The pathophysiological basis of dystonias

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.     

Paying the price at the pump: dystonia from mutations in a Na+/K+ -ATPase

Dystonia is a disorder of involuntary sustained muscle contraction, which usually affects a focal region of the body but may be generalized and results in twisting contorted movements or abnormal postures. Several clinical subtypes of dystonia have been delineated and many have a strong inherited basis. In this issue of Neuron, de Carvalho Aguiar and colleagues report the identification of missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) as a cause of rapid-onset dystonia-parkinsonism (RDP, DYT12).     

Hereditäre Dystonien

Dystonias are a clinically and causally heterogeneous group of movement disorders characterized by involuntary muscle contractions that lead to twisting, turning and repetitive movements that can be very painful. Isolated (primary) dystonia is classified clinically as a disease in which dystonia is the only neurological symptom (with or without tremor). Dystonia accompanied by other clinical symptoms (such as parkinsonism or myoclonus) is classified as combined dystonia (dystonia-plus). However, dystonia can be a symptom of any disease of the central nervous system that affects the motor system (e.g. neurodegenerative, ischemic, traumatic processes). During the last 20 years, the development of new molecular genetic technologies has led to the discovery of new genes underlying many dystonia subtypes and to a deeper understanding of the pathophysiology of dystonia. Furthermore, new classification schemes have emerged. This review provides an overview of the genetically determined dystonias, with emphasis on the so-called isolated and combined forms. The summary of phenotypic characteristics associated with specific genetic mutations should enable the clinician to initiate appropriate molecular genetic diagnostics on the basis of concrete clinical manifestations.     

Towards a question of formation mechanisms of muscular hand dystonia

Studies on the mechanisms of hand muscle dystonia, as exemplified by writer??s cramp (WC). WC is a specific movement disorder characterized by excessive involuntary muscle contractions leading to abnormal posture during selective motor activity, including skilled repetitive movements. WC pathophysiology remains obscure. Incomplete inhibition at various levels of the sensorimotor system is assumed to be a major mechanism of muscle dystonia. The following approaches are used for studying WC muscle dystonia: genetic and neurophysiologic examinations (transcranial magnetic stimulation, TMS; evoked motor potentials, EMP); and the methods of neuroimaging (functional MRI, positron emission tomography, PET; and three-dimensional kinematic analysis).     

Abnormal Movement Preparation in Task-Specific Focal Hand Dystonia

Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self-initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia.     

Sensory representation abnormalities that parallel focal hand dystonia in a primate model

In our hypothesis of focal dystonia, attended repetitive behaviors generate aberrant sensory representations. Those aberrant representations interfere with motor control. Abnormal motor control strengthens sensory abnormalities. The positive feedback loop reinforces the dystonic condition. Previous studies of primates with focal hand dystonia have demonstrated multi-digit or hairy-glabrous responses at single sites in area 3b, receptive fields that average ten times larger than normal, and high receptive field overlap as a function of horizontal distance. In this study, we strengthen and elaborate these findings. One animal was implanted with an array of microelectrodes that spanned the border between the face and digits. After the animal developed hand dystonia, responses in the initial hand representation increasingly responded to low threshold stimulation of the face in a columnar substitution. The hand-face border that is normally sharp became patchy and smeared over 1 mm of cortex within 6 weeks. Two more trained animals developed a focal hand dystonia variable in severity across the hand. Receptive field size, presence of multi-digit or hairy-glabrous receptive fields, and columnar overlap covaried with the animal's ability to use specific digits. A fourth animal performed the same behaviors without developing dystonia. Many of its physiological measures were similar to the dystonic animals, but receptive field overlap functions were minimally abnormal, and no sites shared response properties that are normally segregated such as hairy-glabrous combined fields, or multi-digit fields. Thalamic mapping demonstrated proportionate levels of abnormality in thalamic representations as were found in cortical representations.     

Sensory representation abnormalities that parallel focal hand dystonia in a primate model

In our hypothesis of focal dystonia, attended repetitive behaviors generate aberrant sensory representations. Those aberrant representations interfere with motor control. Abnormal motor control strengthens sensory abnormalities. The positive feedback loop reinforces the dystonic condition. Previous studies of primates with focal hand dystonia have demonstrated multi-digit or hairy-glabrous responses at single sites in area 3b, receptive fields that average ten times larger than normal, and high receptive field overlap as a function of horizontal distance. In this study, we strengthen and elaborate these findings. One animal was implanted with an array of microelectrodes that spanned the border between the face and digits. After the animal developed hand dystonia, responses in the initial hand representation increasingly responded to low threshold stimulation of the face in a columnar substitution. The hand-face border that is normally sharp became patchy and smeared over 1 mm of cortex within 6 weeks. Two more trained animals developed a focal hand dystonia variable in severity across the hand. Receptive field size, presence of multi-digit or hairy-glabrous receptive fields, and columnar overlap covaried with the animal's ability to use specific digits. A fourth animal performed the same behaviors without developing dystonia. Many of its physiological measures were similar to the dystonic animals, but receptive field overlap functions were minimally abnormal, and no sites shared response properties that are normally segregated such as hairy-glabrous combined fields, or multi-digit fields. Thalamic mapping demonstrated proportionate levels of abnormality in thalamic representations as were found in cortical representations.     

