#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

#11. Revised Motor Scheme [neuroscience]

NE

Red, theory; black, fact

How skilled behavior may be generated on the assumption that it is acquired by an experimentation-like process.

A revised version of the motor control theory presented in the last post 

The revision was necessitated by the fact that there is no logical reason why a motor command cannot go to both sides of the body at once to produce a mid line-symmetrical movement. The prediction is that mid-line-symmetrical movements are acquired one side at a time whenever the controlling corticofugal pathway allows the two sides to move independently.

#10. The Two–test-tube Experiment: Part II [neuroscience]

NE

Red, theory; black, fact

This is how the brain would have to work if fragments of skilled behaviors are randomly stored in memory on the left or right side, reflecting the possibility that the two hemispheres play experiment versus control, respectively, during learning.

The Significance of Hemispheric Asymmetry 

The experimenting-brain theory predicts zero hard-wired asymmetries between the hemispheres. However, the accepted theory of hemispheric dominance postulates that this arrangement allows us to do two things at once, one task with the left hemisphere and the other task with the right. The accepted theory is basically a parsimony argument. However, this argument predicts huge differences between the hemispheres, not the subtle ones actually found.

Hard-wired hemispheric dominance may be an imperfection of symmetry in the framework of the experimenting brain caused by the human brain being still in the process of evolving, in light of the hypothesis that brain-expanding mutations individually produce small and asymmetric expansions. Our left-hemispheric speech apparatus is the most asymmetric part of our brain and these ideas predict that we are due for another mutation that will expand the right side, thereby matching up the two sides, resulting in an improvement in the efficiency of operant conditioning of speech behaviour.

These ideas also explain why speech defects such as lisping and stuttering are so common and slow to resolve, even in children, who are supposed to be geniuses at speech acquisition.

Motor Control in an Experimenting Brain

The illustration shows the theory of motor control I was driven to by the implications of the theory of the dichotomously experimenting brain already outlined. It shows how hemispheric dominance can be reversed independently of the side of the body that should perform the movement specified by the applicable rule of conduct in the controlling hemisphere. The triangular device is a summer that converges the motor outputs of both hemispheres into a common output stream that is subsequently gated into the appropriate side of the body. This arrangement cannot create contention because at any given time, only one hemisphere is active. Anatomically, and from stroke studies, it certainly appears that the outputs of the hemispheres must be crossed, with the left hemisphere only controlling the right body and vice-versa.

In healthy individuals, either hemisphere may control either side of the body, and the laterality of control may switch freely and rapidly during skilled performance so as to always use the best rule of conduct at any given time, regardless of the hemisphere in which it was originally created during REM sleep.

Laterality Control Mechanism

The first bit would be calculated and stored in the basal ganglia. It would be output from the reticular substantia nigra (SNr) and gate sensory input to thalamus to favour one hemisphere or the other, by means of actions at the reticular thalamus and intermediate grey of the superior colliculus. The second bit would be stored in the cerebellar hemispheres and gate motor output to one side of the body or the other, at the red nucleus. Conceivably, the two parts of the red nucleus, the parvocellular and the magnocellular, correspond to the adder and switch, respectively, that are shown in the illustration.

Role of the Corpus Callosum

Under these assumptions, the corpus callosum is needed only to distribute priming signals from the motor/premotor cortices to activate the rule that will be next to fire, without regard for which side that rule happens to be on. The callosum would never be required to carry signals forward from sensory to motor areas. I see that as the time-critical step, and it would never depend on getting signals through the corpus callosum, which is considered to be a signaling bottleneck.

Brain Mechanism of Operant Conditioning 

Evaluation 

How would the basal ganglia identify the "best" rule of conduct in a given context? I see the dopaminergic compact substantia nigra (SNc) as the most likely place for a hemisphere-specific "goodness" value to be calculated after each rule firing, using hypothalamic servo-error signals processed through the habenula as the main input for this. The half of the SNc located in the inactive hemisphere would be shut down by inhibitory GABAergic inputs from the adjacent SNr. The dopaminergic nigrostriatal projection would permanently potentiate simultaneously-active corticostriatal inputs (carrying context information) to medium spiny neurons (MSNs) of enkephalin type via a crossed projection, and to MSNs of substance-P type via uncrossed projections. The former MSN type innervates the external globus pallius (GPe), and the latter type innervates the SNr. These latter two nuclei are inhibitory and innervate each other. 

