Neurologist and psychiatrist Mark George, MD, was studying brain imaging and depression in 1990 at London’s Queen Square Hospital, a center for neurological diseases renowned for a century as a hotbed of discovery, when he bumped into a man in an elevator with an astonishing report.

“He said, ‘You’ll never believe it, but this person put a magnet to my head, and it made my thumb move,’” recalls George, who was fresh from South Carolina, where he’d just finished residencies in neurology and psychology. In fact, the man was part of a study in which researchers were experimenting with magnets to treat malfunctions of the brain’s motor cortex — the part of the brain that controls voluntary movements.

The encounter left George, then in his early 30s, with the “crazy idea” that it might be possible to use magnets to influence the brain in other ways and perhaps alter an individual’s mood. After all, he thought, if a magnet could stimulate the brain enough to cause movement, might it be possible to position it over a spot where it might affect feelings and emotions?

Back in the United States, George took a research position at the National Institutes of Health and persuaded his boss to let him test the theory in healthy people, aiming magnets through their skulls to the area just behind their foreheads — the site of the prefrontal cortex, the brain’s planning and decision-making center. Scientists then were just learning about the brain’s interconnectedness, so he speculated that in stimulating the cortex, he could reach deeper structures involved in depression and other mood disorders. It was a risky move, in that scientists were concerned that if magnets were powerful enough to move a thumb, they could be powerful enough to cause a seizure.

But, notes George, “It could be a window to the cortex and it could make people better.” Now a professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina, George became the first U.S. psychiatrist to use the technique, known as transcranial magnetic stimulation, to treat depression. About 3,000 patients received TMS in the past year, not including those in research studies, according to estimates from Neurostar, manufacturer of the only TMS device used for depression. 

Psychiatrists are turning to TMS and other forms of brain stimulation as alternatives to drug treatment, which is often ineffective. Some 20 to 30 percent of people with severe depression fail to get relief from currently available medications; about 0.5 percent of adults in the United States suffer severe depression unaided.

 “These patients can’t work. They’re not functioning. Their lives are pretty miserable,” says Charles DeBattista, MD, professor of psychiatry and behavioral sciences at Stanford.

“It cuts across the economic spectrum,” he adds. “We have former CEOs, doctors and university professors who become debilitated — they can’t think or can’t get out of bed. Sometimes they’ve lost the will to eat. I have seen patients wither away and die. So we need some options for those who don’t respond to standard treatments.” 

Drugs, together with psychotherapy, have been the mainstay of treatment since the advent of the first antidepressants in the 1950s and 1960s, followed by the ever-popular SSRIs — medications like Prozac, Zoloft and Lexapro. But drugs are not foolproof, and some patients either don’t respond or become resistant to them over time. Moreover, there are few new drugs in the pipeline, says Alan Schatzberg, MD, professor of psychiatry and behavioral sciences.

“It’s relatively quiet, and that’s unfortunate. Some companies are pulling out, and a lot of people are very worried about that,” Schatzberg says. “Some people feel we need better animal models or a better sense of biology. We need to come up with innovative targets. The bottom line is companies are investing less, and we’re looking at a potential shortage of new drug options over the next decade.”

So attention has turned to such techniques as TMS and deep brain stimulation, which involves placing an electrode in deep brain structures and has long been used to reduce tremors and other symptoms of Parkinson’s disease. Radiosurgery, used to treat tumors, is also being explored at Stanford as a treatment for depression.

The stimulation methods rely on the brain’s design as an exquisite piece of electrochemical machinery.  When a nerve cell is exposed to electricity during normal function or as part of treatment, it opens its gates to a rush of ions, mostly sodium and calcium. This triggers an electrical impulse that travels down the length of the cell and activates connections with other cells.

With each movement or thought, that process is repeated thousands of times with neurons communicating via electrical signals in a complex system of circuitry. In depressed patients, the circuits involved in regulating mood don’t function normally; connections are faulty or lost altogether. In theory, electrical stimulation may be able to jump-start the process and repair some of these broken circuits, thus relieving sufferers of their overwhelming despair. It would be something akin to rebooting an errant computer.

