#74. Protein Batteries and Protein Misfolding Diseases [biochemistry]

CH

Red, theory; black, fact

Disclaimer 

If you are a PD or AD patient or at risk and are seeking a cure outside the medical mainstream, this is not for you. This is written for researchers. 

Inside Alzheimer’s and Parkinson’s 

The commonest protein misfolding disease, Alzheimer disease, features an accumulation of insoluble proteins as amyloid plaques that damage neurons and lead to dementia and death. 

The amyloid precipitates from a solution of amyloid beta protein, which forms by a two-step proteolysis of amyloid precursor protein (APP), an integral membrane protein of neurons.

APP is thought to play a role in the initial stage of synaptic plasticity and contains a copper binding site. 

What is the Power Source Driving Precipitation?

Oxidation of the coordinated copper upon insertion of nascent APP in the plasma membrane could shift the coordination geometry of the copper ion from planar-triangular to pyramidal, with huge changes in the preferred bond angles. If the coordinating protein cannot accommodate these changes without input of activation energy, the result would be a “protein battery”: a protein carrying a metastable “charge” of conformational strain energy. A set mousetrap would be a familiar example of this. 

Role of the Power Source in the Healthy Brain

The local availability of this energy cache may be necessary to allow brief pre- and post-synaptic electrical coincidences to be rapidly captured as preliminary synaptic morphological changes. The calcium-binding site next to the copper binding site (growth factor-like domain) may be the electric field sensor. Coincidence detection would involve same-molecule binding of APP molecules on opposite sides of the synaptic cleft, triggered by propagation of unleashed conformational changes from the copper site into the main extracellular domain, called the heparan-binding domain. (Better known parts of the coincidence detecting system are the NMDA receptor and CAM kinase II).

How the Power Source Goes Wrong

Protein misfolding diseases of the brain may be powered by a short circuiting of the APP energy caches, or analogous caches in proteins subserving other functions. One of those other functions could be replenishing the supply of docked synaptic vesicles in response to a sudden increase in the average neuron firing rate. In that case, the relevant battery protein would be alpha synuclein, which is implicated in Parkinson disease. Local energy caches are also present in humanly engineered electronic circuits, where they are called decoupling capacitors.

Loss of Control of the Stored Energy

 The secretases implicated in Alzheimer disease etiology would serve to degrade the discharged APP molecules. Secretase alpha would act rapidly to clear action-potential-discharged APP that did not make a cross link, and secretase beta would act slowly to clear cross links. Secretase gamma completes the cleavage in both cases. Secretase alpha would have a recognition site for discharged APPs and secretase beta would have an allosteric recognition site for cross links. Secretase beta action releases amyloid beta, the battery part of APP. The stored energy in amyloid beta would drive the polymerization process that leads to amyloid formation. This energy release would involve a conformational change, consistent with the finding that amyloid protein is misfolded. The conformational change could expose hydrophobic residues on the surface of the protein, an energy-requiring step that could lead directly to precipitation due to hydrophobic bonding among the amyloid beta molecules.

This action is easier to imagine for the central hydrophobic domain of alpha synuclein, the immediate effect being not precipitation but pulling two arbitrary ligands on different alpha synuclein molecules into closer proximity for a faster reaction between them. The trigger appears to be phosphorylation of alpha synuclein, not electric field change.

Closing a Fatal Positive Feedback Loop

By mischance, the soluble amyloid beta oligomers that form as intermediates along the amyloid-generating pathway are able to spoof APP cross links, thereby driving ectopic secretase beta activity and closing a feedback loop. This feedback leads to an out-of-control production of amyloid beta that produces Alzheimer disease.

#73. The Self-exciting Small-world Network in Behavioral States and Disease [Neuroscience, Biochemistry]

NE   CH

Red, theory; black, fact

Seen at the Red Roots Trading Co. 

Disclaimer

If you are a cancer patient or at risk and are seeking a cure outside the medical mainstream, this is not for you; this post is written for researchers.

Conventional Thinking on the Nature of Cancer

The refractoriness of cancer (its treatment resistance) is thought by a few authors I read forty years ago to be due to a kind of in-body evolutionary process made possible by the high mutation rate characteristic of these cells. The anticancer drugs we apply to kill the cancer exert an evolutionary selection pressure on the individualistic cancer cells, killing most of them but leaving a residue of accidentally resistant cells that happen to have mutations conferring resistance. These resistant cells then grow back the cancer in a relapse, even harder to kill than before. And so it goes through treatment after treatment until the patient is dead.

