Reaching In, Reaching Out
As more children are diagnosed with autism, scientists search for its neurological origins.
By Taylor McNeil
Michael sits on the carpet in a small mirrored room on the Medical Campus, looking at first glance like an average toddler. His mother watches from a chair along the wall, while a research assistant calls Michael’s name repeatedly in a cheerful voice. But Michael is not paying attention. He’s staring ahead, a distant look in his eyes. The researcher tries to engage him by blowing bubbles and calling his name again. After each attempt to make contact, she marks a chart. Finally, she touches Michael’s face gently as she says his name, but there is little visible response. Michael is not ignoring her. He’s simply living in his own world, unconnected with his surroundings.
Michael’s world is called autism, and in the last decade it has been the focus of increasing national attention. A developmental disorder that emerges early in life, autism affects a child’s social skills, communication, and behavior. The latest statistics from the U.S. Centers for Disease Control show that one in 150 children in the United States is afflicted with an autism-related disorder. As interest in autism has grown exponentially in the last decade, so have research efforts. At Boston University, scientists are looking for ways to diagnose the disorder early, even in infancy, and they are trying to puzzle out its neurological origins in the hopes that one day it can be better treated.
Autism is difficult to pin down. There is no one single diagnosis, and the boundaries of the disorder sometimes seem like moving targets. Often diagnosed around age two or three, its classic signs are linguistic and cognitive deficits, lack of eye contact, social isolation, and lack of communication for much beyond basic needs, according to Helen Tager-Flusberg, a School of Medicine professor of anatomy and neurobiology and director of the National Institutes of Health Autism Research Center of Excellence at BU. “There is a huge variability in its expression,” she says. Other symptoms include obsessive interest in certain things to the exclusion of others, an abnormal need for structure, and certain motor behaviors, such as rocking or arm-flapping.
In classic autism cases, says Tager-Flusberg, who has been studying the disorder for twenty-five years, “people have lots of symptoms that make them fit.” There are similar developmental disorders that look like autism, she says, but may be milder. One is Asperger syndrome, in which cognitive abilities are normal, but conversation and aspects of discourse show delays. That and other diagnoses fall under the wide range of what the CDC calls autism spectrum disorder.
“It’s tough, because there’s no test you can do,” says Elizabeth Caronna, a MED assistant professor of pediatrics and director of the Pediatric Assessment of Communication Clinic at BU-affiliated Boston Medical Center. “It’s really a behavioral diagnosis. It depends on a clinician with an appropriate level of specialized training to have eyes that can see the right things.”
Children can have one or two symptoms — some kids might not want to look people in the eye, others might have an obsessive interest in dinosaurs, still others might flap their arms a lot — but the tipping point in a diagnosis is impairment, says Caronna, whose clinic at Boston Medical Center assesses several hundred children for autism each year. “We try to consider things very broadly, thinking about developmental delays, language delays, and what might look like it, and we consider other issues, such as anxiety or depression,” she says. “You have to have some level of impairment.”
But it seems an increasing number of children do have autism. For a disorder that was first described only in 1943, the current statistics on children affected by autism spectrum disorder are extraordinary. Tager-Flusberg and Caronna both caution that it’s important to keep in mind that the definition of autism is steadily broadening, and with heightened awareness of the disorder, more parents and pediatricians are on the alert for symptoms. Indeed, a study published two years ago in Current Directions in Psychological Science argues that the rise in autism cases is mostly the result of “purposely broadened diagnostic criteria” in the Diagnostic and Statistical Manual of Mental Disorders, the bible for mental health assessments. And most experts agree that children diagnosed with mental retardation or childhood schizophrenia in previous generations are now more often categorized as autistic.
The Words to Say It
Any way you count, a vast number of children are affected by autism-related problems. For Tager-Flusberg, who has received several million dollars in funding from the NIH for autism research, early assessment of the disorder is critical. That’s because with current behavioral treatments — mostly centered on intensive efforts to establish communication with the autistic child — many symptoms of autism can be mitigated, enabling the children to lead more normal lives.
