Five Years Later: Long COVID’s Lasting Impact on the Brain
Researchers are still unpacking how SARS-CoV-2 affects brain function and its lasting impact on cognitive health.
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Five years after SARS-CoV-2 first surfaced in Wuhan, China, researchers are still trying to understand COVID-19 and its long-lasting impact. Long COVID, or post-COVID-19 syndrome, remains an unsolved puzzle, with no consensus on how to treat or prevent the condition.
The term “long COVID” first emerged in the spring of 2020 to describe the persistent and complex symptoms some individuals experienced after a COVID-19 infection. The condition is now estimated to affect 1.8% of the population in the UK alone.
While symptoms of long COVID can vary greatly, several studies have shown a link between the condition and persistent cognitive health problems. A recent study showed that a concerning 4.5% of post-COVID-19 participants met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
“The severity of acute infection with both viral and nonviral agents is known to increase the risk for ME/CFS,” Dr. Suzanne D. Vernon, research director at the Bateman Horne Center, previously told Technology Networks.
“That [an increased risk of ME/CFS] has been shown following infection with Epstein-Barr virus, West Nile virus and SARS, so it is (unfortunately) not surprising that there is a significantly increased rate of ME/CFS following SARS-CoV-2 infection given the vast number of people that got sick with COVID-19,” said Vernon.
Another study, following individuals hospitalized during the first wave of the pandemic, found that many patients continued to have cognitive and psychiatric problems two-to-three years post-infection.
These alarming statistics highlight the need to understand the link between COVID-19 infection and the brain. Projects like the National Institutes of Health (NIH) RECOVER initiative and the University of Liverpool’s COVID-19 Clinical Neuroscience Study (COVID-CNS) have set out to try to find answers.
The scale of long COVID cognitive decline
Investigating the long-term impact of severe COVID-19, the COVID-CNS consortium has found that 12–18 months after hospitalization, COVID-19 patients have worse cognitive function than matched control participants.
Alarmingly, the cognitive deficits observed in the patients were equivalent to 20 years of normal aging. However, the researchers emphasized that the patients had required hospitalization following infection with SARS-CoV-2, therefore, the results shouldn’t be too widely generalized.
The cognitive deficits were associated with elevated brain injury proteins in the blood and reduced brain volume, revealed in magnetic resonance imaging (MRI) scans. The researchers now hope to understand if the mechanisms they’ve identified for COVID-19 are the same for other severe infections with neurological implications.
How long COVID impacts the brain
Leaky blood vessels and brain fog
To determine how SARS-CoV-2 impacts brain function, researchers at Trinity College Dublin and investigators from FutureNeuro have examined the integrity of blood vessels in the brains of long COVID patients reporting brain fog.
What is brain fog?
Brain fog is often described as a feeling of disassociation, fatigue, forgetfulness and reduced cognitive ability. The experience of brain fog has been associated with a variety of diseases and drugs and is one of many symptoms reported by patients suffering from long COVID.
Using a novel form of MRI, the researchers investigated the function of the blood-brain barrier (BBB) in these patients. This revealed evident BBB disruption.
Further transcriptomic analysis revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. When brain endothelial cells were exposed to serum from patients with long COVID, expression of inflammatory markers was induced.
Together these findings suggest that sustained systemic inflammation and persistent localized BBB dysfunction are key features of long COVID-associated brain fog, the researchers concluded.
Discussing the next steps of this research, Dr. Matthew Campbell, a professor in genetics at Trinity College Dublin and principal investigator at FutureNeuro, previously told Technology Networks, “Future studies should be focused on examining in greater detail if BBB restoration aligns with the improvement of clinical symptoms. At present, we don’t know if this is the case. We also don’t know how the BBB changes in other post-viral illnesses and that remains to be elucidated.”
Abnormalities between body and mind
Post-mortem studies have demonstrated that patients dying from SARS-CoV-2 infection frequently have abnormalities in their brainstem. This part of the brain connects to the spinal cord and is crucial to breathing and coordinating movements among other vital life functions.
