DOI: 10.

1093/brain/awh043 Brain (2004), 127, 330±339

The basal ganglia and inhibitory mechanisms in

response selection: evidence from subliminal
priming of motor responses in Parkinson's disease
Ellen Seiss1 and Peter Praamstra1,2
1Behavioural Brain Sciences Centre and 2Department of Correspondence to: P. Praamstra, Behavioural Brain
Clinical Neurology, Queen Elizabeth Hospital, University Sciences Centre, University of Birmingham, Birmingham
of Birmingham, Birmingham, UK B15 2TT, UK E- mail: p.praamstra@bham.ac.uk

Summary

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Subliminal response priming was used to investigate
inhibitory control processes relevant to response selec-
tion impairments in Parkinson's disease. Using a back-
ward masking technique, covert activation of left- or
right-hand responses was induced without subjects con-
sciously perceiving the stimuli (right- or left-pointing
arrows). The masked priming stimuli were followed by
visible arrow stimuli, instructing for a left- or right-
hand response, at a delay (interstimulus interval, ISI) of
0 or 100 ms. Motor cortex activation was recorded by
means of the electroencephalographic lateralized readi-
ness potential (LRP). Parkinson's disease patients (n =
12) were compared with age-matched controls (n = 12)
and young controls (n = 10). In young controls, the ISI
= 100 ms task effectively invoked inhibition of the sub-
liminally primed responses, as demonstrated by a rever-
sal of prime±target compatibility effects compared with
the ISI = 0 ms task. This reversal implied that there
was a so-called negative compatibility effect with faster
responses and fewer errors when prime and target
arrows pointed in opposite directions than when they
required the same response. This negative compatibility
effect turned into a positive compatibility effect in
Parkinson's disease patients, while age-matched controls
produced intermediate values. Together, these results
support the view that response selection involves com-
petitive, mutually inhibitory interactions between
response alternatives, in¯uenced by basal ganglia±thala-
mocortical mechanisms. As indicated by the reduced
inhibition of partially activated responses, Parkinson's
disease and, to a lesser degree, normal ageing affect the
ef®ciency of these inhibitory interactions.

Keywords: basal ganglia; Parkinson's disease; subliminal priming; inhibition; lateralized readiness potential

Abbreviations: ERP = event-related potential; LRP = lateralized readiness potential; ISI = interstimulus interval;
RT = reaction time; TMS = transcranial magnetic stimulation; UPDRS = Uni®ed Parkinson's Disease Rating Scale
Received July 15, 2003. Revised September 15, 2003. Accepted September 18, 2003. Advanced Access publication November 25, 2003

Introduction
Effects of basal ganglia dysfunction are often conceived in
terms of an altered balance of facilitatory and inhibitory
in¯uences on the frontal cortex (Alexander et al., 1990). In
the motor domain, excess of movement in Huntington's
disease and restriction of movement in Parkinson's disease
are typically explained by disinhibition and overinhibition
of thalamocortical projection neurons, respectively, result-
ing in overexcitable versus depressed neural activity in
motor areas of the cortex (Albin et al., 1989; DeLong,
1990). However, on the basis of various sources of
evidence that have emerged in recent years, this model
may need revision, at least where Parkinson's disease is
concerned. Goldberg et al. (2002) emphasized three
relevant lines of evidence. First, transcranial magnetic
stimulation (TMS) studies have shown reduced motor
cortex inhibition in Parkinson's disease (Ridding et al.,
1995; Strafella et al., 2000). Secondly, functional imaging
studies have yielded evidence for overactivity of motor
cortical areas in Parkinson's disease (Sabatini et al., 2000;
Haslinger et al., 2001; Turner et al., 2003; but see
Buhmann et al., 2003). Finally, investigations in the MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned
monkey indicate that motor cortex neuronal activity is
characterized by abnormal ®ring patterns rather than a
decrease in activity (Goldberg et al., 2002; see also Doudet
et al., 1990; Watts and Mandir, 1992).

