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ASPartOfMe
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06 Feb 2023, 12:11 pm

This thread is an attempt to deal with the issue of studies “suggesting” negative outcomes and “linking” autism to bad things triggering people. In the body of a post you can put a spoiler alert to hide triggering information but not in the title. Putting “Trigger Warning” in the title is impractical. Members by instinct will end up seeing the triggering words and the software allows too few characters in the title as is. Taking away characters to put a warning in will often make the title irrelevant to what is in the body.

While Joe90 has been most open about this problem I suspect plenty of other members are triggered by study threads or become depressed constantly reading bad news.

Unfortunately the research sector is the most negative medical model part of the Autism community. It is the nature of their job. Researchers are being paid to fix problems.

I think this can work. The “Emergence of the Deadly Coronavirus” thread handles a wide variety of COVID related issues. Some COVID topics do get their own threads usually because they are most relevant to the news or PPR sections. That will happen here, there will be studies that will belong in the Autism Politics section. An example is the thread for quackery. The separate COVID threads have not altered the “Emergence” thread status as the main thread for news and discussion of the coronovirus.


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06 Feb 2023, 12:17 pm

Fishing for protein partners nets clues to autism

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A new map of the binding partners for 13 autism-linked proteins in excitatory neurons. The work may help researchers understand how autism-related proteins talk to one another and could point to new therapeutic targets, the team behind the work says.

The genetic architecture of autism is well documented, but the connections among proteins derived from autism-linked genes have been hazy, says Michael Ronemus, research assistant professor at Cold Spring Harbor Laboratory in New York, who was not involved in the study. Some catalogs of these proteins’ partners have used data from cancer cells, which don’t express neuronal proteins. Another relied on postmortem brain samples in which the jumble of cells — only some of which are implicated in autism — could have skewed the results.

In the new work, researchers turned to excitatory neurons, a key cell type that may go awry in autism. The team grew the neurons from human stem cells and used antibodies to fish out the proteins encoded by 13 autism-linked genes — including PTEN, ANK2 and SYNGAP1 — along with any proteins bound to them.

A mass spectrometry analysis uncovered 1,021 associations, more than 90 percent of which have not been previously described. A similar analysis involving proteins the team captured from postmortem human brain samples generated a comparable list of contacts, validating the results.

Discovering so many new companions is not surprising, says lead investigator Kasper Lage, managing director of the Novo Nordisk Foundation Center for Genomic Mechanisms of Disease at the Broad Institute in Cambridge, Massachusetts. “We’re fishing with a biochemical hook in a pond that no one has fished in before. You’re bound to find new things,” he says.

The findings were published on 24 January in Cell Genomics.

The researchers plan to expand the network to include more autism-linked genes. So far, they have been limited by the availability of effective antibodies capable of fishing out proteins. Adding tags via CRISPR could help catch proteins that don’t have a good antibody hook — something the team is pursuing, Pintacuda says. They also plan to document protein interactions in other cell types, including inhibitory neurons. “Excitatory neurons are not the only cells relevant to autism,” she says.


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07 Feb 2023, 11:58 am

I'm sorry I overreact... I wasn't doing it to make you feel bad, it's just I have what I call "autism dysphoria", and when I see information that makes autism a doom to deadly illness as well as a neurological disorder, I freak out. If I were religious I'd just shout at God for making me Aspie.


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07 Feb 2023, 1:48 pm

Joe90 wrote:
I'm sorry I overreact... I wasn't doing it to make you feel bad, it's just I have what I call "autism dysphoria", and when I see information that makes autism a doom to deadly illness as well as a neurological disorder, I freak out. If I were religious I'd just shout at God for making me Aspie.

As you have explained because of your past you have legitimate reasons to feel the way you do about autism. There is no need to apologize for that, quite the opposite. You self advocated and were persistent about it. I hope this idea solves the issue or at least eases the problem. I am sorry it took me so long to think of this idea.


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07 Feb 2023, 8:05 pm

ASPartOfMe wrote:
Joe90 wrote:
I'm sorry I overreact... I wasn't doing it to make you feel bad, it's just I have what I call "autism dysphoria", and when I see information that makes autism a doom to deadly illness as well as a neurological disorder, I freak out. If I were religious I'd just shout at God for making me Aspie.

As you have explained because of your past you have legitimate reasons to feel the way you do about autism. There is no need to apologize for that, quite the opposite. You self advocated and were persistent about it. I hope this idea solves the issue or at least eases the problem. I am sorry it took me so long to think of this idea.


I'm glad you understand me instead of just calling me a troll (not saying you ever did).
I also understand that you like to post research updates, and that doesn't make you a troll.

Some of your posts are interesting. :)


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08 Feb 2023, 12:24 am

Joe90 wrote:

I also understand that you like to post research updates, and that doesn't make you a troll.

Some of your posts are interesting. :)

Well, thank you.

I have noticed your posts involve a greater variety of topics these days. Interesting to read your opinions on these topics.


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08 Feb 2023, 11:53 am

Lower attention to ‘motherese’ may help diagnose autism early

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Lower levels of attention to infant-directed speech, also known as “motherese” or “parentese,” by toddlers could be an early indicator of autism spectrum disorder, according to a study published in the journal JAMA Network Open.

Researchers observed more than 600 toddlers in eye-tracking tests during side-by-side playback of videos with an actress speaking in parentese next to a video with traffic noise or techno music. They also conducted a version of the test showing two videos of the same actress, one where she spoke in parentese and one where she spoke with flat intonations.
The team measured the percentage of time the toddler was visually fixated on the person speaking parentese and found that toddlers with autism spectrum disorder (ASD) ranged from 0 to 100 percent fixation, compared to median values of about 83 and 81 percent fixation in toddlers without ASD on the traffic and techno tests.

Many of the toddlers with ASD paid attention to the videos of parentese. However, nearly a quarter of toddlers with ASD showed low levels of attention, some as low as 1 or 2 percent.
In addition, the toddlers with ASD and a percent fixation rate below the threshold of 30 percent were consistently diagnosed with ASD using a separate assessment.

These children also had lower social and language abilities. On the other hand, children with ASD but who had high attention levels on the tests scored higher on expressive language assessments.



Level of Attention to Motherese Speech as an Early Marker of Autism Spectrum Disorder


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14 Feb 2023, 11:51 am

New research could help explain how sense of smell is impacted in individuals with autism

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New research from New York Institute of Technology College of Osteopathic Medicine (NYITCOM) could help explain how the sense of smell is impacted in individuals with autism.

