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

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

The impact of Levodopa on implicit learning in patients with Parkinson's disease

In zahlreichen Studien zum Belohnungslernen konnte gezeigt werden, dass Dopamin Verhaltensweisen verstärkt, die für das Individuum positive Konsequenzen haben. Ob und, wenn ja, welche Funktionen Dopamin in Lernsituationen hat, in denen Handlungen weder belohnt noch negativ bewertet werden, ist allerdings noch unklar. In der vorliegenden Studie wurde der Einfluss von Dopamin auf Feedback-unabhängiges, implizites Lernen unter der grundsätzlichen Annahme analysiert, dass Lernmodulation durch Dopamin allgemein und nicht ausschließlich im Kontext bewusst erlebter Verhaltensgratifikation oder -sanktion stattfindet. Dazu bearbeiteten nebst gesunden Kontrollprobanden Levodopa-behandelte Parkinsonpatienten im medikamentösen OFF und ON zwei Aufgaben. Den Probanden wurden wiederholt vier gleichhäufige Stimuli in pseudorandomisierter Reihenfolge präsentiert. Einer dieser Stimuli fungierte als Zielreiz‚ dem während einer ‚Konditionierungsphase’ zunächst immer der gleiche Stimulus (Precue) vorausging. In der nachfolgenden ‚Dekonditionierungsphase’ wurde diese Precue- Zielreiz-Kopplung aufgehoben, ohne dass dieses Schema den Teilnehmern bewusst (gemacht) wurde. In der Go-Aufgabe sollte nach Erscheinen des Zielreizes ein Tastendruck erfolgen, während keine Reaktion nach allen anderen Stimuli gefordert war. In der Nogo-Aufgabe sollte nach jedem nicht-Zielreiz ein Tastendruck erfolgen, während nur nach Erscheinen des Zielreizes der Tastendruck unterdrückt werden sollte. Kernergebnis der Untersuchung war, dass die Aufgabenperformanz von Patienten im OFF der von gesunden Kontrollprobanden ähnelte, sich jedoch deutlich von der Performanz im ON unterschied: Patienten im OFF und Kontrollprobanden zeigten einen Fehleranstieg in der Dekonditionierungsphase der Nogo-Aufgabe, während sich im Verlauf der Go- Aufgabe keine Unterschiede der Fehlerrate entwickelten. Umgekehrt trat ein Fehleranstieg bei Patienten im Levodopa-ON nur in der Dekonditionierungsphase der Go-Aufgabe auf, während dies in der Nogo-Aufgabe nicht der Fall war. Die Fehleranstiege in der Dekonditionierungsphase können in erster Linie als ‚Carry-Over-Effekte’ im Sinne der Fortführung von in der Konditionierungsphase erlernten Verhaltensmustern verstanden werden. Die Modulation dieser Effekte durch Levodopa-Medikation weist darauf hin, dass die Verfügbarkeit von Dopamin das Erlernen ‚neutraler’, also weder belohnter noch sanktionierter, Verhaltensweisen beeinflusst. Die differentiellen Effekte in Go- versus Nogo- Aufgabe wurden als Hinweis darauf verstanden, dass hohe Spiegel (in erster Linie innerhalb des dopaminergen mesokortikalen Systems) in pro-exekutiven Zusammenhängen (Go-Aufgabe) ‚habituelles’ Verhalten verstärken, während sie ─ entsprechend Ergebnissen aus dem Bereich des Belohnungslernens ─ implizite Lernleistungen eher abschwächen, sofern eine inhibitorische Leistung zu erbringen ist (Nogo-Bedingung). Aus klinischer Sicht ist diese Interpretation vor allem hinsichtlich verstärkter Passivität von Parkinsonpatienten von modellhaftem Interesse. Entsprechenden Verhaltensweisen könnten demnach ─ nebst Krankheits-inhärenten ─ auch erlernte Faktoren zugrunde liegen, da dopaminerge Medikation in allen selektiven Handlungszusammenhängen (in denen auf nur einen aus vielen ‚neutralen’ Reizen zu reagieren bzw. zu handeln ist) das inaktive Grundverhalten verstärken würde.Several studies investigating the effect of Levodopa on reward-based learning in Patients with Parkinson’s disease (PD) showed a Levodopa-dependent reinforcement of behaviors resulting in positive consequences for the individual. Whether an impairment of reward - independent implicit learning in PD is linked to dopaminergic medication or to the disease itself remains uncertain. In This study we analyzed the performance of 16 PD patients on and off Levodopa monotherapy and a healthy control group of 14 volunteers in two implicit learning tasks. In both tasks, four different stimuli were presented on a computer screen in pseudorandmized order. One of the stimuli was marked as a Target - Stimulus. In the first task, called the “Go” task, participants were instructed to perform a button press only whenever a Target stimulus appeared. On the appearance of the other three stimuli the button press had to be withheld. In the second task, called the “Nogo” task the button press had to be withheld on the appearance of the target stimulus, whereas it had to be performed after every non-target stimulus. During a set of 120 stimuli, called conditioning – sequence, the target was always preceded by the same non- target, called precue. Thereafter, a set of 40 stimuli, called deconditioning sequence, without precue-target coupling followed. The overall number of conditioning - deconditioning blocks was 5, so one task consisted of 800 stimuli. Our results showed that, once off levodopa, Patients did not perform significantly different than the participants in the control group. However, on levodopa patients made significantly more omission - mistakes in the deconditioning – sequence of the Go-task and significantly less commission – mistakes in the Nogo task than participants in the control group. These results indicate that the substitution of Levodopa in PD influences implicated learning in a way that promotes passive behavior under pro-executive conditions

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

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

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

Errors in the NoGo version of the task.

<p>In the NoGo version of the task, erroneous reactions to target signals were executed responses (commission errors). The average rate of target commission errors 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 commission errors during deconditioning compared to any of the conditioning blocks in healthy subjects and patients with Parkinson's disease off levodopa (indicated by asterisks), whereas in patients on levodopa this effect could not be detected.</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