Physiologic Changes Associated with Cerebellar Dystonia

Abstract

Dystonia is a neurologic disorder characterized by sustained involuntary muscle contractions. Lesions responsible for unilateral secondary dystonia are confined to the putamen, caudate, globus pallidus and thalamus. Dysfunction of these structures is suspected to play a role in both primary and secondary dystonia. Recent evidence has suggested that the cerebellum may play a role in the pathophysiology of dystonia. The role of the cerebellum in ataxia, a disorder of motor incoordination is well established. How may the cerebellum contribute to two apparently very different movement disorders? This review will discuss the idea of whether in some cases, ataxia and dystonia lie in the same clinical spectrum, and whether graded perturbations in cerebellar function may explain a similar causative role for the cerebellum in these two different motor disorders. The review also proposes a model for cerebellar dystonia based on the available animal models of this disorder.

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

“…In fact, studies in humans based on novel insights from these simpler models have already begun to emerge. The majority of these studies so far appear to confirm the concept originating from animal work that dystonia is a motor network disorder that is not due exclusively to defects in the basal ganglia [4, 13–17]. …”

Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration

“…For example, during elbow flexion, contraction of the biceps is accompanied by relaxation of the triceps. Loss of this process could be at core of ataxia and dystonia, since both diseases exhibit forms of prolongation of agonist activity and mistimed antagonist activity (Shakkottai, 2014). Given the ataxia and dystonia observed in Car8 wdl (Jiao et al, 2005), our data showing the convergence of VGLUT2-expressing spinocerebellar and VGLUT1-expressing cuneocerebellar projection zones might provide the anatomical substrate for the muscle incoordination (Fig.…”

Cerebellar synaptogenesis is compromised in mouse models of DYT1 dystonia

“…To date, most of the studies conducted in DYT1 mouse models has been performed in adult age, revealing important neuronal dysfunctions in specific brain areas as key factors in its pathophysiology (Quartarone and Hallett, 2013;Quartarone and Pisani, 2011;Shakkottai, 2014;Wilson and Hess, 2013). However, most of the DYT1 mouse models show, in adult age, modest anatomical and phenotypic abnormalities, making difficult to link the molecular and cellular consequence of torsinA dysfunction to dystonic movements.…”

“…However, both clinical and experimental evidence recently suggest that the cerebellum may play a role also in some forms of dystonia (Prudente et al, 2014;Shakkottai, 2014), a different movement disorder characterized by sustained involuntary muscle contractions, causing twisting movements and abnormal postures (Fahn, 1988;Breakefield et al, 2008). Most forms of "isolated" generalized dystonia lack a degenerative neuropathology and have been categorized as "neurofunctional" disorders (Breakefield et al, 2008).…”

“…Most forms of "isolated" generalized dystonia lack a degenerative neuropathology and have been categorized as "neurofunctional" disorders (Breakefield et al, 2008). These forms are thought to originate from subtle abnormalities of neural connectivity, plasticity and/or synaptic regulation (Breakefield et al, 2008;Quartarone and Pisani, A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 2011) affecting two major motor circuits, the basal ganglia and the cerebellum (Prudente et al, 2014;Shakkottai, 2014;Wilson and Hess, 2013).…”