#45. The Denervation-supersensitivity Theory of Mental Illness [neuroscience, evolution, genetics]

NE     EV     GE     

Red, theory; black, fact.

People get mental illness but animals seemingly do not, or at least not outside of artificial laboratory models such as the unpredictable, mild-stress rodent model of depression. A simple theory to account for this cites the paleontological fact that the human brain has been expanding at breakneck speed over recent evolutionary time and postulates that this expansion is ongoing at the present time, and that mental illness is the price we are paying for all this brain progress.

In other words, the mentally ill carry the unfavorable mutations that have to be selected out during this progress, and the mutation rate in certain categories of mutation affecting human brain development is elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes here to indicate that the adaptation inheres in changes in the standard deviation of traits, not the average, and is therefore not Lamarkian.

In brain evolution, the growth changes in the various parts very probably have to be coordinated somehow. I conjecture that there is no master program doing this coordination. Rather, I conceive of the human brain as comprising scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. (This idea is consistent with the finding of about 400 genes in humans that participate in establishing body size.) All harmonious symmetry, even left-right symmetry, would have to be painstakingly created by brute-force selection, involving the early deaths of millions of asymmetrical individuals. This idea was outlined in post 10.

Assuming that left and right sides must functionally cooperate to produce a fitness improvement, mutations affecting parcel growth must occur in linked, left-right pairs to avoid irreducible-complexity paradoxes. I have previously conjectured in these pages that the crossing-over phenomenon of egg and sperm maturation serves to create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. (See "Can Irreducible Complexity Evolve?")

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which I conjecture implements if-then rules, like those making up the knowledge bases familiar from the field of artificial intelligence. The "if" part of the rule would be evaluated in post-Rolandic cortex, i.e., in temporal and parietal association cortices, and the "then" part of the rule would be created by the pre-Rolandic association cortex, i.e., the prefrontal cortex. The white matter tracts running forward in the brain would connect the "if" part with the "then" part, and the backward running white-matter tracts would carry priming signals to get other rules ready to "fire" if they are commonly used after the rule in question.

Due to such tight coordination, I would expect that the ideal brain will have a fixed ratio of prefrontal cortex to post-Rolandic association cortex. However, the random nature of the growth-gene bi-mutations (perhaps at mutational hot-spots) permitting human brain evolution will routinely violate this ideal ratio, leading to the creation of individuals having either too much prefrontal cortex or too much temporal/parietal cortex. In the former case, you will have prefrontal cortex starved of sensory input. In the latter case, you will have sensory association cortex starved of priming signals feeding back from motoric areas.

Denervation supersensitivity occurs when the normal nerve supply to a muscle is interrupted, resulting in a rapid overexpression of acetylcholine receptors on the muscle. This can be seen as an attempt to compensate for weak nerve transmission with a tremendous re-amplification of the signal by the muscle. Analogous effects have been found in areas of the cerebral cortex deprived of their normal supply of sensory signals, so the effect seems to be quite general.

In cases of genetically-determined frontal-parietal/temporal imbalance, I conjecture that the input-starved side develops something like denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in a person with schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia. Depression may originally have been an adaptation to the presence of a man-eating predator in the neighborhood, but in civilized contexts, it can get activated by the unpredictable (to the sufferer) punishments resulting from manic activity. If the mania is sufficiently mild to co-exist with depression, as in type II bipolar disorder, then the overall effect of the depressive component may be like a band-aid on the mania.

The non-overgrown association cortex might even secondarily develop the opposite of denervation supersensitivity as the result of continual bombardment with autonomous activity from the other side of the Rolandic fissure. This could account for the common observation of hypoprefrontality in cases of schizophrenia.

#40. The 1950 Ramp [population, genetics, evolutionary psychology, engineering, neuroscience]

PO     EN     EP     NE     GE     

Red, theory; black, fact.

6-01-2018; Since about 1950, the world population has been increasing along a remarkably steady ramp function with no slackening in the rate of increase yet apparent, although one cycle of oscillation in the slope occurred during the Sixties. Malthusian reasoning predicts an exponential increase, which this is not. From several lines of evidence, I keep coming back to the idea that humans must have a subconscious population controller in their heads, and yet such a controller would have leveled out the increase by now. Until now, no theory has sufficed to explain the facts.

