Immunology

Long COVID Research Is a Bit of a Mess – Technology Networks

Back in March 2020, as the COVID-19 pandemic descended over the world, Naima was a busy tech worker, zipping around London, speaking to clients and jogging on the weekends.

I was very, very busy, she says. I did triathlons and [was] running 10Ks all the time. I was living a normal life, a full life.

Then, like every other person in the UK, her life came to a standstill as the countrys first lockdown began. Only, Naima was even more sedentary than most; she was ill with COVID-19.

I had quite a few symptoms: headache, fever, full-body soreness, sore throat, a bit of a cough and I felt very weak, she explains. That lasted a couple of weeks.

It would have been easy to panic, contracting the very virus that had just shut down the world, but Naima was relatively calm. Because I was so fit, I wasnt too worried, she says. The only real story that was happening was the hospitalizations. The line was: Unless you have underlying conditions or youre much older, youll be fine.

And for a while she was, mostly.

I had this niggling sensation in my chest that would pop up every couple of days, just for a few seconds. And in those few seconds, I couldnt breathe properly. But that didnt develop into anything else for several months.

When it did, Naima wasnt just troubled with a tight chest; she was debilitated with palpitations and crippling fatigue. She could barely walk. My world was turned upside down from that point in October, when those severe symptoms kicked in. I spoke to general practitioners; I said, I cant move at all. It feels like there are bricks on my chest and shooting pains that come whenever I get up. They said, You know, youre so young and fit, but this sounds like a heart attack.

It wasnt. It was long COVID. Naima was part of the first batch of people in the world to develop ongoing, disabling complications following an un-hospitalized COVID-19 infection. And shes still ill, more than three years later.

How could a fit and healthy 26-year-old go from running triathlons to being bed-bound for months, just from a passing viral infection? Why were she and people like her left with life-altering symptoms, while others could move on from their infections, seemingly unchanged? Back in 2020, no one had answers to these questions. No one really knew how to help those struggling with the illness. Research was desperately needed.

And, as 2021 dawned, research arrived. The UK government awarded 18.5 million to four studies that set out to define long COVID. The European Union gave 27.9 million to a larger research initiative, known as ORCHESTRA, to study how COVID-19 was impacting peoples health. And in February 2021, the US National Institutes of Health (NIH) raised the bar and allocated $1.15 billion to research the causes of long COVID and its possible treatments.

So, nearly three years later, what has been learned? Perhaps more importantly, have any treatments been produced?

The short answers: a lot. And not quite.

To begin with, researchers set about defining long COVID as a starting point. Many understood the condition to involve persisting symptoms after a SARS-CoV-2 infection, but that was about it. They didnt know exactly what these symptoms were or who they were affecting. To gather insights, they began profiling patients.

A lot of these patients were actually young and healthy, in their 20s and 30s, says Dr. Ziyad Al-Aly, a clinical epidemiologist at Washington University. And everybody at the time [in March 2020] was telling them that, If youre young and healthy, then SARS-CoV-2, its not a big deal; youll recover. But weeks later, these people were not recovering. So we decided to research long COVID to try to understand what it is.

Al-Aly and his colleagues began by looking at patient medical records. They recently published two years worth of observations in Nature, comparing the medical data of 138,818 individuals who had had a SARS-CoV-2 infection and 5,985,227 who hadnt. There were some stark differences.

Among the non-hospitalized, long COVID took away 80.4 disability-adjusted life years (DALYs), a standard measure of disease burden, per 1,000 people. For comparison, others studies have estimated that chronic obstructive pulmonary disease, for instance, costs between 3.6 and 6.7 DALYs per 1,000 people.

Disability-adjusted life years (DALYs) summarizes the burden of healthy years of life lost due to premature mortality and disability.

Long COVIDs high disease burden is partly explained by its sheer number of possible symptoms; Al-Aly and his colleagues observed more than 80 within the medical records. These included atrial fibrillation, cardiac arrest, anemia, diabetes, fatigue, acute gastritis, myalgia, memory problems and peripheral neuropathy. Just over 30% of these sequalae remained significant in non-hospitalized patients for two years.

Long COVID is literally the long-lasting legacy of this pandemic, Al-Aly says.