But what if that’s wrong?

An Alternative Explanation of Cancer Refractoriness

This seems possible in terms of a “cancer state” that is sustained by re-entrant (circulating) metabolic signaling pathways that form a small-world network (SWN). Curing the cancer requires extinguishing the reentrant activity, but this is difficult because of the robustness of the SWN. If one node in the network is pharmacologically ablated, the signaling can always flow around it by alternative pathways through the network. Thus, robustness becomes refractoriness.

Hub Nodes

The robustness of SWNs depends on their hub nodes—nodes with an unusually large number of connections. The state theory of cancer articulated here therefore directs us to pharmacologically target the hub nodes for greatest therapeutic efficacy. However, a practical therapy also requires selectivity. If we make the leap to assuming that all cellular actions involve entering and leaving states, that all states are identifiable with particular re-entrant SWNs, and that due to the parsimony of evolution, there is much overlap among SWNs and sharing of nodes, it seems possible that the set of hub nodes of a particular SWN can be used as a biochemical address for that SWN, leading to the desired selectivity. The other overlapping SWNs in the treated cell can survive the loss of only one or two hub nodes due to treatment, but not the targeted SWN, which loses all of them.

Problems with the Facts

However, these ideas predict zero response to a single drug, not a large but temporary response. Progress in resolving this will involve consideration of state-trait relationships. For example, a predilection for entering a particular state could be a genetically determined trait, and some states could exist that suppress DNA repair, leading to increasing genetic diversity. Lack of selectivity of anticancer drugs could also be a factor, so that the same drug could delete multiple hub nodes but not all of them.

SWNs in the Brain

Behavioral states such as aggression and siege mentality (the foibles of, respectively, capitalism and communism) also show refractoriness that may have the same cause. In these cases, some likely hub nodes are the neuromodulatory cell groups of the brainstem. An example is the locus ceruleus (LC), which distributes noradrenalin widely in the brain. (Noradrenalin is also the postganglionic transmitter of most of the sympathetic nervous system.) The existence of disciplines such as meditation suggests that some of the SWNs incorporating the LC also incorporate hub nodes in cerebral regions accessible to consciousness, probably including the brain’s language areas. More visceral hub nodes such as blood sugar level are probably also included.

Ancient Foreshadowings of this Theory

The need to treat multiple hub nodes simultaneously to extinguish maladaptive reentrant signaling may have been stated before, but in proto-scientific terms:

“Put on the whole armour of God…”

Saint Paul

#70. How the Cerebellum May Adjust the Gains of Reflexes [neuroscience]

NE

Red, theory; black, fact

The cerebellum is a part of the brain involved in ensuring accuracy in the rate, range, and force of movements and is well known for its regular matrix-like structure and the many theories it has spawned. I myself spent years working on one such theory in a basement, without much to show for it. The present theory occurred to me decades later on the way home from a conference on brain-mind relationships at which many stimulating posters were presented.

Background on the cerebellum

The sensory inputs to the cerebellum are the mossy fibers, which drive the granule cells of the cerebellar cortex, whose axons are the parallel fibers. The spatial arrangement of the parallel fibers suggests a bundle of raw spaghetti or the bristles of a paint brush. These synapse on Purkinje cells at synapses that are probably plastic and thus capable of storing information. The Purkinje (pur-kin-gee) cells are the output cells of the cerebellar cortex. Thus, the synaptic inputs to these cells are a kind of watershed at which stimulus data becomes response data. The granule-cell axons are T-shaped: one arm of the T goes medial (toward the midplane of the body) and the other arm goes lateral (the opposite). Both arms are called parallel fibers. Parallel fibers are noteworthy for not being myelinated; the progress of nerve impulses through them is therefore steady and not by jumps. The parallel fibers thus resemble a tapped delay line, and Desmond and Moore proposed this in 1988.

The space-time graph of one granule-cell impulse entering the parallel-fiber array is thus V-shaped, and the omnibus graph is a lattice, or trellis, of intersecting Vs.

