Perceptual factors contribute to akinesia in Parkinson’s disease

Exp Brain Res (2007) 179:245–253 DOI 10.1007/s00221-006-0783-1

R E SEARCH ART I CLE

Perceptual factors contribute to akinesia in Parkinson’s disease B. Ballanger · R. Gil · M. AudiVren · M. Desmurget

Received: 27 October 2005 / Accepted: 30 October 2006 / Published online: 5 December 2006 © Springer-Verlag 2006

Abstract Parkinson’s disease (PD) patients have longer reaction time (RT) than age-matched control subjects. During the last decades, conXicting results have been reported regarding the source of this deWcit. Here, we addressed the possibility that experimental inconsistencies originated in the composite nature of RT responses. To investigate this idea, we examined the eVect of PD on diVerent processes that compose RT responses. Three variables were manipulated: the signal quality, the stimulus–response compatibility and the foreperiod duration. These variables have been shown to aVect, respectively, the ability to extract the relevant features of the stimulus (perceptual stage), the intentional selection of the motor response (cognitive stage) and the implementation of the muscle command (motor stage). Sixteen PD patients were tested on and oV-medication and compared with an age and gendermatched control group. Results indicated that degrading the legibility of the response stimulus aVected the latency of simple key-press movements more dramati-

This work was supported by the French Ministry of Education, Research and Technology. B. Ballanger · M. AudiVren Laboratoire Performance Motricité et Cognition, University of Poitiers, Poitiers, France B. Ballanger · R. Gil Neurology Department, Poitiers University Hospital, Poitiers, France B. Ballanger (&) · M. Desmurget INSERM, U 371, Brain and Vision Research, 18, Avenue du Doyen Lepine, 69500 Bron, France e-mail: [email protected]

cally in the oV-medication PD group than in the control population. The stimulus–response compatibility and the foreperiod duration had similar eVects in the two groups. Interestingly, the response slowing associated with the degradation of the stimulus was the same whether the patients were on or oV dopaminergic medication. This suggests that the high-level perceptual deWcits observed in the present study do not have a dopaminergic origin. Keywords Parkinson’s disease · Akinesia · Choice reaction time · Levodopa · Perceptual slowing

Introduction Parkinson’s disease (PD) patients have longer reaction time (RT) than age-matched healthy controls. During the last decades, extensive investigations have been carried out to determine the origin of this deWcit. Highly discordant results were reported (for a review, Gauntlett-Gilbert and Brown 1998). A potential explanation for this heterogeneity might lie in the belief that akinesia is mainly a motor deWcit. This belief has led many authors to disregard the potential inXuence of perceptual and cognitive factors on motor RT. The present experiment was carried out to investigate how perceptual, cognitive and motor factors inXuence akinesia. To achieve this goal, we manipulated in the same experiment three variables whose eVects on choice-RT have been well established in normal subjects: the signal quality (to aVect speciWcally perceptual processings), the stimulus–response compatibility (to aVect speciWcally cognitive processings) and the foreperiod duration (to aVect speciWcally motor processings).

