Mahlon DeLong profile part 1

The fruits of Mahlon DeLong’s research career have brought relief to Parkinson’s patients and others. At the center of his work: the once underappreciated basal ganglia.

by Aalok Mehta

April 16, 2009

[part one of two]

If not for a chance encounter late in college, noted neuroscientist Mahlon DeLong might well have become an astrophysicist instead.

Once he had become a neuroscientist, another sheer coincidence—a nearly full lab—matched DeLong with the basal ganglia, the brain structures that have become virtually synonymous with his name.

But for millions of people suffering from the debilitating effects of neurological diseases, those fateful encounters were fruitful, indeed. Because of DeLong’s pioneering work, people with Parkinson’s disease now have access to deep brain stimulation and other surgical techniques that can help alleviate symptoms when all else has failed. Help for people with other conditions, from Tourette’s syndrome to obsessive-compulsive disorder, may not be far behind.

In his 40 years of research and clinical work, DeLong, who eventually rose to chair of the neurology department at Emory University in Atlanta, has transformed our understanding of the basal ganglia, an irregular collection of connected structures located deep in the cerebral cortex just above the brainstem. Once thought to be involved primarily in movement, the structures are now believed central to processes as diverse and important as cognition, emotions, decision making and reasoning.

“I went to the National Institutes of Health, and that was really where my career started,” DeLong says. “When I got there, there was only one place left [to work on] ... and that was the basal ganglia. I always said that was probably the best thing that could have happened to me. I couldn’t imagine a better place to be.”

On Friday, colleagues, friends and grateful patients will converge at Emory Medical School to honor his numerous contributions to neuroscience and neurosurgery and learn more about the brain areas that have been his lifelong occupation.

“We hope that the symposium will provide attendees with a state-of-the-art understanding of how the basal ganglia function in health and disease, thus helping them to practice the best medicine possible today or to develop insights into the research questions that need to be answered tomorrow,” says Dennis Choi, Emory’s vice president for academic health affairs and part of the symposium’s organizing team.

But it’s not just DeLong’s scientific achievements that drew people to the symposium. For many, his keen analytical mind pales in comparison with his gentle demeanor, easygoing personality and able mentoring. “A kinder man you won’t find,” says Jerrold Vitek, a neurologist at the Cleveland Clinic who first worked with DeLong as a neurology resident and has collaborated with him for almost 20 years since. “I’d have to say that I owe my success to Mahlon.”

Lucky chances

DeLong’s first foray into neuroscience—back before the field even had a proper name, he says—came in 1960, during his senior year at Stanford University. “I always did [plan to become a scientist], but I was in a very different mindset through high school and a good bit of college. I was very much into hard science, physics, astrophysics,” he says. “It was very late in my college time at Stanford that I got interested in biology or more particularly neuroscience.”

The reason for the switch was “a very lucky chance exposure” with neuroanatomy researcher Donald Kennedy, which inspired DeLong to stay in Palo Alto for a year of graduate research before setting off for Harvard Medical School.

At the time, he couldn’t have known just how an auspicious a start it was. Though Kennedy, then working on crayfish, was in his first year at Stanford, his star was on the rise. He would eventually become the university’s president and, later, editor in chief of the research journal Science.

DeLong followed up medical school with three years of residency and internship in Boston before returning to pure research in 1968, setting his sights on working in the laboratory of Edward Evarts at the National Institute of Mental Health in Bethesda, Md. Evarts pioneered techniques for recording the activity of single neurons in awake monkeys that had been trained to perform certain tasks. “I would have been happy to have done anything with behaving, in that venue of single-cell behavioral studies,” DeLong says.

Though he ended up with a research area of last resort—scientists who’d arrived earlier had taken up higher-profile areas such as the cerebellum and motor cortex—DeLong quickly made his mark on the field during his five-year stint in Evarts’ lab.

“Very little was known about basal ganglia function and organization, and so for Mahlon this was like exploring and charting unmapped Africa or the Amazon,” says Peter Strick, a professor of neurobiology and psychiatry at the University of Pittsburgh who worked with DeLong in the lab for about two years. “This really was quite uncharted territory, and Mahlon’s first paper is very much a landmark.” The study describes the resting activity of neurons in the striatum and the globus pallidus, two structures in the basal ganglia.

