Brain (2001), 124, 21312146

REVIEW ARTICLE

Pathophysiology of bradykinesia in Parkinsons

disease
A. Berardelli,1 J. C. Rothwell,2 P. D. Thompson3 and M. Hallett4
1Dipartimento

di Scienze Neurologiche, Istituto

Neurologico Neuromed IRCCS, Universita` di Roma La
Sapienza, Rome, Italy, 2MRC Human Movement and
Balance Unit, The Institute of Neurology, London, UK,
3The Royal Adelaide Hospital, The University Department
of Medicine, Adelaide, Australia and 4Human Motor
Control Section, NINDS, NIH, Bethesda, Maryland, USA

Correspondence to: Professor Alfredo Berardelli,

Dipartimento di Scienze Neurologiche, Viale Universita` 30,
00185 Roma, Italy
This paper is dedicated to the memory of Professor
C. D. Marsden

Summary
Bradykinesia means slowness of movement and is one
of the cardinal manifestations of Parkinsons disease.
Weakness, tremor and rigidity may contribute to but do
not fully explain bradykinesia. We argue that
bradykinesia results from a failure of basal ganglia output
to reinforce the cortical mechanisms that prepare and
execute the commands to move. The cortical deficit is
most apparent in midline motor areas. This leads to
particular difficulty with self-paced movements,
prolonged reaction times and abnormal pre-movement
EEG activity. Movements are often performed with
normally timed EMG bursts but the amount of EMG
activity is underscaled relative to the desired movement
parameters. There are also abnormalities in sensory
scaling and sensorimotor integration. The brain appears

to be able to compensate to some degree for the basal

ganglia deficit. There is overactivity in the lateral
premotor areas during task performance and movements
can be speeded by giving sensory cues. Attention to
movement is also beneficial. However, we propose that
the engagement of compensatory processes may also lead
to reduced performance in other tasks. For example,
patients problems in performing more than one task at
the same time could result from lack of sufficient resources
both to compensate for their basal ganglia deficit and to
run two tasks simultaneously. Surgical therapies are
unlikely to work solely by normalizing basal ganglia
output to that seen in healthy individuals. It seems more
plausible that surgery removes an interfering signal that
allows more efficient compensation by other structures.

Keywords: bradykinesia; Parkinsons disease; movement; motor control

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

Introduction
The term bradykinesia was first used by James Parkinson to
describe one of the cardinal features of the disease that
now bears his name. It is now recognized, however, that
bradykinesia may be part of the motor dysfunction in many
movement disorders.
Bradykinesia is often used synonymously with two other
terms: akinesia and hypokinesia. Strictly speaking,
bradykinesia describes the slowness of a performed
movement, whereas akinesia refers to a poverty of
Oxford University Press 2001

spontaneous movement (e.g. in facial expression) or

associated movement (e.g. arm swing during walking). Other
manifestations of akinesia are freezing and the prolonged
time it takes to initiate a movement. Hypokinesia refers to
the fact that, in addition to being slow, the movements are
also smaller than desired, as in the micrographia of patients
handwriting. Although these three symptoms are related, they
must also be separate to some extent, since they may not be
well correlated with each other in individual patients (Evarts

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A. Berardelli et al.

et al., 1981). Parkinsons disease patients often appear clumsy,

and it is likely that this results from several aspects of the
motor disorder.
In this review we will use the term bradykinesia to
encompass all these problems of slowness or absence of
movement. However, where we think that separate
mechanisms are involved we will always define the particular
functional deficits that we think are relevant in each case.
Before discussing the central mechanisms of bradykinesia
and how they relate to the basal ganglia dysfunction that is
at the heart of Parkinsons disease, it will be useful first
to consider other secondary factors that can contribute to
bradykinesia.

It is not clear whether attention might affect the results of

strength testing. The fact that patients fail to energize their
muscles fully, especially when OFF drug treatment, indicates
only that they lack some part of the normal volitional input
to lower motor centres. Why this occurs is unclear. There is
no obvious lack of effort by patients and there does not
appear to be any lack of concentration. Patients will frequently
say they are trying as hard as possible. Similarly, the existence
of physiological differences in the EMG activity in patients
compared with normal subjects suggests that the voluntary
drive to contract is not organized in the same way as usual.
However, phenomena such as paradoxical kinesia suggest
that there are mechanisms that can overcome this apparent
lack of volitional drive but this is probably not an attentionrelated phenomenon.

Secondary causes of bradykinesia

There are five factors that can potentially contribute to
bradykinesia in Parkinsons disease. These are muscle
weakness, rigidity, tremor, movement variability and slowing
of thought.

Muscle weakness
Several studies (Stelmach and Worringham, 1988; Stelmach
et al., 1989; Jordan et al., 1992) have compared the strength
of patients with Parkinsons disease and healthy age-matched
subjects. All of them found a mild reduction of strength in
a variety of muscle groups, even though this sometimes
failed to reach statistical significance. One probable reason
for this lack of agreement is that it is difficult to match
patient and control groups for the amount of daily exercise
and diet.
A recent study by Corcos and colleagues attempted to
resolve this problem by measuring strength at the elbow in
patients when ON and OFF L-dopa following overnight
withdrawal of therapy (Corcos et al., 1996). When OFF
medication, there was a 30% reduction in the strength of
maximum elbow extension and a 10% decrease in elbow
flexion. Because intrinsic muscle properties could not have
changed in the short period between the OFF and ON
conditions, the difference in strength must have been due to
an inability of patients to activate the elbow muscles
maximally. In that study, the patients appeared to be highly
motivated to produce strong contractions when OFF and ON
therapy, so that lack of volitional drive was not thought to
be a factor. A later study by Brown and colleagues on the
wrist extensors showed that one physiological reason for the
reduction in strength is the persistence of action tremor
during maximal contraction (Brown et al., 1997). Tremor at
~10 Hz in patients OFF therapy prevents maximum fusion
of motor unit contraction and can contribute to weakness.
However, this cannot account for the decrease in strength in
all muscle groups, so that other, presumably central, factors
must also be involved. The conclusion is that patients with
Parkinsons disease can be weak in some muscle groups and
this will inevitably contribute to slowness of movement.

