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Major cause of dementia discovered in the brain

An international team of scientists have confirmed the discovery of a major cause of dementia, with important implications for possible treatment and diagnosis.

Professor Garth Cooper from The University of Manchester, who leads the Manchester team, says the build-up of urea in the brain to toxic levels can cause brain damage – and eventually dementia.

The work follows on from Professor Cooper’s earlier studies, which identified metabolic linkages between Huntington’s, other neurodegenerative diseases and type-2 diabetes.

The team consists of scientists from The University of Manchester, the University of Auckland, AgResearch New Zealand, the South Australian Research and Development Institute, Massachusetts General Hospital and Harvard University.

The latest paper by the scientists, published today in the Proceedings of the National Academy of Sciences, shows that Huntington’s Disease – one of seven major types of age-related dementia – is directly linked to brain urea levels and metabolic processes.

Their 2016 study revealing that urea is similarly linked to Alzheimer’s, shows, according to Professor Cooper, that the discovery could be relevant to all types of age-related dementias.

The Huntington’s study also showed that the high urea levels occurred before dementia sets in, which could help doctors to one day diagnose and even treat dementia, well in advance of its onset.

Urea and ammonia in the brain are metabolic breakdown products of protein. Urea is more commonly known as a compound which is excreted from the body in urine. If urea and ammonia build up in the body because the kidneys are unable to eliminate them, for example, serious symptoms can result.

Professor Cooper, who is based at The University of Manchester’s Division of Cardiovascular Sciences, said: “This study on Huntington’s Disease is the final piece of the jigsaw which leads us to conclude that high brain urea plays a pivotal role in dementia.

“Alzheimer’s and Huntington’s are at opposite ends of the dementia spectrum – so if this holds true for these types, then I believe it is highly likely it will hold true for all the major age-related dementias.

“More research, however, is needed to discover the source of the elevated urea in HD, particularly concerning the potential involvement of ammonia and a systemic metabolic defect.

“This could have profound implications for our fundamental understanding of the molecular basis of dementia, and its treatability, including the potential use of therapies already in use for disorders with systemic urea phenotypes.”

Dementia results in a progressive and irreversible loss of nerve cells and brain functioning, causing loss of memory and cognitive impairments affecting the ability to learn. Currently, there is no cure.

The team used human brains, donated by families for medical research, as well as transgenic sheep in Australia.

Manchester members of the team used cutting-edge gas chromatography mass spectrometry to measure brain urea levels. For levels to be toxic urea must rise 4-fold or higher than in the normal brain says Professor Cooper.

He added: “We already know Huntington’s Disease is an illness caused by a faulty gene in our DNA – but until now we didn’t understand how that causes brain damage – so we feel this is an important milestone.

“Doctors already use medicines to tackle high levels of ammonia in other parts of the body Lactulose – a commonly used laxative, for example, traps ammonia in the gut. So it is conceivable that one day, a commonly used drug may be able to stop dementia from progressing. It might even be shown that treating this metabolic state in the brain may help in the regeneration of tissue, thus giving a tantalising hint that reversal of dementia may one day be possible.”

Photo credit: Reigh LeBlanc
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Music Has Powerful (and Visible) Effects on the Brain

It doesn’t matter if it’s Bach, the Beatles, Brad Paisley or Bruno Mars. Your favorite music likely triggers a similar type of activity in your brain as other people’s favorites do in theirs.

That’s one of the things Jonathan Burdette, M.D., has found in researching music’s effects on the brain.

“Music is primal. It affects all of us, but in very personal, unique ways,” said Burdette, a neuroradiologist at Wake Forest Baptist Medical Center. “Your interaction with music is different than mine, but it’s still powerful.

“Your brain has a reaction when you like or don’t like something, including music. We’ve been able to take some baby steps into seeing that, and ‘dislike’ looks different than ‘like’ and much different than ‘favorite.’”

To study how music preferences might affect functional brain connectivity – the interactions among separate areas of the brain – Burdette and his fellow investigators used functional magnetic resonance imaging (fMRI), which depicts brain activity by detecting changes in blood flow. Scans were made of 21 people while they listened to music they said they most liked and disliked from among five genres (classical, country, rap, rock and Chinese opera) and to a song or piece of music they had previously named as their personal favorite.

