NEW YORK —
In a room as cold as a refrigerator, Dr. Maura Boldrini bends over a plastic box filled with pale slices of human brain, each piece nestled in its own tiny, fluid-filled compartment.
She uses purple-gloved hands to indicate that the cortex folds are where higher cognition occurs. The putamen is what helps our limbs move. The emotion-processing amygdala is shown here with its distinctive bumps.
Each piece in this box came from a single brain — one whose owner died of COVID-19. There are many more containers like this one, all stored in freezers at Boldrini’s New York State Psychiatric Institute.
” Each of these boxes are one person,” she says with a soft Italian accent. Each will play a crucial role in helping to unravel COVID-19’s effects on the brain.
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The disease may be best known for its ability to rob people of their breath, but as the pandemic spread, patients began reporting a disconcerting array of cognitive and psychiatric issues — memory lapses, fatigue and a mental fuzziness that became known as brain fog. Paranoia, hallucinations and thoughts of suicide were some of the more severe symptoms. This strange combination of symptoms led researchers to believe that the disease is attempting to attack the brain. Researchers are trying to determine how and what the long-term effects of this assault may be.
Boldrini, a neuroscientist at Columbia University, studies the biology of suicide and the physiological markers of resilience in brain tissue. She is also a psychiatrist.
That combination makes her uniquely suited to investigate the underpinnings of “long COVID.” She has gathered more than 40 brains from COVID-19 victims to guide her in her quest.
What Boldrini and her colleagues learn 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 unlock the disease’s secrets they will need to carefully dissect each brain, count its cells and track its gene expression. Boldrini states that there is still much to be done.
New York City was one of the coronavirus’ early targets, and it didn’t take long for Boldrini to notice surprising issues among COVID-19 patients, including serious mood and psychiatric symptoms.
” These symptoms were very strange, she says. They also appeared in patients with no family history or personal history of similar conditions. These conditions often appear later in life than they do in childhood and young adulthood, which adds to their mystery.
I feel like this dread that I’m feeling is something organic in my brain, one patient told her. Psychologically, it’s not something that I am anxious about.
“It’s a very different kind of symptomatology compared to people that have 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 died of suicide. But one case did hit her university close to home: Dr. Lorna Breen, an emergency department physician at Columbia who worked on the front lines before becoming ill herself during the pandemic’s brutal first wave.
Breen, a dedicated and talented doctor, took up salsa dancing and snowboarding in her spare time. Soon after her return to work, her mental state deteriorated. She committed suicide in a matter of weeks.
“She was diagnosed with COVID and her brain was altered by it,” Jennifer Feist, her sister, said last year on NBC’s Today.
If so, how?
Researchers have found signs that the virus can establish a foothold of sorts on the periphery of the brain, where the protective blood-brain barrier opens up to allow key molecules to slip through. One of those places 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. Scientists have not yet found any evidence that the virus can penetrate deeper than this. They have seen strokes and blood clots that could have caused them.
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 an essential role in the brain damage experienced by COVID-19 patients.
Inflammation can trigger blood clots, and once a clot forms, inflammation increases around it. This is similar to what happens in those who suffer from traumatic brain injuries, such as football players, veterans, and car accident victims.
“People that have this kind of trauma in the brain have presented with 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.
To gain a deeper understanding of what’s happening on a cellular and molecular level, scientists need to study the brains of people who died of COVID-19. Boldrini doesn’t like to work with brains from others. She needs to understand everything about how the tissue was collected, preserved and used so that she can interpret the results.
“Depending how you freeze, store and fix the brain, you can get very different results,” she says.
She and her colleagues at Columbia examine autopsies to ensure that they are in complete control of how precious tissue is treated.
Boldini would like to determine which genes are being expressed, to track molecular markers for inflammation, to observe how microglia (the brain’s immune cells) were acting; and to document the state and connections of neurons.
