentmechanism from hypo- or hyperkinesia. However, analysisof the nature of the bradykinesia indicates that even this onesymptom may have more than one cause. The maximumspeed of simple voluntary arm movement is slower than inhealthy subjects in patients with either Huntington’s diseaseor dystonia (Hefter et al., 1987; Thompson et al., 1988; vander Kamp et al., 1989; Berardelli et al., 1998, 1999), but thepattern of EMG activity underlying the slowness of movementin patients with either of these conditions differs from thatin patients with Parkinson’s disease. In Huntington’s diseaseand dystonia, the EMG bursts are often prolonged and thefinal position and peak velocity are more variable than inParkinson’s disease.

Patients with Huntington’s disease are also abnormal inexecuting simultaneous and sequential movements(Thompson et al., 1988; Agostino et al., 1992) and, likepatients with Parkinson’s disease, have difficulty inperforming a sequence of movements without external cues(Georgiou et al., 1995).

Experimental parkinsonism and lessons fromsurgeryThe majority of the basal ganglia output, particularly that inthe ‘motor loop’ (Albin et al., 1989; Alexander and Crutcher1990a; Alexander et al., 1990b), projects back to the cortexvia the thalamus. The projection neurones of the main outputnuclei (the internal globus pallidus and the substantia nigrapars reticulata) are GABAergic and inhibitory. When thepresent model of basal ganglia function was being developedin the late 1980s, it was proposed that there was a directrelationship between the level of discharge in the outputnuclei and the amount of observable movement, a high outputcausing hypokinesia and a low output causing hyperkinesia(Wichmann and De Long, 1996). Several observations seemedto confirm this idea. The level of resting pallidal dischargewas increased when monkeys were made parkinsonian byinjection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine) (DeLong, 1990) and microelectrode recordings

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Fig. 5 Firing rate histogram of a neurone recorded in the globuspallidus internus (GPi), showing an inhibitory effect ofapomorphine on the activity of the cell. Bin width � 1 s. FromHutchinson et al., 1997.

made during neurosurgery suggested the same might be truein human patients with Parkinson’s disease (Hutchinsonet al., 1997). Indeed, injection of apomorphine to reducebradykinesia during the course of surgery for Parkinson’sdisease produced a reduction in the firing rate of pallidalneurones (Hutchinson et al., 1997; Merello et al., 1999)(Fig. 5). The most recent recordings from patients undergoingpallidotomy for hemiballism or dystonia also suggest that, inthese hyperkinetic conditions, pallidal neurones fire at ratessubstantially less than those observed in patients withParkinson’s disease (Lenz et al., 1998; Vitek et al., 1999).

However, a simple relationship between the level of pallidalactivity and movement cannot fully explain some of the mostimportant results of stereotaxic surgery. Marsden and Obesocalled this ‘the paradox of stereotaxic surgery’ (Marsden andObeso, 1994). Since its revival in the early 1990s, pallidotomyhas been used to treat several hundred patients worldwide,yet lesioning this major output of the basal ganglia neverresults in hyperkinesias, as might have been predicted ifthere were a strict relationship between movement andpallidal output. In fact, the opposite is observed: pallidotomyis an excellent procedure to reduce or even abolish the drug-induced dyskinesias that are common after several years ofL-dopa treatment. Pallidotomy has even been usedsuccessfully to treat hyperkinetic basal ganglia disorders,such as hemiballism and dystonia (Lozano et al., 1997;Suarez et al., 1997; Vitek et al., 1999). Despite its successin treating or preventing hyperkinesias, pallidotomy has onlya mild effect on bradykinesia or hypokinesia. In patients withParkinson’s disease, there is only a 30% improvement inclinical bradykinesia scores in patients OFF treatment withL-dopa and virtually no effect on clinical scores evaluated inthe best ON condition (e.g. Samuel et al., 1998).

Explanations that try to account for this basic paradox fallinto two main categories: (ii) physiological abnormalities dueto changes in neural noise; and (ii) anatomical explanationsdue to the anatomical complexity of the basal ganglia output

structures. At the present time it is not possible to determinewhether any of these explanations is true.

