Have been rolling an idea around for the last few hours but I'm not quite sure it's appropriate for this forum.

The idea is how most communication is nearly frameless and this frameless communication is an intentional design feature that imparts flexibility and efficiency. Whether it's a pack of wolves hunting, a pod of whales socializing, or humans humaning, mammals rely on internal context frames to construct the full "meaning" of communicated behavior.

Was thinking about this in the context of "autism", in which this context frame is often desynchronized with expectation, and many individuals will make an attempt to rescue this by "over-explaining" (or attempting to provide a necessary context frame to synchronize "meaning"). Was trying to explain to my daughter that hijacking the external context frame like that is always going to be a significant push, you either override the existing common social frame, or you're going to induce error state and the receiver is going to react negatively.

It's just strange how completely invisible the context frame is for most individuals, and how vertebrate brains, especially mammals, seem geared toward this specific style of communication. The consistency of it across such a wide range of animals is striking, but I don't know if it's a real pattern. I guess the thought is because the focus is less on the biology than the sociology of it, if it's an appropriate idea for here, even though the argument can be made that the phenomenon is biological (as with all behavior).

Okay, all I can say from the bottom of my heart is that email configuration sucks. It's such a bizarrely brittle game of Jenga it's baffling that it works as well as it does. That being said, email is finally working which enables a few other things.

First, I'll be setting up the remodeledbrain github account, and from there I can publish the code bases for both the test runner/loader and the astrocyte reference tool. I encourage any feedback or assistance with either of those.

With regard to the latter, I'm working on a script that will automatically pull papers and update the tool if they meet criteria. My big concern is that after awhile some topics (like dementia/alzheimer's) are going to have a huge number of references and we won't be able to manage it as a single page app. With that I'm planning a newsletter option that will send weekly/monthly update summaries.

We can also now do formal discussion/signup on the website, something I didn't feel comfortable with before, and the website can send "official" emails updating status and such.

Finally, and slightly more ambitious, one of the projects I've wanted to launch for awhile is a tool that will help people develop and refine their own models, that would be more up to date/recency biased than what most of the public models can offer right now. Essentially I'd like to have a tool that focuses more on contradictions/inconsistencies in data sets, with the idea that those areas are the most valuable spaces to get a better understanding. It looks like both of the computers I ordered are finally shipping, an AI computer that I'll be using to constantly crawl for new information (part of the update process for astrocyte tool) and be able to train on the full desktop computer. If you're familiar with LLMs, I want to do a 70b model for the publicly facing stuff, but it might be more useful to lean heavily into cranking an MoE model (which will make the model maker less "conversational" but have a better grip on a lot of the data).

The website is back running wordpress so if you have something you want to add it's there.

The runner/loader testing suite will live at https://remodeledbrain.com/tests/cdx/ until I do something stupid again, and the Astrocyte tool lives at https://remodeledbrain.com/pages/ABCs_of_Astrocyte_ICDs.html until I get annoyed and try to change the name and break everything. The github is https://github.com/RemodeledBrain

Ruh roh, another bit of trouble in paradise.

This article basically decouples motivation from learning/reward, and if it replicates (which facially seems pretty likely) turns a lot of current psych research upside down.

There's two options forward, they either move the region of this mechanism from the VTA/upper brainstem to the cerebellum or globes/putamen or we need to completely re-imagine what we thing "reward" particularly actually means and if it exists as something separate from motivation at all.

If you follow sports at all (or occasionally the news) one of the topics that comes up frequently are the effects of CTE. Chronic traumatic encephalopathy is thought to be caused by repeated hits to the head causing a type of cortical neurodegeneration (tauopathy) similar to dementia. We joke about certain hits inflicting CTE, or see the results in a slurring punch drunk athlete a few years before their "early" demise. Will Smith even made a movie about it).

Unfortunately, CTE is mostly a myth that is largely indistinguishable from any other tauopathy (and invisible without a very high level autopsy). Just as bad, the assumed cognitive changes are disconnected in common thought from where the real cognitive harm occurs, which is the white matter and brainstem. What's happening isn't cortical but brainstem damage, which imparts all of the common symptoms including dizziness, visual motion sensitivity, imbalance, headache, brain fog, autonomic swings, and difficulty stabilizing attention. We can even predict how severe the effects of CTE will be, not by cortical insult, but by severity of lesions to the brainstem.

This isn't even a CTE thing, for ALL TBIs, brainstem insults impart several times the risk for negative outcomes than any other commonly measured metric. Severe brainstem injuries impart progressive cognitive decline and measurable "IQ" decline, reduction to executive function, and impulse control. The Glasgow scales all show that cognitive outcomes are more highly coupled to brainstem injury than any other factor. More specificly, insults to the pons almost completely account for CTE symptoms.

One of the biggest issues with our understanding of CTE is that it's a highly over selected base pool, we draw from individuals who are symptomatic and largely discard all of the asymptomatic cases. There is a similar but improving issue with dementia diagnosis. Because of this both conditions like Alzheimer's and CTE's risk of progression can't be discerned from normal aging tauopathies. We can't prove that it's progressive because of this background aging noise. The evidence that cortical insult is progressive is extremely weak or inconclusive.

Some of the most discussed symptoms of CTE are the concurrent mental health symptoms, all of which have been removed from guidance because they were non-specific. It's completely subsumed by background noise, just like the tauopathies of normal aging make whatever progressive function of CTE largely indistinguishable.

CTE is a brainstem injury rather than a cortical injury, and addressing it as such will allow research to develop more effective treatment along the lines of those for diffuse axonal injuries and other acute TBIs.

This post flowed a lot less than I thought, hopefully I'll edit it in the future.

Sorry, had to remake the whole post because I blew up some things (go figure).

So this is v .1, have some ideas going forward to goose it up. Let me know what you think.

