Brain Advance Access originally published online on November 25, 2003
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Brain, Vol. 127, No. 2, 330-339, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh043
The basal ganglia and inhibitory mechanisms in response selection: evidence from subliminal priming of motor responses in Parkinson’s disease
1 Behavioural Brain Sciences Centre and 2 Department of Clinical Neurology, Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
Correspondence to: P. Praamstra, Behavioural Brain Sciences Centre, University of Birmingham, Birmingham B15 2TT, UK E- mail: p.praamstra{at}bham.ac.uk
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Summary |
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Subliminal response priming was used to investigate inhibitory control processes relevant to response selection impairments in Parkinson’s disease. Using a backward masking technique, covert activation of left- or right-hand responses was induced without subjects consciously 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 readiness 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 subliminally primed responses, as demonstrated by a reversal 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 competitive, mutually inhibitory interactions between response alternatives, influenced by basal ganglia–thalamocortical mechanisms. As indicated by the reduced inhibition of partially activated responses, Parkinson’s disease and, to a lesser degree, normal ageing affect the efficiency of these inhibitory interactions.
Key Words: 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 = Unified Parkinson’s Disease Rating Scale
Received July 15, 2003. Revised September 15, 2003. Accepted September 18, 2003.
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Introduction |
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Effects of basal ganglia dysfunction are often conceived in terms of an altered balance of facilitatory and inhibitory influences 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, resulting 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 firing patterns rather than a decrease in activity (Goldberg et al., 2002; see also Doudet et al., 1990; Watts and Mandir, 1992).
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 compensatory activation of lateral premotor areas (Dick et al., 1989; Cunnington et al., 1995), Praamstra et al. (1996) acknowledged that a loss of specificity 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 conflict 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 findings do not readily conform to the notion of thalamocortical underactivation, and we have proposed that they reflect a disinhibition of the motor cortex that may be related to the deficient motor cortical inhibition revealed by TMS investigations (Ridding et al., 1995).
The present investigation sought to further delineate the extent to which deficient 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 influence 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 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 evaluation of inhibitory motor processes elicited by subliminal stimuli may provide more direct evidence for deficient inhibitory control processes in Parkinson’s disease than has been available hitherto from conflict tasks. Based on the evidence from the latter type of task, discussed above, the prediction is that the negative compatibility effect is attenuated 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.
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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 ± SD, 60 ± 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 (Oldfield, 1971
). Motor symptoms were assessed using the Unified 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 ± 7 years) formed the age-matched control group. The young control group consisted of five men and five women (age 27 ± 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 fixation 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 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.
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The stimuli were presented on a computer monitor in black on a grey background. Left- and right-pointing double arrows (<< and >>, size 0.6° x 0.4°) were used as prime and target stimuli. Masking stimuli consisted of 20 randomly drawn lines on a virtual grid (0.8° x 0.5°). The lines were newly drawn in each trial. The fixation cross had a size of 0.2° x 0.2°. The fixation 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 efficiency was evaluated by means of a staircase procedure determining the individual prime identification thresholds. Subjects remained sitting in front of the computer screen, where a fixation 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 fixed-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, identification 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 amplified with a bandpass of 0.16–128 Hz by BioSemi Active-One amplifiers 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 ±75 µV. 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 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 incompatible), 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. Significant effects were further analysed using post hoc tests (t tests for paired and independent samples) and the critical 
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 coefficients.
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).
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Results |
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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 directions, as will be explained below. This was expressed in a significant ISI x Group x 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 ± 60 ms (young controls), 435 ± 39 ms (age-matched controls) and 437 ± 57 ms (Parkinson’s disease). These differences yielded a significant 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 quantified 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-matched controls (55 ms), followed by young controls (41 ms). While differences across the three groups were expressed in a significant Group x Compatibility effect [F(2,31) = 4.4, P = 0.021], the difference between Parkinson’s disease and age-matched control groups was not significant.
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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 incompatible condition [Group x 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 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 x 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 comparison of the compatibility effect in Parkinson’s disease patients and aged controls confirmed a significant 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 significant Group x 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 confirmed a significant 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 significant 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 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 activation 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 first 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 fits the slightly larger size compatibility effect of patients in terms of reaction time.