The physiological (neural noise) explanation suggests thatthe mean level of discharge from the globus pallidus internusand substantia nigra pars reticulata is not the only importantphysiological measure of basal ganglia function. The temporaland spatial pattern of output, as well as its absolute level, islikely to be relevant. This pattern might help focus corticalactivation so that appropriate muscles are activated and otherssuppressed during the performance of a task (e.g. Mink,1996). It is speculated that this output becomes disorderedin Parkinson’s disease. Certainly, in human patients and inmonkeys rendered parkinsonian by MPTP, there is an increasein the temporal variability of pallidal discharge and there isa tendency for the discharge to be more synchronized betweendistant cells than in the healthy state (Bergman et al., 1998).

It is reasonable to imagine that pallidotomy removes inputto the thalamus from a noisy and disordered system. If onepattern of noise gave rise to bradykinesia, then this mightexplain the 30% improvement in OFF-treatment clinicalscores; if another pattern provoked dyskinesias, then lesioningwould abolish these also. Nevertheless, the most importantfeature of this development of the basal ganglia model, andone that is often not appreciated by those who use it, is thatthere is no implication that lesioning the pallidum in anyway normalizes basal ganglia function. Unlike the simplemodel, in which lesioning reduces, and therefore normalizes,the overall level of pallidal output, the newer model viewsthe lesion as a means to remove basal ganglia outputcompletely. The implication is that if the lesion causes anyimprovement in function this must be due to other parts ofthe brain being able to compensate more readily for the usualbasal ganglia contribution. This proposal is explored below.

The anatomical solution to the paradox of pallidal surgeryis that the arrangement of pallidal output is more complexthan had been envisaged originally (for a review, see e.g.Parent and Hazrati, 1995). Results of chronic high-frequencystimulation of the globus pallidus internus, which producesan effect similar to that of a reversible lesion, are particularlysuggestive. The electrodes that are usually implanted havefour possible stimulation sites that allow activation ofdifferent areas inside the globus pallidus internus. With thistechnique, Krack and colleagues found that there are twodifferent functional zones within the globus pallidus internus(Krack et al., 1998). Stimulation in the ventral zone was ableto reduce drug-induced dyskinesias and improved rigiditybut had the side-effect of abolishing the anti-akinetic effectsof L-dopa treatment. Stimulation at a more dorsal site nearthe border of the globus pallidus internus and the globuspallidus externus improved OFF-drug bradykinesia but couldalso induce dyskinesias in some patients. If effects onbradykinesia and dyskinesias can be separated anatomically,it is possible that the initial model of basal ganglia functioncan still be applied. Reducing output in one part of the systemmight reduce bradykinesia, whereas interrupting function inanother part of the loop might abolish dyskinesias. In contrast

Pathophysiology of bradykinesia in Parkinson’s disease 2141

with the physiological explanation above, this theory stillimplies that improvement in motor function is theconsequence of normalizing basal ganglia output rather thanremoving it entirely.

At this point it is useful to enquire further into the detailsof the effects of surgery on bradykinesia in patients withParkinson’s disease. The results suggest that surgery mayproduce a combination of normalized function and improvedcompensation.

Neurophysiological studies of the effect ofsurgery and deep brain stimulation onbradykinesiaA large number of clinical studies have examined theeffectiveness of pallidotomy; rather fewer have beenpublished on chronic stimulation of the subthalamic nucleusor globus pallidus. However, a general rule is that, in termsof bradykinesia, pallidotomy produces an improvement of~30% in OFF-period symptoms on the side contralateral tothe lesion that is sustained for 2 years or more after theoperation. There is less effect on measures of postural stabilityor on the best ON-therapy scores (Bronstein et al., 1999;Lang et al., 1999). Pallidal stimulation has similar effects,but is considered to be potentially safer in terms of adversecognitive side-effects if bilateral procedures are performed(Brown et al., 1999). Chronic stimulation of the subthalamicnucleus may be more effective than pallidotomy or pallidalstimulation in improving OFF-treatment bradykinesia scores.Improvements in balance and posture are also more evident(Limousin et al., 1998). It is usually possible to reducethe dose of L-dopa, and this ameliorates problems withdyskinesias.

Several studies have used physiological techniques inaddition to clinical measures to try to understand moreprecisely the nature of the improvement produced by theseprocedures in patients OFF their normal drug therapy. Ingeneral, the main improvement is in execution rather thanpreparation for movement. Thus, both pallidotomy andstimulation of the subthalamic nucleus speed up simpleand complex movements and improve the recruitment ofmaximum muscle force (Pfann et al., 1998; Brown et al.,1999; Kimber et al., 1999; Limousin et al., 1999; Siebneret al., 1999). However, there is much less effect onreaction times and no effect on the early (BP1) componentof the BP (after pallidotomy; Limousin et al., 1999).Interestingly, the late (BP2) component of the BP isimproved, which is consistent with the idea that one effectof surgery is to improve compensation by non-midlinecortical structures.

