Department of Experimental Psychology, University of Cambridge, Downing Street,, 1 Cambridge Centre for Brain Repair and Department of Neurology, University of Cambridge, Robinson Way and, 2 Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
Trevor W. Robbins, University of Cambridge, Department of Experimental Psychology, Downing Street, Cambridge CB2 3EB, UK. Email: twr2{at}cam.ac.uk.
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Abstract |
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Introduction |
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A different approach to addressing the role of DA in human cognition is investigating disorders that implicate the DA system. Parkinson's disease (PD), associated with nigrostriatal and mesocorticolimbic DA depletion, is accompanied by subtle cognitive impairments even in the early stages, resembling those seen in frontal lobe patients (Taylor et al., 1986; Owen et al., 1995
). Although medication with L-Dopa, a precursor affecting primarily levels of DA (Maruyama et al., 1996
), ameliorates the motor symptoms in PD, effects of such medication on cognitive functioning are more complex: deleterious, as well as beneficial effects of L-Dopa have been reported (Gotham et al., 1988
; Kulisevsky, 1996,2000
; Swainson et al., 2000
). For example, Gotham et al. observed beneficial effects of L-Dopa on alternating fluency, but detrimental effects on conditional associative learning. They speculated that L-Dopa doses necessary to remedy the DA lack in the putamen may overdose any area where DA regions are relatively intact, such as for example the PFC (Gotham et al., 1988
). However, the relationship between their tasks and the supposed dissociable underlying neuronal circuitry is unclear. Moreover, there was no significant difference when the on and off patients were compared directly, but only when the two groups were compared separately with controls.
At the time of Gotham et al.'s study (Gotham et al., 1988), clear evidence for an imbalance in different brain regions in PD was not yet available. More recently, studies have shown that, in early PD, DA depletion is restricted to the putamen and the dorsal caudate nucleus, only later progressing to more ventral parts of the striatum and the mesocorticolimbic DA system (Kish et al., 1988
; Agid et al., 1993
). These different parts of the striatum are connected to dissociable cortical areas in relatively segregated cortico-striatal circuits (Rosvold, 1972
; Alexander et al., 1986
) and accumulating evidence indicates that there is functional differentiation between these circuits (Dias et al., 1996
).
Swainson et al. (Swainson et al., 2000) used tasks that have been differentially associated with such dissociable corticostriatal circuitry, among others a spatial recognition memory task and two reversal learning tasks. Whereas spatial recognition memory has been associated with dorsolateral prefrontal areas (Owen et al., 1996
), reversal learning has been linked to ventral striatal-orbitofrontal areas in both monkeys (Divac et al., 1967
; Jones and Mishkin, 1972
; Dias et al., 1996
) and humans (Rolls, 1999
). Their results indicated that non-medicated PD patients, although impaired on a spatial recognition task, performed significantly better on tasks of reversal learning than medicated PD patients. It was suggested that medication doses sufficient to restore DA function in the worst affected region (the dorsal striatum) could be excessive for less affected systems (i.e. functions subserved by the ventral striatum). Thus, these findings were consistent with the overdose hypothesis. However, the medicated patients in this study were clinically more severely disabled than the non-medicated patients, which forms an alternative explanation of the impairment in the medicated and more severely affected PD patients. Therefore, direct evidence for DA-dependent impairments and improvements within the same human subjects has not yet been provided.
In the current study we intended to test more directly whether the imbalance of DA in different segregated functional cortico-striatal circuitries (Alexander et al., 1986) in PD underlies dissociable effects of L-Dopa on different cognitive tasks (Gotham et al., 1988
; Swainson et al., 2000
). To this end, we examined the effects of DA-ergic withdrawal on the functioning of differentially depleted areas in patients with PD, by studying three tasks of learning and cognitive flexibility that have been reliably associated with dissociable cortico-striatal circuits. We predicted that, whereas L-Dopa doses would remedy regions suffering from DA depletion, such as the putamen, the dorsal caudate nucleus and thereby its connections to the dorsolateral prefrontal cortex, it may overdose relatively spared regions, such as the ventral caudate nucleus, the nucleus accumbens and thereby its connections to the orbitofrontal cortex. This DA overdose hypothesis is consistent with the above-mentioned findings of detrimental effects on cognition of both excessive and insufficient DA levels in animals (Arnsten, 1998
) and also with a YerkesDodson account of effects of arousal on cognitive performance (Eysenck, 1982
).
