Auto-Tune, or De-Tune, Keeps the Brain Humming

A more granular investigation into the control of brain waves in setting up transient connections between anatomical locations.

Electrical brain waves (now called neural oscillations) have been a long-standing interest of this blog. They were a relatively early discovery, are tantalizingly dynamic and diverse, but have been resistant to full understanding. But now that understanding is gradually developing, through the relentless process of normal science. A theory put out several years ago laid out in some detail how communcation in the brain can only happen when different locations are in "sync", which is to say that they are firing with the same rhythm, such that the receiving neurons are ready at the right time to process and relay the messages they are getting. But not all areas of the brain can be in sync at the same time, and different areas are positioned at different distances. The model posits dynamic coalitions of co-firing neurons that are in communication at the moment, but which then quickly decay as the thought passes. It also posits that time lags between locations are accounted for in the physiological design, so that for instance, bi-directional communication is not instantaneous, but separated in time such that A-->B happens first, then B-->A happens sequentially, in cases where feedback is an important element. While one of the typical partners of the oscillation entrainment system is stimulus from sensory inputs, another is attention from upper levels, which can emphasize and sustain some coalitions (thoughts) while shunting others to die out.

"Local cortical neuronal groups synchronize by default in the alpha band. During alpha-band synchronization, network excitation fluctuates at 100 ms cycles, but is tracked by network inhibition within 3 ms. This curtails effective communication and renders the respective activity invisible to other neurons. ...Visual scenes induce many local gamma rhythms with varying strength and frequency, reflecting the bottom-up stimulus salience and stimulus history. The gamma landscape in e.g. V1 thus in the end reflects stimulus properties, experience and top-down influences. At a given time point, one out of these coexisting gamma rhythms succeeds in entraining postsynaptic neuronal groups. This gamma entrainment allows to transmit a stimulus representation and to selfishly shut out competing stimuli's representations. The entrainment establishes a cycle-to-cycle memory of the active link that maintains until it is terminated at the end of a theta cycle. The presynaptic gamma rhythm allows network excitation to escape its ever chasing network inhibition." - From a discussion of how the visual processing system may use gamma oscillations (vs other frequencies- alpha, theta) to offer salient results to higher visual areas.

Well, how is all this managed? The core properties of neuronal firing are pretty well understood, particularly that each firing is followed by a brief refractory phase, imposing some of the cyclicity on the system. The anatomy is set in a relatively static way (on this scale) but with connections going in all directions. How can oscillatory entrained coalitions be created in so many different directions? Additional complications and opportunities are introduced by oscillations happening at different frequencies. A recent paper (with review) dives into the particular cells and layers of the hippocampus to lay out one example of how such a system is managed, to a very small degree, by inhibitory neurons.

These researchers are as usual working with mice, and have given up on actual mazes in favor of video mazes so that the mouse's head can be held still. This mouse is running (virtually) through a maze, so is accessing its memories of place and time actively while the researchers get into its head. The image below shows (green) how one of their electrodes pierces the mouse's hippocampus, sampling several layers at once. The neuron of interest (dark red) is gl-B182a, which is an inhibitory (neurogliaform) neuron. Its output is a bit diffuse and slow-acting, compared to the other neurons in the system that are being sampled (the u1 and u2 neurons in the trace shown at bottom. The main trace shows the gamma rhythm, (roughly 75 Hz) whose amplitude rises and falls in time within a slower theta rhythm (bottom, roughly 11 Hz). 

An electrode (green) is stuck through a mouse's brain, in the hippocampus, and records from several cells, including one inhibitory neuron, dubbed gl-B182a. The recording is below, compared to several other traces, such as the incoming gamma rhythm (gray, idealized in black), firing of specific target cells, and an idealized theta rhythm (bottom, black). gl-B182a has a very specific and peculiar firing pattern, right at the trough of gamma waves that are at the high points of the theta rhythm.

