Field of dreams
Good news for depressives - a simple electronic device that creates a magnetic field can improve the condition of serioulsy afflicted patients. Israeli scientists, leading the world in this field, are now looking for new applications, such as helping addicts break their drug habit.
Israeli scientists are at the forefront of international research and development in the field of treating psychiatric disorders with magnetic stimulation of the brain. The word "magnetic" requires an explanatory note at the very outset: There is no connection between this form of treatment and the magnetic devices that are marketed as magic, "alternative health" solutions to a broad range of problems. In fact, the new treatment does not make use of a magnet, but uses an electric instrument, creating a magnetic field that stimulates the brain. For a decade, scientists have been investigating possible applications of this method in psychiatric treatment, and the findings show that it has positive effects in treating depression. For many patients it may replace the recommended treatment by electric shock. Already now magnetic treatment for depression is available in Israel, albeit only on a private basis.
In contrast to the scientific aura associated with such treatment, an encounter with the instruments that are in use is a disappointment. The powerful generator, which, the manuals explain, creates a magnetic field that dwarfs that of the earth (though only for a fraction of a second), is no more than a boring metal box that resembles an outmoded amplifier. Attached to it is a cable at whose end is a wire coil, either in the form of the number eight or in a rectangular shape.
The experimental procedure in which it is being used locally at present is also far from what might be expected from a device that is at the forefront of scientific research. "In Israel, as is known, psychiatry is not recognized as a treatment that deserves to be funded, so there is no money to build a respectable system," Prof. Leon Grunhaus, director of the Jerusalem Mental Health Center says sadly. "We are using an old-fashioned method: We place the coil on the head of the patient, who wears a bathing cap, on which it is easier to designate the exact points that provoke a reaction. We then look for the area at which the stimulus activates the thumb maximally. That is how the system is calibrated. The rest of the stimuli are given in relation to that point and in relation to the strength that the specific patient needs to bring about a reaction."
The method is reliable, Grunhaus explains, but when he thinks about the most advanced instrument of magnetic stimulus, which is manufactured in Finland and costs half-a-million euros, he cannot conceal his envy: "The Finnish instrument is fantastic. It provides an anatomic picture of the brain and makes possible a very accurate stimulus, not to mention that the patient's head is in a fixed position, and the magnet is placed at a permanent spot."
The equipment that is needed to operate the instruments at the psychiatric centers in Be'er Sheva and at Sheba Medical Center near Tel Aviv include buckets of cold water to cool the coils, which heat up quickly. It's hard to believe that this is how some of the leading studies in the world in this field are carried out.
Grunhaus prefers thinking about the future: "In my imagination I see an institute for this purpose that will run by the assembly-line method. In the first room the patient will undergo an magnetic resonance imaging [MRI] test, which will provide a clear, full picture of which areas in the brain are underactive or overactive. The patient will then proceed to the next room, where he will put on a magnetic helmet that will send precise stimuli to the different areas of the brain."
Grunhaus' dream institute will also have a third room, where the patient will receive psychological treatment (completely human) to help him cope with the tremendous changes fomented in him by brain stimulation lasting only a few minutes.
It all began by chance. Scientists at a few neurological laboratories around the world noticed a strange phenomenon: Family members of Parkinson's sufferers reported that the patients would return home in an elevated mood after routine checkups - not a common side effect. The medical teams soon found that this was an unexpected side effect of testing with the use of a transcranial magnetic stimulator (TMS). The instrument's manual said nothing about possible good feelings afterward, but neurologists began discussing among themselves the positive effects produced by the metal box, which was intended to examine basic nerve conduction.
The TMS, developed in the 1980s, is a power generator to which a metal coil is attached. When activated, the electric current that passes through the coil creates a powerful magnetic field around it. When the instrument is placed on the patient's head, this field penetrates the brain and activates nerve cells in a particular area.
