Genes, ozone, and autism

A new analysis shows that individuals with high levels of genetic variation and elevated exposure to ozone in the environment are at an even higher risk for developing autism than would be expected by adding the two risk factors together. The study is the first to look at the combined effects of genome-wide genetic change and environmental risk factors for autism, and the first to identify an interaction between genes and environment that leads to an emergent increase in risk that would not be found by studying these factors independently. A paper describing the research appears online in the journal Autism Research.

“Autism, like most human diseases, is complex,” said Scott B. Selleck, professor of biochemistry and molecular biology at Penn State and one of the leaders of the research team. “There are probably hundreds, if not thousands, of genes involved and up until now — with very few exceptions — these have been studied independently of the environmental contributors to autism, which are real. Our team of researchers represents a merger of people with genetic expertise and environmental epidemiologists, allowing us for the first time to answer questions about how genetic and environmental risk factors for autism interact.”

The team looked at copy-number variation — deletions and duplications of repeated elements in the genome that lead to variation among individuals in the number of repeated elements — as a general measure of genetic variation and five types of air pollution — traffic-related air pollution, nitrogen oxides, two sizes of particulate matter, and ozone — in a large set of individuals with autism and a well-matched set of typically developing controls. The study participants — obtained through the Childhood Autism Risks from Genetics and Environment (CHARGE) Study, a population-based case-control study led by Irva Hertz-Picciotto, professor of epidemiology and chief of the Division of Environmental and Occupational Health at University of California Davis, and one of the leaders of the research team — includes cases and controls matched for age, sex, and geographic location. Each of 158 cases and 147 controls were genetically scored for genetic deletions, duplications, and total changes in copy number. Environmental exposures for each participant were determined based on residential histories using data from the U.S. Environmental Protection Agency (EPA) Air Quality System.

“This study used unique resources,” said Hertz-Picciotto. “By mapping the homes of the mothers during their pregnancies, we were able to estimate their levels of exposure to several types of air pollutants that are monitored by the U.S. EPA. This allowed us to examine differences between cases of autism and typically developing controls in both their prenatal pollutant exposure and their total load of extra or deleted genetic material.”

Evaluation of each of the risk factors showed that duplications, total copy-number variation, and particulate matter in the environment had the largest individual impact on risk for autism. However, when the researchers evaluated interactions among the various risk factors they saw a large effect of ozone among children with either duplications or total copy-number variation. Ozone on its own had very little effect on risk for autism, such that in studies that did not take interactions among risk factors into consideration, it may have been ignored. Interactions among the various other factors, even those with large individual effects, appeared to have very little effect on risk.

“This study showed the effect of a pollutant not previously associated with autism risk. This study may be one example of how taking genomic variation into account can help us identify new risk factors for autism,” said Heather Volk, assistant professor in the Department of Mental Health at the Johns Hopkins Bloomberg School of Public Health.

“If we just look at the raw numbers, before any statistical assessment, we see a ten-fold increase in the risk of autism for individuals in the top 25 percent for level of genetic variation and in the top 25 percent for exposure to ozone as compared to the individuals in the bottom 25 percent for each of these measures,” said Selleck. “This increase in risk is striking, but given what we know about the complexity of diseases like autism, perhaps not surprising. It demonstrates how important it is to consider different types of risk factors for disease together, even those with small individual effects.”

The researchers speculate that the large effect of the interaction between ozone exposure and copy-number variation could be the result of the fact that ozone is an oxidizing agent, and is known to produce reactive oxygen species, like peroxides, that cause cellular stress and can alter cell function in many ways. High levels of copy-number variation may indicate a compromised state that is primed for the type of damage that ozone can cause.

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System detects, translates sarcasm on social media

Researchers in the Technion-Israel Institute of Technology Faculty of Industrial Engineering and Management have developed a system for interpreting sarcastic statements in social media. The system, developed by graduate student Lotam Peled, under the guidance of Assistant Professor Roi Reichart, is called Sarcasm SIGN (sarcasm Sentimental Interpretation GeNerator).

“There are a lot of systems designed to identify sarcasm, but this is the first that is able to interpret sarcasm in written text,” said Peled. “We hope in the future, it will help people with autism and Asperger’s, who have difficulty interpreting sarcasm, irony and humor.”

Based on machine translation, the new system turns sarcastic sentences into honest (non-sarcastic) ones. It will, for example, turn a sarcastic sentence such as, “The new ‘Fast and Furious’ movie is awesome. #sarcasm” into the honest sentence, “The new Fast and Furious movie is terrible.”

Despite the vast development in this field, and the successes of sentiment analysis applications on “social media intelligence,” existing applications do not know how to interpret sarcasm, where the writer writes the opposite of what (s)he actually means.

In order to teach the system to produce accurate interpretations, the researchers compiled a database of 3,000 sarcastic tweets that were tagged with #sarcasm, where each tweet was interpreted into a non-sarcastic expression by five human experts. In addition, the system was trained to identify words with strong sarcastic sentiments — for example, the word “best” in the tweet, “best day ever” — and to replace them with strong words that reveal the true meaning of the text. The system was examined by a number of (human) judges, who gave its interpretations high scores of fluency and adequacy, agreeing that in most cases it produced a semantically and linguistically correct sentence.

Automatic identification and analysis of sentiment in text is a very complex challenge being explored by many researchers around the world because of its commercial potential and scientific importance. Sentiment identification could be used in social, commercial, and other applications to improve communication between people and computers, and between social media users.