“We don’t know how to predict which of the children are going to have the better outcomes when we first diagnose them,” she says. “A small number will adapt and be OK, but it’s a very small minority. The majority of children don’t have full, independent outcomes, and therefore it behooves us as a society to make sure that all children who are at risk for autism be identified and that we develop for them the kinds of interventions that are going to influence their course of development.”
Tager-Flusberg looks first at language. “It’s one of the core domains,” she says. “Language is the single best predictor of how well you’re going to do in later life. People with better language skills are able to use them to gain the skills they don’t come to naturally,” such as social skills. “I’m interested in the question, what predicts who’s going to have a better language outcome?” For the past two years she has monitored a group of almost 200 toddlers, who were enrolled in her study when they were between eighteen and thirty-three months old. Michael is one of them.
Children like Michael are tested by Tager-Flusberg’s staff in the room with two-way mirrors on the Medical Campus. With a parent close by, a researcher tries to engage the child in conversation and in play — blowing up a balloon and letting it go, blowing bubbles, calling out the child’s name — all in an effort to test language, imitation, motor and nonverbal cognitive abilities, and ability to respond to social or communication signals, Tager-Flusberg says, such as making eye contact and sharing interest or pleasure in an activity. The children come back annually for another round of testing.
When the children in the study were first seen, they were all essentially nonverbal. By the time they were three, they began to show much more variability in language ability, and by age four their developmental patterns were becoming clear.
“Some really stay essentially flat, making very few gains, and some make huge gains,” Tager-Flusberg says. “What are the things we saw that might predict these different outcomes? If we knew that, then a language assessment at age two could incorporate not just looking at their language — because their language is terrible — but looking at other things that might be related.”
Preliminary data from year two suggest that toddlers with better imitation skills, such as copying an experimenter’s action, and early social gestures, such as shaking their head for no, are more likely to show significant gains in language one year later.
Now Tager-Flusberg and her colleagues are trying to push back the point of diagnosis and figure out how to spot infants at risk for autism. Because studies have shown a fairly strong genetic link to the disorder, she is looking at infant siblings of children with autism. “You simply cannot diagnose the disorder until twelve months or later — you just don’t have enough language or behavior to even look at, that early on,” she says. “We absolutely don’t know what the criteria would be for an autistic baby.”
By closely following these infants at risk for autism — and a control group as well — the researchers hope to discern behavior patterns that might provide clues about which infants go on to develop autism.
But that also raises a question: what is the balance between predicting that a baby will have autism and the risk of labeling and pathologizing the baby at such an early age?
“I think I would be more comfortable in saying that this is a child at very high risk,” Tager-Flusberg says. With the possibility that earlier treatment will mitigate later symp-toms of autism, she is strongly in favor of a preventive approach. She draws a parallel with developments in cardiovascular disease prevention. “Thirty years ago, you had a heart attack and then you had cardiovascular disease.
Now we don’t wait for the heart attack; we monitor all the risk factors associated with it and take preventive measures. We want to do the same in autism.”
Nancy Wiseman (COM’81) agrees that early diagnosis is crucial. The author of Could It Be Autism? (Broadway Books), Wiseman has a daughter who was diagnosed with autism at age two. “She had no words, she had no eye contact, she had no play skills or social skills,” says Wiseman. “I knew I needed to do something about it quickly. Within just the first week with early intervention, I saw the progress she could make — she spoke her first word. I saw with intensive round-the-clock intervention you could prevent a developmental delay from progressing into a full blown disorder such as autism if you catch it early enough.”
Early intervention, which is provided by state public health services, comes in many varieties, but the two main approaches are behaviorally based, such as applied behavioral analysis (ABA), or more relationship-based, such as Floortime, a form of therapeutic play developed by psychologist Stanley Greenspan. MED’s Caronna says that research suggests that ABA is more effective, but she adds that “it seems that kids do better with one type or another, and some kids might do well with all types, and some kids might make no progress regardless of how high-quality the services are.”