I here propose that the natural population curve for humans in good times is a saw-tooth waveform, with population ramps alternating with political convulsions that result in a large group being expelled permanently, resulting in the precipitous but limited drop in local population density that ends the saw-tooth cycle. This cycle accomplishes the ecological dispersal function to which I allude many times in these pages. The population must ramp up for a time to sustainably create the numbers needed for the expulsions. The WHO population curve shows only a ramp because it is a worldwide figure and therefore population losses in expelling regions are balanced by population increases in welcoming regions. This also implies that human population has been increasing in a way unrestrained by food or resource availability or any other external constraint since 1950, to now.

Clearly, human population is being controlled by instinctive factors, but not to a constant absolute density, but rather to a constant rate of increase. Population density would go up along the much faster, steeper, and more disastrous exponential curve of Malthus if there were actually no controller.

My formal training in engineering and neuroscience justifies a bit of speculation as to mechanisms at this point. Look first for such a controller in the hypothalamus, already known to control other variables, such as temperature, by feedback principles.

In school, I was taught that nature does not reinvent the wheel, which I understand to mean that once a brain structure evolves to serve a particular computational function, it will be tapped for all future needs for such a calculation. This process may make it grow larger or develop sub-nuclei, but additional, independent nuclei for the same computation will never evolve.

I will continue to assume that the controller is a conventional PID controller, as in previous posts. To make it control rate of increase rather than absolute population density, you put a differentiator in the feedback pathway. Look first in the amygdala for such a differentiator. If you are of the opinion that human population control is urgent, then you must knock out this differentiator and replace it with a simple feed-through connection. Fortunately, one common way for evolution to implement differentiation in mammals is to begin with such a feed-through connection and supplement it with an inhibitory, slow, parallel feed-forward connection. If this is the case here, then you just inhibit the feed-forward pathway pharmacologically as specifically as may be, and the job is done. Subjectively, the effect of such a drug would be to take away people's ability to get used to higher population density in deciding how many children to have. An increased propensity to riot should not occur.

I assumed in the last post that the political convulsions that produce dispersal are triggered by the value on the integrator of the PID controller rising above a threshold. However, in the above design solution, the convulsion would be triggered by the raw, undifferentiated population-density signal rising above some threshold. Look in the amygdala for this signal as well. Consistent with this, bilateral removal of the amygdalae and hippocampi in monkeys is known to have a profound taming effect accompanied by hypersexuality, known as the Kluver-Bucy syndrome.

6-17-2018: To be consistent, I would have to say that the differentiator for the population signal is more likely to be in the hippocampal formation by the argument of nature not reinventing the wheel, because in an earlier post, I interpreted the hippocampus as the site of four successive differentiations that carry out a Fourier transform by mapping sinusiodal waves back onto themselves at a particular best frequency, in the presence of a map of such best frequencies.

However, this setup would require the creation of two neuron-to-neuron connections for its evolution; a first connection to send the amygdalar raw population signal to the hippocampus, and a second to send the differentiated result back for further processing. At best, this would require two simultaneous mutations. Either change by itself would be at best useless and could never be selected. This appears to be another example of irreducible complexity requiring the bi-mutation mechanism described in the previous post. 

The mechanisms usually offered to explain cases of apparent irreducible complexity, such as spandrelling, exaptation, and scaffolding, all appear to lack time efficiency and processiveness. I previously said that in evolution there are no (absolute)  deadlines, but relative deadlines can easily be created by an interaction of processes. In the presence of relative deadlines, such as adaptive footraces to be the first clade to exploit a newly-habitable area or a new niche, time is of the essence and selection for speed and evolvability can be expected. Such selection will create mechanisms such as crossing over that enhance evolvability.

#39. Can Irreducible Complexity Evolve? [genetics, evolution]

EV     GE     

Red, theory; black, fact.

5-26-2018: Influential biologist Richard Dawkins wrote in "The God Delusion" that a genuine case of irreducible complexity will never be found in biology. A case of irreducible complexity would be some adaptation that would require an intelligent designer because it could never evolve one mutation at a time, and Dawkins believes there is no such intelligent designer in biology.

In classic natural selection, each mutation must be individually beneficial to its possessor in order for selection to increase its prevalence in the population to the point where the next incremental, one-mutation improvement becomes statistically possible. In this way, all manner of wondrous things are supposed to evolve bit by tiny bit.

