ieee spectrum |march 2006 |na a long trunk, called an axon. to communicate with another cell, it...

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www.spectrum.ieee.org March 2006 | IEEE Spectrum | NA 25

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Imagine a crushing sadness so severeit keeps you from eating, sleeping, or socializing. Though youcan’t sleep, you lack the energy and the will to get out of bed.Everyday decisions, like which clothes to wear, leave you para-lyzed. You’ve no desire to do the things you once thought werefun; in fact, you can’t bring yourself to do much of anything. Now,add to all that the realization that you’ve tried everything knownto medicine, it hasn’t worked, and there’s a good chance you won’tfeel any different. Ever.

“I had nothing to lose,” says Karmen McGuffee, who sufferedfrom severe depression for a decade and was hospitalized five timesfor it. So she had surgeons cut open her neck, gently wrap an elec-trode around one of the nerves there, and plug the electrode intoa pulse generator, which theyslipped under the skin of herchest. About every 5 minutes,the pocket-watch-size devicesends a buzz of current throughthe nerve and into her brain.

Six months after doctorsswitched on the pulse generator,called a vagus nerve stimulator,McGuffee’s world looked totallydifferent. “I had no idea that lifedidn’t have to have a dark veilover it all the time,” she says. Onceunable to concentrate enough toread a newspaper, McGuffee isnow an executive secretary.

Depression is distressinglycommon, affecting more than120 million people around theworld and sucking tens of bil-lions of dollars out of the globaleconomy through the cost ofcare and lost productivity. It’salso deadly. Every year 850 000people worldwide take theirown lives, and 9 out of 10 ofthem are suffering from depres-sion, another mental illness,or substance abuse. Statisticsshow that of those who had hadtreatment for depression justthrough visits to a doctor’s of-fice, 2 percent ultimately com-mitted suicide, as did 4 percentof those who had to be hospi-talized for depression.

Twenty-five percent of people with depression have no accessto any form of mental health care; of those who do have accessto care, only a quarter seek treatment. Of those who consult doc-tors, some 80 percent find relief in the form of drugs or some kindof talk therapy, such as cognitive therapy. But for the rest—peo-ple like McGuffee, prone to the most severe and chronic formsof depression, about 11 million of them in the developed worldalone—drugs don’t work.

For decades, the only other option for these people was electro-convulsive therapy, which because of the frightening side effectof amnesia is often rejected by patients. But this grim outlook is atlast beginning to change. McGuffee was one of the first to benefitfrom a new crop of electromagnetic brain stimulation technologiesthat psychiatrists are testing, with the hope of curing—or at least

helping—patients for whom little else works. By electricallymanipulating specific portions of the brain with implanted elec-trodes, electric current, or magnetic fields, doctors aim to succeedwhere drugs fail, by producing long-lasting changes in the brain—and to do it without electroshock’s significant side effects.

For a variety of reasons, including the large number of poten-tial patients and the accumulated knowledge of how the diseaseworks, depression is the primary target of most of these tech-nologies. But some of these methods are already showing greatpromise for treating such other mental maladies as bipolar dis-order, obsessive-compulsive disorder, and bulimia.

The technology McGuffee uses, vagus nerve stimulation, wasthe first to enter routine clinical use. A pacemakerlike device about

the size of a pocket watch, im-planted under the skin of thechest, pulses a nerve in the neck[see illustration, “Vagus NerveStimulation”]. In about 16 per-cent of patients like McGuffee,according to clinical studies,that electric pulsing completelyquashes the symptoms ofdepression. It was approved asa depression therapy, for use inconjunction with drugs, bygovernment regulators in theEuropean Union and Canada in2001. Last June, it became thefirst psychiatric device to bereviewed and approved in theUnited States, which has morestringent requirements formedical devices. Nevertheless,a number of psychiatrists re-main unconvinced that thetherapy works in enough peo-ple to outweigh the risk andcost of surgery.