Those fMRI scans showed a consistent pattern: The listeners’ preferences, not the type of music they were listening to, had the greatest impact on brain connectivity – especially on a brain circuit known to be involved in internally focused thought, empathy and self-awareness. This circuit, called the default mode network, was poorly connected when the participants were listening to the music they disliked, better connected when listening to the music they liked and the most connected when listening to their favorites.

The researchers also found that listening to favorite songs altered the connectivity between auditory brain areas and a region responsible for memory and social emotion consolidation.

Source & further reading:

#neuroscience #music #functionalconnectivity #brainactivity #neuroimaging
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Spiking Suppression Precedes Cued Attentional Enhancement of Neural Responses in Primary Visual Cortex


Attending to a visual stimulus increases its detectability, even if gaze is directed elsewhere. This covert attentional selection is known to enhance spiking across many brain areas, including the primary visual cortex (V1). Here we investigate the temporal dynamics of attention-related spiking changes in V1 of macaques performing a task that separates attentional selection from the onset of visual stimulation. We found that preceding attentional enhancement there was a sharp, transient decline in spiking following presentation of an attention-guiding cue. This disruption of V1 spiking was not observed in a task-naïve subject that passively observed the same stimulus sequence, suggesting that sensory activation is insufficient to cause suppression. Following this suppression, attended stimuli evoked more spiking than unattended stimuli, matching previous reports of attention-related activity in V1. Laminar analyses revealed a distinct pattern of activation in feedback-associated layers during both the cue-induced suppression and subsequent attentional enhancement. These findings suggest that top-down modulation of V1 spiking can be bidirectional and result in either suppression or enhancement of spiking responses.

By Michele A Cox, Kacie Dougherty, Geoffrey K Adams, Eric A Reavis, Jacob A Westerberg, Brandon S Moore, David A Leopold, Alexander Maier

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Deadly brain tumors halted by blocking telomere protein

Glioblastoma brain tumors are notoriously difficult to treat, and the prognosis is poor for people with this type of brain cancer. However, a new study may have discovered a way to halt glioblastoma growth and increase patient survival.

By inhibiting a protein called telomeric repeat binding factor 1 (TRF1), researchers were able to stop the growth and division of murine and human glioblastomas.

Senior study author Maria A. Blasco, head of the Telomeres and Telomerase Group at the Spanish National Cancer Research Centre (CNIO) in Madrid, Spain, and colleagues recently reported their findings in the journal Cancer Cell.

According to the American Brain Tumor Association, glioblastoma accounts for around 15.4 percent of all primary brain tumors in the United States.

Fast-growing and difficult to treat, glioblastoma is one of the deadliest brain tumors. It is estimated that for people with aggressive glioblastoma who are treated with a combination of temozolomide — a chemotherapy drug — and radiation therapy, the median survival is just 14.6 months.

Blocking TRF1 reduced glioblastoma growth

Glioblastomas develop from star-shaped brain cells called astrocytes. These tumors also contain a subset of cells called glioblastoma stem cells (GSCs), which enable the tumors to regenerate. This is one reason why glioblastoma is so difficult to treat.

The researchers note that stem cells contain high levels of the TRF1 protein. TRF1 is a component of shelterin, which is a protein complex that helps to safeguard telomeres — that is, the protective caps at the end of chromosomes.

Additionally, TRF1 plays a significant role in the tumor-regenerating abilities of GSCs. With this in mind, Blasco and her colleagues sought to determine how blocking TRF1 might influence glioblastoma growth.

The researchers removed TRF1 during the formation of glioblastoma tumors in mouse models. This reduced glioblastoma growth in the rodents and increased their survival by 80 percent.

When the team blocked TRF1 in glioblastomas that had already formed in the mice, the rodents' survival rose by 30 percent.

On further investigation, the researchers found that blocking the TRF1 protein in glioblastoma tumors caused damage to the DNA of telomeres in GSCs, which prevented these cells from proliferating.

A major therapeutic effect on glioblastoma

Next, the team moved its experiments to human glioblastoma cells. This involved removing GSCs from glioblastoma tumors in people with the brain cancer, before transplanting them into rodents.

The researchers then treated the rodents with compounds developed at CNIO that block TRF1, and their outcomes were compared with mice that were treated with a placebo.

