Dystonia Linked To Specific Brain Defect

November 21, 1997

St. Louis, Nov. 20, 1997 -- Three separate observations have spawned a new idea about dystonia, a brain disorder that makes muscles contract and go into spasms. More than 250,000 North Americans are known to have the condition, which distorts posture and movement, often causing limbs to jerk and twist.

In the November issue of Neurology, researchers at Washington University School of Medicine in St. Louis suggest that dystonia results from a shortage of cellular receptors for dopamine, one of the brain's chemical messengers. Problems with the dopamine system already are known to underlie Parkinson's disease, another movement disorder.

The major treatment for dystonia is to inject affected muscles with a bacterial toxin that temporarily puts them out of commission. "If we could understand the disorder better, maybe we could find a better treatment," says lead author Joel S. Perlmutter, M.D., an associate professor of neurology and radiology. "I'd much rather give patients a pill to cure the disease than put a needle in the vocal cords or eye muscles to treat the symptoms."

Dystonia can affect the whole body or specific parts such as the eyelids, mouth, vocal cords, neck or hand. Symptoms may appear when a person tries to use that part, hampering activities such as reading, eating, speaking or driving. Muscle spasms in the eyelids, for example, may squeeze the eyes shut for a good part of the day, making a person functionally blind. Spasms in the vocal cord may reduce the voice to a whisper.

As few as 5 percent of people with the disorder have been correctly diagnosed or are under appropriate treatment, according to the Dystonia Medical Research Foundation. The disorder frequently is confused with ailments such as stiff neck, psychiatric problems, arthritis, tennis elbow or laryngitis.

A malfunction in the basal ganglia is thought to cause dystonia -- some dystonic patients have structural abnormalities in this region. Located deep within the brain, the basal ganglia regulate both voluntary and involuntary movements.

Previous attempts to explain dystonia have suggested the overproduction of dopamine in the basal ganglia. "Our work reveals this isn't the case," Perlmutter says.

In the study reported in Neurology, the researchers gave eight baboons a neurotoxin named MPTP (methylphenyltetrahydropyridine) to induce symptoms of Parkinson's disease, which they also study. Because of their expertise in distinguishing the two disorders, they noticed that the baboons transiently displayed signs of dystonia on their way to developing Parkinson symptoms.

The animals began extending and twisting their limbs a few days after they received MPTP. The symptoms appeared only on one side of the body because the drug was injected into the opposite side of the brain through the carotid artery.

The dystonic symptoms peaked at 11 days and lasted for 2 weeks to 3 months, whereas Parkinson symptoms -- slow movements, tremor at rest, unstable posture and inwardly bent limbs -- appeared around 50 days, plateaued by 3 to 5 months, and persisted for as long as 16 months.

The researchers analyzed two regions of the basal ganglia -- a shell-shaped structure called the putamen and the caudate. During the dystonic phase, dopamine levels in these structures were 97 percent to 98 percent lower on the treated side than on the untreated side of the brain. They also were about 98 percent lower than those in untreated baboons.

"It's well known that MPTP produces a substantial reduction of dopamine associated with Parkinsonism," Perlmutter says. "The surprising feature here is that reduced dopamine levels also coincided with dystonic symptoms. Therefore additional factors must determine whether dystonia or Parkinson's results from a deficiency in dopamine function."

Dopamine regulates neurons by interacting with cell surface proteins called dopamine receptors, which come in several types. Perlmutter and colleagues measured the amounts of three different dopamine receptors in the MPTP-treated baboons. In the Dec. 1, 1996, issue of The Journal of Neuroscience, they reported that levels of a dopamine receptor named D2 fell by 20 to 40 percent 17 to 18 days after MPTP treatment. The level rose to four-to-eight times higher than normal by the time the Parkinson symptoms peaked. "So the timing of D2 receptor depletion coincided closely with the appearance of dystonic symptoms," Perlmutter says. "There was no correspondence between D2 receptor levels and Parkinsonism."

Surprisingly, D2 receptor levels changed on both sides of the brain, even though dopamine itself was depleted only on the affected side. Perlmutter is hoping to determine whether the signal that regulates the receptors crosses the brain via a factor carried in the blood or is transmitted through a nerve pathway.

The third observation came from two positron emission tomography (PET) studies of dystonic patients with hand or forearm cramps -- patients who could lie still in a PET scanner without too much difficulty. When the researchers touched vibrators to the hands of study participants, blood flow to the brain's primary sensory motor cortex and supplementary motor area -- areas that process both motor and sensory information -- was considerably less than in normal subjects. Alterations in putamen D2 receptors could alter these brain responses to vibration by nerve pathways that connect the basal ganglia and the cerebral cortex, the researchers reasoned.

In the second study, reported in the Jan. 15, 1997, issue of The Journal of Neuroscience, the researchers found a 29 percent reduction in D2 receptor binding in the putamen of patients with hand or forearm dystonia compared with normal patients. "This is the first demonstration of a receptor abnormality in dystonia," Perlmutter says.

The three observations -- decreased D2 receptor binding in dystonic patients, reduced levels of dopamine and dopamine receptors in MPTP-treated baboons, and reduced cortical responses to hand vibration -- fit together. "Therefore we suggest that a decrease in D2 receptors in the putamen leads to dystonia," Perlmutter says.
Perlmutter JS, Tempel LW, Black KJ, Parkinson D, Todd RD. MPTP induces dystonia and Parkinsonism: Clues to the pathophysiology of dystonia. Neurology, November 1997

The research was funded by the National Institute of Neurological Disorders and Stroke, the Greater St. Louis Chapter of the American Parkinson's Disease Association, the Charles A. Dana Foundation, the National Alliance for Research on Schizophrenia and Depression, the Sam and Barbara Murphy Fund for Dystonia Research, and Washington University's McDonnell Center for the Study of Higher Brain Function.

Washington University School of Medicine

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