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Anoxic Brain Injury: Causes, Symptoms, and Treatment | Shepherd Center

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What are anoxic brain injuries and hypoxic brain injuries?

Unlike traumatic brain injuries, in which brain damage is induced by direct physical trauma, anoxic brain injuries and hypoxic brain injuries are characterized by brain damage from a lack of oxygen to the brain. These brain injuries are commonly associated with strokes, although strokes are not the only cause of this type of brain damage.
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What Is an Anoxic Brain Injury?

Anoxic brain injuries are caused by a complete lack of oxygen to the brain, which results in the death of brain cells after approximately four minutes of oxygen deprivation.

What Is a Hypoxic Brain Injury?

Hypoxic brain injuries are brain injuries that form due to a restriction on the oxygen being supplied to the brain. The restricted flow of oxygen causes the gradual death and impairment of brain cells.

Causes of Anoxic Brain Injuries and Hypoxic Brain Injuries

Hypoxicischemic injury, also known as stagnant anoxia, may:

occur when oxygen-carrying blood cannot reach the brain, resulting in oxygen deprivation.

be caused by strokes, but can also be caused by other pulmonary conditions, such as cardiac arrest or cardiac arrhythmia.

Anemic anoxia: Anemic anoxia occurs when the blood cannot properly carry enough oxygen or if there is not enough blood in the body itself to support the oxygen needs of the brain (i.e., lack of oxygen to the brain).

Toxic anoxia: Toxic anoxia occurs when chemicals or poisons hinder the ability of the brain to receive oxygen from blood cells.

Anoxic anoxia: Anoxic anoxia is caused by the lack of oxygen in the air, resulting in suffocation.

Lack of Oxygen to the Brain Symptoms

Anoxic brain injuries and hypoxic brain injuries often cause an initial loss of consciousness, which can be short-term or long-term, depending on the severity and length of oxygen deprivation. Initial loss of consciousness may result in a comatose state. Other anoxic or hypoxic brain injury symptoms may include slurring and difficulties with speech, confusion, disorientation, or facial drooping.

Upon regaining consciousness, the effects and symptoms are often similar to that of a traumatic brain injury, depending on severity of the injury. More severe anoxic or hypoxic brain damage may leave the patient in a vegetative state. The effects of an anoxic brain injury may include:

headache

difficulty coordinating balance

vision problems

seizures

changes in sensory perception

trouble speaking and swallowing

changes in sleep pattern

lack of bowel and bladder control

changes in sexual function

motor impairment

personality changes

difficulty forming sentences

confusion

trouble communicating

difficulty with reason, focus and logic

memory impairments

depression

poor concentration

mood swings

limited attention span

disorientation

forgetfulness

acting inappropriately

Prognosis of Anoxic Brain Injuries or Hypoxic Brain Injuries

Projecting the recovery and care for anoxic brain injuries or hypoxic brain injuries is difficult because each case is unique. A full recovery from severe anoxic or hypoxic brain injury is rare, but many patients with mild anoxic or hypoxic brain injuries are capable of making a full or partial recovery. Furthermore, symptoms and effects of the injury are dependent on the area(s) of the brain that was affected by the lack of oxygen.

Anoxia and Hypoxia Treatment

The overall life expectancy for patients with anoxic brain injuries or hypoxic brain injuries can vary based on the severity of the brain damage from lack of oxygen and is something that should be discussed with a patient's physician. Reach out to Shepherd Center today to discuss treatment options for anoxia or hypoxia and learn about our specialists now.
Meet Our ABI Specialists

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Anoxic Brain Injury: Causes, Symptoms, and Treatment | Shepherd Center

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Discover the causes, symptoms, and treatment options for anoxic brain injury and anoxic encephalopathy at Shepherd Center.

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Scientists Are Giving Dead Brains New Life. What Could Go Wrong? (Published 2019)

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Scientists Are Giving Dead Brains New Life. What Could Go Wrong? (Published 2019)

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In experiments on pig organs, scientists at Yale made a discovery that could someday challenge our understanding of what it means to die.

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SARS-CoV-2 Crosses Placenta and Infects Brains of Two Infants

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Neonatal brain injury Via Covid Infected Mother 

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Neonatal brain injury Via Covid Infected Mother 

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Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics.

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

"This is a first," said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children's Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children's Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby's.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

"However, (these) two babies had a very unusual clinical picture," Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

"We had absolutely no good explanation for the early seizures and the degree of brain injury we saw," Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center's multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant's autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, "I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That's what triggered the investigation."

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies' presentations was hypoxic ischemic encephalopathy. "But it wasn't lack of blood flow to the placenta that caused this," he said. "As best we can tell, it was the viral infection."

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, "This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We're trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies."

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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SARS-CoV-2 Crosses Placenta and Infects Brains of Two Infants

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It is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.

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Spike Protein Accumulates in Brain and Skull and Causes Damage. Brand New Study

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Spike Protein Accumulates in Brain and Skull and Causes Damage. Brand New Study

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Brand New Study: Spike Protein Accumulates in Brain and Skull and Causes DamageIf you like this content and want more, I am doing a special lifetime membersh...

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Can COVID-19 alter your personality? Here's what brain research shows.

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At the height of the COVID-19 tsunami that engulfed New York City in early 2020, a highly respected emergency room doctor, Lorna Breen, died by suicide. She had been serving as medical director at Manhattan's NewYork Presbyterian Allen Hospital, and she was regarded as brilliant, energetic, and organized. She had no history of mental illness. But that changed after Breen contracted the virus.

The 49-year-old doctor first showed symptoms on March 18. After a 10-day illness, she returned to work. Her family was alarmed: She was confused, hesitant, nearly catatonic, exhausted. Something was wrong. They brought her home to Charlottesville, and Breen checked into a psychiatric ward at University of Virginia Medical Center. Soon after she was released on

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Can COVID-19 alter your personality? Here's what brain research shows.

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At the height of the COVID-19 tsunami that engulfed New York City in early 2020, a highly respected emergency room doctor, Lorna Breen, died by suicide. She had been serving as medical director at Manhattan's NewYork Presbyterian Allen Hospital, and she was regarded as brilliant, energetic, and organized.

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COVID can cause long-term damage to lungs, brain and kidneys, study finds

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COVID can cause long-term damage to lungs, brain and kidneys, study finds

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The research was carried out by Betty Raman, Associate Professor of Cardiovascular Medicine , at the University of Oxford.

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Even mild Covid is linked to brain damage months after illness, scans show

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During at least the first few months following a coronavirus infection, even mild cases of Covid-19 are associated with subtle tissue damage and accelerated losses in brain regions tied to the sense of smell, as well as a small loss in the brain's overall volume, a new British study finds. Having mild Covid is also associated with a cognitive function deficit.

These are the striking findings of the new study led by University of Oxford investigators, one that leading Covid researchers consider particularly important because it is the first study of the disease's potential impact on the brain that is based on brain scans taken both before and after participants contracted the coronavirus.