Individuals with autism have an "insistence on sameness," and often avoid unfamiliar elements, including new smells and foods, which can impact their quality of life. While many studies have focused on the behavioral features of autism, additional research is needed to help explain its sensory aspects.

Now, a study led by NYITCOM Assistant Professor of Biomedical Sciences Gonzalo Otazu, Ph.D., published in the journal Nature Communications, analyzes a mouse model of autism and reports differences in the neurological processes responsible for smell.

The team trained two groups of mice-;one group with a mutation in a gene linked to autism (CNTNAP2 knockout mice) and one neurotypical group-;to recognize familiar scents. When they successfully identified the target scent, the mice were rewarded with a sip of water. Both groups succeeded in identifying the target. Then, the mice were given a more challenging task: identifying target scents as unfamiliar odors were introduced in the background. Otazu, an electrical engineer, likens this task to Internet captchas, which require humans to visually identify letters and numbers set in a busy or obscured background. While the neurotypical mice were able to "filter out" new background odors and identify the target scents, the CNTNAP2 knockout mice struggled to do so.

To better understand where the processing error was occurring in the brains of the CNTNAP2 knockout mice, the researchers visualized the neural activity at the input of each animal's olfactory bulb, the part of the brain that initially processes smell. An imaging technique called intrinsic optical imaging was used to visualize neural activity near the surface of the olfactory bulb. Here, "scent signals" are transmitted to other parts of the brain for further processing, playing a key role in how the brain computes smell.

However, the input signals were very similar between the CNTNAP2 knockout mice and neurotypical mice. This suggests that scent processing in the autism model was impaired at a later step-;after signals were processed at the olfactory bulb input. This finding was also replicated when the researchers "reverse-engineered" the brain's processes for identifying target scents in unfamiliar backgrounds. Leveraging machine learning, a form of artificial intelligence that uses algorithms to replicate the brain's processes, the team applied the olfactory bulb input signals to a sophisticated algorithm that matched the high performance of neurotypical mice. The neurotypical mice filtered out novel background scents and identified targets, but this complex processing was impaired in CNTNAP2 knockout mice.

”We speculate that the olfactory bulbs in the mouse model of autism might be more easily overwhelmed by processing new background odors. These findings illustrate why more studies related to the sensory aspect of autism are so important. By documenting the neural processes in the mouse model of autism, our findings may help to explain the brain circuitry of humans with autism and one day lead to advancements that improve these individuals' quality of life."

Gonzalo Otazu, Ph.D., NYITCOM Assistant Professor of Biomedical Science


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14 Feb 2023, 11:58 am

Tracking of geometric shapes a reliable biomarker of autism in toddlers

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A new study has found that checking toddlers’ visual attention to geometric images is a reliable biomarker for the early identification of autism.

Led by Karen Pierce, PhD, from the University of California, San Diego, the study expanded upon Pierce’s previous research, which had examined the disproportionate amount of time toddlers with ASD spent looking at geometric images when given the opportunity.

A large sample of 1,863 toddlers was drawn from the community, with an average age of around two years. After performing an in-depth diagnostic evaluation, the sample was divided into groups: children with ASD, children with ASD features, children with global developmental delay, children with language delay, and typically developing children.

Pierce hypothesized that the preference for geometric images was a valid, measurable biomarker, or biological indicator, for identifying children with autism within their first years of life.

The toddlers were shown a one-minute video with geometric images on one side of the screen and images of children doing yoga on the other. Using eye-tracking technology, researchers measured the time the toddlers spent fixated on the geometric images.

Data showed that toddlers with ASD spent more time looking at geometric images than toddlers in the other subject groups who preferred the social, non-geometric images. Some toddlers with ASD were found to fixate on geometric images more than 90% of the time, and the research found that those toddlers with a strong preference for those images also had higher symptom and lower cognitive ability scores than toddlers with ASD who preferred to look at the images containing children.

Additional data suggested that the preference for geometric images remained stable over the 12 months after the initial eye-tracking session.


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15 Feb 2023, 11:05 am

A Drug That Cures Autism? Neuroscience Study Yields Promising Results

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The behavioral disorders observed in autism are associated with a multitude of genetic alterations. Scientists from the Hector Institute for Translational Brain Research (HITBR) have now found another molecular cause for this condition. The transcription factor MYT1L normally protects the molecular identity of nerve cells. If it is genetically switched off in human nerve cells or in mice, the functional changes and symptoms typical of autism occur. A drug that blocks sodium channels in the cell membrane can reverse the consequences of MYT1L failure and alleviate the functional and behavioral abnormalities in mice.

Scientists are intensively searching for the molecular abnormalities that contribute to this complex developmental disorder. A multitude of genetic factors that influence the molecular programs of the nerve cells have already been linked to the development of autism.

Moritz Mall from the Hector Institute for Translational Brain Research (HITBR) has long been researching the role of the protein MYT1L in various neuronal diseases. The protein is a so-called transcription factor that decides which genes are active in the cell and which are not. Almost all nerve cells in the body produce MYT1L throughout their entire life span.

Mall had already shown a few years ago that MYT1L protects the identity of nerve cells by suppressing other developmental pathways that program a cell toward muscle or connective tissue, for example. Mutations in MYT1L have been found in several neurological diseases, such as schizophrenia and epilepsy, but also in brain malformations. In their current work, which is funded by the European Research Council ERC, Mall and his team examined the exact role of the “guardian of neuronal identity” in the development of an ASD. To do this, they genetically switched off MYT1L — both in mice and in human nerve cells that had been derived from reprogrammed stem cells in the laboratory.

The loss of MYT1L led to electrophysiological hyperactivation in mouse and human neurons and thus impaired nerve function. Mice lacking MYT1L suffered from brain abnormalities, such as a thinner cerebral cortex. The animals also showed several ASS-typical behavioral changes such as social deficits or hyperactivity.

What was particularly striking about the MYT1L-deficient neurons was that they produced an excess of sodium channels that are normally mainly restricted to the heart muscle cells. These pore-shaped proteins allow sodium ions to pass through the cell membrane and are thus crucial for electrical conductivity and thus also for the functioning of the cells. If a nerve cell produces too many of these channel proteins, electrophysiological hyperactivation can be the result.

