Brain scans of close relatives of children with autism reveal clear abnormalities that parallel those seen in autism.

The brain scans reveal clear signs: abnormalities that parallel those seen in autism. But these are not scans of the children who have the disorder; rather, they belong to close relatives of those children. The studies, which two teams of researchers reported at the conference, are part of a surge of research that has advanced our understanding of the underlying neurobiology of autism and helped separate inherited traits from the array of behaviors that are lumped together as “autism spectrum disorder.” Autism affects as many as 24,000 infants born in the United States each year, and some experts believe the incidence is increasing (see “An Epidemic of Autism?”). Children with the disorder may have a range of deficits in communication and language and in social interactions, some of which are not obvious in infancy. Repetitive or restrictive movements are also common. The causes of autism are not known, but genetic influences factor heavily, so finding the genes involved is critical. “Autism is the most genetic of the neuropsychiatric syndromes,” said Daniel Geschwind, an autism expert at the University of California, Los Angeles, who led a discussion high-lighting the new findings. Identical twins of affected children are 10 times more likely to develop autism than fraternal twins, he said, and 90 percent of children born to a parent with autism will develop the condition themselves. A gene search is in full swing, but the task is daunting. Autism is not a categorical disease, Geschwind said, but rather a spectrum of behavioral traits that manifest along a continuum of severity in different people. At one end of the continuum are children who are severely developmentally disabled, while at the other are children who maintain a high level of functioning. It is likely that each aspect of the syndrome has a unique genetic mark, which could involve very subtle variations or replications in bits of DNA that are difficult to detect in genetic studies. In addition, several genes likely interact with one another and with unknown environmental factors to produce variable symptoms in different subsets of affected children. To overcome these challenges, scientists have had to get creative. One strategy is to compare children with autism and their unaffected family members to identify any areas of over-lap in neurobiology or behavior. Researchers can then use this data to determine which brain areas to focus on and which troubling traits are inherited—critical steps in narrowing down the search for genes. Avoiding the Eyes Brendon Nacewicz, a neuroscience graduate student at the University of Wisconsin-Madison, and Kim Dalton, an assistant scientist in the brain imaging center there, used this strategy to examine whether siblings of children with autism showed any signs of “gaze avoidance,” the tendency to avoid eye contact that is a cardinal feature of autism and often one of the earliest indications that an infant may be autistic. Abnormal eye contact and underresponsiveness to facial cues are thought to be central causes of the social impairments typical in autism. Using new technology that tracks where a person is looking when presented with pictures on a screen, Nacewicz tracked gaze patterns in nine boys with autism and their unaffected brothers, along with nine normal, unrelated boys as a control group. Somewhat surprisingly, the unaffected siblings showed the same level of gaze avoidance faces as the children with autism did, even if the faces were familiar friends or family members. “The siblings’ results looked just like the autism group,” Nacewicz said. The researchers then compared magnetic resonance scans of the affected and unaffected siblings, focusing on the amygdala, a part of the brain associated with eye-tracking and recognition of facial expressions. The amygdala was smaller in both groups. “Even though the siblings lacked most signs of autism, we saw exactly the same decreases in amygdala volume in the autistic and nonautistic siblings,” Nacewicz said. The results suggest that multiple brain systems are involved in face processing and that the unaffected siblings’ brains may have developed other ways to compensate for the amygdala’s shortcomings, he said. This finding points to the possibility of using behavioral therapies to stimulate the kinds of compensatory mechanisms that unaffected siblings have naturally developed. To help further define the role of the amygdala, Nacewicz and his colleagues used functional magnetic resonance imaging to examine patterns of brain activity into and out of the amygdala when children with autism view pictures of faces showing various emotions. They concluded that the amygdala is improperly connected in autism, with too few connections to the pre-frontal cortex and other higher brain areas, and too many connections to more primitive brain structures involved in emotional processing, including the hippocampus. The degree of abnormality in these connections correlated with behavioral measures of emotional face processing, suggesting that disruption in these pathways may directly contribute to social impairments in autism, the researchers said. Parents’ Brains Examined To better understand patterns of heritability, Eric Peterson, a psychiatrist at the University of Colorado, has used magnetic resonance scanning to look for brain abnormalities in parents of children with autism. His research team performed brain scans on 36 parents and compared them to 36 adults who have no family members with autism, zeroing in on any differences in the volume of gray and white matter (measures of neuron bodies and neuron fiber tracts, respectively) across the whole brain and in specific regions of interest. Overall, the researchers found consistent, complex patterns of brain differences in the parents of children with autism vs. the control adults. In particular, the parents had abnormalities in brain regions associated with social cognitive processes, a finding that Peterson said is consistent with published reports about children with autism. But the researchers also saw some unexpected abnormalities, with some brain areas smaller and others larger than normal. For example, they found more gray matter in the deep fissures at the front of the brain, the pre- and post-central gyri. These folds represent the motor and somatosensory areas of the cortex, which help plan, execute and inhibit movements and are involved in understanding complex facial structures. In contrast, the researchers found that white matter tracts, the bundles of nerve fibers that transmit nerve signals, were significantly smaller in a part of the cerebellum linked to face processing. White matter volume was also decreased in the frontal cortex, an executive-control area that plays a central role in the ability to understand other people’s mental states and act accordingly. The study is only the second to investigate brain abnormalities in parents of children with autism, so the novel results need to be replicated. Still, these discoveries shed light on the types of brain changes that are inherit-ed and point to possible risk factors that should be considered in selecting participants for genetic studies. The next step, Peterson said, is to identify in the parents any subtle behavioral traits that might fit into the autism syndrome, even if they do not meet the diagnostic bar, and determine if there are correlations between these behaviors and the brain changes. As these studies demonstrate, autism researchers are employing brain imaging in novel ways, especially as the search for genes heats up. As scientists gain new understandings about autism, their work also is helping pinpoint the brain regions and pathways involved in complex social interactions, an area of broad interest to neuroscience. The prospect of finding genes that may be involved in social cognition is particularly noteworthy because this high-level executive brain function has been difficult to unravel. “By understanding autism, we’re going to understand a lot more about the brain,” Geschwind said.

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