"This study design overcomes some of the major limitations of most brain-related studies of Covid-19 to date, which rely on analysis and interpretation at a single time point in people who had Covid-19," said Dr. Serena S. Spudich, a neurologist at the Yale University School of Medicine, who was not involved in the research.

Full coverage of the coronavirus pandemic
The research, which was published Monday in Nature, also stands out because the lion's share of its participants apparently had mild Covid - by far, the most common outcome of coronavirus infections. Most of the brain-related studies in this field have focused on those with moderate to severe Covid.

Gwenaëlle Douaud, an associate professor at the Nuffield Department of Clinical Neurosciences at Oxford and the paper's lead author, said that the excess loss of brain volume she and her colleagues observed in brain scans of hundreds of British individuals is equivalent to at least one extra year of normal aging.

"It is brain damage, but it is possible that it is reversible," she said. "But it is still relatively scary because it was in mildly infected people."

Douaud and her team relied on a rich data source: the United Kingdom Biobank. Before the Covid pandemic began, this mammoth database already had on hand tens of thousands of brain MRIs of people in Britain, along with responses to surveys about their diets and lifestyles and results from cognitive function tests.

The investigators focused on 401 people between 51 and 81 years old who had tested positive for Covid according to clinical data linked to the Biobank study. They were invited back for a second brain scan, which they received an average of about five months after contracting the coronavirus. Covid was apparently mild in the vast majority of these participants; only 15 of them were hospitalized with the disease.

The researchers compared these pairs of scans to those of a control group of 384 U.K. Biobank participants who had not tested positive for Covid and were matched according to the Covid-positive group's rates of obesity, blood pressure, smoking and diabetes, as well as their socioeconomic status, age and sex.

Between the pairs of MRIs, which were separated by an average of about three years, the researchers observed a striking trend among those who had Covid: a greater loss of what's known as gray matter in the brain, as well as a higher rate of abnormalities in the brain tissue. Gray matter, which appears gray on certain brain scans, is comprised of various cells, including neurons.

It would be normal for adults within the study's age range to lose a small amount of brain tissue after three years of aging, the researchers note. But compared with the control group, those who had Covid experienced an additional 0.2 percent to 2 percent loss of brain tissue in regions which are mostly associated with the sense of smell - specifically, in the parahippocampal gyrus, the orbitofrontal cortex and the insula.

The overall brain volume in people with Covid declined by an extra 0.3 percent over those without the disease.

Older participants experienced all these excess brain-related declines more profoundly.

The study offers no indication whether a Covid vaccination would mitigate the risk of such changes. The participants tested positive for the disease between March 2020 and April 2021, before the vaccines were widely available in the U.K.

On cognitive function tests, those who had Covid demonstrated a slower ability to process information and had lower marks on what's known as executive function, which is an umbrella measure of the brain's ability to manage complex tasks. Again, these Covid-linked deficits were more pronounced among older individuals.

Dr. Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, said that these findings "have long-term implications, since we would be concerned about the possibility of similar cognitive dysfunction in a large population worldwide."

"It needs to be determined if these patients could further deteriorate over a period of time," he said.

The investigators had no access to data on any Covid-related symptoms the participants may have experienced. So they don't know if the participants actually lost their sense of smell or have experienced long-term symptoms in the disease's wake. Some likely had asymptomatic cases.

That said, the loss of smell was particularly prevalent among those infected with the coronavirus during the first two major waves of the pandemic. And when particular regions of the brain go unused, they are inclined to atrophy. Nevertheless, the study's authors don't know whether the coronavirus caused a loss of smell through a nonbrain-based mechanism and this, in turn, prompted the brain damage, or if possibly the brain damage caused the loss of smell.

A study published in Cell in February found that a coronavirus infection of various cells in the nasal cavity gives rise to inflammation that inhibits the functioning of smell-receptor proteins on nerve cells, leading to smell loss.

"The brain is plastic, which means it can reorganize and heal itself. This is true even in older people.
Gwenaëlle Douaud, University of Oxford
Covid's link to declines in the smell-related brain regions, Douaud said, does not discount the other ways that it might impact the brain in regions unrelated to smell. The disease has proved maddeningly variable from patient to patient, and other studies have identified various means by which severe Covid in particular might damage the brain. What the study revealed is that changes to the smell-related regions were the most consistent brain-related trend tied to Covid in the study cohort.

Whether these changes will persist over the long term remains unknown. Douaud is hoping to conduct a third round of brain scans.

"The brain is plastic, which means it can reorganize and heal itself," she said. "This is true even in older people."

Experts in long Covid praised Douaud's paper.

"This study provides the most definitive clinical data available to date that SARS-CoV-2 directly or indirectly damages nerves and that this, in turn, can have systemic effects, including changes in the brain," said Dr. Steven Deeks, a veteran HIV researcher at the University of California, San Francisco. "It contributes to an emerging theme that nerve damage was common during the first few waves of the pandemic."

Deeks, who is directing a major cohort study of people suffering from persistent symptoms following a coronavirus infection, noted a limitation of the new study. Those who got Covid, he pointed out, had some differences in their baseline cognitive function and in some of the initial brain scans compared with those who did not get the disease.

"It is possible, but perhaps unlikely," he said, "that those who had higher risk for becoming infected were destined to progress more rapidly in the changes in their brain for other unmeasured reasons."

That said, having the pairs of brain scans before and after an infection provided Douaud and her colleagues with a unique ability to factor out brain abnormalities that might have already been present before individuals developed Covid and therefore were not likely connected to the disease.

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Even mild Covid is linked to brain damage months after illness, scans show

# data[].attributes.attachment_link.description
During at least the first few months following a coronavirus infection, even mild cases of Covid-19 are associated with subtle tissue damage and accelerated losses in brain regions tied to the sense of smell, as well as a small loss in the brain's overall volume, a new British study finds.

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Remotely controlled chemomagnetic modulation of targeted neural circuits - Nature Nanotechnology

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Authors and Affiliations

1. Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA

Siyuan Rao, Michael G. Christiansen, Alexander W. Senko, Po-Han Chiang, Georgios Varnavides, Seongjun Park, Junsang Moon & Polina Anikeeva

2. Simons Center for Social Brain, Massachusetts Institute of Technology, Cambridge, MA, USA

Siyuan Rao & Ritchie Chen

3. Department of Bioengineering, Stanford University, Stanford, CA, USA

Ritchie Chen

4. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

Ava A. LaRocca, Michael G. Christiansen, Alexander W. Senko, Cindy H. Shi, Georgios Varnavides, Junsang Moon & Polina Anikeeva

5. Department of Health Sciences and Technology at the Swiss Federal Institute of Technology in Zürich (ETHZ), Zürich, Switzerland

Michael G. Christiansen

6. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

Georgios Varnavides & Ruihua Ding

7. McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA

Jian Xue, Yang Zhou, Guoping Feng & Polina Anikeeva

8. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

Jian Xue, Yang Zhou, Guoping Feng & Polina Anikeeva

9. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA

Seongjun Park

10. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

Ruihua Ding

Contributions

S.R., R.C. and P.A. designed all the experiments and performed all the analyses. M.G.C. and A.W.S. designed and constructed the magnetic field coils. S.R., R.D. and J.M. developed the magnetoliposome preparation methods. P.-H.C. constructed the DNA plasmids. S.R. and J.X. packaged the viral vectors. S.R., A.A.L., C.H.S. and Y.Z. conducted behavioural experiments and analyses. S.R., A.A.L. and C.H.S. conducted the immunohistochemistry analyses. G.V. and A.A.L. wrote the scripts for the automatic classifier used for the FST assays. C.H.S. wrote the scripts for calcium imaging visualization and social behaviour analyses. G.F. advised on social preference assays and facilitated the analysis of behavioural data. S.R. and S.P. conducted the statistical analysis. All the co-authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to Polina Anikeeva.

