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Energy for neurons

Stimulation with low-intensity electrical current has matured as a promising technique for treating depression

Artistic rendering of the effects of electrical stimulation

Léo RamosArtistic rendering of the effects of electrical stimulationLéo Ramos

On a late afternoon in January, Dr. Leandro Valiengo, a psychiatrist, opened one of the cabinets on the now nearly deserted fourth floor of the Hospital Universitário (HU) of the University of São Paulo (USP), removed a black bag, placed it on the blue mattress of a stretcher and arranged the equipment that is being seen as a new form of treatment for depression and other neuropsychiatric disorders: it is a device for transcranial direct current stimulation (tDCS). “It’s very simple,” he says. The device comes in the shape of a box, approximately the size of a laptop computer, with a keyboard to record the code of each patient in treatment and some buttons to adjust the power supply. Two wires extend from its side, each of which has an electrode on the end—one positive and one negative—which are placed on the patient’s temples by means of a headband. The electrodes generate a low-intensity electrical current that runs through the cerebral cortex, the brain’s outermost layer, for 20 to 30 continuous minutes, thereby helping to restore normal functioning to the neurons.

Through studies conducted in several countries, thousands of people—approximately 250 of them in Brazil—have been treated by using tDCS, an experimental technique that continues to mature at a steady pace. It apparently has few side effects, and is consistently gaining strength as an alternative or complement to the use of drugs, especially in the treatment of depression, the most widespread mental disorder. A survey coordinated by researchers from the Federal University of São Paulo (Unifesp) found that almost one third of the Brazilian population had symptoms of depression. New treatment techniques are indeed welcome because 30% of people with depression do not respond to current medications which, when taken, may cause unwanted side effects such as weight gain, loss of libido and insomnia, which limit adherence to treatment.

In October 2013, Dr. André Brunoni, a psychiatrist, and his team at the Hospital Universitário of USP began an extensive test in which 240 participants with severe depression were divided into three groups; they had to receive daily treatment for 10 weeks, actual or simulated electrical stimulation, an antidepressant known as escitalopram (Lexapro) or a placebo. Performed at the HU-USP, Center for Clinical and Epidemiological Research in collaboration with the Institute of Psychiatry at the USP School of Medicine, this study is known as a double-blind study, because neither the participants nor the researchers  know until the end whether or not an actual or simulated treatment was applied (a nurse places the electrodes on the participant’s temple, but does not know if there is actually an electrical current between the electrodes). If all goes well, this test should indicate whether the effect of electrical stimulation is equal to or superior to drug treatment. Moreover, it should be able to create a profile of people with depression who might respond well to one or another type of treatment, based on their genetic and behavioral profiles, which will be assessed through blood tests, CT scans and interviews over a four-year period.

In a previous 6-week study involving 103 participants with severe depression, Dr. Brunoni and his team found that electrical stimulation was able to amplify the effect of a widely used antidepressant, sertraline (brand name Zoloft), which, like escitalopram, has the same action mechanism as fluoxetine (brand name Prozac)—all of which prolong the action of neurotransmitters such as serotonin, which are essential to neuron functioning.

Mannequin with headband and electrodes of the electrical stimulation device, used to sharpen cognitive functions (images in the background)

Léo RamosMannequin with headband and electrodes of the electrical stimulation device, used to sharpen cognitive functions (images in the background)Léo Ramos

According to an article that describes the findings published in JAMA Psychiatry in 2013, the effect of the combined treatment—electrical stimulation and sertraline—was not only stronger, but also faster, since the participants in this group reported remission of symptoms by the second week of treatment. In contrast, the other groups who took only the medication, electrical stimulation, or the placebo reported improvements in their well-being after 6 weeks of therapy. “Apparently the effects are complementary and reach different regions, the sertraline is more active in the subcortical region and the electrical stimulation is more strongly active in the cortical region,” says Dr. Brunoni. Perhaps because of this amplified effect, the group with the combined treatment of tDCS and sertraline had a higher number of people (five, compared with just one in each of the other groups) who experienced euphoria, the opposite effect of depression, which lasted a maximum of two weeks.

The next stage involved 42 study participants who were taking a placebo but were asked to take both the antidepressant medication and undergo the actual electrical stimulation. This time, the study participants were treated for six weeks and followed up for six months, and what was noted was that after cessation of the treatment, symptoms returned in 25% of the patients with less severe clinical pictures and in 70% of those that were resistant to any of the drugs. Dr. Valiengo, a member of Brunoni’s team, says this finding is not without merit, because the benefits of antidepressant medications also cease when people stop taking them.

