SEPTEMBER / OCTOBER 2005

AROUND HARVARD

This article originally appeared in the August 2005 Harvard Mental Health Letter and is provided courtesy of Harvard Health Publications.

Magnetic stimulation of the brain: An update

In recent decades, scientists have developed electrical and magnetic devices for observing the brain in action — remembering, deciding, experiencing emotion — in ways that were once unimaginable. Functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) are among the most revolutionary of these techniques. Changing brain activity in any meaningful or lasting way by electromagnetic means has proved more difficult, but glimmers of progress are appearing.

The chief established electromagnetic technique used in psychiatry is electroconvulsive therapy (ECT), in which a strong electrical current applied to the scalp induces generalized seizures (spreading to the whole brain) for the relief of severe intractable depression and other psychiatric disorders. The treatment is highly effective but produces short-term confusion and occasionally some memory loss. Patients often must be hospitalized and always require general anesthesia and muscle relaxants.

Less disruptive alternatives may now be provided by a group of techniques involving magnetic stimulation that are coming into wider use.

Repetitive TMS
A growing body of research suggests that the best known of these techniques, transcranial magnetic stimulation (TMS) may be a weapon against depression, schizophrenia, and other psychiatric disorders.

It works this way: An electrical generator operating in very short on–off bursts produces a series of strong magnetic fields in a wire coil, generally in the shape of a figure 8, that is mounted on a paddle and positioned on or near a patient’s forehead or scalp. Unlike electrical currents, magnetic fields are not absorbed and scattered by the bone of the skull — the reason high voltages are required for ECT. The fluctuating magnetic force penetrates to a depth of about an inch, producing an electrical current that influences neurons in the area directly under the coil. The signals do not reach subcortical brain regions but may eventually be used to change activity in some of these regions via connections that are now being mapped. Researchers are also experimenting with different types and numbers of coils to achieve deeper penetration.

Stimulation by TMS is much milder and more localized than ECT. The magnetic field can be applied to fully conscious patients, who feel no pain; at most, they notice a slight clicking or pinching sensation. They can read or talk during the treatment and drive themselves home afterward. Memory is not affected. Single pulses have no reported side effects; repetitive TMS can cause muscle tension headaches, which are usually mild and easily treated with aspirin. Accidental seizures, a rare complication, have not been reported since safety guidelines were clarified in the mid-1990s. In animal studies, rats receiving TMS weekly for as long as three months suffered no learning or memory impairment.

With more powerful apparatus now available, TMS can be administered at frequencies up to 60 cycles a second (60 Hz). Although there is considerable individual variation, lower-frequency signals apparently lower blood flow and suppress activity in the cerebral cortex, while higher-frequency signals, above 20 Hz, have the opposite effect. By varying the frequency of the pulse and the position of the coil, researchers can turn different brain regions on and off and study how they are involved in vision, motor control, memory, attention, and language.

For example, by placing the coil over the motor cortex, they can make a thumb twitch or a leg jerk to learn more about how the brain controls the body’s muscles. They can also temporarily block or enhance some aspect of vision or speech. Previously, the only way to stimulate small regions of the brain directly was to apply electrodes during surgery.

Treating mood disorders
The main psychiatric use of TMS is in the treatment of depression. For this purpose, therapists usually place the coil over the left prefrontal cortex, just behind the forehead, where fMRI and other brain scans suggest that activity is often low in depressed persons. This area, a seat of planning and decision-making, is linked to the emotional centers in the limbic system. Typically, high-frequency magnetic impulses are applied for a half-hour a day five days a week for about two weeks — in some cases, up to six weeks. Researchers have also been experimenting with low-frequency TMS directed at the right prefrontal cortex.

Although results are still inconsistent, the news from what now amounts to a large number of controlled studies is getting better. For example, in one study, high-frequency TMS directed at the left prefrontal cortex combined with low-frequency TMS to the right prefrontal cortex improved depression in patients who had not responded to drugs. Researchers have also found TMS helpful as a weekly maintenance treatment for adults with bipolar depression who were taking lithium. And interestingly, high-frequency TMS to the right prefrontal cortex may improve symptoms of bipolar mania.

Results of direct comparisons with ECT have been conflicting, but in one study, patients not helped by antidepressant medications who received five sessions a week of TMS for four weeks did as well as those who received similar ECT treatment.