Brain Vol. 127 No. 2 ã Guarantors of Brain 2003; all rights reserved

Fig. 1 Trial structure for the ISI = 0 ms task (A) and the ISI = 100
ms task (B).
Electroencephalographic event-related potential (ERP)
studies have also contributed to a reconsideration of the
view that motor cortical activity is depressed in Parkinson's
disease. While changes in the distribution of movement-
related potentials are often interpreted in terms of compen-
satory activation of lateral premotor areas (Dick et al., 1989;
Cunnington et al., 1995), Praamstra et al. (1996) acknow-
ledged that a loss of speci®city and impaired focusing of
neural activity might produce such changes. Furthermore,
recordings of the movement-related lateralized readiness
potential (LRP) during so-called interference or con¯ict tasks
have shown that voluntary response activation in Parkinson's
disease patients is susceptible to interference by inappropriate
motor cortex activation evoked by irrelevant information
(Praamstra et al., 1998; Praamstra and Plat, 2001). Such
®ndings do not readily conform to the notion of thalamocor-
tical underactivation, and we have proposed that they re¯ect a
disinhibition of the motor cortex that may be related to the
de®cient motor cortical inhibition revealed by TMS investi-
gations (Ridding et al., 1995).
The present investigation sought to further delineate the
extent to which de®cient inhibitory control is responsible for
response selection impairments in Parkinson's disease. For
this purpose, we exploited a recently discovered feature of
subliminal priming, namely self-inhibition. It is well-known
that masked visual stimuli, the conscious perception of which
is prevented by a short presentation duration and backward
masking, can nevertheless in¯uence behaviour (e.g. Taylor
and McCloskey, 1990; Neumann and Klotz, 1994). For
instance, a masked arrow (the `prime' stimulus) pointing to
the left speeds up the response to a subsequently presented
visible arrow stimulus (the `target' stimulus) when that arrow
points to the left, but induces a delay when that arrow is
directed to the right. Eimer and Schlaghecken (1998) made
the important discovery that the expected facilitation by
Response selection in Parkinson's disease 331
prime±target compatibility turns into inhibition when a delay
is introduced between the presentation of prime and target.
They proposed that an initial covert response tendency,
induced by the prime stimulus, is checked automatically by a
self-inhibition process intrinsic to the motor system (Eimer,
1999; Schlaghecken and Eimer, 2002). Depending on the
interval between prime and target, the inhibition phase may
coincide with the preparation of the required response and
thus reverse normal priming effects, yielding a so-called
negative compatibility effect, both in reaction times and in
error rates. Importantly, the prime-induced motor activation
and the subsequent inhibition phase have distinct correlates in
movement-related LRP recordings (Eimer and Schlaghecken,
1998).
The combined behavioural and electrophysiological evalu-
ation of inhibitory motor processes elicited by subliminal
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stimuli may provide more direct evidence for de®cient
inhibitory control processes in Parkinson's disease than has
been available hitherto from con¯ict tasks. Based on the
evidence from the latter type of task, discussed above, the
prediction is that the negative compatibility effect is attenu-
ated in Parkinson's disease. Of note, Aron et al. (2003)
predicted an increased negative compatibility effect in
Parkinson's disease, based on subliminal response priming
results in Huntington's disease.
Methods
Participants
The investigation included three experimental groups: Parkinson's
disease patients (n = 12), age-matched controls (n = 12) and young
participants (n = 10). All participants gave informed consent and the
investigation was approved by the South Birmingham Research
Ethics Committee. The Parkinson's disease group consisted of nine
men and three women (mean age 6 SD, 60 6 8 years). All patients
were on dopaminergic medication and had moderate disease
severity. All patients but one were right-handed, as determined
with the Edinburgh Handedness Questionnaire (Old®eld, 1971).
Motor symptoms were assessed using the Uni®ed Parkinson's
Disease Rating Scale (UPDRS; Lang and Fahn, 1989). The median
score on the motor subsection was 29 (range 24±36). The
investigation and the UPDRS rating were performed after overnight
withdrawal from medication (>12 h). In view of the known visual
contrast sensitivity changes in Parkinson's disease (Bodis-Wollner,
1987; Tebartz van Elst, 1997; Pieri et al., 2000), contrast sensitivity
was determined using the Pelli±Robson chart (Pelli et al., 1988).
Nine men and three women (age 58 6 7 years) formed the age-
matched control group. The young control group consisted of ®ve
men and ®ve women (age 27 6 5 years). All control subjects were
right-handed and without a history of neurological or psychiatric
diseases.
Stimuli and procedures
Figure 1 gives a schematic representation of the trial structure. Each
trial started with a ®xation cross that was presented for 1500 ms and
disappeared 200 ms before the appearance of the prime stimulus.
The prime consisted of arrows positioned to the left and to the right
332 E. Seiss and P. Praamstra
of the screen centre and pointing in the same direction, i.e. either left
or right. The prime stimuli were presented for 32 ms and were
immediately followed by masking stimuli consisting of random lines
displayed for a duration of 100 ms. The stimulus that conveyed the
response instruction, i.e. the target, consisted of arrows identical to
the prime stimuli in shape and size, and was presented at the centre
of the screen for a duration of 100 ms. The target appeared either at
the same time as the mask or after a delay of 100 ms. Thus, the
interstimulus interval (ISI) between prime and target was either 0 ms
(ISI = 0 ms task) or 100 ms (ISI = 100 ms task). The next trial started
300 ms after target offset.
The stimuli were presented on a computer monitor in black on a
grey background. Left- and right-pointing double arrows (<< and >>,
size 0.6° 3 0.4°) were used as prime and target stimuli. Masking
