More than a decade ago, I was diagnosed with several autoimmune diseases, one after another, including Guillain-Barré syndrome, which left me paralyzed twice while raising two young children. All told I spent six years in and out of bed and hospitals, learning, between crises, to use a cane or walker to navigate life as a working-mother-with-chronic-illness.
My immune system was repeatedly and mistakenly attacking my body, causing the nerves in my arms, legs, and those I needed to swallow and breathe to stop working, leaving me, all too often, to raise my children from bed.
As I slowly began to recover and learn to walk again, I noticed that along with distinct physical losses (I could walk but not run), I had experienced shifts in my mood and clarity of mind. Although I'd always been an optimistic person, I felt a bleak unshakeable dread. When I read Harry Potter to my son, it felt, to me, as if those “dementors,” who steal away hope and joy, had cast their dark spell on my brain, too.
I also noticed cognitive glitches. Names, words, facts, were hard to bring to mind. I can still recall cutting up slices of watermelon, putting them in a bowl, and staring down at them thinking, "What is this called again?"I knew the word but couldn't remember it. I'd cover my lapse by bringing the bowl to the table and waiting for my children to call out, "Yay! Watermelon!" And I'd think, "Yes. Of course. Watermelon." I recall trying to tie my daughter’s shoe and struggling to remember how it was done.
As a science journalist whose niche spans neuroscience, immunology, and human emotion, I knew at the time that it did not make scientific sense that inflammation in the body could be connected to — much less cause — illness in the brain. At that time, scientific dogma held that the brain was the only organ in the body not ruled by the immune system. The brain was considered to be "immune privileged."
In the early 2010s, that began to change. As neuroscience and immunology started to merge, they began dismantling that century-old tenet. Scientists pivoted away from believing that the brain and body function as church and state entities, and began to embrace an entirely new brain-body paradigm that tells us that the brain is also governed by the immune system.
This ground-breaking science couldn’t come a moment too soon. As we look back over the past decade, one thing is disturbingly apparent: We are increasingly a people in despair. For many, when despair becomes depression, or untenable anxiety, the standard answers — antidepressants with a dose of therapy — are not enough to assuage suffering.
We know this because the rates of mental health disorders and suicide are rising. Nearly a third of the 264 million people who suffer from major depression around the world don’t respond to any antidepressant treatments, and many who do find that medications stop working over time. A surprising number of young people who attempt suicide are already taking antidepressants. As Gregory Plemmons, M.D., at Children’s Hospital at Vanderbilt put it recently, pediatric beds in hospitals used to be for kids fighting off pneumonia; now they’re full of kids who don’t want to live.
As other areas in medicine move rapidly forward with findings in their fields — for instance, targeted cancer therapies are extending the lives of oncology patients — psychiatry lags behind in providing new answers. In some ways that makes sense: the brain has long remained the black box of science, and it’s only very recently that we’ve had the tools necessary to peer inside the brain on a cellular level.
Still, even as neuroscience and neuroimmunology rapidly advance, and the two fields become one, the options we give an individual suffering from depression, or anxiety, or a mood disorder today, are largely the same ones we offered a patient 30 years ago.
The past decade has been a golden era in brain research, one in which scientists have offered extraordinary hope for today’s mental health crisis by rewriting our basic understanding of how disorders of the human brain develop, and how we might help prevent or ameliorate them. And they all come down to one tiny, elusive cell, called microglia (remember that name!), which turn out to be game-changers for mental health.
In 2012, Harvard researchers Beth Stevens and Dori Schafer used new visual tools to unmask the behavior of these previously little understood cells, called microglia, mapping their actions in the brain in exquisite detail. Under the right circumstances, microglia keep the brain healthy; they twirl around neurons like tiny dancers stretching out their long, elegant limbs, soothing and bathing neurons in anti-inflammatory factors that help protect the brain’s all-important neural circuitry.
But microglia, it turns out, also have a dark side. When they sense incoming threats — the same triggers that can overwhelm our body’s immune system: chronic stressors (including adverse childhood experiences), environmental toxins, trauma, infections— microglia can morph from angels into frenzied assassins. They can begin to spit forth inflammatory toxins and engulf and destroy the very neural synapses they once protected — those fundamental to our mind state, mental processing, mood, behavior, and memories. Indeed, the root causes of depression and anxiety, stem not so much from chemical imbalances but from microglia gone rogue — when microglia spit out inflammation that alters levels of dopamine and serotonin.
Because these microglia-led inflammatory changes appear differently in the brain from one person to another, we give it a hundred different names: OCD, ADHD, anxiety, depression, bipolar disorder, memory loss.
It also turns out that people who have high levels of chronic inflammation, as measured by simple blood tests, have higher levels of microglial activation in the brain, a keen and worrisome indicator that too many synapses are being lost.