Mapping the multifaceted effects of one disease is an ambitious endeavor, and it requires painstaking work. One student in the lab begins by collecting a sample of the amygdala with a scallop edge and placing it on a layer of dry ice. Drop by drop she covers the tissue with sugar water. This eventually freezes and keeps the sample in place.
Next, she slices off pieces that are a mere 50 microns thick — just wide enough to contain a single layer of brain cells. The delicate cut pieces are then immersed in water and placed on a slide using fine-tipped paintbrushes.
The slides are stained with dyes that allow the researchers to see different types of cells in the tissue. These cells are counted using a microscope. Partly by the human eye, part with the aid of a computer algorithm.
Boldrini looks over the student’s shoulder at one of the slides magnified on a computer screen. This section of brain tissue looks like a galactic mass of stars spread across a darkened sky. The blue stars in the background are glia, which are the brain’s protective cells. The neurons are densely packed together. The red stars represent immature, young neurons.
” “It’s beautiful,” Boldrini said. “Anatomy is very beautiful.”
The red stars are the rarest of the three, and they’re even more sparse in many patients who had COVID-19 — about 10 times less abundant. This is a problem as these young neurons are essential for learning, memory, coping with stress and integrating emotions with memories.
Boldrini suspects these immature cells are done in by stress hormones and inflammation.
” This would explain brain fog,” she said.
A few days before, the researchers had gone through the same steps for the hippocampus. This is a delicate brain structure that affects mood and memory.
Other scientists have found that COVID-19 damages the hippocampus. That could help explain why some patients have lingering issues with depression and anxiety. If inflammation is causing the damage, it can cause havoc in many ways. Scientists believe it causes a disruption in the flow of serotonin (a hormone implicated in depression) and prompts the body make kynurenine instead. However, it is toxic to neurons.
Inflammation also triggers coagulation, creating clots that can block blood flow to cells and kill them. It activates microglia which may try to take out more neurons than normal.
Boldrini’s work will help scientists disentangle the factors driving that damage.
“She’s an expert at that,” says Dr. James Goldman, a neuropathologist at Columbia University. “We’re looking forward to seeing what she comes up with.”
In a nearby room, research assistant Cheick Sissoko checks to see whether the DNA fragments obtained from the tissue are too big or too small for proper analysis. If they’re the right size, Sissoko will use them to better understand the gene expression in these brain cells — particularly in the young neurons that seem to be taking a hit in COVID-19 patients.
“Ideally, we can look at every single gene expressed by a single cell,” he says.
On other days, Sissoko focuses on RNA, the molecule that helps turn DNA’s instructions into actual proteins. The brain tissue containing RNA may contain clues to how the body responded to the coronavirus.
Sissoko uses a sophisticated new technique to sequence the RNA on a slide-by-slide basis. This allows him to observe how RNA expression changes in different areas of the brain.
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Ultimately, the researchers aim 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 ravaged 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 swath of neurodegenerative diseases, including depression and dementia. This pandemic is almost a natural experiment in which you have a lot inflammation like in an unusual way,” she said. “We hope that this is going to clarify some mechanisms of brain damage independently of COVID itself.”
That, in turn, may help people understand that mental health is a crucial part of physical health. Boldrini states that this could help to combat stigmatization of psychiatric illnesses. “The brain is an organ, like any other one.”
Dr. Christian Hicks Puig, a psychiatrist at Columbia Medical Center who works at the long COVID clinic, agreed. Many mental health problems are related to biological processes. Boldrini says, “It’s all extremely connected.”
As researchers such as Boldrini map COVID-19’s assault on the brain, they may help doctors more deeply understand the relationships among mental health, cognitive health and disease. They may also gain insight into the long-term needs of COVID-19 survivors. This progress wouldn’t be possible without the efforts of those who weren’t able to make it, Goldman states.
” We are grateful to the families that have allowed us to perform these autopsies,” says he.
Boldrini agrees, adding that she and others feel immense pressure to handle these organs with care.
“These are people,” she says. What they reveal about COVID-19 is crucial. They are irreplaceable.