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Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.


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Authors

Borchert, Robin J 
Ye, Zheng 
Sami, Saber 

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.

Description

Keywords

Adrenergic Uptake Inhibitors, Aged, Atomoxetine Hydrochloride, Brain Mapping, Cross-Over Studies, Double-Blind Method, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neural Pathways, Parkinson Disease, Prefrontal Cortex

Journal Title

Neuropsychopharmacology

Conference Name

Journal ISSN

0893-133X
1740-634X

Volume Title

41

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G0001354)
Medical Research Council (G1000183)
Parkinson's UK (K-1702)
James S McDonnell Foundation (220020289)
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MC_U105597119)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Medical Research Council (G1100464)
Medical Research Council (MR/M009041/1)
Wellcome Trust (093875/Z/10/Z)
Medical Research Council (MR/M024873/1)
Medical Research Council (G1100464/1)
This work was funded by the Wellcome trust (103838), Parkinson’s UK, National Institute for Health Research’s Cambridge Biomedical Research Centre and the Medical Research Council (MC_US_A060_0016 and RG62761) and the James F McDonnell Foundation (21st century science initiative on Understanding Human Cognition). The BCNI is supported by a joint award from the Wellcome Trust and Medical Research Council.