Tag Archives: #autism

Gene Associated With Autism Linked To Itch Response (Biology)

A pilot study from North Carolina State University has found that a gene associated with autism spectrum disorder (ASD) and pain hypersensitivity may actually decrease itch response. Atopic dermatitis and pain hypersensitivity are both conditions associated with some types of ASD.null

The gene in question, contactin associated protein 2 (CNTNAP2), is thought to be linked to a mutation associated with some forms of autism. This gene is found throughout the dorsal root ganglia (DRG), which are clusters of sensory cells located at the root of the spinal nerves. The DRG is the superhighway that transmits sensations of both pain and itch from the skin through the spinal cord to the brain.

“Since atopic dermatitis is often associated with ASD and CNTNAP2 is both linked to pain hypersensitivity in ASD and expressed in almost all DRG sensory neurons, we wondered whether CNTNAP2 might also contribute to itch behavior,” says Santosh Mishra, assistant professor of neuroscience at NC State and author of the study.

Mishra compared itch response in mice with the CNTNAP2 gene to those without it. In the presence of both histamine and non-histamine based stimuli, the CNTNAP2 knock-out mice, or mice without the gene, had a reduced itch response compared to mice with the gene.

“If there is a link between ASD and atopic dermatitis, then mice without a normal CNTNAP2 gene would be expected to have an increased itch response just as they have increased sensitivity to pain,” Mishra says. “There are several possible explanations for this finding, ranging from standard physiological differences between humans and animals to CNTNAP2’s potential role in releasing neuropeptides that could affect this response.

“But we also know that pain can suppress itch sensation and vice versa. Just as some humans with ASD have higher pain sensitivity, so do mice without CNTNAP2. That pain sensitivity may be inhibiting the itch sensation.”

Mishra hopes that this pilot study may pave the way to further exploration of the role of CNTNAP2 in itch.

“The functional role of CNTNAP2 in the neural transmission of itch is unknown,” Mishra says. “While this study sheds light on the possible linkage between ASD and itch, it’s limited because it is primarily based on behavioral, not cellular or molecular, results. Future studies may be required to dissect the molecular underpinnings of CNTNAP2 and itch sensation.”

Reference: Santosh K. Mishra, The Role of CNTNAP2 in Itch Sensation, Journal of Investigative Dermatology (2021). DOI: 10.1016/j.jid.2021.07.152

Provided by North Carolina State University

Brain Organoid Study Highlights Potential Role of Genetic and Environmental Interaction in Autism Spectrum Disorder (Neuroscience)

Study illustrates a quicker and less expensive way to explore gene-plus-environment causes of autism spectrum disorder and other conditions

Researchers at Johns Hopkins Bloomberg School of Public Health have shown in a brain organoid study that exposure to a common pesticide synergizes with a frequent autism-linked gene mutation.

The results represent one of the clearest pieces of evidence yet that genetic and environmental factors may be able to combine to disturb neurodevelopment. Researchers suspect that genetic and environmental factors might contribute to the increased prevalence of autism spectrum disorder, a developmental disorder characterized by cognitive function, social, and communication impairments.

The study’s use of brain organoids also points the way towards quicker, less expensive, and more human-relevant experimentation in this field when compared to traditional animal studies.

The brain organoid model, developed by the Bloomberg School researchers, consists of balls of cells that are differentiated from human stem cell cultures and mimic the developing human brain. The researchers found in the study that chlorpyrifos, a common pesticide alleged to contribute to developmental neurotoxicity and autism risk, dramatically reduces levels of the protein CHD8 in the organoids. CHD8 is a regulator of gene activity important in brain development. Mutations in its gene, which reduce CHD8 activity, are among the strongest of the 100-plus genetic risk factors for autism that have so far been identified.

The study, which appears online July 14 in Environmental Health Perspectives, is the first to show in a human model that an environmental risk factor can amplify the effect of genetic risk factor for autism.

“This is a step forward in showing an interplay between genetics and environment and its potential role for autism spectrum disorder,” says study lead Lena Smirnova, PhD, a research associate in the Department of Environmental Health and Engineering at the Bloomberg School.

Clinically rare as recently as 40 years ago, autism spectrum disorder now occurs in roughly two percent of live births, according to the Centers for Disease Control and Prevention.

“The increase in autism diagnoses in recent decades is hard to explain—there couldn’t have been a population-wide genetic change in such a short time, but we also haven’t been able to find an environmental exposure that sufficiently accounts for it,” says study co-author Thomas Hartung, MD, PhD, professor and Doerenkamp-Zbinden Chair in the Bloomberg School’s Department of Environmental Health and Engineering. Hartung is also director of the Center for Alternatives to Animal Testing at the Bloomberg School. “To me, the best explanation involves a combination of genetic and environment factors,” says Hartung.

How environmental factors and genetic susceptibilities interact to increase risk for autism spectrum disorder remains mostly unknown, in part because these interactions have been difficult to study. Traditional experiments with laboratory animals are expensive and, especially for disorders involving the brain and cognition, of limited relevance to humans.

