Discovery of how blood clots harm brain and body in COVID-19 points to new therapy

In a study that reshapes what we know about COVID-19 and its most perplexing symptoms, scientists have discovered that the blood coagulation protein fibrin causes the unusual clotting and inflammation that have become hallmarks of the disease, while also suppressing the body's ability to clear the virus.

Importantly, the team also identified a new antibody therapy to combat all of these deleterious effects.

Published in Nature, the study by Gladstone Institutes and collaborators overturns the prevailing theory that blood clotting is merely a consequence of inflammation in COVID-19. Through experiments in the lab and with mice, the researchers show that blood clotting is instead a primary effect, driving other problems -- including toxic inflammation, impaired viral clearance, and neurological symptoms prevalent in those with COVID-19 and long COVID.

The trigger is fibrin, a protein in the blood that normally enables healthy blood coagulation, but has previously been shown to have toxic inflammatory effects. In the new study, scientists found that fibrin becomes even more toxic in COVID-19 as it binds to both the virus and immune cells, creating unusual clots that lead to inflammation, fibrosis, and loss of neurons.

"Knowing that fibrin is the instigator of inflammation and neurological symptoms, we can build a new path forward for treating the disease at the root," says Katerina Akassoglou, PhD, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. "In our experiments in mice, neutralizing blood toxicity with fibrin antibody therapy can protect the brain and body after COVID infection."

From the earliest months of the pandemic, irregular blood clotting and stroke emerged as puzzling effects of COVID-19, even among patients who were otherwise asymptomatic. Later, as long COVID became a major public health issue, the stakes grew even higher to understand the cause of this disease's other symptoms, including its neurological effects. More than 400 million people worldwide have had long COVID since the start of the pandemic, with an estimated economic cost of about $1 trillion each year.

Flipping the Conversation

Many scientists and medical professionals have hypothesized that inflammation from the immune system's rapid reaction to the COVID-causing virus is what leads to blood clotting and stroke. But even at the dawn of the pandemic in 2020, that explanation didn't sound right to Akassoglou and her scientific collaborators.

"We know of many other viruses that unleash a similar cytokine storm in response to infection, but without causing blood clotting activity like we see with COVID," says Warner Greene, MD, PhD, senior investigator and director emeritus at Gladstone, who co-led the study with Akassoglou.

"We began to wonder if blood clots played a principal role in COVID -- if this virus evolved in a way to hijack clotting for its own benefit," Akassoglou adds.

Indeed, through multiple experiments in mice, the researchers found that the virus spike protein directly binds to fibrin, causing structurally abnormal blood clots with enhanced inflammatory activity. The team leveraged genetic tools to create a specific mutation that blocks only the inflammatory properties of fibrin without affecting the protein's beneficial blood-clotting abilities.

When mice were genetically altered to carry the mutant fibrin or had no fibrin in their bloodstream, the scientists found that inflammation, oxidative stress, fibrosis, and clotting in the lungs didn't occur or were much reduced after COVID-19 infection.

In addition to discovering that fibrin sets off inflammation, the team made another important discovery: fibrin also suppresses the body's "natural killer," or NK, cells, which normally work to clear the virus from the body. Remarkably, when the scientists depleted fibrin in the mice, NK cells were able to clear the virus.

These findings support that fibrin is necessary for the virus to harm the body.

Mechanism Not Triggered by Vaccines

The fibrin mechanism described in the paper is not related to the extremely rare thrombotic complication with low platelets that has been linked to adenoviral DNA COVID-19 vaccines, which are no longer available in the U.S.

By contrast, in a study of 99 million COVID-vaccinated individuals led by The Global COVID Vaccine Safety Project, vaccines that leverage mRNA technology to produce spike proteins in the body exhibited no excessive clotting or blood-based disorders that met the threshold for safety concerns. Instead, mRNA vaccines protect from clotting complications otherwise induced by infection.

Protecting the Brain

Akassoglou's lab has long investigated how fibrin that leaks into the brain triggers neurologic diseases, such as Alzheimer's disease and multiple sclerosis, essentially by hijacking the brain's immune system and setting off a cascade of harmful, often irreversible, effects.

The team now showed that in COVID-infected mice, fibrin is responsible for the harmful activation of microglia, the brain's immune cells involved in neurodegeneration. After infection, the scientists found fibrin together with toxic microglia and when they inhibited fibrin, the activation of these toxic cells in the brains of mice was significantly reduced.

"Fibrin that leaks into the brain may be the culprit for COVID-19 and long COVID patients with neurologic symptoms, including brain fog and difficulty concentrating," Akassoglou says. "Inhibiting fibrin protects neurons from harmful inflammation after COVID-19 infection."

The team tested its approach on different strains of the virus that causes COVID-19, including those that can infect the brain and those that do not. Neutralizing fibrin was beneficial in both types of infection, pointing to the harmful role of fibrin in brain and body in COVID-19 and highlighting the broad implications of this study.

A New Potential Therapy

This study demonstrates that fibrin is damaging in at least two ways: by activating a chronic form of inflammation and by suppressing a beneficial NK cell response capable of clearing virally infected cells.

"We realized if we could neutralize both of these negative effects, we could potentially resolve the severe symptoms we're seeing in patients with COVID-19 and possibly long COVID," Greene says.

Akassoglou's lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on fibrin's inflammatory properties without adverse effects on blood coagulation and protects mice from multiple sclerosis and Alzheimer's disease.

In the new study, the team showed that the antibody blocked the interaction of fibrin with immune cells and the virus. By administering the immunotherapy to infected mice, the team was able to prevent and treat severe inflammation, reduce fibrosis and viral proteins in the lungs, and improve survival rates. In the brain, the fibrin antibody therapy reduced harmful inflammation and increased survival of neurons in mice after infection.

A humanized version of Akassoglou's first-in-class fibrin-targeting immunotherapy is already in Phase 1 safety and tolerability clinical trials in healthy people by Therini Bio. The drug cannot be used on patients until it completes this Phase 1 safety evaluation, and then would need to be tested in more advanced trials for COVID-19 and long COVID.

Looking ahead to such trials, Akassoglou says patients could be selected based on levels of fibrin products in their blood -- a measure believed to be a predictive biomarker of cognitive impairment in long COVID.

"The fibrin immunotherapy can be tested as part of a multipronged approach, along with prevention and vaccination, to reduce adverse health outcomes from long COVID," Greene adds.

The Power of Team Science

The study's findings intersect the scientific areas of immunology, hematology, virology, neuroscience, and drug discovery -- and required many labs across institutions to work together to execute experiments required to solve the blood-clotting mystery. Akassoglou founded the Center for Neurovascular Brain Immunology at Gladstone and UCSF in 2021 specifically for the purpose of conducting multidisciplinary, collaborative studies that address complex problems.

"I don't think any single lab could have accomplished this on their own," says Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology and co-author of the study, noting important contributions from teams at Stanford, UC San Francisco, UC San Diego, and UCLA. "This tour-de-force study highlights the importance of collaboration in tackling these big questions."

Not only did this study address a big question, but it did so in a way that paves a clear clinical path for helping patients who have few options today, says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease.

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Mitochondria are flinging their DNA into our brain cells

As direct descendants of ancient bacteria, mitochondria have always been a little alien.

Now a study shows that mitochondria are possibly even stranger than we thought.

Mitochondria in our brain cells frequently fling their DNA into the nucleus, the study found, where the DNA becomes integrated into the cells' chromosomes. And these insertions may be causing harm: Among the study's nearly 1,200 participants, those with more mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with fewer insertions.

"We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence," says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.

"It's stunning that it appears to be happening several times during a person's lifetime, Picard adds. "We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analyzing blood DNA missed this phenomenon."

Mitochondrial DNA behaves like a virus

Mitochondria live inside all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand with about three dozen genes. Mitochondrial DNA is a remnant from the organelle's forebears: ancient bacteria that settled inside our single-celled ancestors about 1.5 billion years ago.

In the past few decades, researchers discovered that mitochondrial DNA has occasionally "jumped" out of the organelle and into human chromosomes.

"The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome," says Mills.

The insertions are called nuclear-mitochondrial segments -- NUMTs ("pronounced new-mites") -- and have been accumulating in our chromosomes for millions of years.

"As a result, all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors," Mills says.

Mitochondrial DNA insertions are common in the human brain

Research in just the past few years has shown that "NUMTogenesis" is still happening today.

