Long COVID brain fog: What happens in the brain?

Evan Walker
Evan Walker TheMediTary.Com |

The peak of the COVID-19 pandemic may be behind us, but for many people, long COVID continues to cause symptoms weeks, months, or even years after the initial illness. Among the more than 200 symptoms reported for long COVID, brain fog — problems with thinking, understanding, focus and memory — is one of the most widespread and long-lasting.

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What does the latest research tell us about brain fog in long COVID? Image credit: davit85/Getty Images.

The World Health Organization (WHO) declared COVID-19 a pandemic on March 11, 2020. Since then, the WHO has recorded almost 775 million confirmed cases worldwide. But there have, almost certainly, been many more that have not been confirmed, particularly with the decline in testing in most countries.

According to the Centers for Disease Control and Infection (CDC), infection with SARS-CoV-2, the virus that causes COVID-19, leads to an illness with some, or all, of the following symptoms, which may be mild or severe:

  • fever or chills
  • cough
  • shortness of breath or difficulty breathing
  • fatigue
  • muscle or body aches
  • headache
  • new loss of taste or smell
  • sore throat
  • congestion or runny nose
  • nausea or vomiting
  • diarrhea.

For most people, these symptoms resolve within 1 to 2 weeks. However, for some people, the acute illness is followed by lingering symptoms, a condition termed long COVID, or post-acute sequelae of COVID-19 (PASC).

Long COVID can occur in anyone infected by SARS-CoV-2, whether their initial infection was severe, mild, or even asymptomatic.

One study, published in Nature Reviews Microbiology in January 2023, suggests that around 10% of people experience long COVID following acute infection, with 50–70% of people who are hospitalized with COVID-19 experiencing lasting symptoms.

According to the United Kingdom’s Office of National Statistics Coronavirus (COVID-19) Infection Survey self-reported data, almost 3% of the U.K. population was experiencing long COVID in March 2023. Of these, 41% were still experiencing symptoms 2 years after initial infection with SARS-CoV-2.

In the United States, the CDC notes that 6.4% of adults have, at some time, reported long COVID symptoms.

These may be a continuation of those experienced in the acute infection, or may change, and can affect almost any part of the body, with one study — published ineClinicalMedicine in 2021 — finding that symptoms “affect multiple organ systems, with significant impacts on morbidity, mortality, and quality of life”.

The study from Nature Reviews Microbiology outlines lasting impacts on the heart, lungs, immune system, pancreas, gastrointestinal tract, kidneys, spleen, liver, blood vessels, reproductive system and neurological system.

Of course, a person with long COVID will not experience all of the 203 symptoms recorded by the wide-ranging international study from eClinicalMedicine. In this study, 91.8% of the cohort reported symptoms that lasted more than 35 weeks after initial infection, the most common and debilitating of which were fatigue, breathing issues and cognitive dysfunction, or brain fog.

This “classic” long COVID, characterized by brain fog, fatigue, dysautonomia, and postexertional malaise, is more common in younger adults and in females. Older people and those with comorbidities are more likely to experience cardiovascular and metabolic effects.

Reports of COVID-19’s effects on the central nervous system (CNS) started early in the pandemic, and evidence has accumulated since then.

Those who have had more severe COVID-19, with hypoxia, a need for ventilation, and psychological trauma, are at higher risk of lasting psychological effects or cognitive dysfunction.

But anyone who has had COVID-19 has a Health">greater risk of neurological or psychiatric symptoms following their initial illness than someone who has not had a SARS-CoV-2 infection.

Some symptoms, such as mood and anxiety disorders, increase for a short time after infection, but then reduce back to baseline levels. However, others continue for much longer. And one of these is brain fog, which a recent study published in Scientific Reports found in 89% of people with long COVID.

In this study, 89% of participants also reported fatigue, and 77% difficulty concentrating. When researchers assessed them using the Montreal Cognitive Assessment, they found that 46% had mild cognitive dysfunction.

Often the result of, among other things, inflammation, concussion, hormonal changes, or medication, brain fog is one of the most common symptoms reported by people with long COVID.

A person with brain fog may have problems with memory, focus, thinking and understanding, as well as often experiencing stress and fatigue.

