The pathophysiological basis of dystonia

Department of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Nature Reviews Neuroscience (Impact Factor: 31.43). 04/2008; 9(3):222-34. DOI: 10.1038/nrn2337
Source: PubMed


Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.

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    • "Primary dystonia is characterized by involuntary co-contraction of agonist and antagonist muscles resulting in abnormal movements and postures (Bressman, 2004). The DYT1 mutation, a GAG deletion at the TOR1A locus on chromosome 9q, is the most common inherited form of the disorder (Breakefield et al., 2008). Imaging studies of resting state cerebral metabolism and pathway microstructure (Carbon et al., 2008; Niethammer et al., 2011; Lerner et al., 2013) have revealed consistent changes in the structure and function of sensorimotor networks in human and mouse carriers of this mutant gene. "
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    ABSTRACT: Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.
    No preview · Article · Sep 2015 · Brain
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    • "Dystonia is often attributed to abnormalities of the basal ganglia, however damage to the basal ganglia is not always present in children with dystonia (Sanger, 2003). Due to the common observation that symptoms of dystonia have a delayed onset relative to the causative brain injury, it has been suggested that dystonia arises as a result of functional changes in the basal ganglia secondary to overt structural changes due to injury in other brain regions (Breakefield et al., 2008). Others hypothesize that there is a network of brain regions, including the basal ganglia, cerebral cortex, cerebellum, thalamus, midbrain, and brainstem, within which abnormalities can be associated with the presence of dystonia (Neychev et al., 2011). "
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    ABSTRACT: Dystonia is a disabling motor disorder often without effective therapies. To better understand the genesis of dystonia after childhood stroke, we analyzed electroencephalographic (EEG) recordings in this population.Methods Resting spectral power of EEG signals over bilateral sensorimotor cortices (Powrest), resting inter-hemispheric sensorimotor coherence (Cohrest), and task-related changes in power (TRPow) and coherence (TRCoh) during wrist extension were analyzed in individuals with dystonia (age 20±3 years) and healthy volunteers (age 17±5 years).ResultsIpsilesional TRPow decrease was significantly lower in patients than controls during the more affected wrist task. Force deficits of the affected wrist correlated with reduced alpha TRPow decrease on the ipsilesional and not the contralesional hemisphere. Cohrest was significantly lower in patients than controls, and correlated with more severe dystonia and poorer hand function. Powrest and TRCoh were similar between groups.Conclusions The association between weakness and cortical activation during wrist extension highlights the importance of ipsilesional sensorimotor activation on function. Reduction of Cohrest in patients reflects a loss of inter-hemispheric connectivity that may result from structural changes and neuroplasticity, potentially contributing to the development of dystonia.SignificanceCortical and motor dysfunction are correlated in patients with childhood stroke and may in part explain the genesis of dystonia.
    Full-text · Article · Nov 2014 · Clinical Neurophysiology
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    • "Other adjunctive treatments are also often required. Dystonia, especially, can be difficult to manage in a number of disorders [72]. Symptomatic management aims to relieve abnormal postures, reduce discomfort, and improve function and range of movement, and thus requires the combined approach of pharmacotherapies with physical therapy and orthotic management to prevent contractures. "
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    ABSTRACT: Childhood neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the monoamine neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, neurotransmitter disorders are frequently misdiagnosed. The diagnosis of neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for monoamine neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase monoamine substrate availability, boost enzyme co-factor levels, reduce monoamine breakdown, and replace depleted levels of monoamines with pharmacological analogs as clinically indicated. Most monoamine neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa's syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood monoamine neurotransmitter disorders.
    Full-text · Article · Jul 2014 · Paediatric Drugs
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