Of Many Minds

In the battle against Parkinson’s disease, the Ruvo Center’s Ryan Walsh gives science a human touch

drwalshlook3059b.jpgIt’s August 2011, and a stylish, dark-haired 81-year-old named Rhoda Starker waits in an exam room at the Cleveland Clinic Lou Ruvo Center for Brain Health to see the newest doctor in the building. She’s been having problems with balance and tremors—and she’s arrived at this Frank Gehry-designed building in downtown Las Vegas today with the mix of anxious hope and weary patience that comes with having a disease that has no cure.

Ryan Walsh comes into the room, blue-eyed, a runner’s build. He smiles and takes Starker’s hand. He has been at Ruvo for less than a month, fresh from the University of Alabama-Birmingham, where he had become a nationally respected expert on Parkinson’s disease. He asks what’s been going on and listens carefully to her answers. He has her walk around and move her hands and feet, arms and legs.

“Rhoda,” he says, “you are being under-medicated.”

He wants to add a drug to her regimen. She replies that she’s tried that one before, and it made her sick. “The way I give it to you,” he says, “you will not get sick.”

And she doesn’t. Instead, after a month of slowly increasing the dosage, Starker is once again lifting weights, riding her stationary bike, hitting golf balls and bowling with friends.

“Dr. Walsh made me a completely new person,” she says, still feeling great five months later. “He gave me back my life.”

Starker doesn’t talk about being treated by one of the rising stars in the scientific community studying Parkinson’s disease. She talks about having a kind, comforting doctor who sincerely seems to care about her.

In this way, Walsh embodies his mission as director of the Parkinson’s Disease & Movement Disorders Program at the center: to translate cutting-edge scientific discovery into compassionate patient care quickly and seamlessly.

“That’s much easier said than done,” Walsh says. “Going with efficiency from the discovery side of science to meaningful clinical impact is really hard—especially in neuroscience.”

By all accounts, the 38-year-old Walsh is a brilliant researcher. He earned two consecutive post-doctoral grants from the Parkinson’s Disease Foundation, which only gives out a handful of the awards each year, and his mentors (scientific superstars in their own right) describe his work as being on the cutting edge of their field.

It might surprise outsiders, then, that, in his own work, Walsh isn’t looking for a cure for Parkinson’s. Instead, he’s looking for something he believes is more imminently promising: a straightforward way to diagnose the disease.

The diagnostic riddle

Doctors use a combination of brain scans, patient history and physical examination to diagnose Parkinson’s. They give tests, such as the Unified Parkinson’s Disease Rating Scale, or UPDRS, and look for four main types of motor impairment: imbalance, rigidity, slowness of movement and tremor. They’ll have patients make certain motions with their limbs and simulate falling backward. It’s an imperfect method.

Walsh and others need a better diagnostic tool for Parkinson’s—urgently, he believes.

The disease affects two main age groups: the first, a smaller group, consists of people diagnosed in their 30s (such as actor Michael J. Fox); the second, comprising the majority of patients, is made up of people diagnosed in their 60s. Considering average life spans, this means most people live 20 years or more beyond diagnosis. With baby boomers hitting retirement age, the number of people living with Parkinson’s is expected to double by 2030, with the disease affecting, by some estimates, as many as 2 million Americans.

Without a reliable diagnostic tool, neurologists are hampered in their ability to develop new therapies, treat Parkinson’s patients and track their progress over time. Moreover, Walsh says, if you scan the brain of someone in the early stages of Parkinson’s disease, the resulting image looks like that of a normal brain. If doctors could reliably call out the disease at that point, it would pay off tremendously over the long haul. Patients such as Starker could do things they enjoy and put off the disease’s late-stage ravages longer.

In the last decade or so, Walsh says, understanding of the neurological processes underpinning this and other movement disorders has started to reach critical mass. Technological advances are producing better tools. With scores of science’s best and brightest working on it, a diagnostic test seems within reach.

“This is a big public health problem. A big one,” Walsh says. “And it’s going to impact our society on a number of levels. We potentially have just the beginning of a chance now to do something really meaningful about these diseases and fundamentally change what that impact will be. Of course it’s not guaranteed, but the chance, I really do think, is there.”

Seeing blue

Walsh learned as a kid to blend left- and right-brain ways of looking at life. His father is a driven cardiologist who heads the department of medicine at Cleveland’s prestigious Case Western Reserve University; his brother, five years older than him, is a poet good enough to have earned his living at it for a while. The two, he says, were the main influences on his intellectual development.

