Zapping the Brain and Nerves Could Treat Long COVID

New Year's Day marked a dispiriting milestone for one New Jersey woman: 20 months of symptoms of COVID-19. The woman, who asked for anonymity to protect her medical privacy, suffers from a variety of neurological problems that are associated with long COVID, including brain fog, memory problems, difficulty reading, and extreme fatigue. In her search for treatment, she came across neurologists at New York University (NYU) who were trying electrical neurostimulation for long COVID patients. She signed up for experimental treatments five days per week that send gentle electric currents through her skull and into her cortex.

It might sound weird, she says, but the reality is quite mundane. People ask me, You're putting electricity in your brain? Where do you go to do that?' And I say, I do it in my house, I just put on a headband and make a call.' "

The woman was part of a wave of people who started turning up at NYU's neurology clinic in the late spring of 2020, several months after the first wave of COVID-19 cases hit New York City. They were saying, I can't function, I can't return to work,' " remembers Leigh Charvet, a professor of neurology at NYU Grossman School of Medicine. To make matters worse, doctors had little to offer these patients.

Even as the world continues to grapple with new waves of acute illness, doctors are trying to understand and find treatments for long COVID, which can trouble patients for many months after their recovery from the initial infection. The syndrome, technically known as post-acute sequelae of SARS-CoV-2 infection (PASC), is associated with a long list of possible symptoms, including heart palpitations, breathing problems, and a wide variety of neurological issues. We need to do so much work to understand what long COVID is," Charvet says. But we also need to reach people now with something that we know is safe and deployable."

Researchers Step Up

Neurostimulation refers to electrical stimulation of the brain or peripheral nerves with either implanted or external devices; it's part of a growing field that's sometimes called bioelectronic medicine or electroceuticals. When the pandemic hit, researchers who had been working on neurostimulation for other maladies looked for ways to help the medical response. This was a chance for neuromodulation to step up," says Marom Bikson, codirector of neural engineering at the City College of New York and cofounder of the neurotech company Soterix Medical, which supplied stimulation gear to several research groups.

Some researchers began investigating whether neurostimulation could help with the acute phase of infection. In Brazil, Suellen Andrade of the Federal University of Paraiba recently concluded a study using transcranial direct current stimulation (tDCS) to help patients in the intensive care unit. While her team is still preparing a publication on the results, she says that patients who received the stimulation (instead of a sham treatment) required significantly less time on ventilators and were discharged sooner.

Others, including Charvet, took on long COVID. The U.S. Food and Drug Administration (FDA) was seeking remote and scalable treatment options for COVID-19 patients, and actively solicited proposals for neurostimulation trials that could be carried out by patients in their own homes. While the trials so far have been very small, the results have been promising enough to support larger studies to optimize the technology and to test the efficacy of these treatments.

Charvet has tried tDCS with a handful of people so far. A patient puts on an electrode-studded headband that's attached to a controller and calls the study coordinator, who provides a unique code to enable that day's stimulation. During the 20-minute stimulation session, the patient also does a therapeutic activity such as a cognitive game, and may also do some physical exercise after the session. Charvet says the research so far has been a testing ground-it's not scientific, it's not controlled." Patients have come to her for help with brain fog, fatigue, headaches, emotional dysregulation, and other problems, and she tweaks the treatment protocols based on each person's symptoms.

She's now planning a larger trial with NYU patients that's intended to optimize the technology for at-home treatments. The trial will debut a tDCS headband that also tracks heart-rate variability; she and her colleagues hope that this biomarker will serve as an indicator of the patient's response to treatment. They'll use a headset made by Soterix Medical that measures the impedance in the electrodes and translates that signal into heart-rate data. What drives us is that there's a tremendous unmet need," Charvet says. And our patients are getting better."

At the Medical University of South Carolina, psychiatry professor Mark George tried a different neurostimulation approach in a pilot study of 20 patients that he began in late 2020; his study used an at-home device that stimulated the vagus nerve through the ear. George's team assembled a real tough briefcase with a whole bunch of good stuff inside,' " he says, likening the equipment to Mission Impossible supplies. Each patient got an iPad for telemedicine consultations and for symptom surveys, the stimulation device, and a portable ICU" with wearables that measured heart rate, oxygen saturation, and blood pressure. George's patients did 1-hour sessions each morning and evening, six days per week, while seated and doing whatever they wished.

We showed you could do this kind of stimulation at home; the safety data was impeccable," George says. And we saw reductions in brain fog, improvements in energy, some improvement in anxiety." He's now applying for funding for a larger study.