Rigidity
Long-latency stretch reflexes are enhanced in Parkinsons
disease (Tatton and Lee, 1975; Berardelli et al., 1983;
Rothwell et al., 1983). They could potentially contribute to
bradykinesia if they were elicited in an antagonist muscle
during an active isotonic contraction of the agonist. Johnson
and colleagues tested this hypothesis by using a torque motor
to stretch muscles unexpectedly during active sinusoidal
movements of the wrist (Johnson et al., 1991). They showed
that reflexes elicited in the antagonist muscle were not
suppressed as much as in normal subjects, and that the
degree of abnormality was related to the amount of clinical
bradykinesia. The one flaw in this argument was that the
amount of activity in the antagonist muscle during
unperturbed flexion/extension movements was no greater
than that seen in normal subjects. Thus, there was no evidence
in the actual movements tested that antagonist co-contraction
could have been a limiting factor. Indeed, co-contraction has
never been described as an important feature even in very
rapid movements, in which the triphasic ballistic movement
EMG pattern has been analysed in some detail. The conclusion
must be that the role of rigidity in bradykinesia has yet to
be proven conclusively.

Rest and action tremor

We noted above that action tremor can contribute to weakness
in Parkinsons disease. In addition, rest and action tremor
can also be a factor in prolonging reaction times. Hallett
and colleagues and Wierzbicka and colleagues showed that
patients with Parkinsons disease tend to time the onset of
agonist muscle activity at the elbow or wrist with the time
of 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 of
voluntary alternating movements. Logigian and colleagues
showed that voluntary movements are entrained by action
tremor if patients attempt to move at frequencies close to

Pathophysiology of bradykinesia in Parkinsons disease

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

Movement variability
The movements of patients with Parkinsons disease are less
accurate than normal, particularly if they have to move as
fast as possible (Sanes, 1985; Sheridan and Flowers, 1990;
Phillips et al., 1994). In other words, the speedaccuracy
trade-off is less efficient in patients than in healthy subjects.
Sheridan and Flowers suggested that bradykinesia might be
due to an active strategy of patients to move more slowly in
order to improve their accuracy (Sheridan and Flowers,
1990). Although this is a plausible strategy, other factors
must also be involved since bradykinesia remains in tasks
in which spatial accuracy constraints have been removed
(Teasdale et al., 1990).

Bradyphrenia
Slowness of thought, or bradyphrenia, could lead to
bradykinesia by interfering with movement planning and, for
example, increasing reaction time. Whether bradyphrenia
exists in Parkinsons disease has been controversial. In part,
this is due to the fact that many patients with Parkinsons
disease do develop dementia from several aetiologies, and
there is certainly slowing of thinking in dementia (Berry
et al., 1999). Additionally, there is slowing of thought in
ageing and depression (Cooper et al., 1994), and these factors
need to be considered. Lastly, many cognitive studies have
employed 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 of
studies that have not taken these factors into consideration.
Moreover, thinking is not just one process and whether it is
slow might depend on the nature of the task. Some studies
have claimed to find bradyphrenia (Cooper et al., 1994; Pate
and 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 for
slowing when dementia is not present and the patient is not
on drugs, such as anticholinergics, that might interfere with
cognitive processes.

Primary bradykinesia
Although all the factors above can contribute to bradykinesia,
they must be distinguished from the core disorders of
central movement control that are responsible for primary
bradykinesia. In this section we describe those features of
bradykinesia that cannot be explained by secondary factors.
Bradykinesia could potentially be due to slowness in
formulating the instructions to move (programming) or to
slowness in executing these instructions. Although
programming and execution are usually thought of as separate

2133

and sequential operations, they could well overlap, at least

to the extent that programming could continue during
execution. It is possible, therefore, to study some of the
processes involved in programming if we confine ourselves
to measurements such as reaction times or EEG/magnetic
encephalography (MEG) studies made before the onset of
movements. Measurements made after movement onset may
reflect both execution as well as programming.