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To challenge the perceptual processings, we manipulated the signal quality (SQ). This was done by presenting intact or degraded stimuli. In controls, this approach has been shown to aVect RT: the latency of the motor response increases when the degradation of the signal intensiWes (Sternberg 1969; Sanders 1980, 1983; Davranche and AudiVren 2002, 2004). To our knowledge this protocol has not been used to investigate RT deWcits in PD patients. In this population, one study has investigated the potential role of perceptual slowing on akinesia (Low et al. 2002). Results showed that more diYcult size discriminations increased RT by a similar amount in PD patients and control subjects. Two factors might explain this negative outcome. First, the patients were tested on medication and one may not exclude the possibility that dopamine restores perceptual functions in PD patients. Second, the size discrimination task used in this study was perhaps not demanding enough to reveal a perceptual deWcit. In the present work a more challenging perceptual task was used and the patients were tested on and oV medication. To challenge the cognitive stage, we manipulated the subjects’ ability to map the spatial stimulus code onto the spatial response code (Zimmermann et al. 1992; Reeve and Proctor 1990; Sanders 1980, 1998). This was done by controlling the level of stimulus-toresponse compatibility (SRC). This procedure is commonly thought to aVect the process of response selection (Kornblum et al. 1990). It was Wrst used by Fitts and Deininger (1954) who reported that certain visuomotor mapping resulted in faster and more accurate responses than others. Typically, subjects respond faster when the relative spatial positions of stimulus and response match (compatible condition), than when the positions do not match (incompatible condition). During the last decade, several studies have suggested that the basal ganglia were involved in the process of response selection (Brown and Marsden 1998; Kropotov and Etlinger 1999; Redgrave et al. 1999). The present experiment addresses this hypothesis. We used a paradigm in which the relative positions of the visual stimulus and response-key did or did not match spatially. Using a similar approach, a recent study has failed to provide evidence that the motor selection process was impaired in PD (Wylie et al. 2005). However, in this study, the patients were studied on medications leaving open the possibility that the negative results reXected the therapeutic eVect of the dopaminergic medication. To challenge the motor stage, we manipulated the so-called foreperiod duration (FD) (Sanders 1998; Sternberg 2001; Tandonnet et al. 2003). This variable

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characterizes the delay separating a non-informative warning signal (WS) from the response signal. Human choice RT are known to be longer for long (2,500 ms) than for short (500 ms) foreperiod durations (Bertelson 1967). Several studies, carried out in humans and animals, have shown that the duration of the foreperiod acts by aVecting the motor adjustment stage (Spijkers and Walter 1985; Sanders 1998; Courtiere et al. 2003; Bonin-Guillaume et al. 2004). Indeed, FD has been shown to modulate the excitability of the cortico-spinal tract (Hasbroucq et al. 1997, 1999). This modulation is thought to increase the speed of the muscle contraction by optimizing the sensitivity of the motor structures to the forthcoming voluntary command (Hasbroucq et al. 1995; Tandonnet et al. 2003). It is therefore possible that the deWcit in the rhythm of rise of the electromyographic (EMG) response in PD patients (Godaux et al. 1992) reXects, for a part, an impaired capacity to properly modulate the excitability of the cortico-spinal tract prior to movement. To our knowledge, this is the Wrst study to address this hypothesis. To sum up, the present study was designed to address the following two questions (1) what is the respective contribution of perceptual, cognitive and motor factors to parkinsonian akinesia? (2) how does dopaminergic depletion interact with these factors?

Method Subjects The protocol was approved by the local ethical committee and informed consent was obtained from all participants. Sixteen parkinsonian patients (Table 1) and 16 healthy controls individually matched with the patients for age and sex (nine males, seven females; mean age 59 § 9) participated in the experiment. PD patients fulWlled the UK Parkinson’s Disease Brain Bank criteria for idiopathic Parkinson’s disease. The patients did not exhibit major signs of tremor. No control subject had history of psychiatric or neurological disease. Visual acuity of all participants was normal or corrected to normal. The subjects who showed cognitive dysfunction were excluded. To this end, the control and the patients were screened with the Folstein mini mental state examination (MMSE; Folstein et al. 1975). All included participants scored at least 26 or above, indicating no serious signs of dementia. The two groups did not diVer with respect to their age (F(1,30) = 0.01; P = 0.94) or the mean MMSE score (F(1,30) = 2.91; P = 0.09).

