Category Archives: Neuroscience

Summary: Those with treatment-resistant depression showed significant improvement in symptoms and became more receptive to positive experiences following a one-week ketamine treatment regimen.

Source: Paris Brain Institute

Researchers from Inserm, CNRS, Sorbonne University and clinicians from the AP-HP and at Paris Brain Institute identified one of the mechanisms explaining ketamine effect as an antidepressant.

Ketamine, usually used as an anesthetic, was administered to patients with severe resistant depression. This treatment led patients to present an increased ability to overcome their negative beliefs about themselves and the world when researchers presented them positive information.

These results, published in JAMA Psychiatry, open new therapeutic avenues for the management of antidepressant-resistant mood disorders.

Depression is the most common psychiatric disorder: it is estimated that 5 to 15% of the French population will experience a major depressive episode during their lifetime. All age groups and all social backgrounds are affected.

The disease is characterized by sadness and loss of hedonic feelings that positive events do not improve. Depressed patients progressively develop negative beliefs about themselves, the world, and the future, that may develop into suicidal thoughts. These negative beliefs remain even when the patient receives positive information.

About one-third of people with depression do not respond to the most prescribed antidepressants, leading to a diagnosis of treatment-resistant depression (TRD). For these people, finding new and effective therapies is a priority.

Ketamine, a commonly used anesthetic, has been shown to influence resistant depression. While conventional antidepressant treatments take time to be efficient (on average three weeks), ketamine has a rapid antidepressant effect, only a few hours after administration. The mechanisms associated with this fast-acting antidepressant effect are still unknown.

To identify these mechanisms, Dr. Hugo Bottemanne and the research team co-led at the Paris Brain Institute by Pr Philippe Fossati and Liane Schmidt, Inserm researcher, coordinated a clinical study involving 26 antidepressant-resistant patients (TRD) and 30 healthy controls.

During the protocol, patients and healthy subjects were first asked to estimate the probability of 40 negative events which could occur in their lives (e.g., have a car accident, get cancer, or lose their wallet).

After being informed of the actual occurrence risks in the general population, patients and healthy subjects were again asked to estimate the probability of these events occurring in their lives. The research team was interested in the updating of beliefs after getting information.

Results showed that healthy subjects tended to update their initial beliefs more after receiving factual and positive information, which was not the case in the depressed patient population.

In the suite of the study, TRD patients received three administrations of ketamine at a subanesthetic dose (0.5 mg/kg over 40 minutes) in one week.

Only four hours after the first administration, patients ability to update their beliefs after receiving a positive information was increased. They became less sensitive to negative information and recovered an ability to update their knowledge com parable to that of control subjects.

Moreover, improvement in depressive symptoms after ketamine treatment was associated with these changes in belief updating, suggesting a link between clinical improvement and changes in this cognitive mechanism. In other words, the more patients belief updating ability was increased, the greater the improvement in symptoms was.

In conclusion, in this study, patients with antidepressant-resistant depression showed a significant decrease in symptoms and became more receptive to positive experiences after one week of ketamine treatment.

This work highlights for the first time a cognitive mechanism potentially involved in the early effect of ketamine. It paves the way to new research on antidepressant therapies modulating the mechanisms of belief updating.

Author: Nicolas BrardSource: Paris Brain InstituteContact: Nicolas Brard Paris Brain InstituteImage: The image is in the public domain

Original Research: Open access.Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression by Hugo Bottemanne et al. JAMA Psychiatry

Abstract

Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression

Importance

Clinical research has shown that persistent negative beliefs maintain depression and that subanesthetic ketamine infusions induce rapid antidepressant responses.

Objective

To evaluate whether ketamine alters belief updating and how such cognitive effects are associated with the clinical effects of ketamine.

Design, Setting, and Participants

This study used an observational case-control protocol with a mixed-effects design that nested 2 groups by 2 testing time points. Observers were not blinded. Patients with treatment-resistant depression (TRD) and healthy volunteer participants aged 34 to 68 years were included. Patients with TRD were diagnosed with major depressive disorder or bipolar depression, had a Montgomery-sberg Depression Rating Scale score greater than 20, a Maudsley Staging Method score greater than 7, and failed to respond to at least 2 prior antidepressant trials. Exclusion criteria were any other psychiatric, neurological, or neurosurgical comorbidities, substance use or addictive disorders, and recreational ketamine consumption. Data were collected from January to February 2019 and from May to December 2019, and data were analyzed from January 2020 to July 2021.

Exposures

Patients with TRD were observed 24 hours before single ketamine infusion, 4 hours after the infusion, and 4 hours after the third infusion, which was 1 week after the first infusion. Healthy control participants were observed twice 1 week apart without ketamine exposure.

Main Outcomes and Measures

Montgomery-sberg Depression Rating Scale score and belief updating after belief updating when patients received good news and bad news measured by a cognitive belief-updating task and mathematically formalized by a computational reinforcement learning model.

Results

Of 56 included participants, 29 (52%) were male, and the mean (SEM) age was 52.3 (1.2) years. A total of 26 patients with TRD and 30 control participants were included. A significant grouptesting time pointnews valence interaction showed that patients with TRD updated their beliefs more after good than bad news following a single ketamine infusion (controlled for age and education: =0.91; 95% CI, 1.58 to 0.24;t216=2.67;P=.008) than controls. Computational modeling showed that this effect was associated with asymmetrical learning rates (LRs) after ketamine treatment (good news LRs after ketamine, 0.51 [SEM, 0.04]; bad news LRs after ketamine 0.36 [SEM, 0.03],t25=3.8;P<.001) and partially mediated early antidepressant responses (patha*b: =1.00 [SEM, 0.66];t26=1.53;z=1.98;P=.04).

Conclusions and Relevance

These findings provide novel insights into the cognitive mechanisms of the action of ketamine in patients with TRD, with promising perspectives for augmented psychotherapy for individuals with mood disorders.

