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An FDA-approved asthma drug has shown the ability to restore memories in mice (thedebrief.org)
104 points by BoardsOfCanada on Feb 11, 2023 | hide | past | favorite | 42 comments



Whenever I read articles or studies about scientific approaches to "restoring" memories, particularly approaches involving pharmaceuticals, I instinctively assume there's a significant metacognitive counterpart. Surely mental/psychological techniques and external stimuli have an equal or greater impact on memory retrieval?

I have a bizarre personal anecdotal experience with spontaneous memory activation. I was leaving work one evening, and I'm recounting a dream from the night prior to a colleague as we left.

Suddenly, in what felt like an instant, I began to rapidly recall a chain of lucid dreams I've had. Dreams I hadn't remembered in years. I remembered not only the dreams themselves, but my life's circumstances when I had them. I describe this as a chain, but it felt to me more of a... portal. As if inside each of these dreams was a connection to the next.

I awkwardly paused, said a brief goodbye, and returned inside to look at myself in the mirror. My pupils were very dilated, and I felt like I was on psychedelics.

The strangest part is that this... connection has persisted. If I try to recall any of these dreams, including writing this comment, I'm unwillingly transported through these memories, and I have to consciously focus elsewhere.

No idea what to make of this, but it's definitely interesting.


Funny, I have a similar cognitive sensation for a kind of deja vu I sometimes get, where I'll remember remembering something and my train of thought about it, but also remember remembering remembering all the previous times I remembered remembering it, and along with it, unwillingly, I'll remember all the trains of thought I had at the times I remembered remembering, sort of replaying all at once, cacaphonously.

It's sort of like looking down a well, but it's well of time, where each time I look, the well is one unit deeper and there's another new snapshot of me looking down the well added to the top.

It's honestly kind of annoying, because it's almost the cognitive equivalent of an earworm — I have to willfully dismiss it from my focus, otherwise it sticks around.

I wonder if this is the original meaning of the term "navel gazing"?


> It's sort of like looking down a well, but it's well of time, where each time I look, the well is one unit deeper and there's another new snapshot of me looking down the well added to the top.

I had to go digging, but it reminds me of the novella Cascade Point by Timothy Zahn. In it, spaceships can travel through hyperspace, but skimming the edge of parallel universes in this way causes the occupants of the spaceship to see visions/hallucinations of their parallel-universe-selves standing nearby. Being able to see the various results of major decisions in your life -- some which lead to the death or grievous injury of the parallel-universe-self -- is quite a shock to most people, and thus it is customary for all passengers to be asleep for the hyperspace travel portion. But all captains are required by regulation to be awake for the transit, and thus in the story this captain must muse on his life-choices, alone on the bridge, because he runs a passenger liner.

It's a bit of a wooden, flat story, with a somewhat basic plot, but I thought it was a neat concept-and-consequence of FTL.

A blog post with a quick mostly-spoiler-free review: http://speculiction.blogspot.com/2014/01/review-of-cascade-p...


This matches my experience eerily well, especially the "one unit deeper" aspect. I feel like I can voluntarily summon this experience in my mind and travel through it forever. It feels frightening, in a way, being confronted with the depths of an unexplored internal mental chasm.

Do you have other "threads" with similar phenomena, or is there a singular thread that branches?


Out of curiosity, how do you know you’re remembering things that actually happened? Keep in mind the “felt sensation” of remembering is itself also generated in your head, and we know people can have that sensation while “remembering” things that never happened.


I suppose it's impossible for me to "prove" whether these memories were/are more-or-less accurate. However they're self-consistent: since this phenomena emerged I've been recording my experiences and the referenced details within the dreams have remained unchanged. The circumstances also map correctly to knowable context: in one of these dreams, I was traveling for work and staying at a hotel. I have the email confirmation from that hotel, and a note from the same day with a simple remark about that lucid dream.

Beyond this, I feel a deep, unshakeable confidence that this experience of recollection is unmistakably true. Who knows?


You should try eating mushrooms in a sensory deprivation chamber.[1]

[1] https://www.imdb.com/title/tt0080360/


Dreams have this tendency to disappear from memory even as one is thinking about them in the morning. Keywords written quickly in a dream journal at night can amazingly trigger entire scenes back into memory.