stimuli consisted of 20 randomly drawn lines on a virtual grid (0.8°
3 0.5°). The lines were newly drawn in each trial. The ®xation cross
had a size of 0.2° 3 0.2°. The ®xation cross and target stimuli
appeared at the centre of the screen, whereas prime and mask stimuli
were presented at a distance of 0.8° to the left and right from the
centre. The experiment was performed in a dimly lit room, with the
computer screen placed 100 cm in front of the participant's eyes in
the centre of the horizontal straight-ahead line of sight.
The experiment consisted of eight experimental blocks of 128
trials each, divided into four consecutive blocks for the ISI = 0 ms
task and four blocks for the ISI = 100 ms task. Each task was
preceded by a practice block of 32 trials. The order of the two tasks
was balanced across subjects. Each block contained an equal number
of trials with a compatible and an incompatible prime±target
relation, presented in a pseudorandomized order. Participants
responded with the hand corresponding to the direction of the target
arrow and the instruction emphasized response speed. Left- and
right-hand responses were recorded using hand grip force
measurements.
At the end of the experiment, masking ef®ciency was evaluated
by means of a staircase procedure determining the individual prime
identi®cation thresholds. Subjects remained sitting in front of the
computer screen, where a ®xation cross was presented for the
duration of the entire block, which consisted of 126 trials. Prime and
mask stimuli were presented in the same way as in the main
experiment. Participants had to identify the direction of the arrows
and to respond with the corresponding hand. They were instructed to
respond spontaneously when they thought they could not identify the
arrow direction. The number of the random lines in the mask was
adjusted from trial to trial according to the performance of the
participant. A ®xed-step, 1-up/2-down procedure was employed: one
random line was added in trials following correct responses and two
lines were removed after incorrect responses. The block started with
the presentation of an unmasked prime (zero line mask). With this
procedure, identi®cation performance converges on a 66% correct
level (Kaernbach, 1991).
Data acquisition and preprocessing
The EEG was recorded continuously with Ag/AgCl electrodes from
82 scalp electrodes relative to a linked mastoids reference. The
electrodes were placed according to the International 10±10
electrode system, with additional electrodes at electrode sites
FCC3h, FCC4h, FCC5h, FCC6h, CCP5h and CCP6h (American
Electroencephalographic Society, 1994; Oostenveld and Praamstra,
2001), using a carefully positioned nylon cap. Eye movements were
monitored by bipolar horizontal and vertical electro-oculogram
(EOG) derivations. EEG and EOG signals were ampli®ed with a
bandpass of 0.16±128 Hz by BioSemi Active-One ampli®ers and
sampled at 512 Hz.
The continuous EEG recordings were segmented off-line in
epochs measuring from 100 ms before prime onset to 700 ms after
target onset. Individual trials containing artefacts were rejected
before averaging, using a threshold of 675 mV. The EEG data of two
Parkinson's disease patients and two age-matched controls were
excluded from the ERP analysis because of a poor signal-to-noise
ratio. The behavioural data were used.
LRPs were calculated for each condition separately, in order to
separate movement-related EEG activity from overlapping stimulus-
related activity (cf. Praamstra et al., 1998). Activity at electrode sites
ipsilateral to the responding hand was subtracted from the activity at
contralateral electrode sites, yielding difference waveforms for left-
and right-hand responses. Subsequently, these difference waveforms
were averaged across response sides to obtain LRPs. Lateralized
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movement-related activity, i.e. the LRP, is typically measured at
electrodes C3 and C4 overlying the hand area of the motor cortex. To
improve the signal-to-noise ratio of the LRP we pooled the C3 and
C4 electrodes with four adjacent electrodes (FCC3h/4h, C1/2,
CCP5h/6h and CP3/4). In this paper, EEG data analyses mainly
concern amplitude and latency measurements of the LRP. The
amplitude of the prime-induced response activation was measured in
a time window of 8 ms around the individual peak latency (baseline
to peak). The amplitude of the subsequent inhibition phase was
analysed relative to the amplitude of the preceding prime-induced
activation (peak to peak) (time window around peak, 20 ms).
Force signals were recorded and stored with the EEG data.
Response latencies for each trial were determined with a force onset
detection algorithm. When both response hands were activated, a
trial was counted as error whenever the wrong response channel was
activated earlier than the correct response and reached an amplitude
>10% of the force amplitude on the correct side.
Data analyses
For the statistical analysis of behavioural [force onset (reaction time,
RT), error rates] and electrophysiological data (amplitudes and
latencies), analyses of variance (ANOVAs) were performed with the
within-subject factors Compatibility (compatible versus incompat-
ible), prime±target ISI (0 versus 100 ms) and the between-subjects
factor Group (Parkinson's disease patients, age-matched controls,
young control subjects). Within-subject effects were corrected for
non-sphericity using the Huynh±Feldt correction. Signi®cant effects
were further analysed using post hoc tests (t tests for paired and
independent samples) and the critical a level was adjusted with the
Bonferroni correction. Planned comparisons were used to compare
the magnitude of compatibility effects between Parkinson's disease
patients and age-matched controls. The hypothesis of a positive
correlation between disease severity and reduction of the negative
compatibility effect was evaluated (one-tailed) using Spearman's
rank coef®cients.
Pelli±Robson scores of contrast sensitivity for binocular vision
were obtained from a subset of the participants consisting of 11
Parkinson's disease patients, nine age-matched controls and 10
young controls (Pelli et al., 1988). The ranking scores were
compared between groups using non-parametric tests (Kruskal±
Wallis test, Mann±Whitney test).

