microglia diagram

For far too many people, depression and chronic illness go together like peanut butter and jelly.  Chronic illness is hard.  And, we are too often told by medical professionals, family, and friends alike, it must just be all in our heads. It’s just stress, right? 

But what if the symptoms of depression, anxiety, and brain fog weren’t just a “normal” psychological reaction to illness, but instead came about as a result of real, physical changes to a specific type of brain cell? What if it wasn’t just stress after all? And what if there were real, concrete changes to be made to treatment protocols as a result of this new understanding?

That scenario is exactly where science journalist, Donna Jackson Nakazawa’s, newest book, The Angel and the Assassin, finds us today.  Nakazawa eloquently writes about the evolution of our understanding of microglial cells, a subset of the “housekeeper” cells called glial cells that provide support and insulation to the neurons in the brain.  

This emerging research re-writes long-held scientific paradigms and opens up a brand-new world of novel treatment options targeting the microglia, the glial cells that have turned out to be far more than simply cellular janitors.

Descartes Was Wrong.

The brain was historically thought to be immune privileged, completely separated from the body by the blood-brain barrier, having nothing at all to do with the immune system.  And when microglial cells were discovered in Spain in the 1920s, researchers weren’t much interested in them.  But they were prodigious, up to 10% of the total brain cells, and confounding. 

Microglia were everywhere, and often blamed for “ruining” experiments done on the neurons, the more “important” brain cells, long considered the darlings of the research world.  But as it turns out, microglial cells are important in their own right and crucial to our health and well-being.  Really, they are the brain’s own immune cells, the missing link between the brain and the body for so long.

Experiments at the Mt. Sinai School of Medicine in New York, published in 2010, showed that the microglia are, in fact, derived from the body’s immune cells, the white blood cells.  They split off early in fetal gestation, within the first ten days.  From that point, they travel up to the brain where they remain throughout the lifetime, forever sealed in by the layer of red blood cells making up the blood-brain barrier.  

Red, Hot, Swollen and Painful”?

One reason no one really thought to look for inflammation in the brain was due to the lack of characteristic swelling.  While white blood cells are responsible for the usual red, hot, painful signs of swelling in the body at the site of an injury or infection, except for in the most traumatic of insults, the brain doesn’t typically swell, thanks to the restrictions of a hard skull.  In those cases, the pressure must be relieved mechanically to avoid devastating consequences. 

It was a double whammy – the inflammation didn’t look like “normal” swelling elsewhere in the body and researchers weren’t able to see these cells due to technological limitations.  However, recent advances have finally allowed us a look at these important cells.  And it turns out that just like the immune cells in the body, the microglia can fall out of balance, causing chronic, debilitating inflammation in the brain.

Hungry Microglia Eat Synapses

Synapses are the small gaps between neurons where signals pass from one to the next.  This neuronal communication forms the heart of the connectome, the comprehensive map of neural connections in the body, and is the basis of the Human Connectome Project.   In fact, most brain disorders, from depression to learning disorders and more, have historically been conceptualized as circuitry problems; the neurons no longer wiring and firing together properly.

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In a revolutionary observation and set of experiments, neurology researcher, Dr. Beth Stevens, noticed that when the synapses were tagged by a type of molecule called complement, they seemed to disappear. Stevens, along with her postdoc at the time, Dr. Dori Schafer, stained and re-stained the microglial cells until they were completely certain of their work.  

The microglial cells were, in fact, responding to the synapses tagged by complement protein.  The microglia then morphed into PAC-MAN-like cells and ate the synapses.  In further experiments, Stevens and Schafer showed that the synapse fragments, stained red, could actually be seen inside the green microglial cells.  

And microglial research exploded. 

The Brain Drains

The story picks up again in 2016, in another research lab, this time at the University of Virginia where Dr. Jony Kipnis found something else that was not supposed to exist in the human body.  According to all the textbooks, the brain did not participate in the lymphatic system, the underground waterway that is responsible for waste removal and drainage throughout the body. 

However, Kipnis observed lymphatic vessels in the brain were not only there but were carrying immune cells in an open pipeline neatly past the supposedly immune-privileged blood-brain barrier.  Transported into the meningeal spaces surrounding the brain, these immune cells facilitate the long-suspected communication between the brain and the body. 

A worm on the ground

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These meningeal lymphatic vessels also control the newly discovered glymphatic system surrounding the spine and skull.  Like the lymphatics of the body, the glymphatic system is responsible for eliminating waste from the central nervous system. This “washing” of the brain occurs nightly, while we sleep, and is facilitated by the secretion of melatonin.

Stop the presses; the textbooks would all need to be re-written!  The brain IS a part of the immune system and is in constant communication with the body.  In retrospect, how could anyone have ever thought otherwise?  

