In the middle of room #11 in the Cleveland Clinic's surgical center, Diane Hire lies on an operating table, the back half of her shaven head hidden behind a plastic curtain. Four pins, one driven into either side of her forehead, the other two in back, hold a titanium halo fast to her skull. An anesthesiologist, several nurses and her psychiatrist cluster around the bed.
Behind the curtain, neurosurgeon Ali R. Rezai surveys Hire's brain, white and snaked with thin red arteries, through a pair of small holes he's drilled in the top of her skull. Because so few pain receptors are located in the brain, only local anesthetic numbs Hire's head. She is awake during the procedure-or as awake as she can be. For the past 20 years, she has suffered from severe depression, a crippling strain of the disease that afflicts as many as four million people. Years of therapy, at least 10 different drugs and six courses of the whole-brain shock technique known as electroconvulsive therapy (ECT) all failed to bring Hire lasting relief.
Her final hope is this operation, a radical form of neurosurgery called deep-brain stimulation, or DBS. Whereas ECT-a treatment that's been demonized in movies like One Flew over the Cuckoo's Nest but is still used on roughly 100,000 patients a year-floods the brain with electricity from the outside, this technique delivers a smaller dose of better-targeted current to an area of the brain believed to be a key regulator of mood. Wires thread beneath the skin from their place in the brain and plug into two battery-run stimulators implanted in the chest. About the size of an iPod nano, each stimulator constantly pumps out current, bathing a small region of brain tissue in electricity. If ECT is the equivalent of slapping defibrillators against a heart-attack victim's chest, deep-brain stimulation is the pacemaker that prevents the attack in the first place.
On the operating table, Hire closes her eyes. Rezai slowly inserts a wire as thin as a fishing line through the left hole in her skull, using the halo as a guide. His team has already mapped out his route using a precise 3-D reconstruction of Hire's brain compiled from 180 MRI scans. His target is a chunk of neurons associated with energy and mood. After the tip of the wire is in the right spot, he repeats the process on the other side.
Within 90 minutes of the first cut, Hire has two electrodes lodged in the center of her brain. Now it's time to charge them up. On the other side of the curtain, Donald A. Malone, Jr., Hire's psychiatrist, tells her that everything's ready. Malone has a clear, soothing voice and a comforting, boyish face. He's the kind of person you'd want to talk to if someone was about to shock your brain.
At his signal, two volts of electricity, enough to power a wristwatch, course through the wires and radiate outward from the tip a few millimeters in every direction. Millions of neurons bask in the electricity, and the effect is fairly immediate. Hire feels warm at first, a bit flushed.
And then it happens. The room looks brighter to her. The faces, the big, circular lights overhead, the ceiling-they all seem clearer. Malone asks her how she feels. "I'm really happy," she replies, clearly surprised. "I feel like I could get up and do all sorts of things." But even more telling than her words is the look on her face. For the first time in 20 years, with a halo bolted to her head and two freshly drilled holes in her skull, Hire smiles.
Deep-brain stimulation began as a treatment for movement disorders in the mid-1990s, and the surgery has been performed on more than 40,000 patients, most of them Parkinson's sufferers, since then. In those cases, the current normalizes activity in the basal ganglia and thalmus-which dictate motor control, among other things-and can calm their shaking hands and limbs.
But the clinical trial in which Hire is enrolled, along with 16 other patients, is among the first to tackle depression. Other major trials are under way at Emory University and the University of Toronto. Exact numbers are hard to ascertain, but it's estimated that fewer than 50 patients in North America are walking around with wires in their brain.
In some ways, severe depression is a far more challenging disease to treat than Parkinson's. It can manifest in dozens of different ways and arises from a variety of complex factors, some genetic and some environmental. For instance, scientists are just starting to identify a class of what they call vulnerability genes. In essence, they come in two forms: lucky and unlucky. "If you have one version, you are relatively resilient in the face of stress," says Brown University psychiatrist Ben Greenberg, who is collaborating with the Cleveland Clinic group. "But if you have another, the more severe the stress you have in your life, the more likely you are to develop depression."
Most depression therapies address the disease as a kind of communications problem in the brain. When all is healthy, a neuron receives a chemical message from a neighboring neuron and dispatches a corresponding electrical signal along a nerve fiber called an axon. Then, at the other end, the neuron pumps chemicals on to the next cells.
