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Johns Hopkins UniversityArts and Sciences Magazine

A Mystery of Misinterpretation

After a decade of research, cognitive scientist Barbara Landau is mapping new territory in Williams syndrome—a rare condition that has long baffled scientists.

Suppose you had a winning personality, you loved music, you could ski, ride a bike, and were about to start college. But when faced with a simple test of matching four painted toy blocks, you fumbled around like a 4-year-old.

How can someone be proficient in so many ways, yet stymied by such a seemingly simple task?

It's a mystery that scientist Barbara Landau—the Dick and Lydia Todd Professor of Cognitive Science at the Zanvyl Krieger School of Arts and Sciences—has spent more than a decade trying to understand.

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Landau first began working with Patrick Borden when he was 8. He’s now a college freshman.

 

Now, she and a colleague at the University of Delaware are on the verge of publishing the groundbreaking results of their research into Williams syndrome, a rare birth defect that leaves children profoundly impaired in some areas of their spatial awareness yet possessed of strong language skills.

Landau and James Hoffman, a professor of psychology at Delaware, have tested scores of children with Williams syndrome and compared the results against those of normal children. In terms of basic spatial-cognitive systems, those with Williams syndrome appear to develop normally—although at an extremely slow rate. Then, at about the level of a typical 4-year-old, something causes that development to stop.

Landau and Hoffman believe they have come to grips with the nature of that halt in spatial development and now understand where in the brain the cognitive disconnect originates. They also have substantiated theories as to how and why Williams syndrome causes such disparity between language and spatial skills.

Last spring, in recognition of her work on Williams syndrome, Landau was awarded a prestigious Guggenheim fellowship. That work also played a key role in her recent election to the American Academy of Arts and Sciences.

"Barbara has reset the research in Williams syndrome," says Apostolos P. Georgopoulos, a professor in the departments of Neuroscience and Neurology at the University of Minnesota. "She did a very systematic and exhaustive study of a very misunderstood system. It's a major advance for the benefit of everyone."

Landau, who started her career studying language acquisition skills in normal children, sees Williams syndrome as the kind of natural accident that scientists can use to discover things they wouldn't have been able to otherwise.

"Language acquisition is just about the most complex system of cognition we knowof," says Landau. "I was interested in the relationship between what we see in the world and how we perceive it and then how we come to be able to talk about that experience. When I first heard about Williams I started wondering how the two systems—spatial understanding and language—talked to each other in these children."

It was in 1961 that J.C.P. Williams, an eccentric New Zealand physician (he would later vanish without a trace) noticed similarities among children taken to his Auckland hospital for heart surgery. They all had a constricted aorta and were small for their age, their faces elfin-like with upturned noses, broad foreheads, and angular chins. Each was also unusually sociable and gabby. For more than 30 years after that such children with the syndrome Williams had defined were simply classified as mentally retarded because of an IQ in the 60 to 65 range—although some do score close to the 100 IQ of the average person.

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The “Hand Test”

 

A collaboration among Landau, cognitive science professor Brenda Rapp, and the Mind-Brain Institute's Takashi Yoshioka, the task is one of several for Williams volunteers in Landau's lab. With eyes closed, subjects indicate where on their hands an examiner tapped them. Many people with Williams syndrome cannot do it with accuracy—the arrows and blue circles above represent the subject's perception of taps and the actual location of them, respectively. The results help explain why a person with Williams syndrome might have difficulty reaching out to grasp an object.

In the early 1990s, geneticists realized that people with Williams syndrome were missing a string of genes from chromosome seven—a deletion that occurs at the moment of conception and affects about one in 20,000 births, according to the Williams Syndrome Association. Basic development in these children—walking, talking, toilet-training--is delayed, yet many have a highly developed sense of music and literally go through the day with a song in their hearts, according to the association.

"Their level of functioning varies a lot," says Landau. "While there is some suspicion that one of those deleted genes is involved in the retardation profile, in some people with Williams syndrome, this gene is not deleted. Their IQs range from about 50 through 100 and sometimes even higher. Some even go to college."

Such is the case of 19-year-old Patrick Borden, diagnosed with Williams syndrome at age 1, but high functioning enough today to have enrolled as a freshman at a community college in Wilmington, Del.

"He's always done well on our tests," says Landau. "Part of it is that he has a family environment that's been extremely supportive of good schooling."

Landau first began working with Borden when he was 8, just after she had moved from the University of California at Irvine to the University of Delaware as a professor of psychology and linguistics. At Delaware, in 1997, Landau began recruiting families whose children had been diagnosed with Williams syndrome.

"We'd go to her lab and do studies with her group," recalls Patrick's mother, Mary Borden. "We didn't have any expectations. We were doing it from the point of view of research. We thought it could be helpful."

Landau says that while Patrick has struggled with basic tests that tap into the typical spatial deficits among those with Williams syndrome, he has also shown an IQ in the normal range and has noticeably matured. "When Patrick was younger it was not as striking," says Landau, "but in the past five years he's been at the top of his group. So there is development. People do grow up and change."