Results
Behavioural data
An omnibus ANOVA was applied to the collective reaction
time data set from the task with prime±target ISI = 0 ms and
the task with ISI = 100 ms. This analysis showed that the
groups had priming effects in the same direction at ISI = 0 ms.
At ISI = 100 ms, by contrast, there were marked differences
between the groups, with priming effects in opposite direc-
tions, as will be explained below. This was expressed in a
signi®cant ISI 3 Group 3 Compatibility interaction for
reaction times [F(2,31) = 3.8, P = 0.034] and for error rates
[F(2,31) = 4.0, P = 0.029]. This expected result focuses our
main interest on the ISI = 100 ms task. For clarity of
exposition the two ISI tasks are further presented separately,
except for the overall RTs per group, which were 381 6 60
ms (young controls), 435 6 39 ms (age-matched controls)
and 437 6 57 ms (Parkinson's disease). These differences
yielded a signi®cant main effect of Group [F(2,31) = 3.9,
P = 0.032]. Of note, while force onsets (i.e. reaction times)
were comparable for Parkinson's disease patients and aged
controls, patients demonstrated a slower rate of force
generation [t(12.1) = 3.8; P = 0.002], as quanti®ed by the
time from force onset to peak force.
ISI = 0 ms task
Responses were faster when the target arrows were preceded
by arrows that pointed in the same direction (compatible
prime) than when they were preceded by arrows instructing
the opposite hand (incompatible prime). This was manifested
in a main effect of Compatibility [F(1,31) = 293.2,
P < 0.001]. The size of this compatibility effect (Fig. 2A)
was largest in Parkinson's disease (64 ms), followed by age-
Fig. 2 Reaction times and error rates for the ISI = 0 ms task (A) and the ISI = 100 ms task (B).
Response selection in Parkinson's disease 333
matched controls (55 ms), followed by young controls
(41 ms). While differences across the three groups were
expressed in a signi®cant Group 3 Compatibility effect
[F(2,31) = 4.4, P = 0.021], the difference between
Parkinson's disease and age-matched control groups was
not signi®cant.
The error pattern matched the RT results, with more errors
when the prime±target relation was incompatible than when it
was compatible [F(1,31) = 35.0, P < 0.01]. Moreover, the
susceptibility to interference by an incompatible prime
differed between the groups, with especially Parkinson's
disease patients generating a high error rate in the incompat-
ible condition [Group 3 Compatibility interaction, F(2,31) =
4.7, P = 0.016]. Furthermore, the compatibility effect in terms
of error rate was larger in Parkinson's disease patients than in
aged controls [t(13.5) = 2.7; P = 0.018]. Disease severity in
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the Parkinson's disease group, measured by the UPDRS, did
not show any correlation with compatibility effects in
reaction time or error rate.
ISI = 100 ms task
Here, in contrast to the previous task, the direction of priming
effects differed between the groups [Group 3 Compatibility
interaction, F(2,31) = 20.0, P < 0.01]. The young control
group demonstrated a performance characterized by a
negative compatibility effect, with faster responses when
there was an incompatible prime±target relation than when
the relation was compatible, yielding an incompatible±
compatible difference of ±31 ms (Fig. 2B). In the other
participant groups, by contrast, the compatibility effect had a
positive sign, measuring +8 ms in aged controls and +25 ms
in Parkinson's disease patients. One-tailed planned compari-
son of the compatibility effect in Parkinson's disease patients
334 E. Seiss and P. Praamstra

