“The recent mapping of an entire adult fruit fly brain—a watershed achievement that made headlines worldwide—offers a glimpse of what’s possible. But this breakthrough almost didn’t happen. It required the serendipitous alignment of support from three non-traditional funders: Scientists at the Howard Hughes Medical Institute’s Janelia Research Campus imaged the complete fly brain; the Intelligence Advanced Research Projects Activity drove the development of tools for scalable neural-circuit mapping through its MICrONS program; and the National Institutes of Health BRAIN Initiative provided sustained support for data analysis.”
it might cost $1B to fully map & model the brain. ARPA-style and FRO-style research orgs are essential.
optogenetically perturb each neuron in C. elegans and see what happens to neural output in all 302 neurons
fit this as a simple multivariate dynamical system—each neuron’s output at time t is a linear function of all the neurons’ output at time t-1, plus a linear function of the neurons’ history of optogenetic stimulation, plus error.
compare to a simpler, connectome-constrained model, where each neuron’s output is only a function of its presynaptic input neurons (and direct optogenetic stimulation). this is actually a good approximation!
in fact, it’s better than a fully-connected model, OR a “shuffled-connectome” model based on a made-up C. elegans connectome with similar topological properties to the real one. the true connectome matters.
if you train a connectome model without one neuron, it predicts something about what activity “should” be there. correlation at 0.30 with the real one, much higher than a “fake” connectome model’s correlation with reality.
model weights don’t reflect synapse counts, though. “multi-hop” trajectories have significant influence on correlations (i.e. neuron A and neuron B’s activity may still be highly correlated even if A and B are more than one step away on the “connectome graph”).
it would be shocking if connectomes didn’t matter, so in a sense this is not a surprising set of results; but this is a first example of collecting data with the optogenetic perturbation method, which is a major step towards true neural simulations.
a simulation should be able to predict what every neuron would do under various circumstances.
gathering data on the worms in varying behavioral/environmental contexts could approximate this, but manipulating each neuron one at a time gives a much more thorough picture of the input-output relationships of the nervous system.
NMDA receptors (for glutamate) are important in long-term potentiation, in which “a neuron becomes highly sensitive to excitatory transmission for days or weeks” following recurrent stimulation.
long-term potentiation is important in associative memory. it “strengthens” a neural connection that has been sufficiently strongly/repeatedly made.
NMDAr inhibitor drugs reduce this effect.
so does schizophrenia
Neurons have “summation” effects.
“spatial summation”—if two neurons stimulate a third, the effect is stronger than if only one did.
“temporal summation”—repeated stimulation has a stronger effect than a one-off.
it is a form of coincidence detection; multiple “simultaneous” events are treated as a bigger deal, less likely to be flukes or errors.
the NMDAr inhibitor dexmethorphan inhibits this effect.
so does schizophrenia.
normal subjects have “prepulse inhibition”, aka the reaction to a loud startling noise is less intense if preceded by a small pulse sound.
this is a form of temporal summation; signals generated by the prepulse accumulate and prepare the brain for further sound, preventing the startle response.
schizophrenics don’t have this; they get startled both ways, indicating (?) that the prepulse sound doesn’t “accumulate” properly.
“desummation” or “cognitive atomization” is like a failure to anticipate; new stimuli are fresh, not expected.
this coincides with the subjective effects of NMDAr inhibitors: at low doses there is “increasing perceptual acuity for things usually unnoticed” and at high doses there is “inability to notice a lot of previously learned meaning”, “inability to recognize familiar stimuli”, added “noise”, and loss of “definition and meaning.”
visual agnosias are a common reported ketamine effect
NMDAr inhibition causes amnesia effects in patients
patients on low-dose ketamine do not retain things they learned while on the drug
“PsychonautWiki lists ‘memory suppression’ as a distinct effect from amnesia as a side effect of NMDAr antagonists. In the description of this effect it notes that short-term memory is suppressed much earlier than long-term memory. At very high doses, the Wiki suggests that one may even forget who they are, where they live, or even a failure to remember what humans are”
impaired short-term memory relates to sensations of unfamiliarity and dissociation (if you can’t remember stuff, you don’t know what it is)
notice that these are plausibly fatal accidents or suicides while under the influence. this is a potential danger of recreational use that won’t show up in stats about medical use or experimental administration to animals.
