The three factors have different weights, and jointly build up to the diagnosis of autism. CREDIT University of Gothenburg

The development of autism may now become easier to understand, thanks to an explanatory model presented in a thesis from University of Gothenburg, Sweden. This model provides new insights into how various risk factors give rise to autism and why there is such great variability between individuals.

Autism, a neurodevelopmental condition, affects how people perceive the world around them and how they interact and communicate with others. Among individuals with autism, there are major differences in terms of personal traits and manifestations alike. The disorder is therefore usually described as a spectrum, with numerous subtle variations.

The new explanatory model is theoretical but simultaneously practical in application, since its various components are measurable through, for example, questionnaires, genetic mapping, and psychological tests. The model describes various contributing factors and how they combine to prompt an autism diagnosis and cause other neurodevelopmental conditions.

Three contributing factors

The model links three contributing factors. Together, these result in a pattern of behavior that meets the criteria for an autism diagnosis:

1. Autistic personality — hereditary common genetic variants that give rise to an autistic personality.

2. Cognitive compensation — intelligence and executive functions, such as the capacity to learn, understand others, and adapt to social interactions.

1. Exposure to risk factors — for example, harmful genetic variants, infections, and other random events during gestation and early childhood that adversely affect cognitive ability.

“The autistic personality is associated with both strengths and difficulties in cognition but does not, as such, mean that diagnostic criteria are fulfilled. Still, exposure to risk factors that inhibit people’s cognitive ability may affect their capacity to tackle difficulties, which contributes to individuals being diagnosed with autism,” says Darko Sarovic, physician and postdoctoral researcher at Sahlgrenska Academy, University of Gothenburg, who wrote the thesis.

The model makes it clear that it is the many different risk factors combined that bring about the major differences among individuals on the spectrum. The various components of the model are supported by results from previous research.

Adaptive ability

High executive functioning skills may enable people to compensate for their impairment in such a way as to mitigate the symptoms, which reduces their risk of meeting the diagnostic criteria for autism. This may explain why, at group level, researchers observe a lower degree of intelligence among people diagnosed with autism, as well as other neurodevelopmental conditions. It also affords an understanding of why intellectual disability is more common among these groups. Thus, the model indicates that low cognitive ability is not part of the autistic personality but, rather, a risk factor that leads to diagnostic criteria being met.

“The autistic personality is associated with various strengths. For example, parents of children with autism are overrepresented among engineers and mathematicians. The parents themselves have probably been able to compensate for their own autistic personality traits and thus not met the criteria for an autism diagnosis. The impact of the disorder has then become more noticeable in their children owing, for instance, to an exposure to risk factors and relatively low cognitive ability,” Sarovic says.

Difference between girls and boys

The diagnosis of autism is more common among boys than girls, and girls often get their diagnosis later in life. Some girls reach adulthood before being diagnosed, after many years of diffuse personal difficulties.

“Girls’ symptoms are often less evident to other people. It’s well known that girls generally have more advanced social skills, which probably means that they’re better at compensating for their own difficulties. Girls also tend to have fewer autistic traits and be less susceptible to the effects of risk factors. Accordingly, the model can help to answer questions about the gender gap,” Sarovic says.

Research and diagnostics

The model also proposes ways of estimating and measuring the three factors (autistic personality, cognitive compensation and exposure to risk factors). This makes it possible to use the model in the planning of research studies and interpretation of their results.

Diagnostics is another conceivable area of ​​use. In a pilot study in which 24 participants had been diagnosed with autism and 22 controls had not, measuring the three factors of the model enabled more than 93 percent to be correctly assigned to the right category. The model can also be used to explain the inception of other neurodevelopmental disorders, such as schizophrenia.

Every day across America, hundreds of children and teens with depression, anxiety, autism and other conditions end up in their local hospital’s emergency department because of a mental or behavioral health crisis.

And 12 hours later, 1 in 5 of them will still be in the ED, a study finds.

Another 12 hours after that – a full day after they arrived – 1 in 13 of them will still be in the ED. More than 60% of these patients are suicidal or have engaged in self-harm.

Meanwhile, virtually all the children who went to the same hospital for non-mental health emergencies have already received treatment and gone home, or been admitted to the hospital, within 12 hours, the study shows.

