#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.

#62. Storming South [evolution, evolutionary psychology]

EP   EV

Red, theory; black, fact

This is a theory of the final stages of human evolution, when the large brain expansion occurred.

H. sapiens appears to have arisen from Homo erectus over the last 0.8 million years due to climate instability in the apparent origin area, namely East Africa. During this time, Europe was glaciated every 0.1 million years because of the astrophysical Milankovitch cycle, a rhythm in the amount of eccentricity in the Earth's orbit due to the influence of the planet Jupiter.

However, consider the hominins who had settled in Europe (or Asia, it doesn't matter for this argument) during the interglacial periods (remember that H. erectus was a great disperser) and when the ice began advancing again, were now facing much worse cooling and drying than in Africa, and thus much greater selection pressures. At least during the last continental glaciation, the ice cap only extended to the Baltic Sea at the maximum, but long before the ice arrives, the land is tundra, which can support only a very thin human population. In any given glaciation, the number of souls per hectare the land could support was relentlessly declining in northern Europe/Asia, and eventually the residents had to get out and settle on land further south, almost certainly over the dead bodies of the former owners. This would have selected early Europeans or Asians for warlike tendencies and warfaring skills, which explains a lot of human history. 

Our large brains

However, our large brains seem to be great at something else besides warfaring: that is, environment modification. It's clear that the first thing someone living in the path of a 2-km wall of ice needs is to keep from freezing to death, and this would have been the first really good reason to modify environments. Unlike chipping a stone axe, environment modification involves fabricating something bigger than the fabricator. Even a parka has to be bigger than you or you can't get into it. This plausibly would have required a larger brain to enable a qualitatively new ability: making something you can't see all at once when it is at working distance.

Our rhythmic evolution

After parkas, early northerners might have evolved enough association cortex on the next glaciation cycle to build something a little bigger, like a tent or a lean-to. On the next cycle, they might have been able to pull off a decent longhouse made of wattle. On the next, a castle surrounded by cultivated lands and drainage ditches. These structures would have delayed the moment of decision when you have to go and take on the hominins to the south. This will buy you time to build up your numbers, and I understand that winning battles is very much a numbers game. Therefore, environment modification skill would have been selected for in tandem with making like army ants.

The fossil evidence for this theory

Fossil evidence of all this in Europe or Asia may exist in the form of Neanderthal and Denisovan discoveries, hominins who have been difficult to account for in terms of previous theories of human origins. My scenario can be defended against the fossil evidence for a human origin in East Africa in general terms by citing the well-known incompleteness of the fossil record and its many biases. Moreover, a detailed explanation begins by citing what else is in East Africa: the Suez, a land bridge to both Europe and Asia via the Arabian tectonic block, which was created by plate tectonics near the end of the Miocene, thus antedating both H. sapiens and H. erectus. Not only can hominins disperse through it to other continents during interglacials, but they can come back in, fiercer and brainier than before, when the ice is advancing again, to then deposit their fossil evidence in the Rift Valley region of East Africa. The Eurasian backflow event of 3000 years ago may be a relatively recent example of this. The Isthmus of Suez is low-lying and thus easily drowned by the sea, but the probability of this was minimal at times of continental glaciation, when sea levels are minimal. This argument has similarities with the Beringia theory of how North America was populated. Early hominins may have expanded like a gas into whatever continent they could access. Increasing glaciation/tundrafication of that continent would have recompressed the "gas" southward, causing it to retrace its path, partly back into Africa. 

Pleistocene selection pressures

This process would have been accompanied by great mortality and therefore, potentially, much selection. Moreover, during the period we are considering, temperatures were declining most of the time; the plot of temperature versus time has a saw-tooth pattern, with long declines alternating with short warming events, and it is the declines that would have been the times of natural selection of hominins living at high latitudes.

A limestone block in Canada showing scratches left by stones embedded in the underside of a continental glacier. The rock has also been ground nearly flat by the same process.

#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

#56. Stress and Schizophrenia [neuroscience]

NE

Red, theory; black, fact

Introduction

The main positive symptoms of schizophrenia, namely hallucinations, word salad, and loosening of associations, all seem to be variations of the latter, so loosening of associations will here be taken as the primary disorder. Stress and the brain's dopaminergic system are strongly implicated in the causation of schizophrenia. In connection with stress, psychologists speak of "the affective [emotional] pathway to schizophrenia." 

