Science Watch

It's about the size of the letter "o" in this sentence and may have the power to lift deep, unrelenting depression. Through a process known as deep brain stimulation (DBS), an electrode emits small pulses of electricity in the brain, showing promise as a high-tech last resort for people with highly treatment-resistant major depression disorders, according to neurologists.

DBS was first recognized as a treatment for motor symptoms of Parkinson's disease, but now researchers are harnessing the procedure to normalize misfiring brain circuits in people whose depression won't respond to behavioral therapy or medicine. Some, however, fear it comes at the cost of cognitive performance.

In DBS therapy, doctors use MRI to identify target areas they think are causing the disorders. Then, they cut two nickel-sized holes on both sides of the skull and implant the electrodes in the same location in each brain hemisphere. The electrodes are connected to a pacemaker that is surgically implanted beneath the collarbone.

The electrodes immediately begin emitting three or four volts of electricity, 24 hours a day, seven days a week. Doctors can use a remote control to adjust their intensity until they settle on what they think is the right setting.

Since 2005, more than 60 people worldwide have received DBS for treatment-resistant mood disorders. For about 60 percent of them, there's a "striking improvement in their symptoms of depression," says Andres Lozano, MD, PhD, a neuroscientist at the University of Toronto who performs DBS surgery.

What about the brain?

Deep brain stimulation existed as a treatment for managing Parkinson's disease symptoms such as tremors and paralysis before it was used to treat mental disorders, Lozano explains. In 2005, Lozano and Helen Mayberg, PhD, a neurologist at Emory University in Atlanta, published a paper in Neuron examining what would happen if they applied that brain stimulation technique to people whose depression was particularly resistant to behavioral therapy and medication (Vol. 45, No. 5).

The study was motivated by a shift in the way science looks at depression, says Mayberg.

"People are thinking about depression in a new way," she says. "Now we don't think about many brain diseases as being low on some chemical or purely some psychological complex."

Researchers are paying closer attention to the circuits that connect different areas of the brain, rather than localizing disorders to particular brain regions, Mayberg says. In the Neuron study, she and Lozano used MRI to identify a brain area, the subgenual cingulate cortex, that's known to be hyperactive in severely depressed patients.

From past studies, they knew that lesions made in this area could help people with severe depression. Mayberg and Lozano figured that electrical stimulation might work similarly, except it wouldn't permanently damage the brain as lesions do.

The initial trial included six people who met diagnostic criteria for major depressive disorder. The two researchers and their colleagues implanted electrodes in the white matter adjacent to their patients' subgenual cingulate cortexes and fired up their pacemakers. All the patients, who were awake during the procedure, reported a "sudden calmness or lightness," Mayberg and Lozano reported in the paper.

The researchers followed up with the patients by administering monthly depression scales. After six months, four of the six showed significantly fewer depressive symptoms. To make sure they weren't getting a placebo effect, Mayberg and Lozano secretly switched off the electrodes in their best-responding patient. After about two weeks, the patient's scores began to drop. After about a month, his depressive symptoms had returned. The researchers switched it back on and six weeks later he was back up to non-depressive levels.

"It's a chronic treatment," Mayberg says. "But it's not like Parkinson's disease where if you turn it off the tremor comes back immediately, like flicking a light switch. The depressive symptoms creep up on you."

That in itself reveals something about the intractable nature of depression in the brain. "This isn't just, 'Give the system a rest long enough and then it'll be fine,'" she says. "You need [the pacemaker] on."

Sadness in overdrive

Exactly what the electrodes do to the brain remains unclear, but researchers have some ideas. According to Lozano, most researchers think depression occurs in these chronic, unremitting cases because the "set point" for activity in that brain circuit is higher than normal.

"It's as if the thermostat in your house is set at 100 degrees instead of 70 degrees," he says. "For genetic reasons or environmental reasons or both, the set point is high in this mood area of the brain. We think that their sadness is in overdrive."

That, in turn, suppresses activity in other areas of the brain, such as the frontal lobes, which are involved in motivation and executive function.

DBS can turn down the dial, Lozano says. "When we turn down the activity in the subgenual cingulate, the frontal lobes come back online."

Patients improve not only because their mood improves, he explains, but also because they regain their motivation and ability to engage with the world.