Electroshock and beyond

The principle was first applied in the 1930s in the form of electroshock treatment, which delivers a jolt of electricity directly to the brain. The treatment, known today as electroconvulsive therapy or ECT, is used in 100,000 Americans annually and remains unquestionably the most effective therapy for major depression, freeing as many as 80 percent of patients from their symptoms. In the early days, however, it was crudely applied and subject to abuse, becoming the bête noire of the psychiatric field.  Though it has evolved into a sophisticated therapy, with rigorous patient safeguards, it has never completely shed its early reputation (immortalized in the 1975 film One Flew over the Cuckoo’s Nest). Moreover, the treatment can cause some disquieting side effects, including memory loss and effects on cognition. The fear of side effects and stigma around the treatment are a deterrent for some physicians and would-be patients.

“So there has been a major effort to develop therapies that can help people with treatment-resistant disease without significant side effects,” says Brent Solvason, MD, PhD, medical director of psychiatric interventional therapy at Stanford.

In transcranial magnetic stimulation, a magnetic field passes unimpeded and uncharged through the skull, creating an electrical spark only when it bumps against neural tissues. As a result, the side effects — scalp discomfort, pain at the site and temporary headache — are minimal in comparison with ECT.

Amit Etkin, MD, PhD, a psychiatrist who comes to the field from the perspective of a neuroscientist, says he was drawn to TMS because he could apply it to manipulate small sections of the brain and then use brain imaging technology to see the response. That makes it very useful for understanding brain networks, as well as for treating mood and anxiety disorders.

He sees TMS as the ultimate replacement for ECT, which distributes electricity widely through the brain, inducing a seizure in patients, and thus requiring anesthesia and muscle relaxers. TMS, on the other hand, precisely targets a specific area of about a square centimeter, or the size of a fingertip, Etkin says. The procedure is done without anesthesia, while the patient is fully awake.

‘It feels like a woodpecker tapping on the side of my head. It doesn’t hurt. When you get used to it, it kind of feels good.’

The magnetic field quickly loses its potency, so it penetrates only a few centimeters into the skull. But because the brain is so interconnected, it can have an indirect impact on deeper structures like the amygdala, two almond-sized nerve bundles that process emotion, memory and fear.

“So you’re stimulating one area, but it has wide effects,” says Solvason, associate professor of psychiatry and behavioral sciences. Solvason, who has a background in cell and molecular biology, began experimenting with TMS in 1998 because existing treatments had been of little help to his patients, he says. He has used the technique in about 100 patients and, together with DeBattista, was involved in one of the TMS trials that led to Food and Drug Administration approval.

One woman’s experience

Like many patients, Myrl, a 58-year-old Pacifica, Calif., resident, turned to TMS out of desperation. Haunted by depression for more than two decades, she had tried at least 10 different drugs, virtually everything on the market. Some gave her brief relief, in which she felt like a veil on the world had been lifted, and she could enjoy a simple walk outside. But then the curtain would fall again.

“It’s paralyzing. There is no motivation there, even though I have lots of interests,” she says. “And there is the isolation. Sometimes I find it hard to talk. Everything takes energy. It’s just swimming upstream. Just getting up and taking a shower to get ready is overwhelming. I feel like I’m not really living — I’m just existing.”

She learned about TMS from a friend and thought it was worth a try. She already had rejected ECT because of the possible cognitive side effects, including memory loss.

“I didn’t feel I could afford to lose any more brainpower,” she says, as there are days when her mind feels foggy. “So when I heard about this, I thought, ‘Boy, this sounds really good.’ There wasn’t any radiation involved. It was pretty benign, and I was willing to try it because I had run out of other options.”

At the Stanford Mood Disorders Clinic, Myrl, a spare, gray-haired woman in blue jeans, reclined in a light blue leather dentist’s chair, hands resting on a magazine in her lap. DeBattista attached a 1-inch, T-shaped plastic strip to her forehead, which helped define the anatomy so he could properly position the magnet — heavy, figure-eight-shaped coils about the size of two fists. The insulated magnet has the strength of 1.5 Tesla, similar to those used in a standard MRI, and is placed against the left side of the head. A wire connects it to a computer, which DeBattista programmed to emit a series of pulses. Then the magnet began its rat-a-tat-tat, sounding like mini-jackhammer against the head without actually striking it.

