Corollary Discharge and Inner Speech: Clues for Psychosis

A central feature of psychosis is the disintegration of the sense of self. A healthy person, during the course of the day, talks to themselves, and rehashes past or hypothetical arguments with friends and family. The healthy person may even speak out loud during these episodes*, but they know all these thoughts and imagined voices are exactly that, coming from their own head, under their control. In contrast, the voices that psychotic people describe is that very often (actually, in my experience, usually) they are people that the person can identify - usually friends and family. Again in my experience, voices of parents are the most common. What's more, I've witnessed more than once a person who had badly decompensated and told me in the emergency department that he could hear his friend's voice talking to him and wasn't able to reality-test that the voice must be coming from his own brain; but as he reconstituted over several days with medication, the voice eventually became an internal monologue he was having with his friend, with full recognition by the patient that it was indeed an internal monologue - just like anyone else rehashing an argument in the shower.

An interesting study in Psychological Science by Mark Scott from UBC gives evidence that our capacity for inner speech is related to our ability to tune out our own voices when speaking; the neural correlate of this suppression is called corollary discharge. This of course leads to speculations about whether this mechanism underlies the origins of language and cognitive modernity, but psychiatrists and clinical psychologists will find it immediately interesting for another more immediately practical reason: as a way to measure and possibly target auditory hallucinations in psychosis. Of note, this study had no direct measurement of neural correlates, instead relying on the Mann effect, a phenomenon of context-dependent perception of vocal sound (McDonald-McGurk is another example.) That said, a 2011 by Greenlee et al at U of Iowa showed with intracranial electrode measurements in humans that corollary discharge in hearing speech is unsurprisingly located in the auditory cortex.


*More than once, while I was out running on what I thought was a deserted trail, I have been caught talking to myself by an alarmed trail user coming the other way. Invariably as soon as I see them I act like I was singing to myself the whole time. Somehow this never seems to comfort them.

Lewy Body Dementia and Alpha Synuclein as a Lipid Manipulator

In terms of understanding moment-to-moment awareness, cognitive hypofunction disorders with clear genetic contributions are often uninteresting. That is, the problem is usually that the wiring isn't there, or is wrong. The reason this is uninteresting is that if you're interested in what underlies moment-to-moment consciousness, you have to look for properties of the brain that change on the same time-scale, allowing our subjective awareness to represent some of the information in the outside world.

For this reason, pharmacology often presents more research opportunities than disease states, in particular NMDA antagonists and HT2A agonists. But there is a disease state which is notorious for hour-to-hour (or more) fluctuations in cognitive status, dementia with Lewy bodies. As you can see from the linked reference, it's not yet clear whether the disease is a sub-type of Alzheimers, or a distinct condition.

Lewy bodies are alpha-synuclein plus ubiquitin inclusions that appear in neurons specific parts of the brain in disease states; the ubiquitin suggests that these are clumps of protein the neuron is trying to degrade. Their presence is not necessarily indicative that the patient had any of the additional symptoms of Lewy body dementia. Clinical Lewy body dementia is associated with symptoms above and beyond what Alzheimers patients suffer. It also has significant overlap with Parkinson's; specifically, patients exhibit both the motor decline of PD as well as REM sleep disorder. Unlike Alzheimers, onset is not insidious. Unlike either Alzheimers or PD patients and most relevant here, Lewy body dementia patients usually have recurrent visual hallucinations, and are extremely sensitive to dopaminergic- and cholinergic-modifying medications.

When we think of real-time changes to nervous systems, we usually think of information being transmitted in an electrochemically-mediated way by neurotransmitter vesicle diffusion and membrane depolarization. Membrane potentials would also be dramatically and rapidly effected by changes in lipid membrane properties, so I had considered previously whether there were proteins expressed in brain that manipulated or maintained membrane lipid contents. It's interesting that alpha synuclein a) is known to be located on the cell membrane in some fraction, b) is natively unfolded in the cytosol, c) interacts with polyunsaturated fatty acids, d) interacts with membranes correlating with serine phosphyorylation and e) still hasn't been assigned a clear function.

This is why a recent Journal of Molecular Neuroscience paper by Riedel et al at the University of Oldenburg is important. Using an oligodendroglial cell line, they demonstrated the creation of a-synuclein aggregates (in vitro Lewy bodies) both in cells that had a point mutation in a-synuclein predisposing them to aggregate formation, as well as in wild-type cells. This was done by adding DHA (by the way, an omega 3 polyunsaturated fatty acid) and then hydrogen peroxide for oxidative stress. Alpha synuclein aggregates formed both in the mutant cell line as well as in the wild type, though the mutant cells' aggregates were bigger (all compared to non-treated controls).