"The instrument was intended to serve as a diagnostic tool in illnesses in which nerve conduction from the brain to the body's organs is affected," explains Prof. Eldad Melamed, director of neurology at Rabin Medical Center (Beilinson Hospital) in Petah Tikva. "It allows us to see, for example, whether the neural paths that pass from the central system along the spine to the muscles are functioning properly." To diagnose the condition of the neural conduction system, the physician measures the time it takes from the instant the brain is stimulated in the area responsible for moving the thumb, for example, until the thumb itself reacts.
In the early 1990s Israeli psychiatrist Nimrod Grisaru heard testimonies about additional effects of TMS (which also stands for the act of "transcranial magnetic stimulation") on patients, besides thumb movements. Grisaru, together with Prof. Haim Belmaker, also from the Be'er Sheva Mental Health Center, wrote to Prof. Mark Hallett, the director of the National Institutes of Health (NIH) in the U.S., asking whether proven information about the phenomenon existed. "The brief reply we received," recalls Grisaru, who today is director of the emergency room at the Be'er Sheva center, "was that TMS is an instrument that was created for neurological diagnosis. It was made clear to us that it has nothing to do with psychiatry."
Later, at the first international conference on magnetic brain stimulation, it was the same Mark Hallett who explained the limits of the instrument's use and its possible side effects. It was clear already then that TMS was the "next big thing" in psychiatry.
That conference was held in 1996, about two years after Grisaru and Belmaker, together with the neurobiologist Jacob Abarbanel, completed a study on the reactions of schizophrenics and depressives to the magnetic stimulation of the brain. Theirs was one of the first research projects in the field. A small group of people suffering from those problems underwent the test for which the instrument was originally intended. The researchers' evaluations afterward showed a significant improvement in the frame of mind of a few of the patients suffering from depression. Even though the study involved only a small number of subjects, without a control group, these were important initial results.
Instead of coffee?
Israeli researchers are disproportionately present in the professional literature about TMS. In the principal areas of research - treatment of depression, mania and post-traumatic stress - local researchers did pioneer research in possible uses of TMS during the past decade.
These applications go far beyond anything envisioned 10 years ago. In an article entitled "Stimulating the Brain," published in the September 2003 issue of Scientific American, Mark S. George, a pioneer in the field, presented a few of the lesser known possibilities. One of them, not yet feasible, involves replacing coffee as a stimulant.
George describes the cockpit of a plane on a long-distance flight to a disaster area on a humanitarian mission. Instead of asking the stewardesses for more coffee, the weary pilot "flips a switch. A `rat-a-tat-tat' sound, like that of a staple gun, echoes through his helmet, and his fatigue abruptly disappears." The sounds were made by the TMS, which send a precise stimulus to the brain area responsible for the feeling of tiredness. Within seconds the pilot is "clear-headed for the first time in what seems like days" and is ready to continue his mission. Switch the humanitarian aid with the bombing of a reactor in a hostile country and it becomes obvious which brains in our region are eagerly awaiting the potential development of the magnetic stimulus.
Meanwhile, researchers are at work on many other potential applications. In psychiatry, for example, use of TMS in the treatment of anorexia, bulimia and various addictions is being examined, and neurologists are now returning to magnetic brain stimulation in the hope of developing instruments that will help patients with diseases of the nervous system.
On the way to realizing the vast potential of TMS treatments, researchers require a better understanding of the human brain and of the reciprocal relations between it and body-mind functions. Ten years ago the scientists were in the dark even about the desirable methods of utilizing the instrument.
TMS can be implemented via different frequencies. A magnetic field that is activated at a frequency of less than 1 hertz (a unit of frequency equal to one cycle per second) is considered "slow" and is usually thought to bring about a slowdown in the reciprocal activity between the neurons in the brain and thereby to depress activity. Frequencies above 1 hertz are considered "high" and have a stimulating effect on cell activity. In order to "treat" depression, for example, the physician must understand whether it is due to overactivity or underactivity of the relevant area of the brain. Only thus will he know which frequency to use.
