Brain scans challenge inflammation theory in long COVID, point to mood-related brain activity

For months, researchers have suspected that long COVID's stubborn symptoms—the fog that clouds thinking, the exhaustion that doesn't lift, the anxiety and depression that settle in—might stem from inflammation smoldering inside the brain itself. It was a plausible theory. The virus had invaded the body, perhaps it lingered in the brain, triggering an immune response that refused to quiet down. But a new study from the University of Turku in Finland has found something unexpected: when they looked directly at the brains of long COVID patients using advanced imaging, the inflammation simply wasn't there.

The research team, led by neuroimmunologist Laura Airas, scanned 14 people living with long COVID symptoms, compared them against 11 healthy volunteers and 13 patients with multiple sclerosis—a disease known to cause clear, measurable inflammation in the brain. Using PET scans designed to detect neuroinflammation and MRI imaging to assess brain structure and white matter changes, the researchers looked for the telltale signs of an inflamed brain. They also tested blood samples for biological markers that would indicate damage to neurons and the cells that support them. What they found was striking: the long COVID patients showed far less inflammatory activity in their brain's white matter than the MS patients did. When compared to healthy controls, there were no meaningful differences in markers linked to brain inflammation or neurodegeneration at all.

This doesn't mean inflammation played no role in long COVID's origins. Earlier studies of severe acute COVID-19 had documented clear signs of brain inflammation during the acute phase of illness. But the Finnish team noticed something revealing: patients scanned within 16 months of infection showed higher levels of inflammatory activity in white matter than those who had been sick for longer periods. The implication is that inflammation may be most prominent early on, then gradually fade as time passes. For many of the study participants, that window had already closed.

Yet the researchers uncovered a different pattern that may better explain why some patients suffer more severely than others. Those with higher levels of anxiety and depression, and those reporting poorer quality of life, showed increased cellular activity in two specific brain regions: the hippocampus and the amygdala. These areas are central to memory formation, emotional regulation, and how the brain processes stress. The finding suggests that the severity of long COVID symptoms in some patients may be less about lingering inflammation and more about how these emotion-processing regions of the brain are functioning. It's a shift in focus—from a purely inflammatory model to one that acknowledges the role of mood and emotional dysregulation in driving the illness forward.

The implications for treatment could be substantial. If widespread brain inflammation isn't the culprit for most long COVID patients, then flooding the system with anti-inflammatory drugs may not be the answer. Instead, Airas and her colleagues suggest that some patients might benefit more from therapies aimed at stress management and emotional regulation—approaches that address the brain activity patterns the imaging revealed. This doesn't negate the reality of long COVID's burden. Millions of people worldwide continue to experience symptoms that persist for months or years after initial infection, disrupting work, relationships, and daily life. But it does suggest that the path forward may require a more nuanced understanding of what's actually happening inside the brain, and a willingness to treat the condition as something more complicated than a simple inflammatory process. The study, published in the Journal of Neurology, represents one step toward that more precise understanding—and toward treatments tailored to what patients actually need.