(Written in a hurry. I was almost going to title this “My poorly-researched pet theory of schizophrenia”. Hoping for feedback and pointers to relevant prior literature. I am very far from a schizophrenia expert. Really. I cannot emphasize this enough. Like, if I took an undergraduate psych test on schizophrenia right now, I might well flunk it.)

1. What’s my hypothesis?

My hypothesis is that the root cause of schizophrenia is (…drumroll…) a deficiency in medium- to long-range cortex-to-cortex connections. Some elaboration:

  • When I say “deficiency”, I mean either “the connections aren’t there in their normal numbers” or “the connections are there, but for some reason they’re not accomplishing what they accomplish in neurotypical people”.
  • When I say “cortex-to-cortex connections”, I think the main culprit is direct connections between Cortex Region A and Cortex Region B, but it’s also possible that the relevant thing is indirect connections between Cortex Region A and Cortex Region B, e.g. via the thalamus or cerebellum.
  • When I say “medium- to long-range”, this definitely includes e.g. connections between different lobes, and it probably also includes connections across a few centimeters of cortex in humans. I haven’t really thought about what would happen if there was a deficiency in all connections of any length, including the very short ones, but I would weakly guess that this would present as schizophrenia as well.

2. How did I originally come up with that hypothesis?

I can pinpoint the exact moment: I was reading about visual processing abnormalities in schizophrenia, and more specifically the paper Weak Suppression of Visual Context in Chronic Schizophrenia (Dakin, Carlin, Hemsley 2005). They showed people pictures like this:

The task was to match the image contrast in the red circle to one of the circles on the left. The eye-popping results were:

  1. the schizophrenics did better than the control group,
  2. …with a p-value of 0.0000002!
  3. Indeed, “12 out of 15 [subjects with schizophrenia] were more accurate than the most-accurate control.”
  4. …i.e., there were only three subjects with schizophrenia who did not outperform each and every one of the 33 people in the control groups. And one of those three was later re-diagnosed as not schizophrenic after all!

Back to the task, the control group gets misled by the contrast level outside of the red circle, and the schizophrenic group didn’t. Here’s how I interpreted that:

Each part of the visual cortex is trying to make sense of (more specifically, predict) the sensory inputs that it’s getting. To do a good job at that task, in normal life, it’s helpful to take account of information happening elsewhere in the visual field. After all, distant parts of the visual field are conveying information about ambient light levels, textures and slopes, and things like that. When a neurotypical person grows up viewing naturalistic images, they form lots of predictive models that are near-optimally incorporating all that distant “context” information, pulled in from all across the visual cortex and maybe elsewhere in the brain too. And that screws them up in this particular task. The goal of this task is to ignore all context and look at the red circle contents in isolation. The visual system does not have a set of predictive models that are tailored for accomplishing this task, so the control groups tend to do poorly.

But schizophrenics are succeeding at the same task. Why? Well, presumably for them, the distant “context” information is not available in the first place. So their visual cortex is generally unable to leverage it for better predictive models. This makes their sensory predictions generally worse in a naturalistic setting. But it allows them to do better in this unnatural setting, where the contextual information is only there to trip them up.

3. Is this an existing hypothesis in the literature?

I assume by default that everything I have ever written about neuroscience is either unoriginal or wrong. (Sometimes both!)

I haven’t seen anyone write down a hypothesis superficially similar to the above, as far as I can recall. But I haven’t really gone looking for it either.

It does seem to have significant overlap with Dehaene’s theory that schizophrenia is a “disease of consciousness”. I’ll get back to that at the end. I would suggest that readers interested in the literature around these ideas should maybe consider starting with Dehaene’s schizophrenia discussions, and the papers that he cites, and papers that cite him, etc. Let me know what you find.

If you know of other relevant discussion, please share in the comments!

4. Does this hypothesis elegantly explain everything about schizophrenia?

Well, let’s try!

4.1 The onset of schizophrenia is typically in the late-teens-to-twenties

I propose to center this sub-story around synaptic pruning, which suggestively “continues into the late-20s” according to wikipedia. Maybe the symptoms of schizophrenia kick in when there is so little flow of information between different parts of the cortex that they fail to constrain each other—they get out sync, they come unmoored, they start spinning their wheels independently. And maybe there’s kind of a soft threshold of how much information flow between regions is needed to prevent that from happening.

For a 10-year-old, relatively little synaptic pruning has happened so far, so maybe neurotypical people are way way way above that threshold, while future-schizophrenics are “merely” way above that threshold. Then by age 25, everybody has pruned lots of synapses, so the neurotypical people are somewhat above that threshold, while the schizophrenics have fallen below that threshold.

