Zapping depression

In the late 1700s, Italian anatomist Luigi Galvani made a dead frog's muscles twitch when struck by a spark, a discovery that paved the way for the modern understanding of electricity's role in living things. It is the basis for countless medical technologies like the pacemaker.

But electricity does not travel easily through the skull to the brain, the organ responsible for every purposeful twitch and altered mood. So when a group of British scientists in 1985 used magnetic pulses from outside the head to induce an electrical field inside the brain - and got a subject's hands to move - their colleagues clamored for a chance to zap themselves.

That breakthrough, known as transcranial magnetic stimulation (TMS), led to the Food and Drug Administration's approval last month of the first noninvasive, non-pharmacological treatment for depression.

As a practical matter, approval of the device made by Neuronetics Inc., a five-year-old Malvern company, is intended for patients with major treatment-resistant depression who do not respond to any one medication. Millions of Americans fail to benefit from antidepressants, and millions more quit because of side effects.

Symbolically, the federal action is a big deal - another advance in a group of emerging fields that involve electrical stimulation of the brain.

"Our view of the brain is changing," said Mark S. George, a professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina.

Just 10 or 15 years ago, scientists thought of the brain as a single entity - what he called "the brain-as-soup" model. "But really you want to treat specific regions in the brain."

George is editor in chief of a year-old journal named Brain Stimulation, and he is a champion for the cause. After decades of success with psychiatric drugs, he said, "we had forgotten that the brain is really an electrical organ."

Researchers worldwide are testing therapies ranging from highly invasive electrical implants to hardly noticeable magnetic fields on dozens of psychiatric and neurological disorders. Success has been limited - but so are current treatment options.

When a major depression enveloped Ernie Mercer in the late 1980s, Prozac had just come on the market, and it worked. When depression struck again five years ago, it didn't. Neither did Effexor or a third drug. Worse, they made him nervous and constipated.

For Mercer, a retired engineer who lives near Atlantic City, depression was withdrawal from life. "Nothing was fun anymore," he said.

He answered an ad seeking research volunteers for an experimental treatment in 2005.

The clinical trial of transcranial magnetic stimulation went like this: He'd show up at a University of Pennsylvania clinic five times a week, answer the same set of questions about his mood, and then sit in what resembled a dentist's chair for 40 minutes with earplugs in his ears and an apparatus strapped to the top left of his head. He heard loud clicking sounds but felt nothing.

After four weeks, a sensation suddenly matched the clicking - "kind of like somebody tapping on your scalp like 10 times a second," he said - and his depression began to lift. He had been initially assigned to the sham (placebo) group; now he was getting TMS. After several weeks of the real thing, he felt fine. He still does.

Mercer, 65, paid nothing for either the treatment series or twice-monthly maintenance sessions ever since. The research grant ends this month, however, and the clinic will charge him $150 on its sliding scale if health insurance doesn't cover it; most of the clinic's patients are likely to pay at least $200. Insurers are just now beginning a review.

The new treatment is not a panacea. An unrelated study two years ago found that, of patients who failed to benefit from one antidepressant medication, just one-third responded adequately to a second. TMS produced a similar response rate (as does talk therapy, according to other studies), although the effect was described as greater.

The biggest difference is side effects, which cause many patients to stop taking antidepressants. The most commonly reported side effects to the brain stimulation were headaches and scalp irritation, both temporary.

TMS poses a slight risk of seizure. No incidents were reported in data on 10,000 sessions submitted to the FDA.

Neuronetics didn't seek approval to treat all major depression; when antidepressants work well, they are hard to beat. Still, the FDA rejected the initial application last year to use the NeuroStar TMS device for treatment-resistant cases generally.

A reanalysis of data on the 301 patients in the multicenter trial found the strongest response among those who had tried and failed with just one drug, and that's what the agency approved. Patients like Mercer, who gave up on three, can be treated "off label," which may be less likely to qualify for reimbursement.

Oddly enough, Tufts University psychiatrist Daniel Carlat said he would be more likely to steer those patients - the ones least likely to respond - toward TMS because they've run out of easy alternatives.

Carlat, who has no connection with the manufacturer or drugmakers, has written skeptically about TMS in past issues of his Carlat Psychiatry Report. He said the latest findings changed his mind.

