Does Covid-19 Infect the Brain?

At the time of this writing, over 200 million people throughout the world are thought to have been infected by the SARS-CoV-2 virus (2019 coronavirus). This is proposed to have directly contributed to over four million deaths. Like other coronaviruses, SARS-CoV-2 was quickly identified as preferentially affecting the lungs and causing respiratory issues. But widespread reports of Covid-19-associated symptoms have included foggy thinking, worse mental health, headaches, and even strokes — prompting many to question how the virus is affecting our brains. But while it’s tempting to assume that SARS-CoV-2 is infecting our brains and directly causing these symptoms, the data to date present a more nuanced picture.

Background

Prior to Covid-19, there was a strong existing precedent connecting immunological diseases and brain function. Microbes ranging from HIV to Zika virus have been described for their effects on cognition. Rabies and toxoplasmosis have been linked to changes in human behavior and psychiatric state. Autoimmune diseases including lupus are linked to a range of cognitive changes. More specifically, two recent coronavirus outbreaks including SARS in 2003 and MERS (Middle East respiratory syndrome) in 2012 were correlated with high rates of depression, anxiety, impaired memory, confusion, and trouble concentrating, in addition to changes on brain imaging and pathology reports.

Of course, few immune challenges in the past several hundred years can rival the massive scope of Covid-19. Even if a tiny fraction of patients experienced brain effects from infection, the total number of afflicted could number in the millions. To date, the data connecting Covid-19 and brain function have been at times concerning, confusing, and occasionally, reassuring. One of the key questions is whether brain-related Covid-19 symptoms are the result of SARS-CoV-2 entering and infecting the brain, or whether other pathways may better explain these prevalent complaints.

How could SARS-CoV-2 actually get into the brain?

1. Blood-based (hematogenous) spread

Testing for Covid-19 infection commonly involves nasal swabs, as the virus is known to concentrate in the respiratory system. However, the virus may often escape from the nose and lungs and make its way into the bloodstream, which could increase the chances of infecting other organs like the brain. Higher levels of SARS-CoV-2 RNA in the blood have been associated with worse outcomes from Covid-19, and may represent the central mechanism connecting infection elsewhere in the body with brain invasion by the virus.

In theory, the brain is relatively protected against pathogens like SARS-CoV-2 by virtue of its blood brain barrier (BBB) — a physical border between the blood and our brain tissue. This boundary helps keep microbes and other damaging molecules out of our brain tissue. So how could SARS-CoV-2 bypass this barrier? There are two proposed mechanisms.

First, it’s thought that viruses in our blood may be able to bind to the Angiotensin-converting enzyme 2 (ACE2) receptor on cells that make up the BBB. This would enable them to then transfer across into our brain tissue. Research published in the Journal of Medical Virology suggests this could be the most likely path for the virus to reach the brain. Another hypothesis involves infection of immune cells in the bloodstream, which then make their way into the brain through the BBB or through the choroid plexus or the meninges (other areas where blood comes into close contact with the brain). This second pathway has been dubbed the “Trojan horse” mechanism, but it’s unclear how relevant this is to Covid-19.

2. Retrograde neuronal transport

There’s another, rather unexpected route by which the virus may reach the brain — by hijacking our nerves. It’s been proposed that the SARS-CoV-2 virus may be capable of retrograde transport along our cranial nerves, essentially turning the vagus, trigeminal, and the olfactory nerve into viral ladders into the brain. Most of the research here has focused specifically on the olfactory nerve, which has nerve endings in our nose that carry smells into the brain. Evidence for the role of the olfactory nerve in retrograde transport comes from a paper published in Nature Neuroscience. In this highly cited work, researchers found evidence of the SARS-CoV-2 virus in the olfactory nerve tissue. To date, there’s not much evidence that the olfactory nerve is enriched in ACE2 receptors. However, the nasal mucosa near the olfactory nerve endings has been shown to be rich in this receptor, suggesting that the nerve may still be exposed to high concentrations of virus. Despite these interesting findings, the data for retrograde viral invasion of the brain by way of nerves remains rather limited.

Data showing that SARS-CoV-2 infects the brain

Brain tissue analysis

Unlike other parts of the body, it’s tough to justify taking samples of brain tissue unless it’s essential to a diagnosis or a patient is already deceased. Because of this, pathology data on the brains of those with Covid-19 tends to be isolated to those who died, making it difficult to generalize who may have had less severe cases. With this said, pathology reports provide some objective evidence for both the ability of the virus to enter the brain and its effects on brain cells.

To date, the brain pathology related to Covid-19 has been rather mixed in its findings. Some of the more consistent findings include brain bleeding (hemorrhages) as well as blood flow blockages (infarcts). Other studies showed evidence of damage due to low oxygen (hypoxia) as well as inflammation and activation of brain immune cells. It’s notable that while damage to neurons has been described, a helper brain cell called an astrocyte (which also makes up part of the BBB) may be particularly susceptible to the virus.