"Jumping mitochondrial DNA is not something that only happened in the distant past," says Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. "It's rare, but a new NUMT becomes integrated into the human genome about once in every 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes."

The realization that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

"Inherited NUMTs are mostly benign, probably because they arise early in development and the harmful ones are weeded out," says Zhou. But if a piece of mitochondrial DNA inserts itself within a gene or regulatory region, it could have important consequences on that person's health or lifespan. Neurons may be particularly susceptible to damage caused by NUMTs because when a neuron is damaged, the brain does not usually make a new brain cell to take its place.

To examine the extent and impact of new NUMTs in the brain, the team worked with Hans Klein, assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different regions of the brain using banked tissue samples from more than 1,000 older adults.

Their analysis showed that nuclear mitochondrial DNA insertion happens in the human brain -- mostly in the prefrontal cortex -- and likely several times over during a person's lifespan.

They also found that people with more NUMTs in their prefrontal cortex died earlier than individuals with fewer NUMTs. "This suggests for the first time that NUMTs may have functional consequences and possibly influence lifespan," Picard says. "NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline, and lifespan."

Stress accelerates NUMTogenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be cultured and aged in a dish over several months, enabling exceptional longitudinal "lifespan" studies.

These cultured cells gradually accumulated several NUMTs per month, and when the cells' mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

"This shows a new way by which stress can affect the biology of our cells," Karan says. "Stress makes mitochondria more likely to release pieces of their DNA and these pieces can then 'infect' the nuclear genome," Zhou adds. It's just one way mitochondria shape our health beyond energy production.

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New brain-computer interface allows man with ALS to 'speak' again

A new brain-computer interface (BCI) developed at UC Davis Health translates brain signals into speech with up to 97% accuracy -- the most accurate system of its kind.

The researchers implanted sensors in the brain of a man with severely impaired speech due to amyotrophic lateral sclerosis (ALS). The man was able to communicate his intended speech within minutes of activating the system.

A study about this work was published today in the New England Journal of Medicine.

ALS, also known as Lou Gehrig's disease, affects the nerve cells that control movement throughout the body. The disease leads to a gradual loss of the ability to stand, walk and use one's hands. It can also cause a person to lose control of the muscles used to speak, leading to a loss of understandable speech.

The new technology is being developed to restore communication for people who can't speak due to paralysis or neurological conditions like ALS. It can interpret brain signals when the user tries to speak and turns them into text that is 'spoken' aloud by the computer.

"Our BCI technology helped a man with paralysis to communicate with friends, families and caregivers," said UC Davis neurosurgeon David Brandman. "Our paper demonstrates the most accurate speech neuroprosthesis (device) ever reported."

Brandman is the co-principal investigator and co-senior author of this study. He is an assistant professor in the UC Davis Department of Neurological Surgery and co-director of the UC Davis Neuroprosthetics Lab.

The new BCI breaks the communication barrier

When someone tries to speak, the new BCI device transforms their brain activity into text on a computer screen. The computer can then read the text out loud.

To develop the system, the team enrolled Casey Harrell, a 45-year-old man with ALS, in the BrainGate clinical trial. At the time of his enrollment, Harrell had weakness in his arms and legs (tetraparesis). His speech was very hard to understand (dysarthria) and required others to help interpret for him.

In July 2023, Brandman implanted the investigational BCI device. He placed four microelectrode arrays into the left precentral gyrus, a brain region responsible for coordinating speech. The arrays are designed to record the brain activity from 256 cortical electrodes.

"We're really detecting their attempt to move their muscles and talk," explained neuroscientist Sergey Stavisky. Stavisky is an assistant professor in the Department of Neurological Surgery. He is the co-director of the UC Davis Neuroprosthetics Lab and co-principal investigator of the study. "We are recording from the part of the brain that's trying to send these commands to the muscles. And we are basically listening into that, and we're translating those patterns of brain activity into a phoneme -- like a syllable or the unit of speech -- and then the words they're trying to say."

Faster training, better results

Despite recent advances in BCI technology, efforts to enable communication have been slow and prone to errors. This is because the machine-learning programs that interpreted brain signals required a large amount of time and data to perform.

"Previous speech BCI systems had frequent word errors. This made it difficult for the user to be understood consistently and was a barrier to communication," Brandman explained. "Our objective was to develop a system that empowered someone to be understood whenever they wanted to speak."

Harrell used the system in both prompted and spontaneous conversational settings. In both cases, speech decoding happened in real time, with continuous systemupdates to keep it working accurately.

The decoded words were shown on a screen. Amazingly, they were read aloud in a voice that sounded like Harrell's before he had ALS. The voice was composed using software trained with existing audio samples of his pre-ALS voice.

At the first speech data training session, the system took 30 minutes to achieve 99.6% word accuracy with a 50-word vocabulary.

"The first time we tried the system, he cried with joy as the words he was trying to say correctly appeared on-screen. We all did," Stavisky said.

In the second session, the size of the potential vocabulary increased to 125,000 words. With just an additional 1.4 hours of training data, the BCI achieved a 90.2% word accuracy with this greatly expanded vocabulary. After continued data collection, the BCI has maintained 97.5% accuracy.

"At this point, we can decode what Casey is trying to say correctly about 97% of the time, which is better than many commercially available smartphone applications that try to interpret a person's voice," Brandman said. "This technology is transformative because it provides hope for people who want to speak but can't. I hope that technology like this speech BCI will help future patients speak with their family and friends."

The study reports on 84 data collection sessions over 32 weeks. In total, Harrell used the speech BCI in self-paced conversations for over 248 hours to communicate in person and over video chat.

"Not being able to communicate is so frustrating and demoralizing. It is like you are trapped," Harrell said. "Something like this technology will help people back into life and society."

"It has been immensely rewarding to see Casey regain his ability to speak with his family and friends through this technology," said the study's lead author, Nicholas Card. Card is a postdoctoral scholar in the UC Davis Department of Neurological Surgery.

"Casey and our other BrainGate participants are truly extraordinary. They deserve tremendous credit for joining these early clinical trials. They do this not because they're hoping to gain any personal benefit, but to help us develop a system that will restore communication and mobility for other people with paralysis," said co-author and BrainGate trial sponsor-investigator Leigh Hochberg. Hochberg is a neurologist and neuroscientist at Massachusetts General Hospital, Brown University and the VA Providence Healthcare System.

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Cleaning up the aging brain: Scientists restore brain's trash disposal system

Alzheimer's, Parkinson's, and other neurological disorders can be seen as "dirty brain" diseases, where the brain struggles to clear out harmful waste. Aging is a key risk factor because, as we grow older, our brain's ability to remove toxic buildup slows down. However, new research in mice demonstrates that it's possible to reverse age-related effects and restore the brain's waste-clearing process.

"This research shows that restoring cervical lymph vessel function can substantially rescue the slower removal of waste from the brain associated with age," said Douglas Kelley, PhD, a professor of Mechanical Engineering in the University of Rochester Hajim School of Engineering and Applied Sciences. "Moreover, this was accomplished with a drug already being used clinically, offering a potential treatment strategy." Kelley is one of the lead authors of the study, which appears in the journal Nature Aging, along with Maiken Nedergaard, MD, DMSc, co-director the University's Center for Translational Neuromedicine.

First described by Nedergaard and her colleagues in 2012, the glymphatic system is the brain's unique waste removal process that uses cerebrospinal fluid (CSF) to wash away excess proteins generated by energy hungry neurons and other cells in the brain during normal activity. This discovery pointed the way for potential new approaches to treat diseases commonly associated with the accumulation of protein waste in the brain, such Alzheimer's (beta amyloid and tau) and Parkinson's (alpha-synuclein). In healthy and young brains, the glymphatic system does a good job of flushing away these toxic proteins, however, as we age, this system slows, setting the stage for these diseases.

A network of tiny pumps draws waste from the brain

Once laden with protein waste, CSF in the skull needs to make its way to the lymphatic system and ultimately the kidneys, where it is processed along with the body's other waste. The new research combines advanced imaging and particle tracking techniques to describe for the first time in detail the route via the cervical lymph vessels in the neck through which half of dirty CSF exits the brain.

In addition to measuring the flow of CSF, the researchers were able observe and record the pulsing of lymph vessels in the neck that helps draw CSF out of the brain. "Unlike the cardiovascular system which has one big pump, the heart, fluid in the lymphatic system is instead transported by a network of tiny pumps," said Kelley. These microscopic pumps, called lymphangions, have valves to prevent backflow and are strung together, one after another, to form lymph vessels.

