Mysteries of the Mind: Researchers work to unravel causes of autism

The second of four parts: Scientists hope new initiatives will lead to treatments and prevention



"It's so remarkable that for a brain disease like this we still have no medical treatments."

-- Thomas Insel

"I always feel apologetic we haven't done more faster. Sometimes parents will come to us wanting to try a desperate treatment -- and we don't have the evidence to even say don't waste your money on that."

-- David Amaral

The two men are talking about autism. And they are hardly fringe critics of the scientific establishment.

Thomas Insel is director of the National Institute of Mental Health and head of the federal Interagency Autism Coordinating Committee. David Amaral is a leading autism researcher at the MIND Institute at the University of California, Davis.

They are quick to point to the enormous strides autism research has made over the past 20 years, but they also are honest in describing what a long way we are from understanding its basic mechanisms or how to treat it or prevent it.


Mysteries of the Mind


Scientists have identified hundreds of genes that seem to be abnormal in people with autism. They have done imaging studies that show some of the ways that autistic people's brains function differently. And they have developed early behavioral therapies that seem to help many children move closer to normal social and intellectual functioning.

Unlike physical ailments such as heart disease, though, there is not a consensus explanation for what causes autism or clearly defined ways to fix it. And despite all the genetic anomalies that have been identified, researchers don't know exactly which brain pathways they disrupt.

While some scientists think that environmental contaminants or infections may play a role in the disorder, there is no agreement yet on what they might be or how they affect the development of the fetus.

On top of all that, it may turn out that autism is a condition where several highways lead to the same city; in other words, there may be myriad causes for the communication difficulties, social withdrawal and repetitive behaviors that mark the disorder.

Scientists "want to be able to sample the population fully and give an account of the underlying mechanisms that apply as generally as possible," said Marlene Behrmann, a brain imaging and autism expert at Carnegie Mellon University, "but it's really hard to do that, because it's possible that there are many different autisms."

Despite all those challenges, there are many exciting initiatives under way in autism research. Here are just a few.

Heavy brains

One of the challenges that autism researchers face is not having enough real brains to examine after death, both because autistic people make up a small percentage of the population and because it is difficult to persuade people to donate their brains for autopsy.

That is one reason why Eric Courchesne and Karen Pierce, a husband-wife team who co-direct the autism center at the University of California, San Diego, made a big impact in 2011 when their group autopsied the brains of six autistic children who had died of other causes and compared them with the brains of seven non-autistic children.

They found that the autistic brains were significantly heavier and had nearly 70 percent more neurons in their frontal cortex -- the brain's thinking area -- than those without the disorder.

The result seemed counterintuitive. Why would someone with a brain abnormality actually have more neurons than other people?

In an interview earlier this year, the two researchers said that the extra neurons in the autism brains were underdeveloped, and the findings could fit with a concept emerging in several labs -- that autistic brains have weaker long-distance connections from one part of the brain to another, but have too many noisy short-distance connections within various brain regions.

Such skills as socially appropriate behavior and good communication seem to depend on the coordination of several brain modules at once, and the poorer connections among those areas in autistic people's brains could help explain why they struggle with those skills. On the other hand, the intense interest in narrow topics that many people with autism have, as well as their repetitive behaviors like rocking or hand flapping, might be linked to the abnormally numerous connections within localized brain areas.

Eric Courchesne said the extra neurons his team found might be the result of a malfunction in brain growth in the womb.

In the first six months of development, he said, a fetal brain region called the outer subventricular zone generates billions of brain cells -- almost twice as many as the child eventually will need.

Normally, those extra cells disappear in the final three months in the womb and in the first six to nine months after birth. But in children with autism, it's possible that process may have been interrupted, he said. One piece of evidence? The extra neurons usually disappear from the back of the brain to the front, and in autistic brains, the rear portions of the brain have a typical number of neurons, while the extra ones are in the front, suggesting this normal pruning process has been interrupted.

As time goes on, autistic children's brains do lose their extra neurons, he said, and by their teenage years, many of them appear to have a normal number.