Preparation to move: studies of reaction times

Patients with Parkinsons disease react more slowly than
healthy subjects of the same age and this contributes to
akinesia. The more advanced the disease, the slower the
reaction times. A question is whether patients are slow in
starting to move because they have a problem in preparing
the instructions to move, or whether the problem is in
releasing those instructions.
Some information about preparatory processes can be
obtained by comparing reaction tasks in which the movement
component is constant but the amount of preparation is
variable. In a simple reaction task, the same response is made
on every occasion and healthy subjects can prepare the
response fully in advance of the imperative signal. In a
choice reaction task, the response depends on the reaction
signal. Subjects know the set of possible moves they might
have to make but not the precise one that will be needed on
any particular trial. They cannot prepare the movement fully
in advance and have to complete more of the preparation
after the imperative signal is given. The result is that choice
reaction times are longer than simple reaction times.
Simple reaction times are prolonged in Parkinsons 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 also
Zimmerman et al., 1992; Harrison et al., 1993; Revonsuo
et al., 1993). The situation with choice reaction times is
more complex. Some authors have reported that they are the
same as normal (Evarts et al., 1981; Bloxham et al., 1987;
Sheridan et al., 1987) and have suggested that patients have
slow simple reaction times because they fail to take advantage
of the opportunity to programme their response fully in
advance. However, other authors have reported that choice
reaction times are longer than normal (Wiesendanger et al.,
1969; Stelmach et al., 1986; Mayeux et al., 1987; Dubois
et al., 1988; Lichter et al., 1988; Reid et al., 1989; Pullman
et al., 1988; Jahanshahi et al., 1992; Brown et al., 1993b).
It is not clear why there is so much variety in the results
reported. Some may arise because different patient groups
were studied at different stages of the disease; some may be
due to elements in the design of the task, such as stimulus
response compatibility, which may be handled differently in
patients with Parkinsons disease (e.g. Brown et al., 1993b).
Whether or not patients can take full advantage of prior
programming, 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 of
programming deficits in Parkinsons disease, there is much
clearer evidence that slowness in executing motor commands
is an important factor in prolonging reaction times. The reason
is that motor excitability has to build up to a certain threshold
level before movement or even EMG activity can be detected.
If this is slow, the threshold is reached later than normal. For
example, EMG activity in patients usually rises slowly after
its onset, and this can delay the time at which movement is
detected. The same argument can be applied to the interval
before the onset of EMG: motor excitability has to build up to
threshold before motor neurones are discharged. Experiments
with magnetic transcranial stimulation have confirmed that
pre-movement excitability increases more slowly than normal
in patients with Parkinsons disease (Pascual-Leone et al.,
1994). The conclusion is that little of the increase in simple
reaction times is due to problems in starting the commands
to move. The deficit arises either because the wrong (slow)
commands have been chosen or because the correct commands
are executed more slowly than normal.
Our conclusion from these reaction time studies is that
slowness in simple reaction tasks is as much due to problems
in the execution of a stored motor command as it is to
maintaining that command in store at an appropriate state of
readiness. The situation for choice of reaction tasks requires
further study.

Preparation to move: activation of specific brain

areas
EEG, MEG, PET, functional MRI (fMRI) and magnetic
stimulation techniques have all been used in an attempt to
understand which parts of the motor system are functioning
abnormally in akinetic patients with Parkinsons disease.
However, because brain activity during movement reflects
both outgoing motor commands and the sensory input that
results from moving, studies of motor activity have
concentrated on the period just before the onset of movement
when changes in sensory input are minimal. In most instances,
the movements are self-paced; reaction tasks involve premovement sensory input that can complicate the interpretation
of the data obtained. A general finding from these studies is
that there is underactivity of midline [supplementary motor
cortex (SMA) and nearby areas] cortical motor areas, perhaps
coupled with extra activation of lateral premotor areas. The
former may be related to difficulties in preparing instructions
to move; the latter may be an active process of compensation
and may be related to the improvement in performance that
can be observed when external cues are given to guide
movement (see below).
The pre-movement EEG potential, sometimes called the
Bereitschaftspotential (BP), is a slowly rising negativity that
occurs over widespread areas of the scalp before the onset

of a self-paced voluntary movement. It has two major

components. The early component (sometimes known as BP
but here referred to as BP1) begins 12 s before movement.
It is bilaterally symmetrical and is largest at the vertex. The
second component (sometimes known as NS1 or NS but
here called BP2) rises more steeply, beginning ~650 ms
before the onset of EMG activity. Recent recordings from
subdural electrodes suggest that the BP1 predominantly
reflects bilateral activity in the motor and supplementary
motor areas, whereas the BP2 also has a contribution from the
contralateral motor and premotor cortex (Ikeda et al., 1992).
In early studies, there was some debate over whether the
BP was abnormal in Parkinsons disease. Some of the
controversy was resolved by Dick and colleagues, who
showed that L-dopa could affect the amplitude of the BP
both in normal subjects and in patients, and that a difference
between patients with Parkinsons disease and normal subjects
was crucially dependent on the level of dopaminergic function
(Dick et al., 1989). They went on to show that the BP in
patients 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 the
same in the patients as in normal subjects. They suggested
that underactivity of a source in the SMA was responsible
for the reduction of the early component, and that this was
compensated for by overactivity in lateral motor areas nearer
the time of onset of movement. Recent studies have tended
to confirm this idea. For example, Jahanshahi and colleagues
noted that pre-movement EEG activity was normal in patients
with Parkinsons disease when they performed an externally
triggered task compared with the reduction that is seen in
self-paced movements (Jahanshahi et al., 1995) (Fig. 1).
Cunnington and colleagues proposed that underactivation of
the SMA in Parkinsons disease patients made them more
reliant on external cues so that they did not use predictive
models when cues were available (Cunnington et al., 1995,
1997). Pre-movement activity could, however, be induced in
patients if they were asked to attend to the time of the next
movement, and this improved task performance (Cunnington
et al., 1999). The authors suggested that attentional processes
allow lateral premotor systems, which are less impaired by
basal ganglia dysfunction, to compensate for deficiencies in
midline motor systems that are normally active in internally
generated tasks.
In these early studies the subjects repeated the same
movement over many trials. Later studies have required the
subjects to choose to make different movements (e.g. moving
a joystick up, down, left or right) on each trial. In healthy
subjects, the BP is much larger than when subjects make the
same movement on each occasion, perhaps reflecting the
additional processing necessary to choose between
movements on each trial (Touge et al., 1995; Praamstra et al.,
1996a, b, 1998; Dirnberger et al., 2000). Praamstra and
colleagues used dipole modelling to show that the most likely
source for the extra activation was the SMA (Praamstra et al.,

Pathophysiology of bradykinesia in Parkinsons disease

2135

Fig. 1 (A) Premotor potentials preceding self-initiated movements for normal subjects (continuous line) and patients with Parkinsons
disease (broken line). (B) Premotor potentials preceding externally triggered movements for normal subjects (continuous line) and
patients with Parkinsons disease (broken line). The mean time of stimulus presentation is 253 ms prior to EMG onset for patients with
Parkinsons disease and 212 ms for normal subjects. Pre-movement EEG activity was normal in patients with Parkinsons disease when
they 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 with