This arrangement sets up a winner-take-all competition between GPe and SNr, with choice of the winner being exquisitely sensitive to small historical differences in dopaminergic tone between hemispheres. The "winner" is the side of the SNr that shuts down sensory input to the hemisphere on that side. The mutually inhibitory arrangement could also plausibly implement hysteresis, which means that once one hemisphere is shut down, it stays shut down without the need for an ongoing signal from the striatum to keep it shut down.

Process Control

Each time the cerebral cortex outputs a motor command, a copy would go to the subthalamic nucleus (STN) and could plausibly serve as the timing signal for a "refresh" of the hemispheric dominance decision based on the latest context information from cortex. The STN signal presumably removes the hysteresis mentioned above, very temporarily, then lets the system settle down again into possibly a new state.

Launching an Experiment 

We now need a system that decides that something is wrong, and that the time to experiment has arrived. This could plausibly be the role of the large, cholinergic interneurons of the striatum. They have a diverse array of inputs that could potentially signal trouble with the status quo, and could implement a decision to experiment simply by reversing the hemispheric dominance prevailing at the time. Presumably, they would do this by a cholinergic action on the surrounding MSNs of both types.

Coding Analogies 

Finally, there is the second main output of the basal ganglia to consider, the inner pallidal segment (GPi). This structure is well developed in primates such as humans but is rudimentary in rodents and even in the cat, a carnivore. It sends its output forward, to motor thalamus. I conjecture that its role is to organize the brain's knowledge base to resemble block-structured programs. All the instructions in a block would be simultaneously primed by this projection. The block identifier may be some hash of the corticostriatal context information. A small group of cells just outside the striatum called the claustrum seems to have the connections necessary for preparing this hash. Jump rules, that is, rules of conduct for jumping between blocks, would not output motor commands, but block identifiers, which would be maintained online by hysteresis effects in the basal ganglia.

The cortical representation of jump rules would likely be located in medial areas, such as Brodmann 23, 24, 31, and 32. Brodmann Areas 23-24 are classed as limbic system, and areas 31-32 are situated between these and neocortex. This arrangement suggests that, seen as a computer, the brain is capable of executing programs with three levels of indentation. Dynamic changes in hemispheric dominance might occur independently in neocortex, medial cortex, and limbic system.

#9. The Two–test-tube Experiment: Part I [neuroscience]

NE

Red, theory; black, fact

Your brain is like this.

The motivating challenge of this post is to explain the hemispheric organization of the human brain. That is, why we seem to have two very similar brains in our heads, the left side and the right side.

Systems that rely on the principle of trial-and-error must experiment. The genetic intelligence mentioned in previous posts would have to experiment by mutation/natural selection. The synaptic intelligence would have to experiment by operant conditioning. I propose that both these experimentation processes long ago evolved into something slick and simplified that can be compared to the two–test-tube experiment beloved of lab devils everywhere.

Remember that an experiment must have a control, because "everything is relative." Therefore, the simplest and fastest experiment in chemistry that has any generality is the two-test-tube experiment; one tube for the "intervention," and one tube for the control. Put mixture c in both tubes, and add chemical x to only the intervention tube. Run the reaction, then hold the two test tubes up to the light and compare the contents visually (Remember that ultimately, the visual system only detects contrasts.) Draw your conclusions.

The two hemispheres of the brain may be like the two test tubes. Moreover, the two copies of a given chromosome in a diploid cell may also be like the two test tubes. In both systems, which is which may vary randomly from experiment to experiment to simplify control. The hemisphere that is dominant for a particular action is the last one that produced an improved result when control passed to it from the other. The allele that is dominant is the last one that produced an improved result when it got control from the other. Chromosomes and hemispheres will mutually inhibit to produce winner-take-all dynamics in which at any given time only one is exposed to selection, but it is fully exposed. 