They note that the neuron they are following fires around the peaks of the general theta rhythm, and precisely at a trough in the fast gamma rhythm. The whole paper is about how this class of inhibitory neurons is specially tuned to fire with the gamma rhythm, (which is coming in from cortical inputs, through the entorhinal cortex), but is also inhibitory, and has the effect of throwing its target cells (called CA1 pyramidal neurons) off this rhythm again, almost immediately. The interesting thing is that they do not inhibit the firing of their targets overall, but only their timing. Thus the paper claims that they have found a novel class of cells that actively, rapidly, and specifically de-tunes target cells that would otherwise merrily just keep humming along with the incoming rhythm. The point of this is that the cells have already been entrained for a couple of gamma cycles before the effects of this new inhibitory cell kick in, which might be enough to communicate what they have to communicate. So it falls to this inhibitory system to break up the party and reset the local cells so that they can be drawn into new and different coalitions / thoughts.

A model of what is going on above with these inhibitory NGFC cells. The gamma rhythm from elsewhere (teal) comes through the hippocampus and recruits select cells such as the CA1 pyramidal cells (purple). When local synchrony is achieved, the neurogliaform cell (NGFC) steps in with an inhibitory burst, enough to knock them out of rhythm again, without significantly lowering their firing rate.

Granted, this is not a full explanation of what is going on with local information processing or with neural oscillations. Especially, it does not imply that the inhibition is being controlled by higher cortical inputs to these cells that might constitite attention or its opposite, and therefore constitutes some kind of transistor-like gating mechanism. But it is an important ingredient in their usefulness, by modulating how thoroughly local cells get caught up in them. The oscillation keeps on going, but thanks to these inhibtory cells, it is highly selective in which local cells it recruits, and how briefly. Note that since we are talking about the gamma rhythm here, these phenomena go by in a matter of milliseconds, far below our range of awareness. They are thoroughly unconscious, as most of our mental processes are.

• Let's hang Ukraine out to dry.
• Or not.
• Working from home is good.
• The great firewall is coming to you.
• David Ruffin puts in an amazing performance.

Why Did we Have a Civil War?

It is still a hard one to figure out.

One of the dividends of winning the Cold War was internal division. With no outside enemies or competing ideologies, we were left to become irritated with each other, Newt Gingrich leading the way. It is a general feature of humanity that we are competitive and find points of irritation with each other if there are no supervening projects or conflicts to bind us together. One would think large projects like climate change might be such an overwhelming common challenge and project, but no, it doesn't seem have the immediacy and social drama we need. Thinking and caring deeply about the biosphere is a specialized affair. 

No, our divisive dramas are much more trivial. But in the US there is a pattern, and that is the role of the South as a political / cultural block. It is reminiscent of the process leading up to our first Civil War, where a morally progressive North irritated and alienated a traditional and depraved South. Not that both sections of the country were not fully complicit in slavery, dispossession of the native peoples, and other forms of oppression. It was a matter of degree. But at some point of cultural and moral advancement, it becomes untenable to express our greed and competitiveness in terms of slavery. Slavery requires, as Harriet Beecher Stowe illustrated, a comprehensive deadening of moral sensibility, even while one's senses of honor, greed, religion, not to mention social propriety, may remain fastidious. Dedication to social competition rather than social justice is the order of the region. 

I have been listening to a lengthy podcast narrating the events of the Civil War, which is particularly strong on the introductory phase, explaining various proximate and deep causes of the conflict. What strikes me again and again is the contingency of the whole thing. And its nobility, in a way. The North could easily have washed its hands of the whole conflict, and let the South secede and go its own way. That is what the South was counting on, and many foreign countries, and many (Democrats) in the North as well. As the Union was battered in battle after battle, the mood in the North came perilously close to letting go. 

It took two converging arguments to hold the Northern coalition together- union and abolition. Each one was somewhat abstract and each one alone would probably not have been sufficient to force a war. Abolition was a minority position all the way through the war, and evidently afterwards as the South slid back into de facto slavery. Yet it fired a key segment of the Northern population with great fervor, to take an active interest in what the South was doing, and force an end to slavery rather than let it continue in an independent breakaway nation. There were religious arguments, and arguments of simple humanity, but why young men from Maine should kill those in Virginia about it was not entirely obvious.

