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

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. Author summary: Apathy is a common and harmful consequence of many neuropsychiatric diseases. Its underlying causes are not fully understood, which prevents the development of new treatments. We approach the problem in a new way, modelling human behaviour in terms of the continuously updated interaction between sensory information and brain-based predictions or 'priors' about the consequences of our actions. We have previously shown that apathy is related to a loss of precision of these 'priors'. We proposed that the precision is controlled by noradrenaline (like adrenaline, but made in the brain). We tested whether the noradrenaline-enhancing drug called atomoxetine can restore the priors' precision in apathetic people. We enrolled participants with Parkinson's disease, which is associated with both apathy and noradrenaline loss. We used ultra-high field MRI to measure individual differences in the integrity of specialist region called the locus coeruleus–the brain's source of noradrenaline. We found that the effect of treatment with atomoxetine on prior precision depended on locus coeruleus integrity: Participants with a degenerated locus coeruleus had a more positive change in prior precision. Our results highlight how individual differences in neuroanatomy can predict the potential benefit of noradrenaline treatments in people suffering from apathy. [ABSTRACT FROM AUTHOR]