Mao et.al study finds that 36.4% of the COVID-19 patients surveyed presented neurologic symptoms, such as acute cerebrovascular events, impaired consciousness and skeletal muscle injury. Neurologists conducted a study (Jan. 16 - Feb. 19) (n=214, from 3 designated Wuhan hospitals) by retrospectively reviewing patient charts. Nervous system symptoms were found to be more prevalent in severe patients, affecting them disproportionately to their counterparts with regards to CNS function and muscle injury.

Increased neurologic symptoms in severely infected COVID-19 patients

- Encephalopathy (overall)
- Ischemic Stroke
- Multisystem Inflammatory Syndrome in Children (MIS-C)
- Induce brain and spine demyelinating lesions
- Mast cell activation
- Acute cerebrovascular disease 
- Intracranial hemorrhage
- Seizure (caused by meningitis)
- Neuroinflammatory syndromes 
- Post-infection cerebral changes

COVID-19 Reports on Patient Neurological Symptoms, Organized by Symptoms Affecting the CNS

- Multisystem Inflammatory Syndrome in Children (MIS-C)
- Guillain-Barré Syndrome
- Loss of smell (hyposmia/anosmia) and taste (hypogeusia/ageusia)
- Serious damage to cranial nerves, peripheral nerves, and muscles


COVID-19 Reports on Patient Neurological Symptoms, Organized by Symptoms Affecting the PNS

It was found early on that population with respiratory problems is at greater risk but risk factors include pre-existing diagnoses such as dementia, subarachnoid hemorrhage and epilepsy.  Increased risk is found when the acute care uses sedation, ventilation and delirium. 


Who is likely to suffer from neurocognitive symptoms

Up to 20% of COVID-19 patients who enter the intensive care unit (ICU) with neurological issues or deficits have a higher mortality risk. Even after recovering and leaving the ICU, patients may develop long-term neurological conditions such as depression, obsessive compulsive disorder, psychosis, Parkinson’s disease, and Alzheimer’s disease. ICU patients who take numerous medications or have pre-existing medical conditions can develop memory loss, slow processing speed, delirium, or even coma. Patients with multiple sclerosis, amyotrophic lateral sclerosis, and respiratory dysfunction may struggle to survive ICU hospitalization, and those on immunosuppressive medications may decline faster.


Effects of ICU Admission on COVID Patients with Neurological Issues

Effects on the nose, cranial nerves and brain
1) Anosmia and ageusia caused by inhibition of nasal and gustatory epithelial cells
2) Vessel occlusion in cerebral arteries caused by activation of cytokines and hypercoagulation pathways in the blood
3) Blood clots in the cerebral veins leading to cerebral venous thrombosis.
4) Seizures and/or encephalopathy from high levels of cytokines in the cerebral vessels damaging the blood-brain barrier, infiltrating the brain, and damaging neurons and glia 
5) Meningitis from artery damage
6) Cranial nerve damage from formation of auto-antibodies (molecular mimicry)

Figure 2. Pathophysiology of Neurological Abnormalities in COVID-19

Most researchers believe the neurological effect of the virus are an indirect result of either oxygen starvation to the brain (the “happy hypoxia” exhibited by many patients), or the byproduct of the body’s inflammatory response (the famed “cytokine storm”).  A pateints MRI brain scan showed signs of viral meningitis (inflammation of the brain), and a lumbar puncture detected Sars-CoV-2 in his cerebrospinal fluid.  Another patient had viral particals detected in the  endothelial cells lining the blood vessels of the brain itself. In fact, some scientists now suspect that the virus causes respiratory failure and death not through damage to the lungs but through damage to the brainstem.

