Posted on by Dr. Francis Collins
While primarily a respiratory disease, COVID-19 can also lead to neurological problems. The first of these symptoms might be the loss of smell and taste, while some people also may later battle headaches, debilitating fatigue, and trouble thinking clearly, sometimes referred to as “brain fog.” All of these symptoms have researchers wondering how exactly the coronavirus that causes COVID-19, SARS-CoV-2, affects the human brain.
In search of clues, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have now conducted the first in-depth examinations of human brain tissue samples from people who died after contracting COVID-19. Their findings, published in the New England Journal of Medicine, suggest that COVID-19’s many neurological symptoms are likely explained by the body’s widespread inflammatory response to infection and associated blood vessel injury—not by infection of the brain tissue itself .
The NIH team, led by Avindra Nath, used a high-powered magnetic resonance imaging (MRI) scanner (up to 10 times as sensitive as a typical MRI) to examine postmortem brain tissue from 19 patients. They ranged in age from 5 to 73, and some had preexisting conditions, such as diabetes, obesity, and cardiovascular disease.
The team focused on the brain’s olfactory bulb that controls our ability to smell and the brainstem, which regulates breathing and heart rate. Based on earlier evidence, both areas are thought to be highly susceptible to COVID-19.
Indeed, the MRI images revealed in both regions an unusual number of bright spots, a sign of inflammation. They also showed dark spots, which indicate bleeding. A closer look at the bright spots showed that tiny blood vessels in those areas were thinner than normal and, in some cases, leaked blood proteins into the brain. This leakage appeared to trigger an immune reaction that included T cells from the blood and the brain’s scavenging microglia. The dark spots showed a different pattern, with leaky vessels and clots but no evidence of an immune reaction.
While those findings are certainly interesting, perhaps equally noteworthy is what Nath and colleagues didn’t see in those samples. They could find no evidence in the brain tissue samples that SARS-CoV-2 had invaded the brain tissue. In fact, several methods to detect genetic material or proteins from the virus all turned up empty.
The findings are especially intriguing because there has been some suggestion based on studies in mice that SARS-CoV-2 might cross the blood-brain barrier and invade the brain. Indeed, a recent report by NIH-funded researchers in Nature Neuroscience showed that the viral spike protein, when injected into mice, readily entered the brain along with many other organs .
Another recent report in the Journal of Experimental Medicine, which used mouse and human brain tissue, suggests that SARS-CoV-2 may indeed directly infect the central nervous system, including the brain . In autopsies of three people who died from complications of COVID-19, the NIH-supported researchers detected signs of SARS-CoV-2 in neurons in the brain’s cerebral cortex. This work was done using the microscopy-based technique of immunohistochemistry, which uses antibodies to bind to a target, in this case, the virus’s spike protein. Also last month, in a study published in the journal Neurobiology of Disease, another NIH-supported team demonstrated in a series of experiments in cell culture that the SARS-CoV-2 spike protein could cross a 3D model of the blood-brain barrier and infect the endothelial cells that line blood vessels in the brain .
Clearly, more research is needed, and NIH’s National Institute of Neurological Disorders and Stroke has just launched the COVID-19 Neuro Databank/Biobank (NeuroCOVID) to collect more clinical information, primarily about COVID-19-related neurological symptoms, complications, and outcomes. Meanwhile, Nath and colleagues continue to explore how COVID-19 affects the brain and triggers the neurological symptoms often seen in people with COVID-19. As we learn more about the many ways COVID-19 wreaks havoc on the body, understanding the neurological symptoms will be critical in helping people, including the so-called Long Haulers bounce back from this terrible viral infection.
 Microvascular Injury in the Brains of Patients with Covid-19. Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. N Engl J Med. 2020 Dec 30.
 The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. Nat Neurosci. 2020 Dec 16.
 Neuroinvasion of SARS-CoV-2 in human and mouse brain. Song E, Zhang C, Israelow B, et al. J Exp Med (2021) 218 (3): e20202135.