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Mechanism for the Antidepressant Effect of Ketamine Revealed - Neuroscience News

Neuroscience

Brennand named Elizabeth Mears and House Jameson Professor of Psychiatry – Yale News

October 12, 2022 medical

Kristen Brennand

Kristen Brennand, who in her research integrates expertise in genetics, neuroscience, and stem cells to identify the mechanisms that underlie brain disease, was recently appointed the Elizabeth Mears and House Jameson Professor of Psychiatry.

She is also co-director of the Yale Science Fellows Program, a Yale School of Medicine initiative aimed at recruiting, supporting, and promoting outstanding young scientists from groups traditionally underrepresented in science and medicine.

Brennand completed her Ph.D. at Harvard University in the laboratory of the noted stem cell biologist Dr. Douglas Melton. During her postdoctoral fellowship at the Salk Institute, she drew international notice for publishing the first cellular model for schizophrenia. She developed a new method for reprogramming skin samples from patients into human induced pluripotent stem cells and then she differentiated these stem cells into neurons. Her initial report demonstrated that neurons derived from schizophrenia patients had profound deficits in synaptic connectivity, i.e., were less well connected to each other.

While on the faculty at the Icahn School of Medicine at Mount Sinai, Brennand developed a highly productive laboratory and a network of collaborations. By combining stem cell biology, psychiatric genetics, and neurobiology, she pioneered a new approach to studying brain disease. She and her collaborators shed light on the genetics and biology of schizophrenia, bipolar disorder, and other conditions. She was interim director of the Pamela Sklar Division of Psychiatric Genomics and then director of the Alper Stem Cell Center.

Although Brennand arrived at Yale during the pandemic, she rapidly established a productive laboratory, created new interdepartmental collaborations, and distinguished herself as a valued teacher and mentor. Her laboratory also is quite well funded with competitive grants from the National Institutes of Health (NIH).

She also has received numerous honors. The Brain and Behavior Research Foundation awarded her the Maltz Prize for Schizophrenia Research and elected her to its Scientific Council. This year, she was elected to the Connecticut Academy of Science and Engineering and named as a finalist for the 2022 Blavatnik Awards for Young Scientists. She also has developed a reputation as a mentor to her trainees and other young scientists. In 2019, she received the Friedman Brain Institute Neuroscience Mentorship Distinction Award. She serves as a standing member of NIH study section and the editorial boards of seven journals in psychiatry, stem cell biology, and neuroscience.

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Brennand named Elizabeth Mears and House Jameson Professor of Psychiatry - Yale News

Neuroscience

NYU Neuro Grad Program – Home

October 3, 2022 medical

Understanding the brain is one of the great scientific challenges. How does the nervous system allow us to sense, move, learn, decide, remember, and think? How are the underlying neural circuits built by genetic and molecular programs? How do neurons communicate via synapses to transmit and store information? What goes wrong in neurodevelopmental disorders like autism and schizophrenia, and in neurodegenerative diseases like Alzheimers and Parkinsons disease? And how can we model neurons, circuits and systems to better understand the brain?Graduate students in our PhD program in neuroscience are addressing these questions at labs located across NYU, using cutting-edge tools drawn from genetics, molecular biology, biochemistry, electrophysiology, microscopy, computer science, data science, and mathematics.This website is designed for you to learn about graduate training in neuroscience at NYU.Our program arises from two cooperative centers located just a few city blocks apart: the Center for Neural Science (CNS) and the Neuroscience Institute (NI). CNS, located at NYUs Washington Square campus, is home to core neuroscience labs, has affiliate labs in biology, psychology, physics and data science, and is NYUs portal for undergraduate neuroscience education. The NI is located at NYUs school of medicine and houses additional core neuroscience labs, as well as affiliates from clinical departments and the Nathan Kline Institute. Together, CNS and NI serve as the joint pillars of graduate training in neuroscience at NYU, with research spanning genetic, molecular, cellular, developmental, systems, behavioral, and computational levels. Prospective graduate students apply through a single online portal and applications are jointly reviewed by a single admissions committee that spans CNS and NI.

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NYU Neuro Grad Program - Home

Neuroscience

Providing new pathways for neuroscience research and education – MIT News

October 3, 2022 medical

Payton Dupuiss interest in biology research began where it does for many future scientists witnessing a relative struggling with an incurable medical condition. For Dupuis, that family member was her uncle, who suffered from complications from diabetes. Dupuis, a senior at Montana State University, says that diabetes is prominent on the Flathead Reservation in Montana, where she grew up, and witnessing the impacts of the disease inspired her to pursue a career in scientific research. Since then, that passion has taken Dupuis around the country to participate in various summer research programs in the biomedical sciences.

Most recently, she was a participant in the Bernard S. and Sophie G. Gould MIT Summer Research Program in Biology (BSG-MSRP-Bio). The program, offered by the departments of Biology and Brain and Cognitive Sciences, is designed to encourage students from underrepresented groups to attend graduate school and pursue careers in science research. More than 85 percent of participants have subsequently enrolled in highly ranked graduate programs, many of them returning to MIT, just as Dupuis is considering.

Her journey from witnessing the impacts of her uncles diabetes to considering graduate school at MIT was made possible only by Dupuiss love of science and her ability to find a positive, as she says, in every experience.

As a high-schooler, Dupuis made her first trip to the Northeast, participating in the Summer Academy of Math and Sciences at Carnegie Mellon University. For Dupuis, who hadnt even taken calculus yet, the experience was a welcome challenge. That definitely made me work hard, she laughs, comparing herself to other program participants. But I proved to myself, not for anyone else, that I belonged in that program.

In addition to being a confidence booster, the Carnegie Mellon program also gave Dupuis her first taste of scientific research working in a biomedical lab on tissue regeneration. She was excited about the possibilities of growing new organs such as the insulin-producing pancreas that could help regulate her uncles diabetes outside of the body. Dupuis was officially hooked on biology.

Her experience that summer encouraged Dupuis to major in chemical engineering, seeing it as a good pipeline into biomedical research. Unfortunately, the chemical engineering curriculum at Montana State wasnt what she expected, focusing less on the human body and more on the oil industry. In that context, her ability to see a silver lining served Dupuis well.