I have occasionally experienced disassociative episodes where memories of dreams start to mingle with real memories and I have a hard time telling them apart. Has happened to me a few times.


I don't think the mice in the study are doing much meta-cognition about the experiment.


It’s called prompting ;)


The Headline is misleading: "Recovering object-location memories after sleep deprivation-induced amnesia"

This is possibly only effective in stress induced amnesia.

This effect of Roflumilast has been known since 2015: https://www.sciencedirect.com/science/article/abs/pii/S00142...

Roflumilast is a PDE4B and PDE4D inhibitor.

The enzyme, PDE4 (https://www.uniprot.org/uniprotkb/P27815/entry) uses Zinc and/or Magnesium as a cofactor.

What is the function of PDE4? It metabolizes cAMP (3',5'-cyclic AMP + H2O = AMP + H+) stimulated by Nitric Oxide which is responsible for LTP, or memory formation.

http://learnmem.cshlp.org/content/13/1/35/F7.expansion.html

This is what Viagra does as well but Roflumilast works in the brain because of its' PDE4B and PDE4D selectivity.

So what does this have to do with stress and nitric oxide? Everything! https://pubmed.ncbi.nlm.nih.gov/28061969/

But IMO this is a healthy function of the body. We should NOT be remembering our stressful experiences!


You are confusing PDE5 and PDE4 inhibitors. PDE5 inhibitors are popular erectile dysfunction drugs and work via nitric oxide. PDE4 inhibitors are anti-inflammatory in the lungs and also have cognitive enhancing effects by potentiation of cAMP secondary messenger systems that trigger LTP encoding in neurons. Nitric oxide is not involved in the action of PDE4.


> You are confusing PDE5 and PDE4 inhibitors

Yes, sorry for the oversight.

> Nitric oxide is not involved in the action of PDE4.

?

Phosphodiesterase type 4 inhibition enhances nitric oxide- and hydrogen sulfide-mediated bladder neck inhibitory neurotransmission https://www.nature.com/articles/s41598-018-22934-1

cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.110.9...

PDE4 inhibitors are most likely anti-inflammatory because they affect NO.


Nitric oxide effects are downstream from cAMP which is degraded by PDE4. cAMP increases usually come from g-protein coupled receptors releasing it and then there's a cascade that depending on the cell type may create Nitric oxide. However, nitric oxide is upstream of cGMP metabolically and is degraded by PDE5.

https://www.reading.ac.uk/nitricoxide/intro/no/cgmp.htm


Is that likely to interfere with the forgetting of dreams? I can't imagine how cluttered my mind would be if that bizarre stuff didn't blissfully fade within a few minutes of waking up.


> I can't imagine how cluttered my mind would be if that bizarre stuff didn't blissfully fade within a few minutes of waking up.

Not necessarily true, if (as the hypothesis goes) dreams are just an alternate (incorrect) decoding of your existing memories, experienced as a side-effect of the process of memory reconsolidation — the https://en.wikipedia.org/wiki/Mojibake of what's in your short-term memory buffer.

If that hypothesis holds, then "remembering" dreams wouldn't be like "remembering" regular memories, requiring independent storage of the data about them, but rather would be "free" as long as you retain the memory that the dream is an incorrect decoding of — the "memory" for the dream just being a pointer to the original memory, plus a pointer to the mental trick to reinterpret it. Such data wouldn't take up more than a trivial amount of space to "remember", any more than procedurally-generated background art in old video games take up space to "store."

(But, of course, the downside is these dream-pointers are probably not "strong references" to the things they point at from the brain's memory garbage-collection perspective — which is why dreams are so easily forgotten in the first place. Forget the original thing, and you forget the dream, whether you intend to remember the dream or not!)


Take that stuff only to be overwhelmed with all the cringe moments you ever had in your entire life and successfully suppressed until that very moment.


Joke’s on you: I never forget my cringe moments.


One workaround is to catch yourself in those moments and say, under your breath, "The person who did that is dead. I'm his/her replacement. I'll do better."


That sounds pretty depressing. It's also a great way to hate your past self. They were such a jerk!


Oh god what have you done to me.


…in mice.

