Blood pressure drug holds promise for treating PTSD

January 5, 2023

Science Daily/Medical College of Georgia at Augusta University

There is new evidence that a 50-year-old blood pressure drug could find new purpose as a treatment to mitigate the often life-altering effects of increasingly prevalent PTSD, scientists say.

Clonidine is commonly used as a high blood pressure medication and for ADHD. It's also already been studied in PTSD because clonidine works on adrenergic receptors in the brain, likely best known for their role in "fight or flight," a heightened state of response that helps keep us safe. These receptors are thought to be activated in PTSD and to have a role in consolidating a traumatic memory. Clonidine's sister drug guanfacine, which also activates these receptors, also has been studied in PTSD. Conflicting results from the clinical trials have clonidine, which has shown promise in PTSD, put aside along with guanfacine, which has not.

Scientists at the Medical College of Georgia at Augusta University say it's time for another look at clonidine.

They have laboratory evidence that while the two drugs bind to the same receptors, they do different things there, says Qin Wang, MD, PhD, neuropharmacologist and founding director of the Program for Alzheimer's Therapeutics Discovery at MCG.

Their results published in the journal Molecular Psychiatry suggest that clonidine could provide immediate treatment to the significant number of people emerging from the current pandemic with PTSD, as well as from longer-established causes like wars and other violence.

Large-scale clinical trials of clonidine in PTSD are warranted, the scientists write. Their studies also indicate that other new therapies could be identified by looking at the impact on activation of a key protein called cofilin by existing drugs.

The new studies looked in genetically modified mice as well as neurons that came from human stem cells, which have the capacity to make many cell types.

In the hippocampus, the center of learning and memory, they found that a novel axis on an adrenergic receptor called ɑ2A is essential to maintaining fear memories in which you associate a place or situation, like the site of a horrific car accident or school shooting, with fear or other distressing emotions that are hallmarks of PTSD.

In this axis, they found the protein spinophilin interacts with cofilin, which is known to control protrusions on the synapses of neurons called dendritic spines, where memories are consolidated and stored.

A single neuron can have hundreds of these spines which change shape based on brain activity and whose changing impacts the strength of the synapse, the juncture between two neurons where they swap information.

"Normally whenever there is a stimulation, good or bad, in order to memorize it, you have to go through a process in which the spines store the information and get bigger," Wang says, morphing from a slender profile to a more mushroom-like shape.

"The mushroom spine is very important for your memory formation," says corresponding author Wang, Georgia Research Alliance Eminent Scholar in Neuropharmacology. For these mushroom shapes to happen, levels of cofilin must be significantly reduced in the synapse where the spines reside. That is where clonidine comes in.

The scientists found clonidine interferes with cofilin's exit by encouraging it to interact with the receptor which consequently interferes with the dendritic spine's ability to resume a mushroom shape and retain the memory. Guanfacine, on the other hand, had no effect on this key player cofilin.

The findings help clarify the disparate results in the clinical trials of these two similar drugs, Wang says. In fact, when mice got both drugs, the guanfacine appeared to lessen the impact of clonidine in the essential step of reconsolidating -- and so sustaining -- a traumatic memory, indicating their polar-opposite impact at least on this biological function, Wang says.

There was also living evidence. In their studies that mimicked how PTSD happens, mice were given a mild shock then treated with clonidine right after they were returned to the place where they received the shock and should be recalling what happened earlier. Clonidine-treated mice had a significantly reduced response, like freezing in their tracks, compared to untreated mice when brought back to the scene. In fact, their response was more like the mice who were never shocked. Guanfacine had no effect on freezing behavior.

Obviously, Wang says, they cannot know for certain how much the mice remember of what previously happened, but clearly those treated with clonidine did not have the same overt reaction as untreated mice or those receiving guanfacine.

"The interpretation is that they don't have as strong a memory," she says, noting that the goal is not to erase memories like those of wartime, rather diminish their disruption in a soldier's life.

When a memory is recalled, like when you return to an intersection where you were involved in a horrific car wreck, the synapses that hold the memory of what happened there become temporarily unstable, or labile, before the memory restabilizes, or reconsolidates. This natural dynamic provides an opportunity to intervene in reconsolidation and so at least diminish the strength of a bad memory, Wang says. Clonidine appears to be one way to do that.

Adrenergic drugs like clonidine bind to receptors in the central nervous system to reduce blood levels of the stress hormones you produce like epinephrine (adrenaline) and norepinephrine, which do things like increase blood pressure and heart rate.

Studies like one that came out 15 years ago, which only looked at guanfacine, indicated it was of no benefit in PTSD. But then in 2021, a retrospective look at a cohort of 79 veterans with PTSD treated with clonidine, for example, indicated 72% experienced improvement and 49% were much improved or very much improved with minimal side effects.

Previous basic science studies also have indicated that manipulating the adrenergic receptor can impact fear memory formation and memory, but how has remained unknown.

PTSD has emerged as a major neuropsychiatric component of the COVID-19 pandemic, affecting about 30% of survivors, a similar percentage of the health care workers who care for them and an estimated 20% of the total population, Wang says, which means the impact on human health and health care systems could be "profound."

Psychotherapy is generally considered the most effective treatment for PTSD, and some medications, like antidepressants, can also be used, but there are limited drug options, which include only two drugs which have Food and Drug Administration approval specifically for the condition, she says. The lack of approved drugs has led to off-label uses of drugs like clonidine.

Cofilin is a key element in helping muscle cells and other cell types contract as well as the flexibility of the cytoskeleton of the dendritic spine. A single neuron can have thousands of dendritic spines which change shape based on brain activity and whose changing shape impacts the strength of the synapse.

The U.S. Department of Veterans Affairs defines post-traumatic stress disorder as a mental health problem that some people develop after experiencing or witnessing a life-threatening or traumatic event. While problems like feeling on edge, trouble sleeping and/or nightmares may last a few weeks or more after the event, if symptoms like these as well as flashbacks and increasingly negative thoughts continue, it's likely PTSD. Sometimes symptoms don't surface until months after the initial event.

https://www.sciencedaily.com/releases/2023/01/230105083101.htm

People sleep the least from early 30s to early 50s

December 23, 2022

Science Daily/University College London

People sleep less in mid-adulthood than they do in early and late adulthood, finds a new study led by UCL, University of East Anglia and University of Lyon researchers.

Sleep duration declines in early adulthood until age 33, and then picks up again at age 53, according to the findings published in Nature Communications.

The study, involving 730,187 participants spread over 63 countries, revealed how sleep patterns change across the lifespan, and how they differ between countries.

Study participants were playing the Sea Hero Quest mobile game, a citizen science venture designed for neuroscience research, created by Deutsche Telekom in partnership with Alzheimer's Research UK, UCL, UEA and game developers Glitchers. Designed to aid Alzheimer's research by shedding light on differences in spatial navigational abilities, over four million people have played Sea Hero Quest, contributing to numerous studies across the project as a whole.

In addition to completing tasks testing navigational ability, anyone playing the game is asked to answer questions about demographic characteristics as well as other questions that can be useful to neuroscience research, such as on sleep patterns.

The researchers, led by Professor Hugo Spiers (UCL Psychology & Language Sciences) and Dr Antoine Coutrot (CNRS, University of Lyon) found that across the study sample, people sleep an average of 7.01 hours per night, with women sleeping 7.5 minutes longer than men on average. They found that the youngest participants in the sample (minimum age 19) slept the most, and sleep duration declined throughout people's 20s and early 30s before plateauing until their early 50s and increasing again. The pattern, including the newly-identified key time points of age 33 when declining sleep plateaus and 53 for sleep to increase again, was the same for men and women, and across countries and education levels.

The researchers say the decline in sleep during mid-life may be due to demands of childcare and working life.

Professor Spiers said: "Previous studies have found associations between age and sleep duration, but ours is the first large study to identify these three distinct phases across the life course. We found that across the globe, people sleep less during mid-adulthood, but average sleep duration varies between regions and between countries."

People who report sleeping the most are in Eastern European countries such as Albania, Slovakia, Romania and the Czech Republic, reporting 20-40 minutes extra sleep per night and the least in South East Asian countries including the Philippines, Malaysia and Indonesia. People in the United Kingdom reported sleeping slightly less than the average. People tended to sleep a bit less in countries closer to the equator.