The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty CSF flowing out of the brains of older mice was 63 percent slower compared to younger animals.

Known drug restarts flow of brain cleaning fluids

The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction. The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.

"These vessels are conveniently located near the surface of the skin, we know they are important, and we now know how to accelerate function," said Kelley. "One can see how this approach, perhaps combined with other interventions, could be the basis for future therapies for these diseases."

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New clues point towards how exercise reduces symptoms of depression

The processes in the brain and body through which physical exercise reduces depressive symptoms have been explored by UCL researchers.

Depression is the leading cause of disability worldwide and is associated with disruptions to several brain and psychological processes, including impaired learning and memory. Physical activity, especially aerobic exercise, has been found to reduce depressive symptoms, but until now the processes behind this have been poorly understood.

In a new review article published in Translational Psychiatry, researchers propose a novel hypothesis to understand the antidepressant effects of exercise. They believe that the process may hinge on motivation, which is very important for alleviating a number of symptoms of depression, such as anhedonia (a lack of interest or joy in life's experiences), low energy and 'brain fog'.

The team summarised research papers that explored the mechanisms of depression in both humans and animals and concluded that depression, especially anhedonia, is associated with elevated inflammation (caused by the body's immune response). Importantly, inflammation is also linked to disrupted dopamine transmission. These biological changes may represent key processes leading to changes in motivation, and in particular a lower willingness to exert physical or mental effort.

Meanwhile, exercise reduces inflammation, boosts dopamine function, and enhances motivation. The researchers believe that this could be an important reason as to why exercise exerts an antidepressant effect.

Lead author, Dr Emily Hird (UCL Institute of Cognitive Neuroscience) said: "The antidepressant effect of aerobic exercise has been convincingly demonstrated through randomised controlled trials, but its mechanism is not well understood. This is, in part, because it likely involves a variety of biological and psychological processes.

"For example, alongside its positive effect on inflammation, dopamine and reward processing, exercise also reduces oxidative stress and improves self-esteem and self-efficacy.

"However, we are proposing that exercise -- particularly aerobic activities that make you sweaty and out of breath -- decreases inflammation and boosts dopamine transmission, which in turn increases the desire to exert effort, and therefore boosts motivation generally."

The team hope that this understanding of how exercise reduces symptoms of depression will help to inform the development of new treatment strategies -- such as personalised exercise programmes.

Dr Hird said: "Understanding the mechanisms that underly the antidepressant effects of physical activity in depression could also inform our understanding of the mechanisms causing depression and the development of novel intervention strategies, in particular personalised intervention, and social prescribing."

To further test their hypothesis, the researchers advise that large randomised controlled trials need to be conducted that assess the antidepressant effects of exercise, whilst also measuring the effect on variables including inflammation, dopamine transmission and motivation.

It would also be important to investigate any potential barriers to exercise.

Dr Hird said: "Addressing barriers to exercise -- particularly in people with depression -- is crucial, as regular physical activity may be able to alleviate symptoms, enhance mood and empower individuals on their path to recovery. As part of this, finding strategies to encourage exercise is key."

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Good timing: Study unravels how our brains track time

Ever hear the old adage that time flies when you're having fun? A new study by a team of UNLV researchers suggests that there's a lot of truth to the trope.

Many people think of their brains as being intrinsically synced to the human-made clocks on their electronic devices, counting time in very specific, minute-by-minute increments. But the study, published this month in the latest issue of the peer-reviewed Cell Press journal Current Biology, showed that our brains don't work that way.

By analyzing changes in brain activity patterns, the research team found that we perceive the passage of time based on the number of experiences we have -- not some kind of internal clock. What's more, increasing speed or output during an activity appears to affect how our brains perceive time.

"We tell time in our own experience by things we do, things that happen to us," said James Hyman, a UNLV associate professor of psychology and the study's senior author. "When we're still and we're bored, time goes very slowly because we're not doing anything or nothing is happening. On the contrary, when a lot of events happen, each one of those activities is advancing our brains forward. And if this is how our brains objectively tell time, then the more that we do and the more that happens to us, the faster time goes."

Methodology and Findings

The findings are based on analysis of activity in the anterior cingulate cortex (ACC), a portion of the brain important for monitoring activity and tracking experiences. To do this, rodents were tasked with using their noses to respond to a prompt 200 times.

Scientists already knew that brain patterns are similar, but slightly different, each time you do a repetitive motion, so they set out to answer: Is it possible to detect whether these slight differences in brain pattern changes correspond with doing the first versus 200th motion in series? And does the amount of time it takes to complete a series of motions impact brain wave activity?

By comparing pattern changes throughout the course of the task, researchers observed that there are indeed detectable changes in brain activity that occur as one moves from the beginning to middle to end of carrying out a task. And regardless of how slowly or quickly the animals moved, the brain patterns followed the same path. The patterns were consistent when researchers applied a machine learning-based mathematical model to predict the flow of brain activity, bolstering evidence that it's experiences -- not time, or a prescribed number of minutes, as you would measure it on a clock -- that produce changes in our neurons' activity patterns.

Hyman drove home the crux of the findings by sharing an anecdote of two factory workers tasked with making 100 widgets during their shift, with one worker completing the task in 30 minutes and the other in 90 minutes.

"The length of time it took to complete the task didn't impact the brain patterns. The brain is not a clock; it acts like a counter," Hyman explained. "Our brains register a vibe, a feeling about time. ...And what that means for our workers making widgets is that you can tell the difference between making widget No. 85 and widget No. 60, but not necessarily between No. 85 and No. 88."

But exactly "how" does the brain count? Researchers discovered that as the brain progresses through a task involving a series of motions, various small groups of firing cells begin to collaborate -- essentially passing off the task to a different group of neurons every few repetitions, similar to runners passing the baton in a relay race.

"So, the cells are working together and over time randomly align to get the job done: one cell will take a few tasks and then another takes a few tasks," Hyman said. "The cells are tracking motions and, thus, chunks of activities and time over the course of the task."

And the study's findings about our brains' perception of time applies to activities-based actions other than physical motions too.

"This is the part of the brain we use for tracking something like a conversation through dinner," Hyman said. "Think of the flow of conversation and you can recall things earlier and later in the dinner. But to pick apart one sentence from the next in your memory, it's impossible. But you know you talked about one topic at the start, another topic during dessert, and another at the end."

By observing the rodents who worked quickly, scientists also concluded that keeping up a good pace helps influence time perception: "The more we do, the faster time moves. They say that time flies when you're having fun. As opposed to having fun, maybe it should be 'time flies when you're doing a lot'."

Takeaways

While there's already a wealth of information on brain processes over very short time scales of less than a second, Hyman said that the UNLV study is groundbreaking in its examination of brain patterns and perception of time over a span of just a few minutes to hours -- "which is how we live much of our life: one hour at a time. "

"This is among the first studies looking at behavioral time scales in this particular part of the brain called the ACC, which we know is so important for our behavior and our emotions," Hyman said.

The ACC is implicated in most psychiatric and neurodegenerative disorders, and is a concentration area for mood disorders, PTSD, addiction, and anxiety. ACC function is also central to various dementias including Alzheimer's disease, which is characterized by distortions in time. The ACC has long been linked to helping humans with sequencing events or tasks such as following recipes, and the research team speculates that their findings about time perception might fall within this realm.

While the findings are a breakthrough, more research is needed. Still, Hyman said, the preliminary findings posit some potentially helpful tidbits about time perception and its likely connection to memory processes for everyday citizens' daily lives. For example, researchers speculate that it could lend insights for navigating things like school assignments or even breakups.

"If we want to remember something, we may want to slow down by studying in short bouts and take time before engaging in the next activity. Give yourself quiet times to not move," Hyman said. "Conversely, if you want to move on from something quickly, get involved in an activity right away."

Hyman said there's also a huge relationship between the ACC, emotion, and cognition. Thinking of the brain as a physical entity that one can take ownership over might help us control our subjective experiences.

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Scientists define new type of memory loss in older adults

Researchers at Mayo Clinic have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. The good news: Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis, and is now more clearly defined for doctors working to find answers for memory loss patients.

Prior to the researchers developing clinical criteria published in the journal Brain Communications, the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

The criteria were developed and validated using data from more than 200 participants in databases for the Mayo Clinic Alzheimer's Disease Research Center, the Mayo Clinic Study of Aging and the Alzheimer's Disease Neuroimaging Initiative.

