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Motor sequence learning deficits in idiopathic Parkinson’s disease are associated with increased substantia nigra activity

Elinor Tzvi, Richard Bey, Matthias Nitschke, Norbert Brüggemann, Joseph Classen, Thomas F. Münte, Ulrike M. Krämer, Jost-Julian Rumpf
doi: https://doi.org/10.1101/2020.11.19.386193
Elinor Tzvi
1Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
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  • For correspondence: elinor.tzvi-minker@medizin.uni-leipzig.de
Richard Bey
2Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Matthias Nitschke
2Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Norbert Brüggemann
1Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
4Institute of Neurogenetics, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Joseph Classen
1Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
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Thomas F. Münte
2Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
3Department of Psychology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
5Center of Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Ulrike M. Krämer
2Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
3Department of Psychology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
5Center of Brain, Behavior and Metabolism, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Jost-Julian Rumpf
1Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany
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Abstract

Previous studies have shown that persons with Parkinson’s disease (pwPD) share specific deficits in learning new sequential movements, but the neural substrates of this impairment remain unclear. In addition, the degree to which striatal dopaminergic denervation in PD affects the cortico-striato-cerebellar motor learning network remains unknown. We aimed to answer these questions using fMRI in 16 pwPD and 16 healthy age-matched control subjects while they performed an implicit motor sequence learning task. While learning was absent in both pwPD and controls assessed with reaction time differences between sequential and random trials, larger error-rates during the latter suggest that at least some of the complex sequence was encoded. Moreover, we found that while healthy controls could improve general task performance indexed by decreased reaction times across both sequence and random blocks, pwPD could not, suggesting disease-specific deficits in learning of stimulus-response associations. Using fMRI, we found that this effect in pwPD was correlated with decreased activity in the hippocampus over time. Importantly, activity in the substantia nigra (SN) and adjacent bilateral midbrain was specifically increased during sequence learning in pwPD compared to healthy controls, and significantly correlated with sequence-specific learning deficits. As increased SN activity was also associated (on trend) with higher doses of dopaminergic medication as well as disease duration, the results suggest that learning deficits in PD are associated with disease progression, indexing an increased drive to recruit dopaminergic neurons in the SN, however unsuccessfully. Finally, we found no differences between pwPD and controls in task modulation of the cortico-striato-cerebellar network. Notably, in both groups Bayesian model selection revealed cortico-cerebellar connections modulated by the task, suggesting that despite behavioral and activation differences, the same cortico-cerebellar circuitry is recruited for implementing the motor task.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    DCM
    dynamic causal modelling
    fMRI
    functional magnetic resonance imaging
    LED
    levodopa equivalent dose
    MSL
    motor sequence learning
    pwPD
    persons with Parkinson’s disease
    RT
    reaction times
    RND
    random
    SEQ
    sequence
    SN
    substantia nigra;
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    Posted November 20, 2020.
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    Motor sequence learning deficits in idiopathic Parkinson’s disease are associated with increased substantia nigra activity
    Elinor Tzvi, Richard Bey, Matthias Nitschke, Norbert Brüggemann, Joseph Classen, Thomas F. Münte, Ulrike M. Krämer, Jost-Julian Rumpf
    bioRxiv 2020.11.19.386193; doi: https://doi.org/10.1101/2020.11.19.386193
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    Motor sequence learning deficits in idiopathic Parkinson’s disease are associated with increased substantia nigra activity
    Elinor Tzvi, Richard Bey, Matthias Nitschke, Norbert Brüggemann, Joseph Classen, Thomas F. Münte, Ulrike M. Krämer, Jost-Julian Rumpf
    bioRxiv 2020.11.19.386193; doi: https://doi.org/10.1101/2020.11.19.386193

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