At the height of the COVID-19 tsunami that engulfed New York City in early 2020, a highly respected emergency room doctor, Lorna Breen, died by suicide. She had been serving as medical director at Manhattan’s NewYork Presbyterian Allen Hospital, and she was regarded as brilliant, energetic, and organized. She had no history of mental illness. But that changed after Breen contracted the virus.
The 49-year-old doctor first showed symptoms on March 18. After a 10-day illness, she returned to work. Her family was alarmed: She was confused, hesitant, nearly catatonic, exhausted. Something was wrong. They brought her home to Charlottesville, and Breen checked into a psychiatric ward at University of Virginia Medical Center. Soon after she was released on April 26, she took her own life.
“She had COVID, and I believe that it altered her brain,” her sister Jennifer Feist said on NBC’s Today show.
At the time, doctors were just learning that this new coronavirus doesn’t target only the lungs and heart. It also impacts other organs, including the brain. “People arrived at the hospital with severe depression, hallucinations, or paranoia—and then we diagnosed them with COVID,” says Maura Boldrini, a neuroscientist and psychiatrist at Manhattan’s Columbia University Irving Medical Center.
Now, almost two years into the pandemic, it’s become clear that neurological problems from COVID-19 can linger or intensify. After recovering from the virus, an alarming numberof patients remain shrouded in brain fog, suffering from anxiety or depression, unable to think straight or hold on to memories, and fumbling for words. Not all had been hospitalized; some had only mild infections.
Today these neurological problems are an established element of a larger syndrome known as long COVID that includes at least 203 symptoms in 10 organ systems.
Boldrini notes that some long COVID symptoms mirror those caused by various chronic brain- and personality-altering conditions, including other viral infections, traumatic brain injuries, and neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s. These conditions can radically change how people experience, interpret, and understand the world; destabilize emotions; and influence how people think about themselves or interact with others.
While little is known about the mechanisms behind many of these symptoms, researchers increasingly believe that inflammation may play a key role. With COVID-19, a storm of inflammatory cytokine proteins can trigger an out-of-control immune response that might permanently damage or destroy brain cells.
And with damage to the brain, Boldrini says, “we may not be the same person anymore.”
Personality, behavior, and the brain
Human personality is the set of deeply ingrained characteristics and habits that influence how people think, feel, and behave. It’s created by a complex interaction of nature and nurture: Inherited traits encoded in our DNA are influenced by our social environment and modified during early developmental experiences.
“The brain is obviously so important in defining who we are. It’s our ego; it’s everything about our identity,” says Ann McKee, who studies repetitive head trauma as a neurologist, neuropathologist, and head of Boston University’s Chronic Traumatic Encephalopathy (CTE) Center. “It’s a highly specialized organ, with each part doing fantastically specific things.”
While basic personality tends to remain constant throughout adult life, conditions that disrupt brain function can induce extreme shifts in personality—and evidence is mounting that this happens for some people who contract COVID-19.
Some patients have developed impulsive or irrational behavior, like Ivan Agerton. The 50-year-old former Marine and documentary photographer experienced psychosis in early 2021 after he recovered from a COVID-19 infection. He grew paranoid, terrified that people were following him and convinced that a SWAT officer was encamped outside his Seattle home. He was ultimately hospitalized in a psychiatric ward, twice.
For some patients, this so-called COVID psychosis resolves with time. By June, Agerton said he’d fully recovered. But no one knows how long such COVID-induced symptoms might persist. A study of 395 people who were hospitalized with COVID-19 found that 91 percent had cognitive issues, fatigue, depression, anxiety, sleep problems, or struggled with routine activities six months after they returned home.
Healthcare workers and researchers are on the hunt for ways to treat these long-lasting symptoms, and that starts with figuring out why they happen in the first place.
Recognizing changes in the brain
In 1906 psychiatrist and neuroanatomist Alois Alzheimer detailed the results of a brain autopsy on a 55-year-old woman named Auguste D. In the years before her death, she’d progressively lost her connection to reality, becoming an aggressive insomniac beset by increasing paranoia and suspicions about her family. She’d also suffered profound loss of memory.
Upon examination, Alzheimer observed that her brain had shrunk dramatically. It was riddled with sticky clumps of plaque, abnormal deposits that nearly 80 years later would become the hallmark of Alzheimer’s disease. These jumbles of beta-amyloid protein had accumulated between neurons in the brain. We now know that they block electrical signals from reaching other parts of the brain, muscles, and organs. Alzheimer also found tangles of another protein, tau, that also disrupted communication between neurons.
As neurons stop functioning and die, the brain shrinks and a person’s behavior becomes more erratic. With fewer neurons in the brain’s learning and memory regions, these functions begin to suffer, Boldrini says. People with Alzheimer’s disease forget where they put things and become disoriented. They become easily upset, confused, angered, belligerent, or lash out at loved ones or caregivers, whom they may not recognize.
Damage to the cerebral cortex then impacts language, reasoning, and social behavior; it ultimately spreads and destroys much of the brain. The dementia becomes debilitating, and the disease eventually proves fatal, says Antonio Terracciano, a professor in the department of geriatrics at Florida State University.
Alois Alzheimer’s discovery was a milestone in neurological research, linking changes in behavior to changes in the brain. Since Alzheimer’s seminal observations, researchers have recognized that many diseases can spark shifts in personality or mood disorders.
Huntington’s, an inherited disease that breaks down neurons in a brain region called the basal ganglia, can cause people to lose their inhibitions or become more impulsive. It’s part of the reason why suicide rates among people with Huntington’s are up to 10 times the national average.
In Parkinson’s disease, which is likely caused by a combination of genetics and environmental factors, neurons that produce the neurotransmitter dopamine break down or die. Without enough dopamine, the disease’s hallmark tremors appear, and movements become slow.