For her child, Wiseman chose Floortime. “I did very intensive Floortime for hours every day,” she says. “That’s basically trying to get connected with the child at their own pace and own interest, getting an interaction going. It’s that social reciprocity that is key to getting these kids moved along the developmental ladder. If that’s not in place, the other rungs of the ladder don’t fall into place.” Wiseman, who founded the autism advocacy group First Signs, notes that speech and language therapy and occupational therapy are also widely used in early intervention programs. Thanks to the intensive early intervention, Wiseman says, her daughter’s linguistic and social skills improved substantially. Having seen those kinds of results, she urges parents to have their children tested early and get quick treatment.
It Is in Your Head
Back in the 1940s and 1950s, the conventional wisdom about the cause of autism was simple: it was entirely the mother’s fault. “It must have been really horrific for the mother to go through that — not only to deal with this child, but to also be blamed for it,” says Gene Blatt, a MED associate professor of anatomy and neurobiology who specializes in autism research. By the late 1960s, researchers started talking about its being a biological disorder, “but we didn’t have the tools to study it,” says Tager-Flusberg. In the 1980s, two BU professors, Margaret Bauman and Thomas Kemper, pioneered neuropathological studies in autism and saw abnormalities in the brains of autistic adults. That pointed the way to a crucial finding: autism is a neurological disorder.
Blatt and his colleagues are continuing Bauman and Kemper’s work in the MED Laboratory of Autism Neuroscience Research, where the two researchers are still active members. Using postmortem specimens from the Harvard Brain Tissue Resource Center, they are finding evidence that the changes in the autistic brain appear to be directed toward particular systems, or parts, of the brain. New research, funded by a grant from the Nancy Lurie Marks Family Foundation, focuses on areas responsible for speech and language. “We look at the neurotransmitters and their receptors in the brain,” Blatt says, “to see their localization and see how it may be different in autism.”
He and his colleagues began publishing their research, which showed the role of a particular receptor, GABA, in autism, in 2001. “We’ve followed that since then, and it’s almost like anywhere we look in the brain where neuropathology has been described, we see GABA receptor changes,” Blatt says. “It’s more extensive than that, but this is one of the players.”
GABA is a chemical messenger distributed widely in the brain. An inhibitory receptor, it reduces the activity of the neurons to which it binds.
Some researchers think one of GABA’s purposes is to modulate information processing throughout the brain. How GABA works, says Blatt, is complex, but it seems to help the brain maintain a delicate balance between excitatory and inhibitory input into neurons. “If you disturb that balance, you will potentially alter the firing and the outcome from that brain area,” he says. When inhibitory receptors like GABA are reduced, as they are in autism cases, there is greater potential for increased excitation, throwing off the delicate balance.
Blatt hopes to create a model of all these mechanisms, incorporating their GABA findings, and to make predictions about what goes wrong in particular areas of the brain in autism, based on altered connectivity and neurochemistry. “It’s a real challenge for us,” he says, “but we are making much progress.”
Building a model, he admits, is a long way from medical intervention, but it’s a helpful first step. “By having an understanding of when these changes occur and what receptors might aid in therapeutic intervention,” he says, “we could target those specific transmitter types rather than giving medication that is simply controlling behavior.”
In other words, “instead of, ‘Johnny is agitated, he’s aggressive, so let me give him some-thing to quiet down,’ you could potentially provide pharmacotherapeutic intervention to actually target the problem,” Blatt says. “Clinically that’s important.”
Because the brain is known to have great plasticity, researchers are hopeful. The brain’s adaptability explains why the earlier the diagnosis of autism, the greater potential there is for help, says Blatt.
Tager-Flusberg agrees. “The interventions for very young children are enormously effective in reducing symptom severity,” she says. “In our longitudinal study we see children making huge gains, especially in language, which is so central — gains we wouldn’t have seen earlier.”
Wiseman also concurs, based on her daughter’s experience and that of others she’s seen. “The earlier you intervene the better the outcome is. But recovery is a tricky word. I never use the word cure; at this point, there is no cure,” she says. Still, there is hope that autistic children can adapt and lead better lives than they otherwise would. “I like to say that a child can lose his or her diagnosis,” Wiseman says.
