We might think of Covid-19 as a respiratory disease – but infection poses implications for virtually every aspect of our physiology. Science reporter Jamie Morton looks at what scientists are learning about coronavirus and the brain.
Stacey King can't leave her Wellington home without a wheelchair.
Nor can she drive.
Or climb a flight of stairs without struggling to put one foot in front of the other.
"I suffer from brain-fog, fatigue, constant physical pain and ongoing neurological issues that impact on my fingers and legs, from the knee down," she said.
"I use so much energy to simply get around I need to ensure that I pace myself, otherwise, I'm physically exhausted by the afternoon and I can't do anything else."
Officially, King has functional neurological disorder – a complex and costly condition that affects the nervous system and how the brain and body sends and receives signals.
Unofficially, she's another victim of long Covid.
She finds it puzzling that her diagnosis still hasn't been linked – besides a vague reference in her hospital discharge summary - to coronavirus, despite the onset of conditions happening to coincide with a severe bout of Covid-19 in February.
"Because my local hospital doesn't have a neurological department, they exhausted all the testing they had available," she said.
"What I was left with though, is a diagnosis that, because it has a psychological onset of stress in almost every instance, means I am quite literally instructed to stay positive, not worry about what has happened to me, and that 'one day' I'll be completely back to normal."
After being put on a four-month wait list, she decided to seek out a private neurologist – adding another big bill on top of what this year has already cost her.
"But there's no other options available to me," she said.
"I have nowhere I can go – the local hospital has said there's nothing more that they can do for me."
University of Auckland cellular immunologist Dr Anna Brooks, who's leading a crowd-funded long Covid study, was concerned doctors arrived at a psychological diagnosis for King when her symptoms still couldn't be fully explained.
"We need better tests. We know that this virus can harm our nervous system."
King's is an all-too-familiar story for the many people whose lives have fundamentally changed since they caught a virus that scientists are only beginning to understand.
What exactly causes long Covid – a constellation of lingering symptoms estimated to come with at least 10 per cent of Covid-19 infections – remains unknown.
There's no diagnostic test or treatment for it and support for sufferers here and abroad is woefully lacking.
For a health system already struggling with a tsunami of Omicron cases, long Covid meant a "subsequent flood of Noah-like proportions", said Otago University lecturer Dr Rob Griffiths, the convenor of an online symposium being held this week.
"The addition of long Covid to New Zealand's existing chronic disease burden is likely to be significant, and we don't yet know how large the problem will be. There are so many unknowns."
As with King, "brain fog" is one of the most commonly reported symptoms among Covid-19 long-haulers.
"A number of people have reported getting Parkinson-like symptoms, along with long-term fatigue, or a loss of sense of smell and taste," University of Auckland neuroscientist Professor Maurice Curtis said.
"All of this gets nicknamed Covid brain, and it can be a bit like the end of a cold or flu, where you just don't feel as sharp as you were before.
"In the case of long Covid, however, we can live with it for weeks or months."
Brooks felt that, in the context of Covid-19 especially, brain fog was an innocuous, catch-all term that hid the very real problems behind it.
"What we're talking about is neurological impairment or cognitive dysfunction."
Her work aims to pinpoint the causative role of long Covid: likely a combination of direct effects from infection, and indirect ones from the defensive immune response our body mounts against the virus.
"While we don't specifically know what are causing these symptoms, one possibility is unresolved inflammation – or essentially inflammatory molecules contributing to symptoms."
Because long Covid was an immensely complex illness driven by dysfunctions spanning our immune, nervous and circulatory systems, untangling Covid-19's specific impact on the brains wasn't straightforward.
Besides MRI scans and post-mortem brain tissue examinations, scientists had few ways of gaining direct, physical insights.
"It's an intriguing area – but we do know, certainly, that the brain is impacted," Brooks said.
"It depends on how loosely we're talking about impacts on the brain. Does that include the nervous system? Because we clearly know the nervous system is disrupted by the virus."
A particularly common example was dysautonomia – or a disruption of "autopilot" functions of our nervous system functions like heart rate, breathing and digestion.