That wasnt really what I wanted, but it was still interesting because there were ways that I could apply it to the body, she explains. Like fluid mechanics instead of water flowing through a pipe, I was thinking about blood flowing through veins.

Dupuis adds that the chemical engineering program also gave her problem-solving skills that have been valuable as shes undertaken biology-focused summer programs to help refine her interests. One summer, she worked in the chemistry department at Montana State, getting hands-on experience in a wet lab. I didnt really know any of the chemistry behind what I was doing, she admits, but I fell in love with it. Another summer, she participated in the Tufts Building Diversity in Biomedical Sciences program, exploring the genetic side of research through a project on bone development in mice.

In 2020, a mentor at the local tribal college connected Dupuis with Keith Henry, an associate professor of biomedical sciences at the University of North Dakota. With Henry, Dupuis looked for new binding sites for the neurotransmitter serotonin that could help minimize the side effects that come with long-term use of selective serotonin reuptake inhibitors (SSRIs), the most common class of antidepressants. That summer was Dupuiss first exposure to brain research, and her first experience modeling biological processes with computers. She loved it. In fact, as soon as she returned to Montana State, Dupuis enrolled as a computer science minor.

Because of the minor, Dupuis needs an extra year to graduate, which left her one more summer for a research program. Her older sister had previously participated in the general MSRP program at MIT, so it was a no-brainer for Dupuis to apply for the biology-specific program.

This summer, Dupuis was placed in the lab of Troy Littleton, the Menicon Professor in Neuroscience at The Picower Institute for Learning and Memory. I definitely fell in love with the lab, she says. With Littleton, Dupuis completed a project looking at complexin, a protein that can both inhibit and facilitate the release of neurotransmitters like serotonin. Its also essential for the fusion of synaptic vesicles, the parts of neurons that store and release neurotransmitters.

A number of human neurological diseases have been linked to a deficiency in complexin, although Dupuis says that scientists are still figuring out what the protein does and how it works.

To that end, Dupuis focused this summer on fruit flies, which have two different types of complexin humans, in comparison, have four. Using gene editing, she designed an experiment comparing fruit flies possessing various amounts of different subtypes of the protein. There was the positive control group, which was untouched; the negative control group that had no complexin; and two experimental groups, each with one of the subtypes removed. Using fluorescent staining, Dupuis compared how neurons lit up in each group of flies, illuminating how altering the amount of complexin changed how the flies released neurotransmitters and formed new synaptic connections.

After touching on so many different areas of biological research through summer programs, Dupuis says that researching neuronal activity in fruit flies this summer was the perfect fit intellectually, and a formative experience as a researcher.

Ive definitely learned how to take an experiment and make it my own and figure out what works best for me, but still produces the results we need, she says.

As for whats next, Dupuis says her experience at MIT has sold her on pursuing graduate work in brain sciences. Boston is really where I want to be and eventually work, with all the biotech and biopharma companies around, she says. One of the perks of the MSRP-Bio program is professional development opportunities. Though Dupuis had always been interested in industry, she says she appreciated attending career panels this summer that demystified what that career path really looks like and what it takes to get there.

Perhaps the most important aspect of the program for Dupuis, though, was the confidence it provided as she continues to navigate the world of biomedical research. She intends to take that back with her to Montana State to encourage classmates to seek out similar summer opportunities.

Theres so many people that I know would be a great researcher and love science, but they just dont either know about it or think they can get it, she says. All Id say is, you just got to apply. You just have to put yourself out there.

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Providing new pathways for neuroscience research and education - MIT News

Neuroscience

Neuroscience | OhioHealth

October 3, 2022 medical

At OhioHealth, we provide the most comprehensive neuroscience care to diagnose, treat and heal patients with conditions like ALS, multiple sclerosis, Parkinsons disease, epilepsy, spine pain, stroke and more. We involve the highest-skilled specialists, the latest medical advancements, clinical trials and exclusive wellness programs to develop individualized treatment plans.

Love Hormone Oxytocin Could Mend a Broken Heart – Neuroscience News

October 3, 2022 medical

Summary: Oxytocin, a hormone connected with bonding and love, could help to heal damage following a heart attack. Researchers found oxytocin stimulates stem cells from the hearts outer layer and migrates into the middle layer where it develops into muscle cells that generate heart contractions. This could be used to promote the regeneration of heart cells following a heart attack.

Source: Frontiers

The neurohormone oxytocin is well-known for promoting social bonds and generating pleasurable feelings, for example from art, exercise, or sex. But the hormone has many other functions, such as the regulation of lactation and uterine contractions in females, and the regulation of ejaculation, sperm transport, and testosterone production in males.

Now, researchers from Michigan State University show that in zebrafish and human cell cultures, oxytocin has yet another, unsuspected, function: it stimulates stem cells derived from the hearts outer layer (epicardium) to migrate into its middle layer (myocardium) and there develop into cardiomyocytes, muscle cells that generate heart contractions. This discovery could one day be used to promote the regeneration of the human heart after a heart attack.

The results are published inFrontiers in Cell and Developmental Biology.

Here we show that oxytocin, a neuropeptide also known as the love hormone, is capable of activating heart repair mechanisms in injured hearts in zebrafish and human cell cultures, opening the door to potential new therapies for heart regeneration in humans, said Dr Aitor Aguirre, an assistant professor at the Department of Biomedical Engineering of Michigan State University, and the studys senior author.

Stem-like cells can replenish cardiomyocytes

Cardiomyocetes typically die off in great numbers after a heart attack. Because they are highly specialized cells, they cant replenish themselves. But previous studies have shown that a subset of cells in the epicardium can undergo reprogramming to become stem-like cells, called Epicardium-derived Progenitor Cells (EpiPCs), which can regenerate not only cardiomyocytes, but also other types of heart cells.

Think of the EpiPCs as the stonemasons that repaired cathedrals in Europe in the Middle Ages, explained Aguirre.

Unfortunately for us, the production of EpiPCs is inefficient for heart regeneration in humans under natural conditions.

Zebrafish could teach us how to regenerate hearts more efficiently

Enter the zebrafish: famous for their extraordinary capacity for regenerating organs, including the brain, retina, internal organs, bone, and skin. They dont suffer heart attacks, but its many predators are happy to take a bite out of any organ, including the heart so zebrafish can regrow their heart when as much as a quarter of it has been lost.