The cerebellar cortex is also innervated by climbing fibers, which are the axons of neurons in the inferior olive of the brainstem. These carry motion error signals and play a teacher role, teaching the Purkinje cells to avoid the error in future. Many error signals over time install specifications for physical performances in the cerebellar cortex. The inferior olivary neurons are all electrically connected by gap junctions, which allows rhythmic waves of excitation to roll through the entire structure. The climbing fibers only fire on the crests of these waves. Thus, the spacetime view of the cortical activity features climbing fiber impulses that cluster into diagonal bands. I am not sure what all this adds up to, but what would be cute?

A space-time theory

Cute would be to have the climbing fiber diagonals parallel to half of the parallel-fiber diagonals and partly coinciding with the half with the same slope. Two distinct motor programs could therefore be stored in the same cortex depending on the direction of travel of the olivary waves. This makes sense, because each action you make has to be undone later, but not necessarily at the same speed or force. The same region of cortex might therefore store an action and it’s recovery.

The delay-line theory revisited

As the parallel-fiber impulses roll along, they pass various Purkinje cells in order. If the response of a given Purkinje cell to the parallel-fiber action potential is either to fire or not fire one action potential, then the timing of delivery of inhibition to the deep cerebellar neurons could be controlled very precisely by the delay-line effect. (The Purkinje cells are inhibitory.) The output of the cerebellum comes from relatively small structures called the deep cerebellar nuclei, and there is a great convergence of Purkinje-cell axons on them, which are individually connected by powerful multiple synapses. If the inhibition serves to curtail a burst of action potentials in the deep-nucleus neuron triggered by a mossy-fiber collateral, then the number of action potentials in the burst could be accurately controlled. Therefore, the gain of a single-impulse reflex loop passing through the deep cerebellar nucleus could be accurately controlled. Accuracy in gains would plausibly be observed as accuracy in the rate, range, and force of movements, thus explaining how the cerebellum contributes to the control of movement. (Accuracy in the ranges of ballistic motions may depend on the accuracy of a ratio of gains in the reflexes ending in agonist vs. antagonist muscles.)

Control of the learning process

If a Purkinje cell fires too soon, the burst in the deep-nucleus neuron will be curtailed too soon, and the gain of the reflex loop will therefore be too low. The firing of the Purkinje cell will also disinhibit a spot in the inferior olive due to inhibitory feedback from the deep nucleus to the olive. I conjecture that if a movement error is subsequently detected somewhere in the brain, this results in a burst of synaptic release of some monoamine neuromodulator into the inferior olive, which potentiates the firing of any recently-disinhibited olivary cell. On the next repetition of the faulty reflex, that olivary cell reliably fires, causing long-term depression of concurrently active parallel fiber synapses. Thus, the erroneous Purkinje cell firing is not repeated. However, if the firing of some other Purkinje cell hits the sweet spot, this success is detected somewhere in the brain and relayed via monoamine inputs to the cerebellar cortex where the signal potentiates the recently-active parallel-fiber synapse responsible, making the postsynaptic Purkinje cell more likely to fire in the same context in future. Purkinje cell firings that are too late are of lesser concern, because their effect on the deep nucleus neuron is censored by prior inhibition. Such post-optimum firings occurring early in learning will be mistaken for the optimum and thus consolidated, but these consolidations can be allowed to accumulate randomly until the optimum is hit.

Role of other motor structures

The Laplace transform was previously considered in this blog to be a neural code, and its output is a complex number giving both gain and phase information. To convert a Laplace transform stored as poles (points where gain goes to infinity) in the cerebral cortex into actionable time-domain motor instructions, the eigenfunctions corresponding to the poles, which may be implemented by damped spinal rhythm generators, must be combined with gains and phases. If the gains are stored in the cerebellum as postulated above, where do the phases come from? The most likely source appears to be the basal ganglia. These structures are here postulated to comprise a vast array of delay elements along the lines of 555 timer chips. However, a delay is not a phase unless it is scaled to the period of an oscillation. This implies that each oscillation frequency maps in the basal ganglia to an array of time delays, of which none are longer than the period. These time delays would be applied individually to each cycle of an oscillation. Such an operation would be simplified if each cycle of the oscillation were represented schematically by one action potential.

Photo by Robina Weermeijer on Unsplash

#63. How Noncoding RNA May Work [chemistry]

 CH

Red, theory; black, fact

Back, DNA; red, long noncoding RNA; green, transcription complex. A loop closes through an RNA running from bottom to top (not shown).

No junk DNA

The junk-DNA concept is quite dead, killed by the finding that the noncoding sections (sections that do not specify functional proteins) have base-pair sequences that are highly conserved in evolution and are therefore doing something useful.