How COVID-19 can damage the brain

- Stage I: anosmia, ageusia

- Stage II: blood clots, PNS damage

-Stage II: seizures, coma, encephalopathy


Figure 4. NeuroCovid Stages (a Theoretical Framework of Neurological Decline in Patients with COVID-19)

Even in the absence of typical respiratory symptoms such as fever, cough, and shortness of breath, various patients diagnosed with COVID-19 have presented neurological symptoms, such as:

- acute cerebrovascular diseases

- impaired consciousness

-  skeletal muscle injury

- encephalopathy (symptoms: ischemic stroke)

- loss of smell (anosmia) and taste (ageusia)

- stroke

- cranial nerve deficits

- delirium

- meningitis

- paralysis

- seizures

- neuroinflammatory syndromes

- high pressure CSF

- muscle stiffness

The list below includes less-common neurological symptoms of COVID-19:
- Guillain–Barré syndrome (GBS)
- Multisystem Inflammatory Syndrome in Children (MIS-C)

Smith College

University of Michigan - Ann Arbor

Syracuse University

Michigan State University

COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Effects of COVID-19 on the Central Nervous System

Nervous system diseases affect the brain, spinal cord and nerves. These include structural, biochemical and electrical damages. Below are a few lists of diseases covered in 1Cademy:
- Guillain–Barré syndrome (GBS)
- Encephalopathy
- Anosmia
- Seizures
- Stroke
- Paralysis
- Ageusia

Neurological Diseases

Some COVID-19 patients have presented with peripheral neurological symptoms. Although it is not a common complication of COVID-19, it is worth investigating all possible causes of the neurological symptoms that arise.

Effects of COVID-19 on the Peripheral Nervous System

The most common symptoms of COVID-19 are fever, tiredness, and dry cough. Some patients may have aches and pains, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are usually mild and begin gradually. Most people (about 80%) recover from the disease without needing special treatment. 

Symptomatic COVID-19 Infection

The scientific field of study of nervous system function and development. The human nervous system is comprised of the central (brain and spinal cord) and peripheral  (nerves and ganglia branching from brain and spinal cord) nervous systems. These are referred to as the CNS and PNS, respectively.

Neuroscience (Neurobiology)

Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., ... & Li, Y. (2020). Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study.

https://jamanetwork.com/journals/jamaneurology/fullarticle/2764549

Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study

Fotuhi, M., Mian, A., Meysami, S., & Raji, C. A. (2020). Neurobiology of COVID-19. Journal of Alzheimers Disease, 76(1), 3-19. doi:10.3233/jad-200581
https://content.iospress.com/articles/journal-of-alzheimers-disease/jad200581

Neurobiology of COVID-19

Many of the known coronaviruses are neurotropic, meaning they are able to infect neuron cells.  If these observed trends carry over to SARS-CoV-2, they could help to elucidate how the CNS is affected by COVID-19.  Some of the key observations include:

- human coronavirus OC43 was shown to transmit itself to different neurons via axons in mice
- neuronal ACE2 expression in mice was found to be in different pre-autonomic regions of the brain which could explain why infected COVID-19 patients with dangerously low blood oxygen levels don't gasp for air
- SARS-CoV was found to infect regions of the brain that deal with cardiopulmonary regulation in human ACE2 knock-in mice
- SARS-CoV patient autopsies showed that the virus affected neurons more than any other kind of cell

Trends in Other Coronaviruses Affecting the CNS
 Relevant to COVID-19

- Neuronal ACE2 Expression as a Risk Factor for COVID-19
- Neuronal ACE2 Internalization in COVID-19
- ACE2 Expression in BBB
- ACE2 Expression in neuroglial cells
- ACE2 Expression in the ENS and Choroid Plexas

ACE2 and its Implications in SARS-CoV2 infection of the CNS

- Autoimmune Response Contribution to Neurological Symptoms.
- Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Indirect/Downstream effects of SARS-CoV-2 on the CNS.

Neurological symptoms Presented in COVID-19 Patients

- Brain degeneration

- Cognitive decline

- Mental disorders


Expected Long-Term Outcomes of Acute SARS-Cov2 Infection on CNS

- Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS
- Controversy: Is SARS-CoV-2 "Neuroinvasive"?

Direct Effects of SARS-CoV-2 on the CNS.

