Early research suggests that SARS-CoV-2 can enter the brain easily through a person's nose, infiltrating brain cells where it lurks unchecked, possibly leading to lasting neurological symptoms, such as trouble with thinking and memory.
Two new studies — from the California National Primate Research Center and the Rotman Research Institute in Toronto — suggest that the virus directly infects neurons in the brain, potentially offering clues as to why some people suffer from a range of symptoms long after their initial Covid infection.
Neither of the studies, presented Wednesday during a meeting of the Society for Neuroscience, has been peer-reviewed, and neither is expected to answer all questions surrounding long Covid.
But they come as researchers worldwide are urgently trying to learn more about the mysterious and debilitating illness that is estimated to affect at least one-third of the more than 46 million people who have been infected in the U.S., as well as millions more globally.
Zeroing in on how the virus invades and affects the brain has the potential to defog the window into long Covid, an illness that doctors so far have been unable to appropriately define, diagnose or treat.
“We’re still in the phase where it doesn’t even have a name. That’s a problem," said Dr. Nir Goldstein, director of the Center for Post Covid Care and Recovery at National Jewish Health in Denver. Goldstein was not involved with the new research.
Invading the brain
The body's natural blood-brain barrier usually does a good job at halting things like viruses before they can cross into the brain, though it is possible for viruses to sneak through. SARS-CoV-2 can do this, as well as other viruses, such as viral encephalitis and HIV. When those breaches occur, immune cells in the brain work to attack the invader.
But one of the new studies presented Wednesday suggests it is increasingly clear that SARS-CoV-2 can also take a different, less-guarded route through the nose, heading straight to the brain.
That research, from the California National Primate Research Center, found that rhesus monkeys infected with the virus had significant evidence of infection inside the brain's neurons just seven days after exposure. This was particularly true for older, diabetic animals.
Proof that neurons can be infected would be a key finding. Such brain cells send information from the brain to other parts of the body via electrical impulses. Because neurons are so critical to normal function of the body, the immune system doesn’t want to attack even those that are diseased.
The virus, having hitched a ride on neurons, is then free to move about the brain’s circuitry.
“This, I believe, is a much more dangerous kind of infection,” said John Morrison, who led the research and is a professor of neurology at the University of California, Davis. If the virus can travel the brain's circuitry, he said, "it can get to multiple brain regions that mediate things like cognition and memory, and emotion and mood.”
Those are precisely the issues reported so often among people with long Covid.
Previous research on neural infection has been mixed, and not all experts agree that the findings offer definitive proof.
During a media briefing at Wednesday’s meeting, Dr. Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, said he remained unconvinced that SARS-CoV-2 can infect neurons, adding that much more research is necessary.
Dr. Greg Vanichkachorn, an occupational medicine specialist who works with long Covid patients at the Mayo Clinic in Rochester, Minnesota, said brain samples taken from people who died of Covid-19 earlier in the pandemic largely haven't shown this kind of infection.
But, he added, it is possible that Covid-19 affected those patients in a different way. Indeed, not all patients develop the same kind of illness. And it may turn out that people with less severe illness, albeit one that smolders on for months, are infected differently.
"I have always felt from very early on in treating patients with this condition that it's more than just a respiratory condition," Vanichkachorn, who had no role in the new research, said. "I am not surprised about these findings."
It’s not all in their heads
Another study presented at Wednesday's meeting, provided additional evidence of neural infection. Researchers at the Rotman Research Institute in Toronto used electroencephalography, or EEG, to measure how well the brain is functioning in terms of its electrical signals.
The study was small, just 41 Covid-positive patients and 14 others who had some symptoms, but ultimately tested negative. All had mild illnesses and were never hospitalized.
The EEGs showed different brain wave patterns in the Covid patients that lasted at least seven months following their initial infection.
Put simply, their brains weren’t working as efficiently or as effectively, on average, compared to those who did not have Covid, said Allison Sekuler, who led the research and also serves as the Institute's Sandra A. Rotman Chair in Cognitive Neuroscience.
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Sekuler's research, too, should be considered early and preliminary. And it is unlikely that the new findings can fully explain the types of brain fog and other cognitive issues reported by those with long Covid.
But Sekuler said the results so far "clearly show" monthslong changes in brain function. If proven in future analyses, the findings could offer reassurance to long-haulers whose loved ones may be skeptical about ongoing, ambiguous symptoms.
“It is very frustrating for many of my patients” who say they have family members who don’t believe that Covid exists in the first place, Vanichkachorn said. "Patients often get accused of malingering or making this all up for attention."
Sekuler also dismissed those who claim long Covid symptoms are “just all in a person’s head.”
"Yeah, OK, but that’s because the brain controls everything,” she said, "your sense of smell, your memory, the way you see the world, even the way you feel."