This post will be difficult to write. Not only because it takes a deeper dive into a topic that I did not have to think about for some time. But also because I recently fell ill with Covid and had symptoms of brain fog myself.
Under normal circumstances I can do focused work for an extended period of time - 4 hours can pass without me feeling like my focus is fading. When I was still testing positive a few weeks ago, I noticed that my attention was drifting fast.
This was in the last week of Advent of Code. I wasn’t able to finish the last days because I could not keep my focus long enough to figure out the necessary data structures and algorithms to use. I got better for some time, but now I feel fatigued very easily.
Seeing this large discrepancy between what I’m normally able to do and what I currently can, I wondered how the virus facilitates this change in brain function.
Finding a good source
When trying to look into a specific scientific topic, finding good and reliable sources is key. I started by googling but soon realized that the press releases and popular science articles will not give me the kind of information I was looking for.
So I did what every person with a background in medicine would do: I opened PubMed and looked there. To my surprise a lot, if not all, articles that covered the topic of long covid or covid related brain fog was open access. If you have some experience with scientific papers, you know how refreshing it is to not have to pay 40 bucks to read a paper.
The papers I found and will summarize here, are the following (no, I won’t conform to the typical quoting standards, this is a blog, not a paper):
- Chen Y et al. COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction. J Neuroinflammation. 2022
- Monje M et al. The neurobiology of long COVID. Neuron. 2022
- Hosp JA et al. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain. 2021
Another source that I can not mention directly is mostly my own degree as a medical doctor and tapping into knowledge that is not yet lost.
Points of entry
The virus has to find a way to get into brain, which is not an easy task that not many pathogens achieve. If you catch the common cold, you will for sure feel a lot of symptoms, but a reduction of your cognitive function is typically not one of them.
The brain is the most important organ in our body (according to the brain) and has to be secured from pathogens more thoroughly than others. Enter: the blood-brain-barrier (or BBB) which is made up of endothelial cells (the cells of the innermost layer of our blood vessels) and glial cells (“helper” cells in our brain cells in our brain).
There are of course more cells involved (pericytes, astrocytes, some neurons), but for the sake of this post, let’s keep it at that. The individual cells are sealed by tight junction proteins and junctional adhesion molecules to limit diffusion between inside and outside.
This barrier is pretty tough to get through. Fats for example have a hard time passing the BBB which is why the brain relies almost exclusively on glucose for its energy.
Not many pathogens (bacteria or viruses) can pass the BBB, and if they do, they pretty often interact with components of the barrier. So does SARS-CoV-2: it binds to the ACE2-receptor, mostly found in the lungs and heart, but also in other cells, with the spike protein which then allows the virus to unload its RNA to healthy cells. These healthy cells now replicate the RNA and virus that can now be found inside the brain (in this case meaning brain, glial cells, cerebrospinal fluid, everything on the inside of the BBB).
There are more possible points of entry:
- The olfactory nerve and its olfactory sensory neurons/axons can also be infected directly by some pathogens. This could also explain the anosmia (lack of smell) in a large percentage of Covid patients.
- The vagus nerve which connects part of the brain to vital organs like the heart or the lungs (among others) has been shown to be a possible entrance point in mice.
- Some branches of the trigeminal nerve can also be directly infected by pathogens.
What do these three different options have in common? They are cranial nerves that come directly from the brain and not the spinal cord as all other nerves. (If you’re a nerd like me and want to know the numbers: there are 12 cranial nerves, olfactory nerve being N. I, vagus being N. X and trigeminal nerve being N. V)
Having a direct connection to the brain it makes sense that the virus could spread to the brain more easily from these nerves.
Mechanism
The most logical explanation would be that Covid causes some kind of inflammation in the brain. But the inflammation could theoretically also come from the outside with cytokines passing through a damaged BBB (it could be damaged by hypoxia or local coagulopathy). These cytokines, a result of the respiratory infection, could trigger an immune response in the brain by dedicated immune cells of the brain (which would then be called neuroinflammation).
Cognitive functions rely on homeostatic states to regulate neuronal activity, glial health and normal connectivity. But as can be seen with other neurotropic viruses that trigger inflammation in the brain (like Herpes or TBEV), disrupting this homeostatic state can have detrimental effects on brain functions.
The most important disruption would be in the of “cleaning up” dead cells along with demyelination. Myelin is the insulator around our nerves (not all, but most of them) to ensure faster signal transmission among other things.
Brain imaging using MRI has also shown structural abnormalities in the limbic system (which would explain memory issues) and also a small global decrease of brain volume. But this is not uncommon and does not necessarily lead to permanent damage.
Another possible mechanism could be hypoxia or vasculopathy/coagulopathy. If the brain does not get the correct amount of blood for its oxygen and nutrient supply, of course its function will be impaired. Speaking of nutrients, apparently Covid also might change the metabolism of glucose in the brain as shown in specific type of PET scans.
Conclusion
What does this all mean? Well, it’s safe to say that SARS-CoV-2 is a pretty nasty virus that targets a lot of different structures throughout the body and can wreak havoc in various ways on the brain. But most mechanisms that could explain the disruption of brain functionality require a more severe disease course. Thankfully something I did not experience.
Does it make me feel better to know why my brain is currently not working the way it normally does? Not really, but it was fascinating to read some new literature on this topic, which was not available at the time of me still practicing medicine. I can’t wait for the brain fog to clear. But writing this was easier than expected - a pleasant surprise!