The following tasks were used. The probabilistic reversal learning paradigm, the same task as was used by Swainson et al. (Swainson et al., 2000) measured the capacity to alter behaviour with changing reinforcement contingencies. Such stimulus reward shifting is impaired by lesions of the orbitofrontal cortex (OFC) and the ventral striatum circuitry in both monkeys (Divac et al., 1967
; Dias et al., 1996
; Rolls, 1999
) and humans (Rolls, 1999
). The intra-/extra-dimensional shift (ID/ED) paradigm measured extra-dimensional (ED) set shifting, i.e. the ability to alter behaviour according to changes in dimensional relevance of stimuli, and controlled for set formation and set maintenance abilities within the same task. Impairments in this form of higher-level attentional control have been associated with lesions of the monkey lateral PFC (Dias et al., 1996
), with DL-PFC-striatal damage in human diseases such as PD and Huntington's disease (Downes et al., 1989
; Lawrence et al., 1999
) and recent brain imaging studies revealed significant activation in the DL-PFC during ED shifting (Rogers et al., 2000
; Nagahama et al., 2001
). Previous attempts to clarify the effect of L-Dopa on ED shifting were inconclusive because of a confounding effect on discrimination learning (in a relatively small number of severely disabled PD patients) (Lange et al., 1992
). To avoid such confounding problems of new learning in the ID/ED paradigm, we employed a task-set switching paradigm which requires shifting between well-established stimulusresponse mappings (see Fig. 1a
). Several brain imaging studies have shown that performance of task-set switching is accompanied by activity in the DL-PFC and the posterior parietal cortex (PPC), both thought to be connected to the dorsal striatum in so-called cortico-striatal loops (Meyer et al., 1998
; MacDonald et al., 2000
; Sohn et al., 2000
). Thus, whereas reversal learning has been associated with OFC-ventral striatal circuitry, extra-dimensional shifting and task-set switching have been related to DL-PFC/PPC-dorsal striatal circuitry.
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Materials and methods |
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These studies were approved by the Cambridge Local Research Ethics committee and all subjects gave informed consent.
Patients
Twenty-nine PD patients participated in the study. All patients presented to a general neurology clinic and were diagnosed by a consultant neurologist (R.A.B.) as having idiopathic PD according to UK PDS brain bank criteria. Patients with a significant medical history not related directly to their PD (e.g. stroke, head injury, clinical dementia or depression) were not referred for the study. Patients who scored 24 or lower on the Mini Mental State Examination (MMSE) (Folstein et al., 1975) were excluded. The severity of clinical symptoms was assessed according to the Hoehn and Yahr, five-point rating scale (Hoehn and Yahr, 1967
) and the Unified Parkinson's Disease (44-point) Rating Scale (UPDRS) (Fahn et al., 1987
). Hoehn and Yahr ratings ranged between I and III. All 29 patients included in the study were receiving daily L-Dopa preparations, DA receptor agonists and/or selegiline (monoamine activity enhancer), all were stable on their medication doses for at least 3 months and responding well. Patients receiving additional medication likely to confound interpretation of the findings were excluded as far as possible. Moreover, exclusion of the three patients taking such medication (anti-cholinergics) did not affect the statistical significance of our findings. Fifteen out of the 29 patients were asked to abstain from their medication the night before the assessment was scheduled to take place, at least 18 h prior to the experiment. Fourteen out of the 29 patients were taking their medication as normal. Other clinical details are summarized in Table 1
.
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Previously collected data from age and NART IQ (Nelson, 1982) matched control subjects were used to compare performance of the patients to baseline levels. A group of 27 controls was tested on the task-set switching paradigm, a subset of 20 controls on the ID/ED shift paradigm and a different group of 23 controls was tested on the probabilistic reversal learning paradigm. There was no difference between any of the control groups and the two patient groups in terms of age or premorbid IQ. Other details are summarized in Table 2
.
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Cognitive tasks |
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Subjects were shown a display with a letter and/or number (or vice versa) and required to name the letter or digit as fast as possible without making a mistake. Subjects switched between (A) letter- and (B) digit-naming tasks on every second trial, so that switch and non-switch trials alternated in a predictable way. Thus, the sequence of trials employed was AABBAA and so on, which enabled the measurement of switching (i.e. A to B or B to A) against a baseline of non-switching (i.e. A to A or B to B). The colour of the stimulus window indicated which task was to be performed. Switch costs were calculated by subtracting performance (i.e. reaction times and errors) on non-switch trials from performance on switch trials. Two conditions were distinguished. In the cross-talk condition, both a letter and a number were presented on most trials. Therefore, stimuli primed the previously relevant, but currently distracting task-set and demands on selection mechanisms were increased. In the no-cross-talk condition, the stimulus consisted of attributes, which were associated only with the relevant task (only a letter or only a number was presented).