The researchers found that navigational ability was unaffected by sleep duration for most of the sample, except for among older adults (aged 54-70) whose optimal sleep duration was seven hours, although they caution that the findings among older adults might be impacted by underlying health conditions.

https://www.sciencedaily.com/releases/2022/12/221223103424.htm

Scientists find key reason why loss of smell occurs in long COVID-19

The inflammatory mechanism could also help explain other long COVID-19 symptoms

December 21, 2022

Science Daily/Duke University Medical Center

The reason some people fail to recover their sense of smell after COVID-19 is linked to an ongoing immune assault on olfactory nerve cells and an associated decline in the number of those cells, a team of scientists led by Duke Health report.

The finding, publishing online Dec. 21 in the journal Science Translational Medicine, provides an important insight into a vexing problem that has plagued millions who have not fully recovered their sense of smell after COVID-19.

While focusing on the loss smell, the finding also sheds light on the possible underlying causes of other long COVID-19 symptoms -- including generalized fatigue, shortness of breath, and brain fog -- that might be triggered by similar biological mechanisms.

"One of the first symptoms that has typically been associated with COVID-19 infection is loss of smell," said senior author Bradley Goldstein, M.D., Ph.D., associate professor in Duke's Department of Head and Neck Surgery and Communication Sciences and the Department of Neurobiology.

"Fortunately, many people who have an altered sense of smell during the acute phase of viral infection will recover smell within the next one to two weeks, but some do not," Goldstein said. "We need to better understand why this subset of people will go on to have persistent smell loss for months to years after being infected with SARS-CoV2."

In the study, Goldstein and colleagues at Duke, Harvard and the University of California-San Diego analyzed olfactory epithelial samples collected from 24 biopsies, including nine patients suffering from long-term smell loss following COVID-19.

This biopsy-based approach -- using sophisticated single-cell analyses in collaboration with Sandeep Datta, M.D., Ph.D., at Harvard University -- revealed widespread infiltration of T-cells engaged in an inflammatory response in the olfactory epithelium, the tissue in the nose where smell nerve cells are located. This unique inflammation process persisted despite the absence of detectable SARS-CoV-2 levels.

Additionally, the number of olfactory sensory neurons were diminished, possibly due to damage of the delicate tissue from the ongoing inflammation.

"The findings are striking," Goldstein said. "It's almost resembling a sort of autoimmune-like process in the nose."

Goldstein said learning what sites are damaged and what cell types are involved is a key step toward beginning to design treatments. He said the researchers were encouraged that neurons appeared to maintain some ability to repair even after the long-term immune onslaught.

"We are hopeful that modulating the abnormal immune response or repair processes within the nose of these patients could help to at least partially restore a sense of smell," Goldstein said, noting this work is currently underway in his lab.

He said the findings from this study could also inform additional research into other long-COVID-19 symptoms that might be undergoing similar inflammatory processes.

https://www.sciencedaily.com/releases/2022/12/221221154434.htm

Smoking increases chances of mid-life memory loss, confusion

Study findings support quitting for brain benefits, researchers say

December 21, 2022

Science Daily/Ohio State University

Middle-aged smokers are far more likely to report having memory loss and confusion than nonsmokers, and the likelihood of cognitive decline is lower for those who have quit, even recently, a new study has found.

The research from The Ohio State University is the first to examine the relationship between smoking and cognitive decline using a one-question self-assessment asking people if they've experienced worsening or more frequent memory loss and/or confusion.

The findings build on previous research that established relationships between smoking and Alzheimer's Disease and other forms of dementia, and could point to an opportunity to identify signs of trouble earlier in life, said Jenna Rajczyk, lead author of the study, which appears in the Journal of Alzheimer's Disease.

It's also one more piece of evidence that quitting smoking is good not just for respiratory and cardiovascular reasons -- but to preserve neurological health, said Rajczyk, a PhD student in Ohio State's College of Public Health, and senior author Jeffrey Wing, assistant professor of epidemiology.

"The association we saw was most significant in the 45-59 age group, suggesting that quitting at that stage of life may have a benefit for cognitive health," Wing said. A similar difference wasn't found in the oldest group in the study, which could mean that quitting earlier affords people greater benefits, he said.

Data for the study came from the national 2019 Behavioral Risk Factor Surveillance System

Survey and allowed the research team to compare subjective cognitive decline (SCD) measures for current smokers, recent former smokers, and those who had quit years earlier. The analysis included 136,018 people 45 and older, and about 11% reported SCD.

The prevalence of SCD among smokers in the study was almost 1.9 times that of nonsmokers. The prevalence among those who had quit less than 10 years ago was 1.5 times that of nonsmokers. Those who quit more than a decade before the survey had an SCD prevalence just slightly above the nonsmoking group.

"These findings could imply that the time since smoking cessation does matter, and may be linked to cognitive outcomes," Rajczyk said.

The simplicity of SCD, a relatively new measure, could lend itself to wider applications, she said.

"This is a simple assessment that could be easily done routinely, and at younger ages than we typically start to see cognitive declines that rise to the level of a diagnosis of Alzheimer's Disease or dementia," Rajczyk said. "It's not an intensive battery of questions. It's more a personal reflection of your cognitive status to determine if you're feeling like you're not as sharp as you once were."

Many people don't have access to more in-depth screenings, or to specialists -- making the potential applications for measuring SCD even greater, she said.

Wing said it's important to note that these self-reported experiences don't amount to a diagnosis, nor do they confirm independently that a person is experiencing decline out of the normal aging process. But, he said, they could be a low-cost, simple tool to consider employing more broadly.

https://www.sciencedaily.com/releases/2022/12/221221121301.htm

Evening hot spring soaks lower cases of hypertension in older Japanese adults

December 21, 2022

Science Daily/Kyushu University

Nothing beats a good soak in a hot bath, and when it really hits the spot, you can almost feel your worries and ailments diffusing out into steam.

Perhaps there is nowhere better to treat what ails you than the hot springs at the historical city of Beppu, located on the north-east shores of Kyushu. Not only does the city boast the most onsen -- Japanese for hot springs -- in the country, it is also a research hotbed for investigating the health benefits of onsen and treatments based on them.

In a paper published in Scientific Reports, researchers from Kyushu University's Beppu Hospital report that onsen bathing in the evening hours is linked to lower prevalence of hypertension in Japanese adults over 65.

Humanity's history with hot springs can be found as far back as ancient Egypt over 5,000 years ago. Onsen themselves are even referenced in Japan's oldest books and creation myths, and people have touted the health benefits of soaking in hot springs well into the modern age.

In 1931, Kyushu University founded the 'Onsen Therapy Research Institute' in the historical city of Beppu to study the therapeutic benefits of onsen. Over the 90 years since, the institute has grown to cover a range of modern medical fields including internal and external medicine, rehabilitation, gynecology, and cardiology. Nonetheless, it still conducts research on the health benefits of onsen and continues to make a name for itself as a national hot spring treatment research center.

"In 2011, the institute partnered with the city and conducted a massive survey of Beppu residents over 65 about their health and onsen habits," explains Satoshi Yamasaki, a Lecturer of internal medicine at the Beppu Hospital and first author of the study. "This is something we can uniquely do here in Beppu because onsen are a part of everybody's daily lives, especially for the elderly. There are local onsen facilities everywhere, and you can even connect onsen to your home utilities."

The survey collected information regarding medical history, onsen habits, and even the type of onsen frequented from over 11,000 people -- nearly one-third of Beppu city residents over 65. Since then, researchers like Yamasaki have been going through the trove of data, analyzing the connection between health and onsen use.

"I wanted to find out if long-term onsen bathing had any preventative effects on hypertension. Past research has shown that traditional thermal therapy and hot spring bathing are effective against various diseases including hypertension," continues Yamasaki. "In Japan especially, it is the leading cause of hospital visits and long-term prescription medication use."

In their data set, the team was able to pull out 4,001 individuals who currently have, or a history of, hypertension. Their first analysis found that having hypertension also increased the likelihood for the individual to have a history of other pathologies.