Al-Alys study documented, in unprecedented detail, just how wide-ranging the effects of long COVID-19 can be. But what exactly is causing these symptoms? Parallel research has shed some light.

One study found that long COVID patients had 100 times the levels of SARS-CoV-2-specific T cells normally seen in people who recovered from the virus a finding that suggests the virus is still active in the bodies of people with long COVID, surviving in reservoirs, plaguing sufferers for months. Tiny blood clots have been found in patients clots that could be blocking oxygen from reaching cells, starving patients of their energy. The brains of people with long COVID are also more active in certain areas than the brains of those without the post-viral illness an observation that could explain the memory loss and confusion experienced by many with the condition.

Theres a lot going on under the skin of long COVID patients, multiple etiologies affecting multiple organ systems.

And this is where the field of long COVID research gets sticky, because highly variable diseases are difficult to study further. What kind of clinical researcher is best suited to the job? A cardiologist? A neurologist? An infectious disease specialist? Based off the mounting data, it seems like long COVID is a job for all three.

This issue is partly why, more than three years on from when the illness was identified, long COVID research is still stuck in its characterization phase. Have a Google of long COVID research these days and one will still come across new papers decrying how blurry the definition of the disease is and arguing for more thorough studies to detail it better.

But people with this condition cant wait any longer for such preliminary studies. Theyre desperate for interventional clinical trials now. People are hanging their hopes on these trials, says Al-Aly. They want them to be done yesterday. And yet were moving forward at a turtles pace.

Ironically, its the same kind of characterization research that demonstrates this desperation best. Almost one in five UK doctors responding to a recent BMJ survey said that they had lost their ability to work due to their post-COVID ill-health. A US study, published last year, estimated that long COVID potentially accounted for 15% of the countrys whole labor shortage.

Even those who have managed to keep working through their illness report life-altering levels of fatigue (the most common symptom of long COVID), enough to rob them of their prior quality of life. One survey of patients at a long COVID clinic, published in BMJ Open this year, found that, on average, the patients fatigue scores were worse or similar to those of people with severe kidney disease. The respondents quality of life scores were also lower than those of people with stage four lung cancer.

Most concerning of all, due to the toll of the illness, people with long COVID seem to be at a higher risk of suicide. One US patient-led survey found that 45% of respondents had experienced recent suicidal thoughts more than 11 times the national average (4%). Sadly, these data are supported by a growing number of anecdotal reports within the long COVID patient community from grieving loved ones.

So, with no approved treatments for the illness or standardized care plan and a disease duration that can span over three years in certain cases its perhaps no wonder people with long COVID are crying out for trials. Fortunately, a few have been greenlit.

In August 2023, there were 386 trials underway around the world relating to long COVID, according to the ClinicalTrials.govdatabase. A promising figure, one might think. Only 94 of those studies, however, were classed as interventional and were recruiting, and only 12 trials were testing pharmacological interventions; the rest were testing the effects of food supplements, psychological support, acupuncture and other non-drugs.

What are the 12 drug trials testing, though? Well, one led by Yale University is studying whether Paxlovid (a COVID-19 antiviral made by Pfizer) could benefit people with long COVID, perhaps by eliminating any rogue remnants of SARS-CoV-2 that may still be lingering in their bodies. Another led by a private US company is seeing whether a novel drug designed to remove pro-inflammatory nucleic acids could reduce the levels of vascular inflammation observed in long COVID patients, thereby reducing their fatigue.

But perhaps the most highly anticipated trial within the long COVID community is that undertaken by the relatively small biotech company Berlin Cures. The German start-up made headlines back in 2021 when it announced that it had effectively treated four people with long COVID with just a single infusion (per person) of its proprietary drug, BC007. Encouraged by these initial results, the company has since launched a Phase 2 clinical trial of its neutralizing functional auto-antibody formula, which recently completed a Phase 2 open study for heart failure.

We know, and others have shown, that these functional auto-antibodies play a key role in the pathogenesis of various debilitating diseases, says Oliver von Stein, Berlin Cures CEO. Long COVID, we believe, is one of them, heart failure is potentially another.

To be included as a participant in the companys trial, potential patients have to test positive for these pernicious auto-antibodies, so the Berlin Cures team can later test if a reduction in auto-antibody levels correlates with a reduction in fatigue (the prime symptom assessed by the study).