These flip-flops do not necessarily involve the whole system, but may be happening independently in each sub-region of a hemisphere or chromosome (e.g., Brodmann areas, alleles). Some objective function, expressing the goodness of the organism's overall adaptation, must be recalculated after each flip-flop, and additional flip flopping suppressed if an improvement is found when the new value is compared to a copy of the old value held in memory. In case of a worsening of the objective function, you quickly flip back to the allele or hemisphere that formerly had control, then suppress further flip flopping for awhile, as before. 

The foregoing implies multiple sub-functions, and these ideas will not be compelling unless I specify a brain structure that could plausibly carry out each sub-function. For example, the process of comparing values of the objective function achieved by left and right hemispheres in the same context could be mediated by the nigrostriatal projection, which has a crossed component as well as an uncrossed component. More on this in the next post.

#6. Mental Illness as Communication [neuroscience, genetics]

NE   GE

Red, theory; black, fact

The effects of most deleterious mutations are compensated by negative feedback processes occurring during development in utero. However, if the population is undergoing intense Darwinian selection, many of these mutations become unmasked and therefore contribute variation for selection. (Jablonka and Lamb, 2005, The MIT Press, "Evolution in Four Dimensions")

Basic Darwinism Is So Inefficient

However, since most mutations are harmful, a purely random process for producing them, with no pre-screening, is wasteful. Raw selection alone is capable of scrubbing out a mistake that gets as far as being born, at great cost in suffering, only to have, potentially, the very same random mutation happen all over again the very next day, with nothing learnt. Repeat ad infinitum. This quarrels with the engineer in me, and I like to say that evolution is an engineer. 

Evolution of Evolution 

Nowadays, evolution itself is thought to evolve. A simple example of this is the evolution of DNA repair enzymes, which were game-changers, allowing much longer genes to be transmitted to the next generation reliably, resulting in the emergence of more complex lifeforms.

What I Would Like to See

A further improvement would be a screening, or vetting process for genetic variation. Once a bad mutation happens, you mark the offending stretch of DNA epigenetically in all the close relatives of the sufferer, to suppress further mutations there for a few thousand years, until the environment has had time to change significantly.

Obviously, you also want to oppositely mark the sites of beneficial mutations, and even turn them into recombination hotspots for a few millennia, to keep the party going. Hotspots may even arise randomly and spontaneously, as true, selectable epi-mutations. 

A Problem With Mutation Hotspots on the DNA Strand

The downside of all this is that even in an adaptive hotspot, most mutations will still be harmful, leading to the possibility of "hitchhiker" genetic diseases that cannot be efficiently selected against because they are sheltered in a hotspot. Cystic fibrosis may be such a disease, and as the hitchhiker mechanism would predict, it is caused by many different mutations, not just one. It would be a syndrome defined by the overlap of a vital structural gene and a hotspot, not by a single DNA mutation. I imagine hotspots to be much more extended along the DNA than a classic point mutation.

It is tempting to suppose that the methylation islands found on DNA are these hotspots, but the scanty evidence available so far is that methylation suppresses recombination hotspots, which are generally defined non-epigenetically, by the base-pair sequence.

Mental Illness In Evolution 

The human brain has undergone rapid, recent evolutionary expansion, presumably due to intense selection, presumably unmasking many deleterious mutations affecting brain development that were formerly silent. Since the brain is the organ of behavior, we expect almost all these mutations to indirectly affect behavior for the worse. Does that explain mental illness?

Mental illnesses are not random, but cluster into definable syndromes. My reading suggests the existence of three such syndromes: schizoid, depressive, and anxious. My theory is that each is defined by a different recombinant hot spot, as in the case of cystic fibrosis, and may even correspond to the three recently-evolved association cortices of the human brain, namely parietal, prefrontal, and temporal, respectively. 

How Mental Illness Could Be Beneficial 

The drama of mental illness would derive from a communication role in warning nearby relatives that they may be harbouring a bad hotspot, causing them to find it and cool it by wholly unconscious processes. Mental illness would then be the push-back against the hotspots driving human brain evolution, keeping them in check and deleting them as soon as they are no longer pulling their weight fitness-wise. The variations in the symptoms of mental illness would encode the information necessary to find the particular hot spot afflicting a particular family.