Good story? Yeah, I think it’s a pretty good story—I don’t think it’s special pleading / rationalization. In particular, I was guessing that this was the story before I knew the age range of synaptic pruning, and then when I looked that up, I was surprised and pleased at how good a match it was.

4.2 Positive symptoms—auditory hallucinations (hearing voices), “distortions of self-experience”, etc.

I figure, when a neurotypical person is subvocalizing, there’s communication between the motor cortex parts that are issuing the subvocalization commands (assuming that that’s how subvocalization works, I dunno), and the sensory cortex parts that are detecting the subvocalization which is now happening. Basically, the sensory cortex has ample warning that the subvocalization is coming. It’s not surprised when it arrives.

But in schizophrenia, different parts of the cortex can’t reliably talk to each other. So maybe sometimes the sensory cortex detects that a subvocalization is now happening, but hadn’t gotten any signal in advance that this subvocalization was about to be produced endogenously, by a different part of the same cortex. So when it arrives, it’s a surprise, and thus is interpreted as exogenous, i.e. it feels like it’s coming from the outside.

Wikipedia also suggests that psychotic episodes often include “feeling as if one's thoughts or feelings are not really one's own” and “believing that thoughts are being inserted into one's mind”. I think my hypothesis can explain them in a similar way.

Good story? Hmm, a priori, I think my hypothesis would more naturally predict that schizophrenics would experience these symptoms constantly, and not just during psychotic episodes. Not sure what to make of that. Hmmmm. Maybe I should hypothesize that different parts of the cortex are “completely unmoored from each other” only during psychotic episodes, and the rest of the time they’re merely “mediocre at communicating”? Or something like that? Still, I’m mostly pretty happy with how my hypothesis is pointing in a direction that’s consistent with the symptoms.

(EDITED TO ADD: For a better discussion, see my follow-up post, Model of psychosis, take 2.)

4.3 Negative symptoms

Wikipedia lists five common ones: “blunted affect – showing flat expressions or little emotion; alogia – a poverty of speech; anhedonia – an inability to feel pleasure; asociality – the lack of desire to form relationships, and avolition – a lack of motivation and apathy.”

What does my hypothesis predict for emotions in schizophrenia? I think it would predict that emotions should become generally less responsive to what you’re thinking, planning, expecting, seeing, hearing, etc. After all, suppose you see a friend in the crowd and feel an emotional response; this requires transferring information, via a long-range connection, from the face-detection part of the cortex (in the temporal lobe) to cortical areas involved in visceral reactions (probably amygdala, medial prefrontal cortex, and/or hippocampus). If the long-range connections are not there, or not effective, then seeing the friend won’t evoke any feelings at all.

So again, my hypothesis seems to predict that emotions / affects should be relatively unresponsive to what you’re thinking, seeing, etc. But my hypothesis does not seem to make any specific prediction about what those unresponsive emotions should be. If schizophrenics were deliriously happy all the time, regardless of what they were thinking, what was happening in the world, etc., that would also be consistent with my hypothesis, as far as I know.

I think my hypothesis could issue a more specific prediction, but it would require knowing a whole lot of nitty-gritty details about emotion-related circuitry in the amygdala and brainstem and so on. I have a major professional interest in that topic, but am nowhere near knowledgeable enough to make a first-principles prediction on this topic. I don’t think anyone can right now.

Good story? Yup, I’m pretty happy, I think this is a natural consequence of my hypothesis. I wish the hypothesis had made more specific predictions, but oh well, that shouldn’t really count against it.

4.4 Creativity

There’s a spectrum from “different parts of the cortex are all closely tied together into globally-coherent, self-consistent models” and “all the different parts of the cortex are totally unmoored from each other, each doing its own thing”, with schizophrenics closer to the latter end than neurotypical people. It seems very plausible to me that creativity would increase as you move forward along that spectrum. After all, if Cortex Region A and Cortex Region B are almost-independently generating (components of) thoughts, you’re sampling from a much broader space of A+B combinations than if the state of Region A is tightly correlated with the state of Region B at all times. Thus, in the former case, you’d wind up with more unexpected and “creative” A+B composite thoughts / analogies.

Good story? Yeah, I think so. To keep myself honest, I pretended for a moment that schizophrenics were less creative, and tried in good faith to “explain” why that is exactly what my hypothesis predicted all along. I couldn’t come up with anything. Good!

4.5 Anticorrelation with autism

(This section needs to be read in conjunction with my earlier post The Intense World Theory of Autism.)

Scott Alexander wrote a 2018 blog post called Diametrical Model Of Autism And Schizophrenia.