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Remotely controlled chemomagnetic modulation of targeted neural circuits - Nature Nanotechnology

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Controlled delivery of neuromodulators in the brain might improve the understanding of the molecular basis of behaviour. In this letter, magnetic liposomes injected in deep brain regions release small molecules under remote magnetic stimulation, activating specific neuronal circuits in freely moving mice.

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Genetically targeted magnetic control of the nervous system - Nature Neuroscience

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Michael A Wheeler orcid.org/0000-0002-0689-6384 1,2,

Cody J Smith 1 na1,

Matteo Ottolini 3 na1,

Bryan S Barker 2,3,

Sarah Kucenas 1,5,

Christopher D Deppmann 1,5,6 &

...

Ali D Güler 1

Show authors
Nature Neuroscience 19, 756-761 (2016) Cite this article

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Abstract

Optogenetic and chemogenetic actuators are critical for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or slow on/off kinetics. We have overcome these disadvantages by synthesizing a single-component, magnetically sensitive actuator, "Magneto," comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin. We validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together our results present Magneto as an actuator capable of remotely controlling circuits associated with complex animal behaviors.

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Change history

28 March 2016

In the version of this article initially published online, first, a relevant citation was omitted. To correct this, the sixth sentence of the introduction, which originally read "one study employed nonthermal magnetogenetic control of somatic tissues to regulate blood glucose ¹¹, but a genetically encoded, single-component magnetogenetic system has yet to be applied to the nervous system," has been rewritten to say "one study employed nonthermal magnetogenetic control of somatic tissues to regulate blood glucose ¹¹ and another utilized a naturally occurring iron-containing magnetoreceptor to trigger neuronal activity ⁴⁸, but a genetically encoded, single-component magnetogenetic system has yet to be applied to the nervous system of behaving vertebrates." Ref. 48 is provided as follows: Long, X., Ye, J., Zhao, D. & Zhang, S.J. Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor. Sci. Bull. (Beijing) 60, 2107-2119 (2015). Second, the author contribution statement incorrectly listed M.P.B as having performed experiments. This has been corrected to say that M.P.B. provided conceptual help during the development of the prototype channel. Finally, the reporter construct in the right panel of Figure 2e was mislabeled Camk2a::Cre-EGFP. This control construct should have been labeled Camk2a::EGFP. The errors have been corrected for the print, PDF and HTML versions of this article.

References

Jeong, J.W. et al. Wireless optofluidic systems for programmable in vivo pharmacology and optogenetics. Cell 162, 662-674 (2015).

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Acknowledgements

We thank members of the Condron, Beenhakker, Kucenas, Patel, Deppmann and Güler labs for comments and suggestions. In particular, we are thankful for technical assistance provided by A. Morris, P. Neff, A. Rainwater and S. Young. We are thankful for comments on the manuscript from M. Caterina, I. Cheng, B. Condron, K. Gamage and I. Provencio. We acknowledge the UVa Keck Center for Cellular Imaging staff for use of the Leica confocal microscopy system, supported by US National Institutes of Health (NIH) National Center for Research Resources RR025616. This work was supported by NIH National Institute of General Medical Sciences (NIGMS) 5T32GM008328, NIH NIGMS 5T32GM008136, a Neuroscience Center of Excellence fellowship and a Wagner Fellowship (M.A.W.); NIH National Institute of Neurological Disorders and Stroke (NINDS) F32NS087791 (C.J.S.); NIH NINDS R01NS072212 (S.K.); NIH NINDS R01NS075157 (M.K.P.); NIH NINDS R01NS072388 (C.D.D.); and UVa startup funds (A.D.G.).

Author information

Author notes

Cody J Smith and Matteo Ottolini: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Biology, University of Virginia, Charlottesville, Virginia, USA

Michael A Wheeler, Cody J Smith, Aarti M Purohit, Ryan M Grippo, Anthony J Spano, Sarah Kucenas, Christopher D Deppmann & Ali D Güler

2. Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA

Michael A Wheeler & Bryan S Barker

3. Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA

Matteo Ottolini, Bryan S Barker, Ronald P Gaykema & Manoj K Patel

4. Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA

Mark P Beenhakker

5. Department of Cell Biology, University of Virginia, Charlottesville, Virginia, USA

Sarah Kucenas & Christopher D Deppmann

6. Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA

Christopher D Deppmann

Contributions

M.A.W. and A.D.G. designed the study. M.A.W., C.J.S., M.O., B.S.B., A.M.P., R.M.G., R.P.G. and A.J.S. performed the experiments. M.A.W., C.J.S., M.O., B.S.B., A.M.P., R.M.G., M.K.P., C.D.D. and A.D.G. analyzed the data. M.P.B. provided conceptual help during the development of the prototype channel. S.K., M.K.P., C.D.D. and A.D.G. supervised the research. M.A.W. and A.D.G. wrote the manuscript with input from coauthors.

Corresponding author

Correspondence to Ali D Güler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

( a) The cation channel, TRPV4, is gated by stretch (among other diverse classes of stimuli), to depolarize cells. For simplicity, only two of the four homomeric subunits are shown. ( b) Coupling ferritin to the TRPV4 C-terminus converts TRPV4 to a magnetic field detector. Gating properties were extrapolated from published descriptions of TRPV1 and TRPA1 gating mechanisms ⁴⁸⁻⁵⁰.

48. Cao et al. (2013) Nature 504, 113-118.

49. Liao et al. (2013) Nature 504, 107-112.

50. Paulsen et al. (2015) Nature 520, 511-517.

Empirical determination of the strength of several electromagnets over distance powered by an identical current. Dashed line represents distance between HEK cells and electromagnet during calcium imaging assays. A 3 cm diameter magnet was used for all calcium imaging assays. Δx represents distance between magnet and cells used in calcium imaging.

Source data

( a) Mammalian expression vector schematic of Magneto1.0. ( b-g) Representative images of HEK293 cells used for in vitro magnetic stimulation Fluo-4 calcium imaging. ( h) Quantification of relative calcium fluorescence in response to magnetic stimulation of mCherry+ cells. Replicates are shown as individual coverslips equaling n=6 (TRPV4/ferritin), n=8 (Magneto1.0), and n=6 (Magneto1.0+RR). Total cells analyzed for each condition are n=545 (TRPV4/ferritin), n=565 (Magneto1.0), and n=437 (Magneto1.0+RR). One-way ANOVA, Bonferroni post-test, (F 2,17=7.509, p=0.0046). ( i) Representative images of temporal association between calcium fluorescence and magnetic field pulses in an individual Magneto1.0-expressing cell (arrow). Field was pulsed for alternating 10 second periods of on/off. *p<0.05. Data are shown as mean±SEM.

