by Valerie R. Gregg

hen the mighty Muhammad Ali lit the Olympic torch in 1996, the world was touched by the tremor in his hand, his stiff, labored gait, and the whispery hesitation of his once eloquent voice. But at least he was still fighting. Without the medical treatment he has sought, Ali's Parkinson's disease would by now have rendered him trapped within an inert body - unable to walk, speak, dance, feed, or dress himself - utterly dependent on others.

The losses of Parkinson's disease differ for each patient and multiply and intensify over the years. Patients often live with it for decades. Drugs can offer relief for years and then fail for a variety of reasons. But Emory University researchers and clinicians are making strides toward finding long-term strategies to deal with this degenerative disease, which affects more than 1 million people in the United States alone.

Recently named a Parkinson's Disease Research Center of Excellence by the National Institutes of Health (NIH) - a designation enhanced by $7.5 million in research funding - Emory boasts one of the most comprehensive Parkinson's programs in the world. The NIH grant will fund five Emory studies over the next five years, giving neuroscientists here a chance to contribute even more to expanding knowledge about brain function.

"There are more movement disorders specialists here than at any other center in the country - maybe the world," says neurologist Jerrold Vitek. "We have many extremely well-respected basic scientists and clinicians and a huge cadre of patients. Our surgeons are booked up months and months in advance. People come here from across the country and the world for Parkinson's treatment."

The Center of Excellence studies run the gamut: from molecule to neuron, from brain circuitry to the whole patient. And they offer real hope to patients with Parkinson's disease and other movement disorders, says Mahlon DeLong, chairman of the Department of Neurology and director of the Center of Excellence.

"We're focused on areas that may have a real payoff in terms of new drugs and surgeries, and that payoff could come relatively soon," he says. "Better understanding of the mechanisms behind a disease gives you a better understanding of opportunities to improve treatment."

Working in tandem with neurologists who
map the brain, neurosurgeon Roy Bakay
performs surgical procedures such as
pallidotomy and deep-brain stimulation.
Other clinicians and researchers at Emory
are trying to determine how these proce-
dures work, as well as how to develop
better drugs for patients for whom
surgery is not an option.

Somewhere near the root of Parkinson's disease is a deficiency of the neurotransmitter dopamine in the basal ganglia -- the portion of the brain controlling movement. This deficiency sets off a mysterious neurological chain reaction that creates the debilitating symptoms of the disease.

DeLong's team found that low dopamine levels cause a tiny group of basal ganglia cells called the subthalamic nucleus to become especially hyperactive. They then flood the area with an excitatory neurotransmitter called glutamate, which is toxic in large quantities. This finding led to a new understanding of standard Parkinson's treatments like the drug levodopa and surgery.

In the 1950s, the prognosis for Parkinson's patients was so grim that neurosurgeons resorted to experimental surgery. Through trial and error, they discovered that making a lesion in the globus pallidus, a surgery called pallidotomy, sometimes alleviated symptoms.

"It was based on very vague notions," says DeLong. "But in those days patients were just lying there inert, rigid and stiff, but with their awareness intact. They were cared for by spouses or institutionalized. There were no effective treatments. It was tragic. It was a curse. It was so desperate that surgeons tried all kinds of things. A little bit of luck and serendipitous discovery opened the door to the pallidotomy."

Because surgical techniques were then less sophisticated, pallidotomy often created more problems than it solved. Mortality and morbidity were very high, but desperate patients had no alternatives.

When the dopamine-boosting drug levodopa was discovered in the 1960s, it appeared to cure most patients almost overnight, and surgeons stopped performing pallidotomies and other such procedures. Unfortunately, the drug's effect proved to be short-lived. After taking it for three to five years, Parkinson's patients often see their symptoms return and often develop side effects that make the drug intolerable. It remains, however, the drug of choice for most patients.

Pallidotomy made a comeback in the 1980s, in large part because of research findings on the mechanism of the disorder and studies by DeLong's team showing that lesions of the subthalamic nucleus and the globus pallidus reduced symptoms dramatically. Surgeons destroy misfiring cells using a heating probe guided by precise measurements of brain activity to locate misfiring neurons.

Scientists still don't know exactly why levodopa stops working or how brain lesions eliminate symptoms, but the answers are within reach.

Mahlon DeLong proved that many
Parkinson's symptoms result from
overactive, not underactive, cells.

Because of that, surgery that helps one Parkinson's patient may not help another. The same goes for drugs.

Scientists at the Yerkes Primate Research Center at Emory are looking to the intricacies of neural function in monkeys to find new treatments. For several years, they have studied different treatments and behaviors using monkeys with drug-induced Parkinson's disease symptoms. The current drug, however, induces symptoms instantly. One important study to be funded by the NIH grant will try to create a primate model of Parkinson's disease that develops slowly and progressively, as it does in humans.

Another study will try to find new drugs to treat Parkinson's symptoms or eliminate levodopa side effects like severe involuntary movement. Yerkes researcher Yoland Smith and his team are painstakingly mapping the locations of a slow-acting glutamate receptor found in basal ganglia neurons. Not only are Smith and his colleagues trying to find the neurons that misfire, they also are trying to locate the exact spots along the edges of the synapses where faulty communication occurs. Learning how to adjust glutamate flow selectively by modulating these receptors could pave the way for new drugs to treat Parkinson's symptoms locally, without affecting the rest of the brain.

"If we stopped glutamate from working completely, the patient would go into a coma," says Smith. "Glutamate is an essential neurotransmitter for all kinds of activity. We want to stop the overactivity of glutamate in the subthalamic nucleus that is causing the symptoms. A lesion does that by killing the whole group of neurons. We hope to find drugs that modulate the actions of glutamate from only a particular type of slow-acting glutamate receptor."