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Table 1 Clinical data for Parkinson’s disease subjects Patients

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Sex

F M F M M F F M F M F M M F M M

Age (years)

MMS

50 55 68 62 59 51 60 52 71 70 54 67 62 37 58 69

30 30 27 28 27 27 30 30 27 30 29 26 28 30 28 29

H&Y (on medication)

2 2 2 2 2 2.5 1.5 2 2.5 2 2 2 2 2.5 2.5 2

Motor UPDRS (on medication)

(oV medication)

Disease duration (years)

7 5 2 3 6 9 2 12 15 4 2 15 9 3 7 10

30 31 10 14 22 31 7 34 19 9 26 31 31 25 27 20

10 5 9 7 16 13 2 13 5 3 7 8 7 6 12 5

Medication in Ldopa equivalent (mg/day) 1,000 1,500 750 500 700 750 375 500 500 500 412.5 600 300 412.5 750 375

F female, M male, H&Y Hoehn and Yahr scale (1967), mg/day milligram per day, Ldopa equivalent: 100 mg Ldopa = 10 mg bromocriptine = 5 mg ropinirole = 1 mg pergolide = 50 mg piribédil

Apparatus and procedure The apparatus is schematically represented in Fig. 1a. Participants were seated in front of a horizontal table in a dimly lit room. The height of the table was adjusted to be level with the lower part of the subjects’ sternum. A rectangular response box with four large response keys (2 cm £ 3 cm) was placed on the table (two response keys for the index and middle Wngers of each hand), and aligned with the body midline of the subjects. These subjects were also facing a 16 in. screen. The center of the screen was placed at eye level in the midline plane, 50 cm in front of the subjects. Visual stimuli were displayed at the center of the screen. The set of stimuli consisted of four arrows which sides and directions were varied within a 4 £ 4 cm rectangular frame. At the beginning of each trial, a WS was provided for 300 ms in the form of an auditory cue and a visual

Fig. 1 a Schematic representation of the experimental apparatus. b Examples of intact (top line) and degraded stimulus (bottom line)

Wxation cross at the center of the screen. After a delay (see below) a response signal was presented. This response signal was removed when a key was pressed. RT was measured as the delay elapsed between the presentation of the response signal and the key-press. The response was considered an error when the subject did press the wrong button. The four stimuli were presented randomly and with equal probability. The intertrial duration was 1,500 ms and the subjects were informed about the response speed at the end of each trial. When no button was pressed within 3,000 ms after the presentation of the visual stimulus, the trial was aborted and represented latter in the session. These trials were disregarded. The instruction was to “respond as fast and accurately as possible”. Three experimental factors were manipulated. The signal quality (SQ): Stimuli were either intact or degraded (Fig. 1b). Degradation was obtained by moving dots associated with the intact stimuli to random positions in order to impair the identiWcation of the stimulus. Each stimulus could be degraded in four equivalent, randomly presented, ways. The signal response compatibility (SRC): In the compatible condition, participants were instructed to give a response with the hand and Wnger indicated by the arrow (black key Fig. 1a). In the incompatible condition, the rule was reversed. Participants had to respond with the contralateral hand and with the Wnger in the direction symmetrically opposed to the direction indicated by the arrow (gray key Fig. 1a). For example, if the arrow indicated the location left-up, the correct response in compatible condition was to press the left middle Wnger. In the

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incompatible condition it was to press the right index. The foreperiod duration (FD): The time between the warning signal and the response signal was manipulated. The FD was either short (500 ms interval) or long (2,500 ms interval). The PD patients were tested twice, in two consecutive days. Eight patients were tested in the “on-medication” state Wrst (on/oV group: six males and two females) and eight were tested in the “oV-medication” state Wrst (oV/on group: three males and Wve females). All patients were tested in the morning (1) about 60 min after taking their anti-parkinsonian medication for the “on-medication” state; (2) after a minimum of 12 h without any medication for “oV-medication” state. Like the patients, the controls were tested twice, in two consecutive days. The combination of the three experimental factors resulted in eight experimental conditions that were tested in separate blocks of 40 trials leading to a total of 320 trials per experimental session. The order of presentation of the blocks was randomized across subjects. For any participant, the same order of presentation was used in the two testing days. Prior to the each block, participants were given practice trials until they were able to perform eight consecutive trials without error. Statistical analysis Statistical analyses were carried out to address two issues. First, how is RT aVected by PD? Second, how is RT aVected by dopaminergic medication (Ldopa)? To investigate the Wrst question, we compared the performance of the control subjects with the performance of the PD patients in the oV-medication state. For this purpose, the data of the control group were matched with the data of the PD “oV” group. For example, if a PD patient Wrst performed the task in the oV condition, Fig. 2 Mean reaction time (RT) as a function of the diVerent experimental factors for the oV-med patient population (open squares dashed lines) and the control group (black circles continuous lines). For SQ the diVerence between the patients and controls is larger for the degraded than for the intact signal. No such interaction is observed for the other factors