Advances in stem cell methods in the past decades have allowed researchers to use human skin cells that can be transformed first into stem cells and then into almost any cell type and studied in the lab. In recent years, scientists have expanded beyond simple lab-dish cell cultures to make cultures of three-dimensional organoids that better represent the complexity of human organs.

For their study, the researchers used brain organoids to model the effects of a CHD8 gene disruption combined with exposure to chlorpyrifos. A group led by co-author Herbert Lachman, MD, professor at Albert Einstein College of Medicine, engineered the cells that make up the organoids to lack one of the two normal copies of the CHD8 gene. This modeled a substantial, but less-than-total, weakening of the CHD8 gene’s activity, similar to that seen in people who have CHD8 mutations and autism. The researchers then examined the additional effect of exposure to chlorpyrifos, which is still widely used on agricultural produce in the U.S. and abroad.

“High-dose, short-term experimental exposures do not reflect the real-life situation, but they give us a starting point to identify genetic variants that might make individuals more susceptible to toxicants,” says Smirnova. “Now we can explore how other genes and potentially toxic substances interact.”

The researchers found that the brain organoids with just one copy of the CHD8 gene had only two-thirds the normal level of CHD8 protein in their cells, but that chlorpyrifos exposure drove CHD8 levels much lower, turning a moderate scarcity into a severe one. The exposure demonstrated clearly how an environmental factor can worsen the effect of a genetic one, likely worsening disease progression and symptoms.

As part of their study, the researchers compiled a list of molecules in blood, urine, and brain tissue that prior studies have shown to be different in autism spectrum patients. They found that levels of several of these apparent autism biomarkers were also significantly altered in the organoids by CHD8 deficiency or chlorpyrifos exposure, and moreso by both.

“In this sense, we showed that changes in these organoids reflect changes seen in autism patients,” Smirnova says.

The findings, according to the researchers, pave the way for further studies of gene-environment interactions in disease using human-derived organoids.

“The use of three-dimensional, human-derived, brain-like models like the one in this study is a good way forward for studying the interplay of genetic and environmental factors in autism and other neurodevelopmental disorders,” Hartung says.

“Gene–Environment Interactions in Developmental Neurotoxicity: A Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres” was written by Sergio Modafferi, Xiali Zhong, Andre Kleensang, Yohei Murata, Francesca Fagiani, David Pamies, Helena Hogberg, Vittorio Calabrese, Herbert Lachman, Thomas Hartung, and Lena Smirnova.

The study was funded in part by the Alternatives Research and Development Foundation and the Environmental Protection Agency (R839505).


Thomas Hartung, Helena Hogberg, and David Pamies are named inventors on a patent by Johns Hopkins University on the production of mini-brains (also called BrainSpheres), which is licensed to AxoSim, New Orleans, Louisiana, USA. Thomas Hartung, Lena Smirnova, David Pamies, and Helena Hogberg are consultants for AxoSim, New Orleans, and Thomas Hartung is also a consultant for AstraZeneca and American Type Culture Collection (ATCC) on advanced cell culture methods. All other authors declare they have no actual or potential competing financial interests.

Featured image credit: gettyimages

Provided by Johns Hopkins Bloomberg School of Public Health

New Genetic Driver Of Autism And Other Developmental Disorders Identified (Neuroscience)

research group including Kobe University’s Professor TAKUMI Toru (also a Senior Visiting Scientist at RIKEN Center for Biosystems Dynamics Research) and Assistant Professor TAMADA Kota, both of the Physiology Division in the Graduate School of Medicine, has revealed a causal gene (Necdin, NDN) in autism model mice that have the chromosomal abnormality*1 called copy number variation*2.

The researchers hope to illuminate the NDN gene’s molecular mechanism in order to contribute towards the creation of new treatment strategies for developmental disorders including autism.

These research results were published in Nature Communications on July 1, 2021.

Main points

  • The research group identified Ndn as a causal gene of autism by conducting a screening based on synaptic expression in an animal model of the disorder (15q dup mouse).
  • The Ndn gene regulates synapse*3 development during the developmental stage.

Research Background

Even though the number of patients diagnosed with autism (autism spectrum disorder) has been greatly increasing, many aspects of this developmental disorder are still not well understood. Its causes are divided into genetic factors and environmental factors. Within these genetic factors, particular copy number variations have been found in autistic patients; for example, chromosome 15q11-q13 duplication. These abnormalities in the 15q11-q13 region are divided into maternally derived and paternally derived chromosomal duplication cases. It is understood that the Ube3a gene drives maternally derived chromosomal duplication. However, it is not known which gene is vital for paternally derived duplication.

This research group previously succeeded in developing a mouse model of 15q11-q13 duplication (15q dup mouse). Using this mouse model, they identified numerous abnormalities in paternally derived chromosomal duplication cases, including autism-like behaviors, and abnormalities in dendritic spine*4 formation. However, the researchers were unable to identify which gene is responsible for autism-like behavior because this region contains many non-coding RNA molecules and genes that code proteins.

