Psilocybin, a neural connectivity paradox

[Mindlusion]

Many of you might have come across this paper: From the Cover: Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin
The fMRI study with psilocybin. It is very often posted in psychedelic news posts, social media, etc. It's a popular study.

Conclusions from fMRI study are essentially:

As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects.

And then the Aldous Huxley assumption:

These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Recently, I stumbled on another paper, that I hadn't seen before, maybe some of you have though, I will attach it below.

This study takes a look at networks, rather than overall brain activity:

Here, we study the characteristics of functional brain networks at the
mesoscopic level from a novel perspective that highlights the role of inhomogeneities
in the fabric of functional connections. This can be done by focusing
on the features of a set of topological objects—homological cycles—associated
with the weighted functional network.

As a proof of principle, we apply these tools to compare resting-state
functional brain activity in 15 healthy volunteers after intravenous infusion
of placebo and psilocybin—the main psychoactive component of magic mushrooms.
The results show that the homological structure of the brain’s functional
patterns undergoes a dramatic change post-psilocybin, characterized by the
appearance of many transient structures of low stability and of a small
number of persistent ones that are not observed in the case of placebo.

I find this extremely fascinating, because it correlates with my underlying assumption. The state induced by psilocybin doesn't just disrupt normal brain connectivity to result in decreased overall activity, but it introduces a new network, one with it's own reproducible structure. A fundamentally different processing network.

I said in the title it is a paradox, but it is not really, just seems to be based on my limited understanding. Losing connectivity, at the same time gaining it, in some way or another.

Let me know what you think!

 

[brilliantlydim]

Greater efficiency perhaps?

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~ND

 

[pau]

!!! A biochemist (at UC Berkeley, for what it's worth) explained to me in 1975 almost exactly the same thing. Always made good sense.

 

[anon_003]

This is some fascinating stuff, thanks for sharing!!! And Nathanial, thank you for elaborating a bit. You made that very easy to understand. Do you speculate that LSD works in a similar fashion, moving the brain to a more entropically chaotic state?


In addition, there is a theory on consciousness called Integrated Information Theory that I, as a completely not knowledgeable speculator, am a fan of. Examining the topic at hand through the lens of integrated information theory has been quite fun. For those who haven't heard about it, here is a very sensationalist but easily digestable read up, Integrated Information Theory article - WIRED

For a little more thorough of a read up on IIT, check out An information integration theory of consciousness.

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~ND

 

[entheogenic-gnosis]

These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Correct me if I'm wrong, but my understanding was that all the signals entering the brain (except smell) do so via the thalamus, the thalamus then "filters" these signals down to the essentials which it then sends to the cortex regions, the cortex region is where higher processing occurs, now, it's true that psychedelics are "shutting down" parts of the brain, the part of the brain it's mainly "shutting down" is the thalamus, the filter, so you go from getting a filtered section of signals to build into reality, to getting all the signals entering the body...your basically switching off a filter...

...but again, I'm learning chemistry, and I only have a very basic understanding of physiology, so I'm not sure how accurate these statements are...

Also in this lecture

or maybe it was this one

David e. Nichols discusses The raphe nuclei as "firing" while your awake, and slowing as you get tired, then stopping when you sleep. He goes on to explain how while on psychedelics your brain is "fully awake" though your raphe nuclei have stopped "firing", so in a sense your conscious while parts of your brain are in a deep sleep stage...

Again I apologize for my lack of knowledge in this area, and was merely trying to confirm if the above assumptions are accurate, or if I'm misunderstanding the situation entirely...

-eg

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~ND

 

[Warrior]

I find this extremely fascinating, because it correlates with my underlying assumption. The state induced by psilocybin doesn't just disrupt normal brain connectivity to result in decreased overall activity, but it introduces a new network, one with it's own reproducible structure. A fundamentally different processing network.

I said in the title it is a paradox, but it is not really, just seems to be based on my limited understanding. Losing connectivity, at the same time gaining it, in some way or another.

I'm not sure I see the paradox. The default mode network goes quiet, and another network stabilizes in its own dynamical phase space.

Years ago I was working on a behavioral experiment involving a 3-dimensional central pattern generator and it's potential for a multitude of behaviors. In the intact animal we observed 5 distinct behaviors emerge from pattern changes in firing from 3 neurons. Our modeling predicted 17 possible behaviors. What were they? We had no idea, but the system of ODEs predicted they were already hardwired and possible. We could account for swimming, crawling, feeding, mating, and a crude hunting behavior. What the heck else could it do? No one had any idea. We could remove the nervous system, and under a variety of conditions, record firing patterns that our modeling predicted, but we were unable to reproduce it in an intact animal.

