The cerebellum plays an important role in motor learning as part of a cortico-striato-cerebellar network. Patients with cerebellar degeneration typically show impairments in different aspects of motor learning, including implicit motor sequence learning. How cerebellar dysfunction affects interactions in this cortico-striato-cerebellar network is poorly understood. The present study investigated the effect of cerebellar degeneration on activity in causal interactions between cortical and subcortical regions involved in motor learning. We found that cerebellar patients showed learning-related increase in activity in two regions known to be involved in learning and memory, namely parahippocampal cortex and cerebellar Crus I. The cerebellar activity increase was observed in non-learners of the patient group whereas learners showed an activity decrease. Dynamic causal modeling analysis revealed that modulation of M1 to cerebellum and putamen to cerebellum connections were significantly more negative for sequence compared to random blocks in controls, replicating our previous results, and did not differ in patients. In addition, a separate analysis revealed a similar effect in connections from SMA and PMC to M1 bilaterally. Again, neural network changes were associated with learning performance in patients. Specifically, learners showed a negative modulation from right SMA to right M1 that was similar to controls, whereas this effect was close to zero in non-learners. These results highlight the role of cerebellum in motor learning and demonstrate the functional role cerebellum plays as part of the cortico-striato-cerebellar network.

Acknowledgements:We would like to thank Susanne Schellbach and Christian Erdmann for assisting with data acquisition, Steffan Frässle for helpful advice on dynamic causal modelling, and Matthias Liebrand for helpful discussions on this work. This study was supported by internal funding of the University of Lübeck. UMK and TFM are supported by the DFG.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/136820 doi: bioRxiv preprint first posted online May. 11, 2017; AbstractThe cerebellum plays an important role in motor learning as part of a cortico-striato-cerebellar network. Patients with cerebellar degeneration typically show impairments in different aspects of motor learning, including implicit motor sequence learning. How cerebellar dysfunction affects interactions in this cortico-striato-cerebellar network is poorly understood. The present study investigated the effect of cerebellar degeneration on activity in causal interactions between cortical and subcortical regions involved in motor learning. We found that cerebellar patients showed learning-related increase in activity in two regions known to be involved in learning and memory, namely parahippocampal cortex and cerebellar Crus I. The cerebellar activity increase was observed in non-learners of the patient group whereas learners showed an activity decrease. Dynamic causal modelling analysis revealed that modulation of M1 to cerebellum and putamen to cerebellum connections were significantly more negative for sequence compared to random blocks in controls, replicating our previous results, and did not differ in patients. In addition, a separate analysis revealed a similar effect in connections from SMA and PMC to M1 bilaterally. Again, neural network changes were associated with learning performance in patients. Specifically, learners showed a negative modulation from right SMA to right M1 that was similar to controls, whereas this effect was close to zero in non-learners. These results highlight the role of cerebellum in motor learning and demonstrate the functional role cerebellum plays as part of the cortico-striato-cerebellar network.peer-reviewed)

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-thalamo-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, there were no differences between pwPD and controls in task modulation of the cortico-striato-thalamo-cerebellar network. However, a restricted nigral-striatal model showed that negative modulation of SN to putamen connection was larger in pwPD compared to controls during random trials, while no differences between the groups were found during sequence learning. We speculate that learning-specific SN recruitment leads to a relative increase in SN- > putamen connectivity, which returns to a pathological reduced state when no learning takes place.

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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.