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the data of the Wrst session were selected for a control subject. To investigate the second question, we compared the performance of the patients in the ON and oV-medication states. For the Wrst analysis (PD eVect), a four-way ANOVA was conducted with one between (group: controls vs. PD) and three repeated-measure factors (SQ: intact vs. degraded; SRC: compatible vs. incompatible; FD: short vs. long). For the second analysis (medication eVect), a four-way factors ANOVA was conducted with four repeated-measure factors (medication: on vs. oV; SQ; SRC; FD). For these analyses, error rates were arcsin-transformed to stabilize the variances and to minimize the incidence of potential violation the normality prerequisite (Winer 1971). The statistical threshold was set at P = 0.05. Post hoc analyses were conducted using the Newman Keuls test.

Results EVect of Parkinson’s disease Reaction time As shown by statistical analyses, all the factors tested in the present study had a signiWcant eVect on the mean RT (Fig. 2). The group eVect indicated that the patients were slower than the controls when oV medication (1,155 vs. 924 ms; F(1,30) = 17.96; P < 0.001). The SQ eVect showed that degraded signals led to longer RTs than intact signals (1,069 vs. 1,010 ms; F(1,30) = 34.23; P < 0.001). The SRC eVect demonstrated that incompatible mapping led to longer RTs than compatible mapping (1,119 vs. 961 ms; F(1,30) = 189.08; P < 0.001). Finally, the FD eVect revealed that RTs were increased for long with respect to short FD (1,050 vs. 1,030 ms; F(1,30) = 7.63; P = 0.01).

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Only the SQ by group interaction reached the statistical threshold (F(1,30) = 4.75; P = 0.04). Investigation of this interaction indicated that degrading the quality of the signal had a larger eVect in the patient group (
= 81 ms) than in the control group (
= 37 ms; Newman Keuls, P < 0.01). This result indicates that PD becomes a stronger handicap when the perceptual treatments become more complicated. This worsening eVect was not observed for the two other experimental factors (SRC and FD, F(1,30) < 0.6; P > 0.4; Fig. 2). Error data Errors were only inXuenced by the SRC factor. Participants made more errors in the incompatible (3%) than in the compatible (1.7%) mapping condition (F(1,30) = 13.17; P = 0.001). No signiWcant eVect of the group (controls: 2.1%, PD: 2.7%, F(1,30) = 0.23; P = 0.64), the SQ (intact: 2.1%, degraded: 2.7%; F(1,30) = 1.65; P = 0.21) and FD (short 2.5%, long: 2.3%; F(1,30) = 0.76; P = 0.39) factors was observed. No interaction reached the signiWcance threshold (F(1,30) < 1; P > 0.3). EVect of Ldopa medication Reaction time Statistical analyses indicated that the patients exhibited faster responses when medicated (1,074 vs. 1,155 ms; F(1,15) = 8.14; P = 0.01, Fig. 3). Other signiWcant eVects were observed for SQ (F(1,15) = 60.66; P < 0.001), SRC (F(1,15) = 110.59; P < 0.001) and FD (F(1,15) = 10.17; P = 0.006). These eVects were consistent with the ones reported in the Wrst analysis: degraded signals led to longer RTs than intact signals (1,159 vs. 1,070 ms), incompatible mapping led to

