The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson’s disease: support from functional MRI

Abstract

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson's disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson's disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson's disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson's disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities.

Levodopa/Carbidopa Intestinal Gel for Treatment of Advanced Parkinson’s Disease: An Update on the Effects of Cognitive Functions

“…Siepel et al [26] reported that reduction of striatal tracer binding at DAT-Scan imaging was associated with executive but not visual-spatial or memory dysfunctions in early PD patients. Pathophysiological, neuropathologic and neuroimaging studies confirmed the presence of cognitive alterations in PD patients devoid of cortical pathology [27]- [33]. These findings, therefore, suggest that the basal ganglia dysfunction driven by nigrostriatal dopamine depletion may produce cognitive symptoms per se.…”

Action Reprogramming in Parkinson's Disease: Response to Prediction Error Is Modulated by Levels of Dopamine

“…Recently, it has been suggested that the ventral striatum is important for the general learning of stimulus-response associations, whereas the dorsal striatum promotes integration of various influences on action selection (MacDonald et al, 2011). Because dopamine depletion is not uniform but more pronounced in the dorsal striatum compared with the ventral striatum in the early stages of PD (Bernheimer et al, 1973;Frey et al, 1996;Kwak et al, 2010), it may not be surprising that we specifically observed a deficit in trial-by-trial AR that was ameliorated by dopamine medication.…”

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).…”