Understanding the condition will lead to better management of symptoms and more tailored therapies for patients suffering from this type of cognitive decline, distinct from Alzheimer's disease, says David T. Jones, M.D., a Mayo Clinic neurologist and senior author of the study.

"In our clinical work, we see patients whose memory symptoms appear to mimic Alzheimer's disease, but when you look at their brain imaging or biomarkers, it's clear they don't have Alzheimer's. Until now, there has not been a specific medical diagnosis to point to, but now we can offer them some answers," Jones says. "This research creates a precise framework that other medical professionals can use to care for their patients. It has major implications for treatment decisions, including amyloid-lowering drugs and new clinical trials, and counseling on their prognosis, genetics and other factors."

Decades of work to understand and classify different types of dementia is ongoing, says Nick Corriveau-Lecavalier, Ph.D., the paper's first author. These findings build upon scientists' continued efforts to untangle neurological conditions that often have similar symptoms or can occur simultaneously, but can have drastically different treatments and prognoses.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today," Corriveau-Lecavalier says. "With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains, so the prognosis is better than with Alzheimer's disease."

Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit -- a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed, the authors say.

With clinical criteria established by Jones, Corriveau-Lecavalier and co-authors, practitioners could soon diagnose LANS in patients so those living with memory loss might better understand options for treatment and potential progression of the disease, opening doors for research to further illuminate the characteristics of the disease.

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Scientists find that small regions of the brain can take micro-naps while the rest of the brain is awake and vice versa

Sleep and wake: they're totally distinct states of being that define the boundaries of our daily lives. For years, scientists have measured the difference between these instinctual brain processes by observing brain waves, with sleep characteristically defined by slow, long-lasting waves measured in tenths of seconds that travel across the whole organ.

For the first time, scientists have found that sleep can be detected by patterns of neuronal activity just milliseconds long, 1000 times shorter than a second, revealing a new way to study and understand the basic brain wave patterns that govern consciousness. They also show that small regions of the brain can momentarily "flicker" awake while the rest of the brain remains asleep, and vice versa from wake to sleep.

These findings, described in a new study published in the journal Nature Neuroscience, are from a collaboration between the laboratories of Assistant Professor of Biology Keith Hengen at Washington University in St. Louis and Distinguished Professor of Biomolecular Engineering David Haussler at UC Santa Cruz. The research was carried out by Ph.D. students David Parks (UCSC) and Aidan Schneider (WashU).

Over four years of work, Parks and Schneider trained a neural network to study the patterns within massive amounts of brain wave data, uncovering patterns that occur at extremely high frequencies that have never been described before and challenge foundational, long-held conceptions of the neurological basis of sleep and wake.

"With powerful tools and new computational methods, there's so much to be gained by challenging our most basic assumptions and revisiting the question of 'what is a state?'" Hengen said. "Sleep or wake is the single greatest determinant of your behavior, and then everything else falls out from there. So if we don't understand what sleep and wake actually are, it seems like we've missed the boat."

"It was surprising to us as scientists to find that different parts of our brains actually take little naps when the rest of the brain is awake, although many people may have already suspected this in their spouse, so perhaps a lack of male-female bias is what is surprising," Haussler quipped.

Understanding sleep

Neuroscientists study the brain via recordings of the electrical signals of brain activity, known as electrophysiology data, observing voltage waves as they crest and fall at different paces. Mixed into these waves are the spike patterns of individual neurons.

The researchers worked with data from mice at the Hengen Lab in St. Louis. The freely-behaving animals were equipped with a very lightweight headset that recorded brain activity from 10 different brain regions for months at a time, tracking voltage from small groups of neurons with microsecond precision.

This much input created petabytes -- which are one million times larger than a gigabyte -- of data. David Parks led the effort to feed this raw data into an artificial neural network, which can find highly complex patterns, to differentiate sleep and wake data and find patterns that human observation may have missed. A collaboration with the shared academic compute infrastructure located at UC San Diego enabled the team to work with this much data, which was on the scale of what large companies like Google or Facebook might use.

Knowing that sleep is traditionally defined by slow-moving waves, Parks began to feed smaller and smaller chunks of data into the neural network and asked it to predict if the brain was asleep or awake.

They found that the model could differentiate between sleep and wake from just milliseconds of brain activity data. This was shocking to the research team -- it showed that the model couldn't have been relying on the slow-moving waves to learn the difference between sleep and wake.. Just as listening to a thousandth of a second of a song couldn't tell you if it had a slow rhythm, it would be impossible for the model to learn a rhythm that occurs over several seconds by just looking at random isolated milliseconds of information.

"We're seeing information at a level of detail that's unprecedented," Haussler said. "The previous feeling was that nothing would be found there, that all the relevant information was in the slower frequency waves. This paper says, if you ignore the conventional measurements, and you just look at the details of the high frequency measurement over just a thousandth of a second, there is enough there to tell if the tissue is asleep or not. This tells us that there is something going on a very fast scale -- that's a new hint to what might be going on in sleep."

Hengen, for his part, was convinced that Parks and Schneider had missed something, as their results were so contradictory to bedrock concepts drilled into him over many years of neuroscience education. He asked Parks to produce more and more evidence that this phenomena could be real.

"This challenged me to ask myself 'to what extent are my beliefs based on evidence, and what evidence would I need to see to overturn those beliefs?" Hengen said. "It really did feel like a game of cat and mouse, because I'd ask David [Parks] over and over to produce more evidence and prove things to me, and he'd come back and say 'check this out!' It was a really interesting process as a scientist to have my students tear down these towers brick by brick, and for me to have to be okay with that."

Local patterns

Because an artificial neural network is fundamentally a black box and does not report back on what it learns from, Parks began stripping away layers of temporal and spatial information to try to understand what patterns the model could be learning from.

Eventually, they got down to the point where they were looking at chunks of brain data just a millisecond long and at the highest frequencies of brain voltage fluctuations.

"We'd taken out all the information that neuroscience has used to understand, define, and analyze sleep for the last century, and we asked 'can the model still learn under these conditions?'" Parks said. "This allowed us to look into signals we haven't understood before."

By looking at these data, they were able to determine that the hyper-fast pattern of activity between just a few neurons was the fundamental element of sleep that the model was detecting. Crucially, such patterns cannot be explained by the traditional, slow and widespread waves. The researchers hypothesize that the slow moving waves may be acting to coordinate the fast, local patterns of activity, but ultimately reached the conclusion that the fast patterns are much closer to the true essence of sleep.

If the slow moving waves traditionally used to define sleep are compared to thousands of people in a baseball stadium doing the wave, then these fast-moving patterns are the conversations between just a few people deciding to participate in the wave. Those conversations occurring are essential for the overall larger wave to take place, and are more directly related to the mood of the stadium -- the wave is a secondary result of that.

Observing flickers

In further studying the hyperlocal patterns of activity, the researchers began to notice another surprising phenomenon.

As they observed the model predicting sleep or wake, they noticed what looked at first like errors, in which for a split second the model would detect wake in one region of the brain while the rest of the brain remained asleep. They saw the same thing in wake states: for a split second, one region would fall asleep while the rest of the regions were awake. They call these instances "flickers."

"We could look at the individual time points when these neurons fired, and it was pretty clear that [the neurons] were transitioning to a different state," Schneider said. "In some cases, these flickers might be constrained to the area of just an individual brain region, maybe even smaller than that."

This compelled the researchers to explore what flickers could mean about the function of sleep, and how they affect behavior during sleep and wake.

"There's a natural hypothesis there; let's say a small part of your brain slips into sleep while you're awake -- does that mean your behavior suddenly looks like you're asleep? We started to see that that was often the case," Schneider said.

In observing the behavior of mice, the researchers saw that when a brain region would flicker to sleep while the rest of the brain was awake, the mouse would pause for a second, almost like it had zoned out. A flicker during sleep (one brain region "wakes up") was reflected by an animal twitching in its sleep.

Flickers are particularly surprising because they don't follow established rules dictating the strict cycle of the brain moving sequentially between wake to non-REM sleep to REM sleep.

"We are seeing wake to REM flickers, REM to non-REM flickers -- we see all these possible combinations, and they break the rules that you would expect based on a hundred years of literature," Hengen said. "I think they reveal the separation between the macro-state -- sleep and wake at the level of the whole animal, and the fundamental unit of state in the brain -- the fast and local patterns."