Organismal responses to stress

Stress is known to increase genetic variability in bacteria, a process known as transformation. Stress is likewise known to increase the meiotic recombination rate in sexually reproducing organisms such as fruit flies. (Stress-induced recombination and the mechanism of evolvability. Zhong W, Priest NK. Behavioral ecology and sociobiology. 2011;65:493-502.) It seems that when an organism is in trouble, it begins casting about ever more widely for solutions. If evolution is the only mode of adaptation available, this casting about will take the form of an increase in the size and frequency of mutations. In conscious humans, however, this casting about in search of solutions in the face of stress may well take the form of a loosening of associations during thought. Should the person find the solution he or she needs, then presumably the stress levels go down and the thought process tightens up again, so we have a negative feedback operating that eventually renormalizes the thought process and all is well. In optimization theory, this process is called "simulated annealing."

Disorder of a cognitive stress response

But what if the person does not find the solution they need? Then, presumably the loosening of associations gets more and more pronounced ("reverse annealing") until it begins to interfere with the activities of daily living and thus begins to contribute net stress, thus making matters worse, not better. Now we have a pernicious positive feedback operating, and it rapidly worsens the state of the sufferer in what is known as a psychotic break, resulting in hospitalization. That these psychotic breaks are associated with tremendous stress is made clear by the fact that post-traumatic stress disorder is a common sequel of a psychotic episode.

 

Stress: molecular aspects

Messenger substances (i.e., hormones and neuromodulators) known to carry the stress signal are: CRF, ACTH, cortisol, noradrenaline, adrenaline, dopamine, NGF, and prolactin. The well-known phenomenon of stress sensitization, which may be part of the disease mechanism of schizophrenia, probably inheres in long-term changes in protein expression and will not be apparent in a simple blood test for any of the above substances without a prior standardized stress challenge. (e.g., the process of getting the needle itself. In that case, you would install a catheter through the needle to permit repeated blood sampling and collect the baseline sample long after the intervention sample, not before, as is customary in research.)

Other mental illnesses

Bipolar disorder may result from an analogous positive feedback affecting another problem solving adaptation of the brain, which would be modelled by the alternation of brainstorming sessions (mania) with sessions in which the brainstormed productions are soberly critiqued (depression).

Brain mechanisms

How does the loosening of associations of schizophrenia arise? I conjecture that one activated sensory memory represented in the posterior cortex does not activate another directly, but indirectly via an anatomically lengthy but fast relay through the prefrontal cortex, which has a well known dopaminergic input from the ventral tegmental area of the midbrain. A higher vertebrate may have a free-will spectrum, with machine-like performance and high dopaminergic tone at one end, and at the other, a carefully considered performance verging on overthinking, with low dopaminergic tone. Persons with schizophrenia have pushed past the latter end of the spectrum into dysfunction. Dopamine could orchestrate movement along the free-will spectrum by a dual action on the prefrontal cortex: inhibiting associational reflexes passing back to posterior cortex while facilitating direct outputs to the motor system. Dual actions of neuromodulators are a neuroscientific commonplace (e.g., my PhD thesis) and dopamine is a neuromodulator. The NMDA receptor, which is also strongly implicated in schizophrenia, enters the picture as the source of excitation of the ventral tegmental area.

Photo by Ameer Basheer on Unsplash

#51. Advanced Human Depopulation Model [population, evolutionary psychology]

PO   EP

Red, theory; black, fact

Picture 1: A four-stage model of a human depopulation event. C = cycle; growth = growth phase; depop = depopulation

Picture 1 shows a four-stage model of human depopulation events that is intended to account for more data than heretofore. The same two emotional programs, the anger cycle and the sadness cycle occur in two "generations," with the second generation having greater violence and using modified signals.

• Stage 1: depopulation by emigration; accomplishes dispersal of the human species; coordinated by an exchange of anger signals;
• Stages 2-4: depopulation by mass murder: accomplishes long-term population density confinement within limits;
• Stage 2: coordinated by an asymmetric exchange of contempt and sadness signals; has similarities with cannibalism;
• Stage 3: total war program; coordinated by an exchange of anger signals with mimicry added;
• Stage 4: loss of civilization; triggered by a repudiation of the social contract by trusted elites with grudges: coordinated by increasing paralysis on the part of victims and increasing cynicism on the part of perpetrators. May be too recent an evolutionary development to have an efficient halting signal.

Nevertheless, the modes of worship of Islam are the best place to look for such a signal or other remedy if it exists. In this connection, the Islamic prayer discipline has potential to alter brain physiology, based on variations in blood flow to this organ, known to be highly sensitive to same. The variations would come about as a result of the highly regimented posture changes occurring during Islamic prayer. I have coded these postures according to the probable effect on blood pressure measured at the brain, and the result looks like this:

Picture 2. The inferred brain physiology of Islamic prayer. Source of data: YouTube, "Time to pray with Zacky," accessed 05-23-2019.