“Havekes is quick to note that “this is all speculation,” but given the successes his team had in the lab, he believes his work can serve as a guidepost for researchers and pharmaceutical companies who are trying desperately to help folks retrieve their lost memories. Finally, and perhaps unsurprisingly, the researcher is just as enthusiastic about the new questions his work opens up as he is about the previously accumulated knowledge it may reveal.”


The title does end with the magic word pair now if it didn't earlier.


Thanks, good edit. The title of the linked page (and therefore iirc the original title on the post here) was “"Magic" Drug Restores Lost Memories and Unleashes Hidden Knowledge”, which is considerably more misleading than the current title.


I doubt the claim in the title, but I'll add something probably more useful. I only personally know one person with an eidetic memory (what people think is "photographic"). That "superpower" affects them in a pretty negative way. People think of this power through very rose colored glasses, but there is also a dark side to it. You don't just have a high recall for good times, your tool's documentation, etc but you also have a high recall for any trauma and bad things that have happened to you. Since you have such high recall with high precision it is much closer to reliving the experience than a typical person's memory would be. (there's that popular image floating around of how well you can visualize an apple in your head. Eidetic people are on the extreme end while Aphantasia people are on the other) People with eidetic memories often over think things because they can recall a large swath of historical information to make judgements upon (and this leads to overload). It also freaks people out when you can recall what they had for breakfast several years ago on a specific day.

There are definitely advantages to this level of memory, but there are often disadvantages that come along with it. There was a reason evolution selected for brains that could forget and fuzz information. Fuzzing helps with abstraction. We even see some of this usefulness of forgetting when training neural networks (DNNs are __NOT__ akin to brains. Neither in respect to {hard,wet}ware nor algorithmically. But there are a weak similarities and similar abstractions).

It's probably also worth adding that our memories are terrible in a different way. Not just in recall, but in that sometimes we just make shit up. This can be hard to distinguish and be problematic too. If you know any vivid or lucid dreamers ask them about their experiences (if someone is keeping a dream journal they're likely to be a vivid dreamer. I stopped keeping a dream journal for this reason).

I'm sure someone that is way more knowledgeable about this could say more, fill in many gaps, and correct misunderstandings I have. I am not an expert (I study NNs, not brains). So if you are an _expert_ in this area, I'd love to learn more. Domain knowledge is often hard to come by and nuances matter.

https://en.wikipedia.org/wiki/Eidetic_memory


> I doubt the claim in the title

There's a few reasons for this. Choline used in cell walls is also used in the connections to neurons and is also used in the alveoli to lower the pressure of the fluid to enable the gas exchange in a passive diffusion way.

So something causing inflammation in the lungs will likely be increasing the requirement for choline. This is why you see brain fog with Covid and asthma is probably no different in some situations when experience a debilitating bout of attacks.

Some Cancer's and treatment cause brain fog. Again a need for choline exists.

Pregnancy when the foetus starts growing quickly, again brain fog occurs and the need for choline exists.

However there is an additional factor. There is an oestrogen-choline pathway, which means if calorie intake falls below 750 calories, unless you are a reproductive capable female or reproductive capable male with high levels of aromatase, you will experience a variety of damage to organs and elsewhere throughout the body. Its this oestrogen-choline pathway which off-sets/mitigates the brain fog experienced by some women during pregnancy. If men have high levels of aromatase, aromatase converts testosterone into oestrogen. This is why effeminate males have high mental abilities. Omega-3 is an aromatase inhibitor.

When choline levels are low, the connections between neurons shrink eventually breaking the connection between neurons leaving what can best be described as stumps, thats when your memories disappear from your consciousness.

When enough choline enters the diet or the sex hormones increase for the oestrogen-choline pathway, you get your memories back, these stumps on the neurons start growing again and the connections get reformed. I used to think it might have been possible to mix up memories from cross wired neuronal connections, but having seen how these connections branch out, eventually the cross wired connections should resolve themselves and make it possible to get the original memories back, but I think recall might be an issue, which is what you might be experiencing. Different triggers to previous triggers but perfect memory recall.

This is why I disagree with your title doubt, but you are right about the negativity of the eidetic memory as it does also bring back my child abuse at the hands of state employees. Dont ever see a psychologist, they will just bring all that trauma back and then it messes you up. The State know this which is why some laws exists and some dont, like why people are considered a child incapable of making decisions until the age of 18, the obfuscation with the idea of consent as another example. The state give away their knowledge with their actions and inactions and thus their complicity in crimes carried out on people. Its very clever stuff, that they like to pass off as incompetence.

