title: Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.
abstract: Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Borchert
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|National Research Council, Institute of Bioimaging and Molecular Physiology, Catanzaro, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Passamonti
authors.affiliation: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Saber
authors.initials: S
authors.lastname: Sami
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Jones
authors.affiliation: Systems and Automatic Control Engineering, Technical University of Cartagena, Cartagena, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nombela
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Vázquez Rodríguez
authors.affiliation: Division of Anaesthesia, University of Cambridge, Cambridge, UK.
authors.forename: Deniz
authors.initials: D
authors.lastname: Vatansever
authors.affiliation: Sackler Centre for Consciousness Science, University of Sussex, Brighton, UK.|Department of Psychiatry, Brighton and Sussex Medical School, Brighton, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Rae
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hughes
authors.affiliation: University of Cambridge Behavioural and Clinical Neuroscience Institute, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.|MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.|University of Cambridge Behavioural and Clinical Neuroscience Institute, Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage*; D000368:Aged; D000069445:Atomoxetine Hydrochloride / Q000008:administration & dosage*; D001931:Brain Mapping; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D010300:Parkinson Disease / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride
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