Source data

( a-e) HEK293 cells transfected with mCherry-fused variants of Magneto1.0 with combinations of various inwardly rectifying K+ channel 2.1 (Kir2.1) trafficking signals. ( a) Magneto1.0-mCherry shows diffuse cellular localization, poor membrane expression, and poor transfection efficiency. ( b) Addition of ER export signal from Kir2.1 to C-terminus of Magneto1.0-mCherry peptide partially improves Magneto expression. ( c) Addition of Kir2.1 membrane trafficking signal (TS) significantly improves membrane expression of Magneto. ( d) Dual addition of membrane trafficking and ER export signals improves expression relative to Magneto1.0 but not relative to a single membrane trafficking signal. ( e) Tandem Kir2.1 membrane trafficking/ER export signals on Magneto1.0 C-terminus improves expression but not relative to c. n=2 coverslips and >100 cells analyzed per trafficking modification examined.

( a-d) Viability of Magneto2.0 transfected HEK293 cells several days post transfection (DPT). Images show bright field and mCherry fluorescence. Zoom increased in ( c-d) to increase single cell resolution following significant cell division. Images are representative of n>100 cells examined.

( a) Graph of Fluo-4 fluorescence using HEK293 cells transfected with Magneto2.0-p2A-mCherry and treated with thapsigargin over a period of 60 minutes. Arrow indicates addition of 1 μM thapsigargin to the imaging chamber after a 30 second baseline recording of calcium fluorescence. Dashed box indicates analysis window for "thapsigargin" experiments in panel b. n=114 cells analyzed from 3 independent replicates. ( b) Time course showing the magnetic activation of Magneto2.0 expressing cells in the presence and absence of thapsigargin. All cells from one replicate shown per condition, n=102 cells (Magnet) and n=52 cells (Thapsigargin). In the "thapsigargin" condition, cells were pre-treated with 1μM thapsigargin and calcium imaging was initiated 30 minutes post-thapsigargin treatment during the window (dashed box) shown in panel a. ( c) Quantification of maximal calcium fluorescence of HEK293 cells expressing Magneto2.0 and subjected to the above conditions using Fluo-4 calcium imaging 24 hours post-transfection. Values shown are the average maximal Fluo-4 fluorescence values per cell relative to baseline for each condition. Data points are shown as total cell averages among individual coverslips. n=114 (Thapsigargin) and n=396 (Magnet) cells analyzed from n=3 (Thapsigargin) and n=5 (Magnet) independent replicates. Welch's two-tailed unpaired t-test, (t 2.882=4.457, p=0.0395). "Magnet" data are duplicated from Figure 1. *p<0.05. Data shown as mean±SEM.

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( a) Representative trace showing that injection of depolarizing current evokes spikes in doubly transduced EGFP+ Magneto2.0 expressing neurons. ( b) No change in AP latency between conditions of current injection or magnetic field application in transduced neurons (measured from time immediately preceding depolarization). Unpaired two-tailed t-test, (t ₂₂=1.628, p=0.1178) (threshold), (t ₂₂=1.676, p=0.1079) (peak). ( c-g) Membrane properties are unchanged under conditions of either current injection or magnetic stimulation in hippocampal neurons doubly transduced with CMV::DIO-Magneto2.0 and CaMKIIα::Cre-EGFP. Unpaired two-tailed t-test, (t ₂₂=0.1926, p=0.8498) in c, (t ₂₂=1.335, p=0.1954) in d, (t ₂₂=0.1290, p=0.8985) in e, (t ₂₂=1.052, p=0.3042) in f, (t ₂₂=0.4086, p=0.6868) in g. ( h) Injection of depolarizing current evokes APs in Cre-negative DIO-Magneto2.0 transduced EGFP+ neurons. n=12 neurons analyzed for each condition shown in ( b-g). ns: not significant. Data shown as mean±SEM.

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( a) Paired traces depicting the onset of action potentials following current injection (black) and magnetic stimulation (red) for the same neuron co-transduced with AAVs carrying CaMKIIα::Cre-EGFP and CMV::DIO-Magneto2.0. Overlay shows a modest delay of action potential onset (50-100 ms) when neurons are stimulated with static magnetic fields. ( b) Magnified traces of the resting state from three additional neurons co-transduced with the above viruses. Neurons are shown immediately prior to action potential initiation as static magnetic fields are brought more closely to the cells using a micromanipulator, a process requiring roughly 1 second. Traces do not show interference coming from ∼50 mT static magnetic fields in close proximity to the recording apparatus.

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( a) Schematic of trans cardiac myosin light chain 2 (cmcl2)::GFP element and its expression in 24 hpf zebrafish embryos for positive transgenic selection. n>100 fish examined. ( b) Schematic of Magneto1.0 construct used: Tol2: Tol2 transposon sites; ß-Actin: promoter; IRES: internal ribosomal entry site; nls-EGFP: nuclear localized enhanced GFP. ( c) Quantification of the number of coils in WT (uninjected) and ß-actin::Magneto1.0 expressing 24 hpf zebrafish embryos in response to magnetic stimulation. n=43 WT, n=25 ß-actin::Magneto1.0 fish. Statistics determined by Chi-squared analysis, (Chi ² ₃=36.51, p<0.0001). ( d) Quantification of coiling rate in WT (uninjected) and ß-actin::Magneto1.0 expressing zebrafish. Replicates (number of individual fish) shown in columns. Statistics determined by one-way ANOVA, Bonferroni post-test, (F 3,64=3.89, p=0.0129). ***p<0.001, *p<0.05. Data are shown as mean±SEM.

Source data

( a) Maximal GCaMP3 calcium fluorescence change of mCherry+ (n=20 from 5 fish) and mCherry- (n=33 from 5 fish) neurons in response to magnetic field stimulation. Dashed line indicates average GCaMP3 fluorescence value for mCherry- neurons. (17/20 mCherry+ neurons exceed this fluorescence value). Unpaired two-tailed t-test, (t ₅₁=3.373, p=0.0014). ( b) Schematic of behavioral paradigm for induction of zebrafish coiling behaviors using magnetic stimulation. ( c) Schematic of Rohon-Beard neuron projections. ( d) Magneto2.0 expression construct. Tol2: transposon site; ngn1: neurogenin-1 promoter; IRES: internal ribosomal entry site; nls: nuclear localization signal; EGFP: enhanced green fluorescent protein; polyA: polyadenylation signal. ( e-f) In vivo imaging of Rohon-Beard neuron projections into the skin, n=10 fish examined per genotype. Inset: Magneto2.0+ (EGFP+/RFP+) and Magneto2.0- (EGFP-/RFP+) neurons. Data pooled from 2 injections per genotype. **p<0.01. Data shown as mean±SEM.

