Scientists thought brain inflammation was driving long COVID but the scans told a different story

Long COVID has often been suspected to involve ongoing inflammation in the brain caused by SARS-CoV-2 infection. Scientists have explored this theory as a possible explanation for symptoms such as fatigue, brain fog, anxiety, and depression. However, direct proof has remained limited.

To investigate the issue more closely, researchers at the University of Turku in Finland used advanced brain imaging techniques to examine people with long COVID who continued to experience symptoms long after infection.

"We did not observe evidence of widespread brain inflammation in patients with long COVID when compared to healthy controls," says Professor of Neuroimmunology and InFLAMES Research Flagship group leader Laura Airas, who led the study.

Comparing Long COVID Patients With Healthy Volunteers and MS Patients

The study included 14 people with long COVID, 11 healthy participants, and 13 individuals with multiple sclerosis (MS), a neurological disease known to involve inflammation in the brain.

All participants underwent PET scans designed to detect neuroinflammation, along with magnetic resonance imaging (MRI) scans to evaluate brain structure and changes in white matter. Researchers also analyzed blood samples for biological markers associated with damage to neurons and supporting brain cells.

Compared with patients who had MS, the long COVID group showed much lower inflammatory activity in the brain's white matter. Researchers also found no meaningful differences between long COVID patients and healthy volunteers in markers linked to brain inflammation or neurodegeneration.

Inflammation May Fade Over Time After Infection

Previous neuropathological studies of severe acute COVID-19 have reported clear signs of inflammation in the brain. In this new study, researchers noticed that participants scanned within 16 months of infection showed higher levels of inflammatory activity in white matter than those who had been sick for a longer period.

According to Airas, this may indicate that inflammation is more noticeable during the earlier stages of the disease before gradually decreasing over time.

The study also uncovered another important pattern. Patients with higher levels of anxiety and depression, along with poorer quality of life, showed increased cellular activity in the hippocampus and amygdala. These brain regions play major roles in memory, emotional regulation, and responses to stress.

Researchers say the findings suggest that altered activity in these emotion-related areas of the brain could be connected to the severity of symptoms experienced by some people with long COVID.

Findings Could Influence Future Long COVID Treatments

The researchers believe the results help refine the scientific understanding of long COVID and challenge the idea that persistent brain inflammation is the main cause of prolonged symptoms in every patient.

Instead, the findings point toward a more complicated condition in which inflammatory changes may be strongest shortly after infection and then weaken over time.

Long COVID remains a major global health issue, affecting millions of people whose symptoms can continue for months or even years after the initial illness.

Based on the findings, researchers suggest that some patients with persistent symptoms may benefit more from treatments focused on stress management and emotional regulation rather than therapies aimed only at reducing inflammation.

"This study highlights the need to continue investigating the complex biological mechanisms underlying long COVID. Understanding these processes is essential for developing targeted treatments," notes Airas.

The study by Airas and colleagues was published in the Journal of Neurology.

InFLAMES Flagship is a joint initiative between the University of Turku and Åbo Akademi University in Finland. The program aims to combine immunology and related research fields to develop new diagnostic tools and personalized medical treatments. InFLAMES is part of the Research Council of Finland's Flagship Program.