“from the very first announcement of successes in cloning DNA (the foundational technology of recombinant insulin) in 1973, the first reaction of the National Academy of Sciences and the National Institute of Medicine was to try to stop research into it and, simultaneously, to prevent any patenting of it. The National Institute of Health followed shortly thereafter with their own restrictions, as did a number of cities, including Cambridge and Berkeley, the towns where the universities most likely to do the research were located”
Genentech, a tiny garage startup, was able to escape those restrictions.
https://polypharmacy.substack.com/p/whats-alprazolams-deal alprazolam (Xanax) is reputed to have a fast onset and fast diminution of its anti-anxiety effect, compared to lorazepam (Ativan), making it more abusable and less useful for anxiety disorders. but why? all the theories seem wrong!
also, diazepam (Valium) has exactly the same fast onset/fast diminution, but doctors don’t seem to worry about it the same way!
it looks like the difference isn’t about half-life, elimination, or the blood-brain barrier, but something about ligand-receptor binding.
links 1/8/2025: https://roamresearch.com/#/app/srcpublic/page/01-08-2025
https://neuromatch.io/ company courses & networking opportunities in fields like neuroscience, climate science, AI, etc; matching collaborators
https://birdflurisk.com/ H5N1 risk dashboard
https://www.thetransmitter.org/neuroai/solving-intelligence-requires-new-research-and-funding-models/ the case for big funding of brain mapping & modeling, by David A. Markowitz
“The recent mapping of an entire adult fruit fly brain—a watershed achievement that made headlines worldwide—offers a glimpse of what’s possible. But this breakthrough almost didn’t happen. It required the serendipitous alignment of support from three non-traditional funders: Scientists at the Howard Hughes Medical Institute’s Janelia Research Campus imaged the complete fly brain; the Intelligence Advanced Research Projects Activity drove the development of tools for scalable neural-circuit mapping through its MICrONS program; and the National Institutes of Health BRAIN Initiative provided sustained support for data analysis.”
it might cost $1B to fully map & model the brain. ARPA-style and FRO-style research orgs are essential.
https://www.biorxiv.org/content/10.1101/2024.02.13.580186v4.full if you just use neural nets to model the output of C. elegans’ 302 neurons, bigger networks are better.
continuous-time RNNs scale the best—even better than transformers.
https://www.biorxiv.org/content/10.1101/2024.09.22.614271v2.full
optogenetically perturb each neuron in C. elegans and see what happens to neural output in all 302 neurons
fit this as a simple multivariate dynamical system—each neuron’s output at time t is a linear function of all the neurons’ output at time t-1, plus a linear function of the neurons’ history of optogenetic stimulation, plus error.
compare to a simpler, connectome-constrained model, where each neuron’s output is only a function of its presynaptic input neurons (and direct optogenetic stimulation). this is actually a good approximation!
in fact, it’s better than a fully-connected model, OR a “shuffled-connectome” model based on a made-up C. elegans connectome with similar topological properties to the real one. the true connectome matters.
if you train a connectome model without one neuron, it predicts something about what activity “should” be there. correlation at 0.30 with the real one, much higher than a “fake” connectome model’s correlation with reality.
model weights don’t reflect synapse counts, though. “multi-hop” trajectories have significant influence on correlations (i.e. neuron A and neuron B’s activity may still be highly correlated even if A and B are more than one step away on the “connectome graph”).
it would be shocking if connectomes didn’t matter, so in a sense this is not a surprising set of results; but this is a first example of collecting data with the optogenetic perturbation method, which is a major step towards true neural simulations.
a simulation should be able to predict what every neuron would do under various circumstances.
gathering data on the worms in varying behavioral/environmental contexts could approximate this, but manipulating each neuron one at a time gives a much more thorough picture of the input-output relationships of the nervous system.
https://arxiv.org/abs/2308.06578
roadmap document for full reverse-engineering simulation of the C. elegans nervous system, by Adam Marblestone and many others
includes perturbation!
https://en.m.wikipedia.org/wiki/Asha Zoroastrian concept of “truth” or “right”
https://www.complexsystemspodcast.com/episodes/outside-view-yatharth/ Patrick McKenzie interviewed by Yatharth
https://mad.science.blog/2020/07/07/desummation/ theory that NMDA receptor antagonists’ hallucinogenic and “psychotomimetic” effects come from inhibition of memory.
NMDA receptors (for glutamate) are important in long-term potentiation, in which “a neuron becomes highly sensitive to excitatory transmission for days or weeks” following recurrent stimulation.
long-term potentiation is important in associative memory. it “strengthens” a neural connection that has been sufficiently strongly/repeatedly made.
