While the Covid-19 pandemic put many human research studies on hold, neuroscientist Grainne McAlonan of Kings College London saw it as a fortuitous opportunity — a chance to accelerate her search for early signs of neurodevelopmental disorders in fetuses and newborns.
McAlonan knew that if a mother is infected by a virus during pregnancy, her child has a slightly greater chance of developing such disorders, including autism, although the overall risk is very low. The novel coronavirus gave her a way to study how viral infection and the immune response affect the developing brain, and why a small number of infants are susceptible to neurological changes while the vast majority are not. By imaging the brains of babies who were exposed to Covid-19 while in utero, McAlonan plans to compare their development patterns and perhaps find similarities and additional risk factors among the infants who later develop mental disorders.
“It’s a strange study to do because you wish you weren’t in a situation where it’s important to do it,” McAlonan said. “But it’s a natural experiment we should be looking at.”
The immune system is intricately entwined with brain development, particularly before birth, but researchers have never been able to determine exactly how. Now, by studying Covid-19 patients, psychiatrists hope to gain new insights about how disorders like schizophrenia and autism arise, as well as why people with these conditions tend to suffer worse effects from viral infection.
The ability to trace infection to a particular virus and particular time may be just what the neurodevelopment field needs to finally understand why fetuses’ brains can be vulnerable to the fluctuations of their mothers’ immune systems. With some viruses, like rubella, 20% of people whose mothers were infected develop schizophrenia as adults. With Covid-19, though, scientists stress that the vast majority of infants who were exposed to the virus in utero will not have any problems.
Links between infection and mental disorders were first identified hundreds of years ago, with 19th-century European medical journals writing about people “driven to the brink of madness” following a bout of influenza. After the 1918 flu epidemic, researchers documented numerous “psychoses of influenza,” accompanied by an increase in the number of people committed to mental institutions.
Covid-19 may act similarly. A number of case reports have shown a small number of Covid-19 patients developing symptoms such as paranoia and hallucinations after recovering from the disease, despite never having had a mental illness before. Brad Pearce, an epidemiologist at Emory University, said that a key question is how long these symptoms last and whether they can be distinguished from other conditions like delirium that may result from long hospitalization and infection.
But the hypothesis makes sense, Pearce said. Coronaviruses are known to be able to enter the brain, and postmortem analyses of people who died of Covid-19 have found the SARS-CoV-2 coronavirus in their brains. It’s also possible that the psychosis is caused by the inflammatory response to Covid-19. A ramped-up immune system may continually attack the brain and account for the lingering “brain fog” seen in many patients. “The mechanisms we don’t know yet,” Pearce said. “There’s a lot to be done, and we’re going to know more in the next year or two.”
The links between mental illness and infection seem to go the other way as well. People with schizophrenia are significantly more likely to die from viral infections – their risk of death from pneumonia, for instance, is seven times that of the general population. And Covid-19 appears to be no exception: Several recent studies have found that schizophrenia greatly increases the risk of dying from the infection.
Some of the risk may be due to confounding factors. People with schizophrenia are less likely to have housing and medical care, as well as more likely to have diabetes or obesity. But even when controlling for these issues, a study published in January found that schizophrenia increases the risk of death from Covid-19 threefold, making it one of the greatest risk factors following age.
Psychiatrist and paper author Katlyn Nemani of NYU Langone Medical Center said her team is now looking at the immune systems of people with schizophrenia who have recovered from Covid-19. They hope to find patterns among the inflammatory molecules in the patients’ blood, or antibodies that attack the brain, which may give clues to how the brain and immune system are connected.
If the researchers can find specific immune targets, they may be able to find ways to dampen the inflammatory response when people with schizophrenia are exposed to a virus. “It may not be that unique to Covid,” Nemani said. “It’s just the first time we can see the effects of a single virus affecting so many people at a single point in history where we can control for all other risk factors.”
The evidence linking viral infection to mental illness is so strong that scientists use it to make mouse models of human disorders like schizophrenia and autism. In one widely used system known as the maternal immune activation model, researchers ramp up the immune systems of pregnant mice by injecting them with chemicals that mimic viruses. This gives the animals’ offspring characteristics such as anxiety and repetitive behavior, which are similar to human symptoms. Researchers then use these mice to study the characteristics of neurodevelopmental disorders or test potential treatments.
But these mice do not actually have schizophrenia or autism, which are distinctively human conditions. “We really need to be looking at risk mechanisms in humans,” McAlonan said. “Unfortunately, Covid gives us a chance to do that.” Understanding these mechanisms in humans could even help researchers create better mouse models.
Researchers have a number of questions about how infection leads to mental illness, said Robert Yolken, a pediatric neurovirologist at Johns Hopkins University. For instance, no one knows at which stage of development fetuses are most vulnerable to the effects of maternal infection. It’s also unclear whether the developmental disorders are caused by the mother’s inflammation, the fetus’s own immune system, or the virus itself. The placenta can stop most viruses from infecting the fetus. But some, like cytomegalovirus and rubella, are known to cross and cause severe neurodevelopmental problems. It’s unclear yet whether SARS-CoV-2 can do this, although antibodies against the virus do appear to cross into the fetus.
These are the types of questions that McAlonan and others hope to answer by studying the offspring of women who contracted Covid-19 during pregnancy. Her group plans to follow infants for two years after birth, scanning their brains periodically and testing their learning abilities to see whether they can find commonalities between those who go on to develop autism.
While McAlonan and others said most infants exposed to Covid-19 in utero will be unaffected, in the minority who are predisposed to neurodevelopmental disorders due to genetics or other environmental factors, infection may tip the brain into disease.
Others suspect that rather than harming fetuses, prenatal Covid infection could make most babies more resilient to future viruses. “As more of our population live through and survive coronavirus, that just builds up our armor,” said Moriah Thomason, a child psychiatrist at NYU Langone.
Still, the stress of lockdowns and general anxiety about Covid could be harmful to fetuses’ developing brains, Thomason said. While acute stress tends to dampen the immune system, chronic stress drives it up in ways that can ultimately be detrimental, and inflammation in the mother might affect her fetus. Thomason’s group is studying how the stress of the pandemic affects fetuses, by surveying close to 1,000 mothers and studying their stress hormones and immune profiles. They are also scanning the infants’ brains and planning to track them for years to see whether problems develop.
“If we can really understand the biology and why this exposure is impacting the brain, we might be able to design some prevention strategies like anti-inflammatories,” said Lisa Croen, an epidemiologist with the Kaiser Permanente health care network.
Working with immunologist Judy Van de Water of the University of California, Davis, Croen is trying to tease apart the differences between stress and viral infection by mining Kaiser Permanente’s database for the medical records of 45,000 women in Northern California who were pregnant during the pandemic. About half of these women filled out surveys about their stress levels, Covid-19 symptoms, and general health, which the researchers can use to determine similarities and differences between those who had Covid and those who were simply stressed.
The team is collecting blood spots taken from the heels of 550 newborns from this cohort and studying the cells, antibodies, and other components of their immune systems to form a profile of how they responded to Covid-19 infection. They also hope to find immune markers common to those infants with impaired neurodevelopment.
“It’s an incredible opportunity to look at this in real time, so we have to move very quickly,” Van de Water said. “We’ve got this moment in time to address this.”