Researchers discover molecular difference in autistic brains | Hacker News Reader

Researchers discover molecular difference in autistic brains

medicine.yale.edu

224 pointsamichail138 comments

Homeostasis across the blood brain barrier makes me suspect trivial approaches to boosting glutamate won't work. But this even begs the question if boosting available glutamate would be the right thing.

There are perverse consequences in brain chemistry and signalling: flooding a brain deficient in glutamate processing receptors with glutamate may not help, it may overload pathways and cause hindrance, not compensation.

Signs like this may be consequential, or related but not causal, or may simply turn out to be wrong.

IF a small sample effect turns out to be indicative of a larger property, and IF it's shown to be causal and IF remeditation involves boosting blood borne glutamate or precursors is 3 stacked IF.

IF its detectable in a young brain it could be diagnostic.

IF its detectable in a young brain and amenable to gene therapy and IF it's causative then treatment would be useful.

IF excess glutamate is not a problem and dietary supplemented sources cross the blood brain barrier and don't trip over homeostasis then it's possibly worth exploring.

(Not a scientist, not a biologist)

It seems you are assuming that because the majority of people have a certain quantity of glutamate receptors, that they are the healthy ones and that we should be trying to bring autistic people up to that level. Is that right?

Why not consider the opposite, that the most beneficial quantity of glutamate receptors could be somewhere below the typical amount? If that were true, then we could try to help others reduce their glutamate receptor level to become healthier and more successful (and a little more autistic).

If we found, say, an association between a lower level of neurological characteristic X and concert-level piano skill, then those who aspire to play that instrument at an elite level might try to decrease X. The fact that most of us are rubbish piano players would not be evidence that lower levels of X are harmful, but very much the opposite.

You're absolutely right that assumption was implicit. The answer was written totally in that framework. I'm not here to say what's right or wrong in determining something about people who lie outside of normal in these things, or what normal means.

So what I wrote should be read with a "if it is held to be a condition which deserved remediation or avoidance of it's manifestation" attached.

Most medical conditions are couched in this sense, that a deficit or departure from the normal is a problem. In matters of brain chemistry it pays to be more nuanced.

It is an interesting idea, but let’s not assume autistic traits make you more talented in anything. There certainly is very highly intelligent people with autistic traits that are able to use hyper-focusing to help them work very hard and succeed in academia or at work. I doubt any rational person is looking for ”a cure” for the Alan Turings and Albert Einsteins of this world. Nor even for a regular, albeit slightly odd, chap like myself, who likes reading books alone with his cat and studying math instead of seeing other people.

However there are people with severe autism that makes it more or less impossible for them to communicate with other people or live independently. If these people could have their life improved it might make huge difference to them and their families.

> All autistic participants in the study had average or above average cognitive abilities. McPartland and collaborators are also working together on developing other approaches to PET scans that will enable them to include individuals with intellectual disabilities in future studies.

Simply put they didn't even touch the keeners, nonverbalists, the piss-in-your-pants, or the perpetual 1 year old autistics. They went after people who previously would be called "Aspergers syndrome".

But everything cognitive seems to be called 'autism spectrum disorder' these days.

Of course they didn't. It would be unethical to perform non-medically-necessary PET scans on people who are unable to give informed consent due to the radiation exposure.

First, 1 PET scan is around 25mSv. 50mSv is yearly limit for radiation workers. And those are being overly safe to allow accidental overage. 100mSv is start of detectable cancer risk. So the risk for 1 scan is basically 0.

Secondly, someone has medical power of attorney over the non-functional autistics. And in reality, they are the ones at most need of (almost passive) study to help them. Us high functioning autistics dont need anywhere near the help.. And we have no way to know an Aspergers and traditional autism are even similar, other than the spectrum brigade keeps adding more and more under 'autism'.

Simply put, guardian says yes to do a single scan a year, and I see no problem with it. More than 1 a year, and we start getting into potential damage. Maybe with some pie-in-the-sky-IRB whatif situation, sure. But 1 scan/yr has no demonstrable damage.

I imagine it was a lot easier to get this version where the study participants can consent for themselves past an ethics panel. Now that there's a result suggesting something of value might be learned, there's a stronger argument for studies with greater ethical risk.

I am not sure what conclusion you would like us to draw from this. Presumably it is simpler to get people for this sort of study if you can, y’know, ask them. Next step would be to repeat the study with a larger group, eventually adding also those, who really really need help. I doubt there’s a Noble waiting for someone for creating a drug that helps a chap who likes trains to look you into eyes while they are speaking to you.

> boosting glutamate won't work.

You would not want to boost glutamate. It's the opposite. You want to reduce glutamate and/or increase GABA. The problem is overexcitation, not underexcitation.

The reason the number of receptors might be low in the first place is downregulation from too much glutamate.

"many neurodivergent people aren’t hindered by autism"

This is more or less not true. If it doesn't hinder a person in any aspect of their life, they don't fit the DSM-V criteria for a diagnosis.

(Many neurodivergent people aren't hindered by autism because they have some other neurodivergence, but that's a different issue with this sentence)

Maybe they meant neurodivergent as a broader category? Like "some people are neurodivergent but don't have autism"

That would be a bit weird though...

EDIT: Neurodivergent is very much a broader category. What I meant would be weird is to state the obvious... Very much sounded like they were trying to say some people with autism may not want to get "cured" but using the wrong words

Neurodivergent doesn't mean autistic. There are tonnes on non-autistic neurodivergent people. All the dyslexics, ADHDers and so on

Almost all of those conditions include some kind of hinderance in their definition though.

The only possible exception I can think of is synaesthesia.

