Dystonia as a network disorder: what is the role of the cerebellum?

Abstract

The dystonias are a group of disorders defined by sustained or intermittent muscle contractions that result in involuntary posturing or repetitive movements. There are many different clinical manifestations and causes. Although they traditionally have been ascribed to dysfunction of the basal ganglia, recent evidence has suggested dysfunction may originate from other regions, particularly the cerebellum. This recent evidence has led to an emerging view that dystonia is a network disorder that involves multiple brain regions. The new network model for the pathogenesis of dystonia has raised many questions, particularly regarding the role of the cerebellum. For example, if dystonia may arise from cerebellar dysfunction, then why are there no cerebellar signs in dystonia? Why are focal cerebellar lesions or degenerative cerebellar disorders more commonly associated with ataxia rather than dystonia? Why is dystonia more commonly associated with basal ganglia lesions rather than cerebellar lesions? Can answers obtained from animals be extrapolated to humans? Is there any evidence that the cerebellum is not involved? Finally, what is the practical value of this new model of pathogenesis for the neuroscientist and clinician? This article explores potential answers to these questions.

Keywords: PET; SCAs; cerebellum; dystonia; network model; positron emission tomography; spinocerebellar ataxias.

Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1

Conceptual model for accommodating differences and similarities among the many different types of dystonia. The basic concept for pathogenesis involves a series of events at the molecular, cellular, anatomic, and/or systems levels (A). In dystonia, pathological changes associated with an array of initial insults may converge in shared downstream pathways to produce the final syndrome. Some may converge at the molecular or biochemical levels, for example by affecting the same neurotransmitter system (B). Others may converge at the cellular level, by affecting the same type of cell to cause dystonia (C). Still others may converge at higher biological levels, such as physiological or anatomical pathways. Presumably, of these pathways converge at some final common pathway that produced excessive involuntary muscle contractions common to all dystonias. However this is a conceptual model only, and it remains feasible that there are multiple entirely independent pathways that produce a similar final phenotype.

Figure 2

Different consequences of cerebellar lesions. Lesions of the cerebellum may cause different phenotypes depending on the nature of the lesion and its consequences. Normal cerebellar structure and output from the cerebellum result in normal patterns of movements (A). Decreased cerebellar output due to cerebellar atrophy (B) or stroke (C) may cause ataxia. In contrast, irritative lesions causing distorted cerebellar output (represented in red) may lead to dystonia (D).

Figure 3

The network model for dystonia. Normal movements are known to require combined action of distinct motor systems including the motor cortex, basal ganglia, cerebellum, and brainstem (A). Dystonia may arise from dysfunction of one, or another node in the network (B). Dystonia may alternatively require abnormal communication between nodes (C), or dysfunction of both nodes as proposed by the two-hit hypothesis (D). In the diagram above, dysfunction in any part of the network is represented in red.

Figure 4

Contributions of human and animal studies. Both human and animal studies are required to provide a complete view of the pathogenesis of dystonia. Clinical observations and results from human studies can be used to guide experimental questions and hypotheses when designing animal studies (A and B). On the other hand, findings from animal studies can be applied in human research to validate or refute conceptual models as well as to aid in the development of more targeted interventions (A and B). To avoid potential problems related to cross-species translation of results, we propose an iterative approach, in which answers to experimental questions obtained from simple models are verified in more advanced animal models, and subsequently validated in human studies (B). For example, results from rodents or fruit fly studies can be verified first in nonhuman primates before validation in humans. Similarly, findings from cell culture models can be tested in rodents before application to human studies.