Brain Damage May Be a Cause of Chronic Anxiety in Long COVID Patients, Study Finds

People living with long COVID often experience lingering symptoms, including brain fog and anxiety, even after surviving a mild case of the disease.

Without a solid understanding of the neurological outcomes from COVID-19, health providers may dismiss or neglect health concerns from long COVID patients.

In a new study, researchers at Northwestern University found that brain inflammation and nerve cell damage in long COVID patients, including those who were never hospitalized, are linked to the development of anxiety.

“Many patients probably feel that their symptoms are dismissed or might be all in their head,” Barbara Hanson, PhD, a co-author of the study and a neurology professor at Northwestern University, said in a press conference. “Finding evidence like this—empirical evidence that shows that there is likely to be a biological basis of these kinds of symptoms—is very validating and important for these patients.”

How the Study Was Conducted

The researchers enrolled 64 participants, including long COVID patients who had been hospitalized, patients who had a mild case, patients who were hospitalized for encephalopathy, a severe type of brain disease, as well as healthy individuals who hadn’t been infected with the disease.

The participants answered questions about their quality-of-life months after recovering from COVID-19 infection. They also completed standardized tasks that tested their cognition, processing speed, attention, executive function, and working memory.

Patients who had been hospitalized for COVID-19 showed similar levels of cognitive decline and decreased quality of life as those who had a milder case, researchers found. Cognitive outcomes, then, weren’t dependent on the severity of the disease, Hanson said.

To understand the underlying causes, researchers homed in on two biomarkers found in the blood. The first indicated damage to nerve cells and the other signaled activation of glial cells, a system of cells that support the neurons. Glial cell activation indicates brain inflammation and is often seen in autoimmune diseases like multiple sclerosis.

Researchers analyzed the patients’ blood for these biomarkers once, at least three months after recovering from acute COVID-19 infection or whenever the patient began experiencing neurological symptoms of long COVID. On average, the researchers sampled the participants seven months after their disease onset.

The researchers found that the biomarker for brain inflammation was more prevalent in people who experienced anxiety. Additionally, individuals with more severe anxiety had a higher rate of the inflammation marker than those who had less severe anxiety.

This held true even when researchers accounted for demographic differences like age, sex, and body mass index.

“These markers have been looked at in other COVID populations, but our study population was unique because we have matched cognitive and quality of life measures in addition to the typically studied COVID symptoms like shortness of breath, fatigue and brain fog,” said Igor Koralnik, MD, chief of neuroinfectious diseases and global neurology in the Ken & Ruth Davee Department of Neurology at Northwestern Medicine.

Neurological Outcomes Develop From the Disease Itself

Some have suggested that anxiety or depression in long COVID patients is a result of environmental changes during the pandemic or stigmas associated with being infected, Hanson said. But the connection between anxiety symptoms and these biomarkers indicate that there are physical changes to the brain in some patients, Hanson said.

“That’s encouraging,” Hanson said. “It does give us a suggestion that there might be a mechanistic cause to that neuropsychiatric symptom of anxiety.”

Researching this relationship in people who experienced only mild to moderate COVID-19 is important to better understanding what is happening in the central nervous system, according to Jacqueline Becker, PhD, clinical neuropsychologist at Mount Sinai Health System who is unaffiliated with the study.

Studies have long shown that patients who are hospitalized for critical illnesses sometimes suffer neurological consequences due to treatments that require intubation or restrict oxygen to the brain.

Comparing this group with those who were never hospitalized for COVID-19 indicates that there is something specific to the COVID-19 virus that is causing neurological issues, Becker said.

The Impact on the Patient Experience

Samantha Lewis, 34, a patient in the Neuro COVID-19 Clinic at Northwestern Memorial Hospital, became sick with COVID-19 in October 2020. While her case was, she said, only “mild to fairly moderate,” her symptoms were long-lasting.

Lewis said she often felt disoriented and tired, and that it was odd for someone her age to struggle staying awake past noon or remembering the steps to brushing her teeth.

“It became a very frustrating process to get through recovery,” she added.

While Lewis’s cognitive difficulties have subsided, her symptoms remain. When she “uses up” all her energy in a day, she feels extreme fatigue, pain in her extremities, and brain fog.

“We were being told, before there was a lot of research, that we were just depressed or we were just anxious—our heart rates were high because we were just anxious, and we were just tired because we were depressed,” Lewis said, adding that new studies that affirm physical changes in the brain can feel validating for patients like her.

Studies on long COVID should account for healthy control groups, as well as both hospitalized and non-hospitalized patients, as the Northwestern study did, Becker said.

“There are many factors from the pandemic that can impact cognitive functioning, like social isolation, stress, and depression,” Becker said. “If we can find two groups that both lived in the pandemic—one that was infected and one that was merely affected—and still show that there is a difference, I think that’s really important.”

Another Piece in the Long COVID Puzzle

This study is relatively small, Becker said. For these findings to be applicable to the general population, there should be further research with more participants, including patients who recovered from COVID-19 without neurologic symptoms, she added.

Still, the study contributes to an ever-growing body of knowledge on the neuropsychiatric implications of long COVID. Hanson said it may even help researchers better understand chronic anxiety not associated with COVID-19.

More than half of COVID-19 survivors may develop long-term complications. With nearly 80 million documented cases of infection in the U.S., the health implications could be massive.

Scientists still have a lot to learn about the precise mechanisms leading to long COVID outcomes.

“Long COVID is unlikely to be a single consideration. It’s most likely to have many different presentations and be caused by several different factors in a wide number of people,” Hanson said.