Dystonia

INDEX

The physiology of dystonia is advancing rapidly and interested readers are encouraged to review recent literature as well the reviews referenced in this section.

Basal ganglia involvement in dystonia is strongly supported by findings from neuropathological studies and clinical evidence that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is beneficial in dystonia. Nevertheless, dystonia is characterized by a widespread impairment of motor control, with increasing evidence that regions other than the basal ganglia are involved in dystonia.

Involvement of cortex includes altered excitability of the primary motor area, the supplementary motor area, and the dorsal premotor cortex. Structural imaging has demonstrated changes in grey matter volume in the sensorimotor area of cortex and the globus pallidus in focal hand dystonia.

Dystonia may result from a single-node dysfunction involving cerebral cortex, cerebellum, thalamus, and brainstem.  Alternatively, dystonia may arise from an involvement of multiple nodes, or from aberrant communication among the nodes. The delay between a lesion and the emergence of secondary dystonia suggests the possibility of a progressive maladaptive plasticity in remote nodes. Similarly, the delayed effects of DBS are in keeping with a massive rearrangement within multiple nodes of the motor loop15.

As with tremor, isolated dystonia is presently regarded as a circuit disorder, involving the basal ganglia-thalamo-cortical and cerebello-thalamo-cortical pathways, emphasizing recent proposals concerning the role of the cerebellum in the pathogenesis of dystonia.

It should also be noted that many disorders combine both dystonia and parkinsonism, (including PD), and are characterized by reduced levels of striatal dopamine due to loss of nigral neurons. Similarly, genetic disorders resulting in deficiencies of the enzymes involved in the dopaminergic synthesis pathway can present with dopa-responsive dystonia (DRD), parkinsonism in isolation, or both.

 

Overview of the main pathophysiologic mechanisms underlying phenomenologic features of dystonia. Neurophysiologic studies identified functional abnormalities in two networks: the basal ganglia-sensorimotor network and, more recently, the cerebellothalamocortical pathway. Maladaptive sensorimotor plasticity with lack of spatial specificity and loss of surround inhibition seem to be specific alterations of dystonia.

From: Morgante F, Klein C. Dystonia. Continuum (Minneap Minn). 2013;19(5 Movement Disorders):1225-1241. doi:10.1212/01.CON.0000436154.08791.67 13.

 

Proposed mechanisms of dystonia include:

1.            At the cellular level, there  are demonstrable abnormalities in neural inhibition: loss of inhibition has been described for several different types of dystonia at multiple levels of the nervous system including the spinal cord, brainstem, and cortex15.  This is related to surround inhibition, which is the suppression of excitability in an area surrounding an activated neural network, and which is a physiological mechanism which focuses neuronal activity and aids in the selection of appropriate neuronal responses. For example, when the motor cortex produces an accurate voluntary movement, there is a widespread inhibition of muscles not involved in the task. Surround inhibition is thought to be an essential mechanism in the motor system, where it could aid the selective execution of desired movements.  Surround inhibition is reduced in patients with focal hand dystonia who are making finger movements or even imagining a voluntary movement16. Abnormal intracortical inhibition may be found in both hemispheres despite unilateral symptoms and even in asymptomatic body parts, but is also accepted to be a non-specific finding.

 

2.            Abnormalities of sensorimotor integration

Evidence for abnormalities in sensorimotor integration include:

•             Abnormal sensory modulation in response to movement, so-called sensory gating, in focal hand dystonia

•             Deranged somatotopic representation in the sensory cortex (perhaps due to lack of surround inhibition)

•             Sensory tricks

•             Anaesthesia may improve dystonia

 

3.            Maladaptive plasticity

Abnormalities of neural plasticity have also been reported for many different types of dystonia.This mechanism may be most relevant to task-specific dystonias, for example, dystonia involving the hand is typically triggered by a period of intensive training of a particular movement. Primate models of focal dystonia have demonstrated larger receptive fields and overlapping representations of the individual digits in somatosensory cortex.  It is postulated that overtraining may lead to changes in connectivity in the sensory and motor cortices. These changes may bring inappropriate associations between sensory input and motor outputs, and result in errors in selection of muscles used in voluntary movements.

It should be emphasized that general changes in plasticity, inhibition or somatosensory representation are unable to explain why only an individual task, as in focal dystonia, is affected.

Older hypotheses emphasized firing rates of neurons (16) in the direct and indirect pathways involving the cortex-basal ganglia and thalamus have suggested opposite states in dystonia and parkinsonism. By contrast, recent reviews have highlighted the importance of spatial and temporal patterns of activity in the GPi and STN in generating normal movements, rather than the levels of output from these nuclei.  

In particular, microelectrode recorded local field potentials (LFP) recorded from the GPi in patients with dystonia have demonstrated a relatively high power of low-frequency oscillations (3- to 12-Hz), which is believed to be integral to the pathophysiology of dystonia.

As opposed to dystonia, in PD, the LFPs recorded during STN DBS surgery have demonstrated an increased oscillatory activity in the beta frequency band.  The extent of synchrony in the subcortical beta band correlates with motor impairment.  The synchrony is reduced by dopaminergic therapy and DBS17, and the degree of clinical improvement correlates with the beta band suppression.

Similarly, an increased synchronization in the subcortical alpha-theta band (4-12 Hz), has been recorded from the GPi in dystonia, which also correlates with symptom severity, and is suppressed by pallidal DBS.

Contrasting the findings in PD and dystonia, it has been proposed that exaggerated synchrony negatively affects information coding capacity and circuit performance. The resulting impairment, depending on the synchronizing frequency range, can lead to hypo- or hyperkinetic movement disorders, including dystonia18.

Furthermore, the increased beta synchronization in the STN of PD patients relies on transient bursts of synchrony, which, as recorded from the GPi, are abnormally skewed toward prolonged beta bursts, and with a longer duration of bursts seen in untreated PD patients18. In dystonia, these pallidal beta bursts are significantly shorter, resembling the findings obtained from PD patients in the ON state, likely resembling a more physiological pattern.