# Model of psychosis, take 2

*(I am not by any stretch of the imagination an expert on psychosis. This is more like “live-blogging my thinking as I go”. I’m hoping to spur discussion and get feedback and pointers.)*

1\. Introduction
================

I suggested a model of psychosis in my blog post [“Schizophrenia as a deficiency in long-range cortex-to-cortex communication”, Section 4.2](https://www.lesswrong.com/posts/H2epKysvFgPcTwC2f/schizophrenia-as-a-deficiency-in-long-range-cortex-to-cortex) last February. But it had some problems. I finally got around to taking another look, and I think I found an easy way to fix those problems. So this post is the updated version.

**For the tl;dr, you can skip the text and just look at the two diagrams below**.

2\. Background: My “Model of psychosis, take 1” from earlier
============================================================

The following is what I was proposing in [“Schizophrenia as a deficiency in long-range cortex-to-cortex communication”, Section 4.2](https://www.lesswrong.com/posts/H2epKysvFgPcTwC2f/schizophrenia-as-a-deficiency-in-long-range-cortex-to-cortex):

![](https://39669.cdn.cke-cs.com/rQvD3VnunXZu34m86e5f/images/5e4adb1d8ac02dee95b14789d7a16161d4cde5331ac964fc.png)

The idea is that, in psychosis, the green arrow is active and effective, but the red arrow isn’t, and therefore neither is the purple arrow. The result might be a kind of feeling that my arm was moved by an external force. That’s just one example—for different types of cortical outputs on the left, the corresponding first-person experience of psychosis would be different. But I claim that all symptoms of psychosis broadly fit into this template (update: I elaborated on “all symptoms of psychosis” in [this comment](https://www.lesswrong.com/posts/tgaD4YnpGBhGGbAy5/model-of-psychosis-take-2?commentId=k2BKxswCuCsesihMv) and also [Section 7.5 of this later post](https://www.lesswrong.com/s/qhdHbCJ3PYesL9dde/p/k8uMmw45k3qp8LPNc#7_5_Hallucinations_and_delusions_via_disjointed_cognition__schizophrenia___mania_)).

3\. Three areas where that first model seemed to be missing something important
===============================================================================

*   As I understand it, psychosis can come and go in people with schizophrenia, whereas (I believe) the deficiency in cortex-to-cortex communication is characteristic of schizophrenic brains, and is structural and permanent (absent future advances in medical technology).
*   Antipsychotics reduce psychosis, but the diagram above offers no way to explain that.
*   Psychosis can occur in other conditions besides schizophrenia. I think the most common example is the manic phase of bipolar. The diagram above cannot explain that.

4\. My “Model of psychosis, take 2”
===================================

*(The only change to the top part of the diagram is the new green text on the left that says “Signal strength = **B**”.)*

![](https://39669.cdn.cke-cs.com/rQvD3VnunXZu34m86e5f/images/0d73a0fc4116622530bb1cc8cbf867c8df766089dde8bab0.png)

Think of a part of the cortex as having an adjustable “volume”, in terms of how strongly and clearly it is announcing what it’s up to right now. For example, if the thought crosses your mind that *maybe* you *might* move your finger, then you might find (if you look closely and/or use scientific equipment) that your finger twitches a bit, whereas if you strongly intend to move your finger, then your finger will actually move.

![](https://39669.cdn.cke-cs.com/rQvD3VnunXZu34m86e5f/images/a99f6fbe1e3b8453c9f04c44b85b44ddef7bf8569272694f.png)

The illustrated configuration would be a situation where psychotic delusions could happen.

Anyway, imagine a big black analog slider for the “volume” of some part of cortex (“Cortex Area 1” in that diagram).

*   Make a mark next to the slider at the volume threshold where Cortex Area 1 is “shouting” loud enough that its **A** messages start getting through and having an effect.
*   Separately, Make a mark at the volume threshold where Cortex Area 1 is “shouting” loud enough that its **B** messages start getting through and having an effect.

…To avoid psychosis, we want the A mark to be at a *lower* volume setting than the B mark. That way, there will be no possible “volume level” in which the **B** messages are transmitting but the **A** messages are not.

(UPDATE: A bit more discussion in [Section 7.5 of this later post](https://www.lesswrong.com/s/qhdHbCJ3PYesL9dde/p/k8uMmw45k3qp8LPNc#7_5_Hallucinations_and_delusions_via_disjointed_cognition__schizophrenia___mania_).)

