Updates on long Covid and the brain

Current research estimates that 1 in 10 Covid cases result in long Covid, a constellation of often debilitating symptoms that develop four to twelve weeks following initial infection. 

According to figures released by the Office of National Statistics, the condition now affects the daily lives and functioning of millions of people in the UK. And, with SARS-CoV-2 (the virus which causes Covid) still widely circulating, the risk of developing long Covid is ongoing, and increases with each infection.

As a widely stigmatised condition, often assumed by clinicians and the general public to be psychological, it's important for us as psychologists to understand and share new developments, digest what they mean for those with long Covid, and integrate these understandings into our field. In that spirit, let's take a look at some recent brain-related long Covid findings. 

What is long Covid?

Long Covid is a multisystemic post-acute infection syndrome. Its symptoms can manifest in many organs and bodily systems, and often follow a relapsing and remitting pattern. Common symptoms include fatigue, post-exertional malaise (PEM), orthostatic intolerance, brain fog, and more; however, not everyone with long Covid will have the same symptoms, and several subtypes with potentially different mechanisms (several of which appear to have neural involvement) seem to exist. 

Symptoms often leave those with the condition unable or severely limited in their ability to carry out daily activities. At their most severe, they can significantly limit tolerance for sensory input (see Figure 6 here), leaving those at the severe end of the spectrum with no option but to lay in silent, dark rooms, with no social or physical interaction until symptoms allow. Though many recover, given time and rest, in many cases such respite does not materialise. The psychological impact of such symptoms is self-evident.

Biomedical researchers have identified issues within several bodily systems which appear to contribute to long Covid's symptoms: overexpression of WASF3 in mitochondria, which limits energy production; amyloid build-up and microclots in skeletal muscles, affecting oxygenation of tissues; and hormone-mediated sex differences (pre-print) in symptom presentation and immune profiles, to name just a few of the more prominent recent findings. 

Recently, several findings relating to the brain have joined this growing list, offering insight into symptoms of cognitive and neural dysfunction often seen in the condition. 

A leaky blood-brain barrier

On February 22nd, Nature Neuroscience published a paper by Chris Greene and colleagues at Trinity College Dublin identifying that the blood-brain barrier (BBB) is dysfunctional in those with long Covid brain fog. 

The BBB is a semi-permeable membrane that allows water, gases, and nutrients to pass into the brain from the blood while acting as a barrier to toxins. Using dynamic contrast-enhanced MRI brain scans, the team were able to see that in patients experiencing brain fog, the BBB was particularly permeable, with evidence of disruption up to one year after initial Covid infection. Multiple brain regions were affected, including the temporal lobes and frontal cortex. 

Blood analyses also uncovered irregularities in blood coagulation and dampened immune responses in this population, further details of which can be found in this accessibly written article. Taken as a whole, the results of this study suggested that ongoing inflammation and a dysfunctional BBB are key factors associated with long Covid brain fog.

Further studies will be needed to see how these factors affect patients over time, but the authors do note that their findings may point towards a potential therapeutic approach. In their words, "targeted regulation of BBB integrity could now potentially be considered for the treatment of patients with brain fog associated with long Covid."

Ongoing injury

Late last year, a study by Professor Benedict Michael of the University of Liverpool and colleagues found signs of ongoing brain injury in long Covid patients with neurological symptoms. 

The team looked for blood-based biomarkers of brain injury in their the participants, all of whom had previously been hospitalised due to Covid. In those with ongoing neurological symptoms beyond 6 weeks after initial infection, levels of NfL and GFAP were notably high, indicating ongoing injury.

The authors postulate that these markers of neuroglial injury may be related to a dysregulated immune response elsewhere in the body, though the exact chain of events leading to this has yet to be fully defined. 

Cognitive deficits were seen in all patients, both in acute and post-acute phases of illness, and it is as of yet unclear if this decline is permanent. For an accessible write-up on this research, be sure to check out this article by Sara Novak.

Cognition and memory deficits

Research by Hampshire et al., published February 29th in the New England Journal of Medicine, presented a rounded look at cognition and memory in those with long Covid. 

This study utilised eight online cognitive tasks from the Cognitron platform, probing previous participants' of the REACT study's capabilities in various memory tasks, mental rotation, verbal reasoning and more, two years after their initial contributions.

The resulting data, collected from around 130,000 England-based participants, indicated a decline in executive functioning and memory equivalent to roughly 6 IQ points in those who had developed long Covid symptoms since their initial REACT participation. For those admitted to intensive care for their Covid infection, the authors state that the drop was equivalent to around 9 IQ points.

Analyses also identified a downwards shift in cognitive abilities in those who recovered fully after their initial Covid infection. The authors state that the drop observed in recovered participants was equivalent to approximately 3 IQ points.

The largest deficits were seen in domains of memory, reasoning, and executive function, however these symptoms correlated only weakly with reports of recent symptoms, including poor memory and brain fog. Those who had been hospitalised, as well as those infected earlier in the pandemic, showed larger deficits than those who were infected when later SARS-CoV-2 variants were dominant. You can find an accessible write-up of this study and further input from the authors in this piece from Hannah Devlin. 

The latest chapter for post-acute infection syndromes

Long Covid appears to share many physical traits with myalgic encephalomyelitis (MECFS, hereafter ME, also known as 'Chronic Fatigue Syndrome'); for example, similar patterns of dysautonomia (dysfunction in the autonomic nervous system) are seen in both conditions. Some researchers suspect that both these, and potentially other post-acute infection syndromes, may share common physical mechanisms.

Like those with ME and other post-acute infection syndromes before them, people with long Covid often face significant barriers to accessing healthcare. Stigma and disbelief related to these conditions, as well as the complexity of their presentation, has been shown (in the following preprint) to leave patients with considerable self-doubt, "question[ing] their deservedness of seeking healthcare support for their symptoms." 

This same study found that these factors also led UK-based would-be patients to avoid treatment, for fear of overburdening the healthcare system. Added to the toll of this sudden, often new-onset disability, it becomes easy to imagine the mental health struggles that may arise for many.

Post-acute infection syndromes have historically been a "significant blind spot" for medical research. However, with the pressing issue of long Covid upon us, the medical community is now turning its attention to finding mechanisms, treatments, and (perhaps one day) a cure.

Specialist readers interested in learning more about what is now known about the physical alterations in long Covid and ME may find the recent NIH MECFS Roadmap webinars helpful.