“Faces are like water in my head”: What happens when COVID-19 affects the brain?
Scientists are increasingly recognising that COVID-19 can have lasting and debilitating neurological symptoms, as well as causing structural changes to the brain.
- 2 June 2023
- 10 min read
- by Linda Geddes
The first sign that something might be wrong with Annie's brain happened when she walked past her family in a restaurant and didn't recognise them. It was only when her father called out to her that she did a double take. "It was as if my dad's voice came out of a stranger's face," she said.
This wasn't the only unusual symptom that Annie was experiencing. She felt disorientated, struggled to navigate between the bread and milk sections of her local grocery store and had to use the pin function on Google maps to remember where she had parked her car.
Annie caught the attention of brain specialists at Dartmouth College in Hanover, US, because this specific combination of symptoms usually arises in people who have experienced brain damage or were born with a developmental disorder. Yet, Annie had developed them approximately seven weeks after catching COVID-19.
Although COVID-19 was initially thought to be primarily a respiratory illness, as the pandemic has continued it has become increasingly clear that it can affect the brain and nervous system as well.
Although COVID-19 was initially thought to be primarily a respiratory illness, as the pandemic has continued it has become increasingly clear that it can affect the brain and nervous system as well, triggering ongoing fatigue, headaches and brain fog in a substantial proportion of patients. In a sign of how seriously such neurological symptoms are now being taken, the American Academy of Physical Medicine and Rehabilitation last month published consensus guidance on how patients exhibiting them should be assessed and treated.
The guidance emphasised the importance of identifying patients with progressive or ominous 'red flag' neurological symptoms, such as sudden or progressive weakness or sensory changes, which could indicate the development of a serious condition, such as a stroke or problem with the spinal cord, requiring immediate medical care. It also called for further research to understand how SARS-CoV-2 might be contributing to such problems, and to develop and test new treatments for those affected. Some of this work is already underway, beginning to provide new insights into how COVID-19 affects the brain, and what to do about it.
Some of the first indications that SARS-CoV-2 might have neurological consequences came from observations that many people who caught COVID-19 during earlier waves of the pandemic lost their sense of smell or taste. By October 2020, reports of strokes, hallucinations, behaviour changes and numb or tingling hands were also described in the medical literature, while growing numbers of individuals were complaining of ongoing and often debilitating fatigue.
Face blindness
Previously fit and healthy, Annie, 28, had been working as a customer service representative and part-time portrait artist when she caught COVID-19 in March 2020. At first, her symptoms had broadly matched the official list of symptoms recognised at the time: cough, fever, shortness of breath, loss of smell and taste, and diarrhoea. After three weeks, Annie felt well enough to start working from home, but a month later many of her original symptoms returned.
"That's when she noticed that there was something wrong with her face processing," says Marie-Luise Kieseler, a doctoral student at Dartmouth College who studies acquired prosopagnosia. This is a relatively rare condition in which people develop face blindness following some kind of damage to the brain – often to the right temporal lobe, which sits above and behind the right ear.
Kieseler first heard about Annie's symptoms while reading through conversations about COVID-19 on social media. Annie mentioned her problems recognising faces, so Kieseler contacted her and asked if she'd like to participate in a study.
"Usually, people with acquired prosopagnosia have experienced some sort of traumatic brain injury, a stroke, or herpes simplex encephalitis – a rare inflammatory disorder that happens when herpes simplex virus enters the brain," says Kieseler. It can also occur after brain surgery.
Arriving in the laboratory, Kieseler and her colleagues put Annie through a series of tests to evaluate the severity of symptoms, including testing her ability to identify familiar celebrities, and to learn and subsequently recognise unfamiliar faces – both of which Annie struggled with. However, she could identify the presence of a face in an image, and match identical faces, suggesting that her problems related to memory for faces, rather than faces per se. She could also recall images of landscapes that she had previously been shown.
These severe and highly selective problems, which appeared to have developed because of catching COVID-19, prompted Kieseler and her colleagues to investigate whether this phenomenon might be more widespread.
So, they analysed self-reported data from 54 people with COVID symptoms lasting for longer than 12 weeks, and 32 others who had fully recovered from the infection. Sure enough, those with ongoing symptoms reported a reduced ability to track characters while watching TV, to navigate their environments or find items in a cluttered scene, to remember phone numbers and to understand speech or reading.
"A lot of these could be associated with brain fog, but we think there might be other reasons than just brain fog," says Kieseler. "For instance, some people also complained that their colour vision had changed after COVID."
Since publishing these findings in the journal Cortex in late March, she has been contacted by many more people reporting face blindness or spatial awareness issues. "Some people are describing objects being all of a sudden much bigger or much smaller than they should be," Kieseler says.
While the physical cause of these deficits hasn't yet been investigated, brain damage is increasingly being implicated in other COVID-related neurological symptoms as well.
Overwhelming exhaustion
Fatigue is among the most common and debilitating problems reported by Long COVID patients, with one recent meta-analysis suggesting that the proportion of people still experiencing it 12 weeks or more after a COVID diagnosis is as high as 32%.
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Characterised by overwhelming feelings of weakness, exhaustion and decreased capacity for physical or mental work disproportionate to recent activity, fatigue is also associated with other post-viral conditions, as well as autoimmune diseases affecting the nervous system.
