Pathophysiology Of Focal Dystonia Research Articles

The role of sensory information in the pathophysiology of focal dystonias.

Over the past few decades, abnormalities in sensory functions, such as tactile, proprioceptive and nociceptive processing, have been increasingly recognized in patients with focal dystonias. In this Review, we ask whether sensory system abnormalities are specific to particular types of dystonia, whether a causal link exists between sensory alterations and dystonic motor activity and how mechanisms underlying the sensory abnormalities fit in with the proposed 'network model' of dystonia. We suggest that alterations in the various sensory modalities participate at three different levels in the pathophysiological cascade that leads to dystonia: a background level that predisposes individuals to dystonia, a disease-related level that is evident only when dystonia becomes manifest and a causative level that triggers dystonia. We conclude that it is crucial to study sensory as well as motor pathophysiology to fully understand focal dystonias.

Structural brain network fingerprints of focal dystonia.

Background:Focal dystonias are severe and disabling movement disorders of a still unclear origin. The structural brain networks associated with focal dystonia have not been well characterized. Here, we investigated structural brain network fingerprints in patients with blepharospasm (BSP) compared with those with hemifacial spasm (HFS), and healthy controls (HC). The patients were also examined following treatment with botulinum neurotoxin (BoNT).Methods:This study included matched groups of 13 BSP patients, 13 HFS patients, and 13 HC. We measured patients using structural-magnetic resonance imaging (MRI) at baseline and after one month BoNT treatment, at time points of maximal and minimal clinical symptom representation, and HC at baseline. Group regional cross-correlation matrices calculated based on grey matter volume were included in graph-based network analysis. We used these to quantify global network measures of segregation and integration, and also looked at local connectivity properties of different brain regions.Results:The networks in patients with BSP were more segregated than in patients with HFS and HC (p < 0.001). BSP patients had increased connectivity in frontal and temporal cortices, including sensorimotor cortex, and reduced connectivity in the cerebellum, relative to both HFS patients and HC (p < 0.05). Compared with HC, HFS patients showed increased connectivity in temporal and parietal cortices and a decreased connectivity in the frontal cortex (p < 0.05). In BSP patients, the connectivity of the frontal cortex diminished after BoNT treatment (p < 0.05). In contrast, HFS patients showed increased connectivity in the temporal cortex and reduced connectivity in cerebellum after BoNT treatment (p < 0.05).Conclusions:Our results show that BSP patients display alterations in both segregation and integration in the brain at the network level. The regional differences identified in the sensorimotor cortex and cerebellum of these patients may play a role in the pathophysiology of focal dystonia. Moreover, symptomatic reduction of hyperkinesia by BoNT treatment was associated with different brain network fingerprints in both BSP and HFS patients.

Distinct roles of brain activity and somatotopic representation in pathophysiology of focal dystonia

Two main neural mechanisms including loss of cortical inhibition and maladaptive plasticity have been thought to be involved in the pathophysiology of focal task-specific dystonia. Such loss of inhibition and maladaptive plasticity likely correspond to cortical overactivity and disorganized somatotopy, respectively. However, the most plausible mechanism of focal task-specific dystonia remains unclear. To address this question, we assessed brain activity and somatotopic representations of motor-related brain areas using functional MRI and behavioral measurement in healthy instrumentalists and patients with embouchure dystonia as an example of focal task-specific dystonia. Dystonic symptoms were measured as variability of fundamental frequency during long tone playing. We found no significant differences in brain activity between the embouchure dystonia and healthy wind instrumentalists in the motor-related areas. Assessment of somatotopy, however, revealed significant differences in the somatotopic representations of the mouth area for the right somatosensory cortex between the two groups. Multiple-regression analysis revealed brain activity in the primary motor and somatosensory cortices, cerebellum, and putamen was significantly associated with variability of fundamental frequency signals representing dystonic symptoms. Conversely, somatotopic representations in motor-related brain areas were not associated with variability of fundamental frequency signals in embouchure dystonia. The present findings suggest that abnormal motor-related network activity and aberrant somatotopy correlate with different aspects of mechanisms underlying focal task-specific dystonia.