Drugs attempt to improve communication by altering chemical signals. Prozac, the popular antidepressant, blocks the action of a pump that sucks serotonin, a key mood-regulating chemical, out of the gaps between two neurons. This leaves more serotonin in those spaces, supposedly improving the flow of messages between neurons. But why (or whether) this makes people happy remains unclear. Antidepressants may generate billions of dollars in revenue for pharmaceutical companies, but recent studies suggest that pills work only 50 percent of the time-and they don't do much at all for the millions like Hire who are severely depressed.
Deep-brain stimulation takes another approach, targeting the electrical signals that facilitate the chemical communication. The exact mechanism affected is still undetermined, but Rezai suspects that DBS works on axons, the central conduits of each nerve cell. These protein-sheathed fibers act like miniature telecommunications cables, passing messages from one end of a cell to the other. Rezai thinks the added voltage may be increasing bandwidth in the axons, possibly allowing them to carry more information-and more of the right information. In the long run, he hopes, identifying damaged axons could help scientists develop new methods of diagnosing and treating depression.
The New Lobotomy?
But first Rezai must convince his colleagues that attacking depression with electrical current is a good idea. Patients like Hire, who don't respond to drugs, therapy or ECT, reveal how little modern science really understands about depression, which is one reason why DBS tends to raise thorny scientific and ethical questions. Most Parkinson's patients are in their 60s or older, but victims of depression might only be in their 20s. Will it be safe, wonders psychiatrist Neal Swerdlow of the University of California at San Diego, for them to have the hardware implanted for six or seven decades?
Then there's the fundamental problem of delivering happiness on demand. Hire's psychiatrist uses a handheld device to tune the voltage and frequency of the stimulators implanted in her chest. Although some patients might wish to manipulate the device themselves, Malone says self-control is unlikely. There's a risk of cranking the volts too high, potentially causing brain damage. "This is not cosmetic neurology," he says. "This is about treating a fatal illness." Yet the trial-and-error process of banishing depression is still as much art as it is science.
To some, acting on this rudimentary understanding of DBS and its effects on the brain recalls the notorious history of operating on the brain to treat mental disorders. One psychiatrist, Jeffrey Schwartz of the University of California at Los Angeles, has compared the procedure to a lobotomy. Swerdlow is more hopeful. He thinks DBS, or some future derivation of it, truly could help patients and advance neuroscience along the way. His main concern is that the trials are happening too fast.
But Malone can't imagine going much slower. Time is dangerous in depression, with suicide-the eleventh leading cause of death in the U.S.-claiming more than 32,400 lives every year. For Hire, DBS isn't about unlocking the mysteries of the brain; it's about being able to get out of bed in the morning.
Some Rare Good News
Depression started controlling Hire's life in her early 30s. At 36, after 12 years of service in the Navy, she was medically discharged because of the disease. She went back to school and became a physical therapist. She worked and worked, trying to ignore her growing unease and inability to relate to family and friends, let alone strangers. She tried various drugs and met frequently with therapists. Yet the depression only grew stronger.
In 1999 she stopped working for good. She started semi-regular courses of ECT. The treatment failed to improve her mood and affected her short-term memory, a common side effect. Then, in 2005, Hire heard about Malone's work with DBS and applied to be part of one of the first clinical trials of its use to treat depression. She and her therapist submitted a dictionary-thick stack of papers to Malone, documenting Hire's long battle with mental illness, but they got no reply.
By 2006, Hire rarely left her sofa, spent most days in sweatpants, and watched television from morning to night. It took her four weeks to work up the motivation to clean the house. That fall, she called her therapist and told her that she couldn't handle it anymore. "It was a really black, dismal existence," Hire recalls. "I just couldn't function."
As fate would have it, the very next day Malone called Hire's therapist with some excellent news: He wanted to meet Hire, if she was still interested, to begin the long process of determining whether she was a suitable candidate for the trial. The vetting could take months, but Hire didn't care. "I was at the end of my rope," she says.
