Although deep brain stimulation (DBS) is currently approved by the Food and
Drug Administration for Parkinson's disease treatment, researchers are also
exploring its use in patients with treatment-resistant depression, with some
Helen Mayberg, M.D., describes the dramatic effect of deep brain
stimulation on patients with treatment-resistant depression.
Credit: David Hathcox
At a lecture at APA's 2008 annual meeting last month, Helen Mayberg, M.D.,
a professor of psychiatry and neurology at Emory University, presented
exciting evidence that not only offers hope to those whose depression has not
been relieved with conventional treatments but also brings into focus the
pathways in the brain that are directly involved in depression.
Clinical research has repeatedly shown that about one-third of patients
with depression have little or no response to antidepressant treatment.
Although electroconvulsive therapy (ECT) is effective for a proportion of
patients who have inadequate or no response to pharmacotherapy, many remain
resistant to the treatment.
Enter DBS, a surgical procedure that directly modulates certain neural
wirings with constant electricity. Two electrodes are planted bilaterally at
specific spots in the brain where they release continuous, low-voltage
electrical shocks directly to the neurons around their tips. The electrical
impulses suppress the physiological electrical currents transmitted among
neurons and in effect "wipe out" the signal transmission in
certain neural circuits.
The electrical current is supplied by a small battery implanted under the
skin near the patient's chest.
The surgery to implant the device can be performed under local anesthesia,
which allows the patient to remain conscious throughout the procedure. Because
the precise placement of the electrode is critical, the operation is guided by
brain-imaging tools such as magnetic resonance imaging (MRI).
The risks and side effects of electrode brain implantation are similar to
those for the procedure in Parkinson's disease.
One advantage of the procedure is its reversibility. In addition, the
voltage and frequency of the electric impulses delivered can be adjusted by
the treating physician according to patient response.
More than one brain circuitry is being explored as the target for
depression treatment. In her presentation, Mayberg said her research focuses
on stimulating the circuitry in the subgenual cingulate (sCg) area, also known
as Brodmann area 25.
Although scientists are only scratching the surface of the neurological
mechanisms that contribute to depression's pathology, the mysterious area 25
inside the anterior cingulate cortex has attracted much attention. It has been
shown to be overactive in patients with depression or in healthy people
experiencing artificially induced sad feelings. Antidepressants seem to
suppress this overactivity.FIG1
This area of white matter sits on the crossroads of an extensive web of
important pathways. It is heavily involved in cortisol regulation and stress
response, sleep modulation, serotonin modulation and trafficking, emotion
regulation in the limbic system, and motivation and drive.
"It's at the hub of all the tracks that can wreak havoc on all the
core systems that are affected by major depression," Mayberg said.
The premise of DBS is similar to that for ECT, as both approaches use
externally applied electricity to alter the brain's own electrical
transmission. Mayberg called ECT a matter of "rebooting the
system," while DBS continuously tinkers with a specific piece of neural
In a pilot study conducted at the University of Toronto in 2002, six
patients who had prolonged, debilitating depression and experienced no relief
after taking at least four different antidepressants (five of the patients had
failed ECT as well) received MRI-guided surgeries for DBS. Two electrodes were
implanted through two small holes in the skull into the targeted areas.
Patients were kept awake during the operation. To monitor for side effects,
the researchers instructed them to report anything they might feel.
The effect was dramatic. "In the first operation, as we turned up the
[electric] current slowly from zero to four volts, the patient suddenly said,
'Did you do something? I have a sudden sense of calmness," explained
Mayberg. "The phenomenon was seen not in every patient but [was] quite
Unlike transcranial stimulation, the electric stimulation in the brain does
not create a direct sensation. The immediate sense of calm, quiet, relief, and
lightness reported by some study subjects occurred only when a specific spot
was stimulated with a particular dose of electricity. These spontaneous
reports of a "weight being lifted" were followed by patients'
increased awareness, interest, attention, speech, and engagement with others
in the room about 10 to 15 seconds later. They also mentioned changes in
visual perception. "Patients said they thought the light in the room had
been turned up, and the colors seemed more saturated," Mayberg said.
The acute effects in the operating room are not, however, predictive of
long-term efficacy in patients getting DBS, Mayberg reported. But with chronic
stimulation in their brain a majority of the severely depressed patients got
significantly better. Four of the six patients in the Toronto study achieved
response (defined as a 50 percent reduction in scores on the Hamilton Rating
Scale for Depression) by the end of six months after the implantation, and the
response continued for a year. The study results were published in the March
3, 2005, Neuron.
The four patients who responded in the 2002 pilot study continued with the
treatment and, after almost five years, remained well, Mayberg said. The study
has since been expanded to 20 patients, and researchers have seen a comparable
response rate and a consistent pattern: patients who responded early stayed
well. The results of this new study will be published soon.
DBS alone will not cure those who have suffered from severe and prolonged
depression for years. "If you've been sick for that long, you need
behavioral rehabilitation," Mayberg emphasized. "You cannot just
put the stimulators in and send people on their way. This requires a highly
coordinated collaboration between neurosurgeons and psychiatrists."
The procedure carries risks inherent in any brain surgery, such as
infection, hemorrhage, and seizure. The subcutaneously implanted battery and
wires may pose risks for superficial infections. There has been no evidence of
autonomic, motor, or overt mood changes observed in study participants so far,
including in at least one person who had been receiving continuous stimulation
for five years.
Mayberg cautioned that as promising as these data are, DBS is still
experimental in relieving treatment-resistant depression. More trials must be
conducted to clarify unanswered questions such as why certain patients still
do not respond to the treatment, what long-term side effects may emerge, and
what the safe and effective doses of electrical impulses should be.
Researchers are also investigating the effect of DBS on depression in bipolar
II patients. Other DBS studies are being conducted in New York, France,
Argentina, Germany, and elsewhere. ▪