In clinical medicine, drugs that block sodium channels have been used for a long timel

Apparently, drug treatment in adulthood can alleviate brain cell dysfunction and thus counteract the behavioral abnormalities typical of autism — even after the absence of MYT1L has already impaired brain development during the developmental phase of the organism,” explains Moritz Mall. However, the results are still limited to studies in mice; clinical studies in patients with disorders from the ASD spectrum have not yet been conducted. The first clinical studies are in the early planning phase.

underlining=mine


MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention - Molecular Psychiatry
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Abstract
MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

Introduction
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder (NDD) characterised by behavioural changes, including altered social patterns . ASD is often associated with coexisting conditions, including epilepsy, intellectual disability, and hyperactivity. Gene mutations affecting neuronal communication confer increased risk for ASD and offer possible therapeutic targets. However, the genetic heterogeneity of ASD is enormous, and multiple transcriptional regulators have recently been associated with this group of disorders. Indeed, mouse models show that mutations of chromatin remodelers, such as Chd8 and BAF complex members like Smarcc2, can induce behavioural phenotypes, suggesting a potential causal role in ASD. Yet, their contribution to disease and their clinical relevance often remains elusive, which limits the development of targeted treatments for gene regulator-associated mental disorders at the time of diagnosis.

Of the 91 chromatin or gene regulators most strongly associated with ASD (category 1;), MYT1L is specifically and continuously expressed in virtually all neurons throughout life. MYT1L is a conserved zinc finger transcription factor and mutations have been reported in patients diagnosed with intellectual disability, schizophrenia, epilepsy, and ASD , suggesting that MYT1L-mediated gene regulation may be important in preventing NDDs including ASD. Indeed, 98% (50 out of 51) of currently reported cases with heterozygous MYT1L deletion or loss-of-function mutations were diagnosed with ASD and/or intellectual disability. Besides behavioural features, several patients with MYT1L mutations also display developmental delays, obesity, seizures, and brain malformations. MYT1L was one of the three original factors able to directly reprogram fibroblasts into functional neurons upon overexpression. MYT1L is a transcriptional repressor that can enhance neuronal identity in vitro by actively repressing several developmental pathways, including WNT and NOTCH. This is achieved in part through recruitment of epigenetic silencers such as SIN3/HDAC. Unexpectedly, reprogramming experiments have also revealed that MYT1L binds and represses several non-neuronal gene programs, such as muscle and fibroblast genes, suggesting a role as pan-neuronal safeguard that silences other lineage-specific genes. Indeed, recent studies described that Myt1l haploinsufficiency, caused by frameshift mutation of Myt1l exon 15 or deletion of exon 9, induced altered brain development and behaviour phenotypes in mice. However, a number of important questions remain unanswered. For example, it is unclear whether distinct MYT1L mutations cause overlapping phenotypes, as suggested based on patient reports. Further, no studies present the effects of MYT1L depletion in human neurons. Finally, the molecular mechanisms causing the neurological phenotypes, and whether they are amenable to intervention, are unknown.

Here, we used genetically-engineered mice and human induced neurons to investigate the role of MYT1L during development and as a new preclinical platform to study MYT1L-associated NDDs. Using these translational models, we show that MYT1L deficiency is sufficient to induce autism-associated phenotypes, ranging from deregulation of gene expression and delayed neurogenesis to cortical thinning and altered behaviour. MYT1L target genes, including WNT and NOTCH regulators, were activated early upon MYT1L depletion in human neurons and chemical pathway inhibition could rescue associated differentiation defects. We found that MYT1L loss also caused upregulation of non-neuronal genes, including the cardiac sodium channel SCN5A, and triggered an unexpected neuronal network hyperactivity that can be rescued by MYT1L overexpression or SCN5A knockdown. Furthermore, acute application of the approved drug lamotrigine rescued the electrophysiological phenotypes in postmitotic mouse and human neurons, as well as behaviour phenotypes in adult mice, providing a potential therapeutic avenue for patients with MYT1L syndrome.

Discussion
Unlike most neuropsychiatric disease-associated chromatin regulators, the transcription factor MYT1L is specifically expressed in virtually all neurons and remains expressed throughout life. However, whether and how MYT1L mutations can cause neuropsychiatric disease remains poorly understood. In this study, we present evidence that MYT1L haploinsufficiency is sufficient to cause phenotypes associated with NDDs and ASD in human neurons as well as in mouse models due to failure to repress target genes resulting in (i) delays during developmental neurogenesis and (ii) synaptic malfunction in mature neurons. MYT1L deficiency in our human and mouse models caused significant deregulation of genes associated with epilepsy, schizophrenia, and ASD, which have been diagnosed in patients carrying MYT1L mutations. We also found that gene expression changes in Myt1l-mutant mouse brains directly resembled those observed in ASD patient brains, demonstrating that MYT1L deficiency can lead to ASD-associated transcriptional profiles. Additional phenotypes linked to ASD and MYT1L-associated NDDs include neurodevelopmental delays and changes in brain anatomy. Using transcriptomic analysis, we observed altered maturation dynamics in MYT1L-deficient human neurons upon transcription factor-mediated neuronal differentiation in vitro and impaired neurogenesis in the prefrontal cortex of Myt1l-mutant mice in vivo. Even at E18.5, Myt1l-mutant mice displayed activation of early-foetal gene expression programs and downregulation of mid-foetal programs, which has also been described in other ASD models. Previous studies showed that acute depletion of Myt1l or the closely related family member Myt1 by shRNA treatment impaired neurogenesis in utero by repressing Hes1 expression and Notch signalling. Here, we expand these findings by showing that germline Myt1l mutation impaired cell cycle exit of cortical progenitors during development and increased the number of SOX2+ neural stem cells in the SVZ at birth, which resembles Hes1 overexpression phenotypes [46]. Indeed, combined chemical inhibition of WNT and NOTCH could restore early induction of proneuronal genes in human induced neurons. This confirms impaired neurogenesis upon MYT1L deficiency and could explain the thinned cortex observed in Myt1l-mutant mice and neurodevelopmental delays in human and mouse models.