"These were the usual suspects of pathologies correlated with hypertension such as gout, arrhythmia, renal disease, and diabetes," Yamasaki explains. "But it was when we looked at an individual's onsen habits that we found something interesting. We found that individuals who bathed in onsen after 19:00 were roughly 15% less likely to have hypertension."

The team hypothesizes two main reasons for these findings: lower stress and faster sleep onset. Previous research has shown that faster onset of sleep can improve sleep quality and improved hypertension control. Moreover, thermal therapies such as sauna bathing have been shown to alter levels of stress markers in the blood and lead to better mitigation of hypertension.

"Of course, we must acknowledge some limitations in our study. Selection bias is expected whenever a questionnaire is used. We also could not account for the respondent's daily lifestyle that could affect hypertension, or if they are being treated for hypertension medically or with onsen," concludes Yamasaki. "Nonetheless, we found that habitual nighttime onsen bathing was associated with a lower prevalence of hypertension. To understand these results further, we will need more data from patients."

https://www.sciencedaily.com/releases/2022/12/221221090621.htm

During sleep, brain regions synchronize to create motor memory

December 19, 2022

Science Daily/University of California - San Francisco

When the Golden State Warriors' Steph Curry makes a free throw, his brain draws on motor memory. Now researchers at UC San Francisco (UCSF) have shown how this type of memory is consolidated during sleep, when the brain processes the day's learning to make the physical act of doing something subconscious.

The study, published Dec. 14, 2022, in Nature, shows the brain does this by reviewing the trials and errors of a given action. In the analogy, that means sorting through all the free throws Curry has ever thrown, weeding out the memory of all the actions except those that hit the mark, or that the brain decided were "good enough." The result is the ability to make the free throw with a high degree of accuracy without having to think about the physical movements involved.

"Even elite athletes makes errors, and that's what makes the game interesting," said Karunesh Ganguly, MD, PhD, a professor of neurology and member of the UCSF Weill Institute for Neurosciences. "Motor memory isn't about perfect performance. It's about predictable errors and predictable successes. As long as the errors are stable from day to day, the brain says, 'Let's just lock this memory in.'"

Ganguly and his team found that the "locking in" process involves some surprisingly complex communication between different parts of the brain and takes place during the deep restorative slumber known as non-REM sleep.

Sleep is important because our conscious brains tend to focus on the failures, said Ganguly, who previously identified the sleep-associated brain waves that influence skill retention.

"During sleep, the brain is able to sift through all the instances it's taken in and bring forward the patterns that were successful," he said.

Earthbound Motor Skills Wouldn't Work on Avatar's Planet Pandora

It was once thought that learning motor skills only required the motor cortex. But in recent years a more complex picture has emerged.

To look into this process more closely, Ganguly set rats on a task to reach for pellets. Then, the team looked at their brain activity in three regions during NREM sleep: the hippocampus, which is the region responsible for memory and navigation, the motor cortex and the prefrontal cortex (PFC).

Over the course of 13 days, a pattern emerged.

First, in a process called "fast learning," the PFC coordinated with the hippocampus, likely enabling the animal to perceive its motion with respect to the space around it and its location in that space. In this phase, the brain seemed to be exploring and comparing all the actions and patterns created while practicing the task.

Second, in a process called slow learning, the PFC appeared to make value judgements, likely driven by reward centers that were activated when the task was successful. It engaged in crosstalk with the motor cortex and the hippocampus, turning down the signals related to failures and turning up the ones related to successes.

Finally, as the electrical activity of the regions became synchronized, the role of the hippocampus diminished and the instances the brain had noted as rewarding came to the fore, where they were stored in what we call "motor memory."

While the rats were initially learning the task, their brain signals were noisy and disorganized. As time went on, Ganguly could see the signals synchronizing, until the rats were succeeding about 70 percent of the time. After that point, the brain seemed to ignore mistakes and maintained the motor memory as long as the level of success was stable. In other words, the brain starts to expect a certain level of error and does not update the motor memory.

Just like NBA players, the rats mastered a skill based on a mental model of how the world works, which they created from their physical experience with gravity, space and other cues. But this kind of motor learning wouldn't easily transfer to a situation where the cues and physical environment were different.

"If all that changed, for example, if Steph Curry was in the world of Avatar, he might not look as skilled initially," Ganguly said.

The Best Way to Break a Habit

What if Curry hurt a finger and had to learn to shoot baskets a little differently? The study offered an answer.

"It's possible to unlearn a task, but to do that, you have to stress the situation to a point where you're making mistakes," Ganguly said.

When the researchers made a slight change to the rats' pellet procurement task, the rats would make more mistakes and the researchers saw more noise in the rats' brain activity.

The change was small enough that the rats didn't have to go all the way back to the beginning of their learning, only to the "breaking point," and relearn the task from there.

But because motor memory gets ingrained as a set of motions that follow each other in time, Ganguly said, changing motor memory in a complex motion like free throwing a basketball might require changing a motion that is used to initiate the whole sequence.

If Curry usually bounces a basketball twice before he throws, Ganguly said, "It might be best to retrain the brain by bouncing it only once, or three times. That way, you'd start with a clean slate."

https://www.sciencedaily.com/releases/2022/12/221219164831.htm

Casting light on, and through, your eyelids

Science Daily/Osaka Metropolitan University

Summary:

Scientists measured the light transmittance of the eyelids when the eyes are closed, and found that perceived closed-eye brightness is significantly stronger than previously reported. The influence of color was also observed, with red light perceived as brighter and blue light perceived as darker. Additionally, there were significant differences between experimental participants; for some, their perception of brightness barely differed between open- and closed-eye conditions.

Can't sleep when your partner is on his or her smartphone? This may not be oversensitivity on your part; your eyelids probably deserve some of the blame. A scientist from Osaka Metropolitan University shows that eyelids transmit much more light than previously thought. The findings were published in Color Research and Application.

Sleep deprivation and sleep disorders are detrimental to health and interfere with daily life. Studies have been conducted to elucidate the mechanisms underlying various factors that affect sleep. One major factor is the lighting environment. Changes in light exposure during the daytime and nighttime or during sleep have been reported to influence circadian rhythms and sleep quality.

Currently, indices to describe the lighting environment, such as illuminance and color temperature, are based on visual characteristics under well-lit conditions when the eyes are open. However, given that the eyes are closed while sleeping, understanding the light transmittance of the eyelids and perceived closed-eye brightness is essential to properly describe the lighting environment during sleep. Although several studies have been carried out to measure eyelid transmittance, experimental conditions differed significantly from lighting environments in daily life: evaluations were conducted under extremely low illuminance, for example, or with only one eye.

Professor Hideki Sakai, from the Graduate School of Human Life and Ecology at Osaka Metropolitan University, applied a new method to measure the light transmittance of the eyelids when the eyes are shut. His results indicate that closed-eye perception of brightness is remarkably stronger than previously reported.

Professor Sakai conducted experiments on a total of 33 participants under relatively bright conditions (illuminance of 100 lux) in which each participant's entire face was illuminated. A lighting device was used to increase or decrease facial illuminance, and closed-eye light transmittance was measured by having the participants make adjustments to match the levels of brightness they perceived with their eyes closed and with their eyes open. Monochromatic red, yellow, green, and blue LEDs and a white LED were used as light sources.

The experiment results show that eyelid transmittance values were up to 10 times higher than those (i.e., 0.3%-14.5%) reported in the past. The color of the light also made a difference, with red light perceived as brighter and blue light perceived as darker. Additionally, Professor Sakai noted significant differences between individual participants; for some, their perception of brightness remained almost unchanged between the open- and closed-eye conditions.

"By properly understanding and utilizing the lighting environment when the eyes are closed, I hope to advance research on appropriate lighting not only during normal sleep but also in various other situations, such as during naps or riding late-night transportation," stated Professor Sakai. "Since light colors with low transmittance are perceived as dark only when people close their eyes, I think that this finding could be useful for designing lighting in spaces with both awake and sleeping people, such as evacuation centers."

https://www.sciencedaily.com/releases/2022/12/221219094858.htm

New support for a serotonin deficit in depression

Since the 1960s, researchers have postulated that major depression stems from disruptions in the serotonin neurotransmitter system, but the evidence for that idea, though plentiful, was indirect. In fact, a recent comprehensive analysis of existing studies concluded that there was not strong evidence to support the "serotonin hypothesis." In its wake, some in the field have called for a reexamination of the hypothesis. Not so fast, says a new study that provides direct evidence of disrupted serotonin release in the brains of individuals with depression.

