Psychedelic experience may not be required for psilocybin’s antidepressant-like benefits

So-called ‘magic mushroom’ drug seems to work through multiple brain mechanisms for its different effects

University of Maryland School of Medicine (UMSOM) researchers have shown that psilocybin–the active chemical in “magic mushrooms”– still works its antidepressant-like actions, at least in mice, even when the psychedelic experience is blocked. The new findings suggest that psychedelic drugs work in multiple ways in the brain and it may be possible to deliver the fast-acting antidepressant therapeutic benefit without requiring daylong guided therapy sessions. A version of the drug without, or with less of, the psychedelic effects could loosen restrictions on who could receive the therapy, and lower costs, making the benefits of psilocybin more available to more people in need.

In all clinical trials performed to date, the person treated with psilocybin remains under the care of a guide, who keeps the person calm and reassures them during their daylong experience. This can include hallucinations, altered perception of time and space, and intense emotional and spiritual encounters.

Researchers in the field have long attributed psilocybin’s effectiveness to the intense psychedelic experience.

“We do not understand the mechanisms that underlie the antidepressant actions of psilocybin and the role that the profound psychedelic experience during these sessions plays in the therapeutic benefits,” says Scott Thompson, Ph.D., Professor and Chair, Department of Physiology at UMSOM and senior author of the study. “The psychedelic experience is incredibly powerful and can be life-changing, but that could be too much for some people or not appropriate.”

Several barriers prevent the wide-spread use of psychedelic compounds. For example, there is fear that the psychedelic experience may promote psychosis in people who are predisposed to severe mental disorders, like bipolar disorder and schizophrenia, so the clinical therapy sessions performed to-date have been limited to a highly selected screened group without a family history of these disorders.

Dr. Thompson adds that there may also be an equity issue because not everyone can take several days off work to prepare and engage in the experience. The costs of staffing a facility with at least one trained guide per treated person per day and a private space may also be prohibitive to all but a few. He says it is conceivable that a depression treatment derived from psilocybin could be developed without the psychedelic effects so people can take it safely at home without requiring a full day in a care facility.

For their study, led by UMSOM MD/PhD student Natalie Hesselgrave, the team used a mouse model of depression in which mice were stressed for several hours a day over 2-3 weeks. Because researchers cannot measure mouse moods, they measure their ability to work for rewards, such as choosing to drink sugar water over plain water. People suffering from depression lose the feeling of pleasure for rewarding events. Similarly, stressed mice no longer preferred sugar water over plain water. However, 24 hours after a dose of psilocybin, the stressed mice regained their preference for the sugar water, demonstrating that the drug restored the mice’s pleasure response.

Psilocybin exerts its effects in people by binding to and turning on receptors for the chemical messenger serotonin. One of these receptors, the serotonin 2A receptor, is known to be responsible for the psychedelic response. To see if the psychedelic effects of psilocybin were needed for the anti-depressive benefits, the researchers treated the stressed mice with psilocybin together with a drug, ketanserin, which binds to the serotonin 2A receptor and keeps it from being turned on. The researchers found that the stressed mice regained their preference for the sugar water in response to psilocybin, even without the activation of the psychedelic receptor.

“These findings show that activation of the receptor causing the psychedelic effect isn’t absolutely required for the antidepressant benefits, at least in mice,” says Dr. Thompson, “but the same experiment needs to be performed in depressed human subjects.” He says his team plans to investigate which of the 13 other serotonin receptors are the ones responsible for the antidepressant actions.

“This new study has interesting implications, and shows that more basic research is needed in animals to reveal the mechanisms for how these drugs work, so that treatments for these devastating disorders can be developed” says Albert E. Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.

https://www.eurekalert.org/pub_releases/2021-04/uoms-pem041321.php

COVID-19 survivors seeing long-term effects on mental health

by: Alex Stokes

COVID-19 has taken a physical toll on millions of people. Now, a new study from the UK suggests survivors are seeing long-term effects on their mental health as well.

“Sometimes it’s you know the things that we don’t think about as much after a hospitalization or an illness that can really have an impact on a patient and their family,” said University Hospitals Psychiatrist Susan Padrino. “This was a medical record review study and they had very large population that they looked at and very large comparison populations.”

Published recently in the journal The Lancet Psychiatry, researchers found that of the more than 230,000 participants mostly in the United States; 1 in 3 COVID survivors suffered from a neurological or mental disorder within 6 months of infection.

Padrino says they knew before that infectious diseases like the flu have been related to brain and psychiatric symptoms, however, “COVID-19 infections seem to have a greater likelihood of causing brain or psychiatric symptoms after an infection, even when the infection isn’t very severe.”

The most common mental health diagnoses were anxiety and mood disorders. 

“Anxiety is not uncommon again, after hospitalization, especially one in which the person might be in the ICU, it can be very frightening,” she said.

Although neurological diagnoses were more uncommon, they were more prevalent in patients who had severe symptoms during their covid infection.