My hypothesis is that alpha-synuclein is responsible for lipid processing of neuronal membranes to maintain electrochemical constancy, in response to physiologically rapid (minutes to hours) changes in the environment of the cell. In addition to the specific deficits in Lewy body dementia (associated with the brain region where the Lewy bodies appear), this may also explain the rapid fluctuation in cognitive status - cell membranes are unable to respond to a changing electrochemical environment because there's a problem with the protein that controls their lipid content. When alpha-synuclein catches up or the triggering physiological change (pH, solute concentration) reverses to previous levels, the cognitive deficits may disappear.

These findings, though they show an interaction, are therefore causally backwards - here, changes to lipids are initiating aggregation. It could be that once aggregation begins, alpha-synuclein function is off-line, and any new alpha-synuclein produced by the cell gets immediately caught in the tangle and can't perform. (There's evidence that there's more than normal at the membrane in disease states.) Here are future experiments, which in my quick survey of the literature I may have missed: 1) patch clamp recordings of dopamine receptors on cells in culture with loss-of-function mutations or knockouts of alpha synuclein, especially in response to differences in charge, pH, and buffer concentration (to mimic physiologic changes in extracellular fluid). 2) Measurement of individual fatty acid chains in knockout relative to control, in terms of their incorporation into cell membranes.

I'm both excited and nervous because in the coming weeks I will be interacting with patients in the clinic who have this disease, which is why I'm motivated to understand it.

Hints That You're Living in a Simulation; Plus, What Is a Simulation?

See Bostrom's simulation argument for background. From a practical standpoint, you might be suspicious that you live in a simulation if you inhabit a world with the following characteristics:

Hint #1) Limited resolution. A simulation would be computation intensive. It would be useful to have tricks that increase the economy of operations, but in ways that do no compromise the consistency of the simulation to the players. One such trick would be to set an absolute upper limit to resolution (or a lower limit to the size of the elements that make up the "picture") that is below the sensory threshold of the players. These elements could variously be called pixels or quarks. Similarly, it would behoove the simulators to set a maximum time resolution, i.e. maximum frames-per-second, also called Planck times. Furthermore, the simulation's computing power is spared by a statistical method of calculating relationships between entities in the simulation (i.e quantum mechanics) even though it may look, at the scale of the game players or simulated entities, as if the universe maintained quantitative relationships in terms of integers calculated to arbitrary precision. (Related question: is it possible in principle given the physics of our universe for something the size of a bacterium or virus to "be conscious of" this gap in the behavior of the Newtonian and quantum realms, at a very basic sensory level? If not, isn't it interesting that our universe is such that there can be no consciousness operating on scales that would expose the twitching gears behind the scenes?)

Hint #2) There are limitations in what spaces within the game can be occupied by players or sims. In the old Atari 2600 Pole Position game, you couldn't just randomly go off driving off the track and through the crowd even if you didn't care about losing points; the game just wouldn't let you. Similarly, the total space in our apparent universe that we occupy, or directly interact with, or for that matter even get any significant amount of information from, is an infinitesimally small part of the whole. Unless you're in a submarine or in orbit, you don't go more than 200 meters below sea level or 13,000 m above it. (That's a volume of 2.1 x 10^18 m^3 that for all practical purposes the entirety of human history has occurred in; double that figure, and that's the volume that all of evolutionary history has occurred in.)

Hint #3) Beyond the "active game volume" as described above, dab a few pixels here and there in an otherwise almost entirely dark and empty volume. Make them so far away that sims can't possibly interact with them. Reveal additional detail as necessary whenever someone happens to look more closely at them. (And there's another trick: objects in this simulation are only loosely
defined until one of the players interacts with them, "collapsing the wave function". Yeah, that's what the programmers will call it, that's the ticket.)

Hint #4) Even in that limited location, make the active game volume wrap around. That way the simulators get rid of edge-distortion problems, as in Conway's Life. A sphere is the best way to do this. Therefore, work out the physics rules of the simulation to favor spheres.

Hint #5) Make each state of the simulation dependent on previous states of the simulation, but simplify by dramatically limiting the number of inputs with any causal weight. The simulators can limiting computations by having only mass, charge, space and their change over time determine subsequent frames.

Hint #6) If for some reason it is important for the entities in the simulation to remain ignorant to their existence as part of a simulation, the simulators could make sure the entities are accustomed to not only these kinds of stark informational discontinuities but to profound differences in the quality of awareness, both within themselves and each other. That is, the sims will accept not just that the vast majority of the universe (as seen in the sky at night) is interactively off-limits to them, but they'll also accept that their own awareness thereof and ability to connect the dots will dramatically vary over time. That way, if there is any need to interfere and make adjustments (to stop someone from figuring out the game) it won't strike the sims as strange. (Forgetfulness, deja vu, mental illness, drugs, varying intelligence or ability to concentrate on math, death of player-characters before they can learn too much?)

