title: Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson's disease.
abstract: Apathy is a debilitating and under-recognized condition that has a significant impact in many neurodegenerative disorders. In Parkinson's disease, it is now known to contribute to worse outcomes and a reduced quality of life for patients and carers, adding to health costs and extending disease burden. However, despite its clinical importance, there remains limited understanding of mechanisms underlying apathy. Here we investigated if insensitivity to reward might be a contributory factor and examined how this relates to severity of clinical symptoms. To do this we created novel ocular measures that indexed motivation level using pupillary and saccadic response to monetary incentives, allowing reward sensitivity to be evaluated objectively. This approach was tested in 40 patients with Parkinson's disease, 31 elderly age-matched control participants and 20 young healthy volunteers. Thirty patients were examined ON and OFF their dopaminergic medication in two counterbalanced sessions, so that the effect of dopamine on reward sensitivity could be assessed. Pupillary dilation to increasing levels of monetary reward on offer provided quantifiable metrics of motivation in healthy subjects as well as patients. Moreover, pupillary reward sensitivity declined with age. In Parkinson's disease, reduced pupillary modulation by incentives was predictive of apathy severity, and independent of motor impairment and autonomic dysfunction as assessed using overnight heart rate variability measures. Reward sensitivity was further modulated by dopaminergic state, with blunted sensitivity when patients were OFF dopaminergic drugs, both in pupillary response and saccadic peak velocity response to reward. These findings suggest that reward insensitivity may be a contributory mechanism to apathy and provide potential new clinical measures for improved diagnosis and monitoring of apathy.media-1vid110.1093/brain/aww188_video_abstractaww188_video_abstract.
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 2 Department of Experimental Psychology, University of Oxford, Oxford, UK kinan.muhammed@ndcn.ox.ac.uk.
authors.forename: Kinan
authors.initials: K
authors.lastname: Muhammed
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 2 Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Manohar
authors.affiliation: 2 Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Ben Yehuda
authors.affiliation: 3 Department of Cognitive Science, Macquarie University, Sydney, Australia.
authors.forename: Trevor T-J
authors.initials: TT
authors.lastname: Chong
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: George
authors.initials: G
authors.lastname: Tofaris
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Lennox
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Marko
authors.initials: M
authors.lastname: Bogdanovic
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Hu
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 2 Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Masud
authors.initials: M
authors.lastname: Husain
mesh_terms: D000368:Aged; D057565:Apathy / Q000187:drug effects / Q000502:physiology*; D015331:Cohort Studies; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005133:Eye Movements / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000523:psychology; D010775:Photic Stimulation / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D012201:Reward
chemical_list: D015259:Dopamine Agents; D004298:Dopamine
keywords: Parkinson’s disease; apathy; drug treatment; neuropsychology; vision