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Over the past couple of years, we have learned that covid-19 can have profound consequences for the brain, both in the short and long term.

Now, researchers are beginning to get a clearer picture of how the coronavirus might be causing a range of symptoms that include brain fog, depression, confusion and even stroke. These latest insights suggest that the virus seldom infects brain cells directly, but instead harms the brain indirectly by causing blood clots or spurring a harmful immune response.

The encouraging news is that some of the latest research indicates that many of these harmful changes in the brain are likely to be reversible.

Early on in the pandemic, it became clear that severe cases of covid-19 could lead to stroke, confusion and muscle weakness. It is estimated that, in the early stages of infection, . Longer term, though, the neurological and mental health toll may be even higher: an analysis of medical records for more than 230,000 people who recovered from covid-19 found that roughly .

In a with longer-term covid-19 symptoms, 47 per cent reported persistent brain fog, difficulty concentrating or forgetfulness.

Does the virus infect brain cells?

It isn鈥檛 uncommon to have effects on the brain after a viral infection 鈥� it has been seen with viruses including Zika, polio, measles and flu. But rates of lingering effects such as mental health conditions or anxiety appear to be higher after covid-19 than after infections such as flu, for instance.

Some neuroscientists hypothesised that the virus itself might be causing such symptoms by attacking cells in the brain, something that other viruses, such as HIV and the virus that causes herpes, are able to do. But the emerging picture suggests that, while the virus can get into the brain, it doesn鈥檛 seem to replicate there or damage brain tissue directly, says at Yale University.

Spudich points to several autopsy studies of people who died after a coronavirus infection. They found traces of the virus or viral proteins in the brain, but if the virus were actually replicating there, we would expect to see clusters of contaminated cells, and these were not found.

Infected cells are also typically surrounded by immune cells. These hallmarks haven鈥檛 been found in the brains of people with covid-19, says Spudich, who, along with Avindra Nath of the US National Institute of Neurological Disorders and Stroke, has summarised some of the latest findings.

While the virus has been found in the cerebrospinal fluid that bathes the brain and spinal cord, it is rare. 鈥淎cross hundreds and hundreds of published studies鈥� looking for virus in the spinal fluid in acute cases, it鈥檚 been detected in less than 3 per cent of the studies,鈥� says Spudich. 鈥淭hat was a surprise.鈥�

Immune response and abnormal clotting

Two other factors appear to play an important role in the effects seen in the brain. One is the impact of the virus on blood vessels. Multiple studies have found abnormal clotting in people with severe cases of covid-19, which is what can cause strokes. 鈥� vessel walls become thinner, and the vessels themselves appear to leak proteins that might trigger an immune response.

This second factor, the immune response, has come to the fore as potentially the most significant culprit when it comes to the neurological and mental health symptoms of covid-19, including those that persist for months after infection in long covid.

When researchers look at cerebrospinal fluid samples taken from people with covid-19, they find changes in immune cells. Some appear to be producing more chemicals, which might be toxic to some brain cells, for example. And , the immune cells of the central nervous system, across the brain.

It isn鈥檛 yet clear if something similar is happening in the brains of people who had mild infections, who can still develop long covid. 鈥淧eople who were convalescing at home鈥� had a mild form of covid-19, recovered, but then afterwards noticed that they were having trouble with concentration, memory, ability to function at work, severe mood disorders like anxiety and depression,鈥� says Spudich.

Spudich herself has treated such cases. 鈥淭hey developed delusions, paranoia, violent behaviour, really terrible symptoms, out of the blue,鈥� she says. One individual didn鈥檛 respond to antipsychotic treatment, so Spudich鈥檚 team offered him a therapy designed to dampen down his immune system, with some success. When the team studied his cerebrospinal fluid in more detail, they found antibodies that appeared to attack brain tissue.

Of course, that is only one case, and long covid symptoms can look very different across individuals. It is also difficult to know for certain which symptoms are triggered by covid-19 and which could be coincidental after infection, but gathering evidence suggests lingering changes to the immune response are more common after covid-19 than after other illnesses such as flu.

Similarities with 鈥渃hemo brain鈥�

The next step is to figure out the mechanisms of these immune responses. at Stanford University in California and her colleagues have made some headway. As a neuro-oncologist, Monje saw parallels between the brain fog symptoms of long covid and 鈥渃hemo brain鈥�, the thinking and memory problems that can result following chemotherapy for cancer.