But the problems caused by the early surplus of immature neurons may already have set the stage for the hallmark deficits of autism.

Hypersensitive responses

Because behaviors like social interaction and communication are so complex, Marlene Behrmann has gone back to basics, studying the way that autistic people's brains respond to sights, sounds and touch.

In comparing high-functioning autistic people to non-autistic people, the Carnegie Mellon University psychologist and her colleagues have found that autistic individuals' brains react unpredictably to visual, auditory and tactile tests while they lie inside a functional magnetic resonance imaging machine.

In the tests, people with autism would sometimes have an intense response to a tone or a puff of air on the hand, and at other times show a muted reaction. This might help explain the experience some autistic people report of being hypersensitive to noise or light or the texture of clothing, she said. In a new study that hasn't been published yet, she is testing them with a sandpaper-like substance and finds they register the same erratic sensations.

Her group also found that the more variable an autistic person's response pattern was, the more severe the person's autistic symptoms were overall.

While the tests may seem simplistic, the unreliable brain responses might shape many of the problems autistic people experience and could be the result of differences in the way autistic people's brains are wired, she said.

It also might explain why people with autism withdraw from social contact or practice repetitive behaviors, she said. "The idea is that because sensory information is so overwhelming, these kids tend to withdraw and it's a way to block out this confusing flurry of input. But we need more than a just-so story and this is where the next scientific step for me will be."

Making neurons in the lab

The research at Carnegie Mellon has detected abnormalities in autistic people's brains by getting images of the blood flow to different parts of the brain.

But Ricardo Dolmetsch, the global head of neuroscience at Novartis Institutes for Biomedical Research, is finding the same kind of evidence in individual neurons that he is growing in the laboratory.

Using techniques developed just in the past few years, he is taking skin cells from people with rare autistic syndromes and converting them into stem cells that he can then coax to become living neurons in the laboratory.

One of the disorders he is focusing on is Timothy syndrome, which causes autism in most of the children who have it. In the lab, Timothy syndrome neurons show a malfunction in how much calcium they let in when they are active, and as a result, the dendrites that grow from the neurons -- tiny tree-like arbors that connect one neuron to several others -- are narrower and more dense than normal dendrites.

He also has found that the mixture of neurons in Timothy syndrome is abnormal, and contains a much lower proportion of neurons that extend to distant regions in the brain.

So, this time at a microscopic level, there is evidence that the neurons from one autism syndrome show overconnections locally, and underconnections over longer distances.

The researcher, who previously was based at Stanford University, doesn't want to stop at simply defining the problem, though. Working with Novartis, the second largest pharmaceutical company in the world, he hopes to find drugs and other treatments to counteract the abnormal growth patterns in neurons.

His lab already has identified one compound that seems to restore normal dendrite growth in the Timothy syndrome neurons. "It's not like we've identified a beautiful complete pathway to restore normal functioning, but it's a hopeful advance," he said.

The Colombia native has a personal motivation for his work. His son was diagnosed with autism at age 4, and from that point on, he switched the focus of his lab toward trying to understand the disorder.

Today his son, now 11, is doing pretty well in a mainstream school. "He has language and he knows a lot about certain things, but if you were to meet him, you would know something is off. For a little while it seemed pretty desperate, but within the spectrum, we're pretty lucky."

He is hopeful about future autism research. "When I started, we had no genetics, we had no targets. And over the last eight years, things have progressed dramatically and we now have drug development programs."

Animal studies

While scientists do not yet have a laboratory animal that perfectly mimics human autism, they do have some animal models that are showing promising results.

At the University of California, Davis, Jacqueline Crawley is working with "knockout" mice -- species in which certain genes have been deleted -- to develop possible treatments for the symptoms of autism.

Her team has one breed of mice that groom themselves repeatedly and show aversion to social contact. Another breed will jump in the air over and over again.