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Serotonin improves sociability in mouse model of autism

Scientists at the RIKEN Brain Science Institute (BSI) in Japan have linked early serotonin deficiency to several symptoms that occur in autism spectrum disorder (ASD). Published in Science Advances, the study examined serotonin levels, brain circuitry, and behavior in a mouse model of ASD. Experiments showed that increasing serotonergic activity in the brain during early development led to more balanced brain activity and improved the abnormal sociability of these mice.

As group leader Toru Takumi explains, “Although abnormalities in the serotonin system have been thought to be part of the ASD pathophysiology, the functional impact of serotonin deficiency in ASD was totally unknown. Our work shows that early serotonergic intervention rescues regional excitatory/inhibitory abnormalities in the brain as well as behavioral abnormalities.”

Although the causes and symptoms of ASD are varied, many people with ASD have too many genomic mutations. Previously, Takumi’s group generated a mouse model of ASD by duplicating in mice one of the most frequent copy variations found in people with ASD. These mice show many behavioral symptoms of ASD, including poor social interaction and low behavioral flexibility. The model mice also have reduced levels of serotonin in the brain during development, another symptom that has been found in patients with ASD.

In the newly published work, the researchers focused on this finding and examined how it affected the behavior of neurons in the brain as well as the behavior of the mice themselves.

After determining that the part of the brain that contains the highest amount of serotonin neurons was less active in the ASD model mice than in wild-type mice, the group examined a sensory region of the brain that receives input from these serotonergic neurons.

Patients with ASD often exhibit abnormal responses in sensory regions of the brain, and the RIKEN scientists found similar abnormalities in the brain region of the model mice that detects whisker movement. Although specific whisker movements are normally tightly mapped across this brain region, calcium imaging showed that a given whisker movement activated a much larger region of sensory cortex in the ASD model mice. This means that the responses of neighboring regions were more overlapped, which reduces the ability to distinguish sensations.

The overlap in sensory maps indicated that normally inactive neurons were somehow active. This pointed to reduced inhibitory activity, and the group confirmed this by showing that the ASD model mice had fewer inhibitory synapses and a lower frequency of naturally occurring inhibitory inputs in the sensory region.

These findings indicated an abnormality in cortical excitatory/inhibitory balance. First author Nobuhiro Nakai notes, “Because the sensory region was receiving abnormally low serotonin input, we reasoned that giving infant mice serotonin therapy might reduce the imbalance and also rescue some of the behavioral abnormalities.”

To test this hypothesis, the team administered a selective serotonin reuptake inhibitor, commonly referred to as an SSRI, to infant mice during the first three weeks after birth. This time period corresponded to the time period in which reduced serotonin was observed in the model mice. Researchers found that sensory neurons in the model mice treated with the SSRI showed more normal inhibitory responses, which improved the excitatory/inhibitory balance.

They also found that this intervention improved the social behavior of the model mice in adulthood. Social behavior was measured with a test in which mice are exposed to a cage with an unknown mouse or an empty cage. Normal mice spend more time near the cage with the unknown mouse, while the ASD model mice prefer the empty cage. After the SSRI treatment, ASD model mice spend more time around the cage with the unknown mouse, indicating more normal social behavior. Another improvement was seen in the communication behavior of the ASD mouse pups. While these pups displayed anxiety by produced more vocalizations than normal, this behavior was rescued by the SSRI treatment. These findings suggest that serotonin may have be potentially therapeutic for discrete ASD symptoms.

Looking toward the future, Takumi is optimistic, yet cautious. “Our genetic model for ASD is one of many and because the number of genetic mutations associated with ASD is so high, we need to investigate differences and common mechanisms among multiple genetic ASD models. Additionally, before we can administrate SSRIs to patients with ASD, we must study the effects of SSRIs in more detail, especially because adverse effects have been reported in some animal studies.”

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New statistical method finds shared ancestral gene variants involved in autism's cause

The way you measure things has a lot to do with the value of the results you get. If you want to know how much a blueberry weighs, don’t use a bathroom scale; it isn’t sensitive enough to register a meaningful result.

While much more is at stake, the same principle applies when scientists try to measure genetic factors that cause disease. In a paper appearing in the Proceedings of the National Academy of Sciences, geneticist Michael Wigler of Cold Spring Harbor Laboratory (CSHL), Kenny Ye (Albert Einstein) and colleagues use a new mathematical method to assess the role of genetic variants in determining a trait — in this case, autism. (Autism is to be understood as interchangeable with autism spectrum disorder, or ASD, in this story.)

The new approach finds what Wigler believes is the first rigorous statistical evidence that ancient variations in the human genome contribute to autism — each, most likely, having a very small effect. (Devastating variants tend to be recent and are regularly weeded out of the genome; those who have them rarely are less likely to have offspring, meaning the damaging gene is less likely to be transmitted.)

Past studies have sought to identify causal autism variants by comparing the genomes of affected people and unaffected people who are not related to them. Professor Wigler is skeptical of the significance of the results obtained with such “case/control” studies. He argues that ethnic and other biases cannot be completely teased out, and produce a result cannot be assessed properly for statistical significance.

The method Wigler and colleagues used in the new study was family-based. The team analyzed data on common variants from two cohorts. One cohort consisted of “discordant siblings,” one of whom has autism and the other does not. These discordant pairs, gathered in the Simons Simplex Collection (SSC), were compared with the genomes of individuals with autism collected by the Autism Genetic Resource Exchange (AGRE). Overall, over 16,000 genomes from people in nearly 4,000 families were used in the analysis.

By comparing the discordant siblings in the SSC with unrelated people with autism in the AGRE collection, the team was able to find a clear signal of ancient variants contributing to autism, shared among those with the disorder in both collections — who, by definition, are not related.

Those in the AGRE sample — all “affected” — were genetically more like the affected children in the Simons Collection than their unaffected siblings.