Brain Plasticity and the Concept of Metaplasticity in Skilled Musicians.

Early and extensive musical training provides plastic adaptations of the nervous system and enhanced sensory, motor, and cognitive functions. Over decades, neuronal mechanism underlying the plastic adaptation through musical training has been investigated using neuroimaging and transcranial stimulation techniques. Recently, plastic changes in neuroplastic functions through musical training have gradually gained some interest, so-called metaplasticity. Metaplasticity enables faster and more stable skill acquisition for individuals with a history of prior musical training. This mechanism may also serve for prevention of developing maladaptive changes in the nervous system, being pathophysiology of focal dystonia in musicians. The present chapter introduces neurophysiological mechanisms and functional significances of brain plasticity and metaplasticity of the sensory and motor systems of musicians.

Abnormal dorsal premotor–motor inhibition in writer's cramp

The authors hypothesized that a deficient premotor-motor inhibitory network contributes to the unwanted involuntary movements in dystonia. The authors studied nine controls and nine patients with writer's cramp (WC). Dorsal premotor-motor cortical inhibition (dPMI) was tested by applying conditioning transcranial magnetic stimulation (TMS) to the dorsal premotor cortex and then a test pulse to the ipsilateral motor cortex at an interval of 6 ms. The authors used an H-reflex in flexor carpi radialis paired with TMS over the premotor cortex to assess for spinal cord excitability change. Finally, the authors interrupted a choice reaction time task with TMS over dorsal premotor cortex to assess performance in a nondystonic task. The results showed that WC patients exhibited dPMI at rest (88.5%, the ratio of conditioned to unconditioned test pulse), in contrast to controls, who did not show dPMI (109.6%) (P = 0.0198). This difference between patients and controls persisted during contraction (100% vs. 112%) and pen-holding (95.6% vs. 111%). The H-reflex in the arm was not modulated by the premotor cortex stimulation. The WC patients made more errors, and the error rate improved with TMS over the premotor cortex. These results suggest that abnormal premotor-motor interactions may play a role in the pathophysiology of focal dystonia. The dPMI was not modulated by task in either group, but was constantly greater in the patients. The significance of the increased inhibition is likely to be compensatory. It appears to be a robust finding and, in combination with other features, could be further explored as a biomarker.

Alteration in forward model prediction of sensory outcome of motor action in focal hand dystonia

Focal hand dystonia in musicians is a movement disorder affecting highly trained movements. Rather than being a pure motor disorder related to movement execution only, movement planning, error prediction, and sensorimotor integration are also impaired. Internal models (IMs), of which two types, forward and inverse models have been described and most likely processed in the cerebellum, are known to be involved in these tasks. Recent results indicate that the cerebellum may be involved in the pathophysiology of focal dystonia (FD). Thus, the aim of our study was to investigate whether an IM deficit plays a role in FD. We focused on the forward model (FM), which predicts sensory consequences of motor commands and allows the discrimination between external sensory input and input deriving from motor action. We investigated 19 patients, aged 19–59 and 19 healthy musicians aged 19–36 as controls. Tactile stimuli were applied to fingers II–V of both hands by the experimenter or the patient. After each stimulus the participant rated the stimulus intensity on a scale between 0 (no sensation) and 1 (maximal intensity). The difference of perceived intensity between self- and externally applied (EA) stimuli was then calculated for each finger. For assessing differences between patients and controls we performed a cluster analysis of the affected hand and the corresponding hand of the controls using the fingers II–V as variables in a 4-dimensional hyperspace (chance level = 0.5). Using a cluster analysis, we found a correct classification of the affected finger in 78.9–94.7%. There was no difference between patients and healthy controls of the absolute value of the perceived stimulus intensity. Our results suggest an altered FM function in focal hand dystonia. It has the potential of suggesting a neural correlate within the cerebellum and of helping integrate findings with regard to altered sensorimotor processing and altered prediction in FD in a single framework.

