New study settles how social understanding is performed by the brain

A new study settles an important question about how social understanding is performed in the brain. The findings may help us to attain a better understanding of why people with autism and schizophrenia have difficulties with social interaction.

In a study to be published in Psychological Science, researchers from Aarhus University and the University of Copenhagen demonstrate that brain cells in what is called the mirror system help people make sense of the actions they see other people perform in everyday life.

Using magnetic stimulation to temporarily disrupt normal processing of the areas of the human brain involved in the production of actions of human participants, it is demonstrated that these areas are also involved in the understanding of actions. The study is the first to demonstrate a clear causal effect, whereas earlier studies primarily have looked at correlations, which are difficult to interpret.

One of the researchers, John Michael, explains the process:

“There has been a great deal of hype about the mirror system, and now we have performed an experiment that finally provides clear and straightforward evidence that the mirror system serves to help people make sense of others’ actions,” says John Michael.

Understanding autism and schizophrenia

The study shows that there are areas of the brain that are involved in the production of actions. And the researchers found evidence that these areas contribute to understanding others’ actions. This means that the same areas are involved in producing actions and understanding others’ actions. This helps us in everyday life, but it also holds great potential when trying to understand why people with autism and schizophrenia have difficulties with social interaction.

“Attaining knowledge of the processes underlying social understanding in people in general is an important part of the process of attaining knowledge of the underlying causes of the difficulties that some people diagnosed with autism and schizophrenia experience in sustaining social understanding. But it is important to emphasise that this is just one piece of the puzzle.”

“The findings may be interesting to therapists and psychiatrists who work with patients with schizophrenia or autism, or even to educational researchers,” adds John Michael.

Facts about the empirical basis

The participants (20 adults) came to the lab three times. They were given brain scans on the first visit. On the second and third, they received stimulation to their motor system and then performed a typical psychological task in which they watched brief videos of actors pantomiming actions (about 250 videos each time). After each video they had to choose a picture of an object that matched the pantomimed video. For example, a hammer was the correct answer for the video of an actor pretending to hammer. This task was intended to gauge their understanding of the observed actions. The researchers found that the stimulation interfered with their performance of this task.

Innovative method

The researchers used an innovative technique for magnetically stimulating highly specific brain areas in order to temporarily disrupt normal processing in those areas. The reason for using this technique (called continuous theta-burst stimulation) in general is that it makes it possible to determine which brain areas perform which functions. For example, if you stimulate (and thus temporarily impair) area A, and the participants subsequently have difficulty with some specific task (task T), then you can infer that area A usually performs task T. The effect goes away after 20 minutes, so this is a harmless and widely applicable way to identify which tasks are performed by which areas.

With continuous theta-burst stimulation, you can actually determine that the activation of A contributes as a cause to people performing T. This method thus promises to be of great use to neuroscientists in the coming years.

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.

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.

A single spray of oxytocin improves brain function in children with autism

A single dose of the hormone oxytocin, delivered via nasal spray, has been shown to enhance brain activity while processing social information in children with autism spectrum disorders, Yale School of Medicine researchers report in a new study published in the Dec. 2 issue of Proceedings of the National Academy of Sciences.

“This is the first study to evaluate the impact of oxytocin on brain function in children with autism spectrum disorders,” said first author Ilanit Gordon, a Yale Child Study Center adjunct assistant professor, whose colleagues on the study included senior author Kevin Pelphrey, the Harris Professor in the Child Study Center, and director of the Center for Translational Developmental Neuroscience at Yale.

Gordon, Pelphrey, and their colleagues conducted a double-blind, placebo-controlled study of 17 children and adolescents with autism spectrum disorders. The participants, between the ages of 8 and 16.5, were randomly given either oxytocin spray or a placebo nasal spray during a task involving social judgments. Oxytocin is naturally occurring hormone produced in the brain and throughout the body.

“We found that brain centers associated with reward and emotion recognition responded more during social tasks when children received oxytocin instead of the placebo,” said Gordon. “Oxytocin temporarily normalized brain regions responsible for the social deficits seen in children with autism.”

Gordon said oxytocin facilitated social attunement, a process that makes the brain regions involved in social behavior and social cognition activate more for social stimuli (such as faces) and activate less for non-social stimuli (such as cars).

“Our results are particularly important considering the urgent need for treatments to target social dysfunction in autism spectrum disorders,” Gordon added.

Scientists Pinpoint Cell Type and Brain Region Affected by Gene Mutations in Autism

A team led by UC San Francisco scientists has identified the disruption of a single type of cell – in a particular brain region and at a particular time in brain development – as a significant factor in the emergence of autism.

