Sleep Disturbances and Chronic Fatigue After COVID-19 Infection

If you're among the one in 10 U.S. adults who developed long COVID after being infected with the virus, it may feel like you have too many symptoms to count. Researchers have identified 200 ways that COVID can keep on giving long after you've received the all-clear with a negative test, according to the National Institutes of Health (NIH). And trouble sleeping may be a major post-viral symptom that tops your list.

A new study from the Cleveland Clinic may help explain why. It found that 67% of participants with long COVID experienced moderate-to-severe sleep disturbances. "We don't know exactly how long COVID affects sleep," says Cinthya Pena Orbea, M.D., an assistant professor of medicine at the Cleveland Clinic Sleep Disorders Center in Ohio, and lead author of the study. "But one hypothesis is that viral replication causes inflammation in the brain, likely in areas that are responsible for sleep regulation."

To learn more about how COVID may lead to chronic sleep problems—which may help unpack another common long COVID symptom, chronic fatigue—we examined the latest research and asked top viral experts to discuss the COVID-insomnia-chronic-exhaustion connection.

COVID Can Kill Nerve Cells in the Brain

According to additional research, one way that COVID may get into the brain is via nerve fibers in the nose that make their way to the hypothalamus and frontal cortex, two likely initial stops for COVID's attack, before traveling to other parts of the brain. The hypothalamus is responsible for regulating respiration, how we respond to stress, body temperature, metabolism, cardiovascular function, and—you guessed it—sleep.

"It makes sense, then, that insomnia, along with other seemingly unrelated symptoms like fatigue, brain fog, and weight gain, are manifestations of hypothalamic dysfunction from [COVID] viral attack," says Jacob Teitelbaum, M.D., an internist in integrative medicine who specializes in treating patients with chronic fatigue, pain, and related insomnia in Maui, HI.

Ann-Charlotte Granholm-Bentley, Ph.D., a professor of neurosurgery at the University of Colorado Denver-Anschutz Medical Campus, takes it further in a July 2023 Journal of Clinical Medicine review of research on SARS-CoV-2's effects on the brain. Her aim for the review, she says, was to make "people pay attention to long COVID and think about the neurological consequences" of COVID infection.

In it, Granholm-Bentley references studies that examined brains from people with severe COVID showing COVID viral particles lingering in the brain. This is significant, she says, because "there are nerve cells in the hypothalamus containing orexin, [which are] neuropeptides that are particularly involved in the sleep/wake cycle. These nerve cells [in the hypothalamus] are sensitive to infection, so they die easily during a viral attack like COVID, never to regenerate," she adds. When that occurs, you may find yourself waking frequently during the night, having difficulty falling asleep on a regular basis, or both, all of which can leave you chronically exhausted—and may even set you up for developing other neurodegenerative disorders down the line, Granholm-Bentley notes.

Although the research team at the Cleveland Clinic says more research is needed to better understand this possible connection, the "viral immune-mediated mechanisms of COVID-19 [that are] responsible for persistent inflammation and autoimmune influence of certain areas of the brain [that are] responsible for regulating the sleep-wake cycle—including the hypothalamus—[may] result in the sleep disturbances that are so prevalent in PASC [post-acute sequelae SARS-CoV-2 infection, a.k.a., long COVID]," says co-author of the study Reena Mehra, M.D., a physician scientist at the Sleep Disorders Center.

Interestingly, increasing orexin levels in the brain may one day treat chronic sleep disturbances, according to a paper published by the Stanford Center for Narcolepsy, which is researching potential therapies for sleep disorders surrounding the hypothalamus.

Mitochondria May Play a Role, Too

It seems like a case of direct cause-and-effect, right? Chronic sleep dysregulation caused by a viral attack drives the deep exhaustion that so many COVID long-haulers experience and report? Not so fast, says Granholm-Bentley: Turns out, hypothalamic dysfunction due to COVID orexin loss may not be the sole culprit to point a finger at. This damage in the brain may partner with changes to the body and other brain regions, too, after COVID infection, which together may be behind chronic insomnia and chronic fatigue, as well as a host of other long COVID symptoms, experts say.