The DSM-V criteria are not a good description of the natural category, and most people don't actually use them. They are, at best, a vague gesture in the direction of the natural category. The ICD-11 criteria (6A02) are better, but are still contradicted by, for instance, studies evidencing the double-empathy problem. Trained psychologists know which diagnostic criteria to take literally, and which to interpret according to the understanding of the authors.

If someone doesn't have any deficits or impairments at all then they won't qualify under ICD-11 either:

"Deficits are sufficiently severe to cause impairment in personal, family, social, educational, occupational or other important areas of functioning..."

Virtually none of the definitions in the ICD or DSM are entirely correct: that doesn't mean they're not useful. For example, you stop meeting the literal diagnostic criteria of many conditions if they're being treated adequately, but that doesn't mean you no longer have those conditions. Someone on antiretrovirals with no detectable HIV viral load still has HIV, and still needs to take the antiretrovirals. No competent doctor would diagnose them as "cured". Yet, they would not meet the diagnostic criteria described in the ICD-11:

> A case of HIV infection is defined as an individual with HIV infection irrespective of clinical stage including severe or stage 4 clinical disease (also known as AIDS) confirmed by laboratory criteria according to country definitions and requirements.

and rarely they may never have met these criteria. This is HN, so a computer analogy might be more helpful: ask a non-technical friend to read through some of the POSIX.1-2024 spec, then ask them to explain the signal handling, or the openat error codes. They will totally misunderstand it, because the POSIX specs are not actually clear: their purpose is to jog the memory of the expert reader, and describe the details they might have forgotten, not to provide a complete and accurate description suitable for teaching.

(Edit: pointless confrontational passage excised. Thanks for the criticism.)

This bit:

> Are you a trained psychologist?

seems a bit confrontational, unless you yourself are a trained psychologist, in which case it would seem fitting to volunteer those credentials along with this challenge.

Why is someone on HIV antivirals if no test ever confirmed them to have HIV? Presumably, they were confirmed as having HIV and have reduced its load to beneath detectable levels but that doesn't erase the previous confirmation.

I think that's all an aside, though, if not the ICD (as suggested by another poster) or the DSM definition initially used, which definition is correct?

OP, I think, is clearly harkening back to a previous post on HN (article at: https://www.psychiatrymargins.com/p/autisms-confusing-cousin...) by a professional discussing that the public often misunderstands and ignores key aspects of the definition. This seems rather a bit like you pointing out laypeople might read and not understand what they got out of the POSIX.1-2024 spec. Except it seems you're suggesting instead that the layperson understanding is correct.

> Why is someone on HIV antivirals if no test ever confirmed them to have HIV?

Mu. If it was confirmed, but not "confirmed by laboratory criteria according to country definitions and requirements", then they do not meet the diagnostic criteria (interpreted literally). Suppose, for instance, that there was a procedural error that might have messed up the diagnosis (so is forbidden by regulation), but in this case didn't mess up the diagnosis.

I can produce as many of these literally-correct, deliberate misinterpretations as you like. They have no bearing on actual medical practice.

> which definition is correct?

Which definition of "carbon atom" is correct? Our definitions have, for 200 years, been sufficient to distinguish "carbon atom" from "not carbon atom", but those definitions have changed significantly in that time. Autism is that category into which autistic people fall, and into which allistic people do not fall, which is distinguished from several other categories with which it is often confused. (The ICD-11 spends way more words on distinguishing autism from OCD, Tourette's, schizophrenia, etc than on defining it directly.)

They still are an individual with HIV infection, except that it is in the stage of "remission" or "undetectable" but they have previously been diagnosed with HIV at a different clinical stage.

So the definition is perfectly correct, assuming you know what "clinical stages" there are.

But going by the strict notion of DSM-V criteria of providing a hindrance, we hit the somewhat problematic definition whereby a person can have autism at one point in their life (when it hinders them in a context), moves into another point or context in their life (where it does not) and therefore they do not or would not meet the criteria for having autism if they sought a diagnosis at that point in time, and then move back into another point or context in their life where it hinders them and so now they meet the criteria and presumably have autism again.

Now, needless to say, this is not how anyone actually thinks about psychiatric or psychological issues in practice, especially with conditions such as autism, and just highlights the relative absurdity of some of the diagnostic metrics, practices and definitions.

What we tend to do is tie the diagnosis of autism to the individual identity and assume that it is a consistent category and applicative diagnosis that stays with a person over time because it is biological. We know, of course, that this is despite not having any working biological test for it, and diagnosing it via environmental and behavioural contexts. And don't even get me started on tying in diagnosis of aspergers/autistic individuals with broadly differing abilities and performance metrics on a range of metrics under the one condition such that the non-verbals and low-functioning side of neurotypicals get lumped in with the high iq and hyper-verbal high-functioning aspergers as having the same related condition even though neurotypicals are closer to the non-verbals and low-iqs on the same metrics and scores.

The entire field and classification system, along with the popular way of thinking about the condition is, if i might editorialise, an absolute mess.

Being reliant on a particular life situation does strike me as a hindrance in and of itself. Maybe more of a macro limitation than a day-to-day one, but a reasonable definition could encompass that, too.

A person without legs does not stop being disabled because they have no need or desire to walk. The fact remains that should they need or desire to walk in the future the hinderance will still very much exist.

A similar example could be made of someone with gluten intolerance. If they do not eat foods that contain gluten they are still gluten intolerant. They are however still disabled by needing to stay in that situation.

Ah yes, but that results in two problems.

Firstly a fish without legs objectively does not have legs, but we do not necessarily call it disabled, even though it clearly lacks a facility.

