The Tiny Cell that Connects our Physical and Mental Health, and Solves a Decades-old Mystery of Why Toxic Stress Leads to Brain Changes that Spark Depression, Anxiety

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.

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