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COVID-19 ‘brain fog’ inspires search for causes and treatments

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

Since she fell ill with COVID-19 around Thanksgiving, Pamela Furr has been waiting for her old self to return. A radio news anchor in Tennessee for more than 10 years, she now sometimes finds herself stuck midsentence grasping for simple words; she is prone to forget events and conversations if she doesn’t write them down. “I’m not the same person that I was before COVID,” she says. “I kind of miss me.”

The true prevalence of cognitive problems in COVID-19 survivors is elusive, and the underlying causes of lingering symptoms are the subject of ongoing studies. But it’s now clear that trouble thinking, concentrating, and remembering can be among the most debilitating “long-haul” symptoms and can persist for months. As more and more people seek help to overcome their brain fog at clinics set up for post–COVID-19 care, researchers and physicians are turning to treatments developed for stroke and traumatic brain injuries. And a few are setting out to test cognitive training video games they hope will expand the reach of therapy.

“Even if it’s a fairly small percentage [of survivors] who report cognitive problems, the number of overall people in that category … represents a tremendous problem,” says James Jackson, a clinical psychologist at the Vanderbilt University School of Medicine’s ICU Recovery Center, where Furr will participate in a support group for COVID-19 long haulers.

Cognitive impairment is common after serious illness. It’s among the symptoms of a condition called post–intensive care syndrome that can follow the isolation, immobility, and sedation of a hospital stay. And severe COVID-19 can itself damage the brain during its acute phase. SARS-CoV-2 may rarely invade brain tissue directly; most neurological damage is thought to stem from the indirect effects of infection, such as inflammation, stroke, and lack of oxygen.

“I’m not sure that what we’re seeing post-COVID is different” from impairments after other serious respiratory illnesses, says Faith Gunning, a neuropsychologist at Weill Cornell Medicine (WCM). She and colleagues reported in February that of 57 recovering COVID-19 patients referred for neuropsychological evaluation before hospital discharge, 81% had cognitive impairment. Most experienced problems with attention and executive function, which includes skills like planning, organization, and multitasking.

And such symptoms aren’t limited to people who wound up hospitalized. The majority of people visiting post–COVID-19 outpatient clinics had a relatively mild acute phase of illness, says Igor Koralnik, a neurologist at Northwestern University’s Feinberg School of Medicine. He oversees the Neuro COVID-19 Clinic at Northwestern Memorial Hospital, which has seen more than 400 patients since it opened in May 2020. Among the first 100 patients with confirmed COVID-19 infections whose symptoms lasted at least 6 weeks, 81 experienced “brain fog,” the most common neurologic symptom, Koralnik’s team reported last month in the Annals of Clinical and Translational Neurology.

After brain injury, cognitive rehab typically involves testing to identify cognitive weaknesses and training to help patients navigate daily life. Often, the focus is on compensating for deficits, not eliminating them outright. Jackson’s team at Vanderbilt recommends a rehabilitation program called goal management training, originally developed to manage impairments after stroke, traumatic brain injury, or age-related decline. It trains patients in “metacognitive skills” such as observing their own thought processes, identifying situations where they’re prone to make cognitive errors, and reflecting on how to approach a new task.

It can be “a game changer” for patients, Jackson says. He expects such training to benefit people with post–COVID-19 impairments—but only if their primary care physicians refer them as they would people who had a stroke or traumatic injury. For now, that happens rarely, he says.

Any time you’re developing a treatment, you need to understand the mechanism. But we can’t afford to wait. We need to do something now.

Ana-Maria Vranceanu, Harvard Medical School

Complicating matters for doctors is that the nature of the injuries is often far from clear. “We don’t really know what happened to them,” says Serena Spudich, an infectious disease neurologist at the Yale School of Medicine. When cognitive dysfunction appears after mild COVID-19, it raises the possibility that an immune response that was protective in the acute phase has become overactive and triggered continuing inflammation, she says. Spudich leads a study using brain imaging along with analyses of spinal fluid and other biological samples to look for signs of inflammation and other abnormalities in patients with persistent post–COVID-19 neurological symptoms.