Parkinsons disease, consistent with the model outlined above.
Abnormalities in cortical activation prior to and during
movement have been also found with the technique of eventrelated desynchronization (Defebre et al., 1996; Magnani
et al., 1998). The amount of power in the alpha (10 Hz) and
beta (20 Hz) ranges of EEG activity decreases ~1 s before
the onset of movement and remains lower than at rest while
movement occurs. It has been suggested that the 1020 Hz
rhythm occurs because the activity of cortical neurones tends
to become synchronized during periods of relative inactivity.
If so, event-related desynchronization is a measure of cortical
activation that reflects uncoupling of the population activity
into more discrete temporal and spatial patterns. In patients
with Parkinsons disease the duration of the event-related
desynchronization prior to voluntary movements is shorter
and the pattern of movement-related attenuation of the alpha
and beta rhythms during various types of motor tasks is
abnormal. Brown and Marsden found that dopaminergic
stimulation in Parkinsons disease restores the movementrelated attenuation of the alpha and beta rhythms (Brown

and Marsden, 1999). This effect was specific for the motor
areas involved in the motor task and correlated with the
improvement of bradykinesia. Wang and colleagues reported
similar findings in their study of simple and complex
movements (Wang et al., 1999). The above studies suggest
that the basal ganglia have a role in releasing cortical elements
from idling rhythms during voluntary movement. In a recent
report, Brown carried this idea one stage further by examining
the effect of dopaminergic stimulation on the coupling of
activity between different nuclei of the basal ganglia (Brown
et al., 2001). They recorded local potentials from patients
with implanted electrodes in the subthalamic nucleus and
internal pallidum, and found that they were coupled by
activity at 2030 Hz when the patients were OFF medication,
whereas ON medication this changed to 6070 Hz.

Motor execution
Single ballistic movements at a single joint
Single movements made as fast as possible about a single
joint are slower than normal in patients with Parkinsons

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A. Berardelli et al.
triphasic EMG pattern in which the time and duration of the
bursts varies in a highly predictable way depending on the
amplitude and other parameters of movement. This pattern
is present in patients with Parkinsons disease, but the first
agonist burst is small. As Hallett and Khoshbin pointed out,
the result is that patients often add further bursts of EMG to
the pattern in order to achieve enough force to move the
limb to the required end position (Hallett and Khoshbin,
1980). Despite this, if patients aim for a movement of larger
amplitude, the size of the agonist burst can increase. In
effect, this means that the size of the agonist burst is not
always a limiting factor in slowing movement: if the burst
for the large movement had been used for the smaller
movement the speed would have been normal. The conclusion
is that there is a second cause of bradykinesia in simple
movement: inappropriate scaling of the dynamic muscle force
to the movement parameters (Berardelli et al., 1986b).

Simultaneous, sequential or repetitive movements

Fig. 2 Rapid movements performed at a single joint in a normal

subject (15 and 60 of movement amplitude) and in a patient
with Parkinsons disease (OFF and ON therapy, 15 of movement
amplitude). The normal subject performed the movement with a
single triphasic EMG pattern in the agonist and antagonist
muscles, whereas the patient performed the movement with
multiple EMG bursts. EMG activity was recorded from the
forearm 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 agonist
muscle discussed above, but much must be due to other
factors. For example, even though maximum contraction
strength of the biceps decreases by 10% in the OFF condition,
the speed of elbow flexion may halve. Similarly, EMG
records show that there is no excessive co-contraction of the
antagonist that might slow the movement down more than
expected from the decline in strength. It seems instead that
slowness of movement is caused by problems in recruiting
the appropriate level of muscle force sufficiently fast.
There are two parts to this problem. First, patients may
find it difficult to activate a muscle rapidly. This is certainly
true in more advanced disease: it can take several seconds
for some patients to produce a maximum voluntary
contraction (e.g. Corcos et al., 1996). However, the rate of
contraction is not the only cause of bradykinesia in simple
movements. The fastest movements are accompanied by a

If any additional complexity is added to a simple movement,

either by repeating the movement or by combining it with
other tasks, bradykinesia becomes more prominent. Clinical
tests of bradykinesia often make use of this phenomenon.
Repetitive sequential movement involving isolated finger
movements, hand opening/closing or wrist pronation/
supination become smaller (hypokinesia) and slower with
repetition of the movement (fatigue) (Agostino et al.,
1998). Schwab and colleagues asked patients to squeeze a
sphygmomanometer bulb in one hand and outline a drawing
with the other (Schwab et al., 1954). They had much more
difficulty if they had to do both tasks together than if each
one was performed alone. Indeed, in most cases, patients
tended to alternate between the tasks rather than perform
them at the same time.
Experimental studies have analysed these features of
bradykinesia in some detail. In essence, they show that
bradykinesia is more than the slowness seen in simple single
movements. There are additional problems in combining or
sustaining complex movements. Benecke and colleagues
examined rapid elbow flexion movements combined with a
simultaneous or sequential hand movement performed with
either the same or the opposite arm (Benecke et al., 1986,
1987). In contrast to normal subjects, in whom there was no
decrement of performance when two tasks were combined,
patients with Parkinsons disease showed (i) a marked slowing
of movement over and above that seen in each task alone
when both had to be performed together, and (ii) a longer
pause between each element of a sequential task. Indeed, these
two extra deficits correlated better with clinical measures of
bradykinesia than the slowness in each simple movement.
Similar problems in performing simultaneous movements
have been described in bilateral reaching (Stelmach and
Worringham, 1988; Castiello and Bennett, 1997) and cranking
tasks (Johnson et al., 1998). In sequential movements,
prolonged pauses between each element have been observed