For example, seven percent of patients admitted to intensive care had a stroke and two percent were diagnosed with dementia. 

“To the degree as being diagnosed with dementia, that is a little bit surprising, especially just in six months,” said Padrino while noting it’s an area that will need to be studied further.

The study found many people reporting these impairments had never experienced them before.
Padrino says these results do worry her. 

“It’s partly the scope of the behavioral health symptoms, and it’s partly the number of people that are being impacted all at the same time,” she added.

She says in the healthcare system there should be more of an effort to combine behavioral health and medical health as they are often intertwined. 

“We really can’t understand the full scope of what people are going through without addressing both,” said Padrino.

Padrino says if you’re having any symptoms after infection especially after 8 weeks you should be reaching out to your health care provider. She also recommends COVID recovery clinics that are open throughout the city, including at University Hospitals, as a resource.

Researchers discover new way to monitor & prevent nerve cell deterioration after TBI

Potential mechanistic link shown between Traumatic Brain Injury and Alzheimer’s disease

Violent blows or jolts to the head can cause traumatic brain injury (TBI), and there are currently about five million people in the U.S. living with some form of chronic impairment after suffering a TBI. Even in a mild form, TBI can lead to lifelong nerve cell deterioration associated with a wide array of neuropsychiatric conditions. Tragically, there are no medicines to protect nerve cells after injury. Behind aging and genetics, TBI is the third leading cause of Alzheimer’s disease (AD), yet the link between these two conditions is not understood.

In a new study, published online today in Cell, researchers have discovered a new way to prevent brain nerve cells from deteriorating after injury, which also revealed a potential mechanistic link between TBI and AD. Their discovery also yielded a new blood biomarker of nerve cell degeneration after injury, which is significant because there is an urgent need for mechanism-based blood biomarkers that can diagnose TBI and stage its severity.

Prior to this study, it had been previously reported that a small protein in nerve cells, called tau, was modified by a chemical process called acetylation in the post-mortem brains of AD patients. But how this modification came about, as well as its role in the disease process, was not understood.

“Normally, tau functions in nerve cells to maintain the appropriate structure of the axon, which is the nerve cell extension required for nerve cells to communicate with one another,” said Andrew A. Pieper, MD, PhD, senior author on the study, Harrington Discovery Institute (HDI) Investigator and Director of the HDI Neurotherapeutics Center at University Hospitals (UH), Morley-Mather Chair in Neuropsychiatry at UH, Director of the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center, and VA Geriatric Research, Educational and Clinical Care (GRECC) Investigator. “Given the relationship between AD and TBI, we wondered whether elevated acetylated-tau (ac-tau) might also occur in TBI, and if so, then whether this could provide an experimental platform to study its potential role in nerve cell deterioration.”

Dr. Pieper’s lab discovered that ac-tau increased rapidly in multiple forms of TBI in mice and rats, and persisted chronically when nerve cell degeneration was untreated. They also showed that the increased ac-tau in human AD brain was further exacerbated when the AD patient also had a prior history of TBI.

“Our research showed that after ac-tau rises, a specific structure at the junction of the nerve cell body and its axon, called the axon initial segment, breaks down,” explained Min-Kyoo Shin, PhD, co-first author of the study. “As a result, tau is no longer appropriately sequestered in axons. This leads to axonal degeneration, followed by neurologic impairment.”

The team tested therapeutic interventions after TBI at each of the three nodal points in the new signaling pathway that they identified as leading to increased nerve cell ac-tau after injury. Using known medicines or experimental drugs, they saw that all three points provided effective therapeutic opportunity.

Strikingly, they found that two FDA-approved medicines of the NSAID class (anti-inflammatory medicines commonly used as pain relievers), salsalate and diflunisal, were potently neuroprotective after TBI in mice. Relative to all other NSAIDs and distinct from their anti-inflammatory property, these two medicines inhibit the acetyltransferase enzyme in nerve cells that adds the acetyl group onto tau protein after brain injury.

Next, they examined more than seven million patient records and learned that usage of either salsalate or diflunisal was associated with decreased incidence of both AD and clinically diagnosed TBI, compared to usage of aspirin in other patients for the same time period. The protective effect was stronger in diflunisal and salsalate, which correlates with diflunisal’s superior potency in inhibiting the acetyltransferase enzyme, relative to salsalate. The NSAID aspirin was used as a comparison group because it does not inhibit the acetyltransferase.

Lastly, because the tau protein freely diffuses from the brain into the blood, the researchers examined whether ac-tau might also be elevated in the blood after TBI. In mice, they found that blood levels of ac-tau correspond tightly with brain levels, and that blood levels return to normal when mice are treated with therapeutics that lower brain ac-tau and thereby protect nerve cells. Importantly, they also found that ac-tau was significantly increased in the blood of human TBI patients.

