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New York-In a room as cold as a refrigerator, Dr. Maura Boldrini bent over and looked at a plastic box filled with pale human brain slices, each in a liquid-filled In the cubicle.

She gestured with her fingers wearing purple gloves: This is a fold in the cortex, where advanced cognition takes place. There is a putamen, which can help our limbs move. This is the amygdala for emotional processing, with obvious bumps.

Every piece in this box comes from a brain-its owner died of COVID-19.

In Boldrini's laboratory at the New York State Institute of Psychiatry, there are dozens of containers, as if they were stacked in a refrigerator.

"Each box is a person," she said in a brisk Italian accent. Everyone will play a key role in helping to clarify the impact of COVID-19 on the brain.

The disease may be known for its ability to take people’s breath away, but as the pandemic spread, patients began to report a series of disturbing cognitive and mental problems-memory loss, fatigue, and confusion, which were later called For brain fog. There are more serious problems, including paranoia, hallucinations, suicidal thoughts and mental illness.

This strange cluster of symptoms makes researchers suspect that this disease is directly attacking the brain. Researchers want to figure out what and how the long-term effects of an attack might be.

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

This combination makes her very suitable for researching the basis of "long-term COVID". She collected more than 40 brains from COVID-19 victims to guide her exploration.

What Boldrini and her colleagues have learned may have effects far beyond COVID-19, revealing the origin of mental illness, dementia, and the myriad ways in which viral infections affect the brain.

In order to uncover the secrets of this disease, they must carefully disassemble each brain, count its cell number, track its gene expression and record its protein.

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

New York City was one of the early targets of the coronavirus, and Boldrini soon noticed that COVID-19 patients had surprising problems, including severe emotional and mental symptoms.

"Very strange symptoms," she recalled-becoming even stranger because they appeared in people with no personal or family history of such problems. What is even more mysterious is that these symptoms appear relatively late in the life of the patient, rather than in adolescence and early adulthood.

"I think this fear is something organic in my brain," a patient told her. "Psychologically, I don't worry about anything."

"This is a very different symptom compared to people who are normally anxious," Boldrini said.

Then there are rarer but more disturbing cases of suicidal ideation.

Boldrini has not encountered a COVID-19 patient who died by suicide. But one case did hit the university near her home: Dr. Lorna Breen, an emergency physician at Columbia University, who worked on the front lines and fell ill during the cruel first wave of the pandemic.

Breen is a talented and dedicated doctor who engages in skiing and salsa dancing in her spare time. Soon after returning to work, her mental health deteriorated and she committed suicide within a few weeks.

"She was infected with COVID-19, and I believe it changed her brain," her sister Jennifer Fester said on NBC's "Today" show last year.

Researchers have found signs that the virus can establish various footholds on the periphery of the brain, where the protective blood-brain barrier opens to allow key molecules to slip through. One of these places is the olfactory bulb, which can be reached through the nose—a fact that explains why so many COVID-19 patients lose their sense of smell.

However, so far, scientists have found almost no evidence that the penetration depth of the virus is deeper than this. Instead, they saw the type of damage caused by the stroke, and the blood clots that might precipitate them.

This is why Boldrini and many others suspect that inflammation-the overall response of the immune system to invaders-may play an important role in the brain damage experienced by COVID-19 patients.

Inflammation causes a blood clot, and once the clot forms, the inflammation around it increases. This is similar to people suffering from traumatic brain injury, including football players, veterans, and car accident victims.

"People with this kind of brain trauma experience sudden changes in behavior and personality, as well as suicide and other brain symptoms," Boderini said. This is very similar to the situation faced by many COVID-19 patients-she believes this is not a coincidence.

In order to gain a deeper understanding of what is happening at the cellular and molecular level, scientists need to study the brains of people who have died of COVID-19. But Boldrini doesn't like to use brains collected by other people-she must understand all the information about how the organization collects and saves so that she can understand the results of her experiments.

"Depending on how you freeze, store and repair your brain, you can achieve very different results," she said.