Vagus nerve stimulation isn’tthe only technology being toutedfor treatment of the severelydepressed. Another technique,repetitive transcranial magneticstimulation, uses powerful mag-nets to generate current in well-defined portions of the brain[see illustration, “RepetitiveTranscranial Magnetic Stimu-lation”]. Many research groups

around the world have experimented with the technology. At lastcount the results of more than 60 depression trials performed inAustralia, Israel, Taiwan, the United States, Europe, and elsewherehad been published. But clinical use is just beginning. The tech-nology is winding its way toward a review by U.S. regulators, andthe company behind it, Neuronetics Inc., in Malvern, Pa., says itcould be approved within the year.

And these two are just the ones closest to the clinic. Re-searchers are exploring three other, more experimental tech-nologies. One uses direct current to produce a change in the brainsimilar to that of magnetic stimulation. Another uses transcranialmagnetic stimulators to spark seizures just as electroconvulsivetherapy does but, it is hoped, without the amnesia that can accom-pany it. The third experimental technology borrows a device used

A pulse generator implanted in apatient’s chest sends electric pulses tothe vagus nerve, one of 12 nerves thatemanate from your brain rather thanyour spinal cord. The pulses sendsignals into the brain that reduce oreliminate severe chronic depression insome people.

Approved for sale in the UnitedStates, Canada, and the European

Union as a depression treatment.Unlike other treatments, including drugs,it appears to keep working for years.

Completely eliminates depressionin only one out of six patients.

Requires surgery.

Vagus Nerve Stimulation

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to control the tremors of Parkinson’s disease. Surgeons havebegun implanting electrodes in patients’ brains to switch off mal-functioning brain circuits involved in depression and obsessive-compulsive disorder.

The coming clutch of medical devices, if proven to work, couldrepresent not just hope for the hopeless but a profound changein psychiatry. “I think it’s not too big a jump to say we haven’t hada new [nondrug] treatment for 40 years,” says Paul Fitzgerald,an associate professor of psychiatry at Monash University, anddeputy director of the Alfred Psychiatry Research Center, both inMelbourne, Australia. Fitzgerald, who does transcranial magneticstimulation research, notes that even the drug therapies are largelyderivative of each other. “Now we’re really faced with the poten-tial for a significant expansionof treatments, as long as theyare introduced carefully,” headds. Noting psychiatry’s oftendisastrous history of nondrugtreatments, such as the embraceof prefrontal lobotomy in themid-20th century, he thinks thefield is approaching a water-shed, for the better. “We’re get-ting it right this time.”

THAT PSYCHIATRISTS CAN USE bothdrugs and electricity to battleillness testifies to the fact thatthe brain is both a chemical andan electrical organ. Every braincell has a halo of short projec-tions attached to its body anda long trunk, called an axon.To communicate with anothercell, it sends a pulse of voltagedown the axon. The axon usu-ally terminates at one of theshort projections of anotherbrain cell. Rather than make adirect electrical connection,two brain cells communicatevia a puff of chemical trans-mitters released from the endof the axon when the voltagepulse reaches it. These trans-mitters cross the nanometersbetween the end of the axonand the next cell’s projectionsand bind with receptor mole-cules there. Depending on the type of chemical signal, this bind-ing can lead to a variety of things, but the simplest is an influxor outflow of current that briefly raises or drops the target cell’svoltage. The cell integrates the voltage changes from its manyprojections, and, if the combination of them is big enough, it willtrigger a voltage pulse down the target cell’s axon. The processof integration and signaling continues as signals propagatethrough the brain’s millions of specialized circuits and is the basisof everything that occurs inside our heads: thoughts, emotions,moods, memories, and dreams.

Psychoactive drugs, such as Prozac, work on the chemical sideto ultimately affect electrical signals. Depression, at least in part,involves a problem with the electrical signaling between certain partsof the brain whose cells signal with a chemical transmitter called

serotonin. By inhibiting the reabsorption of serotonin, Prozac letsmore of the chemical accumulate in the space between the end ofthe axon and the next brain cell, thus restoring the signaling.

One problem with this approach is that drugs work everywherein the brain that their chemical target exists, regardless of whetherthose parts have anything to do with depression or any other dis-ease, and that leads to side effects. Prozac, for example, has beenknown to reduce sex drive and can cause insomnia. Another prob-lem is that brain chemistry varies from person to person, so nosingle drug will work in everyone.