“This work has a number of potential clinical implications,” explained Edwin Vázquez-Rosa, PhD, co-first author on the study. “First, it shows that the medicines salsalate and diflunisal provide previously unidentified neuroprotective activity by this new mechanism, and that in the course of being prescribed these medicine for traditional indications patients appear to also be relatively protected from developing neurodegenerative conditions. Accordingly, these medicines may also help protect TBI patients from developing AD. Finally, our work provides a new blood biomarker of neurodegeneration in the brain after TBI that could be harnessed to stage severity and progression of nerve cell deterioration after injury.”

Robert A. Bonomo, MD, Associate Chief of Staff at VA Northeast Ohio Healthcare System and professor at Case Western Reserve School of Medicine added, “Many of our patients suffer from TBI or AD. These important findings will have a tremendous, long-term impact on our Veteran population.”

Next steps in the research involve further investigation of the applicability of ac-tau as a biomarker in neurodegenerative disease and the potential utility of diflunisal or salsalate as neuroprotective medicines for people, as well as deeper study of the mechanisms by which ac-tau causes nerve cell deterioration.

###

The findings from the Pieper lab represent an outgrowth of collaborative efforts from investigators across the Cleveland community at UH, HDI, Case Western Reserve, VA Northeast Ohio Healthcare System, Cleveland Clinic and The MetroHealth System.

This study was also supported by the Brockman Foundation; the AHA/Allen Initiative in Brain Health and Cognitive Impairment; The Neuropathology Core of Northwestern University; Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center; and the Departments of Neurology and Neurosurgery of McGovern Medical School of The University of Texas Health Science Center at Houston.

Shin, M, Vázquez-Rosa, E., et al. “Reducing acetylated-tau is neuroprotective in brain injury.” Cell. DOI: 10.1016/j.cell.2021.03.032.

New research reveals why some of us are hungry all the time

New research shows that people who experience big dips in blood sugar levels, several hours after eating, end up feeling hungrier and consuming hundreds more calories during the day than others.

A study published today in Nature Metabolism, from PREDICT, the largest ongoing nutritional research program in the world that looks at responses to food in real life settings, the research team from King’s College London and health science company ZOE (including scientists from Harvard Medical School, Harvard T.H. Chan School of Public Health, Massachusetts General Hospital, the University of Nottingham, Leeds University, and Lund University in Sweden) found why some people struggle to lose weight, even on calorie-controlled diets, and highlight the importance of understanding personal metabolism when it comes to diet and health.

The research team collected detailed data about blood sugar responses and other markers of health from 1,070 people after eating standardized breakfasts and freely chosen meals over a two-week period, adding up to more than 8,000 breakfasts and 70,000 meals in total. The standard breakfasts were based on muffins containing the same amount of calories but varying in composition in terms of carbohydrates, protein, fat and fiber. Participants also carried out a fasting blood sugar response test (oral glucose tolerance test), to measure how well their body processes sugar.

Participants wore stick-on continuous glucose monitors (CGMs) to measure their blood sugar levels over the entire duration of the study, as well as a wearable device to monitor activity and sleep. They also recorded levels of hunger and alertness using a phone app, along with exactly when and what they ate over the day.

Previous studies looking at blood sugar after eating have focused on the way that levels rise and fall in the first two hours after a meal, known as a blood sugar peak. However, after analyzing the data, the PREDICT team noticed that some people experienced significant ‘sugar dips’ 2-4 hours after this initial peak, where their blood sugar levels fell rapidly below baseline before coming back up.

Big dippers had a 9% increase in hunger, and waited around half an hour less, on average, before their next meal than little dippers, even though they ate exactly the same meals.

Big dippers also ate 75 more calories in the 3-4 hours after breakfast and around 312 calories more over the whole day than little dippers. This kind of pattern could potentially turn into 20 pounds of weight gain over a year.

Dr. Sarah Berry from King’s College London said, “It has long been suspected that blood sugar levels play an important role in controlling hunger, but the results from previous studies have been inconclusive. We’ve now shown that sugar dips are a better predictor of hunger and subsequent calorie intake than the initial blood sugar peak response after eating, changing how we think about the relationship between blood sugar levels and the food we eat.”

Professor Ana Valdes from the School of Medicine at the University of Nottingham, who led the study team, said: “Many people struggle to lose weight and keep it off, and just a few hundred extra calories every day can add up to several pounds of weight gain over a year. Our discovery that the size of sugar dips after eating has such a big impact on hunger and appetite has great potential for helping people understand and control their weight and long-term health.”

Comparing what happens when participants eat the same test meals revealed large variations in blood sugar responses between people. The researchers also found no correlation between age, bodyweight or BMI and being a big or little dipper, although males had slightly larger dips than females on average.

There was also some variability in the size of the dips experienced by each person in response to eating the same meals on different days, suggesting that whether you’re a dipper or not depends on individual differences in metabolism, as well as the day-to-day effects of meal choices and activity levels.

Choosing foods that work together with your unique biology could help people feel fuller for longer and eat less overall.