The team found that the mice that received the TRF1 inhibitors not only showed an 80 percent reduction in tumor TRF1 levels, but they also experienced a decrease in the growth and size of glioblastoma tumors and increased survival when compared with mice that received a placebo.

The researchers note that inhibiting TRF1 appeared to have no adverse effects in the rodents.

Overall, Blasco and team believe that their study points to TRF1 inhibition as a potential treatment for one of the deadliest brain cancers.

"It has a major therapeutic effect on glioblastoma. We see that inhibiting TRF1 is an effective strategy for treating glioblastoma both by itself and in combination with current radiation and temozolomide therapies."

---- Maria A. Blasco

The researchers now plan to assess the efficacy of TRF1 inhibitors in combination with other drugs already used in the treatment of glioblastoma.

By Honor Whiteman
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Scientists have designed virtual human brain cells

For centuries, scientists who have dedicated their lives to studying the human brain have attempted to unlock its mysteries. The role the brain plays in human personality — as well as the myriad of disorders and conditions that come along with it — is often difficult to study because studying the organ while it’s still functioning in a human body is complicated. Now, researchers at The Allen Institute for Brain Science have introduced a new tool that could make such study a whole lot easier: functioning virtual brain cells.

The fully 3D computer models of living human brain tissue are based on actual brain samples that were left over after surgery and present what could be the most powerful testbed for studying the human brain ever created.

The samples used to construct the virtual models was healthy tissue that was removed during brain operations and represents parts of the brain that are typically associated with thoughts and consciousness, as well as memory. Those are vital areas for the research of mood disorders and various psychiatric ailments.

The models aren’t just a 3D representations of brain cells, but rather fully functional doppelgängers, producing electrical signals just like the real deal. This was made possible by the fact that the tissue is kept on a sort of “life support” while it was transported to the research lab for study and modeling. Being able to see the brain cells communicating and interacting helped to inform the development of the software.

A total of 36 different patients and hundreds of brain cells played a role in the construction of the virtual models, with the goal being to create a tool that is far more accurate in modeling human brain activity than the rodent brain tissue that is often used as a stand-in.

The researchers hope that their models can be used and improved over time, aiding in the continued study of the human brain and, potentially, treatments or even cures for various conditions.
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Building a medical map of the body

Medical science can seem to zig and zag from one study to the next. One study says one thing while another study appears to contradict it.

What may not be obvious is that, behind the apparent contradictions, is a process called the scientific method. Over time, the scientific method, starting with basic research, straightens out these contradictions and points to the best answer science can provide.

This process and how basic research supports medical breakthroughs is the subject of a new exhibit at Mayo Clinic’s Research Information Center, “Discovery Science: Building a Medical Map of the Body.”

“For the discovery center, we use a road map superimposed on the silhouette of a person. This conveys the concept of a roadmap to health, the roadmap of disease, the complexity of being healthy, and complication of disease,” says Mark McNiven, Ph.D., director of the Center for Biomedical Discovery.
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Cell biologists discover crucial ‘traffic regulator’ in neurons

Cell biologists led by Utrecht University’s Professor Casper Hoogenraad have discovered the protein that may be the crucial traffic regulator for the transport of vital molecules inside nerve cells. When this traffic regulator is removed, the flow of traffic comes to a halt.

The resulting ‘traffic jams’ are reported to play a key role in neurodegenerative diseases such as Alzheimer and Parkinson’s disease. The discovery of this traffic regulator may therefore be crucial for a better understanding of the development of neural disorders. The results of their research were published in the scientific journal Neuron on Wednesday 19 April.

Source & further reading:

Journal article:

#neuroscience #sensoryneurons #MAP2 #nervecells #neurodegenerativediseases #axonaltransport
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Neuroscience Is Making Significant Progress In Understanding Emotional Pain

What are the most recent breakthroughs in neuroscience? originally appeared on Quora: the place to gain and share knowledge, empowering people to learn from others and better understand the world.

Answer by Nicole Gravagna, PhD Neuroscience & Genetics and Heredity, on Quora:

We are learning a lot right now about the neuroscience of emotions. Specifically, we are learning that there is a lot of overlap between the way we process physical pain and the way we process emotional pain.

Understanding emotional pain could be powerful in understanding a lot of the common emotional maladies that are regularly treated with psychotherapy or mood altering medications. Depression, anxiety, trauma, social pain, these are all debilitating disorders that are poorly understood and often poorly treated.