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longer RTs than compatible mapping (1,189 vs. 1,040 ms), and long FD led to longer RTs than short FD (1,129 vs. 1,100 ms). No interaction reached the signiWcance threshold (F(1,15) < 1.6; P > 0.2). Error data The percentage of errors did not diVer between the two conditions of medication (2.6 vs. 2.7%; F(1,15) = 0.02; P = 0.89). A signiWcant increase of the error rate was observed when the signal was degraded (SQ: 2.9 vs. 2.3%; F(1,15) = 4.99; P = 0.04) and the response was incompatible (SRC: 3.5 vs. 1.8%; F(1, 15) = 13.91; P = 0.002). FD did not reach the signiWcance level (F(1,15) = 0.03; P = 0.87). No interaction was observed between the experimental factors (F(1,15) < 0.4; P > 0.5).

Discussion There are Wve main Wndings in the present study: (1) PD patients respond more slowly than normal subjects; (2) part of this slowing is associated with perceptual diYculties; (3) the level of akinesia is not aVected when the motor adjustment stage and the complexity of the cognitive selection processes are manipulated; (4) the dopaminergic system is involved in akinesia; (5) this involvement does not seem exclusive and assuming the contribution of other systems is necessary to account for our data. These results are brieXy discussed below. Akinesia in PD In the present study, PD patients were slower to respond than control subjects. This slowing was present irrespective of the experimental manipulations. In other words, akinesia was observed whether (1) the signal

Fig. 3 Mean reaction time (RT) as a function of the diVerent experimental factors for the oV-med (open squares dashed lines) and on-med (black squares continuous lines) patient populations

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was intact or degraded, (2) the stimulus to response mapping was compatible or incompatible, (3) the delay between the initial WS and the actual presentation of the stimulus was short or long. These results indicate that one or several “hidden” factors accounted for most of the response slowing observed in the patients. Unfortunately, our data do not allow us to identify the nature of these “hidden” factors. They might reXect a deWcit in the planning of some movement parameters such as force (Turner et al. 2003; Desmurget et al. 2004), a perturbation in the rhythm of rise of the EMG (Godaux et al. 1992), a concomitant of brain damage (Jahanshahi et al. 1992) and/or an impairment in the process allowing extraction of the elementary sensory signals by the visual system (Marx et al. 1986; Djamgoz et al. 1997; Jackson and Owsley 2003). Perceptual stage When the visual signal was degraded and therefore more diYcult to decode, the subjects needed more time to respond. This detrimental eVect was more pronounced in the patient group than in the control population. To our knowledge, this is the Wrst study to show that akinesia can have a perceptual origin. With respect to this conclusion, one may argue that the patients did use a more conservative response strategy than the controls. This hypothesis is not supported by the error analyses (Sanders 1998). Indeed, the errors occurred with a comparable frequency in both experimental groups. In addition, the error rate followed a similar pattern of variation as a function of the experimental factors in the patient and control populations (no interaction). On the basis of these observations, it seems that the most likely explanation for our results is that PD slows perceptual operations. This conclusion extends previous Wndings gathered in the context of non-motoric judgment tasks (Bachmann et al. 1998; Shipley et al. 2002; Johnson et al. 2004). It is also compatible with a recent functional neuroimaging study suggesting that an anterior network is associated with the processing of visually degraded percepts (Deary et al. 2004). This network involves activations within the fronto-opercular area, the intrasylvian area, the medial frontal gyrus and the anterior cingulate cortex. The latter region is commonly hypoactivated in PD patients (Playford et al. 1992; Jenkins et al. 1992). Cognitive selection stage In our study, when the complexity of the stimulus– response association was increased, the subjects needed more time to respond. The magnitude of this detrimen-

