08 April 2010

Deep Brain Stimulation Mechanisms in Depression

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 (see table). It was recently approved by the US Food and Drug Administration to treat obsessive compulsive disorder. _NS
The effect of deep brain stimulation (DBS) on a depressed brain is turning out to be more complex than at first thought. DBS is not merely affecting the part of the brain near the electrode. DBS appears to be affecting entire circuits of brain interaction -- performing a type of fine-tuning or calibration of the circuitry.
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."

...His [Thomas Schlaepfer] 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 (see diagram). 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.

...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. _NS

One of the aims of psycho-neurologists at the Al Fin Institutes of Psycho-Neurology, is to place the diagnoses of mental disorders on a sound scientific foundation. The demonstration of physical changes in brain circuits as a result of successful treatment would go a long way toward making the treatment of mental disorders more respectable within medicine and society.

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