Many of the genes that increase risk of autism decrease risk of schizophrenia, and vice versa. Autists have a smaller-than-normal corpus callosum; schizophrenics have a larger-than-normal one. Schizophrenics smoke so often that some researchers believe they have some kind of nicotine deficiency; autists have unusually low smoking rates. Schizophrenics are more susceptible to the rubber hand illusion and have weaker self-other boundaries in general; autists seem less susceptible and have stronger self-other boundaries. Autists can be pathologically rational but tend to be uncreative; schizophrenics can be pathologically creative but tend to be irrational. The list goes on.

I’ve previously been skeptical of this kind of thinking because there are many things that autists and schizophrenics have in common, many autistics who seem a bit schizophrenic, many schizophrenics who seem a bit autistic, and many risk factors shared by both conditions. …

As far as I can understand, our task is to explain two things: (1) autism and schizophrenia seem generally anticorrelated (as in the first paragraph), and (2) there is definitely such a thing as “a person who has both autism and schizophrenia” (example ref) (as in the second paragraph). I claim that my hypotheses predict both of those things.

As in my autism blog post, I claim that the diagnostic criteria for autism are all downstream from “hypersensitivity”—things that would be pleasantly stimulating (or even barely noticeable) for a neurotypical person, are overwhelming and aversive for someone with autism.

One possible cause of hypersensitivity is “there are unusually many (or unusually effective) cortex-to-cortex connections”.

If that’s the cause, and if many of those connections are medium- or long-range, then this cause of autism would simultaneously be a protective factor against schizophrenia. And I suspect that this is the thing that very often happens.

However, you could get both schizophrenia and autism if the autism had a different cause from the one I mentioned just above. For example:

  • Maybe someone could have an extreme excess of local cortical connections (thus causing autism) while also lacking longer-range cortical connections (thus causing schizophrenia).
  • Maybe the long-range cortical connections could be messed up in a way that makes them fire way more than usual (thus causing autism) while mostly failing to communicate useful information (thus causing schizophrenia).

Stuff like that.

OK, now let’s look at the sentences in the above excerpt one-by-one:

  • For the first sentence (on genes): Consider a gene that says “Hey neurons! When in doubt, make more synapses! Grow more axons! Make bigger dendritic trees!” This gene would probably be protective against schizophrenia and a risk factor for autism, for reasons discussed just above. And vice-versa for the opposite kind of gene. Nice!
  • For the second sentence (on the corpus callosum), my hypotheses straightforwardly predict the opposite (unusually large corpus callosum in autism, unusually small in schizophrenia). Oops! I was very weirded out by this, and in my first draft I had a bunch of text about how my hypothesis had made a flagrantly wrong prediction. (It was peppered with words like “Dang” and “Hmm”.) But then I checked google, and e.g. this says that the corpus callosum is unusually big in autistic kids, and this finds “a relative absence of crossing fibers” in the corpus callosum in schizophrenia, which are both consistent with my hypotheses. So maybe Scott accidentally typed it in backwards? Granted, it does seem to be the case that lacking a corpus callosum altogether (“corpus callosum agenesis”) puts one at unusually high risk of autism, which is counter to my prediction. But on the other hand, this paper (IIUC) says that corpus callosum agenesis puts one at an even higher risk of schizophrenia, which matches my prediction! Anyway, I’m mostly inclined to ignore corpus callosum agenesis in the first place. It’s a pretty extreme and unusual case, and presumably induces other downstream changes, and I’d bet that corpus callosum agenesis patients have an unusual combination of symptoms that might not fit well into our usual classification schemes. So anyway, I think my hypotheses are basically fine in regards to the corpus collosum.
  • For the third sentence (nicotine), it seems a natural consequence of nicotine creating strong feelings, which would be appealing to schizophrenics who have blunted affect in general (see discussion of “Negative symptoms” above), and aversive to autistic people who are feeling overstimulated in general (see my autism post). [UPDATE: "Slimepriestess" in the comments section says I’m super-wrong about this bullet point. Oops! I’ll look into it more carefully when I get a chance.]
  • For the fourth sentence (rubber hand illusion), see the discussion under “Auditory hallucinations” above for the schizophrenia side. On the autism side, this is probably related to most (not all) people with autism having unusually strong long-range connections, as discussed above.
  • For the fifth sentence (creativity), see previous section and above.

Good story? I think everything hangs together remarkably well, unless I’m mistaken about the corpus callosum thing.