Research Methodology

In 15q dup mice, there is a great number of genes as the duplication extends to the 6Mb region. Previous research showed that behavioral abnormalities were not induced by maternally derived chromosomal duplication, therefore around 2Mb was excluded. As for the remaining 4Mb, the researchers first created a new 1.5Mb duplication mouse model and investigated behavior abnormalities. From the results, they were unable to identify any autism-like behavioral abnormalities in 1.5Mb duplication mice. Consequently, the researchers excluded this 1.5Mb, leaving them with three protein-encoding genes as possible candidates.

Next, these three genes were individually introduced into the cerebral cortex of mice via in utero electroporation*5. The researchers measured the spine turnover rate (formation and elimination of dendritic spines over a 2 day period) in vivo using a two-photon microscope*6 and discovered that the number of spines drastically increased when the Ndn gene was introduced (Figure 1A-C). Furthermore, morphology classification of these spines indicated that the majority were immature. This reveals that the Ndn gene regulates the formation and maturation of dendritic spines during the developmental stage (Figure 1D).

Figure 1: A: Illustration of the experiment. Green fluorescent proteins were introduced so that the target gene and the entire neuron could be observed. B: Each target gene was separately introduced into the cerebral cortex and dendritic spine dynamics were tracked for a period of 2 days (on the 21st and 22nd days after birth). Yellow arrows indicate newly formed spines and red arrowheads indicate spine elimination. C: The quantified results of B in graph form. D: Spine morphology classification data on the spines that formed when Ndn was introduced. Filopedia, a type of immature spine formation, significantly increased upon Ndn introduction. © Kobe University

Using CRISPR-Cas9*7, the researchers subsequently removed the one copy of the Ndn gene from the 15q dup mouse model to generate mice with a normalized genomic copy number for this gene (15q dupΔNdn mouse). Using this model, they demonstrated that the abnormalities observed in 15q dup mice (abnormal spine turnover rate and decreased inhibitory synaptic input) could be ameliorated (Figure 2).

Figure 2. A: Creation diagram of the 15q dupΔNdn mouse. The copy of the Ndn gene was removed from the original 15q dup mouse model of autism. B: Dendritic spine formation rate in 15q dupΔNdn mice. C and D: Quantification of inhibitory synapses. © Kobe University

Lastly, the researchers investigated whether the previously observed autism-like behaviors in 15q dup mice (including increased anxiety in a new environment, reduced sociability and increased perseveration) were evident in 15q dupΔNdn mice. They showed that in the majority of behavioral test results for 15q dupΔNdn mice, abnormal behaviors related to sociability and perseveration were ameliorated (Figure 3).

Figure 3. A: The Results of the Open Field Test. When a mouse is placed in a box, it will begin to investigate its environment. Mice usually prefer corners and avoid central, open areas when in a new environment. By calculating the time spent in each area and the distance moved, it is possible to evaluate the mouse’s level of anxiety. The 15q dup mice used in this research up until now displayed a high level of anxiety in this experiment. B: The results of the Social Interaction Test. Two mice that have never encountered each other before are placed in the same box. Sociability is evaluated by observing how long it takes them to interact and their physical contact. In the research group’s studies up until now, 15q dup mice’s sociability during this test was lower than that of normal mice. C: The results of the Reverse Learning Test using a Barnes maze. A Barnes maze is a circular plate with 12 holes in it where only one of the holes is the ‘target’. The target hole has a box below it that the mouse can enter. A bright light is positioned above the circular plate. Mice generally dislike bright light and prefer dark places, so if a mouse is put on the plate, it will look for somewhere to hide. Using this characteristic, the mouse can be made to learn the target hole’s location over a period of days (C, upper illustration). Once the mouse has learned the target’s location correctly, the target’s location is reversed and relearned (C, lower illustration). It is understood that normal mice learn the new target location comparatively quickly compared to 15q dup mice who are slow to learn the new target, and persist in going to the original target’s location (perseveration). For the learning test, the target is removed and learning is evaluated by observing which hole(s) the mouse goes to and how long it stays there (Figure 3- right: TA= the new target hole and the two holes on either side. AJ1, AJ2: The three holes in each adjacent sector, OP: The previously learned target, and the two holes on either side.). © Kobe University

Further Research

This research study revealed that in 15q dup autism model mice, the NDN gene does not only play an important role in autism-like behaviors, but also affects aspects such as excitation/inhibition imbalance in synaptic dynamics and the cerebral cortex. Next, the research team hopes to clarify the NDN gene’s functions. By artificially regulating these functions or identifying and controlling their downstream factors, the researchers hope to understand the onset mechanism of developmental disorders like autism, and develop new treatment strategies.


※1 Chromosomal abnormality: Chromosomes are structures that contain genes and are located inside the cell nucleus. Abnormalities such as duplications or deletions in specific regions of the chromosome are often seen in those with autism.

※2 Copy number variation: A chromosomal abnormality where the number of copies of a region on the genome is abnormal (duplications or deletions). Normally there should be 2 copies (diploid). If there are 3 copies or just one copy, then this is a copy number variation.

※3 Synapse: A junction between two nerve cells (neurons), which is involved in neuronal activities such as transmitting signals.

