MOVING FORWARD
The brain's ability to sort through a chaotic system of messages in order to keep muscles and limbs repsponding appropriately is an intricate riddle for researchers.
by Richard Cox
These days Martin Beck can look straight at the camera when someone snaps his picture.
It wasn't always so, but not because Beck was camera-shy.
For much of his life, the 58-year-old stage and screen actor has suffered from cervical dystonia, a type of movement disorder that wrenches the neck muscles into something akin to a chronic disfiguring cramp.
"In order to look at the camera, I would have to twist my body to one side," recalls Beck, who was able to compensate for his condition until it began to worsen in the last decade.
Since 1993, however, Beck has been undergoing a novel treatment at the University of Southern California School of Medicine that enables him to keep his head upright for weeks at a stretch. Although he is not cured, he gains enough temporary relief from his symptoms so that even previously difficult tasks such as driving a car are once again within his grasp.
Beck's case is representative of the many small, but significant, victories that physicians are scoring against movement disorders-victories made possible by an increased understanding of how the brain and muscles work together to put our bodies in motion.
Movement disorders actually encompass a broad spectrum of diseases involving impaired mobility, explains Cheryl Waters, M.D., associate professor of neurology, and director of the Movement Disorders Program at USC. Some make it difficult for patients to initiate movement, while others produce excessive, involuntary muscle contractions.
"Parkinson's disease is a good example of where movement is deficient and patients move slowly," Waters says. "Some patients even experience akinesia, an inability to move."
By contrast, other disorders are marked by excessive, uncontrolled movements that are either rapid (tremor, Tourette's syndrome, Huntington's chorea, tardive dyskinesia) or slow (dystonia).
Despite their differences, all movement disorders seem to share a common origin in the brain that differentiates them from other diseases-multiple sclerosis or epilepsy, for example-that can also impair movement. "These are all diseases of an area of the brain known as the basal ganglia," says Waters.
Movement involves a fairly complex and chaotic series of interactions among different areas of the brain. Luckily, the basal ganglia are around to make the whole process look easy. These paired clusters of nerve cells act as a central command center, processing incoming sensory information and orchestrating the brain's commands to flex muscles and move limbs.
The basal ganglia are also the main circuitry through which flow the nerve signals controlling movement. Those signals are carried from nerve cell to nerve cell by chemical messengers called neurotransmitters.
There are several neurotransmitters in the brain, each with its own special properties. One in particular-dopamine-is abundant in the basal ganglia, and nearly all movement disorders can be traced to problems in the way the body manufactures and utilizes this chemical. Dopamine is the common language of movement-controlling communications; take it away, and the brain's instructions to the muscles start to resemble a story with some of the words missing.
That's exactly what happens in Parkinson's disease.
With Parkinson's disease, cells in a dopamine-producing region of the basal ganglia inexplicably begin to die, gradually depleting the brain of this critical neurotransmitter. Patients may first notice a characteristic tremor. As the disease progresses, muscles become rigid, posture is stooped and the act of walking is reduced to a series of halting, shuffling steps.
For nearly a quarter of a century, the mainstay of anti-Parkinson's treatment has been levodopa, a substance that is converted to dopamine in the brain, replenishing the lost neurotransmitter. It works well-for a while.
"After a period of time, levodopa loses its effectiveness and starts to wear off before the next dose is due. That interval of time gets shorter and shorter, and ultimately patients lose their ability to control their response," Waters says.
Worse yet, some patients develop a hypersensitivity to the drug that causes them to suffer dyskinesia, or involuntary movements. These side effects have forced researchers to seek alternative medications to supplant, augment or delay traditional therapy. The search has paid off.
"I anticipate there will be five new drugs to treat Parkinson's disease coming out in the next 1-2 years," Waters says. "We've studied all of these drugs at USC, so they are all quite familiar to us. We are very optimistic."
One category of medications-dopamine agonists-are chemicals that mimic neurotransmitters. These have shown especially promising results in patients who are in the early stages of the disease by delaying the need for levodopa or reducing its dosage requirements.
Another group of medications neutralizes the enzymes that normally break down dopamine after it delivers its chemical message. These drugs can lower a patient's dependence on levodopa by helping the brain maximize the use of its diminishing dopamine supply.
One class of these drugs, called MAO-B inhibitors, has been in general use for the past several years with largely favorable results. Now government approval of a new class of drugs, COMT inhibitors, is imminent, according to Waters. "COMT inhibitors work along the same lines as the MAO-B inhibitors, but they work on a different enzyme. So in a way they represent another fundamental breakthrough in drug design," says Waters.
Since all drugs used to treat Parkinson's disease merely mask the symptoms-leaving the disease to progress unchecked-there has been considerable interest in finding a treatment that will actually restore the brain's dopamine-producing capability.
So far, research has centered on two highly experimental surgical procedures. In the first, dopamine-producing cells from the patient's own adrenal glands are implanted in the brain. This technique has yielded widely inconsistent results, however, and is now rarely performed. A more hopeful approach involves transplanting fetal brain tissue into patients, but scientific investigations into technique have been dogged by political controversy and hampered by lack of funding.
Although surgeons have yet to offer a definitive cure for Parkinson's disease, they have hit upon a remarkably simple means for alleviating symptoms in the most severely affected patients. If the basal ganglia act as a sort of central circuit box for the nerve impulses governing movement, why not short-circuit some of the errant signals?
"Assuming the basic science premise that all movement is mediated through this circuitry, then a movement disorder should be rectified by blocking the circuit at some point," says John Peter Gruen, M.D., assistant professor of neurological surgery at USC. That point can either be the pallidum or thalamus, two nerve nuclei within the basal ganglia, and the way Gruen and the team of USC surgeons block it is by creating a tiny scar in the affected tissue.