`Magnetic holy grail'
The strength of the magnetic field decreases in conjunction with the distance from the instrument that generates it. The magnetic fields created by existing TMS devices are very limited in their ability to penetrate the brain, and succeed mainly in affecting external regions of the cortex. Increasing the strength of the magnetic fields might enable deeper penetration, but it also heightens the risk of pain and other side effects. Just how serious this limitation is can be gleaned from researchers' expectations of a technological breakthrough. George, in his article in Scientific American, compares the quest for an instrument that is safe to use and will penetrate the recesses of the brain, beyond the outer two centimeters, to the quest by Christians for the Holy Grail. However, the "magnetic holy grail" has already been found, or invented. George even mentions the inventor: Dr. Abraham Zangen, a 35-year-old scientist from the Institute for Brain Research at the Weizmann Institute of Science in Rehovot.
It's unlikely that Zangen, a religiously observant Jew from Jerusalem, would choose the Holy Grail as a symbol for his quest and invention. However, his work is generating great excitement in the field, certainly in this country. And descriptions of him such as "the brilliant scientist whose invention may change the world of psychiatry" are common.
Zangen, who in 2003 returned from postgraduate studies at NIH, developed a device that enables the magnetic field to penetrate the brain at a depth of six or even seven centimeters. "The principle is quite simple," he explains. "Instead of activating the magnetic field at just one point, a field is activated in the same direction at several points on the perimeter of the head. This creates `constructive billowing,' an accumulation, like a group of small waves that gather into one large one."
Zangen's instrument also makes use of a contrary physical law, "destructive billowing," which can be likened to two waves that cancel each other out. "The principle is to heighten the field so that it will penetrate deep into the brain and at the same time reduce the field in other areas, where a powerful magnetic field could cause pain, a reaction by the interior muscles and even an epileptic attack," Zangen explains.
"Another principle of the invention is minimization of radical components of the coil, which diminish the ability of the magnetic field to penetrate deep into the cranium."
Also involved in developing the new system was Yiftach Roth, from the MRI unit at Sheba Medical Center, who is currently completing his doctoral studies in physics. The invention, called the H-Coil, was registered as a patent in the U.S. in 2002. Zangen and his partners tested the device in the U.S. on healthy individuals to determine whether it enabled the stimulation of regions located deep in the brain.
"In light of the good results in the U.S., we are now in the final processes of getting authorization for a similar study in Israel," says the psychiatrist Dr. Hilik Lewkovich, director of the outpatient department at Shalvata Psychiatric Center in Hod Hasharon, who specializes in treating depression. According to Lewkovich, an adviser in the trials of the new TMS system, the proposed study, which will also be done on healthy volunteers, will examine the effect of the magnetic stimulation of deeper recesses of the brain on mood, memory and other functions.
Zangen himself is also studying the "brain reward system," which is involved in processes connected with feelings of pleasure and apparently also with stressful situations. In such instances the brain releases beta-endorphin, which has a calming effect. Thus, the reward system secretes a substance that is intended to help cope with stressful situations - and perhaps even to reduce tension.
The coming revolution
The owners of the American company Brainsway (www.brainsway.com), which is behind the development of the H-Coil, are Israelis. CEO Uzi Sofer, who is also one of the company owners, notes that the product is now in the first phase of receiving approval from the U.S. Food and Drug Administration, and from the FDA's European counterparts. "So far we have invested a few million shekels in the development of the archetype of the device," Sofer says. "On the way to getting it onto the shelf, maybe at the end of 2006, an additional large monetary outlay awaits us, mainly for the clinical studies."
Although the patent is lawfully registered in the U.S., Zangen is still apprehensive about revealing exact details about it, even though to the best of his knowledge no scientists abroad are working on this or similar developments.