For Wigler, there is more at stake in the result. “There is more power in family studies than we actually know how to tap into at this point,” he says. “There is more information in a family structure than in the isolated person who’s got a disorder. Certainly this is true when dealing with de novo or germline mutation, but true even when examining transmission, as we did in the current study.”

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The importance of time and space in brain development and disease

Exactly when and where individual neurons develop is as important to our understanding of brain diseases as the underlying genetics, experts have shown.

New research from Newcastle University, UK, and published today in the academic journal Trends in Cognitive Science, shows for the first time how morphological changes in the brain help shape its neural networks — the human connectome.

Carrying out a review of brain research carried out over the past 15 years, the study shows that in addition to genetic and environmental drivers, the exact time of development of each neuron and its position in the brain are key to ensuring the right connections are made.

Ultimately determining how the brain is wired as an adult, changes in cognition and behaviour for developmental diseases such as schizophrenia, autism, and ADHD are linked to changes in the network organisation in the brain.

Study author Marcus Kaiser, Professor of Neuroinformatics at Newcastle University, explains:

“A great deal of work has been done on genetic factors of developmental brain disorders but the importance of the spatial layout and of the exact time when regions and connections originate during brain development has largely been forgotten.

“In fact, our work shows that time and space during brain maturation are critical and if we can better understand these physical changes then it could lead to new treatments and better diagnosis of a variety of conditions.”

Timing is key

In humans, brain development begins from the very early stages of life and continues right through into adult life. In fact, new studies show changes up to the age of 40 years in humans.

While some work has been done to understand connections on a micro-scale within specific areas of the brain, such as with epilepsy, we are only just beginning to understand how connections are formed on a macro scale, between brain regions and through the spinal cord.

Brain neurons tend to grow in straight lines, searching out other neurons to form a connection with. Only if the neuron hits an obstacle — an impassable molecule or chemical trigger — will it change direction.

“Imagine trying to pass through a crowded room in a straight line to get to someone at the other side,” explains Professor Kaiser.

“It is more likely you will bump into someone early on than simply passing through without hitting anyone until you hit your final, faraway target. In the same way, short-distance connections occur more often than long-distance connections during brain development.”

Forming long-distance connections

The distance a neuron needs to travel before it hits its target is also critical to development, says Professor Kaiser.

“Neurons generally follow chemical signals but the cells can only detect chemicals over a distance of 1cm.

“In adult humans, connections between different brain regions are often longer than 10cm and through the spinal cord they can be longer than 1m.

“So to get these connections right the neurons must develop the connections very early on in development while the organism is small.

“Timing in brain development is absolutely key. Indeed, experimental studies that link delays during brain maturation to developmental brain diseases are now starting to appear.”

Professor Kaiser adds: “Analysing the network of connections, or the connectome, and using computer simulations of brain development now gives us the tools to better understand the formation of the human brain.”

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Molecule may help maintain brain's synaptic balance

Many neurological diseases are malfunctions of synapses, or the points of contact between neurons that allow senses and other information to pass from finger to brain. In the brain, there is a careful balance between the excitatory synapses that allow messages to pass, and the inhibitory synapses that dampen the signal. When that balance is off, the brain becomes unable to process information normally, leading to conditions like epilepsy.

Now researchers at Jefferson have discovered a molecule that may play a role in helping maintain the balance of excitatory and inhibitory neurons. The results were published in the journal eLife, a project of the Howard Hughes Medical Institute, the Wellcome Trust and the Max Planck Institute.

Timothy Mosca, Ph.D., Assistant Professor in the Department of Neuroscience at the Vickie and Jack Farber Institute for Neuroscience of Thomas Jefferson University, discovered that a molecule called LRP4, was important in creating excitatory synapses — the ones that keep a message passing from one neuron to the next. When the researchers knocked out the LRP4 gene in fruit flies, they saw a 40 percent loss of excitatory synaptic connections in the brain, but no such loss of inhibitory synapses, suggesting that the molecule was specific to one kind of synapse.

The researchers used a new technology called expansion microscopy to get a better view of the fruit fly neurons. “In most cases, if you want to see very small things with better resolution, you get a better microscope,” says Mosca. “The other option is to make the small things bigger.” By infusing the neurons they were studying with the chemical in diapers that swells as it absorbs water, they were able to make the neurons and their synapses enlarged enough to see them more clearly.

“Most molecules involved in synapse biology are vital to both excitatory and inhibitory neurons,” says Mosca. “The idea that we now have a molecule that appears to be specific to excitatory synapses suggests there is probably a parallel molecule that exists that helps form inhibitory ones, that we just haven’t found yet.”

A better understanding of the unique biology of excitatory and inhibitory synapses may go a long way in helping researchers untangle the many diseases that are thought to be related to synapse dysfunction such as epilepsy, but also autism and schizophrenia.

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Musical mystery: Researchers examine science behind performer movements

Researchers at McMaster are one step closer to solving one of the mysteries of social interaction: how musicians communicate during a performance and anticipate one another’s moves without saying a word.

The findings are important because a clearer appreciation of how musicians silently work together — across tempo changes, phrasing and musical dynamics — will improve our understanding of nonverbal communication. That could lead to better techniques to reach those with conditions such as autism or dementia, say researchers.

Using sophisticated technology, which included infrared markers, motion capture sensors and mathematical modelling, scientists examined the movements of musicians from two professional string quartets. They found they could predict from the body sway of one musician, what another would do next.

While some assumed the role as leaders, and others followers, researchers found the leaders were far more influential in the ensemble.

They also found the degree of body sway communication among the musicians was connected to their perceptions of how well they performed together.

