Abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions in cervical dystonia

T Popa,S Meunier,A Kishore,P James,E Roze,A Richard,S Krishan,M Russo,S Pradeep,C Hubsch

doi:10.1038/s41598-018-20510-1

Abstract

The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway. Previous TMS studies showed that cerebellar cortex excitation can block the increase in M1 excitability induced by a paired-associative stimulation (PAS), while cerebellar cortex inhibition would enhance it. Since cerebellum is known to be affected in many types of dystonia, this bidirectional modulation was assessed in 22 patients with cervical dystonia and 23 healthy controls. Exactly opposite effects were found in patients: cerebellar inhibition suppressed the effects of PAS, while cerebellar excitation enhanced them. Another experiment comparing healthy subjects maintaining the head straight with subjects maintaining the head turned as the patients found that turning the head is enough to invert the cerebellar modulation of M1 plasticity. A third control experiment in healthy subjects showed that proprioceptive perturbation of the sterno-cleido-mastoid muscle had the same effects as turning the head. We discuss these finding in the light of the recent model of a mesencephalic head integrator. We also suggest that abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions of the integrator in cervical dystonia.

Highlights

The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway
When the subjects were divided in only two groups, cervical dystonia (CD) patients and controls (Fig. 1B), the ANOVA did not reveal any effect of individual factors (GROUP: CD and controls; INTERVENTION: ShamCB → paired-associative stimulation (PAS), continuous theta-burst stimulation over the right cerebellum (cTBSCB) → PAS, and intermittent theta-burst stimulation over the right cerebellum (iTBSCB) → PAS; TIME: T10, T20, T30), but one significant interaction
The cTBSCB enhanced the responsiveness to PAS in the group with the head in the midline, but decreased it to the same extent in the other two groups (Fig. 3), the one maintaining the head turned and the one with the head in the midline but receiving SCM vibration (GROUP: F2,15 = 4.4, P = 0.03, TIME: F2,30 = 2.8, P = 0.07; GROUP*TIME: F4,30 = 0.9, P = 0.5; post-hoc unpaired t-tests: head straight vs vibration P = 0.001, head straight vs head turned P < 0.0001, vibration vs head turned P = 0.78). These results demonstrate for the first time that proprioceptive feedback from the neck plays a crucial role in the way in which the cerebellum can influence the plasticity of the primary motor cortex

Summary

Introduction

The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway. When the dynamic relation between the cerebellum and M1 was explored either with double-pulses[12] or with two consecutive repetitive transcranial magnetic stimulations[13] in patients with writer’s cramp (one over the cerebellum followed by one over M1), no effective output was found from the cerebellum to M1 for the dystonic hand representation. This seemed to play a direct role in generating dystonic symptoms[13]. We reasoned that if the defective cerebellar modulation of M1 plasticity participates in the hand cramping in focal hand dystonia, the same modulation might be spared in cervical dystonia patients whose hands are normal

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Conclusion