The case for union was even more abstract. The union of the states was ostensibly a voluntary affair, and while no mechanism was offered to secede, no formal bar to secession was enshrined in the constitution either. The logic of union was that a nation made up of voluntary associations that could crumble at will was no sound nation at all, and not the kind of country that the prosperous, growing, Manifest Destiny United States was supposed to become. Lincoln labored long and hard to articulate this argument, in his debates and other speeches, including eventually the Gettysburg Address. 

But I think it remains difficult to grasp, even in retrospect. The Southern states felt understandably snookered into a constitutional deal that did not explicitly say it was a one-way trap, but turned out to be one, depending on the (military) willingness of the North to keep them in chains, as it were. The Northern states had many commercial, cultural, and other reasons to regard the South as an indissoluble part of the nation, (most Founders were Southern, for one thing), but fighting a war over it? That was a lot to ask, especially when the result would be at best the forced subservience of half the states and population- what kind of union is that? On the other side, the South didn't fully realize that once you start a war, positions harden and emotions heighten, such that the North felt increasingly bound to see it through to the bitter end. A bit like Ukraine today.

Which feeling was stronger, that of Southerners for preservation of their independence, prerogatives, and economic basis, that of Northerners in their revulsion over the retrograde moral environment of slavery? Or that of Northerners over the preservation of the unique constitutional / democratic experiment as a precious, indissoluble inheritance? The motivations of the South were clear enough, however base. But the motivations of the North, while understandable, seem insufficient to fully justify an extremely bloody war (not that they imagined that extremity at the outset). Thus I see the Northern policy as in some degree idealistic and noble, going far beyond the minimum needed to keep its business going and people happy. 

The North could never have kept the union together and abolished slavery without a war. Some in the North were more abolitionist than pro-Union, and some more pro-Union. Despite the manifest breakdown in North-South relations and the various ante-bellum compromises that kept the union together, keeping those factions aligned was very difficult, before the war, during the war, and through the endless aftermath of reconstruction, Jim Crow, and the Civil Rights movement, and now Southern Republicanism (of all things!) and Trumpism. 

Was the outcome beneficial, in any historical sense? It is very difficult to know how the counterfactual would have turned out. The South might have become a vast banana republic, incorporating Cuba and other territories to its own south. The North would doubtless have continued its ascent to be an industrial collusus and leader of the next century. They might well have remained at peace, despite many points of competition and contention, and traded so that the North would have retained effective access key raw materials from the South. Slavery would have continued, and it is very hard to tell for how long and in what form.

This is where the diplomatically inclined would jump in to say.. it would have been better to negotiate a deal and avoid war. There is always a deal out there that is better than war, which is an ultimate failure and disaster. Compromise after compromise had been made before the war, and shattered by increasingly divergent views on states rights, voting rights, and human rights. If every party had clairvoyance about the future course of events, they might have seen a better way. But we are not clairvoyant, and war is a way to change the conditions of the future rather than to split differences. Wars are certainly the last resort, but remain the final way to decide fundamental existential and power issues, and to change the basis of the future. That is the simple fact of the matter, in a world that is fundamentally competitive. In the words of Vegetius, "Let him who desires peace prepare for war".

Do we today have the capacity to conceive of and adhere to such esoteric and high principles as actuated the North in the last civil war? Our recent president tried to stage a coup, and we can hardly bestir ourselves to care about it. The Supreme Court is impersonating the Taney court, finding that our constitution does not, in fact, protect elementary human rights, such as privacy. We are facing climatic catastrophe that is leading to mass migration, war, and challenges to our fundamental basis of existence, (farming, and addiction to fossil fuels), not to mention imperiling the biosphere at large. And we can hardly bestir ourselves to care about it. Again, half the country, centered in the South, feels morally condescended to and responds with spite and revanchism. Again, the rich fight with every tool to keep things the same and shut our eyes to the dangers ahead. 