One limitation of our study is that we modelled only frameshift mutations predicted to result in premature STOP codons of both human and mouse MYT1L, similar to a reported patient with a nonsense mutation at aa 75 . Our mouse model presented a frameshift in exon 6 that generated non-functional MYT1L protein isoforms missing essential domains such as the nuclear localisation signal, while conditional deletion of exon 7 in our human model resulted in nonsense-mediated RNA decay. Of note, both models exhibited similar gene deregulation and electrophysiology phenotypes, suggesting that loss-of-function results in overlapping defects independent of the mutation type. Notably, two recent studies describe additional Myt1l mouse models; Chen et al. generated a frameshift mutation in exon 15, and Kim et al. used an exon 9 excision mutant. All three models have in common that homozygous Myt1l knockout results in postnatal lethality and altered brain morphology, emphasising the crucial role of MYT1L for development. In addition, all three studies found behavioural phenotypes including hyperactivity. In line with our study, Kim et al. reported decreased anxiety. Chen et al. reported male-specific impaired social behaviour, which we also found in our model although using different assays and developmental stages. Nevertheless, the three Myt1l-mutant mouse models exhibit distinct gene expression and neurodevelopmental defects. In contrast to our study, Chen et al. report an increased Q fraction and a decrease in SOX2+ neural stem cells in Myt1l-deficient mice at E14.5 and suggested MYT1L mainly acts as a transcriptional activator. However, in a recent preprint the same authors found that MYT1L bound and repressed promoters and enhancers of genes involved in early neuronal development programs [71]. Here, using single cell transcriptomics, we show that MYT1L-bound genes are indeed activated in cortical neurons upon loss of MYT1L, supporting its role as a repressor. In line with this, both Chen et al. and our study found increased expression of early neurodevelopmental gene signatures later in development. Notably, all studies report a significant overlap of deregulated genes with ASD gene sets. Hence, while the differences between these three Myt1l mouse models might reflect the distinct nature of mutations, genetic mouse background, and experimental conditions, their overlap emphasises the important role of MYTL for neurodevelopment. In addition to loss-of-function variants, several de novo missense variants, indels and genomic duplications and deletions encompassing MYT1L have been reported in individuals with neuropsychiatric disease. Since MYT1L patients display diverse phenotypes, including both macro- and microcephaly, and are diagnosed with different neuropsychiatric disorders like ASD and schizophrenia, future studies will be needed to clarify how specific mutations or genetic backgrounds affect these phenotypes by engineering additional mouse and human stem cell models or by generating patient-derived neurons from induced pluripotent stem cells.

Alongside destabilization of neuronal cell identity, which manifested as gene expression changes and neurogenesis delays, we observed striking electrophysiological phenotypes in MYT1L-deficient neurons. Unexpectedly, primary mouse and induced human neurons displayed a three to four-fold increase in neuronal network activity, underpinned by an increase in sEPSC amplitude and mEPSC frequency. Since, the frequency of sIPSCs was increased in MYT1L-deficient pyramidal neurons, increased network activity is not likely caused by decreased inhibition in our model. However, in newborn Myt1l (−/−) mice, we observed a slight increase in the fraction of cortical layer I neurons along with decreased Cdca7+ interneuron populations based on single cell analysis. Therefore, the effect of MYT1L mutations on inhibitory neurons remains elusive and requires future studies. Network phenotypes could be explained by multiple factors, such as changes in neuronal morphology or synapse density as well as general mechanisms regulating neurotransmitter release, including deregulation of voltage-gated sodium and calcium channels. Interestingly, the upregulation of channels that are normally not specifically expressed in neurons, such as SCN5A, could also impair normal synaptic transmission in MYT1L-mutant neurons. We therefore tested whether MYT1L overexpression, shRNA-mediated SCN5A knockdown or lamotrigine treatment, which is reported to block sodium and calcium channels could rescue the MYT1L mutation-induced network hyperactivity. Strikingly, MYT1L overexpression decreased expression of target genes such as Scn5a and Hes1 in postmitotic MYT1L-deficient mouse neurons, and MYT1L overexpression and SCN5A knockdown both rescued electrophysiological network hyperactivity phenotypes. In addition, acute application of lamotrigine normalised not only the network hyperactivity phenotypes of post-mitotic MYT1L-deficient human and mouse neurons, but also several behavioural hyperactivity phenotypes observed in mice. This suggests that specific MYT1L haploinsufficiency-associated phenotypes can be rescued by genetic intervention or small-molecule drugs even later in development.

Overall, we present the first evidence that MYT1L mutations destabilise neuronal cell fate and function, and are sufficient to cause ASD-associated phenotypes in human and mouse models. Hence, failure to silence non-neuronal gene expression in neurons represents a novel mechanism that, at least in part, could contribute to ASD aetiology. MYT1L is a unique neurodevelopmental disease-associated transcription factor that is specifically expressed in virtually all neurons throughout life. It is therefore tempting to speculate that active lifelong repression of non-neuronal programs is an evolutionarily-conserved pathway critical for the prevention of brain disorders. Interestingly, MYT1L levels decrease during aging in both mice and humans (Supplementary Fig. S1A), and loss of neuronal cell identity has recently been suggested to play a role in Alzheimer’s disease models, which suggests that neurodegeneration could also be regulated by the novel MYT1L-mediated mechanism presented here. Finally, we show that unexpected electrophysiological network hyperactivity upon MYT1L deficiency in post-mitotic mouse and human neurons, and associated behaviour phenotypes in mice, can be acutely targeted by the approved drug lamotrigine, which could provide an opportunity for therapeutic interventions.



If this turns out like the other “cures”, everybody will get excited, the researchers will get money, and it will be another false lead.


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21 Feb 2023, 9:10 am

A.J. Drexel Autism Institute Finds Strong Performance of Autism Screener When Used as Intended

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Developed by Diana Robins, PhD, director of Drexel University’s A.J. Drexel Autism Institute, in 1999 with her colleagues Deborah Fein and Marianne Barton at the University of Connecticut, the Modified Checklist for Autism in Toddlers (M-CHAT) and the updated version M-CHAT, Revised with Follow-Up (M-CHAT-R/F) are the most commonly used autism-specific screening tools for young children. Both versions – noted as M-CHAT(-R/F) – are available for clinical, research and educational purposes globally.

However, Robins and her colleague Andrea Wieckowski, PhD, an assistant professor in the Autism Institute, have found that use of these measures in research and clinical practice often differs from the original validation studies. This limits people’s ability to understand and measure how M-CHAT(-R/F) performs in detecting autism.

Newly published in JAMA Pediatrics, a study by Wieckowski, Robins and their co-authors systematically reviewed and analyzed factors that may lead to different performance estimates of the M-CHAT(-R/F) tests. The research team reviewed studies published between January 2001 and August 2020 and found 50 studies that provided information on M-CHAT(-R/F)’s performance as an autism screener.

“M-CHAT(-R/F) shows strong performance as an autism screener,” said Wieckowski “We found that across the studies, there was 83% sensitivity, or ability to detect autism when present. Specificity, or ability to accurately rule out autism, was 94%, indicating its strong performance.”