Secondly, the autism spectrum disorders are, as I previously mentioned, not obviously just about deficits of behaviours or functions but also can take in extended and exceptional abilities in some areas and greater sensitivities rather than deficits or lack of an ability, so it is not clear that the entire diagnosis can be defined by deficits or lacking things. The high functioning and Asperger's type diagnosis is not about a universal deficit diagnosis and we do not generally call neuro-typical humans disabled because they lack prodigious activity or interest in math, language, or other subjects, even though that can also objectively be measured and called a deficit.

> The high functioning and Asperger's type diagnosis is not about a universal deficit diagnosis

To get an Asperger's diagnosis under the DSM-IV you needed some amount of impairment. "Disorder" is in the title of the DSM, if something isn't conceptualized as a disorder it isn't in there.

https://www.kennedykrieger.org/stories/interactive-autism-ne...

The "broader autistic phenotype"- that is, related traits but without impairment- exists but it is not a diagnosis.

Perhaps your thinking on this lacks grey areas. A healthy percentage of extremely successful people in computing are referred to as “on the spectrum” - are these people helped by having some of the aspects of autism or hindered by it? Why do we need to have a diagnosis for people to have aspects of this pathology?

I think the point was that the colloquial use of "on the spectrum" is incorrect, as is a majority of layperson derived psychiatrical diagnosing.

Are you really saying most people can’t discern autistic spectrum behaviour in their peers?

To the level of a clinical diagnosis, yeah it seems quite likely to me that most people can’t discern autistic spectrum behaviour in their peers. I bet most people couldn't even accurately say what those behaviours would be.

Definitely nobody in this thread struggling to see the grey areas and wanting to make sure everything is very cleanly defined, as if it’s difficult for them to deal with situations that are outside of rigorously defined clinical diagnostic criteria, for example… BTW just to be crystal clear - I’m obviously making a silly joke here it’s not intended to be serious :-D

A clinical diagnosis isn't the only way to look at what's going on here. We can have differences that aren't medical problems. Differences that are measurable and nameable, even. Those categories can overlap with or be congruent to medical terms while still being valid and useful.

"On the spectrum" has more or less become code for "introverted, obsessive, socially inept, and a little scary."

That can certainly be a syndrome, but the official DSM definition of autism is not based on those criteria.

Clinical autism tends to be much harsher in its presentation.

Clinical autism and clinical ADHD are notoriously difficult to diagnose in adults. In some countries it's even illegal to prescribe stims unless there's a childhood ADHD diagnostic.

Adults have been socialised to mask the more problematic behaviours, and they can also be unaware that what they're doing is masking: they can believe that everyone struggles like that.

Only difficult because the criteria are misaligned. We diagnose school children more consistently, because we subject school children to strict measured criteria (school), and can point to the data (grades/homework) as objective evidence.

Why do we care so much about objective evidence? Because of prohibition. Prescribing stimulants isn't illegal because it is difficult to diagnose ADHD. It's difficult to diagnose ADHD for the very same reason it's illegal to prescribe stimulants: our society values prohibition of drugs over actual healthcare. An ADHD diagnosis implies a compromise of prohibition, so our society has structured the means to that diagnosis accordingly.

Experts in the field estimate a very high incidence of undiagnosed ADHD in adults. During the height of the COVID-19 epidemic, telehealth services were made significantly more available, which lead to a huge spike in adult ADHD diagnoses. Instead of reacting to that by making healthcare more ADHD accessible, our society backslid; lamenting telehealth providers as "pill mills", and generating a medication shortage out of thin air.

Very well said. I think it's hard for people to understand that ADHD is simultaneously over diagnosed and under diagnosed.

> Why do we care so much about objective evidence? Because of prohibition.

That may be true for ADHD, but autism diagnoses don't "unlock" any particularly sought-after prescription medication, so I don't think that can be the whole story. In kids, diagnoses do unlock accommodations in schools, but not so much for adults.

That's mostly true, but there is a huge overlap in ASD and ADHD diagnosis. It's very common to be diagnosed with both, and that expectation (from a healthcare provider's perspective) has implications.

The autism itself, depending on the person, is often less of a problem than societal expectations. For example- in a world where everyone was red/green colorblind, such a condition would not be considered a handicap. And in a world where everyone was autistic, many things would be different.

Society punishes us severely for not being able to see the difference between red and green, to use that metaphor. And they seem to expect that if they punished us just a little harder, we would suddenly become normal. Thats the big problem. Non conforming behavior is always treated as a crime or offense on some level, but we cannot conform, and therefore must adjust to a life of endless punishment doled out by both authorities and peers.

Its quite difficult to go through life that way without developing a negative self image. This goes for people with autism, adhd and other types of neurodivergence.

It's like being tortured to extract information that we do not have. They'll only believe it once they've completely broken you down.

And then you meet the next person, who has not yet tortured and broken you, so they again do not believe that you "don't have the intel", and you get to go through it all over again.

The worst part is when you start believing for yourself that they're right, that you're holding back, and that it's all your fault for not giving them what they want, just for the life of you you can't figure out how.

Getting certainty about my condition did so much to heal me.

Buddy. If you're building your world view around the DSM you're in serious trouble.

The only people who take the DSM seriously are insurance agents and charlatans.

The autism that's being examined in the referenced study is the DSM-V one, though. They are certainly picking people for the study that are diagnosed.

There is a map-territory problem here.

There is some underlying reality to what autism is, even if we do not have a good understanding of it; and even if turns out to be multiple unrelated things that happen to have similar symptoms.

Of the people with those actual conditions, it seems entirely plausible that some will not be hindered.

The authors of the DSM-V needed to create a diagnostic criteria for a condition that they do not understand, and for which no objective test is known. Further, their objective was designing something useful in a clinical setting. Giving those constraints, saying "if it is not a problem, we don't care about it" is entirely reasonable; despite not being reflective of the underlying reality.

This is an important point.