While the political dramas of today will likely pass away without taking to arms, despite the militant recklessness of the Southern end of the political spectrum, it is hard to be as optimistic about our other challenges. When the US looks ahead today, it sees change, constraint, and decline. It is a hard future to face, and many quail from doing so, (whatever their vacuous and delusory slogans). But face it we must, lest it turn from a challenge into a rout.

• The polycrisis of capitalism.
• Krugman on pessimism and division.
• Such a deal!
• Either a carbon tax or a crypto tax.
• We have not even hit peak oil yet.
• The war we really don't need. Not that I generally agree with Chris Hedges.

Links

Due to the press of business, only links this week.

Tom Tomorrow surveys our moment.

• Good grids have powerful effects on price stability and renewable production.
• Were Trump voters and militants fooled, or complicit?
• The US can do more than lies. We can do truth.
• In memoriam and tribute.

Tooth Development and Redevelopment

Wouldn't it be nice to regrow teeth? Sharks do.

Imagine for a minute if instead of fillings, crowns, veneers, posts, bridges, and all the other advanced technologies of dental restoration, a tooth could be removed, and an injection prompt the growth of a complete replacement tooth. That would be amazing, right? Other animals, such as sharks and fish, regrow teeth all the time. But we only get two sets- our milk teeth and mature teeth. While mature mammalian teeth are incredibly tough and generally last a lifetime, modern agriculture and other conditions have thrown a wrench into human dental health, which modern dentistry has only partially restored. As evolution proceeded into the mammalian line, tooth development became increasingly restricted and specialized, so that the generic teeth that sharks spit out throughout their lives have become tailored for various needs across the mouth, firmly anchored into the jaw bone, and precisely shaped to fit against each other. But the price for this high-level feature set seems to be that we have lost the ability to replace them.

So researchers are studying tooth development in other animals- wondering how similar they are to human development, and whether some of their tricks can be atavistically re-stimulated in our own tissues. While the second goal remains a long way off, the first has been productively pursued, with teeth forming a model system of complex tissue development. A recent paper (with review) looked at similarities between molecular details of shark and mammalian tooth development.

Teeth are the result of an interaction between epithelial tissues and mesenchymal tissues- two of the three fundamental tissues of early embryogenesis. Patches of epithelium form dental arches around the two halves of the future mouth. Spots around these arches expand into dental placodes, which grow into buds, and as they interact continuously with the inner mesenchyme, form enamel knots. The epithelial cells of the knot then eventually start producing enamel as they pull away from interface, while the mesenchymal cells produce dentin and then the pulp and other bone-anchoring tissues of the inner tooth and root as they pull away in the opposite direction. 

Embryonic tooth development, which depends heavily on the communication between epithelial tissue (white) and mesenchymal tissue (pink). An epithelial "enamel knot" (PEK/ SEK) develops at the future cusp(s), where enamel will be laid down by the epithelial cells, and dentin by the mesenchymal cells. Below are some of the molecules known to orchestrate the activities of all these cells. Some of these molecules are extracellular signals (BMP, FGF, WNT), while others are cell-internal components of the signaling systems (LEF, PAX, MSX).

Naturally, all this doesn't happen by magic, but by a symphony of gene expression and molecular signals going back and forth. These signals are used in various combinations in many developmental processes, but given the cell types located here, due to the prior location-based patterning of the embryo in larger coordinate schemes, and the particular combination of signals, they orchestrate tooth development. Over evolution, these signals have been diverse in the highest degree across mammals, creating teeth of all sorts of conformations and functions, from whale baleen to elephant tusks. The question these researchers posed was whether sharks use the same mechanisms to make their teeth, which across that phylum are also highly diverse in form, including complicated cusp patterns. Indeed, sharks even develop teeth on their skin- miniature teeth called denticles.

Shark skin is festooned with tiny teeth, or denticles.