Parkinson’s also lowers levels of a neurotransmitter called serotonin, which regulates mood, appetite, and sleep. These changes in brain chemistry can cause neurological symptoms that frequently manifest years before the tremors begin, says Jeff Bronstein, who directs the Movement Disorders Program at the David Geffen School of Medicine at University of California, Los Angeles.
Patients may grow anxious, struggle to concentrate or shift between tasks. About half of patients grow depressed, Bronstein says. He has also seen patients slump into apathy, pulling into themselves. As their speech suffers or they grow forgetful, they avoid conversations with family and friends, becoming more withdrawn as depression deepens.
Uncharacteristic irritability or mood swings can also signal Lyme disease. This bacterial infection from a tick bite causes inflammation that can set off swelling of the brain or its lining, inducing short-term memory loss, difficulty focusing, and symptoms such as anxiety and depression.
Many viruses are already known to wreak havoc in the brain. Boldrini recounted what happened in the early days of the HIV epidemic, before antiviral medications were available that blocked replication of the pathogen and reduced viral load.
“We used to see people who had HIV-AIDS with paranoia, hallucinations, but also cognitive symptoms, memory problems, concentration problems,” Boldrini says. As the viral infection spread through the brain, the membranes of the brain and spinal column swelled, and this AIDS dementia complex worsened.
Many of the changes in behavior seen in COVID long-haulers also mirror those from traumatic brain injuries incurred in a car crash, a concussion from a contact sport like football or rugby, or from wartime military service. Damage to the frontal lobes, which sit behind the forehead, can impair executive functioning: organizing, planning, and multitasking. Memory and self-awareness may slip, and patients may not be aware of what they’ve lost.
Some head injury survivors lose emotional control, says Boston University’s McKee, including young, previously easy-going people. She’s seen cognitive changes in athletes as young as 17 who play contact sports, and playing football before the age of 12 increases the odds.
The COVID connection
One common theme among these conditions is a sustained inflammatory process. It’s been implicated in head injuries and in neurological diseases such as Alzheimer’s, where it causes additional loss of brain cells and exacerbates the formation of plaques.
When the immune system launches an attack against a virus or another invader, waves of inflammatory cells circulate through the bloodstream like foot soldiers. With COVID-19 and other conditions, those immune cells may permeate the normally protective blood-brain barrier. If inflammation gets out of hand, the process may kill neurons, Bronstein says.
Kriegstein notes that “most of the neurological manifestations of SARS-CoV-2 infection appear to be the result of indirect effects likely mediated through inflammation or immune responses.”
Inflammation also seems to interfere with brain metabolism. Researchers suspect that the process interrupts the flow of serotonin and prompts the body to instead produce a cascade of substances that are toxic to neurons.
Boldrini was among the first to examine the brains of humans and research animals who’d died of COVID-19 to see what was happening on a cellular level. Under a microscope, Boldrini and her team examined brain samples stained with brightly colored dyes to characterize different types of cells. They observed changes to the hippocampus, a brain region that is embedded deep in the temporal lobe and plays a major role in learning and memory. She and her team counted about a tenth as many new neurons as are normally present in the hippocampus.
“The brain fog made a lot of sense to me when I saw that there is loss of these neurons from COVID,” Boldrini says. The team also found damage to the medulla, which controls respiration and movement. Boldrini notes that they will continue to examine other brain regions for possible damage.
Other researchers using brain imaging data from the U.K. recently discovered evidence of tissue damage, a thinner cortex, and loss of gray matter in people who had tested positive for the virus. The authors noted that there was “significantly greater cognitive decline” in patients who had been hospitalized.
In addition to causing inflammation, the virus may be able to directly infect brain cells. “We discovered evidence that certain cells within the brain are capable of being infected with SARS-CoV-2, where the virus can replicate and infect other cell types,” says Joseph G. Gleeson, a neurologist at the University of California, San Diego.
Other researchers have found that key support cells in the brain called astrocytes were the main cell types vulnerable to infection, says Madeline Andrews, a postdoctoral neuroscience scholar at the University of California, San Francisco. These star-shaped cells, abundant in the brain and spinal cord, regulate how neurons communicate, ensure that the barrier between the brain and the rest of the body is intact, and more.
“Infected astrocytes may function differently and might not be able to maintain their typical roles in healthy brain homeostasis,” says Andrews.
The virus that causes COVID-19 may also reduce blood flow to neurons by constricting capillaries—tiny blood vessels—or by interfering with their function. This may explain why the virus induces strokes: by starving the brain of oxygen. “The brain is very delicate, and alterations to blood flow or cellular health can lead to permanent changes to brain function,” Gleeson says.
Many questions remain, though, including how to prevent the virus from causing significant cognitive damage. The key, Boldrini says, is to not let the immune system fight too long or too aggressively.
Various treatments are being used to prevent the immune system from overreacting. Remdesivir, an intravenous antiviral treatmentis approved for hospitalized patients; two new oral antivirals, Merck’s molnupiravir andPfizer’s Paxlovid, have been shown to reduce hospitalizations and death in patients at risk of serious illness. These drugs prevent the virus from reproducing, which may prevent an overactive immune response.
Other drugs are used specifically to modulate the response: corticosteroids, Interleukin-6 inhibitors, and Janus kinase inhibitors.
Understanding how COVID-19 affects the brain may have far broader implications. Boldrini has preserved a few dozen brains from patients who died of the virus. By comparing tissues from patients who had experienced neurological symptoms with those who hadn’t, she hopes to shed light on the role of inflammation in a wide swath of neurodegenerative diseases.
“As devastating as this disease is,” she says, “maybe it will help us better understand how the brain works.”