※4 Dendritic spine: These are protrusions on the dendrites of excitable neurons that receive input from synapses.

※5 in utero electroporation: A method of introducing outside DNA into the brain. DNA is injected through the wall of the uterus and is induced to enter the cells using electric waves.

※6 Two-photon microscope: A microscope with powerful laser, which enables the brains of mice to be observed while they are still alive. In this study, it was used to track changes in dendritic spines over a 2 day-period.

※7 CRISPR-Cas9: Technology that enables a specific region of a genome to be precisely cut and altered. This genome editing method won the 2020 Nobel Prize in Chemistry. In this study, it was used to remove the Ndn gene from the genome.


This research was partially funded by KAKENHI grants from the Japan Society for the Promotion of Science (JSPS), including in the innovative area entitled: ‘Dynamic regulation of brain function by Scrap & Build system’, and the Takeda Science Foundation among others.

Journal Information

  • Title: “Genetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications”
  • DOI10.1038/s41467-021-24359-3
  • Authors: Kota Tamada, Keita Fukumoto, Tsuyoshi Toya, Nobuhiro Nakai, Janak R Awasthi, Shinji Tanaka, Shigeo Okabe, Francois Spitz, Fumihito Saitow, Hidenori Suzuki, Toru Takumi
  • Journal: Nature Communications

Provided by Kobe University

Autistic Children Can Benefit From Attention Training (Neuroscience)

Attention training in young people with autism can lead to significant improvements in academic performance, according to a new study.

Researchers at the University of Birmingham in the UK along with institutions in São Paolo, in Brazil, tested a computer programme designed to train basic attention skills among a group of autistic children aged between eight and 14 years old.

They found participants achieved improvements in maths, reading, writing and overall attention both immediately after undergoing the training and at a three-month follow up assessment. Their results are published in Autism Research.

Lead researcher, Dr Carmel Mevorach, in the University of Birmingham’s Centre for Human Brain Health, and School of Psychology, says: “It’s only recently that we have started to focus on the way autistic people pay attention in addition to, for example, how they interact and socialise. Attention is a fundamental cognitive process and better controlling it can have an impact on other behaviours, as well as on learning ability.”

In the study, the team worked with 26 participants with Autistic Spectrum Disorder (ASD) in the São Paolo ASD Reference Unit, a specialist children’s treatment unit. The children took part in 45-minute training sessions twice a week for 8 weeks.

Half of the group took part used a computer programme called CPAT – Computerised Progressive Attentional Training, that was developed in an earlier project by the Birmingham team in partnership with researchers at Tel-Aviv University in Israel. The CPAT programme includes training games targeting different types of attention, and at progressively more difficult levels.

The second half of the group were a control group and were given ordinary computer games to play. The trial was conducted so that none of the children, their families, or the researchers assessing them knew which group they were in and they were each simply told that they would be playing games that could help them in school.

Immediately after completing the training the CPAT group showed improvements in the number of isolated words they could correctly identify and read in 10 minutes (an increase from around 44 to around 53). They were also able to increase the number of words they could copy from around 18 to around 25. In maths, the CPAT group improved their scores by more than 50 per cent. All these improvements were maintained when the children were re-tested three months after completing the programme.

In contrast, the control group participants showed no evidence of improvement in any of the three areas.

The CPAT programme is currently included within the Teacher Training in Attention in Autism (TTAA) Erasmus+ project which has partners in Greece, Spain, Israel and the UK. The team is also carrying out local pilot projects with schools in each of the countries to enable teachers to embed it within their setting in whichever way they think will work best.

Dr Mevorach adds: “We’ve found that by giving teachers the freedom to experiment with CPAT we are finding out much more about its potential benefits. Autism is highly individual, so developing an intervention that can be tuned to a particular individual or setting is really key to success.”

The next stage for the research is to carry out a larger clinical trial to establish the potential impact of the intervention. The research was funded in the UK by the Economic and Social Research Council, part of UK Research and Innovation, and by the European Union’s Erasmus Programme.

Featured image Credit: Thomas Park/Unsplash

Notes to editor:

Provided by University of Birmingham

Feel-good Hormone Dopamine Affects Passion And Autism (Neuroscience)

Dopamine is often called the “happy” or “feel-good” hormone. It can help explain both autistic behaviours and men’s need for passion in order to succeed.

Men – more often than women – need passion to succeed at things. At the same time, boys are diagnosed as being on the autism spectrum four times as often as girls.

Both statistics may be related to dopamine, one of our body’s neurotransmitters.

“This is fascinating. Research shows a more active dopamine system in most men” than in women, says Hermundur Sigmundsson, a professor at NTNU’s Department of Psychology.

He is behind a new study that addresses gender differences in key motivating factors for what it takes to become good at something. The study uses men’s and women’s differing activity in the dopamine system as an explanatory model.

An abstract illustration showing the chemical formula to dopamine and a man with a smiling brain
Among other things, dopamine can affect our feeling of happiness. Illustration: Shutterstock, NTB

Not just a “happy hormone”

“We looked at gender differences around passion, self-discipline and positive attitude,” Sigmundsson says.