Botulinum toxin modulates basal ganglia but not deficient somatosensory activation in orofacial dystonia

The etiology of idiopathic orofacial dystonia is incompletely understood. Neurophysiological studies indicated that a sensory dysfunction could play a key role in the pathophysiology of focal dystonia. To explore if central sensory processing is abnormal in patients with blepharospasm and Meige's syndrome and to study the effects of botulinum toxin (BTX) treatment, we systematically mapped the somatotopic representations of punctate tactile stimuli in these patients before and after therapy. Standardized tactile stimuli were pseudorandomly applied to the forehead, upper lip, and hand by a MR-compatible stimulation device during event-related fMRI. Patients showed a deficient activation in primary and secondary somatosensory representations of affected and unaffected (right hand) body regions compared to healthy controls. Although clinically effective BTX treatment did not modulate this impaired cortical activation, it reduced the activation of the thalamus and contralateral putamen during forehead stimulation. This study reveals a more generalized dysfunction of the somatosensory cortex including asymptomatic body representations in orofacial dystonia. Deficient cortical sensory activation may be due to a dedifferentiation of somatosensory representations and could represent a critical functional change within the basal ganglia-thalamocortical loops facilitating dystonic movements. Modulation of basal ganglia activation might reflect an indirect remote effect of BTX treatment on these sensorimotor circuits.

New advances in the pathophysiology of focal dystonias

New advances in the pathophysiology of focal dystonias

Abnormal cortical mechanisms of voluntary muscle relaxation in patients with writer's cramp: an fMRI study.

Although it is hypothesized that there is abnormal motor inhibition in patients with dystonia, the question remains as to whether the mechanism related to motor inhibition is specifically impaired. The objective of the present study was to clarify the possible abnormalities of the mechanisms underlying voluntary muscle relaxation during motor preparation and execution in patients with writer's cramp, using event-related functional MRI. Eight patients with writer's cramp and 12 age-matched control subjects participated in the study. Two motor tasks were employed as an experimental paradigm. In the relaxation task, subjects were asked to hold their right wrist in the horizontal plane by maintaining moderate contraction of wrist extensor muscles in the premotor phase; they relaxed those muscles voluntarily just once during each fMRI scanning session. In the contraction task, subjects extended the right wrist voluntarily from the same premotor state as for the relaxation task. Five axial images covering the primary sensorimotor cortex (SMC) and supplementary motor area (SMA) were obtained once every second. Activated volumes in the left SMC and the SMA were significantly reduced in patients for both muscle relaxation and contraction tasks. These data suggest that there is impaired activation in both SMC and SMA in voluntary muscle relaxation and contraction in patients with writer's cramp. This implies that abnormalities of both inhibitory and excitatory mechanisms in motor cortices might play a role in the pathophysiology of focal dystonia.

Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp.

To study the short-term effects of slow repetitive transcranial magnetic stimulation (rTMS) of the motor cortex on cortical excitability and handwriting in patients with writer's cramp. Cortical excitability of the primary motor cortex is abnormally enhanced in patients with writer's cramp. Therefore, reducing cortical excitability by low-frequency rTMS of the motor cortex might result in beneficial effects on handwriting in writer's cramp. We studied the effects of subthreshold 1-Hz rTMS on motor threshold and cortico-cortical excitability using the paired-pulse technique in seven patients and seven controls. In another 16 patients and 11 age-matched controls we evaluated changes in cortical excitability by measuring the stimulus-response curve and the postexcitatory silent period before and after subthreshold 1-Hz rTMS. In addition, we analyzed the handwriting before and 20 minutes after 1-Hz rTMS. In the first experiment, low-frequency rTMS resulted in a normalization of the deficient cortico-cortical inhibition in the patients without affecting motor threshold. In the second experiment, 1-Hz rTMS resulted in a significant prolongation of the postexcitatory silent period without affecting the stimulus-response curve in the patient group. Moreover, the dystonic patients showed a significant reduction of mean writing pressure after subthreshold 1-Hz rTMS that was associated with clear but transient improvement in six patients. In some patients 1-Hz rTMS can reinforce deficient intracortical inhibition and may improve handwriting temporarily. Our data support the notion that reduced intracortical inhibition plays a part in the pathophysiology of focal dystonia.