Visits of both kinds dropped dramatically in spring 2020, and even a year and a half later, non-mental health emergency visits by kids were still below pre-pandemic levels. But mental health emergency visits climbed steadily. By early 2021 they had exceeded their pre-pandemic levels and stayed there, with seasonal variation.

The study, published in the Journal of the American College of Emergency Physicians Open by a team led by an emergency physician from the University of Michigan and VA Ann Arbor Healthcare System, adds more evidence of the strain faced by the pediatric mental health system. It builds on previously reported data from large teaching hospitals and children’s hospitals.

“Insufficient access to mental health care stands out among the factors that contribute to prolonged stays in the nation’s emergency departments,” said first author Alex Janke, M.D., M.H.S., a National Clinician Scholar at VAAHS and the U-M Institute for Healthcare Policy and Innovation. “There are too few options outside of emergency care for patients in many communities.”

About 1 in 8 children who go to a community hospital for a mental health emergency end up getting admitted for at least one night or transferred to another hospital, the study finds. That number rose beyond pre-pandemic numbers by early 2021 and has stayed high ever since. Meanwhile, children’s admissions and transfers for other types of emergencies have stayed flat.

Because the hospitals in the study are not part of major academic systems, they likely do not always have child psychiatrists or other specialists in-house to work with emergency medicine teams in assessing and creating treatment plans for children in mental health crisis.

Janke and his colleagues from Yale University, the American College of Emergency Physicians and Columbia University used data from the Clinical Emergency Data Registry, with data from 107 community hospitals from January 2020 to December 2021, plus data from 2019 from 33 of those hospitals.

The majority of emergency department visits by children and teens in the United States happen in such hospitals, Janke notes. More resources that could help families get care in the local community or via telehealth could reduce the need to seek emergency care for their child, he says. Also needed are more resources to support local emergency medicine teams who find themselves caring for a child or teen in mental health crisis.

“While others are studying the epidemiology of mental health concerns among American’s youth at this point in the pandemic, our study focuses on whether the mental health system is ready for what’s coming in the door,” he said. “And the length of emergency department stays that we’re seeing here shows that it is not.”

The data source does not contain information about individual characteristics of the patients seeking care, such as what kinds of mental health care they’ve received, their demographic information, or what caused their families to seek emergency mental health care.

Janke and colleagues are working on further research on this topic. But the study does show that hospitals in the northeastern part of the country were most likely to have longer ED stays than other regions, especially the south and west.

The study does not measure “boarding” times, which is the time between an emergency care clinician’s decision to admit a patient to the time that patient actually leaves the ED for a bed in that hospital or another facility. But in a paper published earlier this year, Janke and colleagues showed that by the end of 2021, median boarding times for adult emergency patients were approaching the nationally recommended level of 3.4 hours.

If you, your child or someone you know is having a mental health crisis or considering suicide, contact the national 988 Suicide and Crisis Lifeline by calling or texting 988, or visiting 988lifeline.org for crisis chat services or for more information.

Expression of the MEF2C protein (green) in the nuclei of neuronal cells (stained with a neuronal marker protein in red) in the inner ear of a young adult mouse. Nuclei were stained with Dapi (blue). Image courtesy of Dr. Hainan Lang of the Medical University of South Carolina.

A cross-disciplinary team of researchers in the College of Medicine at the Medical University of South Carolina (MUSC) has discovered hearing impairment in a preclinical model of autism . More specifically, the researchers report in the Journal of Neuroscience that they observed mild hearing loss and defects in auditory nerve function. Closer examination of the nerve tissue revealed abnormal supportive cells called glia, aging-like degeneration and inflammation. The findings from this study highlight the importance of considering sensory organs and their interactions with the brain in understanding autism.

Many autistic people show increased sensitivity to sound. While many scientists in the past have looked to the brain for an underlying cause, the MUSC team took a different approach by studying the peripheral hearing system.

“Hearing impairment may have an impact on the higher-level auditory system and, eventually, cognitive function,” said Hainan Lang, M.D., Ph.D., professor in the Department of Pathology and Laboratory Medicine at MUSC and one of two senior authors of the study. Jeffrey Rumschlag, Ph.D., a postdoctoral researcher in the MUSC Hearing Research Program, is a co-first author of the manuscript.