The Bordens are among the many families who started with Landau while she was a faculty memeber at Delaware and have continued to meet with her at Hopkins, where she moved in 2001.

"Barbara is doing wonderful studies in her lab: I wouldn't be driving to Baltimore otherwise," says Lynne Sklar, mother of 21-year-old Alex, who joined Landau's research program at Delaware when he was 9.

Mary Borden says she almost feels Landau is part of her family. "Barbara treats children and adults in her studies with such respect. She's very kind and will sit and listen as they bring her up to date on what they've been doing."

Both Alex and Patrick are high-functioning young adults. Their parents believe that an official diagnosis of Williams syndrome helped their sons navigate the public school system without trouble.

"From when he was 2 he started in an early intervention program and got physical therapy and occupational therapy and speech therapy," says Mary Borden, "things that really helped him along the way."

The mothers also agree that the science coming out of Landau's lab has motivated them and other families to commit to her long-range testing.

"We've always felt that research was important, that it made a difference," says Lynne Sklar. "For so long we knew Williams existed, but we didn't know why. You'd go to meetings with Williams families, and they'd have another little bit of news. Every year or two we found out a little more."

That information, she says, gave her the leverage to challenge teachers and others who saw a child seemingly normal and couldn't understand why he wasn't performing up to par.

"I'd say, 'He has Williams syndrome,' and they would say, 'Oh, yeah, right.' Now I can say, here's the literature. It's key for me to know this. Researchers keep opening doors for us."

When Williams syndrome volunteers like Alex and Patrick come to see Landau at Hopkins, they typically spend part of two days undergoing a battery of tests in her lab in Krieger Hall. Some of the tests are standardized, but Landau has designed or adapted most over the years.

"She uses very sophisticated methods," says Helen Tager-Flusberg, director of the Developmental Cognitive Neuroscience Laboratory at Harvard University. "I think everyone would acknowledge that her work is top of the line."

Today, of the half-dozen research groups involved in Williams syndrome research worldwide, Landau and Hoffman alone focus on the issue of spatial cognition. Much of their work has been funded by grants from the March of Dimes, National Institutes of Health, and National Science Foundation.

The bulk of their testing takes place in what is known as the coding room—actually two rooms separated by a two-way mirror. Parents can watch and listen as their children work through their tests, including the "hand test" and those that measure language skills.

"People with Williams syndrome show an extraordinary capacity to understand very complex structures," enabling them to carry on articulate conversations, says Landau. "They are delightful to be around." She notes, however, that the intelligence of their conversation "is limited by just how high functioning the person is."

As her research progressed, Landau found that their language capabilities carried over to conversing about spatial objects.

"We showed them very simple animated events with little dolls jumping in and out of bowls. We wanted to see if they could describe the events and whether uses of spatial terms—prepositions 'in' and 'on,' 'into' and 'out of,' and 'above' and 'below'—were used appropriately and whether they could learn them. They gave very good descriptions of all the components. Their spatial language was extremely good."

Yet in spite of being able to talk about spatial components, volunteers in Landau's lab showed deficiencies in overall spatial understanding.

"Even within many areas of spatial competence they show peaks and valleys," says Landau. "They are very good at some things and very poor at others."

A good example of that is the block test. Participants are shown an assembly of four toy blocks, some with solid colors, some half black and half yellow. They must pick from a bin of varied blocks to copy the assembly.

"They are extremely impaired at that," she says. "Even an adult with Williams syndrome performs at the level of a 4-year-old." The same, she says, is true in copying simple things such as drawings.

Delaware's Hoffman offers up the example of a young woman he tested who is a lead singer in a band. "She's an excellent performer," he says. "She also has close to an average IQ, up around 90. She's living on her own. If you talk to her you'd never guess she had Williams syndrome. I gave her spatial tests—[including] a simple task of copying a shape. When she finished, parts of the shape were scattered all over the page. She looked up and said, 'I'm sorry, I'm not good at this.' She could see that what she had drawn is wrong. It didn't appear to be her perception that was the problem but the process between perception and the copying of the object."

At Hopkins, Landau and her team test volunteers year after yearin some of the tests to measure any improvement. Some people do get better with the blocks over time, she says, but not by much. "You're talking about someone at 8 functioning as a 4-year-old and when they are 20 functioning at the 5-year-old level."

It's often frustrating to them, she says. "It especially gets hard with some quite high-functioning individuals who will not be driving when they get to be 17 or 18 because of their spatial representations and limitations."

In an effort to derive more precise measurements, Landau and Hoffman have created a computerized version of the block test that includes a small camera inside the monitor, which photographs eye movement as the subject views the screen areas and manipulates the blocks using a mouse.

"A person might spend as much time looking in the block bin as looking at the model," says Landau. "That can tell you there's confusion, even if they pick the right block. Once they place the block in the copy area they might go back and see if they put it in the right spot."

"I've learned a great deal from her use of eye tracking," says Tager-Flusberg at Harvard, who has used the technique in several of her published studies on autism—her research specialty.