The shared goal behind the new electromagnetic therapies, onthe other hand, is to use electricity itself to restore the signaling,ideally, only in those parts of the brain affected by disease. Decades

ago, neuroscientists demon-strated that electrically stimu-lating a neuron alters, in thelong term, the strength of itsconnections to other neurons—making an electrical signal fromone neuron more likely or lesslikely to jump to the next neu-ron. Though little is known indetail about how the new thera-pies work, it’s likely that, tovarying degrees, they depend onthat phenomenon.

BECAUSE THEY ARE NEWand in somecases relatively unproven, thedevice-based technologies arebeing tested exclusively in peo-ple for whom all the availabledrugs have failed to work. Fora minority of these patients,electroconvulsive therapy, a70-year-old technique, is thetreatment of last resort. So it iswith electroconvulsive therapythat the new technologies aregenerally compared.

Unfortunately, your view ofelectroconvulsive therapy, likethat of many potential patients,was probably formed by the 1975movie One Flew Over the Cuckoo’sNest, in which it was used as ameans of punishment and con-trol. Even if Jack Nicholson’s per-formance has no influence on

your view of psychiatry, the idea of the therapy’s main side effect,amnesia, is far more fearsome than Prozac’s decreased libido or eventhe maladies associated with more powerful drugs, because mem-ory is so tied up with our sense of self. But the reality is that theseverity of electroconvulsive therapy’s side effects has been mini-mized over the years, its use is carefully controlled, and, quite sim-ply, nothing is as effective at breaking through the worst forms ofdepression. Still, in the United States, only about 100 000 people ayear agree to it, despite the millions whom no drug helps.

“Electroconvulsive therapy can be dramatically effective atrestoring a person’s health and getting their life back on track,”says Sarah H. Lisanby, director of the Brain Stimulation andNeuromodulation Division of the Columbia University MedicalCenter, in New York City. “The potential for the new brain stimu-

A powerful electromagnet positionedover a part of the brain implicated indepression induces the flow of current inneurons there. Though the stimulationis done only for minutes a day over aperiod of weeks, it alters the activity ofthe neurons in the long term.

Few side effects. Could gainapproval by U.S. government

regulators this year.

Long-term risks and long-termeffectiveness are unknown.

Repetitive TranscranialMagnetic Stimulation


Positioning gantry

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lation techniques is to get those kinds of dramatic effects inmedication-resistant populations without the downside.”

VAGUS NERVE STIMULATION began in the 1980s with Jacob Zabara, aneurophysiologist at Temple University, in Philadelphia, demon-strating that he could quell epileptic seizures in a dog by elec-trically jolting its vagus nerve, one of twelve pairs of nerves thatemerge from the brain instead of the spinal cord. He showed thetechnique to pacemaker designer Reese Terry, and a few years laterthey formed a company called Cyberonics Inc., in Houston, todevelop a treatment for epilepsy.

Using off-the-shelf integrated circuits, design help fromfriends in the field, and a new kind of helical electrode, Terryput together an implantable de-vice that periodically shocksthe vagus nerve. Cyberonics hasmade more than 30 000 of them,using the same basic design.The implantable device looksand acts like a heart pacemaker.Though a doctor can programin a wide range of stimuli, thedevice typically delivers 1- to2-milliampere, 250-microsec-ond pulses at 20 to 30 hertz for30 seconds every 5 minutes.

Terry and his co-workers al-ways envisioned uses beyondepilepsy. Depression was a goodplace to start, because the mal-ady has been linked to epilepsyfor so long that even Hippo-crates wrote about it. About aquarter of people with severeepilepsy also have chronic de-pression—a far greater ratiothan in either the general pop-ulation or other groups withchronic illnesses. Also, intrigu-ingly, early in Cyberonics’ tests,some epilepsy patients reportedthat the device had improvedtheir mood.