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( a) Quantification of the change in firing rate relative to baseline for low-frequency and high-frequency firing single units in the striatum in response to the D1R agonist SKF81297, n=7 (<5 Hz), n=8 (>5 Hz) units examined from one Drd1a::Cre mouse transduced with CMV::DIO-Magneto2.0, unpaired two-tailed t-test, (t ₁₃=2.192, p=0.0472). ( b) Picture of magnetic open field behavioral chamber. ( c) Quantification of change in linear velocity in open field for both groups (n=6 per genotype), unpaired two-tailed t-test, (t ₁₀=0.08856, p=0.9312). *p<0.05, ns: not significant. Data shown as mean±SEM.

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Supplementary information

Supplementary Figures 1-11 and Supplementary Table 1 (PDF 2785 kb)

Representative movies of ngn1::Magneto2.0-expressing zebrafish coiling behavior without magnetic field. Individual embryos are each roughly 0.5 mm in diameter. Movies shown at 8× speed. Length of original behavioral analysis is 2-3 min per video. (MP4 10104 kb)

Representative movies of ngn1::Magneto2.0-expressing zebrafish coiling behavior with magnetic field. Individual embryos are each roughly 0.5 mm in diameter. Movies shown at 8× speed. Length of original behavioral analysis is 2-3 min per video. (MP4 11210 kb)

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Wheeler, M., Smith, C., Ottolini, M. et al. Genetically targeted magnetic control of the nervous system. Nat Neurosci 19, 756-761 (2016). https://doi.org/10.1038/nn.4265
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Genetically targeted magnetic control of the nervous system - Nature Neuroscience

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Elucidation of structure-function relationships in the nervous system necessitates biological circuit control with genetic and temporal precision. Here the authors engineer a genetically encoded magnetically sensitive actuator, "Magneto," and remotely manipulate behavior in live zebrafish and mice. The magnetogenetic control over neural activity promises greater access to previously intractable tissues.

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How COVID-19 Affects the Brain, Even Long After an Infection

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Basic infection Is Causing Brain & Neuro Change For Some

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How COVID-19 Affects the Brain, Even Long After an Infection

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It’s been linked to brain fog, dementia, stroke, and more.

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Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic - Neurochemical Research

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The Role of Astrocytes in the Brain: May the Homeostatic Cells Par Excellence Become SARS CoV-2 Damage Effectors?

Astroglia control such a huge number of functions that they can be considered to take part in any circumstance in which there is a disturbance of cerebral homeostasis. In fact, following any brain insults, these cells become reactive by profoundly modifying their morphology and functions. This complex response is part of the homeostatic tasks that glial cells perform physiologically and has as its objective the containment of the damage and the return to a homeostatic condition. However, glia changes are not always restored in a timely manner thus causing brain damage. At the beginning of 2021, we hypothesized that the neuropsychiatric consequences of COVID-19 are maladaptive glial recovery to blame [ 1, 2]. This hypothesis is now reinforced by growing evidence which is summarized in the following paragraphs.

Glial cells are heterogeneous neural cells exerting a plethora of functions mainly aimed at preserving the central nervous system (CNS) homeostasis. Glial cells are usually classified into microglia and macroglia. This latter includes astrocytes, oligodendrocytes, and oligodendrocyte precursors, also known as NG-2 glia or synantocytes [ 3, 4]. Microglia are of myeloid origin; their precursors migrate into the neural tube early in development. Microglial cells undergo profound metamorphosis acquiring specific 'neural'-like morphology and expressing numerous receptors for neurotransmitters and neurohormones [ 5]. Microglial cells contribute to CNS physiology and are mounting CNS defence in pathology being the main immunocompetent cells of the nervous tissue. Microglia scan the tissue and modify their morphology and functions if and when necessary [ 6]. Microglia are crucial for the formation, shaping, and functioning of synapses [ 7, 8], fundamental for brain development during pre- and post-natal periods. Erratic execution of synaptic elimination by microglia during early post-natal life is associated with anomalous functional connectivity, hippocampal long-term potentiation impairment, and aberrant behaviours [ 9, 10]. Microglia activate phagocytosis to incorporate waste products, cellular debris, and pathogens. They could react to pro-inflammatory stimuli by releasing cytokines, chemokines, and reactive oxygen and nitrogen species [ 11].

Oligodendrocytes are macroglial cells chiefly responsible for the formation of the myelin sheath around axons, thus being a fundamental element of the brain connectome [ 12]. Oligodendrocytes also support axons through cytoplasmic-rich myelinic channels that allow bidirectional movement of macromolecules under the myelin sheath [ 12, 13, 14]. Oligodendrocytes originate from precursor cells mainly localized in the ventricular zones of the brain, from which they migrate to colonise the developing CNS and became mature cells. This process starts shortly before birth and continues lifelong. The maturation of oligodendrocytes is usually accelerated in case of CSN injury, aging, or brain diseases, in order to replace the lost myelin [ 15]. Functions of oligodendrocyte precursors, also known as NG-2 glia, remain to be fully characterised. These cells express several receptors and ion channels, their receive synaptic contacts and may contribute to homeostatic control of the nervous tissue. Since NG-2 glia can differentiate into oligodendrocytes, they play a role in myelination and brain plasticity [ 16, 17].

Any insult to the CNS, including invasion of pathogens, triggers glial response, known as reactive astrogliosis [ 29]. Reactive glia play a fundamental defensive role, starting a series of responses aimed at restoring the lost homeostasis. Peripheral proinflammatory cytokines may induce microgliosis and astrogliosis whenever a CNS insult occurs, including viral infections [ 30]. Whenever glial cells lose their homeostatic activities, neuronal cells suffer. If the alteration of glial cells persists the irreversible damage to the nervous tissue may occur [ 3, 31, 32, 33, 34].

The Neurotropism of SARS-CoV-2 and the Neurological Manifestations of COVID-19

SARS-CoV-2 which causes COVID-19 emerged from China in 2019. The virus spread rapidly through the world triggering the pandemic. SARS-CoV-2 is a positive-sense single-stranded β-coronavirus belonging to the family of Coronaviridae, the largest group of viruses causing respiratory and gastrointestinal infections [ 35, 36]. Historically, coronaviruses received little attention due to their scant effects on humans. This changed in 2002 when atypical pneumonia spread from the Guangdong province to more than twenty countries. This illness was named severe acute respiratory syndrome (SARS) and the identified etiological β-coronavirus was named SARS-CoV [ 37]. Although COVID-19 seems to have a lower case-fatality rate than SARS (about 2.3% versus about 6.4%, respectively [ 38]), the massive spread of the infection has claimed over 6.3 million casualties worldwide (WHO web-dashboard data updated on June 29th, 2022). The majority of the infected people appear to have eliminated the coronavirus from their bodies after a few weeks and resume normal activity. However, about the 40% of infected people experience a variety of symptoms (loss of smell and/or taste, fatigue, cough, aching pain, "brain fog," insomnia, shortness of breath, and tachycardia) after several weeks and are diagnosed with the so-called long COVID syndrome.

