How Does COVID-19 Impact Our Brain?

Post by D. Chloe Chung

What's the deal with COVID-19 and our brain?

Since the outbreak of human coronavirus disease 2019 (COVID-19) back in December 2019, countless lives have been lost. As of April 2021, it is projected that 140 million people have become infected by the 2019 novel coronavirus (2019-nCoV) that causes COVID-19 and about 3 million people have died from the disease globally. COVID-19 is primarily a highly contagious respiratory illness similar to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) both of which are caused by different strains of coronavirus.

At the very beginning of this pandemic, healthcare professionals and researchers focused primarily on the respiratory symptoms of COVID-19, as symptoms include severe coughing, breathing difficulties, and pneumonia. However, it was soon discovered that COVID-19 entails multiple non-respiratory symptoms including anosmia (loss of smell and taste) as well as various short- and long-term psychiatric symptoms. For example, the “brain fog” that some COVID-19 patients experience during or after acute COVID-19 infection has been highlighted by the media and is characterized by substantial and persistent deficits in cognition or attention. Notably, SARS or MERS patients also experienced cognitive deficits such as memory decline and poor concentration. Neuropsychiatric symptom presentation varies widely across COVID-19 patients. In addition to brain fog, patients can experience neuropsychiatric symptoms such as psychosis, insomnia, depression, and anxiety. More severe but also rarer, some patients even suffer from severe strokes and suicidal thoughts. The biological mechanisms underlying the contribution of COVID-19 to psychiatric illness need to be investigated further.

The link between COVID-19 and neuropsychiatric issues

Many research studies — mostly retrospective — have been conducted to understand the critical association between COVID-19 and neurological symptoms. For example, a recent study that examined more than 60,000 COVID-19 patients in the United States reported that people who were infected and recovered from COVID-19 were significantly more likely to develop various psychiatric issues such as anxiety, dementia, and insomnia. Interestingly, the severity of these psychiatric issues was shown to be modestly associated with the severity of COVID-19: psychiatric symptoms tend to be more prominent if the patient suffered from a more severe case of COVID-19. This association suggests that these neurological symptoms could be at least partially induced by COVID-19-related pathobiology, such as the degree of inflammation or the amount of virus these patients contracted. Moreover, this study found that individuals with a history of psychiatric disorders were at a higher risk of being diagnosed with COVID-19, suggesting that psychiatric disorders can be a risk factor in addition to an outcome of the disease. A more recent study assessing the prevalence of neurological and psychiatric disorders 6 months after COVID-19 diagnosis in 236 000 patients found that 33% developed such a disorder in the 6 month period. This study also found that for most of the disorders studied, the chances of developing the disorder were higher post-COVID-19 infection compared to the risk for a control group recovering from other respiratory tract infections. Finally, a relationship between COVID-19 severity and the chances of developing of a neurological or psychiatric disorder was also noted.

Another study administered cognitive tests to people who were infected and recovered from COVID-19 and compared them to age-matched control participants who have never contracted the virus. From these tests, COVID-19 survivors showed worsened continuous and selective attention compared to controls. Of note, when blood samples collected from the study participants were analyzed for signs of inflammation, a positive correlation was found between the level of one of the inflammatory factors and the degree of impairment in attention. While further investigation is needed (this study was not longitudinal and had a small number of participants), it can be speculated that there could be an important link between inflammation and COVID-19-related psychiatric symptoms.

How does the novel coronavirus affect the brain?

As COVID-19 patients and survivors continue to report various psychiatric problems, researchers began to wonder how the novel coronavirus can affect our brain – is it possible that this virus enters the human brain? How might this virus damage our brain? Since the angiotensin-converting enzyme 2 (ACE2) has been discovered as the cellular receptor for the novel coronavirus, many researchers have tried to understand whether this receptor can facilitate the entry of the virus into the brain. While the role of the receptor in virus entry to the brain remains to be investigated, analyses of publicly available transcriptomics datasets revealed that ACE2 is widely expressed in both the human and mouse brain. Specifically, in the human brain, ACE2 was expressed in excitatory and inhibitory neurons as well as astrocytes and oligodendrocytes, while its expression level varied across different brain regions. These results collectively suggest that ACE2 in the brain could potentially serve as an entry point for the novel coronavirus into the central nervous system.

