Effect on the brain explains loss of smell

Dr. de Erausquin recently published a paper along with colleagues, including senior author Dr. Sudha Seshadri, a professor of neurology at the same institution and director of the university’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.

“The basic idea of our study is that some of the respiratory viruses have affinity for nervous system cells,” Prof. Seshadri explains. She adds, “Olfactory cells are very susceptible to viral invasion and are particularly targeted by SARS-CoV-2, and that’s why one of the prominent symptoms of COVID-19 is loss of smell.”

Olfactory cells are concentrated in the nose. Through them, the virus reaches the olfactory bulb in the brain, which is located near the hippocampus, a brain area involved in short-term memory.

“The trail of the virus, when it invades the brain, leads almost straight to the hippocampus,” explains Dr. de Erausquin. “That is believed to be one of the sources of the cognitive impairment observed in COVID-19 patients. We suspect it may also be part of the reason why there will be an accelerated cognitive decline over time in susceptible individuals.”

The link with neurological disorders

In their paper, the scientists refer to existing evidence that makes them particularly wary of SARS-CoV-2’s impact on the brain. For example, researchers have found that:

• “Intranasal administration of SARS‐CoV‐2 in mice results in rapid invasion of the brain.”
• “SARS‐CoV‐1 viral particles can be detected post mortem in the cerebrum […] in humans.”
• In post mortem brain tissue, angiotensin-converting enzyme 2 (ACE2) receptors are expressed in the vasculature of the brain’s frontal cortex. Through these receptors, SARS-CoV-2 enters healthy cells.
• In vitro studies have shown that viral spike proteins can damage the blood‐brain barrier.
• A headache, reduced taste, and loss of smell occur before the onset of respiratory symptoms in most COVID-19 patients.
• Delirium, a neuropsychiatric symptom of reduced cognition and memory, “can be the only presenting symptom of SARS‐CoV‐2 infection, even in younger patients. The incidence of delirium in severely ill COVID‐19 patients [in intensive care units (ICUs)] is reported to be as high as 84%,” note the authors.
• Finally, “Abnormal brain imaging has emerged as a major feature of COVID‐19 from all parts of the world,” the team writes.

By 2022, the authors plan to have learned more about how COVID-19 affects the brain. A consortium of researchers from over 30 countries — funded by the Alzheimer’s Association — will conduct concerted research into the neurological effects of the novel coronavirus.

Study participants will be recruited from a pool of millions of people with COVID-19, in addition to some already enrolled in international studies. The researchers will take key measures of brain health — using MRI scans and assessments of brain volume, cognition, and behavior — initially and at 6, 9, and 18 months of the study.

The aim is to understand how having COVID-19 increases the risk, severity, and progression of neurodegenerative conditions, such as Alzheimer’s, or psychiatric conditions, such as depression.

A call for lighter ICU sedation

Other research adds to the concerns expressed by Dr. de Erausquin, Dr. Seshadri, and their colleagues — specifically regarding the risk of delirium and coma.

A new study appearing in The Lancet Respiratory MedicineTrusted Source found a much higher rate of these outcomes among COVID-19 patients than what is usual among patients with acute respiratory failure.

The authors of this study looked at 2,088 COVID-19 patients admitted to 69 adult ICUs across 14 countries. They found that about 82% of the patients were in a coma for an average of 10 days, and 55% had delirium for an average of 3 days. On average, acute brain dysfunction, manifested as a coma or delirium, lasted for 12 days.

“This is double what is seen in non-COVID ICU patients,” explains co-first study author Brenda Pun, an advanced care nurse at the Vanderbilt University Medical Center’s Division of Allergy, Pulmonary, and Critical Care Medicine, in Nashville, TN. Pun is also the director of data quality at the Vanderbilt Critical Illness, Brain Dysfunction, and Survivorship Center.

The study was observational, so it could not draw conclusions about the causes of these rates of acute brain dysfunction. However, the authors speculate that strong sedatives and reduced family visitations may both play a role.

The research showed that patients who had received benzodiazepine sedative infusions — which act as a depressant for the nervous system — were 59% more likely to develop delirium. The study also found that patients who had received in-person or virtual family visitations were 30% less likely to develop delirium.

The authors caution that because of the pressures of the pandemic, many healthcare professionals have reverted to older practices, while newer protocols have clear provisions in place for avoiding acute brain dysfunction.