“The effects of electrical stimulation last a few weeks, which is similar to what happens with convulsive electrotherapy,” he says. This technique, known as electric shock therapy or EST, involves the application of a single, high electrical discharge—up to one ampere—for which patients have to be anesthetized. It is still widely used, despite the side effects such as memory loss, because it is the only effective method of treatment for people with major depression who do not respond to any other treatment. In tDCS a direct current of two milliamperes is applied for 20 to 30 minutes to patients who are awake; this is 400 times less than in EST. “Electrical stimulation is much simpler and safer than convulsive electrotherapy,” says Dr. Brunoni, who in 2011 evaluated the use of tDCS in 14 patients with bipolar disorder and found the results encouraging.

Electrical stimulation is also simpler than magnetic stimulation by direct current, in which a coil, when activated, forms a magnetic field, which in turn generates a low-intensity electric field in the cortex. Adopted in 2008 in the United States and in 2009 in Brazil for treatment of depression, magnetic stimulation is considered an expensive treatment, requires medical supervision because of the risk of seizures, and can be applied only in specialized centers. It is believed that electrical stimulation could be more widely used, because the cost of the device is less and, if approved by regulatory authorities, could be adopted at health centers and used by doctors and other health professionals.

Portable versions of electrical stimulation devices, which, if approved, could facilitate treatment for depression

Léo ramosPortable versions of electrical stimulation devices, which, if approved, could facilitate treatment for depressionLéo ramos

There are indications that it could either stimulate or inhibit the activity of neurons, depending on how the electrodes are positioned—magnetic stimulation and convulsive electrotherapy only stimulate neurons. This possibility could expand its application. Since 2006, double-blind studies—initially with an elevated electrical current of 500 milliamperes—have indicated that tDCS, in addition to being well tolerated, could alleviate the symptoms of a number of diseases. Dr. Felipe Fregni, a Brazilian physician, is evaluating the response to this technique in patients with Parkinson’s Disease being treated at Spaulding Rehabilitation Hospital at the Harvard University Medical Center, and in patients with fibromyalgia, a syndrome characterized by chronic muscle pain throughout the body, being treated at hospitals in São Paulo in combination with aerobic exercise.

So far the side effects experienced with electrical stimulation are minimal, which greatly contributes to the continuation of tests for its efficacy. It has been found that the passage of current through electrodes placed on the skull cause only a tingling sensation for a few seconds and redness for about 20 minutes in the region over which a sponge block with positive or negative electrodes is applied. Dr. Valiengo says that these effects are much milder and temporary than those of antidepressant drugs, which can cause tachycardia or loss of sexual interest.

Some adjustments still need to be made. Studies such as those at the Hospital Universitário at USP documenting the return of symptoms of depression after treatment are important, because they show the limits of the desired effect and underscore the need to define clinical details. This is especially important when it comes to the most appropriate dosage and frequency of each application, which are usually done with new treatments. “One session of electrical stimulation every 15 days was not enough so perhaps once or twice a week would be better,” Dr. Brunoni notes. “This is a new world we need to know better,” says Dr. Valiengo. He too is evaluating tDCS as an alternative treatment for depression in patients who have suffered a stroke (CVA) and for whom drug side effects can be very harmful. In a double-blind study involving 48 participants, 33 have already received simulated or actual treatment. At USP’s Lucy Montoro Rehabilitation Institute, Dr. Marcel Simis, a neurologist, uses electrical stimulation, though it is experimental, in double-blind studies as a complementary technique in the rehabilitation of stroke patients. He believes it may be possible to stimulate the injured area of the brain and inhibit the preserved area, thereby preventing overload of the cerebral hemispheres—an injury to one side of the brain causes the other side to work harder. “Electrical stimulation, in combination with other techniques, will expand our knowledge of the limits of neuronal plasticity,” Dr. Simis says.

Since the technique is still experimental, study participants must go to hospitals to receive the treatments using electrical current. Portable devices, however, are already being developed and evaluated. If approved and adopted by physicians and patients, this will perhaps reduce the cost of treatment by avoiding hospitalizations. Experts also believe that tDCS would facilitate even greater control over treatments, more than that obtained with drugs, since patients are free to take more or less than the recommended dosage.

Devices for electrical brain stimulation are simple and low cost (about R$6,000)—essentially a DC generator with an ammeter and an outlet for the electrodes. These characteristics can facilitate their handling, but also increase the risk of accidents and misuse. “Some people have already tried to build the device, by following instructions found on the Internet, and burned their skin,” says Dr. Valiengo. A U.S. company produces and sells brain stimulation devices over the Internet to boost the performance of video game players, arguing that the devices do not need to be registered with government agencies because they are not medical devices. Since there is no proof of real benefits or potential risks for their use, experts are concerned. “The configuration of the electrodes makes no sense,” says Paulo Sergio Boggio, a researcher at Mackenzie Presbyterian University and one of the pioneers in this area in Brazil, showing on his computer screen the device from the American company.