Neuroscientists are beginning to understand how emotional pain and physical pain are very similar [1]. Physical pain is obvious in its purpose. Physical pain tells you that you are at risk of injury or death. Emotional pain seems a little more mysterious. As a species we seem overly concerned with social rejection even by strangers. How is that beneficial?

Humans are a unique species in two ways that account for our intense response to social rejection. We are born physically immature because of our enormous heads, and we require a lot of care early on. Because of our immaturity at birth, our species has selected for a deeply innate sense of bonding between individuals. The other unique feature of our species is that we require a lot of calories, probably also due to our oversized brains. Brains are calorie intensive organs and our brains are huge. So, humans burn about 400 more calories per day than other primates when you account for size [2]. Since we burn so much food, we as a species, have an innate drive to share food, which may have allowed us to get through bad hunting or gathering days in early human history. So, humans are naturally drawn to bond with others and to be conscious of aligning with a group of people where food sharing is possible.

It makes sense then, that losing a friend, or being rejected by a group might register to a person as a very dangerous thing. Emotional pain might result if a person discovers that they weren’t invited to a dinner party with friends.

So, what can we learn from understanding emotional pain that might help people in a real life context? If we can better understand pain sensitivity and pain thresholds, we might be able to raise the pain threshold so that a simple lack of dinner invitation no longer feels like pain. We might also understand how to help people who are paralyzed by social interactions. Depression might be the opposite of pain - an unwillingness to feel at all, lest the feelings be painful.

One thing we do know is that people who have a lot of friends have high pain thresholds [3]. Some scientists theorize that having relationships raises the pain threshold through a pleasure response of having closeness. Perhaps it could be the other way around - that people who have high pain thresholds are capable of tolerating and managing the pain associated with experiencing empathy and interaction with others.

Could this be a hint at a solution for those living in loneliness? By raising one’s pain thresholds, they may be able to navigate the social lows and highs that come with maintaining relationships.

Physiologists, especially scientists who study athletes, study pain thresholds and the effects of pain thresholds on athletic ability. Taking a Tylenol before exercise makes it possible to increase athletic output. Interestingly, taking a Tylenol before interacting socially, allows for less emotional pain and therefore a deeper engagement in social interactions [4].

Look for cutting edge neuroscience coming out in the next few years that helps us understand how to raise the social pain threshold. We could, very soon, have some practical answers for people with debilitating social anxiety, depression, and loneliness.




[3] Pain tolerance predicts human social network size

[4] Acetaminophen reduces social pain: behavioral and neural evidence.

This question originally appeared on Quora - the place to gain and share knowledge, empowering people to learn from others and better understand the world.
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Neuroscience predicts that Mayweather will beat McGregor in highly anticipated boxing match

In Las Vegas, on August 26, the unbeaten American boxer Floyd Mayweather Jr. and the immensely popular Irishman Conor McGregor will face off in a boxing ring, where only striking with hands while standing is allowed.

It would be just another boxing match, albeit a huge one, except that McGregor is not even a boxer.

Instead, he holds the lightweight and welterweight titles in mixed martial arts (MMA), an emerging combat sport where striking and grappling with both hands and legs is allowed, both while standing and on the ground.

It is an unprecedented match-up and some people believe that McGregor, with his speed, athleticism and youth (he is 11 years younger than Mayweather) has a shot at doing something that 49 professional boxers before him have not been able to accomplish.

But scientific evidence from the neuroscience of expertise, an emerging field investigating the brain functioning of experts, warns against betting on an MMA fighter – even one as skilled as McGregor – upsetting a boxer in a boxing match.

The neuroscience of expertise
The performances of experts often leave us speechless, wondering how it is humanly possible to pull off such feats. This is particularly the case in sports. Consider the serve in tennis. Once the ball is in the air, the brain needs time to process the ball’s trajectory and prepare an appropriate course of action, but by the time the body actually executes the required movements in response to these mental processes, the racket will do no more than slice the air, as the ball will have already passed by.

This is the paradox of fast reaction sports such as tennis or boxing: it is only when the ball or the punch is in the air that we can tell with certainty what is going to happen, but by then it is far too late to react in time, even for the quickest humans. The expert brain adapts to this problem by "reading" the intention of the opponent. The positioning and movements of feet, knees, shoulders and the serving hand in tennis give away clues about the direction and power of a tennis serve.