 Shown are my inferred variations in brain oxygenation during two rakat, or units of prayer. Bowing is coded the same as sitting, namely 1. Prostration is coded as 2 and standing is coded as 0. Some forms of Islam prescribe up to 19 rakat per day. Special procedures (Sujud Sahwi) exist for fixing prayers performed erroneously due to "forgetfulness" but this "forgetfulness" I find suggestive of temporary brain dysfunction due to lack of oxygen from getting up too quickly, possibly at about minute 2, above.

The above observation is to help establish that Islamic prayer manipulates a variable that matters, always an important issue at the outset of a research project. You don't want to waste taxpayer money blindly researching variable after variable and concluding at great expense merely that none of them was relevant.

#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).

#46. Body-mod Bob's [evolution, evolutionary psychology]

EP   EV

Red, theory; black, fact

Techno-evolution 

Evolution may be operating in cooperation with a general capacity for technology. Natural selection would operate on the brain pathways underlying our aesthetic preferences concerning our own appearance and that of possible reproduction partners, and then a technology would automatically be developed to satisfy the new preferences.

In the Past

As a first example, consider the oil and brush technology previously assumed for differentiating women from men by hair smoothness. A further step in this direction is to posit that hair color may have been used to code gender. The first step would have been selection for a blond(e) hair colour in both women and men. Since this is a very light colour, it will show the effect of dyeing maximally. Concurrently with this, the aesthetic preferences of men and women would have been differentiated by selection, resulting in blonde women who experience a mild euphoria from being blonde and blond men who experience a mild dysphoria from the same cause. The men would predictably get busy inventing hair-dyeing technologies to rectify this. The necessary dyes are readily obtained from plant sources such as woad and walnut shells. The result would be an effective blonde-female/nonblond-male gender code.

Theory

This style of evolution could be very fast if the brain pathways of aesthetic preferences require few mutations for their modification compared with the number required for the equivalent direct modification of the body. If technologically assisted evolution has general advantages, then we can expect its importance to grow with increases in the reach of technology. 

In the Present

Today, we seem to be at a threshold, with male-to-female and female-to-male gender transitions becoming well known. Demand for this service is probably being driven by disordered neural development during fetal life due to contamination of the fetus by environmental pollutants that have estrogenic properties (e.g., bisphenol A, PCBs, phthalates, etc.). The result would be the birth of individuals with disordered and mutually contradictory gendered aesthetic preferences. 

In the Future 

With further development of cell biology in the direction of supporting body-modification technology, who knows what bizarre hankerings will see the light of day on demand from some customer? Remember that in evolution, the mutation comes first, and the mutation is random. Most such cases will be punished by reduced employability and reduced reproductive success, doubtless exacerbated by prejudice on the part of the normal, normative majority.

However, the very occasional success story is also to be expected, involving the creation of fortuitously hyperfunctional individuals, and thus the technologically assisted creation of a new pre-species of human.

If the engineering details learned by the body-modification trade during this process are then translated into germ-line genetic engineering, then a true artificial humanoid species will have been created.

Photo by Levi Stute on Unsplash

#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

#43. Sunshine in Covey's Gap [evolutionary psychology, neuroscience]

EP   NE

Red, theory; black, fact

It is difficult to make a disagreeable emotion go away before one weakens and act it out, to their detriment. Techniques of true emotional control, i.e., making the bad feelings disappear rather than white-knuckle, open-ended resistance to acting them out, are not impossible, just non obvious. You just have to persuade yourself that this bad is good and believe it.

For the modern person, that second part, the believing, is difficult to achieve robustly if one is using religious solutions to the problem, the domain of soteriology (being "saved"), easier with psychoanalytical solutions, and easiest of all with scientific solutions. "Believing," here means being prepared to bet your life on the truth of a proposition.

Steven Covey writes in "The Seven Habits of Highly Effective People" that between stimulus and [emotional] response, humans have a gap in the causal chain and animals do not. In the gap are  imagination, self-awareness, conscience, and self will. George Santayana seems to have grasped this truth when he wrote: "Our dignity is not in what we do but in what we understand. The whole world is doing things." [source, Wiki quotes, accessed 11-06-2018]

Neuroscientist Joseph LeDoux has elucidated what could be the neural pathways that make Covey's gap possible. A direct pathway from the thalamus to the amygdala mediates the basic fear response, but an indirect pathway that leads from the thalamus up to the cerebral cortex and then down to the amygdala provides a more nuanced, intelligent amendment to the first response. Full cancellation of the direct pathway by the indirect would account for Covey's gap, and this could be done by a cortical relay through the inhibitory interstitial neurons of the amygdala that terminate on the amygdalar projection cells.

The doctrines of classical religion probably lead to such cancellation of emotions such as hate and fear by activating the same circuits that are used by a parent to reassure a needlessly fearful infant.

Apparently, classical religion is about getting people to do the right things for the wrong reasons. When the discipline of evolutionary psychology is sufficiently developed, we can look forward to the age when people do the right things for the right reasons.