• Clinicians have found that COVID-19 is associated with neurological symptoms.
• Scientists need to conduct more research to understand how COVID-19 is linked to these neurological symptoms.
• Researchers have presented their findings on these links at Neuroscience 2021, the annual conference of the Society for Neuroscience.

Researchers have been exploring the way COVID-19 affects a person’s nervous system, causing neurological symptoms.

This week, they presented their findings at Neuroscience 2021. This event is the annual meeting of the Society for Neuroscience, which is the largest global society for scientists and clinicians focused on issues of brain and nervous system health.

The findings indicate how SARS-CoV-2 — the virus that causes COVID-19 — gains access to a person’s brain. They also provide insight into the effects it has once it has entered this part of the body.

Neurological symptoms

For most people, the primary symptoms of COVID-19 are respiratory. According to the World Health Organization (WHO), the most common symptoms of COVID-19 are fever, a cough, tiredness, and the loss of taste or smell.

These symptoms and other, less common ones can range in severity from mild to life threatening. Some people who acquire a SARS-CoV-2 infection may even remain asymptomatic.

As well as these respiratory symptoms, clinicians and researchers have also observed various neurological symptoms associated with COVID-19.

Researchers have linked COVID-19 to headaches, brain inflammation, muscle weakness or pain, and numbness or weakness in a person’s hands, feet, or limbs.

However, further research is necessary to understand how COVID-19 affects a person’s nervous system.

Access to the brain

At Neuroscience 2021, a number of papers detailed findings exploring how SARS-CoV-2 is likely to affect a person’s brain.

Dr. Ashutosh Kumar, an assistant professor in the Department of Anatomy at the All India Institute of Medical Sciences, Patna, India, presented findings that identified a possible receptor that may give SARS-CoV-2 access to a person’s brain.

In other parts of the body, SARS-CoV-2 gains access to cells by binding to the protein angiotensin converting enzyme 2 (ACE2) with the help of transmembrane serine protease 2 (TMPRSS2). However, ACE2 and TMPRSS2 are not significantly present in a person’s brain.

Speaking with Medical News Today, Dr. Kumar said: “We know that COVID-19 patients show prominent neuropsychiatric symptoms and [that] virus-induced injuries — including evidence of the replicating virus in brain tissue — have been noted in the postmortem studies. However, a negligible expression of the ACE2 and TMPRSS2 left a key question [un]answered: How does SARS-CoV-2 enter the brain cells?”

“By [the middle] of the last year, another receptor — neuropilin-1 precursor (NRP1), a cell surface protein implicated in the brain development and causation of cancers — was shown capable of binding to furin-cleaved SARS-CoV-2 spike protein[s]. Uniquely, binding to the NRP1 didn’t require TMPRSS2.”

“By curiosity, we checked the expressions of NRP1 and furin in the postmortem human brain tissue, which [revealed] that both of these molecules are abundant in all key brain regions — chiefly, the olfactory and hippocampus.”

“Olfactory nerves present a way for the entry of the virus into the brain through the nose, and their infection can also explain the loss of smell as a key symptom in COVID-19. Further, the involvement of the hippocampus can explain the prominence of psychiatric symptoms in COVID-19 patients during and after recovery from acute illness,” said Dr. Kumar.

For Dr. Kumar, his team’s findings may help identify future drugs to protect against or treat the neurological symptoms of COVID-19.

“Our findings are important in the sense that they indicate the putative drug targets for preventing and treating neuropsychiatric symptoms in COVID-19. The binding sites of NRP1 and furin at the SARS-CoV-2 spike protein can be targeted with various approaches, such as with monoclonal antibodies or decoy receptors,” said Dr. Kumar.

The findings appear in both the Journal of Neuroscience Research and Frontiers in Immunology.

Monkey models

Prof. John H. Morrison, director of the California National Primate Research Center at the University of California, Davis, presented research on a study using rhesus monkeys. These findings also suggest that the olfactory system could be the way in which SARS-CoV-2 gains access to the brain.

Prof. Morrison told MNT: “The monkeys were infected both through the nose and the trachea and sacrificed [7] days after infection. We were particularly interested in whether or not aged type 2 diabetic (T2D) monkeys were more vulnerable to neuroinvasion by the virus than young monkeys, given that aging and T2D are key comorbidities in humans.”

