Aristotle is known as the father of modern science, which means he’s got some pretty serious scientific street cred. I mean, being talked about in the same breath with other giants like Archimedes, Newton, and Einstein means you can talk the talk and walk the walk.   Think this is hype?  Aristotle’s “natural philosophy” covered, if not started, dozens of fields of science, including biggies, like physics, astronomy, geology, and biology.  As great as he was, however, Aristotle completely missed the boat when it came to the brain.  In Aristotle’s mind (pun intended for sure) sensory perceptions arise, emotions are generated, and creative thoughts blossom in the heart.  Worse yet, he thought the brain was just a radiator for the heat generated by the heart.  Fortunately for patients over the next two millennia, Aristotle’s views, at least on this subject, were not widely accepted.  Instead, Galen, the Roman physician, whose teachings in medicine completely overshadowed Aristotle’s, set the stage for brain science for the next two millennia.

Galen’s teachings about the brain were surprisingly accurate, given that the closest thing he had to a microscope was a water-filled glass orb.  Even more amazing were the advances on Galen’s work that Ibn Sina (a.k.a. Avicenna) made a thousand years later, given the fact that Islamic Law prevented him from doing postmortem studies on dead bodies.  Despite their limitations, these men figured out quite a bit about nerves, and how they carried information to different areas of the brain for processing.  Deducing that sensory information was carried to the brain by nerves and that other nerves carried instructions to muscles was pretty brilliant.  I mean, as oversimplified as this is, Galen’s ideas that motor neurons carried “the force of will” led to strong-willed people being described as having “nerves of steel”.  Similarly, sensory nerves were supposedly soft and malleable, so intense experiences could make a “strong impression” on people.

Just knowing that thoughts and perceptions were the stuff of nerves and brains, however, didn’t solve a more basic mystery.  How did those experiences generate perceptions, feelings, and ideas?  I mean, the former are pretty easy to see as physical objects and forces.  Ideas and perceptions, however, seemed ethereal in nature.  If you spend a moment pondering this, you can see why this miracle would be mysterious.  Imagine, you’re looking down the street and you hear a siren blaring and see a firetruck barreling down the road towards you.  In a split second, you turn to look for a cloud of smoke from a fire that the truck must be headed toward.  You might wonder if the firemen could be headed to a home of someone you know.  Or worse, if they are traveling in the direction of your home, your mind might flash back to the oven you were using this morning to recall if you turned it off.  The fact is, a torrent of thoughts is streaming through your mind, all as a result of hearing a siren and seeing a firetruck. How does that happen?  This question becomes a thousand times more complicated because that stream of thoughts is unique to each observer.  How can all of these different reactions arise from the same physical forces?  If you put aside the modern explanations of how brains work, the individual nature of perceptions, thoughts, and memories really are different from most things in the physical world in which things interact with other things following relatively strict and predictable laws.  The process of thoughts arising from sensory experiences seems almost chaotic.

In an attempt to explain how the mind worked, Rene Descartes concocted a theory in which he imagined a connection from the physical to an immaterial world.  He claimed that this wormhole to an alternate reality happened in the pineal gland (a pinecone shaped structure in the middle of the brain).  This theory, and it is really a stretch to call it a theory at all, suffered from both logical and physiological errors.  I mean, all Descartes really did was come up with a fairy tale, and then point to a spot in the brain and claim that was where God had sprinkled the pixie dust.  On a physiological level, as you probably guessed, the pineal gland has no such connection to an alternate universe, no matter how many mushrooms you and Alice eat.  

Over the past century, discoveries about the brain, relating to the dynamics of synaptic clefts, neurotransmitters, ion channels coupled to receptors, fast and slow transmission mechanisms, reuptake pathways, and other aspects of neuronal interaction helped reveal the basics of how thoughts and feelings come into existence.  In a sense, these pieces alone don’t fix the problem of how experiences are converted into thoughts, but these first pieces formed the equivalent of a black and white movie with mono sound.  Neurons were seen communicating with one another through electrochemical signals traveling down long axons, these signals causing the release neurotransmitters from one side (the pre-synaptic side) of synapses, the neuron on the post-synaptic side gathered up multiple signals, weighed them, and decided whether to fire its own action potential down its axon as a result.  It wasn’t until 1944, when a couple of University of Chicago professors, Warren McCullough and Walter Pitts, actually started doing the math around neural networks (or modeling simple neurons as receiving a series of inputs and determining with basic rules, whether or not to fire an output) and showed how observations could be processed into meaning.

It was a huge step in decoding the brain’s ability to decipher meaning from sensory nerve impulses, but this explanation was a very limited view of the brain.  Eighty-six billion (give or take a few billion) certainly is a lot of neurons.  And each one having an average of a thousand connections makes for close to a hundred trillion connections spanning the brain (more than the number of stars in the galaxy).  How did the right connections come to be formed, and how did they work in such a dynamic and changing way to allow for learning and growth?

