Differential Influence of Levodopa on Reward-Based Learning in Parkinson's Disease

The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the “overdose hypothesis” which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients’ actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks

Modulation of Habit Formation by Levodopa in Parkinson's Disease

Dopamine promotes the execution of positively reinforced actions, but its role for the formation of behaviour when feedback is unavailable remains open. To study this issue, the performance of treated/untreated patients with Parkinson's disease and controls was analysed in an implicit learning task, hypothesising dopamine-dependent adherence to hidden task rules. Sixteen patients on/off levodopa and fourteen healthy subjects engaged in a Go/NoGo paradigm comprising four equiprobable stimuli. One of the stimuli was defined as target which was first consistently preceded by one of the three non-target stimuli (conditioning), whereas this coupling was dissolved thereafter (deconditioning). Two task versions were presented: in a ‘Go version’, only the target cue required the execution of a button press, whereas non-target stimuli were not instructive of a response; in a ‘NoGo version’, only the target cue demanded the inhibition of the button press which was demanded upon any non-target stimulus. Levodopa influenced in which task version errors grew from conditioning to deconditioning: in unmedicated patients just as controls errors only rose in the NoGo version with an increase of incorrect responses to target cues. Contrarily, in medicated patients errors went up only in the Go version with an increase of response omissions to target cues. The error increases during deconditioning can be understood as a perpetuation of reaction tendencies acquired during conditioning. The levodopa-mediated modulation of this carry-over effect suggests that dopamine supports habit conditioning under the task demand of response execution, but dampens it when inhibition is required. However, other than in reinforcement learning, supporting dopaminergic actions referred to the most frequent, i. e., non-target behaviour. Since this is passive whenever selective actions are executed against an inactive background, dopaminergic treatment could in according scenarios contribute to passive behaviour in patients with Parkinson's disease

The Neural Basis of Following Advice

Learning by following explicit advice is fundamental for human cultural evolution, yet the neurobiology of adaptive social learning is largely unknown. Here, we used simulations to analyze the adaptive value of social learning mechanisms, computational modeling of behavioral data to describe cognitive mechanisms involved in social learning, and model-based functional magnetic resonance imaging (fMRI) to identify the neurobiological basis of following advice. One-time advice received before learning had a sustained influence on people's learning processes. This was best explained by social learning mechanisms implementing a more positive evaluation of the outcomes from recommended options. Computer simulations showed that this “outcome-bonus” accumulates more rewards than an alternative mechanism implementing higher initial reward expectation for recommended options. fMRI results revealed a neural outcome-bonus signal in the septal area and the left caudate. This neural signal coded rewards in the absence of advice, and crucially, it signaled greater positive rewards for positive and negative feedback after recommended rather than after non-recommended choices. Hence, our results indicate that following advice is intrinsically rewarding. A positive correlation between the model's outcome-bonus parameter and amygdala activity after positive feedback directly relates the computational model to brain activity. These results advance the understanding of social learning by providing a neurobiological account for adaptive learning from advice

Functional Roles of the Thalamus for Language Capacities

Early biological concepts of language were predominantly corticocentric, but over the last decades biolinguistic research, equipped with new technical possibilities, has drastically changed this view. To date, connectionist models, conceiving linguistic skills as corticobasal network activities, dominate our understanding of the neural basis of language. However, beyond the notion of an involvement of the thalamus and, in most cases also, the basal ganglia in linguistic operations, specific functions of the respective depth structures mostly remain rather controversial. In this review, some of these issues shall be discussed, particularly the functional configuration of basal network components and the language specificity of subcortical supporting activity. Arguments will be provided for a primarily cortico-thalamic language network. In this view, the thalamus does not engage in proper linguistic operations, but rather acts as a central monitor for language-specific cortical activities, supported by the basal ganglia in both perceptual and productive language execution

Intact lexicon running slowly--prolonged response latencies in patients with subthalamic DBS and verbal fluency deficits.

BACKGROUND: Verbal Fluency is reduced in patients with Parkinson's disease, particularly if treated with deep brain stimulation. This deficit could arise from general factors, such as reduced working speed or from dysfunctions in specific lexical domains. OBJECTIVE: To test whether DBS-associated Verbal Fluency deficits are accompanied by changed dynamics of word processing. METHODS: 21 Parkinson's disease patients with and 26 without deep brain stimulation of the subthalamic nucleus as well as 19 healthy controls participated in the study. They engaged in Verbal Fluency and (primed) Lexical Decision Tasks, testing phonemic and semantic word production and processing time. Most patients performed the experiments twice, ON and OFF stimulation or, respectively, dopaminergic drugs. RESULTS: Patients generally produced abnormally few words in the Verbal Fluency Task. This deficit was more severe in patients with deep brain stimulation who additionally showed prolonged response latencies in the Lexical Decision Task. Slowing was independent of semantic and phonemic word priming. No significant changes of performance accuracy were obtained. The results were independent from the treatment ON or OFF conditions. CONCLUSION: Low word production in patients with deep brain stimulation was accompanied by prolonged latencies for lexical decisions. No indication was found that the latter slowing was due to specific lexical dysfunctions, so that it probably reflects a general reduction of cognitive working speed, also evident on the level of Verbal Fluency. The described abnormalities seem to reflect subtle sequelae of the surgical procedure for deep brain stimulation rather than of the proper neurostimulation

Reaction times during conditioning and deconditioning.

<p>Average reaction times are displayed per group over blocks of 40 presentations, exemplified by the responses to non-target cues in the NoGo task version with the highest number of responses (no difference was obtained between task versions). Since conditioning-deconditioning sequences comprised 120 presentations during conditioning followed by 40 presentations during deconditioning, block 1 to 3 (labelled C1, C2 and C3) reflect performance during conditioning, whereas block 4 (labelled D) equates to deconditioning. The error bars indicate the standard error of the mean. Note that reaction times increased significantly during deconditioning compared to any of the conditioning blocks (indicated by asterisks) over all groups.</p

Task structure.

<p>Four neutral and equiprobable symbols were presented in pseudorandomised order, one of which was defined as target signal. During a conditioning phase of 120 signal presentations, the target was always preceded by one of the three non-target signals (precue). Over the subsequent 40 presentations, this precue-target coupling was dissolved (deconditioning phase). The conditioning-deconditioning sequence (comprising 160 presentations) was repeated five times with alternating precues. To avoid conscious recognition of the task structure, one-minute pauses were held every 200 trials. Thus, conditioning and deconditioning phases never appeared at the same point in time with respect to the breaks.</p

Errors in the Go version of the task.

<p>In the Go version of the task, erroneous reactions to target signals were response omissions. The average target omission rate is displayed per group over blocks of 40 presentations over the 120 presentations during conditioning (blocks 1 to 3, labelled C1, C2 and C3) and the subsequent 40 presentations during deconditioning (block 4, labelled D). The error bars indicate the standard error of the mean. Note the significant increase of response omissions during deconditioning compared to any of the conditioning blocks in patients with Parkinson's disease on levodopa (indicated by asterisks), which was not found in patients in and patients off levodopa and healthy subjects.</p

Clinical data.

<p>Patients differed between on and off levodopa states and from controls with respect to the scores in the Unified Parkinson's Disease Rating Scale (UPDRS). Normal values without significant differences between groups were obtained in the Beck Depression Inventory (BDI), the Mini Mental State Examination (MMSE) and the Fatigue Severity Scale (FSS). All data are provided as mean values ± standard deviation.</p