Abstract
Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.
Highlights
Parkinson’s disease is a complex disorder, in which the cardinal features of bradykinesia, rigidity and tremor are often accompanied by cognitive changes, even at diagnosis (Nombela et al, 2014b; Yarnall et al, 2014)
We examined the change in connectivity values (ÁATOPLA) between Parkinson’s disease (PD)-placebo and PD-atomoxetine in the connectivity parameters from Bayesian Model Averaging of the four non-linear pre-supplementary motor area (preSMA) models
We found that atomoxetine can enhance the interaction between the preSMA and inferior frontal gyrus, two regions that act together to influence the subthalamic nucleus for successful response inhibition
Summary
Parkinson’s disease is a complex disorder, in which the cardinal features of bradykinesia, rigidity and tremor are often accompanied by cognitive changes, even at diagnosis (Nombela et al, 2014b; Yarnall et al, 2014). A dysexecutive syndrome is common, including impairment of response inhibition even in the absence of clinically severe impulse control disorders (Napier et al, 2014). Despite bradykinesia, Parkinson’s disease impairs performance on a stop-signal task (Obeso et al, 2011a; Nombela et al, 2014a; Ye et al, 2014). To restore inhibitory control in Parkinson’s disease, we drew on animal models that indicate a role for noradrenaline in regulating response inhibition and impulsivity (Eagle and Baunez, 2010; Bari et al, 2011; Bari and Robbins, 2013), notwithstanding the contributory role of fronto-striatal anatomical connections that are abnormal in Parkinson’s disease (Rae et al, 2012). The potential for the selective noradrenaline reuptake inhibitor (SNRI) atomoxetine to modulate response inhibition systems is suggested by recent studies in Parkinson’s disease (Kehagia et al, 2014; Ye et al, 2015, 2016; Borchert et al, 2016), attention deficit hyperactivity disorder (Chamberlain et al, 2007; Cubillo et al, 2014), and healthy subjects (Chamberlain et al, 2009)
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