For all I know it could have been telepathic, higher dimensional, or maybe it can play a musical instrument! Who knows... Anything magical or mundane. The point is, even a simple animal with a simple nervous system, we have no idea what it is capable of. We have no idea what conditions must arise to see novel behavior emerge in response.

So when it comes to the human brain.... Holy Moly! We have no idea what we've wired ourselves for over the last 100k years. No idea! We have NO IDEA what we are capable of. It's stupid to think we're even beginning to figure it all out. With every question we answer, another 1000 questions emerges. That's the fractal pattern of scientific discovery for you.

 

[Warrior]

Because I'm a geometrically minded person, I like to think of the possible states of the brain represented in some kind of polydimensional phase space (Tononi proposed something similar with his hypothetical 'qualia space' ), with different basins of attraction representing different states of consciousness. If you're stuck in a deep basin (say, depression), you might find it very difficult to get out, so if you take psilocybin, you get artificially punted up the entropy scale, and will hopefully roll back down into a healthier basin.

Sounds like a Boltzmann machine!

 

[Nathanial.Dread]

Because I'm a geometrically minded person, I like to think of the possible states of the brain represented in some kind of polydimensional phase space (Tononi proposed something similar with his hypothetical 'qualia space' ), with different basins of attraction representing different states of consciousness. If you're stuck in a deep basin (say, depression), you might find it very difficult to get out, so if you take psilocybin, you get artificially punted up the entropy scale, and will hopefully roll back down into a healthier basin.

Sounds like a Boltzmann machine!

:thumb_up:

I'm curious, do you do neuroscience research?

Blessings
~ND

 

[ॐ]

I've been meaning to open a new thread for discussing something very similar to this.
With the new research on psilocybin and the default mode network, I'm wondering how Aldous Huxley's theory of "mind at large" with the brain acting as a reducing valve rather than a generator of consciousness measures up now. The new findings sure seem to support much of what he described way back when, although I'm not the person to jump on conclusions like these that quickly. Moreover, I'm not a neuroscientist, so I don't know what is necessarily proof or still speculation. What do you think?

All of this seems to carry some very heavy implications in terms of world-view, yet it doesn't seem to be shocking world news for most

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~ND

 

[Chan]

This has some interesting implications: for example, the Amazon rainforest may, in fact, be "more conscious" than a single human (especially since there are humans who are part of the rainforest), even though the rainforest is probably not capable of language. It may have a completely different set of conscious percepts that we wouldn't recognize.

The idea that consciousness is an emergent function of any living network really resonates with me. A series of deep salvia trips seemed to emphasise this possibility. Obviously the rain-forest isn't capable of "speech" as we understand it, but there's clearly a vast amount of signalling (primarily chemical) going on which I imagine is more than capable of carrying messages, information and even instructions. And as Wittgenstein said, even if a lion could talk, we would not necessarily be able to understand it, because we don't have any access/insight to the world as experienced by a lion, let alone the Amazon. Nature is all about scaling functionality, and re-using components, and I think it is only a pernicious case of exceptionalism which has led us down the frankly unconvincing path which suggests that only humans, and maybe a few other primates and whales have anything like 'proper' consciousness. I can easily imagine a smooth continuum running all the way from a single amoeba, to yes, even Gaia.

Serotonin, and other neurotransmitters (and psychedelics of course :d ) were created by plants hundreds of millions of years before humans showed up to the party, and primarily for signalling purposes it would appear. I see parallels in how mainstream science has only recently come to acknowledge that the gut-brain axis is actually a thing, say, despite aspects of it being common figures of speech, throughout the world, for millennia. Bearing in mind the concepts in the Vedic texts, I think the default position should be "things are connected, and probably communicating with one another too, except where this is clearly impossible." This is possibly why "reductivist" is often used pejoratively now. An approach based primarily on dissection, isolation and reduction is probably unsuited to studying complex, interdependent systems, in the same way as a microscope makes a poor view-finder.

It might even go some way to explaining why 'divide and conquer' works so well as a strategy, but that's a whole other pan of haddock...