“Although we are often not consciously aware of it, non-verbal communications between people is common in many situations and influences who we like and who we don’t like,” explains Dan Bosnyak, a researcher and technical director at McMaster’s LIVELab, where the work was conducted.

“The methodology developed in this study could be useful for understanding many different types of group behaviour, such as understanding communication problems in autistic children or determining the best crowd control procedures for an emergency evacuation,” he says.

Researchers also plan to analyze whether body sway influences other forms of social interaction, such as romantic relationships.

They plan to run a speed dating study this summer, where they will investigate whether the amount of body movement coordination between two people interacting for a very short period of time — just three minutes — can predict a romantic match.

The study was published online in the journal PNAS.

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Neuroimaging technique may help predict autism among high-risk infants

Functional connectivity magnetic resonance imaging (fcMRI) may predict which high-risk, 6-month old infants will develop autism spectrum disorder by age 2 years, according to a study funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), two components of the National Institutes of Health. The study is published in the June 7, 2017, issue of Science Translational Medicine.

Autism affects roughly 1 out of every 68 children in the United States. Siblings of children diagnosed with autism are at higher risk of developing the disorder. Although early diagnosis and intervention can help improve outcomes for children with autism, there currently is no method to diagnose the disease before children show symptoms.

“Previous findings suggest that brain-related changes occur in autism before behavioral symptoms emerge,” said Diana Bianchi, M.D., NICHD Director. “If future studies confirm these results, detecting brain differences may enable physicians to diagnose and treat autism earlier than they do today.”

In the current study, a research team led by NIH-funded investigators at the University of North Carolina at Chapel Hill and Washington University School of Medicine in St. Louis focused on the brain’s functional connectivity — how regions of the brain work together during different tasks and during rest. Using fcMRI, the researchers scanned 59 high-risk, 6-month-old infants while they slept naturally. The children were deemed high-risk because they have older siblings with autism. At age 2 years, 11 of the 59 infants in this group were diagnosed with autism.

The researchers used a computer-based technology called machine learning, which trains itself to look for differences that can separate the neuroimaging results into two groups — autism or non-autism — and predict future diagnoses. One analysis predicted each infant’s future diagnosis by using the other 58 infants’ data to train the computer program. This method identified 82 percent of the infants who would go on to have autism (9 out of 11), and it correctly identified all of the infants who did not develop autism. In another analysis that tested how well the results could apply to other cases, the computer program predicted diagnoses for groups of 10 infants, at an accuracy rate of 93 percent.

“Although the findings are early-stage, the study suggests that in the future, neuroimaging may be a useful tool to diagnose autism or help health care providers evaluate a child’s risk of developing the disorder,” said Joshua Gordon, M.D., Ph.D., NIMH Director.

Overall, the team found 974 functional connections in the brains of 6-month-olds that were associated with autism-related behaviors. The authors propose that a single neuroimaging scan may accurately predict autism among high-risk infants, but caution that the findings need to be replicated in a larger group.

Telehealth reduces wait time, improves care for children with autism living in remote areas

Long wait times have been a persistent issue for families waiting to see an autism specialist, with waits often exceeding a year. Additionally, children with autism living in rural areas have added costs associated with traveling long distances for health care. To address these issues, ECHO Autism, a University of Missouri program, has been successfully training primary care providers to diagnose and manage autism spectrum disorders. Now, Kristin Sohl, associate professor of child health and the director of ECHO Autism, is preparing to expand the program with ECHO Autism partner sites serving Alabama, Alaska and under-served Navajo communities in New Mexico and Arizona. ECHO Autism also is set to expand globally through partner sites in Kenya. In the past year, Sohl has conducted autism specific trainings for ECHO Uruguay.

“Since the initial studies of ECHO Autism, nearly 250 health providers have received training on best-practice care,” Sohl said. “The program effectively increases the capacity for health care in underserved communities, which means that families can get the answers they need without traveling or waiting to see a specialist.”

Launched in March 2015, ECHO Autism is a partnership between the MU Thompson Center for Autism and Neurodevelopmental Disorders, MU Health, and the Missouri Telehealth Network Show-Me ECHO program. ECHO Autism clinics are conducted using high-quality, secure video conferencing technology to connect participating primary care clinics to a panel of experts.

Initial studies of the program have found that participating primary care providers demonstrated significant improvements in confidence across all sectors of health care for children with autism, including screening and identification, assessment and treatment of medical and psychiatric conditions, and knowledge of and referral to available resources.

“The success we have seen in Missouri and in other areas where ECHO Autism has been replicated means that this model can work in even more remote areas,” Sohl said. “Expanding the program from Africa to Alaska will help families around the world.”

Micah Mazurek, associate professor of health psychology in the School of Health Professions, and Rachel Brown, professor of clinical psychiatry in the MU School of Medicine, co-authored the recently published paper, “ECHO Autism: using technology and mentorship to bridge gaps, increase access to care, and bring best practice autism care to primary care,” which was featured in Clinical Pediatrics. ECHO Autism is modeled after Project ECHO at the University of New Mexico.

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Health care process a roadblock for adolescents with autism and their caregivers

For most people, trips to the doctor can be quite scary. For adolescents and young adults with autism, taking control of health care decisions is not only frightening, it also can be a barrier to independence. Now researchers from the University of Missouri have found that the health care process not only impacts adolescents with autism, but caregivers also feel they lack the skills and support necessary to help those adolescents achieve health-related independence. As more children with autism enter adulthood, improved communication between providers, adolescents and caregivers is needed to help those with autism transition to independence.

