Improving response inhibition in Parkinson's disease with atomoxetine.
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ABSTRACT: Background
Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm.Methods
This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging.Results
Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity.Conclusions
This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease.
SUBMITTER: Ye Z
PROVIDER: S-EPMC4384955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dopaminergic medications improve the motor symptoms of Parkinson's disease (PD), but their effect on response inhibition, a critical executive function, remains unclear. Previous studies primarily enrolled patients in more advanced stages of PD, when dopaminergic medication loses efficacy, and patients were typically on multiple medications. Here, we recruited 21 patients in early-stage PD on levodopa monotherapy and 37 age-matched controls to perform the stop-signal task during functional magnetic resonance imaging. In contrast to previous studies reporting null effects in more advanced PD, levodopa significantly improved response inhibition performance in our sample. No significant group differences were found in brain activations to pure motor inhibition or error processing (stop success vs. error trials). However, relative to controls, the PD group showed weaker striatal activations to salient events (infrequent vs. frequent events: stop vs. go trials) and fronto-striatal task-residual functional connectivity; both were restored with levodopa. Thus, levodopa appears to improve an important executive function in early-stage PD via enhanced salient signal processing, shedding new light on the role of dopaminergic signaling in response inhibition.
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