“It is clear in our findings that many ICUs reverted to sedation practices that are not in line with best practice guidelines,” says Pun, “and we’re left to speculate on the causes. Many of the hospitals in our sample reported shortages of ICU providers informed about best practices.”

“There were concerns about sedative shortages, and early reports of COVID-19 suggested that the lung dysfunction seen required unique management techniques including deep sedation. In the process, key preventive measures against acute brain dysfunction went somewhat by the boards.”

“These prolonged periods of acute brain dysfunction are largely avoidable. Our study sounds an alarm: As we enter the second and third waves of COVID-19, ICU teams need, above all, to return to lighter levels of sedation for these patients, frequent awakening and breathing trials, mobilization, and safe in-person or virtual visitation.”

– senior study author Dr. Pratik Pandharipande, a professor of anesthesiology at Vanderbilt University Medical Center

Infecting neurons ‘with devastating consequences’

Other researchers have focused on how the new coronavirus infects neurons and damages brain tissue.

For example, a team led by Akiko Iwasaki, the Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular, and Developmental Biology at the Yale School of Medicine, in New Haven, CT, used lab-grown, miniature 3D organ reproductions to analyze how SARS-CoV-2 invades the brain.

The study, which appears in the Journal of Experimental Medicine, showed that the new coronavirus was able to infect neurons in these lab-grown organoids and replicate itself by boosting the metabolism of infected cells. Simultaneously, healthy, uninfected neurons in the vicinity died as their oxygen supply was cut off.

The researchers also determined that blocking the ACE2 receptors prevented the virus from infecting the human brain organoids.

The scientists also analyzed the effects of SARS-CoV-2 on the brains of mice genetically modified to produce human ACE2 receptors. Here, the virus altered the brain’s vasculature, or blood vessels. This could, in turn, cut off the brain’s oxygen supply.

Furthermore, the mice with an infection that had spread to the brain had much more severe illness than those with an infection limited to the lungs.

Lastly, Prof. Iwasaki and her team examined the postmortem brains of three patients who died from COVID-19. They found SARS-CoV-2 in the cortical neurons of one of the three. The infected areas were associated with ischemic infarcts, wherein a limited blood supply caused tissue damage and cell death. All three patients had microinfarcts in their brains.

“Our study clearly demonstrates that neurons can become a target of SARS-CoV-2 infection, with devastating consequences of localized ischemia in the brain and cell death. […] Our results suggest that neurologic symptoms associated with COVID-19 may be related to these consequences and may help guide rational approaches to the treatment of COVID-19 patients with neuronal disorders.”

– co-corresponding author Dr. Kaya Bilguvar, director of the Yale Center for Genome Analysis

‘Once it infects the brain, it can affect anything’

Another study supports the idea that COVID-19’s attack on the brain is what makes the disease very severe.

A team of researchers, including senior study author Mukesh Kumar, a virologist specializing in emerging infectious diseases and assistant professor at Georgia State University, in Atlanta, infected the nasal passages of mice with the new coronavirus. This caused severe illness in the rodents, even after the infection had cleared from their lungs.

The scientists then analyzed levels of the virus in several organs, comparing the intervention group of mice with a control group, which had received a dose of saline solution instead of the virus.

The results — published in the journal Viruses — revealed that viral levels in the lungs peaked around day 3 after the infection, but levels in the brain persisted on days 5 and 6, coinciding with the symptoms being most severe and debilitating.

The scientists also found that the brain contained 1,000 times higher levels of the virus than other parts of the body.

This may explain, the senior researcher says, why some people seem to recover after a few days and have improved lung function, only to then relapse and have more severe symptoms, some of which can prove lethal.

“Our thinking that [COVID-19 is] more of a respiratory disease is not necessarily true,” Kumar says. “Once it infects the brain, it can affect anything because the brain is controlling your lungs, the heart, everything. The brain is a very sensitive organ. It’s the central processor for everything.”

“The brain is one of the regions where viruses like to hide,” he continues, “because unlike the lungs, the brain is not as equipped, from an immunological perspective, to clear viruses.”

“That’s why we’re seeing severe disease and all these multiple symptoms like heart disease, stroke, and all these long-haulers with loss of smell, loss of taste,” explains the senior researcher. “All of this has to do with the brain, rather than with the lungs.”

Kumar cautions that the brain damage may mean that many people with COVID-19 continue to be at high risk of neurodegenerative diseases, such as Parkinson’s, multiple sclerosis, or general cognitive decline, after recovering.