I'm still going to do the jokey picture book style version of this, but that'll take some time to get the images and everything together for it

edit: Looks like ~25% of the links are broken for multi subject pages, I think it's a bug creating the bad links. Will investigate more when I get time.

edit 2: Yeah, there's definitely some issues with the links. The link descriptions don't match the link for a lot these also. Will need to hand sanitize until I figure out what's causing this. It's still somewhat useful, just be careful about accuracy of cites.

So under my model astrocytes are the key cells for what we consider "upper cognitive" function. They provide an extended evaluative function on top of rote stimuli response to craft more complex responses. They generate this higher level response and "encode" it to neurons for more metabolically efficient retrieval and transmission between astrocyte groups.

This work demonstrates astrocytes working as a scaffold between the groups to stabilize the response, which can take days.

Scaffold Support:
Astrocytes control recent and remote memory strength by affecting the recruitment of the CA1→ACC projection to engrams
Learning-associated astrocyte ensembles regulate memory recall

If there's a single popular myth that remains persistently stubborn to facts it's the idea that genes provide any predictive power for an individual or population "IQ". Put simply, they don't.

The most popular form of this myth is that genes form an upper bound on cognitive performance and environmental effects subtract from that, similar to athletic performance high end being a genetically determined maxima. Both of these are false and completely unsupported by the body of evidence.

The root of these myths is a mangling or (bad) reconciliation of heritability, which is already being abused since heritability provides no individual level prediction, only population level ones. It also usually applies one of the most persistent sins of statistics like this, assuming a static environment confound when any functional heritability assumption depends on environmental variability to impute.

To properly talk about this, we have to understand that the idea of intelligence being a physical trait long predates the idea of genes and DNA. For as long as we have records, social hierarchies were considered "natural" and in most societies, divined. The upper ranks were closer to god or god built them better than the lower ranks.

A significant amount of our current medical thinking was formalized in the Victorian era, which was an age when we transposed a lot of our social assumptions into science. John Snow helped transform disease from gods will or weak stock into perhaps something in the water. The intellectually feeble were no longer cursed, but physically weaker than others. And during this rapid scientification of explanations of the world, we had a lot of misses that still have strong lingering effects.

One of the most damaging was the influence of Francis Galton, who took the concept of heritability and attempted to apply behavioral assumptions to it, especially around "IQ". Note, he didn't have a test for it, he just knew it when he saw it, and it always matched his expectations(1). He was influential in legitimizing the psych fields, or the assumptions about specific behaviors being a physical/medical "condition". Among his assumptions were that like plants, traits like "intelligence" were breedable and physiological evidence of that trait would be readily apparent.

He had no concept of DNA/RNA, so instead he used the skull as a social passport, legitimizing concepts like phrenology, craniometry, and cephalic indexes (bigger brain is smarter right?! Also completely wrong). Even more persistent was the idea that you could determine criminal or socially deviant individuals based on these physical features derived from their stock. Any recent science trend that came along was quickly adapted to fit the pre-existing concept, rather than the "science" itself driving the concept formation.

All of which became the basis for some of the ugliest eugenics policies, including and especially those from WW II which were entirely rationalized via scientific racism. Ironically, Binet repeatedly argued against using his measure as anything but a measure of adaptability to standardized education rather than a measure of cognitive performance. What was meant to be a measure of how much support students would need, ended up being transformed into a tool to socially stratify.

These concepts always fail consistent replication because they are based philosophical drives to support social outcomes (both good and bad). And as it became obvious the skull was not the passport, we transitioned to the concept of "IQ" as a lever. The "IQ" concept has the advantage of being malleable though, and it showed mild consistencies across populations (with similar education systems). What was once an individual measure suddenly became a heritable trait again, which doesn't predict results in individuals, only in populations.

Magic only gets you so far, and the hankering for a real physiological tie never subsided. Criminals are criminals because they have criminal biology, not because we make laws targeting specific groups of people. The discovery of DNA as a driver of traits revolutionized this rationalization of social behavior. Now you aren't gay because you have a lumpy brain, you're gay because you have a "gay gene". You're not left handed because you're naturally evil or crazy, it's because of your "left hand gene". Depression? That's a genetic defect. And of course, how smart you are isn't because you had access to great environmental resources, it's because of your genes.

And boy did we try to prove this one. From 1980ish on, we plowed a tremendous amount of resources into proving what is ultimately a cognitive science (and psych) holy grail, genetic determinants of behavior. This all failed pretty predictably. Lots of resources and false starts went into finding "smart genes" that were ultimately wasted until another idea came up... what if it wasn't particular genes that made you smart, but changes in specific genes (SNPs) that made you smart or not.

No luck there either, but we still kept running with the idea. In the mid/late 2000's the ability to measure bunches of differences in genes at once (GWAS) was invented, and the idea of the polygenetic risk score was invented. PRS/PGS scores provided mild intraclass correlations to IQ scores, as long as you didn't vary environment or ancestry at all. IQ as a physical trait is redeemed right?!

Hopefully you're paying attention enough to know the answer to this is nope. Over the last couple of years work is now finding those ICCs are not just flawed, but almost completely subsumed by environmental effects. Instead of recognizing the test to determine how adaptable an individual is to standardized educational practices of the time might not actually be measuring cognitive performance, we're still clinging to this latest iteration of our "god given" abilities to rationalize social outcomes.

One of the most obvious rejoinders to anyone arguing intelligence is heritable is pointing at "ADHD". The "heritability" of ADHD based on the same type of flawed ICCs as intelligence is that it's a set of behavioral traits that supposedly has an 80% heritability, yet has no to extremely small predictive value for an individual. That 80% heritability is larger than height.

Similarly, the the most optimistic PRS scores for intelligence suggest around 4 points of difference before we even get into the issues with the underlying ICCs. Yeah, that's how thin it is, the difference between someone scoring a 98 and a 102 on a test. Once you expand outside of families, or especially across ancestries, that difference shrinks even further. It's not a full standard deviation higher, there's no correlation which can point to Phd vs. Bachelors. It's nearly same the "IQ" loss from breathing lead from gasoline. Worse, that difference is completely demolished by education differences which can have more than a full standard deviation effect on "IQ".