However, there was also wide variability in results. Higher performance was reported in studies that used low-likelihood of autism samples — also known as “population-based” samples — as opposed to high-likelihood samples, such as samples of children with older siblings on the autism spectrum or other factors that increase likelihood of autism.

Performance of M-CHAT(-R/F) also varied according to confirmation strategies and use of Follow-Up. Specifically, whether case-confirmation strategies occurred around the same time as screening (concurrent) or when children were older (prospective), or whether the study used the structured Follow-Up for children who scored in the moderate range on the initial questionnaire impacted the screener’s performance. Other factors that influenced performance of M-CHAT(-R/F) screening included use of non-English translations of the test, versus primarily English screening, and the size of the study sample.

The authors suggest that the finding of high variability in the sensitivity and specificity based on these factors should be considered when using the test in clinical and research settings. Overall, the results of this study support the current recommendations from the American Academy of Pediatrics (AAP) for universal autism screening at 18- and 24-month well-child check-ups.

“For screening to be effective, protocols should adhere to the recommended use, and children who screen positive should be referred for evaluation and early intervention without delay,” said Wieckowski.

According to the research team, currently many pediatric practices do not adhere to the AAP guidelines to screen all children. Others deviate from recommended use by not administering follow-up, not repeating screening, and not referring positive cases for evaluation and early intervention. They add that findings from the U.S. Preventive Services Task Force, which found insufficient evidence to support universal screening, lead to confusion about best practices for early detection of autism.

Robins acknowledges that she is a co-owner of M-CHAT, LLC, which licenses use of the M-CHAT and M-CHAT-R/F to commercial entities. She also serves on the advisory board of Quadrant Biosciences, Inc. and the Program Quality Committee of Bancroft.


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21 Feb 2023, 11:28 am

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A Drug That Cures Autism? Neuroscience Study Yields Promising Results
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The behavioral disorders observed in autism are associated with a multitude of genetic alterations. Scientists from the Hector Institute for Translational Brain Research (HITBR) have now found another molecular cause for this condition. The transcription factor MYT1L normally protects the molecular identity of nerve cells. If it is genetically switched off in human nerve cells or in mice, the functional changes and symptoms typical of autism occur. A drug that blocks sodium channels in the cell membrane can reverse the consequences of MYT1L failure and alleviate the functional and behavioral abnormalities in mice.

Scientists are intensively searching for the molecular abnormalities that contribute to this complex developmental disorder. A multitude of genetic factors that influence the molecular programs of the nerve cells have already been linked to the development of autism.

Moritz Mall from the Hector Institute for Translational Brain Research (HITBR) has long been researching the role of the protein MYT1L in various neuronal diseases. The protein is a so-called transcription factor that decides which genes are active in the cell and which are not. Almost all nerve cells in the body produce MYT1L throughout their entire life span.

Mall had already shown a few years ago that MYT1L protects the identity of nerve cells by suppressing other developmental pathways that program a cell toward muscle or connective tissue, for example. Mutations in MYT1L have been found in several neurological diseases, such as schizophrenia and epilepsy, but also in brain malformations. In their current work, which is funded by the European Research Council ERC, Mall and his team examined the exact role of the “guardian of neuronal identity” in the development of an ASD. To do this, they genetically switched off MYT1L — both in mice and in human nerve cells that had been derived from reprogrammed stem cells in the laboratory.

The loss of MYT1L led to electrophysiological hyperactivation in mouse and human neurons and thus impaired nerve function. Mice lacking MYT1L suffered from brain abnormalities, such as a thinner cerebral cortex. The animals also showed several ASS-typical behavioral changes such as social deficits or hyperactivity.

What was particularly striking about the MYT1L-deficient neurons was that they produced an excess of sodium channels that are normally mainly restricted to the heart muscle cells. These pore-shaped proteins allow sodium ions to pass through the cell membrane and are thus crucial for electrical conductivity and thus also for the functioning of the cells. If a nerve cell produces too many of these channel proteins, electrophysiological hyperactivation can be the result.

In clinical medicine, drugs that block sodium channels have been used for a long timel

Apparently, drug treatment in adulthood can alleviate brain cell dysfunction and thus counteract the behavioral abnormalities typical of autism — even after the absence of MYT1L has already impaired brain development during the developmental phase of the organism,” explains Moritz Mall. However, the results are still limited to studies in mice; clinical studies in patients with disorders from the ASD spectrum have not yet been conducted. The first clinical studies are in the early planning phase.

underlining=mine


MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention - Molecular Psychiatry
Quote:
Abstract
MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

Introduction
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder (NDD) characterised by behavioural changes, including altered social patterns . ASD is often associated with coexisting conditions, including epilepsy, intellectual disability, and hyperactivity. Gene mutations affecting neuronal communication confer increased risk for ASD and offer possible therapeutic targets. However, the genetic heterogeneity of ASD is enormous, and multiple transcriptional regulators have recently been associated with this group of disorders. Indeed, mouse models show that mutations of chromatin remodelers, such as Chd8 and BAF complex members like Smarcc2, can induce behavioural phenotypes, suggesting a potential causal role in ASD. Yet, their contribution to disease and their clinical relevance often remains elusive, which limits the development of targeted treatments for gene regulator-associated mental disorders at the time of diagnosis.

Of the 91 chromatin or gene regulators most strongly associated with ASD (category 1;), MYT1L is specifically and continuously expressed in virtually all neurons throughout life. MYT1L is a conserved zinc finger transcription factor and mutations have been reported in patients diagnosed with intellectual disability, schizophrenia, epilepsy, and ASD , suggesting that MYT1L-mediated gene regulation may be important in preventing NDDs including ASD. Indeed, 98% (50 out of 51) of currently reported cases with heterozygous MYT1L deletion or loss-of-function mutations were diagnosed with ASD and/or intellectual disability. Besides behavioural features, several patients with MYT1L mutations also display developmental delays, obesity, seizures, and brain malformations. MYT1L was one of the three original factors able to directly reprogram fibroblasts into functional neurons upon overexpression. MYT1L is a transcriptional repressor that can enhance neuronal identity in vitro by actively repressing several developmental pathways, including WNT and NOTCH. This is achieved in part through recruitment of epigenetic silencers such as SIN3/HDAC. Unexpectedly, reprogramming experiments have also revealed that MYT1L binds and represses several non-neuronal gene programs, such as muscle and fibroblast genes, suggesting a role as pan-neuronal safeguard that silences other lineage-specific genes. Indeed, recent studies described that Myt1l haploinsufficiency, caused by frameshift mutation of Myt1l exon 15 or deletion of exon 9, induced altered brain development and behaviour phenotypes in mice. However, a number of important questions remain unanswered. For example, it is unclear whether distinct MYT1L mutations cause overlapping phenotypes, as suggested based on patient reports. Further, no studies present the effects of MYT1L depletion in human neurons. Finally, the molecular mechanisms causing the neurological phenotypes, and whether they are amenable to intervention, are unknown.

