Autistic Brains Create More Information at Rest

New research from Case Western Reserve University and University of Toronto neuroscientists finds that the brains of autistic children generate more information at rest – a 42% increase on average. The study offers a scientific explanation for the most typical characteristic of autism – withdrawal into one’s own inner world. The excess production of information may explain a child’s detachment from their environment.

Published at the end of December in Frontiers in Neuroinformatics, this study is a follow-up to the authors’ prior finding that brain connections are different in autistic children. This paper determined that the differences account for the increased complexity within their brains.

“Our results suggest that autistic children are not interested in social interactions because their brains generate more information at rest, which we interpret as more introspection in line with early descriptions of the disorder,” said Roberto Fernández Galán, PhD, senior author and associate professor of neurosciences at Case Western Reserve School of Medicine.

The authors quantified information as engineers normally do but instead of applying it to signals in electronic devices, they applied it to brain activity recorded with magnetoencephalography (MEG). They showed that autistic children’s brains at rest generate more information than non-autistic children. This may explain their lack of interest in external stimuli, including interactions with other people.

The researchers also quantified interactions between brain regions, i.e., the brain’s functional connectivity, and determined the inputs to the brain in the resting state allowing them to interpret the children’s introspection level.

“This is a novel interpretation because it is a different attempt to understand the children’s cognition by analyzing their brain activity,” said José L. Pérez Velázquez, PhD, first author and professor of neuroscience at University of Toronto Institute of Medical Science and Department of Pediatrics, Brain and Behavior Center.

“Measuring cognitive processes is not trivial; yet, our findings indicate that this can be done to some extent with well-established mathematical tools from physics and engineering.”

This study provides quantitative support for the relatively new “Intense World Theory” of autism proposed by neuroscientists Henry and Kamila Markram of the Brain Mind Institute in Switzerland, which describes the disorder as the result of hyper-functioning neural circuitry, leading to a state of over-arousal. More generally, the work of Galán and Pérez Velázquez is an initial step in the investigation of how information generation in the brain relates to cognitive/psychological traits and will begin to frame neurophysiological data into psychological aspects. The team now aims to apply a similar approach to patients with schizophrenia.

Researchers identify gene that influences the ability to remember faces

New findings suggest the oxytocin receptor, a gene known to influence mother-infant bonding and pair bonding in monogamous species, also plays a special role in the ability to remember faces. This research has important implications for disorders in which social information processing is disrupted, including autism spectrum disorder. In addition, the finding may lead to new strategies for improving social cognition in several psychiatric disorders.

A team of researchers from Yerkes National Primate Research Center at Emory University in Atlanta, the University College London in the United Kingdom and University of Tampere in Finland made the discovery, which will be published in an online Early Edition of Proceedings of the National Academy of Sciences.

According to author Larry Young, PhD, of Yerkes, the Department of Psychiatry in Emory’s School of Medicine and Emory’s Center for Translational Social Neuroscience (CTSN), this is the first study to demonstrate that variation in the oxytocin receptor gene influences face recognition skills. He and co-author David Skuse point out the implication that oxytocin plays an important role in promoting our ability to recognize one another, yet about one-third of the population possesses only the genetic variant that negatively impacts that ability. They say this finding may help explain why a few people remember almost everyone they have met while others have difficulty recognizing members of their own family.

Skuse is with the Institute of Child Health, University College London, and the Great Ormond Street Hospital for Children, NHS Foundation Trust, London.

Young, Skuse and their research team studied 198 families with a single autistic child because these families were known to show a wide range of variability in facial recognition skills; two-thirds of the families were from the United Kingdom, and the remainder from Finland.

The Emory researchers previously found the oxytocin receptor is essential for olfactory-based social recognition in rodents, like mice and voles, and wondered whether the same gene could also be involved in human face recognition. They examined the influence of subtle differences in oxytocin receptor gene structure on face memory competence in the parents, non-autistic siblings and autistic child, and discovered a single change in the DNA of the oxytocin receptor had a big impact on face memory skills in the families. According to Young, this finding implies that oxytocin likely plays an important role more generally in social information processing, which is disrupted in disorders such as autism.

Additionally, this study is remarkable for its evolutionary aspect. Rodents use odors for social recognition while humans use visual facial cues. This suggests an ancient conservation in genetic and neural architectures involved in social information processing that transcends the sensory modalities used from mouse to man.

