ARTICLE IN BRIEF
- ✓ A new study found that patients who had had deep brain stimulation implants for Parkinson disease showed impulsive behavior when their stimulator was on, compared to when it was off.
The man was wheelchair bound and crippled by Parkinson disease (PD). But he literally jumped at the idea to sit in a more comfortable chair clear across the room. It was the first time that University of Arizona scientist Michael J. Frank, PhD, saw the fruits of his research in action.
Dr. Frank studies the possible negative effects of deep brain stimulation (DBS), and his latest study — published Nov. 23 in the journal Science—suggests that PD patients are far more impulsive when the stimulators are turned on. And so they were when his wheelchair-bound patient stood and began walking. His wife shouted in fear, and Dr. Frank and his assistant kept him from falling.
Dr. Frank and his colleagues designed a study to test impulsivity in 17 PD patients who had had DBS. They found that patients made poorer choices when their stimulator was on, compared to when it was off. Still, it is hard to say what this means for their everyday lives.
Investigators who work with DBS patients every day called the study elegant. “They worked hard to figure this out,” said Michele Tagliati, MD, associate professor of neurology and division chief of movement disorders at Mount Sinai School of Medicine in Manhattan.
“We clearly need more research,” the Mount Sinai doctor said. The problem in designing any study to test the benefits and side effects of DBS is that there are literally thousands of possible electric settings that can be made once the electrodes are in place, he said.
Doctors can alter the amplification, frequency, and pulse rate, Dr. Tagliati said. What's more, each electrode has four different contacts, each placed on a different spot in the subthalamic nucleus. To complicate things even further, the electricity can spread across the region like a wave, making it almost impossible to figure out why and how it works in calming the motor symptoms of Parkinson disease.
Impulsivity in PD
Several years ago reports started surfacing warning that some PD drugs — dopamine agonists — can trigger uncharacteristic predilections, including gambling, obsessive housecleaning, overeating, compulsive tinkering with electrical components, and a robust increase in sex.
Similar clinical observations are beginning to be discussed in the DBS world, Dr. Frank said. “There are some reports of impulsive behavior with DBS, including gambling — just not to the same extent as the dopamine agonists,” he explained. But still, he said, these problems are rare, and the benefits of the technology far outweigh any of these risks.
“We are in no way advocating that patients stop either of these treatments, which are often quite effective,” he explained. But he said the investigators would want patients to be aware of the associated, though rare, risks for impulsivity with DBS so they can discuss it with their doctors should any of these problems arise during the treatment. As the medication studies show, stopping the medicine eliminates these obsessive and impulsive behaviors.
Dr. Frank and his colleagues decided to test for impulsive tendencies on and off the electrical device to determine what the treatment is doing in the brain to bring out impulsivity. They tested two groups of patients — 17 who had DBS and 15 taking dopamine medications — and age-matched healthy controls. Patients were tested on an off medication and with DBS on and off.
The investigators designed a computer game, training the patient to choose a symbol associated with positive feedback. They used Japanese symbols in lieu of English letters so the patients would not figure out a system based on letters they know. Instead, they were shown two symbols — one paired with positive feedback 80 percent of the time, the other one with negative feedback 80 percent of the time. Then, they presented new combinations of symbols so that the positive and negative feedback symbols were each presented together with other more neutral symbols.
They defined “win-win” conflict situations as those in which one symbol was rewarding 80 percent of the time and another was rewarding 70 percent of the time, and lose-lose situations where there was little reward for choosing either symbol.
Patients off medicine were good at avoiding the most negative symbol but did not do well when forced to choose a more rewarding symbol. When they were on medicine, the opposite occurred: they were poor at avoiding the most negative symbol.
To see whether patients on DBS had changes in impulsive behavior, they designed a slightly different model to test whether stimulation leads to impulsive decision-making. DBS patients chose the more rewarding symbol and avoided the less rewarding symbol when their devices were shut off.
But the results were different when the patients had to make high-conflict choices where there was little reward for choosing either symbol. Whereas healthy participants and patients on and off medication slowed down for high-conflict choices, DBS patients did not, the study team showed. In the high conflict choices, they even sped up their responses, and the more they sped up, the less likely they were to make the best choice. In other words, they were more impulsive when the stimulators were turned on. When the device was turned off, they had no problems slowing down for high conflict situations relative to low conflict decisions.
“If this is confirmed by other groups, the next step is to determine whether stimulation settings can be altered to prevent these cognitive problems while maintaining effective motor treatment,” Dr. Frank said.
Another problem is that most DBS patients have had the disease much longer than patients taking medication and this could also factor in for some side effects.
The Arizona researchers are now studying the effects of other stimulator settings — lowering the voltage and frequency to see whether that would reduce the cognitive side effects of treatment. Indeed, the Mount Sinai group is heading in the same direction to figure out what can be done to avoid these side effects without giving up the benefits of DBS.
The Role of DBS and Dopamine in Rewards and Decision-Making
Dopamine wears many hats in the brain. In the 1950s, Swedish scientist Arvid Carlsson discovered the neurotransmitter dopamine and described the depletion in Parkinson disease. He and others noted the loss in substantia nigra and that more than 80 percent had to be wiped out before symptoms appeared. For decades, doctors focused on the motor symptoms. Over time, scientists also found that dopamine circulates in major cerebral reward circuits, and these deficits affected cognitive and mood changes as well.
To be a good king of rewards, dopamine in the system must go up when the rewards are high and go down when they are not. If things are good, dopamine goes up, and the reward — the good feeling — strengthens the learning that took place on the road to the experience. But medicines keep dopamine levels artificially high all the time, and thus the reward systems are bound to go slightly off center. And that is precisely what Dr. Frank and his colleagues have found.
“Normally, when you make a decision that is not rewarding, dopamine goes down,” Dr. Frank explained. “And that should drive learning to avoid actions preceding the negative stimulus so that they are not likely to do that behavior again. Medication continuously releases dopamine and doesn't allow the brain to experience low dopamine levels when it should, when the chips are down,” he added.
Unlike medications that keep dopamine levels artificially high all the time, DBS has a different effect, the scientists discovered, supporting the idea that the subthalamic nucleus is required to “hold your horses.”
The dopamine levels lost in the disease trigger overactivity of the subthalamic nucleus and lower the ability of the basal ganglia to function properly in motor actions.
DBS disrupts the overactivity of subthalamic function, but in truth scientists still don't understand exactly why it works so well. What they can say is that DBS does not act on the dopamine system itself, but addresses the “effects” of the depleted dopamine in the basal ganglia by counteracting these effects in a different way.