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COVID-19 can affect the brain. New clues indicate how


For more than a year now, scientists have been running to understand how the mysterious new virus that causes COVID-19 not only damages our bodies, but our brains as well.

At the onset of the pandemic, some infected people noticed a curious symptom: loss of smell. Reports of other brain-related symptoms followed: headaches, confusion, hallucinations, and delirium. Some infections were accompanied by depression, anxiety and sleep problems.

Recent studies suggest that leaking blood vessels and inflammation are involved in some way in these symptoms. But many basic questions remain unanswered about the virus, which has infected more than 145 million people worldwide. Researchers continue to try to find out how many people experience these psychiatric or neurological problems, who is most at risk, and how long these symptoms can last. And the details of how the pandemic virus, called SARS-CoV-2, exerts its effects are still unclear.

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“We haven’t yet established what this virus does in the brain,” says Elyse Singer, a neurologist at the University of California, Los Angeles. There are probably many answers, she says. "It's going to take years to separate this."

Getting the numbers

For now, some scientists are focusing on the basics, including how many people experience these types of brain-related problems after COVID-19.

A recent study of electronic health records reported an alarming response: in the six months following an infection, one in three people experienced a psychiatric or neurological diagnosis. That result, published April 6 in Lancet Psychiatry, came from the health records of more than 236,000 COVID-19 survivors. The researchers counted diagnoses of 14 disorders, ranging from mental illness such as anxiety or depression to neurological events such as strokes or cerebral hemorrhages, in the six months following COVID-19 infection.

“We didn’t expect it to be such a high number,” says study co-author Maxime Taquet of Oxford University in England. One in three “may look scary,” he says. But it is unclear whether the virus itself causes these disorders directly.

The vast majority of these diagnoses were depression and anxiety, "disorders that are already extremely common in the general population," notes Jonathan Rogers, a psychiatrist at University College London. What’s more, depression and anxiety increase among everyone during the pandemic, not just people infected with the virus.

Mental health disorders are "very important things to treat," says Allison Navis, a neurologist at the post-COVID clinic at Mount Iinahn School of Medicine in Mount Sinai, New York City. “But they’re very different from those from stroke or dementia,” he says.

About 1 in 50 people with COVID-19 has suffered a stroke, Taquet and colleagues found. However, among people with severe infections who presented with delirium or other altered mental states, the incidence was much higher: 1 in 11 had a stroke.

In people with COVID-19, severe neurological damage occurs, such as these strokes caused by blocked blood vessels.K. Thakur et al / Brain 2021

Taquet’s study includes warnings. It was a look back at diagnostic codes, often introduced by hurried doctors. They are not always reliable. And the study finds a relationship, but it cannot conclude that COVID-19 caused any of the diagnoses. Still, the results show how COVID-19 affects the brain.

The blood vessels examined

At the start of the pandemic, loss of smell suggested that the virus could directly attack nerve cells. Perhaps SARS-CoV-2 could break the skull by rising along the olfactory nerve, which carries odors from the nose to the brain, some researchers have thought.

That terrifying scenario doesn’t seem to happen much. Avindra Nath, a neurologist studying central nervous system infections at Bethesda National Institutes of Health, Md. Nath and his colleagues hoped to see signs that most of the studies conducted so far have failed to produce many viruses in the brain. the virus in the brains of people with COVID-19 but did not find it. “I kept telling people,‘ Let’s look again, ’Nath says.

That absence suggests the virus is affecting the brain in other ways, possibly involving blood vessels. Thus, Nath and his team digitized the blood vessels in post-mortem brains of people infected with the virus with such a powerful MRI machine that it is not approved for clinical use in living people. “We were able to look at the blood vessels in a way that no one else could,” he says.

The damage abounded, the team reported Feb. 4 in the New England Journal of Medicine. Small clots sat in the blood vessels. The walls of some ships were unusually thick and inflamed. And blood came out of the vessels to the surrounding brain tissue. “You can see all three things happen at once,” Nath says.

