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June 27, 2005

Like Flipping a Switch — Researching Magnetic Fields to Treat Depress
By Matthew L. Robb
Radiology Today
Vol. 6 No. 13 P. 22

After undergoing fMRI scans by McLean Hospital’s specially calibrated scanner, many depressed bipolar patients reported feeling happier. That’s when researchers began to look for the reason why.

When a chronically depressed woman underwent a unique type of MRI scan at a Boston psychiatric hospital in 2001, she raised a few eyebrows when she emerged smiling, joking, and saying how good she felt.

Another woman also reported the same happy results. Before leaving, she even merrily asked the staff, “What did you do to me?” Researchers could only scratch their heads in disbelief.

Soon came 30 more subjects diagnosed with bipolar disorder, typically characterized by extreme emotional highs and lows. After undergoing scans by the hospital’s specially calibrated functional magnetic resonance imaging (fMRI) scanner, most reported feeling happier, as though a murky veil had lifted. At this point, one researcher spoke for all when he murmured “amazing.”

In one fell swoop, researchers using echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) might have accidentally and instantly done for a stubborn mental illness what psychotropic medications and “talk therapy” traditionally achieves (or fails to achieve) only after weeks or months. Today, they speculate that magnetic waves may someday yield breathtaking new treatments for mental illness.

20 Million Patients
The need is acute. Depression afflicts an estimated 20 million Americans and 350 million people worldwide. Of these, upward of 30% are unresponsive to even the best conventional medical treatment—treatment that is often costly and sometimes causes unpleasant side effects. Left untreated, bipolar episodes typically increase in frequency while becoming more resistant to medication. Approximately 30,000 depressed people commit suicide each year in the United States, according to the National Institutes of Mental Health.

The accidental discovery of the link between magnetism and depression arose during a study on brain chemistry led by imaging physicist Michael Rohan, MS, and Perry Renshaw, MD, PhD. Both work in the Brain Imaging Center at McLean Hospital, a Harvard Medical School psychiatric affiliate. Rohan and Renshaw are joined by an international coterie of researchers chipping away at the mysteries of mental illness using technologies borrowed from the imaging sciences.

Among the scientists is Sarah H. Lisanby, MD, director of Columbia University’s Brain Stimulation Division, who is currently studying transcranial magnetic stimulation (TMS). By harnessing intense magnetic fields, Lisanby and colleagues have quickly relieved depression in some subjects with drug-resistant depression. Meanwhile, pioneers at the Mayo Clinic last year reported having tapped the powers of MR spectroscopy to accurately diagnose bipolar disorder. Over the past 10 to 15 years, imaging tools have shed insight on early brain development, schizophrenia, the metabolic basis of anxiety, and the role of neurotransmitters in attention-deficit/hyperactivity disorder.

Preliminary Work
To be sure, the McLean team’s work on low-field magnetic stimulation (LFMS) is preliminary and requires far more study before becoming a standard clinical tool, if it ever does. But as researchers investigate using electromagnetic fields to alter brain biology, observers are left to wonder: Where will these trails lead and just how benign is MRI anyway?

While the diagnostic power of magnetic imaging is beyond dispute, the notion of using magnetic waves to treat human disorders—especially disorders of the mind—until recently belonged in the realm of science fiction.

Intrigued but cautiously skeptical of early findings, Rohan, Renshaw, and their McLean Hospital colleagues designed a rigorous follow-up, dividing healthy and bipolar subjects into three groups. Healthy subjects would receive normal EP-MRSI scans, while one-half of the bipolar subjects would receive normal scans and the remainder would undergo bogus or “sham” scans.

The results confirmed the original 2001 observations. A stunning 77% of bipolar subjects receiving the real EP-MRSI tests reported mood improvement. McLean researchers saw a 100% response rate in subjects not on medication vs. a 63% response rate among those on medication. The absence of mood improvement in the other two groups suggests that the mood improvement was not caused by placebo effect.

In March, a McLean team headed by William Carlezon, director of the hospital’s Behavioral Genetics Laboratory, announced corroborating evidence in an animal-model study, wherein fMRI scans produced similar effects in rats as those produced by standard antidepressant drugs.