“We studied the brains of four groups: 1) young [with neither the infection nor diabetes], 2) young [with the infection but without diabetes], 3) aged [with neither the infection nor diabetes], and 4) aged [with both the infection and diabetes]. The major findings are that:

For Prof. Morrison, the findings make it clear that COVID-19 is a neurological condition as well as a respiratory one.

“There has been an ongoing debate over whether or not SARS-CoV-2 can infect neurons,” said Prof. Morrison. “These findings demonstrate unequivocally that neurons can be infected in our monkey model of COVID-19 and that the virus appears to enter the brain through olfactory connections from the nose.”

“The direct entry through [the] olfactory system, productive infection of neurons, and transport to multiple brain regions by SARS-CoV-2 is the likely cause of neurological complications in COVID-19, such as anxiety, memory loss, and ‘brain fog.’ The heightened vulnerability of aged T2D monkeys suggests that such comorbidities in humans may also lead to more extensive neurological complications.”

“Thus, COVID-19 is potentially a brain disorder as well as a respiratory disease, and prevention and treatment of patients with long-term symptoms of COVID-19 should target protecting the brain as well as [the] heart and lungs. In addition, such treatments need to be applied very early after infection given that this occurred in [7] days.”

For Prof. Morrison, better understanding the neurological effects of COVID-19 is likely to help in researchers’ understanding of long COVID.

“Many of the symptoms associated with ‘long COVID’ are neurologic in nature and likely to be caused by neuroinvasion and infection of neurons. We do not know if such symptoms are linked to ongoing infection of neurons linked through circuits or through damage that occurred early and outlasts the infection,” said Prof. Morrison.

Prof. Morrison noted that the finding that older, T2D monkeys had more severe neurological infections was backed up by research in humans.

“Clinical studies have shown that [older people] are far more likely to display neurological symptoms. In addition, the virus is getting to some brain regions that are highly vulnerable to Alzheimer’s disease as well, but we don’t know if such an infection leaves a patient more vulnerable to Alzheimer’s disease in the future,” said Prof. Morrison.

Peripheral nervous system

In another study, researchers found that SARS-CoV-2 is also likely to be able to gain access to a person’s brain via nerves that convey touch and pain.

Jonathan Joyce — a graduate student in the laboratory of Dr. Andrea S. Bertke in the Department of Population Health Sciences at Virginia Tech, Blacksburg, VA — used a mouse model to explore whether SARS-CoV-2 could infect the peripheral nerves. Dr. Bertke worked closely with Joyce throughout the study.

Speaking with MNT, Joyce said that “[w]hile most of the attention paid to assessing the ability of SARS-CoV-2 to invade the nervous system has focused on the central nervous system — for example, the brain — we have found that SARS-CoV-2 can infect neurons of the peripheral nervous system.”

“Previous studies have shown that SARS-CoV-2 can infect nerves in the peripheral nervous system, but they only looked at nerves responsible for smell.”

“We have shown that SARS-CoV-2 is capable of infecting additional nerves of the peripheral nervous system in the head, neck, and body responsible for carrying out automatic bodily — for example, superior cervical ganglion — functions and relaying sensory information, particularly those that convey touch and pain, to the brain and spinal cord — for example, trigeminal ganglion and dorsal root ganglion.”

“We also found that various regions of the brain, impacted in COVID-19, are capable of being infected by SARS-CoV-2. It is worth noting that these findings are based on a mouse model of infection and will have to be repeated in other animal models for verification,” said Joyce.

According to Joyce, the value of the research is that it demonstrates that SARS-CoV-2 is not restricted to infecting the central nervous system but can also infect the peripheral nervous system at multiple points.

“Many studies that investigate how SARS-CoV-2 enters the nervous systems focus on how it enters the brain using neurons in the nose responsible for smell,” said Joyce.

“Our findings show that the virus can infect the peripheral nervous system at multiple points, particularly among nerves that convey touch and pain, and that some of these points have connections to regions of the brain impacted by COVID-19.”

“Presence of the virus in these nerves may contribute to the symptoms [that] people with COVID-19 [experience].”

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