Evidence indicates that dopaminergic medication in Parkinson's disease may impair certain aspects of cognitive function, such as reversal learning. We used functional magnetic resonance imaging in patients with mild Parkinson's disease to investigate the neural site at which L-DOPA acts during reversal learning. Patients were scanned both ON and OFF their normal dopamine-enhancing L-DOPA medication during the performance of a probabilistic reversal learning task. We demonstrate that L-DOPA modulated reversal-related activity in the nucleus accumbens, but not in the dorsal striatum or the prefrontal cortex. These data concur with evidence from studies with experimental animals and indicate an important role for the human nucleus accumbens in the dopaminergic modulation of reversal learning.
Schematic of the probabilistic reversal learning task. Subjects were presented with the same two abstract visual patterns (A, B) throughout a task block, as displayed in the left panel. They were instructed to choose the pattern that was usually correct, by making right or left button presses. The positive:negative feedback contingencies were always 80:20, so that 20% of correct responses would be accompanied by spurious negative feedback. This response constituted a probabilistic error. Subjects were told that the rule could change, so that, at some point, the other pattern would become correct. The instructions emphasized that they should change responding to the other pattern only when they were certain that the rule had changed. Following contingency reversal, subjects would typically continue to respond to the previously relevant pattern (A) and reverse their responding to the other pattern (B) only after two or three errors.
Al Brooks Reversal Pdf
The following contrasts were computed for each session: (i) final reversal errors minus correct responses, (ii) other nonswitch errors (including the probabilistic and preceding reversal errors) minus correct responses, and (iii) final reversal errors minus other nonswitch errors. These contrast images were taken to second-level group analyses.
In the present study, we predicted that L-DOPA would modulate reversal-related signal change in the NAc and/or the ventral PFC, but not in the dorsal striatum or dorsal PFC. These predictions were assessed using whole-brain analyses with a statistical threshold of P
The above-described statistical models were then reapplied to the average signal within the ROIs for each subject's session, using the MarsBar tool for SPM2 (Brett et al, 2002). Average parameter estimates, representing mean signal change were extracted from each ROI and each subject's session and the mean values across subjects are the values reported in Figures 3, 4 and 5. These mean values were submitted to a repeated measures ANOVA (SPSS 11.0, Chicago, IL) with three within-subjects factors: ROI (eight levels: the NAc, the dorsal striatum, and the six task-related frontal regions), L-DOPA treatment (two levels: ON and OFF) and event-type (the final reversal errors and the baseline correct responses). No epsilon correction was applied, because the sphericity assumption was met (Mauchly's W was not significant for our ROI L-DOPA treatment event-type interaction; Mauchly's W (27)=0.001, P=0.5). For the ROI analyses we report two-tailed P-values (statistical threshold P
Reversal-related signal change across L-DOPA treatment sessions. The BOLD activation pattern during the final reversal errors relative to the baseline correct responses, across both ON and OFF L-DOPA treatment sessions, superimposed on the Montreal Neurological Institute (MNI) template brain (individual brain considered most typical of the 305 brains used to define the MNI template). The figure displays all activation above a threshold of P=0.001 (uncorrected for multiple comparisons). We chose this criterion for display in order to (i) reveal the physiological plausibility of the signal and (ii) facilitate comparison with the data in our previous report (Cools et al, 2002a) in which we also displayed all activation at P=0.001. See Table 2 for peaks that reached significance at P=0.05 (after family-wise error-rate correction for multiple comparisons). Numbers in top left-hand corner of each quadrant indicate Talairach coordinates. R=right hemisphere.
Effects of L-DOPA on reversal-related signal change in the striatum and the prefrontal cortex. Values represent mean parameter estimates (betas, as estimated by SPM2) and error bars represent SE of the mean. Abbreviations: PD=Parkinson's disease; NAc=nucleus accumbens, VLPFC=ventrolateral prefrontal cortex, DLPFC=dorsolateral prefrontal cortex, OFC=orbitofrontal cortex, FEF=frontal eye fields, RCZ=rostral cingulate zone, IFJ=inferior frontal junction. *Significant treatment by event-type interaction.
Postacquisition inspection of the data revealed that some patients were unable to perform the task. It was unclear from simple inspection whether these patients learnt anything or whether they responded at random, thereby reaching learning criteria by chance. For this reason, a learning criterion was imposed on a post hoc basis: Data were included, only if participants completed all nine reversals in each of the three scanning runs and reached an additional criterion of six consecutively correct responses during at least seven out of the 10 learning stages in each scanning run. This criterion led to exclusion of four sessions (two OFF and two ON), resulting in a sample size of eight patients (and 16 scanning sessions).