This is done partly by proliferation of cardiomyocytes, but also by EpiPCs. But how do the EpiPCs of zebrafish repair the heart so efficiently? And can we find a magic bullet in zebrafish that could artificially boost the production of EpiPCs in humans?

Yes, and this magic bullet appears to be oxytocin, argue the authors.

To reach this conclusion, the authors found that in zebrafish, within three days after cryoinjury injury due to freezing to the heart, the expression of the messenger RNA for oxytocin increases up to 20-fold in the brain.

They further showed that this oxytocin then travels to the zebrafish epicardium and binds to the oxytocin receptor, triggering a molecular cascade that stimulates local cells to expand and develop into EpiPCs.

These new EpiPCs then migrate to the zebrafish myocardium to develop into cardiomyocytes, blood vessels, and other important heart cells, to replace those which had been lost.

Similar effect on human tissue cultures

Crucially, the authors showed that oxytocin has a similar effect on human tissuein vitro. Oxytocin but none of 14 other neurohormones tested here stimulates cultures of human Induced Pluripotent Stem Cells (hIPSCs) to become EpiPCs, at up to twice the basal rate: a much stronger effect than other molecules previously shown to stimulate EpiPC production in mice.

Conversely, genetic knock-down of the oxytocin receptor prevented the the regenerative activation of human EpiPCs in culture. The authors also showed that the link between oxytocin and the stimulation of EpiPCs is the important TGF- signaling pathway, known to regulate the growth, differentiation, and migration of cells.

Aguirre said: These results show that it is likely that the stimulation by oxytocin of EpiPC production is evolutionary conserved in humans to a significant extent. Oxytocin is widely used in the clinic for other reasons, so repurposing for patients after heart damage is not a long stretch of the imagination. Even if heart regeneration is only partial, the benefits for patients could be enormous.

Aguirre concluded: Next, we need to look at oxytocin in humans after cardiac injury. Oxytocin itself is short-lived in the circulation, so its effects in humans might be hindered by that. Drugs specifically designed with a longer half-life or more potency might be useful in this setting.

Overall, pre-clinical trials in animals and clinical trials in humans are necessary to move forward.

Author: Mischa DijkstraSource: FrontiersContact: Mischa Dijkstra FrontiersImage: The image is in the public domain

Original Research: Open access.Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury by Aitor Aguirre et al. Frontiers in Cell and Developmental Biology

Abstract

Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury

Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature.

Critical work in the last 2decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development.

Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardium-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells.

In mammals, this process alone is insufficient for significant regeneration, but it might be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function.

Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and transcriptional activity in a model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells.

In addition, we demonstrate that OXT is produced after cardiac cryoinjury in zebrafish, and that it elicits significant epicardial activation promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium development in zebrafish embryos.

The above processes are significantly impaired when OXT signaling is inhibited chemically or genetically through RNA interference. RNA sequencing data suggests that the transforming growth factor beta (TGF-) pathway is the primary mediator of OXT-induced epicardial activation.

Our research reveals for the first time an evolutionary conserved brain-controlled mechanism inducing cellular reprogramming and regeneration of the injured mammalian and zebrafish heart, a finding that could contribute to translational advances for the treatment of cardiac injuries.

Neuroscience

Study Reveals Main Target of COVID-19 in Brain and Describes Effects of Virus on Nervous System – Neuroscience News

October 3, 2022 medical

Summary: SARS_CoV_2, the virus responsible for COVID-19 infects and replicates in astrocytes, reducing neural viability.

Source: FAPESP

A Brazilian study published in the journalPNASdescribes some of the effects infection by SARS-CoV-2 can have on the central nervous system.

A preliminary version (not yet peer-reviewed) posted in 2020 was one of the first to show that the virus that causes COVID-19 can infect brain cells, especially astrocytes. It also broke new ground by describing alterations in the structure of the cortex, the most neuron-rich brain region, even in cases of mild COVID-19.

The cerebral cortex is the outer layer of gray matter over the hemispheres. It is the largest site of neural integration in thecentral nervous systemand plays a key role in complex functions such as memory, attention, consciousness, and language.

The investigation was conducted by several groups at the State University of Campinas (UNICAMP) and the University of So Paulo (USP). Researchers at the Brazilian Biosciences National Laboratory (LNBio), DOr Institute (IDOR) and the Federal University of Rio de Janeiro (UFRJ) also contributed to the study.

Two previous studies detected the presence of the novel coronavirus in the brain, but no one knew for sure if it was in the bloodstream,endothelial cells[lining the blood vessels] or nerve cells. We showed for the first time that it does indeed infect and replicate in astrocytes, and that this can reduce neuron viability, Daniel Martins-de-Souza, one of the leaders of the study, told Agncia FAPESP. Martins-de-Souza is a professor at UNICAMPs Biology Institute and a researcher affiliated with IDOR.

Astrocytes are the most abundant central nervous system cells. Their functions include providing biochemical support and nutrients for neurons; regulating levels of neurotransmitters and other substances that may interfere with neuronal functioning, such as potassium; maintaining the blood-brain barrier that protects the brain from pathogens and toxins; and helping to maintain brain homeostasis.

Infection of astrocytes was confirmed by experiments using brain tissue from 26 patients who died of COVID-19. The tissue samples were collected during autopsies conducted using minimally invasive procedures by Alexandre Fabro, a pathologist and professor at the University of So Paulos Ribeiro Preto Medical School (FMRP-USP). The analysis was coordinated by Thiago Cunha, also a professor in FMRP-USP and a member of the Center for Research on Inflammatory Diseases (CRID).

The researchers used a technique known as immunohistochemistry, a staining process in which antibodies act as markers of viral antigens or other components of the tissue analyzed.

For example, we can insert one antibody into the sample to turn the astrocytes red on binding to them, another to mark the SARS-CoV-2 spike protein by making it green, and a third to highlight the viruss double-stranded RNA, which only appears during replication, by turning it magenta, Martins-de-Souza explained.