Lead author on the study, Patrick Wyatt from ZOE, notes, “This study shows how wearable technology can provide valuable insights to help people understand their unique biology and take control of their nutrition and health. By demonstrating the importance of sugar dips, our study paves the way for data-driven, personalized guidance for those seeking to manage their hunger and calorie intake in a way that works with rather than against their body.”

Tim Spector, Professor of Genetic Epidemiology at King’s College London and scientific co-founder of ZOE, concludes, “Food is complex and humans are complicated, but our research is finally starting to open up the black box between diet and health. We’re excited to have been able to turn this cutting-edge science into an at-home nutrition and microbiome test so that everyone has the opportunity to discover their unique responses to food to best support their metabolism and gut health.”



More information: Wyatt, P., Berry, S.E., Finlayson, G. et al. Postprandial glycaemic dips predict appetite and energy intake in healthy individuals. Nat Metab (2021). doi.org/10.1038/s42255-021-00383-xJournal information:Nature Metabolism

https://medicalxpress.com/news/2021-04-reveals-hungry.html

Treating sleep apnea may reduce dementia risk

A new study finds older adults who received positive airway pressure therapy prescribed for obstructive sleep apnea may be less likely to develop Alzheimer’s disease and other kinds of dementia.

Researchers from Michigan Medicine’s Sleep Disorders Centers analyzed Medicare claims of more than 50,000 Medicare beneficiaries ages 65 and older who had been diagnosed with OSA. In this nationally representative study, they examined if those people who used positive airway pressure therapy were less likely to receive a new diagnosis of dementia or mild cognitive impairment over the next 3 years, compared to people who did not use positive airway pressure.

“We found a significant association between positive airway pressure use and lower risk of Alzheimer’s and other types of dementia over three years, suggesting that positive airway pressure may be protective against dementia risk in people with OSA,” says lead author Galit Levi Dunietz, Ph.D., M.P.H., an assistant professor of neurology and a sleep epidemiologist.

The findings stress the impact of sleep on cognitive function. “If a causal pathway exists between OSA treatment and dementia risk, as our findings suggest, diagnosis and effective treatment of OSA could play a key role in the cognitive health of older adults,” says study principal investigator Tiffany J. Braley, M.D., M.S., an associate professor of neurology.

Obstructive sleep apnea is a condition in which the upper airway collapses repeatedly throughout the night, preventing normal breathing during sleep. OSA is associated with a variety of other neurological and cardiovascular conditions, and many older adults are at high risk for OSA.

And dementia is also prevalent, with approximately 5.8 million Americans currently living with it, Braley says.

https://medicalxpress.com/news/2021-04-apnea-dementia.html

Monkey plays video game – with its brain

Elon Musk’s startup devoted to meshing brains with computers was closer to its dream on Friday, having gotten a monkey to play video game Pong using only its mind.

Musk has long contended that merging minds with machines is vital if people are going to avoid being outpaced by artificial intelligence.

A video posted on YouTube by the entrepreneur’s Neuralink startup showed a macaque monkey named “Pager” playing Pong by essentially using thought to move paddles that bounce digital balls back and forth on screen.

“To control his paddle, Pager simply thinks about moving his hand up or down,” said a voice narrating the video. “As you can see, Pager is amazingly good at MindPong.”

Neuralink devices were implanted on two sides of Pager’s brain to sense neuron activity, then the monkey played the game a few minutes using a joystick to let software figure out the signals associated with hand movements.

Pager’s reward was banana smoothly served through a straw when he successfully batted the digital ball from one paddle to the other, according to the demonstration.

After a few minutes, the “decoder” program figured out what neuron signals to look for and the joystick was no longer needed for Pager to play the game.

“A monkey is literally playing a video game telepathically using a brain chip!!” Musk tweeted triumphantly.https://www.youtube.com/embed/rsCul1sp4hQ?color=white

The decoder could be calibrated to enable a person to guide a cursor on a computer screen, potentially letting them type emails, text messages, or browse the internet just by thinking, according to a blog post at neuralink.com.

“Our first goal is to give people with paralysis their digital freedom back,” the Neuralink team said in the post.

Members of the team last year shared a “wish list” that ranged from technology returning mobility to the paralyzed and sight to the blind, to enabling telepathy and the uploading of memories for later reference—or perhaps to be downloaded into replacement bodies.

For now, Neuralink is being tested in animals with the team working on the potential for clinical trials.

With the help of a surgical robot, a piece of the skull is replaced with a Neuralink disk, and its wispy wires are strategically inserted into the brain, a previous demonstration showed.

The disk registers nerve activity, relaying the information via common Bluetooth wireless signal to a device such as a smartphone, according to Musk.

“It actually fits quite nicely in your skull. It could be under your hair and you wouldn’t know.”