A Possible Mechanism

Now all we need is a communication link from brain to gonads. The sperm are produced by two rounds of meiosis and one of mitosis from the stem-like, perpetually self-renewing spermatogonia, which sit just outside the blood-testes barrier and are therefore exposed to all blood-borne hormones. These cells are known to have receptors for the hypothalamic hormone orexin A, as well as many other receptors for signalling molecules that do or could plausibly originate in the brain as does orexin A. Orexin A is lipophilic and rapidly crosses the blood-brain barrier by diffusion. Some of the other receptors are:

• retinoic acid receptor α
• glial cell-derived neurotrophic factor (GDNF) receptor
• CB2 (cannabinoid type 2) receptor
• p75 (For nerve growth factor, NGF)
• kisspeptin receptor.

PS: for brevity, I left out mention of three sub-functions necessary to the pathway: an intracellular gonadal process transducing receptor activation into germ line-heritable epigenetic changes, a process for exaggerating the effects of bad mutations into signals for purposes of interpersonal communication, and a process of decoding the communication in the brains of the recipients.

Photo by Charlotte Noelle on Unsplash

#5. Why We Dream [neuroscience]

NE

Red, theory; black, fact

The Conjunction of Jupiter and Venus

We Dream Because We Learn

Operant conditioning is the learning process at the root of all voluntary behaviour. The process was discovered in lab animals such as pigeons by B.F. Skinner in the 1950s and can briefly be stated as "If the ends are achieved, the means will be repeated." (Gandhi said something similar about revolutionary governments.)

Learning in the Produce Isle

Operant conditioning is just trial-and-error, like evolution itself, only faster. Notice how it must begin: with trying moves randomly--behavioral mutations. However, the process is not really random like a DNA mutation.  Clearly, common sense plays a role in getting the self-sticky polyethylene bag open for the first time, but any STEM-educated person will want to know just what this "common sense" is and how you would program it. Ideally, you want the  creativity and genius of pure randomness, AND the assurance of not doing anything crazy or even lethal just because some random-move generator suggested it. You vet those suggestions.

How Dreams Help Learning

That, in a nutshell, is dreaming: vetting random moves against our accumulated better judgment to see if they are safe--stocking the brain with pre-vetted random moves for use the next day when we are stuck. This is why the emotions associated with dreaming are more often unpleasant than pleasant: there are more ways to go wrong than to go right. The vetting is best done in advance (e.g., while we sleep) because there's no time in the heat of the action the next day, and trial-and-error with certified-safe "random" moves is already time-consuming without having to do the vetting on the spot as well.  

A Possible Neurobiological Mechanism

Dreams are loosely associated with brain electrical events called "PGO waves," which begin with a burst of action potentials ("nerve impulses") in a few small brainstem neuron clusters, then spread to the visual thalamus, then to the primary visual cortex. I theorize that each PGO wave creates a new random move that is installed by default in memory in cerebral cortex, and is then tested in the inner theatre of dreaming to see what the consequences would be. In the event of a disaster foreseen, the move would be scrubbed from memory, or better yet, added as a "don't do" to the store of accumulated wisdom. Repeat all night.

If memory is organized like an AI knowledge base, then each random move would actually be a connection from a randomly-selected but known stimulus to a randomly-selected but known response, amounting to adding a novel if-then rule to the knowledge base.

Support For a Requirement for Vetting 

In "Evolution in Four Dimensions" [1st ed.] Jablonka and Lamb make the point that epigenetic, cultural, and symbolic processes can come up with something much better than purely random mutations: variation that has been subjected to a variety of screening processes.

An Observation and an Exegesis

Oddly, my nightmares happen just after a turn of good fortune for me. However, in our evolutionary past, my kind of good fortune may have meant bad fortune for someone else, and that someone else will now be highly motivated to kill me in my sleep. Unless I have a nightmare and thus sleep poorly or with comforting others. The dream that warned the Wise Men not to return to Herod may have been just such a nightmare, which they were wise enough to interpret correctly. The content was probably not an angelic vision, but more like Ezekiel's valley of dry bones vision in reverse.