Here's how Smith's project works: Using both normal and Parkinson primate brains, scientists soak a portion of the tissue in a chemical solution that forces gold particles to bind only to the slow-acting glutamate receptors, creating a map of every synapse where they are found. After mapping several areas, researchers will give the animals drugs known to inhibit glutamate effects at these receptors. Behavioral studies will then measure symptoms before and after administration of the drug.

"Better drug therapies are much more accessible to patients than surgery, which is very expensive and inappropriate for some people," says Smith. "Even if we don't have the whole story of the disease, if we can improve the medication and further understanding at the same time, so much the better. I think this study can do both. Patients need new therapies now. They can't wait."

Yerkes researcher Yoland Smith leads a
team that is mapping the locations of a
slow-acting glutamate receptor found in
basal ganglia neurons. He hopes to find
a way to stop the overactivity of gluta-
mate in the subthamalic nucleus that
is causing Parkinson's symptoms.

"With lesioning, we have to be surgically exact because there are land mines all over the place," says Vitek. "If you're a little off, you risk partial loss of vision, paralysis, and stroke."

That's why he thinks electrical stimulation of precise areas of the brain (deep-brain stimulation) offers great promise to Parkinson's patients. "If you get a side effect, you just lower the voltage, turn it off, or insert it somewhere else. You can't take back a lesion."

Approved by the FDA only for use in the thalamus to treat tremor, electrical stimulation of the globus pallidus and subthalamic nucleus shows great promise for treating other Parkinson's symptoms as well. Vitek is now exploring the effects of deep-brain stimulation on these two areas, hoping to determine which locations work best for specific symptoms.

The procedure involves mapping the brain region using a tiny electrode - a wire thinner than a strand of hair - and then implanting the stimulating electrode. That electrode is connected to an electrical pulse generator like a cardiac pacemaker that is implanted under the skin near the collarbone. This device delivers a controlled amount of electricity to the electrode and can be turned on and off by the patient with a handheld magnet.

"Thalamic stimulation is now done worldwide, but it only helps the tremor," Vitek says. Initial human studies indicate that stimulating the subthalamic nucleus and globus pallidus can reduce the rigidity and stiffness of Parkinson's disease as well as drug-induced involuntary movements.

Likewise, making a lesion of the subthalamic nucleus can eliminate many other symptoms. However, it can cause involuntary, uncontrolled movements, maybe making stimulation a better choice.

How electricity eliminates the symptoms remains unclear. It may be inactivating the cells the way a lesion does or activating an inhibitory system within or to the cells. Then again, it may be normalizing the pattern of neuronal activity.

Although Vitek can't explain the whys and hows of deep-brain stimulation yet, he hopes one day to be able to offer every Parkinson's patient treatment for their particular combination of symptoms. "We see some with tremor, others with rigidity, others with gait and balance problems. Some of these problems occur on one side only and others on both sides," he says. "Some have more problems with either their upper or lower body. And we have patients with different combinations of all these things. The question we hope to answer is what works for what symptoms. How does pallidotomy compare to subthalamic nucleus stimulation to globus pallidus stimulation -- across one another and also within different subgroups of patients? Different people have their opinions, but there's now no substantive data to back them up."

Neurologist Jerrold Vitek meets with a
patient who has undergone treatment for
tremor associated with Parkinson's. Vitek
is exploring how deep-brain stimulation
affects other symptoms of
Parkinson's disease.

Parkinson's patient Sybil Guthrie was
wheelchair-bound and virtually immobile
before undergoing deep-brain stimulation.
Now she's free to enjoy simple pleasures
such as gardening with her husband,
dancing, and playing with her grand-
child. Her story was featured on
the news magazine 20/20.

With PET, researchers can turn the stimulator on and off, up or down, and see what happens in various parts of the brain, according to DeLong. "PET allows us to measure activities like glucose metabolism and blood flow, before and after stimulation and as correlated with symptom relief. This type of imaging can reveal areas whose activity has changed because of disease or with behavior."

Another center study uses PET and a technique called microdialysis to measure how remote areas of the Parkinson primate brain are affected by deep-brain stimulation or lesioning of the subthalamic nucleus. In microdialysis, a tiny amount of extracellular fluid is extracted from a portion of the brain and tested for levels of different neurotransmitters.

Microdialysis is involved in another Emory study that attempts to understand a separate branch in the tangled tree of Parkinsonian brain circuitry. "We're trying to solve questions about the role of the external pallidal segment, and how this part of the brain might affect the subthalamic nucleus in Parkinson's disease," says neurologist Thomas Wichman, principal investigator of this study. "How activity in the subthalamic nucleus is regulated, how it becomes abnormal, and how lesioning or stimulation affects that abnormality are all very important in our understanding.

"Microdialysis will allow us to look at the chemical changes in different areas of the circuit that communicate with the subthalamic nucleus. This might help figure out why neurons are overactive in Parkinson's disease and how we can manipulate them with drugs."

Neurologist Thomas Wichman, who
wants to discover how to manipulate
neurons with drugs, uses tiny cathe-
ters in microdialysis studies related
to Parkinson's brain circuitry.

"We have highly effective treatments, but they're not accessible to many people," says Bakay, who performs pallidotomies and other Parkinson's surgeries at Emory. "Surgeries like deep-brain stimulation are expensive, and the devices must be replaced every five or so years at $10,000 a pop. But it works. We have to fully understand how it works and have enough data to prove it works before surgeons will perform it and insurance companies will pay for it."

"We've made more progress with Parkinson's than in any other area of neurology in recent years," says DeLong, "but there's a great deal left to understand. We've barely scratched the surface."

Valerie R. Gregg is a freelance science and health writer in Atlanta.