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December 20, 2010

MRI and Autism
By Carolyn Gutierrez
For The Record
Vol. 22 No. 23 P. 24

The neuroscience community hopes to tap into the power of this noninvasive tool to get an earlier and more clear read on the brain disorder.

MRI is increasingly being used by neuroradiology researchers to assess brain disorders such as autism. Its noninvasive quality, coupled with its versatility, makes MRI an appealing alternative to other powerful imaging technologies. In a recent study completed at the University of Utah, researchers examining brain connectivity in autism patients concluded that MRI may be a viable diagnostic tool for children with autism.

How MRI Works
According to Michael F. Huerta, PhD, associate director of the National Institute of Mental Health (NIMH) and director of the National Database for Autism Research, MRI has revolutionized biomedical research. Its noninvasiveness is a key benefit. “For PET [positron emission tomography] scanning, you have to inject radioactive isotopes—that’s invasive. Even CT scans—since x-rays give you the information—are invasive,” he says. “Having one every couple of years for a particular problem is not such a big deal, but when running studies on people—especially if you want to look at the developing brain of an individual—you don’t want to do that over time with x-rays.”

MRI is a complex and nuanced imaging tool that allows researchers to examine the brain in a variety of ways. Using the measurement of voxels (three-dimensional pixels), MRI looks at brain anatomy based on the location and density of hydrogen atoms, essentially mapping out water in the brain. Various tissues in the brain, such as white matter (which contains myelinated nerve fibers) and gray matter (the cerebral cortex), contain different amounts and densities of protons. MRI can chart the protons in these cerebral tissues, generating an intricate and extensive visualization of the brain.

Long fiber bundles that connect one part of the brain to another carry axons that relay information. MRI technology can visualize the fiber bundles by examining the water moving in and around these fiber bundles. Since water diffusion is being examined, this type of imaging is known as diffusion MRI.

Researchers also use MRI to analyze changes in blood flow and blood volume in the brain. The blood’s magnetic state changes when a patient performs a task and oxygen that is carried on blood cells is released into brain tissues. “That difference in magnetic state of the blood can be detected with MRI,” Huerta explains. “It turns out that when different parts of the brain are activated, you can actually see changes in this blood oxygenation level. By looking at how the blood oxygenation level changes across the entire brain while a person is doing a particular task gives you an idea of what parts of the brain are active during that task.” This capability has allowed scientists to study the brain’s functional organization.

In what is known as functional MRI (fMRI), researchers examine blood oxygenation levels while patients are in a resting state. “If you start looking at different parts of the brain with the fMRI, you’ll see that a particular part of the blood oxygenation level goes up and then down and then up and then down—a kind of oscillation,” says Huerta. “If you pick a point in the brain and look at the oscillation there and then you say, ‘OK, now I want to see all of the other voxels in this MRI where the oscillation of the blood oxygenation is exactly the same,’ when you look at those voxels across the brain, it turns out that they are the same voxels that one would think are connected together. This is based on studies from monkeys, primarily. And so this resting state is thought to give an indication of which parts of the brain are linked either directly or indirectly. By combining all of these different approaches, we can get a good sense of how the brain is connected and how these connections support particular functions.”

Interhemispheric Connectivity Study
Using resting state fMRI, lead investigator Jeffrey S. Anderson, MD, PhD, an assistant professor and director of functional neuroimaging in the neuroradiology department at the University of Utah School of Medicine, and his colleagues observed a distinct lack of brain connectivity in the left and right hemispheres of the 53 autistic patients enrolled in their study.

“Before we performed the study, there was already evidence that autism may be a connectivity disorder,” Anderson says. “In autistic individuals there were several examples of specific locations in the brain that were less strongly connected than in normally developing individuals. We tried an approach that could measure not just a few connections but many thousand connections by taking advantage of the symmetry of the brain.

“The brain is organized into left and right halves that are mirror images, and the left and right hemispheres are pretty strongly connected, so we measured the connection strength at each point in the brain with the other hemisphere,” Anderson continues. “This allowed us to get a ‘whole brain’ picture of connection strength in autism. Not only did we find that connection strength was decreased in autism but that it was decreased most in areas that were involved in functions known to be abnormal in autism.”

The study, which was limited because it examined only high-functioning adolescents and young men in the autism group, looked at the brain’s “hot spots” that control functions such as motor skills, attention, facial recognition, and social functioning. Compared with the control group of 39 typically developing men in the same age range, the autism group clearly showed deficits in interhemispheric connectivity, as clear disruptions were seen in the corpus callosum (which connects one hemisphere of the cortex to the other).

“Autism is a very mysterious disorder,” notes Huerta. “It is extremely heterogeneous. There are some people with autism who are essentially not verbal. There are other people on what is called the autism spectrum that have certain deficits that put them on the spectrum but are highly verbal, clearly engaged with intellectual things. And there’s a host of other symptoms that vary in their severity and distribution across the syndrome. The other mysterious part about autism is that it appears that over the last several decades, the prevalence of this disorder is genuinely increasing. This is a complicated, very puzzling disorder, and it’s one that people are increasingly looking at with neuroimaging approaches.”