4.6 Relation to myelination

My hypothesis would seem to predict that if someone’s brain is producing defective myelin, such that their long-range axons were lousy at transmitting information, this person would probably be highly prone to schizophrenia. So I google-searched for “schizophrenia myelination”, and found a bunch of results that appear to confirm this prediction (e.g. 1,2). But, this might be less impressive than it sounds; I kinda assume that if you search for any pair of neuroscience words you’ll probably find a bunch of papers about how they’re deeply related ¯\_(ツ)_/¯

4.7 Schizophrenia and blindness

There’s a story that blindness prevents schizophrenia. This is counter to my hypothesis; my hypothesis predicts that schizophrenia and blindness should have more-or-less nothing to do with each other. So then I was questioning whether the “blindness prevents schizophrenia” story was true in the first place. I spent a few hours looking into it last summer, and wound up feeling like it probably wasn’t. I wrote that up as a short blog post: I’m mildly skeptical that blindness prevents schizophrenia.

5. Dehaene’s related discussion of schizophrenia as a “disorder of consciousness”

See Dehaene’s book “Consciousness and the Brain” chapter 7 (I had read the book a long time ago and completely forgot about that section, then was reminded of it here).

I mostly wrote this post before (re)reading that book chapter, and it does seem like some of the things I wrote in this post are rehashing ideas in the literature. Yay! That’s very reassuring! For example, it seems like Fletcher and Frith have written this with a qualitatively similar idea to my Section 4.2.

Also, more direct evidence:

Diffusion tensor imaging reveals massive anomalies of the long-distance bundles of axons that link cortical regions. The fibers of the corpus callosum, which interconnect the two hemispheres, are particularly impaired, as are the connections that link the prefrontal cortex with distant regions of the cortex, hippocampus, and thalamus [59]. The outcome is a severe disruption of resting-state connectivity: during quiet rest, in schizophrenic patients the prefrontal cortex loses its status as a major interconnected hub, and activations are much less integrated into a functional whole than in normal controls [60].

At a more microscopic level, the huge pyramidal cells in the dorsolateral prefrontal cortex (layers 2 and 3), with their extensive dendrites capable of receiving thousands of synaptic connections, are much smaller in schizophrenic patients. They exhibit fewer spines, the terminal sites of excitatory synapses whose enormous density is characteristic of the human brain. This loss of connectivity may well play a major causal role in schizophrenia.

What does any of this have to do with “consciousness” though? Well, Dehaene is the leading advocate of “global workspace theory”, which I don’t want to get into, but which centrally involves (a subset of) long-range cortex-to-cortex connections.

I think calling schizophrenia a “disease of consciousness” is slightly misleading. Some long-range cortex-to-cortex connections are related to the “global workspace”, others aren’t, but I think they’re all generally impacted by schizophrenia. For example, I think the visual perception example that I opened with in Section 2 is probably (although not necessarily) related to schizophrenia’s impact on few-cm-long connections within visual cortex. If so, that kind of neuronal connection is almost definitely not part of the “global workspace” or “consciousness”, I would argue. But it’s still part of schizophrenia.

That said, I’m kinda nitpicking, and really if someone describes this post as “an amateurish restatement / endorsement of Dehaene’s theory of schizophrenia”, I wouldn’t be particularly upset.


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29 comments, sorted by Click to highlight new comments since: Today at 4:52 AM
  • For the third sentence (nicotine), it seems a natural consequence of nicotine creating strong feelings, which would be appealing to schizophrenics who have blunted affect in general (see discussion of “Negative symptoms” above), and aversive to autistic people who are feeling overstimulated in general (see my autism post).

this feels precisely backwards to me. I use nicotine because it reduces hypersensitivity and the downstream effect of reducing that hypersensitivity is that it reduces my psychotic symptoms. Nicotine doesn't seem at all to "create strong feelings" to me, it does the reverse and blunts strong feelings, it makes the world less intense and more tolerable. So, I really don't think it's acting on the negative symptoms of schizophrenia, I think it's acting on the positive symptoms.

Interesting!! Thanks for sharing!!

(It’s now on my to-do list to look into / think about the nicotine connection more carefully. Meanwhile, I have added a warning to that part of the OP. )

Some quick thoughts, can expand later with refs:

  • there are other similar results where schizophrenics do better than neurotypical. Two I remember are (1) an experiment where the experimenter pushes on the arm (or palm of hand I dont remember) of the subject with a particular force, and then the subject is asked to recreate that force by pushing on themselves. Neurotypicals push harder on themselves than when pushed on by an external source. (2) Motion tracking of a moving ball especially when there are non-predictive jumps in the balls trajectories.
  • The theories for both of these tend to be similar to what you said, an error in the signaling having to do with predictions of upcoming sensory stimulii, usually assumed to take place via long range cortex-cortex connections (feedback).
  • For the moment I can recommend a chapter in Surfing Uncertainty, which I'm pretty sure is where I got these examples. Though there are probably predictive processing reviews that cover this.

People with schizophrenia are also less susceptible to hollow mask illusion

Any thoughts on what this implies for a cure? 