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New research demonstrates potential for increasing effectiveness of popular diabetes, weight-loss drugs

A network of proteins found in the central nervous system could be harnessed to increase the effectiveness and reduce the side effects of popular diabetes and weight-loss drugs, according to new research from the University of Michigan.

The study, appearing today in the Journal of Clinical Investigation, focused on two proteins called melanocortin 3 and melanocortin 4 found primarily on the surface of neurons in the brain that play a central role in regulating feeding behavior and maintaining the body's energy balance.

Melanocortin 3 and melanocortin 4 impact everything from sensing long-term energy stores to processing signals from the gut regarding short-term fullness, or satiety, said U-M physiologist Roger Cone, who led the study.

The class of drugs known as GLP-1 agonists, which includes semaglutides (e.g., Ozempic) and tirzepatides (e.g., Mounjaro), have received substantial attention recently for their effectiveness in treating not only type 2 diabetes, but also obesity, heart disease and potentially addiction. They work by mimicking a natural hormone that the gut produces when it is full, triggering the brain to reduce feeding behavior.

"So the obvious question for us was: How do these GLP-1 drugs, which work by manipulating satiety signals, function when we prime the melanocortin system?" said Cone, professor of molecular and integrative physiology at the U-M Medical School and director of the U-M Life Sciences Institute where his lab is located.

Working in mouse models, Cone and his colleagues tested the effects of several hormones that reduce food intake. They compared the results in normal mice with mice that genetically lacked the MC3R protein, in mice that were given chemicals to block the activity of MC3R, and in mice that were given a drug to increase the activity of MC4R. (Because MC3R is a natural negative regulator of MC4R, meaning it decreases the activity of MC4R, blocking MC3R and increasing MC4R activity has similar effects.)

In all cases, Naima Dahir, first author of the study and a postdoctoral research fellow in Cone's lab, and colleagues found that adjusting the melanocortin system -- either by inhibiting MC3R or increasing MC4R activity -- made the mice more sensitive to GLP-1 drugs and other hormones that affect feeding behavior. The mice that were given a GLP-1 drug in combination with an MC4R agonist or MC3R antagonist showed up to five times more weight loss and reduced feeding than mice receiving only the GLP-1 drugs.

"We found that activating the central melanocortin system hypersensitizes animals to the effects of not just GLP-1s, but to every anti-feeding hormone we tested," Cone said.

The researchers also measured activity in parts of the brain thought to trigger nausea in response to GLP-1 drugs and observed no increased activation when GLP-1 drugs were combined with alterations to the melanocortin system. In contrast, priming of the melanocortin neurons significantly increased GLP-1 drug activation of neurons in hypothalamic feeding centers in the brain.

The findings indicate that pairing the existing GLP-1 drugs with an MC4R agonist could increase sensitivity to the desired effects of the drugs by up to fivefold, without increasing unwanted side effects.Ultimately, this approach could enable patients who are sensitive to the side effects to take a lower dose, or could improve the results in patients who have not responded to the existing drug dosages. Further drug development and clinical testing are needed before this can occur.

While this research has been conducted only in mouse models, Cone is optimistic that the results will translate well to humans.

"The melanocortin system is highly conserved in humans," he said. "Everything we've observed in the mouse over the past decades studying these proteins has also been found in humans, so I suspect that these results would also be translatable to patients."

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Origins of creativity in the brain

Have you ever had the solution for a tough problem suddenly hit you when you're thinking about something entirely different? Creative thought is a hallmark of humanity, but it's an ephemeral, almost paradoxical ability, striking unexpectedly when it's not sought out.

And the neurological source of creativity -- what's going on in our brains when we think outside the box -- is similarly elusive.

But now, a research team led by a University of Utah Health researcher and based in Baylor College of Medicine has used a precise method of brain imaging to unveil how different parts of the brain work together in order to produce creative thought.

Their findings published in BRAIN on June 18.

The new results could ultimately help lead to interventions that spark creative thought or aid people who have mental illnesses that disrupt these regions of the brain.

Outside the bo

Higher cognitive processes like creativity are especially hard to study. "Unlike motor function or vision, they're not dependent on one specific location in the brain," says Ben Shofty, MD, PhD, assistant professor of neurosurgery in the Spencer Fox Eccles School of Medicine and senior author on the paper. "There's not a creativity cortex."

But there's evidence that creativity is a distinct brain function. Localized brain injury caused by stroke can lead to changes in creative ability -- both positive and negative. That discovery suggests that narrowing down the neurological basis of creativity is possible.

Shofty suspected that creative thought might rely strongly on parts of the brain that are also activated during meditation, daydreaming, and other internally focused types of thinking. This network of brain cells is the default mode network (DMN), so called because it's associated with the "default" patterns of thought that happen in the absence of specific mental tasks. "Unlike most of the functions that we have in the brain, it's not goal-directed," Shofty says. "It's a network that basically operates all the time and maintains our spontaneous stream of consciousness."

The DMN is spread out across many dispersed brain regions, making it more difficult to track its activity in real time. The researchers had to use an advanced method of brain activity imaging to understand what the network was doing moment-to-moment during creative thought. In a strategy most commonly used to pinpoint the location of seizures in patients with severe epilepsy, tiny electrodes are implanted in the brain to precisely track the electrical activity of multiple brain regions.

Participants in the study were already undergoing this kind of seizure monitoring, which meant that the research team could also use the electrodes to measure brain activity during creative thinking. This provided a much more detailed picture of the neural basis of creativity than researchers had been able to capture before. "We could see what's happening within the first few milliseconds of attempting to perform creative thinking,"Shofty says.

Two steps toward originality

The researchers saw that during a creative thinking task in which participants were asked to list novel uses for an everyday item, like a chair or a cup, the DMN lit up with activity first. Then, its activity synchronized with other regions in the brain, including ones involved in complex problem-solving and decision-making. Shofty believes this means that creative ideas originate in the DMN before being evaluated by other regions.

What's more, the researchers were able to show that parts of the network are required specifically for creative thought. When the researchers used the electrodes to temporarily dampen the activity of particular regions of the DMN, people brainstormed uses for the items they saw that were less creative. Their other brain functions, like mind wandering, remained perfectly normal.

Eleonora Bartoli, PhD, assistant professor of neurosurgery at Baylor College of Medicine and co-first author on the paper, explains that this result shows that creativity isn't just associated with the network but fundamentally depends on it. "We moved beyond correlational evidence by using direct brain stimulation," she says. "Our findings highlight the causal role of the DMN in creative thinking."

The activity of the network is changed in several disorders, such as ruminative depression, in which the DMN is more active than normal, possibly related to increased dwelling on negative internally directed thoughts. Shofty says that a better understanding of how the network operates normally may lead to better treatments for people with such conditions.

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Scientists identify new brain circuit in mice that controls body's inflammatory reactions

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia's Zuckerman Institute.

"The brain is the center of our thoughts, emotions, memories and feelings," said Hao Jin, PhD, a co-first author of the study published online today in Nature. "Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body."

Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.

"This new discovery could provide an exciting therapeutic venue to control inflammation and immunity," said Charles S. Zuker, PhD, the study's senior author, a principal investigator at Columbia's Zuckerman Institute and a Howard Hughes Medical Institute investigator.

Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.

"We found all these ways in which the body is informing the brain about the body's current state," said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. "We wanted to understand how much farther the brain's knowledge and control of the body's biology went."

The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve -- a bundle of thousands of nerve fibers linking the brain and the body's internal organs -- could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain's modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.

The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.

The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.

"Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner," said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker's lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. "In retrospect, it makes sense to have a master arbiter controlling this vital response."

Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.

"A lot of psychosomatic effects could actually be linked to brain circuits telling your body something," Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. "This opens up a new window into how the brain monitors and modulates body physiology," said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia's Vagelos College of Physicians and Surgeons.

Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn's disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.

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Sleep resets brain connections -- but only for first few hours

During sleep, the brain weakens the new connections between neurons that had been forged while awake -- but only during the first half of a night's sleep, according to a new study in fish by UCL scientists.

The researchers say their findings, published in Nature, provide insight into the role of sleep, but still leave an open question around what function the latter half of a night's sleep serves.

The researchers say the study supports the Synaptic Homeostasis Hypothesis, a key theory on the purpose of sleep which proposes that sleeping acts as a reset for the brain.