Pathophysiology of bradykinesia in Parkinsons disease

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

What is the nature of the extra deficits in

performance of complex movements?
The problem of combining tasks or switching from one task
to another is not confined to movement. It can be observed
in cognitive tasks or combined cognitive and motor tasks
(Brown and Marsden, 1991; Oliveira et al., 1998). Such
observations are important since they indicate that the extra
deficit seen in complex movements is not necessarily a
purely motor problem. They raise the possibility that global
processing mechanisms, perhaps involving attention, are also
a factor. Brown and Marsden suggested that patients either
have a limited processing resource that interferes with their
ability to run more than one task at the same time, or that
they have difficulty in switching this resource between tasks
(Brown and Marsden, 1991). An alternative is that the global
resource is the same in patients, but that tasks are performed
less automatically than in normal subjects. In this case, each
task would consume more of the processing resource, and
lead to difficulties in performing several tasks at once, or in
switching between tasks. Effectively, patients may be trying
to compensate for lack of basal ganglia input by devoting
more resources to each single task they perform. When
required to perform more than one task at once, this becomes
a limiting factor.

2137

also squeeze the object more than normal when lifting it in

the air (Fellows et al., 1998). The authors thought that the
latter effect was due to problems in sensorimotor processing.
We conclude that kinaesthesia may have a role in the
pathophysiology of Parkinsons disease, but that its
importance still needs to be clarified.
Abnormalities in the contingent negative variation (CNV)
can also be explained in terms of abnormal sensorimotor
processing. The CNV is a slow negative potential that occurs
between a warning (S1) and an imperative (S2) stimulus. It
is best recorded at frontal and central electrodes and reflects
processes related to planning a forthcoming movement and
anticipation of the imperative stimulus. Activity of the
prefrontal cortex contributes to the amplitude of the CNV.
In Parkinsons disease, the amplitude of the CNV is reduced
by an amount related to the severity of disease and levodopa
treatment (Amabile et al., 1986; Ikeda et al., 1997;
Gerschlager et al., 1999). In general, the CNV is more clearly
affected in Parkinsons 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 a
self-paced task there is no trigger. Thus, if patients OFF
therapy fail to prepare for the forthcoming movement in the
S1S2 interval, they can still rely on S2 as an external trigger
to retrieve the instructions to move. In such conditions, the
CNV would be substantially reduced because there would
effectively be no contribution at all from processes involved
in movement preparation. In contrast, in a self-paced task,
preparation of some kind must have been complete before
the movement; hence the effect on the BP will always be
less pronounced than on the CNV.

Transcranial stimulation
Sensorimotor processing
Some authors have reported abnormalities in sensorimotor
processing in Parkinsons disease. Schneider and colleagues
reported a decrease of precision in two-point discrimination
and proprioceptive position sense (Schneider et al., 1986)
and Klockgether and colleagues, in a study of arm movements
testing the effects of both visual and kinaesthetic information,
suggested that peripheral afferent feedback is impaired in
patients with Parkinsons disease (Klockgether et al., 1995).
A problem in matching somatosensory and visual inputs was
demonstrated by Demirci and colleagues (Demirci et al.,
1997). The authors postulated that this was due to an
abnormality of sensory scaling and drew parallels with the
abnormal scaling of motor output reported by Berardelli and
colleagues (Berardelli et al., 1986b).
A deficit in sensorimotor integration may also be observed
in precision grip/lift tasks. These are complex acts that are
performed by gripping an object with the correct amount of
force so that it does not fall between the fingers when it is
lifted off a supporting surface. Parkinsonian patients take
longer to develop peak grip force and show a pronounced
slowing in the rate at which grip force is generated. They

Studies using electrical and magnetic stimulation techniques

have shown that the corticomotoneurone connection is normal
in Parkinsons disease (Dick et al., 1984). Indeed, movements
that are elicited by direct stimulation of the motor cortex are
the same whether the stimulus is given when patients are
immobile and OFF therapy or dyskinetic and ON therapy.
As noted above, this means that bradykinesia is not primarily
the result of any deficit in the final output pathways of the
motor areas of the cortex. Despite this, cortical stimulation
has revealed subtle changes in cortical circuits. Some of
these may contribute to bradykinesia whilst others may be
compensatory.
Most authors report that the motor cortex of patients with
Parkinsons disease has the same threshold for stimulation
as in healthy subjects (Priori et al., 1994; Valls-Sole` et al.,
1994; Ridding et al., 1995). However, when patients are
tested at rest, the slope of the inputoutput relationship
between stimulus intensity and response size is steeper than
normal. Perhaps as a result of this, voluntary contraction
facilitates responses less than in normal subjects (Valls-Sole`
et al., 1994) (Fig. 3). The implication is that the distribution
of cortical excitability at rest is skewed towards higher values

2138

A. Berardelli et al.

Fig. 3 Mean motor-evoked potential (MEP) area in normal subjects and in patients with Parkinsons
disease at various stimulus intensities and degrees of muscle activation. In Parkinsons disease, the slope
of the inputoutput 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 primary