E.g. one could try to grow new connections. But how would that affect existing cognition? Do your models say anything about the consequences of adding new connections in mid-life?

No idea. But uninformed armchair speculation is fun so I’ll keep writing anyway. :) (Assume for the sake of argument that I’m basically right about the root cause.)

If we split symptoms into {positive, negative, cognitive}, then on this theory, the cognitive symptoms are pretty closely tied to the root cause, whereas the positive and negative symptoms are a bit downstream of the root cause.

Can we intervene on the root cause? I’m pretty skeptical. I think the typical case (see Section 5) is that the long-range connections are not there in the first place. I’d be pretty surprised if it were possible to grow new long-range connections in adulthood, although I’m not an expert. OTOH, I can imagine that there’s a subset of schizophrenia patients for which the long-range connections are present but ineffective—let’s say for lack of some protein or whatever. For that subset, I’d be more hopeful for a miracle-cure that successfully treats the root cause. But it might be a tiny subset of patients, if any, I dunno.

So I’m generally not holding out much hope about the cognitive symptoms. By contrast, the positive & negative symptoms are obviously treatable by existing drugs (not sure exactly how well they work). I think pos & neg symptoms a bit more distant from the root cause and can be mitigated by other pathways.

But again, I don’t know, that’s just off-the-cuff uninformed speculation. ¯\_(ツ)_/¯

I’d be pretty surprised if it were possible to grow new long-range connections in adulthood

Do you agree that with sufficiently advanced technology, this would be possible? 

With sufficiently advanced technology, we can upload everyone to whole-brain-emulations, and then add or subtract whatever connections we want :)

I don't believe uploads would be conscious, but let's put that aside for a moment... Suppose long-range connections were somehow added to an already adult brain that had lacked them. Do your cognitive models say anything about what the effects would be?

I think everything would be fine. I don’t see any issues. As long as the relevant learning rates is set to more than zero, I think the cortical learning algorithm would “do its thing”, and it would learn newer better predictive models that bring together spatially-distant information streams, and all the schizophrenia symptoms (including cognitive) would gradually go away.

Interesting theory and very important topic. 

I think the best data source here is probably neuroimaging. Here's a recent review: https://www.frontiersin.org/articles/10.3389/fnins.2022.1042814/full. Here are some quotes from that: 

For functional studies, be they fluorodeoxyglucose positron emission tomography (FDG PET), rs-fMRI, task-based fMRI, diffusion tensor imaging (DTI) or MEG there generally is hypoactivation and disconnection between brain regions. ...

Histologically this gray matter reduction is accompanied by dendritic and synaptic density decreases which likely signals a lack of communication (disconnection theory) across selected neural networks... 

According to Orliac et al. (2013), patients with schizophrenia have reduced functional connectivity in the default mode network and salience network. Furthermore, decreased connectivity in the paracingulate cortex is associated with difficulties with abstract thought, whereas decreased connectivity in the left striatum is associated with delusions and depression. Longer memory response time for face recognition was also associated with functional connectivity abnormalities in early-schizophrenia, centered in the anterior cingulate...

This is in line with the frontotemporoparietal network disruption theory in schizophrenia that is well-known (Friston and Frith, 1995). ...

In a study that conducted by Lottman et al., patients with schizophrenia showed an increased connectivity between auditory and subcortical networks ...

Both increased and decreased functional connectivity has been observed in patients with schizophrenia vs. controls, in resting state and during various tasks

Mondino et al. (2016) found that transcranial direct current stimulation can decrease negative symptoms course and the severity of auditory verbal hallucination in patients with schizophrenia. This improvement was associated with reduction in functional connectivity between the left anterior insula and left temporoparietal junction (middle and superior temporal gyri and Wernicke’s area)

Overall I think it's pretty complicated. I imagine that when you wrote explaining "everything" was tongue in cheek, but I think there are a lot of things that need to be explained about schizophrenia beyond the seven that you wrote about. I hope you keep doing some research in this area and continue to refine your theory. 


I imagine that when you wrote explaining "everything" was tongue in cheek

Sorta. I kinda feel like my hypothesis (or something very close to it) really is an elegant explanation for everything about schizophrenia. Of course, I don’t know that—among other things, I don’t know everything about schizophrenia (obviously). I was writing this partly in the hopes that you or other commenters would tell me about aspects of schizophrenia that my hypothesis can’t explain, or contradicts, if such aspects exist. And then I can drop that hypothesis and find something better to believe. :)

Do you think that anything in your excerpt contradicts my hypothesis? Seems to be almost entirely decreases in connectivity, right?

