Update on the latest research
This article explores what may be going on in the brain when a person has dystonia. There are a number of different theories about how dystonia arises. There are persuasive arguments for each but, as explained below, also still some gaps and/or contradictory evidence so none can yet provide a full explanation. How these theories fit together and which will turn out to be most important remains to be seen.
1. INHIBITION THEORIES
The brain/nervous system is a complex network composed of neurons operating in a system of highly specialised, distinct neural circuits. Every aspect of our behaviour, from reflexes to movement, relies on the processes performed by these neural circuits. For these to work effectively in harmony, they need to be switched on (excitation) and switched off (inhibition) with exquisitely precise timing.
Excitatory/inhibitory systems are enabled by the passage of chemicals (neurotransmitters) across the neurons. Some neurotransmitters inhibit neuronal activity while others excite it. In dystonia, it appears that some inhibitory circuits are defective causing a process called co-contraction. Normally muscles work harmoniously in pairs: one muscle (the agonist) is the prime mover while its partner (the antagonist) must relax to allow the movement to happen. This enables a smooth controlled movement. To achieve this the activity of the agonist must be excited while that of the antagonist is inhibited. In co-contraction this harmony is disrupted as the failure of inhibitory messages causes too much activity in the antagonist resulting in the abnormal movements or postures seen in dystonia.
Evidence supporting inhibition theories
Researchers have shown that in healthy people, at the onset of a voluntary muscle contraction, the neighboring muscles are less readily stimulated (so more inhibited). In this way, the motor system can focus muscle activity and facilitate precise, individual movements. So it appears inhibition is playing an important role in effecting smooth movement.
Researchers have also compared the activity in the agonist and antagonist muscles of people with dystonia to healthy controls. They have shown that in people with dystonia the inhibition of the antagonist muscle is lower than in the controls while the excitation of the agonist muscle appears normal. So it appears very likely that inhibition failure is playing a causal role in co-contraction.
Further evidence is provided by the effectiveness of some medications such as gabapentin and benzodiazepines in improving symptoms in some cases. These medications stimulate the transmission of a neurotransmitter called GABA which inhibits muscle activity so, if the medications can reduce symptoms, it suggests inhibition was insufficient previously. In addition, it is this lack of inhibition that Deep Brain Stimulation (DBS) treatment may address as DBS is thought to stimulate GABA inhibitory neurons.
Evidence against inhibition theories
Abnormally reduced inhibition has been found in carriers of the DYT1 gene whether or not they have dystonia symptoms (around 7 in 10 of those who inherit the DYT1 gene never develop dystonia). So reduced inhibition can be present without the symptoms of dystonia appearing.
Also reduced inhibition may be found in both the left and right sides of the brain in some people even where the dystonia symptoms are only present on the one side.
Conclusion on inhibition theories
Inhibition has been shown to be abnormal in people with dystonia and seems a plausible explanation of dystonic symptoms. However, as these abnormalities can be present in clinically unaffected parts of the body and in non-manifesting DYT1 gene carriers, reduced inhibition cannot be the whole explanation and additional factors must be necessary to produce dystonia.
2. ABNORMAL NEUROPLASTICITY
Neuroplasticity is the ability of the brain to reorganise its structure/function and change its connections and behaviour in response to new information, stimulation, development, damage, or dysfunction. Neuroplasticity is a perfectly normal process and occurs when neurons in the brain sprout and form synapses. As the brain processes information, frequently used junctions (synapses) are strengthened while unused synapses weaken. Eventually, unused synapses are eliminated completely leaving behind efficient networks of neural connections. It is thought that in the field of neuroplasticity, “if it fires, it wires”, meaning that every time a person thinks about something, or does something, a neural pathway is either being strengthened or reinforced. This is how we learn and change.
In some types of dystonia, excessive neuroplasticity has been observed. This could underlie the generation of dystonic movements. A simple analogy is to view neuroplasticity like creating a path in freshly fallen snow—(the snow representing the plastic brain).At first, the result is a few footsteps in the snow but walk it again and again and it becomes a track then a footpath. However, if this path is overused it can become harder and harder to use any other path through the snow, as it requires too much effort to start again.
This is fine if the path is useful but, in dystonia, plasticity may reinforce abnormal movements. Each time the body repeats these movements, they claim more control of the brain’s map of the body and prevent the relearning of normal movements. If the brains of people with dystonia have a tendency to develop new tracks too quickly, the tracks for abnormal movements may become hard wired too easily.
Evidence supporting abnormal plasticity theories
Abnormal plasticity has been measured in task specific focal dystonias such as musician’s dystonia, where repetitive activity is believed to be a trigger for the development of dystonia.