“When we really got fundamental insight into the anatomic organization of the basal ganglia,” Delong adds, “that was something that was like a light bulb going off for me, that this was how things had to be put together, which was very different from how the people had thought.”

Strick, who had first met DeLong in graduate school and has been friends with him ever since, appreciated the genesis of a rare kind of talent. “One could recognize that is was the beginning of something special,” Strick says. “The tonic activity of neurons that Mahlon described in his 1971 paper provides the roadmap for clinicians today to know where they are … to be able to accurately know where they are in the basal ganglia when recording to place deep-brain-stimulating electrodes.”

By the time DeLong left Evarts’ lab, he had already laid the groundwork for a profound shift in how to view the basal ganglia. “When I came into the field, the basal ganglia were viewed as primarily motor—they were thought to be important for transmitting commands from different cortical areas to the motor cortex,” he says. “A lot of our early work changed the thinking about that. We identified a family of circuits that ran through the basal ganglia involved not only in motor function but cognitive, associative and limbic functions. And that broadened the whole thinking about the basal ganglia as being involved in the whole spectrum of behavior.”

“I don’t know anyone who talks about basal ganglia physiology or anatomy without using his cartoons,” Vitek says of DeLong’s hand illustrations of the basal ganglia. “They may add a pathway here or there, but they are still using his cartoons.”

Move to Parkinson’s

For Parkinson’s patients, however, DeLong’s most noteworthy research wouldn’t come until later—and it would revolve around a bad batch of street drugs. In the early 1970s, with heroin in short supply, drug sellers were turning increasingly to synthetic opioids such as MPPP.

Users of the drug sometimes began exhibiting bizarre, Parkinson’s-like symptoms, including movement problems, tremors and slurred speech. A bit of scientific detective work revealed why. MPPP manufacturers often ended up making a close relative instead, the neurotoxic MPTP. Because MPTP caused the same symptoms in primates as in humans, it quickly led to the first animal model of Parkinson’s.

By then, DeLong had moved a short distance northeast from Bethesda, to Baltimore’s Johns Hopkins Medical School. After completing a neurology residency, he started his own lab to delve further into the basic anatomy and function of the basal ganglia.

Using some of the techniques he had learned in Evarts’ lab, DeLong eventually turned his attention to neural activity in MPTP-afflicted animals, with dramatic results.

“He was very good at putting things in their perspective and thinking conceptually, sort of systematically about how things might work, which in neuroscience really is important because it’s so complicated,” says William Miller, a professor of medicine at the University of North Carolina School of Public Health who as a postdoctoral researcher worked with DeLong on some of the early MPTP studies.

They found that the Parkinson’s story was more nuanced than the conventional belief at the time: that the disease’s symptoms were due in part to reduced activity in the globus pallidus. Instead, they found less activity only in the external segment of the pallidus; the internal segment became more active.

“I think we were surprised that in Parkinson’s there were very obvious changes in activity in the brain,” DeLong says. “There were skeptics, but on Day One we saw that the activity patterns and firing rates were quite altered, and that the output from the basal ganglia was actually increased rather than decreased.”

DeLong and his colleagues then found that the increased activity in the internal pallidus traced back to increased input from the subthalamic nucleus, another area of the basal ganglia. In a landmark 1990 paper in Science, DeLong reported that a lesioning procedure—in which surgeons map and then destroy a precise brain area with chemicals, radiation or heat—done on the subthalamic nucleus reversed many of the animals’ movement problems.

It was quite a remarkable result that Mahlon would suggest making a lesion in this region to restore the balance of activity in Parkinson’s disease, and lo and behold he got that result,” Strick says. “I can’t overemphasize what a significant leap this was, because the one constant that people had known for more than 50 years is that if you make a lesion in the subthalamic nucleus, you produce an abnormal movement disorder, and here Mahlon proposed treating Parkinson’s disease by putting a lesion just in that region and in fact got the results he predicted.”

The work at Hopkins marked a notable shift in DeLong’s interests. There and later at Emory, he would spend an increasing amount of time away from the laboratory bench and in the operating room, helping to develop revolutionary, and sometimes controversial, new surgical treatments for Parkinson’s and other neuropsychiatric diseases. Building on his previous studies, his new clinical work would again dramatically alter thinking about what to do when the brain becomes damaged.

Next: Targeting Parkinson’s with surgery and electrical stimulation 

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