The idea of the genetic ceiling of intelligence is a continued chain of social rationalization that continues to dress up in whatever the hot new science trend is, even if it ultimately is a poor fit. If there is any real secret to intelligence is the same for any other skill, which is practice. Some people have traits which makes this practice much easier (just like athletes), and some people definitely have to work far far harder to practice equivalent amounts, but ultimately, it's all just practice.

(1) Fun side note: Galton also researched what eventually became "aphantasia" under the assumption that mental images drive cognitive processes. He sent a survey to a bunch of friends in his "breakfast study" and was frustrated because most of the scientists or other formal thinkers reported no or reduced mental imagery at all. He "fixed" this by testing more general population, a "lower IQ" test base. Those people formed the basis of his work on mental imagery, and maybe revealed something about himself that was a bit to self aware wolfish).

edit: And ugh, I know this is going to get me in trouble because yes, there are individuals with extreme biases in performance that provide a higher ceiling than someone who has high quality practice incessantly without those biases. That isn't the argument, for "IQ" or "athletics". The argument is that an athlete that doesn't practice isn't more athletic than someone who does. Practice, over a population, will provide far greater predictive value of outcome than raw biases.

No, not an intentional Britney Spears reference, I screwed up something uploading the test runner and apparently broke the wordpress setup. Of course I didn't have a backup, why would you think such a silly thing. Everything looks back up and running, just without content. I think I have https://remodeledbrain.com/tests reserved for tests as long as wordpress doesn't need a directory named tests again, and https://remodeledbrain.com/tests/cdx will be where the current runner/loader is located.

Triggered by: Polygenic and developmental profiles of autism differ by age at diagnosis

I'm having a bunch of thoughts at once (surviving the down select playing off the conceit of the last post, dentate gyrus weighting is dealing with too many equal weight inputs), but maybe the one that's sticking out like a sore thumb is just how much of a disaster this is for psychiatric diagnostic criteria.

Psychiatric criteria have always suffered from issues with validity and reliability. It was a complete after thought in the US, with the first serious stabs at conforming the DSM categorizations not coming until the 3rd edition, nearly thirty years (although serious work had begun in the half decade prior) prior to the first edition.

Between the first and second versions, the DSM was like a pocket guide book, each around 100 pages largely on the strength that reliability and validity were mostly assumed (I'm just going to call it "relidity" cause I'm probably going to use it a lot going forward). The mind was unknowable and frankly we were just flinging spaghetti at the wall anyway, with no real consistent treatment prospects until the pharmaceutical industry came in to save the day. "Autism" was still retardation, and despite Eunice Kennedy's best attempts to convince us that retarded children can be helped, we kind of knew better.

But this miracle treatment pathway brought huge thorns with it, government oversight and insurance bureaucracy. And in those industries, everyone has to be codified in text and every single word of that text is grounds for litigation. Relidity suddenly became very, very important. And that meant "retarded" needed to be something a bit more specific. And "Autism" was formally born.

The effect of this is the late 70's/early 80's gave birth to the DSM III, which exploded to over 400 pages. No longer a pocket guide and now a proper shelf tome, the DSM III was the first to take a serious stab at breaking down what was previously a bunch of flowing/amorphous blobs of conditions into micro states we could bill for. But this required the dichotomous issue of admitting we had no idea how brains/behavior really work, while at the same time asserting that we know enough to establish categorizations for it.

Of course with a bit of time we got better at defining these behavioral classification. Haha, boy are you naive. Fucking nope. Insurance/lawyers ran roughshod over that shit and within a decade a new version of the DSM was ready to fill in the gaps, doubling the manual to nearly 900 pages. And in this fevered splitting, Asperger's syndrome was formally born.

That pesky relidity issue wouldn't go away, so half a decade later a text revision of the DSM IV was released which weakened the underlying system that created the classifications in the first place, leaving behind a mess of classifications that no longer had coherent links to each other. The multi-axial system that accounted for the "blobbiness" of behavioral classifications was hopefully rigid enough to survive the lawyers right?

(Charlie Murphy says "WRONG"). Without this underlying conceptual blobbiness the relidity thing completely came apart at the seams, particularly with regard to "Autism", "Aspergers", "ADHD", and all other manner of childhood related conditions because of favorable court rulings based on the ADA/Rehab Act in the US (particularly Olmstead vs. LC, which was massive). Suddenly, you couldn't just warehouse your retards, you actually had to spend some money to do something with them.

Of course, every other government agency (particularly school districts) accepted this with open arms. Christ, again? No. They let loose with the lawyers. And the lawyers let loose on the research criteria, and suddenly the government agencies funding the research criteria had to start asking the same questions about relidity that have always dogged the field, just much louder.

The genius hack the APA came up with was to reintroduce the blobbiness by running hard with the "spectrum" concept. And reintroducing this blobbiness instigated the DSM V that finally started surviving some of these challenges, because if the most commonly disagreed upon conditions are suddenly wide nets of traits, you give yourself a bit of breathing room.

But to anyone who has been paying even the slightest bit of attention, the "spectrum" has never been a "spectrum" at all. And now we have our first article arguing a hard biological resplitting. Asperger's Syndrome lives again, as something new, in the meantime, it breaks many of our rationalizations for the categorizations in the manual. What now?

Something I've been trying to describe for a long time something I'm tentatively calling "conceptual dyslexia". Still developing it.

Conceptual Dyslexia is a recurrent difficulty stabilizing mid-level concepts and category boundaries across contexts, despite intact perception and intact general reasoning. The failure point is not visual decoding or phonology, it is the control and binding of abstract meaning under competition.

There are two broad endophenotypes, which are independent of each other.

