Deep Brain Stimulation Offers Hope in Depression

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There is a new hope for patients who have severe depression. An
experimental surgical procedure, deep brain stimulation, is proving to
reverse the effects of unrelenting depression by stimulating a precise
network of brain cells. Jamie Talan reveals how some of the top
scientists are using this procedure.

Deanna Cole-Benjamin’s depression sneaked into her world through the
back door of her happy, balanced life. By her mid-30s, she had a job
as a public health nurse, a husband and three children. Growing up in
Ottawa, Ontario, she knew nothing about deep sadness. But as the new
millennium began, depression descended without warning. Years of
traditional therapy were of little help; finally an experimental
surgical procedure to implant stimulating electrodes into the white
fibers in her brain made it possible for her to find a way back.

If depression had to shatter her world and push her into a psychiatric
hospital for four years off and on, it arrived at a propitious moment
in the history of modern medicine. Deep brain stimulation for
depression was a technique borrowed from the world of movement
disorders that showed hints of working for psychiatric conditions in
some patients but no proof—yet. Deanna took her place on the operating
table only a year into the first attempts to stop unrelenting
depression by stimulating a precise network of brain cells. And it
worked.

The practice of putting electrodes into the brain and electrically
stimulating at high frequency to calm abnormal hyperactive networks
has helped patients with Parkinson’s disease, essential tremor and
dystonia for more than 15 years. But using the technology to treat
depression developed from the pioneering work of Helen Mayberg, a
neurologist who began her career when brain scanning technology
promised to reveal the secrets of the sick brain.

First, Mayberg mapped the depressed brain on medications, then on
therapy and then on a placebo pill. Each step of the way, she
carefully charted the brain as if it were a city of streets and
avenues. She realized that treatments took different roads but
ultimately arrived at the same address. That was why people with
depression could get better many different ways, even with a placebo
pill.

The limbic structures that regulate mood feed into the frontal cortex,
striatum, thalamus, hypothalamus and brain stem. These regions
communicate with one another all the time, and problems in the circuit
could lead to difficulty with thinking, attention, mood and behavior.
Mayberg found that these circuits, particularly a hyperactive network
of brain cells in the subgenual cingulate region, also called Brodmann
area 25, are abnormally overactive in depression. When treatments
work, the activity of these networks appears to return to normal. It
made sense that so many brain areas are involved in depression, which
encompasses more than just negative mood. People lose their motivation
to get out of bed, to work, to love. Many have problems paying
attention and thinking clearly. Eating and sleeping patterns can be
way out of kilter.

For Mayberg, deep brain stimulation was the next logical step in
figuring out how the network was broken. In the late 1990s, she
approached Andres Lozano of the University of Toronto, who was well
known for his work in movement disorders. Lozano had begun implanting
stimulating electrodes in patients with Parkinson’s and dystonia in
the early 1990s. For many, the crippling symptoms of tremors, rigidity
and slowed movements disappeared with a flick of the switch. Mayberg
wondered if deep brain stimulation could alter mood and behavior as
well.

“These are the circuits for depression,” she told Lozano, pulling out
a scan of the depressed brain. “Can we do something about it?”

***
By the time Deanna Cole-Benjamin came to the University of Toronto in
2004, Mayberg had already spent five years in Canada. For part of that
time she worked with Lozano and psychiatrist Sidney Kennedy to design
a small clinical study to test deep brain stimulation for patients who
had exhausted all other treatment options. In 2002 they were granted
approval to operate on five patients. Within a year they brought their
first depressed patient into the operating room.

During the two-step surgical procedure, neurosurgeons use computerized
maps and brain scans to identify the precise target within the
“depression” network. The patient’s head is kept perfectly still in a
metal frame, the skull bolted into the gear with screws to allow
scientists a steady route into the brain. Surgeons use local
anesthesia: The patient feels no pain, yet is awake during surgery so
that the team can ask the patient questions about his or her mood,
thoughts or symptoms as they approach the target and can also keep a
sharp eye on any potential side effects. Surgeons enter the brain
through two holes in the skull and thread an electrode with four leads
in the white matter tracts of the subgenual cingulate region on both
sides of the brain. Once the electrode is in place, the surgeons send
electricity to it to test its effects—the goal is to stimulate the
network that is affected through that specific tissue target. After
testing is completed, the patient is placed under general anesthesia,
and a small battery pack is implanted near the collarbone and
connected to the implanted leads and extension wires in the brain.