Researchers don’t really knowwhy the device works againstdepression. But they do havesome theories. Phillip C. Jobe atthe University of Illinois Col-lege of Medicine, in Peoria, pro-poses that the brain’s naturaldefenses against both epilep-tic seizures and depression are weakened by chemical and struc-tural flaws in the same two systems of neurons buried deep withinthe most primitive part of the brain. Vagus nerve stimulation altersactivity in both those areas, although the nerve does not connectdirectly to either of them.

Terry, naturally, takes an engineer’s view of things. “The way Ilook at it,” he says, “the brain is a very finely controlled feedback sys-tem.” For some diseases, he suggests that the “control system is alittle bit out of balance.” The periodic pulses from his device in effect“pace” the vagus nerve, he believes, restabilizing the control system.

But a bigger question than how it works, and one the companyis still trying to answer for doctors, is whether or not it actually

does work. In the late 1990s, a pilot study of patients with chronicor recurrent depression that resisted treatment with drugs gavepromising results. McGuffee was among the first patients toreceive an implant, in February 1999. One month after she got theimplant, her family began to see an improvement; a few monthslater, McGuffee noticed it, too.

The pilot study was enough to convince European andCanadian regulators to allow the stimulator’s use in their juris-dictions. To get more conclusive data that might satisfy thetougher U.S. regulations, Cyberonics embarked on a 235-patient,eight-week study. To tease out any placebo effect, all the patientsreceived implants, but only half of the implants were turned on.Here again, too few patients improved to tell if the device was the

cause of the improvement. Soat the end of the study thecompany asked doctors to turnon the implant for anyone whowanted it and instructed themto continue treating the pa-tients with anything that mightbenefit them. “It would havebeen inappropriate to withholdtreatment,” says chief medicalofficer Richard Rudolph. “Butnow we had nothing to comparethe outcomes with.”

Strapped for cash but notready to give up on a groupof patients with no options,to say nothing of a potentialUS $1 billion market, the com-pany continued to try to provethe stimulator would work fordepression. Plan B, according toRudolph, was to follow thepatients from the original study,find a group of very similarpatients without stimulators,and compare how they faredover two years, a much longerperiod than is generally usedin a trial of a new antidepres-sant drug.

After one year, one in sixpatients treated with the nervestimulator was free of depres-sion, and 56 percent got somemeaningful benefit—as meas-ured by a standardized ques-tionnaire used to rate theseverity of a patient’s depres-

sion. Of those who did respond, about 70 percent continued tobenefit after two years. But waiting a year to see if the treatmentworked in a disease that comes at irregular intervals was highlyunusual. The lack of a control group that had the device implantedbut not turned on to counteract the placebo effect was strangerstill. In August 2004, the U.S. Food and Drug Administration,which regulates the marketing of medical devices, decided notto allow Cyberonics to sell the vagus nerve stimulator as a depres-sion treatment, overruling its own advisors in the process.

Cyberonics’ CEO, Robert P. (“Skip”) Cummins, who lost bothhis mother and grandfather to depression-related suicide, refusedto give up. His company gathered more data, and went straight to

Could be more effectivethan other brain stimulation

techniques.

Requires daily anesthesia andcareful medical monitoring

for a period of weeks. Fewpatients have undergone thistreatment; little is known abouthow well it works or its sideeffects.

This therapy uses a more powerfulelectromagnet than repetitive transcranialmagnetic stimulation does; it is basicallya magnetic version of electroconvulsivetherapy. Magnetic seizure therapy inducesa high-frequency current in a small portionof the brain until it sparks a seizure. Thehope is that a magnetically induced seizurewill be as effective at treating depression asan electrically induced seizure while causingless memory loss.

Magnetic Seizure Therapy


Pulsed magnetic field

Seizure

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the FDA’s top brass. By February 2005 the company had won con-ditional approval. But it still had hoops to jump through on theway to full approval: there was controversy when Public Citizen,a prominent Washington, D.C., advocacy group, questionedwhether the device worked at all. At the same time, an investorlawsuit began regarding the timing of some executive stock sales.And then there was a halfhearted investigation by a U.S. Senatecommittee into why the FDA had decided against the device. Fullapproval finally came last July.