and aged controls con®rmed a signi®cant difference [t(22) =
1.9; P = 0.034]. A further analysis evaluated the correlation
between Parkinson's disease severity, as expressed in the
UPDRS motor subscale, and the size of the compatibility
effect in the Parkinson's disease group, yielding a positive
correlation (r = 0.54, P = 0.034). That is, more severely
affected Parkinson's disease patients had a more positive
compatibility effect.
Like the RTs, the errors showed opposite patterns in young
controls and Parkinson's disease patients, the aged controls
demonstrating an intermediate behaviour (Fig. 2B). Thus, the
young control group had more errors in the compatible
condition, whereas Parkinson's disease patients had more in
the incompatible condition, with approximately equal error
rates in the two conditions for the age-matched control group.
This was expressed in a signi®cant Group 3 Compatibility
interaction [F(2,31) = 12.0, P < 0.01]. One-tailed planned
comparison of the compatibility effects of Parkinson's
disease patients and aged controls con®rmed a signi®cant
difference [t(12.9) = 3.0; P = 0.005]. In contrast to the
compatibility effect for RTs, the compatibility effect for
errors did not show a signi®cant correlation with Parkinson's
disease severity.
Movement-related potentials
ISI = 0 ms task
Stimulus-locked LRP waveforms are presented in Fig. 3A.
Recall that the LRP measures differential activation of the

