A landmark imaging study has offered a unique insight into the effects of mild COVID-19 on the brain by investigating scans from hundreds of people taken before and after viral infection. The research indicates the impact of COVID-19 on the brain is both “significant” and “deleterious” but experts urge caution as it is still unclear whether these brain changes lead to long-term cognitive deficits.
From brain fog and fatigue to disruptions in taste and smell, the neurological effects of COVID-19 are well-known. What is less clear is exactly what kind of direct effect a SARS-CoV-2 infection has on brain tissue – particularly in relation to a mild infection.
So far, most published research on the effects of SARS-CoV-2 on the brain have looked at tissue taken from deceased patients, while other studies have investigated brain imaging from severe hospitalized cases of COVID-19. But no studies have offered comparative analyses of brain imaging before and after COVID-19.
The new study, published in the journal Nature, looked at a unique dataset from an ongoing project tracking the health of half a million participants in the UK. The researchers focused on data from 401 subjects, with brain imaging conducted both before and after a positive case of COVID-19. The second brain scan for each subject was conducted, on average, 141 days after the initial COVID-19 diagnosis.
The cohort was compared against a control group of 384 subjects. Each control subject was matched against a member of a COVID cohort for age, sex, ethnicity and time elapsed between the two scans.
“Our longitudinal analyses revealed a significant, deleterious impact associated with SARS-CoV-2,” the researchers wrote in the new study. “This impact could be seen mainly in the limbic and olfactory cortical system, for instance with a change in diffusion measures – that are proxies for tissue damage – in regions functional connected with the piriform cortex, olfactory tubercle and anterior olfactory nucleus, as well as a more pronounced reduction of grey matter thickness and contrast in the SARS-CoV-2 infected participants in the left parahippocampal gyrus and lateral orbitofrontal cortex.”
The research has been referred to as “one of the most important studies of the pandemic”, however, the findings do raise a whole host of new questions. Are these brain changes permanent? And do they correlate with specific lasting behavioral or cognitive changes?
Alan Carson, a researcher from the University of Edinburgh, is concerned these new findings are being incorrectly interpreted. According to Carson, since the majority of brain changes noted in the study seem to be linked to olfactory regions in the brain it is likely they are a straightforward neural response to the loss of smell caused by the viral infection. In other words, the plasticity of the brain may be responding to the virus's impact on nose cells.
“The size and magnitude of brain changes found is very modest and such changes can be caused by a simple change in mental experience,” noted Carson. “What this study almost certainly shows is the impact, in terms of neural changes, of being disconnected from one’s sense of smell. It serves to highlight that the brain connects to the body in a bidirectional relationship that is both structurally and functionally dynamic.”
Carson’s concern echoes one of the biggest unanswered questions at the moment – what is the underlying cause of these brain changes?
Some researchers have argued the persistent and broad systemic effects of a SARS-CoV-2 infection are due to lingering autoimmune activity following the acute infection. Basically, our immune system goes into hyperdrive when the virus strikes and inflammation begins to damage other organs in the body.
Another hypothesis suggests the virus can directly infiltrate the brain and damage brain cells. James St John, an expert in olfactory and spinal cord regeneration, says this is a plausible hypothesis that could lead to COVID-19 accelerating the progression of neurodegenerative diseases such as Alzheimer’s.
“Numerous pathogens are now known to be able to enter the brain using the olfactory nerve within the nasal cavity, and they can contribute to a range of neurological and neurodegenerative conditions including stroke and Alzheimer’s disease,” St John said. “It is still not certain whether SARS-CoV-2 virus can enter the brain, but at a minimum it certainly can destroy the nerve cells responsible for the sense of smell which may then set off a cascade of events that lead to pathologies further in the brain.”
The researchers behind this new imaging study acknowledge the possibility these viral-induced brain changes could either trigger or accelerate age-related dementia. Although the researchers did not detect memory deterioration in the mild COVID-19 cases studied, a worsening of executive function was identified, characterized by a general slowing of cognitive response.
“The overlapping olfactory- and memory-related functions of the regions shown to alter significantly over time in SARS-CoV-2, including the parahippocampal gyrus/perirhinal cortex, entorhinal cortex and hippocampus in particular, raise the possibility that longer-term consequences of SARS-CoV-2 infection might in time contribute to Alzheimer’s disease or other forms of dementia,” the researchers wrote in the study.
To validate these brain changes weren’t just a byproduct of general illness or viral infection the researchers collected similar before-and-after brain imaging data from subjects who contracted pneumonia and influenza. The brain changes after mild COVID-19 were found to be unique and much more significant compared to those two conditions.
It is important to note the patients studied spanned a period before variants such as Delta or Omicron emerged. So it is unclear whether newer SARS-CoV-2 variants lead to these kinds of brain changes. It is also unclear what impact vaccination has on these brain changes. For example, does a mild COVID-19 case in a vaccinated individual lead to similar brain changes as a mild case in an unvaccinated individual?
Sarah Hellewell, a researcher from Curtin University, calls the new study novel and the findings “remarkable." The new research certainly offers strong evidence indicating mild COVID-19 can lead to brain changes, but Hellewell says this should not be a cause for panic in those who have experienced infections.
“The brain changes observed were relatively small and on a group level, so not everyone had the same effects,” Hellewell added. “More research is needed to know whether these changes remain, reverse or get worse over time, and whether there are treatments which could help."
The new study was published in the journal Nature.
Source: University of Oxford