Cyberonics says it has trained 2000 psychiatrists in vagus nervetherapy so far, but many physicians are still skeptical. PerminderSachdev, a professor of psychiatry at the University of New SouthWales, Sydney, Australia, thinks the technology has shown somepromise but has a way to gobefore the results are convinc-ing. “It’s a hard area to investi-gate,” he says. The placebo effectis difficult to eliminate, thenature of depression is that itwaxes and wanes, and the treat-ment takes a long time to showan effect. The combination of allthat means you need a greatmany patients to prove a deviceis working, he believes. Sachdevand others expect the picture toclear somewhat after the resultsof a study going on now in Eu-rope are reported. In the mean-time Cyberonics is running pilottrials to see if the device willwork to control other mentalillnesses, such as bulimia andobsessive-compulsive disorder.

CYBERONICS’ DUEL with U.S. regu-lators was watched closely bypsychiatrists, patients, and com-peting companies. Executivesat Neuronetics were particu-larly interested, because theirdevice, a repetitive transcranialmagnetic stimulator speciallydesigned for treating depres-sion, will be the next such tech-nology weighed by the FDA.The company plans to send itsdata to the agency next monthand could get a decision beforethe year is out.

How the vagus nerve stimulator fared offers some importantlessons for Neuronetics, says Mark Riehl, the company’s vicepresident of product development and operations and the leaderof the team that designed the device. “The FDA and the mar-ket expect a trial modeled after pharmaceutical trial design,”he says. Drug tests are designed so that patients are selected atrandom to get the treatment or get a placebo—and neither thepatients nor their doctors know which patients are getting thetreatment. So that’s what Neuronetics is doing (and, of course,that’s what Cyberonics originally set out to do).

The basic idea behind repetitive transcranial magnetic stim-ulation (rTMS) is to use a strong, varying, and concentratedmagnetic field to induce the flow of current in a few cubic

centimeters of the part of your brain above your eyeballs. Thisblock of neurons, the prefrontal cortex, has to do with makingdecisions, but neuroscientists have also implicated it in depres-sion, and it connects directly to mood-regulating structuresdeeper in the brain. The neural activity in the prefrontal cortexis abnormal in people with depression, but electroconvulsivetherapy and drugs like Prozac alter it to restore normal mood.The theory is that you can get the same restoration by repeat-edly generating a magnetically induced current there. To treatdepression, the current must be strong enough to trigger spikesof voltage in brain cells but not so strong or high in frequencythat it sparks a seizure.

A transcranial magnetic stimulation device is simple. Basically,it’s just a very big capacitor thatdischarges into the coil of anelectromagnet, which generatesthe magnetic field. But the mag-netic field it generates is im-pressive. At 2 tesla, the field is50 percent stronger than that ofa typical full-size magneticresonance imager. To make afield like that, 8000 amperes,driven by more than a kilovolt,typically course through thecoil’s windings.

Early research on the useof rTMS to fight treatment-resistant depression showedinconsistent results and rela-tively small rates of response,providing a benefit on averageto only about 30 percent of pa-tients. The problem with theearly work, according to Mon-ash University’s Fitzgerald, wasthat there was little consistencyas to exactly where in the brainthe stimulator was producingits current.

But incorporating magneticresonance maps of patients’brains and other techniques haveimproved the therapy’s accu-racy. And now a few carefullydone direct comparisons betweenrTMS and electroconvulsivetherapy, hitherto the most effec-tive treatment, suggest that with

certain exceptions, the same proportion of patients would benefitfrom either. There are many, however, who think the seizures pro-voked by the long-used electroconvulsive therapy will prove moreeffective than rTMS.

Columbia’s Lisanby is one. Electroconvulsive therapy “had greatvalue in helping patients who were extremely depressed, but italso had some drawbacks,” she says, referring to the possibleamnesia. So she has been developing magnetic seizure therapy, aversion of rTMS that triggers seizures [see illustration, “MagneticSeizure Therapy”].

Electroconvulsive therapy triggers seizures with pulses of cur-rent that are spread over a large area of the brain. Because rTMSlimits current to well-defined, centimeter-scale portions of thebrain, Lisanby reasons, magnetic seizure therapy could allow doc-

Simple and cheap.