5\. Nice things about this new model
====================================

5.1 Slow variations in the **B/A** ratio are at least *a priori* plausible, because **B** & **A** come from different neurons in different cortical layers (Layer 5 and Layer 2/3 respectively)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

I think it’s very plausible that the ratio **B/A** is a parameter that can vary, because:

*   Signal **B** is sent exclusively by a subset of neurons in **Layer 5** of the cortex
*   Signal **A** is sent at least partly (and maybe mostly?) by a subset of neurons in **Layer 2/3** of the cortex
*   In general, different cortical layers have different types of neurons with different inputs, different relations to the dopamine system, etc.

So, a theory that involves long-term variation in the **B/A** ratio is at least *plausible*.

5.2 At least one paper seems to suggest that antipsychotics are better at suppressing layer 5 signals than layer 2/3 signals
----------------------------------------------------------------------------------------------------------------------------

See [Heindorf & Keller 2023](https://elifesciences.org/reviewed-preprints/86805). They found that “clozapine…decreased correlations of cortical activity in \[layer 2/3\] excitatory neurons. However, this reduction was significantly weaker than the reduction we observed in … \[layer 5 intratelencephalic\] neurons”. (The p-values for this particular comparison were $p < 0.005$ for short-range correlations and $p < 10^{-8}$ for long-range).

If I’m understanding the paper correctly (a big “if”!), this is suggestive and encouraging, but not *clear* support for my theory, because, first of all, that paper was measuring the wrong type of layer 5 pyramidal neurons compared to the ones sending Signal **B**, and second of all, the kind of correlation that the authors were measuring *could* be caused by the layer 5 neurons having weak signals in general (such that spatial correlations quickly fall below the noise floor) but there are other possible causes too (*directly* related to spatial correlations—I think that’s what the authors believe is going on).

6\. Things I’m still unsure about
=================================

6.1 Which D2 receptors explain how antipsychotics work?
-------------------------------------------------------

The thing that every antipsychotic has in common is blocking dopamine D2 receptors. So presumably that’s how they work. But there are D2 receptors in neurons all over the brain. Presumably, a subset of those neurons-with-D2-receptors are the secret to how antipsychotics work, and the rest are related only to side effects. Which is which?

When I try to flesh out my model, the most simple and elegant story that I’ve thought of so far involves D2 receptors *in the cortex* playing the starring role. In particular, different cortical layers have different densities of D2 receptors, and the sign seems to be correct for antipsychotics to decrease the **B/A** ratio, if I’m not mistaken.

But that’s funny because practically everyone else seems to think that D2 receptors *in the striatum* are how antipsychotics work, I think? I was trying to figure out why people seem to believe that, but couldn’t figure it out. All the evidence I could find for antipsychotics working via the striatum was pretty weak and indirect. Please comment (or email me) if you know anything about this.[^30kgi54wlos]

6.2 What about other causes of psychosis?
-----------------------------------------

For various reasons, I have a sorta vague rule-of-thumb in my head that, other things equal, more dopamine tends to increase the **B/A** ratio (and hence, beyond some threshold, to cause psychosis). That seems to nicely explain the psychosis associated with mania (I loosely associate mania with “lotsa dopamine”, at least in certain channels and with various caveats), and the fact that psychosis is a side-effect of L-DOPA treatment for Parkinson’s.

I’m more confused about psychotic depression. (In bipolar, I understand that psychosis is much more common in mania than depression, but it *can* happen in depression.) I normally think of depression as the “opposite” of mania, and involving unusually *little* dopamine, again in certain channels and with various caveats. So I’m a bit confused that psychotic depression can happen at all. I dunno. The dopamine system is just one of many things that has an impact on the **B/A** ratio anyway. Or maybe the purple signal on the right side of the diagram above isn’t getting through? Or maybe all the things I just said about dopamine are too oversimplified? Or maybe it’s a different story entirely.

(UPDATE OCT 2024: I now think that psychotic depression is “a different story entirely”. I think the delusions are just a stronger version of [emotional reasoning](https://en.wikipedia.org/wiki/Emotional_reasoning), and the occasional hallucinations are a generic consequence of bursts of strong emotion. See [Section 7.6 of this later post](https://www.lesswrong.com/s/qhdHbCJ3PYesL9dde/p/k8uMmw45k3qp8LPNc#7_6_Hallucinations_and_delusions_via_strong_emotions__BPD___psychotic_depression_) for details.) 

[^30kgi54wlos]: Update 2023-08-24: A friend sent me this paper (free version) which seems to support my tentative beliefs that both (1) it is currently conventional wisdom that antipsychotics work by preventing dopamine from inhibiting D2-receptor striatal neurons, and (2) this conventional wisdom is wrong. …If I’m understanding it correctly. Thanks for the tip, and keep ’em coming!