The study appears in Biological Psychiatry, published by Elsevier.

Depression is among the most common mental illnesses and causes of disability worldwide. Despite the lack of direct evidence for disrupted serotonin signaling in the depressed brain, medications used to treat depression overwhelmingly target the serotonin signaling system to increase extracellular serotonin, also known as 5-hydroxytryptamine (5-HT). Only about half of patients respond to antidepressants, and fewer than 30% experience total remission. A better understanding of 5-HT dynamics in depression could help guide more effective therapies.

"Our thinking about the role of serotonin in depression has evolved significantly over the past decade. We once thought that serotonin changes could account for the entirety of depression. When this simple hypothesis could no longer be supported, some were inclined to dismiss any role for serotonin in depression," said John Krystal, MD, editor-in-chief of Biological Psychiatry. "The current study provides important new support for further exploration of the role of serotonin in depression. This is particularly timely, as drugs targeting serotonin receptors, such as psychedelics, are being explored as potential new treatments for mood disorders."

The study, conducted by Invicro, a global, imaging contract research organization, in collaboration with researchers from Imperial College London, King's College London, Copenhagen University, and the University of Oxford, used a novel imaging technique to look directly at the magnitude of serotonin released from neurons in response to a pharmacological challenge. In previous work, these researchers pioneered the use of positron emission tomography (PET) with the radioligand [11C]Cimbi-36 to detect serotonin release. In the current study, the researchers applied this methodology to compare serotonin release in 17 patients with depression and 20 healthy individuals.

David Erritzoe, MRCPsych, PhD, lead author of the paper, said, "This study used a new and more direct method to measure serotonin in the living human brain, and the results suggest reduced serotonin (release) functioning in depression. This imaging method, in combination with similar methods for other brain systems, has the potential to help us to better understand the varying -- sometimes limited or even lacking -- treatment responses that people with depression have to antidepressant medication."

Participants with depression and healthy controls underwent PET scanning with [11C]Cimbi-36 to measure 5-HT2A receptor availability in the frontal cortex; the two groups did not differ significantly at baseline. Both groups then received a dose of d-amphetamine, a stimulant drug that works to increase 5-HT concentration outside of neurons, where it interacts with 5-HT2A receptors and reduces the binding of [11C]Cimbi-36. In a second scanning session three hours after drug administration, healthy control participants had significantly reduced 5-HT2A receptor availability, indicating an increase in serotonin levels. Participants with depression, however, did not show a significant decrease in binding potential, suggesting they had a blunted serotonin release capacity in key brain regions.

The study found no relationship between the severity of depression and the extent of serotonin release capacity deficits. Of note, all patients were free of antidepressant medication, and 11 out of the 17 had never received antidepressant treatment, indicating that low serotonin release capacity is a feature of depression rather than a result of antidepressant treatment.

This first direct evaluation of serotonin levels in the brain of individuals with depression is a major step forward in laying to rest the speculations questioning the involvement of serotonergic neurotransmission in the pathology of depression. Depression is a multifaceted disorder that may have multiple causes, and different subtypes may involve multiple neurotransmitter systems. Serotonergic dysfunction is unlikely to explain all the clinical features encountered in this disorder. Nevertheless, this study demonstrates that serotonergic deficits are present in unmedicated depressed individuals.

Eugenii Rabiner, MBBCh, FCPsych SA, at Invicro and senior author of the paper said, "It has taken our field over 20 years to develop a method that enables the measurement of serotonin release in the living human brain. I am very pleased that we managed to develop this method and apply it to clarify this important aspect of the pathophysiology of depression. I hope that we can use this technique in future to explore the different symptoms of depression, as well as serotonergic deficits found in other conditions, such as Parkinson's disease."

https://www.sciencedaily.com/releases/2022/12/221215120730.htm

Patterns of lifespan weight gain/loss may predict dementia risk

Monitoring risk indicators such as weight patterns offer opportunities for early intervention

December 15, 2022

Science Daily/Boston University School of Medicine

Dementia is a growing global public health concern currently affecting 50 million people and is expected to rise dramatically to more than 150 million cases worldwide by 2050. Obesity, commonly measured by body mass index (BMI), continues to be a global epidemic and earlier studies suggested that obesity at midlife may lead to increased risk for dementia. But the association between BMI and the risk of dementia remains unclear.

Now, researchers from Boston University Chobanian & Avedisian School of Medicine and Chinese Academy of Medical Sciences & Peking Union Medical College, have found that different patterns of BMI changes over one's life course may be an indicator of a person's risk for dementia.

"These findings are important because previous studies that looked at weight trajectories didn't consider how patterns of weight gain/stability/loss might help signal that dementia is potentially imminent," explained corresponding author Rhoda Au, PhD, professor of anatomy and neurobiology.

Through the Framingham Heart Study, a group of participants was followed for 39 years and their weight was measured approximately every 2-4 years. The researchers compared different weight patterns (stable, gain, loss) among those who did and did not become demented.

They found the overall trend of declining BMI was associated with a higher risk of developing dementia. However, after further exploration, they found a subgroup with a pattern of initial increasing BMI followed by declining BMI, both occurring within midlife, which appeared to be central to the declining BMI-dementia association.

Au points out that for individuals, family members, and primary care physicians, it is relatively easy to monitor weight. "If after a steady increase in weight that is common as one gets older, there is an unexpected shift to losing weight post midlife, it might be good to consult with one's healthcare provider and pinpoint why. There are some potential treatments emerging where early detection might be critical in the effectiveness of any of these treatments as they are approved and become available," she adds.

The researchers hope this study will illustrate that the seeds for dementia risk are being sowed across many years, likely even across the entire lifespan. "Dementia is not necessarily inevitable and monitoring risk indicators such as something as easy to notice as weight patterns, might offer opportunities for early intervention that can change the trajectory of disease onset and progression."

https://www.sciencedaily.com/releases/2022/12/221215104559.htm

Discovery could explain why women are more likely to get Alzheimer's

December 14, 2022

Science Daily/Scripps Research Institute

Scientists at Scripps Research and Massachusetts Institute of Technology (MIT) have found a clue to the molecular cause of Alzheimer's -- a clue that may also explain why women are at greater risk for the disease.

In the study, reported on December 14, 2022, in Science Advances, the researchers found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who had died with the disease, compared to men who had died with the disease. They also showed that estrogen -- which drops in production during menopause -- normally protects against the creation of this form of complement C3.

"Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer's, and may explain, at least in part, why the disease predominantly affects women," says study senior author Stuart Lipton, MD, PhD, professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, California.

The study was a collaboration with a team led by Steven Tannenbaum, PhD, Post Tenure Underwood-Prescott Professor of Biological Engineering, Chemistry and Toxicology at MIT.

Alzheimer's, the most common form of dementia that occurs with aging, currently afflicts about six million people in the U.S. alone. It is always fatal, usually within a decade of onset, and there is no approved treatment that can halt the disease process, let alone reverse it. The shortcomings of treatments reflect the fact that scientists have never fully understood how Alzheimer's develops. Scientists also don't know fully why women account for nearly two-thirds of cases.

Lipton's lab studies biochemical and molecular events that may underlie neurodegenerative diseases, including the chemical reaction that forms a modified type of complement C3 -- a process called protein S-nitrosylation. Lipton and his colleagues previously discovered this chemical reaction, which happens when a nitric oxide (NO)-related molecule binds tightly to a sulfur atom (S) on a particular amino acid building-block of proteins to form a modified "SNO-protein." Protein modifications by small clusters of atoms such as NO are common in cells and typically activate or deactivate a target protein's functions. For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton suspects that "SNO-storms" of these proteins could be a key contributor to Alzheimer's and other neurodegenerative disorders.