To test whether brainstem abnormalities persist in post-COVID patients, researchers used ultra-high field 7T quantitative susceptibility mapping (QSM). 30 patients were recruited for the study and were scanned 93–548 days after hospital admission for COVID-19. Their results were then compared to 51 age-matched controls without a prior history of COVID-19 infection.
The participants’ QSM signals were correlated with their disease severity, inflammatory response during acute infection, functional recovery as well as their depression and anxiety scores.
In COVID-19 survivors, multiple regions of the brainstem showed abnormalities, on average around six months after hospitalization. The differences observed were consistent with a neuroinflammatory response. In addition, patients with the most marked immune response also showed higher levels of depression and anxiety.
The regions affected are common sites of respiratory pathways. The researchers suggest, therefore, that lasting symptoms might be an indirect effect of inflammatory injury to the brainstem following COVID-19. The study highlights ultra-high field 7T QSM as a promising approach for probing the brain for the long-term effects of COVID-19 and other potential SARS-CoV diseases.
Spike protein accumulates in the brain
Using a novel artificial intelligence (AI)-powered imaging technique, researchers identified a mechanism involving SARS-CoV-2 spike proteins that may explain the neurological symptoms of long COVID.
The study found significantly elevated concentrations of spike protein in the skull’s bone marrow and meninges in both mice and post-mortem COVID-19 patient samples. The researchers suggest that the persistence of spike protein could indicate that the symptoms of long COVID stem from the enduring presence of viral proteins, alongside sustained systemic inflammation.
Wanting to understand the effect of existing vaccines on spike protein levels, the researchers vaccinated mice with the BioNTech/Pfizer mRNA COVID-19 vaccine. They found that the vaccine significantly reduced the accumulation of spike protein in the brain. However, the reduction was only around 50%, leaving protein that continues to threaten brain health.
This finding, while derived using mouse models, points to the need for additional interventions to help treat the long-term effects of SARS-CoV-2 infection.
What could a long COVID treatment involve?
Strides have been made in the race to understand long COVID and its effect on the brain. However, treatment and prevention remain elusive. This is despite a total of 178 clinical trial studies actively recruiting participants (data according to the ClinicalTrials.gov database as of January 2025).
The first clinical trial evaluating the impact of therapeutic monoclonal antibodies on the risk of developing long COVID was completed at the end of 2024. Unfortunately, while the antibody combination of amubarvimab and romlusevimab provided protection from hospitalization for COVID-19, there was no significant difference in self-reported symptoms of long COVID.
However, it’s not all bad news; researchers are making breakthroughs in other areas. A recent clinical trial tested a wearable transcutaneous electrical nerve stimulation (TENS) device on 25 individuals with long COVID, with promising results.
In the study, the participants were assigned either a high-dose (active) TENS device or a low-dose (placebo) device. Both groups used the TENS device for three to five hours daily over four weeks. The participants’ pain levels, fatigue and walking performance were measured before and after the therapy period.
The researchers found that the high-dose TENS group experienced notable improvements in pain relief and walking ability. However, while these findings are positive, the limited sample size calls for further research to confirm these findings.
The future of long COVID research
Long COVID continues to be a harrowing reminder of the COVID-19 pandemic five years later. For many people, the condition is a daily reminder of their previous infection.
Improving our understanding of the underlying mechanisms driving long COVID – especially concerning how different therapeutic agents for acute COVID-19 may influence longer-term outcomes – is needed to identify an effective treatment. In addition, “we also need to identify a solid panel of biomarkers that can be used in tandem with any imaging approach so that we can accurately predict how patients are faring with/without any potential therapies that emerge in the years to come,” Campbell previously told Technology Networks.
Long COVID is highly variable among patients with multiple etiologies affecting multiple organ systems. Unpicking the condition will require collaborative efforts from clinicians from a range of backgrounds, including infectious disease specialists, neurologists and others.