Of course, these types of pathological findings aren’t necessarily evidence that the virus itself has infiltrated the brain. This is why it’s notable that several studies have explicitly confirmed the finding of SARS-CoV-2 RNA in brain tissue. While this may seem alarming, it’s important to note that levels of the RNA seem to be quite low compared to other tissues, and that overall, only a few studies have shown evidence for this finding.

Cerebrospinal fluid analysis

As stated, it’s challenging to get access to actual brain tissue in living patients. In an attempt to analyze the immune state of the brain, many clinicians will instead sample cerebrospinal fluid (CSF), a liquid that surrounds and protects the brain. Though it’s not part of any routine testing in Covid-19, CSF has been analyzed in patients with SARS-CoV-2 infection. One of the most common results is an elevation in CSF protein, which in one analysis was seen in 100% of patients with fatal Covid-19. However, it’s worth noting that elevated CSF protein is a relatively nonspecific result that can be seen with everything from stroke to brain infection to brain tumors.

One recent paper has more specifically reviewed evidence for SARS-CoV-2 in the CSF using PCR testing for viral RNA. Despite 76% of these patients presenting with a neurologic complaint, only 6% had positive tests for the virus in their CSF. This was suggested to indicate a relatively low rate of viral penetration into the brain even in the context of brain-related symptoms.

What else may be at play?

On the whole, the current data forms a relatively lackluster connection between high levels of SARS-CoV-2 virus in the brain and the high frequency of reported brain-related symptoms seen in Covid-19 to date. It’s possible that future research will more concretely establish evidence for high viral load within the brain, but in the interim, it seems necessary to consider alternate explanations for the symptomatology and pathology described in conjunction with Covid-19.

1. Inflammatory signals and glial cells

Unlike the somewhat more mixed data on the brain, robust inflammation in the rest of the body has been consistently described in conjunction with Covid-19. In fact, this is the basis for the “cytokine storm,” an intense inflammatory state characterized by elevation in a variety of immune proteins and cells. When high levels of inflammation occur in the body, this could damage the BBB, which would then allow for the penetration of immune cells and inflammatory molecules from the bloodstream into the brain, potentially contributing to altered brain function.

Within the brain, non-neuron brain cells called glia are major drivers of inflammatory status, and changes in glia have been implicated in cognitive as well as mood disorders. Research has shown that one type of glial cell (called microglia) could be involved in the brain changes seen in Covid-19. Activation of the brain’s microglia in Covid-19 could occur by way of bloodstream signals, but also through data imported into the brain through nerves like the vagus.

2. Autoimmunity in the brain

In the process of fighting off Covid-19, it has been suggested that the immune system could at times start reacting to itself, triggering a degree of autoimmunity. Some have proposed that this could also be happening within the brain and that it may help to explain neurological symptoms both during and after the disease. Part of the basis for this idea stems from research showing similarity between SARS-CoV-2 proteins and brain proteins, which indicates a potential for the immune system to misidentify and attack the brain. Though some reports of autoimmune disease have been temporally linked with Covid-19, the overall significance of this mechanism on brain symptoms remains to be seen.

3. Changes in brain blood flow and oxygenation

Another explanation for brain changes in Covid-19 looks at oxygenation issues. Relative to other parts of the body, the brain is a very high user of oxygen, and when deficits occur in the supply — either as a result of low oxygen in the blood or due to clots — it can significantly influence brain function. Some research has suggested that these two pathways may be at play in Covid-19. In one neuroimaging series, Covid-19 patients demonstrated decreased blood flow to the frontotemporal regions of the brain. Additionally, vascular complications including clots and hemorrhage have been described both within and outside the brain in severe SARS-CoV-2 infection.

4. Psychological and environmental factors

A final, but significant pathway to consider links the psychological and environmental effects of Covid-19 with brain function. Many of the patients suffering from severe Covid-19 wind up in the intensive care unit (ICU). Among critically ill patients in the ICU, up to 80% may suffer from delirium, an acute and fluctuating state of altered cognition. Though the exact mechanisms are poorly understood, delirium may be in part driven by the same pathways described above (oxygenation issues, inflammation, blood flow issues) as well as medications, electrolyte imbalances, and changes in neurotransmitters. However, the stress associated with being in the hospital may also play a role.

Even outside the hospital, the stress associated with the Covid-19 pandemic may significantly and negatively influence our brain health. Importantly, while excessive psychological stress as a result of Covid-19 is a sufficient marker of altered brain state, it’s known to also influence immune function. Over time, it may also lead to physical and functional alterations in the brain.

What does it all mean?

Though the Covid-19 pandemic is well into its second year, and despite the efforts of investigators around the world, there’s still much we don’t understand about this virus and how it affects the body. When it comes specifically to interactions between the virus and the brain, we’re just starting to appreciate what may be behind the widespread reports of cognitive and psychological effects related to infection. Data to date doesn’t seem to indicate that viral infection of brain tissue is a major pathway of brain involvement in Covid-19. Instead, it may be the case that other pathways involving the brain’s immune system, blood flow and oxygenation, and psychological stress could contribute to the widespread reports of brain symptoms associated with Covid-19.

Dr. Austin Perlmutter, co-author of BRAIN WASH, is a board-certified internal medicine physician.