Previous studies of aging-related hearing loss showed that the brain can increase its response to make up for reduced auditory signals from the inner ear. Lang wanted to find out if this increase, called central gain, could contribute to abnormal brain response to sound in autism. However, a significant obstacle lay in her path.

“We didn’t have a clinically relevant model to directly test this important fundamental question,” she said.

The preclinical model that would allow Lang to test her hypothesis was developed in the lab of Christopher Cowan, Ph.D., chair of Neuroscience at MUSC. Mice in this model have only one working copy of a gene called MEF2C. Cowan’s group had studied MEF2C in the past for its role in brain development and found that it was important for regulating circuit formation in the brain. They became especially interested in creating a preclinical model when a group of autistic patients tswere identified with MEF2C mutations. Cowan’s models also show autistic-like behaviors, including increased activity, repetitive behavior and communication deficits.

Lang and Cowan’s collaboration began as they presented posters side by side at an orientation for the College of Graduate Studies at MUSC. Lang’s lab had identified molecular regulators, including MEF2C, crucial for inner ear development, and she saw Cowan’s model as something she could use to test her hypothesis about hearing loss in neurodevelopmental diseases. Cowan enthusiastically agreed, and the research team began to assess the ability of the MEF2C-deficient mice to hear.

They first measured the response of the brain to auditory signals, using a modified version of a test that is commonly used to screen newborn infants for hearing loss. Mild hearing loss was observed in the mice with only one working copy of MEF2C while hearing remained normal in those with two working copies. To investigate this loss further, the researchers measured the activity of the auditory nerve, which carries signals from the inner ear to the brain. They found reduced activity in this nerve in mice with only one copy of MEF2C.

With their sights set on the auditory nerve, the researchers used advanced microscopes and staining techniques to determine what was going wrong. Although the overall hearing sensitivity loss was mild, the researchers were excited to see a big difference in auditory nerve response. Nerves from mice with a single copy of MEF2C showed cellular degeneration much like that seen in age-related hearing loss. The researchers also saw signs of increased inflammation, with disrupted blood vessels and activated immune cells called glia and macrophages. This finding was especially surprising to the researchers.

“Glial cells were not my first thought; I thought it was a neuronal change,” said Lang. “Now we understand that auditory nerve activity can also involve the immune system, and that’s the beautiful new direction we want to continue to study.”

Cowan also believes that the finding opens the way for a new area of neuroscience research.

“We have more appreciation now that there is an important interaction between the immune system in your body and the immune system in your brain,” he said. “The two systems play critical roles in shaping how nervous system cells communicate with each other, in part, by pruning excess or inappropriate connections that have formed, and this is an essential aspect of healthy brain development and function.”

The findings from this study could be important not only for patients who are MEF2C deficient but also for autistic people or hearing loss as a whole.

“Understanding how this gene may be participating in ear development and how the inner ear development is affecting brain development has tremendous applicability,” said Cowan.

In future studies, the researchers aim to discover how exactly MEF2C causes the changes that were identified in this study. The research team also hopes to explore these findings in patients with MEF2C deficiency using noninvasive hearing tests.

Lang and Cowan both emphasize the importance of collaboration across disciplines for allowing studies like this to take place.

“The power of collaboration is tremendous for a place like MUSC,” said Cowan. “This collaboration, for us, was ideal because Dr. Lang is an expert in hearing function and development, whereas I am more the genetics and molecular development person. These kinds of collaborations are ideal, and it’s precisely what MUSC is encouraging a lot of us to think about doing more and more.”

“In other words, we each play different instruments so, together, we can make a better harmony,” said Lang.

In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — a novel treatment for children with autism. Specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism , improved following microbiota transfer therapy. CREDIT Shireen Dooling/Arizona State University

Autismcurrently affects 1 in 44 children in the U.S., according to the Centers for Disease Control and Prevention. For reasons that remain murky, these numbers appear to be trending upward as researchers and clinicians struggle to find effective treatments.