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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 confirmed a significant 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 defined, i.e. smeared in time, in the Parkinson’s disease patients and aged controls compared with the young controls, presumably related to latency variability.
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ISI = 100 ms task
Stimulus-locked LRPs are shown in Fig. 3B. The waveforms are characterized by initial deflections 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 following 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 deflection 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 difference in amplitude between groups [F(2,27) < 1]. The latency, by contrast, was significantly 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 quantified relative to the preceding prime-induced activation, yielding peak-to-peak values of 2.1 ± 1.0 µV (young controls), 1.1 ± 1.0 µV (age-matched controls) and 0.9 ± 0.4 µV (Parkinson’s disease). This gave a significant 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 compatibility 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. 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, confirming 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 attenuation of the self-inhibition phase in the LRP of the compatible condition in these groups.
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Control measures
The efficacy 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 ± 4.5 lines for the Parkinson’s disease patients, 6.9 ± 3 lines for the aged controls, and 7.1 ± 3 lines for the young controls. These values were not significantly 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 [
2(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 intermediate between aged and young controls (median 1.8, range 0.3) and did not differ significantly from the values in either of these groups.
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Discussion |
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The present study investigated response selection impairments in Parkinson’s disease, using a masked priming paradigm. In the ISI = 100 ms task that we used, covert 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 confirm 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 deficits the task was designed to measure.
Negative compatibility effects
In masked priming experiments, response activation induced by a subliminal stimulus supports or conflicts with the response demanded by the imperative stimulus, very similar to the effects of flanker (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 conflict tasks in patients with movement disorders is often reported as testing visual attention deficits (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 deficits 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 compatibility 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 incompatible 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 significant differences between Parkinson’s disease patients and aged controls that supported our hypothesis of an inhibitory deficit in Parkinson’s disease. Compared with the negative compatibility effect in young controls (–31 ms), there was a more positive compatibility effect in patients compared with controls (25 versus 8 ms), reflecting 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 reflected 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 significant. However, compatibility effects in error rates were significantly 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 flankers (Praamstra et al., 1998), on which our hypothesis of an inhibitory deficit 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 significant effect of age. While age increases the susceptibility to interference in conflict tasks, commonly attributed to a reduced ability to inhibit prepotent response tendencies (Zeef et al., 1996; Nieuwenhuis et al., 2000), the present investigation identifies 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 activation 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 truncation 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 finding, especially since the delay does not seem to dissipate the activation. If it proves replicable, it will require incorporation in theories of masked response priming, which does not seem straightforward. Masked response priming is often regarded as evidence for the existence of direct perceptuomotor 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 finding 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 conflict tasks, perhaps related to deficient cortical inhibition (Praamstra and Plat, 2001). The confirmation of this prediction supports an inference of deficient response selection in Parkinson’s disease and implicates relatively low-level motor processes rather than cognitive striatofrontal processes relevant to interference control (Cope et al., 1996). The key relevance of the negative compatibility effect, obtained with subliminal priming, is its demonstration that the resolution of response conflict is assisted by active inhibition of partially activated responses. To capture this inhibition electrophysiologically, using the LRP, response alternatives need to be mapped onto opposite hands. The negative compatibility effect, however, is also obtained with the responses defined 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 reflects inhibitory interactions whose normal operation subserves the selection between alternative responses. Consistent with such a view, inhibitory interactions supporting the selection and suppression of competing responses have been identified in premotor areas and in the basal 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 deficient inhibition found in conflict 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 demonstrated 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 influenced 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 identification, 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 finding 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 find 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 attenuation. 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 disconfirmed by the present results. As to what may have caused the bimodal pattern in the behaviour of the Huntington’s disease 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 deficient inhibitory mechanisms revealed by paired-pulse TMS. The function of the circuitry underlying self-inhibition of a partially activated response goes evidently beyond the artificial experimental situation created here. As indicated by the lateralization of the recorded movement-related potentials, inhibition of a partially activated response automatically 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 deflections in young control subjects demonstrates that the inhibitory circuitry is finely 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 reflects the loss of spatial and temporal selectivity in the operation of basal ganglia–thalamocortical mechanisms that influence the selection and suppression of competing responses.
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Acknowledgements |
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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 efficiency, 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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