Many researchers suggest autism is a disorder of brain connectivity across long distances—from one part of the brain to the other—and that fiber bundles in the brain are actually disrupted. Other scientists maintain that molecular evidence suggests the lack of connectivity occurs at a synapse level. In this case, proteins forming the connections between neurons at the cellular level, which are involved in the synapse and the communication across the synapse, are disrupted. It may be that autism has both features: disruption both locally (at the cellular level) and at a long-distance, fiber-bundle level. Increased MRI use by neuroradiologists may someday aid physicians in earlier diagnosis of all these variables.

MRI as Future Diagnostic Tool
“There are many people working right now on an MRI test for autism, and we will have one before too long,” Anderson says. “Most theories of autism, including our work, are tested in autistic adults that can be easily scanned. Once we have worked out what is abnormal in autism, then we need to adapt the techniques to use in children. Because the connection strength of the brain changes dramatically in childhood, many results will need to be repeated in young children, where diagnosis is more useful. After age 3 or 4, diagnosis can be made based on behavior. An MRI test would be most useful before age 3, but that will take additional work.”

Because of its noninvasiveness, MRI lends itself to the pediatric population. Regardless of the types of tests or sequences that are performed, research indicates that for most individuals, there are no known risks of the MRI scan itself. Still, according to Huerta, “MRI is not being used as a diagnostic tool. Right now it’s just a research tool.”

But the neuroscience community sees promise in MRI’s future as a diagnostic indicator. “We hope that MRI will become useful in early childhood when diagnosis is made, hopefully before the age of 3,” says Anderson. “We’re not there yet. But there are other ways that MRI may be helpful in older children or adults as well. MRI may help to subtype different forms of autism. It may also help to identify specific genes that may be responsible for different types of autism. Maybe most important of all, we have reproducible, hard findings now that can be used to trace back one step at a time until we understand exactly what causes the disease in the brain. We know from experience that understanding the mechanism is crucial to identifying treatments.”

One practical issue preventing MRI’s use as a diagnostic tool is cost. Unlike a simple blood test or strep culture, MRI scans generally cost more than $1,000. “The machines are very expensive but are slowly becoming cheaper,” Anderson says. “MRI scans that help diagnose a condition, establish prognosis, or are useful for medical management are usually covered by insurance. We hope that MRI scans for autism and other psychiatric conditions will one day be routine and take some of the guesswork out of diagnosis and treatment, ultimately saving money from failed treatments or the inability to use treatments when they are most effective—the earlier, the better for a child with autism.”

In the meantime, state-of-the-art imaging technologies continue to be utilized in the research laboratory, providing invaluable data for further investigation into the brain.

Human Connectome Project
So large that it will require its own supercomputer to process it, the Human Connectome Project (HCP), consisting of 33 researchers at nine institutions, plans to map out the human brain’s entire circuitry using the best of the latest brain-scanning technologies over a period of five years.

Huerta says, “We are using all of these modalities as well as some electrophysiological modalities such as magnetoencephalography and electroencephalography and combining all of these modalities in the same individual subjects. The same person is going to have the structural magnetic resonance so we can see the white and gray matter; they’re going to have their fiber bundles shown. They’re going to do a functional task so we can see during a particular task which parts of the brain are activated. And we’re going to do a resting state functional MRI to see how all of this information relates to what looks like a functional network. And by putting all of this stuff together, I think we’re going to have a pretty good idea about how that person’s brain is connected. We’re going to do this for 1,200 healthy adults. This is going to be great because it will give us a sense of biological variation. Across these 1,200 different people, we’re going to look at how their brains are connected, and it might turn out that we have the same exact pattern in every person—unlikely—or it might be that there are 1,200 different patterns of connectivity. That’s also unlikely. We’re probably going to see some major trends in connectivity.”

HCP subjects will undergo a battery of behavioral measures to examine attributes such as motor function, vision acuteness, and social cognition. In addition, genotype information will be taken. Bringing all this information together will enable scientists to not only see brain connectivity variants across this group of subjects, but it may also provide hints as to whether a particular pattern of brain connections relates to an enhancement or a deficit in a particular kind of behavior or if it possibly relates to a particular genetic pattern.

“These are all data that right now do not exist anywhere in the world in any comprehensive or systematic way,” says Huerta. “Up until now, until we had this noninvasive way to look at connectivity, we literally didn’t have any modern data on human brain connections. Most of what we know about how the human brain is connected is based on studies that were done on monkeys because until these technologies had been developed with magnetic resonance, they’d all been invasive ways of looking at connections so we couldn’t do it on humans.”

Thanks to endeavors such as HCP, the neuroscience community will have connectivity analysis tools that will navigate them even closer to understanding and treating autism and other enigmatic brain disorders.

— Carolyn Gutierrez is a freelance writer based in New York City.