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Dystonia Can Originate in Part of the Brain Commonly Overlooked

For release: Friday, June 17, 2011

The basal ganglia and the cerebellum

The hand curls inward, the grip involuntarily tightens, the fingers seem to flex and extend of their own accord.  This is writer's cramp, and it is perhaps the most familiar kind of dystonia – a group of disorders that involve sustained, involuntary muscle contractions.  The exact causes of dystonia vary and are not well understood in the majority of cases, but for decades the disorder has been linked to abnormalities in a part of the brain called the basal ganglia.  A study published in Nature Neuroscience* lends support to the notion that a brain structure called the cerebellum also plays an important role.

In the study, researchers developed a mouse model for a rare disorder called rapid-onset dystonia-parkinsonism (RDP).  Using these mice, the researchers were able to separately test the role of the basal ganglia and the cerebellum in RDP.  They found that the mice developed dystonia only if the cerebellum was dysfunctional.  The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS).

"This is the first animal model that replicates a human dystonia, and it clearly implicates the cerebellum," said senior author Kamran Khodakhah, Ph.D., a neuroscientist at the Albert Einstein College of Medicine in New York.  "The results are going to motivate the research community to look at the cerebellum as a factor in other dystonias."

Dystonia exists in many forms.  Focal dystonias, like writer's cramp, affect just one part of the body, while generalized dystonias cause involuntary twisting movements and abnormal posture throughout the body.

Several oral medications relieve the symptoms of dystonia by acting on signaling pathways in the brain.  Injections of botulinum toxin into affected muscles can also help.

For people who do not respond to these treatments, surgery may be an option.  The goal of surgery is to interrupt abnormal signals that travel from the basal ganglia to the spinal cord to muscles.  A practice called lesioning involves destroying a small part of the basal ganglia.  Another treatment option is deep brain stimulation, which typically involves implanting fine wires into the basal ganglia and delivering an electrical current to quiet the abnormal signals.

Dr. Khodakhah's research on RDP suggests that the cerebellum might be another target for therapy.  RDP is a rare hereditary disorder that combines dystonia with Parkinson-like symptoms, such as slow rigid movements.  These symptoms are usually triggered by physical or emotional stress – from fever to strenuous exercise to giving birth – and within hours of onset they can become severe and permanent.

A hint that the cerebellum might be involved in RDP came from genetic studies.  RDP is caused by mutations that alter a protein called the sodium-potassium pump.  This pump works a bit like a battery, charging up neurons so that they can fire. Although the brain has several varieties of the sodium-potassium pump, only one variety – the same one that is mutated in RDP – is found in cerebellar Purkinje cells, which are essential for motor coordination.

This led Dr. Khodakhah and his team to theorize that abnormal cerebellar activity might cause RDP.  They planned to test the idea in mice, but earlier studies had shown that mice with RDP-linked mutations do not develop dystonia.  So the researchers used ouabain, a toxin that acts on the sodium-potassium pump, to acutely shut off the pump in the mouse brain.  By using a small metal tube to perfuse ouabain into the basal ganglia or the cerebellum, the researchers were able to test how loss of the pump's activity in the two brain structures contributes to RDP.

They found that perfusion of ouabain into the basal ganglia produced Parkinson-like symptoms, but not dystonia.  On the other hand, perfusion of ouabain into the cerebellum produced ataxia (problems with balance and coordination) which evolved into dystonia within a day or two.  The dystonia could be prevented either by lesioning a part of the cerebellum, or by lesioning a link between the cerebellum and the basal ganglia.

Although further research is needed, the results suggest that lesions or deep brain stimulation of the cerebellum could hold promise for treating dystonia, Dr. Khodakhah said.  He and his team are currently testing the procedure in mice with ouabain-induced dystonia.

Dr. Khodakhah and his team are also exploring the link between RDP and stress.  In some experiments, they gave mice small perfusions of ouabain directly in the cerebellum and/or basal ganglia.  With this low dose of ouabain, the mice did not develop dystonia unless they were also exposed to stress.  Also, this stress-induced dystonia only occurred when ouabain was perfused into both the cerebellum and the basal ganglia, suggesting that the two brain structures must interact for stress to trigger RDP.

Based on these data, Dr. Khodakhah has a theory for how stress triggers the onset of RDP.  Ouabain is found naturally in some African plants and is used as an arrow poison by tribal people.  Humans make a similar substance called endo-ouabain, which rises during stress and could be the trigger for symptoms in people who are genetically susceptible to RDP, he said.

- By Daniel Stimson, Ph.D.

*Calderon DP, Fremont R, Kraenzlin F and Khodakhah K. "The neural substrates of rapid-onset dystonia-parkinsonism." Nature Neuroscience, March 2011, Vol. 14(3), pp. 357-65.

Last Modified June 23, 2011