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Breakthrough Medicine

Fighting cancer. Curing tremors. Developing drugs. Stemming addictions. Transplanting hands. Treating aneurysms. It’s all in a day’s work for these pioneering Minnesota doctors and researchers.

Breakthrough Medicine

(page 1 of 3)

Aviva Abosch

University of Minnesota
Department of Neurosurgery

Dressed in blue scrubs, a surgical mask, and two pairs of rubber gloves, Dr. Aviva Abosch stands with hunched shoulders over the patient on the table in front of her, preparing to slice into his skull and peer deep into his brain.

She jokes about needing a latté and a lunch break. Then, with six nurses and technicians bustling around her, the 48-year-old neurosurgeon makes an incision into the shaved surface of her patient’s head and pulls back the pink skin like a banana peel, revealing a nickel-sized hole that had already been drilled into the skull during a previous surgery. With steady hands under two massive surgical lights, Abosch pulls out a dysfunctional, one-millimeter-wide wire. Guided by a large metal head frame, which Abosch spent an hour setting up with precision before the surgery, a new wire fitted with four electrodes begins its slow and steady path into the man’s gray brain tissue.

Nearly two hours into the procedure, known as deep-brain stimulation, Abosch moves to a computer monitor and dims the lights in the green-tiled room. With her right hand on the mouse, she watches a skinny red line squiggle up and down on the screen, and she listens to wavering static that resembles someone trying to find a station on an AM radio dial. In fact, the noise is the sound of brain cells firing as the wire moves past them. The pattern of the cellular firing gives the surgeon a clue as to what brain structure the wire is passing through on the way to its target: an almond-sized structure called the subthalamic nucleus.

Abosch suspects excessive firing of nerves in the subthalamic nucleus has been causing a form of involuntary shaking, known as essential tremor—a source of frustration for the patient, a man in his 60s who works as the head painter on a nearby college campus. Once activated, the implanted device will send a series of ongoing electrical impulses to this region of the brain, with the goal of reducing the tremor.

“You awake, Gene? You hear all that noise? That’s your brain working,” Abosch says from her seat by the man’s feet. Suddenly, the speakers squawk loudly as if air is slowly draining from a balloon. “That’s an injured cell, Gene. You’ve got bajillions of those. Don’t cry over the loss of that one cell.”

Abosch’s operating manner is remarkably relaxed, considering she is probing the brain of a conscious patient. But for her, the procedures of deep-brain stimulation (DBS) are routine. She has done more than 250 DBS surgeries for patients with Parkinson’s disease, essential tremor, and related movement disorders since she arrived at the University of Minnesota in 2005.

In addition to the electrodes that are placed directly into the brain, DBS involves a pacemaker-like battery that goes inside the chest and a wire that snakes its way beneath the skin along the neck and behind the ear from battery to electrodes. Doctors program the device to deliver just the right amount of stimulation. Patients remain awake during implantation so that surgeons can make sure they’ve struck the right location. It may sound agonizing, but brain cells have no pain receptors, which means the patient doesn’t feel the wire going in.

As easy as she makes it look, probing the depths of the human brain isn’t necessarily what Abosch thought she would end up doing, even after she left her childhood home in suburban Buffalo for Bryn Mawr College in Pennsylvania and became interested in cognition. As an undergraduate in the early 1980s, she was fascinated by the question of what makes people different from other animals, which drove her to take a psychology course. But the class lacked any mention of how one’s sense of self worked on a fundamental level, and Abosch found the course to be unsatisfying. Instead, she turned to neuroscience, earning both an MD and a PhD at the University of Pittsburgh, where she figured she’d follow in the footsteps of her advisers and study brain development in children.

It was during a two-week rotation in neurosurgery that she had her first medical revelation—and a glimpse into her unexpected future. “It was wild,” she says. “You’re actually standing there in the operating room, you see the brain, and you see what makes us different [from animals]. I didn’t get any closer to understanding it, but it was an epiphany.”