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Fig. 3 Lateralized readiness potentials for the ISI = 0 ms task (A)
and the ISI = 100 ms task (B). The time scale is aligned at target
onset (0 ms) with the onset of the prime stimulus (indicated by
arrowheads) at ±32 ms (ISI = 0 ms task) and ±132 ms (ISI = 100
ms task). Note the grey bar indicating temporary activation of the
incorrect response, due to inhibition of the prime-induced motor
cortex activation.
right and left motor cortices. Hence, the most relevant feature
in the waveforms is the transient activation of the incorrect
response in the incompatible condition, manifested in the
brief dip below the baseline just preceding the activation of
the correct response. The amplitude of the incorrect acti-
vation was measured both in absolute terms and scaled
relative to the magnitude of the correct response activation, to
take into account differences in LRP amplitude between the
groups. The ®rst analysis showed no difference between the
groups [F(2,27) < 1]. However, scaled amplitudes differed
between groups [F(2,27) = 3.9, P = 0.034]. Scaled amplitudes
were larger in Parkinson's disease patients than in age-
matched controls [t(12.6) = 2.5; P = 0.029], which ®ts the
slightly larger size compatibility effect of patients in terms of
reaction time.
Peak latencies of the incorrect, prime-induced response
activation are presented in Table 1, showing differences
clearly determined by age, i.e. markedly longer latencies for
the Parkinson's disease group and the age-matched control
group than for the young controls. Statistical evaluation
con®rmed a signi®cant difference between the groups
[F(2,27) = 3.4, P = 0.05]. Note that the transient incorrect
response activation in the LRP, as pictured in the grand
average of Fig. 3A, was less well de®ned, i.e. smeared in
time, in the Parkinson's disease patients and aged controls
compared with the young controls, presumably related to
latency variability.

Table 1 Latency and amplitude of prime-induced motor cortex activation

ISI Compatibility Group Latency(ms) Amplitude(mV)

0 ms Incompatible Parkinson's disease 270 6 45 1.4 6 0.4

Aged controls 279 6 33 1.4 6 0.6
Young controls 240 6 24 1.5 6 0.5
100 ms Compatible Parkinson's disease 303 6 33 ±0.9 6 0.6
Aged controls 303 6 49 ±0.9 6 0.5
Young controls 240 6 31 ±1.0 6 0.6
100 ms Incompatible Parkinson's disease 315 6 33 1.2 6 0.5
Aged controls 308 6 40 1.4 6 0.4
Young controls 248 6 35 1.1 6 0.4