 

[entheogenic-gnosis]

These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Correct me if I'm wrong, but my understanding was that all the signals entering the brain (except smell) do so via the thalamus, the thalamus then "filters" these signals down to the essentials which it then sends to the cortex regions, the cortex region is where higher processing occurs, now, it's true that psychedelics are "shutting down" parts of the brain, the part of the brain it's mainly "shutting down" is the thalamus, the filter, so you go from getting a filtered section of signals to build into reality, to getting all the signals entering the body...your basically switching off a filter...

...but again, I'm learning chemistry, and I only have a very basic understanding of physiology, so I'm not sure how accurate these statements are...

Also in this lecture

or maybe it was this one

David e. Nichols discusses The raphe nuclei as "firing" while your awake, and slowing as you get tired, then stopping when you sleep. He goes on to explain how while on psychedelics your brain is "fully awake" though your raphe nuclei have stopped "firing", so in a sense your conscious while parts of your brain are in a deep sleep stage...

Again I apologize for my lack of knowledge in this area, and was merely trying to confirm if the above assumptions are accurate, or if I'm misunderstanding the situation entirely...

-eg

The effect of psychedelics on whole-brain connectivity is a different topic than their effects on thalamic sensory gating. Both are taking place, and they may be mechanistically related, but you can, in theory, discuss one without touching on the other.

My theory is that it's a 1-2 Punch: thalamic sensory gating is inhibited, which allows more information into the brain, and that information is then processed in radically novel ways by the increased functional connectivity of the neocortex.

I think the 5-HT2A receptor acts as a kind of 'gating' mechanism, for the salience of a particular signal. If the receptor is activated, the neuron is depolarized, increasing the odds that it will fire. This means that a less salient signal still has a chance of getting over the action potential, when ordinarily it wouldn't.

For thalamic serotonergic neurons, that means that stimuli that would ordinarily get filtered out are allowed through, and for the Layer V pyramidal neurons, that means that signals get access to other cortical regions that they ordinarily wouldn't.

Does that make sense?

Blessings
~ND

Yeah, that coincides with my initial understandings.



----

Huxley seems to have predicted the phenomena of sensory gating, which is the mechanism by which the brain filters out redundant or irrelevant information. A simple example of this is 'prepulse inhibition,' which is an effect seen when you play two beep sounds close together. Most people (unless they're schizophrenic, or on psychedelics), will only here one beep, because the brain edits out the other one since it's redundant.

Huxley was 100% correct as far as I can tell. When Huxley speaks of his "consciousness valve", he is giving a basic description of "thalamic gating"

To make biological survival possible, Mind at Large has to be funneled through the reducing valve of the brain and nervous system. What comes out at the other end is a measly trickle of the kind of consciousness which will help us to stay alive on the surface of this Particular planet. -huxley

-----

I've been particularly fascinated by the raphe nuclei and their functioning while under the influence of psychedelic drugs...

Neurophysiological effects of hallucinogens on serotonergic neuronal systems.
McCall RB.

Abstract
Low intravenous doses of the hallucinogen d-lysergic acid diethylamide (LSD) markedly suppress the discharge of serotonin (5-HT)-containing neurons in the dorsal raphe nucleus of the rat. Microiontophoretically applied LSD also inhibits the firing of 5-HT neurons, indicating that the inhibitory effect is mediated directing on 5-HT neurons. Forebrain neurons receiving a major serotonergic input are relatively insensitive to LSD. Other indole hallucinogens (i.e., psilocin, dimethyltryptamine, and 5-methoxydimethyltryptamine) also preferentially inhibit raphe firing as compared to postsynaptic forebrain neurons. These observations led to the hypothesis that hallucinogens produce their psychoactive effects by acting preferentially upon 5-HT autoreceptors in the dorsal raphe allowing postsynaptic neurons to escape from the tonic inhibitory action of 5-HT neurons. However, problems exist with the concept that hallucinogens produce their psychoactive effects by disinhibiting postsynaptic neurons. First, the time course of the behavioral and neuronal effects of LSD do not correlate. Second, 5-HT neurons do not become tolerant to the inhibitory actions of LSD. Third, the hallucinogen mescaline fails to directly inhibit 5-HT neurons. Finally, the nonhallucinogen lisuride markedly suppresses the discharges of 5-HT neurons. These observations suggest that postsynaptic actions of hallucinogens may be of prime importance in producing their psychedelic effects. Evidence is presented to suggest that the hallucinogens may act postsynaptically to sensitize both serotonergic and noradrenergic receptors. It is suggested that a mechanism of receptor sensitization, in distinction to disinhibition, might account for the altered perceptual reactivity produced by these drugs.

