Rae, Charlotte L, Nombela, Cristina, Vázquez Rodriguez, Patricia, Ye, Zheng, Hughes, Laura E, Jones, P Simon, Ham, Timothy, Rittman, Timothy, Coyle-Gilchrist, Ian, Regenthal, Ralf, Sahakian, Barbara J, Barker, Roger A, Robbins, Trevor and Rowe, James B (2016) Atomoxetine restores the response inhibition network in Parkinson’s disease. Brain, 139 (8). pp. 2235-2248. ISSN 0006-8950

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Abstract

Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect approximately ten percent 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 behavioral effect. In a randomized, double-blind placebo-controlled crossover study, nineteen patients with mild to moderate idiopathic Parkinson’s disease underwent functional MRI during a stop signal task, while on their usual dopaminergic therapy. Patients received 40mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioral 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 twenty Dynamic Causal Models of the response inhibition network, inverted to the functional-MRI 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 behavioral 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, whilst 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 frontostriatal structural connections. The individual differences in behavioral responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson’s disease.

Item Type:	Article
Keywords:	Parkinson's disease, atomoxetine, response inhibition, fMRI, diffusion MRI, stop signal task
Schools and Departments:	Brighton and Sussex Medical School > Neuroscience
Subjects:	Q Science > QZ Psychology R Medicine > RZ Other systems of medicine
Depositing User:	Charlotte Rae
Date Deposited:	16 May 2016 16:24
Last Modified:	23 Jul 2020 09:20
URI:	http://srodev.sussex.ac.uk/id/eprint/61044

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