The task started with a general training session in which the letter- and digit-naming tasks were separately practised. The general training session was followed by the actual experiment, in which the sequence of the cross-talk and no-cross-talk conditions was counterbalanced within the groups. Each experimental condition, consisting of four blocks of 40 trials, was preceded by a practice session, consisting of two blocks of 40 trials. The mapping of the colours green and red with the letter- and the digit-naming tasks was also counterbalanced within the two groups. An IBM-compatible PC was used as a testing machine; a small throat-microphone was used to record reaction times and the program, written in C, was run from real-time MS-DOS to ensure that reaction times (RTs) were measured to millisecond accuracy. Each stimulus consisted of two closely adjacent characters presented side by side. The characters were randomly presented on the left or the right of the stimulus pair. Letters were sampled randomly from the set {G, K, M, P, R, A, E, U}, digits from the set {2, 3, 4, 5, 6, 7, 8, 9} and neutral characters from the set {?, *, %, #}. Each character pair remained on the screen until the subject responded by naming one of the characters. The responsestimulus interval was 1000 ms.
The data were analysed using repeated measures ANOVAs. After exclusion of unreliable trials, RTs were log-transformed to satisfy the assumption of homogeneity of variances. Except for one control subject and two patients off medication, who made between 25 and 36% errors, none of the subjects made >18% errors. Exclusion of the three subjects with many errors did not affect the significance of the RT effects. Proportions of errors were arcsin-transformed (Howell, 1997) (2arcsin
x).
Both the ID/ED shift paradigm and the probabilistic reversal learning paradigm were administered using a Datalux microcomputer with a touch-sensitive screen for recording responses.
Probabilistic Reversal (Lawrence et al., 1999; Swainson et al., 2000
) (see Fig. 1b
)
This task was administered using a Datalux 486 microcomputer with a touch-sensitive screen for recording responses.
The task consisted of two stages, starting with a simple probabilistic visual discrimination, in which subjects were required to make a two-alternative forced choice between two colours. The correct stimulus (which was always the first stimulus touched) received an 80:20 ratio of positive:negative feedback and the opposite ratio of reinforcement was given for the incorrect stimulus. After having completed 40 trials of this initial discrimination, the task proceeded to the second, reversal stage in which contingencies were reversed, without warning, so that the previously incorrect colour was now correct and vice versa for the subsequent 40 trials. Although all subjects received a total of 80 trials, a learning criterion of eight consecutive correct trials was imposed for the purposes of analysis.
Main performance measures were failure or success at each stage, mean errors to criterion and mean latencies. Failure/success rates were analysed using the likelihood-ratio method for contingency tables (Robbins, 1977). Subjects failing stage 1 were excluded from subsequent analyses of error rates and latencies at stage 2. They were included when error rates and latencies at stage 1 were analysed. Square-root transformed errors to criterion [(x + 0.5)1/2] were analysed using one-way ANOVAs. However, the assumption of homogenous variances was violated for errors to criterion at stage 2, so this measure was analysed using the non-parametric MannWhitney test. In addition, measures of perseveration and maintenance were included. For details of these additional measures the reader is referred elsewhere (Lawrence et al., 1999
; Swainson et al., 2000
).
Intra-/extra-dimensional Shift Paradigm (Downes et al., 1989)
Like the reversal learning paradigm, the ID/ED task started with a simple discrimination stage in which subjects were asked to touch one of two patterns. Each response was followed by visual and auditory computer feedback. The task proceeded through several stages, with the crucial extra-dimensional shift (EDS) stage requiring a shift in responding from the initially relevant, but now irrelevant, dimension shapes to the previously irrelevant, but now relevant, dimension lines. For a full description of the further stages of the ID/ED shift paradigm the reader is referred elsewhere (Downes et al., 1989). Main performance measures were failure or success at each stage and errors to criterion. Failure/ success rates were analysed using the likelihood-ratio method for contingency tables (Robbins, 1977
). Subjects failing any of the stages were excluded from analysis of subsequent stages.
