Supplemental Science: Lifting the Fog

Sergei / Adobe Stock, Shacil / Adobe Stock, Photo Illustration / Edward Levine

The cognitive cloud known as brain fog didn’t originate with COVID-19. It has long been identified in the wake of other viral infections, notably Lyme disease and myalgic encephalitis/chronic fatigue syndrome. But the pandemic put it on the medical map with force and urgency, considering that millions were suddenly affected and many remain affected several years after onset.

A colloquial term for persistent cognitive difficulties, brain fog is marked by impairments in executive functions, memory, attention regulation, and motivation. People report problems finding words and other memory lapses. They have difficulty making decisions. They lack mental energy. They find themselves easily confused, experiencing a loss of mental sharpness. They have trouble concentrating and processing information. Some, but not all, suffer headaches.

In their own words, people describe “slow and sluggish thinking,” “fuzziness,” “blur,” being “not their usual self.” Many healthy people have experienced such symptoms briefly, during a bout of the flu, say, or after a night of heavy celebrating. But those who experience brain fog find themselves seriously disabled, unable to resume roles they once mastered.

Patients can lose a significant chunk of cognitive power compared to before infection. In a study conducted at Kings College London, subjects suffering from long COVID exhibited an average 28 percent decrease in memory, attention, and reasoning. Those who reported being the sickest demonstrated a whopping 57 percent decline in cognitive function compared to their pre-illness state.

No one knows what causes post-COVID brain fog, but many ideas have been put forth and are under active investigation. It is possible that the coronavirus directly targets neuronal cells, causing dysfunction of the mitochondria, the power plants in all cells. Recent research shows that the SARS virus can block the expression of core mitochondrial genes in animals; that process is visible in autopsy tissue from patients who had had COVID.

Its high energy requirements—the adult brain weighs three pounds, representing 2 percent of body weight, but consumes 20 percent of the body’s fuel—mean that cerebral tissues have a high metabolic demand. A reduction in energy output due to compromised mitochondrial function would have its most disruptive effect on the most energy-demanding brain operations, such as executive function.

Neural inflammation may be another cause of brain fog. As with chemotherapy, long associated with “chemo brain,” the cognitive dulling many cancer patients experience during treatment, COVID-19 causes neural inflammation. The viral attack activates glial cells, the brain’s immune responders, with downstream effects on cognitive function.

The rampant release of inflammatory molecules such as cytokines can reduce neurogenesis, dendritic sprouting, and other mediators of cognitive resilience, hampering the brain’s ability to remain cognitively normal in the face of insults to it.

Further, virus particles lingering in the body may set off an ongoing or overactive immune response, causing collateral damage. The response may include production of auto-antibodies, proteins misdirecting their protective power against the body. Although the last word has yet to be written on the subject, at least one major study has eliminated neural inflammation as a cause of COVID-induced brain fog.

There’s also evidence that blood clots can cause the brain fog linked to COVID. Early in the pandemic, researchers and clinicians noted a tendency for patients hospitalized with severe COVID to experience organ damage due to blood clots. More recently, a team following patients who had been hospitalized for COVID in 2020 and 2021 identified elevated levels of two clot-inducing proteins (fibrinogen and D-dimer) in the blood of those who later had cognitive difficulties.

Patients who had higher than average levels of fibrinogen and D-dimer in their blood at the time of hospitalization later rated their general cognitive abilities as poorer in questionnaires than did low-fibrinogen patients. The high-fibrinogen group also tended to score worse on objective measures of memory and attention. The study, reported in Nature Medicine, supports the possibility that blood clots triggered during the acute stages of viral infection led to lingering symptoms, such as brain fog.

Researchers recently proposed a surprising additional pathway to brain fog—the gut. Persistent viral RNA, often found in the gut of patients with long COVID, triggers the immune system to release inflammatory molecules that, in their attempt to fight infection, do collateral damage, preventing the absorption of the amino acid tryptophan from food. Tryptophan is the precursor to serotonin. The resulting dearth of serotonin—most of the body’s supply of the neurotransmitter is produced in the gut—impedes communication between the gut and the brain, normally conducted via the vagus nerve. Most affected may be the hippocampus, resulting in memory difficulty.

Research on the cognitive consequences of COVID, however, suffers from one glaring problem—there’s no agreed-on definition of brain fog and no standardized way to assess it, hampering comparison of the results of studies. Nor is there clarity about the neuropsychological processes involved.

Into this diagnostic nebula has stepped a team of Polish psychologists. In the Journal Personality and Individual Differences, Agata Debowska and colleagues report the development of a brain fog scale to provide a common method of assessment.

Not only does it set out to capture all the symptoms but it finds they sort themselves into three distinct domains
—mental fatigue, impaired cognitive acuity, and confusion. Because the instrument is a self-report measure, individuals can test themselves.

Although scientists can’t say for sure yet what causes brain fog, and there are no specific remedies, antioxidant supplements may help maintain the brain’s oxygen supply. A Yale team studying brain fog has found that a small group of patients given the antioxidant N-acetylcysteine (NAC) had improved memory, organizational skills, and ability to multitask. Patients took a dose of 600 milligrams of NAC once a day; in some, brain fog resolved so completely they were able to return to their jobs.

NAC is currently available without a prescription. The researchers are also formally testing NAC as a treatment for traumatic brain injury.

The Brain Fog Scale

These statements capture the components of brain fog. The full scale includes 23 items.

Factor 1: Mental Fatigue

• My thinking has been slow.
• I have felt mentally exhausted.

Factor 2: Impaired Cognitive Acuity

• I have felt it difficult to remember and understand new information.
• I have found myself forgetting certain words, such as the names of objects.

Factor 3: Confusion

• I have had a hard time understanding what others say.
• I have felt spacey.