Similarly, the positioning of feet, hips and shoulders provide enough information for the boxing brain to anticipate a punch well in advance.

This anticipation power of experts is the reason why the very best practitioners can look like characters from The Matrix, giving the impression of having all the time in the world in an environment where split-second responses decide who wins and who loses.

Being fast and having good reflexes in general is certainly helpful in rapidly changing environments like sports.

But no speed in this world will be enough if the brain hasn’t experienced and stored tens of thousands of movement patterns, which can then be reactivated and used for reading the situation at hand.

Muhammad Ali vs Jim Brown

This is illustrated by another unofficial cross-discipline event that occurred 50 years ago between the legendary Muhammad Ali and Jim Brown, National Football League (NFL) legend. Jim Brown was a force of nature. He was incredibly quick, immensely powerful, and his extraordinary coordination and reflexes made him one of the greatest NFL players.

In the mid 1960s, aged 30, Jim Brown was bored with the NFL and was pondering other ways of making a living. One of them was boxing, a sport where his immense quickness and sheer power would seem to be especially useful.

He persuaded his manager to organize a meeting with Muhammad Ali, at that time at the peak of his powers, who happened to be in London, where Jim Brown was shooting a film at that time. They met in Hyde Park, where Ali used to work out while preparing for the next bout.

Ali tried to persuade Brown to give up on his dream of being a boxer. Brown maintained that he was as quick and as powerful as Ali, if not more so, and if boxing suited Ali, it should suit him too.

A "sparring session" ensued, where Ali asked Brown to hit him as hard as possible. The problem was that Ali was never to be found at the spot where he had been standing a moment earlier.

According to the legendary promoter Bob Arum, after about 30 seconds of swinging and missing by Brown, Ali pulled off one of his lightning quick one-two combinations and stopped Brown momentarily in his tracks.

At that moment, Brown, visibly winded, clocked the situation and simply said: "OK, I get the point."

Don’t expect McGregor to be so totally embarrassed, as Brown was. After all, MMA includes aspects of boxing and McGregor has had experience with the sport, unlike Brown. Still, that experience is limited because boxing is just a part of the MMA skill set (not to mention embedded in a context where one needs to employ leg strikes and takedowns). One can be certain that McGregor’s brain has stored vastly fewer kinematic boxing patterns than the brain of a person who has boxed all their life, such as Mayweather Jr.

Mayweather Jr. may be 40, he may have ring rust after being absent from the ring for almost two years, and McGregor is not only 11 years his junior but also possibly faster and stronger; but everything we know about the way experts’ brains work tells us that the smart money is on Mayweather Jr. recording a convincing win.

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Your brain’s got rhythm

Not everyone is Fred Astaire or Michael Jackson, but even those of us who seem to have two left feet have got rhythm—in our brains. From breathing to walking to chewing, our days are filled with repetitive actions that depend on the rhythmic firing of neurons. Yet the neural circuitry underpinning such seemingly ordinary behaviors is not fully understood, even though better insights could lead to new therapies for disorders such as Parkinson’s disease, ALS and autism.

Recently, neuroscientists at the Salk Institute used stem cells to generate diverse networks of self-contained spinal cord systems in a dish, dubbed circuitoids, to study this rhythmic pattern in neurons. The work, which appeared online in February 14, 2017, issue of eLife, reveals that some of the circuitoids—with no external prompting—exhibited spontaneous, coordinated rhythmic activity of the kind known to drive repetitive movements.

“It’s still very difficult to contemplate how large groups of neurons with literally billions if not trillions of connections take information and process it,” says the work’s senior author, Salk Professor Samuel Pfaff, who is also a Howard Hughes Medical Institute investigator and holds the Benjamin H. Lewis Chair. “But we think that developing this kind of simple circuitry in a dish will allow us to extract some of the principles of how real brain circuits operate. With that basic information maybe we can begin to understand how things go awry in disease.”

Source & further reading:

Journal article:

Image: Confocal microscope immunofluorescent image of a spinal cord neural circuit made entirely from stem cells and termed a “circuitoid”.
Credit: Salk Institute

#neuroscience #circuitoids #neuralcircuits #research #brain #science #medicine
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