ReviewThe functional neuroanatomy of dystonia
Introduction
Dystonia is defined as a syndrome of involuntary sustained or intermittent muscle contractions leading to twisting or repetitive movements or abnormal postures (Fahn, 1984, Fahn, 1988). The core problem involves over-contraction of the primary muscles normally used for a movement, along with over-flow contraction of nearby muscles that sometimes antagonize the primary muscles. The patterns and strengths of the muscles involved determine the character of the resulting abnormal movement. Very mild dystonias appear as slight exaggerations or distortions of otherwise normal movements. More obvious manifestations include movements that are overtly stiff, slow, twisting, or jerky. The most serious expressions involve unnatural postures or fixed deformities associated with significant disability.
Virtually any region of the body may be affected, and the region affected provides a convenient means for subgrouping (Fahn, 1988, Geyer and Bressman, 2006, Tarsy and Simon, 2006). Focal dystonias involve an isolated body region. Commonly recognized focal dystonias include the neck in cervical dystonia (torticollis), the upper face (blepharospasm), the larynx (spasmodic dysphonia), or a limb (writer's cramp). Segmental dystonias involve two or more contiguous body regions, such as the neck and one arm. Multifocal dystonias involve two or more non-contiguous regions, while generalized dystonias encompass a broad distribution.
The dystonias also can be grouped according to etiology, with both inherited and acquired forms (Bressman, 2003, deCarvalho Aguiar and Ozelius, 2002, Nemeth, 2002). Dystonia is associated with mutations in more than 30 different genes, is a feature of several neurodevelopmental or neurodegenerative disorders, and can arise from a vast array of acquired insults to the nervous system. Traditionally, etiological subgroups of dystonia have included primary dystonia, dystonia-plus syndromes, developmental or degenerative disorders, and acquired insults. Primary dystonias include disorders where dystonia is a relatively isolated neurological problem and there is no histopathological evidence for developmental or degenerative anomalies. Many primary dystonias are idiopathic, but some are due to known genetic defects. The dystonia-plus syndromes include dystonia with other neurological problems, again without significant histopathological correlates. In contrast, the developmental and degenerative syndromes include specific histopathological hallmarks. Acquired forms are defined by specific causes; some have histopathological correlates (e.g. stroke or traumatic brain injury), while others do not (e.g. drug-induced dystonias).
The current review addresses regions of the nervous system underlying the dystonias. Delineating the functional neuroanatomical substrates for dystonia is of fundamental importance for both clinical and basic research. Knowing the responsible brain regions is a pre-requisite for more precise studies of neuronal physiology and biochemistry, and for designing both medical and surgical treatment strategies. In keeping with currently used definitions of dystonia, this review focuses on dystonia as a syndrome of abnormal movements, not a specific disease entity. Although etiological heterogeneity raises the possibility that different dystonias may have different neuroanatomical substrates, the working premise is that some dystonias share common biological substrates (Defazio et al., 2007, Jinnah and Hess, 2008).
Section snippets
Historical perspective
Historically, delineating a new neurological disease as a distinct nosological entity required linking specific clinical features with consistent neuropathological changes. Hammond was among the first to describe pathology of the basal ganglia in an individual with athetosis (Hammond, 1890), a diagnosis that historically overlapped with dystonia (Morris et al., 2002, Salam-Adams and Adams, 1997, Twitchell, 1961). Hammond's report stimulated others to focus on the basal ganglia, but results were
Evidence for involvement of the basal ganglia
The evidence supporting a role for the basal ganglia in dystonia is strong; but it will be summarized here only briefly, since it has been reviewed many times by others (Berardelli et al., 1998, Breakefield et al., 2008, Hallett, 2006). As noted above, the role of the basal ganglia originated with studies showing neuropathological defects in the basal ganglia of individuals with various secondary forms of dystonia (Hedreen et al., 1988, McGeer and McGeer, 1995). These early studies later were
A reappraisal of the evidence
In this section the evidence supporting a role of for the basal ganglia in dystonia is critically reappraised and updated. The goal is not to refute the evidence supporting the involvement of the basal ganglia in dystonia, but to accommodate evidence implicating other brain regions. The evidence comes from a wide array of sources including neuropathology, neuroimaging, links with other disorders, neurophysiology, neurosurgery, and animal models. Because much of the evidence is indirect and
A revised model for the functional anatomy of dystonia
The accumulating evidence reviewed above renders traditional models that focus on basal ganglia circuits as the central cause for all forms of dystonia obsolete. It is becoming increasingly clear that many brain regions contribute to dystonia, including the cerebral cortex, cerebellum, thalamus, and midbrain/brainstem. It also is becoming increasingly clear that etiological heterogeneity among dystonias is important, as the relative importance of different brain regions seems to vary among
Conclusions
The localization of function and dysfunction in the nervous system is a core part of neuroscience and clinical neurology. Although the traditional view localizes dystonia to basal ganglia circuits, there is increasing recognition that this view is inadequate for accommodating a substantial portion of available clinical and experimental evidence. Unfortunately, there has been a tendency to dismiss experimental findings that do not fit the prevailing traditional view. Rather than dismiss
Acknowledgments
Supported in part by grants from the NIH Office of Rare Diseases Research and the National Institutes of Neurological Disorders & Stroke (NS033592, NS040470, NS967501).
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