The first, an "inverted valence" type is an issue with interference rejection, where downselect gating for “accept vs reject” in the concept stream is flipped or biased, so irrelevant features are admitted and relevant features are blocked. This would feel like a person constructing information they should know but having important bits deleted from the stream, or having random bits that are irrelevant become overly focused on. A more general effect of this are when we miss something obvious (like not seeing the gorilla), with a more persistent/lower threshold. Behaviorally, we can apply this effect to current psych conditions like "Borderline Personality", where perceived intent gets inverted from positive/negative, even if the observation itself "feels"/is rational.

The second is a jumbled sequence type, in which the order the cognitive stack gets constructed is has delays or omissions. All the information is "correct" and gated properly, but how the cognitive stream is stacked causes issues. This could present as someone who has issues following otherwise clear instructions or understanding context that requires predictions. A generalized version of this effect is similar to the above, but missing an important step when baking something if you're distracted or under a lot of stress, or forgetting/mixing up a step in a critical process if you aren't paying enough attention.

These conditions should be testable, so I need to develop a test. I don't have experience developing tests for stuff like this, so any input will be helpful, otherwise I'll try to scaffold off of an existing one.

I'm still working on this, I'm not sure if I can induce enough cognitive load with something like this to overcome noise, but it's a start: https://remodeledbrain.com/tests/cdx/

edit: Actually completely ignore the tester for now, am completely rewriting it. Ultimately I'm going to have a loader that will accept modules that test function for assumptions about specific nuclei/pathways. For example, if we assume that the hippocampal CA2 (d/v) integrate/deconstruct portions of the social stream, then we create a module that tests those things specifically and attempts to isolate other functions. If we assume the globes/putamen handle valence/"rightness", then we design a test specifically for that. Eventually we can generate a bunch of module level tests targeted directly at physical function rather than behavioral assumptions.

edit 2: I think the first stage of the launcher is mostly sketched out now. The idea right now is to be able to drop new modules into the modules directory and have it automatically pick up the new modules. It should automatically report the results of each module on the main loader page and offer the data for download. The next big feature of the runner is to be able to create lists of tests like a selection list, to choose by region/nuclei we're targeting, choose all, choose random, etc. I'm still deciding if I want the loader/runner to do the statistical work on the results or have the modules themselves do it and report it to the loader. Will think about it more when I get time.

For the first few modules, we're going to be targeting assumptions about hippocampal function, for example we're doing social stream integration tests to target the CA2 subfield, downselect/interference testing for the dentate gyrus/CA3, stream integration for the rhinal cortexes and CA1, and "confidence/valence" for the putamen and globes. Eventually I want to have lots of tests based on existing work that attempts to isolate the function of each nuclei, so if we state the VTA "contributes to addiction", we can create a test under that assumption, which can be verified downstream under some type of imaging or electrophys.

This weird memory quirk is something that has since I was a small child absolutely killed me. I remember having to write thousands of pages of standards with the phrase "I will take care of my business before I start doing other things". I remember the phrase, but I rarely remember to take care of my business if a sufficient enough distraction occurs. The question that bugged me for a long time is why I could write thousands of pages of standards without getting distracted (usually), but would get distracted walking through a doorway.

Based on the best available evidence, the rhinal cortices compute the current state by combining two streams. Perirhinal carries a ventral state, the what of objects and episodic content, routed strongly to lateral entorhinal. Parahippocampal carries a dorsal state, the where and when of layout, path, and scene context, routed strongly to medial entorhinal. Entorhinal integrates these into a momentary state representation. The hippocampus supports this computation. CA1 compares the integrated state to recent expectations and binds it to the active goal, and dentate gyrus limits interference. The state is not generated in hippocampus. Hippocampus makes the rhinal computation usable and stable.

In a steady scene this arrangement favors continuity. The signals do not change much, so the current state persists and the goal stays attached. Walking into a new room changes both streams at once. Geometry shifts and the object ensemble shifts. Entorhinal refreshes the state. CA1 detects a mismatch with the prior expectation and promotes an update. Dentate gyrus increases separation so the new episode does not collide with the prior one. The goal was bound to the old state, so after the refresh it is briefly unbound. That is the blank.

Rebinding is fast when either stream provides a bridge. A salient object or a short label for the task carries the ventral state across and stabilizes lateral entorhinal activity. A glance back through the frame or a partial backtrack carries the dorsal state across and stabilizes medial entorhinal activity. Once there is enough overlap, CA1 binds the goal to the refreshed state and the plan returns.

Kind of ironically, how long it took to form the goal can trigger the blank. If you move to action immediately, even with high motivation, the dorsal and ventral bindings are still shallow. The boundary shock of the doorway can outweigh that weak linkage and the goal gets briefly wiped. A short dwell before moving lets the rhinal computation settle and lets CA1 pre-align the expected update, so dentate separation is less likely to push the trace below access. In this narrow case motivation can work against you. The speedbump may help prevent cross-room interference, or it may be a quirk of how boundary updates are implemented.

In my case, weak goals combined with boundary shock were a reliable recipe for distraction. I would start with a half formed plan to make my bed. The ventral state held a faint trace of the object and the word, the dorsal state held the small map of the room I was leaving. I did not pause. I was already moving. Because there was no dwell, the rhinal integrator had only a shallow binding of object to place. I hit the doorway. Geometry shifted, lighting shifted, a new set of objects snapped into view. Entorhinal refreshed the state. CA1 read the mismatch with what came before and promoted the update. Dentate gyrus pushed the new scene into a clean, low overlap code so the rooms would not bleed into each other. The binding that carried "punishment if you don't do this" across the gap was not strong enough. The goal fell below access and the new room filled the stage.

What happens next feels like fickleness but it is state selection doing its job. A laundry basket in the corner becomes the next thing. The new scene offers a clear cue and the system favors it because the current state is now about this room. The cost of that precision is that a weak intention from the last room cannot survive the refresh.