The implications for this research were immense, and ultimately found to be repeatable by other labs, the scientific litmus test for a novel finding. 

Angels or Assassins?

In utero, far more synapses are created than are ultimately necessary.  It is the microglia’s job to prune these synapses as required for normal development.  Over the lifetime, appropriate synaptic pruning continues, resulting in a fine-tuning of neurological processes crucial to brain function.  In a healthy brain, “angel” microglial cells also secrete nutrients to support neuronal growth and repair.  

The “angel” microglial cells are a vital part of our response to daily life.  Without the ability to mount an effective immune offensive, we would not be able to survive.  The importance of these cells cannot be overemphasized.  Positive states like mental stamina, hope, and joy result from properly functioning synapses maintained by microglia.

Once the immune system is overloaded, however, symptoms invariably begin to appear as the microglial cells morph into their dangerous “assassin” role.  No longer the good gardener of the brain, improving synaptic connections for proper wiring and firing of the neurons, the microglial cells now not only inappropriately eat the synapses, but are also able to spew out a noxious cocktail of inflammatory neurotoxins, further hampering the functioning of the brain.

Immune Load

The immune system is resilient and can handle much in the way of insults such as toxins, physical or emotional stress, chemical exposures or infectious pathogens.  All of the things we eat, breathe, or are exposed to through our skin contribute to our personal immune load.  Yet, exposed to far more toxins than ever before, our immune system often just can’t keep up.  

Because the specific triggers are unique to the individual, based on environmental exposures, personal stressors, and genetics, this means a wide variety of names get assigned to the resulting symptom constellations.  Emotional regulation, memory and thought processes are essentially hijacked.  For many, the world just stops making sense.  

Mental illnesses, such as anxiety, depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder may be diagnosed at this stage.  Neurodegenerative diseases like Alzheimer’s and Parkinson’s have also been implicated in this research, as well as autism.  Even viral or bacterial infections can shift the microglia from their role as protective caretakers of the neuron into rampant destroyers.  

And It Gets Worse

Once the microglial cells become over-activated, they become super-vigilant, essentially functioning on a hair trigger.  Neuroinflammatory processes become a runaway cascade; a vicious cycle of damage and destruction caused by reacting to every insult encountered.  This process is akin to how over-activated immune cells called macrophages inappropriately attack healthy body tissues in more familiar autoimmune diseases like multiple sclerosis or rheumatoid arthritis.  

Early research also shows that when there are high levels of inflammation in the body, there are also inappropriately high levels of microglial activation in the brain.  Logically, this makes sense because the brain and body are both responding to the same inflammatory insults in their own specific way.  

We recognize this constellation of symptoms as “sickness behavior”.  People expect to feel tired, depressed, unmotivated and cranky when they are dealing with an active infection.  The microglial cells are responsible for this appropriate response as well.  But when they can’t, or don’t, turn off after the threat has passed, this sickness behavior can carry on chronically, impacting function for weeks or years to come.  

Further, chronic pain is at epidemic levels and this country, in particular, is grasped by a devastating opioid crisis.  Pain is a normal response to trauma, but when it doesn’t resolve, it becomes chronic and intractable.  This also happens as a result of over-activated microglial cells.  Neural pathways in the brain are restructured to amplify pain signals and decrease levels of dopamine, the neurotransmitter associated with pleasure and reward.  A microglial reboot can help relieve this type of pain far more safely in the long run than our current approaches to pain management.

The Most Important Questions

Moving forward, research has some important questions to investigate.  Number one, how do we identify when microglial cells have shifted from angels to assassins?  And two, how do we help shift them back so that they are no longer pruning the healthy synapses we need to function optimally?

Someday it’s very likely that a simple blood test will be able to detect microglial activation in the lab, just like we test for anything else.  This kind of test is already in the works, to help identify those after a concussionwho are recovering well and those who will need additional brain support.  Instead of just going home to quietly rest and wait, cell death and neurotoxicity can be greatly reduced by a program of suitable aerobic exercise, fasting and computer brain training.

Another new technology called droplet sequencing (Drop-seq) allows researchers to read the DNA of the microglial cells.  Gathered into a giant database, this information will eventually allow identification of various states of activation and promote early intervention efforts.

Many Opportunities to Intervene

We stew in a soup of new toxic chemicals, most of which are currently EPA-approved, but have never been tested for their effects when combined together.  Examples include pesticides and glyphosate in the food supply, dioxins in car exhaust, and flame retardants in furniture and carpets.  Even cosmetics and baby toys contain chemicals known to disrupt endocrine system function.

Any one of these items may not make a big difference alone, but together they add up and can snowball quickly once a certain personal threshold has been passed.   And cumulatively they also make up multiple opportunities for positive intervention, many times a day.  These opportunities inform our choices in terms of the kind of foods we eat, the products we choose for cleaning, and the kind of cosmetics and personal hygiene products we use.  These opportunities also include stress management and solid sleep hygiene.  

