Switching off the Symptoms of Parkinson's Disease

Decades of discovery lead to a Lasker Award for Emory's Mahlon DeLong

By Paige Parvin 96G

Delong

In 2013, DeLong was named one of the School of Medicine's Game Changers, outstanding faculty performing breakthrough research. Photo by Jack Kearse.

As you read this story, your eyes will follow the words on the page; you will hold your head and hands relatively still; and your body might perform an action associated with concentration, such as tapping a foot or grasping the upper corner of the page in anticipation of turning it.

All this is more or less automatic, done without conscious thought—although you can choose to change these behaviors if you wish. But deep in the cerebral hemispheres of your brain, an intricate system of structures called basal ganglia are going about their work, helping to direct movements as seemingly minor as eye tracking.

When Emory’s Mahlon DeLong began his research on the brain in the late 1960s, little was known about the basal ganglia; they were, in his words, “uncharted waters.” In the ensuing decades, DeLong made discoveries about these mysterious nuclei that have led to revolutionary treatments for diseases marked by movement disorders, most notably Parkinson’s disease.  

In September, DeLong, the William Timmie Professor of Neurology at the School of Medicine, received the 2014 Lasker-DeBakey Clinical Medical Research Award from the Albert and Mary Lasker Foundation. DeLong shares the award with Alim-Louis Benabid of Université Joseph Fourier of Grenoble, France. 

The two scientists were honored for their roles in developing deep brain stimulation of the subthalamic nucleus, a surgical technique that reduces tremor and restores motor function in patients with advanced Parkinson’s disease. Their work has resulted in an effective treatment for more than one hundred thousand patients worldwide.

“I join numerous other scientists and physicians at Emory, as well as patients and families around the world who have benefited from his work, in our gratitude to Dr. DeLong and our admiration for his scientific insights, his creative genius, and his perseverance in helping resolve one of the most devastating diseases of our time,” says Christian Larsen 80C 84M 91MR, dean of the School of Medicine. “We are extremely proud of his accomplishments and this outstanding recognition.”

The Lasker Awards, which are among the most respected science prizes in the world, honor visionaries whose insight and perseverance have led to dramatic advances that will prevent disease, reduce disability, and diminish suffering. The awards have championed major advances in medical research for sixty-nine years. 

DeLong is the second Emory faculty member to receive a Lasker Award. In 2001, William Foege, Presidential Distinguished Professor of International Health in the Rollins School of Public Health, accepted the Mary Woodard Lasker Award for Public Service in Support of Medical Research and Health Sciences. According to the foundation, Foege received the award for “his courageous leadership in improving worldwide public health, and his pivotal role in eradicating smallpox and preventing river blindness.” 

“For nearly seventy years, the Lasker Awards have honored extraordinary individuals who have made fundamental biological discoveries, developed therapies to dramatically improve patient care, and provided mentorship and leadership to pave the way for the next generation of scientists,” says Claire Pomeroy, president of the Lasker Foundation. “This year’s laureates join that tradition and illustrate to the public why science is so worthy of our support.”

When he took the podium at the awards ceremony in New York City on September 19, DeLong cast back to his early days in the field, when he first encountered the basal ganglia almost by chance.

“I don’t recall when I realized I wanted to do research, but I have always enjoyed understanding how things work. A grow-ing fascination with how the brain controls behavior led me to medicine and then to neurology.” DeLong said. “This took a clear direction when I found a choice research position at the NIH in the laboratory of renowned researcher Edward Evarts. Because the other obvious brain regions were already assigned to other fellows, I was asked to work on the basal ganglia, a cluster of poorly understood brain structures, and to determine their role in the control of bodily movements.”

DeLong began studying and mapping the basal ganglia around the same time a promising therapy for Parkinson’s disease, known as levodopa or L-dopa, was just starting to show its dark side. 

Before the emergence of L-dopa, doctors mainly treated the disease surgically, by inflicting intentional damage—or lesions—on regions of the brain thought to be the source of the debilitating symptoms. This technique often worked, significantly reducing the symptoms of the disease, but targeting sites in the brain by trial and error also resulted in complications and, in some cases, neural destruction that could not be reversed. 

By the 1960s, scientists had established that Parkinson’s disease originates from a deficiency of the neurotransmitter dopamine in the basal ganglia. Leading researchers also had identified L-dopa, the metabolic precursor of dopamine, as a potential treatment—but its toxicity presented a challenge. 

Portrait

Photo courtesy of The Albert and Mary Lasker Foundation

The late George Cotzias, a Greek American scientist, developed a meticulously phased approach to treatment that transformed the drug into a viable and effective option for Parkinson’s patients. Cotzias received the Lasker Award for Clinical Medical Research for this work in 1969. 

Although levodopa is still widely used to treat Parkinson’s disease, it has not proven to be the miracle cure that Cotzias and other scientists once hoped. For many patients, after several years, the window of the drug’s effectiveness begins to narrow, upsetting the balance between its benefits and the considerable side effects it can cause. L-dopa, DeLong says, “was only part of the answer.”

During the 1970s, deeply immersed in the painstaking process of developing a model of the basal ganglia, DeLong didn’t know that his work would eventually reveal another answer to Parkinson’s disease. What he did find, studying primate models, was that the basal ganglia are a network of distinct neural circuits, similar to stations along a path, emitting signals alongside one another to guide particular tasks. 