For the new study, the researchers used novel methods for detecting S-nitrosylation to quantify proteins modified in 40 postmortem human brains. Half of the brains were from people who had died of Alzheimer's, and half were from people who hadn't -- and each group was divided equally between males and females.

In these brains, the scientists found 1,449 different proteins that had been S-nitrosylated. Among the proteins most often modified in this way, there were several that have already been tied to Alzheimer's, including complement C3. Strikingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer's brains compared to male Alzheimer's brains.

The complement system is an evolutionarily older part of the human immune system. It consists of a family of proteins, including C3, that can activate one another to drive inflammation in what is called the "complement cascade." Scientists have known for more than 30 years that Alzheimer's brains have higher levels of complement proteins and other markers of inflammation, compared to neurologically normal brains. More recent research has shown specifically that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses -- the connection points through which neurons send signals to one another. Many researchers now suspect that this synapse-destroying mechanism at least partly underlies the Alzheimer's disease process, and loss of synapses has been demonstrated to be a significant correlate of cognitive decline in Alzheimer's brains.

Why would SNO-C3 be more common in female brains with Alzheimer's? There has long been evidence that the female hormone estrogen can have brain-protective effects under some conditions; thus, the researchers hypothesized that estrogen specifically protects women's brains from C3 S-nitrosylation -- and this protection is lost when estrogen levels fall sharply with menopause. Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (?-estradiol) levels fall, due to the activation of an enzyme that makes NO in brain cells. This increase in SNO-C3 activates microglial destruction of synapses.

"Why women are more likely to get Alzheimer's has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains the increased vulnerability of women as they age," Lipton says.

He and his colleagues now hope to conduct further experiments with de-nitrosylating compounds -- which remove the SNO modification -- to see if they can reduce pathology in animal models of Alzheimer's and eventually in humans.

https://www.sciencedaily.com/releases/2022/12/221214180658.htm

Not-so private eyes: Eye movements hold clues to how we make decisions

December 13, 2022

Science Daily/University of Colorado at Boulder

New research led by scientists at the University of Colorado Boulder suggests that eyes may really be the window to the soul -- or, at least, how humans dart their eyes may reveal valuable information about how they make decisions.

The new findings offer researchers a rare opportunity in neuroscience: the chance to observe the inner workings of the human brain from the outside. Doctors could also potentially use the results to, one day, screen their patients for illnesses like depression or Parkinson's Disease.

"Eye movements are incredibly interesting to study," said Colin Korbisch, doctoral student in the Paul M. Rady Department of Mechanical Engineering at CU Boulder and lead author of the study. "Unlike your arms or legs, the speed of eye movements is almost totally involuntary. It's a much more direct measurement of these unconscious processes happening in your brain."

He and his colleagues, including researchers at Johns Hopkins University in Baltimore, published their findings in November in the journal Current Biology.

In the study, the team asked 22 human subjects to walk on a treadmill then choose between different settings displayed on a computer screen: a brief walk up a steep grade or a longer walk on flat ground.

Researchers discovered that the subjects' eyes gave them away: Even before they made their choices, the treadmill users tended to move their eyes faster when they looked toward the options they ended up choosing. The more vigorously their eyes moved, the more they seemed to prefer their choice.

"We discovered an accessible measurement that will tell you, in only a few seconds, not just what you prefer but how much you prefer it," said Alaa Ahmed, senior author of the study and associate professor of mechanical engineering at CU Boulder.

Shifty eyes

Ahmed explained that how or why humans make choices (Tea or coffee? Dogs or cats?) is notoriously difficult to study. Researchers don't have many tools that will easily allow them to peer inside the brain. Ahmed, however, believes that our eyes could provide a glimpse into some of our thought processes. She's particularly interested in a type of movement known as a "saccade."

"The primary way our eyes move is through saccades," Ahmed said. "That's when your eyes quickly jump from one fixation point to another."

Quickly is the key word: Saccades usually take just a few dozen milliseconds to complete, making them faster than an average blink.

To find out if these darting motions give clues about how humans come to decisions, Ahmed and her colleagues decided to hit the gym.

In the new study, the team set up a treadmill on the CU Boulder campus. Study subjects exercised on various inclines for a period of time then sat down in front of a monitor and a high-speed, camera-based device that tracked their eye movements. While at the screen, they pondered a series of options, getting 4 seconds to pick between two choices represented by icons: Did they want to walk for 2 minutes at a 10% grade or for 6 minutes at a 4% grade? Once done, they returned to the treadmill to feel the burn based on what they chose.

The team found that subjects' eyes underwent a marathon of activity in just a short span of time. As they considered their options, the individuals flitted their eyes between the icons, first slowly and then faster.

"Initially, the saccades to either option were similarly vigorous," Ahmed said. "Then, as time passed, that vigor increased and it increased even faster for the option they eventually chose."

The researchers also discovered that people who made the hastiest decisions -- the most impulsive members of the group, perhaps -- also tended to move their eyes more vigorously. Once the subjects decided on their pick, their eyes slowed again.

"Real-time read-outs of this decision-making process typically require invasive electrodes placed into the brain. Having this more easily measured variable opens a lot of possibilities," Korbisch said.

Diagnosing illness

Flicks of the eye could matter for a lot more than understanding how humans make decisions. Studies in monkeys, for example, have suggested that some of the same pathways in the brain that help primates pick between this or that may also break down in people with Parkinson's -- a neurological illness in which individuals experience tremors, difficulty moving and other issues.

"Slowed movements aren't just a symptom of Parkinson's but also appear in a lot of mental health disorders, such as depression and schizophrenia," Ahmed said. "We think these eye movements could be something that medical professionals track as a diagnostic tool, a way to identify the progress of certain illnesses."

Eyes, in other words, could be windows to a lot more than just the soul.

https://www.sciencedaily.com/releases/2022/12/221213094812.htm

A Mediterranean diet not only boosts health, but also improves fertility

December 13, 2022

Science Daily/University of South Australia

With an emphasis on fruits, vegetables and legumes, the Mediterranean diet has long been applauded for its multiple health benefits. Now, new research shows that it may also help overcome infertility, making it a non-intrusive and affordable strategy for couples trying to conceive.

Conducted by Monash University, the University of the Sunshine Coast, and the University of South Australia, the review found that the Mediterranean diet can improve fertility, assisted reproductive technology (ART) success, and sperm quality in men.

Specifically, researchers identified that the anti-inflammatory properties of a Mediterranean diet can improve couples' chances of conception.

Infertility is a global health concern affecting 48 million couples and 186 million individuals worldwide.

UniSA researcher, Dr Evangeline Mantzioris, says modifying preconception nutrition is a non-invasive and potentially effective means for improving fertility outcomes.

"Deciding to have a baby is one of life's biggest decisions, but if things don't go as planned, it can be very stressful for both partners," Dr Mantzioris says.

"Research shows inflammation can affect fertility for both men and women, affecting sperm quality, menstrual cycles, and implantation. So, in this study we wanted to see how a diet that reduces inflammation -- such as the Mediterranean diet -- might improve fertility outcomes.

"Encouragingly, we found consistent evidence that by adhering to an anti-inflammatory diet -- one that includes lots of polyunsaturated or 'healthy' fats, flavonoids (such as leafy green vegetables), and a limited amount of red and processed meat -- we can improve fertility."

The Mediterranean diet is primarily plant-based, and includes whole grains, extra virgin olive oil, fruits, vegetables, beans and legumes, nuts, herbs, and spices. Yoghurt, cheese, and lean protein sources such as fish, chicken, or eggs; red and processed meats are only eaten in small amounts.

In comparison, a western diet comprises excessive saturated fats, refined carbohydrates, and animal proteins, making it energy-dense and lacking dietary fibre, vitamins, and minerals. Typically, a western diet is associated with higher levels of inflammation.

Monash University researcher, Simon Alesi, says understanding the association between anti-inflammatory diets such as the Mediterranean diet, and fertility, could be a gamechanger for couples hoping to start a family.

"The Mediterranean diet is consistently ranked among the healthiest diets in the world. But knowing that it may also boost your chances of conceiving and having a baby is extremely promising," Alesi says.

"Modifying your diet is a non-intrusive and affordable strategy that could potentially improve infertility.