Role of long non-coding RNA

So-called junk DNA is useful because the RNA transcripts made from it are useful, serving as controllers of the transcription process itself and thus, indirectly, of protein expression. Changes in protein expression may be considered the immediate precursor of a cell's response to its environment, analogous to muscle contractions in an intact human. Small noncoding RNAs seem to be repressors of transcription and long noncoding RNAs (lncRNA) may either repress or promote. Despite the accumulation of much biochemical information, summaries of what lncRNA does seem to me unfocussed and unsatisfactory.

Background on control of gene transcription 

The classical scheme of protein expression, due to Jacob and Monod, was discovered in bacteria, in which a signal molecule from the environment (lactose in the original discovery) acts by binding to a protein to change its conformation (folding pattern). The changed protein loses the ability to bind to DNA upstream from the sequence that specifies the lactase enzyme, where it normally acts to block transcription. The changed protein then desorbs from DNA, which triggers transcription of lactase messenger RNA, which is then translated into lactase enzyme, which confers on the bacterium the ability to digest lactose. Thus, the bacterium adapts to the availability of this food source.

All this can be modelled in neurobiological terms. Clearly, it's a reflex comparable to the spinal reflexes in vertebrates. An elementary sensorium goes in and an elementary response comes out. However, vertebrates also have something higher than spinal reflexes: operations by the brain.

A neuron-inspired theory of long non-coding RNA

Noncoding RNAs may have a coordinating role: rather than relying on a set of independently acting "reflexes," eukaryotic cells may be able to sense many promoter signals at once, as a gestalt, and respond with the expression of many proteins at once, as another gestalt. An entire brain is not needed to model this process, just one neuron. The synaptic inputs to the dendrites of the neuron can model the multiple promoter activations, and the eventual output of a nerve impulse (action potential) can represent the signal to co-express a certain set of proteins, which is hard-wired to that metaphorical neuron by axon collaterals. In real neurons, action potentials are generated by a positive feedback between membrane depolarization and activation of the voltage-gated sodium channel. This positive feedback can be translated into molecular biology as a cyclic, autocatalytic pattern of lncRNA transcription, in which each lncRNA transcript in the cycle activates the enhancer (which is like a promoter) of the DNA of the next lncRNA in the cycle. The neuron model suggests that the entire cycle has a low level of baseline activity (is "constitutively active" to some extent) but the inhibitory effect of the small noncoding RNAs (analogous to what is called the rheobase current in neurons) suppresses explosive activation. However, when substantially all the promoters in the cycle are activated simultaneously, such explosive transcription occurs. The messenger RNA of the proteins to be co-expressed as the coordinated response is generated as a co-product of lncRNA hyper-transcription, and the various DNA coding regions involved do not have to be on the same chromosome.

#61. Consciousness is Google Searches Within Your Brain [neuroscience]

NE

Red, theory; black, fact

The brain is like this because the long connections define the computations.

The Google search is too good a trick for Nature to miss and she didn't, and it's called consciousness.

Brain mechanism of consciousness

I conjecture that the human brain launches something like a Google search each time an attentional focus develops. This is not necessarily a literal focus of activity on the cortex; it is almost certainly a sub-network activation. The sub-net activity relays through the prefrontal cortex and then back to sensory cortex, where it activates several more sub-nets; each of these, in turn, activates further sub-nets via the prefrontal relay, and so on, exponentially. At each stage, however, the degree of activation declines, thereby keeping the total cortical activation limited.

Accounting for subjective experience

The first-generation associations are likely to be high in the search rankings, and thus subjectively "close" to the triggering attentional focus and relatively strongly in consciousness, although still in the penumbra that is subjectively "around" the attentional focus. Lower-ranking search results would form a vast crowd of associations only dimly in consciousness, but would give conscious experience its richness. Occasionally, an association far out in the penumbra will be just what you are looking for and will therefore be promoted to the next attentional focus: you get an idea.

The role of emotions

The evaluation process responsible for this may involve the mediolateral connections of the cortex, which lead back to the limbic system, where emotions are thought to be mediated, at the cingulate gyrus. Some kind of pattern recognition seems necessary, whereby a representation of what you desire, itself a sub-network activation elaborated by the mediolateral system, is matched to retrieved associations. Your target may be only a part of the retrieved association, but will suffice to pull the association into the attentional focus.