Some of the answers lie among the other hundred billion cells in the brain that aren’t neurons.  It turns out that the brain includes many other cells that are intricately intertwined and interacted with each other and with neurons.  At first, deciphering what these cells did wasn’t as exciting as their electrically-firing cousins, the neurons.  The natural assumption was that astrocytes, which wrap themselves around the synapses and the blood vessels, were simple support cells.  Similarly, oligodendrocytes that wrap around long axons, turning certain neurons into white matter, seemed like another type of support cell.

Then there were the little microglia; cells that, for half a century, were actually just considered glue for the network (the name actually means “little nerve glue”).  Over the past few decades, however, the amazing roles of these cells has turned the entire view of the brain on its head.  Yes, neurons still make up the neural network and do a lot of communicating and data processing, but the What, Where, When, How, and Why of it all is deeply controlled by these little cells that aren’t even neuronal by nature.  Microglia are innate immune cells – the resident macrophages of the brain – and their story starts long before any neurons are born and connected into a neural network.

Like any superhero, microglia have a compelling origin story, and in this case, it begins just a few days after conception, at a time when the embryo is little more than a few layers of cells.  At this moment in development, within the placenta, there is a separate structure called the yolk sac.  Think of the yolk sac like the mobile home that a contractor puts up on a piece of land where he is going to build a skyscraper.  All the design, planning, and coordination of the construction takes place in the mobile home, at least until enough of the building is in place that a construction office within the structure can be built.  From this yolk sac pour a group of cells called macrophage progenitor cells, and they invade the tiny embryo, just like contractors coming to work to build the 100-story office building.  The earliest ones are the iron workers (the liver), the plumbers (the heart), the glass workers (the skin), and the electricians (the brain).

The macrophage progenitor cells produce the electrical subcontractors – the microglia in this analogy – that move in and start from scratch, building wiring harnesses, conduits, and switches as much as they are laying wires and connecting outlets.  Microglia build the neurovasculature.  They promote the neural progenitor cells to produce neurons.  They tell the neurons where to migrate, and they gobble up and recycle the neurons that don’t do what they are told.  They send out signals that cause axons to grow along the right paths, and they hook the axons up to the dendrites to form synapses.  In ways that are still not fully understood, these microglia create the regional differences between the brainstem nuclei, the neocortex, the corpus collosum, and every other specialized area of the brain.  All of this and more is going on throughout gestation.

After the microglia conduct this first symphony, they shift gears and begin a new developmental stage, during which they continuously remodel the environment, promoting the functions of astrocytes and oligodendrocytes, as well as pruning the network they built.  This makes them, not only the construction crew, but also the maintenance team.  This pruning function they perform is so critical that it requires a deeper dive.  If the microglia do their job correctly, the network is created with connections everywhere.  In fact, in early childhood, estimates are that the human brain has nearly 670 million synapses per cubic millimeter.  By age ten, however, that same healthy brain has fewer than 320 million synapses in the same volume. Where do they all go?

Why are the microglia dismantling the synapses right after they managed their construction?  It turns out that the early version of the network is substantially over-connected during development, and the microglia are programmed to build and then prune back the network (starting in certain areas, like vision, before areas that require more fine tuning, like language processing) in order to optimize the performance of the system.  I think of it using the analogy to an artist who first creates a big pile of clay, and then removes large portions of it to reveal the sculpture beneath.  Failure to prune the network correctly is a big part of neurodevelopmental conditions like schizophrenia (too much pruning) and autism (too little pruning).  There is plenty more about these conditions on blogs I’ve written.

The cool part is that this pruning process is all activity- and sensory-dependent.  What does that mean?  It means that microglia prune based on the environment and a person’s interaction with it.  For example – and this study was actually done on cats – take away any light from entering the eyes of a newborn animal and activating the freshly built network of synapses connecting the optic nerve with the retinae, and the microglia that built the network will tear the connections right back down and leave the animal blind.  Let light in, and the retinal connections will be pruned to provide stereoscopic vision (deleting connections from the left eye to the right optic nerve, and the right eye to the left optic nerve).  Use it or lose it is literally the rules of the pruning game.  If a synapse is used, it gets reinforced (through a process called long term potentiation) , but if it isn’t, the synapse gets eaten away (trogocytosed) by the microglia.

There are areas of the brain where these steps of creating new neurons, having them migrate into proper position, connecting them (with synapses) into the established network with lots of connections, and then subjecting these new synapses to a pruning process, happens all through life.  The hippocampus is a very important one of these areas, because it’s responsible for memory formation and learning.  A healthy eighty-year-old person can learn a new dance, a new language, or even an entirely new hobby or subject.  This means that microglia have to remain in a state where they keep conducting and managing all the housekeeping tasks necessary to make it all possible.

