Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

Abstract

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

Keywords: Ataxia; Cerebellum; Circuits; DYT1; Dystonia; Networks.

Fig. 1

The role of animal models in exploring the pathogenesis and treatment of human disorders. a An experimental question about the human disorder can be explored in animal models. The relevance of the result from the animal model must ultimately be confirmed in humans. b In some cases, an experimental question about a human disorder can be explored in a simple animal model, such as a rodent. Results from the simple model can be explored further in non-human primates before confirming in humans

Fig. 2

Cerebellar connections with the basal ganglia. Schematic representation of the anatomical connections between the cerebellum and basal ganglia in non-human primates. Based on [34] and [36]. DN dentate nucleus, GPe external segment of the globus pallidus, GPi internal segment of the globus pallidus, PN pons, STN subthalamic nucleus

Fig. 3

Schematic of the proposed relationship between locomotor disability and irregularity of cerebellar output in mouse models. A proposed relationship between locomotor disability and irregularity of cerebellar output in mouse models described as having ataxia and/or dystonia. Here, locomotor disability is quantified based on a previously published dyskinesia scale that incorporates symptoms consistent with ataxia and dystonia. As the severity on the dyskinesia scale increases, the motor phenotype transitions from ataxia to dystonia. Irregularity of cerebellar output can be quantified as the coefficient of variation of the interspike intervals (CV ISI) recorded from deep cerebellar nuclei (DCN) neurons. This value takes into account both the standard deviation of the interspike intervals and the average firing rate of the cell. Under normal conditions, the dyskinesia score is low as is the CV ISI for DCN cells (black dot). We propose that there may be a monotonic relationship between disability and irregular cerebellar output such that as cerebellar output becomes more erratic, the disability of the animal increases (gray line). In this scenario, mice exhibiting only mildly irregular DCN output would have symptoms consistent with ataxia (red oval) while mice with more erratic bursting activity would have symptoms more consistent with dystonia (blue oval)