 The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. Neurobiol Dis. 2020 Dec;146:105131.
COVID-19 Research (NIH)
Avindra Nath (National Institute of Neurological Disorders and Stroke/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging; National Institute of General Medical Sciences; National Cancer Institute; National Institute of Mental Health
Posted on by Dr. Francis Collins
Our ability to distinguish the aroma of freshly baked bread from the sweet fragrance of a rose comes from millions of sensory neurons that line the upper nasal cavity. These so-called olfactory sensory neurons activate when the specific types of odor molecules to which they are attuned enter the nose, prompting them to send their sensory alerts onward to the brain, where we become aware of a distinctive scent.
If you look closely at the striking image above from a young mouse, the thin, fluorescently labeled lines (red, green, white) show the neuronal extensions, or axons, of olfactory sensory neurons. These information-conveying axons stretch right to left from the nose through the smell-mediating olfactory bulb (blue) in the forebrain of all vertebrates, ending in just the right spot (white, pink, or red).
But the axons presented here don’t belong to just any olfactory sensory neurons. They represent newly discovered “navigator” neurons, which are essential to forge life’s very first olfactory connections .
The image comes from a recent paper in the journal Neuron from an NIH-supported team led by C. Ron Yu, Stowers Institute for Medical Research, Kansas City, MO. Yu’s team offered the first hints of navigator neurons a few years ago when it showed that young mice could correct errors in their olfactory wiring only when those disruptions occurred within the first week of life .
After that, the mice had lifelong abnormalities in their sense of smell. The findings suggested that the olfactory sensory neurons present very early in life had a unique ability to blaze a trail to the brain to establish a coherent olfactory map.
The new study confirms that navigator neurons indeed have a unique molecular identity. During their short lives, they show more extensive axon growth compared to neurons that arise later. Their axons also travel a more circuitous route to the brain, as if exploring the neural tissue before settling on a path to their final destination. As olfactory neurons in older mice regenerate, they simply follow the trail blazed for them by those early scouts.
While the new findings involve mice, the researchers suspect similar processes are at work in humans too. That means images like this one aren’t just fascinating. They could help pave the way toward new approaches for reviving navigator neurons, potentially making it possible to forge new olfactory connections—and bring back the enjoyment of delightful aromas such as freshly baked bread or roses—in those who’ve lost the ability to smell.
 A population of navigator neurons is essential for olfactory map formation during the critical period. Wu Y, Ma L, Duyck K, Long CC, Moran A, Scheerer H, Blanck J, Peak A, Box A, Perera A, Yu CR. Neuron. 2018 Dec 5;100(5):1066-1082.
 A developmental switch of axon targeting in the continuously regenerating mouse olfactory system. Ma L, Wu Y, Qiu Q, Scheerer H, Moran A, Yu CR. Science. 2014 Apr 11;344(6180):194-197.
Smell Disorders (National Institute on Deafness and Other Communication Disorders)
Yu Lab (Stowers Institute for Medical Research, Kansas City, MO)
NIH Support: National Institute on Deafness and Other Communication Disorders
Posted on by Dr. Francis Collins
You’ve probably learned the hard way about how the grocery list can go out the window when you go shopping on an empty stomach. Part of the reason is that our sense of smell intensifies when we’re hungry, making the aroma of freshly baked cookies, fried chicken, and other tempting goodies even more noticeable. And this beautiful micrograph helps to provide a biological explanation for this phenomenon.
The image, which looks like something that Van Gogh might have painted, shows a thick mesh of neurons in a small cross section of a mouse’s olfactory bulb, a structure located in the forebrain of all vertebrates (including humans!) that processes input about odors detected by the nose. Here, you see specialized neurons called mitral cells (red) that can receive signals from the hypothalamus, a brain region known for its role in hunger and energy balance. Also fluorescently labeled are receptors that detect acetylcholine signals from the brain (green) and the nuclei of all cells in the olfactory bulb (blue).