MRI brain scans of hundreds of people in the UK taken before and after they contracted COVID-19 reveal changes that persisted months after recovery from the disease, a paper published today in Nature reports. These changes, while subtle, included tissue damage in certain brain areas, including those involved in olfaction, and a decline in overall brain size that was larger than the expected decline caused by natural aging. But experts caution that the clinical effects of these changes and whether they will persist in the long-term remain unclear. 

“It is a very novel study with conclusive data,” Avindra Nath of the National Institute of Neurological Disorders and Stroke who wasn’t involved in the research tells Bloomberg. “The findings are very intriguing, with important implications for the population at large.”  

The study considered 785 subjects between the ages of 51 and 81 who were each scanned twice, about three years apart. They were all part of the UK Biobank, a project that collects biomedical data on the health and genetics of half a million UK participants. Of the nearly 800 people whose brains were scanned, 401 contracted COVID-19 between the first and second scan and 15 were hospitalized with the illness. All infections occurred between March 2020 and April 2021, and the second scan took place four and a half months after recovery from COVID-19, on average. Researchers compared the changes between the two scans in these participants to those of 384 matched controls who had also undergone two scans but had not contracted COVID-19. 

The researchers found that, on average, the brains of people who had recovered from COVID-19 showed steeper declines than did controls in certain areas, including the orbitofrontal cortex (which is involved in decision-making) and parahippocampal gyrus (involved in memory), both of which also play a role in smell. Average declines in particular brain areas ranged from 0.2 to 2% greater than those seen in controls over the same time period, the researchers report in their paper. The overall brain volume of COVID-19 survivors also declined more than that of survivors, and declines were greater in the 15 patients who’d been hospitalized for COVID-19 than in those who’d had milder infections. 

“To me, this is pretty convincing evidence that something changes in brains of this overall group of people with Covid,” Yale School of Medicine’s Serena Spudich, who was not involved in the study, tells The New York Times. But, she says, “To make a conclusion that this has some long-term clinical implications for the patients I think is a stretch. We don’t want to scare the public and have them think, ‘Oh, this is proof that everyone’s going to have brain damage and not be able to function.’” 

The authors of the Nature paper gave the participants cognitive tests and found that the former COVID-19 patients performed worse than controls on one task that reflects focus and processing speed. But experts tell the Times that the testing was too rudimentary to draw conclusions about any clinical effects of the brain changes the researchers found. The authors also lacked data on which symptoms individual participants experienced, so they can’t say whether, for example, loss of smell correlated with damage to olfaction-involved areas of the brain. And it’s not clear whether the brain will recover from the effects of COVID-19 over time. 

In comments to the Times, Benedict Michael of the University of Liverpool further cautions that the findings may not be relevant to cognitive symptoms such as “brain fog” that are associated with long COVID.  

“What is going to be pertinent now is to identify the mechanisms that are leading to this degeneration in the acute phase of disease so that we can attempt to intervene,” Leah Beauchamp, a neuropharmacologist at the Florey Institute of Neuroscience and Mental Health in Melbourne, tells Bloomberg.