Prof. Stephen Griffin, virologist at the University of Leeds School of Medicine, and co-chair of Independent SAGE told Medical News Today:

“Symptoms can vary, but some of the major issues include a lack of recall for things like names, places, events, etc., as well as a general inability to process complex tasks, hold concentration over time and multi-task.”

“In some instances, general alertness can be affected as well which, when combined with the intense fatigue experienced by many, can be extremely debilitating in terms of interacting socially or functioning at school or work,” he added.

The study from eClinicalMedicine, which looked into the lasting effects of COVID-19, recorded brain fog, cognitive dysfunction and memory impairment in 85.1% of respondents. And almost 90% of those who worked reported that brain fog impaired their ability to work to some extent.

Research has suggested several potential causes for brain fog in COVID-19, including:

  • persistence of the virus in tissue reservoirs
  • a dysregulated immune response
  • mitochondrial dysfunction
  • vascular (endothelial) and/or neuronal inflammation
  • microbiome dysbiosis.

One theory is that SARS-CoV-2 can cross the blood-brain barrier (BBB) and directly affect cells in the CNS, but this has only been demonstrated in vitro, in isolated cells.

This study found that two SARS-CoV-2 variants, the original wild type and Omicron, were best able to induce cell stress and damage components of the BBB.

However, Dr. Giovanni Schifitto, professor of neurology at the University of Rochester Medical Center, NY, believes that the cause of long covid is likely to be multifactorial.

“The physical presence of SARS-CoV-2 in the brain, especially in the chronic phase, is unlikely to be the culprit. However, systemic virus persistence can create a more chronic systemic inflammatory status and that can contribute to multi-organ dysfunction,” he told us.

There is more support for the suggestion that brain fog in long COVID may result from immune dysfunction and inflammation.

One recent study, which appeared in Nature Communications, showed that people with COVID had raised levels of four brain injury biomarkers, and that two of these persisted long after the initial infection, particularly in those who experienced neurological complications during the acute infection.

The authors of this research suggest these abnormal immune responses may be causing ongoing inflammation. And inflammation can lead to brain fog.

They believe that if they can find out why these immune responses are triggered, treatments could be developed to target them.

Whether the effects are due to viral invasion or immune dysfunction, research has found that SARS-CoV-2 infection can lead to changes in the brain.

A study — published in Nature in March 2022 — using data from the UK Biobank compared brain scans conducted on people before and after they had COVID-19.

Those who had had SARS-CoV-2 infection had a reduction in grey matter thickness, markers of tissue damage in olfactory regions, and changes in brain volume, as well as slightly lower cognitive abilities than those who had not.

Prof. Griffin explained:

“As with many issues around long COVID, brain fog is likely a combination of persistent infection by SARS-CoV-2 [as reported in a new study published in 2023] and host immune/metabolic changes that occur either concomitantly or as a follow-on. Worryingly, changes to the brain, including reductions in grey matter, have been noted even in patients that aren’t necessarily associated with neurological symptoms.”

Research reported in Nature Neuroscience, which used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on people with long COVID with or without reported brain fog, has backed up these findings. The researchers found not only significantly increased BBB permeability in the group with brain fog, but also reduced global brain volume and white matter volume.

The researchers suggest that “long COVID-derived brain fog is associated with BBB disruption and sustained systemic inflammation,” adding that their “data suggest that BBB disruption occurs during acute infection and long COVID, where it is strongly associated with cognitive impairment.”

As has become increasingly clear, COVID, like many other viral diseases, can have effects long beyond the initial infection, and research is only now starting to discover why.

Avoiding infection is, of course, the best way to avoid long-term effects, but there is increasing evidence that vaccination and antiviral treatment in the early stages of infection reduces the risk of long COVID.

But Prof. Griffin is frustrated about the lack of action taken to prevent infection and counter the long-term effects of COVID-19.

“Like a lot of aspects of SARS-CoV-2 infection, because it [brain fog] doesn’t necessarily manifest during acute disease it tends to be overlooked. This, to me, is another reason why the reluctance of western governments to suppress prevalence of this virus is […] mind-bogglingly negligent,” he told us.

“There are already record numbers of people out of work due to chronic illness, also many that struggle on, plus cognitive impairment on this scale makes for a less productive population as a whole,“ said Prof Griffin.

Adding brain fog to the already staggering list of longer term problems caused by COVID must surely make us question what we’re allowing to happen to those being exposed to multiple infections with this virus, including our children,” he emphasized.

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