Dopamine is a neurotransmitter that is released in the brain. It can contribute to a feeling of satisfaction.

The study refers to these qualities as passion, grit and mindset. The researchers also applied theories to possible links with dopamine levels.

Dopamine is linked to learning, attention and our ability to focus.

Dopamine is a neurotransmitter that is released in the brain. It can contribute to a feeling of satisfaction.

Men normally secrete more dopamine, which is often called the “happy hormone,” but it plays a far more complex role than that. The effects of dopamine are linked to learning, attention and our ability to focus.

Dopamine and passion

Previous studies on Icelandic students have shown that men are more dependent on passion in order to succeed at something. This study confirms the earlier findings. Men require more passion. In six out of eight test questions, men score higher on passion than women.

However, the association with dopamine levels has not been established previously.

“The fact that we’ve developed a test to measure passion for goal achievement means that we can now relate dopamine levels to passion and goal achievement,” says Sigmundsson.

An illustration showing the growth mindset
Positive attitude – or mindset – is the basis for a person’s success. Self-discipline – or grit – determines the strength and scope of the effort. Passion determines the direction, that is, what a person becomes good at. Illustration: Hermundur Sigmundsson, NTNU

Women, on the other hand, may have greater self-discipline – or grit – and be more conscientious, according to other studies. Their level of passion may not be as pronounced in general, but they still are able to do what it takes to be good.

The results for the women, however, are somewhat more ambiguous than men’s strong need to burn for something, and this study found no such gender difference.

Nor did the researchers find any difference between the sexes in terms of growth mindset.

Dopamine and autism

In the past, the dopamine system has been associated with many different conditions, such as ADHD, psychoses, manias and Parkinson’s disease. But it may also be related to a certain form of autistic behaviour.

Some individuals with autism may become very interested in certain topics, which can be a bit unusual, or even strange, for most people. People on the autism spectrum can focus intensely on these topics or pursuits, at least for a while. Dopamine may play a role.

“Other research in neuroscience has shown hyperactivity in the dopamine system in individuals with autism, and boys make up four out of five children on the autism spectrum. This, and dopamine’s relationship to passion, might be a mechanism that helps to explain this behaviour,” says Sigmundsson.

The research group tested 917 people aged 14 to 77, consisting of 502 women and 415 men. This is considered a major study in this context.

Sigmundsson collaborated with Stéfan Guðnason from the University of Akureyri and Sigurrós Jóhannsdóttir from the Icelandic State Diagnostic and Counselling Centre (SDCC).

Featured image: Dopamine can help explain why men depend on passion to succeed. But it may also explain a certain behaviour in boys on the autism spectrum. Photo: Shutterstock, NTB

ReferenceHermundur Sigmundsson, StéfanGuðnason, Sigurrós Jóhannsdóttir. Passion, grit and mindset: Exploring gender differences. Science Direct. Available online 3 June 2021. https://doi.org/10.1016/j.newideapsych.2021.100878

Provided by Norwegian SciTech

Bilingualism As A Natural Therapy For Autistic Children (Language)

An international team led by UNIGE demonstrates that the characteristics of bilingualism allow autistic children to compensate for certain fundamental deficits.

Affecting more than one in a hundred children, autism spectrum disorder is one of the most common neurodevelopmental disorders. It has a particular impact on social interaction, including difficulties in understanding other people’s perspectives, beliefs, desires and emotions, known as ‘theory of mind’. Bilingual families with an autistic child often tend – and are sometimes encouraged – to forego the use of one of the home languages, so as not to further complicate the development of their child’s communicative skills. A researcher from the University of Geneva (UNIGE, Switzerland), in collaboration with the Universities of Thessaly (Greece) and Cambridge (Great-Britain), has shown that bilingualism allows autistic children to partially compensate for deficits in theory of mind and executive functions, which are at the root of many of their challenges. These results can be read in the journal Autism Research.

Diagnosed in early childhood, autism spectrum disorder has a particular impact on a child’s social and communicative abilities. “It is a spectrum, which is why the intensity of the symptoms varies greatly”, explains Stéphanie Durrleman, a researcher in the Department of Linguistics at the UNIGE Faculty of Arts and co-author of the study. “But what children with autism have in common is that they have difficulties putting themselves in the place of their interlocutor, focusing on the latter’s point of view and thus disengaging their attention from their own perspective.” Autism therefore affects not only everything that has to do with the theory of mind – understanding the beliefs, emotions, intentions and desires of others – but also often executive functions, including attentional abilities.

Could benefits of bilingualism be applied to children with autism?

Studies on bilingualism have shown that children without autism who use several languages have increased theory of mind and executive function skills compared to monolingual children. “Bilingualism therefore seems to bring benefits precisely where the autistic child has difficulties”, says Stéphanie Durrleman. “We therefore wondered whether bilingual autistic children manage to mitigate the difficulties of their neurodevelopmental disorder by using two languages every day.”