If you are anything like me, you are probably wondering what could make microglia stop doing these housekeeping tasks?  As I mentioned above, microglia are immune cells.  This means that they aren’t only responsible for building and remodeling the brain.  They are also responsible for defending and healing the brain when trouble (pathogens or trauma) arises.  When an attack occurs, or the damage that could be associated with an attack, is sensed through chemical signals called DAMPs and PAMPs, microglia move into inflammation mode.  In this state, they stop doing the housekeeping tasks.  If this is brief, the microglia can shift back into their housekeeping mode pretty easily.  The more severe or chronic the problem, the longer the microglia stay in their inflammation mode, and the more the rest of the brain has problems maintaining optimal functioning.  In fact, if the microglia don’t return to their housekeeping functions, the brain starts to function abnormally and can actually start to break down (i.e., degenerate).

This destructive process can exhibit itself in many different ways that depend on such things as (i) when in life it occurs, (ii) what’s driving the problem, i.e., what triggers the inflammation, and (iii) how long it persists.  It is these microglial cells becoming inflamed that are the basis of the gestational programming for schizophrenia and autism that was mentioned above.  Trauma in childhood can lead to neurological pain conditions later in life, including fibromyalgia.  In another blog I posted about headache, I shared how inflammation disrupts serotonin production, so it is no wonder that inflammation can lead to mental health challenges like depression and anxiety as well as pain (serotonin plays a role in pain and mood).

It is important to note that inflammation doesn’t just have to start in the brain for it to affect microglia.  For example, cognitive dysfunctions ranging from learning, focus, and memory challenges can arise from any sort of inflammation, in the brain or body, including metainflammation that arises with excessive body mass index.  In fact, Alzheimer’s Disease is being referred to as Type-3 diabetes given the fact that its prevalence is that much higher among those with a history of insulin resistance and glucose intolerance.

If disruption of microglial cells, and their failure to perform their constructive tasks, leads to mood, pain, and cognitive issues, it is important to understand what can cause that disruption.  After all, if we understand the problem, we have a better chance of fixing it.  Metainflammation is certainly one of those triggers.  Concussion is obviously another trigger.  Emotional stress can also activate microglia into an inflamed state.  Sleep deprivation is a bidirectional trigger in that lack of sleep can lead to microglial activation, but microglial activation can also lead to sleep disruption.  All of these triggers have potentially damaging effects for adults or the elderly, but there is no question that the damage associated with neuroinflammation is most severe when it happens in children who are still undergoing critical neurodevelopment.

Sleep deprivation, emotional stress, and inflammation that happens from skinned knees, video game playing, sleep overs, too many sweets, and the thousand colds and flus kids share with one another are inevitable.  Given this, I thought it was a reasonable question to ask some neuroimmunologists whether there is there some level of inflammatory activation of microglia that is tolerable and doesn’t do any damage.  The answer I received was a resounding “NO”.  We have all experienced a neurodevelopmental environment that is sub-optimal.  But how can we make it better.  Research for the past century has told us that stable family life, better diets, regular sleep patterns, and intellectual enrichment makes for smarter children.  Some of these things can influence the inflammation levels, increasing the probability that the microglia will do their housekeeping tasks without distraction (and the intellectual stimulation makes sure the microglia don’t swallow up important connections).  This all makes perfect sense, but the natural question is, can we do more to optimize brain function?

So, you may want to experience a better mood, want to feel less pain, sleep better, and be as smart as you can be.  But, if you have children, as I do, you want to know what you can do to optimize their neurodevelopment to give them the best life they can have.  So, what can you do, beyond exercise, a proper night sleep, and good diet, to inhibit the inflammatory response of the microglia in your head and the heads of your kids?

It turns out that there is!  And it something that most people don’t know much about.  It’s called vagus nerve stimulation, or VNS.  It involves activating key fibers in this all-important cranial nerve that makes up half of the autonomic nervous system.  Exercise and sleeping right makes the vagus nerve function more effectively, but directly activating it with short bursts of electrical signals can do more than a massage, meditation, and yoga combined. All of these activities cause important neurotransmitters to be released in higher levels.  As explained in many of my prior blogs, one neurotransmitter in particular, acetylcholine, is responsible for pushing innate immune cells like microglia out of their inflammatory state and back into their housekeeping mode through a series of related mechanisms, collectively called the cholinergic anti-inflammatory pathways.  More recent studies have shown that the benefits of VNS extend to every cell in the body as the same stimulation can help optimize oxidative phosphorylation in mitochondria, the powerplants of every cell.  Having healthy and functioning mitochondria go a long way towards keeping microglia out of trouble. 

In short, VNS shifts microglia from an inflammatory mode, back into their ideal housekeeping state, optimizing everything from mood to cognitive function for adults, and even more importantly, giving children a chance at superior neurodevelopment.

 *Do you get it? The liver is filled with iron and has a huge role in iron metabolism throughout the body.  I thought that was a good pun … but I’m a Dad and my kids cringe and shake their heads at my jokes.

 **DAMPs are Damage-Associated Molecular Patterns, and PAMPs are Pathogen-Associated Molecular Patterns

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