Thanks to this level of rigor built into the trial, and the early results of BC 007, von Stein and his colleagues are expecting promising results by the second half of next year results that they hope will attract a new wave of investment for a Phase 3 trial and, beyond that, other trials for other maladies.

We are optimistic and expect good data from our ongoing Phase 2 study, von Stein says. And, if this is the case, this will provide a lot of momentum to tackle other diseases, similar conditions for example, chronic fatigue syndrome.

Chronic fatigue syndrome or myalgic encephalomyelitis (ME) is the elephant in the long COVID room. For the past three years, much of the media and discussion around long COVID has treated the post-viral condition as an entirely new illness, a view that has been reflected in its research; scientists from around the world have scrambled to study the disease from scratch.

But if ME had been studied more thoroughly or even just believed years ago, much of the foundational work of long COVID research may already have been achieved. Thats certainly the belief of many of those suffering from ME, who often live exceptionally stationary lives due to their condition. Some are bed-bound, quite literally, for decades.

Half of long COVID symptoms are basically equivalent to ME symptoms, says Chris Ponting, a professor at the University of Edinburghs Medical Research Council Human Genetics Unit and lead investigator of its Decode ME project.

If anyone is compensating for these lost years of ME research, its Ponting; he and his colleagues are currently conducting the largest study of ME ever undertaken. By analyzing the DNA samples of 25,000 patients, they hope to identify genetic markers that could underpin a persons susceptibility to the disease. With that information in hand, they could then both validate the existence of the malady and identify targets for future drugs to treat it.

We anticipate that well be able to find a bunch of places in our genomes that scream at us: immunology, or mitochondria or some neurological phenotype in the genome, says Ponting. Then, through joining up the dots, we can make an evidence-based, cogent explanation for what is going wrong.

It all sounds quite promising. But theres an obstacle to follow-up studies, the same one that prevented ME research for decades: funding. Our study was funded prior to the COVID-19 pandemic, Ponting says. There has not been further funding since then.

Contrary to the hopes of many in the ME community, the relative surge of interest in long COVID has not translated into a research boon for other fatigue-inducing, likely post-viral conditions, according to Ponting. There has been a shift in the dial in acceptance of ME, he notes, which has not translated to substantial research funding that this disease deserves.

And unfortunately, at the tail end of 2023, its not just ME thats being starved of vital research. The funding well for long COVID is drying up, too.

All of these scientists, theyre back in the usual hurdles that scientists go through to try and get research up and running in this country. There is no sense of urgency at all, says Margaret OHara, founder trustee of Long Covid Support, a UK-based charity supporting people with long COVID.

OHara liaises with researchers on behalf of the charity. Two years ago, many of the scientists she spoke to were getting their funding from the UKs National Institute for Health and Care Research (NIHR), which launched rounds of commissioned calls that were worth millions in 2021. Now those funding rounds are a distant memory.

Then NIHR said, Right, no more commission calls, says OHara. Long COVIDs not special anymore, and if you want money to research it, you [must] go through the usual channels for example, RFPB [Research for Patient Benefit] and you compete with all the other diseases.' So, what we find now is that [research grant applications] are just getting knocked back.

The situation seems much the same across the Atlantic. Remember that $1.15 billion the US NIH allocated to long COVID research? Well, its pretty much all been spent, largely on observational, characterization research, according to an analysis by STAT, and theres been no announcement of any follow-up funding, despite calls from US researchers. Some long COVID studies in the country have since relied on charitable donations to keep going.

Why has the money dried up? Fittingly, one could blame fatigue. There is a bitter feeling within the long COVID community that the rest of the world has grown tired of all things COVID and no longer wants to hear from or fund studies affecting those damaged by the virus.

We think theres a bit of a message coming from the top to say, Yeah, lets downplay long COVID because, you know, COVIDs over, says OHara.

Whether accurate or not, this sentiment that the top has lost interest in long COVID is a doubly frustrating one for those researching the disease because, right now, the field could really do with some leadership.

[There is] no coherent approach to studying long COVID. No coherent strategy, says Al-Aly. I liken it to if you have a bunch of musicians, and everybody is singing their own tune, and theres no conductor harmonizing all of this.