Here's how: Additional research points to long COVID's continual attack on our mitochondria, the energy sources of every cell in our bodies that are often referred to as the cells' powerhouses. "The virus is able to actually change mitochondrial function, so it is able to replicate, while also reducing the amount of energy that goes to the cells," explains Dr. Teitelbaum. "Usually, the mitochondria just shut down energy production for a few days or weeks until the viral particles are gone. But for some infections, the mitochondria have trouble coming back online on their own. This drop in energy from mitochondrial dysfunction is also what triggers the hypothalamic sleep center to go offline."

Nerve cells, including those in the hypothalamus, "are the most energy-needing cells in the brain because of all the spontaneous activity that goes on," adds Granholm-Bentley. And the hypothalamus uses more energy for its size than any other area of the body, according to Dr. Teitelbaum.

Further, mitochondria use oxygen to produce energy. Granholm-Bentley's review shares findings that show lower oxygen levels in the brains of those with long COVID—yet another reason the virus can prevent mitochondria from producing enough energy.

To make matters worse, "now that the virus has altered the mitochondria to suit its needs, the cell is now busy trying to repair the dysfunctional mitochondria and is no longer able to fight the infection," explains Granholm-Bentley. Dr. Teitelbaum refers to this process as viral hijacking. "Mitochondria still make the energy, but they can't use it, leaving the energy to the viral particles to use to reproduce," he adds. A proverbial insult (in this case) to literal injury.

COVID Can Destroy Microglia in the Brain

But the virus is turning up in other areas of the brain, too—and not all of our sleep function is housed in the hypothalamus, according to Granholm-Bentley. "There are other nerve cells in the brainstem that produce norepinephrine, which is highly involved in our sleep cycle," she says. "These cells are also sensitive to infection."

That's why Granholm-Bentley believes that hypothalamic dysfunction is just part of the fallout from SARS-CoV2 that can damage the brain—and our ability to sleep. "Long COVID appears to be making changes in every cell type in the brain, whether they are highly dependent on mitochondrial energy or not, including blood vessel cells and microglia," she explains. Like T-cells that fight infection in the body, microglia are immune cells in the central nervous system that fight infection in the brain. "When we studied brain tissue in people with COVID, we found that there were fewer microglia than we normally see," she notes. "We think that microglia die when the brain is infected with the SARS-CoV-2 virus—[making] the body less able to fight the infection, especially in the brain, because these cells are dying."

According to Granholm-Bentley, the knowledge that coronaviruses like SARS-CoV-2 can infect the brain is relatively new. "Viruses are not supposed to come into the brain. Now we've learned [some viruses] can cross the blood-brain barrier and reach brain tissue. The barrier is supposed to keep toxic substances out," she adds. "But over the last few decades, viruses may have mutated so they can get into the brain, such as Ebola, West Nile, and now, SARS-CoV-2."

Many symptoms of long COVID are neurological in nature, she adds. Besides sleep disturbances, they include dizziness, fatigue, and memory loss, among others. As a result, neurovirology, a new discipline of neuroscience, is emerging.

This is "an important [development], in view of the recent pandemic," Granholm-Bentley says. "We're finding more and more kinds of viruses in the brain as we start looking … We now know there are viruses that can actually accumulate in the brain and stay there. We have seen large amounts of SARS-CoV-2 in the brain in patients who had the infection a year or more ago, suggesting that the virus remains in the brain for a long time," she adds.

Whether or not you now struggle with sleep disturbances after COVID, understanding how the virus appears to affect the brain and the body is important, since reinfection—and its fallout—is always a possibility. The good news? A recent study from Harvard showed that people who were vaccinated had a 35% lower risk of developing long COVID than unvaccinated people. What's more, a lower risk for developing long COVID was seen in unvaccinated people who became infected with COVID-19 and then received a vaccination, post-infection.

The research on reinfection is crystal clear, too: Every additional bout with COVID ups your odds of developing long COVID. So, consider being boosted this fall. "You can also combat viral infections by staying very strong and by exercising, eating a healthy diet, and not being overweight. All of those things help" protect both your brain and your overall health, adds Granholm-Bentley. Not to mention, a good night's sleep.

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