basal ganglia deficit, it seems likely that it could also be an
attempt to compensate for the slow recruitment of commands
to move by making it easier to recruit activity from a
resting state.
There are also changes in the excitability of cortical
inhibitory circuits. A suprathreshold stimulus given whilst
the subject makes a tonic voluntary contraction evokes a
muscle twitch that is followed by a postexcitatory silent
period. The disappearance of voluntary activity during the
period of silence is thought to be due to the activation of
cortical GABAergic inhibitory systems that suppress motor
cortical output for 100200 ms (Fuhr et al., 1991). The silent
period is shorter in bradykinetic patients (Cantello et al.,
1991; Priori et al., 1994) and is normalized by treatment
with L-dopa (Priori et al., 1994). Cortical inhibition can also
be tested in subjects at rest using the double-pulse paradigm
of Kujirai and colleagues (Kujirai et al., 1993). Again, in
patients the amount of inhibition is smaller than normal
(Ridding et al., 1995). With long interstimulus intervals
and larger (suprathreshold) conditioning and test stimuli, a
different type of abnormality is found. The test response is
significantly inhibited at 100 and 150 ms (Berardelli et al.,
1996b); this suggests that patients with Parkinsons disease
have reduced facilitation during voluntary muscle activation.
It may be that these effects on inhibition and excitation
reflect reduced facilitatory input to the cortical excitatory
and inhibitory circuits from basal ganglia. Both could affect

the speed of recruitment of cortical motor output in

bradykinesia.
Recent transcranial magnetic stimulation studies have
shown that it is sometimes easier to disrupt activity in motor
areas of the cortex in patients than in healthy subjects. For
example, Cunnington and colleagues showed that singlepulse stimulation over the SMA early before the onset of
movement could disrupt task performance in patients, whereas
it may have no noticeable effect in healthy subjects
(Cunnington et al., 1996). Presumably, the compromised
activity in midline cortical areas in patients is more readily
disrupted than usual.

Metabolic imaging (PET and fMRI studies)

Data from metabolic studies are consistent with the electrical
data above, and reveal a relative underactivation of midline
motor areas in many tasks that is sometimes accompanied
by an increase in activation of the lateral premotor areas.
The studies give more information than EEG or MEG about
the precise cortical areas involved, but a special paradigm
has to be used to distinguish preparation and execution.
Many studies have used a self-paced joystick movement
task in which subjects choose on each trial which direction
to move (up, down, left or right). There is less activation
compared with that at rest in the anterior SMA, anterior
cingulate cortex, dorsolateral prefrontal cortex, basal ganglia
and thalamus in patients than in healthy subjects (Jenkins

Pathophysiology of bradykinesia in Parkinsons disease

2139

and supplementary motor cortex, as well as in the ipsilateral

cerebellum, increased as the movement sequences became
longer or more complex. In patients, there was overactivity
compared with normal subjects in the premotor and parietal
cortices. The conclusion is that the parkinsonian brain may
recruit additional circuits during movement that compensate
for the primary basal ganglia deficit.

Bradykinesia and other basal ganglia diseases

Fig. 4 Comparison of the adjusted mean regional cerebral blood

flow between normal subjects and patients with Parkinsons
disease for self-initiated movements relative to the rest condition.
The areas showing differentially greater activation during the selfinitiated movements for normal subjects than for parkinsonian
patients were the anterior cingulate, the supplementary motor
areas bilaterally, the left putamen, the left insular cortex, the left
lateral premotor cortex, the right parietal area 40 and the right
dorsolateral 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 normal
subjects suggest that activity in the anterior SMA and the
dorsolateral prefrontal cortex is related to the selection or
programming of a new movement on each trial (Deiber et al.,
1991, 1996). Thus, the underactivation of these areas in
patients is consistent with the idea that producing or selecting
the appropriate commands for a forthcoming movement is a
fundamental component of bradykinesia. Indeed, injection of
apomorphine reduces the underactivation of these areas at
the same time as it improves measures of bradykinesia
(Jenkins et al., 1992; Rascol et al., 1992). There is frank
overactivity of the SMA (and of the ipsilateral and
contralateral primary motor areas) in dyskinetic patients
(Rascol et al., 1998).
Interestingly, there is evidence that some other areas of
cortex are activated more than normal during sequential finger
movements in bradykinetic patients. Samuel and colleagues
described extra activation in the lateral premotor and parietal
cortices (Samuel et al., 1997a). Sabatini and colleagues,
using fMRI rather than PET, reported similar results but with
additional activation also in the caudal SMA, the anterior
cingulate and even the primary sensorimotor cortex (Sabatini
et al., 2000). Catalan and colleagues examined the
performance of long sequences of finger movements with
similar results (Catalan et al., 1999). In healthy individuals,
they found that activity in the primary sensorimotor, premotor

In Parkinsons disease, slowness of movement (bradykinesia)

occurs in conjunction with a reduction in the amount of
spontaneous movement (hypokinesia or akinesia). However,
in two other basal ganglia diseases, Huntingtons disease
and dystonia, bradykinesia co-exists with hyperkinesia. One
conclusion from this is that bradykinesia has a different
mechanism from hypo- or hyperkinesia. However, analysis
of the nature of the bradykinesia indicates that even this one
symptom may have more than one cause. The maximum
speed of simple voluntary arm movement is slower than in
healthy subjects in patients with either Huntingtons disease
or dystonia (Hefter et al., 1987; Thompson et al., 1988; van
der Kamp et al., 1989; Berardelli et al., 1998, 1999), but the
pattern of EMG activity underlying the slowness of movement
in patients with either of these conditions differs from that
in patients with Parkinsons disease. In Huntingtons disease
and dystonia, the EMG bursts are often prolonged and the
final position and peak velocity are more variable than in
Parkinsons disease.
Patients with Huntingtons disease are also abnormal in
executing simultaneous and sequential movements
(Thompson et al., 1988; Agostino et al., 1992) and, like
patients with Parkinsons disease, have difficulty in
performing a sequence of movements without external cues
(Georgiou et al., 1995).

