The positron emission tomography scan on the top demonstrates overactivity in a brain region called Brodmann area 25, part of the subgenual cingulate cortex, in severe depression. Reduced activity in this region (shown in blue at bottom) is seen with six months of chronic deep brain stimulation. This reduction correlates with the antidepressant effect of the treatment. (Images courtesy of Helen Mayberg)
Monday, March 31, 2008

Deep Brain Stimulation Offers Hope in Depression

By: Jamie Talan

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.

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 a minimum of four 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, but they responded to treatment once these short-term problems were resolved.

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.



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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