This system would allow a mammal to converge everything it knows on every task, rather than having to perform as a blinkered if-then machine.

Brain mechanisms and our evolutionary history

Why should we have this back-and-forthing between the prefrontal cortex and the sensory association cortex? Two possible explanations are: 1) The backward projections serve a priming function, getting certain if-then rules closer to firing threshold in a context-sensitive manner; 2) This action is a uniquely human adaptation for our ecological niche as environment modifiers. 

In ordinary tool use and manufacturing dating back to Homo habilis, the built thing is smaller than the builder's body, but in environment modification, the built thing is larger than the builder's body. Thus, the builder can only see one part of it at a time. Viewings must therefore be interleaved with reorientations involving the eyes, neck, trunk, and feet. These reorientations, being motoric in nature, will be represented frontally, and I place these representations in the prefrontal cortex. The mental representation of the built thing therefore ends up being an interleaved collection of views and reorientations, in other words, a simulation. The reorientations would have to be calibrated by the vestibular system to allow the various views to be assembled into a coherent whole. By this theory, consciousness is associated with environment modification.

Consistent with this theory, the cortical representation of vestibular sense data is atypical. There is no "primary vestibular area." Rather, islands of vestibular-responsive neurons are scattered over the sensory cortex, distributing across the other senses. This seems analogous to a little annotation for xyz coordinates, etc., automatically inserted in a picture, as seen in computer-generated medical diagnostic images.

#59. Neuromodulators as Peril Specialists [neuroscience, evolution]

NE   EV

Red: theory; black, fact

Solanum dulcamara, a plant with anticholinesterase activity.

“Life is difficulty.” -The Buddha Gautama

My PhD thesis was about a neuromodulator (acetylcholine) acting on mammalian brain. It was tough to decapitate so many rats; I never got used to it.

The basic theory

I conjecture that the primordial function of any type of transmitter substance acting on the g-protein-coupled cell-surface receptors or nuclear receptors of neurons was to coordinate the whole-organism response to some class of perils.

Table 1.

Peril	Substance	Failure mode
Extremes of heat and cold	glutamate and GABA	?
Predator	serotonin	depression
Parasite	histamine	phobia
Rival conspecific	noradrenaline	paranoia
Social isolation

#48. The Reentrant-pathway Theory of Mental Illness [neuroscience]

NE

Red, theory; black, fact

If a region of cerebral cortex is overgrown relative to a major synaptic partner, not only will it be starved of synaptic input from the partner, but it will also produce excess axons going to that partner that will have difficulty finding enough dendritic territories on which to synapse. Both difficulties can be solved at one stroke, however, if the overgrown area synapses on itself. The logic is similar to the application of valence rules in chemistry.

This mode of repair will produce cyclic signaling pathways (called “reentrant” in electrophysiology) that could support endlessly circulating neural activity. This is therefore an alternative way of getting autonomous activity from disregulated cortical growth, with no need to invoke the phenomenon of denervation supersensitivity. The loop circumnavigation time would have to be long enough to allow for the recovery of any refractory periods that may follow nerve-impulse firing.

The autonomous activity will give rise to hallucinations (psychotic symptoms) if the reentrant pathway is in sensory cortex, and to manic behavior if in cortex with motoric functions, which would include planning. Since an emotion may be a high-level motor command, a re entrant pathway in frontal limbic cortex would produce an apparent emotion disconnected from conscious experience and if in posterior limbic cortex, an erroneous emotion trigger.

The situation is very similar if a cortical area is normal in size but one of its main synaptic partners is reduced in size by disease. In epileptogenesis, the post-damage remodeling of the local neural networks is known to be associated with new-synapse formation and the sprouting of axon collaterals. The hyperexcitable brain tissue responsible for triggering seizures is known to lie just outside the dead core zone of the damaged region, and can therefore be called “overgrown” relative to the dead zone, which has zero functioning neurons.

All this is compatible with the formation during the epileptogenesis latent period of a pair of counter circulating, polysynaptic “ring roads” around the perimeter of the damaged area. This process would be determined by simple rules of valency satisfaction. Both ring roads would be capable of carrying autonomous activity that progresses to a seizure. This might only happen if inhibitory tone is also compromised. Hallucinations and seizures seem to be different grades of the same phenomenon.  Indeed, auditory hallucinations commonly occur in association with temporal-lobe seizures. The temporal lobe is the location of the auditory cortex (Brodmann areas 41 and 42).