Experts and academics remain cautious about his vision of symbiotically merging minds with super-powered computing.

https://medicalxpress.com/news/2021-04-hands-free-monkey-video-game-.html

For malnourished children, a new type of microbiome-directed food boosts growth

A new study shows that a therapeutic food designed to repair the gut microbiomes of malnourished children is better than standard therapy in supporting their growth. The research, published online April 7, 2021, in The New England Journal of Medicine, was a collaboration between Washington University School of Medicine and the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, where the clinical trial was conducted. Pictured, a mother feeds her child one of the therapeutic foods as part of the clinical trial. Credit: International Centre for Diarrhoeal Disease Research

by Julia Evangelou Strait, Washington University School of Medicine in St. Louis

A new type of therapeutic food specifically designed to repair the gut microbiomes of malnourished children is superior to standard therapy in promoting growth, according to the results of a proof-of-concept clinical trial conducted in Bangladesh.

The study, conducted by an interdisciplinary team of researchers from Washington University School of Medicine in St. Louis and the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh (icddr,b), was designed to supplement the diet of malnourished children with a formulation that contains locally available, culturally acceptable foods selected based on the ability of the ingredients to boost key growth-promoting gut microbes. The work supports the notion that healthy growth of infants and children is closely linked to healthy development of their gut microbial communities—or microbiomes—after birth.

The results of the study are published online in The New England Journal of Medicine.

Childhood malnutrition is a major global health challenge, affecting over 150 million children under the age of 5 worldwide, with a disproportionate impact in South Asia and Sub-Saharan Africa, according to the World Health Organization. The ongoing COVID-19 pandemic is further exacerbating this problem. Numerous studies have shown that malnutrition is not due to food insecurity alone but instead reflects a combination of factors, including an important role for the gut microbiome, which fails to develop properly during the first two years of life in malnourished children.

“Malnutrition has proven extraordinary difficult to treat—standard calorie-dense therapeutic foods have been shown to prevent the deaths of malnourished children, but have been ineffective in overcoming growth stunting and other damaging effects of malnutrition, including impaired brain development, bone growth and immune function,” said senior author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology at the School of Medicine. “In an attempt to address this problem, we are investigating whether repairing the poorly developed microbial communities of malnourished children will impact their growth. This is the first time that a microbiome-directed therapeutic food has been compared with a standard therapy in malnourished children; moreover, it produced a superior rate of weight gain, the key primary clinical outcome of the trial.”

An earlier, one-month long pilot clinical study conducted by the team in Bangladesh had provided evidence for the benefits of the microbiome-directed therapeutic food in a small number children who received it; however, the study was not sufficiently large or long enough to confirm the effects of the new food on growth. The current three-month long clinical trial, overseen by Tahmeed Ahmed, MBBS, Ph.D., executive director of the icddr,b, involved 118 children ages 12 to 18 months who lived in an urban slum called Mirpur in Dhaka, Bangladesh. All these children had been diagnosed with acute malnutrition, a condition in which the body consumes fat reserves and breaks down muscle, resulting in wasting, or weight loss. The immune system is also weakened, making these children more susceptible to other illnesses.

“This work is based on our studies that have shown that a derangement in the gut microbiome is responsible for malnutrition of children,” Ahmed said. “We have successfully used a food made of local ingredients to repair the deranged gut microbiome and thereby improve the growth of children receiving the food. In an era where we so sadly still have staggering numbers of children suffering and dying from malnutrition, our discovery of the microbiome-directed complementary food can be a game changer.”

Half of the children in the current study were randomly assigned to receive the microbiome-directed therapeutic food, and the other half received a standard therapeutic food that was not designed to repair the gut microbiome. The new microbiome-directed food contains a mixture of chickpeas, soy, bananas and peanuts, ingredients that the group had discovered in earlier pre-clinical models to repair the gut microbiome, among other components. The standard therapeutic food is rice- and lentil-based and contains about 20% more calories per serving than the microbiome-directed food.

The children received 25 gram

s of their assigned therapeutic foods twice daily for three months. The children’s height, weight and mid-upper arm circumference were measured at regular intervals throughout the intervention period and for one month after cessation of treatment. Blood and stool specimens were also collected at various times to assess changes in the levels of nearly 5,000 proteins in the blood, and to quantify the effects of the therapies on the representation of specific beneficial microbes in stool samples.

The researchers found that the rate of change in the children’s weight and their mid-upper arm circumferences were significantly greater in the group receiving the microbiome-directed food compared with the standard therapeutic food; this growth superiority was sustained even a month after the children had stopped receiving the nutritional intervention, which is the latest time point to be analyzed so far.

“When we look at the standard clinical measurement for assessing acute malnutrition—the weight-for-length z score—the difference between the two treatment groups was even more significant one month after we stopped the treatment,” said co-first author Robert Chen, a doctoral student in Gordon’s lab. “If this rate of growth was maintained for a year, we estimate an improvement in the weight-for-length z score of almost one full standard deviation.

“Children with acute malnutrition typically have declining or in the best case stable weight, so if this extrapolation holds up, it would be a major clinically relevant improvement in growth outcomes,” Chen added.