“A significant part of adulthood is managing health care, which includes regular trips to the doctor, following treatment plans, and being aware of symptoms and changes in health,” said Nancy Cheak-Zamora, an assistant professor in the MU School of Health Professions and researcher in the Thompson Center for Autism and Neurodevelopmental Disorders. “This can be especially challenging for adolescents and young adults with autism.”

Cheak-Zamora and her team conducted interviews with adolescents with autism and their caregivers. They found that both groups had a strong desire for the adolescents to manage their health care needs and that they attempted to take small steps toward independence, such as using pill boxes to help adolescents manage their own medications throughout the week. However, both groups lacked confidence when it came to building independence with adult health care. In many cases, caregivers were confused about their role in their adolescent’s path toward independence. Decisions about guardianship and who makes legal health care decisions were found to be especially problematic. Adolescents expressed feeling upset that health providers would not talk directly to them, instead speaking only to the caregivers.

“Many caregivers said they felt forced to remain involved in their adolescent’s care, even when their goal for the adolescents was independence,” Cheak-Zamora said. “Meanwhile, adolescents want to overcome their fears. They feel it is important to have alone time with doctors and are frustrated when doctors communicate mainly with caregivers. These findings reiterate the importance of understanding the perspectives of both caregivers and adolescents and improving communication between caregivers, adolescents and providers to achieve shared independence goals.”

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Building better brains: A bioengineered upgrade for organoids

Scientists for the first time combine organoids with bioengineering. Using small microfilaments, they show improved tissue architecture that mimics human brain development more accurately and allows more targeted studies of brain development and its malfunctions, as reported in the current issue of Nature Biotechnology.

A few years ago, Jürgen Knoblich and his team at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) have pioneered brain organoid technology. They developed a method for cultivating three-dimensional brain-like structures, so called cerebral organoids, in a dish. This discovery has tremendous potential as it could revolutionize drug discovery and disease research. Their lab grown organ-models mimic early human brain development in a surprisingly precise way, allowing for targeted analysis of human neuropsychiatric disorders, that are otherwise not possible. Using this cutting-edge methodology, research teams around the world have already revealed new secrets of human brain formation and its defects that can lead to microcephaly, epilepsy or autism.

In a new study published in Nature Biotechnology, scientists from Cambridge and Vienna present a new method that combines the organoid method with bioengineering. The researchers use special polymer fibers made of a material called PLGA) to generate a floating scaffold that was then covered with human cells. By using this ground-breaking combination of engineering and stem cell culture, the scientists are able to form more elongated organoids that more closely resemble the shape of an actual human embryo. By doing so, the organoids become more consistent and reproducible.

“This study is one of the first attempts to combine organoids with bioengineering. Our new method takes advantage of and combines the unique strengths of each approach, namely the intrinsic self-organization of organoids and the reproducibility afforded by bioengineering. We make use of small microfilaments to guide the shape of the organoids without driving tissue identity, “explains Madeline Lancaster, group leader at MRC Laboratory of Molecular Biology in Cambridge and first author of the paper.

This guided self-organization allows engineered cerebral organoids, or enCORs, to more reproducibly form cerebral cortical tissue but maintain the tissue complexity and overall size that comes about when the tissues are still allowed to develop according to intrinsic developmental programs. As a result, enCORs also develop later tissue architecture that more faithfully models the organization seen in an actual developing brain.

Jürgen Knoblich, deputy scientific director of IMBA and last author on the paper, elucidates the implications of the novel technology: “An important hallmark of the bioengineered organoids is their increased surface to volume ratio. Neurons ‘have more space’ and can properly migrate and position themselves in a layer that in an actual developing brain would later become the grey matter. Because of their improved tissue architecture, enCORs can allow for the study of a broader array of neurological diseases where neuronal positioning is thought to be affected, including lissencephaly (smooth brain), epilepsy, and even autism and schizophrenia.”

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Researchers closer to cracking neural code of love

A team of neuroscientists from Emory University’s Silvio O. Conte Center for Oxytocin and Social Cognition has discovered a key connection between areas of the adult female prairie vole’s brain reward system that promotes the emergence of pair bonds. Results from this study, could help efforts to improve social abilities in human disorders with impaired social function, such as autism. In addition to the online posting, the study is expected to be in the June 8 printed edition of Nature.

This Conte Center study is the first to find the strength of communication between parts of a corticostriatal circuit in the brain predicts how quickly each female prairie vole becomes affiliative with her partner; prairie voles are socially monogamous and form lifelong bonds with their partners. Additionally, when researchers boosted the communication by using light pulses, the females increased their affiliation toward males, thus further demonstrating the importance of this circuit’s activity to pair bonding in prairie voles.

“Prairie voles were critical to our team’s findings because studying pair bonding in humans has been traditionally difficult,” says Dr. Elizabeth Amadei, a co-lead author on the research. “As humans, we know the feelings we get when we view images of our romantic partners, but, until now, we haven’t known how the brain’s reward system works to lead to those feelings and to the voles’ pair bonding.”

Building upon previous work in prairie voles that demonstrated brain chemicals, such as oxytocin and dopamine, act within the medial prefrontal cortex and nucleus accumbens to establish a pair bond, the team set out to address finding the precise neural activity leading to a pair bond. The researchers used probes to listen to neural communication between these two brain regions and then analyzed activity from individual female prairie voles as they spent hours socializing with a male — a cohabitation period that normally leads to a pair bond.

The team discovered that during pair bond formation, the prefrontal cortex, an area involved in decision-making, helps control the rhythmic oscillations of neurons within the nucleus accumbens, the central hub of the brain’s reward system. This suggests a functional connection from the cortex shapes neurons activity in the nucleus accumbens.