Al-Alys exasperation is shared by many of his fellow researchers. At a time of disappearing grants, many say the field needs a conductor some governing body with a comprehensive, coordinated plan of action.

We think there should be a coordinated effort by UKRI [UK Research and Innovation] to say, OK, long COVID is a disease of great interest and we need to coordinate responses, says OHara.

We need to put these scientists together so that theyre not all repeating the same thing.

OHara and her colleagues at Long Covid Support have been calling for this kind of managed response since 2020. The charity recently wrote to the UK government, recommending that it declare long COVID a public health emergency and prioritize research into treatments. These pleas have so far gone unheeded, which may be unsurprising given recent political revelations. In October 2020, when presented with the health departments first guidance on long COVID, the then prime minister Boris Johnson scrawled bo***cks, in capitals, on the document.

But this offensive dismissiveness from the top doesnt mean a top-down research strategy, if coordinated by health departments and research funders, is an impractical suggestion, researchers insist.

The funders will say thats up to the scientists to coordinate, says Ponting. And they would have a point; it has to be from the ground-up mostly rather than from the top-down. But top-down does work.

The response to mad cow disease did come from the top, he adds. There have been international efforts on many different diseases going back decades, including polio. So, the answer that it is up to the scientists to organize ourselves in a competitive world, where we compete for funding because theres so little of it, is missing part of what should happen, which is that we need coordination.

While all this disarray between researchers, funders and governments plays out, long COVID patients watch on, many despondent. Some are relatively new to the illness. Some have been coping with it for over three years with little improvement. Others have improved over time, gaining back enough physical capability to return to work. But this remission is fragile. According to a Long Covid Support survey of people who had recovered from the illness, 60% got long COVID again following a reinfection of COVID-19. This happened to Naima, twice.

To protect herself from worsening symptoms, Naima still practices strict infection protocols. She restricts her socializing. She wears a mask on public transport. She routinely tests for COVID-19 and asks others she sees to do the same. Shes still behaving like many people did in 2020. Without long COVID treatments, she cant afford to change her habits.

Ive been lucky in terms of my life beforehand, she says. I no longer feel that way. I live with fear every day of reinfection.

What does she make of the state of long COVID research, then? Does it give her hope for a return to a normal, fear-free future? Not quite. While she is part of a characterization study being conducted at Imperial College London, and is optimistic that such research will one day bear useful results, she says those who have been struggling with their long COVID for years need better outcomes now.

A lot of studies are moving on to: who is getting this? Im part of a study now with Imperial taking blood samples. Its just [about] understanding: why are we so greatly impacted by this? Is there a specific gene that we have? I think that [answer] would really go a long way to understanding this. And then, of course, treatments for people who have been suffering now for years

She pauses.

I think, because Ive had improvement, she adds. I have more hope because I know that I do have better points and worse points. But some people have not had any good moments; theyve been around for three years and had no improvement. I think we really need to be able to offer something to those people, to all of us.

Those interested in following Naimas journey of long COVID recovery can subscribe to her Substack journal.

For those living with long COVID, links to support groups and symptom management guides can be found at Long Covid Support.

Those with ME can find similar support resources at ME Association.

For those struggling with suicidal ideation in the UK, Papyrus and Samaritans offer 24/7 support. Those living in the US can call the 988 Suicide & Crisis Lifeline.

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Anesthesiology

A Perioperative Blood Management Algorithm Aimed at Conservation of Platelets in Clinical Practice: The Role of the … – Cureus

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Anesthesiology

Shortage of Anesthesiologists Creates Logjam at Providence Hospitals – Willamette Week

Patients looking to get knee operations, hernia repair or any other non-emergency surgery at Providence hospitals are in for a monthlong wait because the nonprofit system doesnt have enough anesthesiologists.

Providence Portland on the eastside and Providence St. Vincent in the West Hills are taking only emergency, urgent and pregnancy-related cases through the end of the year, a Providence spokeswoman confirmed. The shortage started Nov. 22, when Providence dumped its local contractor, Oregon Anesthesiology Group, and hired Sound Physicians of Tacoma, Wash.

Unfortunately, the new group will not have enough credentialed anesthesia providers to fully cover the ORs at those facilities when the contract begins, Providence managers told staff in an email Nov. 14. We thank you for your understanding and support as we move through this difficult time.