Early on, many researchers thought these effects were generally the same ones that other scientists had achieved with lesions—namely, that they were basically cutting out the problem. Mayberg says that's not quite correct.

"People thought that instead of cutting out an area that you knew was important in a circuit, you could stimulate it. Stimulating it, then, is kind of like doing a lesion, but you could control it," she says. "It turns out that is woefully over-simplistic."

DBS might work in some cases by interrupting some circuit activity, she says, but it's just as likely to be altering the way brain regions communicate with one another. Mayberg's and Lozano's most recent paper, published in September's Biological Psychiatry (Vol. 64, No. 6), further supports that assertion. In the earlier Neuron paper, Mayberg and Lozano found that DBS altered blood flow not just in the stimulated brain region but in the regions connected to it as well. Most recently, they found the same pattern with metabolic activity in the stimulated and connected regions. That's consistent with the idea that DBS acts on those connections, but it's impossible with current technology to know for sure, Mayberg says.

Targeting therapy

As dramatic and promising as the results are, Mayberg stresses that DBS isn't for everyone. The people she's treated with DBS are those for whom all other techniques have failed. The ideal candidate for DBS is someone who's had major depressive symptoms for four or five years; is enduring a lengthy depressive episode; and hasn't responded to at least four conventional treatment regimens, including pharmacotherapy and electroconvulsive therapy. That's because getting the electrodes implanted isn't a decision that should be made lightly, Mayberg says. It's major surgery.

"It's fairly easy surgery, but you still have to go into someone's brain, you still have to make an opening in someone's skull."

There are also some potential side effects to consider, Lozano says. Of the 30 or so studies using DBS with a variety of patient populations, mostly people with Parkinson's, about three have found a slight decline in cognitive skills such as memory and executive functioning in people who've had the procedure.

But both Lozano and Mayberg stress that studies looking at cognitive functioning in people with DBS to treat depression have found no cognitive declines. In fact, many of them showed improvement.

"I've actually seen an increase in the cognitive functioning in some of my patients, and I think that that may be related to them just not being depressed anymore," Lozano says. In May's Journal of Nervous and Mental Disease (Vol. 196, No. 5), Mayberg and Lozano reported that following implantation, onset and maintenance of the DBS system, only minor slowing of motor skills occurred, and those were back to normal levels within a year.

In addition, there's an ethical riddle in surgically treating depression, says Walter Glannon, PhD, a bioethicist at the University of Calgary, Alberta. At issue is the fact that mood disorders can interfere with rational deliberation and decision-making. If someone's decision-making isn't fully online, can he or she realistically give consent to major brain surgery? That's a question best determined by therapists who can use behavioral criteria to determine whether a DBS candidate is well enough to consent to the surgery.

"The patient must have enough decisional capacity to understand what it means to have a device implanted and stimulated in one's brain," Glannon says.

Beyond the risks of surgery and potential for cognitive decline, instantly lifting the veil of depression can shock those who aren't used to feeling their emotions. In many of these cases, Mayberg explains, chronic depression numbs people's ability to feel happiness or sadness, joy or anger.

"When people go from an intractably ill state to suddenly being able to respond normally, they don't trust it," she says.

When they were sick, they might not have given much thought to the negative aspects of their lives, she explains, but then all of a sudden they can really feel what's weighing them down. "[They] actually have to sort of learn what it's like to have a bad day," she says.

Psychologists can provide the kind of therapy they need to train their brains how to feel and react to emotions, Mayberg says. In fact, some of the people who had gone through cognitive behavioral therapy before undergoing DBS reported that after the surgery they were finally able to employ those therapeutic techniques, she says.

A number of other behavioral and mood disorders might also benefit from DBS. Benjamin Greenberg, MD, PhD, a psychiatrist at Brown University in Providence, R.I., is using DBS to treat obsessive-compulsive disorder, with success rates similar to Mayberg's and Lozano's. Also similar is Greenberg's claim that OCD people who've had DBS are then able to tolerate and respond to behavioral therapy.

This broad success leads Mayberg to believe that DBS is establishing itself as an important tool for treating disorders that otherwise won't budge.

"How we conceptualize how the brain mediates our behavior is certainly going through some reevaluations," she says. "Brain stimulation has been a pretty in-your-face example of acutely changing behavior by being very targeted, by changing activity in a very specific location, very specific circuits."