“It feels like a woodpecker tapping on the side of my head,” Myrl reported. “It doesn’t hurt. When you get used to it, it kind of feels good.”

Her forehead twitched with the pulsing of the magnet. Because of the muscle spasms, some patients complain of headache or pain at the site, but these typically resolve within a day, physicians say.

Myrl lay there calmly for the 37-minute session, submitting to the treatment without complaint. When she spoke, it was in a flat tone; her expression rarely changed. As she did crossword puzzles or tried to read her Architectural Digest, she received the standard 3,000 pulses, with short breaks in between. She returned daily for six weeks, as the therapy has to be repeated to achieve any long-lasting effect.

At the end of her sixth week, she noticed an improvement. Her husband told her she was joking and laughing more. And an incident with a family member that normally would have plunged her into depression has left her feeling unruffled. “There is definitely more resilience there,” she says with a lift in her voice.

She’s also begun thinking about returning to some creative hobbies she’d abandoned, like jewelry making and decorating. “I just feel excited about doing things that I’d put aside because I couldn’t enjoy them like I once did.”

The FDA approved the therapy in 2008 on the basis of a trial in 301 patients, including 30 at Stanford, who had tried all else and failed. Those patients who received TMS were twice as likely (24 percent versus 12 percent) to get better as those who got a sham treatment, in which a shield prevented the magnet from penetrating the brain. DeBattista says in daily clinical practice results are even better, with about half of patients responding. He notes clinic patients are typically on medication (not allowed during the controlled study), which might magnify the effects of TMS.

“Firing those neurons may help the medication work better,” he says.

One of the limitations of TMS, which is available at most academic medical centers and some community hospitals, is its cost — $8,000 to $12,000 for a course of treatment — which is just beginning to be covered by insurance.

Moreover, the treatment is still very much evolving, as clinicians are trying to figure out which brain area to target for best results. Currently, they aim for the prefrontal cortex, as depressed patients appear to have reduced activity there, says Etkin, an assistant professor of psychiatry and behavioral sciences. But clinicians now use a very hit-or-miss approach to locate that spot, and about a third of the time, they miss, he says.

So Etkin has begun a study aimed at making the procedure more exact. For the study, patients lie in a standard MRI machine while undergoing TMS so Etkin and his colleagues can simultaneously expose the patients to TMS and obtain real-time data on what’s happening in the brain. Stanford radiologists have created a special set-up for this purpose, one of the few in the country. This way they can see which regions of the brain are active during TMS and use that to develop new, more precise targets and, they hope, improve treatment results.

“One of the things that is shocking about the field is not only do we not know how to target it but we don’t know how to personalize it,” Etkin says. “We’re really groping at straws in our current method, which I think will be revolutionized by the combined TMS/fMRI.”

He also hopes the TMS/fMRI study will give clinicians a better understanding of the underlying mechanisms of TMS. Though it’s believed to act on abnormal circuitry, either suppressing or stimulating activity there, it could in fact be working through an altogether different mechanism to relieve patient symptoms, he says.

Etkin is also testing the technique in patients with post-traumatic stress disorder. He’s enrolling 64 PTSD sufferers in a new trial in which he and his colleagues will map brain activity associated with psychotherapy treatment and with pre-treatment TMS stimulation in various areas in the prefrontal cortex. He and his colleagues then will look to see where brain activity in response to TMS matches brain activity associated with eventual response to psychotherapy. As with depression treatment, many PTSD patients are helped by psychotherapy — now the most effective treatment — but many are not, and in the case of PTSD, even fewer alternatives exist. “We can look at our scans subject by subject and see what’s going on,” he says. He hopes this work will form the basis for either a novel TMS treatment or a combined, new approach to PTSD, taking advantage of the strengths of both. At Stanford and other institutions, scientists are exploring TMS for treating other psychiatric disorders, including obsessive-compulsive disorder and schizophrenia, as well as non-psychiatric disorders, such as pain, Parkinson’s disease, stroke and tinnitus.