Said co-first author Ishita Mostafa, an assistant scientist at the International Centre for Diarrhoeal Disease Research: “We continue to monitor and collect samples from these children; this is critical in order to determine if the effects of this new treatment are indeed durable over time, or whether the intervention needs to be sustained for longer periods.”

The researchers also found that a group of 23 bacterial strains found in stool samples correlated with the increased rate of weight gain observed in the children receiving the microbiome-directed food. Twenty-one strains were positively correlated—meaning having more of these gut bacteria was linked to increased growth. And two strains were negatively correlated—meaning that having fewer of these gut bacteria was linked to increased growth. The microbiome-directed food was found to increase levels of the 21 positively correlated strains and reduce levels of the two strains that were negatively correlated.

Further, the researchers found 70 proteins in the blood samples that were positively correlated with increased weight, with greater improvements in their levels occurring after the microbiome-directed treatment compared with the standard intervention.

“These proteins are key regulators of bone biology, neurodevelopment and immune function,” Gordon said. “We discovered that this food can nurture and expand the abundance of beneficial microbes, with accompanying boosts in the levels of beneficial proteins in their human hosts that have impactful effects on growth.

“The rate of improvement in the weight of the children receiving the new therapeutic food designed with healthy gut microbes in mind was significantly greater even though its caloric density was 20% lower than the standard food,” Gordon added. “This suggests that the repair of the gut microbiome, and not just additional calories, is key to healthy growth in these children.”

The teams led by Gordon and Ahmed, funded by the Bill & Melinda Gates Foundation, plan to initiate further studies into whether therapeutic foods that nurture beneficial gut microbes can help malnourished children in other parts of the world. This involves a program of developing microbiome-directed foods that contain distinct but functionally “biosimilar” ingredients that are readily available, affordable and culturally acceptable to parents and children living in these other countries. Also, Gordon and his colleagues plan to investigate whether repairing dysfunctional gut microbial communities at younger ages and over longer timeframes could have an even greater impact.

“After the six-month period of breastfeeding recommended by the World Health Organization, we think there may be an early window to introduce these types of microbiome-directed therapeutic foods and potentially have a bigger effect,” said co-author Michael J. Barratt, Ph.D., associate professor of pathology and immunology and executive director of the Center for Gut Microbiome and Nutrition Research at Washington University.

The researchers also are planning studies to investigate the benefits of microbiome-directed therapeutic foods during pregnancy to determine whether they can not only improve the gut microbiomes of the malnourished mothers but also foster the transmission of healthy gut microbial communities to their infants and thus help break the devastating intergenerational cycle of malnutrition.

Added Gordon, “We are also exploring the possibility of bringing a clinical trial of this new therapeutic food to children who would benefit from a nutritional intervention here in St. Louis. We are at the earliest stages of this process, beginning to engage with members of the local community. We can’t begin one of these trials without making sure community leaders, community members, parents and caregivers are fully engaged with the process.”

More information: Robert Y. Chen et al. A Microbiota-Directed Food Intervention for Undernourished Children, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2023294Journal information:New England Journal of Medicine

https://medicalxpress.com/news/2021-04-malnourished-children-microbiome-directed-food-boosts.html

Accelerated Cellular Aging Associated With Mortality Seen in Depressed Individuals

DNA markers in cells of patients with major depressive disorder appear to be two years older than markers in cells of people without the mental health disorder. The individuals with MDD showed no outward signs of age-related pathology, as they and the healthy controls were screened for physical health before entry into the study.

Cells from individuals with Major Depressive Disorder (MDD) were found to have higher than expected rates of methylation at specific sites on their DNA, when compared to cells from healthy individuals without MDD, according to a study by a multidisciplinary team of UC San Francisco scientists, in collaboration with others. Methylation is a process by which DNA is chemically modified at specific sites, resulting in changes in the expression of certain genes.

Methylation of particular sets of genes, called “DNA methylation clocks,” typically change in predictable ways as people age, but the rate of these changes varies between people. Methylation patterns in individuals with MDD suggested that their cellular age was, on average, accelerated relative to matched healthy controls.

In the study, published April 6, 2021 in Translational Psychiatry, blood samples from individuals with MDD were analyzed for methylation patterns using the ‘GrimAge’ clock – a mathematical algorithm designed to predict an individual’s remaining lifespan based on cellular methylation patterns. Individuals with MDD showed a significantly higher GrimAge score, suggesting increased mortality risk, compared to healthy individuals of the same chronological age – an average of approximately two years on the GrimAge clock.

The individuals with MDD showed no outward signs of age-related pathology, as they and the healthy controls were screened for physical health before entry into the study. The methylation patterns associated with mortality risk persisted even after accounting for lifestyle factors like smoking and BMI. These findings provide new insight into the increased mortality and morbidity associated with the condition, suggesting that there is an underlying biological mechanism accelerating cellular aging in some MDD sufferers.