Extrapulmonary manifestations of COVID-19 including neurological symptomatology, primarily anosmia and ageusia, are frequently reported [ 53, 54, 55]. Neurological symptoms in COVID-19 patients are grossly underestimated, especially because many severely ill patients are sedated and on ventilators [ 56]. However, cases of encephalitis, strokes, confusion, seizures, and brain inflammation have been reported [ 57, 58, 59]. A retrospective clinical study has provided evidence for substantial incidence of neurological and psychiatric events in patients during the first 6 months after getting COVID-19. The risk for neurological and psychiatric sequelae seems to be greatest in patients who had severe COVID-19 [ 60]. Cognitive deficits and depression have been seen in patients that recovered from mild COVID-19 [ 61].

Another proposed route for viral entry to the brain is the invasion and consequent lesion of the olfactory system, which is consistent with the clinical data reporting that infection with SARS-CoV-2 is associated with high rates of disturbances in smell and taste perception, including anosmia [ 74, 75, 76, 77, 78]. Recently the cell types in the olfactory epithelium and olfactory bulb that express the SARS-CoV-2 cell entry molecules have been identified. Single-cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons [ 79]. Through the olfactory system, the virus could spread into the brain stem, possibly compromising the respiratory centres [ 80]. Magnetic resonance imaging (MRI) investigations seem to corroborate that virus may enter the brain through the trans-nasal route [ 81, 82, 83, 84], however, further studies are needed to better define their neuroradiologic interpretation.

Alternatively, the SARS-CoV-2 could penetrate through the median eminence, whose capillaries and tanycytes are thought to express ACE2, reaching the hypothalamus [ 85], and from there it could spread to the entire brain.

Brain infiltration of immune cells carrying the virus (a viral reservoir [ 86]) may represent another route of the virus entry. Vessels, meninges, and the choroid plexus have been proposed as entry points for infected monocytes, neutrophils, and T cells. However, conclusive evidence of infection through these routes has yet to be provided [ 87]. As suggested by some authors, some neurological symptoms and damage are the result of the body's own immune system overreacting after encountering the virus. Some subjects inadvertently make 'autoantibodies' that attack their own tissue [ 88]. These autoantibodies can pass via the BBB, and contribute to both short- and long-term conditions, including neurological disorders ranging from brain fog to psychosis.

Evidence has also accumulated that the virus SARS-CoV-2 can affect the brain by reducing blood flow to it. In this way, SARS-CoV-2 infection impairs neurons function and ultimately killing them. Lastly, a leaky or dysfunctional BBB could facilitate the entry of the virus, as in other kinds of infections. For instance, the human immunodeficiency virus (HIV)-1 downregulates the expression of tight junction proteins, compromising BBB integrity [ 89]. Numerous studies highlight that systemic inflammation could damage glia limitans and damage the BBB [ 90]. Thus, the hyperreactive immune response triggered by SARS-CoV-2 may compromise the integrity of the BBB. Severe COVID-19 is often associated with comorbidities, such as CNS hypoxia due to respiratory failure, thrombotic microangiopathy, or pre-existing neurological diseases, which all may increase BBB permeability facilitating the entry of the virus into the brain [ 91]. The reported presence of SARS-CoV-2 in patients cerebrospinal fluid (CSF) and brain tissue suggests that once in the body the virus can reach the brain [ 92, 93, 94]. This is also true for SARS-CoV-1 [ 65, 66].Finally, the observation in post-mortem brain tissues of SARS-CoV-2 signal not coinciding with immune cell infiltration suggests that virus-related neurological complications could be the direct consequence of the neurotropism of SARS-CoV-2 [ 95, 96].

The astrocyte response to viruses, including SARS-CoV-2

Murine coronavirus, MHV-A59, could infect the brain and its CNS effects were mediated by the cytokine release from reactive microglia and astrocytes. The authors documented that the cytokines released from both cell types were complementary, resulting in elevated levels of IL-1β, IL-6, interferon(INF)s, and TNF-α. Of note, they did not detect the release of the anti-inflammatory cytokines IL-4 and IL-10 [ 109]. In a SARS-CoV-1 patient, necrosis of neurons, broad hyperplasia of glial cells, and encephalic oedema have been reported. High plasma level of the chemokine Mig, a monokine induced by the INF-γ, that promotes the host defence by attracting activated T cells, natural killer (NK) cells, and CXCR3 expressing monocytes [ 66] has also been detected. Several studies indicated that SARS-CoV-2 affects astrocytes. A recent post-mortem investigation demonstrated that astrocytes are the main sites of viral infection within the CNS and that SARS-CoV-2-infected cells exhibit marked metabolic changes [ 110]. These authors suggest that astrocyte functions are impaired since they detected a reduction of the metabolites used to fuel neurons and produce neurotransmitters. In cortical tissue cultures and cortical organoids exposed to SARS-CoV-2, it has recently been demonstrated significant infection and viral replication in astrocytes, but minimal infection in other cell types [ 111].The same group reported that infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Signs of astrocyte reactivity have long been proposed in COVID-19 patients. For instance, elevated GFAP was found in the white matter of a COVID-19 patient, with encephalomyelitis-like brain damage, oligodendrocytic apoptosis and axonal injuries [ 112]. Plasma levels of both GFAP and neurofilament light chain protein (NfL), a biomarker predictive of intra-axonal neuronal injury, were measured in 47 patients with mild, moderate, or severe COVID-19 and matched controls. GFAP was found elevated in moderate/severe stages of the disease. This suggests that astrogliosis could be an early response after SARS-CoV-2 infection of the CNS [ 113]. In COVID-19-related acute necrotising encephalopathy virus was detected in the CSF, together with extremely high levels of NfL and GFAP, 19 days after the onset of the symptoms and even after testing negative twice [ 94]. These clinical studies indicate that astrocytes could be in a reactive state in COVID-19 patients. Consistently, the damage of the BBB and the strong lymphopenia observed during COVID-19 could promote the persistence of the virus, thus sustaining neuroinflammation and reactive gliosis. The resulting brain tissue alteration could explain some of the clinical features observed in COVID-19 patients who, despite overcome pneumonia, present cognitive impairment associated with behavioural changes [ 2, 114, 115, 116, 117].

Neuropsychiatric Consequences of COVID-19

Therefore, the risk of increased prevalence of PTSD has also been observed in previous coronavirus pandemics, making its occurrence during this COVID-19 pandemic highly explainable. Some severe cases of COVID-19 result in mortality. The fear of death might be among the many reasons responsible for PTSD amongst these patients. It has been demonstrated that 16% of the severe COVID-19 patients globally had PTSD [ 140].

A meta-analysis of the survivors among emergency-admitted patients with SARS and MERS infection has revealed that about 39% of them had suffered from PTSD. A history of psychiatric disorders, especially anxiety and depressive disorders, was found as a risk factor for PTSD in intensive care unit survivors. Twelve months after infection, psychiatric symptoms among COVID-19 recovered survivors were reported as 18.3% for depression, 17.9% for PTSD, 16.2% for anxiety, and 13.5% for sleep disturbance [ 120].