The Crawley lab found last year that a substance that blocks a certain brain receptor called MGluR5 sharply reduced the repetitive grooming of the one breed and the spontaneous jumping of the other. The treatment also improved social behavior in those mice, so that they spent more time in a chamber with other mice, sniffing them and approaching them from the front.

In some conditions linked to autism in humans, there are too many MGluR5 receptors, so the mouse experiments hold out hope that blocking those receptors might lessen autism symptoms. In fact, one of these blocking compounds is being tested now in patients with Fragile X syndrome, up to 30 percent of whom have an autism diagnosis.

The MGluR5 receptor is involved in the transmission of signals at the synapses of neurons -- the gaps that connect one neuron to another -- and that actually could be a hopeful sign, Jacqueline Crawley said.

"When I first entered the autism research field, it seemed very unlikely that a drug treatment would be useful for a neurodevelopmental disorder" because of the assumption that all the problems were hard-wired from birth. "But now that we know a lot of the problems may be coming from incorrect or incomplete or unusual synapse formation, we recognize you can treat synapse problems with drug treatments."

Another lab at UC Davis is using a different animal model to explore an intriguing and somewhat controversial idea -- the possibility that some autism cases are caused by pregnant mothers forming antibodies against their fetuses' brains.

Researcher Judy Van de Water has discovered that more than 20 percent of mothers with autistic children make one or more of these antibodies.

To test that theory, UC Davis neuroscientist Melissa Bauman took antibodies made by the mothers of autistic children and infused them into pregnant rhesus monkeys. Her group also took antibodies from mothers whose children didn't have autism and gave those to another set of pregnant monkeys.

They then noticed unusual behaviors in the autism-antibody monkeys. After the baby monkeys were born, the neuroscientist said, "the first thing we noticed was an unusual maternal style" in which the mothers approached their infants much more often than normal. "The monkey mothers were picking up on something" atypical, she said.

After about six months, she said, lab workers noticed the young monkeys in the autism-antibody group were approaching typical monkeys more often than normal, but the other monkeys didn't respond by grooming or playing with the autism-group monkeys.

She knows the lab's finding that some mothers' immune systems may be causing autism in their children can be controversial, but "we tell moms that production of antibodies is not under a woman's control or a matter of what diet she has."

"I've met these moms and like any parent who has a child with autism, they want to know what caused it, and I think as scientists we need to emphasize these are biological risk factors and it's nothing they can control."

What does the future hold?

Nancy Minshew, director of the Center for Excellence in Autism Research at the University of Pittsburgh, knows it can be frustrating for families with autistic children to wait for the results of research and controlled trials of experimental drugs, all of which can take years.

But doing careful experiments in animals or humans and comparing them with control groups is vital for making sure the outcomes are accurate, she said.

Without that approach, it just becomes a battleground of opinions, she said.

"I get two to five books a month saying here's a treatment for autism spectrum disorder and here's what you do. But how do they know it works? It's not to say the people who wrote them aren't well-intentioned or don't have experience. But how do we know this will work for your child?"

In the future, she believes autistic people with milder forms of the disorder will get significant help from behavioral therapies like those being developed now at Pitt.

For those with severe autism, "there is no cognitive or any other program we have that's going to address that, and that's why my hope for that group is identifying signaling pathways and drugs that will change the brain toward normal," she said.

David Amaral at UC Davis said he hopes that one day, scientists will be able to pinpoint the exact network of locations in the brain that have gone awry in autism.

"I often say you can have a problem with making long-term memories and that can be caused by a lesion or by post-traumatic stress or by Alzheimer's, but they all converge on the hippocampus," a brain structure that researchers know is critical for making and retrieving memories.

"And so what I would hope is that ultimately we'll find the same places in the brain's social network that are affected by autism."

Dr. Minshew said she is personally optimistic.

"I think that parents of autistic children can have confidence that in the next 20 years or less, they'll see a great number of these treatments come forward and be successful."

nation - health

Mark Roth: mroth@post-gazette.com, 412-263-1130 and on Twitter: @markomar. First Published October 7, 2013 4:00 AM


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