On the point of eidetic memories. I have one everyone has one if their diet is right and/or lifestyle. When my customers would phone up saying a bit of their program was not working, I would visualise the code in my head and knew exactly where to go to fix it. Same with books or text on webpages, I visual the sentences on the page and can tell you exactly where to look.

This is linked to choline, but its also linked to rhodopsin's which you find in your eyes (the rods) or rhodopsin like proteins which we almost certainly ingest from tomatoes as rhodopsin's have the colour attribute of being in the red's, pink's and purple's range, but mainly red's to purples.

This brain visualisation I experience when recalling stuff like program code or facts and figures from stuff I have read may also be linked to the rhodopsin's, its not something I've even considered before until now, but as a kid I grew up on kilo's of wild blackberries, eggs (we had loads of chickens), alot of potatoes which is starch rich and the only sugar the immune system doesn't attack, and plenty of veg. Not a strict vegetarian diet, but perhaps considered an anti-inflammatory diet, very organic, tapped spring water, not even on the mains.

I think Prof Bruce Ames Triage theory can also be proved with choline intake, exercise and memory performance. So if doing alot of aerobic exercise like running, I would surmise that choline diverts to the lungs, but when that exercise plateau is reached, this is mainly a dietary limit which can then be altered with supplements like choline. Exercise also triggers other chemical changes ammonia build up which is normally sweated out, but ammonia can compliment the immune system, namely histidine and histidine intake can affect things like the thickness of the myelin wall around nerves.

So on a fixed diet, there will be a sweet spot where optimum running and mental performance cant be increased any further. Obviously as this is a sort of twin peak thing, it should be possible to increase one of the peaks at the expense of another.

I wouldnt consider myself knowledgeable, I'm not qualified in anything, I have no pieces of paper's from uni's and what exam results I have, I never checked my exam papers against the text books, so I dont accept my grades either.

In my limited experience, I think some exam results are awarded based on behaviour and not intelligence, but thats my opinion.

On the point of testing eidetic memory on the population without anyone recognising, Computer programming is an excellent every day eidetic memory test. Our programming IDE are also everyday stealth tests, like font size for eye sight tests, colour of fonts for colour blindness.

Even opening a PDF in a browser like MS Edge, where the PDF fonts are known can also test eyesight by how much you enlarge a PDF or not, something that can be done to most of the population.

So many subtle tests exist to monitor our physical health, I wonder if MS, Apple and Google have even considered selling this meta data to health insurance companies and govts, if they are not already!!!

To say I haven't been experimented on against my will, would be an understatement.

Anyway, excellent phish!

Edit. One example of govt stealth testing on the population is the removal of grammar schools here in the UK, Edwina Currie Salmonella Egg Scare and Margaret Thatcher removal of milk from schools. If you know what the removal of their effect is mentally and physically, you could quantify the stealth effects of politicians actions.


The drug in the article is roflumilast, which seems to share some structure with the nootropic ampakine CX-546. I've never consumed that, but I've had some experience with IDRA-21 doing something like what the article describes, such as having vivid dreams of minor chart hits from decades ago that I'd previously gone a long time without being reminded of.


I've heard of a Russian medication that can be used in low doses that gives old memories back. It starts with"bro" and it has something to do with dopamine.


Would it be Bromantane by any chance? It's quite a fascinating drug.


Yes. Someone told of a story where he took very low doses and he got childhood memories every night.


Where can one get this ampakine CX-546?



Similar dscussion on Reddit (2020) https://www.reddit.com/r/Nootropics/comments/izplmo/roflumil... also links to a few other studies


... in mice.


Given roflumilast is already used in humans, it does raise the question if asthma patients are reporting extra memories.


Sleep-deprived mice, even


The "magic FDA-approved asthma drug" is roflumilast, just in case you were wondering.

https://en.wikipedia.org/wiki/Roflumilast



I notice they eventually changed the lying headline this was originally posted with.

Is there a better way to prevent lying headlines in the future?


The original title is still the title of the relevant page, and generally hn discourages editorializing the title in the submission.


those murine preschool teachers ought to be running scared now.




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