To a first approximation, the DSM is about what a majority thinks is wrong. Sometimes this is pretty close to universal. Sometimes it isn't: https://en.wikipedia.org/wiki/Homosexuality_in_the_DSM

This study suggests that there are several different things called "autism". That's because "autism" as a term is not about some underlying reality, but a bucket that a bunch of people get tossed when some medical professionals see them as similar. And they come to the attention of those medical professionals because those people either say they have a problem or are called a problem by others.

But a problem with a person is always about a person in a context. Blue-eyed people are hindered by their eyes in bright light. Do we call that a genetic disease and look for cures? Not here, because there are enough "normal" people with blue eyes. But if it was just 1 in 20,000 people with blue eyes, it'd surely be treated as a disease.

Or we could imagine a "Height Deficiency Syndrome" characterized by inability to reach the top shelves in a normal house. With an effort, we could surely cure this impactful genetic problem through early application of hormones and the use of new CRISPR-related technologies. Or we could look at it as normal human variation which only "hinders" people because of how our society is set up to cater to "normal" people.

But we thankfully now have a term for that sort of nonsense: medicalization of deviance.

As I commented in another thread, there's no a priori reason to believe that the "average" glutamate receptor level is the "right" one. Isn't it possible that there are:

1. "Normal" people with a level of glutamate receptors at 10, say, on a scale I'm inventing for this example

2. "Autistic" (according to the DSM) people with a level of, say, 5, who are hindered by the effects of being at this level

3. "A little bit autistic" people at a level of, say, 8, who aren't hindered and don't meet the DSM criteria, but in fact actually benefit from the effects of being at this level

Some "normals" might then want to inhibit their glutamate receptors somewhat to get the benefits of being at an 8 or a 9 on my made-up scale.

There are actually four types of autism, according to new research (and seemingly corroborated by my personal experience, though that's just an anecdote): https://www.medrxiv.org/content/10.1101/2024.08.15.24312078v...

Perhaps. But remember that this is a very complex 3D structure with varying receptor densities, it's not "The Glutamate Level", it's some neural network areas with higher or lower excitability connected to other neural networks.

Just like with ADHD it's likely that medication will at best have limited effectiveness and many side effects.

Certainly, we're at the "bash it with a hammer" stage not ready for anything nuanced. I just wouldn't want to assume that the right outcome is "less autism"; I suspect most people could do with at least a little more!

Groups tend to benefit from neurodiversity (and diversity in general). I'm sceptical of the idea that there is a "right level of autism".

That‘s why we have so many late diagnosed. People who are on the spectrum but were able to mask or were just lucky until luck runs out. Then it becomes a problem and a diagnosis. I knew I am different as long as I can remember. It was obvious in Kindergarten and also in every type of school and later in work. I‘m an old millennial and nobody was trained back then in the 80/90s. Before it became a diagnosis and before awareness started to rise, people unalived them, died homeless or in prisons/wards.

> This is more or less not true. If it doesn't hinder a person in any aspect of their life, they don't fit the DSM-V criteria for a diagnosis.

You're confusing autism itself with Autism Spectrum Disorder. Autism Spectrum Disorder indeed has to do with difficulties ("deficits" / "impairment"). Autism itself on the other paw is a physical, quantifiable difference in neural architecture. Autistic people think and work differently, whether they have been diagnosed with Autism Spectrum Disorder or not.

It's also worth noting that autism is not the only neurodivergence, it's just the most widely known one (IIRC).

For reference, my copy of the DSM-5 states the following diagnostic criteria for Autism Spectrum Disorder: (sub-items elided)

> A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive; see text): [...]

> B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text): [...]

> Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life).

> D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.

> E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

You may be thinking of the "broader autistic phenotype" which does encompass people who are subclinical, and isn't a diagnosis.

https://www.verywellhealth.com/broad-autism-phenotype-117279...

The autism in this study is ASD. This study doesn't have that much to say about people who don't qualify for a diagnosis, since they would not have qualified to take part in it.

Broader autism is four phenotypes :) https://www.medrxiv.org/content/10.1101/2024.08.15.24312078v...

But yes, if you are saying ASD (and not autism itself, as you quoted from the article) is by definition a hindrance, I would be inclined to agree with you, for the reasons you've outlined.

Those four, as studied, are subdivisions of ASD. The paper uses "ASD" and "autism" interchangably (which is I believe standard). Whether they are also subdivisions of something broader is another question. I'm not sure there even is a common scientific definition of autism aside from ASD.

BAP, I think, comes from heritability studies of people who are related to diagnosed people but do not themselves qualify as autistic, they are more likely to have traits associated with ASD despite not being diagnosable.

It's an interesting finding but important to note they are making no claim about causality. In fact, an explicit future question is whether changes in these receptors is present at onset or if it's a result of living with Autism.

Neurons specifically increase / decrease receptor density in response to environmental factors, eg: use of SSRI's. Any excess of neurotransmitter would likely lead to reduction in receptor density as part of the response. So the story can be as much about an excess of neurotransmitter as it is about depletion of the receptor.

Perhaps the main story here is they can use EEGs as a proxy for measuring this effect so they don't need to put people through PET scans to do wider studies.

N=32 and

> We want to start creating a developmental story and start understanding whether the things that we’re seeing are the root of autism or a neurological consequence of having had autism your whole life

Yeah, how many studies are done a year? Random chance is the #1 explanation with that small of a sample size. It doesn't take a degree in stats say that the next thing that needs to be done is to replicate the study a few times before making any claims or searching for any publicity. This subject is so emotional for the families involved that publicizing without more confirmation is a bit irresponsible especially if it is easy to do follow-up studies.

It's a university press release. Hyperbole in practice.

Wish I could read the paper.

