Summary: A precision neuroimaging study challenged the widely held hypothesis that widespread, persistent brain inflammation is the primary driver of Long COVID. The research used advanced PET and MRI scans to compare Long COVID patients against both healthy controls and multiple sclerosis (MS) patients.
The data revealed no significant differences in long-term neuroinflammation or neurodegeneration between Long COVID subjects and healthy controls. Instead, the findings expose a time-dependent disease profile where brain inflammation peaks early post-infection and naturally diminishes over time, shifting the therapeutic focus toward emotional and stress regulation networks.
Key Facts
- Challenging the Widespread Myth: While persistent brain inflammation has long been suspected to cause Long COVID symptoms like fatigue and brain fog, direct, localized evidence has remained scarce. This study refines that narrative by proving widespread neuroinflammation is not the sustained driver of the condition.
- The Clinical Baseline Audit: Researchers utilized highly sensitive positron emission tomography (PET) imaging to track neuroinflammation alongside structural MRI scans and blood biomarker evaluations for glial and neuronal damage.
- No Elevated Long-Term Baseline: When compared to MS patients, Long COVID individuals showed significantly lower inflammatory activity in the brain’s white matter. Crucially, no statistical differences in neuroinflammation or neurodegeneration were found between Long COVID patients and healthy controls.
- The 16-Month Inflammation Window: The study uncovered a clear temporal link: patients scanned within 16 months of their initial SARS-CoV-2 infection exhibited higher white matter inflammatory activity than those with longer disease durations, proving inflammation fades over time.
- Localized Emotional Activation: Higher levels of depression, anxiety, and lowered quality of life correlated directly with elevated cellular activity in the hippocampus and amygdala, the precise brain regions governing memory, stress, and emotional regulation.
- Re-Calibrating Future Therapies: Because the underlying inflammatory changes weaken over time, the research team suggests that long-term sufferers would benefit significantly more from targeted stress and emotional regulation interventions rather than anti-inflammatory drugs.
Source: University of Turku
Long COVID has been suspected to involve persistent brain inflammation following SARS-CoV-2 infection, potentially explaining symptoms such as fatigue, cognitive impairment, anxiety, and depression. While previous studies have suggested this possibility, direct evidence has been limited.
Researchers at the University of Turku, Finland, used advanced brain imaging techniques to investigate whether long COVID patients with persistent symptoms show signs of brain inflammation.
โWe did not observe evidence of widespread brain inflammation in patients with long COVID when compared to healthy controls,โ says Professor of Neuroimmunology and InFLAMES Research Flagship group leader Laura Airas, who led the study.
The study included 14 individuals with long COVID, 11 healthy controls, and 13 patients with multiple sclerosis (MS), a neurological disease known to involve brain inflammation.
All participants underwent PET imaging sensitive to neuroinflammation, along with magnetic resonance imaging (MRI) to assess brain structure and white matter changes. Blood samples were analysed for biomarkers reflecting neuronal and glial damage.
Compared to MS patients, individuals with long COVID showed significantly lower inflammatory activity in the brainโs white matter. No differences in markers of brain inflammation or neurodegeneration were observed between long COVID patients and healthy controls.
Brain inflammation may be present early after infection
Clear signs of brain inflammation have previously been observed in neuropathological studies of severe acute COVID-19. In the current study, individuals scanned within 16 months of infection showed higher white matter inflammatory activity compared to those with longer disease duration.
According to Airas, this suggests that inflammation may be more prominent during the early phase of the disease and decrease over time.
An important finding of the study was that higher levels of depression and anxiety, as well as lower quality of life, were associated with increased cellular activity in the hippocampus and amygdala. They are brain regions involved in memory, emotional regulation, and stress responses.
These findings suggest that altered cellular activation in emotion-regulating brain regions may be linked to symptom severity in some patients with long COVID.
Toward a clearer understanding of long COVID and targeted treatments
The researchers note that the findings refine our understanding of long COVID and challenge the idea that persistent brain inflammation is the primary driver of prolonged symptoms in all patients. Instead, the results point to a more complex disease profile, where inflammatory changes may be strongest right after infection and diminish over time.
