title: Improving response inhibition in Parkinson's disease with atomoxetine.
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.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ellemarije
authors.initials: E
authors.lastname: Altena
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nombela
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Cognition Ltd, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute , University of Cambridge, Cambridge, United Kingdom.
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Housden
authors.affiliation: Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Maxwell
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom.
authors.forename: Chelan
authors.initials: C
authors.lastname: Huddleston
authors.affiliation: Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rae
authors.affiliation: Division of Clinical Pharmacology, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.affiliation: Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Sahakian
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, United Kingdom; Behavioural and Clinical Neuroscience Institute, Cambridge, United Kingdom. Electronic address: James.Rowe@mrc-cbu.cam.ac.uk.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000368:Aged; D000369:Aged, 80 and over; D000069445:Atomoxetine Hydrochloride / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002755:Choice Behavior / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007266:Inhibition, Psychological; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000098:blood supply / Q000196:embryology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy; D011930:Reaction Time / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D010100:Oxygen
keywords: Atomoxetine; Impulsivity; Noradrenaline; Parkinson’s disease; Response inhibition; SSRT