Few studies have been performed;very little is known about how well itworks.

A device drives a small direct currentthrough the front part of a patient’sbrain. Though the stimulation is doneonly for minutes a day over a period ofweeks, it appears to alter the activityof neurons in the long term.


Transcranial Direct Current Stimulation

1-milliampere current

Current source

Electrode

tors to better control where in the brain a seizure originates andwhere it spreads to, with the aim of minimizing side effects.

So far, rTMS practitioners have been studiously avoiding induc-ing seizures in their patients by limiting both the device’s powerand its frequency, so the available technology was not easily suitedto actually inducing seizures by magnetic means. The first system,used in neurology experiments in London in 1985, could generatea single on-off pulse only every four seconds, says Reza Jalinous,its coinventor and vice president of operations at The MagstimCo., in Carmarthenshire, Wales. The device could generate pulsesonly at a low frequency, because all the energy from the chargewas lost as heat in the coil winding, so the capacitor had to becompletely recharged after each pulse. But scientists, and laterpsychiatrists, wanted higher fre-quencies, to more closely matchthe electrical characteristics ofbrain cells. So Jalinous reshapedthe technology.

“To go faster you have to dis-sipate as little energy as possi-ble in the winding in the coil,”he says. It turned out to be asimple matter to go from onepulse every four seconds to fivepulses per second. Jalinous re-placed the on-off pulse with analternating-current sinusoid, socurrent flowed first in one direc-tion and then in the other. Thesystem loses little energy in thecoil and returns about 70 per-cent of it to the capacitor. Sothe power supply can top off thecapacitor quickly, and the stimu-lator can produce its next pulsein a fraction of a second. By up-grading the power supply andmaking a few other improve-ments, Jalinous has produced asystem for Lisanby with a topfrequency of 100 Hz, as opposedto the more typical 20 Hz or less,that can be sustained for up to10 seconds. Lisanby expects tobegin using the new device onpatients this year.

Of course, too many pulsestoo close together will generatetoo much heat for the coil wind-ings to handle. “The bottleneck right now is actually heating in thestimulating coil,” says Angel Peterchev, a power electronics engineerdoing postdoctoral research in Lisanby’s laboratory.

In the devices now in use, there are two types of electromag-netic coils: air-core and iron-core. The air-core types, favoredby Magstim and Medtronic Inc., of Minneapolis, are meant tobe handheld and easier to move, so neurologists can experimentwith their effects on different parts of the brain. But the air-core coils are less efficient and generate more heat. The iron-corekind, used by Neuronetics, is meant for clinical use. Although itconsumes less power and generates less heat, it would have tobe redesigned using a different core material and fewer coil wind-ings to deliver magnetic field strengths of more than 2 T, whichmight be useful in magnetic seizure therapy.

PSYCHIATRISTS ARE BEGINNING to look at an even simpler technologythan transcranial magnetic stimulation to fight depression. “It’slike hooking the patient up to a car battery,” jokes Sachdev. “Butwith safety features,” his colleague Colleen Loo, a senior researchfellow, hastily adds. Crude or not, it’s a pretty accurate descrip-tion of an experimental technique called, or tDCS. Basically, itsubjects the front half of the brain to a minutes-long 1-mA directcurrent once a day for several weeks [see illustration, “TranscranialDirect Current Stimulation”].

The simplicity of tDCS makes it sound almost suspicious, andindeed its origins stretch back into the murk of 19th-centuryquackery. But the principle of how tDCS seems to work in thebrain is roughly the same as that of rTMS. They both seek to make

neurons in the prefrontal cor-tex, the decision-making partof the brain, more excitable,that is, more likely to propagatea signal from neuron to neuron.In tDCS’s case a small current,delivered via electrodes on thetemples, biases brain cells,making them more likely toemit a spike of voltage, saysAlvaro Pascual-Leone, asso-ciate professor of neurologystudying tDCS at Harvard Uni-versity, in Cambridge, Mass.The effect, studies have shown,lasts long after the current isturned off.