Aviva Abosch

Abosch’s first exposure to deep-brain stimulation came during her residency at the University of San Francisco, where in the late-90s, she worked under a surgeon who was using what was then a new, cutting-edge approach to treating movement disorders. DBS was developed in Europe in 1987. But it wasn’t until 1997—a few years after Abosch arrived in San Francisco—that DBS was approved in the United States for treating essential tremor. Approval for Parkinson’s and dystonia followed in 2002 and 2003. Since then, results have been so spectacular for muting these diseases that Abosch and colleagues are now moving into ambitious new applications. She recently treated two patients with obsessive-compulsive disorder—with hopeful, if preliminary, results.

Now, she is starting work on a clinical trial for patients with depression who haven’t responded to any other treatments, including antidepressants or electroshock therapy. Eventually, as part of the double-blinded, controlled trial, Abosch’s team will treat 15 patients with recalcitrant depression, though neither she nor the patients (nor participants undergoing the same procedure at other institutions) will be told if their implants have been activated, thus removing concerns about placebo effects or biased interpretations of results. If the technique proves effective—and there is reason to believe that it will, based on imaging studies that show hyperactivity in a part of the brain called the subgenual cingulate white matter in some people with major depression—the sky may be the limit. Researchers are discussing the possibility of using DBS to treat just about any disease that has roots in the brain, including Tourette’s syndrome, morbid obesity, eating disorders, Alzheimer’s disease, memory loss, paralysis, and more.

For a procedure with such dramatic successes and so many hopes riding on it, though, we still know surprisingly little about how DBS actually works in the brain, says neurosurgeon Kendall Lee, director of the Neural Engineering Laboratory at the Mayo Clinic in Rochester. The foundations for the treatment were actually discovered by accident about 60 years ago, during an operation on a man with Parkinson’s disease. Previously, surgeons had treated Parkinson’s patients by cutting out entire sections of the brain. The method stopped tremors, but it also prevented other kinds of movements, often leaving parts of the body permanently paralyzed, among other side effects.

In 1951, a Mayo surgeon named Irving Cooper tore an artery at the beginning of a surgery on patient with Parkinson’s. After stemming the bleeding, repairing the damage, and aborting surgery, Cooper was surprised to find that his patient awoke not only mobile, but also free of tremors. It was a lightbulb-sparking event that gave surgeons a much more detailed picture of where in the brain certain problems originate, Lee says. Since then, doctors have zeroed in on more specific areas in the thalamus, sub-thalamus, and other regions near the center of the brain that are linked to various neurological disorders. And they have discovered that electrical stimulation can work like brain lesions, altering activity in localized regions—if carefully placed, for the better.

In one of the latest steps toward understanding the details of how DBS actually works, Lee’s group and others have found that electrical stimulation leads to a release of neurotransmitters, the messenger molecules that allow individual nerve cells to communicate with each other inside the brain. The Mayo team has also designed a device that can wirelessly monitor neurotransmitter levels during DBS. With advances like these, the hope is to create “smarter” DBS devices that could alter levels of stimulation as needed. Even if the device could just recognize when a patient is asleep, it would be a major step forward, Abosch says. That way, doctors wouly only have to replace batteries every nine years instead of every three. “Right now, we’re doing electroshock therapy for a lot of psychiatric diseases,” Lee says. “But rather than shocking the whole brain, with DBS we can do more focal treatments. Electroshock therapy is like a shotgun approach where you shoot everything. DBS is more like a rifle.”

After more than four hours in the operating room without a break, Abosch and her team are ready to test the electrodes they’ve placed in the patient’s brain. Earlier that morning, before the new device was in place, his left arm swung wildly when nurses challenged him to draw a spiral on a piece of paper and then write his name. The spiral looked more like a squiggle. The letters looked like they came from the hand of a three-year old. After activation, however, Gene draws concentric circles, drinks steadily from a cup, and keeps his left hand still while holding some papers.

Watching patients witness their own swift and drastic improvement remains an emotional experience, even after several hundred surgeries, Abosch says. “When you have a patient who has dealt with a tremor for 30 years of his or her life and you stop the tremor suddenly and they get all choked up or burst into tears, it’s moving,” she says. “You’ll see patients during the procedure suddenly reach up and look at their hand. And it becomes apparent to you watching the patient that they suddenly realize something is profoundly better. That is a touching moment.”

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