Beyond patients, the clumsy switchover hurts surgeons, who cant operate, and the nurses who assist them. Surgeons are pissed, says one source who works at St. Vincent.

Meantime, the Providence spokeswoman said, nurses can do special projects, work temporarily in other departments, use vacation time, or take unpaid time off.

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Anesthesiology

Lack of Benefit of Adjusting Adaptively Daily Invitations for the Evaluation of the Quality of Anesthesiologists … – Cureus

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Please choose I'm not a medical professional. Allergy and Immunology Anatomy Anesthesiology Cardiac/Thoracic/Vascular Surgery Cardiology Critical Care Dentistry Dermatology Diabetes and Endocrinology Emergency Medicine Epidemiology and Public Health Family Medicine Forensic Medicine Gastroenterology General Practice Genetics Geriatrics Health Policy Hematology HIV/AIDS Hospital-based Medicine I'm not a medical professional. Infectious Disease Integrative/Complementary Medicine Internal Medicine Internal Medicine-Pediatrics Medical Education and Simulation Medical Physics Medical Student Nephrology Neurological Surgery Neurology Nuclear Medicine Nutrition Obstetrics and Gynecology Occupational Health Oncology Ophthalmology Optometry Oral Medicine Orthopaedics Osteopathic Medicine Otolaryngology Pain Management Palliative Care Pathology Pediatrics Pediatric Surgery Physical Medicine and Rehabilitation Plastic Surgery Podiatry Preventive Medicine Psychiatry Psychology Pulmonology Radiation Oncology Radiology Rheumatology Substance Use and Addiction Surgery Therapeutics Trauma Urology Miscellaneous

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Neuroscience

Brain Imaging Reveals Altered Brain Connectivity in Autism – Neuroscience News

Summary: Researchers advanced brain imaging and machine learning to uncover altered functional brain connectivity in individuals with Autism Spectrum Disorder (ASD), acknowledging the diversity within the disorder.

The research distinguishes between shared and individual-specific connectivity patterns in ASD, revealing both common and unique brain alterations. This approach marks a significant shift from group-based analysis to a more personalized understanding of ASD.

The findings open pathways for tailored treatments, addressing the unique needs of individuals with ASD.

Key Facts:

Source: Elsevier

What happens in the brain to cause many neurodevelopmental disorders, including autism spectrum disorder (ASD), remains a mystery. A major limitation for researchers is the lack of biomarkers, or objective biological outputs, for these disorders, and in the case of ASD, for specific subtypes of disease.

Now, anew studyuses brain imaging and machine learning to identify altered functional brain connectivity (FC) in people with ASD importantly, taking into consideration differences between individuals.

The study appears inBiological Psychiatry, published by Elsevier.

John Krystal, MD, Editor ofBiological Psychiatry, said of the work,ASD has long been known to be a highly heterogeneous condition. While genetic studies have provided some clues to different causes of the disorder in different groups of ASD patients, it has been challenging to separate subtypes of ASD using other types of biomarkers, such as brain imaging.

Brain imaging scans are also extremely heterogenous, varying greatly from one individual to another, making such data difficult to use as a biomarker. Previous studies have identified both increased and decreased FC in people with ASD compared to healthy controls, but because those studies focused on groups of participants, they failed to appreciate heterogeneous autism-related atypical FC.

In the new study, the researchers showed that although heterogenous brain imaging subtypes could be distinguished among participants with ASD.

Xujun Duan, PhD, senior author of the work at the University of Electronic Science and Technology of China, explained,In this study, we used a technique to project altered FC of autism onto two subspaces: an individual-shared subspace, which represents altered connectivity pattern shared across autism, and an individual-specific subspace, which represents the remaining individual characteristics after eliminating the individual-shared altered connectivity patterns.

The investigators found that the individual-shared subspace altered FC of autism reflects differences at the group level, while individual-specific subspace altered FC represents individual variation in autistic traits. These findings suggest a requirement to move beyond group effects and to capture and capitalize on the individual-specific brain features for dissecting clinical heterogeneity.