When the images produced during the experiment were overlaid, all three colors appeared simultaneously only in astrocytes.

According to Cunha, the presence of the virus was confirmed in five of the 26 samples analyzed. Alterations suggesting possible damage to the central nervous system were also found in these five samples.

We observed signs of necrosis and inflammation, such as edema [swelling caused by a buildup of fluid], neuronal lesions and inflammatory cell infiltrates, he said.

The capacity of SARS-CoV-2 to infect brain tissue and its preference for astrocytes were confirmed by Adriano Sebolella and his group at FMRP-USP using the method of brain-derived slice cultures, an experimental model in which human brain tissue obtained during surgery to treat neurological diseases such as drug-refractory epilepsy, for example, is cultured in vitro and infected with the virus.

Persistent symptoms

In another part of the research, conducted in UNICAMPs School of Medical Sciences (FCM), 81 volunteers who had recovered from mild COVID-19 were submitted to magnetic resonance imaging (MRI) scans of their brains.

These scans were performed 60 days after diagnostic testing on average. A third of the participants still had neurological or neuropsychiatric symptoms at the time. They complained mostly of headache (40%), fatigue (40%), memory alterations (30%), anxiety (28%), loss of smell (28%), depression (20%), daytime drowsiness (25%), loss of taste (16%) and low libido (14%).

We posted a link for people interested in participating in the trial to register, and were surprised to get more than 200 volunteers in only a few days. Many were polysymptomatic, with widely varying complaints. In addition to the neuroimaging exam, theyre being evaluated neurologically and taking standardized tests to measure performance in cognitive functions such as memory, attention and mental flexibility. In the article we present the initial results, said Clarissa Yasuda, a professor and member of the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN).

Only volunteers diagnosed with COVID-19 by RT-PCR and not hospitalized were included in the study. The assessments were carried out after the end of the acute phase, and the results were compared with data for 145 healthy uninfected subjects.

The MRI scans showed that some volunteers had decreased cortical thickness in some brain regions compared with the average for controls.

We observed atrophy in areas associated, for example with anxiety, one of the most frequent symptoms in the study group, Yasuda said. Considering that the prevalence of anxiety disorders in the Brazilian population is 9%, the 28% we found is an alarmingly high number. We didnt expect these results in patients who had had the mild form of the disease.

In neuropsychological tests designed to evaluate cognitive functioning, the volunteers also underperformed in some tasks compared with the national average. The results were adjusted for age, sex and educational attainment, as well as the degree of fatigue reported by each participant.

The question were left with is this: Are these symptoms temporary or permanent? So far, weve found that some subjects improve, but unfortunately many continue to experience alterations, Yasuda said.

Whats surprising is that many people have been reinfected by novel variants, and some report worse symptoms than they had since the first infection. In view of the novel virus, we see longitudinal follow-up as crucial to understand the evolution of the neuropsychiatric alterations over time and for this understanding to serve as a basis for the development of targeted therapies.

Energy metabolism affected

In IB-UNICAMPs Neuroproteomics Laboratory, which is headed by Martins-de-Souza, experiments were performed on brain tissue cells from people who died of COVID-19 and astrocytes cultured in vitro to find out how infection by SARS-CoV-2 affects nervous system cells from the biochemical standpoint.

The autopsy samples were obtained via collaboration with the group led by Paulo Saldiva, a professor at the University of So Paulos Medical School (FM-USP). The proteome (all proteins present in the tissue) was mapped using mass spectrometry, a technique employed to identify different substances in biological samples according to their molecular mass.

When the results were compared with those of uninfected subjects, several proteins with altered expression were found to be abundant in astrocytes, which validated the findings obtained by immunohistochemistry, Martins-de-Souza said.

We observed alterations in various biochemical pathways in the astrocytes, especially pathways associated withenergy metabolism.

The next step was to repeat theproteomic analysisin cultured astrocytes infected in the laboratory. The astrocytes were obtained from induced pluripotent stem cells (iPSCs). The method consists of reprogramming adult cells (derived from skin or other easily accessible tissues) to assume a stage of pluripotency similar to that of embryo stem cells.

This first part was conducted in the IDOR laboratory of Stevens Rehen, a professor at UFRJ. Martins-de-Souzas team then used chemical stimuli to make the iPSCs differentiate into neural stem cells and eventually into astrocytes.

The results were similar to those of the analysis of tissue samples obtained by autopsy in that they showed energy metabolism dysfunction, Martins-de-Souza said.

We then performed a metabolomic analysis [focusing on the metabolites produced by the cultured astrocytes], which evidenced glucose metabolism alterations. For some reason, infected astrocytes consume more glucose than usual, and yet cellular levels of pyruvate and lactate, the main energy substrates, decreased significantly.

Lactate is one of the products of glucose metabolism, and astrocytes export this metabolite to neurons, which use it as an energy source. The researchers in vitro analysis showed that lactate levels in the cell culture medium were normal but decreased inside the cells. Astrocytes appear to strive to maintain the energy supply to neurons even if this effort weakens their own functioning, Martins-de-Souza said.

As an outcome of this process, the functioning of the astrocytes mitochondria (energy-producing organelles) was indeed altered, potentially influencing cerebral levels of such neurotransmitters as glutamate, which excites neurons and is associated with memory and learning, or gamma-aminobutyric acid (GABA), which inhibits excessive firing of neurons and can promote feelings of calm and relaxation.

In another experiment, we attempted to culture neurons in the medium where the infected astrocytes had grown previously and measured a higher-than-expected cell death rate. In other words, this culture medium conditioned by infected astrocytes weakened neuron viability, Martins-de-Souza said.

The findings described in the article confirm those of several previously published studies pointing to possible neurological and neuropsychiatric manifestations of COVID-19.

Results of experiments on hamsters conducted at the Institute of Biosciences (IB-USP), for example, reinforce the hypothesis that infection by SARS-CoV-2 accelerates astrocyte metabolism and increases the consumption of molecules used to generate energy, such as glucose and the amino acid glutamine.