Skuse credits Young’s previous research that found mice with a mutated oxytocin receptor failed to recognize mice they previously encountered. “This led us to pursue more information about facial recognition and the implications for disorders in which social information processing is disrupted.” Young adds the team will continue working together to pursue strategies for improving social cognition in psychiatric disorders based on the current findings.

Probiotic Therapy Alleviates Autism-like Behaviors in Mice

Autism spectrum disorder (ASD) is diagnosed when individuals exhibit characteristic behaviors that include repetitive actions, decreased social interactions, and impaired communication. Curiously, many individuals with ASD also suffer from gastrointestinal (GI) issues, such as abdominal cramps and constipation.

Using the co-occurrence of brain and gut problems in ASD as their guide, researchers at the California Institute Technology (Caltech) are investigating a potentially transformative new therapy for autism and other neurodevelopmental disorders.

The gut microbiota—the community of bacteria that populate the human GI tract—previously has been shown to influence social and emotional behavior, but the Caltech research, published online in the December 5 issue of the journal Cell, is the first to demonstrate that changes in these gut bacteria can influence autism-like behaviors in a mouse model.

"Traditional research has studied autism as a genetic disorder and a disorder of the brain, but our work shows that gut bacteria may contribute to ASD-like symptoms in ways that were previously unappreciated," says Professor of Biology Sarkis K. Mazmanian. "Gut physiology appears to have effects on what are currently presumed to be brain functions."

To study this gut–microbiota–brain interaction, the researchers used a mouse model of autism previously developed at Caltech in the laboratory of Paul H. Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences. In humans, having a severe viral infection raises the risk that a pregnant woman will give birth to a child with autism. Patterson and his lab reproduced the effect in mice using a viral mimic that triggers an infection-like immune response in the mother and produces the core behavioral symptoms associated with autism in the offspring.

In the new Cell study, Mazmanian, Patterson, and their colleagues found that the “autistic” offspring of immune-activated pregnant mice also exhibited GI abnormalities. In particular, the GI tracts of autistic-like mice were “leaky,” which means that they allow material to pass through the intestinal wall and into the bloodstream. This characteristic, known as intestinal permeability, has been reported in some autistic individuals. “To our knowledge, this is the first report of an animal model for autism with comorbid GI dysfunction,” says Elaine Hsiao, a senior research fellow at Caltech and the first author on the study.

To see whether these GI symptoms actually influenced the autism-like behaviors, the researchers treated the mice with Bacteroides fragilis, a bacterium that has been used as an experimental probiotic therapy in animal models of GI disorders.

The result? The leaky gut was corrected.

In addition, observations of the treated mice showed that their behavior had changed. In particular, they were more likely to communicate with other mice, had reduced anxiety, and were less likely to engage in a repetitive digging behavior.

"The B. fragilis treatment alleviates GI problems in the mouse model and also improves some of the main behavioral symptoms," Hsiao says. "This suggests that GI problems could contribute to particular symptoms in neurodevelopmental disorders."

With the help of clinical collaborators, the researchers are now planning a trial to test the probiotic treatment on the behavioral symptoms of human autism. The trial should begin within the next year or two, says Patterson.

"This probiotic treatment is postnatal, which means that the mother has already experienced the immune challenge, and, as a result, the growing fetuses have already started down a different developmental path," Patterson says. "In this study, we can provide a treatment after the offspring have been born that can help improve certain behaviors. I think that’s a powerful part of the story."

The researchers stress that much work is still needed to develop an effective and reliable probiotic therapy for human autism—in part because there are both genetic and environmental contributions to the disorder, and because the immune-challenged mother in the mouse model reproduces only the environmental component.

"Autism is such a heterogeneous disorder that the ratio between genetic and environmental contributions could be different in each individual," Mazmanian says. "Even if B. fragilis ameliorates some of the symptoms associated with autism, I would be surprised if it’s a universal therapy—it probably won’t work for every single case."

The Caltech team proposes that particular beneficial bugs are intimately involved in regulating the release of metabolic products (or metabolites) from the gut into the bloodstream. Indeed, the researchers found that in the leaky intestinal wall of the autistic-like mice, certain metabolites that were modulated by microbes could both easily enter the circulation and affect particular behaviors.

"I think our results may someday transform the way people view possible causes and potential treatments for autism," Mazmanian says.

Focusing on Faces

Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.

"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team’s findings. “We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally.”

The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.

By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.

"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."

"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.

To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.