Based on the above reported findings it is possible to state that psychiatric involvement is not uncommon and can lead to severe problems if not detected and managed early. It is recommended that clinicians should be vigilant regarding psychiatric involvement in post COVID-19 patients. Neuroinflammation, blood-brain barrier disruption, thrombotic events, peripheral immune cell invasion into the CNS, glial activation, brain homeostasis impairment, all represent interaction pathways between immune systems and psychopathological mechanisms underpinning such disorders (Fig. 1). In support of this, a recent analysis of brain images taken before and after infection with SARS-CoV-2 demonstrated that even mild COVID-19 is associated with brain structure alterations and brain functioning impairments, suggesting that the effects of SARS-CoV-2 on the CNS need to be very seriously considered [ 141].

Putative mechanisms implicated in the neurological manifestations of COVID-19

Although evidence suggests that the virus can enter the brain, it seems, however, to predominantly infect vascular and immune cells. In response to immune over activation (and/or virus direct invasion) astrocytes and microglia become reactive. Also, hemorrhages, microvascular infarcts, and thrombotic events are probably critical in the development of the neurological manifestations of SARS-CoV-2 infection.

Conclusions

COVID-19, initially regarded as specific lung disease, impacts many other organs, affecting their function. Several underlying medical conditions that increase the risk of severe COVID-19 have been identified [ 142]. Evidence accumulated in the past two years indicates that the brain functions and structure are also damaged by the virus. SARS-CoV-2 infection can indeed cause confusion, memory loss, strokes, psychosis, seizures, and other neurological manifestations. There is also evidence of brain-related abnormalities in COVID-19 patients [ 141] that may explain the neurological manifestations observed. A study revealed that neurological symptoms appeared in 80% of the people hospitalized with COVID-19 who were surveyed [ 143]. This depicts a dramatic scenario.

How COVID-19 injuries the brain is becoming clearer. New evidence indicates that the SARS-CoV-2 assault on the brain could be multipronged. The coronavirus might target specific brain cells directly, reduce cerebral blood flow, or trigger the production of immune molecules that can harm brain cells. Astrocytes, tanycytes, infiltrating immune cells, and autoantibodies are probably not the only players in the brain response to the coronavirus leading to the observed neuropsychiatric consequences. Researchers are trying to understand how many brain cells (and what kind of cells) need to be either infected or damaged to cause neurological symptoms. Unfortunately, there isn't a simple answer. Cerebral cells, including neurons, in some regions of the brain will cause more dysfunction than others, if damaged. This opens a new and never explored field of research. Lastly, whether cerebral effects can be partially reversed, or whether these effects will persist in the long term, remains to be investigated.

Funding

Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. The authors have not disclosed any funding.

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Authors and Affiliations

1. Psychiatric Unit, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy

Luca Steardo Jr.

2. Department of Physiology and Pharmacology "Vittorio Erspamer", SAPIENZA University of Rome, Rome, Italy

Luca Steardo & Caterina Scuderi

3. Università Giustino Fortunato, Benevento, Italy

Luca Steardo

Contributions

LS, LS, and CS conceived the review manuscript and contributed to the writing and revision of the paper.

Corresponding author

Correspondence to Caterina Scuderi.

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Steardo, L., Steardo, L. & Scuderi, C. Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic. Neurochem Res 48, 1015-1025 (2023). https://doi.org/10.1007/s11064-022-03709-7
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Keywords

Astrocyte

SARS-CoV-2

COVID-19

Neuroinflammation

Reactive gliosis

Neuropsychiatric disorders

# data[].attributes.attachment_link.title
Astrocytes and the Psychiatric Sequelae of COVID-19: What We Learned from the Pandemic - Neurochemical Research

# data[].attributes.attachment_link.description
COVID-19, initially regarded as specific lung disease, exhibits an extremely broad spectrum of symptoms. Extrapulmonary manifestations of the disease also include important neuropsychiatric symptoms with atypical characteristics. Are these disturbances linked to stress accompanying every systemic infection, or are due to specific neurobiological changes associated with COVID-19?

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The Role of Glial Cells in Neurodegeneration

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Central Nervous System, Blood Brain Barrier, Degeneration

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Central Nervous System, Blood Brain Barrier, Degeneration

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Research studies in neurodegenerative diseases have traditionally focused on the investigation of neuronal dysfunction, while little attention has been brought to the role of glial cells of the CNS or PNS. However, over the last decade, it has become widely accepted that microglia and macroglia (astrocytes, oligodendrocytes) greatly contribute to the degeneration of neurons observed in a variety of neurodegenerative diseases. The contribution of these cell types and the presence of potential non-cell autonomous mechanisms of disease pathogenesis are now extensively being studied using diverse disease model systems. These studies have highlighted a complex regulation between neuron and glia, but also glia and glia, suggesting that any dysfunction among these cellular cross talks contributes to neuronal cell death.

While it is agreed upon that glial cells contribute to neuronal death in neurodegenerative diseases, the precise mechanisms for this contribution and the presence of disease-specific pathways is still unknown. Therefore, the goal of this research topic is to present new data on glia-neuron and/or glia-glia crosstalk in varying neurodegenerative diseases. The use of state-of-the-art model system and technologies will be highlighted and could include single nuclei RNA sequencing, human iPSC model systems (2D, 3D), brain organoid studies, spatial transcriptomics analyses and/or innovative proteomics analyses. In addition, comprehensive review articles summarizing the most recent findings and discoveries on glial regulation of neuronal degenerations will provide important background information and is greatly welcomed as a contribution to this research topic.

The present article collection should cover, but is not limited to, studies on:
* Research articles and review articles
* Glia-neuron interaction
* Glia-glia interaction
* Innovative model systems to study the contribution of glia to neurodegeneration, including human cell models and complex in vivo studies
* Innovative technologies to study glial dysfunction

# data[].attributes.attachment_link.title
The Role of Glial Cells in Neurodegeneration

# data[].attributes.attachment_link.description
Research studies in neurodegenerative diseases have traditionally focused on the investigation of neuronal dysfunction, while little attention has been brought to the role of glial cells of the CNS or PNS. However, over the last decade, it has become widely accepted that microglia and macroglia (astrocytes, oligodendrocytes) greatly contribute to the degeneration of neurons observed in a variety of neurodegenerative diseases.

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Behavioural Change Following Mild Covid Infection (or Vax or both/either)

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Behavioural Change Following Mild Covid Infection (or Vax or both/either)

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This Medical News article discusses a large study that found brain structure and cognitive changes months after SARS-CoV-2 infection.

