Damage to the brainstem – the brain’s ‘control centre’ – is behind the long-lasting physical and psychiatric effects of a severe Covid-19 infection, a study suggests.
Using ultra-high-resolution scanners that can see the living brain in great detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.
The research team scanned the brains of 30 people who were hospitalized with severe Covid-19 early in the pandemic, before vaccines were available. The researchers found that a Covid-19 infection damages the area of the brainstem associated with shortness of breath, fatigue and anxiety.
The powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brainwill help scientists and doctors understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the research started before the long-term effects of Covid were recognised, it will help better understand this condition.
The brainstem, which connects the brain to the spinal cord, is the control center for many basic life functions and reflexes. Clusters of nerve cells in the brain stem, known as nuclei, are responsible for regulating and processing essential body functions such as breathing, heart rate, pain and blood pressure.
Things that happen in and around the brainstem are vital to quality of life, but it has been impossible to scan the inflammation of the brainstem nuclei in living people because of their small size and difficult position. Normally, scientists only get a good view of the brain stem during post-mortem examinations.”
Dr. Catarina Rua, Department of Clinical Neuroscience, University of Cambridge
“The brainstem is the crucial connection box between our conscious self and what happens in our bodies,” says Professor James Rowe, also from the Department of Clinical Neurosciences, who co-led the study. “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.”
In the early days of the Covid-19 pandemic, before effective vaccines were available, post-mortem studies of patients who had died from severe Covid-19 infections showed changes in their brain stems, including inflammation. Many of these changes were thought to be the result of an immune response after the infection, rather than a direct virus invasion of the brain.
“People who were very ill 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,” says Rowe. “Normal hospital-type MRI scanners cannot look into the brain with the kind of chemical and physical detail we need.”
“But with 7T scanners we can now measure these details. The active immune cells interfere with the ultra-high magnetic field, so we can detect how they behave,” says Rua. “Cambridge was special because we were able to scan even the sickest and most contagious patients early in the pandemic.”
Many of the patients hospitalized early in the pandemic reported fatigue, shortness of breath and chest pain as troubling, long-lasting symptoms. The researchers hypothesized that these symptoms were partly due to damage to important brainstem nuclei, damage that persists long after the Covid-19 infection has passed.
The researchers saw that multiple regions of the brainstem, specifically the medulla oblongata, pons and midbrain, showed abnormalities consistent with a neuroinflammatory response. The abnormalities appeared several weeks after hospital admission and in areas of the brain responsible for controlling breathing.
“The fact that we see abnormalities in the parts of the brain related to breathing strongly suggests that long-term symptoms are a result of inflammation in the brain stem after a Covid-19 infection,” Rua said. “These effects transcend the effects of age and gender, and are more pronounced in those who have had severe Covid-19.”
In addition to the physical effects of Covid-19, the 7T scanners provided evidence for some of the psychiatric effects of the disease. The brain stem registers shortness of breath, but also fatigue and anxiety. “Mental health is closely linked to brain health, and patients with the most pronounced immune response also showed higher levels of depression and anxiety,” Rowe said. “Changes in the brain stem caused by Covid-19 infection can also lead to poor mental health outcomes, due to the close link between physical and mental health.”
The researchers say the results could help understand other conditions linked to brainstem inflammation, such as MS and dementia. The 7T scanners can also be used to monitor the effectiveness of various treatments for brain diseases.
“This was an incredible collaboration, right at the height of the pandemic, when testing was very difficult, and I was amazed at how well the 7T scanners worked,” said Rua. “I was very impressed with how, in the heat of the moment, collaboration between many different researchers was achieved so effectively.”
The research was supported in part by the NIHR Cambridge Biomedical Research Centre, the NIHR Oxford Biomedical Research Center and the University of Oxford COVID Medical Sciences Division Rapid Response Fund.