"Of course, more research needs to be done, but at the very least, shifting to a Mediterranean diet will not only improve your overall health, but also your chances of conceiving."

https://www.sciencedaily.com/releases/2022/12/221213094801.htm

Extremely hot and cold days linked to cardiovascular deaths

December 12, 2022

Science Daily/American Heart Association

Extremely hot and cold temperatures both increased the risk of death among people with cardiovascular diseases, such as ischemic heart disease (heart problems caused by narrowed heart arteries), stroke, heart failure and arrhythmia, according to new research published today in the American Heart Association's flagship journal Circulation.

Among the cardiovascular diseases examined in this study, heart failure was linked to the highest excess deaths from extreme hot and cold temperatures.

"The decline in cardiovascular death rates since the 1960s is a huge public health success story as cardiologists identified and addressed individual risk factors such as tobacco, physical inactivity, Type 2 diabetes, high blood pressure and others. The current challenge now is the environment and what climate change might hold for us," said Barrak Alahmad, M.D., M.P.H., Ph.D., research fellow at the Harvard T.H. Chan School of Public Health at Harvard University in Boston and a faculty member at the College of Public Health at Kuwait University in Kuwait City.

Researchers explored how extreme temperatures may affect heart diseases -- the leading cause of death globally. They analyzed health data for more than 32 million cardiovascular deaths that occurred in 567 cities in 27 countries on 5 continents between 1979 and 2019. The global data came from the Multi-Country Multi-City (MCC) Collaborative Research Network, a consortium of epidemiologists, biostatisticians and climate scientists studying the health impacts of climate and related environmental stressors on death rates.

Climate change is associated with substantial swings in extreme hot and cold temperatures, so the researchers examined both in the current study. For this analysis, researchers compared cardiovascular deaths on the hottest and the coldest 2.5% of days for each city with cardiovascular deaths on the days that had optimal temperature (the temperature associated with the least rates of deaths) in the same city.

For every 1,000 cardiovascular deaths, the researchers found that:

• Extreme hot days accounted for 2.2 additional deaths.

• Extreme cold days accounted for 9.1 additional deaths.

• Of the types of heart diseases, the greatest number of additional deaths was found for people with heart failure (2.6 additional deaths on extreme hot days and 12.8 on extreme cold days).

"One in every 100 cardiovascular deaths may be attributed to extreme temperature days, and temperature effects were more pronounced when looking at heart failure deaths," said Haitham Khraishah, M.D., co-author of the study and a cardiovascular disease fellow at the University of Maryland School of Medicine and the University of Maryland Medical Center in Baltimore. "While we do not know the reason, this may be explained by the progressive nature of heart failure as a disease, rendering patients susceptible to temperature effects. This is an important finding since one out of four people with heart failure are readmitted to the hospital within 30 days of discharge, and only 20% of patients with heart failure survive 10 years after diagnosis."

Researchers suggest targeted warning systems and advice for vulnerable people may be needed to prevent cardiovascular deaths during temperature extremes.

"We need to be on top of emerging environmental exposures. I call upon the professional cardiology organizations to commission guidelines and scientific statements on the intersection of extreme temperatures and cardiovascular health. In such statements, we may provide more direction to health care professionals, as well as identify clinical data gaps and future priorities for research," Alahmad said.

The underrepresentation of data from South Asia, the Middle East and Africa limits the ability to apply these findings to make global estimates about the impact of extreme temperatures on cardiovascular deaths.

"This study contributes important information to the ongoing societal discussions regarding the relationship between climate and human health. More work is needed to better define these relationships in a world facing climate changes across the globe in the years ahead, especially as to how those environmental changes might impact the world's leading cause of death and disability, heart disease," said AHA Past President Robert A. Harrington, M.D., FAHA, who is the Arthur L. Bloomfield Professor of Medicine and chair of the department of medicine at Stanford University.

https://www.sciencedaily.com/releases/2022/12/221212140743.htm

Trouble falling asleep at night? Chase that daytime light

December 12, 2022

Science Daily/University of Washington

A study measuring the sleep patterns of students at the University of Washington has turned up some surprises about how and when our bodies tell us to sleep -- and illustrates the importance of getting outside during the day, even when it's cloudy.

Published online Dec. 7 in the Journal of Pineal Research, the study found that UW students fell asleep later in the evening and woke up later in the morning during -- of all seasons -- winter, when daylight hours on the UW's Seattle campus are limited and the skies are notoriously overcast.

The team behind this study believes it has an explanation: The data showed that in winter students received less light exposure during the day. Other research has indicated that getting insufficient light during the day leads to problems at night, when it's time for bed.

"Our bodies have a natural circadian clock that tells us when to go to sleep at night," said senior author Horacio de la Iglesia, a UW professor of biology. "If you do not get enough exposure to light during the day when the sun is out, that 'delays' your clock and pushes back the onset of sleep at night."

The study used wrist monitors to measure sleep patterns and light exposure for 507 UW undergraduate students from 2015 to 2018. Data indicated that students were getting roughly the same amount of sleep each night regardless of season. But, on school days during the winter, students were going to bed on average 35 minutes later and waking up 27 minutes later than summer school days. This finding surprised the team, since Seattle -- a high-latitude city -- receives nearly 16 hours of sunlight on the summer solstice, with plenty evening light for social life, and just over eight hours of sunlight on the winter solstice.

"We were expecting that in the summer students would be up later due to all the light that's available during that season," said de la Iglesia.

Based on student sleep data, the researchers hypothesized that something in winter was "pushing back" the students' circadian cycles. For most humans, including college students, the innate circadian cycle governing when we're awake and asleep runs at about 24 hours and 20 minutes -- and is "calibrated" daily by input from our environment. For UW students in the study, sleep data indicated that their circadian cycles were running up to 40 minutes later in winter compared to summer.

The team focused on light as a potential explanation for this winter delay. But light has different impacts on circadian rhythms at different times of the day.

"Light during the day -- especially in the morning -- advances your clock, so you get tired earlier in the evening, but light exposure late in the day or early night will delay your clock, pushing back the time that you will feel tired," said de la Iglesia. "Ultimately, the time that you fall asleep is a result of the push and pull between these opposite effects of light exposure at different times of the day."

Data showed that daytime light exposure had a greater impact than evening light exposure in the UW study. Each hour of daytime light "moved up" the students' circadian phases by 30 minutes. Even outdoor light exposure on cloudy or overcast winter days in Seattle had this effect, since that light is still significantly brighter than artificial indoor lighting, said de la Iglesia. Each hour of evening light -- light from indoor sources like lamps and computer screens -- delayed circadian phases by an average of 15 minutes.

"It's that push-and-pull effect," said de la Iglesia. "And what we found here is that since students weren't getting enough daytime light exposure in the winter, their circadian clocks were delayed compared to summer."

The study offers lessons not just for college students.

"Many of us live in cities and towns with lots of artificial light and lifestyles that keep us indoors during the day," said de la Iglesia. "What this study shows is that we need to get out -- even for a little while and especially in the morning -- to get that natural light exposure. In the evening, minimize screen time and artificial lighting to help us fall asleep."

https://www.sciencedaily.com/releases/2022/12/221212140707.htm

Unraveling the secrets of a good night's sleep

December 12, 2022

Science Daily/University of Tsukuba

A good night's sleep can work wonders for both mind and body. But what is it that determines how much we need to sleep, and what can cause us to sleep more deeply? In a new study, researchers from the University of Tsukuba have now provided some answers, revealing a signaling pathway within brain cells that regulates the length and depth of sleep.

"We examined genetic mutations in mice and how these affect their patterns of sleep," says senior author of the study, Professor Hiromasa Funato. "We identified a mutation that led to the mice sleeping much longer and more deeply than usual." The researchers found that this was caused by low levels of an enzyme called histone deacetylase 4 (HDAC4), which is known to suppress the expression of target genes.

Previous studies on HDAC4 have shown that it is greatly affected by the attachment of phosphate molecules in a process known as phosphorylation. When this occurs, HDAC4 tends to move away from the cell nucleus, and the suppression of certain proteins is reduced. The researchers were interested in whether this phosphorylation of HDAC4 would affect sleep.