"Our latest study showed that the existing instrumentation can penetrate barely two centimeters into the brain," he says. "True, there is a device that goes three centimeters, but it causes pain. The many applications of penetrating into the brain's deeper regions constitute the potential of the new machine: for dealing with various addictions, autism, Parkinson's and Alzheimer's and, of course, for treating depression, where concrete results have already been demonstrated."
Some of the important studies on using TMS to treat depression have been carried out by Prof. Ehud Klein, director of the psychiatric unit at Rambam Medical Center in Haifa, together with Prof. Moshe Feinsod and others. "Klein did something which at the time was considered revolutionary," Dr. Grisaru says. "In 1999 he presented a study, the first of its kind, whose findings showed distinct improvement in the condition of depressive patients."
According to Klein, there was little information then about the effects of stimulation on mood. "We knew that stimulation of the right side of the brain caused a healthy population to feel sadness," he explains. "We decided to suppress the side responsible for the feeling of sadness - the right lobe - instead of arousing the left region, which is responsible for the feeling of happiness. Theoretically we expected an identical result, but the advantage of this system is that it reduces the possible side effects, which occur mainly during the use of high frequencies with the TMS device."
The great promise of TMS is as an alternative to electroconvulsive therapy (ECT) for depressed states. It is hard to argue with the success of ECT - or "electric shock" - in cases of serious depression in general and psychotic depression in particular. The electric stimulus has come a long way in the past century, but some of its shortcomings have not yet disappeared. Electric shock treatment requires total anesthetic and sometimes has undesirable side effects.
Despite the great enthusiasm of psychiatrists for ECT, for patients it still is a frightening procedure with potentially destructive consequences. Use of the magnetic field alternative promises to bring about the same positive outcome with far fewer, if any, side effects, and it doesn't require anaesthesia because it is not usually painful.
Grunhaus carried out several studies to examine the effects of magnetic stimulation on patients suffering from depression. "I have used electrical treatment for many years," says Grunhaus, former director of the psychiatric unit at the rehabilitative hospital of Sheba Medical Center.
"When I first heard about TMS, about a decade ago, I understood that a genuine revolution was at hand. When Dr. Grisaru published his first study in Israel, important articles on the subject were also published [abroad] ... I felt that I had to study the subject, and did so under Pascual-Leone. Fortunately, I had the good sense to submit a request for a grant in the U.S. We received $100,000 for a research project and thus established the field at Sheba and bought equipment."
Grunhaus conducted studies to compare the two systems - electrical and magnetic - for treating depression: "We found that the success of the treatment depends on the type of depression. People with psychotic depression responded better to ECT. Among sufferers from other forms of depression, we found a similar response for the two methods."
Despite the positive results, people with depression still have a long way to go to magnetic treatment. Grunhaus, who supervised many of the local studies conducted in recent years on magnetic brain stimulation, says: "This procedure is still defined as experimental. At the same time, in Canada there are already centers for treatment with the help of magnetic brain stimulation and in Israel we have the authorization of the Health Ministry to use TMS. However, there are no guidelines for its use in Israel or even directives about who can and should use of it. The obstacle is largely economic. There is clinical approval for this type of treatment, but it is not being budgeted."
A local physician who wants to recommend magnetic stimulation instead of ECT for treatment of depression will not find establishment funding for this. As a result, those who are benefiting from it are patients who agree to take part in research studies, or who are able to pay for the treatment themselves.
One of the many studies conducted by Dr. Grisaru involves the use of TMS to relieve post-traumatic stress. An article he published recently in an American journal summed up the results of this comprehensive study, headed by Dr. Hagit Cohen from the Be'er Sheva Mental Health Center. "The syndrome is characterized by `invasive thoughts'which reconstruct the sights, smells and colors of an event even many years after it occurred and do not fade with time," Cohen explains. As a result, those affected by the event try to avoid similar experiences that are liable to remind them of it.