These authors show detailed patterns of expression of a variety of the known gene-encoded components of tooth development, in a shark. For example, WNT11(C)  is expressed right at the future cusp, also known as the enamel knot, an organizing center for tooth development. Dental epithelium (de) and dental mesenchyme (dm) are indicated. Cell nuclei are stained with DAPI, in gray. Dotted lines indicate the dental lamina composed of he dental epithelium, and large arrows indicate the presumptive enamel knot, which prefigures the cusp of the tooth and future enamel deposition.

The answer- yes indeed. For instance, sharks use the WNT pathway (panel C) and associated proteins (panels A, B, D) in the same places as mammals do, to determine the enamel knot, cusp formation, and the rest. The researchers use some chemical enhancers and inhibitors of WNT signaling to demonstrate relatively mild effects, with the inhibitor reducing tooth size and development, and the enhancer causing bigger teeth, occasionally with additional cusps. While a few differences were seen, overall, tooth development in sharks and mammals is quite similar in molecular detail. 

The researchers even went on to deploy a computer model of tooth development that incorporates twenty six gene and cellular parameters, which had been developed for mammals. They could use it to model the development of shark teeth quite well, and also model their manipulations of the WNT pathway to come out with realistic results. But they did not indicate that the overall differences in detail between mouse and shark tooth development were recapitulated faithfully by these model alterations. So it is unlikely that strict correspondence of all the network functions could be achieved, even though the overall system works similarly.

The authors offer a general comparison of mouse and shark tooth development, centered around the dental epithelium, with mesenchyme in gray. Most genes are the same (that is, orthologous) and expressed in the same places, especially including an enamel knot organizing center. For mouse, a WNT analog is not indicated, but does exist and is an important class of signal.

These authors did not, additionally, touch on the question of why tooth production stops in mammals, and is continuous in sharks. That is probably determined at an earlier point in the tissue identity program. Another paper indicated that a few of the epithelial stem cells that drive tooth development remain about in our mouths through adulthood. Indeed, these cells cause rare cancers (ameloblastoma). It is these cells that might be harnessed, if they could be prodded to multiply and re-enter their developmental program, to create new teeth.

• Boring, condescending, disposable, and modern architecture is hurting us.
• Maybe attacking Russia is what is needed here.

Desperately Seeking Cessation of Desire

Some paradoxes, and good points, of Buddhism.

I have been reading "In the Buddha's Words", by Bhikkhu Bodhi, which is a well-organized collection / selection of translations of what we have as the core teachings of Buddhism. It comes from the Pali canon, from Sri Lanka, where Buddhism found refuge after its final destruction in India after the Arab invasions, and offers as clear an exposition of the Buddhist system as one can probably find in English. A bit like the scriptures of Christianity, the earliest canons of Buddhism originate from oral traditions only recorded a hundred or so years after Buddha's death, but as they are slightly less besotted with miraculous stories, the collection has more of a feeling of actual teaching, than of gnomic riddles and wonder stories, not to mention Odyssean mis-adventures.

Both prophets make audacious claims, one to be god, or its son, the other to have attained a perfectly enlightened state with similar implications for everlasting life (or lack of rebirth, at any rate). Each extends to his followers the tempting prospect of a similarly exalted state after death. Each teaches simple morals, each attracts followers both lay and career-ist, the latter of whom tend to be rather dense. Each launched an international sensation that bifurcated into a monastic/ascetic branch of professional clerics and a more popular branch that attained a leading role in some societies.

But Buddhism has attained a special status in the West as something a bit more advanced than the absurd theology of Christianity. A theology that could even be deemed atheist, along with a practice that focuses more relentlessly on peace and harmony than does what Christianity has become, particularly in the US. It is congenial to seekers, an exotic and edgy way to be spiritual, but not religious.

