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Biomedicine

Brain Pacemakers

Hearts have long been regulated by electronic implants. Now it’s the brain’s turn.

It had been more than six hours since Joan Sikkema first laid her shaven head on the operating table, six hours since a 14-millimeter hole was drilled in her skull and a thin electrode inserted deep inside her brain. Now, swaddled in blankets in the cold operating room and wide awake, Joan (pronounced joe-ann) looked up at half a dozen physicians in surgical gowns, all of whom seemed to be shouting orders at her simultaneously.

“Put your hands out steady!” one said.

“Touch your finger to your nose!”

“Puff out your cheeks!” said another. Pairs of eyes met over surgical masks, and half-nods were exchanged.

This was supposed to be the climactic moment of a surgical session that had begun around 9:00 a.m., when Ali R. Rezai, an Iranian-born and Western-trained neurosurgeon, opened the tiny porthole in the left side of Joan’s skull, about five centimeters behind the hairline. Rezai and a team of functional neurosurgeons, neurologists and nurses at the Cleveland Clinic Foundation in Ohio had spent the next few hours electronically eavesdropping on single cells in Joan’s brain, attempting to pinpoint the precise trouble spot that caused a persistent, uncontrollable tremor in her right hand. Once confident they had found the spot, the doctors had guided the electrode itself deep into her brain, into a small duchy of nerve cells within the thalamus. The hope was that when they sent an electrical current to the electrode, in a technique known as deep-brain stimulation, her tremor would diminish, and perhaps disappear altogether.

“Any tingling in the area?” asked neurologist Erwin B. Montgomery Jr., standing over Joan and tweaking the knob on a device that controls the voltage, frequency and duration of electrical stimulation. He was both testing the electrode’s effectiveness and making sure it wasn’t in a place where a burst of electricity could cause problems. Several millimeters too far back could cause a tingling sensation known as parathesis and possibly speech problems. Several millimeters too far forward, and the electrode might miss the target and have no therapeutic effect at all. Every question the doctors fired at Joan elicited a geographical answer about the exact position of the electrode inside her brain.

“Hold out your hands.” Joan held her hands straight out. There was nary a tremor or shake. “Boy, that looks pretty steady,” Montgomery announced. “Okay, open your mouth.” Joan slowly opened her mouth. “Say, Today is a lovely day.’”

“Todayis,” Joan said, very slowly, “alovelyday.”

If functional neurosurgeons like Rezai are correct, this collaborative medical scene, where patients lie awake in the operating room and help doctors implant a kind of neurological pacemaker, could soon be commonplace. Similar to heart pacemakers, which are surgically implanted in the chest and use electrical stimulation to maintain optimal cardiac rhythm, brain pacemakers consist of an electrode permanently implanted in the brain to maintain neural equilibrium. The electrode emits electric pulses from a power pack in the chest.

Brain pacemakers were first successfully implanted in humans nearly 15 years ago in France, and in 1997, the U.S. Food and Drug Administration approved the first U.S. use of pacemakers to treat essential tremor and Parkinsonian tremor-currently, the only approved indications. But until very recently, the procedure had been performed relatively infrequently, and not surprisingly, it has been viewed with great caution. “Historically, the field has been hindered-appropriately-by the problematic memory of things like the lobotomy, where the science wasn’t there and many of the outcomes were horrific,” says Joseph J. Fins, chief of the Division of Medical Ethics at Weill Medical College of Cornell University.

But now, as the science of brain circuitry has become better understood, and as the long-term outcomes of brain pacemakers have shown the technology to be both effective and safe, that could be about to change. The FDA is now considering-or soon will be asked to consider-several applications that could ultimately open up the technology to tens of thousands of patients with disabling neurological conditions. For instance, the FDA was expected this summer to approve the use of brain pacemakers for the treatment of a number of other Parkinson’s-related symptoms, such as stiffness. The agency recently authorized investigational use of the devices to treat certain forms of epilepsy and approved testing of pacemakers in the treatment of obsessive-compulsive disorder; the first three patients with obsessive-compulsive disorder received implants earlier this year at Butler Hospital in Providence, RI. Within a year, surgeons at the Cleveland Clinic expect to test the devices as a treatment for severe depression. And by the end of this year, the group hopes to begin using deep-brain electrical stimulation to try and “awaken” patients who have suffered severe brain damage and live in a cognitive limbo known as a “minimally conscious state.” In the more distant future, laboratory research suggests that pacemakers may even have a role in controlling behavioral disorders, such as obesity, anorexia and addiction.