By measuring neural activity while monkeys performed trained behaviors, he was able to match circuits with actions and map the organization of the network—which now appeared to be more influential than previously understood, affecting not only movement, but cognitive and emotional processes as well.

“It showed how diseases of the basal ganglia could present in so many ways,” DeLong said in an interview with the Lasker Foundation.

DeLong became particularly interested in a substation of the network, the subthalamic nucleus, which sends excitatory signals to the output portion of the basal ganglia that inhibits motor activity. He and his colleagues developed the hypothesis that this circuit was in overdrive—signaling excessively—and causing slowness of movement and muscular rigidity. But how to find out?

Street heroin might seem an unlikely aid to scientific research. But in the 1980s, a contaminant finding its way into synthetic heroin was linked to a syndrome among drug users that caused Parkinson’s-like symptoms. DeLong discovered that the chemical created a condition in nonhuman primates that closely mirrored the pathology of the disease; the animals stilled, then stiffened, and developed tremors. The stage was set to test DeLong’s theory. The results were, in his words, dramatic.

“The direct test was to inject a neurotoxin into the subthalamic nucleus, into that motor part of the structure that would inactivate these cells,” he told the Lasker Foundation. “And there was dramatic, sudden reversal of Parkinson’s disease. Before our eyes, the animals started to move, the tremor lessened, the stiffness resolved. It was everything you would want—and it could be replicated.”

DeLong had pinpointed a tiny, troublesome area of the brain where many of the worst Parkinson’s symptoms originate, and discovered that destroying or “lesioning” a few millimeters of gray matter could significantly alleviate those symptoms. But damaging the brain is tricky business, especially in the elusive, intricate basal ganglia. And that’s where an accidental finding by neurologist Alim Benabid in Grenoble, France, became another breakthrough.

In 1987, Benabid was preparing to create a lesion on the thalamus of a patient with essential tremor. To make sure he was targeting the correct area of the brain, he inserted a probe and delivered an electrical pulse to the site while observing the awake patient. This was routine, but then Benabid did something different: he increased the frequency of the electrical stimulation to nearly twice what he had previously used. The patient’s hand, which had trembled uncontrollably for many years, became still. 

“That was the ‘ah-ha!’ moment,” Benabid told the Lasker Foundation. “We could stop tremor without having to make a lesion, possibly avoiding a side effect or complication.”

Three years later, DeLong published a major paper detailing his research and findings regarding the subthalamic nucleus and its relationship to Parkinson’s disease. Benabid realized that the region could be a prime target for what is now known as deep brain stimulation (DBS)—the continuous delivery of high-frequency electrical impulses that act to control the abnormal firing of cells, much like a cardiac pacemaker.

In 1995, Benabid reported results from the first Parkinson’s disease patients who received bilateral, high frequency stimulation of the subthalamic nucleus, and eight years later confirmed the results in an expanded study. The surgery restored motor skills, suppressed tremor, improved the ability to conduct normal activities of daily living, and allowed people to significantly reduce their medication doses and avoid side effects. 

In a video interview with the Lasker Foundation, a patient with severe Parkinson’s disease describes experiencing DBS for the first time. “When they hooked me up, right then and there, it was . . . like a light switch,” he says, with tears in his eyes. “He has, in the most literal sense, given me my life back.”

In 2002, the US Food and Drug Administration approved high-frequency stimulation of the subthalamic nucleus for treating advanced Parkinson’s disease. DBS has since been used to treat an ever-expanding range of movement disorders, including essential tremor, dystonia, and Tourette syndrome. More recently, it has shown promise in cases of severe psychiatric illness, such as medication-resistant depression and obsessive-compulsive disorder. Emory’s Helen Mayberg, professor of psychiatry and the Dorothy C. Fuqua Chair in Psychiatric Neuroimaging and Therapeutics, has been at the forefront of that field.

Mayberg spoke with the Lasker Foundation about the impact of DeLong’s and Benabid’s work.  “To see a patient who can’t get out of a chair, to actually watch the instant when someone who can’t hold a cup of coffee flip[s] a switch and watch it stop—it makes you unable to breathe to watch it,” she said. “Their approach, their strategy, their logic has really created a field that allows for neuromodulation of brain circuits across diseases that we never would have thought possible.”

DeLong is a faculty leader of the Jean and Paul Amos Parkinson’s Disease and Movement Disorders Research Program. He also is codirector and founder of ENTICe (Emory Neuromodulation and Technology Innovation Center), whose goal is to foster advancement of neuromodulation and the development of innovative neuromodulation technologies for the treatment of neurological and psychiatric disorders.

“Probably the most remarkable thing is how [DBS] has been extrapolated to treating even psychiatric disorders, such as depression . . . with Helen Mayberg’s work,” DeLong says. “And it all goes back to that original discovery that the basal ganglia are more than movement. What this whole field has experienced is really tremendous growth and application to areas well beyond where it started . . . it’s been a very exciting era.”

In his Lasker Award acceptance speech, DeLong also noted the chance events, occurring across oceans and decades, that ultimately brought together his work and Benabid’s—for instance, his being assigned the basal ganglia for study at the NIH, the contaminated heroin that created Parkinson’s-like symptoms, Benabid’s decision to turn up the electrical pulse to see how it would affect his patient.

“Some of our real progress and breakthroughs are made, I believe, serendipitously, while we are doing other things,” DeLong said, “like just trying to understand how things work.” 

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