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Noradrenergic deficits contribute to apathy in Parkinson's disease through the precision of expected outcomes.

Published version
Peer-reviewed

Type

Article

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Abstract

Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson's disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson's disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson's disease, subject to stratification according to locus coeruleus integrity. More broadly, these results reconcile emerging predictive processing accounts of the role of noradrenaline in goal-directed behaviour with the clinical symptom of apathy and its potential pharmacological treatment.

Description

Funder: Fitzwilliam College scholarship


Funder: Association of British Neurologists, Patrick Berthoud Charitable Trust


Funder: Cambridge Trust Vice-Chancellor's Award Award for Medical Sciences

Keywords

Apathy, Atomoxetine Hydrochloride, Cross-Over Studies, Humans, Norepinephrine, Parkinson Disease

Journal Title

PLoS Comput Biol

Conference Name

Journal ISSN

1553-734X
1553-7358

Volume Title

18

Publisher

Public Library of Science (PLoS)
Sponsorship
British Academy (pf160048)
Medical Research Council (MR/P01271X/1)
Medical Research Council (MR/R007446/1)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Wellcome Trust (220258/Z/20/Z)