Abnormal plasticity also appears to be present in DYT1 dystonia but importantly is not present in DYT1 gene carriers who don’t have dystonic symptoms. This may explain why reduced inhibition doesn’t always cause symptoms to appear - reduced inhibition creates the potential for abnormal movements in all DYT1 carriers but these movements only become hard-wired in the brain of those DYT1 carriers who also have abnormal plasticity.
When DBS is provided to people with dystonia initially their level of plasticity reduces well below normal and then gradually increases toward normal levels. Despite this, it can take several months for the symptoms to be improved. The slow improvement suggests that, even with the plasticity reduced to normal levels or below, the brain still needs to unlearn the abnormal dystonic movements. This strongly suggests plasticity has a role in dystonia.
Evidence against a role for abnormal plasticity in dystonia
Abnormalities of plasticity have been identified in patients with dystonia, but they might not be sufficient to cause the development of dystonic movements and the exact channels by which excess plasticity causes dystonia have not been identified. In addition, if overtraining is a cause of some types of task-specific dystonia, this does not explain why only some people develop dystonia after excessive training whereas others are completely healthy.
Conclusion on neuroplasticity
The evidence strongly suggests that plasticity plays an important role but much work needs to be done to explain how it influences dystonia and how it fits with other causative factors.
3. INVOLVEMENT OF CEREBELLUM
Historically, dystonia was thought to be caused by abnormalities within a part of the brain called the basal ganglia. However, unlike other movement disorders, there is no evidence of degeneration within the brain’s neuronal circuitry. This suggests that the problems causing dystonia result from abnormal connectivity that may occur in a structurally normal appearing brain. Dystonia is therefore considered a system disorder rather than a disease of a particular brain structure.
Recently there is evidence that the cerebellum may also be involved in causing by dystonia suggesting that dystonia may result from disruption of motor networks involving both the basal ganglia and cerebellum, rather than the isolated dysfunction of only one part of the brain.
The cerebellum is located at the base of the brain, just above the brain stem, where the spinal cord meets the brain. The cerebellum receives information from the sensory systems, the spinal cord, and other parts of the brain and then regulates motor (muscle) movements. The cerebellum coordinates voluntary movements such as posture, balance, coordination, and speech, resulting in smooth, balanced muscular activity. It participates in fine tuning and co-ordination of movements produced elsewhere in the brain, and it integrates all of these things to produce movements so fluid and harmonious that people are not even aware of them happening.
Evidence supporting cerebellar involvement
Scans have identified that people with musician’s dystonia and focal hand dystonia show abnormal cerebellar activation during different tapping tasks and abnormal cerebellar activation was also observed during writing in people with writer’s dystonia, in voice dystonia during voice production and in blepharospasm during eye blinking. This abnormal cerebellar activity coupled with evidence of increased energy metabolism within the cerebellum during these tasks provides evidence for its role in dystonia.
Research suggests that the cerebellum and basal ganglia communicate to shared regions of the cerebral cortex. The discovery of this shared connection between the basal ganglia and cerebellum provides a possible structural basis to explain the role of the cerebellum in dystonia.
Involvement of the cerebellum is also supported by the fact that that in many different forms of dystonia, loss of harmony between excitation and inhibition is a problem. These functions are regulated by the basal ganglia and cerebellum, with some evidence that they may exert opposing influences. Therefore, the influences of the basal ganglia and cerebellum seem to overlap on cortical excitability as a common pathway for dystonic movement.
Evidence against a primary role for the cerebellar involvement
Although it is clear that in dystonia the cerebellum often shows abnormal activity, it is as yet uncertain whether this activity plays a primary role or is just a compensation to a problem created elsewhere. The types of symptom usually caused by problems in the cerebellum (such as uncoordinated movement, incorrectly timed movement, dizziness) are different to the slow, writhing movements normally caused in dystonia. Lack of these more common cerebellar symptoms may indicate that in most forms of dystonia the cerebellum has abnormal, probably compensatory activity rather than a primary role.
Conclusion on cerebellum
Cerebellar activity is often abnormal but it is unclear whether all manifestations of dystonia involve both basal ganglia and cerebellar circuitry, or whether there is a spectrum ranging from pure cerebellar dystonia, overlapping basal ganglia and cerebellar dystonia, and pure basal ganglia dystonia. However, it is likely that the cerebellum will have a key place within future models of dystonia.
This article illustrates that there has been considerable progress in understanding what is happening in the brain to cause dystonia but there are still many questions to resolve. The ideas emerging suggest that dystonia may have a combination of causes - for instance abnormal inhibition together with plasticity. In addition, these causes may result from abnormal activity in more than one part of the brain.
Last reviewed April 2015
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