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Results |
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Mean RTs for the cross-talk and the no-cross-talk conditions are presented in Figure 2 as a function of trial-type and group. Consistent with our prediction, patients off medication exhibited increased switch costs relative to patients on medication [F(1,27) = 5.07, P = 0.033]. The three-way interaction of group x switch x cross-talk was highly significant [F(1,27) = 11.2, P = 0.002] and simple interaction effect analyses showed that the switch x group interaction was significant only in the cross-talk condition [F(1,27) = 13.24, P = 0.001] and not in the no-cross-talk condition [F(1,27) = 0.06, P = 0.82]. The cross-talk x switch interaction was significant for patients off medication [F(1,14) = 32.0, P < 0.0001], but not for patients on medication [F(1,13) = 1.34, P = 0.3] or controls [F(1,26) = 0.33, P = 0.6].
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There were no group differences in terms of errors.
The increased switch costs in terms of RTs cannot be explained by generalized slowing of cognitive processes because: (i) the deficit was specific to certain conditions of the experiment; (ii) there were no significant differences in terms of overall RT (patients versus controls, P = 0.13; patients on versus patients off, P = 0.31); (iii) the groups also exhibited significantly different proportional switch costs, which were calculated by dividing the actual switch cost by the mean baseline non-switch reaction time for each individual subject. Again, proportional switch costs were increased in the cross-talk condition (patients versus controls, P = 0.02; patients on versus patients off, P = 0.005) and not in the no-cross-talk condition.
The Probabilistic Reversal Learning Paradigm (Fig. 3)
Almost no subjects failed the initial acquisition stage. Consistent with our prediction, significantly more patients on medication failed the reversal stage than patients off medication (six out of 13 patients on and two out of 15 patients off medication: 2 (1) = 3.8, P = 0.05). Non-parametric analysis revealed that there was no difference in terms of errors at the acquisition stage [mean values (SEM) for patients on, 1.2 (0.6); patients off, 1.5 (0.8); controls, 1.1 (0.5)]. However, at the reversal stage both patients on and off medication made significantly more errors than did controls [mean values (SEM) for patients on, 12.6 (3.4); patients off, 11.1 (3.0); controls, 4.5 (0.9), P = 0.02], while there was no difference between patients on and off medication. There was no difference in terms of perseverative errors and error patterns were generally non-perseverative.
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Significantly more patients (seven out of 28) failed the crucial EDS stage than did controls (one out of 20) [2 (1) = 3.8, P = 0.05], but there was no difference between patients on (three out of 13) and off medication (four out of 15) [
2 (1) = 0.05, P = 0.83]. Patients made more errors at the EDS stage (but not at other stages) than controls, but this difference was not significant (P = 0.13).
There were no significant correlations between the following selected task measures: the number of errors at the EDS stage from the ID/ED shift paradigm; the number of errors and number of stages completed from the probabilistic reversal learning paradigm; and switch costs from the task-set switching paradigm.
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Discussion |
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Hayes et al. (Hayes et al., 1998) reported ameliorative effects of medication on colourshape switching. However, their results were confounded by changes in baseline non-switch reaction times, which, as they admit, present a problem that is difficult to correct for in the onoff manipulation (Salthouse, 1985
). As outlined in the Results section, our findings are unconfounded by generalized slowing of cognitive processes and, therefore, the present study provides much stronger evidence for a beneficial effect of DA-ergic medication on task-set switching.
Finally, the present study provides stronger evidence for contrasting effects of DA-ergic medication than previous studies, because the effects were observed within the same group of patients tested off medication and, consequently, cannot be explained by general changes in affect, arousal or motor symptoms. This also precludes Kulisevsky's proposal that the nature of the DA-ergic effect depends on the progression of the disease and the response to medication (Kulisevsky, 1996,2000), an argument that is strengthened by the fact that our patient groups were well-matched for disease duration and all patients reponded well to their medication. Rather, our results suggest that DA-ergic effects on cognition are task-specific and, in PD, depend on the underlying neural substrates of the tasks.
