Study Explores How COVID-19 Damages the Brain Without Ever Entering It

Over the course of the pandemic, researchers have been trying to understand how COVID-19, a virus that primarily affects the respiratory system and the lungs, causes neurological symptoms in patients. These can range everywhere from brain fog and confusion to loss of sense of taste and smell. A recent study funded by the National Institutes of Health (NIH) allowed researchers to take a closer look.

The December study, published as a correspondence in the New England Journal of Medicine, looks at the brains of 19 patients who died suddenly after contracting the virus between March and July 2020. Researchers found that although some people with COVID-19 had brain damage that appeared to be a consequence of the infection, evidence of the virus was not found in the brain tissue. 

Instead of attacking the brain directly, researchers theorize the damage done could be caused by the inflammatory response triggered by COVID-19.

"The story is always the same," neurologist and lead study author Avindra Nath, MD, tells Verywell. "When a pandemic happens, people always focus on the primary organ, but they forget about the brain."

Nath has studied the neurological effects of many novel viruses, including HIV/AIDS, Ebola, and now COVID-19. To prevent researchers from ignoring the neurological impacts of COVID-19, he says he "tried to sound the alarm very quickly in March," publishing an article questioning the virus's effect on the nervous system, and it worked. "That garnered a lot of attention."

MRIs Reveal Brain Damage

For the study, researchers used a specialized magnetic resonance imaging (MRI) scanner to observe samples of the olfactory bulb, which controls the sense of smell, and the brain stem, which controls breathing and heart rate. These specific brain areas were examined in each patient due to the link between COVID-19, sense of smell, and breathing. If the virus attacked these areas of the brain, it could explain symptoms such as difficulty breathing and loss of smell and taste.

Indeed, researchers found indicators of inflammation and bleeding in both the olfactory bulbs and brain stems in about half of the patients. Many of the blood vessels found were thinner than normal, leaking blood proteins like fibrinogen. ​"I​n the areas where you see t​he​ damage​, ​you see the puff of fibrinogen staining​—a large protein​ that​ w​ould​ never cross into the brain unless there are leaky blood vessels​," Nath says.​

The presence of this leaked protein appears to have then triggered an immune response since T-cells and microglia—immune cells from the blood and brain—were found surrounding these damaged blood vessels.

Nath says each of the people in the study only had minimal COVID-19 symptoms, ​yet ​died ​quickly and ​suddenly.

How the Virus Might Be Affecting the Brain

“Patients can be asymptomatic and still have pathology in the brain,” Nath says, but that pathology doesn't mean the virus is present in the brain itself. 

Jennifer A. Frontera, MD, a neuro-critical care doctor practicing in New York, tells Verywell that the neuro-invasiveness of COVID-19 "has been a big question mark."

"It's not clear if it's directly virulent to the brain," Frontera says, as many studies haven't found significant traces of the virus in brain tissue. Instead, at this point, it seems that brain injury is a consequence of the virus. "That's the bigger story—the whole secondary response, inflammation, and hypoxia," she says.

Nath agrees. It seems that COVID-19 does not itself infect the brain, but rather sets off a harmful chain reaction.

As of right now, that chain could consist of the following links: The virus causes inflammation in the nervous system, which puts pressure on blood vessels. Those blood vessels then become damaged and start to leak blood products into brain tissue, which then triggers an immune response. "Somehow, the virus initiated the process," Nath says. 

This pathology is not exactly like anything else, such as stroke or traumatic brain injury (TBI). "What is remarkable is the amount of endothelial blood vessel damage," or damage on the tissue lining blood vessels, Nath says.

Still, while "the pathology is unique, whenever you get inflammation in the brain, you can accelerate underlying diseases," Nath says. The fact that many of the patients in this study had preexisting conditions could be a necessary part of this story. It is established, for example, that people with certain conditions, including diabetes, obesity, and old age, are more susceptible to the disease.

What About Long-Haulers?

There may be a similar process happening in COVID-19 long-haulers, the patients that had COVID-19 that are still reeling from symptoms, such as brain fog and loss of taste.

"We suspect that there must be this kind of pathology in the long-haulers as well," Nath says. "We don't know that for sure, but that's what we want to study now," by doing a study of the brains of long-haulers, using technologies such as MRI and extracting cerebrospinal fluid (CSF).

Frontera, too, is in the final stages of writing a longer-term follow-up of almost 400 patients, seeking to document trends in their recovery six months out. "Now we have leads," Nath says. "We know what to look for."

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The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our coronavirus news page.