NMDAr inhibitor drugs reduce this effect.
so does schizophrenia
Neurons have “summation” effects.
“spatial summation”—if two neurons stimulate a third, the effect is stronger than if only one did.
“temporal summation”—repeated stimulation has a stronger effect than a one-off.
it is a form of coincidence detection; multiple “simultaneous” events are treated as a bigger deal, less likely to be flukes or errors.
the NMDAr inhibitor dexmethorphan inhibits this effect.
so does schizophrenia.
normal subjects have “prepulse inhibition”, aka the reaction to a loud startling noise is less intense if preceded by a small pulse sound.
this is a form of temporal summation; signals generated by the prepulse accumulate and prepare the brain for further sound, preventing the startle response.
schizophrenics don’t have this; they get startled both ways, indicating (?) that the prepulse sound doesn’t “accumulate” properly.
“desummation” or “cognitive atomization” is like a failure to anticipate; new stimuli are fresh, not expected.
this coincides with the subjective effects of NMDAr inhibitors: at low doses there is “increasing perceptual acuity for things usually unnoticed” and at high doses there is “inability to notice a lot of previously learned meaning”, “inability to recognize familiar stimuli”, added “noise”, and loss of “definition and meaning.”
visual agnosias are a common reported ketamine effect
NMDAr inhibition causes amnesia effects in patients
patients on low-dose ketamine do not retain things they learned while on the drug
“PsychonautWiki lists ‘memory suppression’ as a distinct effect from amnesia as a side effect of NMDAr antagonists. In the description of this effect it notes that short-term memory is suppressed much earlier than long-term memory. At very high doses, the Wiki suggests that one may even forget who they are, where they live, or even a failure to remember what humans are”
impaired short-term memory relates to sensations of unfamiliarity and dissociation (if you can’t remember stuff, you don’t know what it is)
https://en.wikipedia.org/wiki/Autostereogram
excellent explanation of how “magic eye” pictures work; i can now see them for the first time in my life!
https://smoothbrains.net/posts/2023-08-01-ketamine.html personal experience with ketamine
effects:
visual agnosias, “2D vision”, loss of “egocentric coordinates” in spatial perception, “expanded” awareness
music perception is different—complex music is confusing, repetitive drones are hypnotic
tactile feelings are pleasurable, muscle tension is strongly reduced
aversions are dampened, in particular by making them slower—from the usual “100 ms” to “500 ms”.
celebrity cases of ketamine deaths:
https://www.nbcnews.com/news/us-news/arrests-made-connection-accidental-death-actor-matthew-perry-rcna166676 Matthew Perry, found face down in a heated pool
https://en.wikipedia.org/wiki/Gary_Frisch Gary Frisch, found dead beneath an 8th floor window with ketamine in his blood and liver
notice that these are plausibly fatal accidents or suicides while under the influence. this is a potential danger of recreational use that won’t show up in stats about medical use or experimental administration to animals.
https://www.quantamagazine.org/elliptic-curve-murmurations-found-with-ai-take-flight-20240305/ wavy “murmurations” found in elliptic curves with machine-learning algorithms
https://www.quantamagazine.org/behold-modular-forms-the-fifth-fundamental-operation-of-math-20230921/ modular forms!
https://trevorklee.substack.com/p/regulators-almost-killed-biotech
“from the very first announcement of successes in cloning DNA (the foundational technology of recombinant insulin) in 1973, the first reaction of the National Academy of Sciences and the National Institute of Medicine was to try to stop research into it and, simultaneously, to prevent any patenting of it. The National Institute of Health followed shortly thereafter with their own restrictions, as did a number of cities, including Cambridge and Berkeley, the towns where the universities most likely to do the research were located”
Genentech, a tiny garage startup, was able to escape those restrictions.
https://polypharmacy.substack.com/p/whats-alprazolams-deal alprazolam (Xanax) is reputed to have a fast onset and fast diminution of its anti-anxiety effect, compared to lorazepam (Ativan), making it more abusable and less useful for anxiety disorders. but why? all the theories seem wrong!
also, diazepam (Valium) has exactly the same fast onset/fast diminution, but doctors don’t seem to worry about it the same way!
it looks like the difference isn’t about half-life, elimination, or the blood-brain barrier, but something about ligand-receptor binding.