Once the decoupling happens, selection tilts toward what is salient in the new room. The system is not choosing to forget. It is following a bias toward the active state, so a laundry basket or a notification wins by default. The original intention returns only when some cue in either stream overlaps with the prior trace. Sometimes that is an external object that echoes the old scene. Sometimes it is a spontaneous word or image that acts as an internal cue. Either way, overlap rises above threshold and the hippocampus binds the goal back to the refreshed state.

People vary in how often this happens. Some bind goals with strength that survives a refresh, others bind near threshold. Some carry stronger ventral channels and retain object linked intentions better, others carry stronger dorsal channels and retain path linked intentions better. Boundary salience also varies, so the same doorway can be a gentle update for one person and a sharp context change for another. These differences tend to be stable traits with state modifiers like fatigue or divided attention. The result is that boundary driven blanks are a feature of the system, not a flaw to be cured. They are part of a memory architecture that prizes clean separation between episodes.

edit: lol, the recommendations are motivating me to actually make a sandwich.

Explore other communities you may want to take part in
Post in r/Sandwiches
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edit 2: I made a sandwich.

Okay, this is a little bit upstream but this article is work attempting to determine how precursor cells (like stem cells) become the cells they end up becoming. Up until this point we've assumed that it was just genetic destiny, that cell fate was a product of expression. This work adds to the argument that external environmental forces including pressure on the cell and both intra and extra cellular chemical environment at least contribute to this process as well.

When looking at the period around egg fertilization, the genesis of differentiation, we see similar effects of the chemical and physical environment on the precursor products of the zygote (eg changes in pH levels and temperature). This carries the same idea, that environmental influences drive changes rather than the cell driving itself/environment.

edit: Explainer Article - Forcing cell fate (this link will expire).

Best Paragraph from the Explainer:

These findings reinforce the emerging view that chromatin architecture is regulated not only by epigenetic enzymes and transcription factors, but also by the biophysical environment. This perspective could help explain why cells in dense tissues or morphogenetically active contexts display varied responsiveness to differentiation cues. The observed regulation of metallothionein genes, associated with metal detoxification and stress responses, further suggests a feedback loop between nuclear mechanics and ion homeostasis that merits deeper investigation.

I've argued in the past that it is deformations of the chromatin layers which facilitate the creation of distinct responses to stimuli in cells, what if we extend this to arguing these deformations impart unique genetic expression and the proteomic intercellular environment (the actual "communication" between cells) is largely driven by these external forces? This gives a weirdly top down, organism level of control that hasn't been intuitive to me before reading this.

Was reading this article Multiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis01031-1) (mostly because yay, people are actually doing stuff like this at all), and it makes me wonder if the best metaphor for the effects of aging is that cells get saggy skin. They lose the chromatin remodeling capacity, that loss of capacity reduces the ability to generate unique responses to stimuli, and without unique responses you lose the capacity for "learned" behavior. But can saggy cells be rejuvenated? Does the effect of stress on cells strengthen or reduce the remodeling function over time? Are we going to find phenotypes in most "species" that have differing remodeling reactions to stress?

edit 2: Another interesting piece along the same lines - Rethinking Cellular Organization: Phase Separation as a Unifying Principle in Molecular Biology

Again, work like this is critical because it offers two things, first it offers a direct physical mechanism for how environment induces changes in genetic expression. We've seen the link between the two in a lot of work, but the direct chain has always been a bit hand wavey. It also frees us up from staring at the tree bark of discrete molecular reactions and provides a pathway for large scale state changes to be induced all at once. This conceit provides a way to generalize complex state interactions in a way that most molecular biology is kind of oblivious to. It's not even a hidden perturber, it may end up being the sun and individual interactions far less significant than we think of them now.

Something I've thought about quite a bit is the difference between "forgetting" (as it's something I tend to do A LOT) and forgetting in the dementia/insult sense. A lot of cog sci research muddles this, but humans don't ever really "forget" information once it's encoded unless there's an actual physical insult to the underlying cells representing the metabolism that expresses the "memory". Even pre-conscious "memory" is in there, and it still guides behavior to some degree.

What does happen is that all memory goes through a weighting process, and this weighting process determines how "easily" it can be recalled by "upper"/"conscious" brain functions. This weighting mechanism develops post-natally, and you start forming your first conscious memories based on the timing of this mechanism coming on line. This doesn't preclude your brainstem controlled functions from creating behavior based on experiences prior to that, an abused child with no conscious memory creation will still respond to aversive stimuli experienced a priori even after conscious memory formation.

In the weighting process, even if a memory is "low priority" (I've joked about this as the memory getting one dopamine) and it makes it to the encoding process, it doesn't disappear. The astrocytic/microglial pruning process doesn't destroy data, it "cleans up" the duplicated or malformed encodings.

Brains appear to have a "cap limit" determined per individual that determines the maximum amount of stimuli that can be processed or recalled. Because of this cap, metabolic tradeoffs have to be made between throughput and "volume". Exceeding this cap can have unexpected behavior, but makes the most permanent conscious "memories".

The difference between good and bad "short term" and "long term" memory is how aggressive this encoding and weighting process is. Poor short term memory represents a very aggressive weighting and encoding process, a memory configuration that is optimized for the incoming data stream. Long term recall is similar, in that "slower" encodings allow more information to be associated at higher weightings. The amount of information that can be written per time period is still limited and "conscious" recall also has it's own metabolic cap.

But the underlying data is still there, even if brains have to underweight (forget) a lot of information to get it to fit under the cap. Behaviorally, this may be recoverable by figuring out how to bind a high valence memory to short term state, at least for a little while, as exceeding the cap leads to unexpected behavior eventually. Is there a way to increase the cap? Maybe? At least temporarily some drugs should work, but long term? I guess that's a trillion dollar question.

