l-dopa impairs learning, but spares generalization, in Parkinson's disease

Abstract

In this study we examined the effect of dopaminergic modulation on learning and memory.Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.

The role of the orbitofrontal cortex in human discrimination learning

“…Untransformed values are presented in tables and figures. In addition, following Shohamy et al (2006) and Myers et al (2002), we also analyzed whether the subject passed criterion or not on the learn and relearn phases: this was done with a Fisher's exact test on each phase separately.…”

“…Parkinson's disease, PD) were shown previously to be dependent on dopamine medication: medicated but not unmedicated PD patients were impaired on the task Shohamy et al, 2006). It has been suggested that dopaminergic medication may 'overdose' cognitive functions dependent upon ventral striatal-orbitofrontal circuitry (Cools et al, 2001;Cools, Barker, Sahakian, & Robbins, 2003 2000), which are relatively intact in the early stages of PD (Kish, Shannak, & Hornykiewicz, 1988).…”

“…We used two learning tasks that have established sensitivity to striatal pathology: the WPT and an eight-pair concurrent discrimination learning task ('Choose': Johnson, Schmitz, Asthana, Gluck, & Myers, in press;Myers et al, 2002;Shohamy, Myers, Geghman, Sage, & Gluck, 2006). When seen in the light of fronto-striatal connectivity (Alexander, DeLong, & Strick, 1986), the similar behavioural profile of patients with frontal and striatal pathologies (e.g.…”

“…Importantly, the Choose impairment reported by Shohamy et al (2006) in PD patients was dependent on the medication status of the patients: PD patients tested following taking their dopaminergic medication (i.e. l-dopa) were impaired while unmedicated patients were not.…”

The Effect of Dopamine Agonists on Adaptive and Aberrant Salience in Parkinson's Disease

“…Specifically, there is a more pronounced reduction of dopamine in the dorsal than in the ventral striatum (Kish et al, 1988). Therefore, therapies that restore dopamine level in the dorsal striatum result in dopamine 'overdose' in the ventral striatum, which may lead to impaired performance on some cognitive tasks (Gotham et al, 1988;Cools et al, 2001Cools et al, , 2003Shohamy et al, 2006;Jahanshahi et al, 2010;MacDonald et al, 2011) and in some cases psychotic symptoms, including hallucinations and delusions (McGowan et al, 2004;Mehler-Wex et al, 2006;Maia and Frank, 2011). At the same time, there is evidence that dopaminergic therapy enhances learning from reward signals and decreases learning from punishment signals in PD (Frank et al, 2004(Frank et al, , 2007Cools et al, 2006;Bódi et al, 2009;Graef et al, 2010;Kobayakawa et al, 2010), and the ventral striatum has a crucial role in reinforcement learning (Yin and Knowlton, 2006).…”