The system has an external controller so that doctors can program the
device. The DBS team generally gives the patient a week or two to
recover from the procedure before they bring him or her back for a
programming session to begin chronic stimulation. Using the optimal
contact established by a combination of the postoperative magnetic
resonance images showing the location of the electrodes and the
optimal effects seen during the electrode testing, the team sets
standard starting parameters at that contact on each side of the
brain. The patient returns weekly and rates the change in depression
symptoms; then adjustments are made on the basis of the previous
week’s reported improvement. Generally, only minor adjustments in
current are necessary, and once a consistent pattern of improvement
emerges, the settings are kept stable.

Deanna was a strong candidate for the experiment: the depression
exhausted her, and she felt indifferent to her family’s love. She quit
her nursing job in 2000, lost interest in the everyday activities of
her life and spent much of her time in bed. “There was a mountain
between me and everyone around me. I didn’t have the strength to climb
that mountain and reach them,” she explained. That detachment and the
exhaustion kept her under the covers that winter. As a nurse, she
recognized that she was depressed but thought she should be able to
shake it off. She couldn’t. Two days before Christmas, her family
doctor was so afraid that she might hurt herself that her husband
drove her to Kingston Psychiatric Hospital, a large collection of
stone buildings with bars on the windows and locks on the doors. It
became her home, off and on, for nearly four years.

At Kingston, Deanna fantasized about swallowing enough pills to die or
drowning in the chilly waters of Lake Ontario, which was the lone bit
of beauty visible to patients. She spoke openly about her ideas; twice
she grabbed a handful of pills and swallowed them in hopes that a
permanent sleep would end her pain.

Doctors at the hospital tried every medicine and treatment that held
some promise for alleviating depression. Over her four years in and
out of Kingston she had 80 rounds of electroshock therapy and even a
relatively new treatment at the time called transcranial magnetic
stimulation, in which a magnetic current is delivered through the
scalp to stimulate areas of the cortex at the surface of the brain.
Nothing worked. “It was worse than being dead in a way,” said Deanna.

By April 2004 she was out of the hospital and seeing Gebrehiwot
Abraham every few days. Abraham, a psychiatrist at the hospital, had
developed a close relationship with Deanna since she was first
admitted in 2000. When she arrived at his office for one of the
appointments, only weeks after her discharge, she knew that he would
probably have to readmit her. The suicidal thoughts were back. But
this time he handed her a fax that he had just received from Sidney
Kennedy of the University of Toronto. Kennedy was recruiting patients
with treatment-resistant depression for an experimental study on the
deep brain stimulation procedure. He would find his match in Deanna
Cole-Benjamin.

Upon meeting the former nurse, Kennedy agreed that she fit the very
rigorous criteria set for the pioneering experimental treatment. She
spent days taking a battery of neuropsychiatric tests and talking to
many psychiatrists, psychologists and nurses. She had two different
brain scans for insight into the structure and function of her brain
under depression.

When Mayberg, who was working with Kennedy, met Deanna, she asked her
what she wanted from the surgery. “To feel connected to my kids
again,” she said. “To feel their hugs and kisses.” Mayberg agreed she
was an ideal candidate for the study. Deanna and her husband, Gary,
knew they had no other option but to embark on an experiment that had
been tried in only a few other patients. She wondered whether she
would turn into somebody different as a result of the procedure. And
what if it didn’t work?

The surgery was performed June 7, 2004. In the operating room, doctors
positioned the metal stereotactic frame, like a medieval halo, over
her head and used screws to pin the frame into her skull, painlessly
stabilizing it. A computer had already mapped out a trajectory to
their target, the bundle of white matter fibers deep inside the brain
near Brodmann area 25. Other than the local anesthesia used to prevent
skin and skull pain, Deanna was not sedated, so that the medical team
could observe any changes in behavior—good or bad—that might occur
with testing of the contacts once the electrodes had been implanted.