On the probabilistic reversal learning task, although performing significantly better in terms of failure rates than patients on medication, patients off medication made more errors than controls. This result can be reconciled with the finding that there is some degree of DA loss in the ventral striatum and the mesocorticolimbic pathway (Agid et al., 1993). DA loss in these areas, however, is less severe than DA loss in the putamen and the more dorsal striatum (Kish et al., 1988
), at least in the early stages of the disease. Medication doses necessary to remedy DA loss in the more severely affected areas may overdose less severely depleted areas, thereby leading to an impairment in patients on medication compared with patients off medication. It is predicted that further progression of the disease, known to be accompanied by more extensive DA loss in the ventral striatum, would lead to an abolition of this overdose effect on L-Dopa and even to a remediation of this deficit.
The finding that task-set switching, but not ED shifting, was affected by withdrawal of medication suggests that striatal DA is more important for switching between well-learned stimulus response mappings than for shifting to a yet-to-be-established attentional set. This hypothesis is supported by a recently shown impairment in re-engaging a well-established attentional set in monkeys with 6-OHDA-induced DA loss in the caudate nucleus (Collins et al., 2000). Psychopharmacological studies in healthy volunteers (Elliott et al., 1997
; Mehta et al., 1999
; Rogers et al., 1999
) and studies on PD patients (Downes et al., 1989
; Lange et al., 1992
; Owen et al., 1992
) have only provided ambiguous or conflicting results on the role of DA in ED shifting. It is possible that deficits at the ED shift stage in PD patients may be caused by disruption of other ascending neurotransmitter systems, that also degenerate in PD, such as noradrenaline (NA), acetylcholine or serotonin (Agid et al., 1987
), but which are not primarily reinstated by L-Dopa (Maruyama et al., 1996
). A role for NA in ED shifting is plausible given the recent observation of a specific deficit at the EDS stage following the administration of clonidine (an NA agonist) and idazoxan (an NA antagonist) to healthy volunteers (Middleton et al., 1999
) and is consistent with recent theories about the function of the coeruleal-cortical NA pathway (Usher et al., 1999
).
The finding that the effect of DA-ergic withdrawal in the task-set switching paradigm was specific to the cross-talk condition, in which demands for selection mechanisms were increased by the presence of stimuli that primed the competing task-set, is consistent with a proposed gating or focusing role for DA (Gerfen, 1992; Cohen and Servan-Schreiber, 1993
; Schultz et al., 1995
). Braver and Cohen (Braver and Cohen, 2000
) suggested that DA modulates the access of relevant and irrelevant information to active memory mechanisms subserved by the prefrontal cortex. This gating function may provide a mechanism by which DA-ergic medication in our PD patients affects task-set switching, associated with lateral prefrontal-parietal cortex networks (Meyer et al., 1998
; MacDonald et al., 2000
; Sohn et al., 2000
).
The observed deleterious effect of medication on the probabilistic reversal learning task was specific to the reversal stage and performance at the initial acquisition stage was intact in all groups. However, because the correct stimulus at the acquisition stage was always the first colour chosen by the subject, the conclusion that reversal learning (involving the inhibition of previously relevant responses) is more specifically sensitive to DA modulation than probabilistic discrimination learning must be drawn with caution. Indeed, it is conceivable that reversal learning is essentially a difficult learning situation following a rule change (Swainson et al., 2000) and, consistently, the DA system has been implicated in such reward-related learning and PD patients have previously been shown to be impaired on probabilistic learning (Knowlton et al., 1996
). For example, on the basis of electrophysiological data Schultz and colleagues (Hollerman and Schultz, 1998
; Schultz et al., 2000
) proposed a role for the precise timing of the short-latency, burst responses of DA neurons in guiding reward-based learning. These DA responses have been shown to be important for signalling deviations from learned predictions of reward, which is crucial in reversal learning. Repeated L-Dopa was recently shown to increase spike-dependent, phasic DA release in 6-OHDA-lesioned rats (Harden and Grace, 1995
). Abnormally increased phasic DA activity in OFC-ventral striatal circuitry may hypothetically, via such uncalibrated error-prediction signals (Schultz et al., 2000
), lead to over-sensitivity to probabilistic error-feedback following contingency reversal. Although it was not possible in the current study actually to acquire in vivo measurements of DA at the receptors, this hypothesis is consistent with the observed random pattern of errors (as distinct from simple perseveration). Further support for a special sensitivity of probabilistic reversal learning to DA overdosing is provided by a recent study by Mehta et al. (Mehta et al., 2001
), who showed that, in young healthy volunteers, the D2 agonist bromocriptine impairs performance on the same probabilistic reversal task, while improving performance on a spatial memory span task.
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Conclusion |
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Notes |
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References |
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