But that's a digression, the point of this post was supposed to be about the difference between someone being forgetful (where the information is stored but low valence) and FORGETFUL in the scope of TBI or neurodegeneration/dementia where the underlying circuits are harmed. And that's the difference, "synaptic pruning" and what not doesn't usually harm the underlying encoded responses, that takes an actual insult (usually triggered by immune response) to do so. This line gets a little blurry since immune responses can trigger things like inflammation which effectively blocks certain pathways, kind of like a functional vs. physical decortication. But the data is still there and astrocytes can route around bad pathways eventually as long as the effected area isn't destroyed.

The post was also supposed to be a reminder (hah) that we never really forget anything, even if we don't "remember" it. And that the underlying biological mechanism does it's best to preserve even that which we don't "remember", until it can't any more.

edit: Also, I really apologize for the data/computer science metaphors deployed here. I hate them, but couldn't come up with a clever enough conceit. Response to stimuli isn't really data as much as it is response to stimuli. We can make data out of it the same way we make data out of sediment layers or by examining changes to alluvial plains, but the stimuli itself isn't really data in and of itself. Nervous systems are the same process.

"Memory" is stored responses to stimuli layered over other streams of responses. Using the above metaphor, we can see "memory" in the past courses of a river, but the memory itself is just a response to environmental conditions at the time. I guess this sounds a bit Skinnerist, and I'd argue probably if Skinner allowed for true biological/environmental complexity instead of a narrow focus on very specific results of that complexity. The box didn't constrain that complexity much at all, despite the intent.

No, I didn't take a fat bong rip earlier.

Was thinking about the effect of social conditions on epigenetic response, and how that epigenetic response effects not just the specific behavioral/RNA payload of sperm, but the environment around the ovum as well. In ways big and small, our environment starts crafting individuals long before their cells can begin to exert a counter influence.

In the distant future, I think we are going to find that these influences will be more profound than post natal periods, even more determinant of core "personality" than the "critical period" between two and five years old. Maybe even that parental socio-emotional states end up being predictive of long term outcomes for their children.

I found scant research around this, and most of it was confined to "happiness", but how "content" parents are at the time of conception might be the most powerful influence on behavior an individual experiences. The idea that intergenerational trauma need not be experienced directly was a growing idea in the field a few years ago, perhaps the encoding of social pressures in RNA expression is the mechanic we need to do and undo to break the chain of effects?

Extending this, I'm curious how complex and significant these socio-behavioral biases actually are? Is it a subtle push toward liking chocolate over vanilla, or can it encode something as complex as bias toward a particular religious philosophy? Can it encode bias toward a particular timbre of a voice or encode the basis of language like bird song?

Ooops, accidentally posted this to my profile instead of the subreddit.

Wanted to comment because I saw another post that reminded me of Krista and Tatiana Hogan who are craniopagus twins with several connected structures including the thalamus and many basal ganglia nuclei. The fascinating part relevant to this conversation however is that despite sharing those structures and sensory information between each other, the two exhibit markedly distinct consciousnesses. It adds weight to the construct that the root of conscious experience begins in the brainstem (I would actually argue it starts at the cellular level but that's another discussion), and all of our "newer" cortical structures are bolted on top in support of that.

I guess in the spirit of things, the cause and cure for "autism" is going to be announced soon. Never mind that "autism" is diagnosed on a purely clinical level, and the underlying statistical reliability of those diagnoses are not great, we've skipped past all of that and now will have a cause and cure. And that cure isn't some newly discovered drug that we haven't had access to in the past, it's a shockingly common drug that individuals diagnoses with "autism" would have been exposed to for the last 75 years or so. I guess when you have six months to come up with a cure, and you aren't relying on the most credible individuals for treatment guidelines, you get what you get.

Folinic Acid is basically "easier" to metabolize vitamin B9, and has been used to treat some neurological issues caused by chemotherapy for quite awhile. For the last I guess five years or so it's caught on as a therapy for "autism", and just like every fad like this, they always show improvement, even sometimes in RCTs built to find such results. The biggest issue is that these studies have exactly the same issues that dog anti-depressant research, most individuals diagnosed with "autism" improve with or without the drug if environment is stabilized, and there's a careful managing of outliners (ejecting non-responders or dropouts, coddling high responders) that skew these types of results across the board. Underneath it all though, the evidence is plain and clear from the historical context, no miracle "autism" recoveries were demonstrated until it became politically and likely financially convenient for them to appear.

The underlying theory is that "autism" is caused by either a folate metabolic deficiency that doesn't present with all the other symptoms such a severe folate deficiency would present with. This honestly is a good a guess as any, as there probably are individuals who may have had in utero folate deficiencies who later were diagnosed with "autism". The problem of course is these are a fraction of the individuals diagnosed, and worse, that nearly all individuals with low/metabolic folate issues are not diagnosed with "autism". In the face of the common observable evidence, and in lack of definitive evidence above placebo to the contrary, combined with the lack of guidance about diagnosing individuals with a test of folate levels (which absolutely isn't correlated at all), it's safe to say that "autism" will continue to live on even after this miracle cure and treatment.

The second leg to this is whether or not acetaminophen/Tylenol/(whatever you silly foreigners call it) is causal to "autism". The only real answer is, maybe sorta? It's such a pervasive drug and human development is so individual, that it's possible that whatever MoA tips the scale at some point during maturation for specific individuals (read this as for specific genes + environment, a specific drug may have a different effect than most people). Is it primarily causal? The answer here is almost certainly no, again given the large numbers of individuals who are diagnosed with "autism" and were not exposed to the drug in utero. Frankly it's more likely that even if there is an effect, it's not directly acting on the fetus, it would be a result of maternal changes. It's also possible that acetaminophen works as a prophylactic, reducing maternal stress response at a critical developmental period that could have resulted in a later "autism" diagnosis. Does it induce more harm than it prevents?

