Pathophysiology of Dystonia: Models and Mechanisms
Dystonia has generally been considered a basal ganglia disorder. Increasing evidence, however, suggests a more system-wide disruption of brain circuitry involving cerebellar and brainstem pathophysiology reflected in altered firing patterns, synchronized
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Claudia M. Hendrix and Jerrold L. Vitek
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Introduction
Dystonia is a movement disorder characterized by sustained muscle contractions leading to twisting, repetitive movements, and abnormal postures [1]. The diagnosis and treatment of dystonia is complicated by the intricacy of etiology, therapeutic responsiveness, and clinical manifestation of the disease. This raises the question of whether the underlying pathophysiology of dystonia can be linked to the clinical manifestation and therapeutic responsiveness of the disease. It also brings into question whether there is a unifying model that can underlie all forms of dystonia or whether dystonia is a symptom that may manifest from one of a number of physiological changes in multiple circuits or locations across the peripheral and central nervous system. Most hypotheses regarding the pathophysiology of dystonia emphasize alterations in the basal ganglia thalamocortical (BGTC) motor circuit. Indeed this pathway is largely implicated in the pathophysiology of both hypokinetic (e.g., Parkinson’s disease, PD) and hyperkinetic (e.g., dystonia, drug-induced dyskinesia, and hemiballismus) movement disorders [2, 3]. Current and emerging hypotheses characterizing the role of the basal ganglia (BG) in motor control are central to our understanding of BG involvement in movement disorders such as dystonia. This chapter will review BG function and its role within the BGTC motor circuit followed by a discussion of the potential mechanisms underlying the pathophysiology of dystonia and related conditions. These mechanisms are based on observed changes in physiological properties of neurons within key nodal structures of the BGTC circuit recorded from patients with and animal models of dystonia. Pathophysiological properties of dystonia include changes in neuronal discharge C.M. Hendrix • J.L. Vitek (*) Department of Neurology, University of Minnesota, 2001 6th Street SE, Minneapolis, MN 55455, USA e-mail: [email protected] © Springer-Verlag Wien 2015 P. Kanovsky et al. (eds.), Dystonia and Dystonic Syndromes, DOI 10.1007/978-3-7091-1516-9_13
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C.M. Hendrix and J.L. Vitek
rates and patterns as well as changes in receptive field properties of neurons and plasticity within the network. Mechanisms underlying the pathophysiology of dystonia are discussed within the context of normal function but also within the context of other seemingly different but related hypokinetic disorders such as PD. Networklevel properties, including parallel cerebellar (CB) motor circuits and linking pathways, will also be addressed. When pertinent, we also discuss potential contributions of the knowledge obtained from observed pathophysiology in dystonia to the development of rational-based DBS therapies. Finally, we propose a model of dystonia that accounts for the changes in physiological properties discussed, including change in mean discharge rates, distorted receptive fields, and alterations in patterns of neuronal discharge observed in human and animal models of dystonia. Pathways t
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