However, I am seeing irreducible complexity all over the place these days. For example, your upper-jaw dentition must mesh pretty accurately with that of your lower jaw or you can't eat. Thus, the process of evolutionary foreshortening of the muzzle of the great apes to the flat human face could never have happened, assuming that a single mutation affects only the upper or lower jaw. But it did. (Let us gloss over the fact that that is an assumption, because the contrary seems to require non-local rules in development.)

Furthermore, how can any instinctive signaling system evolve one mutation at a time? At a minimum, you always need both the transmitter adaptation and the receiver adaptation, not to mention further mutations to connect the receiver circuit to something useful. The evolution of altruism presents a similar problem. The lonely first altruist in the population is always at a disadvantage in competition with the more selfish non-mutants unless it also has a signaling system that lets it recognize fellow altruists (initially, close relatives) and a further mutation that places the altruistic behavior under the control of the receiver part of this system. Thus, altruists would only be altruistic to their own kind, the requirement for altruism to be selected in the presence of selfishness. Finally, the various parts of this system must be indissolubly linked in a way that the non-altruists cannot fake.

My solution is to label the crossing-over events that occur during meiosis as "tetra-mutations." In crossing over, two homologous chromosomes pair up along their length and swap a long segment of DNA, a process requiring four double chain breaks and their corresponding repairs. Because of the presence of single-nucleotide polymorphisms, the homologous chromosomes are not exactly the same, so that each of the upstream sides of the four chain breaks ends up in a subtly different genetic environment. If the break point falls between a cis-acting regulatory element and the corresponding structural gene, for instance, the former may now control the expression of a slightly different protein. Thus, there could be as many as four distinct functional consequences of one crossing-over event. Why not call that a tetra-mutation?

In this way, a concerted change affecting four distinct sites becomes possible. The two ends of the recombinant segment can in principle be functionally unrelated initially. They become related if both are affected by the same tetra-mutation and the entire change increases fitness and is thus selected.

A single tetra-mutation could in principle produce viable altruism at one stroke because of the number of simultaneous changes involved. 

The probability of a combination of simultaneous local changes being beneficial to the organism is much smaller on mathematical grounds than is the probability of a given single-nucleotide change being beneficial. However, these unfavorable statistics are at least partly offset by the existence of a dedicated system for producing tetra-mutations in large numbers, namely meiosis, part of the process of maturation of egg cells and sperm cells.

In the big picture, tetra-mutations provide a way for a species to discontinuously jump into new niches as they open up, possibly explaining how a capacity for this kind of mutation could spread and become characteristic of surviving species over time. This idea also provides a ready explanation for the lack of transitional forms in the fossil record.

5-30-2018: Here is the search description again, in case you missed it or could not see all of it: Sexual reproduction may allow the evolution of irreducible complexity by increasing the intrinsic complexity of the basic building block of change, the mutation.

6-12-2018: Upon further reflection, it seems that the tetramutation construct described above lacks validity because during gamete maturation it falls apart into two bi-mutations, both of which cannot contribute to the same zygote. The bi-mutation is stable, however, because of the intervening translocated DNA segment. It is harder to see how a complex adaptation like altruism could evolve out of nothing but mono-mutations and bi-mutations, but that does not mean the theory put forward in this post is necessarily wrong. One must not argue from lack of imagination. It is an interesting question, actually, what is the minimum set of all mutation types necessary to account for all known adaptations.

8-27-2019: In my ignorance, I have undersold the bi-mutation idea. A very far-reaching change to the genetic information can occur during crossing-over that is not at all subtle and is termed unequal crossing-over. This form of the process arises because of inaccuracies, sometimes major, in the initial alignment of the homologous chromosomes prior to crossing-over. When the process is finished, one chromosome has been shortened and the other has been lengthened, with gene duplication. This is the major source of gene duplication, which, in turn, is a major source of junk DNA, the part that is classified as broken genes. Two questions come to mind. The first is, are anatomical features such as jaw length and axon targets somehow controlled by variations in gene dose? The second, which is a tangent, is, are broken genes really broken or just temporarily switched off by genetic drift at some mutational hot spot in the recognition site of some transcription factor? The analogy here is to a generator in a power plant that has been placed in stand-down mode because of a temporary decrease in the demand for electrical power.