Fig. 4 Lateralized readiness potentials for the ISI = 100 ms task
realigned at the peak latency of the prime-induced response
activation. Response times relative to this latency are represented
below the waveforms. The left grey bar marks the prime-induced
motor cortex activation, while the right bar marks the subsequent
inhibition. Solid lines and arrowheads indicate the compatible
condition; dashed lines and open arrow heads indicate the
incompatible condition.
ISI = 100 ms task
Stimulus-locked LRPs are shown in Fig. 3B. The waveforms
are characterized by initial de¯ections due to prime-induced
motor cortex activation, most clearly illustrated in the
waveforms of the young control group. Uniquely for this
group, the initial activation by compatible prime stimuli
(continuous line) was followed by activation of the incorrect
response before the correct response was reactivated and
executed. The phase of incorrect response activation follow-
ing a compatible prime represents the self-inhibition process
that was the main interest of this study. In the aged control
and Parkinson's disease groups there was no incorrect
response activation in the same time window, indicating
that self-inhibition of the prime-induced activation was weak.
Note that although the self-inhibition of prime-induced motor
cortex activation stands out as a separate LRP de¯ection in
the compatible condition only, it is presumably equally strong
in the incompatible condition, in which it coincides with
voluntary response activation and drives the RT advantage.
Table 1 shows the peak amplitude and latencies of the
prime-induced motor cortex activation. There was no differ-
ence in amplitude between groups [F(2,27) < 1]. The latency,
by contrast, was signi®cantly different between groups
[F(2,27) = 10.2, P < 0.01], with shorter latencies for the
young controls than for the aged controls and Parkinson's
disease patients. The self-inhibition phase in the compatible
condition was quanti®ed relative to the preceding prime-
induced activation, yielding peak-to-peak values of 2.1 6 1.0
Response selection in Parkinson's disease 335
mV (young controls), 1.1 6 1.0 mV (age-matched controls)
and 0.9 6 0.4 mV (Parkinson's disease). This gave a
signi®cant main effect of Group [F(2,27) = 6.1, P < 0.01],
due to stronger inhibition in the young controls relative to the
other groups.
The differences in the LRP between young controls on the
one hand and age-matched controls and Parkinson's disease
groups on the other hand are consistent with and clarify the
mechanism behind the attenuation of the negative compati-
bility effect in the latter groups. Note, however, that the
waveforms as shown in Fig. 3B are markedly affected by
interindividual latency differences of especially the initial
prime-induced motor cortex activation. Moreover, the latency
difference of this activation between groups (Table 1) was
unexpected and might play a role in the attenuation of the
negative compatibility effect in the older participant groups.
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To facilitate the evaluation of how this delay might have
affected performance, the LRPs were realigned at the peak of
the prime-induced motor cortex activation, as determined for
each participant. The realigned waveforms are displayed in
Fig. 4. The superimposed waveforms illustrate, con®rming
the analysis reported above, that the delayed prime-induced
motor cortex activation in the Parkinson's disease and age-
matched control groups was not reduced in amplitude. The
superimposition of waveforms also emphasizes the attenu-
ation of the self-inhibition phase in the LRP of the compatible
condition in these groups.
Control measures
The ef®cacy of masking was measured with a staircase
procedure. The thresholds, expressed as the mean number of
lines required in the mask to prevent conscious perception,
were 8.6 6 4.5 lines for the Parkinson's disease patients, 6.9
6 3 lines for the aged controls, and 7.1 6 3 lines for the
young controls. These values were not signi®cantly different
between the groups [F(2,31) < 1] and were well below the
number of lines, i.e. 20, used for masking in the main
experiment. Hence, performance differences between the
groups are not likely to be due to differences in perceptual
awareness of the prime stimuli, which seem adequately
masked for all three groups.
Contrast sensitivity differed between the groups [c2(2) =
9.7; P < 0.01]. It was lower in the aged control group (median
1.65, range 0.3) than in the young controls (median 1.95,
range 0.3; Z = 3.1, P < 0.01). The contrast sensitivity
measured in the Parkinson's disease patients was intermedi-
ate between aged and young controls (median 1.8, range 0.3)
and did not differ signi®cantly from the values in either of
these groups.
Discussion
The present study investigated response selection impair-
ments in Parkinson's disease, using a masked priming
paradigm. In the ISI = 100 ms task that we used, covert
336 E. Seiss and P. Praamstra
response activation induced by a subliminal stimulus is
normally subject to inhibition (Eimer and Schlaghecken,
1998). We hypothesized that this inhibition would be reduced
in Parkinson's disease. The results con®rm our hypothesis,
both in terms of response times and in terms of response
errors. Compared with young control subjects, healthy elderly
subjects also showed a reduced inhibition of covert response
activation. As we will explain below on the basis of our
electrophysiological data, this age effect may be partly due to
an age-related delay in the latency of prime-induced response
activation, extraneous to the inhibitory de®cits the task was
designed to measure.
Negative compatibility effects
In masked priming experiments, response activation induced
by a subliminal stimulus supports or con¯icts with the
response demanded by the imperative stimulus, very similar
to the effects of ¯anker (in)compatibility and spatial
stimulus±response (in)compatibility, previously examined
in Parkinson's disease (Brown et al., 1993; Cope et al.,
1996; Praamstra et al., 1998; Lee et al., 1999; Praamstra and
Plat, 2001). What, then, is the added value of examining the
negative compatibility effect? The application of con¯ict
tasks in patients with movement disorders is often reported as
testing visual attention de®cits (Georgiou et al., 1995; Cope
et al., 1996; Lee et al., 1999). We explained the impaired
performance of Parkinson's disease patients on such tasks, by
contrast, in terms of inhibitory de®cits within the motor
system that compromise the selection between competing
responses (Praamstra et al., 1998; Praamstra and Plat, 2001).
Such an explanation would be further strengthened when
Parkinson's disease patients exhibited a reduction of the
negative compatibility effect following subliminal response
priming. One obvious reason for this is that the irrelevant
information is presented subliminally. Hence, impaired
performance cannot be attributed to an inability to ignore
irrelevant information. Of greater import, however, is that an
evaluation of the negative compatibility effect provides direct
information on inhibitory processes, within the motor system,
that come into play when a response is activated but does not
reach threshold (Eimer and Schlaghecken, 1998;
Schlaghecken and Eimer, 2002). An analogy with TMS
studies is suggested, in which the `double-pulse paradigm'
involves the application of a conditioning stimulus to the
motor cortex, followed by a test stimulus (Kujirai et al.,
1993). A conditioning stimulus of subthreshold intensity, i.e.
not evoking an EMG response, does activate inhibitory
circuits that reduce the response to the suprathreshold test
stimulus. This inhibition is reduced in Parkinson's disease
(Ridding et al., 1995; Strafella et al., 2000), and a similar
reduction of the inhibition underlying the negative compati-
bility effect would support the possibility that the relevant
inhibitory circuits have a role in response selection.
Turning now to the results, the task designed to elicit a
negative compatibility effect, i.e. the task where prime and
target were separated by an ISI of 100 ms, produced the
desired effect in young control subjects, with a negative
compatibility effect size of ±31 ms. Moreover, the recorded
LRP demonstrated a robust initial prime-induced response
activation followed by an inhibition phase that, in the
compatible condition, temporarily shifted the balance of
activation between left and right motor cortex towards an
activation of the incorrect response (Fig. 3). Presumably, a
similar yet invisible inhibition phase coincided with the
voluntary activation of the correct response in the incompat-
ible condition. Not only the Parkinson's disease patients but
also the aged controls showed a markedly different pattern,
characterized by a positive instead of negative compatibility
effect. Notwithstanding this age-related attenuation of the
negative compatibility effect, there were signi®cant differ-
ences between Parkinson's disease patients and aged controls
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that supported our hypothesis of an inhibitory de®cit in
Parkinson's disease. Compared with the negative compati-
bility effect in young controls (±31 ms), there was a more
positive compatibility effect in patients compared with
controls (25 versus 8 ms), re¯ecting a pattern in which the
behaviour of aged controls is intermediate between that of
young controls and Parkinson's disease patients. This pattern
was also re¯ected in the error analysis. Aged controls had
equal numbers of errors in the compatible and incompatible
conditions, whereas Parkinson's disease patients made more
errors in the incompatible condition (Fig. 2). The amplitude
of the inhibitory phase of the LRP was not sensitive to the
group difference, most likely due to overlap with voluntary
response activation.
In contrast to the task with 100 ms ISI, with an ISI of 0 ms
the direction of compatibility effects was the same across the
groups, reaction times being always faster in the compatible
than in the incompatible condition. The 9 ms difference in the
size of the compatibility effect between Parkinson's disease
patients and aged controls (64 versus 55 ms) was in the
expected direction, but not signi®cant. However, compatibil-
ity effects in error rates were signi®cantly different between
these groups. In addition, the size of the incorrect LRP
activation was larger in patients than in aged controls.
Together, these results in the ISI = 0 ms task resemble those
obtained with visible instead of subliminally presented
¯ankers (Praamstra et al., 1998), on which our hypothesis
of an inhibitory de®cit was partly based.
Age-related attenuation of the negative
compatibility effect
Reduction of the negative compatibility effect from ±31 ms in
young controls to +8 and +25 ms in aged controls and
Parkinson's disease patients, respectively, suggests a signi®-
cant effect of age. While age increases the susceptibility to
interference in con¯ict tasks, commonly attributed to a
reduced ability to inhibit prepotent response tendencies
(Zeef et al., 1996; Nieuwenhuis et al., 2000), the present