The results obtained by the group led by Jean Pierre Peron indicate that this metabolic alteration impairs the synthesis of a neurotransmitter that plays a key role in communication among neurons.

Unanswered questions

According to Martins-de-Souza, there is no consensus in the scientific literature on how SARS-CoV-2 reaches the brain.

Some animal experiments suggest the virus can cross the blood-brain barrier. Theres also a suspicion that it infects the olfactory nerve and from there invades the central nervous system. But these are hypotheses for now, he said.

One of the discoveries revealed by thePNASarticle is that the virus does not use the protein ACE-2 to invade central nervous system cells, as it does in the lungs.

Astrocytes dont have the protein in their membranes. Research by Flvio Veras [FMRP-USP] and his group shows that SARS-CoV-2 binds to the protein neuropilin in this case, illustrating its versatility in infecting different tissues, Martins-de-Souza said.

At UNICAMPs Neuroproteomics Laboratory, Martins-de-Souza analyzed nerve cells and others affected by COVID-19, such as adipocytes, immune system cells and gastrointestinal cells, to see how the infection altered the proteome.

Were now compiling the data to look for peculiarities and differences in the alterations caused by the virus in these different tissues. Thousands of proteins and hundreds of biochemical pathways can be altered, with variations in each case. This knowledge will help guide the search for specific therapies for each system impaired by COVID-19, he said.

Were also comparing the proteomic differences observed inbrain tissuefrom patients who died of COVID-19 with proteomic differences weve found over the years in patients with schizophrenia. The symptoms of both conditions are quite similar. Psychosis, the most classic sign of schizophrenia, also occurs in people with COVID-19.

The aim of the study is to find out whether infection by SARS-CoV-2 can lead to degeneration of the white matter in the brain, made up mainly of glial cells (astrocytesand microglia) and axons (extensions of neurons).

Weve observed a significant correspondence [in the pattern of proteomic alterations] associated with the energy metabolism and glial proteins that appear important in both COVID-19 and schizophrenia. These findings may perhaps provide a shortcut to treatments for the psychiatric symptoms of COVID-19, Martins-de-Souza pondered.

Marcelo Mori, a professor at IB-UNICAMP and a member of the Obesity and Comorbidities Research Center (OCRC), the study was only possible thanks to the collaboration of researchers with varied and complementary backgrounds and expertise.

It demonstrates that first-class competitive science is always interdisciplinary, he said. Its hard to compete internationally if you stay inside your own lab, confining yourself to the techniques with which youre familiar and the equipment to which you have access.

Author: Press OfficeSource: FAPESPContact: Press Office FAPESPImage: The image is in the public domain

Original Research: Open access.Morphological, cellular, and molecular basis of brain infection in COVID-19 patients by Fernanda Crunfli et al. PNAS

Abstract

Morphological, cellular, and molecular basis of brain infection in COVID-19 patients

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of long COVID-19 syndrome) has been frequently observed after mild infection.

We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain.

Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes.

Supporting the hypothesis of astrocyte infection, neural stem cellderived human astrocytes invitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spikeNRP1 interaction. SARS-CoV-2infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability.

Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Originally posted here:
Study Reveals Main Target of COVID-19 in Brain and Describes Effects of Virus on Nervous System - Neuroscience News

Neuroscience

The Unexpected Cells Helping to Shape Young Brains – Neuroscience News

October 3, 2022 medical

Summary: During brain development, oligodendrocyte precursor cells (OPCs) contribute to the neural pruning process, helping to shape the healthy development of the brain.

Source: CSHL

When the brain first wires itself up in early development, it creates more connections than it actually needs.

Some of these connections, or synapses, will transmit critical signals as young animals begin to sense their surroundings. Others will be eliminated as the brain matures.

Only those that the animal needs to understand and interact with the world are left.

Cold Spring Harbor Laboratory (CSHL) Assistant Professor Lucas Cheadle and colleagues have discovered that cells called oligodendrocyte precursor cells (OPCs) contribute to this pruning process. This helps shape a healthybrainduring early development.

Understanding this vital part of brain development may reveal new strategies for treating neurodevelopmental conditions like schizophrenia andautism spectrum disorder(ASD).

The discovery was sparked while using high-powered microscopes to examine the brains of adult mice. Cheadles team noticed that many OPCs were actively engulfing the connection points between neurons.

The team suspected the cells might be busy eliminating synapses that the brain did not need. Cheadle and his team wondered if OPCs did the same thing in younger brains. A young animals experiences have a particularly profound impact on shaping neural circuits duringearly development.

The researchers raised young mice in the dark. When the mice were first exposed to light, OPCs began engulfingsynapsesin response. The cells were operating in their brains vision-processing circuitry.

OPCs seem to be especially poised to regulate brain connections associated with experiences, Cheadle says. These cells are very responsive to new experiences. They can take that information and use it to shape brain connections.

Published inNature Neuroscience, the Cheadle teams discovery reveals an unexpected role for OPCs. Several kinds of cells help shapeneural circuitsby eliminating unnecessary connections. OPCs had previously only been known for producing cells that surround and support neurons.

Cheadle says, This is a cell type thats really poised to sort of serve as an intermediary between whats going on in the world out there and whats happening inside of our brains.

Cheadle hopes this new information will help understand neurodevelopmental disorders better. He plans to investigate whether faulty OPC pruning plays a role in conditions like schizophrenia and ASD.

Author: Press OfficeSource: CSHLContact: Press Office CSHLImage: The image is credited to Cheadle lab/Imaris software/CSHL, 2022

Original Research: Open access.Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice by Yohan S. S. Auguste et al. Nature Neuroscience

Abstract

Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice

Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes throughout life, but the functions of OPCs are not limited to oligodendrogenesis.

Here we show that OPCs contribute to thalamocortical presynapse elimination in the developing and adult mouse visual cortex. OPC-mediated synapse engulfment increases in response to sensory experience during neural circuit refinement.

Our data suggest that OPCs may regulate synaptic connectivity in the brain independently of oligodendrogenesis.