The finding, reported in the Nov. 21 issue of Cell, was made with techniques developed only within the last few years, and marks a turning point in autism spectrum disorders (ASDs) research.

Large-scale gene sequencing projects are revealing hundreds of autism-associated genes, and scientists have begun to leverage new methods to decipher how mutations in these disparate genes might converge to exert their effects in the developing brain.

The new research focused on just nine genes, those most strongly associated with autism in recent sequencing studies, and investigated their effects using precise maps of gene expression during human brain development.

Led by Jeremy Willsey, a graduate student in the laboratory of senior author Matthew W. State, MD, PhD, chair of the UCSF Department of Psychiatry, the group showed that this set of genes contributes to abnormalities in brain cells known as cortical projection neurons in the deepest layers of the developing prefrontal cortex during the middle period of fetal development.

Though a range of developmental scenarios in multiple brain regions are surely at work in ASDs, the ability to place these specific genetic mutations in one specific set of cells – among hundreds of cell types in the brain, and at a specific time point in human development – is a critical step in beginning to understand how autism comes about.

“Given the small subset of autism genes we studied, I had no expectation that we would see the degree of spatiotemporal convergence that we saw,” said State, an international authority on the genetics of neurodevelopmental disorders.

“This strongly suggests that though there are hundreds of autism risk genes, the number of underlying biological mechanisms will be far fewer. This is a very important clue to advance precision medicine for autism toward the development of personalized and targeted therapies.”

Complex Genetic Architecture of ASDs

ASDs, marked by deficits in social interaction and language development, as well as by repetitive behaviors and/or restricted interests, are known to have a strong genetic component.

But these disorders are exceedingly complex, with considerable variation in symptoms and severity, and there does not appear to be a small collection of mutations widely shared among all affected individuals that always lead to ASDs.

Instead, with the rise of new sequencing methods over the past several years, researchers have identified many rare, non-inherited, spontaneous mutations that appear to act in combination with other genetic and non-genetic factors to cause ASDs. According to some estimates, mutations in as many as 1,000 genes could play a role in the development of these disorders.

While researchers have been heartened that specific genes are now rapidly being tied to ASDs, State said the complex genetic architecture of ASDs is also proving to be challenging.

“If there are 1,000 genes in the population that can contribute to risk in varying degrees and each has multiple developmental functions, it is not immediately obvious how to move forward to determine what is specifically related to autism. And without this, it is very difficult to think about how to develop new and better medications,” he said.

Focusing on Nine Genes

To begin to grapple with those questions, the researchers involved in the new study first selected as “seeds” the nine genes that have been most strongly tied to ASDs in recent sequencing research from their labs and others.

Importantly, these nine genes were chosen solely because of the statistical evidence for a relationship to ASDs, not because their function was known to fit a theory of the cause of ASDs. “We asked where the leads take us, without any preconceived idea about where they should take us,” said State.

The team then took advantage of BrainSpan, a digital atlas assembled by a large research consortium, including co-author Nenad Šestan, MD, PhD, and colleagues at Yale School of Medicine. Based on donated brain specimens, BrainSpan documents how and where genes are expressed in the human brain over the lifespan.

The scientists, who also included Bernie Devlin, PhD, of The University of Pittsburgh School of Medicine; Kathryn Roeder, PhD, of Carnegie-Mellon University; and James Noonan, PhD, of Yale School of Medicine, used this tool to investigate when and where the nine seed genes join up with other genes in “co-expression networks” to wire up the brain or maintain its function.

The resulting co-expression networks were then tested using a variety of pre-determined criteria to see if they showed additional evidence of being related to ASDs. Once this link was established, the authors were then able to home in on where in the brain and when in development these networks were localizing, which proved to be in cortical projection neurons found in layers 5 and 6 of the prefrontal cortex, and during a time period spanning 10 to 24 weeks after conception. Notably, a study using different methods and published in the same issue of Cell also implicates cortical projection neurons in ASDs.

“To see these gene networks as highly connected as they are, as convergent as they are, is quite amazing,” said Willsey “An important outcome of this study is that for the first time it gives us the ability to design targeted experiments based on a strong idea about when and where in the brain we should be looking at specific genes with specific mutations.”

In addition to its importance in ASD research, State sees the new work as a reflection of the tremendous value of “big science” efforts, such as large-scale collaborative genomic studies and the creation of foundational resources such as the BrainSpan atlas.

“We couldn’t have done this even two years ago,” State said, “because we didn’t have the key ingredients: a set of unbiased autism genes that we have confidence in, and a map of the landscape of the developing human brain. This work combines large-scale ‘-omics’ data sets to pivot into a deeper understanding of the relationship between complex genetics and biology.”

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.