Stanford researchers have found signs of inflammation, genetic changes and impaired circuitry in the brains of people killed by COVID-19, important clues to the mysterious “brain fog” and mental struggles reported by many patients.

The research also reveals haunting similarities between the brains of those killed by COVID and other degenerative conditions, such as Alzheimer’s disease and Parkinson’s disease.

“This intense state of this viral infection causes changes in the brain that could explain the symptoms that we see,” said Tony Wyss-Coray, professor of neurology and neurological sciences at Stanford. The research, a collaboration with German scientists, was published in this week’s issue of the journal Nature.

The team found no evidence that the virus invaded and infected the brain, said Wyss-Coray. Perhaps neurological symptoms are caused because the virus lingers in the periphery of the brain, among the tissues that serve as the gate-keeping “blood brain barrier.”

Or the impact may be indirect, the result of the body’s overaggressive immune defense against the virus, he said.

COVID-19 is a disease that mainly attacks the lungs, but also has bewildering mental effects. Patients often experience neurological problems including headaches, delirium, “brain fog,” dizziness, fatigue, and loss of the sense of smell. One patient, a woman in her mid-50s, reportedly suffered from psychosis, seeing lions and monkeys in her house. The disease may also trigger a stroke.

Patients welcomed the research, saying it shows that the mental toll of so-called “Long COVID” is real.

“The fact that so many people are experiencing neurological issues, this is a finding we expected,” said Karyn Bishof, 31, of Boca Raton, Florida, who contracted COVID-19 in March 2020 while working as a firefighter and paramedic.

“Some of the most commonly reported symptoms amongst ‘long haulers,’ including myself, are chronic daily headache, memory loss, brain fog, word recall issues, coordination, ability to follow commands and switching words around,” said Bishof, co-founder of the Long COVID Alliance. “Additionally, if you throw in insomnia, chronic, unrelenting fatigue and full body pain, which come with no explanation or solution as of yet, it’s becomes very clear that this is a systemic inflammatory condition.”

Hunter Howard, a Dallas-based healthcare entrepreneur who contracted the virus in Colorado in March 2020 and now chairs the Global Pandemic Coalition, said “studies like this, on the deceased, help us understand what current imaging modalities are unable to show — but ‘longhaulers’ are sharing that they are experiencing.”

Post-mortem studies to learn how disease works on the brain have been a pillar of neurological research for over a century. But donated brains – hard to find, even under normal conditions – are especially scarce during a pandemic.

The risk of infection calls for arduous safety precautions during autopsies. Health-care systems are stressed. And because the patient may be unconscious and intubated, it is challenging to get consent to donate their body for research. Families are often in shock, and grief-stricken.

“We have a big lab at Stanford here and when this pandemic hit, we were not allowed to work anymore,” said Wyss-Coray. “We wanted to do something for this for this terrible disease to try to understand it.”

Unable to find local brains, he turned to colleagues at Germany’s Saarland University for help. One at a time, eight cherry-sized pieces of brains – preserved for international transport – were shipped to Stanford for analysis.

They were compared to 12 normal brains. In the COVID-19 brains, the team found abnormal patterns of gene activity in all major cell types – many of them linked to inflammatory processes.

They also found signs of distress in neural circuitry of the cerebral cortex, the brain region that plays a key role in memory and reasoning. There was an imbalance between two types of neurons: excitatory and inhibitory. This pattern has also been seen in neurodegenerative conditions such as Alzheimer’s disease.

And they found that the brains were permeated by immune cells called macrophages, which act like garbage trucks — prowling for pathogens and then attacking and removing them. In healthy brains, there are far fewer of these immune cells.

“When something unexpected is happening, these cells get activated and produce all kinds of factors that create what we call inflammation,” said Wyss-Coray.

The Stanford project adds to the growing body of research into troubled brain tissues of COVID-19 patients. National Institutes of Health researchers spotted damage caused by thinning and leaky brain blood vessels. A Japanese team detected brain swelling. Another study described a patient with deterioration of myelin, the neurons’ insulation and the cause of multiple sclerosis.

Even when an active infection is not discovered in brain tissue, neuroinflammation can be caused by a still-active viral infection elsewhere in the body, said Jaime Seltzer, director of scientific and medical outreach for . #MEAction, an advocacy group for people with myalgic encephalomyelitis/chronic fatigue syndrome. Long COVID can mimic that disabling and mysterious illness.

It’s also possible that the virus triggers an autoimmune disorder, with antibodies creating inflammation even if the original infection is long gone, according to Seltzer.

“This research is a start but we need to better understand the processes of neuroinflammation in Long COVID, ME/CFS, and other often post-viral chronic complex diseases,” said Seltzer, urging greater funding.

Chronic inflammation is also believed to be one of the key features of Alzheimer’s disease and neurodegenerative diseases, said Wyss-Coray.

That’s troubling, he said, because it suggests that the chronically inflamed brains of COVID-19 patients might be at risk of other neurological problems, over time.

“Having severe disease is bad for the brain,” he said.