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The Unexpected Cells Helping to Shape Young Brains - Neuroscience News

Neuroscience

What Is the Effect of Hierarchy on Moral Behavior? – Neuroscience News

October 3, 2022 medical

Summary: Powerful hierarchical situations make it easier for individuals to commit harmful actions. The reason for this, researchers say, is because empathy and agency become split across multiple individuals.

Source: KNAW

Researchers from the Netherlands Institute for Neuroscience show that powerful hierarchical situations make it easier to commit harmful actions, asagency and empathy are split across multiple individuals.

There are numerous historical examples where horrific acts and mass destruction have occurred as a result of a hierarchical structure. A superior communicates a plan and a subordinate carries it out. The superior then bears responsibility for the decision but is distanced from the results, while the subordinate experiences authorship over the action but may experience reduced responsibility for its outcomes. And in our daily lives too, hierarchy is acquired throughout our society.

In many organizations, orders are embedded in an even longer chain of commands in which a given commander often merely relays on the orders received from a superior. But what effect does this have on our actions?

A new study from the social brain lab looked at how your position within a hierarchical structure (commander or intermediary) influences the sense of agency and empathy for pain. The aim was to understand how these two different neurocognitive processes differ in commanders and intermediaries.

And guess what? Commanders and intermediaries show reduced activation in empathic brain regions when pain is inflicted on the victim compared to people who can decide and act for themselves.

The results were published in the journaleNeuro.

The team used functional MRI (fMRI) and electroencephalogram (EEG) techniques in order to perform their experiments. fMRI measures brain activity by tracking changes in blood flow over time. The changes visible on the scan are related to change in oxygen levels: when areas of the brain are active, they will need more oxygen, causing them to light up.

Using EEG, brain activity is measured electrically. During this test, small sensors are attached to the scalp to pick up the electrical signals produced by the brain.

Reduced empathy

The fMRI study shows that activity in empathy-related brain regions was low in both the commander and the intermediary, compared to someone who delivered the shock directly of their own free will.

During the both studies, pain was administered by a human or robot.

The EEG results show that the sense of agency did not differ between commanders and intermediaries, regardless of whether the execution was performed by a robot or a human. However, it turned out that the neural response to the pain of the victim were higher when participants commanded a robot compared to a human.

This suggests that when there is a second human involved, the responsibility tends to be diffused and commanders pain processing of the victims pain is reduced. Diffusing such responsibility onto a robot is perhaps more difficult.

Emilie Caspar (first co-author of the paper): The law generally punished those who gave out orders more severely than those who carried out the orders. But what do people feel exactly in a hierarchical chain?

Recently, Khieu Samphan, one of the main Khmer Rouge leaders, was sentenced to life imprisonment for crimes against humanity and genocide. Yet, he claimed that he did not know what was happening during the Khmer Rouge Era, where millions of Cambodians died of execution, starvation, and diseases.

It seems that people commanding may not always experience the responsibility they should, an aspect which would nonetheless be crucial to avoid mass atrocities.

This is why it is important to understand better their subjective experience and how their brain processes the consequences of their orders, to perhaps in the future offer interventions that would prevent a diminution of responsibility in hierarchical chain

Kalliopi Ioumpa (first co-author of the paper): These results complement previous research showing that hierarchy has a measurable effect on peoples behaviour and brain activation, making them less engaged in the harm they cause.

This study can raise questions on how we can ensure that people feel responsibility despite being in a hierarchical chain. Is it easier for executors to take responsibility over their actions since they are the ones acting or for commanders because they bear the responsibility of the order?

We show how powerful hierarchical situations can facilitate committing actions that harm others, as agency and empathy are distributed across multiple individuals.

Prof Dr Christian Keysers (One of the senior author of the study heading the lab in which it was performed): Times are changing. The solder at the forefront, whose empathy sometimes prevented the worst atrocities, is increasingly replaced by drones that feel no empathy. Has this removed any empathy from the chain of command? Indeed, we find that merely commanding someone to deliver pain reduces how much your brain processes the pain you command compared to directly triggering the pain.

What was really exciting to see, however, is that knowing that you command a machine, that you cannot defer the responsibility to, restores some of the reactions to the pain in commanders.

Perhaps there is hope, after all, that the empathy we reduce at the forefront might be replaced at least in part by an increase is the sense of responsibility at higher levels in the hierarchy

Information about the authors:

The study was performed by Dr Emilie Caspar and PhD student Kalliopi Ioumpa under the supervision of Dr Christian Keysers and Dr Valeria Gazzola, who lead together the Social Brain Lab at the Netherlands Institute for Neuroscience, a research institute of the Royal Netherlands Academy of Arts and Sciences. Dr Emilie Caspar has since become an associate professor at Ghent University.

Author: Eline FeenstraSource: KNAWContact: Eline Feenstra KNAWImage: The image is credited to Kalliopi Ioumpa Netherlands Institute for Neuroscience

Original Research: Closed access.Commanding or being a simple intermediary: how does it affect moral behavior and related brain mechanisms? by Kalliopi Ioumpa et al. eNeuro

Abstract

Commanding or being a simple intermediary: how does it affect moral behavior and related brain mechanisms?

Psychology and neuroscience research have shown that fractioning operations between several individuals along a hierarchical chain allows diffusing responsibility between components of the chain, which has the potential to disinhibit antisocial actions.

Here, we present two studies, one using fMRI (Study 1) and one using EEG (Study 2), designed to help understand how commanding or being in an intermediary position impacts the sense of agency and empathy for pain. In the age of military drones, we also explored whether commanding a human or robot agent influences these measures.

This was done within a single behavioral paradigm in which participants could freely decide whether or not to send painful shocks to another participant in exchange for money.

In Study 1, fMRI reveals that activation in social cognition and empathy-related brain regions was equally low when witnessing a victim receive a painful shock while participants were either commander or simple intermediary transmitting an order, compared to being the agent directly delivering the shock.

In Study 2, results indicated that the sense of agency did not differ between commanders and intermediary, no matter if the executing agent was a robot or a human. However, we observed that the neural response over P3 was higher when the executing agent was a robot compared to a human.

Source reconstruction of the EEG signal revealed that this effect was mediated by areas including the insula and ACC. Results are discussed regarding the interplay between the sense of agency and empathy for pain for decision-making.

