Brainstem Abnormalities Linked to Long COVID Symptoms

A recent study reveals long-term microstructural abnormalities in the brainstem of people with ongoing health problems following a COVID-19 infection, suggesting neuroinflammation in the brainstem may contribute to persistent symptoms seen in long-COVID. Identified using ultra-high field 7T MRI imaging, the findings, published in Brain, could lead to future treatments for the condition, according to the researchers

Tying long COVID symptoms to the brain

Long COVID is a condition where individuals experience lingering symptoms for weeks or months after the acute phase of a COVID-19 infection has resolved. Symptoms can vary widely, including fatigue, shortness of breath, brain fog and chest pain, among others. Long COVID can affect multiple organ systems and may occur even in those who had mild or asymptomatic COVID-19 cases. Around 10-20% of those infected with COVID-19 may be at risk of developing the condition. The exact cause is still under research, but it’s believed to involve immune, inflammatory and possibly neurological responses triggered by the virus.

Previous studies have identified neurological changes in patients with severe SARS-CoV-2 infections, with autopsy findings revealing brainstem involvement in COVID-19 cases. This research suggests that damage to the brainstem could contribute to the symptoms observed in Long COVID.

“The brainstem is the critical junction box between our conscious selves and what is happening in our bodies,” said corresponding author Dr. James Rowe, a professor and director of Cambridge Centre for Frontotemporal Dementia and Related Disorders.

The brainstem connects the brain to the spinal cord. It is responsible for controlling many basic life functions, including breathing and heart rate, as well as coordinating movements and reflexes. It also plays a critical role in regulating sleep and consciousness, making it essential for overall brain function and survival.

“People who were very sick early in the pandemic showed long-lasting brain changes, likely caused by an immune response to the virus. But measuring that immune response is difficult in living people. Normal hospital type MRI scanners can’t see inside the brain with the kind of chemical and physical detail we need,” said Rowe.

Brainstem abnormalities were observed post-admission

Ultra-high field (7T) quantitative susceptibility mapping (QSM) was used on 30 patients 93-548 days after hospital admission for COVID-19. The patients were compared with 51 age-matched controls without a prior history of COVID-19 infection. The participants’ QSM signals were correlated with data collected on their disease severity, inflammatory response during acute infection, functional recovery as well as their depression and anxiety scores.

Multiple regions in the brainstem – including the medulla oblongata, pons and midbrain – showed abnormalities consistent with a neuroinflammatory response in the COVID-19 survivors. These changes tended to appear several weeks post-hospital admission.

“The fact that we see abnormalities in the parts of the brain associated with breathing strongly suggests that long-lasting symptoms are an effect of inflammation in the brainstem following COVID-19 infection. These effects are over and above the effects of age and gender, and are more pronounced in those who had had severe COVID-19,” said first author Dr. Catarina Rua, a research associate in the department of clinical neuroscience at the University of Cambridge.

“Mental health is intimately connected to brain health, and patients with the most marked immune response also showed higher levels of depression and anxiety. Changes in the brainstem caused by COVID-19 infection could also lead to poor mental health outcomes, because of the tight connection between physical and mental health,” said Rowe.

Understanding the physical effects of long-COVID

 “The ability to see and understand how the brainstem changes in response to COVID-19 will help explain and treat the long-term effects more effectively,” said Rowe.

“Things happening in and around the brainstem are vital for quality of life, but it had been impossible to scan the inflammation of the brainstem nuclei in living people, because of their tiny size and difficult position. Usually, scientists only get a good look at the brainstem during post-mortem examinations,” said Rua.

Rua and the team hope their findings will enhance the understanding of other conditions linked to brainstem inflammation, such as multiple sclerosis and dementia. The 7T scanners could also serve as a valuable tool for monitoring the effectiveness of various treatments for brain disorders.

Reference: Rua C, Raman B, Rodgers CT, et al. 7-Tesla quantitative susceptibility mapping in COVID-19: brainstem effects and outcome associations. Brain. 2024. doi: 10.1093/brain/awae215

This article is a rework of a press release issued by the University of Cambridge. Material has been edited for length and content.