Scientists Are Just Beginning to Understand COVID-19’s Effect On the Brain

Early in the COVID-19 pandemic, doctors started to notice something striking. For what was originally described as a respiratory virus, SARS-CoV-2 seemed to have a strong effect on the brain, causing everything from loss of taste and smell and brain fog to, in serious cases, stroke.

NYU Langone Health, a New York city research hospital, started collating those anecdotes in hopes of better understanding how the virus affects the brain and nervous system. Years later, the project has morphed from focusing solely on acute symptoms to also tracking the long-term neurologic issues that some people with Long COVID experience, says program director Dr. Sharon Meropol.

The list of neurocognitive issues that Meropol’s team and other researchers must track is extensive: cognitive decline, changes in brain size and structure, depression and suicidal thinking, tremors, seizures, memory loss, and new or worsened dementia have all been linked to previous SARS-CoV-2 infections. In some cases, these longer-term problems occur even in patients with relatively mild COVID-19.

The “Holy Grail” question now, Meropol says, is what’s going on in the brains of COVID-19 patients—and how to reverse the damage.

Gray matters

If you were to look at the brain of someone infected by certain viruses, like rabies, you would see “virus teeming everywhere. It’s black and white” that the brain is infected, says Dr. Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke (NINDS).

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With SARS-CoV-2, there’s more gray area. Early in the pandemic, Nath and his colleagues scanned and physically analyzed the brains of 13 people who died from COVID-19. They didn’t find the SARS-CoV-2 virus in those brains—but they did find significant damage to their blood vessels, which were coated with antibodies. It looked to Nath like the body’s immune system had gone haywire in response to the virus, causing it to attack its own blood vessels and setting off a cascade of effects that led to significant inflammation in the brain, potentially culminating in fatal damage to the part that controls breathing.

In people who survive COVID-19, brain inflammation may also explain years-long symptoms like brain fog and memory loss—though “we don’t know for sure,” Nath says.

Dr. Lara Jehi, who researches COVID-19 and the brain at the Cleveland Clinic, also points to inflammation as a possible trigger for COVID-19’s neurologic symptoms. She’s found evidence of abnormal inflammation in people with chronic post-COVID headaches. And in a 2021 study, Jehi and her colleagues compared the brains of people with Long COVID and Alzheimer’s disease. “We found many areas of overlap between the two, and these areas of overlap centered on…inflammation in the brain and microscopic injuries to the blood vessels,” she says.

Going into that study, Jehi says, her team wanted to determine whether the SARS-CoV-2 virus was entering the brain and causing damage directly, or triggering an immune response that led to brain changes. Their findings pointed to the latter—but researchers still haven’t ruled out the possibility that the virus has direct effects on the brain.

Virus in the brain

Since Nath’s brain-scanning project early in the pandemic, other researchers have found the virus in the brains of people who died from COVID-19.

For a 2022 paper in Nature, researchers analyzed brain tissue of 11 people who had COVID-19 when they died. In all but one of those individuals, the researchers found the virus’ genetic material in central-nervous-system tissue—which, they wrote, “prov[ed] definitively that SARS-CoV-2 is capable of infecting and replicating within the human brain.”

To Nath, however, that’s still an open question, and one worthy of more research. His team has continued to study the brains of COVID-19 patients and has yet to find concrete evidence of the SARS-CoV-2 virus in those organs. In one instance, he says, they found viral proteins—but not the full virus—in biopsied tissue from someone who had COVID-19 at the time they were undergoing brain surgery for epilepsy. Researchers behind an April 2023 study not yet been peer-reviewed also found SARS-CoV-2 spike proteins—which are found on the virus’ surface and allow it to enter human cells—in the brains of people who died from COVID-19.

But the research is “inconsistent,” Nath says. “Some have found it, some have not, and some people who have found it, have found very small amounts. There’s still a gap in knowledge there.”

Dr. Wes Ely, who researches brain disease at Vanderbilt University Medical Center, says he’s convinced SARS-CoV-2 can attack the “support cells” of the brain, or those ensure neurons are able to keep the brain and body functioning normally. Damaging these support cells, Ely says, can kick off a domino effect that leads to tissue death in the brain.

But, Ely says, “almost certainly there are multiple processes going on”—it could be that the virus both directly affects the brain and causes changes to the immune system that lead to neurocognitive issues. “We’re not looking for a magic bullet that will solve all these problems” at once, he says.

While there may not be a single solution, that doesn’t mean there’s no solution. Ely has found that “cognitive rehab,” a process of rebuilding the brain’s function through targeted mental exercises, can help people who develop similar cognitive decline after stays in the intensive-care unit. That approach could be risky for people with Long COVID, many of whom experience worsened symptoms after mental or physical exertion, Ely says—but changing the immune system’s function in hopes of reducing inflammation in the brains of people with Long COVID is another promising route.

NINDS is currently enrolling patients for a study on immunotherapy as a potential treatment for neurologic Long COVID. That approach is particularly exciting, Nath says, because it entails a therapy that is already used to treat a range of autoimmune and neurologic conditions—so if it proves effective, it could be rolled out to Long COVID patients relatively quickly.

Some preliminary research also suggests blood-thinning drugs may help breakup tiny “microclots” in the blood that are linked to systemic inflammation, potentially relieving Long COVID symptoms including fatigue, brain fog, and difficulty concentrating.

As of now, there are no proven therapies for people with Long COVID symptoms, neurologic or otherwise. But Ely says he’s optimistic that COVID-related brain changes are reversible—one way or another. “The brain is incredibly neuroplastic,” he says, “and it can do amazing things.”