Guillain-Barré syndrome occurs when the immune system attacks the peripheral nervous system, causing damage to the nerves. It is characterized by muscle weakness, and in some cases, paralysis. 

Guillain-Barré Syndrome (GBS)

Encephalopathy is an umbrella term for damages and diseases to the brain. They include, but are not limited, to the following:
- Ischemic Stroke
- Ophthalmoparesis

Encephalopathy 

Anosmia, is the temporary or permanent loss of smell. It is also called smell blindness. It can be caused due to inflammation of the nasal passage or due to brain damage. Anosmia caused due to brain damage is permanent and can not be treated. While the loss of smell due to inflammation can be treated with glucocorticoids. This neurological disorder can have a myriad of harmful effects ranging from an increase in gas leak incidents to loss of appetite, as the person is unable to taste food properly.
Anosmia is one of the primary symptom of COVID-19. Around 80% of infected patients face the loss of smell at some point during the infection. 


Anosmia

A seizure is characterised by uncontrolled shaking followed by unconsciousness. It may also lead to loss of bladder control. Seizures are caused due to abnormal excessive or synchronous activity in the brain. Commonly called epileptic seizures, they may take around 2 minutes to subside. They can be caused due to hypoxic ischemic encephalopathy, central nervous system infections, trauma, congenital CNS abnormalities, metabolic disorders, sleep deprivation, brain tumor etc. 

Seizures

Stroke is characterised by the loss of movement or the ability to feel one part of the body, loss of vision, problems understanding or speaking, dizziness. It is caused due to poor blood flow to the brain, which cause faulty functioning. There may be a poor blood flow due to internal bleeding (hemorrhagic stroke) or due to lack of blood flow (ischemic stroke). The symptoms of a stroke may be permanent. 

Stroke

Paralysis is caused by damage to the nervous system and is characterised as the loss of motor function in one or more muscles. It can also accompany loss of sensation if there is a damage to the sensory part too. Apart from nervous system injuries it can be caused due to certain drugs, stroke, trauma, ALS and other neurological diseases. 

Paralysis

Ageusia is characterised as the loss of taste function of the tongue, particularly the loss to detect sweet, salty, bitter and sour flavor. Often times confused with anosmia, it is one of the symptoms of COVID-19. It may be caused due to head injury, upper respiratory tract infection, exposure to toxic substances, medicines etc. 

Ageusia

Delirium is a state of acute confusion, caused due to deteriorating baseline mental functioning. It is characterised by disturbances in attention, consciousness, and cognition, along with neurological defects which may include psychomotor disturbances, impaired sleep-wake cycle, emotional disturbances, and perceptual disturbances. Causes of delirium include disease in the brain, side effect of medication, withdrawal from drugs, over-consumption of alcohol, usage of hallucinogenic deliriants. 

Delirium

Neurodegenerative diseases refers to neurological diseases caused by neuronal death or deterioration due to many factors, including protein aggregation/misfolding, apoptosis, and mitochondrial dysfunction. 

Neurodegenerative Diseases

Support for indirect over direct causes of neurological symptoms:
- Cerebralspinal fluid (CSF) samples in some CoV-2 patients have shown the presence of SARS-CoV-2 antibodies (anti-S1 IgM) and increased multiple cytokines, suggesting a possible CoV-2 direct infection of the CNS (Benameur et. al). However, this coupled with low levels of CSF and plasma viral RNA in patients, suggests that the neurological symptoms present may be a result of autoimmune responses, rather than direct infection.