Here, we used genetically-engineered mice and human induced neurons to investigate the role of MYT1L during development and as a new preclinical platform to study MYT1L-associated NDDs. Using these translational models, we show that MYT1L deficiency is sufficient to induce autism-associated phenotypes, ranging from deregulation of gene expression and delayed neurogenesis to cortical thinning and altered behaviour. MYT1L target genes, including WNT and NOTCH regulators, were activated early upon MYT1L depletion in human neurons and chemical pathway inhibition could rescue associated differentiation defects. We found that MYT1L loss also caused upregulation of non-neuronal genes, including the cardiac sodium channel SCN5A, and triggered an unexpected neuronal network hyperactivity that can be rescued by MYT1L overexpression or SCN5A knockdown. Furthermore, acute application of the approved drug lamotrigine rescued the electrophysiological phenotypes in postmitotic mouse and human neurons, as well as behaviour phenotypes in adult mice, providing a potential therapeutic avenue for patients with MYT1L syndrome.

Discussion
Unlike most neuropsychiatric disease-associated chromatin regulators, the transcription factor MYT1L is specifically expressed in virtually all neurons and remains expressed throughout life. However, whether and how MYT1L mutations can cause neuropsychiatric disease remains poorly understood. In this study, we present evidence that MYT1L haploinsufficiency is sufficient to cause phenotypes associated with NDDs and ASD in human neurons as well as in mouse models due to failure to repress target genes resulting in (i) delays during developmental neurogenesis and (ii) synaptic malfunction in mature neurons. MYT1L deficiency in our human and mouse models caused significant deregulation of genes associated with epilepsy, schizophrenia, and ASD, which have been diagnosed in patients carrying MYT1L mutations. We also found that gene expression changes in Myt1l-mutant mouse brains directly resembled those observed in ASD patient brains, demonstrating that MYT1L deficiency can lead to ASD-associated transcriptional profiles. Additional phenotypes linked to ASD and MYT1L-associated NDDs include neurodevelopmental delays and changes in brain anatomy. Using transcriptomic analysis, we observed altered maturation dynamics in MYT1L-deficient human neurons upon transcription factor-mediated neuronal differentiation in vitro and impaired neurogenesis in the prefrontal cortex of Myt1l-mutant mice in vivo. Even at E18.5, Myt1l-mutant mice displayed activation of early-foetal gene expression programs and downregulation of mid-foetal programs, which has also been described in other ASD models. Previous studies showed that acute depletion of Myt1l or the closely related family member Myt1 by shRNA treatment impaired neurogenesis in utero by repressing Hes1 expression and Notch signalling. Here, we expand these findings by showing that germline Myt1l mutation impaired cell cycle exit of cortical progenitors during development and increased the number of SOX2+ neural stem cells in the SVZ at birth, which resembles Hes1 overexpression phenotypes [46]. Indeed, combined chemical inhibition of WNT and NOTCH could restore early induction of proneuronal genes in human induced neurons. This confirms impaired neurogenesis upon MYT1L deficiency and could explain the thinned cortex observed in Myt1l-mutant mice and neurodevelopmental delays in human and mouse models.

One limitation of our study is that we modelled only frameshift mutations predicted to result in premature STOP codons of both human and mouse MYT1L, similar to a reported patient with a nonsense mutation at aa 75 . Our mouse model presented a frameshift in exon 6 that generated non-functional MYT1L protein isoforms missing essential domains such as the nuclear localisation signal, while conditional deletion of exon 7 in our human model resulted in nonsense-mediated RNA decay. Of note, both models exhibited similar gene deregulation and electrophysiology phenotypes, suggesting that loss-of-function results in overlapping defects independent of the mutation type. Notably, two recent studies describe additional Myt1l mouse models; Chen et al. generated a frameshift mutation in exon 15, and Kim et al. used an exon 9 excision mutant. All three models have in common that homozygous Myt1l knockout results in postnatal lethality and altered brain morphology, emphasising the crucial role of MYT1L for development. In addition, all three studies found behavioural phenotypes including hyperactivity. In line with our study, Kim et al. reported decreased anxiety. Chen et al. reported male-specific impaired social behaviour, which we also found in our model although using different assays and developmental stages. Nevertheless, the three Myt1l-mutant mouse models exhibit distinct gene expression and neurodevelopmental defects. In contrast to our study, Chen et al. report an increased Q fraction and a decrease in SOX2+ neural stem cells in Myt1l-deficient mice at E14.5 and suggested MYT1L mainly acts as a transcriptional activator. However, in a recent preprint the same authors found that MYT1L bound and repressed promoters and enhancers of genes involved in early neuronal development programs [71]. Here, using single cell transcriptomics, we show that MYT1L-bound genes are indeed activated in cortical neurons upon loss of MYT1L, supporting its role as a repressor. In line with this, both Chen et al. and our study found increased expression of early neurodevelopmental gene signatures later in development. Notably, all studies report a significant overlap of deregulated genes with ASD gene sets. Hence, while the differences between these three Myt1l mouse models might reflect the distinct nature of mutations, genetic mouse background, and experimental conditions, their overlap emphasises the important role of MYTL for neurodevelopment. In addition to loss-of-function variants, several de novo missense variants, indels and genomic duplications and deletions encompassing MYT1L have been reported in individuals with neuropsychiatric disease. Since MYT1L patients display diverse phenotypes, including both macro- and microcephaly, and are diagnosed with different neuropsychiatric disorders like ASD and schizophrenia, future studies will be needed to clarify how specific mutations or genetic backgrounds affect these phenotypes by engineering additional mouse and human stem cell models or by generating patient-derived neurons from induced pluripotent stem cells.