That said, I don’t put much stock in functional connectivity comparisons anyway—e.g. you don’t really know if those regions are talking directly to each other vs correlated for some other reason, and even leaving that aside, you can’t disentangle what control-vs-SCZ difference is caused by direct physical connectivity differences versus “when schizophrenics are hanging out in the fMRI machine their wandering minds tend to be thinking about different things than when the control group people are hanging out in the fMRI machine”, or whatever.

[I very generally find it quite hard to learn anything useful from neuroimaging data, compared to most other types of neuroscience data / evidence. But maybe that’s just me. You do you. :-) ]

A lot of the quotes do find decreased connectivity, but some of them find increased connectivity between certain regions. It makes me think that there's a probability there might be something more complicated than just "increased or decreased", but rather specific types of connections. But that's just a guess, and I think an explanation across all cortical connections is more parsimonious and therefore more likely a priori. 

Of your criteria of "things to explain", here are some thoughts: 

4.1 The onset of schizophrenia is typically in the late-teens-to-twenties, 4.2 Positive symptoms—auditory hallucinations (hearing voices), “distortions of self-experience”, etc. 4.3 Negative symptoms - yes these are all critical to explain. 

4.4 Creativity - hm, this is tricky and probably needs to be contextualized. Some people disagree that schizophrenia is associated with increased creativity in relatives, although I personally agree with it. I don't think it's a core aspect. 

4.5 Anticorrelation with autism - I don't think this is a core aspect. I'm not even sure it's true. 

4.6 Relation to myelination - I think this is likely true, but I think it's too low level to call a core aspect of the disease per se. I agree with your point about two terms always yielding search results, this is true of Alzheimer's disease as well. 

4.7 Schizophrenia and blindness - I don't think this is a core aspect, I agree with you it's probably not true. 

Other core aspects I think should be explained: 

1. Specific types of gene pathways that are altered in people with schizophrenia being related to the development/function of whatever the physiologic thing being hypothesized is. Genetics are causal, so this is usually pretty helpful, albeit quite complex. 

2. Cognitive deficits: These include impairments in executive function, working memory, and other cognitive domains. These are usually considered distinct from negative symptoms (anhedonia, blunted affect, etc), and usually involve a decline from functioning premorbid/earlier in life. 

3. Why nicotine is helpful. 

4. Why antipsychotics/neuroleptics seem to be helpful (at least in certain circumstances). 

5. Why there is so much variability in the disorder? Why do some people end up with predominantly delusions, hallucinations, or negative symptoms as the core part of their experience with schizophrenia? 

Just some thoughts. As I said, I'm glad you're focused on this!

Update: there’s some discussion of antipsychotics in my follow-up post: Model of psychosis, take 2  :)

LOL I’m not focused on this at all. I think I’ve spent a whopping four days of my life thinking hard about schizophrenia—one day in 2021 that didn’t go anywhere, one day last summer where I read a bunch of papers and thought of this hypothesis and felt pretty good about it and then moved on to other things, then one more day like a week later to research and write the blindness + schizophrenia post, and yesterday to write this post. Schizophrenia not a significant personal or professional interest of mine. I am very impressed with myself for fooling you. Or maybe you’re just being polite. :)

(Understanding schizophrenia is plausibly indirectly helpful for my professional interests, for various reasons. Also, I have a rule-of-thumb that if I can write a decent blog post in four hours, I should just do it, often it leads to unexpected good things!)

Yeah the “things to explain” could have been more accurately titled “aspects of schizophrenia that I can easily think of right now, from either off the top of my head or skimming the wikipedia article”. :-P

I think the cognitive deficits are very straightforwardly and naturally predicted by my hypothesis.

I wrote something about nicotine but a different commenter said that what I wrote was flagrantly wrong. (I put a warning in the OP.) Guess I need to think about that more. Honestly, I don’t have a great understanding of what nicotine does to the brain in the first place. Something something acetylcholine :-P

I haven’t looked into antipsychotics / neuroleptics, and agree that doing so would be an obvious next step, and indeed maybe I should have done it before posting this. Sorry. I’ll put it on my to-do list.

Interesting, thanks. All makes sense and no need to apologize. I just like it when people write/think about schizophrenia and want to encourage it, even as a side project. IMO, it's a very important thing for our society to think about. 

Good story? Yeah, I think it’s a pretty good story—I don’t think it’s special pleading / rationalization. In particular, I was guessing that this was the story before I knew the age range of synaptic pruning, and then when I looked that up, I was surprised and pleased at how good a match it was.

Maybe this doesn't apply to you, but if I had that experience I'd be very wary of double counting. Sometimes I've thought "X explains Y! Hey, it predicts Z should be true. And look, it is!" and later on I recall that I read about X explaining Y in the past, and oh would you look at that, they talked about Z as evidence. Or I read about Z in the past, which lead to me developing X. I forget where it came from, see Z again, count it as extra evidence, then read my notes and find I wrote about Z in the past. 

