Surprising Insights Open the Door for New Autism Treatments
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NR-11-05 (11/13/05). For more information, please contact Sara Harris at (202) 462-6688 or sharris@sfn.org.
SURPRISING INSIGHTS OPEN THE DOOR FOR NEW AUTISM TREATMENTS
WASHINGTON, DC, November 13, 2005 — New research has found that some of the brain abnormalities and behaviors associated with autism also are present in the parents and siblings of individuals with the disorder. Scientists also have confirmed rare mutations on a specific gene that appear to be risk factors for autism. And they’ve discovered that facial avoidance is not, as previously believed, a central cause of the social impairments observed in autism.
All these studies promise to open the door to more effective methods of diagnosing and treating autism, a disorder that affects as many as 24,000 babies born in the United States each year. Autism is a brain disorder that impairs a person’s ability to think, feel, communicate, and relate appropriately to the outside world. These behaviors can range from mild to severely disabling, but their impact on the lives of individuals with the disorder and on their families is almost always devastating. People with autism often have other debilitating brain disorders, including attention deficit hyperactivity disorder, obsessive-compulsive disorder, epilepsy, and depression.
“These findings reflect the increasing involvement of neurobiologists from many domains in autism research, including neuroimaging, genetics, and mouse models,” says Daniel Geschwind, MD, PhD, Professor of Neurology, Psychiatry, and Genetics at UCLA School of Medicine. “This has led to the emergence of a critical mass of researchers in the field, which is likely to bring a continued high rate of progress in understanding autism’s causes.”
Although the exact cause of autism is unknown, experts in the field now widely accept that the disorder is associated with abnormal brain developments that emerge in part as a result of genetic factors. A better understanding of what exactly goes “wrong” in the development of the brains of autistic children could help scientists identify the genes involved with autism—and thus to develop better methods of diagnosing and treating the disorder.
Many areas of the brain have been implicated in autism, but pinpointing specific brain structures has proven difficult, in part because issues of brain development and cognitive maturation are difficult to control in clinical studies involving autistic children. For this reason, researchers at the University of Colorado, Colorado State University, and the University of Denver decided to study the brains of parents of autistic children to see if they, too, have abnormalities associated with the disorder. If they did, then those abnormalities might be the heritable ones involved in the emergence of autism.
For the study, 40 parents of autistic children and 40 age- and gender-matched controls received magnetic resonance imaging (MRI) brain scans. “We identified many brain regions in which the autism parent group was either smaller or larger than in the brains of the adults with a negative family history,” reports Eric Peterson, PhD, of the University of Colorado. These areas include the cerebellum, which plays a role in cognitive thinking (speech, learning, emotions, and attention) as well as in motor function, and the basal ganglia, a brain region associated with compulsive and ritualistic behavior. People with autism often have difficulty with change and can develop patterns of repetitive behaviors.
These findings offer hints at which brain abnormalities might be heritable with autism. One of the next steps, says Peterson, is to confirm the findings in studies on pairs of twins where only one has autism and to use functional brain imaging on family members to see if the malfunctioning of those same brain regions is also heritable.
At the University of Wisconsin-Madison, researchers have found that the non-autistic brothers of people with autism show the same avoidance of eye contract when viewing images of strangers and family as their autistic siblings. Abnormal eye contact is common in people with autism, and is often one of the behaviors first noticed in children with the disorder. The study also revealed that non-autistic brothers, like their autistic siblings, have a smaller-than-normal amygdala, an area of the brain that plays an important role in understanding emotional facial expressions and in feeling fear in social situations.
Using new computerized technology, the UW researchers tracked and measured the amount of time three groups of participants, aged 6 to 18 years, spent looking at the eyes of people in pictures. The groups included 9 boys with autism, 9 non-autistic brothers of individuals with autism, and 9 typically developing boys. IQs were similar for the non-autistic brothers (average 120) and the control group (average 119), but were lower (95) for the autism group. Nevertheless, the autism group and the non-autistic brothers were most similar when it came to eye contact: both groups showed decreased eye contact relative to the control group. The low eye contact occurred even when the boys were shown pictures of family and friends. Thus, the behavior did not reflect inherited shyness.
The researchers also looked at the brain structure of all three groups. They found that the brothers of individuals with autism had a smaller amygdala compared to the control group. In fact, their amygdala volumes were similar to those of their autistic siblings. “This suggests that other brain systems must be able to compensate for this abnormality in the non-autistic brothers,” says Brendon Nacewicz, one of the authors of the study. “Multiple brain systems must therefore be affected to develop the full syndrome of autism.”
At the University of North Carolina-Chapel Hill, researchers have made the striking discovery that although people with autism tend to avoid looking directly at faces, when they do focus on faces, their brains respond in ways similar to those of people who do not have autism. This finding suggests that specific behavioral interventions may help people with autism improve their ability to socially interact.