The study, which was conducted with Prof. Ze'ev Kaplan, director of the Be'er Sheva center, examined whether treatment with TMS, at low rather than high frequencies, could reduce symptoms related to this disorder. The findings showed the positive effect of stimulating the right frontal lobe of the brain at a high frequency of 10 hertz. The treatment diminished most of the symptoms of the syndrome.
The area of the brain that was treated is connected with processing feelings, but the researchers have not yet identified the mechanism of the possible influence of magnetic stimulation. "The very fact that positive results were obtained is of tremendous significance," Cohen says. "First, because this is actually the only treatment today that indicates an improvement in the symptoms of the sickness. Second, positive influence was recorded even a month after the start of the treatment, a finding which shows the importance of repeat `maintenance' treatments."
Psychiatrist Dr. Revital Amiaz worked with Grunhaus and is now responsible for ECT and magnetic treatments in the psychiatric wing of the rehabilitative hospital at Sheba. She intends to examine the effectiveness of TMS in treating addictions. "Caffeine, and chocolate, as well as smoking, activate reward regions in the brain," she says. "Breaking the smoking habit can be done with the help of certain drugs, which raise the dopamine level in the brain. Stimulating the limbic lobe, which is a relatively ancient part of the brain, can constitute a substitute for the activity the drug generates."
The problem, as Zangen and Amiaz know, is that this lobe is deeply embedded in the brain. Besides the potential of the new instrument that Zangen developed at the Weizmann Institute, Amiaz says there is another possibility for reaching the distant regions of the brain: "Stimulating certain points of the cortex causes the secretion of dopamine at the extremities of the nerve cells, and thus the `message' is sent also to the deep parts of the brain."
Since TMS treatment is available locally only a private basis, for payment, there are a limited number of patients. One of them is A., a 26-year-old woman who in the past suffered from severe depression and anxiety.
"I heard about the option from my psychiatrist," she said last week by phone. "I was disappointed in the various drugs I had been taking to treat the depression. Not one of them brought about a satisfactory improvement, and the side effects bothered me a great deal. When my condition became worse, I wondered whether I shouldn't try electric treatment. My doctor told me about TMSas a less aggresive alternative."
Last August she started to get treatments four times week from Prof. Grunhaus and Dr. Amiaz at the Merom-Basel Heights Medical Center in Tel Aviv. "At first I was given treatment in the left lobe, after which I actually experienced a slight deterioration in my condition," A. notes. "They decide to treat the right lobe. On the evening after the first treatment, I felt a definite improvement. In time the number of weekly treatments decreased and now I go once a week, which is supposed to keep my condition stable. I still also feel ongoing improvement, but that might be attributed to the psychiatric treatment I am undergoing at the same time."
A. says she would prefer to be treated twice a week, but adds: "The weekly treatment lasts 10 minutes and costs NIS 500. I don't have money for more than that ... At first it hurts a bit, or more accurately it is bothersome, but you get used to it quickly. You get used to the ticking and to wearing a bathing cap and using earplugs."
Magnets in ancient Egypt?
On January 18 the British paper The Independent published a comprehensive article on TMS. It began by noting sarcastically that Western science is only now discovering what alternative medicine, such as that practiced by the ancient Egyptians, knew long ago about the healing power of magnetic therapy. There is probably no more effective way to stimulate every possible brain lobe of TMS researchers than by making such comments.
"For some reason people think that there is a connection between the fascinating activity of creating a powerful magnetic field, which activates specific regions in the brain, and all kinds of weirdos who suggest sticking magnets into shoes," retorts Dr. Nimrod Grisaru. "I am constantly astounded by this."
Dr. Raphael Ventura, from the department of archaeology and ancient Near Eastern cultures at Tel Aviv University, is equally shocked by the introduction of ancient Egypt into the world of magnetic fields. "No evidence of the use of magnets there has survived," he asserts, "and certainly not in connection with the brain. After all, the Egyptians did not attribute any importance to the brain. In fact, in certain periods the brain was removed from the body before embalming so it would not interfere."
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