I mostly wrote this post before (re)reading that book chapter, and it does seem like some of the things I wrote in this post are rehashing ideas in the literature. Yay! That’s very reassuring! For example, it seems like Fletcher and Frith have written this with a qualitatively similar idea to my Section 4.2.

Here, I'd also be wary of double counting. Though maybe you've written through notes, or your mind is less of a black box to you, so you note where your ideas came from. 

Thanks! I looked up the synaptic pruning age range this morning. I had a vague recollection that there was such a thing as “synaptic pruning” but really couldn’t remember its age range, and definitely hadn’t previously connected it to schizophrenia. The grand total amount of time I’ve spent thinking hard about schizophrenia was probably like one day in 2021 (which didn’t go anywhere), and one day in summer 2022 (where I had this idea, and felt pretty good about it, and then moved on to other things), and today. (Plus maybe one more day total, also summer 2022, to research and write up the blog post about blindness and schizophrenia.) Schizophrenia is not a significant interest of mine, personally or professionally; I am not concerned that I have figured out a bunch of things about this particular schizophrenia theory sometime in the past, and then mostly forgot them, and then re-discovered them to my delight this morning :-P

For the second thing you mention, yeah I have great confidence that I didn’t remember that chapter of Dehaene. I came at this theory via the path described in Section 2. I only noticed the connection to Dehaene’s “global workspace” stuff this morning when I was about to submit this post, and figured I should first skim through my long-term-to-do list to see if there was anything else about schizophrenia that I had ever marked as worth reading, and one of them was a thing that mentioned that chapter. Hmm, maybe I should have said “Yay! That’s very nice!” instead of “Yay! That’s very reassuring!” The fact that Dehaene and Fletcher and Frith said similar things as me counts for really-not-very-much in my mental calculus. Neuroscientists say all kinds of things, and they’re usually wrong, otherwise they wouldn’t disagree with each other so much. :-P Dehaene in particular has said lots of things that I agree with and lots of things that I disagree with; I don’t see him as more trustworthy on this topic than any of the neuroscientists promoting probably dozens of other contradictory theories of schizophrenia. And I don’t know who Fletcher and Frith are, off the top of my head. I’m still happy to have found that chapter in case I want to dive further with a lit-review someday; it would give me a place to start.

Interesting. One thing ut doesn't seem to explain is gender imbalance in onset time. Women start developing schizophrenia about a decade later I think. On the other hand, IIRC the usual explanation is "sth sth protective estrogens", so if it turned out that estrogens inhibit pruning of medium/long-range cortico-cortical connections, then you get another puece of weak evidence.

Regarding context of discovery, I would expect effects like this one to work through local connections, perhaps not even in the visual cortex but LGN or even retina (?).

Regarding your explanation of "hearing voices", wouldn't it fit better with your hypothesis that the function of the cerebellum is to resuce latency between cortical(/telencephalic) regions by presicting advance what signal arrives where?


gender imbalance in onset time

Yeah, I dunno. Random paper says “there are age-related sex differences in brain maturational processes” and more specifically “males had more prominent age-related gray matter decreases and white matter volume and corpus callosal area increases compared with females”. Guess it could be something like that? But I would want to look into that more. Thanks for the tip :)

Regarding context of discovery, I would expect effects like this one to work through local connections, perhaps not even in the visual cortex but LGN or even retina (?).

Can you say more about why you expect that?

Regarding your explanation of "hearing voices", wouldn't it fit better with your hypothesis that the function of the cerebellum is to [reduce] latency between cortical(/telencephalic) regions by [predicting in] advance what signal arrives where?

I don’t understand what you mean here. Yes I do think the cerebellum reduces latency like you said, but I’m not following how you think that’s related to hearing voices.

Hm, I had a vague memory that contrast detection relies on something like lateral inhibition but when I thought about it a bit more it doesn't really make sense and I guess I conflated it with edge detection in the retina.

Regarding cerebellum in hearing voices: If I understand your model correctly, it goes something like this. Region S (sender) "generates voices" and region R (receiver) "hears voices" generated by S. R expects to receive those signals from S (or maybe even just expects to receive these kinds of signals in general, without specifying where they come from). R gets surprised when it receives unexpected signals and interprets them as "not mine". R would expect to receive them, if it first got a message "hey, S is soon going to send some voice-signals to you". Isn't this exactly the role of the cerebellum, to learn that, e.g. if S activates in this particular way (about to "generate voices"), then R will soon activate in the other way ("hears voices") and therefore it would make sense to preempt R, so that it can expect to get that particular signal from S and act accordingly even before receiving that signal?