"At the same time, we're hearing of people who've been infected and have an inability to collect their thoughts," Brooks said.
"They might not necessarily think they've got long Covid, but in the same breath, they might be realising they're struggling a bit. Right now, we don't know how widespread this is going to be."
She drew striking comparisons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) – another chronic, complex, neuroimmune disease often triggered by infection.
And just like long Covid, there was no diagnostic test, treatment or cure – despite affecting millions of people worldwide, and an estimated 20,000 to 40,000 people here in New Zealand.
"The world is really only just waking up to how we've neglected the aftermath that viral infection can have on our bodies."
Shrinking brains, vanishing smell
In March, Oxford University scientists revealed some of the strongest evidence yet that Covid-19 infections may cause lasting harm to our brains.
After comparing MRI scans of hundreds of people who'd had mostly mild infections with a control group who hadn't caught the virus, they found what they called "significant, deleterious" long-term effects.
These included signs of tissue damage in regions linked to the primary olfactory cortex, which is used for processing and perception of smell, along with linking smells to certain memories – but also reductions in grey matter thickness in the orbitofrontal cortex and parahippocampal gyrus.
The former was a part of the brain involved in cognitive function, mood and decision-making, while the latter played an important role in memory retrieval and spatial awareness – all of which might partly explain post-infection symptoms like brain fog, depression and anxiety.
But their most dramatic finding was that, on average, the brains of the infected had actually shrunk.
Because of the study's relatively small sample size, the researchers cautioned that more work was needed to establish whether their findings did indeed apply to all infections.
Dr Indranil Basak, an Otago University biochemist also investigating Covid-19, pointed out that study was carried out on people who'd had an earlier strain of the virus.
"We also do not know what are implications of vaccination on reducing the impact of the virus on the brain."
What was known, was more than half of Covid-19 patients typically experienced neurological symptoms.
As for whether the virus could actually infect the brain itself, Basak said there still weren't any clear answers.
While there had been reported instances of the virus being detected in the clear, colourless cerebrospinal fluid within the tissue surrounding the brain – and also studies suggesting the virus could infect brain cells that expressed certain receptors – the level of infection tended to be variable between cell types.
The big question, he said, was whether the virus was able to cross the blood-brain barrier – a crucial buffer that protects against pathogens and mediates communication between the periphery and the central nervous system.
One way around the barrier was through our nose: and researchers have already suggested the virus might be able to sneak through this back door to trigger a damaging immune response in the brain.
"With new insights on the involvement of olfactory invasion of Sars-CoV-2, it is possible that the brain cells do get directly infected," Basak said.
"The other explanation behind the neurological symptoms could be the immune response that the body raises against the virus after the infection, and the immune response, in turn, causes changes in the brain environment that affects the health and function of the brain cells."
Curtis similarly pointed to the "significant effects" on the brain that could come with inflammatory processes.
"Essentially, you don't need to have the virus in the brain to be causing damage, when circulating inflammatory molecules can cause that dysfunction."
While it wasn't clear the virus worsened existing neurological conditions, Basak said it was possible viral infection might predispose the brain to future problems.
He added the Oxford study, comprised mostly of Caucasians, similarly didn't shed light on how ethnicity might come into play.
"Race can be a risk factor for certain diseases, even neurological diseases, therefore we still need to learn how 'race' would impact the long-term effect of the virus on our brain."
As scientists continued to hunt for answers to these complex questions, their message to the public remained starkly simple: don't catch the virus in the first place.
"I have heard people saying, 'enough is enough, let's get the disease, and let's get over it'," Basak said.
"We do not know the extent of the long-term effects of the virus, especially on people with underlying conditions."
For those who couldn't avoid it – an estimated half of us haven't - he urged people to take things slow and not rush through their work and daily activities.
"Once the symptoms are gone, it is advised to keep yourself active, keep your brain active by exercising, solving puzzles, and keep doing practical everyday things that reduce the risk of cognitive decline."
For King and other long-haulers, the plea was at least to be listened to.
"We grieve for the lives we used to have; for the ability to meet up with friends and family, to run around with our children, to not be in constant physical pain," King said.
"We fear for our future and we wish this didn't happen to us."