The operating room was filled with the surgical and research team
members. With Mayberg standing midway between Deanna’s head and feet,
Lozano drilled a hole on both sides of her skull and made his way to
the target. Deanna recalled the sound of the saw, the smell of burning
bone, the static from a machine recording the activity of her brain.
Lozano threaded the first electrode into the left part of her brain,
the computer helping to mark his course. Then he headed for the right
side of her brain, placing a second electrode in the mirror-image
location. Their patient was withdrawn, quiet. Mayberg was asking her
questions. How do you feel? What are you thinking? Nothing, she replied
—to both. Lozano turned on the stimulator, with a nod in Mayberg’s
direction.

Deanna recalled turning toward Mayberg, who was wearing blue surgical
scrubs. The thought occurred to her immediately that she had been
living in a black-and-white world. Now there was color. She looked
into Mayberg’s green eyes. They were warm. “I really feel like I know
you,” she told the neurologist.

Then Lozano turned the stimulating electrodes off and her world
darkened again. She grew quiet. “It’s gone,” she said. “It must have
been a dream.”

They turned the stimulators on again. “Wow,” she said. The room had
brightened.

“We knew we were on to something,” said Lozano, who imagined that the
late Wilder Penfield may have felt the same way more than 50 years
earlier when he used electrodes to find the target of seizures in his
epilepsy patients. When Penfield sent electricity through the
electrodes, it would provoke memories, emotions and even specific
behaviors depending on where the electrode was placed. This enabled
him to map the human motor cortex. “It is Penfield revisited,” Lozano
said. “It is like going where no man has gone before and figuring out
what is taking place in the mind.”

With Deanna, as with previous patients, Mayberg was struck by these
instant responses. “When we started, we didn’t know what to expect,”
she said. “We hoped there would be an antidepressant effect over time,
but we had no expectation of any acute effects—certainly not the types
of changes described in the operating room. Patients who had the
effects described a sudden sense of relief and calm as they became
aware that their unrelenting negative mood had suddenly changed. With
many more patients we have learned that while these acute effects are
extremely interesting, not all patients experience them, and [those
who do not] still do well with long-term DBS. That said, this was one
of those aha moments that we could not have imagined. It has given us
many new ideas to test about the nature of antidepressant mechanisms.”

Another patient who had been deeply depressed for years spoke
poetically. “Did you just do something?” Mayberg recalled the patient
asking. “I have this sudden sense of calm—the difference between a
laugh and a smile. Like the first day of spring when you see the
crocuses peeping through the snow.”

The team later received approval to expand the study, first to a sixth
patient and then to 20, and they witnessed similar reactions from many
who received the experimental treatment. Mayberg began to wonder just
what was going on. “Who in their wildest dreams thought that this
would be the phenomenon?” Mayberg said. Besides the patients’ feelings
of relief, there was a renewed social engagement, a feeling of being
awake and aware. “They are paying more attention to us,” she said. But
ultimately the researchers didn’t know whether these initial and
surprising responses meant anything for the bigger picture. Would
patients get better?

Mayberg found the entire experience “scientifically inspiring” and
says she now realizes that further work on deep brain stimulation is
necessary. “It’s hard not to feel exuberant about the notion that
these seriously ill patients might now have access to a procedure that
could actually transform their lives,” Mayberg said later, years into
studying deep brain stimulation as a treatment for depression. “This
is highly selective modulation. It gives us important clues where to
shine the light.”

It takes time for depression to work its way into the brain networks
to cause symptoms, and the return from it is often a slow go for
patients—even with the stimulators, doctors now agree. The results
from the first six Toronto patients showed a two-thirds response rate
at six months; this effect has been maintained in these patients after
more than four years of ongoing, continuous DBS. So far there have
been no long-term side effects with the target that Mayberg and Lozano
are using in the DBS procedure, and at the doses used, batteries are
lasting close to five years. Some patients in the studies have had
infections at the site of the electrodes or problems with the leads or
the device that forced them to have the device replaced.

