title: Pharmacological Fingerprints of Contextual Uncertainty.
abstract: Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses.
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Louise
authors.identifier: http://orcid.org/0000-0002-7885-591X
authors.initials: L
authors.lastname: Marshall
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.|Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London, United Kingdom.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mathys
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom.|Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Dortmund, Germany.
authors.forename: Diane
authors.initials: D
authors.lastname: Ruge
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom.|Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Archy O
authors.identifier: http://orcid.org/0000-0002-3460-7172
authors.initials: AO
authors.lastname: de Berker
authors.affiliation: Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0003-3476-1839
authors.initials: P
authors.lastname: Dayan
authors.affiliation: Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, United Kingdom.|Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland.|Max Planck Institute for Metabolism Research, Cologne, Germany.
authors.forename: Klaas E
authors.initials: KE
authors.lastname: Stephan
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Sven
authors.identifier: http://orcid.org/0000-0002-6867-9545
authors.initials: S
authors.lastname: Bestmann
mesh_terms: D000328:Adult; D015306:Biogenic Monoamines / Q000494:pharmacology; D001921:Brain / Q000502:physiology; D006801:Humans; D016013:Likelihood Functions; D008962:Models, Theoretical; D035501:Uncertainty
chemical_list: D015306:Biogenic Monoamines