"We focused on a protein called salt-inducible kinase 3, otherwise known as SIK3, which phosphorylates HDAC4," says Professor Funato. "We previously found that this protein has strong effects on sleep." The team found that when there was a lack of SIK3 or when HDAC4 was modified to prevent phosphorylation, the mice slept less. In contrast, when the mice had a more active version of SIK3, which increased the phosphorylation of HDAC4, they slept a lot more. They also identified a further protein, LKB1, which phosphorylates SIK3, and has similar sleep-suppressing effects when deficient.

"Our findings indicate that there is a signaling pathway within brain cells from LKB1 to SIK3 and then to HDAC4," says study co-senior author, Professor Masashi Yanagisawa. "This pathway leads to the phosphorylation of HDAC4, which promotes sleep, most probably because it affects the expression of sleep-promoting genes."

The team carried out further experiments to identify the brain cells in which these pathways regulate sleep. This involved altering the amounts of SIK3 and HDAC4 in different cell types and brain regions. The results indicated that signaling within the cells of the cortex regulates the depth of sleep, while signaling within the hypothalamus regulates the amount of deep sleep. For both brain regions, the excitatory neurons, which can activate other neurons, were identified as playing a key role.

These results provide an important insight into how sleep is regulated, which could potentially lead to a greater understanding of sleep disorders as well as the development of new treatments.

https://www.sciencedaily.com/releases/2022/12/221212140635.htm

Light therapy relieves fatigue syndrome in Multiple Sclerosis

December 12, 2022

Science Daily/Medical University of Vienna

Multiple Sclerosis (MS) is almost always accompanied by fatigue, a massive tiredness that is described by the vast majority of patients as the most distressing symptom. In a recent scientific study, a research group led by Stefan Seidel from the Department of Neurology at MedUni Vienna and AKH Vienna identified light therapy as a promising non-drug treatment option: patients included in the study showed a measurable improvement after just 14 days of use. The study results were recently published in the Multiple Sclerosis Journal -- Experimental, Translational and Clinical.

For the first time, Stefan Seidel's research team relied not only on surveys but also on objective measurements when selecting the test persons. For example, sleep-wake disorders were ruled out in the 26 participating MS patients, particularly with the assistance of various sleep medicine examinations. "In this manner, for example, we ensured that MS patients with fatigue do not suffer from sleep apnea or periodic leg movements during sleep. Both are sleep disorders that can lead to fatigue in everyday life," elaborated study leader Stefan Seidel.

Performance improvement

The test persons -- all patients of the Neurology Department at MedUni Vienna and AKH Vienna -- were equipped with commercially available light sources for self-testing at home: Half of the participants received a daylight lamp with a brightness of 10,000 lux, while the other half received an identical lamp that emitted a red light with an intensity of <300 lux due to a filter. While the red light used by the control group showed no effect, the researchers were able to observe measurable successes in the other group after only 14 days: The participants who used their 10,000 lux daylight lamp for half an hour every day showed improved physical and mental performance after only a short period of time. In addition, the group of participants who had consumed bright light displayed less daytime sleepiness in comparison with the other group.

Up to 99 percent of patients

Fatigue is a severe form of tiredness and fatigability that occurs in 75 to 99 percent of people with MS and is described as particularly distressing. Nerve damage triggered by MS is being discussed as the cause. In addition to behavioural measures, such as regular rest breaks, various medications are currently available to alleviate fatigue, but some of these are associated with severe side effects. "The findings from our study represent a promising non-drug therapeutic approach," Stefan Seidel affirms. However, the results still need to be confirmed in a subsequent larger-scale study. The exact background of the invigorating effect of light therapy on MS patients will also be the subject of further scientific research.

https://www.sciencedaily.com/releases/2022/12/221212140501.htm

Adding yoga to regular exercise improves cardiovascular health and wellbeing

December 8, 2022

Science Daily/Elsevier

A three-month pilot study of patients with hypertension appearing in the Canadian Journal of Cardiology, published by Elsevier, demonstrates that adding yoga to a regular exercise training https://www.sciencedaily.com/releases/2022/12/221208123538.htmregimen supports cardiovascular health and wellbeing and is more effective than stretching exercises. Incorporation of yoga reduced systolic blood pressure and resting heart rate and improved 10-year cardiovascular risk.

Yoga is part of spiritual and exercise practices for millions of people worldwide. With yoga practice becoming a widely accepted form of exercise, the body of yoga research is growing. It is a multifaceted lifestyle activity that can positively enhance cardiovascular health and wellbeing. Physical exercises such as stretching exercises and the physical components of yoga practices have several similarities, but also important differences.

"The aim of this pilot study was to determine whether the addition of yoga to a regular exercise training regimen reduces cardiovascular risk," explained lead investigator Paul Poirier, MD, PhD, Quebec Heart and Lung Institute -- Laval University, and Faculty of Pharmacy, Laval University, Quebec, Canada. "While there is some evidence that yoga interventions and exercise have equal and/or superior cardiovascular outcomes, there is considerable variability in yoga types, components, frequency, session length, duration, and intensity. We sought to apply a rigorous scientific approach to identify cardiovascular risk factors for which yoga is beneficial for at-risk patients and ways it could be applied in a healthcare setting such as a primary prevention program."

Investigators recruited 60 individuals with previously diagnosed high blood pressure and metabolic syndrome for an exercise training program. Over the 3-month intervention regimen, participants were divided into 2 groups, which performed 15 minutes of either structured yoga or stretching in addition to 30 minutes of aerobic exercise training 5 times weekly. Blood pressure, anthropometry, high-sensitivity C-reactive protein (hs-CRP), glucose and lipids levels as well as the Framingham and Reynolds Risk Scores were measured. At baseline, there was no difference between groups in age, sex, smoking rates, body mass index (BMI), resting systolic and diastolic blood pressure, resting heart rate and pulse pressure.

After 3 months, there was a decrease in resting systolic and diastolic blood pressure, mean arterial blood pressure and heart rate in both groups. However, systolic blood pressure was reduced by 10 mmHg with yoga vs 4 mmHg with stretching. The yoga approach also reduced resting heart rate and 10-year cardiovascular risk assessed using Reynold's Risk score.

While yoga has been shown to benefit hypertensive patients, the exact mechanism underlying this positive effect is not fully understood. This pilot randomized study shows that its benefits cannot be simply attributed to stretching alone.

"This study provides evidence for an additional non-pharmacologic therapy option for cardiovascular risk reduction and blood pressure control in patients with high blood pressure, in the setting of a primary prevention exercise program," noted Dr. Poirier. "As observed in several studies, we recommend that patients try to find exercise and stress relief for the management of hypertension and cardiovascular disease in whatever form they find most appealing. Our study shows that structured yoga practices can be a healthier addition to aerobic exercise than simply muscle stretching."

https://www.sciencedaily.com/releases/2022/12/221208085826.htm

Co-working spaces limit creativity in the long run

Shared spaces can be inhibitors to new business collaborations, according to researchers

December 8, 2022

Science Daily/City University London

Co-working spaces can limit the creativity and innovation of new businesses, a study has found.

These shared spaces, which have boomed in popularity since the pandemic, may offer initial opportunities to collaborate but, before long, they ultimately inhibit the emergence of collaborative practices.

The study, co-authored by Bayes Business School, investigated how collaborative practices emerge in co-working spaces, using Level 39 -- a leading co-working space in the financial district in Canary Wharf, and one of the largest in Europe, which is mainly occupied by tech and fintech sectors -- as a base.

Findings show that the informal setting of the space initially supported collective explorations between start-ups but inhibited collaborations from developing.

While the space allowed for social interactions and networking in communal kitchen, lounge and breakout areas, findings showed that firms left the space as the collaborative benefits were small and interactions became less meaningful and stilted over time. Also, firms highlighted that the space became increasingly reliant on occupancy and scalability amid its growth which negatively impacted optimal special layout and more tailored relationships with start-ups.

Professor Stefan Haefliger, lead author and Bayes academic, conducted the research with former Bayes PhD student Ghassan Yacoub, and said the findings were of particular significance to managers and hosts of co-working spaces. He highlighted the need for a catalyst -- actors who facilitate and encourage activities that sustain interactions and encourage co-operation -- to drive impactful cross-working.