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

NE  EV  GE    

Red, theory; black, fact

Midplane section of human brain annotated with the Brodmann areas, which are related to different functions

People contract 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.

The Evolution of the Human Brain

In other words, the mentally ill may carry the unfavorable mutations that have to be selected out during this progress. The mutation rate in certain categories of mutation affecting human brain development may be elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes 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. There may not be any master program doing this coordination. Rather, the human brain would comprise scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. This 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. 

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. The crossing-over phenomenon in egg and sperm maturation may create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. Since the two linked mutations are individually random, linkage per se does not eliminate asymmetry. That must be done by natural selection, as previously stated, so there is a subtlety here. Natural selection could equally well create adaptive asymmetry. The human heart and the claws of the fiddler crab are examples.

Functional Human Brain Anatomy 

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which would implement 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.

Possible Disorders of Brain Growth

Due to such tight coordination, 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, prefrontal cortex will be starved of sensory input. In the latter case, sensory association cortex will be 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 is an adaptation to compensate for weak nerve transmission with a 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 general.

In cases of genetically-determined frontal-parietal/temporal imbalance, the input-starved side would develop denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

Differential Growth-Related Brain Disorders 

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia.

The non-overgrown association cortex might 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.

Picture credit: Wiki Commons

#41. Corporate Sin [evolutionary psychology]

EP

Red, theory; black, fact

Not all of humanly willed destruction is due to two persons interacting, either in a sadness cycle or an anger cycle. Wars of depopulation and wars of dispersal represent these interactions promoted to the level of entire societies. This promotion theory assumes that the same hard-wired wetware is being used for both levels, but with the addition of a few more bits of code to support the social level.

Theologians such as Bishop Baycroft, writing in "The Anglican Way," are well aware of this extra dimension of human misery, referring to it as "corporate sin," and admit that it is a more difficult problem than individual sin. The advice I give in "Signaletics for Salvation" will not help you efficiently if your unhappiness has its roots in corporate sin (for example, if you are caught up in a military draft or are a slave), but it may be better than nothing. What about those extra bits of code?

The basic code design seems to be to transform a tiff between two individuals into a tiff between two leaders, then copy the emotions of the leaders into the heads of all the followers on both sides. Thus, a political leader is a kind of emotional conductor. This is why we have leaders.

By this theory, World War II was a tiff between Adolf Hitler and Winston Churchill, both famous for their speeches in which they inspired passions in their followers.

How do you get to be leader? The simplest answer seems to be that you just get famous and you are also someone who doesn't see a way to end his pain without involving the whole world. 

An attractive theory about fame, in turn, is that fame is 90% being-famous-for-being-famous, and 10% is being famous for something else, the predisposing factor. Human intergroup interactions have the form we observe because these predisposing factors are not random but are due to natural selection. Moreover, they are conditional upon prevailing conditions, such as the price of bread relative to wages. Finally, they already exist at the individual level. The process of garnering the absurd 90% of fame is the by-now familiar phenomenon of going viral, and its earlier historical equivalents. 

I imagine that this process is a positive feedback loop in the brain that involves the attentional system and Hebbian plasticity, the latter well known for having a built-in positive feedback. We also know that emotions are contagious (See: Hatfield E, Cacioppo JT, Rapson RL. Emotional Contagion. New York: Cambridge University Press, 1994).

#40. The Sadness Cycle [evolutionary psychology, neuroscience]

EP   NE

Red, theory; black, fact

Niccolo Machiavelli by Tito

The anger cycle and the sadness cycle may reach their full flower in wars of dispersal and wars of depopulation, respectively. 

The Function of the Sadness Cycle 

Wars of depopulation would serve to prevent Malthusian disasters such as general famine. The sadness cycle is a form of altruism that facilitates this depopulation by making a portion of the population sad and suicidal and the remainder contemptuous and entitled. The contemptuous ones take everything the sad ones have, ultimately their lives, and the sad ones let them.

If the sadness signalers were fighting tooth and nail, the transfer of property would leave the contempt signalers with many injuries, which would defeat the purpose of the whole process, which is to leave the residual population stronger and healthier than before under conditions of restricted food supply. Moreover, the sad ones and the contemptuous ones are playing two roles within the same adaptation, and if you can play one role, you can play the other. 

