(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.)
I suggested a model of psychosis in my blog post “Schizophrenia as a deficiency in long-range cortex-to-cortex communication”, Section 4.2 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.
The following is what I was proposing in “Schizophrenia as a deficiency in long-range cortex-to-cortex communication”, Section 4.2:
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).
(The only change to the top part of the diagram is the new green text on the left that says “Signal strength = B”.)
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.
Anyway, if we gradually increase the “volume” of a part of cortex, then at some point in time the A messages will start getting through and having an effect, and meanwhile at some other point in time the B messages will start getting through and having an effect. To avoid psychosis, we want the former to happen first, and the latter second, such that there is no possible “volume level” in which the B messages are transmitting but the A messages are not.
I think it’s very plausible that the ratio B/A is a parameter that can vary, because:
So, a theory that involves long-term variation in the B/A ratio is at least plausible.
See Heindorf & Keller 2023. 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).
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.
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 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!
An interesting theory! But I am confused by why you think that antipsychotics can’t act simply by increasing the strength of A-type signals. Why do they also have to affect the B-type signals? if A signals are disproportionately inhibitory, that would account for why a notorious side-effect of antipsychotics is stiffness and a general reluctance to do stuff. Your claim that the relapsing-remitting nature of schizophrenia doesn’t fit your first theory seems excessive. Lots of nerve problems are relapsing-remitting (eg mutiple sclerosis). And changes to the the balance of the brain that take weeks are very common (eg antidepressant efficacy, or heroin addiction).
An under activity of long-range fibers could perhaps explain the many abnormalities of visual perception seen in schizophrenics. This is a field full of odd symptoms, with as far as I know no unifying theory.
It seems like you’re only trying to explain one symptom of psychosis: the delusion of an external locus of control. Could you extend your theory to explain other symptoms? For example, how do you explain hallucination, where somebody has a sensory impression that they know isn’t real (at least with mild psychosis). It seems like hearing voices is an overactivity of the connection from the language area to consciousness, rather than an underactivity.
Another major symptom that might be explained by your theory is delusions of reference, where stimuli that should be treated as minor are instead freighted with importance. Like “What is the ad on that bus that just drove by trying to tell me? Could it have been sent by God?” It’s not obvious what the cortical areas that are involved in this are. But you’re lots more informed than me; what do you think?
Thanks for your helpful comment!
But I am confused by why you think that antipsychotics can’t act simply by increasing the strength of A-type signals.
I think schizophrenia is characterized by a deficiency in long-range cortex-to-cortex communication, and I suppose that this deficiency can have a variety of causes in principle. For example, it was found in lab experiments that faulty glutamate signaling can cause schizophrenia—hence “the glutamate hypothesis of schizophrenia” which has been floating around for many decades. But that hypothesis never led to any viable drugs. And I think that’s because faulty glutamate signaling is not the usual cause of the deficiency.
Instead, I think in practice the deficiency is almost always caused by the long-range fibers (and/or their terminal synapses) just not being there in the first place, or at least not in sufficient numbers. I mention some direct evidence for that in section 5 of my previous post.
So basically, I think that cortex-to-cortex communication is just going down a lousy communication channel (noisy / low-bandwidth / low-ability-to-impact-downstream-areas / whatever). And that that problem is basically unfixable in almost all schizophrenic people, absent miraculous future medical advances. And it’s not the kind of problem that I expect to come and go, I think. It's structural.
But that communication channel, lousy as it is, can still transmit the information if the source-cortex is “shouting” long enough and loud enough. So I think the only viable approach that treating psychosis is to reduce the ratio B/A.
if A signals are disproportionately inhibitory, that would account for why a notorious side-effect of antipsychotics is stiffness and a general reluctance to do stuff.
Not sure about stiffness but “general reluctance to do stuff” is totally what I would expect from “less B”. I don’t follow how you connect it to A.
An under activity of long-range fibers could perhaps explain the many abnormalities of visual perception seen in schizophrenics.
I think so! I have an example in my previous post.
It seems like you’re only trying to explain one symptom of psychosis
Yeah, moving my arm is just one of many types of cortical output.
Another is subvocalizing / inner speech. I don’t understand all the details, but AFAICT producing a subvocalization involves sending signals to brainstem motor areas, and “hearing” your own subvocalization “activates similar areas of the auditory cortex that are involved in listening” (wiki). So my working hypothesis is that “hearing voices” in psychosis involves inner speech feeling like it’s external. Same diagram. (Low confidence though—again, I’m kinda confused about the mechanics of inner speech / subvocalization.)
Yet another type of cortical output is “attentional”—one part of the cortex can exert (metacognitive) control over the information flows and activities of other parts of the cortex (via signals to various subcortical areas). If you visualize a pen, it activates the same neurons in your temporal lobe as if you see a similar pen. You can flip back and forth by (among other things) voluntary metacognitive control. Nevertheless, for a neurotypical person, you don’t get confused about whether the thing you’re attending to is real or imagined. But I think things can get very screwy when one part of the cortex is manipulating the levers on metacognition / attention-control, and other parts of the cortex are not getting advanced notice that this metacognition / attention-control is happening. So basically, I think a visual hallucination would happen when the metacognitive / attention-control parts of the cortex (prefrontal probably) set part of the visual system (temporal lobe) to imagination-mode rather than attend-to-what’s-in-front-of-you mode, but other parts of the cortex don’t get the memo that we’re in imagination-mode right now, and they interpret the (imagined) current contents of the visual system as a reflection of what’s directly in sight and coming up through V1/V2/etc.
(Or something like that.)