There are other possible explanations for cognitive impairments. “Things like sleep and exhaustion, pain and stress and depression—all of these nonneurological issues also play a role in our cognitive functioning,” says Renee Madathil, a rehabilitation neuropsychologist at the University of Rochester Medical Center. Cognitive impairments rooted in depression or stress aren’t any less “real” than those caused by direct injury to the brain, Madathil and others stress. But different causes may call for different therapies.

“Any time you’re developing a treatment, you need to understand the mechanism,” says Ana-Maria Vranceanu, a clinical health psychologist at Harvard Medical School. “But we can’t afford to wait,” she adds. “We need to do something now.” In prepandemic studies of intensive care unit (ICU) survivors, her team found that elevated emotional distress spelled a slower recovery. Her team developed a training program to help ICU survivors and their families manage distress, anxiety, and depression, which she aims to adapt for COVID-19 recovery.

To help people who neither live near rehabilitation centers nor have access to specialists, a few researchers are exploring a newer category of potential treatments: cognitive training through video games played at home.

In response to what he calls “a tsunami of patients with Long COVID,” Radboud University Medical Center professor of surgery Harry van Goor, with Radboud physical therapy researcher Bart Staal, is testing a virtual reality platform and a set of games that involve physical activity, cognitive skills, and mindfulness. A pilot study in 48 people recovering from COVID-19 suggests the puzzlelike cognitive games were highly motivating, the researchers say; they next hope to launch a controlled trial of the approach versus traditional rehab.

Meanwhile, Jackson’s team at Vanderbilt and Gunning’s at WCM are gearing up to test a “digital treatment” developed by Akili Interactive, which last year became the first company to win approval from the U.S. Food and Drug Administration for a video game as a prescription therapy.

The technology, so far approved for attention deficit hyperactivity disorder (ADHD), “is not just a blunderbuss approach” to treat any condition that involves cognitive dysfunction, says Anil Jina, Akili’s chief medical officer. Instead, it’s designed to improve attention—for example, by having players multitask to collect items in the game while avoiding obstacles. A study of more than 300 children with ADHD published last year showed that those who played the game showed greater improvements in computerized attention tests and on parent and clinician assessments than those who used an educational video game.

A video game developed by Akili Interactive challenges attention with a series of targets and obstacles.

Akili Interactive

Gunning’s study, set to launch next month, aims to include 100 participants who have lingering cognitive deficits after COVID-19; Jackson’s group expects to include more than 50 people with such symptoms. In both studies, half the participants will be assigned to 6 weeks of at-home play. Half will serve as controls but will have access to the game after the assessment is complete.

The brain-training industry has a checkered reputation when it comes to science. In 2016, Lumos Labs, the company behind the popular program Lumosity, agreed to pay the Federal Trade Commission $2 million to settle false advertising charges after promoting its games as a way to stave off Alzheimer’s disease and other conditions without adequate evidence.

In studies of cognitive decline accompanying aging, puzzles and cognitive games haven’t proved as effective as physical activity and an active social life, Vranceanu notes. “If you’re doing Sudoku, you’re getting good at Sudoku,” she says, “but that doesn't necessarily translate to you getting better at not misplacing your keys.”

And in rehabilitation, the transfer of skills from games and exercises in the clinic to everyday life “does not occur easily,” cautions Edward Taub, a behavioral psychologist at the University of Alabama, Birmingham (UAB). He and UAB rehabilitation psychologist Gitendra Uswatte are recruiting post–COVID-19 patients with cognitive impairment to a small pilot study of “constraint-induced cognitive therapy,” based on techniques Taub and colleagues first developed to help patients after strokes. It includes a video game that challenges a player’s processing speed, as well as training on daily activities, such as making a shopping list or organizing medications, and monitored homework to help patients apply skills from the game to their lives.

Jackson knows brain training has its limits. But he argues that emerging evidence supports its value for building attention and processing skills, which he suspects are at the heart of many post–COVID-19 patients’ impairments.

Spudich, too, says she would welcome a web- or app-based attention-training game to help patients take charge of enduring COVID-19 symptoms against which they feel powerless. “Frankly, I think those things will make a difference on outcomes, even if they’re not proven in a clinical trial,” she says. “The hopelessness people feel in this situation is really palpable.”