Professor Haefliger said: "The rise of co-working spaces as new forms of work has redefined our understanding of the traditional physical, temporal and spatial boundaries of organisations.

"It is the responsibility of the host of the space and those that use it to make it a setting that can see booming partnerships and a hotbed of next generation ideas. Entrepreneurs need to embrace the early-stage interactions to take the first step towards collaborative working, with workspace managers working as catalysts to drive these partnerships."

"Post pandemic we can expect more uncertainty in how space is re-appropriated by individuals and entrepreneurial teams forming collaboration. Workspace managers may need to leave room for experimentation and allow flexibility.

"The built environment represents a key strength and characteristic of Dubai and how, post-pandemic, work habits have changed, and how routines of collaboration might require updated spaces and interaction opportunities. How will a city like Dubai attract new work and cater to contemporary collaborative work? Dubai is both a hub for global collaboration and an experimental opportunity to drive change and inspire other global locations who might be slower to change."

https://www.sciencedaily.com/releases/2022/12/221208123538.htm

Researchers gain a better understanding of how the most commonly used ADHD medication works

December 8, 2022

Science Daily/Elsevier

For decades, doctors have treated kids with attention-deficit/hyperactivity disorder (ADHD) with methylphenidate, a stimulant drug sold as Ritalin and Concerta, making it one of the most widely prescribed medications aimed at the central nervous system. One might expect that researchers would know how methylphenidate works in the brain by now, but little is known about the drug's mechanism of action. Now, a new study seeks to close this gap and understand how methylphenidate interacts with cognitive control networks and attentional behavior.

The new study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

What researchers do know is that individuals with ADHD have lower dopamine signaling activity than neurotypical individuals in the interconnected brain networks that control attention and goal-directed behaviors. Specifically, methylphenidate is hypothesized to ameliorate ADHD symptoms by increasing dopamine levels in the nucleus accumbens (NAc), a hub for dopamine signaling.

In the new study, researchers led by Yoshifumi Mizuno, MD, PhD, Weidong Cai, PhD, and Vinod Menon, PhD, used brain imaging to explore the effects of methylphenidate on the NAc and a so-called triple network system that plays a key role in behaviors that require adaptive control of attention. The three networks include the salience, frontoparietal, and default mode networks. Aberrant activity was detected in the NAc and in multiple brain networks in children with ADHD, suggesting that dysregulation in the system may underlie ADHD symptoms, and that correcting the dysfunction might alleviate those symptoms.

"Our findings demonstrate in two independent cohorts that methylphenidate changes spontaneous neural activity in reward and cognitive control systems in children with ADHD. Medication-induced changes in cognitive control networks result in more stable sustained attention. Our findings reveal a novel brain mechanism underlying methylphenidate treatment in ADHD and inform biomarker development for evaluating treatment outcomes," noted Dr. Menon, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine.

The researchers used functional magnetic resonance imaging (fMRI) to measure the effects of methylphenidate on spontaneous brain activity in 27 children with ADHD and 49 typically developing controls. Children with ADHD were scanned during two different visits one to six weeks apart -- once while receiving methylphenidate and once while receiving a placebo. (Typically developing children did not receive medication or placebo.) Outside the scanner, children with ADHD also performed a standardized task to assess sustained attention. Additionally, the researchers tested the replicability of methylphenidate's effects on spontaneous brain activity in a second independent cohort.

Not surprisingly, children performed better on the attention tasks when they were medicated. And as the researchers hypothesized, they also saw greater spontaneous neural activity in the NAc and the salience and default mode networks when methylphenidate was administered. Children with ADHD who displayed enhanced changes in brain activity patterns in the default mode network with medication performed better on the attention tasks with medication. Findings were replicated across two independent cohorts, providing further evidence that methylphenidate may alleviate ADHD symptoms by its actions on the NAc and the triple network cognitive system.

Cameron Carter, MD, editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the study, "The findings, which used the widely available technique of resting-state functional MRI, confirm the positive effects of methylphenidate on attention in children with ADHD and reveal the likely mechanism of action, through improved coordinated brain network activity and a likely key role for enhanced dopamine effects in the NAc region of the brain."

The work advances researchers' understanding of how ADHD affects cognitive control networks in the brain and how methylphenidate interacts with these networks to shift behavior. The findings could guide future work using brain imaging as a clinically useful biomarker of response to treatments.

https://www.sciencedaily.com/releases/2022/12/221208123533.htm

Fearlessness can be learned

December 5, 2022

Science Daily/Ruhr-University Bochum

The absence of a certain serotonin receptor supports the reduction of previously learned fear responses.

The neurotransmitter serotonin plays a key role in both the onset and in the unlearning of fear and anxiety. A research team from the Department of General Zoology and Neurobiology headed by Dr Katharina Spoida and Dr Sandra Süß in the Collaborative Research Centre "Extinction Learning" at Ruhr University Bochum, Germany, has been investigating the underlying mechanisms. The researchers showed that mice lacking a specific serotonin receptor unlearn fear much faster than the wild type. The results of the study provide a viable explanation how drugs that are typically used for the treatment of post-traumatic stress disorder (PTSD) alter our brain activity. The ability to unlearn fear is often impaired in PTSD patients, making it more difficult to carry out therapies. The study was published in the journal Translational Psychiatry on 19 November 2022.

Fear responses triggered by everyday sensory input

People who have been affected by a traumatic experience sometimes suffer from a long lasting exaggerated fear response. In such cases, the fear response is triggered by certain sensory impressions that occur in our everyday environment and which then can become overwhelming. Experts refer to this condition as post-traumatic stress disorder (PTSD). In this disorder, it is not possible, or only with difficulty, for affected individuals to unlearn the once-learned connection between a neutral environmental stimulus and the learned fear response, which impairs the success of therapies.

Knowing that the neurotransmitter serotonin plays an important role in the development of fear, the research team explored its role in extinction learning, i.e. the unlearning of fear, in greater detail. To this end, they examined so-called knock-out mice that lack a certain serotonin receptor -- the 5-HT2C receptor -- due to genetic modifications. These mice learned in one day to associate a certain sound with a mild but unpleasant electrical stimulus. "As a result of this learning process, on the following day they showed a fear response that was characterized by a motionless pause as soon as the tone was played, which we refer to as 'freezing'," explains Katharina Spoida.

Absence of the receptor is an advantage

In the next step, the researchers repeatedly played the tone to the mice without applying the electrical stimulus. "Interestingly, we noticed that knock-out mice learned much faster that the tone does not predict the fear stimulus than mice who lacked this specific genetic modification," says Katharina Spoida. "Consequently, it looks like the absence of the serotonin receptor provides an advantage for extinction learning."

The researchers investigated this phenomenon in more detail and found that the knock-out mice showed changes in their neuronal activity in two different brain areas. One of these is a specific sub-region of the dorsal raphe nucleus (DRN), which is typically the main site of serotonin production in our brains. In addition, the researchers discovered aberrant neuronal activity in the so-called bed nucleus of the stria terminalis (BNST), which is a part of the so called extended amygdala. "In the knock-out mice, we first found an increased basal activity in certain serotonin-producing cells of the dorsal raphe nucleus. In a subsequent step, we showed that the absence of the receptor also alters neuronal activity in two subnuclei of the BNST, which ultimately supports extinction learning," describes first author Sandra Süß. The research results also indicate a connection between the two brain regions, which leads the scientists to assume that an interplay is significant for improved extinction learning.

Possible effect of medication revealed

The results of the study may reveal how drugs typically used in the treatment of PTSD affect the brain regions analysed in this study. "There are already drugs in clinical use that regulate the amount of available serotonin, so-called selective serotonin reuptake inhibitors, or SSRIs for short," points out Katharina Spoida.

"Taking these drugs over a prolonged period of time causes the relevant receptor to become less responsive to serotonin, similar to our knock-out model. Therefore, we assume that the changes we've described could be essential for the positive effect of SSRIs," adds Sandra Süß. The researchers hope that their findings will help to develop more targeted treatment strategies for PTSD patients in the future.

https://www.sciencedaily.com/releases/2022/12/221205104218.htm