The possibility of easy access to electrical stimulation devices raises some ethical dilemmas, which the teams led by Dr. Boggio and Dr. Brunoni discuss in an article to be published in the journal Psychology & Neuroscience. Could doctors recommend or allow healthy people to use this technique to increase academic performance, to remain more focused [KO1] and face competitions with less anxiety, or to reduce impulsivity or restlessness in children? There is also the risk of obligatory use by fighter pilots or air traffic controllers, and we still do not know how to resolve these issues. “We know that the use of stimulation may be beneficial for 30 minutes a day,” notes Dr. Brunoni. “Beyond this limit, we do not know.”

Besides participating in clinical studies with other research groups, Dr. Boggio uses electrical stimulation as a complementary approach to researching cognitive functions. By allowing the stimulation or inhibition of specific regions of the cortex, according to the position of the electrodes, this technique indicated that there could be a causal relationship between activating the right prefrontal cortex and risky behavior. In contrast, a magnetic resonance imaging (MRI) test had indicated only an association between the two. In his laboratory, Dr. Boggio also found that this stimulation technique, by stimulating regions of the cortex associated with decision-making, could help people to overcome their urges to drink, smoke or overeat, which opens up the possibility of applications to control compulsive drug abuse or pathological gambling. “Anodic stimulation in the prefrontal cortex encouraged caution and aided decision-making, which could benefit people not only in the business world, but in any type of behavior,” he says. In another test, done in collaboration with Dora Fix Ventura and Thiago Costa, both from USP’s Institute of Psychology, Dr. Boggio discovered an increase in color perception. “If electrical stimulation interferes positively in the process of visual perception,” he wonders, “could it not be used to help people who are visually impaired?”

Depression in Brazil
The frequency of symptoms is higher among women, and among those who are older, poorer and live in the northern region of Brazil

Nearly one third of the population exhibits symptoms of depression, according to a national survey coordinated by a team from the Federal University of São Paulo (Unifesp). In this study, part of the First National Survey on Alcohol Consumption Patterns in the Brazilian Population, 3,007 people, age 14 and over, were interviewed, representing the demographic profile of the population in 143 cities across the country from November 2005 to April 2006.

Coelho et al., 2013In this first nationwide study, published in Revista Brasileira de Psiquiatria in 2013, the frequency of people with symptoms of depression in the population sampled was 28.27%, the majority (15%) with signs of severe depression. It was a much higher average than in previous surveys, taken separately in São Paulo, Brasilia and Porto Alegre that indicated a rate of depressive symptoms of at most 10% of the sampled population. The survey takes into account the possibility that screening for possible cases of depression can lead to false positives, but the methodology is an internationally approved one. “Depression in Brazil is probably even higher,” says Dr. Cassiano Coelho, a Unifesp psychiatrist.

As in other studies, women were two to three times more likely than men to experience symptoms of depression, and people over age 60 were more inclined than younger people to feel depressed. Unlike in other studies, adolescents between the ages of 14 and 17 had a high frequency of symptoms of depression, higher than those between the ages of 18 and 44, which the authors of the survey considered a cause for concern and a reason for more in-depth analysis. Residents of northern Brazil, who were probably sampled for the first time, had the highest rates, in comparison to the other regions.

The researchers hypothesize that depression could be a phenomenon associated with social isolation and the cumulative effect of unfavorable social and economic conditions, more frequently affecting “people with less education and lower incomes,” says Dr. Coelho. In an extreme situation, a widow without children, friends or neighbors, little education and low income, living alone in a poor area of the northern region, would be more likely to experience depression than a woman with a wider social circle, more education and a greater life expectancy.

Escitalopram and transcranial direct current stimulation in major depressive disorder: a double-blind, placebo-controlled, randomized, non-inferiority trial (nº 12/20911-5); Grant Mechanism Young Investigators Award; Principal investigator Andre Russowsky Brunoni-USP; Investment R$453,591.70.

Scientific articles
Brunoni, A.R. et al. The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry. V. 70, No. 4, p. 383-91. 2013.
COELHO, C.L.S. et al. Higher prevalence of major depressive symptoms in Brazilians aged 14 and older. Revista Brasileira de Psiquiatria. V. 35, No. 2, p. 142-43. 2013.
KRISHNADAS R, CAVANAGH J. Depression: an inflammatory illness? Journal of Neurology, Neurosurgery & Psychiatry. V. 84, No. 5, p. 495-502. 2012.