4-Phenylbutyrate Attenuates the ER Stress Response and Cyclic AMP Accumulation in DYT1 Dystonia Cell Models

Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3′, 5′-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3′, 5′-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway.     

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Huntington's disease (HD) is a progressive, fatal neurodegenerative disease caused by expanded polyglutamine repeats in the HD gene. HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances. Research into mutant huntingtin (Htt) and mitochondria has found that mutant Htt interacts with the mitochondrial protein dynamin-related protein 1 (Drp1), enhances GTPase Drp1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. This article summarizes latest developments in HD research and focuses on the role of abnormal mitochondrial dynamics and defective axonal transport in HD neurons. This article also discusses the therapeutic strategies that decrease mitochondrial fragmentation and neuronal damage in HD.     

Modeling movement disorders--CRPS-related dystonia explained by abnormal proprioceptive reflexes

Humans control their movements using adaptive proprioceptive feedback from muscle afferents. The interaction between proprioceptive reflexes and biomechanical properties of the limb is essential in understanding the etiology of movement disorders. A non-linear neuromuscular model of the wrist incorporating muscle dynamics and neural control was developed to test hypotheses on fixed dystonia. Dystonia entails sustained muscle contractions resulting in abnormal postures. Lack of inhibition is often hypothesized to result in hyperreflexia (exaggerated reflexes), which may cause fixed dystonia. In this study the model-simulated behavior in case of several abnormal reflex settings was compared to the clinical features of dystonia: abnormal posture, sustained muscle contraction, increased stiffness, diminished voluntary control and activity-aggravation. The simulation results were rated to criteria based on characteristic features of dystonia. Three abnormal reflex scenarios were tested: (1) increased reflex sensitivity-increased sensitivity of both the agonistic and antagonistic reflex pathways; (2) imbalanced reflex offset-a static offset to the reflex pathways on the agonistic side only; and (3) imbalanced reflex sensitivity-increased sensitivity of only the agonistic reflex pathways. Increased reflex sensitivity did not fully account for the features of dystonia, despite distinct motor dysfunction, since no abnormal postures occurred. Although imbalanced reflex offset did result in an abnormal posture, it could not satisfy other criteria. Nevertheless, imbalanced reflex sensitivity with unstable force feedback in one of the antagonists closely resembled all features of dystonia. The developed neuromuscular model is an effective tool to test hypotheses on the underlying pathophysiology of movement disorders.     

Genetic testing for early-onset torsion dystonia (DYT1): introduction of a simple screening method, experiences from testing of a large patient cohort, and ethical aspects

Early-onset, generalized primary torsion dystonia (PTD) is an autosomal dominantly inherited disorder, characterized by involuntary movements and abnormal postures. The majority of cases are caused by a 3-bp deletion in the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We developed a simple, reliable, and cost-effective, PCR-based screening method for this mutation. Testing results from a cohort of 550 cases, including patients with different forms of dystonia and unclassified movement disorders, revealed that 72.2% of the patients with typical early-onset generalized PTD carried the GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of the patients with an unclassified movement disorder were GAG positive. Our results confirm a genotype/phenotype correlation in early-onset PTD and show that application of strict clinical criteria leads to accurate prediction of carrier status in more than two-thirds of patients with this type of dystonia. Currently, we suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early-onset PTD. Testing is not recommended in patients with onset of symptoms after 30 years or in asymptomatic individuals under the age of 18.     

Role of computerized transverse axial tomography on stereotactic surgery of the diencephalon. A preliminary report of 67 cases.

67 cases of various functional disorders of the diencephalon were examined by EMI scanner. The patients were composed of 38 cases of parkinsonism, 7 cases of thalamic syndrome, 6 cases of choreoathetoid movement, 2 cases of dystonia, 11 cases of involuntary movement of unknown etiology and 1 case of torticollis, tic, and ballismus, respectively. In parkinsonism, 79% showed diffuse cerebral atrophy, 5% had focal low density in the substantia nigra and the thalamus, whereas 16% remained normal. Pre- and postoperative assessment with CT scan was briefly discussed with reference to stereotactic surgery of the diencephalon.     

Advances in understanding L-DOPA-induced dyskinesia

The crucial role of dopamine (DA) in movement control is illustrated by the spectrum of motor disorders caused by either a deficiency or a hyperactivity of dopaminergic transmission in the basal ganglia. The degeneration of nigrostriatal DA neurons in Parkinson's disease causes poverty and slowness of movement. These symptoms are greatly improved by pharmacological DA replacement with L-3,4-dihydroxy-phenylalanine (L-DOPA), which however causes excessive involuntary movements in a majority of patients. L-DOPA-induced dyskinesia (abnormal involuntary movements) provides a topic of investigation at the interface between clinical and basic neuroscience. In this article, we review recent studies in rodent models, which have uncovered two principal alterations at the basis of the movement disorder, namely, an abnormal pre-synaptic handling of exogenous L-DOPA, and a hyper-reactive post-synaptic response to DA. Dysregulated nigrostriatal DA transmission causes secondary alterations in a variety of non-dopaminergic transmitter systems, the manipulation of which modulates dyskinesia through mechanisms that are presently unclear. Further research on L-DOPA-induced dyskinesia will contribute to a deeper understanding of the functional interplay between neurotransmitters and neuromodulators in the motor circuits of the basal ganglia.     