These toxic, inflammatory changes can especially affect children who have suffered through trauma or emotional stress.  Stress chemicals change the function of the immune system. Children constantly living in “fight or flight” during such important developmental periods are being set up for a lifetime of health challenges.  It’s important to identify those at most risk, using questionnaires or other tools, in order to intervene early with resilience strategies.

Microglial Resets

Already, many different kinds of treatments are being proposed, researched, and used to help combat inappropriate microglial activation.  These treatments range widely, from anti-inflammatory medications to noninvasive electrical stimulation of the brain to neurofeedback, or a specific sort of light therapy called gamma flicker, which is in clinical trials.  

Transcranial magnetic stimulation (TMS) is one such modality already in use.  Recently approved for treatment-resistant depression, TMS uses magnetic fields to stimulate nerve cells in the brain.  Building on that foundation, forward-thinking doctors are now using this therapy more specifically to target precise areas of the brain identified by live , dynamic computer mapping.  These treatments occur frequently, 3-5 times a week, for a number of weeks, but can have the effect of re-booting the microglial cells back to their angel role. 

Some researchers are also already trialing anti-inflammatory drugs in the treatment of ME/CFS and other chronic, disabling conditions with encouraging preliminary results.  Dr. Skip Pridgen has used a combination of an antiviral drug and an anti-inflammatory drug to treat fibromyalgia and other related conditions.  

Dr. Jarred Younger, head of the Neuroinflammation, Pain and Fatigue Laboratory at UAB-Birmingham has also identified a number of microglial inhibitors, like low-dose naltrexone, that may be used to treat conditions like ME/CFS.  Drugs that target specific inflammatory cytokines, like TNF-a or IL-6 show promise.  The recently approved drug, ketamine, turns out to be a microglial inhibitor as well.  It’s likely that some hallucinogenic drugs, like psilocybin, may also work in this manner.

Synapses are the target of most popular antidepressant drugs, the re-uptake inhibitors, like Prozac or Cymbalta.  Studies show that neurotransmitter inhibition starts almost immediately, however, most antidepressant drugs typically take weeks to kick in.  But it happens that microglial cells take about exactly that length of time to reboot and for new neurons to be born, allowing brain communication to pick up more normally.  Neurochemical imbalances are increasingly conceptualized as a symptom of the underlying disease, no longer the cause.  

Neurofeedback is a very old treatment that is getting a new look in the age of microglial research.  The brain is, above all, an electrical organ.  Brain waves (alpha, beta, gamma and theta) are regulated by an underlying electromagnetic field called the direct current (DC) field.  The DC field is therefore a proxy marker, of sorts, for the overall health of the brain.  

When the DC field is functioning properly, individual brain waves are working as well.  But when neurons are being over-sculpted by microglial cells, the waves can become chaotic.  Neurofeedback helps these brain waves work together properly again.  It isn’t possible to know for certain if these changes are a result of changes to the microglia at this time, but it’s certainly likely.  Brain waves just don’t work well without proper microglial function. 

Beyond neurofeedback, treatments that target the vagus nerve, the tenth cranial nerve and foundation of the autonomic nervous system can also help to rebalance the microglia.  Activities that tone the vagus nerve, like breathwork, singing or humming, can benefit the health of the brain.  Specialized listening programs, like Stephen Porges’ Safe & Sound protocol, may also have some utility in this area.  

Messages are constantly sent from the macrophages in the gut to the microglia in the brain in a bidirectional feedback loop.  Fasting, another strategy to improve health, changes these messages dramatically by remodeling the microbiome and thus the immune system.  Prepared box-type programs like the ProLon fasting mimicking diet are now available and other versions of fast mimicking diet plans have appeared online.  Studies are still in progress, but fasting almost certainly has a role in treating conditions like multiple sclerosis and mild cognitive decline. 

Moving Forward – It’s Never Too Late

The brain is never static; it is always changing, no matter how old or young the person.  Neuroplasticity never ends and we can take advantage of this to re-wire the brain in positive ways as long as we are alive and willing to try.  Most importantly, though, is to never stop learning.  Less-active synapses are more likely to be tagged and pruned.  Do puzzles, learn a new language, dance – anything novel and unpredictable helps to keep the synapses active.  

It’s well-documented that scientific discoveries take an average of 17 years to make it from the lab into clinical practice.  But modern advances in technology and communication can shorten this time significantly, allowing people to access these potentially life-saving treatments in a far shorter span of time.  

And finally, this new understanding of how the brain and body work together will go a long way towards finally erasing the line between mental and physical illnesses, replacing stigma with understanding and compassion for all who suffer.


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