The model would be:

  • (1A) there’s a message from S to Motor Area M that says to produce voices;
  • (1B) there’s a message from S to R that updates R on what S is doing (and in particular, it tells (R) that (1A) is happening right now);
  • (2) Motor Area M “does voices” (I’m hazy on the details), and some sensory consequence of those voices make their way back to R.

So then the auditory hallucination in my model would be if (1A) and (2) happen, but (1B) doesn’t happen.

Generally, I don’t think this story is very sensitive to timing. I think the nature of a hallucinated voice is that it feels exogenous not just for a tiny fraction of a second between the (2) signal and the (1B) signal arriving at R, but rather it continues to feel exogenous for many seconds.

I still think that the dopamine system is involved in psychosis.

It is quite difficult for the brainstem to reward accurate perception. If dopamine production by the brainstem is in any way dependent on information that is coming in from the neocortex rather than from the brainstem’s own sensory areas then there is the potential for things to go wrong.

One part of the neocortex might get dopamine for detecting danger, and it can rewire itself to maximise its dopamine reward by hallucinating evil spirits.

Another part of the brain might get dopamine when social status increases, and it can rewire itself to maximise its dopamine reward by finding evidence that said individual is the messiah.

Another part of the brain might get dopamine whenever it comes across a really interesting hypothesis. Of course, the most interesting hypothesis is rarely the correct one.

I still think that the dopamine system is involved in psychosis.

I’m hoping to look into it more, but my initial thinking was that the dopamine system would be involved downstream of the cortex-to-cortex connection root cause. For example, if two parts of the cortex aren’t communicating, then one can “surprise” the other (as in my OP discussion of subvocalization), and that surprise tends to (indirectly) cause dopamine release, cf. evidence cited here. (BTW I disagree with that paper’s interpretations and title, but their experimental results in themselves seem probably fine AFAIK.)

I’ll come back and write another comment when I get around to reading any of the literature on dopamine + psychosis.

One part of the neocortex might get dopamine for detecting danger, and it can rewire itself to maximise its dopamine reward by hallucinating evil spirits.

Insofar as that’s true†, it would be true for everyone, right? Do you have a guess for what’s different in people with psychosis?

† (I don’t exactly agree, but that’s a very long story.)

I think my hypothesis would more naturally predict that schizophrenics would experience these symptoms constantly, and not just during psychotic episodes. Not sure what to make of that. Hmmmm. Maybe I should hypothesize that different parts of the cortex are “completely unmoored from each other” only during psychotic episodes, and the rest of the time they’re merely “mediocre at communicating”?

I am not sure that constant symptoms would be a necessary prediction of your theory: I could easily imagine that the out-of-sync regions with weak connections mostly learn to treat their connections as "mostly a bit of noise, little to gain here" and mostly ignore them during normal functioning (this also seems energetically efficient). But during exceptionally strong activation, they start using all channels and the neighbouring brain regions now need to make sense of the unusual input.

I cannot tell whether this story is more natural than a prediction of constant symptoms, but it does seem plausible to me.

Could be related to the Zizians. 

Why is this downvoted? It's a straightforward connection, and interesting. 

I looked up “the Zizians”. They seem to be some group of people in California, I guess. Anyway, I interpret your comment as “maybe those people have schizophrenia”. OK, maybe they do, maybe they don’t, I dunno. Lots of people have schizophrenia.

I think if you want to discuss which people do or don’t have schizophrenia, and how that does or doesn’t effect their behavior, that’s fine, at least in principle. (In practice, things can go badly when amateurs start trying to give psychological diagnoses to people they don’t like.)

But I don’t see how it would be related to this blog post.

If you want to know how people behave when they have schizophrenia, the right approach is to look at lots of people with schizophrenia and write down how they behave. People have already done this, and you can read the results on wikipedia and many other places. The wrong approach is to read highly-speculative musings on the neuroscience of schizophrenia, like the contents of this blog post. Any information in the latter is screened off by the former, right?

Ok, I appreciate you clarifying. I should have made the connection more clear. The connection is that Ziz's theory is that humans are actually, very literally, two people: one left hemisphere and one right hemisphere, with different personalities, life orientations, and perhaps genders. See for example the links in https://hivewired.wordpress.com/2019/12/02/hemisphere-theory-much-more-than-you-wanted-to-know/  (I haven't read that summary carefully). Some other "Zizians" also say they believe this about themselves, and believe that other people are deluding themselves into thinking that they're just one person. That group of people also seems to be very much outcast from society, and speak in an abnormal way, which some people (unfairly, IMO) describe as crazy / schizo / incomprehensible. Maybe it's not a deep connection, but it just seems interesting; there could be some shared component between the phenomenon Ziz and others describe, with the physiology that you hypothesize is related to schizophrenia.