Even as Landau and Hoffman have seen their Williams syndrome participants struggling with sorting blocks and copying shapes, they have noticed another puzzler: These same people were often very good at a more complicated test: the recognition of biological motion. In it, subjects watch an animation that simulates what one would see if a person was moving in the dark with only light bulbs on his or her joints. They see nothing until the bulbs are lit and the person in the video begins to move. The challenge is to observe the movement of those lights and recognize them as a human form.

"Humans have a specialized system," says Landau, "that allows them to detect motion that describes the figure of a human body. The mechanism for that is very complicated, run through a particular area of the brain. It's clearly spatial. And those with Williams syndrome are very good at that. They can immediately extract a position of a body moving."

Yet the contrast between being unable to copy a shape but able to perceive the human body in motion was troubling.

The question, she says: "What was it about their systems of spatial representation that has gone wrong?"

Over the years, she and Hoffman have combined their work on spatial cognitive systems with research done by others on the brain basis of the deficit. "We've created a sort of map of what goes wrong in those brain areas," she says. Their efforts to map the cognitive systems led them to a new understanding of the effect of Williams syndrome on the brain.

Basically, says Landau, when we observe something, a stream of visual information passes through a number of "processing stations" before branching into two different directions. Each of those streams carries different elements of spatial processing information. Language and the recognition of biological motion are thought to be resolved along the ventral stream—and those with Williams syndrome do well with that type of processing. The dorsal stream, especially the parietal lobe, seems to be the nexus of things that go wrong.

"The requirements of the block task, for example, tap these areas of the brain," says Landau. "It's actually quite a complicated process, drawing on a lot of different components." Each of those components involves the parietal area. "That area has an abnormal organization in people with Williams syndrome," says Landau.

"The conclusion I have come to is that Williams syndrome people have a particular deficit in spatial tasks that generally engage the dorsal stream of the brain. It controls visual spatial attention and visual spatial action. But there are other areas of the brain that do other spatial tasks—such as biological motion—that seem to be fine and not impaired."

Knowing there is no cure for Williams syndrome, parents still frequently ask Landau if there is any way to help their children. Her message is simple: Be involved in the research to discover your child's strengths.

That message rings true for Mary Borden.

"Pat is very good at reading people," she says. "I remember when 9/11 happened. He came home from school, and they hadn't told them what had happened. I was going to meet him outside and sit on the curb and talk about his day and just wait a little while before talking about it. As we were sitting there he said, 'Your mouth is smiling but your eyes are sad.'

"We were told that he might never be able to read or to ride a bike. It was a constant everyday [effort] of trying to make things better for him. Not just taking the word of what was impossible. So seeing him ride a bike and be able to ski and do things he'd been told he probably wouldn't do, that just makes it the best part."

Her son's attitude about Williams syndrome is disarmingly positive.

"I've met a lot of friends from having Williams syndrome," he says. "All my buddies at school know I have it. I don't think it affects me as bad as some people. I can be very smart depending on what the subject is. Social studies is my favorite subject. I've always liked learning about how the world has changed since the beginning of time. My most hated subject is math."

Alex Sklar, too, has had trouble with math. His mother says he still can't tell time on a regular clock. He has a poor concept of money as far as making change goes.

"But he has learned a lot," says Sklar. "Sometimes he surprises me with what he can do. He is a very good athlete. He can hit a golf ball. How could he do that but doesn't know how to draw a stick figure?"

A former teacher, Sklar says she raised Alex as a normal kid. "Alex needed to be able to act appropriately just like our other kids," she says. "He played Little League. He went to the same school as our other kids. We've always joked that Alex was the last person in the world to know he had a disability."

Landau is spending her Guggenheim year writing a book with Hoffman on Williams syndrome. One thing she is sure of: "What we know is not just about Williams syndrome. It has applications to other disorders like autism and Down syndrome and others of a genetic nature."

At Hopkins, Landau's importance on campus goes beyond her research skills, notes Adam Falk, the James B. Knapp Dean of the School of Arts and Sciences. "She has played an important leadership role with issues concerning women faculty," he says. "She's been a powerful advocate for women, and as a senior woman scientist she is an extraordinary role model for students and younger faculty."

Megan Chen, Landau's lab manager, says her mentor is a popular choice for undergraduate and graduate students to work with. "She works pretty closely with undergrads--closer than some professors I have experienced. She is very friendly but very honest. I really like that," says Chen. "She keeps me grounded."

Against such plaudits, Landau seems somewhat amused, especially when someone asks if she has any time in her life for anything else.

"I have a real life!" she laughs, the exclamation point palpable. "I have two fabulous children and a wonderful husband. I like gardening and cooking." She and her family were planning a late summer getaway to the Galapagos to snorkel and "look at the fish." On her return, she planned to finish her book and consider her next challenge.

"We think we have a handle on Williams syndrome," she says. "But there are more questions. Always."
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Patrick A. McGuire, who spent more than two decades as a journalist with The Denver Post and The Baltimore Sun, is the author of two books.