How does COVID-19 change the brain? This scientist finds out. – Community News
Covid-19

How does COVID-19 change the brain? This scientist finds out.

NEW YORK – In a room as cold as a refrigerator, Dr. Maura Boldrini stands over a plastic box filled with pale slices of human brain, each piece nestled in its own small, liquid-filled compartment.

She gestures with purple gloved fingers: Here are the folds of the cortex, where higher cognition takes place. There is the putamen, which helps our limbs move. Here’s the emotion-processing amygdala, with its telltale bumps.

Each piece in this box came from a single brain – one whose owner died of COVID-19.

Dozens of containers remain, just as they were stacked in freezers in Boldrini’s lab at the New York State Psychiatric Institute.

“Each of these boxes is one person,” she says in a lilting Italian accent. Each will play a critical role in helping unravel the effects of COVID-19 on the brain.

The disease may be best known for its ability to take people’s breath away, but as the pandemic spread, patients began to report a troubling array of cognitive and psychiatric problems — memory loss, fatigue and a mental blurriness that came to be known as brain fog. There were also more acute problems, including paranoia, hallucinations, suicidal thoughts and psychosis.

This strange constellation of symptoms has led researchers to suspect that the disease is directly attacking the brain. Researchers want to find out how — and what the long-term effects of the attack might be.

Boldrini, a neuroscientist at Columbia University, studies the biology of suicide and the physiological characteristics of resilience in brain tissue. She is also a practicing psychiatrist.

This combination makes her ideally suited to investigate the substantiation of ‘long-term COVID’. She has collected more than 40 brains from COVID-19 victims to guide her in her quest.

What Boldrini and her colleagues are learning could have implications far beyond COVID-19, shedding light on mental illness, the origins of dementia, and the myriad ways viral infections affect the brain.

To unravel the secrets of the disease, they must carefully disassemble each brain, count the cells, monitor gene expression and document the proteins.

“We have a lot of work to do,” said Boldrini.

New York City was one of the early targets of the coronavirus, and it wasn’t long before Boldrini noticed surprising problems in COVID-19 patients, including severe mood and psychiatric symptoms.

“Very strange symptoms,” she recalls — made even weirder because they showed up in people with no personal or family history of such problems. Adding to the mystery, the appearance of these conditions was relatively late in a patient’s life rather than adolescence and early adulthood.

“I feel like this fear I’m feeling is something organic in my brain,” one patient told her. “Psychologically, I’m not worried about anything.”

“It’s a very different kind of symptomatology compared to people with normal anxiety,” Boldrini says.

Then there were the rarer, but more disturbing, cases of suicidal ideation.

Boldrini has not encountered a COVID-19 patient who has died of suicide. But one case struck her university close to home: Dr. Lorna Breen, a Columbia emergency department physician who worked on the front lines before falling ill herself during the brutal first wave of the pandemic.

Breen was a talented and dedicated physician who enjoyed snowboarding and salsa dancing in her spare time. Shortly after returning to work, her mental health deteriorated and within weeks she died by suicide.

“She had COVID and I believe it changed her brain,” her sister Jennifer Feist said on NBC’s “Today” last year.

If so, how?

Researchers have found signs that the virus may find some sort of foothold in the periphery of the brain, where the protective blood-brain barrier opens to allow important molecules to slip through. One such place is the olfactory bulb, which can be reached through the nose — a fact that could explain why so many COVID-19 patients lose their sense of smell.

Still, scientists have so far found little evidence that the virus penetrates deeper. Instead, they’ve seen the kind of damage caused by strokes, as well as the blood clots they may have caused.

That’s part of why Boldrini and many others suspect that inflammation — the immune system’s all-hands-on-deck response to an invader — may play a vital role in the brain damage experienced by COVID-19 patients.

Inflammation can cause blood clots, and once a clot forms, the inflammation around it increases. It’s similar to what’s seen in people who experience traumatic brain injuries, including football players, military veterans, and car accident victims.

“People with this kind of trauma to the brain have shown sudden changes in behavior and personality and suicide and other brain symptoms,” Boldrini says. It’s eerily similar to what many COVID-19 patients face — and she doesn’t think that’s a coincidence.

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To better understand what happens at the cellular and molecular levels, scientists need to study the brains of people who died from COVID-19. But Boldrini prefers not to work with brains collected by others — she needs to know everything about how the tissue was collected and preserved so she can understand the results of her experiments.

“Depending on how you freeze, store, and repair the brain, you can get very different results,” she says.

At Columbia, she and her colleagues examine tissue from autopsies so that they have complete control over how the precious tissue is treated.