Speaking from his office in Boston, Rohan says McLean Hospital and the Boston area is an ideal setting for studying brain disorders and ruling out flaws in methodology. If the observed magnetism-depression link were suspect, he says, the hospital’s first-class researchers would certainly recognize it. Rohan is a research associate at Harvard Medical School and used to design MRI systems for private industry.

“Here at McLean Hospital,” he says, “we do 100% cutting-edge research. As a psychiatric hospital, we have performed probably 20,000 MRI scans since the first installation of MRI here. We scan a full schedule of psychiatric patients every week. Except for the time we ran this special scan, we have never seen these mood effects before.”

Accidental Discovery
Rohan calls the team’s findings a “totally accidental discovery” and says, “People were walking away from the MRI and immediately saying, ‘I feel better.’ Anecdotally, we got a telephone call a week later from someone saying, ‘I still feel great.’ Remember, these were people diagnosed with bipolar disorder.”

Intrigued, Rohan and colleagues analyzed the scanner’s magnetic fields and eventually narrowed their attention to the most promising gradient coil. “It looked like it was the right strength and had the right timing to maybe do something in the cells,” Rohan recalls. “We finally realized [the effect] was coming from only a small portion of the MRI system, a coil measuring about 14 inches across.” Current thinking hypothesizes that the naturally induced electric fields generated by MRI coils somehow interact with brain nerves “in a very small way,” Rohan says. He adds that the key is the specific timing and amplitude of the magnetic pulses, which allegedly induce low-level electric fields that match and resequence the electrical firing rhythm of brain cells, like a detuned engine brought back to optimal functioning. To retest their hypothesis, the McLean Hospital team built a small tabletop device, wired it to a computer and amplifier, and began testing on rats.

Weak Fields
“Part of the surprise,” Rohan says, “is that the magnetic fields are very, very weak, about 1 volt per meter. Other electromagnetic techniques for treating depression, such as [electroconvulsive therapy (ECT)] and [repetitive transcranial magnetic stimulation (rTMS)] create fields big enough to actually make your skin contract.” The McLean researchers, by contrast, are using an LFMS that creates a magnetic field roughly 200 times weaker than rTMS and so weak that patients feel nothing. ECT, by contrast, is sometimes associated with memory loss and severe headaches.

The team’s success raises obvious questions. Might an enterprising technologist somehow reproduce these results in his or her own MRI suite? Rohan smiles at the notion, but points to a host of daunting technical hurdles. The magic of McLean Hospital’s machine lays in its sophisticated programming and precise timing sequence.
“We use the same strength of magnetic field as a standard MR scanner,” Rohan says, “but our gradient pulse waves are very different. The timing of pulses has everything to do with it.” (Rohan directs those interested in learning specifics to his group’s technical publications.)

In addition, Rohan’s team utilized an unusual spectroscopic technique augmented by advanced programming. “We also happened to turn the field sideways for our application, for a coincidental reason,” he says. “Arguably, we are the only people to have ever run that exact same scan.” With a chuckle, he adds, “When we run the MRI, we run it just so we can emit the magnetic fields. We throw the pictures away.”

The McLean Hospital team will soon begin developing a tabletop system that will accommodate a person and provide greater cost efficiencies than an MRI-based unit. Other research will focus on how long the effect lasts and the mechanisms “that explain why scans make bipolar people happy,” Rohan says.

Slow Work
If MRI scans can instantly alleviate depression, might they have a similar effect on other mental disorders? Rohan says, “That is where we would like to go, but this is slow work. Showing effectiveness requires running a large number of subjects.” Part of the challenge, he says, is that doing a study on depressed subjects when they are actually depressed requires good timing. He notes that, after the initial study was publicly announced, his team received some 200 calls from people seeking treatment. Of these, only nine met stringent recruitment criteria. “It’s difficult to recruit and screen subjects appropriately,” he notes.

Rohan says another promising research avenue involves a possible link between LFMS and alcoholism. “The fact that we have something that looks like it alters mood tells us it might have some promise with substance abuse,” he says. Notably, McLean Hospital does substantial work with substance abusers.

Rohan says treating mental illness is an arduous proposition that entails small, hard-fought gains and not a few setbacks. “These things take time,” he says. “The brain is complicated. Knowing where in the brain things happen is a long way from knowing why someone is depressed or schizophrenic. Developing effective clinical interventions takes longer still.”