Long COVID is a recognised condition affecting millions of people worldwide, with symptoms that can persist for months or even years after the initial infection.
The researchers suggest that patients with prolonged symptoms may benefit more from treatments targeting stress and emotional regulation rather than therapies aimed solely at reducing inflammation.
โThis study highlights the need to continue investigating the complex biological mechanisms underlying long COVID. Understanding these processes is essential for developing targeted treatments,โ notes Airas.
The study by Airas and colleagues has been published in the Journal of Neurology.
Key Questions Answered:
A: The study reveals that your symptoms are completely real, but the biological engine behind them changes over time. While widespread inflammation appears to peak during the early months after infection, long-term symptoms are tied to altered cellular activity in specific emotion and stress-processing hubs, the hippocampus and the amygdala.
A: Multiple sclerosis is a neurological disease known for definitive, aggressive brain inflammation. By scanning Long COVID patients alongside MS patients and healthy individuals, the team created a clear benchmark. The scans revealed that the white matter in Long COVID brains had significantly less inflammation than MS brains, matching the baseline of healthy controls.
A: The data suggests that anti-inflammatory treatments might only be highly effective during the initial phase of the disease, particularly within the first 16 months post-infection. For patients dealing with prolonged, multi-year symptoms, the brain’s inflammatory response has already quieted down, meaning therapies targeting stress paths and emotional regulation will offer much better relief.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Long-COVID and neurology research news
Author:ย Tuomas Koivula
Source:ย University of Turku
Contact:ย Tuomas Koivula โ University of Turku
Image:ย The image is credited to Neuroscience News
Original Research:ย Open access.
โAssociation between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET studyโ by Joel Tuomaala, Maija Saraste, Emma Smith, Matilda Kuusi, Elisabet Westerberg, Eveliina Honkonen, Rahim Kargar, Sini Laaksonen, Jussi Lehto, Amelie Luoma, Markus Matilainen, Olavi Misin, Janne Atosuo, Mari Kanerva, Helena Liira, Sini Laakso, Tatiana Posharina, Virva Saunavaara, Saara Wahlroos, Johan Rajander & Laura Airas.ย Journal of Neurology
DOI:10.1007/s00415-026-13842-w
Abstract
Association between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET study
Background
A subset of individuals experience prolonged neurological and psychiatric symptoms following SARS-CoV-2 infection, a condition referred to as long COVID (LC). Limited evidence implicates ongoing neuroinflammatory processes as a driver of LC. This study investigates neuroinflammation in LC using translocator protein positron emission tomography (TSPO PET).
Methods
14 LC, 11 healthy control (HC) and 13 multiple sclerosis (MS) participants were included in the study. They underwent [11C]PK11195 TSPO PET and 3T magnetic resonance imaging (MRI) to evaluate glial activation, white matter (WM) pathology and brain volumetrics.
Serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured as markers of neuronal and glial damage. LC participants completed neurological examinations and mental health assessments.
Results
TSPO availability, measured as distribution volume ratio (DVR), was not elevated in LC compared to HCs but was significantly lower in LC compared to MS (WM DVR 1.03 vs. 1.06;ย pโ=โ0.007). Individuals imaged within 16ย months of SARS-CoV-2 infection showed higher WM DVR compared to those with a longer disease duration (1.05 vs. 1.02;ย pโ=โ0.04).
Moreover, lower quality of life was associated with higher DVRs in the hippocampus, amygdala and thalamus (ฯโ= โโ0.83-โโโ0.70), and depression and anxiety correlated positively with DVRs in the hippocampus and amygdala (ฯโ=โ0.75โ0.97).
Conclusions
LC TSPO availability did not differ from HCs in any studied brain area. However, lower WM TSPO availability in individuals with longer LC duration suggests COVID-19-associated neuroinflammation may subside with time, while the association between limbic TSPO availability and LC severity may imply a role for limbic activity in LC symptomology.