#6 does raise a very important question: why would the simulators give a damn if we knew we were in a simulation. So what? What would we do about it, sue them? If Pac-Man woke up and deduced that he were a video game character, if he still experienced suffering and mortality the same way, why would it matter? By this same view, there's an easy answer to whether we should behave differently if we're actually in a simulation: no. Whether our universe is in reality just World of Warcraft from the sixth dimension, if we simulated beings can suffer (and I know I can), then the moral rules are exactly the same as before.

It's also worth asking for some humility, and asking why we humans always assume that we would be the purpose of any such simulation. We could be merely incidental consciousnesses that are necessary for harboring the populations of simulated bacteria that the simulators are really studying. Or, the simulators could be cryonicists who preserve pets, and the most popular pets in their dimension look like what we call raccoons, and our universe is actually the raccoon heaven in which their beloved masked companions await a cure for the disease that forced the owners to put them on ice. In fact the raccoon-heaven simulation would contain a whole suite of ecosystem, all of them purely simulated (with the exception of raccoons) to keep up the appearance of a full biosphere. So the point of such a simulation would be to fool raccoons - or maybe even mice (again, why would they care about fooling everyone! If the simulators are reading this, just give me more juicy steaks and I won't make problems. It doesn't cost you anything!)

While the raccoon thought experiment is meant to be whimsical, a healthy respect for our own ignorance is always in order for these kinds of speculations. After all, assuming what we have guessed about the rest of (for the sake of argument simulated) universe is accurate, then there might be "aliens" (other non-human intelligences within the simulation) who may very well be much brighter than us. So even if the simulation is somehow arranged around the most intelligent entities within it (as we assume), those entities need not be human. Even if we're simulated, and we have a real brain and body in the "real" universe that's similar to our form in this one, this simulated universe might be designed for Martians (who are brighter than us) and be much less pleasant than our home dimension.

Finally, the very idea of a simulation is poorly defined. Mostly we think of something like almost completely controlled full-world simulation in the Matrix, but let's explore boundary cases. If I wear rose-colored glasses, is that a simulation (or a red world)? What about LSD that causes me to see unidentified animals scurrying past in my peripheral vision? What about DMT that causes a complete dissociation of external stimuli from subjective experience? What if I have some chip implanted that displays blueprints of machinery in my visual field a la the Terminator, is that a simulation? What about a chip that makes me see a tiger following me around that isn't there? (Hypothetical given current limitations.) What if I hear voices telling me to do things that are produced by tissue inside my own skull, by no conscious intent of anyone? (Not at all hypothetical.)

One of the interesting points in the popular movie Inception is the way that external stimuli appear in dreams. This gives us a hint as to what we mean by simulation, and why we care. Most of us have had experiences where the outside world "intruded" into a dream, with the stimulus obvious after we awoke. I once dreamed that a dimensional portal slid open in front of me with an ominous metallic resonance, and I stepped through it, suddenly speeding over the red, rocky surface of Mars. Then I realized it was my father opening his metal closet door in the next room, and I was looking into that room at the red-orange carpeting. Before I was fully awake I had received the sound stimulus but I had built a world out of it that most of us would not regard as real. (The experience of speeding over Mars was quite real, even if most humans would have a more accurate representation of that auditory stimulus.) So, a better way of saying "how do I know 'this' is reality, rather than another dream, or a simulation?" is to ask "how do I know I am perceiving "true" stimuli, without mapping them unnecessarily onto internal stimuli, giving me as accurate and un-contorted a view of the world as possible?"

And indeed in certain ways, we certainly are dreaming, in the sense of injecting internal stimuli and filtering external stimuli through them. (Notably, it is possible to view schizophrenics as people who experience dreams even while awake and filter their perceptions accordingly.) First and most obviously, because our sense organs are limited in what they can detect, we're obtaining only a slice of possible data. Second, the world we knit together is the result of binding of sensory attributes into object/events, as well as pattern recognition. The limitations of our nervous systems, and the associations we are able to make, profoundly influence the representation we build of the world we're perceiving.

Third, and most significantly, a large part of our experience is non-representational: emotions, pleasure and pain do not exist outside of nervous systems, or rather the events to which those experiences correspond are almost entirely contained within nervous systems. Yes, to be precise the experience of light does not exist until the triggering of a cascade of electrochemical events by radiation incident on pigments in retinal cells; but light, which is what is represented in our experience, exists traveling across the universe. Pain and happiness do not. These are internal stimuli that add a non-representational layer to reality, even more certainly than my dream of the Mars overflight.

A good working definition of a simulation as it is commonly understood is when the majority of one's external stimuli are supplied deliberately by another intelligence to produce experiences that do not correlate to physical reality external to the nervous system (or computational equivalent). This avoids taking a position on AI; the sims may or may not be entities separate from the computation. I.e., you might be in sensory deprivation tank like Neo, or you might be a computer program. The question of reality versus dreams or simulations is not one of discrete "levels" as we've come to think of it in popular culture. It is rather a question about how we know our experiences correspond in some consistent way with events separate from our nervous systems.