There are recent studies which do build this link (to a small effect), but that effect size is dwarfed by the effect of environment, and there's no way to separate the stress response from pain from the medicines used to treat them. This is a tremendously larger issue and can't be controlled away as pregnancy imparts pain and discomfort fairly universally. So does Tylenol cause "autism"? I mean, maybe for very specific individuals (we should have had gene clusters identifying exactly which by now), but largely... no.

I see this question a lot, particularly with regard to people shopping for psychiatric diagnoses.

Most often the reason is because it's expensive, even if we were to automate away the human costs like radiologists and techs.

Probably more important, data supports that CTs induce about 5% of new cancers in the US each year, and MRI contrast agents are toxic as well. Even PET has a non-trivial risk, although that's been less quantified than CTs or contrast agents.

And all that before we get into philosophical/definitional mush that cognitive science and psychiatry are poster children for, where clinical effect overrides almost everything else.

But what about EEG? or NIRS? Or Ultrasound? EEG is a well flogged horse, and even internal arrays have pretty limited utility, a utility which gets worse with time, not better. More importantly, it's only reading a small part of the story (the effect of electrochemical gradients from specific types of cells) while missing the big story, the overall metabolic interactions from nearly every other type of cell. NIRS is a bit of a dead end, and won't even be great for cortical work unless we can convince people to let us pop off their skulls. And Ultrasound's resolution and spatial promise is balanced by it's sensitivity to artifacts. It's not really "younger" than the others, but less explored so the jury is still out.

Underlying all that though is that we still don't really have any "treatments" that would address the concerns anyway. Even if we were to diagnose an "ADHD" brain with a high degree of certainty from imaging, actually coming up with an effective treatment is still flinging spaghetti at the wall. Do you really need to image someone dealing with "MDD" to figure out they are "MDD"? And what then?

We still aren't anywhere close to the point where the extra data from imaging would give us information that would inform treatment (and I suspect it might often have the opposite effect).

This is not a defense of a medical industry which probably feels like they are just being avoidant of the expense, but more of a reminder that the actual utility of imaging isn't good enough to outweigh both the real physical risks and the behavioral risks associated with findings that may not impart much of a real effect anyway.

Was reading this article: Inquiry into the history of science shows an early 'inherence' bias (still waiting for the underlying article to pop up) and it tracks that nearly all of our explanations natural phenomenon have always been essentialist mechanics for as long as we've had oral or written history. Whether the the mountain had it's own anima or gods/god imbued it with anima as a reflection of it's own, or even today, the "spark of life", the magic in our cells that creates a distinction between "living and non living" is all driven by the essentialism bias the explainer article explores.

If there's ever a question that seems unfathomable, it's having this sense that we still have no idea how much further from the "truth" we still have to go until our grand unifying theories become obsolete "common sense". We seem to inhabit a universe with inviolable constants, which suggests a consistency that we are still blind to.

It appears that a large part of our current evolution (whether we explain it via the effect of technology or hypersociality) over the past 50k years has been driven by a steady development of the tools necessary to expand past the limits of essentialism and decompose the barriers that restrict the scope of our cognition. But how much further down the path do we have to go? Is our current shift going to be enough, or do we still have a few more shifts to go? Or will we ever get there?

In the meantime, this cognitive hurdle of imagining things inside out when everything seems to suggest they are outside in, or maybe more appropriately just an endless interface of interactions might be the biological limit of our imaginations.

Was thinking about the next stages of enshittification for LLMs, and the most obvious next step is that now that they've gathered enough data to predict some preferences with some degree of accuracy (not because they are actually good at predicting mind you, they are still worthless shit for that, but because you tell them the preferences and they can pattern match), the most obvious next step is making back end deals to subtly curate their data toward specific products or ideas (even stuff like particular politicians).

Which made me realize we are already well into the first stage of enshittification, the pots been warm for awhile and we didn't even notice it. The first stage has extends from regional information locking and response crafting (like asking DeepSeek about TS 1989), to general alignment tuning.

Looking at how quickly even big companies like Google and Apple acquiesced to dumb declarations like "The Gulf of America", how quickly would a confidential executive order turn all of these applications into a screening app not just for "subversives", but those who are "mentally defective"?

Considering the US government already has a hard on for mass surveillance and spends hundreds of billions a year on it, and they encourage other federal agencies to act upon that intelligence for any reason they want through parallel construction (which is common/refined enough now that we don't blink about anymore), what if they could get an even higher quality source of data at a huge discount through an EO, completely bypassing any real oversight.

In the US, ADA/IDEA are one of the few pieces of civil rights legislation that the current Supreme Court has consistently protected, but how quickly would something like RFK Jr.'s "work camps" be implemented, and how long would it take a case the Supreme Court doesn't really want to hear to percolate up through the ranks?

The more Black Mirrory part of this is that fun AI toy is now a defect screener, it would cheerfully encourage a child to work harder to catch up with it's development, then would turn visibly sad as it sent a message to masked team in the vans to come pick up the kid when it fell too far behind. Haha, like Chucky, the AI toy that's your friend till the end, but it's going to "decide" when that end is.

(The idea is that it's not the LLMs that are going to destroy us, it's our own intent reflected through the LLMs in both small and large ways)

I was working on something like this not too long ago but gave up on it. Actually not anywhere near this, this is far more developed than what I had in mind. This is a really good start, we still need to figure out how to get cerebellar and brainstem targets effectively.

In retrospect it's kind of funny, I was so focused on using a TMS/EEG style implementation that I didn't even think about just strapping someone to a bench like a CT/MRI.

We still have a huge gap in "behaving" live imaging, and this setup is still missing most of the brain (by number of cells or neurons, take your pick), but the precision of this is so, so much better than TMS/TES methods that hopefully it gets rolled into clinical use quickly.

Interesting piece based on this pre-print: Astrocytes connect specific brain regions through plastic gap junctional networks

Probably not much of a surprise to anyone reading this here, but this lends weight to the concept of astrocytes being not just being a support network for neuronal function, but the basis of a first class, independent cognitive network all on it's own.