To test this hypothesis, the researchers from the universities of Geneva, Thessaly and Cambridge followed 103 autistic children aged 6 to 15, 43 of whom were bilingual. “In order to observe the real effects of bilingualism on their socio-communicative skills, we grouped them according to their age, gender and the intensity of their autistic disorder”, explains Eleni Peristeri, researcher at the Faculty of Medicine of the University of Thessaly and co-author of the study. The participants then performed various tasks to assess their theory of mind and executive function skills. The bilinguals quickly distinguished themselves by scoring higher than their monolingual peers. “On tasks relating to theory of mind, i.e. their ability to understand another person’s behaviour by putting themselves in their place, the bilingual children gave 76% correct answers, compared with 57% for the monolingual children”, notes the Greek researcher. The same is true for executive functions: the score for correct responses in bilinguals is twice that of monolinguals. But why are the differences so clear?

“Bilingualism requires the child to work first on skills directly related to theory of mind, i.e. he or she must constantly be concerned with the knowledge of others: Does the person I am speaking to speak Greek or Albanian? In what language should I talk to him or her? Then, in a second phase, the child uses his executive functions by focusing his attention on one language, while inhibiting the second”, explains Eleni Peristeri. This is a real gymnastics for the brain, which acts precisely on the deficits linked to the autistic disorder.

Encouraging bilingualism instead of giving it up

“From our evaluations, we can clearly see that bilingualism is very beneficial for children with autism spectrum disorders”, enthuses Stéphanie Durrleman. In order to certify that the socio-economic level in which the participants grew up did not play a role in the results, this was also recorded and it turned out that the bilingual children were mostly in a lower socio-economic environment than the monolinguals. “We can therefore affirm that benefits in theory of mind and executive functions emerge in bilinguals, even when there is a socio-economic disadvantage”, says the Geneva researcher.

These findings are important for the care of children diagnosed with autism. “Indeed, as this neurodevelopmental disorder often affects language acquisition, bilingual families tend to give up the use of one of the two languages, so as not to exacerbate the learning process. However, it is now clear that far from putting autistic children in difficulty bilingualism can, on the contrary, help these children to overcome several aspects of their disorder, serving as a kind of natural therapy”, concludes Stéphanie Durrleman.

Featured image credit: Garner

Reference: Peristeri, E., Baldimtsi, E., Vogelzang, M., Tsimpli, I. M., & Durrleman, S. (2021). The cognitive benefits of bilingualism in autism spectrum disorder: Is theory of mind boosted and by which underlying factors? Autism Research, 1– 15. https://doi.org/10.1002/aur.2542

Provided by University of Geneve

Autistic People Find it Harder to Identify Anger in Facial Expressions (Neuroscience)

Autistic people’s ability to accurately identify facial expressions is affected by the speed at which the expression is produced and its intensity, according to new research at the University of Birmingham.

In particular, autistic people tend to be less able to accurately identify anger from facial expressions produced at a normal ‘real world’ speed. The researchers also found that for people with a related disorder, alexithymia, all expressions appeared more intensely emotional.

The question of how people with autism recognise and relate to emotional expression has been debated by scientists for more than three decades and it’s only in the past 10 years that the relationship between autism and alexithymia has been explored.

This new study, published in the Journal of Autism and Developmental Disorders, uses new techniques to explore the different impacts of autism and alexithymia on a person’s ability to accurately gauge the emotions suggested by different facial expressions.

Connor Keating, a PhD researcher in the University of Birmingham’s School of Psychology and Centre for Human Brain Health, is lead author of the study. He says: “We identified that autistic people had a specific difficulty recognising anger which we are starting to think may relate to differences in the way autistic and non-autistic people produce these expressions. If this is true, it may not be accurate to talk about autistic people as having an ‘impairment’ or ‘deficit’ in recognising emotion- it’s more that autistic and non-autistic faces may be speaking a different language when it comes to conveying emotion”.

In the study, 29 non-autistic and 31 autistic participants were asked to identify emotions from a series of moving images made up of dots representing the key dynamic points of a facial expression – a little bit like the dots used to translate human movement into CGI animation. The images were displayed at a range of emotional intensities by varying the amount of movement in each expression, and at a variety of speeds.

The team found that both autistic and non-autistic participants had similar recognition capabilities at different speeds and intensities across all the emotions shown, except for one particular aspect – the autistic group were less able to identify angry expressions produced at normal speed and intensity. These represented the sorts of angry expressions that might be encountered in everyday life.

“When we looked at how well participants could recognise angry expressions, we found that it was definitely autistic traits that contribute, but not alexithymic traits,” explained Connor. “That suggests recognising anger is a difficulty that’s specific to autism.”

A key trait that the team found was specific to participants with alexithymia was a tendency to perceive the expressions to be intensely emotional. Interestingly though, people with alexithymia were more likely to give higher correct and incorrect emotion ratings to the expressions. To give an example, those with alexithymia would rate a happy expression as more intensely happy and more intensely angry and sad than someone without alexithymia.

Connor explains: “One idea is that people with alexithymia are less able to gauge the intensity of emotional expressions and are more likely to get confused about which emotion is being presented.”

He adds: “Everyone will know or meet somebody with autism at some point in their lives.By better understanding how people with autism perceive and understand the world we can start to develop training and other interventions for both autistic and non-autistic people to overcome some of the barriers to interacting successfully.”

