title: Atomoxetine restores the response inhibition network in Parkinson's disease.
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.
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rae
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nombela
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Patricia Vázquez
authors.initials: PV
authors.lastname: Rodríguez
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ye
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hughes
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: P Simon
authors.initials: PS
authors.lastname: Jones
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ham
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Coyle-Gilchrist
authors.affiliation: 3 Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, 04107, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.affiliation: 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK 5 Department of Psychiatry, University of Cambridge, CB2 0SZ, Cambridge, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK 6 Department of Experimental Psychology, University of Cambridge, CB2 3EB, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK 4 Behavioural and Clinical Neuroscience Institute, Cambridge, CB2 3EB, UK james.rowe@mrc-cbu.cam.ac.uk.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000368:Aged; D000069445:Atomoxetine Hydrochloride / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects; D015259:Dopamine Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D056344:Executive Function / Q000187:drug effects*; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000187:drug effects; D017063:Outcome Assessment, Health Care; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000188:drug therapy; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects; D012720:Severity of Illness Index
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D000069445:Atomoxetine Hydrochloride
keywords: Parkinson’s disease; atomoxetine; effective connectivity; response inhibition; stop-signal task