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Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

Tom Gilbertson, View ORCID ProfileMark Humphries, J. Douglas Steele
doi: https://doi.org/10.1101/543678
Tom Gilbertson
1Department of Neurology, Ninewells Hospital & Medical School, DD2 4BF
4Division of Imaging Science and Technology, Medical School, University of Dundee, DD2 4BF
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  • For correspondence: tgilbertson@dundee.ac.uk
Mark Humphries
2Division of Neuroscience & Experimental Psychology, University of Manchester, M13 9PL
3School of Psychology, University of Nottingham, NG7 2RD
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J. Douglas Steele
4Division of Imaging Science and Technology, Medical School, University of Dundee, DD2 4BF
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Abstract

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico-striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico-striatal synaptic plasticity contributes to abnormal reward-learning behavior in patients with focal dystonia. Forty patients and forty controls performed a reward-gain and loss-avoidance reversal learning task. Participant’s behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico-striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesised receptor specific abnormalities of cortico-striatal long term potentiation (LTP) and Long Term Depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post-reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient’s motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient’s behavior, suggesting excessive D2 cortico-striatal synaptic depotentiation could underpin biased reward learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioural correlate of D2 specific abnormalities in cortico-striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward-learning behavior in these patients.

  • Abbreviations

    LTP
    Long term synaptic potentiation
    LTD
    Long term synaptic depression
    RPE
    Reward prediction error
    MNI
    Montreal Neurological Institute
    CTRL
    Control
    CD
    Cervical dystonia
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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    Posted February 08, 2019.
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    Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia
    Tom Gilbertson, Mark Humphries, J. Douglas Steele
    bioRxiv 543678; doi: https://doi.org/10.1101/543678
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    Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia
    Tom Gilbertson, Mark Humphries, J. Douglas Steele
    bioRxiv 543678; doi: https://doi.org/10.1101/543678

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