Some regions of the human brain may shrink after a person has caught COVID-19, according to the first study to use brain scans to show a ‘before and after’ look at the brain following infection.
A new U.K. study published Monday in the journal Nature found that there is greater tissue damage and shrinkage in the brains of those who had even mild cases of COVID-19, with most of the changes relating to areas of the brain that have to do with smell.
It’s unclear yet whether these effects are permanent or will improve with time, or what they could mean for overall brain health or function, with researchers noting that some brain loss occurs with age.
To attempt to measure the impact of COVID-19, researchers looked at brain changes in 785 people between the ages of 51 to 81 who had undergone two brain scans and accompanying cognitive tests.
The key part of the data is that 401 participants contracted COVID-19 after their first scan and before their second scan, providing a chance to see whether imaging would show greater changes to the brain in those participants.
Compared to those who had not contracted COVID-19, the brain scans of participants who had contracted the virus showed a greater reduction in grey matter in the brain, particularly in the orbitofrontal cortex and parahippocampal gyrus, which are associated with the sense of smell.
The orbitofrontal cortex is also related to processes of decision-making and emotional and social behaviour, while the left parahippocampal gyrus is described in the study as “a limbic region of the brain that plays a crucial, integrative role for the relative temporal order of events in episodic memory.”
Across the participants who had contracted COVID-19, the brain changes ranged from 0.2-per-cent to two-per-cent more changes than in those with no prior COVID-19 infection.
The data came from UK Biobank, a research resource that regularly collects health data from 500,000 ongoing participants in order to further numerous research projects.
Between January 2021 and February 2022, the project asked for participants who had received imaging scans before the pandemic to return for more imaging in order to help with tracking the long-term effect of the virus on internal organs.
It was this move that made it possible to find participants who had received scans before and during the pandemic.
Previous research has found that COVID-19 can affect the brain, with many researchers pointing out that common symptoms such as losing the sense of taste or smell show neurological impacts. But many studies looking at brain damage in COVID-19 cases have focused on those who had severe cases of the virus that required hospitalization.
In this study, only 15 cases out of the 401 were severe cases of COVID-19 that required hospitalization.
“Using the UK Biobank resource, we were in a unique position to look at changes that took place in the brain following mild – as opposed to more moderate or severe – SARS-CoV-2 infection,” Gwenaelle Douaud, a professor at the University of Oxford and lead author of the study, said in a press release.
“Despite the infection being mild for 96 per cent of our participants, we saw a greater loss of grey matter volume, and greater tissue damage in the infected participants, on average 4.5 months after infection. They also showed greater decline in their mental abilities to perform complex tasks, and this mental worsening was partly related to these brain abnormalities. All these negative effects were more marked at older ages. A key question for future brain imaging studies is to see if this brain tissue damage resolves over the longer term.”
In this study, researchers matched the 401 cases with 384 participants who had received both scans but not contracted COVID-19, in order for them to serve as a control group with similar demographics.
All of the participants who contracted COVID-19 in the research cohort did so between March 2020 and April 2021, a time period when numerous variants, but not Omicron, were active.
The first and the second scans were spaced out by around three years on average, and the second scan occurred as soon as one month after COVID-19 infection for some participants, and as late as six months after for others.
Researchers did not find any significant differences in the results of the second scans based on how much time had passed after the participant had contracted COVID-19.
The majority of the tissue damage and changes in grey matter thickness was connected to regions of the brain that deal at least in part with the olfactory system, but researchers said the impacts may extend beyond those regions.
“While the greater atrophy for the SARS-CoV-2 positive participants was localised to a few, mainly limbic, regions, the increase in [cerebrospinal fluid] volume and decrease of whole brain volume suggests an additional diffuse loss of grey matter superimposed onto the more regional effects observed in the olfactory-related areas,” the study stated.
Those who were infected but had mainly mild symptoms in the study’s cohort did not show any signs of memory impairment, but did show a worsening of executive function, something revealed through six cognitive tasks that participants were asked to do.
When participants did a common test connecting numbers which is sometimes used as a screening tool for dementia, called the Trail Making Test, those who had been infected with COVID-19 took “significantly” longer to complete the test, the study said.
“Significantly greater cognitive decline, which persisted even after excluding the hospitalised patients, was seen in the SARS-CoV-2 positive group between the two timepoints, and this decline was associated with greater atrophy of crus II, a cognitive lobule of the cerebellum,” the study stated, referring to a subsection of the cerebellum, a part at the back of the brain which coordinates physical movement.
Although these impacts on brain can sound frightening, the study noted that the structural changes were “modest”, saying that while there was an “additional loss in the infected participants of 0.7 per cent on average across the olfactory-related brain regions,” this should be analyzed with the knowledge that we know brain loss does occur naturally as well, with older adults who are living on their own sustaining a 0.3 per cent loss of hippocampal volume per year.
However, being able to measure if the virus is associated with additional changes to the brain that may not have been seen otherwise is hugely valuable to further research and potentially therapeutic solutions.
It also could potentially shed some light on lingering symptoms that plague those with long COVID, including persistent brain fog and fatigue, although more research is needed.
Stephen Smith, a professor at the University of Oxford and senior author on the study, said in the press release that being able to look at scans of the same person taken before they contracted COVID-19 allowed them a unique chance to assess with greater certainty the virus’s impact.
“The fact that we have the pre-infection scan helps us distinguish brain changes related to the infection from differences that may have pre-existed in their brains,” Smith said.
“The UK Biobank COVID-19 Repeat Imaging study is the only study in the world to be able to demonstrate “before vs after” changes in the brain associated with SARS-CoV-2 infection,” Naomi Allen, a professor and chief scientist at UK Biobank, added in the release.
“Collecting a second set of multi-organ imaging scans from some people who had been infected with SARS-CoV-2 and from others who had not been infected has generated a unique resource to enable scientists to understand how the virus affects internal organs.”
Although researchers made efforts to investigate potentially confounding causes, including assessing whether influenza that occurred between the first and second scans was associated with brain outcomes, they also acknowledge that because this is an observational study, they can’t say with complete certainty that the brain changes were caused purely by COVID-19.
“Our statistics also represent an average effect; not every infected participant will display brain longitudinal abnormalities,” the study said.