Improving Response Inhibition in Parkinson’s Disease with Atomoxetine

Abstract

BackgroundDopaminergic 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.MethodsThis 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.ResultsPatients 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.ConclusionsThis 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.

The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway Connectivity

“…Events were modeled with a duration of 1 s from trial onset, and convolved with the canonical hemodynamic response function. The design matrix was organized to separate driving inputs (e.g., for all trials) from the modulatory inputs (e.g., successful stopping) for DCM (Friston et al, 2003;Stephan et al, 2008), while accounting for all principal experimental variables across the six trial types (go-specified, go-select, stop-specified-correct, stop-specified-incorrect, stop-select-correct, and stop-select-incorrect) and nuisance terms (e.g., motion parameters). The first regressor represented the driving input of all trial types.…”

“…We used DCM (Friston et al, 2003) to determine the most likely network with interactions between inferior frontal gyrus, preSMA, and the STN during successful response inhibition on the stop-signal task. DCM estimates the effective connectivity between brain regions according to (1) the average connections between the regions (DCM.A matrix), (2) modulatory influences on connections arising through experimental manipulations (namely successfully stopping an action; DCM.B matrix), and (3) condition-specific inputs that drive network activity (namely engaging in a response inhibition task; DCM.C matrix).…”

“…Neuroimaging suggests that, in response to stimuli indicating that a change in action is needed, the inferior frontal gyrus expedites a stopping process, implemented by pathways from the preSMA to subcortical regions such as the STN (Duann et al, 2009;Sharp et al, 2010;Zandbelt et al, 2013). However, electrophysiological evidence suggests that activity in the preSMA can precede activity in the inferior frontal gyrus during response inhibition.…”

“…We have proposed that a fundamental property of the prefrontal cortex is that it can modulate connectivity between other brain regions, so as to reconfigure neural systems according to current task demands (Stephan et al, 2003;Passingham et al, 2013). This raises the hypothesis that to successfully inhibit a response, the inferior frontal gyrus or preSMA influence communication through subcortical pathways to the STN.…”

“…Healthy normal subjects underwent functional magnetic resonance imaging (fMRI) as they performed a manual stop-signal task (Logan et al, 1984). Using dynamic causal modeling (DCM; Friston et al, 2003) to estimate effective connectivity, we specified 20 generative models for the fMRI data that represented alternative hypotheses of the causal interactions between the inferior frontal gyrus, preSMA, and STN. By comparing the models' evidences, we identified the most likely model of prefrontal-subcortical interactions for response inhibition.…”