Dr. Krystal added,Part of the challenge to finding subtypes of ASD has been the enormous complexity of neuroimaging data. This study uses a sophisticated computational approach to identify aspects of brain circuit alterations that are common to ASD and others that are associated with particular ASD traits.

This type of strategy may help to more effectively guide the development of personalized treatments for ASD, i.e., treatments that meet the specific needs of particular patients.

Author: Eileen Leahy Source: Elsevier Contact: Eileen Leahy Elsevier Image: The image is credited to Neuroscience News

Original Research: Open access. Disentangling the Individual-Shared and Individual-Specific Subspace of Altered Brain Functional Connectivity in Autism Spectrum Disorder by Xujun Duan et al. Biological Psychiatry

Abstract

Disentangling the Individual-Shared and Individual-Specific Subspace of Altered Brain Functional Connectivity in Autism Spectrum Disorder

Despite considerable effort toward understanding the neural basis of autism spectrum disorder (ASD) using case-control analyses of resting-state functional magnetic resonance imaging data, findings are often not reproducible, largely due to biological and clinical heterogeneity among individuals with ASD. Thus, exploring the individual-shared and individual-specific altered functional connectivity (AFC) in ASD is important to understand this complex, heterogeneous disorder.

We considered 254 individuals with ASD and 295 typically developing individuals from the Autism Brain Imaging Data Exchange to explore the individual-shared and individual-specific subspaces of AFC. First, we computed AFC matrices of individuals with ASD compared with typically developing individuals. Then, common orthogonal basis extraction was used to project AFC of ASD onto 2 subspaces: an individual-shared subspace, which represents altered connectivity patterns shared across ASD, and an individual-specific subspace, which represents the remaining individual characteristics after eliminating the individual-shared altered connectivity patterns.

Analysis yielded 3 common components spanning the individual-shared subspace. Common components were associated with differences of functional connectivity at the group level. AFC in the individual-specific subspace improved the prediction of clinical symptoms. The default mode networkrelated and cingulo-opercular networkrelated magnitudes of AFC in the individual-specific subspace were significantly correlated with symptom severity in social communication deficits and restricted, repetitive behaviors in ASD.

Our study decomposed AFC of ASD into individual-shared and individual-specific subspaces, highlighting the importance of capturing and capitalizing on individual-specific brain connectivity features for dissecting heterogeneity. Our analysis framework provides a blueprint for parsing heterogeneity in other prevalent neurodevelopmental conditions.

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Brain Imaging Reveals Altered Brain Connectivity in Autism - Neuroscience News

Neuroscience

Mirror Insight: Mice Show Glimpses of Self-Recognition – Neuroscience News

Summary: Mice display behavior akin to self-recognition when viewing their reflections in mirrors. This behavior emerges under specific conditions: familiarity with mirrors, socialization with similar-looking mice, and visible markings on their fur.

The study also identifies a subset of neurons in the hippocampus that are crucial for this self-recognition-like behavior. These findings provide valuable insights into the neural mechanisms behind self-recognition, a previously enigmatic aspect of neurobehavioral research.

Key Facts:

Source: Cell Press

Researchers report December 5 in the journalNeuronthat mice display behavior that resembles self-recognition when they see themselves in the mirror. When the researchers marked the foreheads of black-furred mice with a spot of white ink, the mice spent more time grooming their heads in front of the mirrorpresumably to try and wash away the ink spot.

However, the mice only showed this self-recognition-like behavior if they were already accustomed to mirrors, if they had socialized with other mice who looked like them, and if the ink spot was relatively large.

The team identified a subset of neurons in the hippocampus that are involved in developing and storing this visual self-image, providing a first glimpse of the neural mechanisms behind self-recognition, something that was previously a black box in neurobehavioral research.

To form episodic memory, for example, of events in our daily life, brains form and store information about where, what, when, and who, and the most important component is self-information or status, says neuroscientist and senior author Takashi Kitamura of University of Texas Southwestern Medical Center.

Researchers usually examine how the brain encodes or recognizes others, but the self-information aspect is unclear.

The researchers used a mirror test to investigate whether mice could detect a change in their own appearancein this case, a dollop of ink on their foreheads. Because the ink also provided a tactile stimulus, the researchers tested the black-furred mice with both black and white ink.