Dependent measures were (i) the proportion of errors due to switching after a probabilistic (misleading) error, (ii) the number of perseverative errors following a contingency reversal (excluding the first error), (iii) the number of spontaneous errors (see above for definition), (iv) the mean response latency following final reversal errors, and (iv) the mean response latency following correct responses. Data were analyzed using paired sample t-tests.
Table 2 shows all significant effects revealed by a second-level one-sample t-test group analysis of the critical contrast comparing the final reversal errors with the baseline correct responses (with the ON and OFF sessions collapsed into one group). Consistent with our previous study (Cools et al, 2002a), the final reversal errors induced significant signal change in the bilateral ventrolateral PFC/insulae and the rostral cingulate zone. We also observed effects in areas that were not activated in our previous study: The right orbitofrontal cortex and the dorsolateral PFC (Figure 3). This apparent discrepancy is most likely due to the use of a different MR acquisition sequence, better adjusted for picking up signal in area susceptible to drop out. In addition, this may reflect the fact that the participants in the current study were older PD patients, who found the task more difficult than the participants in the previous study, who were young healthy Cambridge students.
Treatment effects were examined in the a priori defined striatal and all task-related frontal regions of interest (ROIs). Although the omnibus ROI L-DOPA treatment event-type three-way interaction tended towards significance (F7,49=1.9, P=0.08), inspection of the data clearly suggests differences in the effects of L-DOPA in the different ROIs (Figure 4). Moreover, we had a priori hypothesized that L-DOPA would modulate ventral, but not dorsal fronto-striatal circuitry during reversal learning, which allowed us to perform simple interaction effect analyses. These analyses confirmed that the L-DOPA by event-type interaction was significant in the NAc (F1,7=6.9, P=0.03) (Figure 4 and 5). Conversely, there was no L-DOPA treatment by event-type interaction in the dorsal striatum (F1,7=0.0, P=0.99). Moreover, there were no significant interactions in any of the task-related frontal ROIs, including the ventrolateral PFC (F1,7=1.6, P=0.24), the dorsolateral PFC (F1,7=2.4, P=0.17), the orbitofrontal cortex (F1,7=0.35, P=0.6), the rostral cingulate zone (F1,7=2.9, P=0.13), the bilateral superior frontal eyefields (F1,7=2.96, P=0.13) or the inferior frontal junction (F1,7=0.84, P=0.39). Thus, L-DOPA modulated reversal-related signal change in the NAc, but not in the dorsal striatum or the PFC.
Although an L-DOPA treatment by event-type interaction effect in the NAc did not reach significance when the final reversal errors were compared with the other nonswitch errors (F1,7=2.3, P=0.18), inspection of the data in Figure 5b reveals that L-DOPA modulated signal change during the final reversal errors, but not during the other nonswitch errors. We suggest that the finding that there was no significant interaction must reflect the increased variability in the signal during the nonswitch errors, which most likely activated a reversal-related network on some but not all trials. The hypothesis that L-DOPA modulated signal change in the NAc only when error trials consistently activated a reversal-related network was supported by the finding that there was no significant interaction when the other nonswitch errors were compared with the baseline correct responses (F1,7=0.001, P=0.9).
Our findings demonstrate a role for the NAc in the dopaminergic modulation of reversal learning in mild PD patients. Reversal learning was accompanied by increased NAc activity when patients were OFF, but not ON their L-DOPA. L-DOPA did not affect reversal-related activity in the dorsal striatum or PFC.
These data concur with findings from studies with experimental animals showing that reversal learning is altered by (i) damage to the ventral striatum, specifically the NAc (Divac et al, 1967; Annett et al, 1989; Stern and Passingham, 1995; Schoenbaum and Setlow, 2003) and (ii) dopaminergic modulation of the NAc (Taghzouti et al, 1985; Smith et al, 1999). Neurophysiological findings have shown that NAc neurons encode a combination of outcome-predictive information and behavioral switching and may indicate that NAc neurons encode behavioral switching only when they encode outcome-predicting information (Wilson and Bowman, 2005). Those findings may reconcile our observation that the NAc is active during final reversal errors, which signal not only a behavioral switch but also an upcoming rewarding outcome, with previous findings that (i) the NAc subserves switching (Cools, 1980; Redgrave et al, 1999) and (ii) other neurophysiological and neuroimaging data showing NAc-activity during reward-anticipation (Hollerman and Schultz, 1998; Knutson et al, 2001; Carelli, 2004; Knutson et al, 2005). 2ff7e9595c
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