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Over 35 Million Americans reporting LongCovid with neurological and brain dysfunction symptoms like cognitive changes

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Over 35 Million Americans reporting LongCovid with neurological and brain dysfunction symptoms like cognitive changes

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Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown

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Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown https://t.co/aq4uhT9738

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Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown pic.twitter.com/aq4uhT9738
— Moneypenny (@nic_moneypenny) May 15, 2023

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Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown https://t.co/aq4uhT9738

# data[].attributes.attachment_link.metadata.attachment_props.original_text
Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown https://t.co/aq4uhT9738

# data[].attributes.attachment_link.metadata.attachment_props.text
Over 35 Million Americans have #LongCovid That's equivalent to the entire combined population of Australia & United Arab Emirates It's a global health crisis with enormous economic impact and yet governments are still failing to acknowledge #meltdown

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Brain fog after COVID-19 has similarities to ‘chemo brain,’ Stanford-led study finds

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Brain fog after COVID-19 has similarities to ‘chemo brain,’ Stanford-led study finds

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Researchers found that damage to the brain’s white matter after COVID-19 resembles that seen after cancer chemotherapy, raising hope for treatments to help both conditions.

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SARS-CoV-2 is associated with changes in brain structure in UK Biobank - Nature

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UK Biobank Study Shows Structural Brain Changes 

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UK Biobank Study Shows Structural Brain Changes 

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Affiliations

1. FMRIB Centre, Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Gwenaëlle Douaud, Soojin Lee, Fidel Alfaro-Almagro, Christoph Arthofer, Chaoyue Wang, Paul McCarthy, Frederik Lange, Jesper L. R. Andersson, Ludovica Griffanti, Eugene Duff, Saad Jbabdi, Bernd Taschler, Karla L. Miller & Stephen M. Smith

2. OHBA, Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Ludovica Griffanti

3. Department of Paediatrics, University of Oxford, Oxford, UK

Eugene Duff

4. Ear Institute, University College London, London, UK

Peter Keating

5. National Institutes of Mental Health, National Institutes of Health, Bethesda, MD, USA

Anderson M. Winkler

6. Nuffield Department of Population Health, University of Oxford, Oxford, UK

Rory Collins & Naomi Allen

7. UK Dementia Research Institute and Department of Brain Sciences, Imperial College, London, UK

Paul M. Matthews

8. Big Data Institute, University of Oxford, Oxford, UK

Thomas E. Nichols

Corresponding author

Correspondence to Gwenaëlle Douaud.

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SARS-CoV-2 is associated with changes in brain structure in UK Biobank - Nature

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There is strong evidence for brain-related abnormalities in COVID-191-13. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology.

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Forbes Warns About Mental Health & Neurological Issues After Covid

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Forbes Warns About Mental Health & Neurological Issues After Covid

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Emerging studies indicate that as many as one quarter of all those infected with Covid-19 experience long-term brain damage regardless disease severity. New neurological complications, ranging from mild to more debilitating symptoms, persist months after the initial infection.

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Some people who become ill with the coronavirus develop neurological symptoms. Scientists are struggling to understand why.

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Lasting brain impacts of severe COVID-19 equivalent to 20 years of ageing | Imperial News | Imperial College London

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The lasting mental impacts of severe COVID-19 on areas like memory, attention, or problem solving, may be equivalent to 20 years of ageing.

These are the findings of a new study, led by a team of scientists from the University of Cambridge and Imperial College London, which suggest that cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age and is the equivalent to losing 10 IQ points.

The research, published in the journal eClinicalMedicine, indicates the effects are still detectable more than six months after acute illness and that any recovery is at best gradual.

According to the researchers, this is the first time that such rigorous assessment and comparison has been carried out in relation to the after-effects of severe COVID-19.

Professor Adam Hampshire from the Department of Brain Sciences at Imperial College London, and first author of the study, said: "Tens of thousands of people have been through intensive care with COVID-19 in England alone and many more will have been very sick, but not admitted to hospital. This means there are a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people."

Cognitive impacts

There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, 'brain fog', problems recalling words, sleep disturbances, anxiety and even post-traumatic stress disorder (PTSD) months after infection.

In the UK, a study found that around one in seven individuals surveyed reported having symptoms that included cognitive difficulties 12 weeks after a positive COVID-19 test.

There are a large number of people out there still experiencing problems with cognition many months [after COVID-19]. We urgently need to look at what can be done to help these people. Professor Adam Hampshire Department of Brain Sciences

While even mild cases can lead to persistent cognitive symptoms, between a third and three-quarters of hospitalised patients report still suffering cognitive symptoms three to six months later.

Researchers analysed data from 46 people who received in-hospital care (on the ward or intensive care unit) for COVID-19, 16 of whom were put on mechanical ventilation during their stay in hospital.

All of the patients were admitted to Addenbrooke's Hospital in Cambridge between March and July 2020 and were recruited via the NIHR COVID-19 BioResource.

Patients took cognitive tests an average of six months after their illness using the Cognitron platform, which measures different aspects of mental faculties such as memory, attention and reasoning. Scales measuring anxiety, depression and post-traumatic stress disorder were also assessed. Their data were compared against matched controls.

Less accurate and slower

Analysis of the data revealed COVID-19 survivors were less accurate and had slower response times than the matched control population. These deficits were still detectable when the patients were following up six months later.

The effects were strongest for those who required mechanical ventilation. By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that sustained with 20 years ageing, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.

Survivors scored particularly poorly on tasks such as verbal analogical reasoning, a finding that supports the commonly-reported problem of difficulty finding words. They also showed slower processing speeds, which aligns with previous observations post COVID-19 of decreased brain glucose consumption within the frontoparietal network of the brain, responsible for attention, complex problem-solving and working memory, among other functions.

Professor David Menon from the Division of Anaesthesia at the University of Cambridge, the study's senior author, said: "Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine ageing, but the patterns we saw - the cognitive 'fingerprint' of COVID-19 - was distinct from all of these."

Predicting outcomes

While it is now well established that people who have recovered from severe COVID-19 illness can have a broad spectrum of symptoms of poor mental health - depression, anxiety, post-traumatic stress, low motivation, fatigue, low mood, and disturbed sleep - the team found that acute illness severity was better at predicting the cognitive deficits.

The patients' scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual and likely to be influenced by a number of factors including illness severity and its neurological or psychological impacts.

Professor Menon added: "We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement. While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover."

There are several factors that could cause the cognitive deficits, say the researchers. Direct viral infection is possible, but unlikely to be a major cause; instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds. However, emerging evidence suggests that the most important mechanism may be damage caused by the body's own inflammatory response and immune system.

While this study looked at hospitalised cases, the team say that even those patients not sick enough to be admitted may also have tell-tale signs of mild impairment.

The research was funded by the NIHR BioResource, NIHR Cambridge Biomedical Research Centre and the Addenbrooke's Charitable Trust.

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' Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort' by Hampshire, A et al. is published in eClinicalMedicine. DOI: 10.1016/j.eclinm.2022.101417
This article is based on materials from the University of Cambridge See the press release of this article

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Lasting brain impacts of severe COVID-19 equivalent to 20 years of ageing | Imperial News | Imperial College London

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The lasting mental impacts of severe COVID-19 on areas like memory, attention, or problem solving, may be equivalent to 20 years of ageing.