investigation identi®es another cause of age differences in
masked priming. Prime-induced motor cortex activation in
the 100 ms ISI task peaked some 60 ms later in the aged
controls and the Parkinson's disease patients than in the
young controls. As a result, the prime-induced activation
interacted with the target induced activation at a later time
point compared with young controls. Hence, the age-related
attenuation of the negative compatibility effect may partly
depend on differences in timing of automatic and voluntary
response activation. This does not exclude an age-related
decline of inhibitory function, as tested with masked priming.
Interestingly, inhibitory circuits probed with the TMS paired-
pulse technique decline with age (Peinemann et al., 2001).
Note that the incorrect prime-induced motor cortex acti-
vation in the ISI = 0 ms task, elicited by incompatible primes,
also peaked later in aged controls and patients than in young
controls, although the delay was smaller than in the ISI = 100
ms task. Latency and amplitude differences (Table 1) may be
due to the fact that, with ISI = 0 ms, the prime occurs closer in
time to the target, with effects of temporal attention (Miniussi
et al., 1999) on motor cortex excitability leading to a higher-
amplitude prime-induced response. On the other hand, the
close succession of prime and target in the ISI = 0 ms task
makes the delayed prime-induced activation prone to trunca-
tion by the target-elicited voluntary response activation, thus
explaining the smaller delay relative to the ISI = 100 ms task
for the aged participants.
The marked prolongation in the latency of prime-induced
motor cortex activation with age is a novel and intriguing
®nding, especially since the delay does not seem to dissipate
the activation. If it proves replicable, it will require incorp-
oration in theories of masked response priming, which does
not seem straightforward. Masked response priming is often
regarded as evidence for the existence of direct perceptuo-
motor links, possibly mediated by dorsal visual stream
circuitry (Neumann and Klotz, 1994; Eimer and
Schlaghecken, 1998). It is hardly likely that this pathway is
abnormally vulnerable to the effects of ageing. Our ®nding
may be more easily accommodated by accounts of masked
priming in terms of retinotectal connections (e.g. Morris et al.,
1999). But, to our knowledge, there is no evidence either for
disproportionate ageing of retinotectal pathways.
Functional anatomical locus and comparison
with Huntington's disease
Our prediction of a reduced negative compatibility effect in
Parkinson's disease rested on previous work showing
enhanced susceptibility to interference in response con¯ict
tasks, perhaps related to de®cient cortical inhibition
(Praamstra and Plat, 2001). The con®rmation of this predic-
tion supports an inference of de®cient response selection in
Parkinson's disease and implicates relatively low-level motor
processes rather than cognitive striatofrontal processes rele-
vant to interference control (Cope et al., 1996). The key
Response selection in Parkinson's disease 337
relevance of the negative compatibility effect, obtained with
subliminal priming, is its demonstration that the resolution of
response con¯ict is assisted by active inhibition of partially
activated responses. To capture this inhibition electrophysio-
logically, using the LRP, response alternatives need to be
mapped onto opposite hands. The negative compatibility
effect, however, is also obtained with the responses de®ned
on one hand (Eimer and Schlaghecken, 1998), showing that it
is not peculiar to interhemispheric interaction. Presumably,
the underlying inhibition is not unique either to partial
response activation in subliminal priming. More likely, it
re¯ects inhibitory interactions whose normal operation
subserves the selection between alternative responses.
Consistent with such a view, inhibitory interactions support-
ing the selection and suppression of competing responses
have been identi®ed in premotor areas and in the basal
Downloaded from http://brain.oxfordjournals.org/ by guest on September 24, 2015
ganglia (Schall et al., 1995; Basso and Wurtz, 2002; Cisek
and Kalaska, 2002).
As stated earlier, it is tempting to hypothesize a relation
between the de®cient inhibition found in con¯ict tasks and
subliminal priming and the impaired cortical inhibition
demonstrated with TMS in Parkinson's disease (Ridding
et al., 1995). However, such a link remains to be demon-
strated and it is relevant to point out that different TMS
indices of cortical inhibition, i.e. the silent period, short-
interval intracortical inhibition and long-interval cortical
inhibition, probably measure different inhibitory mechanisms
(Sanger et al., 2001). Nonetheless, these measures of cortical
inhibition are in¯uenced by basal ganglia disease and are
responsive to pharmacotherapy and surgical interventions for
Parkinson's disease (Ridding et al., 1995; Ziemann et al.,
1997; Chen et al., 2001; Cunic et al., 2002). The identi®ca-
tion, by means of functional MRI, of the caudate nucleus and
thalamus as structures involved in the inhibitory control
underlying the negative compatibility effect (Aron et al.,
2003) does not, therefore, exclude a relation between this
effect and impaired cortical inhibition measured with TMS.
Caution regarding such a relation is, on the other hand,
suggested by the ®nding that repetitive TMS of the motor
cortex does not affect the negative compatibility effect
(Schlaghecken et al., 2003).
Aron et al. (2003) investigated inhibitory control processes
in subliminal priming in Huntington's disease, expecting to
®nd a reduction of the negative compatibility effect. The
results did not demonstrate an abnormal performance for the
patients as a group, however, as the majority of patients
showed an exaggerated negative compatibility effect while
only a smaller subgroup demonstrated the predicted attenu-
ation. The latter subgroup had higher chorea scores than the
former and the authors proposed that the patients with an
enhanced negative compatibility effect had an akinetic±rigid
variant of Huntington's disease with features resembling
Parkinson's disease. Hence, this reconstruction entails a
prediction regarding Parkinson's disease that is discon®rmed
by the present results. As to what may have caused the
bimodal pattern in the behaviour of the Huntington's disease
338 E. Seiss and P. Praamstra
group, one possibility relates to the latency of the prime-
induced response activation relative to the voluntary response
activation. As suggested by the present investigation, the
relative timing of these activations is probably an important
factor in driving the direction and size of compatibility
effects. The variable extent of extrastriatal pathology in
Huntington's disease patients (Rosas et al., 2003), in
combination with slow and variable voluntary response
activation (Georgiou et al., 1995), may have affected the
timing in a way that produced the bimodal behavioural
pattern.
Conclusions
The present results extend previous evidence for impaired
response inhibition in Parkinson's disease. The experimental
approach, using subliminal priming to induce a competition
between two response alternatives, provides arguments for
impaired inhibition at a fairly low level in the central motor
system (Eimer, 1999), possibly related to the de®cient
inhibitory mechanisms revealed by paired-pulse TMS. The
function of the circuitry underlying self-inhibition of a
partially activated response goes evidently beyond the
arti®cial experimental situation created here. As indicated
by the lateralization of the recorded movement-related
potentials, inhibition of a partially activated response auto-
matically produces activation of the alternative response.
Hence, we infer that the relevant circuitry mediates inhibitory
interactions between competing response alternatives and has
a role in response selection. The rapid alternation of LRP
de¯ections in young control subjects demonstrates that the
inhibitory circuitry is ®nely tuned to admit the release of only
one response. Similar selectivity is required in natural
movement repertoires involving, for instance, bimanual
coordination or sequencing of movements. The reduced
inhibition in Parkinson's disease and, to a lesser degree, aged
controls, is manifested here as impaired control of partial
response activation, leading to a marked change of prime±
target compatibility effects both in response times and error
pattern. In line with current views on basal ganglia function
(Mink, 1996; Boraud et al., 2002), we propose that this
re¯ects the loss of spatial and temporal selectivity in the
operation of basal ganglia±thalamocortical mechanisms that
in¯uence the selection and suppression of competing
responses.
Acknowledgements
The authors wish to thank the patients and volunteers for their
participation in this study, N. Roach, G. Barbieri and C.
Hesse, who provided technical and programming support, F.
Schlaghecken for advice and for making available the
staircase program for testing masking ef®ciency, and M.
Eimer, F. Schlaghecken and H. Siebner, who provided
helpful comments on an earlier draft. The investigation was
supported by the MRC.
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