Mood Swings in an MRI
The day after her surgery, with her scalp sewn up but the wires still sticking out, Hire is moved to the Cleveland Clinic's main imaging center, where she's wheeled into a tightly packed room containing a functional magnetic-resonance-imaging (fMRI) machine. The device generates powerful magnetic fields to measure the metabolic activity in different areas of the brain in real time. It's shaped like a giant, nine-foot-wide doughnut and has a narrow bed inserted through the center hole. The imaging technician, John Cowan, helps Hire position her head inside the opening and outfits her with earphones and a microphone, while neurophysiologist Kenneth Baker squeezes behind the machine to attach the wires from her head to an external stimulator in another room.
From an adjacent room, Cowan, Malone and Baker watch Hire through a window and on a small video screen, talking to her frequently to keep her calm. For the next 48 minutes, while she tries to remain relaxed and perfectly still, Baker turns the voltage on and off as the machine scans her brain. For 30 seconds, she's happy. Then Baker shuts off the electrodes, Hire's smile fades, and the machine maps how her brain reacts. Another 30 seconds pass, and the happiness returns. Cowan later marvels at the effect of the stimulation on Hire and the other depression patients. "They're always laughing, and I'm wondering, how can you be laughing like this so soon after surgery?"
Regardless of how or even whether DBS is curing Hire's depression, the fMRI scans show that physiological changes in her brain accompany the emotional changes. The scientists can watch different brain areas-which they refer to as "nodes" or "hubs" in a larger circuit-become active, one after the other, in a repetitive pattern. "We're putting electrical impulses into a hub that connects large parts of the brain involved in your mood, your anxiety and your energy level," Rezai says. The more that scientists understand about how the diseased brain functions, he explains, the more they will know how to find the faulty wiring or circuits responsible for it, and from there they can design the therapies to fix it.
Keep on Smiling
The results of these limited tests of DBS are impressive so far. In 2005 the Toronto group found that four out of six patients showed significant improvements. Earlier this year, psychiatrist Thomas Schlaepfer's group at the University of Bonn in Germany announced that all three of his patients were benefiting from the surgery. And the Cleveland-Brown collaboration reports improvements in 70 percent of their patients, half of whom are in complete remission.
Medtronic, a company in Minneapolis that manufacturers the hardware for DBS, is working with the Food and Drug Administration to plan the largest study yet of depression and DBS-a 100-patient trial in which the scientists may delay stimulation in half the patients for six months, switch it on in the other half, and compare the results. Emory is also planning to conduct a blind trial.
The Cleveland-Brown group is even starting to think about next-generation versions of the technology. Rezai, for instance, envisions implanted sensors that could detect abnormal activity in key brain circuits and deliver the necessary jolts to correct it. With the help of Cleveland Clinic biomedical engineer Charles Steiner, he's also developing versatile electrodes that send current in a specific direction. These would create a more targeted pulse, enabling the psychiatrist to further fine-tune the stimulation to suit the patient.
In Hire's case, though, the existing technology seems to be working just fine. When I meet with her six months after the surgery, she doesn't look like a person who spent 20 years trapped in a dark mental cave. She's energetic. She shakes my hand firmly and looks me straight in the eye-something she says she simply wouldn't have been able to do before. She laughs often (and my jokes aren't even really funny). She now walks 50 miles a week, talks to her family constantly, chats with strangers at the post office. And her smile is a regular, everyday thing, not a freakish, fleeting appearance in a crowded operating room.
The stimulation has been active since a month after the surgery, when, over the course of several visits, Malone adjusted the electricity, searching for and finding the optimal pulse. Yet Hire's depression hasn't been vanquished. The disease could still be triggered by life events-a death in the family, for example-which is why Malone and the other psychiatrists stay so heavily involved in each patient's life. But now if Hire starts feeling despairing or apathetic again, Malone can adjust the stimulation enough to ward off the darkness.
I ask Diane whether it bothers her to have her mental health regulated by a machine, and she shakes her head. For the most part, she says, she forgets there's a stimulator stuffed under her chest muscles and two wires snaking up her neck, into the depths of her brain. "I wake up every morning and feel like I control how the day's going to be and don't even think about, 'Oh, gosh, I hope it's still on,' " she says. "It feels like I have the power."
Contributing editor Gregory Mone, a known fainter, remained on his feet while witnessing a DBS surgery.
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