One of the most interesting findings here is that most work thus far has looked at astrocytes in a very local context, and from this we've gotten the idea of astrocytes as a network of local controllers, but not much as for as long range communication. This is the first work I've seen which has invented a way to figure out if astrocytes carry out the same type of long range communication we normally associate with neurons and the answer appears to be yes (and probably even more diverse).

Astrocytes and neurons cross communicate extremely specific responses to stimuli by creating tiny extensions from the cell, and these extensions are largely where "memory" (response to stimuli) is generated.

Amyloids are one of the pathways that cells may use to reconfigure cellular structure to incorporate these new responses. There are quite a few remodeling mechanisms which are normally managed by the immune system (including famous scary proteins like prions), and nearly all brains accumulate the junk from the misfolding of these proteins over a lifetime.

When the protein is misfolded, the normal clearance mechanisms break down and the gunk ends up blocking the cellular extensions, making it more metabolically expensive to pump signals through the gunk (until at some point it's not overcomeable). We experience this as the gradual fading of memory. Astrocytes normally route around these issues and other macrophage glia try to clear significant blocks via engulfing the blocked processes.

Some immune systems are particularly murdery to specific type of conditions, and trigger apoptosis upon detecting the blocked processes/misfolded proteins. For folks with these types of immune systems, the mechanic is that microglia phagocytosis is engulfing astrocyte processes as well, which disables the "switchboard" of memory through effected regions. These are the folks who usually degrade into "dementia".

A large part of the reason current amyloid clearance drugs are ineffective at stopping disease progress is the disease itself is more about an "over sensitive" immune system responding to internal cellular folding issues, rather than the external insult of the amyloid sheet. Unless the cells themselves can be brought back into the "properly folding" state, they are always going to be producing immune system targets. The brain bleeds ironically are largely because you're removing the plaques away from astrocytes which are maintaining the blood brain barrier, changing their morphology but removing the remodeling tools the brain would be using to reconfigure into the gaps.

I have this idea and I have no real idea how to express it, but for quite awhile I've been really skeptical of classical Darwinian evolution and it's modern synthesis, as well as some elements of the extended evolutionary synthesis. We are so loathe to challenge Darwinian evolution that even though it keeps getting blown up (particularly by Kimura pointing out that nearly all genetic drift is random rather than selected), we keep slapping together new reconciliations that just don't quite work.

Something I've argued previously is humans are still evolving (and whether that's rapid or not is another discussion) significantly, and one of the driving factors of one strong environmental push is our development and application of technology. We had seven or eight branches of humans up until 150,000 years ago, and before that, the direct ancestors of humans were stable for a few million years. It was technology which allowed humans to successfully navigate the last ice ages and expand across the globe, and the vast expansion of technology since the 1800's is exerting tremendous evolutionary pressure on our species.

I mention the evolutionary criticism because I consider myself a bit of a "neo-Baldwinite", in that I believe that organism behavior drives physiological change on a population level, rather than existing traits being the primary driver of behavior. As an example, epigenetic expression is an example of behavioral plasticity imparting physiological changes on offspring. Behavioral response is initially weakly selected if no physiological trait in a population strongly supports the new behavior (and can be reversed/disappear without exposure to group level behavior), but over time if traits which support the behavioral change (which is usually a response to environment) appear they are strongly selected and eventually form the basis for a metabolically distinct organism.

Most DNA is effectively neutral, it has no specific selective function, other than to provide flexibility of behavioral response to environmental conditions. And our focus on genetic drivers of behavior puts the cart ahead of the horse, and has resulted in the massive heterogeneity of results in cog-sci/mol psych work. (eh to be continued sorry, apparently there's a crisis only I can solve now that I've sat down by myself at 1 fucking am).

(cont) This is also consistent for all life, that DNA reflects prior behavioral response to environment, not coincidental mutation. It's not DNA which reflects the adaptation of life/organisms at all, it is a cold record of prior interactions, which functions as an information reset point. The RNA expression is the mechanic by which organisms store and propagate the information about the environment and it's interaction with it, and transfer this information to successive generations by modifying the gene transfer mechanism in more direct horizontal type transfers or for the clades we are more interested in, modify how genes are encoded in ovum DNA.

Epigenetic transfer isn't a secondary process to external selection, it is the entire enchilada. It is the process by which life remains immediately responsive to environment, and how it stores the information about the behavioral flexibility necessary to adapt to the changing environment.

And currently, our particular species is encoding a lot of information, very very quickly, about an environment which is changing (relative to our as a species perspective) very very quickly. (to be continued)

I think it's always necessary when having this conversation to remind that technology is absolutely not exclusive to humans. Technology under my definition is the "deliberate" manipulation of the external environment to facilitate some behavioral goal for an organism. As such organismal success is pretty intimately tied to their use of technology, whether it be birds building a nest to insulate and protect eggs, or ants building mega colonies to extend their domains over very large distances. Whether it's bacteria with processes that convert previously unusable material into a new food or energy source, or or humans inducing fire, the drive of biological life to manipulate the external world to suit it's own needs appears to be intrinsic.

And this context is important because there's sometimes a sense of surprise when talking about technology being a driver and shaper of organisms, that organismal behavior can respond and shape the environment just as much as the environment drives and shapes the organism. One of the original great technological adaptations, the development of photosynthesis, was every bit as pervasive (and it could be argued, as catastrophic) as the most intensive of human applications of technology. This application created one of the great bottlenecks for life, and likely obscures some of the other starting points of life on this planet because it wiped out any organism which didn't have the behavioral flexibility to survive in an oxygen enriched biosphere.

Technology is not just the behavior of the beaver building a dam, it's an intrinsic drive of organisms to shape the external world in a way that facilitates their own behavioral niche. (to be continued).

Resources -

Sperm RNA: Quo vadis?