Way Too Much Dopamine

Schizophrenia and associated delusions/hallucinations as a Bayesian logic defect of putting priors over observations, partly due to excess dopamine or sensitivity to dopamine.

It goes without saying that our brains are highly tuned systems, both through evolution and through development. They are constantly active, with dynamic coalitions of oscillatory synchrony and active anatomical connection that appear to create our mental phenomena, conscious and unconscious. Neurotransmitters have long been talismanic keys to this kingdom, there being relatively few of them, with somewhat distinct functions. GABA, dopamine, serotonin, glutamate, acetylcholine are perhaps the best known, but there are dozens of others. Each transmitter tends to have a theme associated with it, like GABA being characteristic of inhibitory neurons, and glutamate the most common excitatory neurotransmitter. Each tends to have drugs associated with it as well, often from natural sources. Psilocybin stimulates serotonin receptors, for instance. Dopamine is central to reward pathways, making us feel good. Cocaine raises dopamine levels, making us feel great without having done anything particularly noteworthy.

As is typical, scientists thought they had found the secret to the brain when they found neurotransmitters and the variety of drugs that affect them. New classes of drugs like serotonin uptake inhibitors (imipramine, prozac) and dopamine receptor antagonists (haloperidol) took the world by storm. But they didn't turn out to have the surgical effects that were touted. Neurotransmitters function all over the brain, and while some have major themes in one area or another, they might be doing very different things elsewhere, and not overlap very productively with a particular syndrome such as depression or schizophrenia. Which is to say that such major syndromes are not simply tuning problems of one neurotransmitter or other. Messing with transmitters turned out to be a rather blunt medical instrument, if a helpful one.

All this comes to mind with a recent report of the connection between dopamine and hallucinations. As noted above, dopamine antagonists are widely used as antipsychotics (following the dopamine hypothesis of schizophrenia), but the premier hallucinogens are serotonin activators, such as Psilocybin and LSD, though their mode of action remains not fully worked out. (Indeed, ketamine, another hallucinogen, inhibits glutamine receptors.) There is nothing neat here, except that nature, and the occasional chemical accident, have uncovered amazing ways to affect our minds. Insofar as schizophrenia is characterized by over-active dopamine activity in some areas, (though with a curious lack of joy, so the reward circuitry seems to have been left out), and involves hallucinations which are reduced by dopamine antagonists, a connection between dopamine and hallucinations makes sense. 

"... there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical." - Wiki

So what do they propose? These researchers came up with a complex system to fool mice into pressing a lever based on uncertain (auditory) stimuli. If the mouse really thought the sound had happened, it would wait around longer for the reward, giving researchers a measure of its internal confidence in a signal which may have never been actually presented. The researchers thus presented a joint image and sound, but sometimes left out the sound, causing what they claim to be an hallucinated perception of the sound. Thus the mice, amid all this confusion, generated some hallucinations in the form of positive thinking that something good was coming their way. Ketamine increased this presumed hallucination rate, suggestively. The experiment was then to squirt some extra dopamine into their brains (via new-fangled optogenetic methods, which can be highly controllable in time and space) at a key area known to be involved in schizophrenia, the striatum, which is a key interface between the cortex and lower/inner areas of the brain involved in motion, emotion, reward, and cognition.

Normal perception is composed of a balance of bottom up observation and top-down organization. Too much of either one is problematic, sometimes hallucinatory.

This exercise did indeed mimick the action of a general dose of ketamine, increasing false assumptions, aka hallucinations, and confirming that dopamine is involved there. The work relates to a very abstract body of work on Bayesian logic in cognition, recognizing that perception rests on modeling. We need to have some model of the world before we can fit new observations into it, and we continually update this model by "noticing" salient "news" which differs from our current model. In the parlance, we use observation to update our priors to more accurate posterior probability distributions. The idea is that, in the case of hallucination, the top-down model is out-weighing (or making up for a lack of) bottom-up observation, running amok, and thus exposing errors in this otherwise carefully tuned Bayesian system. One aspect of the logic is that some evaluation needs to be made of the salience of a new bit of news. How much does it differ from what is current in the model? How reliable is the observation? How reliable is the model? The systems gone awry in schizophrenia appear to mess with all these key functions, awarding salience to unimportant things and great reliability to shaky models of reality. 

Putting neurotransmitters together with much finer anatomical specification is surely a positive step towards figuring out what is going on, even if this mouse model of hallucination is rather sketchy. So this new work constitutes a tiny step in the direction of boring, anatomically and chemically, into one tiny aspect of this vast syndrome, and into the interesting area of mental construction of perceptions.

• Another crisis of overpopulation.
• And another one.
• Getting China to decarbonize will take a stiff carbon price, about $500 to $1000/ton.

Various policy scenarios of decarbonization in China, put into a common cost framework of carbon pricing (y-axis). Some policies are a lot more efficient than others.