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Huntington's disease (HD) is a progressive, fatal neurodegenerative disease caused by expanded polyglutamine repeats in the HD gene. HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances. Research into mutant huntingtin (Htt) and mitochondria has found that mutant Htt interacts with the mitochondrial protein dynamin-related protein 1 (Drp1), enhances GTPase Drp1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. This article summarizes latest developments in HD research and focuses on the role of abnormal mitochondrial dynamics and defective axonal transport in HD neurons. This article also discusses the therapeutic strategies that decrease mitochondrial fragmentation and neuronal damage in HD.     

Adaptive movement and food-chain dynamics: towards food-web theory without birth–death processes

Population density can be affected by its prey [resource] and predator [consumer] abundances through two different mechanisms: the alternation of birth [or somatic growth] or death rate and inter-habitat movement. While the food-web theory has traditionally been built on the former mechanism, the latter mechanism has formed the basis of a successful theory explaining the spatial distribution of organisms in the context of behavioral and evolutionary ecology. Yet, few studies have compared these two mechanisms, leaving the question of how similar (or different) predictions derived from birth–death-based and movement-based food-web theories unanswered. Here, theoretical models of the tri-trophic (resource–consumer-top predator) food chain were used to compare food-web patterns arising from these two mechanisms. Specifically, we evaluated the response of the food-chain structure to inter-patch differences in productivity for movement-based models and birth–death-based models. Model analysis reveals that adaptive movements give rise to positively correlated responses of all trophic levels to increased productivity; however, this pattern was not observed in the corresponding birth–death-based model. The movement-based model predicts that the food chain response to productivity is determined by the sensitivity of animal movement to the environmental conditions. More specifically, increasing sensitivity of a consumer or top predator leads to smaller inter-patch variance of the resource or consumer density, while increasing inter-patch variance in the consumer or resource density. In conclusion, adaptive movement provides an alternative mechanism correlating the food-web structure to environmental conditions.     

Toward a network model of dystonia

Dystonia has generally been considered a basal ganglia (BG) disorder. Early models hypothesized that dystonia occurred as the result of reduced mean discharge rates in the internal segment of the globus pallidus (GPi). Increasing evidence suggests a more systemwide disruption of the basal ganglia thalamic circuit (BGTC) resulting in altered firing patterns, synchronized oscillations, and widened receptive fields. A model of dystonia incorporating these changes within the BGTC is presented in which we postulate that this pathophysiology arises from disruptions within the striatum. Alterations in the cerebellothalamocortical (CBTC) pathway to the development of dystonia may also play a role. However, the contribution of CBTC abnormalities to dystonia remains unclear and may vary with different etiologies of dystonia. Finally, the relevance of established and emerging theories related to the pathophysiology of dystonia is addressed within the context of improving conventional approaches for deep brain stimulation (DBS) treatment strategies.     

Rolipram,a selective c-AMP phosphodiesterase inhibitor suppresses oro-facial dyskinetic movements in rats

Since striatal dopamine D2 receptor supersensitivity in the etiology of tardive dyskinesia has been suggested and dopamine D2 receptors are known to inhibit adenylate cyclase activity resulting in a decrease of cyclic adenosine 3′,5′-monophosphate (cAMP) levels, we hypothesized that an increase in cAMP levels ameliorates the condition. In the present study, 21-day haloperidol treatment (1.5 mg/kg I.P.) in rats resulted in an increase in striatal [³H]-spiperone (D2) binding whereas [³H] SCH23390 (D1) binding was unaltered. This haloperidol treatment also induced a significantly increase in the frequency of involuntary chewing movements and tongue protrusions, which are considered as a model of tardive dyskinesia. These dyskinetic movements were suppressed by administration of rolipram (0.5 and 1.0 mg/kg I.P.), an inhibitor of the cAMP phosphodiesterase type IV. The present results suggest that selective cAMP phosphodiesterase type IV inhibitors could be putative therapeutic drugs for tardive dyskinesia.     

Apparent Time Interval of Visual Stimuli Is Compressed during Fast Hand Movement

The influence of body movements on visual time perception is receiving increased attention. Past studies showed apparent expansion of visual time before and after the execution of hand movements and apparent compression of visual time during the execution of eye movements. Here we examined whether the estimation of sub-second time intervals between visual events is expanded, compressed, or unaffected during the execution of hand movements. The results show that hand movements, at least the fast ones, reduced the apparent time interval between visual events. A control experiment indicated that the apparent time compression was not produced by the participants’ involuntary eye movements during the hand movements. These results, together with earlier findings, suggest hand movement can change apparent visual time either in a compressive way or in an expansive way, depending on the relative timing between the hand movement and visual stimulus.