PHOTO: Dr. Helen Mayberg

26 October 2007—Deep-brain stimulators, implanted devices that send pulses of current into small regions of the brain, help thousands of people with Parkinson’s disease get through their daily lives. But while quelling people’s tremors, these implants may also be scrambling their ability to make decisions, according to a report published yesterday on the Web site of the journal Science. In the study, patients with electronic implants in a part of the brain called the subthalamic nucleus acted more impulsively on certain tasks when the stimulator was turned on than when it was temporarily turned off.

Such implants have been used to treat motor disorders since 1987, when Alim-Louis Benabid and Pierre Pollak first tried using one on a subject in France. In the United States, the pacemaker firm Medtronic, in Minneapolis, has offered deep-brain stimulators for people with Parkinson’s since 2002. About 40 000 people around the world rely on Medtronic stimulators today to treat Parkinson’s disease and other motor disorders.

The device has three internal components: a control unit, a wire, and a set of electrodes. The reprogrammable control box is tucked under the skin near the collarbone. It sends high-frequency electronic stimulation through a wire running up the neck and head beneath the skin. The wires terminate at tiny electrodes embedded deep inside the brain. Although no one has convincingly nailed down the mechanism of treatment, it relieves the tremors associated with the disease, which renews patients’ ability to operate a camera, hold a cup of coffee without spilling, and engage in other fine motor tasks.

But clinicians and scientists are just starting to look at the side effects of the treatment, and they are beginning to find cognitive disruptions. “The procedure dramatically improves patients’ motor symptoms, but unfortunately their quality of life doesn’t always improve, due to detrimental effects on cognitive function,” says Michael Frank, a neuroscientist at the University of Arizona and an author on the Science report. “We figured that some of these effects could stem from the stimulator preventing patients from pausing to make decisions.”

In his study, Frank reproduced for his subjects what it’s like to make a decision based on personal preference. But instead of choosing between pepperoni and anchovy pizza, for instance, subjects had to choose one of a pair of symbols in a game. Each of the symbols used in the game—Japanese characters presented on a computer screen (none of the subjects spoke or read Japanese)—had a particular probability of leading to a reward. When patients with their deep-brain stimulators turned on were presented with two options that were both extremely likely to be rewarded, they responded much more quickly than the rest of the test subjects. In other words, if you have a deep-brain stimulator buzzing your subthalamic nucleus and you simply adore both pepperoni and anchovy, you’re going to impulsively grab whichever slice of pizza is closest, while everyone else salivates and really weighs the options.

The results, when they were fit into computational models of brain circuits that the Arizona scientists developed, present the subthalamic nucleus as a crude moderator of decision making. At least one of its roles may be to detect and respond to high levels of input from other parts of the brain as they scream, “Oh, God! Pepperoni! No, anchovy! No, wait, pepperoni!” This conflict, according to Frank, would normally cause the subthalamic nucleus to put the brakes on any immediate action by engaging the brain’s higher centers of decision making to sort things out. Through an unknown mechanism, deep-brain stimulators knock the subthalamic nucleus offline, and, according to Frank and his colleagues’ theory, that prevents the “stop and think” moment from occurring.

Subtle cognitive tasks like the one Frank used might come in handy during the brain-stimulator-implant surgery. When surgeons enter the brain, they take certain precautions to prevent damaging brain tissue dedicated to controlling speech or movement. Neurologists electrically stimulate the tissue as they bore down to the inner folds of the brain. All the while, they ask the patient, who is fully alert during the procedure, to speak, giving a rough assurance that there will be no egregious side effects after surgery.

Something like the preference test might give doctors a better idea of what impact they are having on the patient’s brain beyond quelling their tremors, says Frank. But as it is now, his test is “probably a bit too long and unwieldy.”

Frank’s “pie in the sky” dream is a closed-loop deep-brain stimulation system. Such a system would both suppress the tremor-causing activity of the real subthalamic nucleus and at the same time act as an artificial subthalamic nucleus. The device could detect increased conflict when a choice is being made and activate the brain’s higher decision-making circuits to make the patient stop and think.

Nearer term, the new insight into brain stimulation’s side effects should make doctors stop and think. Perhaps the stimulator or the surgery could be improved to minimize the decision-making side effect. “It’s hard to know whether there would be a fundamental clash between optimizing the motor effects and minimizing the side effects,” and the balance could be tricky, says Frank. “But certainly, with appropriate attention to these issues, the neurologist can help the patient properly manage the side effects.”