Experimental parkinsonism and lessons from

surgery
The majority of the basal ganglia output, particularly that in
the motor loop (Albin et al., 1989; Alexander and Crutcher
1990a; Alexander et al., 1990b), projects back to the cortex
via the thalamus. The projection neurones of the main output
nuclei (the internal globus pallidus and the substantia nigra
pars reticulata) are GABAergic and inhibitory. When the
present model of basal ganglia function was being developed
in the late 1980s, it was proposed that there was a direct
relationship between the level of discharge in the output
nuclei and the amount of observable movement, a high output
causing hypokinesia and a low output causing hyperkinesia
(Wichmann and De Long, 1996). Several observations seemed
to confirm this idea. The level of resting pallidal discharge
was increased when monkeys were made parkinsonian by
injection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (DeLong, 1990) and microelectrode recordings

2140

A. Berardelli et al.

Fig. 5 Firing rate histogram of a neurone recorded in the globus

pallidus internus (GPi), showing an inhibitory effect of
apomorphine on the activity of the cell. Bin width 1 s. From
Hutchinson et al., 1997.

made during neurosurgery suggested the same might be true

in human patients with Parkinsons disease (Hutchinson
et al., 1997). Indeed, injection of apomorphine to reduce
bradykinesia during the course of surgery for Parkinsons
disease produced a reduction in the firing rate of pallidal
neurones (Hutchinson et al., 1997; Merello et al., 1999)
(Fig. 5). The most recent recordings from patients undergoing
pallidotomy for hemiballism or dystonia also suggest that, in
these hyperkinetic conditions, pallidal neurones fire at rates
substantially less than those observed in patients with
Parkinsons disease (Lenz et al., 1998; Vitek et al., 1999).
However, a simple relationship between the level of pallidal
activity and movement cannot fully explain some of the most
important results of stereotaxic surgery. Marsden and Obeso
called this the paradox of stereotaxic surgery (Marsden and
Obeso, 1994). Since its revival in the early 1990s, pallidotomy
has been used to treat several hundred patients worldwide,
yet lesioning this major output of the basal ganglia never
results in hyperkinesias, as might have been predicted if
there were a strict relationship between movement and
pallidal output. In fact, the opposite is observed: pallidotomy
is an excellent procedure to reduce or even abolish the druginduced dyskinesias that are common after several years of
L-dopa treatment. Pallidotomy has even been used
successfully 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 success
in treating or preventing hyperkinesias, pallidotomy has only
a mild effect on bradykinesia or hypokinesia. In patients with
Parkinsons disease, there is only a 30% improvement in
clinical bradykinesia scores in patients OFF treatment with
L-dopa and virtually no effect on clinical scores evaluated in
the best ON condition (e.g. Samuel et al., 1998).
Explanations that try to account for this basic paradox fall
into two main categories: (ii) physiological abnormalities due
to changes in neural noise; and (ii) anatomical explanations
due to the anatomical complexity of the basal ganglia output

structures. At the present time it is not possible to determine

whether any of these explanations is true.
The physiological (neural noise) explanation suggests that
the mean level of discharge from the globus pallidus internus
and substantia nigra pars reticulata is not the only important
physiological measure of basal ganglia function. The temporal
and spatial pattern of output, as well as its absolute level, is
likely to be relevant. This pattern might help focus cortical
activation so that appropriate muscles are activated and others
suppressed during the performance of a task (e.g. Mink,
1996). It is speculated that this output becomes disordered
in Parkinsons disease. Certainly, in human patients and in
monkeys rendered parkinsonian by MPTP, there is an increase
in the temporal variability of pallidal discharge and there is
a tendency for the discharge to be more synchronized between
distant cells than in the healthy state (Bergman et al., 1998).
It is reasonable to imagine that pallidotomy removes input
to the thalamus from a noisy and disordered system. If one
pattern of noise gave rise to bradykinesia, then this might
explain the 30% improvement in OFF-treatment clinical
scores; if another pattern provoked dyskinesias, then lesioning
would abolish these also. Nevertheless, the most important
feature of this development of the basal ganglia model, and
one that is often not appreciated by those who use it, is that
there is no implication that lesioning the pallidum in any
way normalizes basal ganglia function. Unlike the simple
model, in which lesioning reduces, and therefore normalizes,
the overall level of pallidal output, the newer model views
the lesion as a means to remove basal ganglia output
completely. The implication is that if the lesion causes any
improvement in function this must be due to other parts of
the brain being able to compensate more readily for the usual
basal ganglia contribution. This proposal is explored below.
The anatomical solution to the paradox of pallidal surgery
is that the arrangement of pallidal output is more complex
than had been envisaged originally (for a review, see e.g.
Parent and Hazrati, 1995). Results of chronic high-frequency
stimulation of the globus pallidus internus, which produces
an effect similar to that of a reversible lesion, are particularly
suggestive. The electrodes that are usually implanted have
four possible stimulation sites that allow activation of
different areas inside the globus pallidus internus. With this
technique, Krack and colleagues found that there are two
different functional zones within the globus pallidus internus
(Krack et al., 1998). Stimulation in the ventral zone was able
to reduce drug-induced dyskinesias and improved rigidity
but had the side-effect of abolishing the anti-akinetic effects
of L-dopa treatment. Stimulation at a more dorsal site near
the border of the globus pallidus internus and the globus
pallidus externus improved OFF-drug bradykinesia but could
also induce dyskinesias in some patients. If effects on
bradykinesia and dyskinesias can be separated anatomically,
it is possible that the initial model of basal ganglia function
can still be applied. Reducing output in one part of the system
might reduce bradykinesia, whereas interrupting function in
another part of the loop might abolish dyskinesias. In contrast

Pathophysiology of bradykinesia in Parkinsons disease

with the physiological explanation above, this theory still
implies that improvement in motor function is the
consequence of normalizing basal ganglia output rather than
removing it entirely.
At this point it is useful to enquire further into the details
of the effects of surgery on bradykinesia in patients with
Parkinsons disease. The results suggest that surgery may
produce a combination of normalized function and improved
compensation.