Follow-up studies cost money, and you don't get any of that if you don't publish.

Agreed. Publish, but don't publicize. My remarks were aimed at the article, not the paper. This sounds like a promising, very initial, study that needs a lot more data before making claims about having found anything. Qualified headlines like 'Early study hints at..' Or 'Initial research potentially shows a promising....' would be better but even then a study with this little data should be very cautiously approached by any type of science reporting. More than mentioning it in passing as promising is probably not warranted until the n value is a lot higher and involves other teams and other methods.

The reduction of mGluR5 was reported 10 years ago in postmortem tissue.

doi: 10.1016/j.bbi.2015.05.009

Classic academic public relations piece. Not bad but more fluff than insight. Authors often have to grin and bear this PR machine, praying peers will forgive them their trespasses.

But here there’s a basic design flaw. This is a study of 16 ASD cases and 16 neurotypical controls. Small sample sizes like this require careful matching. The problem: the autistic subjects are 100% White but controls are 37.5% White. That imbalance can’t be waved away with statistics or Jedi mind tricks. Recruiting matched neurotypicals would have been straightforward.

One other issue is high heterogeneity within the two groups. In their Figure 1 (sorry behind a paywall), 4 - 6 of the autistic individuals have low mGlu5 levels across all regions. Two or three neurotypicals have high levels. Are these distributions actually normal, or are subgroups driving effects? It would help to know whether the participants’ GRM5 genotypes were informative wrt these subgroups. They weren’t checked.

Whenever you measure two different groups, you find a difference. Can it be solely ascribed to the one variable? Doubtful. You would have to match the groups for all possible contributing factors, and here not even the basic demographics have been matched? Another statistical effect for the irreproducibility bin.

My understanding is that an issue is local hyperconnectivity / long-range underintegration, linked by the E/I imbalance.[1][2]

[1] "The findings support the idea that an imbalance of excitatory and inhibitory signals in the brain could be contributing to traits associated with autism, the researchers say." https://medicine.yale.edu/news-article/molecular-difference-...

[2] "Converging evidence from diverse studies suggests that atypical brain connectivity in autism affects in distinct ways short- and long-range cortical pathways, disrupting neural communication and the balance of excitation and inhibition." https://doi.org/10.3389/fnhum.2013.00609

16 is an incredibly small sample size. Autism has an incredible amount of variability. It seems naive to extrapolate from this that all cases of autism have the same chemical cause.

>It’s only one apple

Interesting indeed. Does such a finding suggest any worthwhile easy-to-try 'treatments' that may help alleviate symptoms?

I don't know much about the biochemistry here, I assume this is not something like GABA that can be directly supplemented. But maybe there are precursor nutritional and supplemental substances that can help these people upregulate how much of the glutamate molecule in question the body can produce.

There isn't enough information to start doing that. Consider: UV exposure results in sunburn, cellular damage, and increased skin pigmentation. We have medication that reduces skin pigmentation. Should we give it to people who experience chronic sunburn?

The third paragraph:

> Now, a new study in The American Journal of Psychiatry has found that brains of autistic people have fewer of a specific kind of receptor for glutamate, the most common excitatory neurotransmitter in the brain. The reduced availability of these receptors may be associated with various characteristics linked to autism.

Reduce receptors. This might suggest a _developmental_ or genetic link. Think of this more like "height" or a particular "facial feature" of a person.

God, why are so many people commenting out of their depth today.

> Reduce receptors. This might suggest a _developmental_ or genetic link. Think of this more like "height" or a particular "facial feature" of a person.

No. This isn't how it works at all. Receptor counts are extremely plastic, able to change within a weeks and in some cases hours. This is how you get drug tolerance.

Sure, but they're also 15% lower in people with autism, and shown with a 60-90% heritability.

Supplimentation would not rewrite SHANK3.

You can go to the dentist and get your teeth aligned, but there's a very good chance your children have similar issues.

Unless you can get the blastocyst and fetus to take supplements, any treatment would be attempting to undo the effects that have already taken place.

For now, your best options are ESDM, occupational therapy, modified CBT, ABA, or neurofeedback, depending on your circumstances and presentation. Except for neurofeedback, these are behavioral approaches, so the architectural and neural activity variations aren't directly addressed.

Receptors quite readily remodel in response to external factors. It is one of the things antidepressants do.

To me it's kind of the biggest red flag here, if it's really about receptors then autism should be far more plastic than it is currently defined to be (which is kind of silly since at the moment any sign of plasticity puts you outside one of the hard criteria for an autism diagnosis - so almost definitionally, it can't be the answer).

A lot of people in the corresponding Reddit threads claim that NAC (N-Acetyl Cysteine) might help.

Meta comment - what a weird comment to downvote. I am expressing curiosity in good faith after reading the article, with a fairly logical follow up. What is the point of commenting in this community if it's primarily cynicism and negativity?

Commenting about voting isn't allowed by the HN guidelines. A link to the guidelines is available at the bottom of the page.

The paper is concerned mainly with one of several glutamate receptor subtypes.

“We have found this really important, never-before-understood difference in autism that is meaningful, has implications for intervention, and can help us understand autism in a more concrete way than we ever have before,”

So we might be able to make all the non-autistic people autistic? What would the world be like if everyone was mildly autistic?

That quote is over the top. Given the imbalance between groups it is also embarrassing to read.

Which autism? There are four: https://www.medrxiv.org/content/10.1101/2024.08.15.24312078v...

My impression is this article and research that generalizes across the entire spectrum is not very useful.

The tiny number of participants, plus the use of EEG to make giant claims about function, and the claims made all make me super skeptical of the results. This shouldn't be published results - at best this should generate a hypothesis.