Neurophysiological effects of hallucinogens on serotonergic neuronal systems - PubMed

-eg

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~Thomas

 

[Warrior]

Sounds like a Boltzmann machine!

:thumb_up:

I'm curious, do you do neuroscience research?

Inspired:

What was, what is, what will be?
States of being, states of mind.
Paths.
Labels.
Hierarchy.
Order.
The competitive game of life.
Love of a field doesn't die,
Even if you pass it by.

 

[entheogenic-gnosis]

The raphe nuclei are certainly interesting, although it has been shown that expression of the 5-HT2A R on Layer V pyramidal neurons is both necessary and sufficient to induce psychedelic effects in animal models (Gonzalez-Maeso et al., 2007). I think it's probably a mixture of many things, but it's those pyramidal neurons that are doing the brunt of the work, I think.

Blessings

Hmmm...
That article says:

All known drugs of this class [psychedelics] are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties

Meaning all psychedelics are agonists of the serotonin-2a receptor (5ht2a), but that compounds such as lisuride, hit many of the same receptors yet produces no psychedelic action..

Lisuride is a dopamine and a partial agonist for several serotonin receptors. It is an antagonist at the serotonin 5-HT2B receptor.[1] It has a high affinity for the dopamine D2, D3 and D4 receptors, as well as serotonin 5-HT1A[2] and 5-HT2A/C receptors.[3] While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoloid N,N-diethyl-lysergamide (LSD) and inhibits dorsal raphe serotonergic neurons in a similar fashion to LSD,[4] it lacks the psychedelic effects of its sister compound -Wikipedia

Lisuride also inhibits the firing of the raphe nuclei! Yet no psychedelic effect...

So why is it that thalamic gating and inhibition of dorsal raphe serotonergic neurons is not sufficient to induce psychedelia? Specially when the keys actions observed by psychedelics involve thalamic gating and inhibition of dorsal raphe serotonergic neurons?

I've been learning about the 5ht2a and 5ht2c receptors, these receptors are composed of alpha-helical proteins, these proteins are made to "bend" into a specific shape when interacting with serotonin, now when compounds similar to serotonin hit the receptor, the generally will fit the initial shape of serotonin, but any extra "bumps" and "edges" provided to a serotonin similar molecule's unique shape, will "bend" the helecies into a different shape, thus producing a different action...it's amazing, these receptors are not simple on/off switches, and are amenable to all sorts of manipulation...

This is what amazes me,

Your bombarded with some outrageous number, like 12 billion, signals per second, all of which enter the thalamus (except smell), the thalamus then filters these signals down to the survival essentials, which are then sent to the cortex regions, this is where higher processing occurs, where your intellectual processing occurs, when on a psychedelic, the thalamus's filtering ability is enabled, your put into a highly receptive state...This action is mediate by 5ht2a + 5ht2c receptors which connect the thalamus to the cortex regions...thalamic gating

simultaneously your raphe nuclei have stopped firing. While your awake your raphe nuclei are consistently firing, as you tire, they begin to slow their firing, and when your asleep they completely stop firing. This inhibition of dorsal raphe serotonergic neurons firing is identical to how they would be functioning in deep sleep...

There's a good deal going on while your on a psychedelic...

It's funny though, as that paper that was posted by nd explains, we can induce these same physiological actions and still fail to produce psychedelia...

So, so far It's 5ht2A/C receptor agonism, thalamic gating, and your raphe nuclei stop firing...I'm.I missing anything?

The above lectures are great, David E. Nichols is a great teacher.

-eg

 

[entheogenic-gnosis]

Entheogens, the Conscious Brain and Existential Reality

There was some fairly cool stuff in the above link.

I'm a chemistry student, I'm also fascinated by psychedelics, so in turn I end up having to learn a good deal of physiology and pharmocology...

I apologize for my lack of knowledge here, please bare with me as I'm still learning...

I've also put all my academic ventures on hold to focus on spirituality, and have not been very active in my studies.

...Though this fascinates me.

Dr. David Nutt and Dr. Robin Carhart-Harris did fmri work in 2013 regarding psilocybin, and are doing work regarding LSD, however, it's been a while since I've followed this research, and I have some catching up to do...

Scientists crowd-funding the first ever LSD brain imaging study

Scientists led by David Nutt are producing the world's first images of human brains on LSD, and using crowd-funding to do it.

psychedelicfrontier.com

-eg

 

[Nathanial.Dread]

EDIT - Removed

Blessings
~ND