Over the years, Walsh made a habit of holding the space for science and humanity to overlap. When he was a junior majoring in philosophy at Georgetown University, a Jesuit institution, a priest-professor challenged his way of explaining the workings of the mind. “He basically said I hadn’t thought about it deeply enough, and I needed to think more,” Walsh recalls with a laugh. “So, I thought about it more.”

Using the color blue as an example (one of his professor’s favorites), he describes everything that goes into it: the wavelength of the light, the object reflecting it, the structure of the eye, the neural impulses to the brain—all happening in a flash. Introduce the individual interpretation of “blue,” and it gets even more complicated. Dissatisfied with philosophy’s explanation of why blue is blue, Walsh switched his major to biology.

Yet he was far from done with abstract thinking. His fascination with the mind led him to neurobiology and medical school at the University of Cincinnati, where he earned an M.D.-Ph.D., training in investigative science and patient care.

“I combined research and medicine so I could both see patients and do research, and hopefully have one feed off the other,” he says.

As his gift for neurology emerged, Walsh developed a fascination for the ways different areas of the brain interact—the outer, younger cortex, with the deeper, older sub-cortex, for instance. One way to understand normal connections between brain regions is to look at dysfunctional connections. And a main area of brain dysfunction is movement disorders, such as Parkinson’s.

The Holy Grail

Two young men lounge in chairs on the rooftop porch of a high-rise in the Hyde Park neighborhood of Chicago. In less than 10 years, one will be leading a Parkinson’s program at a neurological center in Las Vegas; the other will have a rare National Institutes of Health grant to continue his ground-breaking neuroscience research at Hamilton College in New York. But for now, they’re content to enjoy a glass of wine, take in the view of the city and debate their favorite subject: the brain.

This was Walsh and Jeremy Skipper in the mid-2000s during their time at the University of Chicago, where Walsh did his internship and residency, and Skipper earned his Ph.D. The two met in the lab, and immediately bonded as unabashed nerds.

“Ryan was further along in his career, so he was able to take a more mature perspective. He kind of mentored me,” Skipper says. The two would spend hours talking shop, frequently returning to the subject of brain imaging.

“There’s a long history of studying the brain in paradigms that are tightly controlled and don’t resemble what people do in the world,” Skipper says. “Shockingly, nobody knows how the brain functions out in the wild.”

Separately, both men were working toward that goal—Walsh with scanning tools like MRI on the brains of people with movement disorders; Skipper on brain functions related to communication—knowing it was a Herculean challenge that could ultimately only offer miniscule rewards, if any.

The brain has a natural barrier to keep things out, so inventing something—say, a drug—that can get into it is tricky. Getting the drug to accomplish a certain task once it’s inside is even trickier. And ascertaining whether any of this does any good is the trickiest of all.

Generations of scientists before Walsh and Skipper have worked on this problem. For neuroscientists—particularly those who study neurodegenerative diseases and do clinical trials—finding a way to image brain activity and shorten the time it takes to see whether treatment has had any effect is, as Walsh puts it, the Holy Grail.

A key figure in this quest saw promise in Walsh’s work at the University of Chicago. David Standaert, director of the Center for Neurodegeneration and Experimental Therapeutics at the University of Alabama-Birmingham, recruited Walsh to join his team. He took the young doctor on hundreds of rounds, showing him the finer points of interacting with patients, observing and diagnosing them. With dozens of trials going on at UAB, Walsh learned the sausage-making of clinical science.

Standaert also introduced Walsh to David Eidelberg, a world expert in brain imaging who, among other things, has used PET (positron emission tomography) scans to pick Parkinson’s-related aberrations out of normal brain circuitry and see if they were repaired with treatment.

Following in Standaert and Eidelberg’s footsteps, Walsh began his own pilot study. He and two colleagues, Kristina Visscher and Christi Hu, selected 20 people: some were Parkinson’s patients with cognitive impairment, some Parkinson’s patients with no cognitive impairment, and the rest people with no Parkinson’s or cognitive impairment. Using fMRI (functional MRI) and DTI (diffusion tensor imaging) they scanned the group’s brains over time, and overlay functional and structural images to try to extract consistent patterns.

“It’s hard to understand from the outside,” Standaert says. “Lots of people can take pictures of the brain, but they may not know what to do with them. And a lot of doctors can interpret pictures of the brain, but don’t understand the technology. People like Ryan and me, we can do both.”

Their goal, he says, was to understand Parkinson’s effects on cognition, thinking and memory. They’re among a handful of centers working in that area. “This is a big direction in neurology, and Ryan is one of the pioneers,” Standaert says.