"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.

iPads help late-speaking children with autism develop language

The iPad you use to check email, watch episodes of Mad Men and play Words with Friends may hold the key to enabling children with autism spectrum disorders to express themselves through speech. New research indicates that children with autism who are minimally verbal can learn to speak later than previously thought, and iPads are playing an increasing role in making that happen, according to Ann Kaiser, a researcher at Vanderbilt Peabody College of education and human development.

In a study funded by Autism Speaks, Kaiser found that using speech-generating devices to encourage children ages 5 to 8 to develop speaking skills resulted in the subjects developing considerably more spoken words compared to other interventions. All of the children in the study learned new spoken words and several learned to produce short sentences as they moved through the training.

“For some parents, it was the first time they’d been able to converse with their children,” said Kaiser, Susan W. Gray Professor of Education and Human Development. “With the onset of iPads, that kind of communication may become possible for greater numbers of children with autism and their families.”

Augmentative and alternative communication devices—which employ symbols, gestures, pictures and speech output—have been used for decades by people who have difficulty speaking. Now, with the availability of apps that emulate those devices, the iPad offers a more accessible, cheaper and more user-friendly way to help minimally verbal children with autism to communicate. And, the iPad is far less stigmatizing for young people with autism who rely on them for communicating with fellow students, teachers and friends.

The reason speech-generating devices like the iPad are effective in promoting language development is simple. “When we say a word it sounds a little different every time, and words blend together and take on slightly different acoustic characteristics in different contexts,” Kaiser explained. “Every time the iPad says a word, it sounds exactly the same, which is important for children with autism, who generally need things to be as consistent as possible.”

As many as a third of children with autism have mastery of only a few words by the time they are school age. Previously, researchers thought that if children with autism had not begun to speak by age 5 or 6, they were unlikely to acquire spoken language. But Kaiser is encouraged by study results and believes that her iPad studies may help change that notion.

Building on findings from this research, Kaiser has begun a new five-year long study supported by the National Institutes of Health’s Autism Centers of Excellence with colleagues at UCLA, University of Rochester, and Cornell Weill Medical School. She and a team of researchers and therapists at the four sites are using iPads in two contrasting interventions (direct-teaching and naturalistic-teaching) to evaluate the effectiveness of the two communication interventions for children who have autism and use minimal spoken language.

In the direct-teaching approach, children are taught prerequisite skills for communication (such as matching objects, motor imitation and verbal imitation) and basic communication skills (such as requesting objects) in a massed trial format. For example, an adult partner may present five to 10 consecutive opportunities for a child to use the iPad to request preferred objects. During these opportunities, the child is prompted to use the iPad to request and may receive physical assistance if he cannot use the iPad independently.

In the naturalistic-teaching approach, the adult models the use of the iPad during play and conversation. She also teaches turn-taking, use of gestures to communicate, play with objects and social attention to partners during the play. She provides a limited number of prompts to use the iPad to make choices, to comment or make new requests.

In both approaches, children touch the symbols on the screen, listen to the device repeat the words, and sometimes say the words themselves. They are encouraged to use both words and the iPad to communicate, and the adult therapist uses both modes of communication throughout the instructional sessions.

Results from the Autism Speaks study will be available in Spring 2014; the NIH study will continue through Spring 2017; and more information can be found at Kidtalk.org.

New study identifies signs of autism in the first months of life

Researchers at Marcus Autism Center, Children’s Healthcare of Atlanta and Emory University School of Medicine have identified signs of autism present in the first months of life. The researchers followed babies from birth until 3 years of age, using eye-tracking technology, to measure the way infants look at and respond to social cues. Infants later diagnosed with autism showed declining attention to the eyes of other people, from the age of 2 months onwards. The results are reported in the Nov. 6, 2013 advanced online publication of the journal Nature.

The study followed two groups of infants, one at low and one at high risk for having autism spectrum disorders. High-risk infants had an older sibling already diagnosed with autism, increasing the infant’s risk of also having the condition by 20 fold. In contrast, low-risk infants had no first, second, or third degree relatives with autism.

"By following these babies from birth, and intensively within the first six months, we were able to collect large amounts of data long before overt symptoms are typically seen," said Warren Jones, Ph.D., the lead author on the study. Teams of clinicians assessed the children longitudinally and confirmed their diagnostic outcomes at age 3. Then the researchers analyzed data from the infants’ first months to identify what factors separated those who received an autism diagnosis from those who did not. What they found was surprising.