Alongside destabilization of neuronal cell identity, which manifested as gene expression changes and neurogenesis delays, we observed striking electrophysiological phenotypes in MYT1L-deficient neurons. Unexpectedly, primary mouse and induced human neurons displayed a three to four-fold increase in neuronal network activity, underpinned by an increase in sEPSC amplitude and mEPSC frequency. Since, the frequency of sIPSCs was increased in MYT1L-deficient pyramidal neurons, increased network activity is not likely caused by decreased inhibition in our model. However, in newborn Myt1l (−/−) mice, we observed a slight increase in the fraction of cortical layer I neurons along with decreased Cdca7+ interneuron populations based on single cell analysis. Therefore, the effect of MYT1L mutations on inhibitory neurons remains elusive and requires future studies. Network phenotypes could be explained by multiple factors, such as changes in neuronal morphology or synapse density as well as general mechanisms regulating neurotransmitter release, including deregulation of voltage-gated sodium and calcium channels. Interestingly, the upregulation of channels that are normally not specifically expressed in neurons, such as SCN5A, could also impair normal synaptic transmission in MYT1L-mutant neurons. We therefore tested whether MYT1L overexpression, shRNA-mediated SCN5A knockdown or lamotrigine treatment, which is reported to block sodium and calcium channels could rescue the MYT1L mutation-induced network hyperactivity. Strikingly, MYT1L overexpression decreased expression of target genes such as Scn5a and Hes1 in postmitotic MYT1L-deficient mouse neurons, and MYT1L overexpression and SCN5A knockdown both rescued electrophysiological network hyperactivity phenotypes. In addition, acute application of lamotrigine normalised not only the network hyperactivity phenotypes of post-mitotic MYT1L-deficient human and mouse neurons, but also several behavioural hyperactivity phenotypes observed in mice. This suggests that specific MYT1L haploinsufficiency-associated phenotypes can be rescued by genetic intervention or small-molecule drugs even later in development.

Overall, we present the first evidence that MYT1L mutations destabilise neuronal cell fate and function, and are sufficient to cause ASD-associated phenotypes in human and mouse models. Hence, failure to silence non-neuronal gene expression in neurons represents a novel mechanism that, at least in part, could contribute to ASD aetiology. MYT1L is a unique neurodevelopmental disease-associated transcription factor that is specifically expressed in virtually all neurons throughout life. It is therefore tempting to speculate that active lifelong repression of non-neuronal programs is an evolutionarily-conserved pathway critical for the prevention of brain disorders. Interestingly, MYT1L levels decrease during aging in both mice and humans (Supplementary Fig. S1A), and loss of neuronal cell identity has recently been suggested to play a role in Alzheimer’s disease models, which suggests that neurodegeneration could also be regulated by the novel MYT1L-mediated mechanism presented here. Finally, we show that unexpected electrophysiological network hyperactivity upon MYT1L deficiency in post-mitotic mouse and human neurons, and associated behaviour phenotypes in mice, can be acutely targeted by the approved drug lamotrigine, which could provide an opportunity for therapeutic interventions.



If this turns out like the other “cures”, everybody will get excited, the researchers will get money, and it will be another false lead.


These people still use autism as a single biological condition when this is absurd in 2023.

Maybe this will fix the issue with this particular gene and that particular autism.

Others will require a different type of potential treatment


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24 Feb 2023, 1:24 pm

NIH STUDY SUGGESTS ASSOCIATION BETWEEN MOTHERS' EXPERIENCES OF MALTREATMENT IN THEIR OWN CHILDHOOD TO THEIR CHILDREN'S HEALTH OUTCOMES

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Children of mothers who experienced childhood abuse or neglect may have a higher risk for developing asthma, ADHD, autism spectrum disorder, and certain mental health issues, according to a study funded by the Environmental influences on Child Health Outcomes Program (ECHO) at the National Institutes of Health.

This research suggests that a mother's history of being abused or neglected as a child may increase their child's risk for developing one or more of these health outcomes at once. Daughters of these mothers may also be more likely to develop obesity, the study found, as compared to sons.

The researchers surveyed 4,337 mothers from 21 ECHO cohorts across the U.S. on their childhood experiences. About 44 percent of these mothers reported childhood abuse or neglect. The researchers also collected data on the rates of diagnosis for a number of physical and mental conditions among the children of mothers participating in the study.

Since Autism is mostly genetic I doubt the mother being abused is a direct cause of her childrens autism. Genetics means a greater chance the mom is autistic or has autistic traits and thus more likely to be abused.


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27 Feb 2023, 11:17 am

Understanding the roots of autism

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n Fragile X syndrome (FXS), the most common cause of autism, sensory signals from the outside world are integrated differently, causing them to be underrepresented by cortical pyramidal neurons in the brain. That’s according to a new study led by Université de Montréal (UdeM) Professor Roberto Araya and published in the journal PNAS.

With advanced imaging tools and the genetic manipulation of neurons, researchers at the UdeM-affiliated CHU Sainte-Justine Research Centre were able to observe the functioning of individual neurons; specifically, pyramidal neurons of cortical layer 5 — one of the main information output neurons of the cortex. The researchers found a difference in how sensory signals are processed in these neurons.

“Previous work has suggested that FXS and autism spectrum disorders are characterised by a hyperexcitable cortex, which is considered to be the main contributor to the hypersensitivity to sensory stimuli observed in autistic individuals,” Araya said.

“To our surprise, our experimental results challenge this generalised view that there is a global hypersensitivity in the neocortex associated with FXS,” added Diana E Michell, first co-author of the study. “They show that the integration of sensory signals in cortical neurons is underrepresented in a murine model of FXS.”

A protein called FMRP that is absent in the brains of people with FXS modulates the activity of a type of potassium channel in the brain. According to the research group’s work, it is the absence of this protein that alters the way sensory inputs are combined, causing them to be underrepresented by the signals coming out of the cortical pyramidal neurons in the brain.

Soledad Miranda-Rottmann, also first co-author of the study, attempted to rectify the situation with genetic and molecular biology techniques. “Even in the absence of the FMRP protein, which has several functions in the brain, we were able to demonstrate how the representation of sensory signals can be restored in cortical neurons by reducing the expression of a single molecule,” she said.

The phenomenon the team observed not only provides insight into the mechanism of FXS at the cellular level, but also opens the door to new targets for therapeutic strategies “to offer support to those with FXS and possibly other autism spectrum disorders to correctly perceive sensory signals from the outside world at the level of pyramidal neurons in the cortex,” Araya said.

“Even if the overrepresentation of internal brain signals causing hyperactivity is not addressed, the correct representation of sensory signals may be sufficient to allow better processing of signals from the outside world and of learning that is better suited to decision-making and engagement in action.”

Fragile X the most common cause of autism ????