It's somewhat comparable to using a handheld magnifying glass on petri dishes and making broad claims about virus morphology. EEG is great, but I'm not sure I buy the methodology in this case. You need a huge N and much better experimental design and absolutely zero hype unless or until you show results with scientific rigor.

This sort of clickbait almost makes me view this type of research as a flavor of pseudo-science. The framing is misleading at best, but the full throated embrace of the clickbait and hype machine is awful.

It's funding bait, narrative manipulation, etc, and it'll either be part of something replicated and justified with much better experiments, or it'll just fade away into oblivion, with no repercussions for any involved should the outcome not actually benefit anyone or anything. There's not even a negative incentive, mGlu5 and "imbalance" claims have been made for decades, and they keep circling the questions but don't ever seem to actually "do" real science.

Very interesting - wonder when this will be cost effective for testing!

I have exactly 0 faith in this result, exactly what one would expect from Yale, however. The elite universities have become academic skin suits.

16 "autistic brains" were scanned and they are thinking this applies generally to all people with autism?

Shows how shockingly unaware even researchers are on how broad and nonspecific the diagnosis of autism is...

Were these 16 people hypo or hyper sensitive? Which of their five senses were involved? All? Some? Were some senses hyper and others hypo?

Need to start with categorization and specificity before we can make meaningful progress in research

I have not read the paper as I am traveling, but just in case your opinion is based on the news article, let's not confuse that reporting with the actual research.claims or the actual views held by the scientists involved. This was likely a paper demonstrating the technique in preparation of a more comprehensive study.

I would say that as an autism researcher whose focus is in finding autism subgroups that I doubt that any specific receptor differences will not apply to the whole spectrum, probably just to one or several subsets

So glad to hear research is being done in that area.

I'm a dad of two autistic boys who I think would be very different categories. I have friends whose child isn't really autistic, they have a much more rare and specific diagnosis but it's so rare it's hard to get supports so they got him diagnosed as autistic because that criteria is so broad almost anyone can qualify.

Thank you for your work!

The full paper isn't open so I can only read the abstract, method and results.

The part I take issue with: "lower brain-wide mGlu5 availability may represent a molecular mechanism underlying altered excitatory neurotransmission that has the potential to stratify the heterogeneous autism phenotype."

Seems like the very premise is flawed, though. Searching for a single global identifier for autism would be like if we spent research time trying to find a single global identifier for cancer. Noble effort... Way harder than spending effort on subcategorization into "lung" and "heart" cancers and working on research for detection of those subtypes.

The only good categorization we have in autism now is severity.

The anecdote I always like to share is Temple Grandin.

She was hyper-sensitive to auditory and tactile senses. The cause for this hypersensitivity was cerebellar abnormalities in her brain. Right now, someone who is hypo-sensitive to sound and touch because of different cerebellar development will also be put in the same bucket diagnostically speaking. There's not gonna be any universal way to detect that though...

To quote her directly:

"It would be my number one research priority, but one of the problems we’ve got on studying this, is that one person may have visual sensitivity, another one touch sensitivities, another one, auditory sensitivities. And when you study these, you got to separate them out. You can’t just mix them all together." https://www.sensoryfriendly.net/podcast/understanding-my-aut...

I hope emerging research that divides the autism spectrum into four phenotypes[0] eventually gets recognized and incorporated into research like this. I still believe comparing the entire spectrum at once is the wrong approach, especially since the variants of autism express so differently.

As an example: I'm autistic and I learn inside-out, building larger new concepts out of smaller existing ones; those with Asperger's on the other paw, learn outside-in instead, breaking down larger existing concepts into smaller new ones; both are part of the "autism spectrum", but differ very fundamentally.

Given that the origin of "autism" is simply "thinking that differs from usual", there's no evidence that there is a single underlying cause to find, nor that generalizations across the entire spectrum will reveal much of anything other than coincidence.

I believe we need to individualize new research to the variants that we now know exist, because otherwise we will continue to all-but erase anything that isn't common to the entire spectrum.

[0]: https://www.medrxiv.org/content/10.1101/2024.08.15.24312078v...

> As an example: I'm autistic and I learn inside-out, building larger new concepts out of smaller existing ones; those with Asperger's on the other paw, learn outside-in instead, breaking down larger existing concepts into smaller new ones; both are part of the "autism spectrum", but differ very fundamentally.

This is a really interesting observation - can you expand on this a bit more, please? How did you first notice this distinction?

When, for example, learning a new concept in math or physics, what would outside-in look like vs inside out? Would you characterise neurotypical learning in one way or the other?

> This is a really interesting observation - can you expand on this a bit more, please? How did you first notice this distinction?

A year or two ago I interacted with someone with Asperger's, and since that very rarely happens I hit a sort of uncanny valley with the way they wrote to me, because their writing gave me a lot of neurotypical vibes, but at the same time seemed a lot more logical and structured than actual neurotypical writing. They seemed to be building their writing and ideas out of logical tokens and constructs in an evidently autistic way, but so much of their writing looked neurotypical.

It was sort of like Scratch blocks, where they learned general templates for sentences and paragraphs from neurotypicals, and then substituted entire phrases at a time within them to achieve the desired communication. So while their templates and phrases were learned mostly from neurotypicals, the structure of their communication and usage of it still had a sort of logical system to it.

They remembered concepts by the phrases that had been used to explain it to them in the past, and reused those phrases verbatim, slotting them into the templates wholesale. They didn't fully parse everything like I do, they only broke things down as needed to create new logical tokens for new concepts. It's very interesting and fascinating. I mostly only know the one experience I've had, since I didn't get to speak to them again, but I've started to see it absolutely everywhere since.

Plenty of engineering blogs, for example, share that sort of tokenized writing style, like for instance this one I recently noticed: https://www.righto.com/2024/12/this-die-photo-of-pentium-sho...