But how much sense does it really make? For starters, much of the Buddhist mythology and theology is simply taken from its ambient Hindu environment. The cycle of rebirth, the karma that influences one's level of rebirth, the heavens and hells, all come from the common understandings of the time, so are not very particular to Buddhism. Buddhists did away with lots of the gods, in favor of their own heros (Buddha, and the Bodhisattvas), and developed a simplified philosphy of desire, suffering, and the relief of suffering by controlling desire, optimally through advanced meditation practices. Much of this was also ambient or at least implicit, as Buddha himself began as a normal Indian ascetic, trying to purify himself of all taints and mundane aspects. For his Buddhist Sanga, he dialed things back a bit, so that the community could function as a social system, not a disconnected constellation of hermits.

Bodhisattvas floating in heaven. These are Buddhists who have attained enlightenment but not entered permanent heaven, choosing rather to have compassion on humanity in its benighted state.

As a philosophical system, it seems paradoxical to spend so much effort and desire in seeking nirvanna and the benefits of lack of desire. To sit in meditation for years on end demands enormous discipline. To submit to a life of begging and poverty takes great will and desire for whatever is promised on the other side. This is not evidence of lack of desire, much less the kind of wisdom and knowledge that would license its practitioners to advise lay people in their mundane affairs (or politicians in affairs of state). And the ethical system that Buddha promulgated was simple in the extreme- merely to be and do good, rather than being and doing bad, all staked on the age-old promise that just deserts would be coming after death.

No, Buddha was clearly a charismatic person, and his insight was social, not philosphical. Remember that he was a prince by birth and education. I would suggest that his core message was one of nobility- of idealism about the human condition. In his system, nobility is not conferred by birth, but by action. All can be noble, and all can be ignoble, regardless of wealth or birth. For the mass of society, it is control over desire that allows virtue and prosperity- i.e. nobility. Those who are addicts, whether to power, to drugs, to bitterness, to sex, or innumerable other black holes of desire or habit, are slaves, not nobles. This is incidentally what makes Buddhism so amenable to the West- it is very enlightenment-friendly kind of social philosophy.

The monks and Sanga of Buddhism were to be the shock troops of emotional discipline, burning off their normal social desires in fires of meditation and renunciation, even as they were on the hook for a whole other set of desires. Which are, in my estimation, wholly illusory in their aim, despite the various beneficial effects of meditation, in this world. They provide the inspiration and template for the society at large, modeling a form of behavioral nobility that any and all can at least appreciate, if not aspire to, and model in their own circumscribed lives and ethical concerns. I think that is the real strength of the Buddhist system. The monks may be misled in philosophical terms, but they fulfill a critical social role which governs and moderates the society at large. 

The monks provide another benefit, which is population control. One of the greatest pressures on any society is overpopulation, which immiserates the poor, empowers the rich, and can ultimately destroy its resource base. While the monastic institutions are a great burden on their societies, they also help keep them sustainable by taking in excess males who might otherwise become brigands and parents. This is particularly evident in traditional Tibet, despite the corruption of the monastic system by clan rivalries and even occasional warfare.

The fact of the matter is that desire is the staff, even essence, of life. Those who lack desire are dead, and Buddhist monks sitting in endless renunciation are enacting a sort of living death. Nevertheless, they have an important function in their societies, which is one we see replicated in the priests of Orthodox and Catholic Christianity (most of the time) and other ascetics and clerics around the world. Buddha was right that the management of desire is absolutely critical to individual and communal social life. Compare his system, however, with the philosophy of the Greeks, which arose at roughly the same (axial) time. The Greek philosophers focused on moderation in all things- another way, and I would offer, a healthier way, to state the need for discipline over the desires. They additionally fostered desires for knowledge and as complex ethical investigations, which I would posit far outstripped the efforts of the Buddhists, and gave rise, though the Greeks' continuing influence over the Roman and ensuing Christian epochs in Western Europe, to a more advanced culture, at least in philosophical, legal, and scientific terms, if not in terms of social and political peace.

• Meanwhile, a Christian court makes us a Christian nation, like it or not.
•  Length of Covid infection and viral shedding is unaffected by strain or vaccination status.