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What Is the Effect of Hierarchy on Moral Behavior? - Neuroscience News

Neuroscience

Coffee Drinking Is Associated With Increased Longevity – Neuroscience News

October 3, 2022 medical

Summary: Drinking at least two cups of coffee a day, even instant coffee was associated with increased longevity and a lower risk of cardiovascular disease.

Source: European Society of Cardiology

Drinking two to three cups of coffee a day is linked with a longer lifespan and lower risk of cardiovascular disease compared with avoiding coffee, according to research published today in theEuropean Journal of Preventive Cardiology,a journal of the ESC.The findings applied to ground, instant and decaffeinated varieties.

In this large, observational study, ground, instant and decaffeinated coffee were associated with equivalent reductions in the incidence of cardiovascular disease and death from cardiovascular disease or any cause, said study author Professor Peter Kistler of the Baker Heart and Diabetes Research Institute, Melbourne, Australia.

The results suggest that mild to moderate intake of ground, instant and decaffeinated coffee should be considered part of a healthy lifestyle.

There is little information on the impact of different coffee preparations on heart health and survival.

This study examined the associations between types of coffee and incident arrhythmias, cardiovascular disease and death using data from the UK Biobank, which recruited adults between 40 and 69 years of age.

Cardiovascular disease was comprised of coronary heart disease, congestive heart failure and ischaemic stroke.

The study included 449,563 participants free of arrhythmias or other cardiovascular disease at baseline. The median age was 58 years and 55.3% were women.

Participants completed a questionnaire asking how many cups of coffee they drank each day and whether they usually drank instant, ground (such as cappuccino or filtered coffee), or decaffeinated coffee. They were then grouped into six daily intake categories, consisting of none, less than one, one, two to three, four to five, and more than five cups per day.

The usual coffee type was instant in 198,062 (44.1%) participants, ground in 82,575 (18.4%), and decaffeinated in 68,416 (15.2%). There were 100,510 (22.4%) non-coffee drinkers who served as the comparator group.

Coffee drinkers were compared to non-drinkers for the incidence of arrhythmias, cardiovascular disease and death, after adjusting for age, sex, ethnicity, obesity, high blood pressure, diabetes, obstructive sleep apnoea, smoking status, and tea and alcohol consumption.

Outcome information was obtained from medical records and death records. The median follow up was 12.5 years.

A total of 27,809 (6.2%) participants died during follow up. All types of coffee were linked with a reduction in death from any cause. The greatest risk reduction seen with two to three cups per day, which compared to no coffee drinking was associated with a 14%, 27% and 11% lower likelihood of death for decaffeinated, ground, and instant preparations, respectively.

Cardiovascular disease was diagnosed in 43,173 (9.6%) participants during follow up. All coffee subtypes were associated with a reduction in incident cardiovascular disease.

Again, the lowest risk was observed with two to three cups a day, which compared to abstinence from coffee was associated with a 6%, 20%, and 9% reduced likelihood of cardiovascular disease for decaffeinated, ground, instant coffee, respectively.

An arrhythmia was diagnosed in 30,100 (6.7%) participants during follow up. Ground and instant coffee, but not decaffeinated, was associated with a reduction in arrhythmias including atrial fibrillation.

Compared with non-drinkers, the lowest risks were observed with four to five cups a day for ground coffee and two to three cups a day for instant coffee, with 17% and 12% reduced risks, respectively.

Professor Kistler said: Caffeine is the most well-known constituent in coffee, but the beverage contains more than 100 biologically active components. It is likely that the non-caffeinated compounds were responsible for the positive relationships observed between coffee drinking, cardiovascular disease and survival.

Our findings indicate that drinking modest amounts of coffee of all types should not be discouraged but can be enjoyed as a heart healthy behavior.

Author: Justine PinotSource: European Society of CardiologyContact: Justine Pinot European Society of CardiologyImage: The image is in the public domain

Original Research: Open access.The impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality: long-term outcomes from the UK Biobank by Peter Kistler et al. European Journal of Preventative Cardiology

Abstract

The impact of coffee subtypes on incident cardiovascular disease, arrhythmias, and mortality: long-term outcomes from the UK Biobank

Aims

Epidemiological studies report the beneficial effects of habitual coffee consumption on incident arrhythmia, cardiovascular disease (CVD), and mortality. However, the impact of different coffee preparations on cardiovascular outcomes and survival is largely unknown. The aim of this study was to evaluate associations between coffee subtypes on incident outcomes, utilizing the UK Biobank.

Methods and results

Coffee subtypes were defined as decaffeinated, ground, and instant, then divided into 0, <1, 1, 23, 45, and >5cups/day, and compared with non-drinkers. Cardiovascular disease included coronary heart disease, cardiac failure, and ischaemic stroke. Cox regression modelling with hazard ratios (HRs) assessed associations with incident arrhythmia, CVD, and mortality. Outcomes were determined through ICD codes and death records. A total of 449563 participants (median 58 years, 55.3% females) were followed over 12.50.7 years.

Ground and instant coffee consumption was associated with a significant reduction in arrhythmia at 15cups/day but not for decaffeinated coffee.

The lowest risk was 45cups/day for ground coffee [HR 0.83, confidence interval (CI) 0.760.91,P<0.0001] and 23cups/day for instant coffee (HR 0.88, CI 0.850.92,P<0.0001). All coffee subtypes were associated with a reduction in incident CVD (the lowest risk was 23cups/day for decaffeinated,P=0.0093; ground,P<0.0001; and instant coffee,P<0.0001) vs. non-drinkers.

All-cause mortality was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with 23cups/day for decaffeinated (HR 0.86, CI 0.810.91,P<0.0001); ground (HR 0.73, CI 0.690.78,P<0.0001); and instant coffee (HR 0.89, CI 0.860.93,P<0.0001).

Conclusion

Decaffeinated, ground, and instant coffee, particularly at 23cups/day, were associated with significant reductions in incident CVD and mortality. Ground and instant but not decaffeinated coffee was associated with reduced arrhythmia.