> When, for example, learning a new concept in math or physics, what would outside-in look like vs inside out?

I can only guess, because I haven't interviewed someone with Asperger's about this, but I know what it looks like for me and I can guess what it could look like for them (at least for the purposes of the outside-in analogy).

For me, when I learn a new concept in math or physics, I want to build an intuition about that concept so I can come up with strategies about it and involving it. This actually mostly does not consist of algorithms related to the concept, but rather more of a fundamental intuition about the nature of the concept itself; what shape it is, what holes it fills, what types and classes of things it can do or model, etc. With this I can come up with my own algorithms on the fly, and also know when the concept might be relevant.

An outside-in learner, however, would be different. I have very little experience with the learning process or even with the execution process, but it's likely that they would not bother to break the concept all the way down and try to fully fundamentally understand it. Rather they might look to learn examples of it, algorithms and procedures relating to it, and ways to prove that their approach is correct. It would be less of "understand all the intricacies of this thing and every property it could possibly have and integrate that with everything else" and more of "fill a mental knowledge base with examples, applications, procedures relating to this thing".

> Would you characterise neurotypical learning in one way or the other?

I would not. I don't mean to imply that neurotypical logic is inherently more simplistic or inferior to autistic logic, but to me it seems far more like rote learning. They don't necessarily seem to break things down to understand the smaller details, but they don't really commit full logical tokens to memory either. They seem somewhere in the squishy middle, where they can be good at doing something that they don't understand at all, just because they practiced a lot, and they can be terrible at doing something that they understand far better, just because they're not practiced.

I've found that given I understand something well enough, I can perform better on the first try than some others who practice. That's not really a reliable indicator of much, but for me a lot comes from similar sources of truth, whereas it seems for a neurotypical they don't always necessarily organize or canonicalize their learnings, so their knowledge can be completely disjoint in areas that could totally be combined.

This is all just my personal experience/opinion though, fwiw.

> Plenty of engineering blogs, for example, share that sort of tokenized writing style, like for instance this one I recently noticed

Hi, I'm the author of that blog. Can you tell me more about what you mean by a "tokenized writing style"? One confounding factor is that I have a PhD, so I was trained for many years to write in a formalized, academic style. Also, I deliberately put a lot of "signpost" phrases in my posts, since I'm writing about complex subjects and want to avoid readers getting lost.

It's difficult to explain, but it's similar to the Scratch blocks idea that I mentioned up above. To me, a "tokenized writing style" is one that looks composed of nested layers of structure, not exactly grammatical structure but more logical structure. It certainly appears that a lot of the specific patterns could have come from training, but regardless of what, if you don't have Asperger's, you certainly do a good job imitating it :)

You could argue that outside-in versus inside-out is more of a temperament than it is a form of neurodivergence. For example, what you're describing is basically typical of how Keirsey describes concrete versus abstract reasoning in Please Understand Me. And it could be kind of alienating to be the one abstract reasoner in a group of concrete reasoners and if you believe his statistics it's kind of likely that you'll find yourself in that situation a lot because you gravitate toward the abstract rather than the concrete/operational aspects of a concept.

I generally do the same thing when I'm learning something, and I have to fully understand a concept and then attack the concrete applications of the concept. But I've also learned how to go the other way when I need to because much of the technical writing I encounter is written for people who need a lot of examples but don't follow abstract concepts. So I've internalized building up the abstract concept from the concrete examples.

> You could argue that outside-in versus inside-out is more of a temperament than it is a form of neurodivergence.

I believe it is both. You can go against your brain's coding with some extra work; somewhat like an adapter, I suppose. Your brain just still is coded a certain way natively.

> or example, what you're describing is basically typical of how Keirsey describes concrete versus abstract reasoning in Please Understand Me. And it could be kind of alienating to be the one abstract reasoner in a group of concrete reasoners and if you believe his statistics it's kind of likely that you'll find yourself in that situation a lot because you gravitate toward the abstract rather than the concrete/operational aspects of a concept.

This is very interesting. I've never heard of concrete/abstract reasoners before, but that does sound similar to what I've described. Thank you for the book.

> much of the technical writing I encounter is written for people who need a lot of examples but don't follow abstract concepts.

Yes! I love using examples to illustrate applications of an abstract concept, but I always explain the concept first. When the concept isn't explained first, I am sad. :(

> So I've internalized building up the abstract concept from the concrete examples.

I believe you may be better at it than I :)

I have been diagnosed with Aspergers not long before it became part of ASD. I don't really understand why you are disassociating yourself with Aspergers which was another word for "high-function" autism and is still used interchangeably.

Reading from what you have written - that is part of my experience, though I don't think that it has anything to do with being Aspergers or even being on a spectrum, but being alone a lot and educating myself a lot - that basically is what "smart people" in general are doing - including NT. Yes, there are a lot of people that do not actively learn, but that can apply to Aspergers as well as NT. That is not the reason for differences.

Just to save space and not to create another comment - "four phenotypes" are not new attempt to classify. To me it looks like rewording - before there was already quite clear distinction between Aspergers and Aspergers&ADHD combination - both of them are part of "high functioning autism", and they behave wildly differently(people with Aspergers&ADHD part might not be recognized as "weird" but even as NT - by other people). They were all part of spectrum anyway. And from reading the paper it seems, that they have made 2 other types for what was "low functioning" autism. Apparently putting them all in ASD was not helping for bureaucracy - especially when it comes down to finances - it is quite important in Trumps USA and might be also for other countries.

> I don't really understand why you are disassociating yourself with Aspergers which was another word for "high-function" autism and is still used interchangeably.

