Understanding neurological complications of COVID-19

Although SARS-CoV-2, the virus that causes COVID-19, was initially identified as a respiratory virus, its effects on the nervous system have been profound. There were reports in the initial phases of the pandemic that the virus was contributing to large, severe strokes in individuals, including younger people typically at lower risk for such events. From the earliest stages of the pandemic, NINDS has been working diligently to support research to better understand the impact of the virus on the nervous system. For example, findings from NINDS intramural researchers and their collaborators showed the virus was causing severe inflammation around brain blood vessels, which could lead to strokes and other neurological complications. People who were hospitalized with severe illness experienced post-ICU syndrome, which has been known to result in long-term problems in cognitive and emotional function. Now, to help us gain a more complete understanding of the effects of the virus on the nervous system, NINDS recently issued two new funding announcements (RFA-NS-23-021 and RFA-NS-23-022) that will complement existing research opportunities to collectively provide a better understanding of the complications of COVID-19.

Early in the pandemic, it became clear that some people with a mild course of COVID-19, and even some who did not have any obvious symptoms, experienced changes in cognitive ability, known as “brain fog.” These changes included a sense of slower and more effortful thinking, trouble concentrating, and problems with memory, processing speed, and attention. Based on data from the online Household Pulse Survey, CDC’s National Center for Health Statistics estimated that as of March 2023, 13.5-15.7% of adults who had COVID-19 currently have “Long COVID” symptoms, defined as symptoms lasting three or more months after first contracting the virus. Neurological symptoms are among the larger array of symptoms associated with post-acute sequelae of SARS-CoV-2 (PASC) infection, which includes Long COVID.

Long COVID affects different people in different ways-- studies have reported up to 200 symptoms associated with Long COVID, and individuals with the condition experience clusters of symptoms. Some people develop gastrointestinal problems while others suffer with shortness of breath and chronic cough. Fatigue and “brain fog” are the most commonly reported symptoms. In some people, these changes were so severe that they were not able to function at their pre-infection level in their jobs or at school. Many people are still dealing with these symptoms years after being infected with SARS-CoV-2. In addition, we need to be vigilant for effects of COVID-19 infection on the risk for neurological disorders down the road, including Alzheimer’s disease and related dementias, stroke, and others.

During the pandemic, researchers and clinicians have learned a tremendous amount about SARS-CoV-2, identified ways to treat COVID-19, and developed safe and effective vaccines in record time. We have also learned much about the virus’ impact on the nervous system, but we still don’t know the exact mechanisms underlying neurological symptoms following COVID-19, who is at risk, or how to prevent and treat these symptoms.

To help us answer these questions, new NINDS funding opportunities will invite mechanistic research applications that will go beyond the correlational and behavioral studies that NINDS has supported, complementing existing research to gain a better understanding of the complications of COVID-19, including in the neurological and psychiatric domains. These funding announcements invite research applications focused on a wide range of nervous system impacts of COVID-19, including neurological and neuropsychiatric changes during acute COVID-19, neurological symptoms after infection, and the effect of the virus on pre-existing neurological disorders.

Research supported through these new funding opportunities will complement NINDS support for ongoing projects looking at various aspects of neurological complications associated with SARS-CoV-2 that are ongoing at universities and at the NIH Clinical Center.  In January 2021, NINDS announced the launch of the COVID-19 Neuro Databank/Biobank (NeuroCOVID), maintained by NYU Langone Health. The database was established to collect de-identified clinical information and biosamples from people across the country who experienced neurological symptoms after COVID-19. As of December 2022, the project includes information from more than 1600 patients and 26 active sites. The program has expanded to international sites as well, including sites in Europe, Asia, South America, and Africa.

Several studies are applying advanced neuroimaging to evaluate neurovascular dysfunction including alterations in the blood brain barrier in humans and animal models. Other studies are investigating the implications of SARS-COV-2 infection on neurological conditions including pain, cognitive function, headache, sleep disturbances, persistent fatigue, post-exertional malaise, autonomic dysfunction, neuropathy, and loss of sense of smell. NINDS also supports research in immunology and metabolomics to identify possible common biosignatures for PASC and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Finally, NINDS is also supporting a study to better understand health disparities across different populations experiencing cognitive impairment associated with COVID-19.

Given that neurological symptoms are common in Long COVID, NINDS is a leading partner, along with the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID), for the Researching COVID to Enhance Recovery (RECOVER) Initiative, NIH’s large, patient-centered research initiative to understand, prevent, and treat Long COVID. RECOVER includes observational cohort studies, analyses of electronic health records, pathobiology studies, and clinical trials, which will be launching soon. RECOVER’s work has also uncovered that Black and Hispanic Americans appear to experience more symptoms and health problems related to Long COVID than white people, but are not as likely to be diagnosed with the condition. It is my hope that RECOVER, along with our other research efforts on Long COVID, will provide important insights not just for long-term effects of COVID-19, but other post-infectious conditions including ME/CFS as well as dysautonomia, a group of medical conditions caused by problems with the autonomic nervous system, including postural orthostatic tachycardia syndrome.

SARS-CoV-2 has exacted a devastating toll around the world. We continue to grieve millions of lives lost during the pandemic and work to rebuild families, relationships, and a society that has been forever changed. At NINDS, we continue our focus on supporting research to provide much needed answers and relief for those who are still struggling with neurological symptoms resulting from COVID-19.