Functional imaging studies of the effect ofsurgery and deep brain stimulation onbradykinesiaMany imaging studies have been driven by the model of basalganglia function outlined in the early 1990s. Overactivity of

the inhibitory output projections from the basal ganglia tothe thalamus in Parkinson’s disease was supposed to removefacilitatory thalamocortical drive, particularly to midlinecortical motor areas (anterior SMA and cingulate cortex).PET and fMRI activation studies had shown (see above) thatthese areas were less activated during movement in patients,and therefore pallidotomy was expected to improve activationby restoring normal levels of basal ganglia output (e.g.Ceballos-Baumann et al., 1994).

Most studies on movement-related changes in metabolicactivity have reported similar findings both after pallidotomy(Grafton et al., 1995; Samuel, 1997a, b) and duringsubthalamic nucleus stimulation (Limousin et al., 1997;Ceballos-Baumann et al., 1999). In tasks in which a free-choice joystick movement is used, increased activation ofpreSMA and anterior cingulate cortex is usually accompaniedby increased activation of the dorsolateral prefrontal cortex.Although most reports of activation-induced metabolismsuggest that there is no change in the primary motor cortex,there are some suggestions that stimulation of the subthalamicnucleus may reduce activity in the resting state (Limousinet al., 1997; Ceballos-Baumann et al., 1999). Whether thisis related to a general reduction in rigidity or other involuntarymuscle activity or to reduced input to the cortex via pathwaysdirect from the subthalamic nucleus is not known.

Surgery also appears to produce increases in the activationof the premotor areas, even though these are not normallyunderactive, and may even be overactive, in Parkinson’sdisease. This has been noted in both a prehension task(Grafton et al., 1995) and in a freely selected joystickmovement task (Ceballos-Baumann et al., 1999). In an[18F]fluorodeoxyglucose-PET study carried out in patients atrest, Eidelberg and colleagues found increases in metabolismin the premotor cortex as well as in the dorsolateral prefrontalcortex and motor cortex, ipsilateral to a pallidotomy(Eidelberg et al., 1996). Thus, it appears that lateral premotorareas may also be involved in recovery after surgery.

ConclusionThe term ‘bradykinesia’ is often used to cover a range ofrelated problems in the control of movement. However, inall cases the principal deficit is that movements are slow.The data reviewed here suggest that, although secondaryfactors such as muscle weakness, tremor and rigidity maycontribute, the principal deficit is due to insufficientrecruitment of muscle force during the initiation of movement.The result is that patients’ movements undershoot their targetsand end by approaching it in several smaller steps. The twodistinguishing features of parkinsonian bradykinesia are (i)that patients underscale muscle force and (ii) that the deficitis often ameliorated when external cues (vision, sound) aregiven to guide the movement. The former has led to thesuggestion that bradykinesia is a problem of scaling motoroutput appropriately to the task rather than to any intrinsiclimitation in motor execution. The latter is usually interpreted

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in terms of the preferential access of basal ganglia motoroutput to medial rather than lateral motor cortical areas.Medial cortical areas are more active in association withinternally generated movements, whilst lateral areas aremore active during externally cued movement. In summary,bradykinesia seems to result primarily from the underscalingof movement commands in internally generated movements.This may well reflect the role of the basal ganglia in selectingand reinforcing appropriate patterns of cortical activity duringmovement preparation and performance.

Recent imaging and EEG studies have shown that otherregions of the CNS can adapt to the primary basal gangliadeficit of Parkinson’s disease. Thus, the clinical presentationof bradykinesia may be a mixture of the primary deficit andcompensatory processes. We raise the possibility that someaspects of bradykinesia, such as the long intervals betweensuccessive elements of a sequence, difficulty in doing twothings at the same time and the progressive slowing of longsequences of movement, are the result of this interaction.This line of argument can be followed further. One of thenew understandings of basal ganglia pathophysiology is thatdisease may make the basal ganglia output noisy. Surgicalinterventions may work in part by removing or reducing thisnoise. The implication is that surgery improves function bothby normalizing basal ganglia output and by allowing otherstructures to compensate better for the underlying deficit.

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Received August 10, 2000. Revised May 5, 2001.Accepted May 31, 2001