People do often use the terms interchangeably, but that's not how I use it. I use Asperger's to refer to a specific place on the autism spectrum; I don't think there's a better term I can use right now. That place is as opposed to the three other phenotypes. I don't claim to know for absolute certain that the four phenotypes are correct, but I do believe strongly in the idea, because my lived experience appears to match with it closely. It has helped me understand others better, for sure. (Or at least to believe that I do)

I say I don't have Asperger's because I seem to function differently than others who do have it. When I encounter it, I find it interesting, because it's clearly different than how I function and that makes me curious. That makes me think I don't have it, because if I did, then surely I would be able to study myself to learn more about it, yet so far I can only speculate about how my experience must be different.

> Reading from what you have written - that is part of my experience, though I don't think that it has anything to do with being Aspergers or even being on a spectrum, but being alone a lot and educating myself a lot - that basically is what "smart people" in general are doing - including NT. Yes, there are a lot of people that do not actively learn, but that can apply to Aspergers as well as NT. That is not the reason for differences.

Of course neurotypical and neurodivergent people alike can educate themselves and learn. The difference is in how they learn, and what type of learning is most effective for them. Even among autistics, the most effective or natural style of learning can greatly differ. This is also why many schools have entirely different classes for autistic people, because the style of learning that works best for neurotypicals may not be as effective for an autistic person.

What I think has to do with Asperger's is in the type of knowledge that is most useful to you, and the style of learning that is most useful to you. I don't actually know this for sure, but I believe that for any given concept, you would probably use different aspects than I would to understand it. That means if I told you everything that I believe is most essential to my own understanding of something you don't understand yet, you still might not get it, because you might have different requirements to understand that thing, and you might find different things most essential to that understanding.

Of course, in some ways this is true for everyone, for example if my most essential pieces of knowledge relate to or build upon other of my knowledge that you also do not have. But in other ways this is only true across different neurotypes, such as Asperger's and neurotypical, or Asperger's and another type of autism, because generally each phenotype appears to share a largely similar type of logical structure. For Asperger's it appears to be those nested tokens, for myself it seems to be a linear stream of thought or reasoning, for some of my friends it appears to be based on context and metadata, and for others of my friends it appears to be based on emotions and lore (sort of hard to explain). That makes four, and every single autistic person I know or encounter seems to fit into one of those boxes. Sometimes it takes longer to tell for sure, but I believe that I eventually always can.

> Just to save space and not to create another comment - "four phenotypes" are not new attempt to classify. To me it looks like rewording - before there was already quite clear distinction between Aspergers and Aspergers&ADHD combination - both of them are part of "high functioning autism", and they behave wildly differently(people with Aspergers&ADHD part might not be recognized as "weird" but even as NT - by other people). They were all part of spectrum anyway. And from reading the paper it seems, that they have made 2 other types for what was "low functioning" autism. Apparently putting them all in ASD was not helping for bureaucracy - especially when it comes down to finances - it is quite important in Trumps USA and might be also for other countries.

It's entirely possible that Asperger's without ADHD is, well, Asperger's, while Asperger's with ADHD is actually not Asperger's, and is rather another autism phenotype instead. To be honest, I've never heard of Asperger's + ADHD, while I've heard of ADHD for all three of the other types, so maybe that's the difference you are observing. I can't know for sure though.

I believe low-functioning autistics may happen to have brain defects or severe trauma or something else that disables them. I don't believe they are fundamentally different from other autistics in terms of the phenotype. I believe that a lot of the time, whether someone is called low-functioning is based primarily on how well they are able to function and how much support they need, and not really specific indicators that would indicate phenotype. Similar to how the criteria for ASD can diagnose autism, but not specifically Asperger's or specifically my type. I know that all four of the phenotypes certainly can be high-functioning, so that leads me to believe that low-functioning may be on top of that, and not a separate category altogether.

I don't think Trump has anything to do with this -- in fact he has been trying to shut down government benefits for autism (and for other things he views as a disability), so it's hard for me to believe that he cares about better classifying them when he seems to want them dead.

To me this just sounds like the interaction of autism with other variances in neurotype. You can also reasonably categorise non-autistic people into people who learn outside-in and those who learn inside-out.

I want to say that cognitive strategy doesn't meaningfully impact what I'm talking about, but I struggle to define where the line is between cognitive strategy and neural architecture. It appears to me that different neurotypes have different ways of learning and processing information, and that makes for different most effective strategies, and that becomes evident in how the learnings are eventually used. There's a sort of wavy abstract concept called "derived meaning" that sort of helps explain this, but that's even less understood. But basically, how I understand it is that different neurotypes have different frameworks of derived meaning; when they learn something, they persist differing parts of it and in different ways; this results in a different organizational structure, different forms and mechanisms of association between different ideas, different approaches of using the ideas, and so on. I don't know for sure that there isn't a non-autistic neurotype that learns outside-in like in Asperger's ... but if one were discovered it'd probably become part of the autism spectrum for being so uncommon. :D

Inside-out versus outside-in also doesn't really have to do with the order of learning. I could very easily learn the basic metadata of an overall system before I start diving into the details. Black boxes are very common for me to avoid going too deep into research or reverse-engineering rabbitholes (or to paper over an inability for me to learn more about inner workings). It has to do with the structure of learning. For me to model something as a black box, I'll accept that, though there may be parts inside it, I don't need to care how they're implemented. For someone with Asperger's to model something as a black box ... I imagine they already do that by default. How much of that is cognitive strategy or not, I can't really tell, but outside-in learning seems to prefer to pick up entire pieces that have a desired value rather than digging into every detail contributing to that value. While I could mimic that or show behavior that resembles something like that, it's just not really how my brain works on a fundamental level like that? I don't really know how to draw the line. You do raise a decent point.

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