“It’s scary. […] A lot of people think they got COVID, and they recovered, and now they’re out of the woods. Now I feel like that’s never going to be true. You may never be out of the woods.”

What is the central nervous system?

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The CNS consists of the brain and spinal cord.

The brain is protected by the skull (the cranial cavity) and the spinal cord travels from the back of the brain, down the center of the spine, stopping in the lumbar region of the lower back.

The brain and spinal cord are both housed within a protective triple-layered membrane called the meninges.

The central nervous system has been thoroughly studied by anatomists and physiologists, but it still holds many secrets; it controls our thoughts, movements, emotions, and desires. It also controls our breathing, heart rate, the release of some hormones, body temperature, and much more.

The retina, optic nerve, olfactory nerves, and olfactory epithelium are sometimes considered to be part of the CNS alongside the brain and spinal cord. This is because they connect directly with brain tissue without intermediate nerve fibers.

Below is a 3D map of the CMS. Click on it to interact and explore the model.

Now we will look at some of the parts of the CNS in more detail, starting with the brain.

The brain

The brain is the most complex organ in the human body; the cerebral cortex (the outermost part of the brain and the largest part by volume) contains an estimated 15–33 billion neurons, each of which is connected to thousands of other neurons.

In total, around 100 billion neurons and 1,000 billion glial (support) cells make up the human brain. Our brain uses around 20 percent of our body’s total energy.

The brain is the central control module of the body and coordinates activity. From physical motion to the secretion of hormones, the creation of memories, and the sensation of emotion.

To carry out these functions, some sections of the brain have dedicated roles. However, many higher functions — reasoning, problem-solving, creativity — involve different areas working together in networks.

The brain is roughly split into four lobes:

Temporal lobe (green): important for processing sensory input and assigning it emotional meaning.

It is also involved in laying down long-term memories. Some aspects of language perception are also housed here.

Occipital lobe (purple): visual processing region of the brain, housing the visual cortex.

Parietal lobe (yellow): the parietal lobe integrates sensory information including touch, spatial awareness, and navigation.

Touch stimulation from the skin is ultimately sent to the parietal lobe. It also plays a part in language processing.

Frontal lobe (pink): positioned at the front of the brain, the frontal lobe contains the majority of dopamine-sensitive neurons and is involved in attention, reward, short-term memory, motivation, and planning.

Brain regions

Next, we will look at some specific brain regions in a little more detail:

Basal ganglia: involved in the control of voluntary motor movements, procedural learning, and decisions about which motor activities to carry out. Diseases that affect this area include Parkinson’s disease and Huntington’s disease.

Cerebellum: mostly involved in precise motor control, but also in language and attention. If the cerebellum is damaged, the primary symptom is disrupted motor control, known as ataxia.

Broca’s area: this small area on the left side of the brain (sometimes on the right in left-handed individuals) is important in language processing. When damaged, an individual finds it difficult to speak but can still understand speech. Stuttering is sometimes associatedTrusted Source with an underactive Broca’s area.

Corpus callosum: a broad band of nerve fibers that join the left and right hemispheres. It is the largest white matter structure in the brain and allows the two hemispheres to communicate. Dyslexic children have smaller corpus callosums; left-handed people, ambidextrous people, and musicians typically have larger ones.

Medulla oblongata: extending below the skull, it is involved in involuntary functions, such as vomiting, breathing, sneezing, and maintaining the correct blood pressure.

Hypothalamus: sitting just above the brain stem and roughly the size of an almond, the hypothalamus secretes a number of neurohormones and influences body temperature control, thirst, and hunger.

Thalamus: positioned in the center of the brain, the thalamus receives sensory and motor input and relays it to the rest of the cerebral cortex. It is involved in the regulation of consciousness, sleep, awareness, and alertness.

Amygdala: two almond-shaped nuclei deep within the temporal lobe. They are involved in decision-making, memory, and emotional responses; particularly negative emotions.

Spinal cord

The spinal cord, running almost the full length of the back, carries information between the brain and body, but also carries out other tasks.

From the brainstem, where the spinal cord meets the brain, 31 spinal nerves enter the cord.

Along its length, it connects with the nerves of the peripheral nervous system (PNS) that run in from the skin, muscles, and joints.

Motor commands from the brain travel from the spine to the muscles and sensory information travels from the sensory tissues — such as the skin — toward the spinal cord and finally up to the brain.