Support for autoimmunity:
- the anti-neuronal and anti-glial autoantibodies presence in CSF and serum lends support of a causal relationship between autoimmunity and neurological clinical symptoms (Franke et. al)
- transcriptomic data from COVID-19 patients, control samples, and mice studies, reveal evidence of virus-driven cell lysis (Ray et. al)

COVID-19 Neurological Effects as a Result of Autoimmunity in the PNS

1. Mild

2.  Moderate

3. Severe

4. Critical

The Severity of  COVID-19 Symptoms

Studies have identified various trends in symptoms of COVID-19 patients by age groups 

Symptoms of COVID-19 by Age Groups

Until April 26, 2020, CDC warned of the three symptoms that may be indicative of COVID-19; fever, cough and shortness of breath.  As of July 9, 2020, the center added ten more symptoms to the list, now totaling thirteen symptoms listed below that may indicate the existence of the disease: 

As of July 9, 2020:
- Cough
- Shortness of breath or difficulty breathing
- Fever
- Chills
- Repeated shaking with chills
- Muscle pain
- Headache
- Sore throat
- New loss of taste or smell
- Sore throat
- Congestion or runny nose
- Nausea or vomiting
- Diarrhea


CDC List of COVID-19 Symptoms

Studies of COVID-19 Symptoms by Geographic Location

Around 1 out of every 6 people who gets COVID-19 becomes seriously ill and develops difficulty breathing.  Other factors may increase the risk of severe symptoms

Rate of Appearance of Severe Symptoms

As of July 9, 020, the CDC has warned that people look for the following emergency warning signs for COVID-19 that need medical attention:
- Trouble breathing
- Persistent pain or pressure in the chest
- New confusion
- Inability to wake or stay awake
- Bluish lips or face

Symptoms that Call for Medical Attention

This data has been drawn from the research firm Dynata examining symptom reporting by Americans released in July of 2020.  Symptoms are most commonly reported among those living in extreme poverty or extreme wealth, with lower reporting of those among middle incomes.  A similar pattern is demonstrated among those with remarkably little educational achievement and those with remarkably high educational achievement.  Although data is not selected from a representative sample, sample sizes are large.

Symptoms of Covid-19 by Socio-economic Group in US

The study of the physiological basis for cognition.

Cognitive Neuroscience

- Brain
- Neurons
- Peripheral nervous system (PNS)
- Neurological diseases
- Central nervous system (CNS)

Focuses of neuroscience (neurobiology) 

An intersection between psychology, neuroscience and economics that studies how brain activation corresponds with decisions of gains and losses.

Neuroeconomics

As the relapse prevention model discusses, many individuals recovering from addiction return to their behavior at some point during/after treatment. Researchers have begun to look at this idea of relapse and relapse prevention from a neuroscience perspective. This perspective could help further the understanding of why, on a brain level, individuals relapse and how we could possibly help. There is not a large consensus yet, but the research is looking at many factors including pathways, styles, and stages of recovery, as well as the possibility of reversing or diminishing the brain dysregulation that results from addiction.

Neuroscience approach to relapse and relapse prevention

The study of behavior, emotion, and cognition and how they relate to brain function

Neuropsychology

This looks at how behavior and the environment are affecting the neural development of humans through their lifetime.

Behavioral Neuroscience

Discipline that is concerned with hormonal development, its interaction with the nervous system, its secretion and associated physiological and behavioral effects.

Neuroendocrinology

A distinct line of inquiry with the goal of understanding which systems of the brain are activated during mindfulness practice to determine the effects that both short and long-term practice has on brain function and structure.

Neurobiology of Mindfulness

The study of Emotion Regulation within the lens of Neurobiology. More specifically, understanding what brain functions correspond to Emotion Regulation. 

The Neurobiology of Emotion Regulation

Biopsychology, also known as biological psychology, is a subfield of psychology that examines the influence of biological processes on behavior. It typically focuses on the immediate causes of behavior rooted in the physiology of an organism, with a primary emphasis on the nervous system's structure and function. This field is highly interdisciplinary, drawing on expertise from researchers with backgrounds in biology, medicine, physiology, and chemistry, and is considered a key component within the broader field of neuroscience.

Biopsychology (Biological Psychology)

A human's nervous system is in charge of managing our cognitions, movements, and responses. It is comprised of billions of neurons, glial cells, and the central and peripheral nervous systems. 

Nervous System

A person accidentally touches a hot surface and immediately withdraws their hand. Which of the following best analyzes the roles of the two major divisions of the nervous system in this reflex action?

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