Researchers at Columbia University in New York recently analyzed small pieces of the brains, hearts, and lungs of 10 people — six men and four women — who died with COVID-19.
The scientists reported what they found in a paper published earlier this month in the peer-reviewed journal Alzheimer’s & Dementia.
Lead author Andrew Marks calls his team’s findings “quite unexpected.”
Researchers found problems with a critical cellular component
One of the abnormalities they found was a problem with a key piece of cellular infrastructure that ordinarily keeps muscle cells and neurons running smoothly. These ryanodine receptors help individual cells make sure proteins and positively charged calcium ions are in the right place at the right time. Problems with these channels are associated with a range of serious ailments, from heart disease to Alzheimer’s.
“Not only did we find defective ryanodine receptors in the hearts and lungs of deceased COVID patients,” Marks says, “We also found them in their brains.”
For neuroscientist James Giordano, a professor and physician at Georgetown University, the finding is important because it shows how — or at least where — many of the different consequences that cascade from a Covid infection re-converge to affect the function of the brain.
He told IE that it’s “difficult” to say why ryanodine receptors in neurons appear to be an important factor underlying at least some of the neurological symptoms of COVID-19 and long COVID, including brain fog.
“Signaling mechanisms in the brain are exceedingly complicated and very nuanced,” he says. “A disruption of those signaling mechanisms can occur through a variety of different pathways.”
Brain cells, which are constantly communicating with each other and the rest of the body, require such a high degree of precision to produce and transmit the signals they intend to that disruption — no matter where it comes from — can have serious consequences for the overall functioning of the brain.
“The beauty of the nervous system is [its] ability to fine-tune signal in a very hyperactive noisy environment,” he says. “If you do something to disturb that… what ends up happening is you get the equivalent of neurological static.”
Direct brain infection is probably part of the problem
People with COVID-19 generally don’t have a large number of copies of the virus that causes it, the SARS-CoV-2 virus, in their brains. Early in the pandemic, it wasn’t clear if now-familiar neurological symptoms like brain fog, headache, and loss of taste and smell were the direct result of an infection in the brain itself or an indirect consequence of infection elsewhere in the body.
While it’s still too early to be entirely sure, two years of studying the brains of COVID-19 patients have led researchers to believe “that it's not a question of either/or, but it's potentially both/and,” Giordano says.
Millions of years of evolution have placed a lot of obstacles between the brain and the outside world. Most of the sensory systems that provide the brain with information about the outside world send their data through a series of relays, keeping the brain protected from pathogens or damage.
The olfactory system is an exception. Nerves that tell our brains what something smells like project directly into an evolutionarily ancient part of the brain deeply tied to emotion, called the limbic system. It’s why a familiar smell from long ago can be so moving.
It’s also a vulnerability because it opens a path for the SARS-CoV-2 virus to sneak into the brain. Once inside, the virus can infect neurons, causing the ryanodine receptors that control the flow of calcium ions within the neuron to start “leaking” calcium indiscriminately.
“Excessive calcium within the nerve can [ultimately] can cause membrane instability,” Giordano says. Those unstable membranes can then start letting in calcium from outside the cell.
The neurons, which don’t know the calcium isn’t supposed to be there, can grow so excited that they stop clearing away debris as it accumulates. That extra debris can impair the neural networks that enable “things like cognition, emotion, sleep regulation, and behavior,” he says.
COVID-19 is a whole-body disease
The brain isn’t just protected from the outside world — it also has a number of defenses against dangers that come from inside the body itself. The easiest way for the pathogens or toxins to get into the brain from elsewhere in the body is through the bloodstream, which is constantly delivering oxygen and other important materials to the organ.
The blood vessels that deliver fresh blood to the brain have special cells, called pericytes, embedded in the walls of capillaries. These cells have various functions, one of which is to use various clues to let some molecules in and keep others out.
This gateway function is an important constituent of what experts call the blood-brain barrier. It’s effective, but it’s not perfect.
A COVID-19 infection in the throat or lungs can produce various types of molecules that cause inflammation. It seems that they also manage to somehow compromise pericytes, effectively opening up some of the portals that control the blood-brain barrier to molecules that are not supposed to be gain entry.
“This may allow increased penetration of inflammatory proteins to enter the brain space itself,” Giordano says. Those molecules can trigger inflammation in certain brain cells, which in turn release their own inflammatory proteins. This process can lead to further inflammation and even more disruption to the all-important flow of calcium ions.
“Those ions also work as signaling molecules within the cell. And therefore what inflammation can do is to change signaling processes within the cell,” Giordano says.
The effects aren’t necessarily short-lived. Inflammation in the brain can trigger even more problems and ultimately lead to “changes in the manufacture of certain nerve cell proteins that can then interfere with nerve cell function, which induces more long term effects” like structural damage to the cell membranes, Giordano says.
Researchers still have more questions than answers
What seems clear is that COVID-19 affects the brain in many different ways. Other lines of research suggest the virus may cause chemical changes in the cerebrospinal fluid that surrounds the brain. Evidence also seems to suggest that it’s not just neurons that are being damaged. Studies have found damage in glial cells, which are also in the brain.
The brain is an incredible organ, but to do its job right, it has to tune into the right signals from "the level of the individual synapse all the way to [the level of] social interactions," Giordano says. Ultimately, it doesn't matter what the source of interruption is, what matters is that the brain isn't working as precisely as it needs.
"COVID fog brain is sort of like neurological static, on an expanded scale," he says.
The leaky ryanodine receptors are just one piece of the puzzle of COVID-19's neurological symptoms — but there's reason to think might be a corner piece.