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:ObjectivesTo evaluate the effects of atomoxetine on complex attention and other neurocognitive domains in idiopathic Parkinson's disease (PD).MethodsInterventional trials reporting changes in complex attention and other neurocognitive functions (Diagnostic and Statistical Manual of Mental Disorders-5) following administration of atomoxetine for at least 8 weeks in adults with idiopathic PD were included. Effect sizes (Cohen's d), the standardized mean difference in the scores of each cognitive domain, were compared using a random-effects model (MetaXL version 5.3).ResultsThree studies were included in the final analysis. For a change in complex attention in PD with mild cognitive impairment (MCI), the estimated effect size was small and nonsignificant (0.16 (95% CI: -0.09, 0.42), n = 42). For changes in executive function, perceptual-motor function, language, social cognition, and learning and memory, the estimated effect sizes were small and medium, but nonsignificant. A deteriorative trend in executive function was observed after atomoxetine treatment in PD with MCI. For a change in global cognitive function in PD without MCI, the estimated effect size was large and significant.ConclusionIn idiopathic PD with MCI, atomoxetine does not improve complex attention. Also, a deteriorative trend in the executive function was noted.
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