The team then noticed individual voles varied in the strength of this functional connectivity. Importantly, each subject with stronger connectivity showed more rapid affiliative behavior with her partner, measured as side-by-side huddling contact. Furthermore, the pair’s first mating, a behavior that accelerates bonding in voles, strengthened this functional connection, and the amount of strengthening correlated with how quickly the animals subsequently huddled.

According to Larry Young, PhD, co-author and director of the Conte Center, “It is remarkable there are neural signatures of a predisposition to begin huddling with the partner. Similar variation in corticostriatal communication could underlie individual differences in social competencies in psychiatric disorders in humans, and enhancing that communication could improve social function in disorders such as autism.” Young is also chief of the Division of Behavioral Neuroscience and Psychiatric Disorders at the Yerkes National Primate Research Center.

The study results led the team to ask more questions, including whether communication between the prefrontal cortex and nucleus accumbens not only correlates with huddling but also causally facilitates it. To answer this, the researchers used optogenetics, a technique that allowed them to enhance communication between the brain areas using light, and enhanced communication between the prefrontal cortex and nucleus accumbens of female voles during a brief cohabitation without mating, which is not conducive to pair bonding. The team discovered optogenetically stimulated animals showed greater preference toward partners compared to a stranger male when given a choice the following day. “It is amazing to think we could influence social bonding by stimulating this brain circuit with a remotely controlled light implanted into the brain,” says Zack Johnson, PhD, co-lead author.

The study results identify an important reward circuit in the brain that is activated during social interactions to facilitate bond formation in voles. “Now, we want to know if oxytocin regulates functional connectivity and how circuit activity changes the way the brain processes social information about a partner,” says senior author Robert Liu, PhD, associate professor in Emory’s Department of Biology. “Our team’s work is an example of a larger effort in neuroscience to better quantify how brain circuits function during natural social behaviors. Our goal is to promote better neural communication to boost social cognition in disorders such as autism, in which social functioning can be impaired,” Liu continues.

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Century-old drug as potential new approach to autism

In a small, randomized Phase I/II clinical trial (SAT1), researchers at University of California San Diego School of Medicine say a 100-year-old drug called suramin, originally developed to treat African sleeping sickness, was safely administered to children with autism spectrum disorder (ASD), who subsequently displayed measurable, but transient, improvement in core symptoms of autism.

ASD encompasses a group of developmental disorders, often characterized by communication and language difficulties, repetitive behaviors and inability to socialize. The Centers for Disease Control and Prevention estimate that ASD occurs in 1 in 68 children, with the condition 4 times more common in boys than girls. ASD has no single known cause, but may involve both genetic problems and environmental factors, such as viral infections, pollutants or complications during pregnancy. One of the aims of the SAT1 study was to test the cell danger hypothesis as a possible unifying theory that contributes to the pathogenesis of ASD.

Writing in the Annals of Clinical and Translational Neurology, first author Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology at UC San Diego School of Medicine and colleagues describe a novel double-blind, placebo-controlled safety study involving 10 boys, ages 5 to 14 years, all diagnosed with ASD.

Five of the 10 boys received a single, intravenous infusion of suramin, a drug originally developed in 1916 to treat trypanosomiasis (sleeping sickness) and river blindness, both caused by parasites. The other five boys received a placebo. The trial followed earlier testing in a mouse model of autism in which a single dose of suramin temporarily reversed symptoms of the neurological disorder.

The results in humans were equally notable, though the purpose of the SAT1 trial was fundamentally to test the researchers’ underlying theory about a unifying cause for autism and to assess the safety of suramin, which is not an approved treatment of ASD. In fact, there are no approved drugs to treat the core symptoms of ASD.

All five boys who received the suramin infusion displayed improvements in language and social behavior, restricted or repetitive behaviors and coping skills. Assessment of improvements was based upon observational examinations and interviews using standardized tests and questionnaires, such as the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2), the Expressive One Word Picture Vocabulary Testing (EOWPWT), the Aberrant Behavior Checklist (ABC), the Autism Treatment Evaluation Checklist (ATEC), the Repetitive Behavior Questionnaire (RBQ) and the Clinical Global Impression (CGI) questionnaire. To minimize misinterpretation of natural day-to-day variations in symptoms, parents were asked to mark a symptom as changed in the 6-week CGI only if the symptom lasted for at least one week.

The researchers found that ADOS-2 scores were improved in the suramin treatment group at six weeks, but not in the placebo group. Specifically, ADOS-2 scores improved by -1.6 points in the suramin group, but did not change in the placebo. Children who have a score of 6 or lower in ADOS-2 may have milder symptoms but no longer meet the formal diagnostic criteria for ASD. A score of 7 to 8 indicates the child is on the autism spectrum. Nine and above classifies the child as autistic.

Suramin treatment was also associated with improvements in the ABC, ATEC and CGI measurements, but not RBQ. The most changed behaviors, the authors said, were social communication and play, speech and language, calm and focus, repetitive behaviors and coping skills.

Participating families also reported benefits among the children who received suramin. “We saw improvements in our son after suramin that we have never seen before,” said the parent of a 14-year-old who had not spoken a complete sentence in 12 years.

“Within an hour after the infusion, he started to make more eye contact with the doctor and nurses in the room. There was a new calmness at times, but also more emotion at other times. He started to show an interest in playing hide-and-seek with his 16-year-old brother. He started practicing making new sounds around the house. He started seeking out his dad more.

“We have tried every new treatment out there for over 10 years. Nothing has come close to all the changes in language and social interaction and new interests that we saw after suramin. We saw our son advance almost three years in development in just six weeks.”

Cell Danger Response

Naviaux, who is co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, believes that ASD — and several other chronic conditions, including chronic fatigue syndrome and some autoimmune disorders — are caused by metabolic dysfunction or impaired communication between cells in the brain, gut and immune system.

