Summary: A precision neuroimaging study from the University of Turku challenges the widely held idea that persistent, widespread brain inflammation is the main cause of Long COVID symptoms. Using advanced PET and MRI techniques, researchers compared people with long COVID to healthy volunteers and to patients with multiple sclerosis (MS). Their results show no sustained global neuroinflammation or neurodegeneration in long COVID compared with healthy controls. Instead, the data indicate a time-dependent pattern: brain inflammation is more likely to peak early after SARS-CoV-2 infection and decreases over time, while long-term symptoms appear linked to changes in emotion and stress-regulating brain regions.
This study refines our understanding of the biological mechanisms behind Long COVID and suggests new directions for treatment that emphasize emotional and stress regulation rather than chronic anti-inflammatory strategies for long-term sufferers.
Key Facts
- Reassessing a common assumption: Although persistent brain inflammation has been proposed as an explanation for Long COVID symptoms such as fatigue, brain fog, anxiety and depression, localized, direct evidence has been limited. This study shows that widespread neuroinflammation is not maintained in long-term cases.
- High-sensitivity imaging and biomarkers: Researchers combined translocator protein PET imaging (TSPO PET), structural 3T MRI, and blood markers of neuronal and glial damage to assess brain inflammation and tissue integrity.
- Comparison groups provide context: Long COVID participants exhibited significantly lower white matter inflammatory activity than MS patients, who are known to experience aggressive brain inflammation. Crucially, there were no statistical differences in TSPO PET measures or neurodegeneration markers between long COVID subjects and healthy controls.
- Time matters — a 16-month window: Individuals scanned within 16 months of their SARS-CoV-2 infection showed elevated white matter inflammatory signals compared with those whose symptoms persisted beyond that period, indicating that inflammation tends to decline with time.
- Localized limbic activation links to symptoms: Higher depression, anxiety and reduced quality of life correlated with increased cellular activity in the hippocampus and amygdala—key regions for memory, emotion and stress regulation—suggesting a regional, symptom-relevant change rather than global neuroinflammation.
- Implications for treatment: Because inflammatory changes appear strongest early and then wane, patients with persistent, long-duration symptoms may gain more from therapies targeted at emotional regulation and stress pathways than from long-term anti-inflammatory medication.
Source: University of Turku
Long COVID has been suspected to involve lingering brain inflammation after SARS-CoV-2 infection, offering a possible explanation for prolonged symptoms such as fatigue, cognitive difficulties, anxiety and depression. Previous reports hinted at this possibility, but direct evidence from living patients was sparse. To address that gap, a team at the University of Turku employed state-of-the-art imaging to test whether people with persistent post-COVID symptoms show measurable neuroinflammation.
“We did not find evidence of ongoing, widespread brain inflammation in people with long COVID when compared to healthy controls,” says Professor Laura Airas, lead author and neuroimmunology specialist at the InFLAMES Research Flagship. The study enrolled 14 people with long COVID, 11 healthy controls and 13 patients with multiple sclerosis, a condition known for prominent central nervous system inflammation.
All participants underwent [11C]PK11195 TSPO PET scanning to detect glial activation, alongside 3T MRI to evaluate structural changes and white matter integrity. Blood samples measured serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as markers of neuronal and glial injury. Long COVID participants also completed neurological and mental health assessments.
Compared with the MS group, long COVID subjects had significantly lower TSPO signal in white matter. When directly compared to healthy controls, no brain region showed elevated TSPO availability or signs of neurodegeneration in the long COVID group.
Brain inflammation may be present early after infection
Neuropathological studies of severe acute COVID-19 have previously demonstrated inflammatory changes in the brain. In this imaging study, people scanned within 16 months of their initial SARS-CoV-2 infection showed higher white matter TSPO signal than those scanned later, supporting the idea that inflammation is more pronounced early on and tends to subside.
Notably, the researchers observed strong associations between higher TSPO availability in limbic structures—the hippocampus and amygdala—and worse mental health scores, including elevated depression and anxiety and lower quality of life. These links suggest that altered cellular activity in emotion- and stress-related regions may contribute directly to symptom severity for some patients.
Toward clearer understanding and targeted treatments
The findings narrow the role of persistent, widespread neuroinflammation as a universal cause of long COVID and instead point to a more nuanced, time-dependent disease profile. Early post-infection inflammation may affect some patients, but long-term symptoms often align with localized limbic changes rather than sustained global neuroinflammatory activity.
Given these results, therapeutic strategies for patients with prolonged symptoms should prioritize interventions that address emotional regulation, stress responses and related neural circuits. Anti-inflammatory approaches may be most relevant during the early months after infection, while long-duration cases may respond better to treatments aimed at the limbic system and mental health support.
“This study emphasizes the importance of continuing to investigate the diverse biological mechanisms underlying long COVID so that treatments can be matched to the stage and character of each patient’s condition,” says Airas.
The study is published in the Journal of Neurology under the title: “Association between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET study.” DOI: 10.1007/s00415-026-13842-w
Key Questions Answered:
A: Your symptoms are real. The study indicates that the biological drivers can change over time. Widespread inflammation appears to peak in the months after infection, whereas long-term symptoms are more closely associated with altered cellular activity in limbic areas involved in emotion and stress processing.
A: Multiple sclerosis serves as a benchmark for active, high-level brain inflammation. Comparing long COVID to MS and healthy controls helps clarify whether the inflammation seen in long COVID is comparable to known inflammatory disease or more similar to healthy baseline. In this study, long COVID resembled healthy controls rather than the MS group.
A: The results suggest anti-inflammatory treatments may be most effective early after infection, particularly within the first 16 months. For those with persistent, multi-year symptoms, targeting stress regulation, emotional processing and limbic system function may offer greater benefit.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The underlying journal paper was reviewed in full by the editorial team.
- Additional context was provided by the editorial staff.
About this Long-COVID and neurology research news
Author: Tuomas Koivula
Source: University of Turku
Contact: Tuomas Koivula – University of Turku
Image: The image is credited to Neuroscience News
Original Research: Open access. “Association between post-COVID-19 neuropsychiatric symptoms and persistent glial activation in the limbic system: a TSPO PET study” by Joel Tuomaala et al., 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 portion of individuals develop prolonged neurological and psychiatric symptoms following SARS-CoV-2 infection, referred to as long COVID (LC). Evidence for ongoing neuroinflammation as a driver of LC has been limited. This study used TSPO PET imaging to investigate glial activation in people with LC.
Methods
Fourteen individuals with LC, eleven healthy controls and thirteen patients with MS underwent [11C]PK11195 TSPO PET and 3T MRI to measure glial activation, white matter pathology and brain volumes. 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, expressed as distribution volume ratio (DVR), was not elevated in LC compared to healthy controls but was significantly lower in LC than in MS (white matter DVR 1.03 vs. 1.06; p = 0.007). Participants imaged within 16 months of SARS-CoV-2 infection had higher white matter DVR than those with longer illness duration (1.05 vs. 1.02; p = 0.04). Lower quality of life correlated with higher DVRs in the hippocampus, amygdala and thalamus, and depression and anxiety correlated positively with DVRs in the hippocampus and amygdala.
Conclusions
TSPO availability in long COVID did not differ from healthy controls in any brain area studied. Lower white matter TSPO availability in individuals with longer symptom duration suggests that COVID-19-associated neuroinflammation may decrease over time. The association between limbic TSPO availability and symptom severity implies a potential role for altered limbic activity in long COVID symptomatology.