Neurophysiological studies of the effect of

surgery and deep brain stimulation on
bradykinesia
A large number of clinical studies have examined the
effectiveness of pallidotomy; rather fewer have been
published on chronic stimulation of the subthalamic nucleus
or globus pallidus. However, a general rule is that, in terms
of bradykinesia, pallidotomy produces an improvement of
~30% in OFF-period symptoms on the side contralateral to
the lesion that is sustained for 2 years or more after the
operation. There is less effect on measures of postural stability
or 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 adverse
cognitive side-effects if bilateral procedures are performed
(Brown et al., 1999). Chronic stimulation of the subthalamic
nucleus may be more effective than pallidotomy or pallidal
stimulation in improving OFF-treatment bradykinesia scores.
Improvements in balance and posture are also more evident
(Limousin et al., 1998). It is usually possible to reduce
the dose of L-dopa, and this ameliorates problems with
dyskinesias.
Several studies have used physiological techniques in
addition to clinical measures to try to understand more
precisely the nature of the improvement produced by these
procedures in patients OFF their normal drug therapy. In
general, the main improvement is in execution rather than
preparation for movement. Thus, both pallidotomy and
stimulation of the subthalamic nucleus speed up simple
and complex movements and improve the recruitment of
maximum muscle force (Pfann et al., 1998; Brown et al.,
1999; Kimber et al., 1999; Limousin et al., 1999; Siebner
et al., 1999). However, there is much less effect on
reaction times and no effect on the early (BP1) component
of the BP (after pallidotomy; Limousin et al., 1999).
Interestingly, the late (BP2) component of the BP is
improved, which is consistent with the idea that one effect
of surgery is to improve compensation by non-midline
cortical structures.

Functional imaging studies of the effect of

surgery and deep brain stimulation on
bradykinesia
Many imaging studies have been driven by the model of basal
ganglia function outlined in the early 1990s. Overactivity of

2141

the inhibitory output projections from the basal ganglia to

the thalamus in Parkinsons disease was supposed to remove
facilitatory thalamocortical drive, particularly to midline
cortical motor areas (anterior SMA and cingulate cortex).
PET and fMRI activation studies had shown (see above) that
these areas were less activated during movement in patients,
and therefore pallidotomy was expected to improve activation
by restoring normal levels of basal ganglia output (e.g.
Ceballos-Baumann et al., 1994).
Most studies on movement-related changes in metabolic
activity have reported similar findings both after pallidotomy
(Grafton et al., 1995; Samuel, 1997a, b) and during
subthalamic nucleus stimulation (Limousin et al., 1997;
Ceballos-Baumann et al., 1999). In tasks in which a freechoice joystick movement is used, increased activation of
preSMA and anterior cingulate cortex is usually accompanied
by increased activation of the dorsolateral prefrontal cortex.
Although most reports of activation-induced metabolism
suggest that there is no change in the primary motor cortex,
there are some suggestions that stimulation of the subthalamic
nucleus may reduce activity in the resting state (Limousin
et al., 1997; Ceballos-Baumann et al., 1999). Whether this
is related to a general reduction in rigidity or other involuntary
muscle activity or to reduced input to the cortex via pathways
direct from the subthalamic nucleus is not known.
Surgery also appears to produce increases in the activation
of the premotor areas, even though these are not normally
underactive, and may even be overactive, in Parkinsons
disease. This has been noted in both a prehension task
(Grafton et al., 1995) and in a freely selected joystick
movement task (Ceballos-Baumann et al., 1999). In an
[18F]fluorodeoxyglucose-PET study carried out in patients at
rest, Eidelberg and colleagues found increases in metabolism
in the premotor cortex as well as in the dorsolateral prefrontal
cortex and motor cortex, ipsilateral to a pallidotomy
(Eidelberg et al., 1996). Thus, it appears that lateral premotor
areas may also be involved in recovery after surgery.

Conclusion
The term bradykinesia is often used to cover a range of
related problems in the control of movement. However, in
all cases the principal deficit is that movements are slow.
The data reviewed here suggest that, although secondary
factors such as muscle weakness, tremor and rigidity may
contribute, the principal deficit is due to insufficient
recruitment of muscle force during the initiation of movement.
The result is that patients movements undershoot their targets
and end by approaching it in several smaller steps. The two
distinguishing features of parkinsonian bradykinesia are (i)
that patients underscale muscle force and (ii) that the deficit
is often ameliorated when external cues (vision, sound) are
given to guide the movement. The former has led to the
suggestion that bradykinesia is a problem of scaling motor
output appropriately to the task rather than to any intrinsic
limitation in motor execution. The latter is usually interpreted

2142

A. Berardelli et al.

in terms of the preferential access of basal ganglia motor

output to medial rather than lateral motor cortical areas.
Medial cortical areas are more active in association with
internally generated movements, whilst lateral areas are
more active during externally cued movement. In summary,
bradykinesia seems to result primarily from the underscaling
of movement commands in internally generated movements.
This may well reflect the role of the basal ganglia in selecting
and reinforcing appropriate patterns of cortical activity during
movement preparation and performance.
Recent imaging and EEG studies have shown that other
regions of the CNS can adapt to the primary basal ganglia
deficit of Parkinsons disease. Thus, the clinical presentation
of bradykinesia may be a mixture of the primary deficit and
compensatory processes. We raise the possibility that some
aspects of bradykinesia, such as the long intervals between
successive elements of a sequence, difficulty in doing two
things at the same time and the progressive slowing of long
sequences of movement, are the result of this interaction.
This line of argument can be followed further. One of the
new understandings of basal ganglia pathophysiology is that
disease may make the basal ganglia output noisy. Surgical
interventions may work in part by removing or reducing this
noise. The implication is that surgery improves function both
by normalizing basal ganglia output and by allowing other
structures to compensate better for the underlying deficit.

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