This project was supported by the Medical Research Council (MRC, United Kingdom) MR/R015813/1 and the European Union’s Horizon 2020 Research and Innovation Programme under ERC-2017-STG Grant Agreement No. 757583.

Notes for editors:

Provided by University of Birmingham

Prenatal Exposure To Paracetamol Associated With ADHD and Autism Symptoms in Childhood (Medicine)

ISGlobal study of more than 70,000 European children bolsters the findings of previous research

An epidemiological study of more than 70,000 children in six European cohorts has linked symptoms of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum conditions (ASC) to the mothers’ use of paracetamol (acetaminophen) during pregnancy. The study, published in the European Journal of Epidemiology, was led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the “la Caixa” Foundation.

In total, the researchers analysed 73,881 children for whom data were available on prenatal or postnatal exposure to paracetamol, at least one symptom of ASC or ADHD, and main covariates. Depending on the cohort, 14% to 56% of the mothers reported taking paracetamol while pregnant.

The study found that children exposed to paracetamol before birth were 19% more likely to develop ASC symptoms and 21% more likely to develop ADHD symptoms than children who were not exposed.

“Our findings are consistent with previous research,” explained ISGlobal researcher Sílvia Alemany, lead author of the study. “We also found that prenatal exposure to paracetamol affects boys and girls in a similar way, as we observed practically no differences.”

“Our results address some of the weaknesses of previous meta-analyses,” commented Jordi Sunyer, researcher at ISGlobal and last author of the study. “Considering all the evidence on the use of paracetamol and neurological development, we agree with previous recommendations indicating that while paracetamol should not be suppressed in pregnant women or children, it should be used only when necessary.”

At some point during pregnancy, an estimated 46%-56% of pregnant women in developed countries use paracetamol, which is considered the safest analgesic/antipyretic for pregnant women and children. However, mounting evidence has linked prenatal paracetamol exposure to poorer cognitive performance, more behavioural problems, and ASC and ADHD symptoms.

Those previous studies have been criticised for their heterogeneity. In the new study, therefore, “an effort was made to harmonise the assessment of ADHD and ASC symptoms and the definition of paracetamol exposure,” explained Alemany. “The sample is large,” she added, “and it includes cohorts from multiple European countries: the United Kingdom, Denmark, the Netherlands, Italy, Greece and Spain. We also used the same criteria for all of the cohorts, thereby reducing the heterogeneity of criteria that has hampered previous studies.”

The study also analysed postnatal exposure to paracetamol and found no association between paracetamol use during childhood and ASC symptoms. Nevertheless, the research team concluded that further studies are needed, given the heterogeneity of postnatal paracetamol exposure among the various cohorts, which ranged from 6% to 92.8%.

The six cohorts included the study were as follows:

  • Avon Longitudinal Study of Parents and Children (ALSPAC)
  • Danish National Birth Cohort (DNBC)
  • Gene and Environment: Prospective Study on Infancy in Italy (GASPII)
  • Generation R Study
  • INMA (including four subcohorts)
  • Mother-Child Cohort in Crete (RHEA)

Reference: Alemany, S., Avella-García, C., Liew, Z. et al. Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. Eur J Epidemiol (2021). https://doi.org/10.1007/s10654-021-00754-4

Provided by ISGLOBAL

Novel Approach Identifies Genes Linked to Autism and Predicts Patient IQ (Biology)

According to some estimates, hundreds of genes may be associated with autism spectrum disorders (ASD), but it has been difficult to determine which mutations are truly involved in the disease and which are incidental. New work published in the journal Science Translational Medicine led by researchers at Baylor College of Medicine shows that a novel computational approach can effectively identify genes most likely linked to the condition, as well as predict the severity of intellectual disability in patients with ASD using only rare mutations in genes beyond those already associated with the syndrome.

Knowing which genes contribute to ASD, researchers can then study them to better understand how the condition happens and use them to improve predicting the risk of the syndrome and more effectively advise parents of potential outcomes and treatments.

“ASD is a very complex condition and many cases do not have a clear genetic explanation based on current knowledge,” said first author Dr. Amanda Koire, a graduate student in the Dr. Olivier Lichtarge lab during the development of this project. She is currently a psychiatry research resident at Brigham and Women’s Hospital, Harvard Medical School.

There is not one gene that causes the majority of ASD cases, the researchers explained. “The most commonly mutated genes linked to the syndrome only account for approximately 2% of the cases,” said Lichtarge, Cullen Chair and professor of molecular and human geneticsbiochemistry and molecular biology and pharmacology and chemical biology at Baylor. “The current thought is that the syndrome results from a very large number of gene mutations, each mutation having a mild effect.”

The challenge is to identify which gene mutations are indeed involved in the condition, but because the variants that contribute to the development of ASD are individually rare, a patient by patient approach to identify them would likely not succeed. Even current studies that compare whole populations of affected individuals and unaffected parents and siblings find genes that only explain a fraction of the cases.