Further supporting experimental evidence was presented by a recent study that evaluated the possibility of the novel coronavirus invading the brain using multiple different experimental models. First, the study demonstrated using the human brain organoids that the virus can indeed infect neurons and increase their metabolism. Interestingly, the virus was found to replicate by hijacking the innate machinery of infected neurons, while depriving the oxygen supply of neighboring neurons which eventually leads to their death. Importantly, ACE2 was required for the novel coronavirus infection as blocking ACE2 essentially prevented the virus from infecting neurons in the organoids. Second, the study utilized a genetic mouse model that increases the expression of the human version of ACE2 to demonstrate that the novel coronavirus can invade the brain in vivo. On top of this “neuroinvasion”, the novel coronavirus was found to induce rearrangement of blood vessels in the infected brain region, suggesting that the novel coronavirus can damage the brain by changing brain blood supply and potentially resulting in damaging infarcts (tissue death caused by insufficient blood supply).

Another approach to studying neuroinvasion by the novel coronavirus, several studies have examined brain tissues of COVID-19 patients who passed away from severe complications directly. Specifically, in the study described above, patient tissues from different brain regions were stained with antibodies that can detect spike protein of the novel coronavirus. With this staining method, the virus was found in cortical neurons and endothelial cells of COVID-19 patient brain tissues, indicating that the novel coronavirus may be neurotropic. Another study that analyzed brain tissues from about 60 COVID-19 patients also reported infarcts as one of the most prominent pathological features in the brain. Microthrombi, or small blood clots, were also found to be associated with infarcts, consistent with blood clotting commonly reported in COVID-19 patients. High expression of ACE2 protein expression was notably found in blood vessels, which suggests that these endothelial cells may be targeted by the coronavirus, leading to subsequent damage to blood vessels and eventually neuropsychiatric symptoms. 

What can we do for “brain fog” and other neuropsychiatric symptoms?

It has been more than a year now since this devastating disease was named COVID-19 by the World Health Organization (WHO), and we are just at the beginning of understanding the impact of COVID-19 on our brain health. For the next few months or years, we will continue to learn what long-term neuropsychiatric effects are caused by the novel coronavirus, especially in individuals who have survived severe cases. Currently, treatment options suggested for brain fog and other neuropsychiatric issues associated with COVID-19 mostly focus on keeping healthy daily habits, such as sleeping well, eating a balanced diet, and exercising regularly. While adopting these healthy habits may be generally beneficial, there is potential for more tailored treatments. As we learn more about what happens in our brain during the disease course of COVID-19, future studies may find effective therapies against these symptoms and help alleviate the delayed onset of unexpected neuropsychiatric complications in COVID-19 survivors.

In addition to neuropsychiatric symptoms of COVID-19 discussed here, stress and anxiety from uncertainty, social isolation, and economic challenges during this pandemic have had a tremendously negative impact on mental health, even in those who were not directly infected by the virus. With COVID-19 vaccines becoming available to more people, there is further work to be done to prevent further global burden on mental health.

References

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Iadecole et al. Effects of COVID-19 on the Nervous System. Cell (2021). Access the original scientific publication here.

Taquet et al. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry (2021). Access the original scientific publication here.

Bryce et al. Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience. Modern Pathology (2021). Access the original scientific publication here.

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Boldrini et al. How COVID-19 Affects the Brain. JAMA Psychiatry (2021). Access the original scientific publication here.

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Taquet et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. The Lancet (2021). Access the original scientific publication here.