Specifically, this dysfunction is caused by abnormal persistence of the cell danger response (CDR), a natural and universal cellular reaction to injury or stress. “The purpose of CDR is to help protect the cell and jump-start the healing process,” said Naviaux, by essentially causing the cell to harden its membranes, cease interaction with neighbors and withdraw within itself until the danger has passed.

“But sometimes CDR gets stuck,” Naviaux said. “This prevents completion of the natural healing cycle and can permanently alter the way the cell responds to the world. When this happens, cells behave as if they are still injured or in imminent danger, even though the original cause of the injury or threat has passed.”

At the molecular level, cellular homeostasis or equilibrium is altered, creating an abnormal cellular response that leads to chronic disease. “When this happens during early child development,” said Naviaux, “it causes autism and many other chronic childhood disorders.”

Suramin works by inhibiting the signaling function of adenosine triphosphate (ATP), a nucleotide or small molecule produced by cellular mitochondria and released from the cell as a danger signal. When CDR is activated, the effect of extracellular ATP is similar to a warning siren that never stops. Suramin inhibits the binding of ATP and similar molecules to key purinergic receptors, according to Naviaux. It silences the siren, “signaling the cellular war is over, the danger has passed and cells can return to ‘peacetime’ jobs like normal neurodevelopment, growth and healing.”

“There is evidence, gathered over the past 10 to 15 years, that children with ASD can exhibit oxidative stress, an outcome of the cell danger response,” said Pat Levitt, PhD, Simms/Mann Chair in Developmental Neurogenetics at Children’s Hospital Los Angeles and W.M. Keck Provost Professor in Neurogenetics at Keck School of Medicine of University of Southern California. “This can impact how well neurons and circuits function. Why this would impose problems on certain circuits that mediate specific behaviors, such as social communication, is unclear, but this is why understanding how genetic risk and environmental factors combine to increase risk for autism spectrum disorder is important.”

Levitt was not involved in the study.

Dramatic, but Temporary Benefit

“We had four non-verbal children in the study,” said Naviaux, “two 6-year-olds and two 14-year-olds. The six-year-old and the 14-year-old who received suramin said the first sentences of their lives about one week after the single suramin infusion. This did not happen in any of the children given the placebo.”

Additionally, Naviaux said, “that during the time the children were on suramin, benefit from all their usual therapies and enrichment programs increased dramatically. Once suramin removed the roadblocks to development, the benefit from speech therapy, occupational therapy, applied behavioral analysis and even from playing games with other children during recess at school skyrocketed. Suramin was synergistic with their other therapies.”

Naviaux and colleagues do not believe CDR is the cause of ASD, but rather a fundamental driver that combines with other factors, such as genetics or environmental toxins. And suramin, at this stage, is not the ultimate answer.

Unlike treatment for African sleeping sickness, which involves multiple, higher doses of suramin over a period of time and frequently results in a number of adverse side effects ranging from nausea and diarrhea to low blood pressure and kidney problems, researchers said the single, low dose of suramin used in the ASD trial produced no serious side effects beyond a passing skin rash.

But the therapeutic benefit of suramin was temporary: Improvements in the treated boys’ cognitive functions and behaviors peaked and then gradually faded after several weeks as the single dose of suramin wore off.

The primary import of the trial’s findings, said Naviaux, is that it points a way forward, that suramin should be tested in larger, more diverse cohorts of persons with ASD. (Naviaux said his research has been limited by costs; his lab is primarily supported through philanthropy.)

“This work is new and this type of clinical trial is expensive,” he said. “We did not have enough funding to do a larger study. And even with the funding we were able to raise, we had to go $500,000 in debt to complete the trial.”

Larger and longer trials would include multiple doses of suramin over longer periods of time, allowing researchers to map whether improvements continue or if uncommon side effects appear when participant numbers are greater.

If Not Suramin, Maybe Something Like It

Andrew W. Zimmerman, MD, a clinical professor of pediatrics and neurology at the UMass Memorial Medical Center who was not involved in the suramin trial but is conducting similar research, described the study results as “very encouraging for the field of autism, not only for the positive effects of suramin for the children who received the drug, but also for confirmation of the important ‘cell danger response.’

“As the authors point out, many genetic variants have been found in ASD, but few have led to specific treatments. The CDR includes a number of metabolic pathways that may be affected by a number of genetic mutations or by environmental factors that have effects epigenetically — beyond the genes themselves.”

The Food and Drug Administration has not approved suramin for any therapeutic use in the United States. It is not commercially available. Naviaux noted that new trials could prove suramin is not an effective ASD treatment. Its benefits may prove too limited over the long term, he said, or an unacceptable safety issue might arise.

But “even if suramin itself is not the best antipurinergic drug for autism, our studies have helped blaze the trail for the development of new antipurinergic drugs that might be even better,” said Naviaux. “Before our work, no one knew that purinergic signaling abnormalities were a part of autism. Now we do, and new drugs can be developed rationally and systematically.”

Levitt at USC agreed: “The suramin pilot study is too small from which to draw specific conclusions about the treatment, but there is no doubt that the pilot study reports positive outcomes for all five children who received the medication. The findings provide a strong rationale for developing a larger study that can probe functional improvements in children in greater depth.”

The potential financial cost of ASD treatment using suramin cannot yet be determined for several reasons, the study authors said. First, additional trials are required to determine the effective dosage and frequency for different types of patients. Suramin is used much differently for treating sleeping sickness, but the cost for a one month course of treatment is modest: approximately $27. Second, the age of the drug means that, if approved, it would almost certainly result in cheaper, generic formulations, but there is no way to accurately predict how that would play out at this time.