Though the mirror test was originally developed to test consciousness in different species, the authors note that their experiments only show that mice can detect a change in their own appearance, but this does not necessarily mean that they are self-aware.

They found that mice could indeed detect changes to their appearance, but only under certain conditions. Mice who were familiar with mirrors spent significantly more time grooming their heads (but not other parts of their bodies) in front of the mirror when they were marked with dollops of white ink that were 0.6 cm2or 2 cm2.

However, the mice did not engage in increased head grooming when the ink was blackthe same color as their furor when the ink mark was small (0.2 cm2), even if the ink was white, and mice who were not habituated to mirrors before the ink test did not display increased head grooming in any scenario.

The mice required significant external sensory cues to pass the mirror testwe have to put a lot of ink on their heads, and then the tactile stimulus coming from the ink somehow enables the animal to detect the ink on their heads via a mirror reflection, says first author Jun Yokose of University of Texas Southwestern Medical Center. Chimps and humans dont need any of that extra sensory stimulus.

Using gene expression mapping, the researchers identified a subset of neurons in the ventral hippocampus that were activated when the mice recognized themselves in the mirror. When the researchers selectively rendered these neurons non-functional, the mice no longer displayed the mirror-and-ink-induced grooming behavior.

A subset of these self-responding neurons also became activated when the mice observed other mice of the same strain (and therefore similar physical appearance and fur color), but not when they observed a different strain of mouse that had white fur.

Because previous studies in chimpanzees have suggested that social experience is required for mirror self-recognition, the researchers also tested mice who had been socially isolated after weaning. These socially isolated mice did not display increased head grooming behavior during the ink test, and neither did black-furred mice that were reared alongside white-furred mice.

The gene expression analysis also showed that socially isolated mice did not develop self-responding neuron activity in the hippocampus, and neither did the black-furred mice that were reared by white-furred mice, suggesting that mice need to have social experiences alongside other similar-looking mice in order to develop the neural circuits required for self-recognition.

A subset of these self-responding neurons was also reactivated when we exposed the mice to other individuals of the same strain, says Kitamura.

This is consistent with previous human literature that showed that some hippocampal cells fire not only when the person is looking at themselves, but also when they look at familiar people like a parent.

Next, the researchers plan to try to disentangle the importance of visual and tactile stimuli to test whether mice can recognize changes in their reflection in the absence of a tactile stimulusperhaps by using technology similar to the filters on social media apps that allow people to give themselves puppy-dog faces or bunny ears.

They also plan to study other brain regions that might be involved in self-recognition and to investigate how the different regions communicate and integrate information.

Now that we have this mouse model, we can manipulate or monitor neural activity to comprehensively investigate the neural circuit mechanisms behind how self-recognition-like behavior is induced in mice, says Yokose.

Funding: This research was supported by the Endowed Scholar Program, the Brain & Behavior Research Foundation, the Daiichi Sankyo Foundation of Life Science, and Uehara Memorial Foundation.

Author: Kristopher Benke Source: Cell Press Contact: Kristopher Benke Cell Press Image: The image is credited to Neuroscience News

Original Research: Open access. Visuotactile integration facilitates mirror-induced self-directed behavior through activation of hippocampal neuronal ensembles in mice by Takashi Kitamura et al. Neuron

Abstract

Visuotactile integration facilitates mirror-induced self-directed behavior through activation of hippocampal neuronal ensembles in mice

Remembering the visual features of oneself is critical for self-recognition. However, the neural mechanisms of how the visual self-image is developed remain unknown because of the limited availability of behavioral paradigms in experimental animals.

Here, we demonstrate a mirror-induced self-directed behavior (MSB) in mice, resembling visual self-recognition. Mice displayed increased mark-directed grooming to remove ink placed on their heads when an ink-induced visual-tactile stimulus contingency occurred. MSB required mirror habituation and social experience.

The chemogenetic inhibition of dorsal or ventral hippocampal CA1 (vCA1) neurons attenuated MSB. Especially, a subset of vCA1 neurons activated during the mirror exposure was significantly reactivated during re-exposure to the mirror and was necessary for MSB.

The self-responding vCA1 neurons were also reactivated when mice were exposed to a conspecific of the same strain.

These results suggest that visual self-image may be developed through social experience and mirror habituation and stored in a subset of vCA1 neurons.

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