Doctors estimate that brain and neurological conditions afflict more than 50 million Americans. “For all these conditions, conservative therapy like drugs helps, but basically 10 to 20 percent of patients are refractory to these therapies,” says Rezai. “Surgery is not for everybody. At this point, we really have to reserve it for end-stage patients for whom nothing else works. But that’s evolving. I equate it to where heart pacemakers were in the 1950s. Back then, you would tell someone, I’m having a pacemaker put in,’ and people would go, What’s that?’ Now everyone knows what a heart pacemaker is. I think that it will be a similar situation for brain pacemakers in 10 or 20 years.”

The recent operation on Joan Sikkema at the Cleveland Clinic may well be a harbinger of this coming revolution in brain surgery. But like any new medical procedure, it wasn’t without its worrisome moments. Six hours in, the slowness of Joan’s speech began to sound like something other than weariness. The words were mushy and slurred. Someone asked Joan how she felt, and she mumbled a reply that, although hard to hear, didn’t sound cheerful.

“What did she say?” someone asked. “What did she say?” The neurosurgeons were aiming for a target roughly the size of the eraser on a pencil, and clearly they weren’t there yet.

Jump-Start

Humans have been using electric current as a therapeutic agent at least since the Romans employed the Mediterranean torpedo-a kind of stingray that discharged electricity-in treating, presumably, gout and pain in the lower extremities. Electroconvulsive or shock therapy has been used for decades, predominantly as a treatment for severe depression. Nor is electrical stimulation of the brain, strictly speaking, new. The first recorded attempt occurred in 1874, when a doctor in Ohio inserted a needle into the brain of a patient with cancer and applied electricity. In 1948, J. Lawrence Pool of Columbia University tried using electrical stimulation against depression.

By the mid-20th century, electrical stimulation of the brain fell mostly into disuse-in part because of the rise of neuropharmacology, and in part because of a social and ethical hangover from the first, swashbuckling era of psychosurgery. Indeed, the recent evolution and practice of elective neurosurgery, especially for the treatment of psychiatric disorders, has been haunted by the chilling history of the lobotomy. The severing of nerve connections in the prefrontal cortex was first attempted in 1935 by a Portuguese neurologist, Antnio Egas Moniz. The procedure was popularized in this country by Walter J. Freeman in Washington, DC, and commonly used as a treatment for depression until the late 1950s.

Despite the horrific consequences of this crude form of neurosurgery, there was a kernel of scientific merit to lobotomies. Freeman believed the operations disrupted neural connections between the frontal cortex of the brain and the thalamus, which consists of two walnut-sized structures deep in the brain, one in each hemisphere, each composed of 120 distinct neural clusters, or nuclei. The thalamus influences not only emotion but things like movement and sensation, and it is clusters of neural tissue in and around the thalamus that neurosurgeons are now revisiting-not with knives or ice-picks, but with electrodes.

The renaissance in deep-brain stimulation began, serendipitously, toward the end of 1985, in an operating room in France. At the University of Grenoble, neurosurgeon Alim-Louis Benabid was preparing to ablate, or destroy, a portion of the thalamus in a patient whose hand flapped uncontrollably with the condition known as essential tremor. This drastic form of surgery, involving heat or radiation, is typically the last therapeutic option for patients with motor disorders who have exhausted all other treatments. “Before making a lesion on the target,” Benabid says, “you must make sure you are not in a place where the lesion would be inappropriate and cause a permanent deficit.” The way to determine the location, then and now, is to send a short burst of electricity through an electrode and observe the effect. In this case, the effect stunned everyone in the operating room, including the patient.

“What I saw,” Benabid recalls, “was that his hand stopped flapping. I turned off the stimulation, and the tremor came back. So I apologized to the patient and said, That was unfortunate. Was it painful?’ And the patient said, No, no, it was nice. Can I try it again?’ So we tried again, and the tremor stopped. My first thought was, I was relieved that it wasn’t a complication. The concomitant thought was, That’s interesting!’”