Previous research has shown that the symptoms that follow cancer treatment seem to be caused by the body鈥檚 immune response to the drugs, which leads to the release of chemicals that cause inflammation and damage brain cells. The microglia enter a more inflammatory state, particularly in the brain鈥檚 white matter, and change the way other brain cells behave. As a result, less protective myelin is laid down on neurons, and other brain cells are destroyed. Fewer new neurons are generated, too.

To find out whether something similar might be happening in people with long covid, Monje and her colleagues studied mice that can be infected with the coronavirus, but only in their airways 鈥� the virus can鈥檛 directly infect brain cells in these animals because they lack the key ACE2 receptor.

The infected mice had mild symptoms, as far as the researchers could tell, says Monje. But her team found chemicals in the animals鈥� blood and cerebrospinal fluid that suggest they are experiencing something very similar to mouse models of chemo brain. Their brains also showed the same change in microglia cells, and a reduction in the generation of new brain cells. 鈥淲e found really stark parallels,鈥� says Monje.

In that work, which has not yet undergone peer review, who had died from or with covid-19. Some of the deaths were attributable to the disease, but not all 鈥� one person had fallen down a staircase, for example. Microglia seemed to be behaving in the same way in the white matter of all of nine brains, says Monje.

The group noticed that a specific immune substance called CCL11 was found in samples from the mice. This chemical has been linked with cognition problems in people in the past, and . In another experiment, Monje and her colleagues found that CCL11 levels were higher in blood samples from people with long covid who had cognitive symptoms than they were in people with long covid who didn鈥檛 have those symptoms.

Long-term effects?

Altogether, the findings strengthen the hypothesis that immune responses may be responsible for some of the effects of covid-19 on the brain. And while severe impacts like stroke can cause lasting damage, 鈥渘othing that we showed in this paper should be irreversible鈥�, says Monje. She thinks that treatments could be developed that take the brain back to a healthy state. 鈥淚t鈥檚 a message of hope,鈥� she says.

Not all effects on the brain and mind will be caused by immunological factors or blood clots, however. Depression and anxiety are the most common mental health diagnoses that follow cases of covid-19, and many are likely to have been influenced by the experience of having the infection and disease, says at the University of Oxford.

Significant questions remain, including how long neurological and psychiatric symptoms can last. Taquet and his colleagues conducted the study that found that about one-third of people were diagnosed with a mental health or neurological condition within six months of having covid-19. 鈥淎t six months there were no signs that the rates of new diagnoses were plateauing,鈥� says Taquet. He plans to conduct further research to explore diagnoses 12 to 18 months after an initial infection.

Concerns over lingering symptoms have led some neuroscientists to suggest that the brain changes seen in some cases of covid-19 might put some people at a greater risk of developing neurodegenerative conditions such as Alzheimer鈥檚 later in life, but it is difficult to assess that risk given we still don鈥檛 understand the underlying cause of Alzheimer鈥檚 itself.

鈥淲e don鈥檛 have any evidence that covid is going to cause some long-term neurologic problems,鈥� says Spudich.

Vaccination and breakthrough infections

Currently, there is conflicting evidence as to whether vaccination can protect against some of the effects of long covid on the brain. Recent research by Paul Kuodi at the Azrieli Faculty of Medicine at Bar-Ilan University in Safed, Israel, and colleagues suggests that people who experience breakthrough coronavirus infections after two doses of a vaccine are like headache and fatigue than people who didn鈥檛 get infected.

But when Taquet and his colleagues looked at more than 10,000 breakthrough infections, most of which were in people in the US, they found that while vaccinations reduced the incidence of serious respiratory disease, .

Another hugely important question is whether children who experience mild infections might later develop cognitive symptoms. Our brains undergo significant development and remodelling in the first years of life, and this continues to some degree until our late twenties. 鈥淚n younger brains鈥� I worry about the influence on ongoing development,鈥� says Monje. Researchers don鈥檛 yet know if young brains have the same immune response to the virus as adult brains. 鈥淚t may or may not be the same in kids, but I worry about it,鈥� she says.

鈥淚 think we should be very careful with our children, because we just don鈥檛 know,鈥� says Spudich.

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