The concept and technol-ogy are so simple, in fact, thatPascual-Leone and his col-leagues suggested in The BritishJournal of Psychiatry that tDCSbe used in the developing worldas a first-line treatment for de-pression instead of rather ex-pensive antidepressant drugs.But Sachdev thinks this is aterrible idea. “We need to knowa lot more about tDCS beforeit is accepted as an effectivetreatment and must await theresults of many ongoing trials,”he wrote in a rebuttal. “In themeantime, depressed patientsin the developing world shouldbe dissuaded from unplugging

their car batteries and clamping them on their foreheads.” Pascual-Leone says he has results showing tDCS fought treat-

ment-resistant depression as well as rTMS did in experimentsdone at the University of São Paulo School of Medicine, in Brazil,but at press time the study had not yet been published in a peer-reviewed journal.

IF “HOOKING THE PATIENT UP TO A CAR BATTERY” is the least invasive newpsychiatric technology, then deep-brain stimulation is its oppo-site. It is meant only for the most desperate patients, those nothelped even by electroconvulsive therapy. It requires having a sur-geon bore two holes in the skull, insert a pair of electrodes deepinto the brain, run wires beneath the skin of the neck, and con-nect them with a pacemakerlike device implanted in the chest

A stimulator implanted in a patient’schest sends pulses of electricity toelectrodes embedded deep within thebrain. The stimulation switches offneurons within a few millimeters of theelectrodes. It can cure severe depressionby interrupting malfunctioning braincircuits implicated in the disease.

Some effects are almostimmediate and seem to last.

Allows doctors to target braincircuits with great accuracy.

Requires brain surgery. Fewpatients have received implants;

little is known about how well it works.

Deep Brain Stimulation


Electric pulse

Implanted wire

Implanted stimulator

Electrodes

under the skin. The device sends pulses of electricity to the elec-trode tips, shutting down activity in the few cubic millimetersof brain tissue there [see illustration, “Deep Brain Stimulation”].

The results can be instantaneous. Thomas Schlaepfer, vicechair and professor of psychiatry and psychotherapy at theUniversity of Bonn, in Germany, described the case of one of hispatients to IEEE Spectrum. A host of drugs and even electrocon-vulsive therapy had failed to lift her depression and halt her des-perate urge to kill herself. But last August she had one ofMedtronic’s deep-brain stimulators implanted. When Schlaepferturned the device on and asked her how she was feeling, she repliedthat she was still as depressed as ever but that she would like tostart bowling again.

Bowling had once been her favorite pastime, but she had notenjoyed it for years. The inability to enjoy things that once gaveyou pleasure—psychiatrists call it anhedonia—is a key charac-teristic of major depression. The parts of the brain responsiblefor it, the reward centers, are among the prime targets of thenew therapy.

Deep-brain stimulation has been in use for years to treat thetremors of Parkinson’s disease. In that case, 3- to 5-volt pulsesat about 100 Hz are applied to a part of a brain circuit that mal-functions and causes the tremors. The stimulation suppresses theactivity of neurons near the electrode, mimicking their surgicaldestruction, but with a key twist. “Basically, it’s reversible andtunable brain surgery,” says Schlaepfer. Turn the device on, andthat section of the brain goes off-line. Turn it off, and the neu-rons spring back into action. It’s a simplistic view, of course,and scientists still don’t know if the electrode’s current blocksbrain traffic by holding the cells at too high a voltage to propa-gate a signal, exhausts their supply of chemical transmitters, over-lays a meaningless jamming signal on them, or does somethingdifferent entirely.

The device has also been used to treat severe obsessive-compulsive disorder; indeed, this was its first use in psychiatry.In that treatment, neurosurgeons had been destroying a few cubicmillimeters of a particular structure in the brain. Now surgeonshave begun inserting electrodes instead of destroying those tinyparts of the brain.