These results suggest that clots, inflamed linings, and leaks in barriers that normally keep blood and other harmful substances out of the brain may contribute to COVID-related brain damage.

left: Inflamed immune cells around blood vessels. right: cells affected by COVID-19Signs of brain damage in people with COVID-19 involve inflammation, including these immune cells around a blood vessel (left) and changes in cells (right) that could result in low oxygen.J. Lou et al / Free Neuropathology 2021

But several unknowns prevent definitive conclusions about the relationship of these damaged blood vessels to people’s symptoms or outcomes. Not much clinical information is available about the people in Nath’s study. Some probably died of causes other than COVID-19 and no one knows how the virus would affect them if they did not die.

Inflamed body and brain

Inflammation in the body can also cause brain problems, says Maura Boldrini, a psychiatrist at Columbia University in New York. Inflammatory signals released after injury can change the way the brain manufactures and uses chemical signaling molecules, called neurotransmitters, that help nerve cells communicate. Key communication molecules such as serotonin, norepinephrine, and dopamine can stir when there is a lot of inflammation.

Neural messages can be interrupted in people suffering from traumatic brain injury, for example; researchers have found a relationship between inflammation and mental illness in football players and in others who have experienced blows to the head.

Similar evidence comes from people with depression, says Emily Troyer, a psychiatrist at the University of California, San Diego. Some people with depression have high levels of inflammation, studies have found. “We don’t really know what’s going on at COVID,” he warns. "We only know that COVID causes inflammation and inflammation has the potential to disrupt neurotransmission, especially in the case of depression."

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Among the cells that release inflammatory proteins in the brain are microglia, the brain version of the immune system that fights diseases of the body. Microglia may also be involved in the brain's response to COVID-19. Microglia ready for action was found in approximately 43 percent of 184 patients with COVID-19, Singer and others reported in a review published Feb. 4 in Free Neuropathology. Similar results come from a series of brain autopsies of COVID-19 patients; 34 of 41 brains contained activated microglia, researchers at Columbia Medical Irving Medical Center and New York Presbyterian Hospital reported on April 15 in Brain.

With these findings, it is not clear that SARS-CoV-2 affects people’s brains differently than other viruses, Navis says. At his post-COVID-19 clinic on Mount Sinai, he sees patients with fatigue, headaches, numbness, and dizziness, symptoms that are also known to be followed by other viral infections. “I hesitate to say this is exclusive to COVID,” Navis says. "We're just not used to seeing so many people get a specific infection or knowing what a viral infection is."

Eliminate all the ways the brain can suffer in the midst of this pandemic, and how that affects a particular person, is impossible. Depression and anxiety are on the rise, polls suggest. That rise can be especially pronounced in people who have endured stressful diagnoses, illness, and isolation.

coagulation protein in the postmortem brain of a person with COVID-19In a person’s postmortem brain with COVID-19, a clotting protein called fibrinogen (red) indicates that the blood vessels are damaged and leaking.Avindra Nath

Just being in an intensive care unit can cause confusion. A 2013 study found that delirium affected 606 of 821 people, 74 percent, while patients were in intensive care units for respiratory failure and other serious emergencies. Post-traumatic stress disorder that affected one-third of people who had been severely ill with COVID-19 (SN: 3/12/21).

More specific aspects of treatment are also important. Patients with COVID-19 who have spent long periods of time in the stomach may have persistent nerve pain, not because the virus attacked the nerve, but because the prone position compressed the nerves. And people may feel mentally confused, not because of the virus itself, but because the scarcity of propofol, the anesthetic drug, has meant it has been given an alternative sedative that can cause more side effects, says Rogers, a psychiatrist at University College London.

The persistent questions: what does the virus do to the brain, who will suffer the most, and for how long will they remain unanswered and probably not for long. The varied and harmful effects of blockages, the inaccuracy used by doctors and patients to describe symptoms (such as the non-medical term "brain fog"), and the indirect effects the virus can have on the brain fuse, creating a devilishly complex puzzle. .

For now, doctors are busy focusing on ways to help, even among these mysteries, and designing longer, longer studies to better understand the effects of the virus on the brain. That information will be key to helping people move forward. “This won’t be over any time soon, unfortunately,” Troyer says.

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