Deeper treatment

For depressed patients unreachable through TMS, Stanford investigators are looking at another option: deep brain stimulation. Jaimie Henderson, MD, associate professor of neurosurgery, has used DBS in some 600 patients with Parkinson’s disease since 1996, when he was involved in the early trials. Now he’s launching a study with Solvason and DeBattista, part of a multicenter trial in which they will test the stimulation technique in 10 patients with debilitating depression.

It is in many ways a last-resort option: “You don’t get more invasive than opening up the skull and putting a probe in the brain,” DeBattista notes. But if it works, it could be a godsend for those who are simply not able to function otherwise.

The approach is based on work by neurologist Helen Mayberg, MD, at Emory University, and neurosurgeon Andres Lozano, MD, PhD, at the University of Toronto, whose imaging studies showed that severely depressed patients had hyperactivity in a region of the cortex known as the subgenual cingulate, also called Brodmann Area 25. This thumbnail-sized structure, labeled in 1909 by German neurologist Korbinian Brodmann (who first conceived the idea of mapping and numbering sections of the brain), is a bit like the brain’s Grand Central station, connecting networks involved in mood, anxiety, memory and cognition.

In 2005, Mayberg and Lozano began zeroing in on that target, implanting electrodes in five patients. Later they expanded their testing to 20 patients, with 60 percent of them responding gradually over six months. Some of the results were striking, with patients doing so well that they were able to return to work and re-engage in family and social activities.

“Patients described it like the release of a block, the removal of a veil,” Henderson says. “Colors seem brighter. Things seem more interesting. This all-encompassing feeling of despair is relieved.”

In the Stanford trial, he will implant two electrodes into the target area, one on each side, then connect these by wire to a battery pack buried in the patient’s chest wall. Patients will be able to turn the device on and off, making the treatment reversible.

“I’m optimistic,” DeBattista says. But, he notes, “It would be nice to have something less invasive. If we have a target, we might be able to get to that target without opening up someone’s skull.”

That’s the goal of another small study at Stanford using the Cyberknife, a noninvasive form of precision radiotherapy used for more than a decade in cancer patients. The therapy, invented by Stanford neurosurgeon John Adler, MD, uses high-dose precision radiation on a particular target with sub-millimeter accuracy without harming nearby cells.

Since the spring of 2010, he and Solvason have treated three severely depressed patients with the Cyberknife in a safety trial, using it to slow down areas of the brain that are too active in the depressed state. Like the deep brain stimulation trial, this one targets Brodmann 25.

One of the challenges is finding the right radiation dose to disable the cells, but not kill them, while maintaining a sustained antidepressant effect, Solvason says.

Yet another option for those resistant to standard therapy is vagus nerve stimulation, in which clinicians install a stimulator in the armpit and snake the wire to one of the vagus nerves, a major pair of nerves that run from the brainstem through the neck and down to each side of the chest and abdomen. These nerves carry messages between the body’s major organs and areas of the brain that control mood, sleep and other functions. The stimulator is programmed to send out signals along the nerve, in the form of short bursts of energy, to the brain’s mood centers to help relieve depression symptoms.

The FDA-approved technique is commonly used in patients with epilepsy, and has been found to be moderately effective in patients with intractable depression, says John Barry, MD, a professor of psychiatry and behavioral science who was involved in a major trial on the treatment. But he says the therapy hasn’t caught on in the psychiatric community, in part because of its high cost — more than $33,000 for the device alone, not including implantation — which is not typically covered by insurance.

“It’s probably useful, but I don’t think it’s found its place yet,” Barry says.

Scientists say these techniques still need refinement before they can be counted on for wider use.

“We have a lot to learn,” DeBattista says. “We don’t know what will work in the long term. We have a lot of brave patients who are desperate and for whom there are no alternatives.”

Etkin says he envisions a time when these patients, rather than spending years on a hopeless quest of drug after drug, would be referred early on to a specialty TMS diagnosis and treatment center where they would undergo brain imaging and receive a tailored, personalized treatment using one or multiple magnets simultaneously targeting superficial structures in the cortex, as well as deep brain structures. Treatment times would be reduced and side effects minimal. “That would certainly be a triumph for neuroscience in the clinic,” he says.

E-mail Ruthann Richter