A group based at the University of Toronto and led by neuro-surgeon Andres Lozano and neurologist Helen S. Maybergreported the first trial of deep-brain stimulation for depres-sion only a year ago. (Mayberg has since become a professor atEmory University, in Atlanta.) Imaging studies led them toBroadmann area 25, a pair of structures deep in the brain justabove and behind the eyes that become active when people aresad. It has abnormally high blood flow in people with treatment-resistant depression; antidepressant drugs tend to reduce theamount of blood flow there. So the Toronto researchers implantedelectrodes powered by a Medtronic stimulator in that spot insix patients. Five of the six responded well initially, and fourcontinued to do so six months out. According to Lozano, thosefour are still doing well two years later. Lozano, who has beenimplanting deep-brain stimulators for more than a decade, saysthat not enough is known about why patients respond or don’trespond to the procedure to say if there is a need to tweakthe technology. “We don’t know if it’s the electrodes or thepatients,” he says.

Although the seminal work was done using stimulators madeby Medtronic, another maker of implantable stimulators, Ad-vanced Neuromodulation Systems Inc. (ANS), in Plano, Texas,holds the relevant intellectual property rights, according to RohanHoare, the company’s vice president of corporate strategy and

development. ANS is now replicating Mayberg and Lozano’s resultsin a pilot study using its Libra deep brain stimulation system.The main difference between the Medtronic systems used inToronto and Bonn and ANS’s devices is that Medtronic’s deliversa constant-voltage pulse, which allows the current to vary depend-ing on the impedance of the brain, while its competitor deliversconstant current, allowing the voltage to vary. ANS’s vice presi-dent for scientific affairs, Tracy Cameron, notes that most animalresearch has been done using constant-current stimulators andhypothesizes that this approach may be more in tune with thebrain’s physiology.

The debates don’t end with the technology. Researchers alsodisagree about which brain structures to stimulate, althoughall the contenders are in the same neighborhood, behind andabove the eyes. Research at Brown University Medical Schooland Butler Hospital, both in Providence, R.I., stimulate a muchlarger structure than Broadmann 25, called the anterior limb ofthe internal capsule. And Schlaepfer and his colleagues inEurope are working on the area related to anhedonia, called thenucleus accumbens.

ASSUMING THAT ALL THE NEW brain stimulation techniques proveeffective in the many upcoming trials, the psychiatrist’s tool-box will look very different a decade from now. Patients willprobably first be offered the less invasive techniques, such astranscranial direct current and magnetic stimulation; then themore invasive ones, such as the seizure therapies; and finallysuch surgical technologies as deep-brain stimulation and vagusnerve stimulation. “A significant portion of patients will wantto try the less invasive treatment first,” says Monash Univer-sity’s Fitzgerald. “For some it will be sufficient.”

But don’t cash out of your drug company stock just yet. Evenif the more easily applied therapies are proven effective, drugfirms have little to worry about. “Drugs are always the first pref-erence, because you don’t have to show up every day,” says theUniversity of New South Wales’s Sachdev.

Of course, a better way than simply trying one therapy afteranother is to figure out how each works and why they work wellfor some people rather than others. That won’t happen soon,because it will require experience with many patients and amuch better understanding of the brain. And though suchbrain-imaging technologies as positron-emission tomogra-phy have been useful for finding target areas for deep brainstimulation and for understanding the effects of stimulationtechnologies, they can’t yet predict who will respond to a treat-ment and who won’t. “We’ve got the diagnostic tools; we justneed to refine them,” says Harvard’s Pascual-Leone. And whenthat’s done, psychiatrists will have both a road map of the mindand the tools to fix the potholes. �

TO PROBE FURTHER For a more complete roundup of the clinical research into thenew device-based therapies, see Brain Stimulation inPsychiatric Treatment, edited by Sarah H. Lisanby,Washington, D.C., American Psychiatric Publishing (2004).

A Neuronetics executive teaches you how to design atranscranial magnetic stimulator in “Designing TranscranialMagnetic Stimulation Systems,” by K. Davey and M. Riehl,IEEE Transactions on Magnetics, March 2005, pp. 1142–48.

More details of vagus nerve stimulators are laid out in“Vagus Nerve Stimulation for the Treatment of Depression,”by Dorin Panescu, IEEE Engineering in Medicine and BiologyMagazine, November–December 2005, pp. 68–72.


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