In Colombia, she and her colleagues examine the autopsied tissues, so they have complete control over how precious tissues are handled.

Boldrini wants to know which genes are expressed; to track molecular markers of inflammation; to see how microglia-the immune cells of the brain-behave; and to record the state of neurons and their connections with each other.

Mapping the multifaceted effects of a disease is ambitious and requires hard work. A student working in the laboratory first took a sample of the fan-shaped edge of the amygdala and installed it on a bed of dry ice. Drop by drop, she coated the tissue with sugar water, which eventually freezes and fixes the sample in place.

Next, she cut off pieces that were only 50 microns thick-just wide enough to accommodate a single layer of brain cells. Then immerse each fragile cut in water and center it on a glass slide with a fine-tipped paint brush.

The slides are stained with dyes, allowing researchers to see different types of cells in the tissue. These cells are counted under a microscope, partly through the human eye and partly with the help of computer algorithms.

Boldrini looked over the student's shoulder at a slide that was magnified on the computer screen. This piece of brain tissue is similar to the stars of the Milky Way in the dark sky: the scattered blue stars are glial, the protective cells of the brain. The green ones are neurons, packed densely together. Red stars are young, immature neurons.

"It's beautiful," Boldrini said. "The anatomy is very beautiful."

Red stars are the rarest of the three, and in many patients with COVID-19, they are even rarer—about 10 times less in number. This is a problem because these young neurons are essential for learning and memory, coping with stress, and integrating memory and emotions.

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

"This can explain brain fog," she said.

A few days ago, researchers performed the same steps on the hippocampus, a tiny and delicate brain structure related to emotions and memory.

Other scientists have found that COVID-19 can damage the hippocampus. This may help explain why some patients have lingering depression and anxiety problems.

If this damage is caused by inflammation, it can cause severe damage in many ways. Scientists suspect that it disrupts the flow of serotonin, a hormone related to depression, and prompts the body to produce kynurenine, even though it is toxic to neurons.

Inflammation can also cause blood to clot, forming a clot, which prevents blood from flowing to the cells and kills them. It activates microglia and it may try to remove more neurons than usual.

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

"She is an expert in this area," said Dr. James Goldman, a neuropathologist at Columbia University. "We look forward to seeing what she comes up with."

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

"Ideally, we can look at every gene expressed by a single cell," he said.

In other days, Sissoko focused on RNA, a molecule that helps turn DNA instructions into actual proteins. The RNA contained in brain tissue may provide clues about the alarms the body sends in response to the coronavirus and how the body responds to perceived threats.

Sissoko uses a sophisticated new technique to sequence RNA on the basis of a slide. This allows him to see changes in RNA expression in different parts of the brain.

Ultimately, the researchers’ goal is to combine data on RNA, microglia, new and mature neurons, and the connections they make to create a picture of the brain ravaged by COVID-19.

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

"This epidemic is almost like a natural experiment, you will have a lot of inflammation in a very unusual way," she said. "We hope this will clarify some brain damage mechanisms that are independent of COVID itself."

In turn, this may help people understand that mental health is an important part of physical health.

"I think this is very useful for fighting the stigma of mental illness," Boldrini said. "The brain is an organ, just like any other organ."

Dr. Christian Hicks Puig, a psychiatrist at Columbia Medical Center who works in this long-term COVID clinic, agrees. Many mental health problems stem from biological processes. "It's all very interrelated," he said.

Because researchers like Boldrini have mapped the attack of COVID-19 on the brain, they may help doctors gain a deeper understanding of the relationship between mental health, cognitive health, and disease. They can also gain insight into the long-term needs of COVID-19 survivors.

Goldman said that without the contributions of those who did not make progress, it would be impossible to make such progress.

"We are very, very grateful to the family members who allowed us to perform these autopsies," he said.

Boldrini agreed, adding that she and others felt the great pressure to handle these organs carefully.

"These are people," she said. The information they reveal about COVID-19 is crucial. What they represent is irreplaceable.

"Los Angeles Times" Amina Khan

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