Prof Carsten Finke, a cognitive neuroscientist and neurologist at Charité Universitätsmedizin in Berlin, Germany, has previously studied fatigue in the context of multiple sclerosis (MS), a lifelong condition caused by the immune system mistakenly attacking the brain and nerves. Here, previous studies have found a strong association between the severity of fatigue that patients are experiencing and structural alterations in a part of the brain called the basal ganglia, which handles complex processes affecting the whole body, as well as brain networks involved in cognitive and attentional processes.
Wondering if something similar might be happening in Long COVID, Finke and his colleagues used magnetic resonance imaging to scan the brains of 47 patients experiencing moderate to severe post-COVID fatigue, plus 47 healthy people with no history of COVID infection or neurological or psychiatric disease. They also scanned 47 patients with MS-related fatigue and asked all participants to undergo various cognitive and neuropsychiatric tests.
Structural changes
Doing so identified structural changes in the basal ganglia and a brain region called the thalamus, which correlated with the severity of fatigue that the Long COVID patients were experiencing, as well as impairments in their daily activities, daytime sleepiness, and short-term memory problems. The study was published in eClinicalMedicine.
"The basal ganglia are typically thought to be relevant for the control of movement, but they also have other functions, including memory, motivation, and reward-guided behaviour – and one recent hypothesis is that an effort-reward imbalance is a key factor in the pathogenesis of fatigue," says Finke.
The thalamus, meanwhile, acts as a central relay station for incoming sensory and movement-related information to the brain. "Given its role as a hub-like gateway... it is conceivable that disease-related changes to thalamic structure or function could contribute to fatigue-related and cognitive symptoms," Finke says.
"One of the most important impacts of our study is that it may help convince people that fatigue is a real and devastating problem in COVID-19, if they don’t believe it already.”
– Prof Carsten Finke, cognitive neuroscientist and neurologist at Charité Universitätsmedizin
His isn't the only study to have identified structural or functional changes in the brains of people with ongoing COVID-19 symptoms. For instance, a UK Biobank study published last year identified brain atrophy, loss of grey matter, and cognitive decline in around 400 people whose brains had been scanned before and after catching COVID-19. No such changes were seen in individuals who hadn't been infected. Neurologists at The Hospital Clínico San Carlos in Madrid, Spain, also recently identified reduced grey matter in cortical, limbic and cerebellar areas of the brain in their Long COVID patients, as well as altered connectivity between different brain regions.
Mechanisms of injury
Even so, Finke stresses that more work is needed to prove that such brain changes underpin COVID-related fatigue and other cognitive problems, including face blindness. Also needed is further research to identify what is causing these changes in the first place.
There are several theories: One is that the virus damages the brain directly. Although autopsy studies of people who have died from COVID-19 have struggled to identify whole SARS-CoV-2 virus in their brains, some have found evidence of a marked accumulation of the viral spike protein in the skull, brain tissues and membranes lining the brain. Related experiments also revealed that injecting spike protein into the brains of mice killed or injured brain cells and triggered persistent inflammation.
A separate autopsy study found evidence of damage to cells that form the blood-brain barrier – a structure that keeps harmful substances out of the brain and allows necessary ones through – and signs that antibodies may have been involved in the attack, in people who had died after catching COVID-19. Possibly, antibodies produced in response to COVID-19 are mistakenly targeting these barrier cells, allowing proteins to leak into the brain in some patients. These proteins could potentially trigger bleeds or clots that starve nearby brain regions of oxygen.
"Once leakage occurs, immune cells such as macrophages may also come to try and repair the damage, setting up inflammation," says Prof Avindra Nath, clinical director at the National Institute of Neurological Disorders and Stroke in Bethesda, US, who led this research. "This, in turn, causes damage to neurons."
Alternatively, persistent low-grade inflammation elsewhere in the body – triggered by the immune system's initial response to the virus, or ongoing responses to loitering pockets of infection – could be putting immune cells in the brain on high alert, resulting in inflammation there as well. Over time, this could damage brain cells or alter their brain chemistry, affecting things like their mood, energy or sleep.
Serious issue
Growing recognition that COVID-19 can affect the brain doesn't immediately help patients like Annie, who still reports finding herself driving in the opposite direction to the one she had originally intended and remains reliant on people's voices to identify who they are. Faces, she says, "are like water in my head".
Yet, taking such symptoms seriously and investigating them could help point the way to new treatments. For instance, if antibodies triggered by SARS-CoV-2 are mistakenly attacking the blood brain barrier or other tissues, then immune-modulating therapies might help. Researchers are also investigating whether giving people antivirals could improve their symptoms by helping to clear residual virus and reduce inflammation.
For those living with Long COVID, the identification of effective treatments can't come fast enough. In the meantime, the discovery of physical brain changes may help those affected to get their symptoms taken seriously and access the medical and social support that many Long COVID patients have been campaigning for.
"Perhaps, one of the most important impacts of our study is that it may help convince people that fatigue is a real and devastating problem in COVID-19, if they don't believe it already," says Finke. "We have shown that there is a change in the brains of these patients, and although we don't know exactly what it means at this stage, this is not something that you can just neglect."
