Electrical engineering fixes brain's circuit board

Ewen Callaway

DEEP brain stimulation has long been psychiatry's black magic: stick electrodes into a region linked to mental illness, deliver rapid pulses of weak current, and voila! Crippling symptoms of depression, obsessive compulsive disorder and even substance abuse are eased.

Now brain imaging of people undergoing deep brain stimulation (DBS) to treat depression is revealing the mechanism behind these effects - and who it will and won't work on. The crucial discovery is that DBS seems to tune an array of brain regions, not just the area around the electrode.

This once fringe treatment is now creating a new view of mental illness as a condition affecting an interconnected network rather than arising from chemical imbalances in specific regions. "The brain works on a circuit board," says Helen Mayberg of Emory University in Atlanta, Georgia, whose team is lifting the veil on DBS.

DBS involves continually delivering high-frequency pulses of weak current to a particular region via stimulators that are surgically inserted into the brain. Although invasive, it works so well for Parkinson's disease and other movement disorders that it is now mainstream, with tens of thousands of patients implanted.

In the last decade, researchers have tested DBS on a variety of other conditions. It has proved effective at reducing some symptoms of bipolar disorder and Tourette's syndrome . It was recently approved by the US Food and Drug Administration to treat obsessive compulsive disorder.

Meanwhile, firms that manufacture DBS devices are looking to get the technique approved to treat depression, for which it seems to work well. In 2005, Mayberg's team showed that DBS could help people with a type of depression thought to be completely untreatable.

Instant response

The researchers implanted the stimulators into the subgenual area, which is involved in emotion, in six severely depressed patients for whom all other treatments had failed, including several types of antidepressant drugs and electroconvulsive therapy. Four reported vast improvements (Neuron, vol 45, p 651).

The region was selected because brain imaging studies had shown it to be hyperactive in many people with depression. Most researchers thought that DBS worked by silencing activity in that area. This would explain why so many patients responded as soon as their stimulators were switched on: many said the operating room looked brighter than when they had gone in, for example, a sign of a changed outlook on life. It was as if "something painful had suddenly stopped", Mayberg said at a recent lecture on her work at the Massachusetts Institute of Technology.

That wasn't the whole story, however. PET scans revealed that while DBS damped down activity in the subgenual area as expected, other regions appeared affected too, particularly parts of the nearby prefrontal cortex, which is involved in decision-making and evaluating emotions. "We got lucky," says Mayberg. "It worked, but probably not for the reason we thought."

So why does DBS work? Thomas Schlaepfer at University Hospital in Bonn, Germany, says that the brain is increasingly seen as not just a collection of regions but also as consisting of multiple networks, which can become "misconnected" in mental illness. DBS "retrains these dysfunctional networks", he says.

The brain consists of multiple networks, which can become 'misconnected' in mental illness His own recent work on 10 patients with treatment-resistant depression supports this notion. His team used DBS on the nucleus accumbens, an area involved in assessing pleasurable stimuli that is known to behave abnormally in depression (Biological Psychiatry, DOI: 10.1016/j.biopsych.2009.09.013).

PET scans of seven of the patients revealed that the implant didn't seem to affect activity in the nucleus accumbens itself, but instead suppressed the subgenual area - also called Brodmann's area 25 - just as with Mayberg's team . It also had reverberations in parts of the prefrontal cortex.

"There are clear connections between area 25 and the nucleus accumbens," Schlaepfer says. He suspects that the three areas are part of a brain network that his and Mayberg's teams both tapped into.

The experiments also raise the question of why DBS doesn't work in everyone. While all of Schlaepfer's patients felt their lives had improved a year after having the stimulator implanted - be it returning to work, taking up a hobby or making new friends - some fared much better than others. Mayberg noticed similar variation in 20 depressed people she treated with DBS, and 12 treated for bipolar disorder. "From a practical point of view you've got to figure out who you're going to offer this to," she says.

That's where Mayberg's most recent results, which she presented at the MIT lecture, come in. To see if there were any pre-existing differences in the brains of DBS responders and non-responders, which might predict who should go to the trouble of getting a DBS implant, Mayberg's team turned to functional MRI, which allows you to see which regions light up at the same time - indicating that they are "connected".

In depressed patients who went on to respond to DBS, a part of their prefrontal cortex tended to light up in conjunction with the subgenual area. This did not happen in non-responders. In these patients, the amygdala, which is involved in fear and other emotions, tended to be connected to the subgenual area - not the case in responders.

Mayberg cautions that the results are preliminary, but she thinks she may be onto something. "If this pans out in larger numbers, there's a total dissociation between the two groups," she says. The ability to predict who will and won't benefit from DBS should mean the treatment can be offered to a greater number of severely depressed patients.

The technology could have much wider implications. The National Institute of Mental Health in Bethesda, Maryland, is launching an initiative soon to encourage researchers to describe mental illnesses as disorders of networks rather than by how they make people feel - part of a broader shift across neuroscience.

DBS is helping to map these networks, says Thomas Insel, director of the institute. "For us not to understand the parts of the brain involved in mental illness is really unacceptable," he adds. For now, the initiative is only aimed at researchers, but Insel hopes the brain networks idea will be taken up by doctors too.

Insel and Mayberg hope that a better understanding of how brain regions form networks will improve doctors' ability to match drugs and therapies to patients. It could even lead to drugs that target specific networks.

Mayberg also has her sights on the nascent field of optogenetics, in which individual neurons are turned off and on with pulses of light. Its use in mental illness would demand a much better understanding of the circuits, which DBS studies could help provide. Ultimately, the specificity of optogenetics might allow researchers to make far more subtle changes to brain networks. "That's my dream," Mayberg says.

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