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02 Mar 2023, 10:55 am

Do people with autism feel pain more acutely? Study sheds light on a little-discussed phenomenon

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There are many aspects of autism spectrum disorders that remain, for lack of a better word, mysterious. As someone who is on the autism spectrum himself, I can personally attest to such enigmatic realities as the double empathy problem, which describes how autistic and non-autistic people fundamentally differ in how they communicate. People on the autism spectrum sometimes have hard-to-explain physical disabilities in addition to communication issues, and statistics prove that men are more likely to develop autism than women.

And there is the autism-pain problem. As a child, I used to run and hide under the bed whenever I heard a train passing by because the stimuli made me feel uncomfortable. For other autistic people, the problem involves a tendency to be more agitated than usual by physical pain such as being given shots or dealing with routine injuries.

Earlier this month, a study by Israeli researchers in the scientific journal PAIN illuminated this under-explained aspect of autism: Why autistic people seem to be more sensitive to pain, whether it's hypersensitivity to lights and sounds or an unusually acute response to literal physical pain.

After conducting an experiment with 52 adults who were either high-functioning autistic (HFA) or neurotypical, the largest reported sample for a study on pain in autism in the world, the scientists concluded that there are two factors at play in autism: "an increase of the pain signal along with a less effective pain inhibition mechanism."

Yet the researchers also added that much more work will need to be done to understand the exact neurological mechanisms that cause autistic people to experience pain more acutely. Indeed, more broadly, scientists need to understand why the experience of pain is so inherently subjective from person to person.

"People certainly feel pain in different ways and to different degrees," Michelle D. Failla, PhD, Research Assistant Professor at The Ohio State University College of Nursing, told Salon by email. (Failla was not involved in the Israeli study.) "There is variation in how much people feel and express pain that can be related to general individual variation across people, but also different life experiences, medical conditions, gender, race, and many other factors. People also can experience pain differently at different times in their lives – so it can change even by the situation for each person."

When it comes to studying the specific problem of autism and pain, the tricky part is ascertaining exactly how much of a role the autism disorder itself plays in the pain sensation. Dr David Moore, who studies pain psychology at Liverpool John Moores University (and was likewise not involved in the Israeli study), wrote to Salon that he and his colleagues have compared pain thresholds between autistic and non-autistic people. While they have not found evidence of differences when it comes to literal pain thresholds — "the intensity required for a person to report that a sensation is painful" — this is not the case when it comes to how intensely people perceive their pain once it has been registered.

"Once a sensation is painful the intensity of these pains might be higher in autistic adults compared to their non-autistic peers," Moore explained. "This might suggest that once a pain is perceived that suffering is more acute for autistic people." He also noted that autistic people who are more likely to experience conditions like joint hypermobility and gastrointestinal problems, which exacerbate their discomfort.

"We also have reason to suspect that autistic people are more likely to need management within tertiary chronic pain clinics suggesting the greatest levels of care are more likely to be required," Moore told Salon.

In terms of why autistic people seem to feel pain more acutely, Hadjikhani says that "it that has not been proven and shown directly, but it really seems like this is because the autistic brain has an imbalance between excitation and inhibition, it's more susceptible to process signals with more intensity compared with the brains of typical people."


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03 Mar 2023, 11:56 am

UC Davis study uncovers age-related brain differences in autistic individuals

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A new study led by UC Davis MIND Institute researchers confirms that brain development in people with autism differs from those with typical neurodevelopment. According to the study published in PNAS, these differences are linked to genes involved in inflammation, immunity response and neural transmissions. They begin in childhood and evolve across the lifespan.

The researchers aimed to understand how neurons in the brain communicate and the interaction between age and autism. They studied the genetic differences in brain neurons in people with autism at different ages and compared them to those with neurotypical development.

Earlier studies have shown that certain brain regions mark early excess, followed by reductions in volume, connectivity, and cell densities of neurons as people with autism age through adulthood.

“Initial excess and overconnectivity of neurons may make the brain more vulnerable to early aging and inflammation, which may lead to further changes in the brain structure and function,” said co-senior author Cynthia Schumann. Schumann is a professor of neuroscience in the Department of Psychiatry and Behavioral Sciences. She is affiliated with the UC Davis MIND Institute. “Understanding how the brain in a person with autism changes throughout life will provide opportunities for early intervention.”

The researchers analyzed brain tissues from 27 deceased individuals with autism and 32 without autism. The age of these individuals ranged between 2 and 73 years.

The tissues were taken from the superior temporal gyrus (STG) region — an area in the brain responsible for sound and language processing and social perception.

“The STG plays a critical role in integrating information. It helps provide meaning about our surroundings. Despite its importance, it remains relatively unexplored,” Schumann commented. “We wanted to understand how the molecular changes in this critical part of the brain are happening in autism.”

The team analyzed brain tissues as well as isolated neurons using laser capture microdissection techniques. They studied mRNA expression on a molecular level in the STG tissue and the isolated neurons. The mRNA translates the DNA code into instructions the cell machinery can recognize and use to make proteins for different body functions.

The study identified 194 significantly different genes in the brains of people with autism. Of those genes, 143 produced more mRNA (upregulated) and 51 produced less (downregulated) in autistic brains than in typical ones.

The downregulated genes were mainly linked to brain connectivity. This may indicate that the neurons may not communicate as efficiently. Too much activity in the neurons may cause the brain to age faster in autistic individuals.

The study also found more mRNA for heat-shock proteins in autistic brains. These proteins respond to stress and activate immune response and inflammation.

The study identified 14 genes in bulk STG tissue that showed age-dependent differences between autistic and neurotypical individuals and three genes in isolated neurons. These genes were connected to synaptic as well as immunity and inflammation pathways.

The researchers also uncovered different inflammation patterns in autistic brain tissues. Several immune and inflammation-related genes were strongly upregulated, indicating immune dysfunction that may get worse with age.

The study pointed to an age-related decrease in the gene expression involved in Gamma-aminobutyric acid (GABA) synthesis. GABA is a chemical messenger that helps slow down the brain. It works as an inhibitory neurotransmitter.

“GABA is known for producing a dampening effect in controlling neuronal hyperactivity in anxiety and stress. Our study showed age-dependent alterations in genes involved in GABA signaling in brains of people with autism,” Stamova said.

The study found direct molecular-level evidence that insulin signaling was altered in the neurons of people with autism. It also noted significant similarities of mRNA expressions in the STG region between people with autism and those with Alzheimer’s disease. These expressions may be linked to increased likelihood of neurodegenerative and cognitive decline.


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“My autism is not a superpower. It also isn’t some kind of god-forsaken, endless fountain of suffering inflicted on my family. It’s just part of who I am as a person”. - Sara Luterman