Psychiatrist John O'Reardon, who ran the Neuronetics-funded trial at Penn and is beginning to study TMS for Attention Deficit Hyperactivity Disorder in adolescents, believes that many people who can't tolerate antidepressants will find this easier despite the inconvenience of 20 to 30 daily sessions.

"They come in and sit in the chair, we slap a magnet on their head for 30 minutes, and afterward they can go home," said O'Reardon, director of Penn's Treatment Resistant Depression Clinic.

Magnet therapies have been advertised for years, usually to relieve pain, but have not been proved to work in rigorous trials. Most rely on simple, static magnets. The electromagnet in the new device is thousands of times more powerful, similar to that of an MRI, said Neuronetics chief executive officer Bruce Shook.

In repetitive transcranial magnetic stimulation (rTMS), rapid series of pulses pass through the skull and induce an electrical field on the surface of the brain, exciting the neurons below.

For depression, the target is a postage stamp-size part of the left prefrontal cortex that is less active in depressed people. Scans confirm more activity after successful treatment of any kind, although the exact mechanism is not known.

The therapy is being studied for post-traumatic stress; obsessive-compulsive and panic disorders; fibromyalgia; and other conditions.

The most promising results are for dampening the auditory hallucinations that schizophrenics describe as hearing voices. Ralph Hoffman, a Yale psychiatry professor who began studying the treatment 10 years ago, said the latest data showed "a significant effect," although years away from clinical use.

It is the repetition in rTMS that seems to retrain the neurons and bring enduring change. Single-pulses, called sTMS, have a short-term effect.

Neuralieve Inc., of Sunnyvale, Calif., has applied for FDA approval of its portable, handheld sTMS device for the one-third of migraines that are preceded by recognizable visual or sensory symptoms known as auras.

The battery-operated device is about the size of a hair dryer. At the onset of symptoms, you place it against the back of your head and press a button. After 30 seconds to recharge the batteries, you deliver a second pulse. The short-term stimulation disrupts the spread of abnormal brain waves.

It left nearly 40 percent of participants in a recent clinical trial pain-free after two hours, said Terese M. Baker, the company's vice president of marketing. "You can stop the migraine progression before it takes root," she said.

The oldest form of brain stimulation, dating to the 1930s, is electroconvulsive therapy. It is the most effective treatment for major depression. Once stigmatized as "electroshock," ECT has been refined in recent years. But it works by causing seizures, and the risk of serious side effects, especially memory loss, still limits its use to the most serious cases.

A kinder, gentler version may be in the works. Sarah H. Lisanby, a professor of clinical psychiatry at Columbia University, developed magnetic seizure therapy (MST), which uses magnetic pulses to induce seizures.

"With magnetic fields, we have better control," she said. The seizures are more focused and less robust.

Lisanby, who is researching several types of brain stimulation, thinks that part of the potential of these fields lies in the ability to tailor treatments for an individual. Magnetic and electrical fields can be aimed at a variable target. Today's drugs cannot be.

Anthony T. Barker has been following all these developments with interest from afar. Barker led the team that zapped a man's brain with a magnetic pulse in 1985 and got his hand to move. And while none of the new therapies was on his radar screen at the time, so many colleagues wanted to "have a go" that he knew something would come of it.

"It is arguably one of the coolest demonstrations of physics' effect on the human body," said Barker, a professor in medical physics and clinical engineering at Royal Hallamshire Hospital, Sheffield.

"If you were here, I would zap your brain and make your hand move, and you would think it was cool, too."

At least nine methods are being studied.

The most common:

Transcranial magenetic stimulation (TMS)

With the patient awake in the office, external magnetic pulses induce an electrical field on the surface of the brain, activating neurons below. Noninvasive.

Electroconvulsive therapy (ECT)

Electrical stimulation of the scalp under anesthesia induces a wave of activity across the brain - a seizure. A gentler, magnetically triggered version is being tested.

Vegus nerve stimulation (VNS)

A pacemaker in the chest sends electrical impulses to electrodes in contact with the vagus nerve in the neck, and then up to the brain.

Deep brain stimulation (DBS)

This is similar to VNS, but electrodes are surgically implanted in the brain to stimulate precise regions in various disorders. Highly invasive.

Links to a company video showing how TMS works, and how to find clinical trials of all these therapies for dozens of disorders: http://go.philly.com/health

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Contact the University of Pennsylvania School of Medicine's TMS Treatment Program at 215-573-8582, or

go to www.med.upenn.edu/tms EndText