Watching TV

After nearly three years of work, the team is summarizing its findings. Their data, Walsh says, suggests there are changes in the way the cortex interacts with the sub-cortex that vary between the different types of patients. The findings are a step toward better understanding Parkinson’s disease, but Walsh says it’s only an interim step.

The problem is that diagnostic tests such as fMRI and DTI work best when patients are still, so Walsh’s team collected resting-state data, instructing participants to lie still, without falling asleep. But that meant only people with little or no tremor could participate, limiting insight into those with significant impairment due to tremor. Moreover, the strength of the sought-after signals amid the other brain activity going on at the same time was weak, producing what Walsh calls a “low signal-to-noise ratio.”

A good way to improve the signal-to-noise ratio would be to have patients perform tasks that reveal Parkinson’s-related impairments, like those done in the Unified Parkinson’s Disease Rating Scales test. But how can they do UPDRS tests—which rely on motion—in a resting state?

One way, Walsh realized, would be to scan patients’ brains while they watch videos of people doing movements, since scientists already know this activates the same parts of the brain in the watcher (albeit more weakly) as would be activated if he were doing the movements himself. For instance, a video might show someone going to the doctor. She’d have to pick up a pocketbook, turn a doorknob to open the door, walk down the steps to her car, open the car door, and so on—real-world actions that include motor functions tested by the UPDRS.

“What I want to do,” Walsh says, “is develop a technique where we can perhaps engage a lot of those same networks that we’re engaging during the UPDRS testing, but without having patients do those tasks overtly—and still get at the underlying networks of brain activity that are at work.”

The idea didn’t come out of nowhere. It just so happened that Walsh’s old friend Jeremy Skipper had come up with something remarkable in his pursuit of brain functions in the wild, something that Walsh could use. To test brain activity in natural communication, Skipper puts subjects in an MRI scanner and has them watch videos; a TV game show, for instance. He came up with a novel way to annotate what’s going on in the video (someone clapping, laughing, pointing) and cross-reference that with what’s going on in the watcher’s brain. The work has earned him a prestigious NIH award for young investigators.

Walsh wondered: What if he combined Skipper’s video-analysis technique and his own MRI-DTI scanning technique?

“Those could potentially be very powerful when used together,” he says. Although Skipper is more interested in language and Walsh in movement, both are after connections and interactions between brain regions. By pooling their skills, Walsh hopes, each can gain new insight into his particular area.

While still at UAB, Walsh bounced the idea off Skipper, who didn’t bite at first. But Walsh didn’t give up. After a year and a half of late-night phone conversations and lengthy e-mails, the two have decided to give it a go.

They’re in the first stages of a pilot study in which they’ll scan the brains of Parkinson’s patients watching videos of people emulating UPDRS movements in real-world situations. Elements of the trial have been used before, but nobody has applied them to Parkinson’s the way Walsh and Skipper plan.

They have months—maybe years—of tedium ahead before they can start scanning patients and collecting data. Skipper has students working on the video; he and Walsh are developing the assay, which the team will have to test and fine-tune. In the next stage, Walsh will start recruiting patients, paving the way for what he and Skipper hope will be a groundbreaking study.

“It’s a long process,” Skipper says. “The work is long, hard and lonely. But I love it.”

“Believe me, not everyone is going to think this is a good idea,” Walsh says, “and that’s great. That’s what science is all about.”

In the silver building

It’s 6:30 a.m. on the third floor of the Ruvo Center, and it’s quiet except for occasional spurts of keyboard clatter echoing down the halls to doctors’ private offices. With no phones ringing or patients arriving yet, Walsh has a couple of hours, alone at his desk, to focus fully.

Since arriving at the Ruvo Center, he says, he’s been able to start digging into the project with Skipper. “I’ve been really impressed with the patients,” he says. “They’re very eager to be involved in trials and understand their disease.”

Yet his own work is but a small fraction of what he does. He participates in other trials going on at the center, originating both from Cleveland Clinic researchers and from outside pharmaceutical companies. He collaborates with colleagues researching movement disorders. He’s working to establish the Lou Ruvo Center as a Parkinson’s Study Group site—part of a national research network—and to start the state’s first comprehensive clinic for Huntington’s disease.

Most important, he spends time with people like Rhoda Starker, listening to their concerns, answering their questions, making their lives better.

“My goal,” he says, “is to build all these different parts, clinical and research, in an engaged way with the community. How can we help Parkinson’s and other movement disorders patients in Nevada? By doing that the right way, we can do really big things, but the focus has to first be on taking good care of patients and caregivers right here, right now.”

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