Armed with this intriguing chance observation, Benabid jerry-rigged some existing electrical stimulation equipment to attempt deep-brain stimulation experimentally. The first opportunity presented itself in 1987, with a Parkinson’s patient who had already undergone the surgical destruction of the thalamus on one side of the brain. The patient had developed a tremor on the other side, but destroying thalamic tissue on both sides of the brain is exceedingly undesirable, so Benabid offered to implant an electrode instead as a last-gap measure. The patient agreed, and thus began the modern era of deep-brain stimulation.

Nearly 15 years later, the technology has become much more refined. The Grenoble group has reported on the largest group of patients to date; in 148 Parkinson’s-disease patients treated since 1993, the average rate of improvement, measured according to a traditional scale used to assess Parkinson’s symptoms, was 65 percent. And the benefits have not diminished.

“We’re at the cusp of a new era in terms of therapy,” says Montgomery, who with Rezai codirects the Center for Functional and Restorative Neuroscience at the Cleveland Clinic. “Up to now, the field has been dominated by pharmacology. But deep-brain stimulation is going to have a tremendous impact on neurology. Basically, the brain is an electrical device, so it stands to reason that we should be able to influence the brain electrically. And we can offer a specificity and precision that drugs will never be capable of.”

Brain pacemakers also offer significant advantages over traditional neurosurgery, in which, Rezai says, portions of the deep brain are irreversibly destroyed. Implanting electrodes, while minimally invasive, does not destroy chunks of tissue. “In this day and age,” Rezai says, “there’s no reason to have destructive brain surgery. It’s a one-shot deal and you can have side effects that are permanent. With stimulation, you can turn it off and you’re back to where you started, so it’s fully reversible. And you can adjust it, tailor the device to the patient’s needs.”

Electric Cartography

“We’re going to attach your head to this bed, okay?” said Rezai, positioning Joan on the operating table.

“Do I have a choice?” she answered with a laugh.

Opting for invasive brain surgery may seem like a dire solution for shaky hands and compulsive thoughts, but patients with serious neurological ailments are often eager to try it. The day before her doctors implanted her pacemaker, Joan described the trauma of daily life with a condition like essential tremor. Wearing a pink blouse, khaki slacks and sandals, the 52-year-old woman from Byron Center, MI, looked like the youthful, good-natured grandmother that she is. But her hands shook uncontrollably. She rattled off a list of quotidian frustrations that helps explain why patients are willing to let doctors drill holes in their heads and stick electrodes into their brains.

Here are some of the things she could not do: Eat soup (she needed two hands). Put on makeup. Brush her teeth. Dial the phone (she often got wrong numbers). Tie her shoes. Hold her grandchildren. “I used to be a nurse,” she explained, her voice itself a little shaky, “but I had to give it up because of the tremor-you know, giving injections, changing dressings, writing in charts. People like to be able to read the chart,” she added with a laugh, “and my handwriting was worse than a doctor’s.” She held an imaginary pen in her right hand, and it carved wild elliptical arcs in the air, as if she were shaking a thermometer.

Like many people with a severe movement disorder, Joan found that drugs were not effective, and the symptoms grew worse over time. On the eve of having her pacemaker implanted, she did not seem unnerved by the prospect of brain surgery-even when Rezai recited possible complications, including a chance of infection and a one to two percent chance of bleeding in the brain. “Going to a dentist,” she said with a tight smile, “is more traumatic for me than this.”

The procedure, needless to say, is a little more complicated than a root canal. Implanting electrodes deep in the brain combines the latest in imaging and stimulation technology with, paradoxically, a slow, painstaking, hands-on mapping of each patient’s neural terrain during surgery. This kind of cartography is essential, Rezai explains, because the geography of each human brain is different. The lay of this precious land must be custom-mapped by the surgical team, so that when the actual electrode is maneuvered into place, it will provide optimal therapeutic results while minimizing possible side effects.

Like all maps, this one begins to take shape with the establishment of coordinates. With a titanium frame attached to her head, Joan underwent a computed tomography scan before being wheeled into the operating room. Rezai then used a software program to merge the results of that scan, a magnetic resonance imaging scan taken the previous day, and a computerized standard brain atlas to create a 3-D image of Joan’s brain. Within that image, Rezai identified the x, y and z coordinates of the target for the electrode he would implant. Having selected a trajectory that avoided blood vessels, fluid-filled structures and other critical neural regions, Rezai’s team began the process of actually exploring a route to the trouble spot, advancing the preliminary probe about six centimeters into the brain. Once they were within about 15 millimeters of the thalamus, they used a hydraulic device to advance the probe in micrometer increments, and the vast portion of the day was spent traversing a distance smaller than the diameter of a dime.

