Second of two parts [Part One: At the center of DeLong’s work: the once-underappreciated basal ganglia]
It takes just a few seconds on the Web to find a photo of neuroscientist Mahlon DeLong standing next to Muhammad Ali, DeLong serving as the “frontispiece,” as he calls it, of a team of physicians at Emory University in Atlanta who treat the Parkinson’s-afflicted boxing legend.
That prominent relationship is the most public face of DeLong’s gradual shift away from basic research and toward clinical work, focusing on new therapies that have given relief and hope to millions of people with Parkinson’s disease and other neurological disorders.
DeLong’s lab work revealed much of the basic structure of the brain areas known as the basal ganglia and helped shatter the idea that they were involved only in movement. Later, he also upset the standard view of Parkinson’s by showing that certain areas of the basal ganglia, such as a portion of the region known as the globus pallidus, become more active than normal, not less, during the course of the disease. And he found that—at least in animals—lesions in another area, the subthalamic nucleus, could provide relief from the symptoms of Parkinson’s.
For someone who had worked largely on basic neuroanatomy, it was an unexpected turn of events. “I never went into this thinking for a moment that this would have any very practical outcome,” DeLong says. “It was really just trying to understand how these basal ganglia were organized and what contributions they made to behavior.”
Still, DeLong—trained as a medical doctor with a specialty in neurology—was well-suited to taking the discoveries from the laboratory to the hospital. Using his expertise in recording the activity of single neurons, he could help surgeons navigate through the basal ganglia to precisely the right point to successfully complete intricate operations. It would simply take some effort—and time—to convince the rest of the medical community to go along.
Before moving to Atlanta in 1991 to lead Emory’s neurology department, DeLong had begun to investigate potential clinical applications of his work, recruiting experts to explore functional neurosurgery for treating Parkinson’s. At Emory, where he established a movement disorders center, this work kicked into high gear.
With surgeon Roy Bakay and longtime colleague Jerrold Vitek, DeLong began exploring pallidotomy, a surgical lesioning technique that uses low-dose radiation to destroy overactive portions of the globus pallidus. Finnish neurosurgeon Lauri Laitinen had shown some success in using it to treat Parkinson’s patients, but DeLong and his colleagues were hoping their combined expertise in basal ganglia mapping could refine the surgical targets and reduce side effects.
Lesioning, a technique that surgeons had used for years but somewhat indiscriminately, was out of favor in the medical community. “There were actually people who commented that you should not look upon this [discovery] as a reason to do lesions again, or to go back in time to the early era when people were doing destructive lesions,” DeLong says. “I think there was a little apprehension about that.”
Still the team forged ahead, conducting its first pallidotomy on a Parkinson’s patient in late 1992. It was “extremely, remarkably successful,” DeLong says, and patients began flocking to Emory for the surgery. Experimental surgery is a slow process, though, with the presurgical evaluations and surgical waitlist in this case taking as long as four years. A decade later, in 2003, the team released its results, “the only randomized trial that compared pallidotomy to other medical therapies,” Vitek says. The results, published in Annals of Neurology (pdf) showed that the surgery significantly increased the time during which patients were not disabled by their symptoms.
In the meantime, DeLong and his colleagues became increasingly interested in deep brain stimulation (DBS), in which a pacemaker-like device is implanted in chest and feeds energy to electrical leads in the brain to stimulate specific neurons that, the theory goes, are misfiring or not firing enough. One notable advantage over lesioning is that deep brain stimulation is not permanent; the electrodes, activated intermittently, can be turned on and off or removed completely if need be.
French neurosurgeon Alim-Louis Benabid did much of the early DBS work, treating tremor by implanting electrodes in the thalamus. “When he realized from the work we had done that the subthalamic nucleus would be an ideal target for Parkinson’s, he felt that the deep brain stimulation offered the opportunity to test that,” DeLong says. “We had consciously decided not to do the subthalamic nucleus to create a lesion, for fear of the development of involuntary movements.”
In 1999, DeLong and his colleagues began looking at the effects of DBS in Parkinson’s, targeting both the subthalamic nucleus and globus pallidus. Their work and other studies led the Food & Drug Administration to approve DBS in those areas as a treatment for Parkinson’s in 2002 and 2003, respectively, just as it had previously approved stimulation therapy for tremor. A recent study found that DBS works substantially better than drug and behavioral therapies, though it comes with a greater risk of side effects, mostly from the surgery to implant the device.
Why these treatments work is still a bit of a mystery, though. Both lesioning, which destroys brains cells, and stimulation, which activates them, act on the same basal ganglia areas and can offer similar clinical improvements, Vitek says. “We don’t fully understand it,” he says. “It can’t all be about rate. We are now thinking that it involves changes in the pattern of activity, rather than just the rate of neural activity.”
Just as he had earlier found that the basal ganglia have a much greater role in the brain than simply regulating movement, DeLong thinks DBS has far more potential as a treatment method than merely for movement disorders. He and other neuroscientists have already seen promising results in people with conditions as varied as drug-resistant depression, obsessive-compulsive disorder and minimal consciousness.
“We’ve had some personal experience with depression cases, just with working alongside Helen Mayberg here at Emory—the treatment of refractory depression—and also with our own personal experience with Tourette’s,” DeLong says. “I think of these disorders as representing other examples of disordered basal ganglia function and output that these circuits subserve.”
He also believes that the technique offers a chance to learn far more about the human brain than animal studies and freak accidents have displayed.
“I think neurology has always had this idea that you learn about the brain by studying it stroke by stroke. In other words, accidents of nature, strokes and other lesions reveal or uncover functions of the brain by disturbing them,” he says. “I think that deep brain stimulation has given us tremendous new insight into function that comes about not by deadening or interrupting but by activating systems, and it’s giving us a whole, much greater expansion and appreciation of the mechanisms responsible for both normal and abnormal behaviors and disorders.
“Often there are surprises here, like when [we treat] Parkinson’s, stimulating in the subthalamic nucleus, a patient with obsessive-compulsive behaviors gets relief not only from the Parkinson’s but from the compulsions. And you stimulate in the region and you may induce depression if you’re a little bit off target. These are quite insightful in terms of understanding, beginning to appreciate the organization and role of these structures in both movement and non-movement.”
The honorary symposium slated for Friday, “Basal Ganglia: Function, Movement Disorders and Treatment Options,” is less a capstone for DeLong than a brief stop on a continuing journey. Though he is nearing 70, he has no plans to retire from developing better treatments for people with neurological diseases and trying to understand more about the basic structure of the brain.
“I was very flattered and pleased [about the symposium], but I was thinking it would be something kind of low-profile,” DeLong says, laughing. “It’s going to be wonderful, but it’s become quite an event. I’m looking forward to it.”
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