John Rodakis, founder and president of the N of One: Autism Research Foundation, which provided funding support for the study, said that despite all of the necessary caveats and need for additional research, the findings are “promising, hopeful work for a community of affected families that have been given little in the way of answers by medicine.”

Brain anatomy differs in people with 22q genetic risk for schizophrenia, autism

A UCLA study characterizes, for the first time, brain differences between people with a specific genetic risk for schizophrenia and those at risk for autism, and the findings could help explain the biological underpinnings of these neuropsychiatric disorders.

The research, published May 23 in the Journal of Neuroscience, sheds light on how an excess, or absence, of genetic material on a particular chromosome affects neural development.

“Notably, the opposing anatomical patterns we observed were most prominent in brain regions important for social functioning,” said Carrie Bearden, lead author of the study and a professor of clinical psychology at UCLA. “These findings provide clues into differences in brain development that may predispose to schizophrenia or autism.”

Bearden’s earlier research had focused on children with abnormalities caused by missing sections of genetic material on chromosome 22, in a location known as 22q11.2. The disorder, called 22q11.2-deletion syndrome, can cause developmental delays, heart defects and distinct facial features. It also confers the highest-known genetic risk for schizophrenia.

Then she learned that people with 22q duplication — abnormal repetition, or duplication, of genetic material in chromosome 22 — had learning delays and sometimes autism, but a lower risk for schizophrenia than that found in the general population. In other words, duplication of genetic material in this region seemed to provide some protection against schizophrenia.

For the current study, Bearden, who is part of the UCLA Semel Institute for Neuroscience and Human Behavior, conducted MRI scans of 143 study participants: 66 with 22q deletions, 21 with 22q duplications, and 56 without the genetic mutation.

Those in the group with 22q deletion, which carries the risk for schizophrenia, had thicker gray matter, but less brain surface area — a measure which relates to how folded the brain is — compared to those in the duplication group. The people in the 22q duplication group, who at risk for autism, had the opposite pattern, with thinner gray matter and larger brain surface area.

“The next question is how does brain anatomy — and brain function — relate to psychiatric outcomes? These findings provide a snapshot,” Bearden said. “We are now conducting follow-up studies to track predictors of outcome over time. Those are the puzzle pieces that are next on our list to disentangle.”

These structures are not sole determinants of schizophrenia or autism, Bearden said, but rather, more dots in the connect-the-dots puzzle of understanding these disorders. Observing this group of people over time could provide insights on how other risk factors or life events, such as puberty, affect the mind.

Bearden says she and her team are collaborating with other scientists to investigate brain structural differences in animal models, to find out what causes them at the cellular level.

Tracking devices may improve quality of life for parents of children with autism

Many children with Autism Spectrum Disorder face increased risk of injury when they wander away from adults who care for them. Even when parents take safety precautions such as installing window bars at home, studies show parents’ fear of their children wandering is a significant source of stress for families. New research being presented at the 2017 Pediatric Academic Societies Meeting suggests that electronic tracking devices worn by children may reduce how often children wander and help ease parents’ anxiety.

Researchers will discuss the study abstract, “Impact of Tracking Device Technology on Quality of Life for Families with a Child with an Autism Spectrum Disorder,” during a platform presentation on Saturday, May 6, at the Moscone West Convention Center in San Francisco. They will also present 5 other abstracts about studies they conducted using the same cohort, currently the largest national sample of children who have wandered, during a poster session on Tuesday, May 9.

According to national estimates, more than a quarter million children with autism and other developmental disorders wander away from adult supervision each year, said Andrew Adesman, MD, FAAP, a senior investigator for the abstracts being presented and Chief of Developmental & Behavioral Pediatrics at the Seven and Alexandra Cohen Children’s Medical Center of New York.

“In recent years, parents and professionals have become increasingly aware of not only the dangers associated with wandering by children with autism, but also the emotional toll this places on families and the limits it imposes on activities,” Dr. Adesman said.

“Given the magnitude of safety risks and parental concerns, it is important to find evidence-based solutions that reduce the likelihood of injury to children and can provide parents with less reason for worry,” he said.

For the studies, researchers examined online survey responses from 1,345 parents invited to participate through autism organizations nationwide. The parents answered questions about their children’s developmental diagnosis and severity, past wandering behavior and prevention strategies they’d used to address the behavior, including extra locks and physical barriers, child harnesses, and electronic tracking devices that used radio, Bluetooth or global positioning system (GPS) technology to help parents quickly find children who wander off.

Results suggest that that electronic tracking devices reduced parent-rated wandering frequency by nearly a quarter (23 percent) while also having wider effects on household anxiety levels, routines and perceived quality of life. The majority of parents (87 percent) said that before using an electronic tracking device, concerns about wandering affected decisions whether to let their child spend time with friends or family in their absence, for example. This compared to 60 percent of parents who said this was the case while using an electronic tracking device.

Overall, 96 percent of parents who said they were currently using an electronic tracking device said it made their quality of life better (47 percent send it made it “somewhat better,” and 49 percent said “much better.”)

“Despite the development of several types of electronic tracking devices aimed at helping to reduce risks related to wandering by children with autism and other developmental disorders, currently there are no published findings regarding the effectiveness of these devices or their impact on families,” said Laura McLaughlin, Developmental & Behavioral Pediatrics Research Assistant and Principal Investigator for the studies.

Dr. Adesman said the findings suggest physicians who care for children at risk for wandering should become informed about different electronic tracking devices and counsel parents about potential benefits.

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Materials provided by American Academy of Pediatrics. Note: Content may be edited for style and length.