“This is shifting the way we understand depression, from a purely mental or psychiatric disease, limited to processes in the brain, to a whole-body disease,” said Katerina Protsenko, a medical student at UCSF and lead author of the study. “This should fundamentally alter the way we approach depression and how we think about it – as a part of overall health.”

MDD is one of the most prevalent health concerns globally. According to the World health Organization, some 300 million people (4.4% of the population) suffer from some form of depression. MDD is associated with higher incidence and mortality related to increased rates of cardiovascular disease, diabetes, and Alzheimer’s disease among sufferers.

“One of the things that’s remarkable about depression is that sufferers have unexpectedly higher rates of age-related physical illnesses and early mortality, even after accounting for things like suicide and lifestyle habits,” said Owen Wolkowitz, MD, professor of psychiatry and a member of UCSF’s Weill Institute for Neurosciences, co-senior author of the study. “That’s always been a mystery, and that’s what led us to look for signs of aging at the cellular level.”

The researchers collected blood samples from 49 individuals with MDD who were unmedicated prior to the study and 60 healthy control subjects of the same chronological age. They analyzed the methylation rates of both groups using the GrimAge clock. While there are numerous methylation-based longevity algorithms, GrimAge is the only one based specifically on methylation patterns associated with mortality.

The researchers say that they don’t yet know if depression causes altered methylation in certain individuals, or if depression and methylation are both related to another underlying factor. It is possible that some individuals may have a genetic predisposition to produce specific methylation patterns in response to stressors, but this has not been well-studied. Alterations in methylation patterns have previously been observed in individuals with Post-Traumatic Stress Disorder.

Moving forward, the researchers hope to determine whether pharmacological treatments or therapy may mitigate some methylation changes related to MDD in hopes of normalizing the cellular aging process in affected individuals before it advances. Although the GrimAge methylation clock has been associated with mortality in other populations, no studies have yet determined whether this methylation pattern also predicts mortality in MDD.

“As we continue our studies, we hope to find out whether addressing the MDD with anti-depressants or other treatments alters the methylation patterns, which would give us some indication that these patterns are dynamic and can be changed,” said Synthia Mellon, PhD, professor in the Department of Ob/Gyn & Reproductive Sciences at UCSF and co-senior author of the study.

Authors: Katerina Protsenko was the study’s lead author. Owen M. Wolkowitz, MD, Synthia H. Mellon, PhD, and Victor I. Reus, MD were the study’s co-senior authors. The study was conducted in collaboration with Ruoting Yang, Rasha Hammamieh, Marti Jett, Aarti Gautam, and other scientists from the Walter Reed Army Institute of Research, Silver Spring, MD.

New Multiple Sclerosis Subtypes Identified Using Artificial Intelligence

Combining artificial intelligence technology with brain scan data, researchers have identified three novel subtypes of multiple sclerosis.

Scientists at UCL have used artificial intelligence (AI) to identify three new multiple sclerosis (MS) subtypes. Researchers say the groundbreaking findings will help identify those people more likely to have disease progression and help target treatments more effectively.

MS affects over 2.8 million people globally and 130,000 in the UK, and is classified into four* ‘courses’ (groups), which are defined as either relapsing or progressive. Patients are categorised by a mixture of clinical observations, assisted by MRI brain images, and patients’ symptoms. These observations guide the timing and choice of treatment.

For this study, published in Nature Communications, researchers wanted to find out if there were any – as yet unidentified – patterns in brain images, which would better guide treatment choice and identify patients who would best respond to a particular therapy.

Explaining the research, lead author Dr Arman Eshaghi (UCL Queen Square Institute of Neurology) said: “Currently MS is classified broadly into progressive and relapsing groups, which are based on patient symptoms; it does not directly rely on the underlying biology of the disease, and therefore cannot assist doctors in choosing the right treatment for the right patients.

“Here, we used artificial intelligence and asked the question: can AI find MS subtypes that follow a certain pattern on brain images? Our AI has uncovered three data-driven MS subtypes that are defined by pathological abnormalities seen on brain images.”

In this study, researchers applied the UCL-developed AI tool, SuStaIn (Subtype and Stage Inference), to the MRI brain scans of 6,322 MS patients. The unsupervised SuStaIn trained itself and identified three (previously unknown) patterns.

The new MS subtypes were defined as ‘cortex-led’, ‘normal-appearing white matter-led’, and ‘lesion-led.’ These definitions relate to the earliest abnormalities seen on the MRI scans within each pattern.

Once SuStaIn had completed its analysis on the training MRI dataset, it was ‘locked’ and then used to identify the three subtypes in a separate independent cohort of 3,068 patients thereby validating its ability to detect the new MS subtypes.

Dr Eshaghi added: “We did a further retrospective analysis of patient records to see how people with the newly identified MS subtypes responded to various treatments.

While further clinical studies are needed, there was a clear difference, by subtype, in patients’ response to different treatments and in accumulation of disability over time. This is an important step towards predicting individual responses to therapies.”