The Sadness Cycle in Evolution 

Since no altruism can evolve in the presence of selfishness unless the altruists are only altruistic to each other, a signaling cycle is required to lock the altruists together to the exclusion of non-altruists. Thus, sadness induces contempt and contempt induces sadness, and so on in a vicious cycle leading to the complete destruction of the sad ones and the transfer of all their property specifically to the contemptuous ones. This dynamic could be the origin of elder abuse and clinical depression.

History Repeats 

Machiavelli wrote, "He is made contemptible who is held to be changeable, light, effeminate, pusillanimous, irresolute, and from these the Prince must guard himself as from a reef." The traits listed appear to be the symptoms of unacknowledged sadness, and were no doubt quite lethal in Macchiavelli's time. Due to the present skyrocketing of the world population with the concomitant "Calhoun effect" from crowding stress, we are no doubt due for a remachiavellianization of daily life. 

The Anger Cycle 

Much of human unhappiness comes from destructive, escalating signaling cycles, usually between two persons. Examples are arguments, feuds, schools of thought, gang wars, and revolutions. The signals exchanged are initially personal expressions of anger. Importantly, these expressions are multi modal, and therefore highly redundant. (e.g., threatening utterances, tones of voice, facial expressions, gait, crashing and banging things, spying, following, etc.) Your anger comes out of you "through every pore."

The Function of the Anger Cycle

These signals are too many and varied for conscious control, which is why most people remain enslaved by their signals and cycles. The anger cycle may be selected so as to escalate until one of the parties must leave the country. When people are threatened, they seek allies, so all of society eventually gets drawn in and polarized as the escalation proceeds apace, like a black hole. Therefore, it is a group that must eventually leave, not a single individual, which is the basis of the refugee phenomenon. 

Evolution of the Anger Cycle 

In ecological terms, the refugee phenomenon is clearly sub-serving dispersal. However, dispersal-producing behavior is fundamentally altruistic in a backhanded way. The benefit to the supposed loser, the group that eventually gets driven out, is that occasionally they find a newly-emptied vacant habitat in which to settle and therefore can reproduce without competition. This is a tremendous benefit in evolutionary terms and may once have been great enough to redeem all the waste and suffering of human-style dispersal. 

However, altruistic behavior cannot evolve in the presence of non-altruists unless a signaling system is established to ensure that altruists are only altruistic to each other. That is why signaling is emphasized here. The reason why the signals are multimodal is that the altruism program probably breaks down occasionally because of the short-term advantages of being a non-altruist. This has probably happened many times in the past and the broken algorithm was repaired each time by natural selection with the addition of yet another signal component. 

The Bigger Picture 

The various signal cycles may reinforce each other. The four signal cycles that seem to form the framework of human life seem to have such an interdependence. These are: mother-child bonding, which could potentiate man-woman bonding, which could potentiate the anger cycle (via jealousy), which could potentiate the sadness cycle.

 

Picture credit: Wiki Commons

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

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Red, theory; black, fact

A schematic of a simple rate-of-increase controller mechanism

Historical 

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. Several lines of evidence point to the idea that humans 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.

Human Population is Being Controlled for Endless Trouble

The natural population curve for humans in good times may be 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. 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; not to a constant absolute density, but 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.

Neuroscience Aspects

Researchers should look first for such a controller in the hypothalamus, already known to control other variables, such as temperature, by feedback principles.

"Nature does not reinvent the wheel" [quote from my old Professor], 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.

Engineering Aspects 

The population controller may contain a conventional PID controller. To make it control rate of increase rather than absolute population density, you put a differentiator in the feedback pathway. 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. 

Back to Neuroscience 

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  inhibit the feed-forward pathway pharmacologically with sufficient specificity 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.

The political convulsions that produce dispersal would be triggered by the value on the integrator of the PID controller rising above a threshold. The amygdala of the brain may mediate this. Consistent with this, bilateral removal of the amygdala and hippocampus in monkeys is known to have a profound taming effect accompanied by hypersexuality, known as the Kluver-Bucy syndrome.

#36. Two Kinds of War [evolutionary psychology, engineering, neuroscience]

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Red, theory; black, fact

A Nazi Enigma code machine (Canadian War Museum)

There are probably two basic biological uses for human anger: dispersal, and providing an emergency brake on population increase that avoids Malthusian disasters by triggering wars. The second kind of war ends life without being notably efficient in producing mass migration. 

