New research uncovers possible brain mechanisms behind COVID-19 delirium

Researchers at King’s College London have shown that when brain cells are directly exposed to blood taken from delirious patients with COVID-19, there is an increase in cell death and a decrease in the generation of new brain cells. Delirium is a state of confusion that indicates that the brain has been affected by the COVID-19 infection in these patients.

An in vitro study provides insight into possible cellular and molecular mechanisms participates in the development of c delirium in patients with COVID-19, as well as the overall impact of COVID-19 infection on the brain.

Published in Molecular psychiatrythe results of the study indicate the key role of inflammatory proteins (cytokines) that are produced immune system during infection, and may help inform possible treatments to reduce symptoms of confusion, disorientation, and memory deficits in patients with COVID-19.

Dr Alessandra Barsini, NIHR Maudsley BRC Senior Research Fellow, Institute of Psychiatry, Psychology and Neuroscience, first author, said: “More and more research is showing that there is a neurological element to severe COVID-19 infection, but we have little understanding of what occurs in the brain to cause these symptoms. Our study is the first to use blood samples from delirious COVID-19 patients to investigate how the infection affects a process called “neurogenesis” (the generation of new brain cells), which is necessary to maintain intact brain functions, including memory and thought processes.

“We found that there is a significant reduction in the generation of new brain cells and an increase cell deathand these are likely mechanisms of delirium and possibly other neurological symptoms in patients with COVID-19.”

Preliminary studies suggest that 20 to 30% of patients with COVID-19 will develop neurological symptoms such as delirium, with rates of 60 to 70% in severe cases. Delirium is a state of mental confusion that can occur when one is not feeling well and is associated with adverse outcomes, including prolonged hospitalization and death.

Although the respiratory symptoms of COVID-19 are well known, the cellular and molecular mechanisms that explain the delirium and other neurological symptoms are poorly understood. This is the first study to test the direct effect of blood (using serum) taken from hospitalized delirious COVID-19 patients on the generation of new brain cells in the hippocampus region of the brain.

The development of neurological symptoms in patients with COVID-19 is likely due to an overactive immune response called cytokines storm, with the overproduction of these many inflammatory proteins. After being produced by immune cells in the body in response to infection, these cytokines can then travel from the blood to the brain and directly affect brain mechanisms. However, it is currently unknown which cytokines are directly related to the development of neurological symptoms.

The study collected serum samples from 36 patients admitted to Guy’s and St Thomas’ NHS Foundation Trust in London during the first wave of the UK’s COVID-19 pandemic (March-June 2020). Half of these patients were experiencing symptoms of delirium, while the other half had no symptoms at the time of admission.

The researchers used a proven in vitro human cell model consisting of cells from the hippocampus, a part of the brain fundamental to many cognitive functions, memory and learning skills. The researchers treated cells from the hippocampus directly with serum samples and observed the effects on cell generation and death, as well as on the levels of various cytokines.

The results showed that treatment with serum taken from delirious COVID-19 patients increased cell death and reduced the generation of new brain cells. A serum study showed that those patients with delirium had higher levels of the cytokine IL6, while there was no difference between patients taking other cytokines. Treatment of brain cells with the serum did produce higher levels of two other cytokines—IL12 and IL13—suggesting that there is a process or cascade in which IL12 and I1L3 are generated by brain cells in response to inflammation in the body created by IL6, and together they cause delirium.

Author Professor Carmine Pariante, Professor of Biological Psychiatry at the Institute of Psychiatry, Psychology and Neuroscience (IoPPN) and Consultant Perinatal Psychiatrist at South London and Maudsley NHS Foundation Trust, said: “The role of inflammation and our immune response in COVID-19 infection is well known, but research like ours is now revealing how it affects our brains, thinking and mental health.

“Through a series of tests, we have shown that the initial production of cytokine proteins as part of the inflammatory response in a COVID-19 infection triggers a cascade of other cytokines that reduce the generation of new brain cells and increase cell death, leading to cerebral symptoms such as delirium. These neurological symptoms are of great concern to patients and their families, and we hope that our study can help determine which treatments will be most appropriate to reduce or prevent these symptoms.”