He also suggests that the public adopt a more informed long-term perspective. The mainstream media seizes on isolated abreactions with antidepressant medications, he says, and overlooks the many successes—many made possible by the imaging sciences. In the final analysis, expecting miracles of LFMS is neither reasonable nor judicious, he says.

“There is no magic out there, but we’ve seen tremendous strides in the treatment of mental illness,” he says. “Twenty years ago, McLean Hospital was packed. We had 250 acres full of patients who were here for life. Now we have a very small inpatient population.”

Rohan speculates that if LFMS eventually leads to new clinical interventions, depression will not be treated in an MRI suite. “I think depressed people will someday use a tabletop device in their doctor’s office,” he says. “Remember the hairdryers in some beauty salons? The [magnetic] tube would be like that. You would put the top of your head inside and lay down for 20 minutes.”

He pauses and adds, “Of course, that’s if it works. We need to take this one day at a time. I’m convinced that we have a significant effect, but what remains to be proven is whether we have a clinically effective treatment. There are miles between those two situations.”

MRI: Benign or Invasive?
When MRI scans fundamentally alter brain chemistry and neuronal activity, observers start revisiting old, seemingly resolved, questions about MRI itself. Among the leading concerns: Is MRI benign or more invasive than believed?

Rohan says that question has, at this time, no clear answer. Pressed for his best guess, he offers, “One can imagine in the future there will be a set of scans that will not be allowed. Of course, these are the scans we don’t do now anyway.” In another McLean study, researchers offered some tentative answers to this question, asserting that the magnetic waves produced during MRI scans of the brain may indeed be more invasive than commonly believed.

“Renewed caution is warranted when high-speed MRI is used to diagnose or study disorders involving the brain,” they wrote. At present, the absence of evidence of hazardous effect may be due to a lack of long-term studies, rather than confirmation that the technology is benign.

— Matthew L. Robb is a freelance writer based in suburban Washington, D.C., and frequent contributor to Radiology Today.

Transcranial Magnetic Stimulation: More Power
If weak magnetic fields relieve depression, what happens when researchers crank up the intensity of the magnetic waves?

The answer, say officials at the National Institute of Mental Health, is that depressed patients also tend to feel better. Early research suggests the technique works well in people who have “failed” on conventional antidepressant medications and in some studies produces results comparable with that seen in electroconvulsive therapy (ECT), without that treatment’s negative side effects.

The technique, transcranial magnetic stimulation (TMS), finds researchers like Columbia University’s Sarah H. Lisanby, MD, expressing cautious optimism about its eventual clinical application. Unlike low-field magnetic stimulation (LFMS), originally identified by researchers at McLean Hospital, TMS entails a powerful magnetic pulse directly applied to the scalp, inducing in turn a small electrical current that stimulates neuronal activity in the prefrontal cortex.

Lisanby notes key differences between TMS and LFMS. In TMS, she says, “The strength of the magnetic field at the surface of the TMS coil is 2 Tesla. TMS is a rapidly pulsating magnetic field with a rate of change far greater than that of MRI. That’s why TMS induces electricity in the brain and causes neurons to fire, whereas standard MRI scanners do not.”

TMS also sharply differs from ECT, she notes. Whereas ECT entails a relatively powerful electrical stimulation given to the scalp to induce a seizure in a patient under anesthesia, TMS induces a very small electrical current within the brain. Notably, patients are awake and typically do not experience seizure.

Noting the roughly 30 “sham-controlled, randomized trials on the antidepressant efficacy of TMS” already completed across the world, Lisanby says, “The work so far is encouraging, but more work is needed to determine how effective this is and for whom.” Armed with the final results, the FDA will decide whether TMS is safe and effective enough for clinical applications. Already, officials at Health Canada have approved TMS for treatment of drug-resistant depression.

One recent study showed 27% of patients who underwent TMS showed a “full response” to treatment. The more successful TMS treatments entail short, daily TMS procedures for several weeks. Noticeable mood changes typically occur after a week or two.

Says Lisanby, “Recent meta-analyses suggest there is evidence for a statistically significant antidepressant effect of TMS. What is at issue is the strength of that effect.” She notes the world of difference between statistical significance and clinical meaningfulness.

— MLR

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