The Baylor group decided to take a completely different perspective. First, they added a vast amount of evolutionary data to their analyses. These data provided an extensive and open, but rarely fully accessed, record of the role of mutations on protein evolution, and, by extension, on the impact of human variants on protein function. With this in hand, the researchers could focus on the mutations most likely to be harmful. Two other steps then further narrowed the resolution of the study. A focus on personal mutations, that are unique to each individual, and also on how these mutations add up in each molecular pathway. 

Exploring the contribution of de novo missense mutations in ASD

The researchers looked into a group of mutations known as missense variants. While some mutations disrupt the structure of proteins so severely as to render them inactive, missense mutations are much more common but are harder to assess than loss-of-function mutations because they can just tweak the protein’s function a little or severely impair it.

“Some loss-of-function mutations have been associated with the severity of ASD, measured by diminished motor skills and IQ, but missense mutations had not been linked to the same ASD patient characteristics on a large-scale due to the difficulty in interpreting their impact,” said co-author Dr. Panagiotis Katsonis, assistant professor of molecular and human genetics at Baylor. “However, people with ASD are more likely to carry a de novo missense mutation than a de novo loss-of-function mutation and the tools previously developed in our lab can help with the interpretation of this majority of coding variants. De novo or new mutations are those that appear for the first time in a family member, they are not inherited from either parent.”

The researchers took on the challenge to identify, among all the de novo missense mutations in a cohort of patients with ASD and their siblings as a whole, those mutations that would distinguish between the patients and the unaffected siblings.

A multilayered approach

The team applied a multilayered strategy to identify a group of genes and mutations that most likely was involved in causing ASD.

They first identified a group of de novo mutations by examining the sequences of all the protein coding genes of 2,392 families with members with ASD that are in the Simons Simplex Collection. Then, they evaluated the effect of each missense mutation on the fitness or functionality of the corresponding protein using the Evolutionary Action (EA) equation, a computational tool previously developed in the Lichtarge lab. The EA equation provides a score, from 0 to 100, that reflects the effect of the mutation on the fitness of the protein. The higher the score, the lower the fitness of the mutated protein.

The results suggested that among the 1,418 de novo missense mutations affecting 1,269 genes in the patient group, most genes were mutated only once.

“Knowing that ASD is a multigenic condition that presents on a spectrum, we reasoned that the mutations that were contributing to ASD could dispersed amongst the genes of a metabolic pathway when examined at a cohort level, rather than being clustered on a single gene,” Koire said. “If any single component of a pathway becomes affected by a rare mutation, it could produce a clinical manifestation of ASD, with slightly different results depending on the specific mutation and the gene.”

Without making any a priori assumptions regarding which genes or pathways drive ASD, the researchers looked at the cohort as a whole and asked, in which pathways are there more de novo missense mutations with higher EA scores than expected?

The team found that significantly higher EA scores of grouped de novo missense mutations implicated 398 genes from 23 pathways. For example, they found that axonogenesis, a pathway for the development of new axons in neurons in the brain, stood out among other pathways because it clearly had many missense mutations that together demonstrated a significant bias toward high EA scores indicating impactful mutations. Synaptic transmission and other neurodevelopmental pathways were also among those affected by mutations with high EA scores.

“As a result of layering together all these different complementary views of potential functional impact of the mutations on the biology, we could identify a set of genes that clearly related to ASD,” Lichtarge said. “These genes fell in pathways that were not necessarily surprising, but reassuringly related to neurological function. Some of these genes had been linked to ASD before, but others had not been previously associated with the syndrome.”

“We also were very excited to see a relationship between the EA score of the mutations in those genes linked to ASD and the patient’s IQ,” Koire said. “For the new genes we found linked to ASD, the mutations with higher EA scores were related to a 7 point lower IQ in the patients, which suggests that they have a genuine biological effect.”

“This opens doors on many fronts,” said co-author Young Won Kim, graduate student in Baylor’s Integrative Molecular and Biomedical Sciences Graduate Program working in the Lichtarge lab at the time of research. “It suggests new genes we can study in ASD, and that there is a path forward to advise parents of children with these mutations of the potential outcomes in their child and how to best involve external support in early development intervention, which has shown to make a huge difference in outcome as well.”

“Our findings may go beyond ASD,” Lichtarge said. “This approach, we hope, could be tested in a wide set of complex diseases. As many genome sequence data become increasingly accessible for research, it should then be possible to interpret the rare mutations which they yield as we showed here. This may then resolve better than now the polygenic basis of various adult diseases and also improve estimates of individual risk and morbidity.”

Christie Buchovecky, at Baylor and Columbia University, and Stephen J. Wilson at Baylor also contributed to this work.

This work was supported by the National Institutes of Health (grant numbers GM079656-8, DE025181, GM066099, AG061105), the Oskar Fischer Foundation, the National Science Foundation (grant number DBI1356569) and the Defense Advance Research Project Agency (grant number N66001-15-C-4042). In addition, this study received support from RP160283 – Baylor College of Medicine Comprehensive Cancer Training Program, the Baylor Research Advocates for Student Scientists (BRASS), and the McNair MD/PhD Scholars program.

Provided by Baylor College of Medicine