Boldrini wants to know which genes were expressed; to monitor molecular markers of inflammation; to see how microglia – the immune cells of the brain – behaved; and to document the state of the neurons and their connections to each other.

Mapping the multifaceted effects of one disease is an ambitious undertaking and requires painstaking work. One of the students working in the lab begins by taking a shell-rimmed sample of the amygdala and mounting it on a bed of dry ice. Drop by drop, she coats the tissue with sugar water, which eventually freezes and holds the sample in place.

She then cuts off pieces only 50 microns thick — just wide enough to contain a single layer of brain cells. Each fragile cut is then submerged in water and centered on a glass slide with fine brushes.

The slides are stained with dyes that allow the researchers to see different types of cells in the tissue. Those cells are counted under a microscope, partly with the human eye and partly using a computer algorithm.

Boldrini looks over the student’s shoulder at one of the magnified slides on a computer screen. This piece of brain tissue resembles a galactic collection of stars stretching across a dark sky: the scattered blue stars are glia, the protective cells of the brain. The green ones are neurons, tightly packed. The red stars are young, immature neurons.

“It’s beautiful,” Boldrini says. “Anatomy is very beautiful.”

The red stars are the rarest of the three, and they are even scarcer in many patients with COVID-19 — about 10 times less abundant. That’s a problem, because these young neurons are needed for learning and memory, for coping with stress, and for integrating memories with emotions.

Boldrini suspects that these immature cells are caused by stress hormones and inflammation.

“This would explain the brain fog,” she says.

A few days earlier, the researchers went through the same steps with the hippocampus, a small, delicate brain structure involved in mood and memory.

Other scientists have found that COVID-19 damages the hippocampus. That could help explain why some patients have persistent problems with depression and anxiety.

If this damage is caused by inflammation, it is likely doing damage in several ways. Scientists suspect it disrupts the flow of serotonin, a hormone involved in depression, prompting the body to produce kynurenine instead, even though it’s toxic to neurons.

Inflammation also causes coagulation, which creates clots that can block blood flow to cells and kill them. And it activates the microglia, which can try to remove more neurons than they normally would.

Boldrini’s work will help scientists unravel the factors that cause that damage.

“She’s an expert at that,” said Dr. James Goldman, a neuropathologist at Columbia University. “We are curious what she comes up with.”

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In a nearby room, research assistant Cheick Sissoko checks whether the DNA fragments extracted from the tissue are too large or too small for a proper analysis. If they’re the right size, Sissoko will use them to better understand gene expression in these brain cells — especially in the young neurons that seem to take a hit in COVID-19 patients.

“Ideally, we can look at every gene expressed by a single cell,” he says.

On other days, Sissoko focuses on RNA, the molecule that helps convert DNA’s instructions into real proteins. The RNA in brain tissue can provide clues about the alarms that went off in the body in response to the coronavirus, and how the body responded to a perceived threat.

Sissoko uses an advanced new technique to sequence the RNA slide by slide. For example, he can see how RNA expression changes in different parts of the brain.

Ultimately, the researchers want to combine the data on RNA, the microglia, the new and mature neurons, and the connections they make to create a portrait of a brain devastated by COVID-19.

By comparing the brains of COVID-19 patients with and without neurological symptoms, Boldrini hopes to shed light on the role of inflammation in a wide range of neurodegenerative diseases, from depression to dementia.

“This pandemic is almost like a natural experiment where you have a lot of inflammation in a very unusual way,” she says. “We hope this will elucidate some mechanisms of brain damage independent of COVID itself.”

That, in turn, can help people understand that mental health is a critical part of physical health.

“I think this could be really helpful in fighting the stigma of psychiatric illness,” Boldrini says. “The brain is an organ, just like any other.”

dr. Christian Hicks Puig, a psychiatrist at Columbia Medical Center who works at the long COVID clinic, agreed. Many psychological problems are rooted in biological processes. “It’s all very interrelated,” he says.

As researchers like Boldrini map COVID-19’s attack on the brain, they can help doctors better understand the relationship between mental health, cognitive health and disease. They can also gain insight into the long-term needs of COVID-19 survivors.

That progress wouldn’t be possible without the contributions of those who didn’t make it, Goldman says.

“We are very grateful to the families who have allowed us to have these autopsies done,” he says.

Boldrini agrees, adding that she and others feel tremendous pressure to handle these organs with care.

“These are people,” she says. What they reveal about COVID-19 is crucial. What they represent is irreplaceable.

Amina Khan, Los Angeles Times