This surgery-called pallidotomy or thalamotomy, depending upon the location of the lesion-can ameliorate some of the more severe symptoms caused by Parkinson's disease or the medications used to treat it. Thalamotomy appears to work best against tremor, while pallidotomy is used primarily to treat dyskinesia, akinesia and muscle rigidity.
The first such procedure actually occurred years ago and totally by accident when a Parkinson's patient undergoing brain surgery suffered a small stroke in the basal ganglia. To everyone's surprise, the patient had a marked improvement in symptoms afterward.
Today's high-tech surgical technique relies less on serendipity and more on careful planning. Using computer models and radiological images, surgeons plot the location where the lesion is to be made. Then, after making a small hole in the skull, they insert a probe that measures electrical activity in the brain. "Each of those nuclei has distinct electrical properties, so you can be certain of their location and know the probe is in the pallidum," Gruen explains.
Surgeons then insert another probe that emits high-frequency radio waves-similar to microwaves-heating the surrounding tissue and creating a small lesion. Patients are awake during the procedure and provide surgeons with immediate feedback on the results.
Gruen notes that this type of surgery is still in its infancy, with much to be learned about its best application. "We're still at an early stage," he says. "There is not enough data yet to reach a definitive conclusion about the best place to make these lesions."
Consequently, at USC neither procedure is elective; neurologists refer patients for surgery only after they have failed all conventional therapy. Those patients who have the procedure are monitored closely in follow-up research.
With pallidotomy and thalamotomy, nerve signals are "headed off at the pass," before they can command muscles to move. Another approach used to treat dystonia patients intercepts those signals at the other end of the nerve pathway-just before they before they reach the muscle.
In dystonia, the most common movement disorder after Parkinson's disease, muscle movement is a bit more predictable. The most prevalent form of the condition-focal dystonia-affects a single group of muscles, causing sustained, even painful, muscle contractions. It is most often seen in the eyelids (blepharospasm), vocal chords (spasmodic dysphonia) and neck (cervical dystonia, or torticollis). It appears in adults usually after age 30 and can result from certain antipsychotic medications or from subtle brain damage caused during childbirth. A number of cases have no known cause.
"Focal dystonia, can be severely disabling," says Mark Lew, M.D., assistant professor of neurology, and chief of the Dystonia Clinic at USC. Equally frustrating for many patients, he says, is the fact that focal dystonia is sometimes mistaken for a psychiatric problem because it can be exacerbated by stress.
For years, treatment has taken the form of drug therapy that inhibits dopamine and other neurotransmitters, but it comes with a host of intolerable side effects, Lew says, "and the syndrome continues to progress and change, making drug therapy difficult."
Recently researchers discovered they could ease the muscle spasms through injections of a toxin produced by Clostridium botulinum, the same bacteria that causes deadly botulism food poisoning. Here, however, the toxin's impact is limited, temporary and decidedly non-lethal.
Injections are not administered broadly; Lew uses an electromyogram-a probe to measure electrical impulses in the muscle-so the toxin can be delivered to the most affected area. "The toxin seems to be selectively absorbed by the most active muscles," he says. Once it reaches its destination, the toxin severs communications between muscle and nerve.
"The nerve dies, and the muscle atrophies," Lew explains. "It then takes three or four months before the nerve endings grow back." But those three months offer dystonia patients a precious interval of normal living.
"That's when I'm my most active," says Martin Beck, whose initial apprehension at getting the toxic injections was short-lived.
Every 13 weeks Beck receives 300 units of the botulinum toxin, which reaches peak effect in about five weeks. He'd gladly do it more often, but there's a risk that more frequent injections might prompt his body's immune system into forming antibodies against the toxin, rendering future treatment ineffective. To counter this risk, USC and other centers are studying alternate forms of the botulinum toxin.
"When the toxin is wearing off, I have more pain and less mobility," Beck says, "but even at its worst, I can still drive with both hands on the steering wheel, which was impossible before the treatment."
Like many people who have a movement disorder, Beck also benefits greatly from physical therapy. Physical therapy is an integral part of the treatment for every movement disorder, helping patients to master the rules of a game that can change on a daily basis. In Beck's case, therapy consists mostly of exercises aimed at reducing stress and improving relaxation.
"In individuals with dystonia, there is a strong connection between an increase in stress in their daily lives and an increase in their symptoms," explains Mary Hudson, DPT, a physical therapist who specializes in the rehabilitation of neurologically impaired patients at USC University Hospital.
Physical therapists can also teach patients how to use adaptive devices-walkers and canes, for examples-that improve mobility, or help people learn new ways to make once-common and effortless movements.
"We analyze how a person is currently doing a movement, and then we look at how we can modify it so that it will be more efficient, safer and ultimately easier for the patient to perform," Hudson says.
Often that involves devising strategies that enable patients to outsmart their disability, forcing them to think in new ways about movements-like walking-that previously required no thought at all.
"For example, a classic way that a patient with Parkinson's disease will initiate movement is to rock up on their toes and get their body weight so far forward that in essence they are falling. They either step or, unfortunately, continue falling forward," Hudson says.
"So what we do is teach them other ways to initiate their steps, such as using mental imagery or following distinctive patterns on the floor. We try to get them to use a different part of their brain and make it more of a cognitive process."
Call it a matter of mind over movement, but it allows patients with movement disorders to assume some mastery over their lives again-to regain control over something most people take for granted. Along with new medical and surgical treatments, physical therapy offers patients a source of hope until researchers can finally put a halt to movement disorders.