Mayberg moved to Emory University in 2004 and continues to study deep
brain stimulation in severely depressed patients, funded in part by
the Dana Foundation. She maintains a working relationship with the
Toronto team.

On a parallel track, scientists at Brown University, Cleveland Clinic
and Massachusetts General Hospital are also studying deep brain
stimulation for depression. This tight-knit collaboration consists of
Brown psychiatrist Benjamin Greenberg, Cleveland neurosurgeon Ali
Rezai and Mass General psychiatrist Darin Dougherty, as well as a team
of other psychiatrists, neurosurgeons, psychologists, nurses and
technicians. They have identified a different target—the ventral
anterior limb of the internal capsule—that Rezai said is on the same
avenue as Mayberg’s area 25 but on a different block. Their idea to
use DBS in depression followed on earlier work that demonstrated its
success in treating symptoms of obsessive-compulsive disorder (OCD),
Greenberg and Rezai said. Many OCD patients also suffer from
depression, and those symptoms seemed to get better after the device
was turned on. The group at Brown University began performing deep
brain stimulation on patients with obsessive-compulsive disorder in
2000 and it was only a matter of time before their team went after
depression. “The first thing we saw with our OCD patients was a change
in mood,” said Rezai, who joined the Brown University team in 2001.
“They reported that the weight of the world had lifted off their
chests.” Rezai saw similarities in depressed patients and wondered
whether the technique could alter primary depression as well.

One of the first patients the team operated on was Diane Hire, a 54-
year-old woman with a ten-year history of unrelenting depression. She
was so despondent that she barely spoke. Suicide was constantly on her
mind, and she had attempted to end her life several times. She had
tried every medicine known to tackle depression and had had more than
70 sessions of electroshock therapy.

When Rezai turned the stimulator on in the operating room, Diane
immediately brightened and laughed. She said recently that she hadn’t
smiled in a decade. A day later, as scheduled, she had the battery
pack implanted in her chest wall.

A week later the stimulators were turned on. Since then she has
settled into the normal rhythms of everyday life, which is replete
with a mix of emotions. But now her emotions are appropriate to her
experience. In the process, she has also dropped 120 pounds that she
had packed on during her depression. In 2008, Hire told her story at a
conference on DBS and said of the treatment: “I wake up every day
happy to be alive. I wake up looking forward to what is ahead. I am
who I was. I am not a new person or a changed person. I am who I was.”

The future of DBS research
In April 2008 Medtronic, the Minneapolis-based company that
manufactures a deep brain stimulator called Activa, announced plans
for a DBS depression study, in which Greenberg, Rezai and their
collaborators are participating. Elsewhere, Advanced Neuromodulation
Systems, a division of St. Jude Medical Center in St. Paul, Minnesota,
is enrolling patients in a multi-center clinical trial to test its
stimulating device, called Libra. Mayberg and Lozano have a patent
licensed by ANS and will consult on the study. ANS will go after
Mayberg’s area 25. Both studies will accept only the sickest depressed
patients, those for whom nothing else has worked. Investigators will
pursue the various targets they have previously identified.

Apart from these new studies, in the first leg of experimental trials
more than 60 patients in the United States, Canada and Europe have had
stimulators implanted into their brains to treat depression; a few
years after the initial attempts, DBS is still very much an
experimental procedure. The modern-day pioneers of experimentally
treating patients with electrodes implanted in the brain—the Brown/
Cleveland/Mass General team and the Toronto and Emory groups—are
watching this first generation of patients very closely. “We want to
treat depression like we treat heart disease,” said Mayberg. “If
something goes wrong, it’s over. We are being very careful.”

Researchers still have much to learn about deep brain stimulation for
depression: How can the settings be optimized? Is one-sided
stimulation adequate? How does DBS actually work? Finding answers will
require ongoing research and dialogue between academic researchers and
industry.

Today a high level of checks and balances is in place, including those
required by the U.S. Food and Drug Administration, which oversees new
technologies and treatments, and those of individual hospital
institutional review boards. Scientists trying to find ways to alter
the landscape of the human brain are treading slowly and very
carefully.