Lead author Professor Jason Rihel (UCL Cell & Developmental Biology) said: "When we are awake, the connections between brain cells get stronger and more complex. If this activity were to continue unabated, it would be energetically unsustainable. Too many active connections between brain cells could prevent new connections from being made the following day.

"While the function of sleep remains mysterious, it may be serving as an 'off-line' period when those connections can be weakened across the brain, in preparation for us to learn new things the following day."

For the study, the scientists used optically translucent zebrafish, with genes enabling synapses (structures that communicate between brain cells) to be easily imaged. The research team monitored the fish over several sleep-wake cycles.

The researchers found that brain cells gain more connections during waking hours, and then lose them during sleep. They found that this was dependent on how much sleep pressure (need for sleep) the animal had built up before being allowed to rest; if the scientists deprived the fish from sleeping for a few extra hours, the connections continued to increase until the animal was able to sleep.

Professor Rihel added: "If the patterns we observed hold true in humans, our findings suggest that this remodelling of synapses might be less effective during a mid-day nap, when sleep pressure is still low, rather than at night, when we really need the sleep."

The researchers also found that these rearrangements of connections between neurons mostly happened in the first half of the animal's nightly sleep. This mirrors the pattern of slow-wave activity, which is part of the sleep cycle that is strongest at the beginning of the night.

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Illusion helps demystify the way vision works

For the first time, research shows that a certain kind of visual illusion, neon color spreading, works on mice. The study is also the first to combine the use of two investigative techniques called electrophysiology and optogenetics to study this illusion. Results from experiments on mice settle a long-standing debate in neuroscience about which levels of neurons within the brain are responsible for the perception of brightness.

We're all familiar with optical illusions; some are novelties, while some are all around us. Even as you look at the screen in front you, you are being fooled into thinking that you're seeing the color white. What you're really seeing is lots of red, green and blue elements packed so tightly together it gives the impression of being white. Another example is a fast rotating wheel or propeller, which can briefly look like it's reversing direction while it's accelerating to full speed. In any case, it might be surprising to know that optical illusions are not just fun to look at but can also be a useful tool to learn more about eyes, nerves, minds and brains.

Associate Professor Masataka Watanabe from the Department of Systems Innovation at the University of Tokyo is on a mission to understand more about the nature of consciousness. It's a vast subject area so naturally there are many ways to explore it, and amongst other things, he uses optical illusions. His most recent research looked at whether a certain kind of illusion that works on humans would also work on mice. And it turns out, it does. But why is this significant?

"Knowing this kind of illusion, called a neon-color-spreading illusion, works on mice as well as humans, is useful for neuroscientists like myself, as it means that mice can serve as useful test subjects for cases where humans cannot," said Watanabe. "To really understand what goes on inside the brain during perceptual experiences, we need to use certain methods that we cannot use on people. These include electrophysiology, the recording of neural activity with electrodes, and optogenetics, where light pulses enable or disable firing of specific neurons in a living brain."

Watanabe's experiment was the first of its kind to make use of both electrophysiology and optogenetics at the same time in animal test subjects exposed to the neon-color-spreading illusion, which allowed his team to see precisely what structures within the brain are responsible for processing the illusion.

"After a visual stimulus lands on the eye, it's carried to the brain by nerves and is then received by a series of layers of neurons called V1, V2 and so on, where V1 is the first and most basic layer, and V2 and above are considered higher layers," said Watanabe. "There is a long-standing debate in neuroscience about the role higher levels play in the perception of brightness and it was not an easy thing to study. Our experiment on mice has shown us that neurons in V1 responded not just to the illusion, but also to a nonillusory version of the same kind of pattern shown. But only when the illusory version was shown to the mice did neurons in V2 also play a crucial role: that of modulating the activity of neurons in V1, thus proving that V2 neurons do in fact play a role in the perception of brightness."

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Microplastics make their way from the gut to other organs

It's happening every day. From our water, our food and even the air we breathe, tiny plastic particles are finding their way into many parts of our body.

But what happens once those particles are inside? What do they do to our digestive system?

In a recent paper published in the journal Environmental Health Perspectives, University of New Mexico researchers found that those tiny particles -- microplastics -- are having a significant impact on our digestive pathways, making their way from the gut and into the tissues of the kidney, liver and brain.

Eliseo Castillo, PhD, an associate professor in the Division of Gastroenterology & Hepatology in the UNM School of Medicine's Department of Internal Medicine and an expert in mucosal immunology, is leading the charge at UNM on microplastic research.

"Over the past few decades, microplastics have been found in the ocean, in animals and plants, in tap water and bottled water," Castillo, says. "They appear to be everywhere."

Scientists estimate that people ingest 5 grams of microplastic particles each week on average -- equivalent to the weight of a credit card.

While other researchers are helping to identify and quantify ingested microplastics, Castillo and his team focus on what the microplastics are doing inside the body, specifically to the gastrointestinal (GI) tract and to the gut immune system.

Over a four-week period, Castillo, postdoctoral fellow Marcus Garcia, PharmD, and other UNM researchers exposed mice to microplastics in their drinking water. The amount was equivalent to the quantity of microplastics humans are believed to ingest each week.

Microplastics had migrated out of the gut into the tissues of the liver, kidney and even the brain, the team found. The study also showed the microplastics changed metabolic pathways in the affected tissues.

"We could detect microplastics in certain tissues after the exposure," Castillo says. "That tells us it can cross the intestinal barrier and infiltrate into other tissues."

Castillo says he's also concerned about the accumulation of the plastic particles in the human body. "These mice were exposed for four weeks," he says. "Now, think about how that equates to humans, if we're exposed from birth to old age."

The healthy laboratory animals used in this study showed changes after brief microplastic exposure, Castillo says. "Now imagine if someone has an underlying condition, and these changes occur, could microplastic exposure exacerbate an underlying condition?"

He has previously found that microplastics are also impacting macrophages -- the immune cells that work to protect the body from foreign particles.

In a paper published in the journal Cell Biology & Toxicology in 2021, Castillo and other UNM researchers found that when macrophages encountered and ingested microplastics, their function was altered and they released inflammatory molecules.

"It is changing the metabolism of the cells, which can alter inflammatory responses," Castillo says. "During intestinal inflammation -- states of chronic illness such as ulcerative colitis and Crohn's disease, which are both forms of inflammatory bowel disease -- these macrophages become more inflammatory and they're more abundant in the gut."

The next phase of Castillo's research, which is being led by postdoctoral fellow Sumira Phatak, PhD, will explore how diet is involved in microplastic uptake.

"Everyone's diet is different," he says. "So, what we're going to do is give these laboratory animals a high-cholesterol/high-fat diet, or high-fiber diet, and they will be either exposed or not exposed to microplastics. The goal is to try to understand if diet affects the uptake of microplastics into our body."

Castillo says one of his PhD students, Aaron Romero, is also working to understand why there is a change in the gut microbiota. "Multiple groups have shown microplastics change the microbiota, but how it changes the microbiota hasn't been addressed."

Castillo hopes that his research will help uncover the potential impacts microplastics are having to human health and that it will help spur changes to how society produces and filtrates plastics.

Read more at Science Daily

Physical activity reduces stress-related brain activity to lower cardiovascular disease risk

New research indicates that physical activity lowers cardiovascular disease risk in part by reducing stress-related signaling in the brain.

In the study, which was led by investigators at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system and published in the Journal of the American College of Cardiology, people with stress-related conditions such as depression experienced the most cardiovascular benefits from physical activity.

To assess the mechanisms underlying the psychological and cardiovascular disease benefits of physical activity, Ahmed Tawakol, MD, an investigator and cardiologist in the Cardiovascular Imaging Research Center at Massachusetts General Hospital, and his colleagues analyzed medical records and other information of 50,359 participants from the Mass General Brigham Biobank who completed a physical activity survey.

A subset of 774 participants also underwent brain imaging tests and measurements of stress-related brain activity.

Over a median follow-up of 10 years, 12.9% of participants developed cardiovascular disease. Participants who met physical activity recommendations had a 23% lower risk of developing cardiovascular disease compared with those not meeting these recommendations.

Individuals with higher levels of physical activity also tended to have lower stress-related brain activity. Notably, reductions in stress-associated brain activity were driven by gains in function in the prefrontal cortex, a part of the brain involved in executive function (i.e., decision making, impulse control) and is known to restrain stress centers of the brain. Analyses accounted for other lifestyle variables and risk factors for coronary disease.