Recently, a new approach to treat symptoms associated with this disorder has emerged, thanks to the explosion of research on the trillions of non-human cells inhabiting the gastrointestinal tract—collectively known as the gut microbiome. The treatment, called microbiota transfer therapy, is a process where healthy gut bacteria are transferred to children with autism.

In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. 

The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism, improved following microbiota transfer therapy.

In first-of-its-kind research, the research team used a whole genome sequencing technology known as “shotgun metagenomics” to extract detailed data from more than 5,000 bacterial species found in the gut of children with autism spectrum disorder before and after microbiota transfer therapy. The researchers then compared these results with bacterial populations in the guts of healthy children.  

The results showed considerable improvement in overall abundance of bacteria following the microbiota transfer therapy, and this confirmed previous findings. Also, there were substantial increases in populations of beneficial bacterial species typically found in lower numbers in children with autism.

Additionally, two genetic indicators of dysregulation in the gut microbiome of children with autism improved following microbiota transfer therapy. These key genetic markers are the metabolism of sulfur and the failure to detoxify oxidative stress.

The findings are encouraging because the severity of gastrointestinal dysfunction in autistic children appears proportional to the degree of behavioral and cognitive issues, highlighting the importance of the gut-brain axis—a topic of intense interest in the world of microbiomics. The gut-brain axis is the communication system between your brain and your gut.

“This study highlights altered levels of important bacterial species and metabolic genes in children with autism and improvements after microbiota transfer therapy,” says Khemlal Nirmalkar, lead author and post-doctoral fellow working in theRosa Krajmalnik-Brown lab at the ASU Biodesign Institute. Our long-term goal is to understand the functional role of the gut microbiome, fill the knowledge gap of the gut-brain axis in autism, and identify therapeutic targets to improve GI health and behavior in children with autism.”

“Completing more in-depth microbiome sequencing is important because it can help us better understand what microbes in the gut are doing and why they are an important part of the gut-brain axis,” said Krajmalnik-Brown, who directs the newly established Biodesign Center for Health Through Microbiomes. She is also a professor with the ASU School of Sustainable Engineering and the Built Environment in the Ira A. Fulton Schools of Engineering.

Collaborators include James Adams, President’s Professor with the ASU School for Engineering of Matter, Transport and Energy, and researchers with the Rensselaer Polytechnic Institute in New York. The study appears in a special issue of the International Journal of Molecular Sciences titled “The Microbiota–Gut–Brain Axis in Behavior and Brain Disorders.” 

The research team used shotgun metagenomics, or whole genome sequencing, to better understand the bacterial populations at the species level. They also wanted to understand bacterial genes before and after microbiota transfer therapy. The treatment not only increased the abundance of beneficial bacteria but also helped to normalize altered levels of bacterial genes, particularly those related to the synthesis of folate, oxidative stress protection and sulfur metabolism, and importantly, became similar to typically developing children.

Autism remains an enigmatic disorder, often emerging in early childhood and causing lifelong developmental disabilities that affect social skills, communication, personal relationships and self-control. So far, there is no cure for the affliction and therapies for treating associated symptoms remain limited.

The microbiota transfer procedure involves the transfer of gut microbiota from healthy donors to autistic patients over a period of seven to eight weeks. The procedure begins with a 2-week antibiotic treatment and bowel cleanse, followed by an extended transplant of fecal microbiota, applying a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. This treatment was initially studied in children with autism ages 7-16 years old.

In a follow-up study, the same 18 participants were examined two years after treatment was completed. Most improvements in gastrointestinal symptoms were maintained, while autism-related symptoms continued to improve even after the end of treatment, demonstrating the long-term safety and efficacy of microbiota transfer therapy as a therapy for autism.

The treatment reduced the severity of gastrointestinal symptoms by roughly 80% and signs of autism by about 24% by the end of treatment. After two years, the same children showed an approximate 59% reduction in gastrointestinal symptoms and 47% reduction in autism symptoms, compared with baseline levels established prior to treatment.

Krajmalnik-Brown and Adams are currently working on phase-2 double-blind placebo-controlled studies of microbiota transfer therapy for children and adults with autism, and they plan to verify whether these findings hold true in those two studies.

Future research will further explore the role of specific microbial species, functional gene expression and the production of a range of autism -related metabolites before and after microbiota transfer therapy.