"We found a steady decline in attention to other people’s eyes, from 2 until 24 months, in infants later diagnosed with autism," said co-investigator Ami Klin, Ph.D., director of Marcus Autism Center. Differences were apparent even within the first 6 months, which has profound implications. "First, these results reveal that there are measurable and identifiable differences present already before 6 months. And second, we observed declining eye fixation over time, rather than an outright absence. Both these factors have the potential to dramatically shift the possibilities for future strategies of early intervention."

Jones is director of research at Marcus Autism Center and assistant professor in the Department of Pediatrics at Emory University School of Medicine. Klin is director of Marcus Autism Center, chief of the Division of Autism & Related Disorders in the Department of Pediatrics at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.

The researchers caution that what they observed would not be visible to the naked eye, but requires specialized technology and repeated measurements of a child’s development over the course of months.

"To be sure, parents should not expect that this is something they could see without the aid of technology," said Jones, "and they shouldn’t be concerned if an infant doesn’t happen to look at their eyes at every moment. We used very specialized technology to measure developmental differences, accruing over time, in the way that infants watched very specific scenes of social interaction."

Before they can crawl or walk, babies explore the world intensively by looking at it, and they look at faces, bodies, and objects, as well as other people’s eyes. This exploration is a natural and necessary part of infant development, and it sets the stage for brain growth.

The critical implications of the study relate to what it reveals about the early development of social disability. Although the results indicate that attention to others’ eyes is already declining by 2 to 6 months in infants later diagnosed with autism, attention to others’ eyes does not appear to be entirely absent. If infants were identified at this early age, interventions could more successfully build on the levels of eye contact that are present. Eye contact plays a key role in social interaction and development, and in the study, those infants whose levels of eye contact diminished most rapidly were also those who were most disabled later in life. This early developmental difference also gives researchers a key insight for future studies.

"The genetics of autism have proven to be quite complex. Many hundreds of genes are likely to be involved, with each one playing a role in just a small fraction of cases, and contributing to risk in different ways in different individuals," said Jones. "The current results reveal one way in which that genetic diversity may be converted into disability very early in life. Our next step will be to expand these studies with more children, and to combine our eye-tracking measures with measures of gene expression and brain growth."

Theatre offers promise for youth with autism

A novel autism intervention program using theatre to teach reciprocal communication skills is improving social deficits in adolescents with the disorder that now affects an estimated one in 88 children, Vanderbilt University researchers released today in the journal Autism Research.

The newly released study assessed the effectiveness of a two-week theatre camp on children with autism spectrum disorder and found significant improvements were made in social perception, social cognition and home living skills by the end of the camp. There were also positive changes in the participants’ physiological stress and reductions in self-reported parental stress.

Called SENSE Theatre, the Social Emotional Neuroscience & Endocrinology (SENSE) program evaluates the social functioning of children with autism and related neurodevelopmental disorders.

Camp participants ages 8 to 17 years join with typically developing peers who are specially trained to serve as models for social interaction and communication, skills that are difficult for children with autism. The camp uses techniques such as role-play and improvisation and culminates in public performances of a play.

“The findings show that treatment can be delivered in an unconventional setting, and children with autism can learn from unconventional ‘interventionists’ – their typically developing peer,” said lead author Blythe Corbett, Ph.D., associate professor of Psychiatry.

Social perception and interaction skills were measured before and after the camp using neuropsychological measures, play with peers and parental reporting. Significant differences were found in face processing, social awareness and social cognition, and duration of interaction with familiar peers increased significantly over the course of the camp.

Additionally, the stress hormone cortisol was measured through saliva samples taken both at home and throughout the camp to compare the stress level of participants at home, at the beginning of the camp and at the end of the camp. Cortisol levels rose on the first day of camp when compared to home values but declined by the end of treatment and during post-treatment play with peers.

“Our findings show that the SENSE Theatre program contributes to improvement in core social deficits when engaging with peers both on and off the stage,” Corbett said. “This research also shows it’s never too late to make a significant difference in the lives of children and youth with autism spectrum disorder, as [this program] targets children who are much older than kids who are participating in early intervention, yet we are still seeing significant gains in the core deficits of autism, and in a rather brief intervention.”

This research was supported by the Martin McCoy-Jesperson Discovery Grant in Positive Psychology and a grant from the National Institute of Mental Health (Grant No. R01 MH085717).

Corbett will continue using theatre techniques to study areas of social functioning among children with autism through a newly awarded grant from the National Institute of Mental Health (Grant No. R34 MH097793). This forthcoming study will explore treatment length and peer familiarity as factors in optimizing and generalizing gains and will enroll more than 30 youth with autism ages 8 to 16 in a 10-week program model beginning January 2014.