Moreover, reductions in stress-related brain signaling partially accounted for physical activity's cardiovascular benefit.

As an extension of this finding, the researchers found in a cohort of 50,359 participants that the cardiovascular benefit of exercise was substantially greater among participants who would be expected to have higher stress-related brain activity, such as those with pre-existing depression.

"Physical activity was roughly twice as effective in lowering cardiovascular disease risk among those with depression. Effects on the brain's stress-related activity may explain this novel observation," says Tawakol, who is the senior author of the study.

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Parkinson's Disease: New theory on the disease's origins and spread

The nose or the gut? For the past two decades, the scientific community has debated the wellspring of the toxic proteins at the source of Parkinson's disease. In 2003, a German pathologist, Heiko Braak, MD, first proposed that the disease begins outside the brain. More recently, Per Borghammer, MD, with Aarhus University Hospital in Denmark, and his colleagues argue that the disease is the result of processes that start in either the brain's smell center (brain-first) or the body's intestinal tract (body-first).

A new hypothesis paper appearing in the Journal of Parkinson's Disease on World Parkinson's Day unites the brain- and body-first models with some of the likely causes of the disease-environmental toxicants that are either inhaled or ingested. The authors of the new study, who include Borghammer, argue that inhalation of certain pesticides, common dry cleaning chemicals, and air pollution predispose to a brain-first model of the disease. Other ingested toxicants, such as tainted food and contaminated drinking water, lead to body-first model of the disease.

"In both the brain-first and body-first scenarios the pathology arises in structures in the body closely connected to the outside world," said Ray Dorsey, MD, a professor of Neurology at the University of Rochester Medical Center and co-author of the piece. "Here we propose that Parkinson's is a systemic disease and that its initial roots likely begin in the nose and in the gut and are tied to environmental factors increasingly recognized as major contributors, if not causes, of the disease. This further reinforces the idea that Parkinson's, the world's fastest growing brain disease, may be fueled by toxicants and is therefore largely preventable."

Different pathways to the brain, different forms of disease

A misfolded protein called alpha-synuclein has been in scientists' sights for the last 25 years as one of the driving forces behind Parkinson's. Over time, the protein accumulates in the brain in clumps, called Lewy bodies, and causes progressive dysfunction and death of many types of nerve cells, including those in the dopamine-producing regions of the brain that control motor function. When first proposed, Braak thought that an unidentified pathogen, such as a virus, may be responsible for the disease.

The new piece argues that toxins encountered in the environment, specifically the dry cleaning and degreasing chemicals trichloroethylene (TCE) and perchloroethylene (PCE), the weed killer paraquat, and air pollution, could be common causes for the formation of toxic alpha-synuclein. TCE and PCE contaminates thousands of former industrial, commercial, and military sites, most notably the Marine Corps base Camp Lejeune, and paraquat is one of the most widely used herbicides in the US, despite being banned for safety concerns in more than 30 countries, including the European Union and China. Air pollution was at toxic levels in nineteenth century London when James Parkinson, whose 269th birthday is celebrated today, first described the condition.

The nose and the gut are lined with a soft permeable tissue, and both have well established connections to the brain. In the brain-first model, the chemicals are inhaled and may enter the brain via the nerve responsible for smell. From the brain's smell center, alpha-synuclein spreads to other parts of the brain principally on one side, including regions with concentrations of dopamine-producing neurons. The death of these cells is a hallmark of Parkinson's disease. The disease may cause asymmetric tremor and slowness in movement and, a slower rate of progression after diagnosis, and only much later, significant cognitive impairment or dementia.

When ingested, the chemicals pass through the lining of the gastrointestinal tract. Initial alpha-synuclein pathology may begin in the gut's own nervous system from where it can spread to both sides of the brain and spinal cord. This body-first pathway is often associated with Lewy body dementia, a disease in the same family as Parkinson's, which is characterized by early constipation and sleep disturbance, followed by more symmetric slowing in movements and earlier dementia, as the disease spreads through both brain hemispheres.

New models to understand and study brain diseases

"These environmental toxicants are widespread and not everyone has Parkinson's disease," said Dorsey. "The timing, dose, and duration of exposure and interactions with genetic and other environmental factors are probably key to determining who ultimately develops Parkinson's. In most instances, these exposures likely occurred years or decades before symptoms develop."

Pointing to a growing body of research linking environmental exposure to Parkinson's disease, the authors believe the new models may enable the scientific community to connect specific exposures to specific forms of the disease. This effort will be aided by increasing public awareness of the adverse health effects of many chemicals in our environment. The authors conclude that their hypothesis "may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal-prevention."

In addition to Parkinson's, these models of environmental exposure may advance understanding of how toxicants contribute to other brain disorders, including autism in children, ALS in adults, and Alzheimer's in seniors. Dorsey and his colleagues at the University of Rochester have organized a symposium on the Brain and the Environment in Washington, DC, on May 20 that will examine the role toxicants in our food, water, and air are playing in all these brain diseases.

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RNA that doesn't age

Certain RNA molecules in the nerve cells in the brain last a life time without being renewed. Neuroscientists from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have now demonstrated that this is the case together with researchers from Germany, Austria and the USA. RNAs are generally short-lived molecules that are constantly reconstructed to adjust to environmental conditions. With their findings that have now been published in the journal Science, the research group hopes to decipher the complex aging process of the brain and gain a better understanding of related degenerative diseases.

Most cells in the human body are regularly renewed, thereby retaining their vitality.

However, there are exceptions: the heart, the pancreas and the brain consist of cells that do not renew throughout the whole lifespan, and yet still have to remain in full working order.

"Aging neurons are an important risk factor for neurodegenerative illnesses such as Alzheimer's," says Prof.

Dr. Tomohisa Toda, Professor of Neural Epigenomics at FAU and at the Max Planck Center for Physics and Medicine in Erlangen.

"A basic understanding of the aging process and which key components are involved in maintaining cell function is crucial for effective treatment concepts:"

In a joint study conducted together with neuroscientists from Dresden, La Jolla (USA) and Klosterneuburg (Austria), the working group led by Toda has now identified a key component of brain aging: the researchers were able to demonstrate for the first time that certain types of ribonucleic acid (RNA) that protect genetic material exist just as long as the neurons themselves.

"This is surprising, as unlike DNA, which as a rule never changes, most RNA molecules are extremely short-lived and are constantly being exchanged," Toda explains.

In order to determine the life span of the RNA molecules, the Toda group worked together with the team from Prof.

Dr. Martin Hetzer, a cell biologist at the Institute of Science and Technology Austria (ISTA). "We succeeded in marking the RNAs with fluorescent molecules and tracking their lifespan in mice brain cells," explains Tomohisa Toda, who has unique expertise in epigenetics and neurobiology and who was awarded an ERC Consolidator Grant for his research in 2023.

"We were even able to identify the marked long-lived RNAs in two year old animals, and not just in their neurons, but also in somatic adult neural stem cells in the brain."

In addition, the researchers discovered that the long-lived RNAs, that they referred to as LL-RNA for short, tend to be located in the cells' nuclei, closely connected to chromatin, a complex of DNA and proteins that forms chromosomes.

This indicates that LL-RNA play a key role in regulating chromatin.

In order to confirm this hypothesis, the team reduced the concentration of LL-RNA in an in-vitro experiment with adult neural stem cell models, with the result that the integrity of the chromatin was strongly impaired.

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Researchers map how the brain regulates emotions

Ever want to scream during a particularly bad day, but then manage not to? Thank the human brain and how it regulates emotions, which can be critical for navigating everyday life. As we perceive events unfolding around us, the ability to be flexible and reframe a situation impacts not only how we feel, but also our behavior and decision-making.

In fact, some of the problems associated with mental health relate to individuals' inability to be flexible, such as when persistent negative thoughts make it hard to perceive a situation differently.

To help address such issues, a new Dartmouth-led study is among the first of its kind to separate activity relating to emotion generation from emotion regulation in the human brain. The findings are published in Nature Neuroscience.

"As a former biomedical engineer, it was exciting to identify some brain regions that are purely unique to regulating emotions," says lead author Ke Bo, a postdoctoral researcher in the Cognitive and Affective Neuroscience Lab (CANlab) at Dartmouth. "Our results provide new insight into how emotion regulation works by identifying targets which could have clinical applications."