This was done as much by sound as by visualization. The probe, sensitive enough to pick up electrical signals from a single cell, was wired to a laptop computer and amplifier. As one doctor moved it deeper into the brain, the operating room began to fill with the ebb and flow of brain cells firing, talking, reacting; the doctors, meanwhile, stood around with furrowed brows, trying to discern neural nuances in the amplified static. “You can think of the different thalamic nuclei as separate countries,” Rezai explains. “Each country speaks a different language, and we can recognize the language of different cells.”

As the probe neared the thalamus, the surgical team stopped every time it encountered the telltale rat-a-tat of a firing cell. “We’re getting close to one there,” Rezai said, head tilted as if he were listening to a faraway cricket. The crackle grew louder and louder, sounding like heavy rain on a tin roof, or distant gunfire. “We’re in the thalamus now,” he announced.

Every once in a while, the amplifier would spit out a distinctly different sound-a kind of pop or sudden “pfftttt.” “That zip you hear?” Rezai explained. “That’s an injury current,” the sound of a neuron pierced by the probe (it’s unclear if the cells repair themselves, Rezai says, but the damage is considered minimal). The surgeons inserted the probe three times, using slightly different trajectories, to pinpoint the pencil-eraser-sized target of brain tissue.

Five and a half hours into the surgery, satisfied that they had found the right spot in the thalamus, Rezai and his team were ready to insert the permanent electrode. After guiding it into place, the surgeons prepared to test the device. “Okay, Joan,” Rezai said, “I want you to give us your maximum tremor.” She had a hard time doing it, however, because the mere placement of the electrode seemed to dampen her shakiness. “That’s a good sign,” Rezai said.

Why stimulation should even work, actually, is a nagging scientific question. Standing by the electrode’s voltage controller, Erwin Montgomery paid tribute to the fundamental mystery underlying this entire field of surgery. “The $64,000 question is: how the heck does deep-brain stimulation have its effects? Nobody knows the answer.”

Charging Ahead

As even its most enthusiastic practitioners concede, deep-brain stimulation in its current state is still relatively crude. But the future of brain pacemakers-greater sophistication and miniaturization, broader application-is unfolding at a rapid pace. “This is just the tip of the iceberg,” says Hans O. Lders, chairman of neurology at the Cleveland Clinic. Patients with epilepsy, he points out, are usually treated with antiseizure medication and, failing that, with a radical form of elective surgery to remove the part of the brain that becomes hyperactive during repeated attacks. More than two million Americans suffer from epilepsy, and roughly half of them have seizures that originate in the same region of the brain again and again. “At least 20 or 30 percent of these patients cannot be controlled with drugs,” Lders says. “What to do with them? This is where deep-brain stimulation comes in.”

During the past year, the Cleveland group has implanted brain pacemakers in five epilepsy patients: two of the five have shown significant improvement, according to Lders. And the prognosis may soon get even better with new pacemaker technologies. The next generation of stimulation devices will be the so-called closed-loop pacemakers, electrodes designed to both monitor brain electrical activity and deliver stimulation when necessary-rather than provide continuous electrical pulses. Already, a large, external version of this pacemaker has been tested in eight patients at the University of Kansas Medical Center with “excellent results,” according to Ivan Osorio, who heads the research effort. And several groups are working with Minneapolis, MN-based Medtronic, currently the only company marketing these pacemakers, to develop a miniaturized version that could be incorporated into a chip. The strategy is to take advantage of the fact that epileptic seizures are often preceded by an electrical overture, or “aura,” that warns of the coming neural storm minutes before the actual symptoms appear. “You sense what is going on in the brain, and you stimulate only when an epileptic seizure is coming on,” Lders explains.

The power packs used in brain pacemakers are also evolving. Currently, the packs are about the size of a pager and are implanted just below the collarbone-surgery that includes a painful procedure to hook up the pacemaker’s power supply to the electrode. The bioengineering group at Cleveland Clinic is working with Medtronic to miniaturize the power packs to about the size of a quarter, which could potentially allow surgeons to implant the devices behind a patient’s ear.

