Electroconvulsive therapy, or shock therapy, is the most effective treatment known for severe depression. A strong electrical current applied to the skull triggers epilepticlike seizures that somehow jolt the mind free of melancholy. But shock treatment is a famously blunt instrument. It requires the use of general anesthesia, often causes memory loss and confusion, and can bring on a headache that rivals the worst hangover.

Applying a powerful magnet over a specific region changes electrical activity in the brain at that spot. The earplugs protect against the magnet's loud sound.
An ideal version of electroconvulsive therapy would dispense with the seizure and the side effects. It would target only those areas of the brain involved in depression. It would be easy to administer, and it wouldn't hurt. In short, the procedure would look a lot like transcranial magnetic stimulation (TMS), a kinder, gentler way of jolting the brain that is winning the enthusiasm of clinicians and basic researchers alike. Though still unproven, TMS holds promise as an alternative treatment for a number of psychiatric disorders, as well as epilepsy, Parkinson's disease, and even writer's cramp. It's already helping to map the circuitry of the normal brain and reveal faulty wiring.

"TMS is an incredible tool because it has the potential to be both diagnostic and therapeutic," says Mark George of the Medical University of South Carolina, a neurologist and psychiatrist who is one of the technique's pioneers.

Like shock therapy, TMS stimulates the brain with an electrical current. But it delivers the current indirectly rather than directly. When electricity passes through a wire coil, it generates a magnetic field that can, in turn, induce an electrical current in any nearby conducting material. The brain is nothing if not electrically conductive: Nerve impulses are essentially electrical signals passing along a network of neurons. So magnetic stimulation can create electrical fields in the brain.

Shock therapy requires powerful currents in order to penetrate the relatively nonconducting bone of the skull. But weaker currents can be used in TMS because the skull puts up no resistance to magnetic fields. A paddle containing a coiled wire is held close to the head, and an electrical current passed through the wire generates a magnetic field. Where the magnetic field meets brain tissue, it creates an electrical pulse that scrambles nerve signals, causing a kind of blackout in the region of the brain just beneath the paddle. A single pulse causes nearby nerve cells to fire; if the pulses are rapidly repeated, a kind of blackout ensues, scrambling neural activity for some time after treatment. These disruptions aren't evident to subjects.

"You feel a tapping on your head, caused by contractions of the scalp muscles," says psychiatrist Holly Lisanby, who, as director of magnetic brain stimulation at Columbia University College of Physicians and Surgeons, has administered TMS to hundreds of patients. "In some cases, you do get some scalp pain," she says. "But many subjects find it's not painful at all." And because the currents generated are not nearly as strong as those used in electroconvulsive therapy, she says, there's no seizure, no apparent memory loss, and no need for anesthesia. "I have people who go right back to work after TMS treatment. You're alert, you're awake, you're not groggy or disoriented."

Electrodes record muscle responses prompted by the brain stimulation.
The technology for TMS was introduced in 1985 for diagnosing injuries in peripheral nerves that control body movement and sensation. But the technique also offered scientists the unparalleled ability to stimulate specific brain regions and observe the effects on fully conscious, healthy human subjects. Zapping a spot a few inches above the left ear, for example, makes the right thumb twitch. Basic researchers soon began tweaking other nerve pathways involved in vision, language, learning, hormone responses, and drug reactions. "You can't study the brain as directly in humans with any other technique," says Eric Wassermann, who with George conducted some of the first studies on TMS and mood at the National Institutes of Health. "It's an excellent physiological probe."

But clinical practitioners are most excited by TMS's potential to alter regions of the brain affected by mental disorders. In the mid-1990s, researchers worldwide began testing the method's ability to alleviate the symptoms of depression, obsessive-compulsive disorder, mania, and schizophrenia. Some results are encouraging: In one study of depressed patients who didn't respond to medication, more than half showed marked improvement after five days of TMS treatment. In another depression trial, success rates with TMS rivaled those of electroconvulsive therapy. A study of obsessive-compulsive patients reported a decrease in compulsive urges lasting for eight hours after a single treatment. And in some schizophrenic patients, TMS relieved their auditory hallucinations for weeks.

But advocates of the technique have struggled to replicate these results. They often see profound improvements in some patients and no response in others. "There might be a lot of variation in the circuitry between individuals," Lisanby says. And different treatment protocols seem to produce profoundly different results. Despite earlier reports of success in patients with Parkinson's disease, for example, her own TMS studies showed that the treatment could temporarily make symptoms worse.

Experts acknowledge that they have yet to determine the most effective procedures for magnetic stimulation. In a typical TMS treatment for depression, for example, the coil is held just in front of and above the left ear, over a region of the brain called the prefrontal cortex, which has been implicated in mood disorders. The current cycles 10 times per second and lasts for eight seconds at a time. Each half-hour session consists of 20 of these pulses, and a full treatment course is made up of 10 daily sessions. All of these parameters--the placement of the coil; the frequency, intensity, and duration of stimulation; the number of treatments per day; and the length of the treatment period--are arbitrary. Other combinations might work better.

Monitoring these signals shows how the treatment is affecting nerve pathways.
Researchers are hoping to refine TMS as a clinical tool by identifying the kinds of patients it helps most and finding the best location for and pattern of stimulation for each disease and each patient. Eventually, TMS could have a number of possible applications in treating a disease like depression: Along with helping medication-resistant patients, it might be used as an adjunct for psychotherapy and medication--either short term, before drug effects kick in, or as a long-term maintenance strategy. TMS is approved for treating depression in Canada and Europe, but it is available in the United States only in experimental trials.

And TMS isn't likely to be rushed into clinics here for two reasons. First, the machine's manufacturers are small companies that can't compete with the big drug companies that develop antidepressants. Second, researchers are still trying to figure out how the technique works. In animals, magnetic stimulation can produce changes in the levels of neurotransmitters, the activity of nerve-cell receptors, and the expression of genes related to nerve growth in the brain. Lisanby has shown that TMS also alters the structure of rat nerve cells, hinting at long-term changes in brain activity. To explore the treatment's effects in humans, George is using MRI to chart brain blood flow in real time before, during, and after TMS.

"The scientist in me says we're just barely at the surface of this technique," says George. "We need to do a lot of work and understand it before we can proceed effectively." On the other hand, he says, the modes of action of some of the most effective treatments for mental illness, including lithium for manic depression, serotonin enhancers for depression, antipsychotics, and electroconvulsive therapy, are still a mystery too. "The clinician in me says we don't understand almost any of our treatments. Nevertheless, they save lives."









For a comprehensive site about TMS, including links to news, conferences, and scientific articles, see the TMS resources page at www.musc.edu/tmsmirror/TMSresrc.html.