For example, the systems the researchers identified could be good targets for brain stimulation to enhance the regulation of emotion.

Using computational methods, the researchers examined two independent datasets of fMRI studies obtained earlier by co-author Peter Gianaros at the University of Pittsburgh. Participants' brain activity was recorded in an fMRI scanner as they viewed images that were likely to draw a negative reaction such as a bloody scene or scary- looking animals.

The participants were then asked to recontextualize the stimulus by generating new kinds of thoughts about an image to make it less aversive, before a neutral image was presented followed by another dislikable image.

By examining the neural activity, researchers could identify the brain areas that are more active when emotions are regulated versus when emotions are generated.

The new study reveals that emotion regulation, also known in neuroscience as "reappraisal," involves particular areas of the anterior prefrontal cortex and other higher-level cortical hierarchies whose role in emotion regulation had not previously been isolated with this level of precision. These regions are involved in other high-level cognitive functions and are important for abstract thought and long-term representations of the future.

The more people are able to activate these emotion regulation-selective brain regions, the more resilient they are to experiencing something negative without letting it affect them personally. These findings build on other research linking these areas to better mental health and the ability to resist temptations and avoid drug addiction.

The results also demonstrated that the amygdala, which is known as the threat-related brain region responsible for negative emotion and has long been considered an ancient subcortical threat center, responds to aversive experiences the same way, whether people are using their thoughts to self-regulate down-regulate negative emotion or not. "It's really the cortex that is responsible for generating people's emotional responses, by changing the way we see and attach meaning to events in our environments," says Bo.

The researchers were also interested in identifying the neurochemicals that interact with emotion regulation systems. Neurotransmitters like dopamine and serotonin shape how networks of neurons communicate and are targets for both illicit drugs and therapeutic treatments alike. Some neurotransmitters may be important for enabling the ability to self-regulate or "down-regulate."

The team compared the emotion regulation brain maps from the two datasets to neurotransmitter binding maps from 36 other studies. The systems involved in regulating negative emotion overlapped with particular neurotransmitter systems.

"Our results showed that receptors for cannabinoids, opioids, and serotonin, including 5H2A, were especially rich in areas that are involved in emotion regulation," says senior author Tor Wager, the Diana L. Taylor Distinguished Professor in Neuroscience and director of the Dartmouth Brain Imaging Center at Dartmouth. "When drugs that bind to these receptors are taken, they are preferentially affecting the emotion regulation system, which raises questions about their potential for long-term effects on our capacity to self-regulate."

Serotonin is well-known for its role in depression, as the most widely used antidepressant drugs inhibit its reuptake in synapses, which transmit signals from one neuron to another.

5H2A is the serotonin receptor most strongly affected by another exciting new type of treatment for mental health -- psychedelic drugs. The study's findings suggest that the effects of drugs on depression and other mental health disorders may work in part by altering how we think about life events and our ability to self-regulate. This may help explain why drugs, particularly psychedelics, are likely to be ineffective without the right kind of psychological support. The study could help improve therapeutic approaches by increasing our understanding of why and how psychological and pharmaceutical approaches need to be combined into integrated treatments.

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Common household chemicals pose new threat to brain health, study finds

A team of researchers from the Case Western Reserve University School of Medicine has provided fresh insight into the dangers some common household chemicals pose to brain health. They suggest that chemicals found in a wide range of items, from furniture to hair products, may be linked to neurological conditions like multiple sclerosis and autism spectrum disorders.

Neurological problems impact millions of people, but only a fraction of cases can be attributed to genetics alone, indicating that unknown environmental factors are important contributors.

The new study published today in the journal Nature Neuroscience, discovered that some common home chemicals specifically affect the brain's oligodendrocytes, a specialized cell type that generates the protective insulation around nerve cells.

"Loss of oligodendrocytes underlies multiple sclerosis and other neurological diseases," said the study's principal investigator, Paul Tesar, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and director of the Institute for Glial Sciences at the School of Medicine. "We now show that specific chemicals in consumer products can directly harm oligodendrocytes, representing a previously unrecognized risk factor for neurological disease."

On the premise that not enough thorough research has been done on the impact of chemicals on brain health, the researchers analyzed over 1,800 chemicals that may be exposed to humans. They identified chemicals that selectively damaged oligodendrocytes belong to two classes: organophosphate flame retardants and quaternary ammonium compounds. Since quaternary ammonium compounds are present in many personal-care products and disinfectants, which are being used more frequently since the COVID-19 pandemic began, humans are regularly exposed to these chemicals. And many electronics and furniture include organophosphate flame retardants.

The researchers used cellular and organoid systems in the laboratory to show that quaternary ammonium compounds cause oligodendrocytes to die, while organophosphate flame retardants prevented the maturation of oligodendrocytes.

They demonstrated how the same chemicals damage oligodendrocytes in the developing brains of mice. The researchers also linked exposure to one of the chemicals to poor neurological outcomes in children nationally.

"We found that oligodendrocytes -- but not other brain cells -- are surprisingly vulnerable to quaternary ammonium compounds and organophosphate flame retardants," said Erin Cohn, lead author and graduate student in the School of Medicine's Medical Scientist Training Program. "Understanding human exposure to these chemicals may help explain a missing link in how some neurological diseases arise."

The association between human exposure to these chemicals and effects on brain health requires further investigation, the experts warned. Future research must track the chemical levels in the brains of adults and children to determine the amount and length of exposure needed to cause or worsen disease.

"Our findings suggest that more comprehensive scrutiny of the impacts of these common household chemicals on brain health is necessary," Tesar said. "We hope our work will contribute to informed decisions regarding regulatory measures or behavioral interventions to minimize chemical exposure and protect human health."

 Read more at Science Daily

How fear unfolds inside our brains

Our nervous systems are naturally wired to sense fear. Whether prompted by the eerie noises we hear alone in the dark or the approaching growl of a threatening animal, our fear response is a survival mechanism that tells us to remain alert and avoid dangerous situations.

But if fear arises in the absence of tangible threats, it can be harmful to our well-being. Those who have suffered episodes of severe or life-threatening stress can later experience intense feelings of fear, even during situations that lack a real threat. Experiencing this generalization of fear is psychologically damaging and can result in debilitating long-term mental health conditions such as post-traumatic stress disorder (PTSD).

The stress-induced mechanisms that cause our brain to produce feelings of fear in the absence of threats have been mostly a mystery. Now, neurobiologists at the University of California San Diego have identified the changes in brain biochemistry and mapped the neural circuitry that cause such a generalized fear experience. Their research, published in the journal Science on March 15, 2024, provides new insights into how fear responses could be prevented.

In their report, former UC San Diego Assistant Project Scientist Hui-quan Li, (now a senior scientist at Neurocrine Biosciences), Atkinson Family Distinguished Professor Nick Spitzer of the School of Biological Sciences and their colleagues describe the research behind their discovery of the neurotransmitters -- the chemical messengers that allow the brain's neurons to communicate with one another -- at the root of stress-induced generalized fear.

Studying the brains of mice in an area known as the dorsal raphe (located in the brainstem), the researchers found that acute stress induced a switch in the chemical signals in the neurons, flipping from excitatory "glutamate" to inhibitory "GABA" neurotransmitters, which led to generalized fear responses.

"Our results provide important insights into the mechanisms involved in fear generalization," said Spitzer, a member of UC San Diego's Department of Neurobiology and Kavli Institute for Brain and Mind. "The benefit of understanding these processes at this level of molecular detail -- what is going on and where it's going on -- allows an intervention that is specific to the mechanism that drives related disorders."

Building upon this new finding of a stress-induced switch in neurotransmitters, considered a form of brain plasticity, the researchers then examined the postmortem human brains of individuals who had suffered from PTSD. A similar glutamate-to-GABA neurotransmitter switch was confirmed in their brains as well.

The researchers next found a way to stop the production of generalized fear. Prior to the experience of acute stress, they injected the dorsal raphe of the mice with an adeno-associated virus (AAV) to suppress the gene responsible for synthesis of GABA. This method prevented the mice from acquiring generalized fear.

Further, when mice were treated with the antidepressant fluoxetine (branded as Prozac) immediately after a stressful event, the transmitter switch and subsequent onset of generalized fear were prevented.

Not only did the researchers identify the location of the neurons that switched their transmitter, but they demonstrated the connections of these neurons to the central amygdala and lateral hypothalamus, brain regions that were previously linked to the generation of other fear responses.

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