The catalogue of diseases targeted for electronic stimulation is evolving as rapidly as the technology. Obsessive-compulsive disorder, for example, is just now becoming a candidate for the treatment. In 1999, Bart J. Nuttin, a doctor at Catholic University in Leuven, Belgium, reported in The Lancet on the use of brain pacemakers to treat four patients with the disorder who were resistant to any other therapy; three of the four patients benefited from the new therapy. A 39-year-old woman who had suffered severe symptoms for more than two decades, for instance, experienced “an almost instantaneous feeling of being relieved of anxiety and obsessive thinking” when the electrode stimulator was turned on.

It won’t be long before severe depression, too, may be experimentally treated with deep-brain electrical stimulation. Studies have shown that stimulation of the subthalamic nucleus has a significant impact on mood, says Cleveland Clinic’s Montgomery, “and that might translate into therapy for depression.”

Among the most daring potential applications of the technology is the use of electrical stimulation to improve the condition of patients with severe brain injuries. An estimated 5.3 million Americans are currently living with disabilities as a result of brain injuries, and a significant number of them are in minimally conscious states. Nicholas D. Schiff and Fred Plum of Weill Medical College in New York are developing diagnostic tools to identify brain-injured patients who retain some capacity for coordinated neural activity; such patients, they argue, might benefit from deep-brain stimulation. “We’re not talking about people in comas, and we’re not talking about people in semi-vegetative states,” Schiff says. But brain-imaging technologies indicate that some patients have states of awareness that fluctuate. “It’s just a matter of, Can you identify patients that have some cognitive states that are better than others and use deep-brain stimulation to push them into this better state?’ In the next year or so, we might be able to pilot this therapy.”

The University of Grenoble’s Benabid has even shown-in rats, for the time being-that eating behaviors can be affected by brain pacemakers. High-frequency stimulation of the hypothalamus, another deep-brain structure, seems to spur appetite, and thus could be used as a last-resort treatment for severe anorexia nervosa; low-frequency stimulation seems to decrease appetite, and could be used to treat what he calls “malignant obesity.” But Benabid, for one, is in no hurry to rush into behavior modification using brain pacemakers. “We have to be very cautious about this,” he says. “You mention obesity, and people say, Wow, that’s a big market here!’ I don’t like to hear big market.’ We think we could provide some patients with a solution for something when nothing else is available. The danger is that the easier the procedures become-less invasive, less morbidity-the more tempting they are.”

Restored Hope

Toward the end of her very long day in the operating room, Joan Sikkema lay on the table while Erwin Montgomery, the neurologist, stood beside her, adjusting the voltage of her stimulator. This was just a preliminary “tuning,” giving her doctors a sense of how they might ultimately program her pacemaker several weeks later, when swelling from the procedure had subsided and the device could be turned on. But when Montgomery pushed up the voltage, Joan squirmed in discomfort. When Montgomery asked, “How does that feel?” she mumbled out a barely audible answer.

“What did she say?” the doctors asked.

Montgomery lowered his head to Joan’s: “That was really crappy,” she remembers whispering.

As the voltage increased, the stimulation had caused numbness in her mouth and throat, with obvious effects on her speech. Joan’s case turned out to be challenging. Her thalamus was very “speech-dominant,” Rezai said later; the doctors had to be careful about locating the electrode in a way that would control her tremor but not cause slurring or other speech deficits.

Several weeks after the surgery, Joan returned to Cleveland to get “turned on.” She noticed a slight reduction of her symptoms, “but nothing dramatic.” In fact, she even experienced some disquieting side effects and turned the device off (patients are given a magnetic device to shut off the pacemaker). But a week later, after the doctors had readjusted the settings of her pacemaker, she could barely contain her enthusiasm. “This time I was able to write my name, and feed myself without hitting my cheek, and drink from a cup without spilling it,” she says. “I’m doing all the ordinary daily things I used to do.”

It will take another five or six months, her doctors in Cleveland say, to get her pacemaker tuned optimally. Montgomery says that, following her second tune-up, tests showed Joan had 80 to 90 percent improvement in her intentional tremor, and 100 percent resolution of her postural tremor. But there is no quantitative instrument to measure the joy in her voice as she related her feelings after the last tune-up. “I didn’t cry until this morning,” she says, her voice tremulous with emotion, not neural dysfunction. “I think I was steeling myself in case it didn’t work. But I got much more than I expected. It’s like getting my life back.”

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