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tal eVect was similar in the patient and control groups. This observation suggests that the process of response selection is preserved in non-medicated PD patients. This conclusion is consistent with previous studies conducted in medicated patients (Wylie et al. 2005) and in healthy subjects supplemented with Ldopa (Rihet et al. 2002). However, as emphasized in the introduction, it is at odd with recent models that have linked the basal ganglia to the cognitive process of response selection (Brown and Marsden 1998; Kropotov and Etlinger 1999; Redgrave et al. 1999). Experimental diVerences could explain these divergences. Indeed, deWcits in the process of response selection, have been reported in situations that elicit conXicting responses (e.g., the Xanker task; Praamstra et al. 1998, 1999; Wylie et al. 2005) or in situations in which the incompatible stimulus must be ignored (e.g., the Simon task; Praamstra and Plat 2001; Fielding et al. 2005). In these situations, the spatial stimulus information is irrelevant to the task. Our study is diVerent in this respect. Indeed, our subjects had to attend to the incompatible stimulus and produce an opposite response. In other words, our incompatible stimulus was on a dimension that was relevant to the task. The distinction whether the incompatible condition is task-relevant or task-irrelevant could be an interesting way of clarifying the mixed results observed in the literature. In addition to the remarks above, it may be worth noting that most explanations of SRC eVects incorporate two parallel routes of response selection: a direct route subserving automatic, stimulus-driven, response tendencies and an indirect route mediating deliberate response selections on the basis of relevant stimulus features (DeJong et al. 1994; Frith and Done 1986; Kornblum et al. 1990; Zhang et al. 1999; Zorzi and Umilta 1995). According to the dual-processing models, Xankers and spatially compatible S-R associations are processed along the fast, automatic routes while target features are processed along the slow, deliberate route (Ridderinkhof and van der Molen 1995). It is now well documented that PD causes a failure to suppress the automatic responses tendencies associated with the direct route (Jackson and Houghton 1995; Hayes et al. 1998). This could explain why this disease makes the patients especially sensitive to Xankers (Praamstra et al. 1998, 1999; Wylie et al. 2005) and spatially compatible S-R designs (the Simon eVect) (Fielding et al. 2005). In the present study, the central stimulus presentation excluded the kind of stimulusdriven responses observed in the Simon or Xankers tasks (Werheid et al. 2003). In our task the motor response of the subject was likely to have been mediated by the “indirect” (intentional, deliberate)

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response-selection route. In agreement with this view, one may note that RTs were relatively long in our study, in both the patient and the control population (around 1 s). To summarize, the previous remarks seem to suggest that the intentional (indirect) process of response selection is not signiWcantly aVected in PD. Although, this conclusion needs to be tested more directly in the future, it could explain some of the divergent results reported in the S-R literature. Motor stage The foreperiod duration (FD) has been shown to aVect the motor adjustment stage (Spijkers and Walter 1985; Sanders 1998), by modulating the excitability of the cortico-spinal tract (Hasbroucq et al. 1997, 1999). As emphasized in the introduction, this modulation is thought to optimize the sensitivity of the motor structures to the forthcoming voluntary command (Tandonnet et al. 2003). An inability to properly modulate the excitability of the cortico-spinal tract prior to movement could explain why the rhythm of rise of the EMG is compromised in PD patients (Godaux et al. 1992) and healthy subjects medicated with Ldopa (Hasbroucq et al. 2003). In the present study, when FD was increased, the subjects needed more time to respond. The magnitude of this eVect was, however, similar in the patient and control groups. This does not support the idea that PD does aVect the process that modulates cortico-spinal excitability prior to movement onset. This conclusion is compatible with a recent experiment conducted by Rihet and collaborators (Rihet et al. 2002). In this experiment, healthy subjects were given Ldopa to increase dopamine concentration in the central nervous system. Variations of RT as a function of FD were not aVected by this manipulation. It may be worth mentioning that the results above do not mean that motor processes are preserved in PD patients. There is plenty of evidence that they are not (Labyt et al. 2003; Desmurget et al. 2003, 2004; for a review see Berardelli et al. 2001). What our data show is just that the adjustment processes that take place between the WS and the actual response signal are not altered in PD. Dopaminergic medication and akinesia Our data indicate that dopaminergic medication alleviates akinesia. This observation agrees with the hypothesis that dopamine depletion is partly responsible for response slowing in PD (Robbins and Brown 1990; for