Using functional magnetic resonance imaging (fMRI), a technique that permits non-invasive imaging of brain functions, Gabriel Dichter, PhD, and Aysenil Belger, PhD, compared individuals with and without autism as they performed a task that required them to attend to certain items in the environment while disregarding other items. Specifically, participants were shown pictures of arrows (non-social items) and faces (social items), and asked to report the direction (left or right) in which they pointed.
With both social and non-social items, the autistic group showed markedly less activity than the control group in the “executive” regions of the brain (including portions of the frontal lobes) where executive tasks, such as sifting through complex information, selecting task-appropriate responses or inhibiting task-inappropriate ones, take place.
With the social items, however, another feature of the results was highly surprisingly. Although responses in the brain’s executive areas were different in the two groups, responses in the areas of the brain that process faces—including the fusiform gyrus—were remarkably similar.
“Furthermore, the results also indicated that when the direction decision was more difficult and required higher levels of attention and executive control, subjects with autism failed to show evidence of increased brain activity associated with more complex decision making,” Belger indicates. “The mechanisms for the influence of disordered regulation of early sensory processing on higher levels of decision making is not clear, but may involve the engagement of emotional centers of the brain, which in turn may disrupt the top-down modulatory effects of executive regions on sensory processing areas, such as the ‘face’ area .”
This finding breaks new ground as it counters previous reports that the “face area” of the brain is under-responsive in people with autism. Under-responsiveness to faces has been considered a central cause of the social impairments observed in autism.
“Such studies did not account for where participants fixed their gaze during brain scanning,” says Dichter. “Because individuals with autism typically chose to look away from faces, the previous studies could not disentangle the effects of a preference to look away from faces from actual brain deficits in the ability to process faces. We required participants to indicate whether faces were looking to the left or to the right, thereby requiring participants to look at the picture of the face.”
“Our findings also suggest that the primary source of information-processing deficit in autism may lie in anomalous connections between higher-order control regions of the brain and sensory processing areas,” adds Belger, “such that attentional control mechanisms fail to engage enhanced participation from other cortical regions important for the decision making.”
This new research, conducted with support from the NIMH Studies to Advance Autism Research and Treatment (STAART) Network and the UNC Neurodevelopmental Disorders Research Center, has exciting implications for intervention in individuals with autism. “Since the brain seems capable of responding to faces when attention is directed toward faces, purely behavioral interventions that instruct individuals with autism to look at faces may help both to increase the brain’s responsiveness to social cues and to improve the quality of social interactions,” Dichter says.
Genetic studies involving families of individuals with autism has led researchers at Vanderbilt University to report that several rare mutations within a specific gene known as the serotonin transporter (SERT) gene are risk factors for autism. These findings may make it possible one day to test autistic children for these gene variants, as children can now be tested for cystic fibrosis, a disease linked to a single gene but triggered by many different mutations. Evidence suggests that early diagnosis and intervention (before age 3) results in better outcomes for children with autism.
The SERT gene regulates serotonin levels in the brain. Serotonin is a neurotransmitter involved in many biological processes, from sleep and digestion to mood and impulsive behavior. About 25 percent of people with autism have elevated levels of serotonin in their blood, and selective serotonin reuptake inhibitors (SSRIs), drugs used to treat depression, anxiety, and obsessive-compulsive disorders, have been shown to be effective in easing symptoms of autism in some patients.
Previous research attempting to link the SERT gene to autism had been highly promising but inconclusive. “Either this was not the gene, or there had to be different genetic variants that were acting differently in different people,” says James Sutcliffe, PhD, one of the authors of the new study.
Sutcliffe and his colleagues decided to delve deeper into the DNA sequence in hopes of finding rare mutations involved in autism risk. They took DNA samples from 120 families likely to possess a genetic risk factor on chromosome 17 (where the SERT gene resides). They found 19 different SERT mutations (or variants) in families with more than one male with autism. (The finding that families with multiple males with autism had these variants is consistent with the higher prevalence of autism among males. Four times as many males as females are affected by the disorder.)
Four of the 19 SERT mutations were in “coding” regions, or areas of the gene that get translated into protein. “These variants were significantly associated with increased rigid-compulsive behaviors,” notes Sutcliffe. Such behaviors are a common characteristic of autism and of related disorders, such as obsessive-compulsive disorder.
Sutcliffe and his colleagues also have discovered that two intracellular signaling pathways in the brain—p38MAPK and PKG—go haywire in the presence of mutated SERT genes—an explanation, perhaps, of how SERT mutations disrupt serotonin signaling in autism. Interestingly, drugs that target these pathways are being investigated for the treatment of inflammation, cancer, and other disorders unrelated to autism.
However, which particular aspects of the autism syndrome or phenotype are related to a particular genetic risk factor, and whether these risk factors are specific for autism, or cause more general brain dysfunction, remain to be determined.