The spinal cord contains circuits that control certain reflexive responses, such as the involuntary movement your arm might make if your finger was to touch a flame.

The circuits within the spine can also generate more complex movements such as walking. Even without input from the brain, the spinal nerves can coordinate all of the muscles necessary to walk. For instance, if the brain of a cat is separated from its spine so that its brain has no contact with its body, it will start spontaneously walking when placed on a treadmill. The brain is only requiredTrusted Source to stop and start the process, or make changes if, for instance, an object appears in your path.

White and gray matter

The CNS can be roughly divided into white and gray matter. As a very general rule, the brain consists of an outer cortex of gray matter and an inner area housing tracts of white matter.

Both types of tissue contain glial cells, which protect and support neurons. White matter mostly consists of axons (nerve projections) and oligodendrocytes — a type of glial cell — whereas gray matter consists predominantly of neurons.

Central glial cells

Also called neuroglia, glial cells are often called support cells for neurons. In the brain, they outnumber nerve cells 10 to 1.

Without glial cells, developing nerves often lose their way and struggle to form functioning synapses.

Glial cells are found in both the CNS and PNS but each system has different types. The following are brief descriptions of the CNS glial cell types:

Astrocytes: these cells have numerous projections and anchor neurons to their blood supply. They also regulate the local environment by removing excess ions and recycling neurotransmitters.

Oligodendrocytes: responsible for creating the myelin sheath — this thin layer coats nerve cells, allowing them to send signals quickly and efficiently.

Ependymal cells: lining the spinal cord and the brain’s ventricles (fluid-filled spaces), these create and secrete cerebrospinal fluid (CSF) and keep it circulating using their whip-like cilia.

Radial glia: act as scaffolding for new nerve cells during the creation of the embryo’s nervous system.

Cranial nerves

The cranial nerves are 12 pairs of nerves that arise directly from the brain and pass through holes in the skull rather than traveling along the spinal cord. These nerves collect and send information between the brain and parts of the body – mostly the neck and head.

Of these 12 pairs, the olfactory and optic nerves arise from the forebrain and are considered part of the central nervous system:

Olfactory nerves (cranial nerve I): transmit information about odors from the upper section of the nasal cavity to the olfactory bulbs on the base of the brain.

Optic nerves (cranial nerve II): carry visual information from the retina to the primary visual nuclei of the brain. Each optic nerve consists of around 1.7 million nerve fibers.

Central nervous system diseases

Below are the major causes of disorders that affect the CNS:

Trauma: depending on the site of the injury, symptoms can vary widely from paralysis to mood disorders.

Infections: some micro-organisms and viruses can invade the CNS; these include fungi, such as cryptococcal meningitis; protozoa, including malaria; bacteria, as is the case with leprosy, or viruses.

Degeneration: in some cases, the spinal cord or brain can degenerate. One example is Parkinson’s disease which involves the gradual degeneration of dopamine-producing cells in the basal ganglia.

Structural defects: the most common examples are birth defects; including anencephaly, where parts of the skull, brain, and scalp are missing at birth.

Tumors: both cancerous and noncancerous tumors can impact parts of the central nervous system. Both types can cause damage and yield an array of symptoms depending on where they develop.

Autoimmune disorders: in some cases, an individual’s immune system can mount an attack on healthy cells. For instance, acute disseminated encephalomyelitis is characterized by an immune response against the brain and spinal cord, attacking myelin (the nerves’ insulation) and, therefore, destroying white matter.

Stroke: a stroke is an interruption of blood supply to the brain; the resulting lack of oxygen causes tissue to die in the affected area.

Difference between the CNS and peripheral nervous system

The term peripheral nervous system (PNS) refers to any part of the nervous system that lies outside of the brain and spinal cord. The CNS is separate from the peripheral nervous system, although the two systems are interconnected.

There are a number of differences between the CNS and PNS; one difference is the size of the cells. The nerve axons of the CNS — the slender projections of nerve cells that carry impulses — are much shorter. PNS nerve axons can be up to 1 meter long (for instance, the nerve that activates the big toe) whereas, within the CNS, they are rarely longer than a few millimeters.

Another major difference between the CNS and PNS involves regeneration (regrowth of cells). Much of the PNS has the ability to regenerate; if a nerve in your finger is severed, it can regrow. The CNS, however, does not have this ability.

The components of the central nervous system are further split into a myriad of parts. Below, we will describe some of these sections in a little more detail.