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a review see Gauntlett-Gilbert and Brown 1998). Interestingly, this therapeutic eVect could not be linked to any of the processing stages investigated in the present study. Two hypotheses can explain this result. First, the main eVect of medication was spread along the diVerent processing stages making each change too small to be detected. Second, Ldopa inXuenced akinesia through the “hidden” factors evoked earlier in this discussion. Although the Wrst hypothesis above cannot be formally rejected, it seems very unlikely. Indeed, according to this hypothesis the eVect of (1) degrading the signal, (2) imposing an incompatible stimulus-toresponse mapping or (3) using a longer foreperiod duration, should be smaller in the medicated than in the non-medicated state. There was not even a trend suggesting that this was the case in the present study. For SQ degrading the stimulus caused a slightly larger increase in RT in the medicated (96 ms) than in the non-medicated (81 ms) state. The same pattern was observed for FD (on-medication: 34 ms; oV-medication: 26 ms). For SRC, no eVect was found (on-medication: 150 ms; oV-medication: 150 ms). Although the second hypothesis may be surprising at Wrst glance it is not totally unexpected. For the motor adjustment stage, we have already emphasized that the variations of RT as a function of FD were not aVected when healthy subjects were given Ldopa (Rihet et al. 2002). Similar results have been reported for the cognitive selection stage (Rihet et al. 2002). These latter results Wt well with the idea that some aspects of the cognitive slowing observed in PD patients are not dopamine dependent (Rafal et al. 1984; Pillon et al. 1989; Growdon et al. 1998; Broussolle et al. 1999). They are also consistent with the fact that cognitive deWcits correlate more tightly with the motor abnormalities that are the least responsive to dopaminergic medication (gait, dysarthria) than with the motor abnormalities that are the most responsive (akinesia, rigidity; Pillon et al. 1989) Regarding the eVect of the medication factor, the most puzzling observation of the present study is probably the absence of speciWc eVect of the dopaminergic therapy on the perceptual processing stage. Indeed, many studies have linked the dopaminergic system to perceptual functions. A way to resolve the discrepancy would be to argue that Ldopa inXuences mainly the low level visual processing that takes place before the intimate structure of the stimulus is processed, while other non-dopaminergic systems mediate higher-level treatments that allow identiWcation of the stimulus. In agreement with this hypothesis, it has been shown that (1) the perceptual processing stage can be segmented

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into low and high levels sub-processings (Van Der Molen et al. 1991); (2) the dopaminergic systems are mainly associated with early visual treatments (Nissen 1977; Lennie 1998; Rihet et al. 2002) at the level of both the retinal structures and striatal regions (see for review Djamgoz et al. 1997; Jackson and Owsley 2003); (3) PD is associated not only with a destruction of dopaminergic cells but also with a loss of noradrenergic and cholinergic neurons (Mann and Yates 1983); (4) noradrenergic and cholinergic neurons are important for attention and arousal (for reviews see Robbins 1997; Marien et al. 2004) i.e., for two processes that are critically involved in high-level perceptual treatments. On the basis of these observations, it is tempting to suggest that Ldopa speeds early visual processings. This could account for (at least) a part of the positive eVect of the medication on the RT of the patients. Ldopa would have no eVect on the late treatments due to the fact that these treatments rely on non-dopaminergic systems. Stated diVerently, these observations suggest that the main eVect of the dopaminergic system is to speed up the extraction and transfer of the elementary sensory signals to the non-dopaminergic structures that are involved in the treatment of the visual pattern. Of course, additional researches are required to further substantiate this still speculative but nonetheless appealing hypothesis.

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