NIHR Research Professor Olga Ciccarelli (UCL Queen Square Institute of Neurology), the senior author of the study, said: “The method used to classify MS is currently focused on imaging changes only; we are extending the approach to including other clinical information.

“This exciting field of research will lead to an individual definition of MS course and individual prediction of treatment response in MS using AI, which will be used to select the right treatment for the right patient at the right time.”

One of the senior authors, Professor Alan Thompson, Dean of the UCL Faculty of Brain Sciences, said: “We are aware of the limitations of the current descriptors of MS which can be less than clear when applied to prescribing treatment. Now with the help of AI and large datasets, we have made the first step towards a better understanding of the underlying disease mechanisms which may inform our current clinical classification. This is a fantastic achievement and has the potential to be a real game-changer, informing both disease evolution and selection of patients for clinical trials.”

Researchers say the findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and can now be used to define groups of patients in interventional trials. Prospective research with clinical trials is required as the next step to confirm these findings.

Dr Clare Walton, Head of Research at the MS Society, said: “We’re delighted to have helped fund this study through our work with the International Progressive MS Alliance. MS is unpredictable and different for everyone, and we know one of our community’s main concerns is how their condition might develop.

Having an MRI-based model to help predict future progression and tailor your treatment plan accordingly could be hugely reassuring to those affected. These findings also provide valuable insight into what drives progression in MS, which is crucial to finding new treatments for everyone. We’re excited to see what comes next.”

MS is a neurological (nerve) condition and is one of the most common causes of disability in young people. It arises when the immune system mistakenly attacks the coating (myelin sheaths) that wrap around nerves in the brain and spinal cord. This results in the electrical signals, which pass messages along the nerves, to be disrupted, travel more slowly, or fail to get through at all.

Most people are diagnosed between the ages of 20 and 50, however the first signs of MS often start years earlier. Common early signs include tingling, numbness, a loss of balance and problems with vision, but because other conditions cause the same symptoms, it can take time to reach a definitive diagnosis.

Many patients have relapsing MS at first, a form of the disease where symptoms come and go as nerves are damaged, repaired and damaged again. But about half have a progressive form of the condition in which nerve damage steadily accumulates and causes ever worsening disability. Patients may experience tremors, speech problems and muscle stiffness or spasms, and may need walking aids or a wheelchair.

Research reveals why redheads may have different pain thresholds

by Noah Brown, Massachusetts General Hospital

New research led by investigators at Massachusetts General Hospital (MGH) provides insights on why people with red hair exhibit altered sensitivity to certain kinds of pain. The findings are published in Science Advances.

In people with red hair (as in numerous other species of animals with red fur), the pigment-producing cells of the skin—called melanocytes—contain a variant form of the melanocortin 1 receptor. This receptor sits on the cell surface, and if it becomes activated by circulating hormones called melanocortins, it causes the melanocyte to switch from generating yellow/red melanin pigment to producing brown/black melanin pigment. Earlier work by David E. Fisher, MD, Ph.D., director of the Mass General Cancer Center’s Melanoma Program and director of MGH’s Cutaneous Biology Research Center, demonstrated that the inability of red-haired individuals to tan or darken their skin pigment is traced to inactive variants of this receptor.

To investigate the mechanisms behind different pain thresholds in red-haired individuals, Fisher and his colleagues studied a strain of red-haired mice that (as in humans) contains a variant that lacks melanocortin 1 receptor function and also exhibits higher pain thresholds.

The team found that loss of melanocortin 1 receptor function in the red-haired mice caused the animals’ melanocytes to secrete lower levels of a molecule called POMC (proopiomelanocortin) that is subsequently cut into different hormones including one that sensitizes to pain and one that blocks pain. The presence of these hormones maintains a balance between opioid receptors that inhibit pain and melanocortin 4 receptors that enhance perception of pain.

In red-haired mice (and therefore, possibly humans), having both hormones at low levels would seemingly cancel each other out. However, the body also produces additional, non-melanocyte-related factors that activate opioid receptors involved in blocking pain. Therefore, the net effect of lower levels of the melanocyte-related hormones is more opioid signals, which elevates the threshold for pain.

“These findings describe the mechanistic basis behind earlier evidence suggesting varied pain thresholds in different pigmentation backgrounds,” says Fisher. “Understanding this mechanism provides validation of this earlier evidence and a valuable recognition for medical personnel when caring for patients whose pain sensitivities may vary.”

Fisher adds that the results suggest new ways to manipulate the body’s natural processes that control pain perception—for example, by designing new medications that inhibit melanocortin 4 receptors involved in sensing pain.

“Our ongoing work is focused on elucidating how additional skin-derived signals regulate pain and opioid signaling,” adds co-lead author Lajos V. Kemény, MD, Ph.D., a research fellow in Dermatology at MGH. “Understanding these pathways in depth may lead to the identification of novel pain-modulating strategies.”

https://medicalxpress.com/news/2021-04-reveals-redheads-pain-thresholds.html