This science also solves a decades-old mystery: the link between trauma and loss of brain synapses has long confounded the medical community. We’ve known for some time that adverse childhood experiences can alter important synaptic wiring in the brain — we can see this in brain scans of children and teens who’ve experience chronic unpredictable stress, whether that stress is due to parents fighting, emotional neglect, chronic humiliation, poverty, or community violence. Connections between important areas of the brain can become compromised, wanted and necessary brain circuits and synapses can be lost. Gray matter volume decreases. We also know that children facing ACEs have a higher rate of mental health disorders, mood disorders, and Alzheimer’s as the years tick by.
With this science, we now understand why. Our brain is our “Seventh Sense", in a constant, intricate, breathtaking dance with the environment responding to the world around us — including everyone, and everything, in it — in ways that reshape our minds. Our body and brain are constantly chatting in a bidirectional conversation about whether we are safe, or not safe. When our brain gets the message we aren’t safe, this brain immune inflammatory response — led by microglia — can lead to depression, anxiety, and memory loss. In unhealthy or toxic environments, microglia can become the brain’s untimely assassins.
These revelations that microglia function as a kind of “holy grail” cell, one that serves as both the assassin and the guardian of the self, gives a stymied field new hope that extends beyond the serotonin hypothesis — and offers us new possibilities and hope for healing. Neuroscientists are racing to offer up novel, noninvasive ways to gently manipulate microglia to protect and restore the brain to health.
In 2016, neuroscientist Li-Huei Tsai, director of The Picower Institute for Learning and Memory at MIT, programmed software so that LED lights on a handheld wand flickered at the frequency of gamma brain waves, which are compromised in Alzheimer’s, and delivered pulses of light from outside the brain, noninvasively, to mice with a version of Alzheimer’s. This treatment caused microglia to stop spitting out inflammatory toxins and attacking synapses. Instead, microglia bathed neurons in neuroprotective factors, repaired vulnerable synapses, and stimulated new neurons to grow — all while scouring the brain for plaques and tangles and clearing those away, too. Mice showed improvements in memory tasks, with results lasting for up to a week. Human clinical trials are well underway.
Another brain-hacking method, transcranial magnetic stimulation, or TMS, introduces gentle, brief magnetic pulses from the scalp’s surface to the brain areas where synapses have gone offline. These pulses induce a mild electrical current that hands microglia and neurons a fresh, proper set of signals. In 2016, Harvard researcher Alvaro Pascual-Leone demonstrated that TMS can restore healthy brain circuitry in depressed patients who have not responded to medications. Some patients who experienced significant relief after 30 treatments with TMS never experienced a relapse of depression, even years later.
Microglia also communicate with the over 100 trillion nerve cells that line our gastrointestinal tract. Unhealthy alterations in the gut’s microbiota can contribute to depression and other mood disorders in the brain. Valter Longo of University of California and Mark Mattson of Johns Hopkins unveiled in 2014 and in 2018 that one way to influence both the gut and microglia is through intermittent fasting and fasting-mimicking diets, which help increase the resistance of neurons to overpruning. With fasting, we may have some ability to influence microglia to turn from the dark side to the light again.
Scientists are also working to try to reboot microglia by hacking the largest nerve in the body, the vagus nerve, which travels down from the brain stem and throughout our torso, sending its roots into our heart, lungs, and digestive system. The vagus nerve acts as a superconductor, sending bidirectional signals between body and brain. When the body is under emotional or physical stress it zips “fight flight freeze” warning messages up the vagus nerve to the brain, which puts microglia under duress too, leading, over time, to changes in everyday mood and behavior. Work to calm the vagus nerve — like Stephen Porges’s Safe and Sound Protocol — are now more crucial than ever. Meanwhile, human clinical trials are examining whether stimulating the vagus nerve can ameliorate symptoms in chronic pain, memory loss, depression, and autoimmune disease.
The brain has long been inscrutable, as compared to, say, treating heart muscle. Psychiatry is still a long way from being able to connect the dots between the activity of brain cells and a patient's felt experience or "symptoms," much less correlate emotional symptoms to a precise treatment. To date, it's been a guessing game – throw drugs in, and see what happens. But the discovery that microglia are like one giant light switch through which many signals related to diseases of the brain pass gives us a new paradigm. As a result, a sea change is coming to medicine – that is, if physicians and psychiatrists are ready to step up to the plate and help close the interminable lag time between what’s happening in the lab and what’s happening in the clinic.
This new view of the brain — that microglia-led inflammation, triggered by a combination of genes and environmental factors from emotional trauma to toxins, can slowly brew in the brain throughout a lifetime — sheds hopeful new light on the mind-body connection, rewriting our understanding of brain health and illness. Patients have great agency here to ask for more tools in the healing toolbox, and physicians have new insights and options to help patients find relief from suffering.
For those caught in the liminal space of despair — between wanting and not wanting to live this life — the clock is ticking.
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Donna Jackson Nakazawa is a science journalist and the author of six books, including “The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine,” which was published Jan. 21, 2020. Follow her on Twitter, Instagram and Facebook.
A version of this essay first appeared in The Boston Globe on January 21, 2020, and has been modified.
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