Over all, about 40% of patients with medication-resistant depression have shown some improvement after TMS. In two small studies, TMS reduced depressive symptoms by 28%; sham (placebo) treatments, in which the paddle was angled to misdirect the magnetic energy, reduced symptoms by only 7%. Research also suggests that TMS may shorten the time it takes drugs to begin working. Researchers are collaborating on a large rigorous study in which more than 200 patients at 14 sites will receive either TMS or sham treatment, so we may soon have a better idea of its safety and effectiveness.

Schizophrenia
Although ECT is an established treatment for severe schizophrenic symptoms as well as depression, there are few studies of TMS in schizophrenia. Some trials have been disappointing, but there are conflicting reports that TMS can banish hallucinatory voices. In a small study, researchers found that two out of three patients who received low-frequency TMS directed at the auditory region of the cortex stayed free of threatening and abusive voices for more than two weeks — one of them for two months. None responded to sham TMS.

These results were confirmed in another study. Seven out of ten schizophrenic patients who received low-frequency TMS responded, and five of them maintained the improvement for at least two months. In still another (uncontrolled) study, four weeks of TMS produced an improvement in the negative or deficit symptoms of schizophrenia — apathy, emotional constriction, limited speech — that lasted at least a month. But hallucinations and delusions were not affected.

Other conditions
Findings are mixed. Some reports suggest that TMS can relieve the symptoms of post-traumatic stress disorder at least for short periods. In a controlled study, TMS was no more effective than sham treatment for patients with obsessive-compulsive disorder. More than 30 studies are under way in the United States testing the potential of TMS in a variety of conditions including stroke, Parkinson’s disease, and cerebral palsy.

Magnetic seizure therapy
Researchers are exploring new ways of using the TMS apparatus — delivering magnetic fields at a frequency high enough to cause seizures. Magnetically induced seizures, unlike those produced by ECT, are localized rather than general. In theory, they could be directed where they would do the most good and the least harm — avoiding areas critical for memory, for example. But like ECT, magnetic seizure therapy (MST) requires general anesthesia, which increases risk and expense. And because the frequency has to be high, it also requires a more powerful machine than TMS.

MST has been tested in both monkeys and humans, and the preliminary results suggest that it might be effective, with fewer side effects than ECT. In a study under way in 2005, patients have been assigned at random to receive first ECT and then MST or the reverse, with follow-ups after two and six months. Direct comparisons among MST, ECT, and conventional TMS may incidentally help determine whether the generalized seizures produced by ECT are necessary for relieving intractable depression or are only a byproduct of some other, more specific change that supplies the therapeutic effect.

Magnetic resonance spectroscopy
Transcranial magnetic stimulation is not the only magnetic technique that has shown some promise in the treatment of psychiatric disorders. Magnetic resonance spectroscopy (MRS), which uses magnetic fields to map brain chemistry, is best known as a research tool that provides new information about the structure and activity of living cells. The magnetic field involved is weaker than the field generated by TMS but penetrates the whole brain uniformly. In a study reported in 2004, researchers serendipitously found that a form of MRS they were using to examine the brains of depressed patients improved the symptoms of depression, at least for a few days. A comparison with sham treatment confirmed the result.

These findings from a single study with a brief follow-up need confirmation, but there is further evidence from animal experiments. The subjects were rats forced to swim for hours with no possibility of escape. This situation often leads to learned helplessness, a state resembling human depression. Rats given a form of magnetic resonance spectroscopy before forced swimming took longer to give up hope; antidepressant drugs have the same effect.

As of mid-2005, the FDA has not approved magnetic stimulation of the brain for the treatment of any psychiatric condition, and research is just beginning. Many questions are open, and many paths remain to be explored. In therapy, which patients will respond best, and how do individual brain structure and function affect the response? (One early study found that depression in patients with a preference for the left visual field, controlled by the right hemisphere of the brain, did not respond to TMS in the left hemisphere). Do high-frequency and low-frequency TMS affect different types of depression? What is the best timing, how long should treatment continue (there is some evidence that more than two weeks may be better), and what is the best placement of the magnetic coil? How long does the antidepressant effect last?

Further research could also advance early diagnosis of depression and other disorders, help to predict their course, and possibly identify the best medication or other treatment for a given patient. And magnetic stimulation might be used in combination with magnetic resonance imaging and other brain scanning techniques to investigate how different brain regions are coordinated and why coordination fails.

Copyright 2006 Harvard Medical International