One of his patients, a woman in her 60s who asked to be identified only by her first name, Pam, says she suffered from brain fog, memory lapses, fatigue, and mood swings following her case of COVID-19, which sent her to the emergency room in April 2020. When she started the stimulation, she felt a lessening of the uncharacteristic depression and anger that had troubled her, she says. When I started with the treatment, I felt a little brighter, more like myself," Pam says. I think I was a little better mentally." Another participant, a woman in her 50s who asked to be identified only as Beth, spent 23 days in the hospital during her initial battle with COVID-19, including more than a week in the intensive care unit. A few weeks after she started the stimulation, I noticed improvements in my headaches," Beth says, and also with the vertigo." Both women say their symptoms returned when the study ended, although not with the same intensity.

Disentangling Everything

One of the challenges that researchers face as they investigate the utility of neurostimulation for long COVID is the diversity of symptoms that patients report. George says his study deliberately took a shotgun approach," enrolling patients with a variety of neurological symptoms and looking at who responded best to the treatment. More work is needed to clarify which stimulation methods are most effective for which subsets of patients.

What's more, there are a host of confounding factors at play, notes Jennifer Frontera, a professor of neurology at NYU Grossman School of Medicine. It's a very heterogenous group of people describing very heterogenous symptoms," she says. NYU initially become a hub for research on long COVID because the hospital saw so many patients in the first wave of the pandemic and has tracked released patients over time. In September 2021, the National Institutes of Health put the institution in charge of a US $470 million grant to support large-scale studies of Long COVID. Frontera notes that a big part of that project, called the Researching COVID to Enhance Recovery (RECOVER) Initiative, will be disentangling everything.

We don't have a medication for brain fog."
-Jennifer Frontera, NYU

Frontera explains that some people dealing with long COVID may have experienced low levels of oxygen in their brains during their acute illness, while others may have immune systems that went into overdrive following COVID-19 infection. But others may be experiencing a worsening of underlying conditions such as mood disorders and dementia, and still others may be having symptoms that aren't actually related to their COVID-19 infections. Many people are sitting around their houses, they're not out walking around," she says. Some people are more in tune with their bodies and are noticing things they never noticed before." Even the weight gain that's been so common during the pandemic can confuse matters since it can lead to sleep apnea, which in turn can cause sleep problems, fatigue, and headaches.

To get a handle on the basics, Frontera and her colleagues conducted a study about health impacts of the pandemic, surveying 1,000 people whose demographics roughly matched those of the United States in terms of age, gender, and ethnicity. They didn't ask participants if they'd been infected with COVID-19 until the end. They found that pandemic-related stress factors such as financial and relationship problems were equally predictive of anxiety, depression, and insomnia as a history of COVID-19 infection. However, a history of infection was more predictive of cognitive issues.

Frontera doesn't see the study's result as undercutting the severity of the long COVID problem. She notes that the study found that 25 percent of people with a history of COVID-19 had symptoms that persisted beyond a month. If you translate that out to the population of the United States, that would be 6 million people," she says. She's most troubled by the cognitive problems she's seeing, she says: We don't have a medication for brain fog."

Frontera and her colleagues have also been following people who have been hospitalized because of COVID-19; they published a paper regarding the patient's status six months after infection and recently submitted a paper with data from one year after infection. Even after one year, she says, 80 percent of those people were still experiencing symptoms, and 50 percent scored as abnormal on a cognitive screening tool. That's a lot of cognitive disability," she says.

Searching for the Why"

If neurostimulation does help with the neurological symptoms of long COVID, it's not clear why. Stimulation with tDCS has been shown to increase plasticity" in the brain, or the ability of the brain to make new connections between neurons; neuroplasticity is associated with learning, changing thought patterns, and rehabilitation after injury. Vagus-nerve stimulation has been shown to reduce inflammation in the body, which is a component of autoimmune disorders; if some long haulers are suffering from an overactive immune system, vagus-nerve stimulation could help. George in South Carolina hopes to collect biomarkers associated with inflammation in his next study to examine that possible connection.

The researchers are hoping that larger studies will begin to shed light on the ways that neurostimulation impacts the neurology of people with long COVID. And if millions of people in the United States alone are in need of treatment, they may have an unprecedented opportunity for research.

Marom Bikson of Soterix Medical notes that both the research field and the industry of neurostimulation is just getting started. We don't have Pfizers of neuromodulation," he says, but you can only imagine what would happen if it shows an effect on long COVID." It could lead to millions of people having stimulators in their homes, he suggests, which could open other doors. Once you start stimulating for long COVID, you can start stimulating for other things like depression," he says. But he says it's crucial to proceed cautiously and not make unsupported claims for neurostimulation's powers. Otherwise," he says, it could have the opposite effect."