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Substantia nigra/ventral tegmental reward prediction error disruption in psychosis

Molecular Psychiatry volume 13, pages 267–276 (2008)Cite this article

Abstract

While dopamine systems have been implicated in the pathophysiology of schizophrenia and psychosis for many years, how dopamine dysfunction generates psychotic symptoms remains unknown. Recent theoretical interest has been directed at relating the known role of midbrain dopamine neurons in reinforcement learning, motivational salience and prediction error to explain the abnormal mental experience of psychosis. However, this theoretical model has yet to be explored empirically. To examine a link between psychotic experience, reward learning and dysfunction of the dopaminergic midbrain and associated target regions, we asked a group of first episode psychosis patients suffering from active positive symptoms and a group of healthy control participants to perform an instrumental reward conditioning experiment. We characterized neural responses using functional magnetic resonance imaging. We observed that patients with psychosis exhibit abnormal physiological responses associated with reward prediction error in the dopaminergic midbrain, striatum and limbic system, and we demonstrated subtle abnormalities in the ability of psychosis patients to discriminate between motivationally salient and neutral stimuli. This study provides the first evidence linking abnormal mesolimbic activity, reward learning and psychosis.

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Acknowledgements

Graham Murray was supported by a Department of Health Research Capacity Development Award. Paul Fletcher is supported by the Wellcome Trust. The work was completed within the University of Cambridge Behavioural and Clinical Neuroscience Institute, supported by a joint award from the Wellcome Trust and Medical Research Council. CAMEO received pump priming funding from the Stanley Medical Research Institute and GlaxoSmithKline, and now receives support from the UK National Health Service. We are grateful to staff from CAMEO and the Wolfson Brain Imaging Centre for their help with recruitment and data collection, and to the participants.

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Authors and Affiliations

  1. Department of Psychiatry, Brain Mapping Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK

    G K Murray, P R Corlett, A D Blackwell, G Honey, P B Jones, E T Bullmore & P C Fletcher

  2. CAMEO, Cambridgeshire and Peterborough Mental Health Partnership NHS Trust, Cambridge, UK

    G K Murray, P B Jones & E T Bullmore

  3. Behavioural and Clinical Neuroscience Institute, Cambridge, UK

    G K Murray, P R Corlett, L Clark, G Honey, E T Bullmore, T W Robbins & P C Fletcher

  4. Hôpital de la Salpêtrière, Pavillon Claude Bernard, 47 Bd de l’Hôpital, Paris, France

    M Pessiglione

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  1. G K Murray
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Correspondence to G K Murray.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Murray, G., Corlett, P., Clark, L. et al. Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry 13, 267–276 (2008). https://doi.org/10.1038/sj.mp.4002058

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