The Past

I have long wondered why the Four Horsemen of the Apocalypse seem to include two gentlemen in charge of warlike matters. Why the apparent duplication? The above may give the reason: one (with the bow) represents wars of depopulation and the other (with the sword) represents wars of displacement.

The Coventry Blitz produced so much mass migration into the countryside surrounding that city that it was an embarrassment for the British government, calling into question Britain’s willingness to fight. Was Coventry some kind of watershed, before which the conflict was of the displacement type, and afterward, of the depopulation type?

The facts bear this out, considering Nazi treatment of the Jews as a litmus test of the zeitgeist of that time. After coming to power in 1933, the Nazis aimed at forcing the Jews to emigrate, and by the outbreak of hostilities in September, 1939, 250,000 of Germany’s 437,000 Jews had done so. The Coventry Blitz was in November, 1940. The Holocaust began, in terms of men, women, and children all being targeted for execution, in August, 1941, nine months later. The German zeitgeist seems to have shifted gears in the fall of 1940, aiming at depopulation rather than displacement. I am obviously assuming that the evolutionary, selectionist justification of the Holocaust given at the time, in forums such as the 1942 Wannsee conference, was a rationalization.

A Sociological Theory

Wars brought on by population pressure may begin as the displacement type, and if this does not result in sufficient local reduction in population pressure after a certain time, the hostilities shift gears to the depopulation type of conflict. 

If human population is under PID [proportional-integral-derivative] control by the subconscious, the event causing the shift could be the amount of signal accumulated on the integrator rising above some threshold. This may actually be a second threshold, with the first and lower threshold controlling the outbreak of a war of displacement.

A paradoxical outcome of Calhoun's overpopulation experiments on rodents can be explained in terms of such an integrator. 

Calhoun’s Classical Experiment 

By providing unlimited food and water to a founder population of rats or mice, with regular bedding changes and exclusion of predators and parasites, the rodents were allowed to increase their population to fabulous numbers. However, the rodents were given no extra space. As the population soared to incredible densities, all kinds of pathological behaviors appeared along with a great deal of violence. Birth rates plummeted after a "behavioral sink" developed, and remained low, never recovering, as the population decreased all the way to zero.

An Engineering-inspired Theory 

My interpretation of the behavioral sink is that it is integrator windup, a pathology of humanly engineered PID controllers, and possibly natural ones too. The signal accumulated on the integrator has been building for so long, and the population crash is so sudden, that not enough time is spent at population densities below set point to cancel the "control debt" on the integrator, so it continues to insanely command a zero birth rate even as the population is heading for zero.

Philosophers May Have Noticed This

George Santayana wrote that "Fanaticism consists of redoubling your efforts when you have forgotten your aim." [source, Wiki quotes, accessed 06-11-2018] Which sounds like integrator windup to me.

The Future 

A third and highest threshold of the control debt may exist, which, if crossed, leads to the human behavioral sink and the possible destruction of the human race due to essentially psychological causes. In the behavioral sink, I postulate that everyone would be a ZPG (Zero Population Growth) fanatic and unable to change without pharmacological help. (Good old booze? It may not be that simple.)

#27. The Origin of Consciousness [neuroscience]

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Red, theory; black, fact

We begin life conscious only of our own emotions. Then the process of classical conditioning, first studied in animals, brings more and more of our environment into the circle of our consciousness, causing the contents of consciousness to become enriched in spatial and temporal detail. Thus, you are now able to be conscious of these words of mine on the screen. However, each stroke of each letter of each word of mine that now reaches your consciousness does so because, subjectively, it is "made of" pure emotion, and that emotion is yours.

Some analogies come to mind. Emotion as the molten tin that the typesetter pours into the mold, the casting process being classical conditioning and the copy the environmental data reported by our sense organs. Emotion as the area on one side of a fractal line and sensory data the area on the other side. Emotion as an intricately ramifying tree-like structure by which sensory details can send excitation down to the hypothalamus at the root and thus enter consciousness.

The status of "in consciousness" can in principle affect the cerebral cortex via the projections to cortex from the histaminergic tuberomamillary nucleus of the hypothalamus. Histamine is known to have an alerting effect on cortex, but to call it "alerting" may be to grossly undersell its significance. It may carry a consolidation signal  for declarative, episodic, and flash memory. Not for a second do I suppose all of that to be packed into the hippocampus, rather than being located in the only logical place for it: the vast expanse of the human cerebral cortex.